QUINOLINEAMINE COMPOUNDS, PREPARATION METHOD THEREOF AND THEIR MEDICINAL APPLICATIONS

Abstract

The present invention relates to quinolinamine compounds, their preparation methods and their pharmaceutical applications, in particular to quinolinamine compounds represented by general formula (I), their preparation methods and pharmaceutical compositions containing such compounds, as well as their use as therapeutic agents, in particular as miRNA modulators and in the preparation of medicaments for treating diseases or conditions ameliorated by regulating miRNA levels. JPEG2024519993000205.jpg55170

Description

[Technical field]

[0001] The present disclosure belongs to the pharmaceutical field, and relates to quinolinamine compounds, their preparation methods and their pharmaceutical applications.In particular, the present disclosure relates to quinolinamine compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use as therapeutic agents, particularly as miRNA modulators, and in the preparation of medicaments for treating diseases or conditions that are ameliorated by regulating miRNA levels. [Background technology]

[0002] MicroRNA (miRNA) is a type of non-coding single-stranded RNA molecule with a length of about 22 nucleotides that is encoded by endogenous genes and is involved in the regulation of post-transcriptional gene expression in animals and plants. Each miRNA may have multiple target genes, but multiple miRNAs may regulate the same gene. Such a complex network allows precise regulation of target genes. miR-124 is widely expressed in each tissue of the body, and is particularly highly expressed in brain tissue. Research has shown that overexpression of miR-124 can promote the conversion of activated macrophages-microglia to a quiescent state and suppress encephalomyelitis, an autoimmune disease (Ponomarev ED et al., Nat Med, 2011; 17: 67-70). In addition, miR-124 can promote the conversion of macrophages to the M2 type and exert anti-inflammatory effects (Veremeyko T, et.al, Plos One, 2013; 8: e81774). miR-124 also affects T cell differentiation, and T cells treated with miR-124 have reduced levels of both IFN-γ and TNFα. Overexpression of miR-124 exerts anti-inflammatory effects by downregulating STAT3 protein, reducing the expression of the inflammatory cytokine IL-17, and inhibiting the differentiation of Th17 cells (Wei J et.al, Cancer Res, 2013; 73: 3913-3926). A statistical study reported that the levels of miR-124 in pediatric ulcerative colitis were much lower than those in healthy subjects, suggesting that upregulating miR-124 may inhibit intestinal inflammatory responses (Koukos G, et.al, Gastroenterology, 2013; 145: 842-852). Furthermore, Nakamachi's team discovered that miR-124 was significantly downregulated in synovial cells of rheumatoid arthritis patients compared to osteoarthritis patients (Nakamachi, Y, et.al, Arthritis Rheum, 2009;60:1294-1304).As evident from the above studies, upregulation of miR-124 leads to the development of novel small molecule drugs that can be used for the effective treatment of related inflammatory diseases.

[0003] Inflammation is a defensive response of the immune system to local infection or tissue injury, and severe inflammatory responses can damage muscles. Common manifestations of inflammatory responses are pain, fever, redness, swelling, and loss of function. Inflammatory diseases include a variety of diseases, including autoimmune-related inflammatory diseases, inflammatory diseases in the central nervous system (CNS), inflammatory diseases in the joints, inflammatory diseases in the digestive tract, and inflammatory diseases in the skin. Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) are the two most common inflammatory diseases that have received widespread attention.

[0004] Inflammatory bowel disease is an idiopathic intestinal inflammatory disease, and its clinical manifestations include diarrhea, abdominal pain, and even bloody stool. Currently, the etiology and pathogenesis of IBD are not yet fully understood, but it is known that inflammatory responses due to abnormal responses of the intestinal mucosal immune system play an important role in the development of IBD, and many factors, including environmental, genetic, infectious, and immune factors, can lead to this disease. IBD generally refers to ulcerative colitis (UC) and Crohn's disease (CD). Ulcerative colitis is a continuous inflammation of the colonic mucosa and submucosa, which usually first affects the rectum and gradually spreads throughout the colon, while Crohn's disease is a discontinuous full-thickness inflammation that can affect the entire digestive tract, with the terminal ileum, colon, and perianal area being the most commonly affected sites. IBD is generally expressed as the infiltration of excessive immune cells into the intestinal mucosa, an imbalance of T cell subsets, including Th17, Th1, and Treg, and excessive activation of macrophages and dendritic cells. Drugs currently on the market or in clinical trials include JAK inhibitors that attenuate inflammatory responses, TNFα antibodies, IL-12 and IL-23 antibodies that inhibit the differentiation of Th1 and Th17, and integrin α4β7 antibodies that block the infiltration of inflammatory cells.

