Heteroaryl compounds, their manufacturing methods, and their pharmaceutical applications

Abstract

This invention provides heteroaryl compounds, methods for producing the same, and their pharmaceutical applications. Specifically, it provides heteroaryl compounds represented by general formula (I), methods for producing the same, and pharmaceutical compositions and therapeutic agents containing such compounds, particularly their use as Bruton's tyrosine kinase (BTK) inhibitors and for treating and / or preventing various diseases associated with excessive BTK activity, including cancer, autoimmune diseases, inflammatory diseases, allergic diseases, anaphylaxis, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, metabolic / endocrine disorders, and neurological disorders. [Formula 1] JPEG2026534181000174.jpg53135

Description

[Technical Field]

[0001] This disclosure relates to Bruton's tyrosine kinase (BTK) inhibitors (including wild-type and mutant BTK) for the treatment and / or prevention of BTK-related diseases or disorders, such as cancer, autoimmune diseases, inflammatory diseases, allergic diseases, anaphylaxis, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, metabolic / endocrine disorders, and neurological disorders, belonging to the pharmaceutical field. [Background technology]

[0002] Bruton's tyrosine kinase (BTK) is a cytoplasmic non-receptor tyrosine kinase belonging to the TEC family. Its protein structure includes an N-terminal plextrin homology (PH) domain, a TEC homology (TH) domain, SRC homology (SH) domains SH2 and SH3, and an enzyme-active kinase domain (Hendriks RW et al., Nat Rev Cancer. 2014, 14: 219-232). Its PH domain recruits BTK to the cell membrane by interacting with phosphatidylinositol-3,4,5-triphosphate (PIP3) produced by phosphatidylinositol-3 kinase (PI3K). Transmembrane proteins (e.g., B cell receptor (BCR) complexes) promote phosphorylation of BTK at Y551 by SYK or SRC family kinases, leading to activation of BTK kinase and subsequent 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 every stage of B lymphocyte development (Burger JA et al., Nat Rev Cancer. 2018, 18: 148-167). Initially, BTK mutations were shown to occur in human primary immunodeficiency X-linked agammaglobulinemia (XLA). A characteristic feature of XLA patients is a low number of B cells and the near absence of 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 development in the bone marrow, BTK promotes the differentiation of early B cells into mature B cells by regulating IL-7-induced circulating early B cell proliferation and transformation of quiescent early B cells, as well as the expression of immunoglobulin light chains (Rip, J. et al., Crit. Rev. Immunol. 2018, 38: 17-62). Similarly, BTK regulates negative selection of autoreactive immature B cells in the bone marrow.In the peripheral lymphoid system, BTK regulates the migration of B cells to follicles, B cell maturation, and the activation and differentiation of memory B cells and plasma cells (Torke, S. et al. Exp. Opin. Investig. Drugs 2020, 29, 1143-1150).

[0003] While the function of BTK has been studied in detail primarily in BCR signaling, it has also been reported that BTK plays 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, and when the relevant antigen crosslinks IgE, the intracellular ITAM-binding domain of FcεR recruits and activates downstream LYN and SYK kinases, thereby activating other kinases such as BTK, mediating the production of the intracellular second messengers IP3 and DAG, promoting cell activation and degranulation, and activating cytokine expression by downstream transcription factors such as NFAT and AP-1 (Saitoh, S. et al., Immunity. 2000, 12, 525-535). Furthermore, BTK plays a crucial role in IgG-specific Fc receptor (FcγR) signaling in macrophages and microglia, and promotes 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 already been developed, with the aim of treating cancers such as chronic lymphocytic leukemia (CLL). Several covalent BTK inhibitors are used clinically for B-cell malignancies. In addition to B-cell lymphoma, the function of BTK in the immune system is also driving the development of BTK inhibitors for autoimmune and allergic diseases such as rheumatoid arthritis (RA), Sjögren's syndrome, systemic lupus erythematosus, and multiple sclerosis. To date, several compounds, including evobrutinib, tolebrutinib, and fenebrutinib, have all been tested for efficacy in clinical trials for multiple sclerosis, yielding positive results. However, clinical trials of several drugs have been suspended due to hepatotoxicity issues (Montalban X et al., 2019, N Engl J Med, 380(25):2406-17). Therefore, one objective of this disclosure is to explore ways to improve hepatotoxicity, enhance safety, and provide BTK-covalent inhibitors for treating autoimmune diseases. [Overview of the project]

[0005] The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. [ka] Here, G is selected from an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclyl group, where each of the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group can be independently and optionally selected as one or more R G Replaced by, Each R G They are either the same or different, and each is independent of R 1 , R 2a , R 2 and R C Selected from, Each R 1and R 2a are the same or different, and each independently selected from halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, cyano group, amino group, hydroxy group, nitro group, -(CR a R b ) v OR 17 , -(CR a R b ) v NR 18 R 19 , -C(O)R 17 , -C(O)OR 17 , -C(O)NR 18 R 19 , -OC(O)NR 18 R 19 , -OC(O)R 17 , -OC(O)OR 17 , -NR 20 C(O)R 17 , -NR 20 C(O)OR 17 , -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 group, -(CR a R b ) v heterocyclyl group, -(CR a R b ) v aryl group, -(CR a R b ) v heteroaryl group and oxo group, wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optionally substituted with one or more R 0 , or two R1 These, together with the ring atoms linked to them, form a cycloalkyl group or heterocyclyl group, where the cycloalkyl group or heterocyclyl group is optionally composed of one or more R 0 Replaced by, R 2 is -OR A or -alkylene-R B Here, the alkylene group is optionally one or more R 0 Replaced by, R A R is selected from alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups can be independently and optionally selected as one or more R 0 Replaced by, R B R is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, R C R is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group can be independently and optionally selected as one or more R d Replaced by, Each R d These are the same or different, and each independently of the others, halogen, alkyl, alkenyl group, alkynyl group, haloalkyl, hydroxyalkyl, alkoxy group, haloalkoxy group, alkoxyalkyl, aminoalkyl, cyano group, amino group, hydroxy group, nitro group, -(CR a R b ) v Ure 17 ,-(CR a R b ) v NR 18 R 19 , -C(O)R17 , -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 group, -(CR a R b ) v heterocyclyl group, -(CR a R b ) v aryl group, -(CR a R b ) v heteroaryl group and oxo group, wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optionally substituted with one or more R 0 , R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group and a heterocyclylalkyl group, X 1 is CR 4a or N, X 2 is CR 4b or N, X 3 is CR 4c or N, X 4 is CR4d 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 These are the same or different, and each independently consists of a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, cyano group, amino group, hydroxy group, nitro group, -(CR a R b ) v Ure 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 groups, -(CR a R b )v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, Or, R 4b and R 4c These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 4c and R 4d These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 5a and R 5b These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 5b and R 5c These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, R 6This is a hydrogen atom, -NHR 7 and -NHC(O)R 7 Selected from, R 7 This is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. L is CR 8 R 9 , C(O), O, NR 10 Selected from S, S(O) and S(O)2, R 8 and R 9 These are either the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, aminoalkyl groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. Or, R 8 and R 9 The carbon atoms linked together form a cycloalkyl group or a heterocycline group, where the cycloalkyl group or heterocycline group can optionally consist of one or more R atoms. 0 Replaced by, R 10 This is selected from hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclyl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. R 11 , R 12 , R 13 , R 14 , R x and R yThese are the same or different, and each independently consists of a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, hydroxy group, cyano group, amino group, nitro group, -(CR a R b ) v Ure 17 ,-(CR a R b ) v NR 18 R 19 ,-(CR a R b ) v Cycloalkyl groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, Or, R 11 , R 12 , R 13 , R 14 , R x and R y Any two of these may, together with the carbon atoms linked to them, form a cycloalkyl or heterocyclyl group, where the cycloalkyl or heterocyclyl group may optionally consist of one or more R 0 Replaced by, or R 11 and R 12 They come together to form =O, or R 13 and R 14 They come together to form =O, or R on the same carbon atom x and R yThey come together to form =O, R 15 R is selected from hydrogen atoms, alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, arylalkyl groups, and heteroarylalkyl groups, where each of the alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, arylalkyl groups, and heteroarylalkyl groups can be independently and optionally selected as one or more R 0 Replaced by, Or, R 11 , R 12 , R 13 , R 14 , R x and R y Any one of the above and R 15 These, together with the atoms linked to each of them, form a nitrogen-containing heterocycline group, where the nitrogen-containing heterocycline group is optionally composed of one or more R 0 Replaced by, W is -C(O)R 16 -S(O)2R 16 Selected from -CN, R 16 The group is selected from alkenyl groups, alkynyl groups, and alkylene oxides, where each of the alkenyl group, alkynyl group, and alkylene oxide can be independently and optionally selected as an oxo group, halogen, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, hydroxy group, cyano group, amino group, nitro group, -(CR a R b ) v Ure 17 ,-(CR a R b ) v NR 18 R 19 , -C(O)R 17 , -C(O)OR17 -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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Substituted with one or more substituents selected from heteroaryl groups, R 0 Each occurrence may be the same or different, and each may be independently an oxo group, halogen, alkenyl group, alkynyl group, cyano group, nitro group, hydroxyl group, amino group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, -(CR a R b ) v Ure 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 20C(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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, R 17 , R 18 , R 19 and R 20 Each instance may be the same or different, and each may be independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, -(CR a R b ) v Cycloalkyl groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 01 Replaced by, or R 18 and R 19 It forms a nitrogen-containing heterocycline group with the linked nitrogen atom, and the nitrogen-containing heterocycline group optionally contains one or more R 01 Replaced by, R01 Each occurrence may be the same or different, and each is independently selected from oxo group, halogen, hydroxyl group, alkenyl group, alkynyl group, cyano group, nitro group, amino group, -NH alkyl group, -N(alkyl)2, -C(O)O alkyl group, -C(O)OH, -C(O)NH2, -C(O) halogen, -C(O) alkyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, cycloalkyl group, cycloalkylalkyl group, cycloalkyloxy group, heterocyclyl group, heterocyclylalkyl group, heterocyclyloxy group, aryl group, arylalkyl group, aryloxy group, heteroaryl group, heteroarylalkyl group and heteroaryloxy group. R a and R b Each occurrence may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. n is 0, 1, 2, or 3. v is 0, 1, 2, or 3.

[0006] The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. [ka] Here, JPEG2026534181000004.jpg27129 Ring A is selected from a polycyclic aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclyl group. Ring B is a monocyclic aryl group or a monocyclic heteroaryl group. Each R 1 and each R 2aThese are the same or different, and each independently consists of a deuterium atom, halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, deuterated alkoxy group, aminoalkyl group, cyano group, amino group, hydroxy group, nitro group, -(CR a R b ) v Ure 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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl group, -(CR a R b ) v Heteroaryl groups, oxo groups, =S and =CR p R q Selected from, where the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently and optionally selected as one or more R0 Replaced by, Or, two R's 1 These, together with the ring atoms linked to them, form a cycloalkyl group or heterocyclyl group, where the cycloalkyl group or heterocyclyl group is optionally composed of one or more R 0 Replaced by, R 2 is -OR A or -alkylene-R B Here, the alkylene group is optionally one or more R 0 Replaced by, R A R is selected from alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups can be independently and optionally selected as one or more R 0 Replaced by, R B R is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, R C R is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently one or more R d Replaced by, Each R d These are the same or different, and each independently consists of a deuterium atom, halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, deuterated alkoxy group, alkoxyalkyl group, aminoalkyl group, cyano group, amino group, hydroxy group, nitro group, -(CR a R b ) v Ure 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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl group, -(CR a R b ) v Heteroaryl groups, oxo groups, =S and =CR p R q Selected from, where the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently and optionally selected as one or more R 0 Replaced by, R 3 This is selected from hydrogen atoms, alkyl groups, deuterated alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. X 1 CR 4a or N, X 2 CR4b 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 These are the same or different, and each independently consists of 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, and -(CR a R b ) v Ure 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 R19 , -NR 20 S(O)2R 17 ,-(CR a R b ) v Cycloalkyl groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, Or, R 4b and R 4c These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 4c and R 4d These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 5a and R 5b These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 5b and R 5cThese, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, R 6 This is a hydrogen atom, -NHR 7 and -NHC(O)R 7 Selected from, R 7 This is selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, deuterated alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. L is CR 8 R 9 , C(O), O, NR 10 Selected from S, S(O) and S(O)2, R 8 and R 9 These are either the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuterated alkoxy groups, alkoxyalkyl groups, aminoalkyl groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. Or, R 8 and R 9 The carbon atoms linked together form a cycloalkyl group or a heterocycline group, where the cycloalkyl group or heterocycline group can optionally consist of one or more R atoms. 0 Replaced by, R 10This is selected from hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, deuterated alkoxy groups, cycloalkyl groups, heterocyclyl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. R 11 , R 12 , R 13 , R 14 , R x and R y These are the same or different, and each independently consists of 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, and -(CR a R b ) v Ure 17 ,-(CR a R b ) v NR 18 R 19 ,-(CR a R b ) v Cycloalkyl groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, Or, R 11 , R 12 , R 13 , R 14 , R x and R yAny two of these may, together with the carbon atoms linked to them, form a cycloalkyl or heterocyclyl group, where the cycloalkyl or heterocyclyl group may optionally consist of one or more R 0 Replaced by, or R 11 and R 12 They come together to form =O, or R 13 and R 14 They come together to form =O, or R on the same carbon atom x and R y They come together to form =O, R 15 R is selected from hydrogen atoms, alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, arylalkyl groups, and heteroarylalkyl groups, where each of the alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, arylalkyl groups, and heteroarylalkyl groups can be independently and optionally selected as one or more R 0 Replaced by, Or, R 11 , R 12 , R 13 , R 14 , R x and R y Any one of the above and R 15 These, together with the atoms linked to each of them, form a nitrogen-containing heterocycline group, where the nitrogen-containing heterocycline group is optionally composed of one or more R 0 Replaced by, W is -C(O)R 16 -S(O)2R 16 Selected from -CN, R 16The group is selected from an alkenyl group, an alkynyl group, and an alkylene oxide, where the alkenyl group, alkynyl group, and alkylene oxide are each independently and optionally selected as an oxo group, =S, or =CR. p R q , deuterium atom, halogen, alkyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, deuterated alkoxy group, alkoxyalkyl group, aminoalkyl group, hydroxyl group, cyano group, amino group, nitro group, -(CR a R b ) v Ure 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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Substituted with one or more substituents selected from heteroaryl groups, R 0 Each instance is either the same or different, and each is independently an oxo group, =S, =CR.p R q , deuterium atom, halogen, alkenyl group, alkynyl group, cyano group, nitro group, hydroxyl group, amino group, alkyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, deuterated alkoxy group, alkoxyalkyl group, aminoalkyl group, -(CR a R b ) v Ure 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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, R 17 , R 18 , R 19 and R 20 Each instance may be the same or different, and each may be independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, -(CRa R b ) v Cycloalkyl groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 01 Replaced by, or R 18 and R 19 It forms a nitrogen-containing heterocycline group with the linked nitrogen atom, and the nitrogen-containing heterocycline group optionally contains one or more R 01 Replaced by, R 01 Each instance is either the same or different, and each is independently an oxo group, =S, =CR. p R q Selected from deuterium atom, halogen, hydroxyl group, alkenyl group, alkynyl group, cyano group, nitro group, amino group, -NH alkyl group, -N(alkyl)2, -C(O)O alkyl group, -C(O)OH, -C(O)NH2, -C(O) halogen, -C(O) alkyl group, alkyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, deuterated alkoxy group, alkoxyalkyl group, aminoalkyl group, cycloalkyl group, cycloalkylalkyl group, cycloalkyloxy group, heterocyclyl group, heterocyclylalkyl group, heterocyclyloxy group, aryl group, arylalkyl group, aryloxy group, heteroaryl group, heteroarylalkyl group and heteroaryloxy group, R a and R bEach occurrence may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuterated alkoxy groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. R p and R q Each occurrence may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuterated alkoxy groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. q is an integer between 0 and 25. m is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. v is 0, 1, 2, or 3.

[0007] The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. [ka] Here, JPEG2026534181000006.jpg24129 Ring A is selected from a polycyclic aryl group, a polycyclic heteroaryl group, a polycyclic cycloalkyl group, and a polycyclic heterocyclyl group. Ring B is a monocyclic aryl group or a monocyclic heteroaryl group. Each R 1 and each R 2a These are the same or different, and each independently of the others, halogen, alkyl, alkenyl group, alkynyl group, haloalkyl, hydroxyalkyl, alkoxy group, haloalkoxy group, alkoxyalkyl, aminoalkyl, cyano group, amino group, hydroxy group, nitro group, -(CR a R b ) v Ure17 ,-(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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl group, -(CR a R b ) v Selected from heteroaryl groups and oxo groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, Or, two R's 1 These, together with the ring atoms linked to them, form a cycloalkyl group or heterocyclyl group, where the cycloalkyl group or heterocyclyl group is optionally composed of one or more R 0 Replaced by, R 2 is -OR A or -alkylene-R BHere, the alkylene group is optionally one or more R 0 Replaced by, R A R is selected from alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups can be independently and optionally selected as one or more R 0 Replaced by, R B R is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, R C R is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently one or more R d Replaced by, Each R d These are the same or different, and each independently of the others, halogen, alkyl, alkenyl group, alkynyl group, haloalkyl, hydroxyalkyl, alkoxy group, haloalkoxy group, alkoxyalkyl, aminoalkyl, cyano group, amino group, hydroxy group, nitro group, -(CR a R b ) v Ure 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 , -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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl group, -(CR a R b ) v Selected from heteroaryl groups and oxo groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, R 3 This is selected from hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. 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, R4a , R 4b , R 4c , R 4d , R 5a , R 5b and R 5c These are the same or different, and each independently consists of a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, cyano group, amino group, hydroxy group, nitro group, -(CR a R b ) v Ure 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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) vSelected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, Or, R 4b and R 4c These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 4c and R 4d These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 5a and R 5b These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 5b and R 5c These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, R 6 This is a hydrogen atom, -NHR 7 and -NHC(O)R 7 Selected from, R 7This is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. L is CR 8 R 9 , C(O), O, NR 10 Selected from S, S(O) and S(O)2, R 8 and R 9 These are either the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, aminoalkyl groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. Or, R 8 and R 9 The carbon atoms linked together form a cycloalkyl group or a heterocycline group, where the cycloalkyl group or heterocycline group can optionally consist of one or more R atoms. 0 Replaced by, R 10 This is selected from hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclyl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. R 11 , R 12 , R 13 , R 14 , R x and R y These are the same or different, and each independently consists of a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, hydroxy group, cyano group, amino group, nitro group, -(CR a R b ) v Ure 17, -(CR a R b ) v NR 18 R 19 , -(CR a R b ) v (cycloalkyl group, -(CR a R b ) v heterocyclyl group, -(CR a R b ) v aryl group and -(CR a R b ) v heteroaryl group, wherein said alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optionally substituted with one or more R 0 , or any two of R 11 , R 12 , R 13 , R 14 , R x and R y together with the carbon atoms connected thereto form a cycloalkyl group or a heterocyclyl group, wherein said cycloalkyl group or heterocyclyl group is optionally substituted with one or more R 0 , or R 11 and R 12 together form =O, or R 13 and R 14 together form =O, or R on the same carbon atom x and R y together form =O, R 15R is selected from hydrogen atoms, alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, arylalkyl groups, and heteroarylalkyl groups, where each of the alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, arylalkyl groups, and heteroarylalkyl groups can be independently and optionally selected as one or more R 0 Replaced by, Or, R 11 , R 12 , R 13 , R 14 , R x and R y Any one of the above and R 15 These, together with the atoms linked to each of them, form a nitrogen-containing heterocycline group, where the nitrogen-containing heterocycline group is optionally composed of one or more R 0 Replaced by, W is -C(O)R 16 -S(O)2R 16 Selected from -CN, R 16 The group is selected from alkenyl groups, alkynyl groups, and alkylene oxides, where each of the alkenyl group, alkynyl group, and alkylene oxide can be independently and optionally selected as an oxo group, halogen, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, hydroxy group, cyano group, amino group, nitro group, -(CR a R b ) v Ure 17 ,-(CR a R b ) v NR 18 R 19 , -C(O)R 17 , -C(O)OR 17 -C(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 group, -(CR a R b ) v heterocyclyl group, -(CR a R b ) v aryl group and -(CR a R b ) v heteroaryl group, substituted with one or more substituents selected from the group consisting of R 0 is the same or different at each occurrence, and is each independently an oxo group, a halogen, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a hydroxy group, an amino group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, an aminoalkyl group, -(CR a R b ) v OR 17 , -(CR a R b ) v NR 18 R 19 , -C(O)R 17 , -C(O)OR 17 , -C(O)NR 18 R 19 , -OC(O)NR 18 R 19 , -OC(O)R 17 , -OC(O)OR 17 , -NR 20 C(O)R 17 , -NR 20C(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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, R 17 , R 18 , R 19 and R 20 Each instance may be the same or different, and each may be independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, -(CR a R b ) v Cycloalkyl groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 01 Replaced by, or R 18 and R 19 It forms a nitrogen-containing heterocycline group with the linked nitrogen atom, and the nitrogen-containing heterocycline group optionally contains one or more R 01 Replaced by, R 01Each occurrence may be the same or different, and each is independently selected from oxo group, halogen, hydroxyl group, alkenyl group, alkynyl group, cyano group, nitro group, amino group, -NH alkyl group, -N(alkyl)2, -C(O)O alkyl group, -C(O)OH, -C(O)NH2, -C(O) halogen, -C(O) alkyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, cycloalkyl group, cycloalkylalkyl group, cycloalkyloxy group, heterocyclyl group, heterocyclylalkyl group, heterocyclyloxy group, aryl group, arylalkyl group, aryloxy group, heteroaryl group, heteroarylalkyl group and heteroaryloxy group. R a and R b Each occurrence may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. q is an integer between 0 and 25. m is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. v is 0, 1, 2, or 3.