[0005] Rheumatoid arthritis is a systemic inflammatory disease affecting the lining of joints (called the synovium) and is characterized by polyarticular, symmetric, and aggressive joint inflammation of the small joints of the hands and feet, often accompanied by extra-articular organ involvement, which can lead to joint deformity and loss of function. Inflammatory cytokines (e.g., tumor necrosis factor TNFα, interleukins IL-1 and IL-6) play an important role in the pathogenesis of rheumatoid arthritis (RA). RA is usually treated with disease-modifying antirheumatic small molecule drugs (DMARDs) and biological agents such as TNFα inhibitors. However, patients who respond to these drugs generally become unresponsive after several years of use. Therefore, there is a need to develop therapies with novel mechanisms of action that are effective and safe for long-term use.

[0006] Related published patent applications include WO2010143169A2, WO2015001518A1, WO2016009065A2, WO2017158201A1, and WO2020127843A1, etc. Summary of the Invention

[0007] The present disclosure aims to provide compounds of general formula (I) or medicamentable salts thereof: [ka] Among them, Ring A is a cycloalkyl group or a heterocyclyl group; G is a N atom or CR 2a and Each R 1 are identical or different and each independently represent a hydrogen atom, a deuterium atom, a halogen atom, an alkyl group, an alkoxy group, an oxo group, a hydroxyalkyl group, a cycloalkyloxy group, a heterocyclyloxy group, an alkenyl group, an alkynyl group, a hydroxy group, a cyano group, a nitro group, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH2) q NR 9 R10 , a cycloalkyl group, a heterocyclyl group, an aryloxy group, a heteroaryloxy group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a nitro group, an amino group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; Each R 2 are identical or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyano group and an amino group; Each R 3 are identical or different and are each independently selected from a halogen, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; Or, two adjacent R 3 form a cycloalkyl group or a heterocyclyl group together with a carbon atom on the benzene ring to which it is linked, and the cycloalkyl group or the heterocyclyl group is each independently optionally substituted with one or more identical or different substituents selected from a halogen, a hydroxy group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyano group; R 4 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group and the heterocyclyl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen atom, a hydroxy group, a carboxy group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a nitro group, an amino group and a cyano group; R 5 and R 6are identical or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxy group, an amino group, a cycloalkyl group and a heterocyclyl group; R 7 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group; R 8 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, a cycloalkyl group and a heterocyclyl group; R 9 and R 10 are identical or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxy group, an amino group, a cycloalkyl group and a heterocyclyl group; R 2a is selected from a hydrogen atom, a halogen, a hydroxy group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, and an amino group; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; p is 1, 2, 3 or 4; q is 0, 1, 2 or 3.

[0008] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein: Ring A is a cycloalkyl group or a heterocyclyl group; G is a N atom or CR 2a and Each R 1 are identical or different and each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an oxo group, a hydroxyalkyl group, a cycloalkyloxy group, a heterocyclyloxy group, an alkenyl group, an alkynyl group, a hydroxy group, a cyano group, a nitro group, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH2)q NR 9 R 10 , a cycloalkyl group, a heterocyclyl group, an aryloxy group, a heteroaryloxy group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a nitro group, an amino group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; Each R 2 are identical or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyano group and an amino group; Each R 3 are identical or different and are each independently selected from a halogen, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; Or, two adjacent R 3 form a cycloalkyl group or a heterocyclyl group together with a carbon atom on the benzene ring to which it is linked, and the cycloalkyl group or the heterocyclyl group is each independently optionally substituted with one or more identical or different substituents selected from a halogen, a hydroxy group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyano group; R 4 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group and the heterocyclyl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen atom, a hydroxy group, a carboxy group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a nitro group, an amino group and a cyano group; R5 and R 6 are identical or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxy group, an amino group, a cycloalkyl group and a heterocyclyl group; R 7 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group; R 8 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, a cycloalkyl group and a heterocyclyl group; R 9 and R 10 are identical or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxy group, an amino group, a cycloalkyl group and a heterocyclyl group; R 2a is selected from a hydrogen atom, a halogen, a hydroxy group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, and an amino group; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; p is 1, 2, 3 or 4, and q is 0, 1, 2 or 3.

[0009] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is a compound represented by the general formula (IC) or a medicamentable salt thereof: [ka] Among them, Ring A, G, R 1 ~R 3 , n, m and p are as defined in general formula (I).

[0010] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (IC) or a medicamentable salt thereof is [ka] teeth [ka] isn't it.

[0011] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is a compound represented by general formula (I-1) or general formula (I-2) or a medicamentable salt thereof: [ka] Among them, Ring A, G, R 1 ~R 3 , n, m and p are as defined in general formula (I).

[0012] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is a compound represented by general formula (I-3) or general formula (I-4) or a medicamentable salt thereof: [ka] Among them, Ring B is a cycloalkyl group or a heterocyclyl group, wherein the cycloalkyl group or the heterocyclyl group is independently optionally substituted with one or more identical or different substituents selected from a halogen, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyano group; Each R 3a are identical or different and are each independently selected from a halogen, a hydroxy group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyano group; r is 0, 1 or 2; Ring A, G, R 1 , R 2 , R 4, n and m are as defined in general formula (I).

[0013] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is a compound represented by general formula (I-3C) or general formula (I-4C) or a medicamentable salt thereof: [ka] Among them, Ring A, Ring B, G, R 1 , R 2 , R 3a , n, r and m are as defined in general formula (I-3) or general formula (I-4).

[0014] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I-3), general formula (I-3C), general formula (I-4) or general formula (I-4C), or a medicamentable salt thereof, wherein ring B is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably ring B is a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group, and more preferably ring B is a cyclopentyl group.

[0015] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C) or general formula (IC), or a medicamentable salt thereof, wherein ring A is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclyl group, and preferably ring A is a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group.

[0016] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), or general formula (IC), or a medicamentable salt thereof, wherein each R 1are identical or different and each independently represents a hydrogen atom, a deuterium atom, a halogen, -C(O)R 8 , C 1-6 Alkyl group, C 1-6 is selected from an alkoxy group and an oxo group, and is preferably a hydrogen atom, a deuterium atom, a halogen, or -C(O)R 8 and C. 1-6 R is selected from alkyl groups; 8 is as defined in general formula (I).

[0017] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), or general formula (IC), or a medicamentable salt thereof, wherein each R 1 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a fluorine atom, an acetyl group, a methyl group, and an oxo group.

[0018] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), or general formula (IC), or a medicamentable salt thereof, wherein each R 1 are identical or different, and each independently represents a hydrogen atom, a halogen, or -C(O)R 8 , C 1-6 Alkyl group, C 1-6 selected from an alkoxy group and an oxo group; R 8 is as defined in general formula (I).

[0019] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), or general formula (IC), or a medicamentable salt thereof, wherein R 8 is a hydrogen atom, C 1-6 Alkyl and haloC 1-6 alkyl group, preferably R 8 is C1-6 More preferably, R 8 is a methyl group.

[0020] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is a compound represented by the general formula (II) or a medicamentable salt thereof: [ka] Among them, G 1 , G 2 and G 3 are identical or different, and each independently represents an O atom, a S atom, or NR 1a and CR 1b R 1c Selected from R 1a is a hydrogen atom, an alkyl group, -C(O)R 8 , -C(O)(CH2) q NR 9 R 10 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a nitro group, an amino group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 1b and R 1c are identical or different and each independently represent a hydrogen atom, a deuterium atom, a halogen atom, an alkyl group, an alkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, an alkenyl group, an alkynyl group, a hydroxy group, a cyano group, a nitro group, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH2) q NR 9 R 10, a cycloalkyl group, a heterocyclyl group, an aryloxy group, a heteroaryloxy group, an aryl group and a heteroaryl group, or R 1b and R 1c together form an oxo group, in which the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; G, R 2 ~R 10 , m, p and q are as defined in general formula (I).