[0008] The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. [ka] Here, JPEG2026534181000008.jpg25137 Ring A is selected from a polycyclic aryl group, a polycyclic heteroaryl group, a polycyclic cycloalkyl group, and a polycyclic heterocyclyl group. Ring B is a monocyclic aryl group or a monocyclic heteroaryl group. Each R 1 and each R 2aThese are the same or different, and each independently of the others, halogen, alkyl, alkenyl group, alkynyl group, haloalkyl, hydroxyalkyl, alkoxy group, haloalkoxy group, alkoxyalkyl, aminoalkyl, cyano group, amino group, hydroxy group, nitro group, -(CR a R b ) v Ure 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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl group, -(CR a R b ) v Selected from heteroaryl groups and oxo groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, Or, two R's 1These, together with the ring atoms linked to them, form a cycloalkyl group or heterocyclyl group, where the cycloalkyl group or heterocyclyl group is optionally composed of one or more R 0 Replaced by, R 2 is -OR A or -alkylene-R B Here, the alkylene group is optionally one or more R 0 Replaced by, R A R is selected from alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups can be independently and optionally selected as one or more R 0 Replaced by, R B R is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, R 3 This is selected from hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. 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 CR5c or N, R 4a , R 4b , R 4c , R 4d , R 5a , R 5b and R 5c These are the same or different, and each independently consists of a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, cyano group, amino group, hydroxy group, nitro group, -(CR a R b ) v Ure 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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) vSelected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, Or, R 4b and R 4c These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 4c and R 4d These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 5a and R 5b These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, Or, R 5b and R 5c These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R 0 Replaced by, R 6 This is a hydrogen atom, -NHR 7 and -NHC(O)R 7 Selected from, R 7This is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. L is CR 8 R 9 , C(O), O, NR 10 Selected from S, S(O) and S(O)2, R 8 and R 9 These are either the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, aminoalkyl groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. Or, R 8 and R 9 The carbon atoms linked together form a cycloalkyl group or a heterocycline group, where the cycloalkyl group or heterocycline group can optionally consist of one or more R atoms. 0 Replaced by, R 10 This is selected from hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclyl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. R 11 , R 12 , R 13 , R 14 , R x and R y These are the same or different, and each independently consists of a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, hydroxy group, cyano group, amino group, nitro group, -(CR a R b ) v Ure 17,-(CR a R b ) v NR 18 R 19 ,-(CR a R b ) v Cycloalkyl groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 0 Replaced by, Or, R 11 , R 12 , R 13 , R 14 , R x and R y Any two of these may, together with the carbon atoms linked to them, form a cycloalkyl or heterocyclyl group, where the cycloalkyl or heterocyclyl group may optionally consist of one or more R 0 Replaced by, or R 11 and R 12 They come together to form =O, or R 13 and R 14 They come together to form =O, or R on the same carbon atom x and R y They come together to form =O, R 15R is selected from hydrogen atoms, alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, arylalkyl groups, and heteroarylalkyl groups, where each of the alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, arylalkyl groups, and heteroarylalkyl groups can be independently and optionally selected as one or more R 0 Replaced by, Or, R 11 , R 12 , R 13 , R 14 , R x and R y Any one of the above and R 15 These, together with the atoms linked to each of them, form a nitrogen-containing heterocycline group, where the nitrogen-containing heterocycline group is optionally composed of one or more R 0 Replaced by, W is -C(O)R 16 -S(O)2R 16 Selected from -CN, R 16 The group is selected from alkenyl groups, alkynyl groups, and alkylene oxides, where each of the alkenyl group, alkynyl group, and alkylene oxide can be independently and optionally selected as an oxo group, halogen, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, hydroxy group, cyano group, amino group, nitro group, -(CR a R b ) v Ure 17 ,-(CR a R b ) v NR 18 R 19 , -C(O)R 17 , -C(O)OR 17 -C(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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Substituted with one or more substituents selected from heteroaryl groups, R 0 Each occurrence may be the same or different, and each may be independently an oxo group, halogen, alkenyl group, alkynyl group, cyano group, nitro group, hydroxyl group, amino group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, -(CR a R b ) v Ure 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 20C(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 groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, R 17 , R 18 , R 19 and R 20 Each instance may be the same or different, and each may be independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, -(CR a R b ) v Cycloalkyl groups, -(CR a R b ) v Heterocyclyl group, -(CR a R b ) v Aryl groups and -(CR a R b ) v Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R 01 Replaced by, or R 18 and R 19 It forms a nitrogen-containing heterocycline group with the linked nitrogen atom, and the nitrogen-containing heterocycline group optionally contains one or more R 01 Replaced by, R 01Each occurrence may be the same or different, and each is independently selected from oxo group, halogen, hydroxyl group, alkenyl group, alkynyl group, cyano group, nitro group, amino group, -NH alkyl group, -N(alkyl)2, -C(O)O alkyl group, -C(O)OH, -C(O)NH2, -C(O) halogen, -C(O) alkyl group, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, aminoalkyl group, cycloalkyl group, cycloalkylalkyl group, cycloalkyloxy group, heterocyclyl group, heterocyclylalkyl group, heterocyclyloxy group, aryl group, arylalkyl group, aryloxy group, heteroaryl group, heteroarylalkyl group and heteroaryloxy group. R a and R b Each occurrence may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. q is an integer between 0 and 25. m is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. v is 0, 1, 2, or 3.

[0009] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof. [ka] Here, Ring D is a nitrogen-containing heterocyclyl group, p is 0, 1, 2, or 3. G, R 3 , X 1 , X 2 , X 3 , X 4 B 1 B2 B 3 , L, R 6 , R 11 , R 12 , R x , R y , n, W and R 0 This is as defined in general formula (I).

[0010] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof. [ka] Here, Ring C is selected from aryl groups, heteroaryl groups, cycloalkyl groups, and heterocyclyl groups. R 1e R 1 And, c is 0, 1, 2, 3, 4, or 5. 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), and the condition is X 1 , X 2 , X 3 and X 4 At least one of them is N.

[0011] In some embodiments of the present disclosure, a compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein W is -C(O)R 16And R 16 This is defined in general formula (I), and in some embodiments, W is -C(O)-CH=CH2.

[0012] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), or general formula (VI) or a pharmaceutically acceptable salt thereof, where L is O.

[0013] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein B 1 It is N.

[0014] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein B 2 CR 5b And R 5b This is defined in general formula (I), and in some embodiments, B 2 It is CH.

[0015] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 5a These are hydrogen atoms, halogens, and C 1-6 Selected from alkyl groups, in some embodiments, R 5a This is a hydrogen atom.

[0016] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 5b These are hydrogen atoms, halogens, and C 1-6 Selected from alkyl groups, in some embodiments, R 5b This is a hydrogen atom.

[0017] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein B 1 N is B 2 CR 5b B 3 CR 5c or N, R 5b and R 5c This is defined in general formula (I), and in some embodiments, B 1 N is B 2 CH is B 3 is CH or N, and in some embodiments, B 1 N is B 2 CH is B 3 It is N.

[0018] In some embodiments of the present disclosure, a compound represented by general formula (I) or 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 And R 4a , R 4b , R 4c and R 4d This is defined in general formula (I), and in some embodiments, X 1 CR 4a X 2 is N or CR 4b X 3 CR 4c X 4 CR 4d And R 4a , R 4b , R 4c and R 4d This is defined in general formula (I), and in some embodiments, X 1 CR 4a X2 is N or CH, and X 3 CR 4c X 4 CH is, R 4a and R 4c This is defined in general formula (I), and in some embodiments, X 1 CR 4a X 2 CH is, X 3 CR 4c X 4 CH is, R 4a and R 4c This is defined in general formula (I), and in some embodiments, X 1 CR 4a And R 4a C 1-6 Alkyl alkyl group or C 1-6 It is a hydroxyalkyl group, X 2 is N or CH, and X 3 CR 4c And R 4c is a hydrogen atom or a halogen, and X 4 CH is, in some embodiments, X 1 CR 4a And R 4a C 1-6 It is an alkyl group, X 2 CH is, X 3 CR 4c And R 4c It is a halogen, and X 4 CH is, in some embodiments, X 1 CR 4a And R 4a X is a methyl group or a hydroxymethyl group, 2 CH is, X 3 CR 4c And R 4c is a hydrogen atom or F, and X 4 CH is, in some embodiments, X 1 CR 4a And R 4a is a methyl group, X 2CH is, X 3 CR 4c And R 4c F is X 4 It is CH.

[0019] In some embodiments of the present disclosure, a compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein ring C is a phenyl group or a six-membered heteroaryl group, and in some embodiments, ring C is a phenyl group or a pyridyl group, and in some embodiments, ring C is a phenyl group.

[0020] In some embodiments of the present disclosure, a compound represented by general formula (I) or general formula (VI) or a pharmaceutically acceptable salt thereof, wherein it is a compound represented by general formula (VI-1) or a pharmaceutically acceptable salt thereof [ka] Here, 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 general formula (VI), and the condition is X 1 , X 2 , X 3 and X 4 At least one of them is N.

[0021] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), general formula (VI), or general formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein X 1 N is X 2 CR4b X 3 CR 4c X 4 CR 4d And R 4b , R 4c and R 4d This is defined in general formula (I), and in some embodiments, X 1 CR 4a X 2 N is X 3 CR 4c X 4 CR 4d And R 4a , R 4c and R 4d This is defined in general formula (I), and in some embodiments, X 1 CR 4a X 2 N is X 3 CR 4c X 4 CR 4d And R 4a , R 4c and R 4d They are the same or different, and each is independently a hydrogen atom, C 1-6 Alkyl alkyl groups, halogens, and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, X 1 CR 4a X 2 CR 4b X 3 N is X 4 CR 4d And R 4a , R 4b and R 4d This is defined in general formula (I), and in some embodiments, X 1 CR 4a X 2 CR 4b X 3 CR 4c X 4 N is R 4a , R4b and R 4c This is defined in general formula (I), and in some embodiments, X 1 CR 4a X 2 N is X 3 CH is, X 4 CH is, R 4a This is defined in general formula (I) (R 4a In some embodiments, C 1-6 It is a hydroxyalkyl group, R 4a (In some embodiments, this is a hydroxymethyl group).

[0022] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof. [ka] Here, 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 (I).

[0023] In some embodiments of this disclosure, a compound represented by general formula (I), general formula (I-1), or general formula (II) or a pharmaceutically acceptable salt thereof, wherein it is a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof [ka] Here, p is 0, 1, 2, or 3. x is 1, 2, 3, or 4. 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 general formula (I).

[0024] In some embodiments of the present disclosure, a 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 G is optionally one or more R G A polycyclic aryl group substituted with or one or more R groups of any choice G A heteroaryl group substituted with, and in some embodiments, G is optionally one or more R G 8-14 membered polycyclic aryl groups substituted with or one or more R groups of any choice G A 5-14 member heteroaryl group substituted with, and in some embodiments, G is optionally one or more R G 8-14 membered polycyclic aryl groups substituted with or one or more R groups of any choice G A polycyclic heteroaryl group with 8-14 members substituted with, and in some embodiments, G is optionally one or more R G A polycyclic aryl group with 8 to 14 members substituted with, and in some embodiments, G is optionally one or more R G A 5-14 member heteroaryl group substituted with, and in some embodiments, G is optionally one or more R G A polycyclic heteroaryl group with 8-14 members substituted with, and in some embodiments, G is optionally one or more R G A phenyl group substituted with the above R GThis is as defined in general formula (I).

[0025] JPEG2026534181000014.jpg118169

[0026] JPEG2026534181000015.jpg97167

[0027] JPEG2026534181000016.jpg239168JPEG2026534181000017.jpg71169

[0028] In each of the above technical proposals, Q 1 Q 2 Q 3 and Q 4 One of them is C, which is linked to C(O), and the remaining three are either the same or different, and each is independently N or CR. 1a A 1 and A 2 These are the same or different, and each is independent of the bond between C(O), O, NR, S, S(O), S(O)2 and (CR). 1b R 1c ) j Selected from, R 1a , R 1b , R 1c , R e , R f , R j and R k They are either the same or different, and each is independently a hydrogen atom or R 1 And, or, R e and R f The carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Replaced by, or R j and R kThe carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Replaced by, or R f and R j The carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Replaced by, or R 1b and R 1c The carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Substituted by, where j is 0, 1, 2 or 3, r is 0 or 1, q1 is 0, 1, 2 or 3, and R is selected from a hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxyalkyl group, aminoalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, R 1 This is as defined in general formula (I).

[0029] JPEG2026534181000018.jpg127168

[0030] JPEG2026534181000019.jpg250167JPEG2026534181000020.jpg111167

[0031] JPEG2026534181000021.jpg42168

[0032] JPEG2026534181000022.jpg234169

[0033] In some embodiments of the present disclosure, a 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 7-10 membered condensed heterocyclyl group, and in some embodiments, ring A is an 8 or 9 membered condensed heterocyclyl group.

[0034] In some embodiments of the present disclosure, a 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 11-14 member tricyclic aryl group or a 12-19 member tetracyclic aryl group; in some embodiments, ring A is an 11 or 12 member tricyclic aryl group or a 13 member tetracyclic aryl group; in some embodiments, ring A is an 11-14 member tricyclic aryl group; in some embodiments, ring A is an 11 or 12 member tricyclic aryl group; in some embodiments, ring A is an 11 member tricyclic aryl group; in some embodiments, ring A Ring A is a 12-19 membered tetracyclic aryl group; in some embodiments, ring A is a 13-membered tetracyclic aryl group; in some embodiments, ring A is an 8-14 membered polycyclic aryl group or an 8-14 membered polycyclic heteroaryl group; in some embodiments, ring A is an 8-14 membered polycyclic aryl group or a 5-14 membered heteroaryl group; in some embodiments, ring A is an 8-14 membered polycyclic aryl group; in some embodiments, ring A is a 5-14 membered heteroaryl group; in some embodiments, ring A is a 5 or 6 membered heteroaryl group; and in some embodiments, ring A is a 5 membered heteroaryl group.

[0035] JPEG2026534181000023.jpg241170JPEG2026534181000024.jpg250170JPEG2026534181000025.jpg253170

[0036] JPEG2026534181000026.jpg233169JPEG2026534181000027.jpg239169 In each of the above technical proposals, Q 1 Q 2 Q 3 and Q 4 One of them is C, which is linked to C(O), and the remaining three are either the same or different, and each is independently N or CR. 1a A 1 and A 2 These are the same or different, and each is independent of the bond between C(O), O, NR, S, S(O), S(O)2 and (CR). 1b R 1c ) j Selected from, R 1a , R 1b , R 1c , R e , R f , R j and R k They are either the same or different, and each is independently a hydrogen atom or R 1 And, or, R e and R f The carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Replaced by, or R j and R k The carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Replaced by, or R f and R j The carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Replaced by, or R 1b and R 1cThe carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Substituted by, where j is 0, 1, 2 or 3, r is 0 or 1, q1 is 0, 1, 2 or 3, and R is selected from a hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxyalkyl group, aminoalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, R 1 This is as defined in general formula (I).

[0037] JPEG2026534181000028.jpg253163

[0038] JPEG2026534181000029.jpg144167

[0039] JPEG2026534181000030.jpg240166 JPEG2026534181000031.jpg205166

[0040] JPEG2026534181000032.jpg252165 JPEG2026534181000033.jpg195162

[0041] In some embodiments of the present disclosure, a 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 a phenyl group or a 5- or 6-membered heteroaryl group, and in some embodiments, ring B is a phenyl group.

[0042] JPEG2026534181000034.jpg63170

[0043] JPEG2026534181000035.jpg206165

[0044] JPEG2026534181000036.jpg129169

[0045] In some embodiments of the present disclosure, a compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof. [ka] Here, A 1 and A 2 These are the same or different, and each is independent of the bond between C(O), O, NR, S, S(O), S(O)2 and (CR). 1b R 1c ) j Selected from, R 1b , R 1c , R e , R f , R j and R k They are either the same or different, and each is independently a hydrogen atom or R 1 And, Or, R e and R f The carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Replaced by, Or, R j and R k The carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Replaced by, Or, R f and Rj The carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Replaced by, Or, R 1b and R 1c The carbon atoms linked together form a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group optionally has 1, 2, 3, or 4 (1 or 2 in some embodiments, 1 in some embodiments) R 1 Replaced by, R is selected from a hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxyalkyl group, aminoalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group. j is 0, 1, 2, or 3. q1 is 0, 1, 2, or 3. r is either 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 are as defined in general formula (I).

[0046] In some embodiments of the present disclosure, a compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein it is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof [ka] Here, 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 general formula (I).

[0047] In some embodiments of the present disclosure, a 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. [ka] Here, y is 1, 2, or 3, and in some embodiments it is 1. b is 1, 2, 3, 4 or 5, and in some embodiments it is 1. 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 general formula (I).

[0048] JPEG2026534181000040.jpg247169 JPEG2026534181000041.jpg237167

[0049] JPEG2026534181000042.jpg229167JPEG2026534181000043.jpg253169JPEG2026534181000044.jpg178170

[0050] In some embodiments of the present disclosure, a compound represented by 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 They are the same or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 1-6 Haloalkoxy group, C 1-6 Alkoxy C 1-6 Selected from alkyl groups, 3-6 membered cycloalkyl groups, 3-6 membered cycloalkyloxy groups, and cyano groups, in some embodiments, each R 1 They are the same or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, each R 1 These are the same or different, and each is independently a halogen or a 3-6 membered cycloalkyl group, and in some embodiments, each R 1 These are the same or different, and each independently, F or a cyclopropyl group, and in some embodiments, each R 1 They are the same or different, and each is independently a halogen or C 1-6 It is an alkyl group, and in some embodiments, each R 1 They are the same or different, and each is independently a halogen, and each R 1They are either the same or different, and each is independent of C 1-6 It is an alkyl group, and in some embodiments, each R 1 These are the same or different, and independently of each other, a methyl group or F, and in some embodiments, R 1 R is a methyl group, and in some embodiments, 1 It is F.

[0051] In some embodiments of the present disclosure, a 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 R 1 ' is a hydrogen atom, halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, R 1 ' is a hydrogen atom, halogen and C 1-6 Selected from alkyl groups, in some embodiments, R 1 ' is a hydrogen atom or a halogen, and in some embodiments, R 1 ' is a halogen, and in some embodiments, R 1 ' is F.

[0052] In some embodiments of the present disclosure, a 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 each R 1 '' are the same or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, R 1 '' is halogen or C 1-6 It is an alkyl group, and in some embodiments, R 1 '' is C 1-6It is an alkyl group, and in some embodiments, R 1 '' represents a methyl group.

[0053] In some embodiments of the present disclosure, a 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, and in some embodiments, q2 is 0, 1, or 2, and in some embodiments, q2 is 2.

[0054] In some embodiments of the present disclosure, a 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 R 1 '' is C 1-6 It is an alkyl group, and q2 is 2, and in some embodiments, R 1 '' is a methyl group, and q2 is 2.

[0055] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (VI), or general formula (VI-1) or a pharmaceutically acceptable salt thereof, wherein each R 1e They are the same or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Selected from hydroxyalkyl groups and 3-6 membered cycloalkyl groups, where the 3-6 membered cycloalkyl group is optionally a halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl groups, hydroxyl groups and C 1-6 Substituting with one or more substituents selected from hydroxyalkyl groups, in some embodiments, each R 1e They are the same or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6Selected from hydroxyalkyl groups and 3-6 membered cycloalkyl groups, in some embodiments, each R 1e These are the same or different, and each is independently a halogen or a 3-6 membered cycloalkyl group, and in some embodiments, each R 1e These are the same or different, and each independently, a halogen or a cyclopropyl group, and in some embodiments, each R 1e These are either the same or different, and each is independently either F or a cyclopropyl group.

[0056] In some embodiments of the present disclosure, the compound represented by general formula (VI) or general formula (VI-1) or a pharmaceutically acceptable salt thereof, where c is 1, 2, or 3, and in some embodiments, c is 2.

[0057] JPEG2026534181000045.jpg92164

[0058] JPEG2026534181000046.jpg86164

[0059] In some embodiments of this disclosure, hereby R 1f is a hydrogen atom, halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, R 1f R is a hydrogen atom or a halogen, and in some embodiments, 1f is a halogen, and in some embodiments, R 1f It is F.

[0060] In some embodiments of this disclosure, hereby R 1g is a hydrogen atom, halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6Selected from hydroxyalkyl groups and 3-6 membered cycloalkyl groups, where the 3-6 membered cycloalkyl group is optionally a halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl groups, hydroxyl groups and C 1-6 Substituted with one or more substituents selected from hydroxyalkyl groups, in some embodiments, R 1g is a 3-6 member cycloalkyl group, where the 3-6 member cycloalkyl group is optionally a halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl groups, hydroxyl groups and C 1-6 Substituted with one or more substituents selected from hydroxyalkyl groups, in some embodiments, R 1g R is a 3-6 membered cycloalkyl group, and in some embodiments, 1g This is a cyclopropyl group.

[0061] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), general formula (II), or general formula (II-1) or a pharmaceutically acceptable salt thereof, where 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), and 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). (i) 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; and in some embodiments, q is 3.

[0062] In some embodiments of the present disclosure, a compound represented by 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 q1 is 0, 1, or 2, in some embodiments q1 is 0 or 1, in some embodiments q1 is 1, and in some embodiments q1 is 0.

[0063] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1), or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R A This is a 3-6 membered cycloalkyl group or C 1-6 It is an alkyl group, and in some embodiments, R A is a cyclopropyl group or an isopropyl group, and in some embodiments, R A R is a 3-6 membered cycloalkyl group, and in some embodiments, A R is a cyclopropyl group, and in some embodiments, A C 1-6 It is an alkyl group, and in some embodiments, R A This is an isopropyl group.

[0064] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1), or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R B R is a 3-6 membered cycloalkyl group, and in some embodiments, B This is a cyclopropyl group.

[0065] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1), or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2 is -OR A or 3-6 member cycloalkyl C 1-6 It is an alkyl group, RA This is defined in general formula (I), and in some embodiments, R 2 The group is selected from isopropyloxy, cyclopropyloxy, and cyclopropylmethyl groups.

[0066] JPEG2026534181000047.jpg174170

[0067] JPEG2026534181000048.jpg125167

[0068] In some embodiments of the present disclosure, a compound represented by 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 They are the same or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy groups and C 1-6 Selected from haloalkoxy groups, in some embodiments, each R d They are either the same or different, and each is independent of C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy groups and C 1-6 Selected from haloalkoxy groups, in some embodiments, each R d They are the same or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl and C 1-6 Selected from alkoxy groups, in some embodiments, each R d They are the same or different, and each is independently a halogen, C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, in some embodiments, each R d They are either the same or different, and each is independent of C1-6 Alkyl alkyl group, C 1-6 Haloalkyl and C 1-6 Selected from alkoxy groups, in some embodiments, each R d They are either the same or different, and each is independent of C 1-6 The alkyl group or halogen is, in some embodiments, each R d They are either the same or different, and each is independent of C 1-6 It is an alkyl group, and in some embodiments, R d This is a methyl group.

[0069] In some embodiments of the present disclosure, a compound represented by 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 They are the same or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, each R 2a These are the same or different, and each is independently a halogen, and in some embodiments, R 2a It is F.

[0070] In some embodiments of the present disclosure, a compound represented by 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, where m is 0, 1, or 2, and in some embodiments, m is 0 or 1, and in some embodiments, m is 1.

[0071] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R4a is a hydrogen atom, halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, R 4a C 1-6 Alkyl alkyl group or C 1-6 It is a hydroxyalkyl group, and in some embodiments, R 4a C 1-6 It is an alkyl group, and in some embodiments, R 4a R is a methyl group, and in some embodiments, 4a C 1-6 It is a hydroxyalkyl group, and in some embodiments, R 4a R is a methyl group or a hydroxymethyl group, and in some embodiments, 4a This is a hydroxymethyl group.

[0072] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 4b is a hydrogen atom, halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, R 4b This is a hydrogen atom.