[0021] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II) or a medicamentable salt thereof, wherein: G 1 , G 2 and G 3 are identical or different, and each independently represents an O atom, a S atom, or NR 1a and CR 1b R 1c Selected from R 1a is a hydrogen atom, an alkyl group, -C(O)R 8 , -C(O)(CH2) q NR 9 R 10 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a nitro group, an amino group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 1b and R 1care identical or different and each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, an alkenyl group, an alkynyl group, a hydroxy group, a cyano group, a nitro group, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH2) q NR 9 R 10 , a cycloalkyl group, a heterocyclyl group, an aryloxy group, a heteroaryloxy group, an aryl group and a heteroaryl group, or R 1b and R 1c together form an oxo group, in which the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; G, R 2 ~R 10 , m, p and q are as defined in general formula (I).

[0022] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof is a compound represented by general formula (IIC) or a medicamentable salt thereof: [ka] Among them, G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (II).

[0023] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof is a compound represented by the general formula (IID-1) or (IID-2) or a medicamentable salt thereof: [ka] Among them, G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (II).

[0024] In some embodiments of the present disclosure, the compound represented by the above general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a medicamentable salt thereof, wherein 1 and G 2 are identical or different, and each independently represents an O atom, a S atom, or NR 1a and CR 1b R 1c Selected from G 3 is CR 1b R 1c and R 1a , R 1b and R 1c is as defined in general formula (II).

[0025] In some embodiments of the present disclosure, the compound represented by the above general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a medicamentable salt thereof, wherein 1 is an O atom or NR 1a and G 2 and G 3 are each independently CR 1b R 1c and R 1a , R 1b and R 1c is as defined in general formula (II).

[0026] In some embodiments of the present disclosure, the compound represented by the above general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a medicamentable salt thereof, wherein 2 is an O atom or NR 1a and G 1 and G 3 are each independently CR 1b R 1c and R 1a , R 1b and R 1c is as defined in general formula (II).

[0027] In some embodiments of the present disclosure, the compound represented by the above general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a medicamentable salt thereof, wherein 1 and G 2 are both O atoms, and G 3 is CR 1b R 1c and R 1b and R 1c is as defined in general formula (II).

[0028] In some embodiments of the present disclosure, the compound represented by the above general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a medicamentable salt thereof, wherein 1 , G 2 and G 3 are each independently CR 1b R 1c and R 1b and R 1c is as defined in general formula (II).

[0029] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2), or a medicamentable salt thereof, wherein: [ka] teeth [ka] and G 1 and G 2 are identical or different, and each independently represents an O atom, NR 1a and CR 1b R 1c Selected from R 1a , R 1b and R 1c is as defined in general formula (II), preferably [ka] teeth [ka] Selected from R 1a , R 1b and R 1c is as defined in general formula (II), more preferably [ka] teeth [ka] Selected from.

[0030] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is a compound represented by the general formula (III) or a medicamentable salt thereof: [ka] Among them, L 1 , L 2 , L 3 and L 4 are identical or different, and each independently represents an O atom, a S atom, or NR 1d and CR 1e R 1f Selected from R 1d is a hydrogen atom, an alkyl group, -C(O)R 8, -C(O)(CH2) q NR 9 R 10 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a nitro group, an amino group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 1e and R 1f are identical or different and each independently represent a hydrogen atom, a deuterium atom, a halogen atom, an alkyl group, an alkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, an alkenyl group, an alkynyl group, a hydroxy group, a cyano group, a nitro group, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH2) q NR 9 R 10 , a cycloalkyl group, a heterocyclyl group, an aryloxy group, a heteroaryloxy group, an aryl group and a heteroaryl group, or R 1e and R 1f together form an oxo group, in which the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; G, R 2 ~R 10 , m, p and q are as defined in general formula (I).

[0031] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III) or a medicamentable salt thereof, wherein: L 1 , L 2 , L 3 and L 4 are identical or different, and each independently represents an O atom, a S atom, or NR 1d and CR 1e R 1f Selected from R 1d is a hydrogen atom, an alkyl group, -C(O)R 8 , -C(O)(CH2) q NR 9 R 10 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a nitro group, an amino group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 1e and R 1f are identical or different and each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, an alkenyl group, an alkynyl group, a hydroxy group, a cyano group, a nitro group, -NR 5 R 6 , -NHC(O)R 7 , -C(O)R 8 , -C(O)(CH2) q NR 9 R 10 , a cycloalkyl group, a heterocyclyl group, an aryloxy group, a heteroaryloxy group, an aryl group and a heteroaryl group, or R 1e and R 1ftogether form an oxo group, in which the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; G, R 2 ~R 10 , m, p and q are as defined in general formula (I).

[0032] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (III) or a medicamentable salt thereof is a compound represented by general formula (IIIC) or a medicamentable salt thereof: [ka] Among them, G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (III).

[0033] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (III) or a medicamentable salt thereof is a compound represented by general formula (IIID-1) or general formula (IIID-2) or a medicamentable salt thereof: [ka] Among them, G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (III).

[0034] In some embodiments of the present disclosure, the compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or a medicamentable salt thereof, wherein L 1 and L 2 are identical or different, and each independently represents an O atom, a S atom, or NR 1d and CR 1e R 1f Selected from L 3 and L 4 are each independently CR 1e R 1f and R 1d , R 1e and R 1f is as defined in general formula (III).

[0035] In some embodiments of the present disclosure, the compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or a medicamentable salt thereof, wherein L 1 is an O atom or NR 1d And L 2 , L 3 and L 4 are each independently CR 1e R 1f and R 1d , R 1e and R 1f is as defined in general formula (III).

[0036] In some embodiments of the present disclosure, the compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or a medicamentable salt thereof, wherein L 2 is an O atom or NR 1d And L 1 , L 3 and L 4 are each independently CR 1e R 1f and R 1d , R 1e and R 1f is as defined in general formula (III).

[0037] In some embodiments of the present disclosure, the compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or a medicamentable salt thereof, wherein L 3 is an O atom or NR 1d And L 1 , L 2 and L 4 are each independently CR 1e R 1f and R 1d , R 1e and R 1f is as defined in general formula (III).

[0038] In some embodiments of the present disclosure, the compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or a medicamentable salt thereof, wherein L 4 is an O atom or NR 1d And L 1 , L 2 and L 3 are each independently CR 1e R 1f and R 1d , R 1e and R 1f is as defined in general formula (III).

[0039] In some embodiments of the present disclosure, the compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or a medicamentable salt thereof, wherein L 1 and L 2 are both O atoms, and L 3 and L 4 are each independently CR 1e R 1f and R 1e and R 1f is as defined in general formula (III).

[0040] In some embodiments of the present disclosure, the compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or a medicamentable salt thereof, wherein L 1 , L 2 , L 3 and L 4 are each independently CR 1e R 1f and R 1e and R 1f is as defined in general formula (III).

[0041] In some embodiments of the present disclosure, the compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or a medicamentable salt thereof is [ka] teeth [ka] And L 1 and L 2 are identical or different, and each independently represents an O atom or a CR 1e R 1f and R 1e and R 1f is as defined in general formula (III), preferably [ka] teeth [ka] and R 1e and R 1f is as defined in general formula (III), more preferably [ka] teeth, [ka] Selected from.

[0042] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-4), general formula (IC), general formula (I-3C), general formula (I-4C), general formula (IIC), general formula (IIIC), general formula (II), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2) and general formula (III), or a medicamentable salt thereof, wherein each R 2 are identical or different, and each independently represents a hydrogen atom, a halogen atom, and C 1-6 alkyl group, preferably R 2 is a hydrogen atom.