[0073] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 4c is a hydrogen atom, halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C1-6 Alkoxy groups and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, R 4c R is a hydrogen atom or a halogen, and in some embodiments, 4c is a halogen, and in some embodiments, R 4c is a hydrogen atom or F, and in some embodiments, R 4c R is a hydrogen atom, and in some embodiments, 4c It is F.

[0074] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 4d is a hydrogen atom, halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, R 4d This is a hydrogen atom.

[0075] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 4a , R 4b , R 4c and R 4d They are the same or different, and each is independently a hydrogen atom, halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, R 4a C 1-6 Alkyl alkyl group or C 1-6It is a hydroxyalkyl group, R 4b R is a hydrogen atom, 4c is a hydrogen atom or a halogen, and R 4d R is a hydrogen atom, and in some embodiments, 4a C 1-6 It is an alkyl group, R 4b R is a hydrogen atom, 4c It is a halogen, and R 4d R is a hydrogen atom, and in some embodiments, 4a R is a methyl group or a hydroxymethyl group, 4b R is a hydrogen atom, 4c is a hydrogen atom or F, and R 4d R is a hydrogen atom, and in some embodiments, 4a It is a methyl group, and R 4b R is a hydrogen atom, 4c F is R 4d This is a hydrogen atom.

[0076] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 3 C is a hydrogen atom. 1-6 Selected from alkyl groups and cyclopropyl groups, in some embodiments, R 3 is a hydrogen atom or C 1-6 It is an alkyl group, and in some embodiments, R 3 This is a hydrogen atom.

[0077] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 5c These are hydrogen atoms, halogens, and C 1-6 Selected from alkyl groups, in some embodiments, R5c This is a hydrogen atom.

[0078] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein B 3 is CH or N, and in some embodiments, B 3 It is N.

[0079] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 6 -NHR 7 And R 7 This is defined in general formula (I), and in some embodiments, R 6 R is an amino group. In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 7 is a hydrogen atom or C 1-6 It is an alkyl group, and in some embodiments, R 7 This is a hydrogen atom.

[0080] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, where n is 0 or 1, and in some embodiments, n is 0.

[0081] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), or general formula (VI-1), or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 13 and R 14 They are the same or different, and each is independently a hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, in some embodiments, R 11 , R 12 , R 13 and R 14 They are either the same or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, and in some embodiments, R 11 , R 12 , R 13 and R 14 R is the same or different and independently of the other, and in some embodiments, R 11 , R 12 , R 13 and R 14 This is a hydrogen atom.

[0082] In some embodiments of the present disclosure, a compound represented by general formula (I-1) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 They are the same or different, and each is independently a hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, in some embodiments, R 11 and R 12 R is the same or different and independently of the other, and in some embodiments, R 11 and R 12 They are either the same or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, and in some embodiments, R11 and R 12 R is a deuterium atom, and in some embodiments, 11 and R 12 This is a hydrogen atom.

[0083] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), or general formula (VI-1), or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 13 and R 14 n is a hydrogen atom, and / or n is 0.

[0084] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R x and R y They are the same or different, and each is independently a hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, in some embodiments, R x and R y They are either the same or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, and in some embodiments, R x and R y This is a hydrogen atom.

[0085] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), or general formula (VI-1), or a pharmaceutically acceptable salt thereof, wherein R 15 C is a hydrogen atom. 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl groups, C 1-6Selected from haloalkyl groups and 3-6 membered cycloalkyl groups, in some embodiments, R 15 C 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl groups and C 1-6 Selected from haloalkyl groups, in some embodiments, R 15 C is a hydrogen atom. 1-6 Alkyl alkyl group, C 1-6 Selected from deuterated alkyl groups and 3-6 membered cycloalkyl groups, in some embodiments, R 15 C is a hydrogen atom. 1-6 Selected from alkyl groups and 3-6 membered cycloalkyl groups, in some embodiments, R 15 C 1-6 It is an alkyl group or a 3-6 membered cycloalkyl group, and in some embodiments, R 15 C 1-6 Alkyl alkyl group or C 1-6 It is a deuterated alkyl group, and in some embodiments, R 15 C 1-6 It is an alkyl group, and in some embodiments, R 15 is a methyl group or -CD3, and in some embodiments, R 15 R is a methyl group or a cyclopropyl group, and in some embodiments, 15 R is a methyl group, and in some embodiments, 15 is -CD3, and in some embodiments, R 15 R is a cyclopropyl group, and in some embodiments, 15 The group is selected from a methyl group, -CD3, an ethyl group, and -CH2CH2F.

[0086] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), or general formula (VI-1), or a pharmaceutically acceptable salt thereof, wherein R 14 and R 15These, together with the atoms linked to each of them, form a 4-7 member nitrogen-containing heterocyclyl group, and the 4-7 member nitrogen-containing heterocyclyl group optionally has one or more R 0 Replaced with R 0 This is defined in general formula (I), and in some embodiments, R 14 and R 15 These, together with the atoms linked to each of them, form a 5-membered nitrogen-containing heterocycline group, and the 5-membered nitrogen-containing heterocycline group optionally has one or more R 0 Replaced with R 0 They are the same or different, and each is independently a halogen or C 1-6 It is an alkoxy group.

[0087] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), or general formula (VI-1), or a pharmaceutically acceptable salt thereof, wherein R 13 R is a hydrogen atom, 14 and R 15 These, together with the atoms linked to each of them, form a 4-7 member nitrogen-containing heterocyclyl group, where the 4-7 member nitrogen-containing heterocyclyl group is optionally composed of one or more R 0 Replaced with R 0 This is defined in general formula (I), and in some embodiments, R 13 R is a hydrogen atom, 14 and R 15 These, together with the atoms linked to each of them, form a 5-membered nitrogen-containing heterocycline group, where the 5-membered nitrogen-containing heterocycline group optionally consists of one or more R 0 Replaced with R 0 This is defined in general formula (I), and in some embodiments, R 13 R is a hydrogen atom, 14 and R 15 These, together with the atoms linked to each of them, form a pyrrolidinyl group, where the pyrrolidinyl group can optionally consist of one or more R0 Replaced with R 0 This is defined in general formula (I), and in some embodiments, R 13 R is a hydrogen atom, 14 and R 15 These, together with the atoms to which they are linked, form a pyrrolidinyl group.

[0088] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), or general formula (VI-1), or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 13 , R 14 , R x and R y They are the same or different, and each is independently a hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, R 15 C is a hydrogen atom. 1-6 Selected from alkyl groups and 3-6 membered cycloalkyl groups, or R 11 , R 12 , R x and R y They are the same or different, and each is independently a hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, R 13 R is a hydrogen atom, 14 and R 15 These, together with the atoms linked to each of them, form a 4-7 member nitrogen-containing heterocyclyl group, where the 4-7 member nitrogen-containing heterocyclyl group is optionally composed of one or more R 0 Replaced with R 0 This is defined in general formula (I), In some embodiments, R 11 , R 12 , R 13 , R 14 , R x and R yThey are either the same or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, R 15 C 1-6 It is an alkyl group or a 3-6 membered cycloalkyl group, or R 11 , R 12 , R x and R y They are either the same or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, R 13 R is a hydrogen atom, 14 and R 15 These, together with the atoms linked to each of them, form a 5-membered nitrogen-containing heterocycline group, where the 5-membered nitrogen-containing heterocycline group optionally consists of one or more R 0 Replaced with R 0 This is defined in general formula (I), In some embodiments, R 11 , R 12 , R 13 , R 14 , R x and R y R is a hydrogen atom, 15 C 1-6 It is an alkyl group or a 3-6 membered cycloalkyl group, or R 11 , R 12 , R x and R y R is a hydrogen atom, 13 R is a hydrogen atom, 14 and R 15 These, together with the atoms linked to each of them, form a 5-membered nitrogen-containing heterocycline group. In some embodiments, R 11 , R 12 , R 13 , R 14 , R x and R y R is a hydrogen atom, 15 C 1-6 It is an alkyl group, or R 11 , R 12 , R x and R y R is a hydrogen atom,13 R is a hydrogen atom, 14 and R 15 These, together with the atoms to which they are linked, form a pyrrolidinyl group.

[0089] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), or general formula (VI-1), or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 13 and R 14 Each of these is independently a hydrogen atom or a deuterium atom, and R 15 C is a hydrogen atom. 1-6 Alkyl alkyl group, C 1-6 Deuterated alkyl groups and C 1-6 Selected from haloalkyl groups, or R 14 and R 15 These, together with the atoms linked to each of them, form a 4-7 member nitrogen-containing heterocyclyl group, and the 4-7 member nitrogen-containing heterocyclyl group optionally has one or more R 0 Replaced with R 0 They are the same or different, and each is independently a halogen or C 1-6 It is an alkoxy group, and in some embodiments, R 11 , R 12 , R 13 and R 14 R is a hydrogen atom, 15 C 1-6 Alkyl alkyl group or C 1-6 It is a deuterated alkyl group, and in some embodiments, R 11 , R 12 , R 13 and R 14 R is a hydrogen atom, 15 C 1-6 It is an alkyl group, and in some embodiments, R 11 , R 12 , R 13 and R 14 R is a hydrogen atom, 15 This is a methyl group.

[0090] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 16 C 2-6 It is an alkenyl group, where the C 2-6 The alkenyl group can optionally be a halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy groups and -NR 18 R 19 Substituted with one or more substituents selected from R 18 and R 19 Each of these is independently a hydrogen atom or C 1-6 It is an alkyl group, and in some embodiments, R 16 C 2-6 It is an alkenyl group, and in some embodiments, R 16 -CH=CH2.

[0091] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 0 Each time it appears, it may be the same or different, and each independently of the halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, R 0 Each time it appears, it may be the same or different, and each independently of the halogen, C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, in some embodiments, R 0Each instance is either the same or different, and each is independently of a halogen or C 1-6 It is an alkoxy group, and in some embodiments, R 0 Each instance is either the same or different, and each is independently either F or a methoxy group.

[0092] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 01 Each time it appears, it may be the same or different, and each independently of the halogen, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, in some embodiments, R 01 Each time it appears, it may be the same or different, and each independently of the halogen, C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups.

[0093] In some embodiments of the present disclosure, a compound represented by general formula (I-1) or general formula (II-1) or a pharmaceutically acceptable salt thereof, where p is 0 or 1, and in some embodiments, p is 0, and in some embodiments, p is 1.

[0094] 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 heterocyclyl group, in some embodiments ring D is a 5-membered nitrogen-containing heterocyclyl group, and in some embodiments ring D is a pyrrolidinyl group.

[0095] In some embodiments of the present disclosure, the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, where x is 2 or 3, and in some embodiments, x is 2.

[0096] In some embodiments of the present disclosure, a compound represented by 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 is 0, and in some embodiments, r is 1.

[0097] In some embodiments of the present disclosure, a compound represented by 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 t is 1.

[0098] In some embodiments of this disclosure, a compound represented by 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 z is 1.

[0099] In some embodiments of the present disclosure, a compound represented by 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 f is 1 or 2, and in some embodiments, f is 1.

[0100] In some embodiments of the present disclosure, a compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1), or general formula (III) or a pharmaceutically acceptable salt thereof, where 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, and in some embodiments j is 0.

[0101] In some embodiments of the present disclosure, a compound represented by 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 1b and R 1c These are the same or different, and each is independently a hydrogen atom, a halogen, and C 1-6 Selected from alkyl groups, in some embodiments, R 1b and R 1c This is a hydrogen atom.

[0102] In some embodiments of the present disclosure, a compound represented by 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 A 1 It is selected from bond, O and CH2, A 2 is bond, O and CR 1b R 1c Selected from, R 1b and R 1c is a hydrogen atom, or R 1b and R 1c It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, and in some embodiments, A 1 It is selected from bond, O and CH2, A 2 is bond, O and CR 1b R 1c Selected from, R 1b and R 1c is a hydrogen atom, or R 1b and R 1c It forms a cyclopropyl group with the linked carbon atoms, and in some embodiments, A 1 and A 2 These are the same or different, and each is independently selected from bond, O, and CH2, and in some embodiments, A 1 is CH2 or O, and A 2 This is a combination, and in some embodiments, A 1 CH2 is, A 2 This is a combination, and in some embodiments, A 1O is A 2 This is a combination, and in some embodiments, A 1 O is A 2 O is O, and in some embodiments, A 1 is a combination, A 2 is CH2 or O, and in some embodiments, A 1 is a combination, A 2 O is O, and in some embodiments, A 1 is a combination, A 2 CH2 is, in some embodiments, A 1 is O or CH2, and A 2 is a combination, or A 2 is O or CH2, and A 1 It is a combination.

[0103] In some embodiments of the present disclosure, a compound represented by 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 A 2 is bond, O and CR 1b R 1c Selected from, R 1b and R 1c is a hydrogen atom, or R 1b and R 1c It forms a cyclopropyl group with the linked carbon atoms, and in some embodiments, A 2 is a bond or O, and in some embodiments, A 2 This is a combination, and in some embodiments, A 2 is CH2 or O, In some embodiments of the present disclosure, a compound represented by 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 in some embodiments, A 1 O is O, and in some embodiments, A 1 This is a combination, and in some embodiments, A 1 It is either CH2 or O.

[0104] In some embodiments of this disclosure, a compound represented by 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 These are the same or different, and each is independently a hydrogen atom, a halogen, and C 1-6 Selected from alkyl groups, or R e and R f It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, or R j and R k It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, or R f and R j It forms a 4-6 membered cycloalkyl group with the linked carbon atoms, and in some embodiments, R e , R f , R j and R k is a hydrogen atom, or R e and R f It forms a cyclopropyl group with the linked carbon atom, or R j and R k It forms a cyclopropyl group with the linked carbon atom, or R f and R j It forms a cyclobutyl group with the linked carbon atoms, and in some embodiments, R e , R f , R j and R k is a hydrogen atom or C 1-6 It is an alkyl group, or R e and R f It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, or R j and R k It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, and in some embodiments, R e , R f , R j and Rk is a hydrogen atom or a methyl group, or R e and R f It forms a cyclopropyl group with the linked carbon atom, or R j and R k It forms a cyclopropyl group with the linked carbon atoms, and in some embodiments, R e and R f C 1-6 It is an alkyl group, or R e and R f It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, R j and R k R is a hydrogen atom, and in some embodiments, j and R k C 1-6 It is an alkyl group, or R j and R k It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, R e and R f This is a hydrogen atom.

[0105] In some embodiments of the present disclosure, a compound represented by 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 is 0 or 1, and R e and R f It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, R j and R k is a hydrogen atom, or r is 1, R j and R k It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, R e and R f is a hydrogen atom, or r is 1, R f and R j It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, R e and R k is a hydrogen atom, and in some embodiments, r is 0 or 1, R eand R f It forms a cyclopropyl group with the linked carbon atoms, R j and R k is a hydrogen atom, or r is 1, R j and R k It forms a cyclopropyl group with the linked carbon atoms, R e and R f is a hydrogen atom, or r is 1, R f and R j It forms a cyclobutyl group together with the linked carbon atoms, R e and R k is a hydrogen atom, and in some embodiments, r is 1, R j and R k It forms a cyclopropyl group with the linked carbon atoms, R e and R f This is a hydrogen atom.

[0106] JPEG2026534181000049.jpg80166

[0107] JPEG2026534181000050.jpg81164

[0108] In some embodiments of this disclosure, a compound represented by 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 They are either the same or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, or R e and R f It forms a cyclopropyl group with the linked carbon atom, or R j and R k It forms a cyclopropyl group with the linked carbon atom, and r is 0 or 1, A 1 It is selected from bond, O and CH2, A 2 is bond, O and CR 1b R1c Selected from, R 1b and R 1c is a hydrogen atom, or R 1b and R 1c It forms a cyclopropyl group with the linked carbon atom.

[0109] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R 17 , R 18 , R 19 and R 20 Each instance is either the same or different, and each is independently of a hydrogen atom or C 1-6 It is an alkyl group.

[0110] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, where v is 0 or 1, and in some embodiments, v is 0.

[0111] In some embodiments of the present disclosure, a compound represented by 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) or a pharmaceutically acceptable salt thereof, wherein R a and R b These are the same or different, and each is independently a hydrogen atom, a halogen, and C 1-6 Selected from alkyl groups, in some embodiments, R a and R b This is a hydrogen atom.

[0112] JPEG2026534181000051.jpg54165

[0113] JPEG2026534181000052.jpg203169

[0114] JPEG2026534181000053.jpg228166

[0115] JPEG2026534181000054.jpg112168

[0116] JPEG2026534181000055.jpg70168

[0117] JPEG2026534181000056.jpg103168

[0118] JPEG2026534181000057.jpg61168

[0119] In some embodiments of this disclosure, a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen, q1 is 1, and A 1 and A 2 They are either the same or different, and each is independently selected from the bond, O and CH2, where r is 1 and R e , R f , R j and R k They are either the same or different, and each is independently a hydrogen atom or C 1-6 It is an alkyl group, or R e and R f It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, or R j and R k It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, R 3 R is a hydrogen atom, 4a C 1-6 Alkyl alkyl group or C 1-6 It is a hydroxyalkyl group, R 4b R is a hydrogen atom, 4c is a hydrogen atom or a halogen, and R4d is a hydrogen atom, and B 3 N is R 6 is an amino group, R 11 , R 12 , R 13 and R 14 R is a hydrogen atom, 15 C 1-6 Alkyl alkyl group or C 1-6 It is a deuterated alkyl group, where n is 0 and R 16 -CH=CH2.

[0120] In some embodiments of this disclosure, a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen, q1 is 1, and A 1 is O or CH2, and A 2 is a combination, or A 2 is O or CH2, and A 1 is a bond, r is 1, R e , R f , R j and R k are the same or different, and each is independently a hydrogen atom or a methyl group, or R e and R f It forms a cyclopropyl group with the linked carbon atom, or R j and R k It forms a cyclopropyl group with the linked carbon atoms, R 3 R is a hydrogen atom, 4a C 1-6 It is an alkyl group, R 4b R is a hydrogen atom, 4c It is a halogen, and R 4d is a hydrogen atom, and B 3 N is R 6 is an amino group, R 11 , R 12 , R 13 and R 14 R is a hydrogen atom, 15 C 1-6 It is an alkyl group, n is 0, and R 16-CH=CH2.

[0121] JPEG2026534181000058.jpg94168

[0122] JPEG2026534181000059.jpg97168

[0123] JPEG2026534181000060.jpg78169

[0124] In some embodiments of the present disclosure, a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1, and R e and R f It forms a cyclopropyl group with the linked carbon atoms, R j and R k is a hydrogen atom, or r is 1, R j and R k It forms a cyclopropyl group with the linked carbon atoms, R e and R f is a hydrogen atom, or r is 1, R f and R j It forms a cyclobutyl group together with the linked carbon atoms, R e and R k is a hydrogen atom, and A 1 and A 2 They are either the same or different, and each is independently selected from the bond, O, and CH2, where q1 is 1 and R 1 It is a halogen, and R 3 R is a hydrogen atom, 4a C 1-6 It is an alkyl group, R 4b R is a hydrogen atom, 4c It is a halogen, and R 4d is a hydrogen atom, and B 3 is CH or N, and R 6 is an amino group, R 11 , R 12 , R 13 and R 14is a hydrogen atom, n is 0, and R 15 C is a hydrogen atom. 1-6 Selected from alkyl groups and 3-6 membered cycloalkyl groups, R 16 C 2-6 It is an alkenyl group.

[0125] In some embodiments of the present disclosure, a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein r is 1 and R j and R k It forms a cyclopropyl group with the linked carbon atoms, R e and R f is a hydrogen atom, and A 1 CH2 is, A 2 is a bond, q1 is 1, and R 1 It is a halogen, and R 3 R4 is a hydrogen atom, R4a is a C1-6 alkyl group, R4b is a hydrogen atom, R4c is a halogen, R4d is a hydrogen atom, B3 is N, R6 is an amino group, R11, R12, R13 and R14 are hydrogen atoms, n is 0, R15 is a C1-6 alkyl group, and R16 is -CH=CH2.

[0126] In some embodiments of the present disclosure, a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1, A1 and A2 are the same or different and each is independently selected from bond, O and CH2, Re, Rf, Rj and Rk are the same or different and each is independently a hydrogen atom or a C1-6 alkyl group, or Re and Rf form a 3-6 membered cycloalkyl group together with a linked carbon atom, or Rj Rk and R1 form a 3-6 membered cycloalkyl group with the linked carbon atom, q1 is 0 or 1, R1 is a halogen, R3 is a hydrogen atom, R4a is a C1-6 alkyl group, R4b is a hydrogen atom, R4c is a halogen, R4d is a hydrogen atom, B3 is N, R6 is an amino group, R11, R12, R13 and R14 are hydrogen atoms, n is 0, R15 is a C1-6 alkyl group, and R16 is -CH=CH2.

[0127] In some embodiments of the present disclosure, a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein r is 1, A1 is CH2 or O, A2 is a bond, Re, Rf, Rj and Rk are the same or different and each independently a hydrogen atom or a methyl group, or Re and Rf form a cyclopropyl group together with a linked carbon atom, or Rj and Rk form a cyclopropyl group together with a linked carbon atom, q1 is 1, R1 is a halogen, R3 is a hydrogen atom, R4a is a C1-6 alkyl group, R4b is a hydrogen atom, R4c is a halogen, R4d is a hydrogen atom, B3 is N, R6 is an amino group, R11, R12, R13 and R14 are hydrogen atoms, n is 0, R15 is a C1-6 alkyl group, and R16 is -CH=CH2.

[0128] In some embodiments of the present disclosure, a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein R2a is a halogen, m is 1, b is 1, y is 1, Rd is selected from a halogen, a C1-6 alkyl group, a C1-6 haloalkyl group and a C1-6 alkoxy group, R3 is a hydrogen atom, R4a is a C1-6 alkyl group, R4b is a hydrogen atom, R4c is a halogen, R4d is a hydrogen atom, B3 is N, R6 is an amino group, R11, R12, R13 and R14 are hydrogen atoms, n is 0, R15 is a C1-6 alkyl group, and R16 is -CH=CH2.

[0129] JPEG2026534181000061.jpg73169

[0130] [Table 1] JPEG2026534181000063.jpg255155JPEG2026534181000064.jpg219148JPEG2026534181000065.jpg220154JPEG2026534181000066.jpg24115 2JPEG2026534181000067.jpg251155JPEG2026534181000068.jpg207150JPEG2026534181000069.jpg248150JPEG2026534181000070.jpg54152

[0131] Another aspect of this disclosure relates to a compound represented by general formula (IA) or a salt thereof, [ka] Here, G, R 3 , X 1 , X 2 , X 3 , X 4 B 1 B 2 B 3 , R 6 , L, R11 , R 12 , R 13 , R 14 , R 15 , R x , R y And n are as defined in general formula (I).

[0132] Another aspect of this disclosure relates to a compound represented by general formula (I-1A) or a salt thereof, [ka] Here, 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 0 And p are as defined in general formula (I-1).

[0133] Another aspect of this disclosure relates to a compound represented by general formula (IIA) or a salt thereof, [ka] Here, 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).

[0134] Another aspect of this disclosure relates to a compound represented by general formula (II-1A) or a salt thereof, [ka] Here, 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 general formula (II-1).

[0135] Another aspect of this disclosure relates to a compound represented by general formula (IIIA) or a salt thereof, [ka] Here, 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).

[0136] Another aspect of this disclosure relates to a compound represented by general formula (IVA) or a salt thereof, [ka] Here, 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).

[0137] Another aspect of this disclosure relates to a compound represented by general formula (VA) or a salt thereof, [ka] Here, 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 general formula (V).

[0138] [Table 2] JPEG2026534181000079.jpg217161JPEG2026534181000080.jpg247167JPEG2026534181000081.jpg234162JPEG20265341810 00082.jpg213158JPEG2026534181000083.jpg250166JPEG2026534181000084.jpg234161JPEG2026534181000085.jpg230153 JPEG2026534181000086.jpg199157JPEG2026534181000087.jpg255160JPEG2026534181000088.jpg223163JPEG20265341810 00089.jpg246152JPEG2026534181000090.jpg223167JPEG2026534181000091.jpg244160JPEG2026534181000092.jpg233158

[0139] Another aspect of this disclosure relates to a method for producing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes reacting a compound represented by general formula (IA) or a salt thereof with a compound represented by general formula (IB) or a salt thereof to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, Here, X is a halogen, and in some embodiments, it is Cl. W is -C(O)R 16 Or -S(O)2R 16 And, 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 , R15 , R 16 , R x , R y And n are as defined in general formula (I).

[0140] Another aspect of this disclosure relates to a method for producing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes a condensation reaction of a compound shown in general formula (I-1A) or a salt thereof with a compound shown in general formula (IB) or a salt thereof to obtain a compound shown in general formula (I-1) or a pharmaceutically acceptable salt thereof. Here, X is a halogen, and in some embodiments, it is Cl. W is -C(O)R 16 Or -S(O)2R 16 And, 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 general formula (I-1).

[0141] Another aspect of this disclosure relates to a method for producing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes reacting a compound represented by general formula (IIA) or a salt thereof with a compound represented by general formula (IIB) or a salt thereof to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof. Here, X is a halogen, and in some embodiments, it is Cl. 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).

[0142] Another aspect of this disclosure relates to a method for producing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes a condensation reaction of a compound shown in general formula (II-1A) or a salt thereof with a compound shown in general formula (IIB) or a salt thereof to obtain a compound shown in general formula (II-1) or a pharmaceutically acceptable salt thereof. Here, X is a halogen, and in some embodiments, it is Cl. 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 general formula (II-1).

[0143] Another aspect of this disclosure relates to a method for producing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes reacting a compound represented by general formula (IIIA) or a salt thereof with a compound represented by general formula (IIB) or a salt thereof to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof. Here, X is a halogen, and in some embodiments, it is Cl. 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).

[0144] Another aspect of this disclosure relates to a method for producing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes reacting a compound represented by general formula (IVA) or a salt thereof with a compound represented by general formula (IIB) or a salt thereof to obtain a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof. Here, X is a halogen, and in some embodiments, it is Cl. 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).

[0145] Another aspect of this disclosure relates to a method for producing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes reacting a compound represented by general formula (VA) or a salt thereof with a compound represented by general formula (IIB) or a salt thereof to obtain a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof. Here, X is a halogen, and in some embodiments, it is Cl. 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 This is as defined in general formula (V).

[0146] In some embodiments of this disclosure, a method for producing 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) is provided, wherein the condensation reaction is carried out under alkaline conditions, and the reagent providing the alkaline conditions includes organic bases and inorganic bases, wherein 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, and 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, and in some embodiments, the reagent providing the alkaline conditions is N,N-diisopropylethylamine.

[0147] In some embodiments of the present disclosure, a method for producing the above-mentioned formulas (I), (I-1), (II), (II-1), (III), (IV), (V), (VI), or (VI-1) is provided, wherein the condensation reaction is carried out in a solvent, the solvent used including, but 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.

[0148] Another aspect of the present disclosure relates to a pharmaceutical composition comprising the compounds shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0149] This disclosure further relates to the use of compounds represented by 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) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, in the manufacture of drugs for the treatment and / or prevention of BTK-mediated diseases or disorders.

[0150] This disclosure further relates to the use of compounds represented by 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) and the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, in the manufacture of BTK inhibitors.

[0151] This disclosure further relates to the use of compounds represented by 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) and compounds shown in Table A or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the same in the manufacture of drugs for the treatment and / or prevention of diseases or disorders, wherein the disease or disorder is selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, anaphylaxis, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, metabolic / endocrine disorders and neurological disorders, and in some embodiments, the disease or disorder is selected from autoimmune diseases, inflammatory diseases and cancer, and in some embodiments, the disease or disorder is an autoimmune disease or an inflammatory disease, and in some embodiments, Diseases or disorders include B-cell malignancies, multiple myeloma, leukemia (e.g., acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute myeloid 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 exudative lymphoma, follicular lymphoma) (Chronic lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, B-cell lymphoma and follicular lymphoma), Waldenstrom macroglobulinemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstrom macroglobulinemia, bone cancer, bone metastases, arthritis (e.g., rheumatoid arthritis, systemic 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 idiopathic urticaria, chronic induced urticaria, chronic autoimmune urticaria), liver failure, allergies (e.g., atopic dermatitis, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis (e.g.,Atopic dermatitis, pancreatitis, mastitis, meningitis, glomerulonephritis, Goodpasture syndrome, Hashimoto's disease, keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolism, myocardial infarction, angina pectoris, stroke, ischemic injury, pulmonary embolism, The following conditions are selected: gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, hidradenitis suppurativa, myasthenia gravis, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, immune thrombocytopenia, complications of organ transplantation, xenotransplantation, antibody-mediated transplant rejection (AMR), graft-versus-host disease, and B-cell-mediated hyperacute, acute, and chronic transplant rejection.

[0152] The disclosure further relates to a method for inhibiting BTK, which includes administering to a patient in need of it a compound of 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) and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0153] The disclosure further relates to a method for treating and / or preventing BTK-mediated diseases or disorders, which includes administering to a patient in need of it 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0154] This disclosure further relates to a method for treating and / or preventing a disease or disorder, which comprises administering to a patient in need of it a compound of 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) and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein the disease or disorder is selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, anaphylaxis, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, metabolic / endocrine disorders and neurological disorders, and in some embodiments, the disease or disorder is selected from autoimmune diseases, inflammatory diseases and cancer, and in some embodiments, the disease or disorder is an autoimmune disease or an inflammatory disease, and in some embodiments In this context, the aforementioned diseases or disorders include B-cell malignancies, multiple myeloma, leukemia (e.g., acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute myeloid 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 exudative lymphoma, follicular lymphoma) Lymphoma (mantle cell lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, B-cell lymphoma and follicular lymphoma), Waldenstrom macroglobulinemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstrom macroglobulinemia, bone cancer, bone metastases, arthritis (e.g., rheumatoid arthritis, systemic 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 idiopathic urticaria, chronic induced urticaria, chronic autoimmune urticaria), liver failure, allergies (e.g., atopic dermatitis, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis (e.g., atopic dermatitis), pancreatitis, mastitis, meningitis, glomerulonephritis, good The following conditions are selected: Dopasture syndrome, Hashimoto's disease, keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolism, myocardial infarction, angina pectoris, stroke, ischemic injury, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, hidradenitis suppurativa, myasthenia gravis, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, immune thrombocytopenia, complications from organ transplantation, xenotransplantation, antibody-mediated transplant rejection (AMR), graft-versus-host disease, and B-cell-mediated hyperacute, acute, and chronic transplant rejection.

[0155] This disclosure further relates to the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used as drugs.

[0156] This disclosure further relates to compounds represented by 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) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used as BTK inhibitors.

[0157] This disclosure further relates to compounds represented by 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) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, which are used to treat and / or prevent BTK-mediated diseases or disorders.

[0158] This disclosure further relates to 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) and the compounds shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, which are used to treat and / or prevent a disease or disorder, wherein the disease or disorder is selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, anaphylaxis, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, metabolic / endocrine disorders and neurological disorders, and in some embodiments, the disease or disorder is selected from autoimmune diseases, inflammatory diseases and cancer, and in some embodiments, the disease Or the disorder is B-cell malignancy, multiple myeloma, leukemia (e.g., acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute myeloid 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 exudative lymphoma, follicular lymphoma) (Mantle cell lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, B-cell lymphoma and follicular lymphoma), Waldenstrom macroglobulinemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstrom macroglobulinemia, bone cancer, bone metastases, arthritis (e.g., rheumatoid arthritis, systemic 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 idiopathic urticaria, chronic induced urticaria, chronic autoimmune urticaria), liver failure, allergies (e.g., atopic dermatitis, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis (e.g.,Atopic dermatitis, pancreatitis, mastitis, meningitis, glomerulonephritis, Goodpasture syndrome, Hashimoto's disease, keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolism, myocardial infarction, angina pectoris, stroke, ischemic injury, pulmonary embolism, The following conditions are selected: gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, hidradenitis suppurativa, myasthenia gravis, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, immune thrombocytopenia, complications of organ transplantation, xenotransplantation, antibody-mediated transplant rejection (AMR), graft-versus-host disease, and B-cell-mediated hyperacute, acute, and chronic transplant rejection.

[0159] In some embodiments, the arthritis described in this disclosure is rheumatoid arthritis.

[0160] In some embodiments, the diabetes described herein is type 1 diabetes.

[0161] In some embodiments, the urticaria described herein is chronic urticaria or acute urticaria, and in some embodiments, the urticaria described herein is chronic urticaria.

[0162] In some embodiments, the urticaria described herein is chronic spontaneous urticaria (CSU) or chronic inducible urticaria, and in some embodiments, the urticaria described herein is chronic spontaneous urticaria.

[0163] In some embodiments, the dermatitis described herein is atopic dermatitis.

[0164] In some embodiments, the multiple sclerosis described herein is relapsing-relapsing multiple sclerosis (RMS).

[0165] In some embodiments, the allergy described herein is a food allergy.

[0166] In some embodiments, the disease or disorder described herein or the BTK-mediated disease or disorder is selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, anaphylaxis, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, metabolic / endocrine disorders and neurological disorders; in some embodiments, the disease or disorder described herein or the BTK-mediated disease or disorder is selected from cancer, autoimmune diseases and inflammatory diseases; the disease or disorder described herein or the BTK-mediated disease or disorder is an autoimmune disease or an inflammatory disease; in some embodiments, the disease or disorder described herein or the BTK-mediated disease or disorder is a B-cell malignancy, B Large 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, Waldenström macroglobulinemia, multiple myeloma, bone cancer, bone metastases, follicular lymphoma, chronic lymphocytic lymphoma, B-cell pre-lymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasmacytic myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia Lymphoma / leukemia, lymphomatous granuloma, 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 syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome,Idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm-type autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia totalis, Behcet's disease Diseases, chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, vulvodinia, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, Dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrocystis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, localized pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulva Inflammation, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), interstitial lung disease, alveolitis of unknown cause (CFA), bronchiolitis obstructive, bronchiectasis, fatty liver disease, fatty degeneration (e.g., non-alcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol-induced hepatic fibrosis, bile duct injury, cholangiofibrosis, cholestasis or bile duct disease, liver or hepatic fibrosis (including hepatic fibrosis associated with alcoholism) (and not limited to these), viral infections (e.g., hepatitis, hepatitis C, B, or D), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive nodular fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins), renal fibrosis (e.g., chronic renal fibrosis), nephropathy associated with injury / fibrosis (e.g., chronic nephropathy associated with diabetes (e.g., diabetic nephropathy)), lupus, scleroderma renal crisis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy,Selected from renal fibrosis associated with human chronic kidney disease (CKD), chronic progressive kidney disease (CPN), tubulointerstitial fibrosis, urinary tract obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephritis (PGN), endothelial / thrombotic microangiopathy, HIV-associated nephropathy, or fibrosis associated with exposure to toxins, irritants or chemotherapy agents, fibrosis associated with scleroderma, radiation-induced intestinal fibrosis, fibrosis associated with foregut inflammatory disease (e.g., Barrett's esophagus and chronic gastritis), and / or fibrosis associated with hindgut inflammatory disease (e.g., inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease), age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and neovascular glaucoma. In some embodiments, the diseases or disorders described herein or the BTK-mediated diseases or disorders include B-cell malignancies, multiple myeloma, leukemia (e.g., acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute myeloid 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 exudative lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, B-cell lymphoma and follicular lymphoma), Waldenstrom macroglobulinemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstrom macroglobulinemia, bone cancer, bone metastases, arthritis (e.g., rheumatoid arthritis, systemic 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 idiopathic urticaria, chronic induced urticaria, chronic autoimmune urticaria), liver failure, allergies (e.g., atopic dermatitis, contact dermatitis, allergic rhinitis), ankylosing spondylitis, dermatitis (e.g., atopic dermatitis), pancreatitis, mastitis, meningitis, glomerulonephritis, good The following conditions are selected from: Dopasture syndrome, Hashimoto's disease, keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolism, myocardial infarction, angina pectoris, stroke, ischemic injury, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, hidradenitis suppurativa, myasthenia gravis, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, immune thrombocytopenia, complications from organ transplantation, xenotransplantation, antibody-mediated transplant rejection (AMR), graft-versus-host disease, and B-cell-mediated hyperacute, acute, and chronic transplant rejection. In some embodiments, the diseases or disorders described herein or the BTK-mediated diseases or disorders include rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, osteoporosis, diabetes mellitus, arteriosclerosis, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Sjögren's syndrome, autoimmune thyroid disease, lupus, systemic lupus erythematosus, psoriasis, urticaria, hepatic failure, allergies, ankylosing spondylitis, dermatitis, pancreatitis, and mammary gland disease. The following conditions are selected: cervitis, meningitis, glomerulonephritis, Goodpasture syndrome, Hashimoto's disease, keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), thromboembolism, myocardial infarction, angina pectoris, stroke, ischemic injury, pulmonary embolism, gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, hidradenitis suppurativa, and myasthenia gravis.

[0167] In some embodiments, the cancer described herein is a malignant hematological malignancy, and in some embodiments, the cancer is selected from leukemia, multiple myeloma, and malignant lymphoma, and in some embodiments, the cancer is selected from acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, small lymphocytic lymphoma, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, B-cell lymphoma, follicular lymphoma, Waldenström macroglobulinemia, and multiple myeloma.

[0168] In some embodiments, the cancer described herein is Cardiac: Sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma. Lung: Bronchial lung cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, Digestive tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP-producing tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma), Urogenital system: Kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminal epithelium, teratoma, fetal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), Liver: Liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, Biliary tract: gallbladder cancer, papillary cancer, bile duct cancer, Bone: Osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochronoblastoma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor. Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meninges (meningioma, meningiosarcoma, gliomas), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma), Gynecological: Uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-thecal cell tumor, supporting stromal cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, budoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer), Hematological: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, hydatidiform mole dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, The group is selected from those consisting of adrenal gland neuroblastoma.

[0169] The active compounds can be prepared in a form suitable for administration by any appropriate route, and the compositions of this disclosure can be prepared using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compounds of this disclosure can be prepared in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or inhalation. The compounds of this disclosure can also be prepared in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0170] As a general guideline, the active compound is provided in some embodiments in the form of a unit dose or in a form that can be self-administered by a patient as a single dose. The unit dose of the compound or composition disclosed herein may be expressed as a tablet, capsule, cachet, ampoule, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Appropriate unit doses may range from 0.1 to 1000 mg.

[0171] The pharmaceutical compositions of this disclosure may contain one or more excipients in addition to the active compound, the excipients being selected from components such as fillers (diluents), adhesives, wetting agents, disintegrants, or other excipients. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0172] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0173] In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01 to 99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic variant. In some embodiments, the pharmaceutical composition contains 0.1 to 99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic variant. In some embodiments, the pharmaceutical composition contains 0.5 to 99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic variant. In some embodiments, the pharmaceutical composition contains 1 to 99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic variant. In some embodiments, the pharmaceutical composition contains 2 to 98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic variant.

[0174] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% of pharmaceutically acceptable excipients.

[0175] The tablets contain an active ingredient and a non-toxic, pharmaceutically acceptable excipient suitable for manufacturing the tablets. These excipients may be inert excipients, granulators, disintegrants, adhesives, and lubricants. These tablets may be uncoated or may be coated using known techniques that can mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over a long period.

[0176] Oral formulations can also be provided in the form of soft gelatin capsules containing the active ingredient mixed with an inert solid diluent, or the active ingredient mixed with a water-soluble carrier or oil vehicle.

[0177] The aqueous suspension contains an active substance and a mixing excipient suitable for preparing the aqueous suspension. Such an excipient is a suspending agent, a dispersing agent, or a wetting agent. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners.

[0178] An oil suspension can be prepared by suspending the active ingredient in vegetable oil or mineral oil. The oil suspension may contain a thickener. By adding the above-mentioned sweeteners and flavoring agents, a delicious formulation can be provided. By adding antioxidants, these compositions can be preserved.

[0179] The pharmaceutical compositions of this disclosure may be in the form of oil-in-water emulsions. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. A suitable emulsifier may be a naturally produced phospholipid, and the emulsion may contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain mitigating agents, preservatives, colorants, and antioxidants.

[0180] The pharmaceutical compositions of this disclosure may be in the form of sterile aqueous solutions for injection. Acceptable vehicles or solvents are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may also be a sterile oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injection solution or microemulsion can be injected into the patient's bloodstream by large local injection. Alternatively, it is preferable to administer the solution or microemulsion in a manner that can maintain a steady blood concentration of the compounds of this disclosure. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous injection pump.

[0181] The pharmaceutical compositions of this disclosure may be in the form of sterile water or oil suspensions for intramuscular and subcutaneous administration. The suspensions can be prepared using the above-mentioned suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injection preparations may also be sterile injection solutions or suspensions prepared in parenterally acceptable, non-toxic diluents or solvents. Sterile non-volatile oils can be conveniently used as solvents or suspension media. Any compounded non-volatile oil may be used for this purpose. Fatty acids may also be used in the preparation of injections.

[0182] The compounds of this disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions are solid at normal temperatures but liquid in the rectum, and can therefore be prepared by mixing them with a suitable non-irritating excipient that dissolves in the rectum and releases the drug.

[0183] The compounds of this disclosure may be administered in the form of aqueous suspension dispersible powders and granules produced by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0184] 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 activity of the specific compound used, the patient's age, weight, health status, behavior, diet, administration time, method of administration, rate of excretion, drug combinations, and disease severity. Furthermore, the optimal treatment regimen, such as the mode of treatment, the daily dose of the compound, or the type of pharmaceutically acceptable salt, may be verified by conventional treatment regimens.

[0185] Explanation of terms Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0186] The term "alkyl group" refers to an aliphatic hydrocarbon group having a saturated straight or branched chain, which has 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., C 1-20 Alkyl alkyl group). In some embodiments, the alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 It is an alkyl group, and in some embodiments, an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6(Alkyl group). Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, and 5-methylhexyl group. This includes 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking site, and the substituent is one or more selected from a D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group in some embodiments.

[0187] The term "alkylene group" refers to a divalent alkyl group, where an alkyl group is as defined above, and it has 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) (i.e., C 1-20 (Alkylene group). In some embodiments, the alkylene group is an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 An alkylene group) and in some embodiments, an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 The alkylene group is an alkylene group. Non-limiting examples include -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. The alkylene group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking site, and the substituent is one or more selected from a D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group in some embodiments.

[0188] The term "alkenyl group" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, where the definition of an alkyl group is as described above, and it 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 Alkenyl group). In some embodiments, the alkenyl group is an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6The alkenyl group is an alkenyl group. Non-limiting examples include vinyl groups, propenyl groups, isopropenyl groups, butenyl groups, etc. The alkenyl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking site, and the substituent is one or more selected from a D atom, an alkoxy group, a halogen, 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 in some embodiments.

[0189] The term "alkylene oxide" refers to a branched or unbranched hydrocarbon group having 2 to 12 carbon atoms and containing an epoxy group in the molecule, and in some embodiments, C 2-6 These are alkylene oxides. Typical examples of "alkylene oxides" include vinyl oxide, propenyl 1,2-oxide, and butenyl 1,2-oxide.

[0190] The term "alkynyl group" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where the definition of an alkyl group is as described above, and it 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 Alkynyl group). In some embodiments, the alkynyl group is an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6This is an alkynyl group. Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups. The alkynyl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking site, and the substituent is, in some embodiments, one or more selected from a D atom, an alkoxy group, a halogen, 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.

[0191] The term "alkoxy group" refers to an -O-(alkyl group), where the definition of an alkyl group is as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy groups. The alkoxy group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking site, and the substituent may be one or more selected from a D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group in some embodiments.

[0192] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic whole-carbocyclic (i.e., monocyclic cycloalkyl group) or polycyclic system (i.e., polycyclic cycloalkyl group) 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 cycloalkyl group). In some embodiments, the cycloalkyl group is a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12-membered cycloalkyl group), in some embodiments, a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8-membered cycloalkyl group), in some embodiments, a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6-membered cycloalkyl group), or a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered cycloalkyl group), or a cycloalkyl group having 5 ring atoms (i.e., a 5-membered cycloalkyl group).

[0193] Non-limiting examples of the monocyclic cycloalkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclohexyl group, cyclohexenyl group, cyclohexadienyl group, cycloheptyl group, cycloheptatrienyl group, and cyclooctyl group.

[0194] The aforementioned polycyclic cycloalkyl groups include spirocycloalkyl groups, condensed cycloalkyl groups, and crosslinked cycloalkyl groups.