[0043] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (IC), general formula (IIC), general formula (IIIC), general formula (II), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2) or general formula (III), or a medicamentable salt thereof, wherein each R 3 are the same or different, and each independently represents a halogen or C 1-6 is an alkyl group, preferably R 3 is halogen, more preferably R 3 is Cl.

[0044] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I-3), general formula (I-4), general formula (I-3C), or general formula (I-4C), or a medicamentable salt thereof, wherein each R 3a are the same or different, and each independently represents a halogen or C 1-6 is an alkyl group, preferably R 3a is halogen, more preferably R 3a is Cl.

[0045] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (IC), general formula (IIC), general formula (IIIC), general formula (II), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2) or general formula (III), or a medicamentable salt thereof, wherein each R 3 are the same or different, and each independently represents a halogen, C 1-6 Alkyl group, C 1-6 It is selected from an alkoxy group and a cyano group.

[0046] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (IC), general formula (IIC), general formula (IIIC), general formula (II), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2) or general formula (III), or a medicamentable salt thereof, wherein each R 3 are the same or different, and each independently represents a halogen, C 1-6 Alkyl group, C 1-6 is selected from an alkoxy group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, and a cyano group, and preferably each R 3 are identical or different and are each independently selected from Cl, Br, a methyl group, a methoxy group, a cyano group, a cyclopropyl group, a tetrahydropyranyl group and a dihydropyranyl group, more preferably each R 3 are the same or different, and each independently selected from Cl, a methyl group, a methoxy group, a cyano group, a cyclopropyl group and a tetrahydropyranyl group;

[0047] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I-3), general formula (I-4), general formula (I-3C), or general formula (I-4C), or a medicamentable salt thereof, wherein each R 3a are the same or different, and each independently represents a halogen, C 1-6 Alkyl group, C 1-6 It is selected from an alkoxy group and a cyano group.

[0048] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (IC), general formula (IIC), general formula (IIIC), general formula (II), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2) or general formula (III), or a medicamentable salt thereof, wherein p is 2, 3 or 4, and two adjacent R 3 forms a cycloalkyl group or a heterocyclyl group together with a carbon atom on the benzene ring to which it is linked, and the cycloalkyl group or the heterocyclyl group is each independently and optionally substituted with one or more identical or different substituents selected from a halogen, a hydroxy group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyano group, and preferably p is 3.

[0049] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-4), general formula (IC), general formula (I-3C), general formula (I-4C), general formula (IIC), general formula (IIIC), general formula (II), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2) or general formula (III), or a medicamentable salt thereof, wherein m is 0.

[0050] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (IC), general formula (IIC), general formula (IIIC), general formula (II), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2) or general formula (III), or a medicamentable salt thereof, wherein p is 1 or 2.

[0051] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (IC), general formula (IIC), general formula (IIIC), general formula (II), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2) or general formula (III), or a medicamentable salt thereof, wherein p is 3.

[0052] In some embodiments of the present disclosure, the compound is represented by the above general formula (I-3), general formula (I-3C), general formula (I-4C), or general formula (I-4), or a medicamentable salt thereof, wherein r is 1 or 0.

[0053] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (II), general formula (IIC), general formula (IID-1), general formula (IID-2), general formula (III), general formula (IIIC), general formula (IIID-1), general formula (IIID-2), or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 3v , R 3w , R 3x and R 3y are the same or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; or R 3v , R 3w , R 3x and R 3ytwo adjacent ones of these form a cycloalkyl group or a heterocyclyl group together with the carbon atom to which they are linked, and the cycloalkyl group or the heterocyclyl group is independently and optionally substituted with one or more identical or different substituents selected from halogen, hydroxy group, carboxy group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group and cyano group, with the proviso that R 3v , R 3w , R 3x and R 3y are hydrogen atoms when different, preferably [ka] teeth [ka] and R 3v is a halogen, and R 3w , R 3x and R 3y are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 haloalkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl groups, or R 3w , R 3x forms a 3- to 8-membered cycloalkyl group together with the carbon atom to which it is linked, and more preferably [ka] teeth [ka] and R 3v is a halogen, and R 3w , R 3x and R 3y are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C1-6 It is selected from a haloalkoxy group, a cyano group, a 3- to 6-membered cycloalkyl group and a 3- to 6-membered heterocyclyl group.