[0195] The term "spirocycloalkyl group" refers to a polycyclic system in which rings share one carbon atom (called a spiro atom), which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide, and the sulfur may be optionally substituted with oxygen to form a sulfoxide or sulfone, but without -OO-, -OS-, or -SS-), and the conditions are that it contains at least one whole carbon ring, and the linking site is on the whole carbon ring, 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 spirocycloalkyl group). The spirocycloalkyl group is, in some embodiments, a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spirocycloalkyl group), and in some embodiments, a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spirocycloalkyl group). The spirocycloalkyl group includes monospirocycloalkyl groups and polyspirocycloalkyl groups (e.g., bisspirocycloalkyl groups), and in some embodiments, is a monospirocycloalkyl group or a bisspirocycloalkyl group, and in some embodiments, is a 3-member / 4-member, 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 3-member, 5-member / 4-member, 5-member / 5-member, 5-member / 6-member, 5-member / 7-member, 6-member / 3-member, 6-member / 4-member, 6-member / 5-member, 6-member / 6-member, 6-member / 7-member, 7-member / 5-member or 7-member / 6-member monospirocycloalkyl group. Non-limiting examples are: JPEG2026534181000100.jpg71170

[0196] The term "condensed cycloalkyl group" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings, and is formed by the condensation of a monocyclic cycloalkyl group with one or more monocyclic cycloalkyl groups, or by the condensation of a monocyclic cycloalkyl group with one or more heterocyclyl groups, aryl groups, or heteroaryl groups, where the linkage site is located in the monocyclic cycloalkyl group, which may contain one or more double bonds within its 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 condensed cycloalkyl group). In some embodiments, the condensed cycloalkyl group is a condensed cycloalkyl group having 6 to 14 ring atoms (i.e., a 6 to 14-membered condensed cycloalkyl group), and in some embodiments, it is a condensed cycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered condensed cycloalkyl group). The condensed cycloalkyl group includes bicyclic condensed cycloalkyl groups and polycyclic condensed cycloalkyl groups (e.g., tricyclic condensed cycloalkyl groups, tetracyclic condensed cycloalkyl groups, etc.), and in some embodiments, is a bicyclic condensed cycloalkyl group or a tricyclic condensed cycloalkyl group, and in some embodiments, is a 3-member / 4-member, 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 3-member, 5-member / 4-member, 5-member / 5-member, 5-member / 6-member, 5-member / 7-member, 6-member / 3-member, 6-member / 4-member, 6-member / 5-member, 6-member / 6-member, 6-member / 7-member, 7-member / 5-member, or 7-member / 6-member bicyclic condensed cycloalkyl group. Non-limiting examples are: The connection point can be at any position. JPEG2026534181000101.jpg69170

[0197] The term "crosslinked cycloalkyl group" refers to a whole-carbon polycyclic system in which rings share two carbon atoms that are not directly linked, and which may contain one or more double bonds within the rings and have 5 to 20 carbon atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., a 5-20 membered crosslinked cycloalkyl group). In some embodiments, the crosslinked cycloalkyl group is a crosslinked cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6-14 membered crosslinked cycloalkyl group), and in some embodiments, it is a crosslinked cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7-10 membered crosslinked cycloalkyl group). The crosslinked cycloalkyl group includes bicyclic crosslinked cycloalkyl groups and polycyclic crosslinked cycloalkyl groups (e.g., tricyclic crosslinked cycloalkyl groups, tetracyclic crosslinked cycloalkyl groups, etc.), and in some embodiments, it is a bicyclic crosslinked cycloalkyl group or a tricyclic crosslinked cycloalkyl group. Non-limiting examples are: The connection point can be at any position. JPEG2026534181000102.jpg23170

[0198] The cycloalkyl group may be substituted or unsubstituted, and if substituted, may be substituted at any available linking site, and the substituent is one or more selected from a D atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, oxo group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group in some embodiments.

[0199] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl group) or polycyclic heterocycle (i.e., a polycyclic heterocyclyl group) that contains at least one heteroatom (e.g., 1, 2, 3, or 4) selected from nitrogen, oxygen, and sulfur within its ring (the nitrogen may optionally be oxidized to form a nitrogen oxide, and the sulfur may optionally be substituted with oxygen to form a sulfoxide or sulfone, but without -OO-, -OS-, or -SS-), and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3-20 membered heterocyclyl group). In some embodiments, the heterocyclyl group is 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), and 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).

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

[0201] The aforementioned polycyclic heterocyclyl group includes a spiroheterocyclyl group, a condensed heterocyclyl group, and a cross-linked heterocyclyl group. The term "spiroheterocyclyl group" refers to a polycyclic heterocyclic system in which rings share one atom (called a spiro atom), which may contain one or more double bonds within the rings, and which contain at least one heteroatom (e.g., 1, 2, 3, or 4) selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide, and the sulfur may be optionally substituted with oxygen to form a sulfoxide or sulfone, but without -OO-, -OS-, or -SS-), and which, as a condition, contains at least one monocyclic heterocyclyl group, and the linking site is located on the monocyclic heterocyclyl 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 spiroheterocyclyl group). In some embodiments, the spiroheterocyclyl group is 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), and in some embodiments, a spiroheterocyclyl group having 7 or 8 ring atoms (i.e., a 7 or 8-membered spiroheterocyclyl group). The spiroheterocyclyl group includes a monospiroheterocyclyl group and a polyspiroheterocyclyl group (e.g., a bisspiroheterocyclyl group), and in some embodiments, it is a monospiroheterocyclyl group or a bisspiroheterocyclyl group, and in some embodiments, it is 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 monospiroheterocyclyl group. Non-limiting examples are: JPEG2026534181000103.jpg31170

[0202] The term "condensed heterocyclyl group" refers to a polycyclic heterocyclic system in which rings share two adjacent atoms, and which may contain one or more double bonds within the ring, and which may contain 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 a nitrogen oxide, and the sulfur may be optionally substituted with oxygen to form a sulfoxide or sulfone, but -OO-, -OS-, or - (excluding SS-), it is a condensation of a monocyclic heterocyclyl group with one or more monocyclic heterocyclyl groups, or a condensation of a monocyclic heterocyclyl group with one or more cycloalkyl groups, aryl groups, or heteroaryl groups, where the linkage site is located on the monocyclic heterocyclyl group 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 5-20 membered condensed heterocyclyl group). In some embodiments, the condensed heterocyclyl group is a condensed heterocyclyl group having 6 to 14 ring atoms (i.e., a 6 to 14-membered condensed heterocyclyl group), in some embodiments, a condensed heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered condensed heterocyclyl group), in some embodiments, a condensed heterocyclyl group having 7 to 9 ring atoms (i.e., a 7 to 9-membered condensed heterocyclyl group), and in some embodiments, a condensed heterocyclyl group having 8 or 9 ring atoms (i.e., an 8 or 9-membered condensed heterocyclyl group). The condensed heterocyclyl group includes bicyclic and polycyclic condensed heterocyclyl groups (e.g., tricyclic condensed heterocyclyl groups, tetracyclic condensed heterocyclyl groups, etc.), and in some embodiments, is a bicyclic condensed heterocyclyl group or a tricyclic condensed heterocyclyl group, and in some embodiments, is 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 bicyclic condensed heterocyclyl group. Non-limiting examples are: JPEG2026534181000104.jpg98167

[0203] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclic system in which rings share two atoms that are not directly linked, and which may contain one or more double bonds within the rings, and which contain at least one heteroatom (e.g., 1, 2, 3, or 4) selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide, and the sulfur may be optionally substituted with oxygen to form a sulfoxide or sulfone, but without -OO-, -OS-, or -SS-), and which has 5 to 20 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., a 5 to 20-membered bridged heterocyclyl group). The aforementioned crosslinked heterocyclyl group is, in some embodiments, a crosslinked heterocyclyl group having 6 to 14 ring atoms (i.e., a 6 to 14-membered crosslinked heterocyclyl group), and in some embodiments, a crosslinked heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered crosslinked heterocyclyl group). Depending on the number of rings comprising, it may be divided into a bicyclic crosslinked heterocyclyl group and a polycyclic crosslinked heterocyclyl group (e.g., a tricyclic crosslinked heterocyclyl group, a tetracyclic crosslinked heterocyclyl group, etc.), and in some embodiments, it is a bicyclic crosslinked heterocyclyl group or a tricyclic crosslinked heterocyclyl group. Non-limiting examples are, JPEG2026534181000105.jpg33167

[0204] The heterocyclyl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking site, and the substituent is one or more selected from a D atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, oxo group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group in some embodiments.

[0205] The term "aryl group" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl group) or a polycyclic aromatic ring system (i.e., a polycyclic aryl group) having a conjugated π-electron system, which has 6 to 22 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 atoms) (i.e., a 6- to 22-membered aryl group). 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); and 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, a phenyl group. Non-limiting examples of the polycyclic aryl group include naphthyl groups, anthryl groups, phenanthryl groups, and the like. The polycyclic aryl group further includes a condensation of a phenyl group with one or more heterocyclyl groups or cycloalkyl groups, or a condensation of a naphthyl group with one or more heterocyclyl groups or cycloalkyl groups, where the linking site is on the phenyl or naphthyl group, and in such cases the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system (which in some embodiments is a bicyclic aryl group or a tricyclic aryl group), and non-limiting examples include: JPEG2026534181000106.jpg86167

[0206] The aryl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking site, and the substituent is one or more selected from a D atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, oxo group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group in some embodiments.

[0207] JPEG2026534181000107.jpg113167

[0208] JPEG2026534181000108.jpg61167

[0209] The term "heteroaryl group" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl group) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl group) having a conjugated π-electron system, wherein the ring contains at least one heteroatom (e.g., 1, 2, 3, or 4) selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide, and the sulfur may be optionally substituted with oxygen to form a sulfoxide or sulfone, but without -OO-, -OS-, or -SS-), and it has 5 to 22 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22) (i.e., a 5- to 22-membered heteroaryl group). 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, the heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group); in some embodiments, the heteroaryl group having 9 to 14 ring atoms (i.e., a 9 to 14-membered heteroaryl group); in some embodiments, the heteroaryl group having 8 to 14 ring atoms (i.e., an 8 to 14-membered heteroaryl group); in some embodiments, the heteroaryl group is a heteroaryl group having 11 or 12 ring atoms (i.e., an 11 or 12-membered heteroaryl group); in some embodiments, the heteroaryl group is a heteroaryl group having 10 ring atoms (i.e., a 10-membered heteroaryl group); in some embodiments, the heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group); and in some embodiments, the heteroaryl group having 5 ring atoms (i.e., a 5-membered heteroaryl group).

[0210] JPEG2026534181000109.jpg48167

[0211] Non-limiting examples of the polycyclic heteroaryl group (which in some embodiments is a 9- to 14-membered heteroaryl group, and in some embodiments is an 8- to 14-membered heteroaryl group) include indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, and carbazolyl groups. The polycyclic heteroaryl group further includes a monocyclic heteroaryl group fused with one or more aryl groups, where the linkage site is in an aromatic ring, and in such cases, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl group further includes a monocyclic heteroaryl group fused with one or more cycloalkyl groups or heterocyclyl groups, where the linkage site is located in a monocyclic heteroaromatic ring, and in such cases, 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 group or a tricyclic heteroaryl group). Non-limiting examples include: JPEG2026534181000110.jpg94168

[0212] The number of rings in a "tricyclic heteroaryl group" cyclic system is three, and the linking site is located in a monocyclic heteroaromatic ring. In some embodiments, the "tricyclic heteroaryl group" is a tricyclic heteroaryl group having 9 to 14 ring atoms (i.e., a 9 to 14-membered tricyclic heteroaryl group), in some embodiments, a tricyclic heteroaryl group having 10 to 12 ring atoms (i.e., a 10 to 12-membered tricyclic heteroaryl group), and in some embodiments, a tricyclic heteroaryl group having 10 ring atoms (i.e., a 10-membered tricyclic heteroaryl group).

[0213] The heteroaryl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking site, and the substituent is one or more selected from a D atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group in some embodiments.

[0214] The term "cycloalkyloxy group" refers to a cycloalkyl-O- group, where cycloalkyl is defined as described above.

[0215] The term "heterocyclyloxy group" refers to a heterocyclyl-O-, where the heterocyclyl group is as described above.

[0216] The term "aryloxy group" refers to an aryl-O- group, where the aryl group is defined above.

[0217] The term "heteroaryloxy group" refers to a heteroaryl-O-, where a heteroaryl group is defined as described above.

[0218] The term "cycloalkylalkyl group" refers to a group in which an alkyl group is substituted with one or more cycloalkyl groups, where alkyl groups and cycloalkyl groups are defined above.

[0219] The term "heterocyclylalkyl group" refers to a group in which an alkyl group is substituted with one or more heterocyclyl groups, where alkyl groups and heterocyclyl groups are defined above.

[0220] The term "arylalkyl group" refers to a group in which an alkyl group is substituted with one or more aryl groups, where the alkyl group and aryl group are as defined above, for example, -CH2Ph.

[0221] The term "heteroarylalkyl group" refers to an alkyl group substituted with one or more heteroaryl groups, where alkyl groups and heteroaryl groups are defined above.

[0222] The term "haloalkyl group" refers to a group in which an alkyl group is substituted with one or more halogens, where the alkyl group is as defined above.

[0223] The term "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, where the alkoxy group is as defined above, for example, -OCF3.

[0224] The term "hydroxyalkyl group" refers to a group in which an alkyl group is substituted with one or more hydroxyl groups, where the alkyl group is as defined above, for example, -CH2OH.

[0225] The term "alkoxyalkyl group" refers to a group in which an alkyl group is substituted with one or more alkoxy groups, where the alkyl group and alkoxy group are as defined above, for example, -CH2OCH3.

[0226] The term "aminoalkyl group" refers to a group in which an alkyl group is substituted with one or more amino groups, where the alkyl group is as defined above, for example, -CH2NH2.

[0227] The term "methylene group" refers to =CH2.

[0228] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0229] The term "hydroxyl group" refers to the -OH group.

[0230] The term "mercapto group" refers to the -SH group.

[0231] The term "amino group" refers to -NH2.

[0232] The term "cyano group" refers to -CN.

[0233] The term "nitro group" refers to -NO2.

[0234] The term "oxo" or "oxo group" refers to "=O".

[0235] The term "carbonyl group" refers to C=O.

[0236] The term "carboxyl group" refers to -C(O)OH.

[0237] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl groups are as defined above.

[0238] In the general formula (III) of this disclosure, if j is 0, A 1 Or A 2 This corresponds to a combination.

[0239] The compounds of this disclosure may have specific stereoisomer forms. The term “stereoisomer” refers to isomers that have the same structure but different atomic configurations. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, atropisomers, conformational isomers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in the compounds of this disclosure may contain other chiral atoms. All of these stereoisomers and mixtures thereof are within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be produced by chiral synthesis, chiral reagents, or other prior arts. One isomer of a compound in this disclosure can be produced by asymmetric synthesis or by chiral additives, or, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer can be formed with a suitable optically active acid or base, and the diastereomer can be resolved by conventional methods known in the art to obtain the pure isomer. The separation of enantiomers and diastereomers is generally completed by chromatography.

[0240] JPEG2026534181000111.jpg31169

[0241] The compounds of this disclosure may exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms “tautomer” or “tautomer form” refer to structural isomers that exist in equilibrium and are readily convertible from one isomer to another. It includes all possible tautomers, i.e., they exist in the form of single isomers or mixtures of any proportions of said tautomers. Non-limiting examples include keto-enols, imine-enamines, lactam-lactims, and the like.

[0242] JPEG2026534181000112.jpg37169

[0243] All tautomer forms are within the scope of this disclosure, and the naming of the compounds does not exclude any tautomers.

[0244] The compounds of this disclosure include all suitable isotopic derivatives of the compounds. The term “isotopic derivative” refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of this disclosure include stable and radioactive isotopes such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, respectively 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 This includes I, and in some embodiments, it is deuterium.

[0245] Deuterated drugs offer advantages over undeuterated drugs, including reduced toxic side effects, improved drug stability, enhanced therapeutic effects, and extended biological half-lives. All isotopic transformations of the compounds of this disclosure, whether radioactive or otherwise, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom may be independently replaced by a deuterium atom, where the replacement may be partial or complete, with partial replacement meaning that at least one hydrogen atom is replaced by at least one deuterium atom.

[0246] In the compounds of this disclosure, if one position is specifically designated as "deuterium" or "D", it should be understood that the abundance of deuterium at that position is at least 1000 times greater than the natural abundance of deuterium (0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium at 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 at 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 at 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 at 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 in 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 in 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 in 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 in 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 in 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 in each designated deuterium atom is at least 6,000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation).In some embodiments, the abundance of deuterium in 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 in 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 in 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 in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).

[0247] "Optionally" or "optionally" means that the event or environment described later may occur, but does not necessarily have to occur, and refers to two cases: that the event or environment occurs or that it does not occur. For example, "an alkyl group that is optionally (optionally) substituted with a halogen or cyano group" includes cases where the alkyl group is substituted with a halogen or cyano group, and cases where the alkyl group is not substituted with a halogen or cyano group.

[0248] "Substitution" or "being substituted" refers to the substitution of one or more hydrogen atoms in a group, 1 to 6 in some embodiments, and 1 to 3 in some embodiments, independently of each other, by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) with little effort. For example, an amino or hydroxyl group with free hydrogen can become unstable when bonded to a carbon atom with an unsaturated bond (e.g., an olefin).

[0249] "Pharmaceutical composition" means a mixture of one or more compounds described herein or pharmaceutically acceptable salts thereof with other chemical components, and other components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to a living organism, to facilitate the absorption of the active ingredient, and thereby to exert biological activity.

[0250] "Pharmacologically acceptable salt" refers to a salt of the compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in the body of a mammal and possess the desired biological activity. They can be produced in the process of final separation and purification of the compound, or individually by reacting a suitable group with a suitable base or acid. Bases for forming pharmaceutically acceptable salts generally include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids for forming pharmaceutically acceptable salts generally include inorganic acids and organic acids.

[0251] As used herein, the term “pharmaceutically acceptable” means that these compounds, materials, compositions and / or dosage forms are suitable for contact with patient tissue, have a reasonable benefit-risk ratio, and are effective for the desired use, within the bounds of reasonable medical judgment, without excessive toxicity, irritation, anaphylaxis, or other problems or complications.

[0252] As used herein, the singular forms “one,” “one kind,” and “the” include multiple references unless explicitly stated in the context, and vice versa.

[0253] When the term "approximately" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and in some embodiments, within ±5%. As those skilled in the art will understand, when a parameter is not significant, the number is usually given only for illustrative purposes and not as a limitation. [Brief explanation of the drawing]

[0254] [Figure 1] This shows the degree of skin swelling in mice. [Figure 2] The inhibition percentage of compound 3 against skin swelling in mice is shown. [Modes for carrying out the invention]

[0255] The present disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure. [Examples]

[0256] Examples The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR displacement (δ) is 10 -6 The values ​​are given in units of ppm. NMR measurements were performed using a Bruker AVANCE NEO 500M nuclear magnetometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

[0257] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (Manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS). waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS Model Number: waters ACQuity Qda Detector / waters SQ Detector) I will be using the THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model Number: THERMO Q Exactive).

[0258] High-performance liquid chromatography (HPLC) analysis is performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high-performance liquid chromatographs.

[0259] Chiral HPLC analysis is performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0260] High-performance liquid preparative chromatography is performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0261] Chiral preparative chromatography is performed using a Shimadzu LC-20AP preparative chromatograph.

[0262] The CombiFlash high-speed sorting system used is the CombiFlash Rf200 (TELEDYNE ISCO).

[0263] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. Silica gel plates used for thin-layer chromatography (TLC) are specified to be 0.15 mm to 0.2 mm in size, while plates specified to be 0.4 mm to 0.5 mm in size are used for the separation and purification of products by thin-layer chromatography.

[0264] Silica gel column chromatography generally uses 200-300 mesh silica gel as a support.

[0265] Kinase mean inhibition rate and IC 50 A NovoStar plate reader (BMG GmbH, Germany) is used to measure the values.

[0266] The known starting materials of this disclosure can be synthesized by methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., and Dalui Chemicals.

[0267] Unless otherwise specified in the examples, the reactions can all be carried out under an argon or nitrogen atmosphere.

[0268] An argon gas atmosphere or a nitrogen gas atmosphere is created by connecting a balloon containing approximately 1 liter of argon or nitrogen gas to the reaction flask.

[0269] A hydrogen gas atmosphere is created by connecting a hydrogen gas balloon with a volume of approximately 1 liter to the reaction flask.

[0270] For the pressurized hydrogenation reaction, a Parr 3916EKX type hydrogenator and a QL-500 type hydrogen gas generator or an HC2-SS type hydrogenator are used.

[0271] The hydrogenation reaction is typically carried out under vacuum, followed by filling with hydrogen gas, and repeated three times.

[0272] For the microwave reaction, a CEM Discover-S 908860 microwave reactor is used.

[0273] Unless otherwise specified in the examples, the solutions are aqueous solutions.

[0274] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0275] Thin-layer chromatography (TLC) was used to monitor the reaction process in the examples. The developing solvents used in the reaction, the eluent systems for column chromatography and thin-layer chromatography used for purifying the compounds included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvents was adjusted according to the polarity of the compounds and may be adjusted by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0276] Example 1 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 1 [ka]

[0277] Step 1 6-Fluoro-1-oxo-2,3-dihydro-1H-indene-5-carboxylate methyl 1b 5-Promo-6-fluoro-2,3-dihydro-1H-inden-1-one 1a (500 mg, 2.18 mmol, Bi De) was dissolved in N,N-dimethylformamide (5 mL, National Pharmaceutical) and methanol (2.5 mL, National Pharmaceutical). [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (160 mg, 0.22 mmol, Adamas) and N,N-diisopropylethylamine (565 mg, 4.37 mmol, Adamas) were added, the mixture was purged three times with carbon monoxide gas, and the reaction was carried out overnight at 80°C. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain the title compound 1b (170 mg, yield: 37.4%).

[0278] Step 2 6-fluoro-1-methylene-2,3-dihydro-1H-indene-5-carboxylate methyl 1c Compound 1b (170 mg, 0.82 mmol) was dissolved in tetrahydrofuran (5 mL, Annaigi), methyltriphenylphosphonium bromide (584 mg, 1.63 mmol, Shaoyuan) and potassium tert-butoxide (184 mg, 1.64 mmol, Adamas) were added, and 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 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 B to obtain the title compound 1c (90 mg, yield: 53.4%). MS m / z (ESI): 207.3[M+1]

[0279] Step 3 6'-Fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-methyl carboxylate 1d Diethylzinc (1M, 1.75 mL, 1.75 mmol, Adamas) was dissolved in dichloromethane (1 mL, Annaigi), protected with nitrogen gas, and trifluoroacetic acid (200 mg, 1.75 mmol, Adamas) was added dropwise at 0°C. The mixture was reacted at 0°C for 1 hour, then diiodomethane (468 mg, 1.75 mmol, Annaigi) was added dropwise. The mixture was reacted at 0°C for 0.5 hours, and a solution of compound 1c (90 mg, 0.44 mmol) in dichloromethane (1 mL, Annaigi) was added dropwise. The mixture was reacted at room temperature for 3 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 B to obtain the title compound 1d (78 mg, yield: 81.1%). MS m / z (ESI): 221.3[M+1]

[0280] Step 4 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 Compound 1d (39 mg, 0.18 mmol) was dissolved in tetrahydrofuran (1 mL, Anji), and 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (49 mg, 0.20 mmol, prepared by the method disclosed in intermediate INT3 on page 31 of the specification in patent application WO 2015079417A1) was added. The mixture was purged three times with nitrogen gas, and sodium bis(trimethylsilyl)amide (2 M, 0.13 mL, 0.13 mmol, Adamas) was added dropwise at 0°C, and 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 using eluent system B by column chromatography to obtain title compound 1e (30 mg, yield: 38.6%). MS m / z (ESI): 440.5[M+1]

[0281] Step 5 (2-((4-amino-6-(5-fluoro-3-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide)-2-methylphenyl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 1f Crude compound 1e (30 mg, 0.07 mmol) was dissolved in ethylene glycol dimethyl ether (1 mL, National Pharmaceutical) and water (0.3 mL, National Pharmaceutical), and bis(triphenylphosphine)palladium chloride (4.8 mg, 0.01 mmol, Adamas), (2-((4-amino-6-chloropyrimidine-5-yl)oxy)ethyl))methyl)carbamate tert-butyl (25 mg, 0.08 mmol, prepared by the method disclosed in intermediate INT8 on page 39 of the specification in patent application WO 2015079417A1), and sodium carbonate (15 mg, 0.14 mmol, National Pharmaceutical) were added. The mixture was purged three times with nitrogen gas and reacted at 110°C for 1 hour using a microwave. 3 mL of water was added, and 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. The residue was purified by column chromatography using eluent system A to obtain the title compound 1f (30 mg, yield: 75.8%). MS m / z (ESI): 580.2[M+1]

[0282] Step 6 N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 1g Crude compound 1f (30 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL, National Pharmaceutical), trifluoroacetic acid (462 mg, 4.05 mmol, Adamas) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, 3 mL of saturated sodium bicarbonate was added, and 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 crude compound 1 g (24.8 mg). The product was not purified and the reaction proceeded directly to the next step. MS m / z (ESI): 480.6[M+1]

[0283] Step 7 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 1 1 g (24.8 mg, 0.05 mmol) of the crude compound was dissolved in dichloromethane (1 mL, National Pharmaceutical), N,N-diisopropylethylamine (565 mg, 4.37 mmol, Adamas) was added, and acryloyl chloride (4.7 mg, 0.05 mmol, National Pharmaceutical) was added dropwise at -20°C. The mixture was reacted at -20°C for 1 hour. 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 title compound 1 (12 mg, yield: 43.5%).