[0054] In some embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (II), general formula (IIC), general formula (IID-1), general formula (IID-2), general formula (III), general formula (IIIC), general formula (IIID-1), general formula (IIID-2), or a medicamentable salt thereof, [ka] but [ka] If R 3v is Cl.

[0055] In some embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (II), general formula (IIC), general formula (IID-1), general formula (IID-2), general formula (III), general formula (IIIC), general formula (IIID-1), general formula (IIID-2), or a medicamentable salt thereof, [ka] but [ka] If R 3w , R 3x and R 3y are identical or different and are each independently selected from a hydrogen atom, Cl, Br, a methyl group, a methoxy group, a cyano group, a cyclopropyl group, a tetrahydropyranyl group and a dihydropyranyl group, more preferably R 3w , R 3x and R 3yare the same or different, and each independently selected from a hydrogen atom, Cl, a methyl group, a methoxy group, a cyano group, a cyclopropyl group and a tetrahydropyranyl group.

[0056] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof is a compound represented by general formula (II-1) or a medicamentable salt thereof: [ka] Among them, G, R 3 , R 4 , G 1 , G 2 , R 1b and R 1c is as defined in general formula (II).

[0057] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (II) or general formula (II-1) or a medicamentable salt thereof is a compound represented by general formula (II-1C) or a medicamentable salt thereof: [ka] Among them, G, G 1 , G 2 , R 3 , R 1b and R 1c is as defined in general formula (II-1), In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II-1) or (II-1C) or a medicamentable salt thereof, wherein 1 and G 2 are identical or different, and each independently represents an O atom, NR 1a and CR 1b R 1c Selected from R 1a , R 1b and R 1c is as defined in general formula (II).

[0058] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II-1) or (II-1C) or a medicamentable salt thereof, wherein 1 is an O atom or NR 1a and G 2 is CR 1b R 1c Or, G 2 is an O atom or NR 1a and G 1 is CR 1b R 1c and R 1a , R 1b and R 1c is as defined in general formula (II).

[0059] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II-1) or (II-1C) or a medicamentable salt thereof, wherein 1 and G 2 are both O atoms.

[0060] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (III) or a medicamentable salt thereof is a compound represented by general formula (III-1) or a medicamentable salt thereof: [ka] Among them, G, R 3 , R 4 , L 1 , L 2 , R 1e and R 1f is as defined in general formula (III).

[0061] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (III) or general formula (III-1) or a medicamentable salt thereof is a compound represented by general formula (III-1C) or a medicamentable salt thereof: [ka] Among them, G, L 1 , L 2 , R 3 , R 1e and R 1f is as defined in general formula (III-1).

[0062] In some embodiments of the present disclosure, the compound represented by the above general formula (III-1) or general formula (III-1C) or a medicamentable salt thereof, wherein L 1 and L 2 are identical or different, and each independently represents an O atom, NR 1d and CR 1e R 1f Selected from R 1d , R 1e and R 1f is as defined in general formula (III).

[0063] In some embodiments of the present disclosure, the compound represented by the above general formula (III-1) or general formula (III-1C) or a medicamentable salt thereof, wherein L 1 is an O atom or NR 1d And L 2 is CR 1e R 1f Or, L 2 is an O atom or NR 1d And L 1 is CR 1e R 1f and R 1d , R 1e and R 1f is as defined in general formula (III).

[0064] In some embodiments of the present disclosure, the compound represented by the above general formula (III-1) or general formula (III-1C) or a medicamentable salt thereof, wherein L 1 and L 2 are both O atoms.

[0065] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (II-1), general formula (II-1C), general formula (III-1), or general formula (III-1C), or a medicamentable salt thereof, wherein R 3 is halogen, C 1-6 Alkyl group, C 1-6 It is selected from an alkoxy group and a cyano group.

[0066] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (II-1), general formula (II-1C), general formula (III-1), or general formula (III-1C), or a medicamentable salt thereof, wherein R 3 is halogen or C 1-6 is an alkyl group, preferably R 3 is a halogen, more preferably Cl.