[0284] MS m / z (ESI): 534.5[M+1] 1 H NMR (500MHz,DMSO-d6): δ 9.75-9.57 (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),5.60-5.58 (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).

[0285] Example 2 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(1-methylcyclopropyl)benzamide 2 [ka]

[0286] Step 1 1-Promo-2-fluoro-4-(propa-1-en-2-yl)benzene 2b 1-(4-bromo-3-fluorophenyl)ethane-1-one 2a (1 g, 4.61 mmol, Shaoyuan) was dissolved in tetrahydrofuran (20 mL, Annaigi), methyltriphenylphosphonium bromide (3.3 g, 9.24 mmol, Shaoyuan) and potassium tert-butoxide (1.04 g, 9.27 mmol, Adamas) were added, and 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 x 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain the title compound 2b (780 mg, yield: 78.7%).

[0287] Step 2 1-Promo-2-fluoro-4-(1-methylcyclopropyl)benzene 2c Diethylzinc (1M, 6.52mL, 6.52 mmol, Adamas) was dissolved in dichloromethane (3mL, Annaigi), protected with nitrogen gas, and trifluoroacetic acid (743mg, 6.52 mmol, Adamas) was added dropwise at 0°C. The mixture was reacted at 0°C for 1 hour, then diiodomethane (1.75g, 6.54 mmol, Annaigi) was added dropwise. The mixture was reacted at 0°C for 0.5 hours, and a solution of compound 2b (350mg, 1.63 mmol) in dichloromethane (3mL, Annaigi) was added dropwise. The mixture was reacted at room temperature for 3 hours. 15mL of water was added, and the mixture was extracted with ethyl acetate (15mL x 3). The organic phases were combined, washed with 15mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain the title compound 2c (240mg, yield: 64.4%).

[0288] Step 3 2-Fluoro-4-(1-methylcyclopropyl)methyl benzoate 2d Compound 2c (240 mg, 1.05 mmol) was dissolved in N,N-dimethylacetamide (3 mL, National Pharmaceutical) and methanol (3 mL, National Pharmaceutical). 1,3-bis(diphenylphosphin)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 mixture was purged three times with carbon monoxide gas, and the reaction was carried out overnight at 80°C. The mixture was concentrated under reduced pressure, and the residue was purified using eluent system B by column chromatography to obtain the title compound 2d (140 mg, yield: 64.2%).

[0289] Step 4 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 Compound 2d (140 mg, 0.67 mmol) was dissolved in tetrahydrofuran (3 mL, Anji), and 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (186 mg, 0.74 mmol, prepared by the method disclosed in intermediate INT3 on page 31 of the specification in patent application WO 2015079417A1) was added. The mixture was purged three times with nitrogen gas, and sodium bis(trimethylsilyl)amide (2 M, 0.51 mL, 1.02 mmol, Adamas) was added dropwise at 0°C, and 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, concentrated under reduced pressure, and the residue was purified using eluent system B by column chromatography to obtain title compound 2e (85 mg, yield: 29.6%). MS m / z (ESI): 428.3[M+1]

[0290] Step 5 (2-((4-amino-6-(5-fluoro-3-(2-fluoro-4-(1-methylcyclopropyl)benzamide)-2-methylphenyl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 2f Compound 2e (85 mg, 0.20 mmol) was dissolved in ethylene glycol dimethyl ether (2 mL, National Pharmaceutical) and water (0.8 mL, National Pharmaceutical). Bis(triphenylphosphine)palladium chloride (14 mg, 0.02 mmol, Adamas), (2-((4-amino-6-chloropyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl (73 mg, 0.24 mmol, prepared by the method disclosed in intermediate INT8 on page 39 of the specification in patent application WO 2015079417A1), and sodium carbonate (43 mg, 0.41 mmol, National Pharmaceutical) were added, the mixture was purged three times with nitrogen gas, and the mixture was reacted at 110°C for 1 hour using a microwave. 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, concentrated under reduced pressure, and the residue was purified using eluent system A by column chromatography to obtain the title compound 2f (110 mg, yield: 97.4%). MS m / z (ESI): 568.6[M+1]

[0291] Step 6 N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(1-methylcyclopropyl)benzamide 2g Compound 2f (110 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL, National Pharmaceutical), trifluoroacetic acid (770 mg, 6.75 mmol, Adamas) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, 5 mL of saturated sodium bicarbonate 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 concentrated under reduced pressure to obtain 2 g of the crude product of the title compound (90 mg, yield: 99.3%). The product was not purified and the reaction proceeded directly to the next step. MS m / z (ESI): 468.4[M+1]

[0292] Step 7 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(1-methylcyclopropyl)benzamide 2 Two g (90 mg, 0.19 mmol) of the crude compound was dissolved in dichloromethane (2 mL, National Pharmaceutical), and N,N-diisopropylethylamine (125 mg, 0.97 mmol, Adamas) was added. Acryloyl chloride (18 mg, 0.20 mmol, National Pharmaceutical) was added dropwise at -20°C, and the mixture was reacted at -20°C for 1 hour. 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, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to obtain the title compound 2 (18 mg, yield: 17.9%).

[0293] MS m / z (ESI): 522.5[M+1] 1 H NMR (500MHz,DMSO-d6): δ 9.81-9.59 (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),6.10-6.02 (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).

[0294] Example 3 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 3 [ka]

[0295] Step 1 3-Promo-4-Fluorophenylacetate 3b 3-Promo-4-fluorophenol 3a (5 g, 26.18 mmol, Adamas) was dissolved in dichloromethane (100 mL, National Pharmaceutical), triethylamine (5.3 g, 52.38 mmol, National Pharmaceutical) was added, and acetyl chloride (2.88 g, 36.69 mmol, National Pharmaceutical) 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 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 the residue was purified by column chromatography using eluent system B to obtain the title compound 3b (5.52 g, yield: 90.5%).

[0296] Step 2 1-(4-bromo-5-fluoro-2-hydroxyphenyl)ethane-1-one 3c Compound 3b (5.52 g, 23.69 mmol) and aluminum trichloride (6.32 g, 47.40 mmol, TCI) were added to a reaction flask and reacted at 165°C for 3 hours. After cooling to room temperature, 50 mL of ice-dilute hydrochloric acid was added, and 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, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain the title compound 3c (5.12 g, yield: 92.8%). MS m / z (ESI): 231.0[M-1]

[0297] Step 3 2-Promo-1-(4-Promo-5-Fluoro-2-hydroxyphenyl)ethane-1-one 3d Compound 3c (4 g, 17.16 mmol) was dissolved in methanol (40 mL, National Pharmaceutical), and a solution of tetrabutylammonium tribromide (9.11 g, 18.89 mmol, Shaoyuan) in dichloromethane (40 mL, National Pharmaceutical) was added dropwise. The mixture was reacted at room temperature for 12 hours, concentrated under reduced pressure, and the residue was purified using eluent system B by column chromatography to obtain the title compound 3d (5.3 g, yield: 99.0%). MS m / z (ESI): 310.9[M-1]

[0298] Step 4 6-Promo-5-fluorobenzofuran-3(2H)-one 3e Compound 3d (5.3 g, 16.99 mmol) was dissolved in ethanol (120 mL, National Pharmaceutical), sodium acetate (4.18 g, 50.95 mmol) was added, and 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 the residue was purified by column chromatography using eluent system B to obtain the title compound 3e (1.6 g, yield: 40.8%).

[0299] Step 5 6-Promo-5-fluoro-3-methylene-2,3-dihydrobenzofuran 3f Compound 3e (1.6 g, 6.93 mmol) was dissolved in tetrahydrofuran (30 mL, Adamas), methyltriphenylphosphonium bromide (4.95 g, 13.86 mmol, Shaoyuan) was added, the mixture was purged three times with nitrogen gas, and potassium tert-butoxide (1 M 13.9 mL, 13.9 mmol) was added dropwise at 0°C. The mixture was reacted 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, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain the title compound 3f (260 mg, yield: 16.4%).

[0300] Step 6 6-Promo-5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane] 3g Diethylzinc (1M, 4.54 mL, 4.54 mmol, Adamas) was dissolved in dichloromethane (4 mL, Annaigi), protected with nitrogen gas, and trifluoroacetic acid (518 mg, 4.54 mmol, Adamas) was added dropwise at 0°C. The mixture was reacted at 0°C for 1 hour, diiodomethane (1.22 g, 4.56 mmol, Annaigi) was added dropwise, and the mixture was reacted at 0°C for 0.5 hours. A solution of compound 3f (260 mg, 1.14 mmol) in dichloromethane (1 mL, Annaigi) was added dropwise, and the mixture was reacted at room temperature for 3 hours. 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 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 the residue was purified by column chromatography using eluent system B to obtain 3 g (150 mg, yield: 54.4%) of the title compound.

[0301] Step 7 5-Fluoro-2H-Spiro[benzofuran-3,1'-cyclopropane]-6-methyl carboxylate 3h Three g (150 mg, 0.62 mmol) of the compound was dissolved in N,N-dimethylacetamide (2 mL, National Pharmaceutical) and methanol (2 mL, National Pharmaceutical). Palladium acetate (28 mg, 0.12 mmol, Adamas), N,N-diisopropylethylamine (565 mg, 4.37 mmol, Adamas), and 1,3-bis(diphenylphosphin)propane (51 mg, 0.12 mmol, Adamas) were added, the mixture was purged three times with carbon monoxide gas, and the reaction was carried out overnight at 80°C. The mixture was concentrated under reduced pressure, and the residue was purified using eluent system B by column chromatography to obtain 3h of the title compound (100 mg, yield: 72.9%). MS m / z (ESI): 223.1[M+1]

[0302] Step 8 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 Compound 3h (50 mg, 0.23 mmol) was dissolved in tetrahydrofuran (2 mL, Anji), 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 by the method disclosed in intermediate INT3 on page 31 of the specification in patent application WO 2015079417A1) was added. The mixture was purged three times with nitrogen gas, and sodium bis(trimethylsilyl)amide (2 M, 0.17 mL, 0.34 mmol, Adamas) was added dropwise at 0°C, and 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 organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain the title compound 3j (60 mg, yield: 60.4%). MS m / z (ESI): 442.3[M+1]

[0303] Step 9 (2-((4-amino-6-(5-fluoro-3-(5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide)-2-methylphenyl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 3l Crude compound 3j (60 mg, 0.14 mmol) was dissolved in ethylene glycol dimethyl ether (2 mL, National Pharmaceutical) and water (0.6 mL, National Pharmaceutical). Bis(triphenylphosphine)palladium chloride (9.6 mg, 0.02 mmol, Adamas), (2-((4-amino-6-chloropyrimidine-5-yl)oxyethyl))methyl)carbamate tert-butyl 3k (50 mg, 0.17 mmol, prepared by the method disclosed in intermediate INT8 on page 39 of the specification in patent application WO 2015079417A1), and sodium carbonate (29 mg, 0.27 mmol, National Pharmaceutical) were added, the mixture was purged three times with nitrogen gas, and the mixture was reacted at 110°C for 1 hour using a microwave. 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 the residue was purified using eluent system A by column chromatography to obtain 3 L (79 mg, yield: 99.9%) of the title compound. MS m / z (ESI): 582.5[M+1]

[0304] Step 10 N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 3m 3L (79mg, 0.14 mmol) of the compound was dissolved in dichloromethane (1 mL, National Pharmaceutical), trifluoroacetic acid (462 mg, 4.05 mmol, Adamas) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, 3 mL of saturated sodium bicarbonate solution was added, and 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 crude product of the title compound 3m (65 mg, yield: 99.4%). The product was not purified and the reaction proceeded directly to the next step. MS m / z (ESI): 482.1[M+1]

[0305] Step 11 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 3 Crude compound 3m (65 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL, National Pharmaceutical), N,N-diisopropylethylamine (70 mg, 0.54 mmol, Adamas) was added, and acryloyl chloride (6.2 mg, 0.07 mmol, National Pharmaceutical) was added dropwise at -20°C. The mixture was reacted at -20°C for 1 hour. 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, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to obtain the title compound 3 (9 mg, yield: 12.4%).

[0306] MS m / z (ESI): 536.5[M+1] 1H NMR (500MHz,DMSO-d6): δ 9.77-9.55 (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),6.10-6.02 (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).

[0307] Example 4 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 4 [ka]

[0308] Step 1 2-Fluoro-3-((2-methylallyl)oxy)methyl benzoate 4b Methyl 2-fluoro-3-hydroxybenzoate 4a (2.0 g, 11.75 mmol, Bi De) was dissolved in acetonitrile (2 mL), potassium carbonate (1.95 g, 14.11 mmol, Guo Yao) and 3-bromo-2-methylpropene (1.91 g, 14.11 mmol, Adamas) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified using eluent system A by silica gel column chromatography to obtain the title compound 4b (1.92 g, yield: 72.8%). MS m / z (ESI): 225.1[M+1].

[0309] Step 2 2-Fluoro-3-hydroxy-4-(2-methylallyl)methyl benzoate 4c Compound 4b (1.7 g, 7.58 mmol) was dissolved in biphenyl-diphenyl ether (15 mL), and the reaction mixture was heated to 200 °C and stirred for 2 hours. The reaction was cooled to room temperature, and the compound was directly purified using eluent system A by silica gel column chromatography to obtain the title compound 4c (570 mg, yield: 33.5%). MS m / z (ESI): 225.1[M+1].

[0310] Step 3 7-Fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylate methyl 4d 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 was cooled to room temperature, saturated sodium chloride solution (20 mL) was added, 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 4d (440 mg, yield: 98.9%). MS m / z (ESI): 225.1[M+1].

[0311] Step 4 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 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, then sodium bis(trimethylsilyl)amide (245 mg, 1.34 mmol, Adamas) was added, subsequently the reaction solution was warmed to room temperature and stirred for 2 hours. The reaction solution was added to saturated ammonium chloride solution (20 mL), extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to afford the title compound 4e (310 mg, yield: 78.4%). MS m / z (ESI): 444.1 [M+1].

[0312] Step 5 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 Compound 4e (310 mg, 0.70 mmol), compound 3k (211 mg, 0.70 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.07 mmol, Bide), and potassium carbonate (193 mg, 1.40 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), purged with nitrogen gas 3 times, and subjected to microwave reaction 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 afford the title compound 4f (380 mg, yield: 93.1%). MS m / z (ESI): 584.3 [M+1].

[0313] Step 6 N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 4g 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, 3 mL of saturated sodium bicarbonate was added, and 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 4 g of the title compound, which was used directly in the next step without further purification. MS m / z (ESI): 484.3[M+1].

[0314] Step 7 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 4 Four g (314 mg, 0.65 mmol) of the compound and N,N-diisopropylethylamine (420 mg, 3.25 mmol, Adamas) were dissolved in 5 mL of dichloromethane. The reaction mixture was cooled to -40°C, acryloyl chloride (59 mg, 0.65 mmol, Adamas) was added, and the mixture was stirred at -40°C for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 4 (140 mg, yield: 40.1%).

[0315] MS m / z (ESI): 538.2[M+1]. 1H NMR (500MHz,DMSO-d6) δ 9.89-9.68 (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).

[0316] Example 5 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 5 [ka]

[0317] Step 1 3-Promo-2-fluorophenylacetate 5b 3-Promo-2-fluorophenol 5a (5g, 26.18 mmol, Bi De) was dissolved in dichloromethane (100 mL, Guo Yak), triethylamine (5.3g, 52.38 mmol, Guo Yak) was added, and acetyl chloride (2.88g, 36.69 mmol, Guo Yak) 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 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 eluent system B by column chromatography to obtain the title compound 5b (4.37 g, yield: 71.6%).

[0318] Step 2 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethane-1-one 5c Compound 5b (4.37 g, 18.75 mmol) and aluminum trichloride (5 g, 37.50 mmol, National Pharmaceutical Association) were added to the reaction flask and reacted at 165°C for 3 hours. After cooling to room temperature, 50 mL of ice-dilute hydrochloric acid was added, and 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, concentrated under reduced pressure, and purified by eluent system B by column chromatography to obtain the title compound 5c (3.9 g, yield: 89.24%). MS m / z (ESI): 231.0[M-1]

[0319] Step 3 2-Promo-1-(4-Promo-3-Fluoro-2-Hydroxyphenyl)Ethane-1-one 5d Compound 5c (3.7g, 15.87 mmol) was dissolved in ethyl acetate (50 mL, National Pharmaceutical), copper bromide (7.1g, 31.78 mmol, National Pharmaceutical) was added, and the mixture was reacted overnight at 80°C. The reaction mixture was filtered, and the filtrate was concentrated to obtain the title compound 5d (4.95g, yield: 99.94%). MS m / z (ESI): 310.9[M-1]

[0320] Step 4 6-Promo-7-fluorobenzofuran-3(2H)-one 5e Compound 5d (4.95 g, 15.86 mmol) was dissolved in ethanol (50 mL, National Pharmaceutical), sodium acetate (3.92 g, 47.78 mmol) was added, and 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 eluent system B by column chromatography to obtain the title compound 5e (1.59 g, yield: 43.37%).

[0321] Step 5 6-Promo-7-fluoro-3-methylene-2,3-dihydrobenzofuran 5f Compound 5e (1.59 g, 6.88 mmol) was dissolved in tetrahydrofuran (30 mL, Adamas), methyltriphenylphosphonium bromide (4.93 g, 13.80 mmol, Shaoyuan) was added, the mixture was purged three times with nitrogen gas, and potassium tert-butoxide (1 M 13.9 mL, 13.9 mmol) was added dropwise at 0°C. The mixture was reacted 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, concentrated under reduced pressure, and purified by eluent system B by column chromatography to obtain the title compound 5f (190 mg, yield: 12.05%).

[0322] Step 6 6-Promo-7-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane] 5g Diethylzinc (1M, 3.32mL, 3.32 mmol, Adamas) was dissolved in dichloromethane (2mL, Annaigi), protected with nitrogen gas, and trifluoroacetic acid (379mg, 3.32 mmol, Adamas) was added dropwise at 0°C. The mixture was reacted at 0°C for 1 hour, then diiodomethane (889mg, 3.32 mmol, Annaigi) was added dropwise. The mixture was reacted at 0°C for 0.5 hours, and a solution of compound 5f (190mg, 0.83 mmol) in dichloromethane (1mL, Annaigi) was added dropwise. The mixture was reacted at room temperature for 3 hours. 15mL of water was added, and the mixture was extracted with ethyl acetate (15mL x 3). The organic phases were combined, washed with 15mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography using eluent system B to obtain 5g (140mg, yield: 69.43%) of the title compound.

[0323] Step 7 7-Fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-methyl carboxylate 5h 5 g (140 mg, 0.57 mmol) of the compound was dissolved in N,N-dimethylacetamide (2 mL, National Pharmaceutical) and methanol (2 mL, National Pharmaceutical). Palladium acetate (26 mg, 0.116 mmol, Adamas), N,N-diisopropylethylamine (149 mg, 1.15 mmol, Adamas), and 1,3-bis(diphenylphosphin)propane (48 mg, 0.116 mmol, Adamas) were added, the mixture was purged three times with carbon monoxide gas, and the reaction was carried out overnight at 80°C. The mixture was concentrated under reduced pressure and purified using eluent system B by column chromatography to obtain 5 h of the title compound (100 mg, yield: 78.13%). MS m / z (ESI): 223.1[M+1]

[0324] Step 8 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 Compound 5h (50 mg, 0.23 mmol) was dissolved in tetrahydrofuran (2 mL, Annaigi), compound 3i (63 mg, 0.25 mmol) was added, the mixture was purged three times with nitrogen gas, and sodium bis(trimethylsilyl)amide (2 M, 0.17 mL, 0.34 mmol, Adamas) was added dropwise at 0°C, and 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 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 eluent system B by column chromatography to obtain the title compound 5i (65 mg, yield: 65.46%). MS m / z (ESI): 442.3[M+1]

[0325] Step 9 (2-((4-amino-6-(5-fluoro-3-(7-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide)-2-methylphenyl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 5j Crude compound 5i (65 mg, 0.15 mmol) was dissolved in 1,4-dioxane (2 mL, National Pharmaceutical) and water (0.6 mL, National Pharmaceutical). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol, Bi De), compound 3k (54 mg, 0.18 mmol), and potassium carbonate (61 mg, 0.44 mmol, National Pharmaceutical) were added, the mixture was purged three times with nitrogen gas, 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 using eluent system A to obtain the title compound 5j (60 mg, yield: 70%). MS m / z (ESI): 582.5[M+1]

[0326] Step 10 N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 5k Crude compound 5j (60 mg, 0.10 mmol) was dissolved in dichloromethane (1 mL, National Pharmaceutical), trifluoroacetic acid (462 mg, 4.05 mmol, Adamas) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, 3 mL of saturated sodium bicarbonate was added, and 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 crude title compound 5k (49 mg, yield: 98.64%). The product was not purified and the reaction proceeded directly to the next step. MS m / z (ESI): 482.1[M+1]

[0327] Step 11 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-6-carboxamide 5 Crude compound 5k (49 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL, National Pharmaceutical), N,N-diisopropylethylamine (53 mg, 0.41 mmol, Adamas) was added, and acryloyl chloride (5.53 mg, 0.06 mmol, National Pharmaceutical) was added dropwise at -20°C. The mixture was reacted at -20°C for 1 hour. 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, concentrated under reduced pressure, and purified by column chromatography using eluent system A to obtain the title compound 5 (9 mg, yield: 16.51%).

[0328] MS m / z (ESI): 536.5[M+1] 1 H NMR (500MHz,DMSO-d6): δ 9.85-9.64 (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,1H),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).

[0329] Example 6 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-3-fluoro-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamide 6 [ka]

[0330] Step 1 2-Chloro-4,4-dimethylcyclopent-1-ene-1-formaldehyde 6b 3,3-dimethylcyclopent-1-one 6a (700 mg, 6.24 mmol, Bi De) was dissolved in dichloromethane (40 mL), and N,N-dimethylformamide (1.14 g, 15.6 mmol, Guo Yak) was added at room temperature. The reaction mixture was heated to 40°C, followed by the addition of phosphorus oxychloride (2.0 g, 13.1 mmol, Guo Yak), and the mixture was stirred at 40°C for 16 hours. The reaction mixture was cooled to room temperature, and potassium phosphate aqueous solution (2 mL, 4 M) 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 obtain the title compound 6b, which was used directly in the next step without further purification.

[0331] Step 2 5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylate ethyl 6c Compound 6b (500 mg, 3.15 mmol) was dissolved in dichloromethane (5 mL), and ethyl thioglycolate (416 mg, 3.46 mmol, Adamas) and triethylamine (988 mg, 9.77 mmol, National Pharmaceutical Co., Ltd.) were added. The mixture was stirred at 40°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified using eluent system A by silica gel column chromatography to obtain the title compound 6c (340 mg, yield: 48.1%). MS m / z (ESI): 225.1[M+1].

[0332] Step 3 5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-formic acid 6d Compound 6c (200 mg, 0.89 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and lithium hydroxide aqueous solution (60 mg, 1.35 mmol, 2 mL) was added. The mixture was stirred at 60°C for 1 hour. 1 N hydrochloric acid was added to adjust the reaction mixture to pH=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%). MS m / z (ESI): 197.2[M+1].

[0333] Step 4 3-Fluoro-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-formate 6e Compound 6d (83 mg, 0.42 mmol) was dissolved in tetrahydrofuran (3 mL), the reaction mixture 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. Subsequently, N-fluorobisbenzenesulfonamide (333 mg, 1.06 mmol, Shaoyuan) was added, the reaction mixture was raised to room temperature, and the mixture was stirred for 1 hour. The reaction was quenched with saturated ammonium chloride solution (10 mL), 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 6e, which was used directly in the next step without further purification. MS m / z (ESI): 215.1[M+1].

[0334] Step 5 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 Compound 6e (85 mg, 0.4 mmol) and compound 3i (100 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (3 mL), and 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 using eluent system A by silica gel column chromatography to obtain the title compound 6f (70 mg, yield: 39.1%). MS m / z (ESI): 448.2[M+1].

[0335] Step 6 (2-((4-amino-6-(5-fluoro-3-(3-fluoro-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamide)-2-methylphenyl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 6g Compound 6f (70 mg, 0.15 mmol), compound 3k (50 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium (18 mg, 0.015 mmol, Bi De), and potassium carbonate (43 mg, 0.31 mmol, Guo Yao) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), purged three times with nitrogen gas, and microwaved at 110°C for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified using eluent system A by silica gel column chromatography to obtain 6 g (80 mg, yield: 87.0%) of the title compound. MS m / z (ESI): 588.5[M+1].

[0336] Step 7 N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-3-fluoro-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamide6h 6 g (80 mg, 0.14 mmol) of the compound 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, 3 mL of saturated sodium bicarbonate solution was added, and 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. MS m / z (ESI): 488.5[M+1].

[0337] Step 8 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-3-fluoro-5,5-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamide 6 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 mixture was cooled to -40°C, acryloyl chloride (12 mg, 0.13 mmol, Adamas) was added, and the mixture was stirred at -40°C for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 6 (12 mg, yield: 16.3%).

[0338] MS m / z (ESI): 542.3[M+1]. 1 H NMR (500MHz,DMSO) δ 9.17-8.95 (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).

[0339] Example 7 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide7 [ka]

[0340] Step 1 4-Promo-2-fluoro-3-hydroxybenzoate methyl 7b Methyl 2-fluoro-3-hydroxybenzoate 7a (500 mg, 2.94 mmol, Shaoyuan) was dissolved in chloroform (5 mL), and a solution of bromine (564 mg, 3.53 mmol, Guoyao) in acetic acid (5 mL, Guoyao) was added dropwise at 0°C. The mixture was reacted 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 obtain the title compound 7b (730 mg, yield: 99.7%). MS m / z (ESI): 247.0[M-1]

[0341] Step 2 4-Promo-2-fluoro-3-((2-methylallyl)oxy)methyl benzoate 7c Compound 7b (730 mg, 2.93 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (608 mg, 4.40 mmol, National Pharmaceutical) was added, and 3-bromo-2-methylpropa-1-ene (475 mg, 3.52 mmol, Adamas) was added dropwise at 0°C. After the addition was complete, 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 x 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 using eluent system B to obtain the title compound 7c (780 mg, yield: 87.8%).

[0342] Step 3 7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxylate methyl 7d Compound 7c (780 mg, 2.57 mmol) was dissolved in N,N-dimethylformamide (20 mL), and tetraethylammonium chloride (470 mg, 2.84 mmol, Bailingwei), 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, Guoyak) were added. The mixture was purged three times with nitrogen gas and reacted overnight at 100°C. 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 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 using eluent system B to obtain the title compound 7d (40 mg, yield: 6.9%).

[0343] Step 4 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 Compound 7d (40 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL), compound 3i (50 mg, 0.20 mmol) was added, the mixture was purged three times with nitrogen gas, and sodium bis(trimethylsilyl)amide (2 M, 0.14 mL, 0.28 mmol, Adamas) was added dropwise at 0°C, and 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 obtain the title compound 7e (53 mg, yield: 67.0%). MS m / z (ESI): 444.3[M+1]

[0344] Step 5 (2-((4-amino-6-(5-fluoro-3-(7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide)-2-methylphenyl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl7f 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, Bi De), compound 3k (43.5 mg, 0.14 mmol), and potassium carbonate (34 mg, 0.25 mmol, Guo Yao) were added, the mixture was purged three times with nitrogen gas, 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 with eluent system A by column chromatography yielded the title compound 7f (69 mg, yield: 98.9%). MS m / z (ESI): 584.4[M+1]

[0345] Step 6 N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 7g Compound 7f (69 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (770 mg, 6.75 mmol, Adamas) was added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 5 mL of saturated sodium bicarbonate solution 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 to obtain 7 g of the title compound (57 mg, yield: 99.7%). The product was not purified and the reaction proceeded directly to the next step. MS m / z (ESI): 484.5[M+1]

[0346] Step 7 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-7-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide7 7 g (57 mg, 0.12 mmol) of the crude compound was dissolved in dichloromethane (2 mL), N,N-diisopropylethylamine (61 mg, 0.47 mmol, Adamas) was added, and acryloyl chloride (9 mg, 0.10 mmol, National Pharmaceutical) was added dropwise at -20°C. The mixture was reacted at -20°C for 1 hour. 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%).

[0347] MS m / z (ESI): 538.3[M+1] 1 H NMR (500MHz,DMSO-d6): δ 9.92-9.72 (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),6.09-6.03 (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).

[0348] Example 8 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 8 [ka]

[0349] Step 1 4-Promo-2-fluoro-5-hydroxybenzoate methyl 8b Methyl 2-fluoro-5-hydroxybenzoate 8a (1 g, 2.94 mmol, Bi De) was dissolved in chloroform (10 mL), and a solution of bromine (1.41 g, 8.82 mmol, Guo Yao) in acetic acid (10 mL, Guo Yao) was added dropwise at 0°C. The mixture was reacted 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 obtain the title compound 8b (290 mg, yield: 19.8%). MS m / z (ESI): 246.8[M-1]

[0350] Step 2 4-Promo-2-fluoro-5-((2-methylallyl)oxy)methyl benzoate 8c Compound 8b (290 mg, 1.16 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (242 mg, 1.75 mmol, National Pharmaceutical) was added, and 3-bromo-2-methylpropa-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 x 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 using eluent system B to obtain the title compound 8c (320 mg, yield: 90.7%).

[0351] Step 3 5-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxylate methyl 8d Compound 8c (170 mg, 0.56 mmol) was dissolved in N,N-dimethylformamide (8 mL), and tetraethylammonium chloride (102 mg, 0.62 mmol, Bailingwei), 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, Guoyak) were added. The mixture was purged three times with nitrogen gas and reacted overnight at 100°C. 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 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 the residue was purified by column chromatography using eluent system B to obtain the title compound 8d (65 mg, yield: 52.0%).

[0352] Step 4 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 Compound 8d (65 mg, 0.29 mmol) was dissolved in tetrahydrofuran (2 mL), compound 3i (81 mg, 0.32 mmol) was added, the mixture was purged three times with nitrogen gas, 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 obtain the title compound 8e (90 mg, yield: 70.0%). MS m / z (ESI): 444.3[M+1]

[0353] Step 5 (2-((4-amino-6-(5-fluoro-3-(5-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide)-2-methylphenyl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 8f 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, Bi De), compound 3k (74 mg, 0.24 mmol), and potassium carbonate (57 mg, 0.41 mmol, Guo Yao) were added, the mixture was purged three times with nitrogen gas, 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 obtain the title compound 8f (110 mg, yield: 92.8%). MS m / z (ESI): 584.6[M+1]

[0354] Step 6 N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 8g Compound 8f (110 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (770 mg, 6.75 mmol, Adamas) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, 5 mL of saturated sodium bicarbonate solution 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 to obtain 8 g of the title compound (91 mg, yield: 99.9%). The product was not purified and the reaction proceeded directly to the next step. MS m / z (ESI): 484.3[M+1]

[0355] Step 7 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-5-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxamide 8 8 g (91 mg, 0.19 mmol) of the crude compound was dissolved in dichloromethane (2 mL), N,N-diisopropylethylamine (98 mg, 0.76 mmol, Adamas) was added, and acryloyl chloride (10.3 mg, 0.11 mmol, National Pharmaceutical) was added dropwise at -20°C. The mixture was reacted at -20°C for 1 hour. 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%).

[0356] MS m / z (ESI): 538.4[M+1] 1 H NMR (500MHz,DMSO-d6): δ 9.85-9.64 (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),6.09-6.03 (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).

[0357] Example 9 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-fluoro-2,2-dimethyl-2,3-dihydro-1H-inden-5-carboxamide9 [ka]

[0358] Step 1 5-Promo-4-fluoro-2,2-dimethyl-2,3-dihydro-1H-inden-1-one 9b In a dry flask, 5-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one 9a (1 g, 4.37 mmol, Bi De) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydride (418 mg, 10.91 mmol, purity 60%, Guo Yak) was added while stirring at room temperature, and the mixture was stirred for 10 minutes at room temperature. Methyl iodide (4.3 g, 30.56 mmol, Adamas) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was slowly added dropwise to 50 mL of ice water while stirring, extracted with 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 obtain the title compound 9b (800 mg, yield: 71.27%).

[0359] Step 2 4-Fluoro-2,2-dimethyl-1-oxo-2,3-dihydro-1H-indene-5-carboxylate methyl 9c Compound 9b (800 mg, 3.11 mmol), triethylamine (944.6 mg, 9.33 mmol, National Pharmaceutical), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (341.5 mg, 0.47 mmol, Bi De) were dissolved in N,N-dimethylformamide (8 mL) and methanol (24 mL). The mixture was purged twice with nitrogen gas, carbon monoxide gas was added at 3 atm, and the reaction was carried out at 100°C for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified using eluent system B by column chromatography to obtain the title compound 9c (85 mg, yield: 11.56%).

[0360] Step 3 4-Fluoro-2,2-dimethyl-2,3-dihydro-1H-indene-5-carboxylate methyl 9d In a dry flask, compound 9c (70 mg, 0.30 mmol) was dissolved in trifluoroacetic acid (2 mL, National Pharmaceutical), and triethylsilane (172.3 mg, 1.48 mmol, Shaoyuan) was added while stirring at room temperature, and the mixture was stirred at room temperature for 7 hours. 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (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. The residue was purified by column chromatography using eluent system B to obtain the title compound 9d (65 mg, yield: 98.7%).

[0361] Step 4 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 Compound 9d (70 mg, 0.31 mmol) was dissolved in tetrahydrofuran (2 mL), compound 3i (87 mg, 0.35 mmol) was added, the mixture was purged three times with nitrogen gas, 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 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 obtain the title compound 9e (43.7 mg, yield: 31.44%). MS m / z (ESI): 442.3[M+1]

[0362] Step 5 (2-((4-amino-6-(5-fluoro-3-(4-fluoro-2,2-dimethyl-2,3-dihydro-1H-inden-5-carboxamide)-2-methylphenyl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 9f 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, National Pharmaceutical Co., Ltd.) were added, the mixture was purged with nitrogen gas for 10 minutes, and the reaction was carried out at 110°C for 40 minutes using microwaves. 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 obtain the title compound 9f (44 mg, yield: 76.34%). MS m / z (ESI): 582.4[M+1]

[0363] Step 6 N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-fluoro-2,2-dimethyl-2,3-dihydro-1H-inden-5-carboxamide 9g Compound 9f (44 mg, 0.08 mmol) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (1.07 g, 9.42 mmol, Adamas) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, 5 mL of saturated sodium bicarbonate solution 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 to obtain 9 g of the title compound (36 mg, yield: 98.8%). The product was not purified and the reaction proceeded directly to the next step. MS m / z (ESI): 482.4[M+1]

[0364] Step 7 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-fluoro-2,2-dimethyl-2,3-dihydro-1H-inden-5-carboxamide9 9 g (36 mg, 0.07 mmol) of the crude compound 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, National Pharmaceutical) was added dropwise at -20°C. The mixture was reacted at -20°C for 10 minutes. 5 mL of water was added, and the mixture was extracted with dichloromethane (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 high-performance liquid chromatography (chromatography column: Welch Ultimate PFP, 5 μm 30*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%).

[0365] MS m / z (ESI): 536.3[M+1] 1 H NMR (500MHz,CDCl3): δ 8.65-8.59 (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,3H),2.89-2.85 (m,3H),2.26-2.16 (m,3H),2.04-2.02 (m,1H),1.28-1.23 (m,6H).

[0366] Example 10 N-(4-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-3-(hydroxymethyl)pyridine-2-yl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide10 [ka]

[0367] Step 1 6'-Fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-formic acid 10a Compound 1d (560 mg, 2.54 mmol) was dissolved in tetrahydrofuran (10 mL) and water (3 mL), lithium hydroxide (1.07 g, 25.50 mmol, Adamas) was added, and the mixture was reacted 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 obtain the title compound 10a (524 mg, yield: 99.9%). MS m / z (ESI): 207.1[M+1]

[0368] Step 2 6'-Fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 10b Compound 10a (524 mg, 2.54 mmol) was dissolved in N,N-dimethylformamide (7 mL), and ammonium chloride (164 mg, 3.06 mmol, National Pharmaceutical), 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. The mixture was 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 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 obtain the title compound 10b (450 mg, yield: 86.3%). MS m / z (ESI): 206.1[M+1]

[0369] Step 3 N-(4-chloro-3-formylpyridine-2-yl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 10c Compound 10b (200 mg, 0.97 mmol), 2-bromo-4-chloropyridine-3-formaldehyde (257 mg, 1.16 mmol, Bi De), tris(dibenzylideneacetone)dipalladium (89 mg, 0.09 mmol, Bi De), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (113 mg, 0.19 mmol, Shao Yuan), and cesium carbonate (635 mg, 1.95 mmol, Adamas) were dissolved in 1,4-dioxane (10 mL), purged three times with nitrogen gas, and reacted at 90°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified using eluent system A by silica gel column chromatography to obtain the title compound 10c (85 mg, yield: 25.3%). MS m / z (ESI): 345.2[M+1].

[0370] Step 4 (2-((4-acetamido-6-chloropyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 10d Compound 3k (3g, 9.91 mmol) was dissolved in dichloromethane (60 mL), pyridine (3.13 g, 39.57 mmol, National Pharmaceutical) and anhydrous acetic acid (2.02 g, 19.79 mmol, National Pharmaceutical) were added, and the mixture was reacted at room temperature for 16 hours. 50 mL of water was added, and the mixture was extracted with dichloromethane (30 mL x 2). The organic phases were combined, 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 obtain the title compound 10d (2.57 g, yield: 75.2%). MS m / z (ESI): 345.3[M+1]

[0371] Step 5 (2-((4-acetamido-6-(trimethylstannyl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 10e Compound 10d (200 mg, 0.58 mmol) was dissolved in toluene (10 mL), and triphenylarsine (36 mg, 0.12 mmol, Inokai), tetrakis(triphenylphosphine)palladium (67 mg, 0.06 mmol, Bide), and hexamethyldisin (380 mg, 1.16 mmol, Adamas) were added. The mixture was purged with nitrogen gas three times and reacted at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound 10e, and the crude product was used directly in the next step without purification. MS m / z (ESI): 475.2[M+2].

[0372] Step 6 (2-((4-amino-6-(2-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide)-3-formylpyridine-4-yl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 10f Compound 10e (236 mg, 0.50 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 10c (85 mg, 0.25 mmol), cuprous iodide (95 mg, 0.50 mmol, Rakken), and bis(triphenylphosphine)palladium chloride (70 mg, 0.10 mmol, Adamas) were added. The mixture was purged three times with nitrogen gas and reacted at 90°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified using eluent system A by silica gel column chromatography to obtain the title compound 10f (115 mg, yield: 40.0%). MS m / z (ESI): 577.5[M+1].

[0373] Step 7 (2-((4-amino-6-(2-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide)-3-(hydroxymethyl)pyridine-4-yl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 10g Compound 10f (115 mg, 0.20 mmol) was dissolved in methanol (5 mL), sodium borohydride (8 mg, 0.21 mmol, National Pharmaceutical) was added, and the mixture was reacted at room temperature for 30 minutes. The reaction was quenched with 1 N hydrochloric acid (1 mL), 10 mL of water was added, and 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 (58 mg, yield: 50.4%) of the title compound. MS m / z (ESI): 579.2[M+1]

[0374] Step 8 N-(4-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-3-(hydroxymethyl)pyridine-2-yl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide10h 10 g (58 mg, 0.10 mmol) of the compound was dissolved in dichloromethane (2 mL), trifluoroacetic acid (924 mg, 8.10 mmol, Adamas) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, 3 mL of saturated sodium bicarbonate was added, and 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 product of the title compound 10h (47 mg, yield: 98.1%). The product was not purified and the reaction proceeded directly to the next step. MS m / z (ESI): 479.2[M+1]

[0375] Step 9 N-(4-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-3-(hydroxymethyl)pyridine-2-yl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 10 Crude compound 10h (47 mg, 0.10 mmol) was dissolved in dichloromethane (1 mL), N,N-diisopropylethylamine (565 mg, 4.37 mmol, Adamas) was added, and acryloyl chloride (9.5 mg, 0.10 mmol, National Pharmaceutical) was added dropwise at -20°C. The mixture was reacted at -20°C for 1 hour. 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 10 (1.8 mg, yield: 3.4%).

[0376] MS m / z (ESI): 533.2[M+1] 1 H NMR (500MHz,DMSO-d6) δ 10.64-10.37 (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).

[0377] Example 11 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 11 [ka]

[0378] Step 1 N-(3-promo-5-fluoro-2-formylphenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 11a Compound 10b (300 mg, 1.46 mmol), 2,6-dipromo-4-fluorobenzaldehyde (825 mg, 2.92 mmol, Bi-de), tris(dibenzylideneacetone)dipalladium (135 mg, 0.15 mmol, Bi-de), 4,5-bis(diphenylphosphine)-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), purged three times with nitrogen gas, and reacted at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 11a (330 mg, yield: 55.6%). MS m / z (ESI): 407.9[M+2].

[0379] Step 2 N-(3-bromo-5-fluoro-2-(hydroxymethyl)phenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 11b Compound 11a (330 mg, 0.81 mmol) was dissolved in methanol (10 mL), sodium borohydride (31 mg, 0.82 mmol, National Pharmaceutical) was added, and the mixture was reacted at room temperature for 30 minutes. The reaction was quenched with 1 N hydrochloric acid (1 mL), 15 mL of water was added, and 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 obtain the title compound 11b (330 mg, yield: 99.5%). MS m / z (ESI): 406.2[M-2]

[0380] Step 3 2-Promo-4-fluoro-6-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide)benzyl acetate 11c Compound 11b (330 mg, 0.81 mmol) was dissolved in dichloromethane (10 mL), triethylamine (82 mg, 0.81 mmol, Sinopharm) and 4-dimethylaminopyridine (10 mg, 0.08 mmol, Shaoyuan) were added, and anhydrous acetic acid (83 mg, 0.81 mmol, Sinopharm) was added dropwise at 0°C. The mixture was reacted at room temperature for 1 hour. 10 mL of water was added, and 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. The residue was purified by column chromatography using eluent system B to obtain the title compound 11c (225 mg, yield: 61.8%). MS m / z (ESI): 451.9[M+2]

[0381] Step 4 4-Fluoro-2-(6'-Fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 11d Compound 11c (225 mg, 0.50 mmol) was dissolved in 1,4-dioxane (5 mL), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (42 mg, 0.05 mmol, Bi De), bis(pinacolato)diborone (318 mg, 1.25 mmol, Shao Yuan), and potassium acetate (147 mg, 1.5 mmol, Adamas) were added. The mixture was purged three times with nitrogen gas and reacted at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 11d (150 mg, yield: 60.3%). 1 H NMR (500MHz,CDCl3) δ 9.27 (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).

[0382] Step 5 2-(6-amino-5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)pyrimidine-4-yl)-4-fluoro-6-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide)benzyl acetate 11e 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, Bi De), and potassium carbonate (85 mg, 0.61 mmol, Guo Yao) were added, the mixture was purged three times with nitrogen gas, and the reaction was carried out at 110°C for 30 minutes using a microwave. 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 obtain the title compound 11e (191 mg, yield: 99.3%). MS m / z (ESI): 638.3[M+1]

[0383] Step 6 (2-((4-amino-6-(5-fluoro-3-(6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide)-2-(hydroxymethyl)phenyl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl 11f 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 the mixture was reacted 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 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 obtain the title compound 11f (178 mg, yield: 99.7%). MS m / z (ESI): 596.2[M+1]

[0384] Step 7 N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 11g Compound 11f (178 mg, 0.29 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.85 g, 16.2 mmol, Adamas) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, 5 mL of saturated sodium bicarbonate 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 to obtain the crude product of the title compound, 11 g (148 mg, yield: 99.9%). The product was not purified and the reaction proceeded directly to the next step. MS m / z (ESI): 496.4[M+1]

[0385] Step 8 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-6'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 11 11 g (148 mg, 0.29 mmol) of the crude compound was dissolved in dichloromethane (2 mL), N,N-diisopropylethylamine (193 mg, 1.49 mmol, Adamas) was added, and acryloyl chloride (27 mg, 0.29 mmol, National Pharmaceutical) was added dropwise at -20°C. The mixture was reacted at -20°C for 1 hour. 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 title compound 11 (13 mg, yield: 7.9%).

[0386] MS m / z (ESI): 550.1[M+1] 1 H NMR (500MHz,DMSO-d6) δ 10.43-10.29 (m,1H),8.20 (d,1H),8.11 (dd,1H),7.74 (dd,1H),7.12 (s,2H),6.91 (ddd,1H),6.80 (dd,1H),6.67-6.51 (m,1H),6.02 (ddd,1H),5.64 (dt,1H),5.53 (ddd,1H),4.37 (dd,2H),3.60-3.41 (m,4H),3.03 (t,2H),2.74-2.52 (m,3H),2.16 (t,2H),1.04 (d,4H).

[0387] Example 12 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-6-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-carboxamide 12 [ka]

[0388] Step 1 5-Promo-6-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-12b Titanium tetrachloride (332 mg, 1.75 mmol, Bi-de) was dissolved in dichloromethane (3 mL), and under nitrogen gas protection, dimethylzinc (1 M, 2.62 mL, 2.62 mmol, Adamas) was added dropwise at -78°C and the mixture was reacted at -78°C for 20 minutes. Then, a solution of 5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one 12a (200 mg, 0.87 mmol, Bi-de) in dichloromethane (1.5 mL) was added dropwise and the mixture was reacted at room temperature for 12 hours. 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 B to obtain the title compound 12b (180 mg, yield: 84.8%).

[0389] Step 2 6-Fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-carboxylate methyl 12c Compound 12b (180 mg, 0.74 mmol) was dissolved in N,N-dimethylformamide (2 mL) and methanol (2 mL). 1,3-bis(diphenylphosphin)propane (62 mg, 0.15 mmol, Shaoyuan), N,N-diisopropylethylamine (192 mg, 1.49 mmol, Adamas), and palladium acetate (34 mg, 0.15 mmol, Adamas) were added, and the mixture was purged three times with carbon monoxide gas and reacted at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified using eluent system B by column chromatography to obtain the title compound 12c (105 mg, yield: 63.8%).

[0390] Step 3 6-Fluoro-N-(5-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,1-dimethyl-2,3-dihydro-1H-indene-5-carboxamide 12d Compound 12c (105 mg, 0.47 mmol) was dissolved in tetrahydrofuran (2 mL), compound 3i (131 mg, 0.52 mmol) was added, the mixture was purged three times with nitrogen gas, and sodium bis(trimethylsilyl)amide (2 M, 0.35 mL, 0.70 mmol, Adamas) was added dropwise at 0°C, and 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 obtain the title compound 12d (63 mg, yield: 30.2%). MS m / z (ESI): 442.4[M+1]

[0391] Step 4 (2-((4-amino-6-(5-fluoro-3-(6-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-carboxamide)-2-methylphenyl)pyrimidine-5-yl)oxy)ethyl)(methyl)carbamate tert-butyl-12e Compound 12d (63 mg, 0.14 mmol) was dissolved in ethylene glycol dimethyl ether (2 mL) and water (0.8 mL). Bis(triphenylphosphine)palladium chloride (11 mg, 0.02 mmol, Adamas), compound 3k (52 mg, 0.17 mmol), and sodium carbonate (31 mg, 0.29 mmol, National Pharmaceutical Co., Ltd.) were added, the mixture was purged three times with nitrogen gas, and the reaction was carried out by microwave at 110°C for 1 hour. 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 obtain the title compound 12e (63 mg, yield: 75.9%). MS m / z (ESI): 582.6[M+1]

[0392] Step 5 N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-6-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-carboxamide12f Compound 12e (63 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (462 mg, 4.05 mmol, Adamas) was added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 5 mL of saturated sodium bicarbonate solution 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 to obtain the crude product, title compound 12f (52 mg, yield: 99.7%). The product was not purified and the reaction proceeded directly to the next step. MS m / z (ESI): 482.3[M+1]

[0393] Step 6 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-6-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-carboxamide 12 Crude compound 12f (52 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), N,N-diisopropylethylamine (70 mg, 0.54 mmol, Adamas) was added, and acryloyl chloride (9.8 mg, 0.11 mmol, National Pharmaceutical) was added dropwise at -20°C. The mixture was reacted at -20°C for 1 hour. 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 12 (11 mg, yield: 19.0%).

[0394] MS m / z (ESI): 536.5[M+1] 1H NMR (500MHz,DMSO-d6): δ 9.84-9.63 (m,1H),8.21-8.18 (m,1H),7.64-7.50 (m,2H),7.22-6.96 (m,4H),6.66-6.58 (m,1H),6.10-6.03 (m,1H),5.62-5.58 (m,1H),3.59-3.45 (m,4H),2.92-2.81 (m,3H),2.53 (s,3H),2.03-1.93 (m,4H),1.26-1.24 (m,6H).

[0395] Example 13 N-(3-(6-amino-5-(2-(N-methacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4'-fluoro-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-5'-carboxamide 13 [ka]

[0396] Step 1 4-Fluoro-1-oxo-2,3-dihydro-1H-indene-5-carboxylate methyl-13b 5-Promo-4-fluoro-2,3-dihydro-1H-inden-1-one 13a (2 g, 8.73 mmol, Bi-de) was dissolved in N,N-dimethylformamide (10 mL) and methanol (5 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (640 mg, 0.87 mmol, Adamas) and N,N-diisopropylethylamine (2.26 g, 17.46 mmol, Adamas) were added, and the mixture was purged three times with carbon monoxide gas and reacted at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain the title compound 13b (830 mg, yield: 45.7%).

[0397] Step 2 4-Fluoro-1-methylene-2,3-dihydro-1H-indene-5-carboxylate methyl-13c Compound 13b (800 mg, 3.84 mmol) was dissolved in tetrahydrofuran (15 mL), methyltriphenylphosphonium bromide (2.61 g, 7.69 mmol, Shaoyuan) and potassium tert-butoxide (1 M, 7.69 mL, 7.69 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 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 using eluent system B to obta...

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Here, 【change】 Ring A is selected from a polycyclic aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclyl group. 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 each independently represent 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 hydroxy group, a nitro group, -(CR ａ R ｂ ) ｖ OR １７ , -(CR ａ R ｂ ) ｖ NR １８ R １９ , -C(O)R １７ , -C(O)OR １７ , -C(O)NR １８ R １９ , -OC(O)NR １８ R １９ , -OC(O)R １７ , -OC(O)OR １７ , -NR ２０ C(O)R １７ , -NR ２０ C(O)OR １７ , -SR １７ , -S(O)R １７ , -S(O) ２ R １７ , -S(O) ２ NR １８ R １９ , -NR ２０ S(O) ２ R １７ , -(CR ａ R ｂ ) ｖ cycloalkyl group, -(CR ａ R ｂ ) ｖ heterocyclyl group, -(CR ａ R ｂ ) ｖ aryl group, -(CR ａ R ｂ ) ｖ heteroaryl group, oxo group, =S and =CR ｐ R ｑ Selected from, where the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently and optionally selected as one or more R ０ Replaced by, Or, two R's １ These, together with the ring atoms linked to them, form a cycloalkyl group or heterocyclyl group, where the cycloalkyl group or heterocyclyl group is optionally composed of one or more R ０ Replaced by, R ２ is, -OR Ａ or -alkylene-R Ｂ Here, the alkylene group is optionally one or more R ０ Replaced by, R Ａ R is selected from alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups can be independently and optionally selected as one or more R ０ Replaced by, R Ｂ R is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group can be independently and optionally selected as one or more R ０ Replaced by, R Ｃ R is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, where each of the cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently one or more R ｄ Replaced by, Each R ｄ is the same or different, and each independently represents 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 hydroxy group, a nitro group, -(CR ａ R ｂ ) ｖ OR １７ , -(CR ａ R ｂ ) ｖ NR １８ R １９ , -C(O)R １７ , -C(O)OR １７ , -C(O)NR １８ R １９ , -OC(O)NR １８ R １９ , -OC(O)R １７ , -OC(O)OR １７ , -NR ２０ C(O)R １７ , -NR ２０ C(O)OR １７ , -SR １７ , -S(O)R １７ , -S(O) ２ R １７ , -S(O) ２ NR １８ R １９ , -NR ２０ S(O) ２ R １７ , -(CR ａ R ｂ ) ｖ (cycloalkyl group), -(CR ａ R ｂ ) ｖ (heterocyclyl group), -(CR ａ R ｂ ) ｖ (aryl group), -(CR ａ R ｂ ) ｖ (heteroaryl group), an oxo group, =S and =CR ｐ R ｑ Selected from, where the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently and optionally selected as one or more R ０ Replaced by, R ３ This is selected from hydrogen atoms, alkyl groups, deuterated alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. 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 These are the same or different, and each independently, hydrogen atom, deuterium atom, halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, deuterated alkoxy group, alkoxyalkyl group, aminoalkyl group, cyano group, amino group, hydroxy group, nitro group, -(CR ａ R ｂ ) ｖ OR １７ ,-(CR ａ R ｂ ) ｖ NR １８ R １９ , -C(O)R １７ , -C(O)OR １７ , -C(O)NR １８ R １９ , -OC(O)NR １８ R １９ , -OC(O)R １７ , -OC(O)OR １７ , -NR ２０ C(O)R １７ , -NR ２０ C(O)OR １７ , -SR １７ , -S(O)R １７ , -S(O) ２ R １７ , -S(O) ２ NR １８ R １９ , -NR ２０ S(O) ２ R １７ ,-(CR ａ R ｂ ) ｖ Cycloalkyl group, -(CR ａ R ｂ ) ｖ Heterocyclyl group, -(CR ａ R ｂ ) ｖ Aryl group and -(CR ａ R ｂ ) ｖ Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R ０ Replaced by, Or, R ４ｂ and R ４ｃ These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R ０ Replaced by, Or, R ４ｃ and R ４ｄ These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R ０ Replaced by, Or, R ５ａ and R ５ｂ These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R ０ Replaced by, Or, R ５ｂ and R ５ｃ These, together with the carbon atoms linked to each of them, form a cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group, where the cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group can optionally consist of one or more R ０ Replaced by, R ６ is a hydrogen atom, -NHR ７ and -NHC(O)R ７ Selected from, R ７ This is selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, deuterated alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. L is CR ８ R ９ ,C(O),O,NR １０ , S, S(O) and S(O) ２ Selected from, R ８ and R ９ These are either the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuterated alkoxy groups, alkoxyalkyl groups, aminoalkyl groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. Or, R ８ and R ９ The carbon atoms linked together form a cycloalkyl group or a heterocycline group, where the cycloalkyl group or heterocycline group can optionally consist of one or more R atoms. ０ Replaced by, R １０ This is selected from hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, deuterated alkoxy groups, cycloalkyl groups, heterocyclyl groups, cycloalkylalkyl groups, and heterocyclylalkyl groups. R １１ , R １２ , R １３ , R １４ , R ｘ and R ｙ These are the same or different, and each independently, hydrogen atom, deuterium atom, halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, deuterated alkoxy group, alkoxyalkyl group, aminoalkyl group, hydroxyl group, cyano group, amino group, nitro group, -(CR ａ R ｂ ) ｖ OR １７ ,-(CR ａ R ｂ ) ｖ NR １８ R １９ ,-(CR ａ R ｂ ) ｖ Cycloalkyl group, -(CR ａ R ｂ ) ｖ Heterocyclyl group, -(CR ａ R ｂ ) ｖ Aryl group and -(CR ａ R ｂ ) ｖ Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R ０ Replaced by, Or, R １１ , R １２ , R １３ , R １４ , R ｘ and R ｙ Any two of these may, together with the carbon atoms linked to them, form a cycloalkyl or heterocyclyl group, where the cycloalkyl or heterocyclyl group may optionally consist of one or more R ０ Replaced by, or R １１ and R １２ They come together to form = O, or R １３ and R １４ They come together to form = O, or R on the same carbon atom ｘ and R ｙ They come together to form = O, R １５ R is selected from hydrogen atoms, alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, arylalkyl groups, and heteroarylalkyl groups, where each of the alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkylalkyl groups, heterocyclylalkyl groups, arylalkyl groups, and heteroarylalkyl groups is independently and optionally selected as one or more R ０ Replaced by, Or, R １１ , R １２ , R １３ , R １４ , R ｘ and R ｙ Any one of the above and R １５ These, together with the atoms linked to each of them, form a nitrogen-containing heterocycline group, where the nitrogen-containing heterocycline group is optionally composed of one or more R ０ Replaced by, W is -C(O)R １６ , -S(O) ２ R １６ Selected from and -CN, R １６ The group is selected from an alkenyl group, an alkynyl group, and an alkylene oxide, where the alkenyl group, alkynyl group, and alkylene oxide are each independently and optionally selected as an oxo group, =S, or =CR. ｐ R ｑ , deuterium atom, halogen, alkyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, deuterated alkoxy group, alkoxyalkyl group, aminoalkyl group, hydroxyl group, cyano group, amino group, nitro group, -(CR ａ R ｂ ) ｖ OR １７ ,-(CR ａ R ｂ ) ｖ NR １８ R １９ , -C(O)R １７ , -C(O)OR １７ , -C(O)NR １８ R １９ , -OC(O)R １７ , -OC(O)OR １７ , -NR ２０ C(O)R １７ , -NR ２０ C(O)OR １７ , -SR １７ , -S(O)R １７ , -S(O) ２ R １７ , -S(O) ２ NR １８ R １９ , -NR ２０ S(O) ２ R １７ ,-(CR ａ R ｂ ) ｖ Cycloalkyl group, -(CR ａ R ｂ ) ｖ Heterocyclyl group, -(CR ａ R ｂ ) ｖ Aryl group and -(CR ａ R ｂ ) ｖ Substituted with one or more substituents selected from heteroaryl groups, R ０ Each time it appears, it may be the same or different, and each independently, it is an oxo group, =S, =CR ｐ R ｑ , deuterium atom, halogen, alkenyl group, alkynyl group, cyano group, nitro group, hydroxyl group, amino group, alkyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, deuterated alkoxy group, alkoxyalkyl group, aminoalkyl group, -(CR ａ R ｂ ) ｖ OR １７ ,-(CR ａ R ｂ ) ｖ NR １８ R １９ , -C(O)R １７ , -C(O)OR １７ , -C(O)NR １８ R １９ , -OC(O)NR １８ R １９ , -OC(O)R １７ , -OC(O)OR １７ , -NR ２０ C(O)R １７ , -NR ２０ C(O)OR １７ , -SR １７ , -S(O)R １７ , -S(O) ２ R １７ , -S(O) ２ NR １８ R １９ , -NR ２０ S(O) ２ R １７ ,-(CR ａ R ｂ ) ｖ Cycloalkyl group, -(CR ａ R ｂ ) ｖ Heterocyclyl group, -(CR ａ R ｂ ) ｖ Aryl group and -(CR ａ R ｂ ) ｖ Selected from heteroaryl groups, R １７ , R １８ , R １９ and R ２０ Each instance may be the same or different, and each may independently be a hydrogen atom, alkyl group, alkenyl group, alkynyl group, -(CR ａ R ｂ ) ｖ Cycloalkyl group, -(CR ａ R ｂ ) ｖ Heterocyclyl group, -(CR ａ R ｂ ) ｖ Aryl group and -(CR ａ R ｂ ) ｖ Selected from heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group can be independently and optionally selected as one or more R ０１ Replaced by, or R １８ and R １９ It forms a nitrogen-containing heterocyclyl group together with the linked nitrogen atom, and the nitrogen-containing heterocyclyl group optionally has one or more R ０１ Replaced by, R ０１ Each time it appears, it may be the same or different, and each independently, it is an oxo group, =S, =CR ｐ R ｑ Deuterium atom, halogen, hydroxyl group, alkenyl group, alkynyl group, cyano group, nitro group, amino group, -NH alkyl group, -N (alkyl) ２ -C(O)O alkyl group, -C(O)OH, -C(O)NH ２ Selected from -C(O) halogen, -C(O) alkyl group, alkyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, deuterated alkoxy group, alkoxyalkyl group, aminoalkyl group, cycloalkyl group, cycloalkylalkyl group, cycloalkyloxy group, heterocyclyl group, heterocyclylalkyl group, heterocyclyloxy group, aryl group, arylalkyl group, aryloxy group, heteroaryl group, heteroarylalkyl group and heteroaryloxy group, R ａ and R ｂ Each occurrence may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuterated alkoxy groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. R ｐ and R ｑ Each occurrence may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuterated alkoxy groups, hydroxyl groups, cyano groups, amino groups, cycloalkyl groups, and cycloalkylalkyl groups. q is an integer between 0 and 25. m is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. v is 0, 1, 2, or 3, and is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

2. A compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, 【Chemistry 2】 Here, 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 A compound represented by general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is as defined in claim 1.

3.

4. A compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, 【Transformation 3】 Here, A １ and A ２ They are the same or different, and each is independent of the other, bonded, C(O), O, NR, S, S(O), S(O) ２ and (CR １ｂ R １ｃ ) ｊ Selected from, R １ｂ , R １ｃ , R ｅ , R ｆ , R ｊ and R ｋ They are either the same or different, and each is independently a hydrogen atom or R １ And, Or, R ｅ and R ｆ The carbon atoms linked together form a cycloalkyl group or a heterocycline group, and the cycloalkyl group or heterocycline group optionally has 1, 2, 3, or 4 R atoms. １ Replaced by, Or, R ｊ and R ｋ The carbon atoms linked together form a cycloalkyl group or a heterocycline group, and the cycloalkyl group or heterocycline group optionally has 1, 2, 3, or 4 R atoms. １ Replaced by, Or, R ｆ and R ｊ The carbon atoms linked together form a cycloalkyl group or a heterocycline group, and the cycloalkyl group or heterocycline group optionally has 1, 2, 3, or 4 R atoms. １ Replaced by, Or, R １ｂ and R １ｃ The carbon atoms linked together form a cycloalkyl group or a heterocycline group, and the cycloalkyl group or heterocycline group optionally has 1, 2, 3, or 4 R atoms. １ Replaced by, R is selected from a hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxyalkyl group, aminoalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group. j is 0, 1, 2, or 3. q1 is 0, 1, 2, or 3. r is either 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 A compound represented by general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is as defined in claim 1.

5. Each R １ They are the same or different, and each is independently a halogen, C １－６ alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy groups and C １－６ Selected from hydroxyalkyl groups, preferably each R １ These are the same or different and each independently a halogen, more preferably R １ F is a compound represented by general formula (I) as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ They are the same or different, and each is independently a hydrogen atom, halogen, C １－６ alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy groups and C １－６ Selected from hydroxyalkyl groups, preferably R ４ａ C １－６ Alkyl alkyl group or C １－６ It is a hydroxyalkyl group, R ４ｂ is a hydrogen atom, and R ４ｃ is a hydrogen atom or a halogen, R ４ｄ is a hydrogen atom, and more preferably, R ４ａ R is a methyl group or a hydroxymethyl group, ４ｂ is a hydrogen atom, and R ４ｃ is a hydrogen atom or F, and R ４ｄ The compound represented by general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

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

8. R １１ , R １２ , R １３ and R １４ is a hydrogen atom, and / or n is 0, and / or R １５ C is a hydrogen atom. １－６ alkyl group, C １－６ Selected from deuterated alkyl groups and 3- to 6-membered cycloalkyl groups, preferably R １５ is a methyl group or -CD ３ A compound represented by general formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. R １６ C ２－６ It is an alkenyl group, where the C ２－６ The alkenyl group can optionally be a halogen, C １－６ alkyl group, C １－６ Alkoxy groups and -NR １８ R １９ Substituted with one or more substituents selected from R １８ and R １９ They are either the same or different, and each is independently a hydrogen atom or C １－６ It is an alkyl group, preferably R １６ -CH=CH ２ A compound represented by general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. A １ and A ２ They are the same or different, and each is independent of the bond between O and CH. ２ Selected from, preferably A １ CH ２ or O, A ２ The compound represented by general formula (I) as described in any one of claims 4 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound is a bond.

11. R ｅ , R ｆ , R ｊ and R ｋ These are the same or different, and each is independently a hydrogen atom, a halogen, and C １－６ Selected from alkyl groups, or R ｅ and R ｆ It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, or R ｊ and R ｋ It forms a 3-6 membered cycloalkyl group with the linked carbon atoms, or R ｆ and R ｊ The compound represented by general formula (I) according to any one of claims 4 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound forms a 4- to 6-membered cycloalkyl group together with the linked carbon atoms. 【Request Item 12】 【Chemistry 4】 【change】 【change】 A compound represented by general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from any one of the compounds.

13. A compound represented by general formula (IA) or a salt thereof, 【Transformation 5】 Here, 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 A compound represented by general formula (IA) or a salt thereof, wherein n is as defined in claim 1. 【Request Item 14】 【Chemistry 6】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound or a salt thereof, selected from any one of the following compounds.

15. A method for producing a compound represented by general formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, wherein the method is: 【Transformation 7】 This includes a condensation reaction of a compound represented by general formula (IA) or a salt thereof with a compound represented by general formula (IB) or a salt thereof to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. Here, X is a halogen, preferably Cl. W is -C(O)R １６ or -S(O) ２ R １６ And, 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 A method wherein n and n are as defined in claim 1.

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

17. Uses of the compound represented by formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16, in the manufacture of a drug for treating and / or preventing a BTK-mediated disease or disorder.

18. Uses of a compound represented by formula (I) in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a drug for treating and / or preventing a disease or disorder, wherein the disease or disorder is selected from cancer, autoimmune diseases, inflammatory diseases, allergic diseases, anaphylaxis, respiratory diseases, cardiovascular diseases, viral infections, transplant rejection, metabolic / endocrine disorders and neurological disorders, preferably, the disease or disorder is autoimmune Selected from autoimmune diseases, inflammatory diseases, and cancer, and more preferably, the disease or disorder is B-cell malignancy, multiple myeloma, leukemia, malignant lymphoma, Waldenström macroglobulinemia, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenström macroglobulinemia, bone cancer, bone metastases, arthritis, multiple sclerosis, amyotrophic lateral sclerosis, osteoporosis, diabetes mellitus, arteriosclerosis, irritable bowel syndrome, inflammation Intestinal diseases, ulcerative colitis, Crohn's disease, Sjögren's syndrome, autoimmune thyroid disease, Alzheimer's disease, lupus, systemic lupus erythematosus, psoriasis, urticaria, liver failure, allergies, ankylosing spondylitis, dermatitis, pancreatitis, mastitis, meningitis, glomerulonephritis, Goodpasture syndrome, Hashimoto's disease, keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, tracheitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, Graves' disease, asthma, chronic obstructive pulmonary disease (COPD), Applications selected from thromboembolism, myocardial infarction, angina pectoris, stroke, ischemic injury, 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 of organ transplantation, xenotransplantation, antibody-mediated transplant rejection (AMR), graft-versus-host disease, and B-cell-mediated hyperacute, acute, and chronic transplant rejection.

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