[0067] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (I-3), general formula (I-4), general formula (II), general formula (II-1), general formula (III) or general formula (III-1) or a medicamentable salt thereof, wherein R 4 is a hydrogen atom or a 3- to 8-membered heterocyclyl group, and the 3- to 8-membered heterocyclyl group is substituted with one or more identical or different substituents selected from a hydroxy group and a carboxy group, and preferably, R 4 teeth [ka] or [ka] It is.

[0068] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (I-3), general formula (I-4), general formula (II), general formula (II-1), general formula (III) or general formula (III-1) or a medicamentable salt thereof, wherein R 4 is a hydrogen atom.

[0069] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1) or general formula (III-1C), or a medicamentable salt thereof, wherein R 1a or R 1d is a hydrogen atom, C 1-6 Alkyl groups and -C(O)R 8 Selected from R 8 is C 1-6 is an alkyl group, preferably R 1a and R 1d are the same or different and each independently represents a methyl group or an acetyl group.

[0070] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1) or general formula (III-1C), or a medicamentable salt thereof, wherein R 1b and R 1c or R 1e and R 1f are identical or different, and each independently represents a hydrogen atom, a deuterium atom, a halogen atom, and C 1-6 alkyl group, preferably R 1b and R 1c or R 1e and R 1f are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a fluorine atom, and a methyl group.

[0071] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1) or general formula (III-1C), or a medicamentable salt thereof, wherein R 1b and R 1c or R 1e and R 1f are identical or different, and each independently represents a hydrogen atom, a halogen atom, and C 1-6 alkyl group, preferably R 1e is a hydrogen atom or a halogen atom, and R 1f is a hydrogen atom or a halogen.

[0072] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1) or general formula (III-1C) or a medicamentable salt thereof, wherein G is CR 2a and R 2a is as defined in general formula (I).

[0073] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1) or general formula (III-1C), or a medicamentable salt thereof, wherein R 2aare hydrogen atoms, halogens and C 1-6 alkyl group, preferably R 2a is a hydrogen atom.

[0074] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein ring A is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclyl group, and G is an N atom or a CR 2a and R 2a are hydrogen atoms, halogens and C 1-6 alkyl groups, each R 1 are identical or different and each independently represents a hydrogen atom, a deuterium atom, a halogen, -C(O)R 8 , C 1-6 Alkyl group, C 1-6 selected from an alkoxy group and an oxo group; R 8 is C 1-6 is an alkyl group, n is 0 (i.e., R 1 is a hydrogen atom), 1, 2, 3 or 4, and each R 2 are identical or different, and each independently represents a hydrogen atom, a halogen atom, and C 1-6 alkyl group, m is 0 (i.e., R 2 is a hydrogen atom), 1 or 2, and each R 3 are the same or different, and each independently represents a halogen, C 1-6 Alkyl group, C 1-6 alkoxy and cyano, p is 1, 2 or 3, R 4 is a hydrogen atom or a 3- to 8-membered heterocyclyl group, and the 3- to 8-membered heterocyclyl group is substituted with one or more identical or different substituents selected from a hydroxy group and a carboxy group.

[0075] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein ring A is a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group, and G is CR 2a and R 2a is a hydrogen atom, and each R 1are identical or different and each independently represents a hydrogen atom, a deuterium atom, a halogen, -C(O)R 8 , C 1-6 Alkyl groups and C 1-6 alkoxy groups, R 8 is C 1-6 is an alkyl group, n is 0 (i.e., R 1 is a hydrogen atom), 1, 2, 3 or 4, and each R 2 is a hydrogen atom, and each R 3 are the same or different, and each independently represents a halogen, C 1-6 Alkyl group, C 1-6 alkoxy and cyano, p is 1, 2 or 3, R 4 is a hydrogen atom or a 3- to 8-membered heterocyclyl group, and the 3- to 8-membered heterocyclyl group is substituted with one or more identical or different substituents selected from a hydroxy group and a carboxy group.

[0076] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] Selected from R 1a is a hydrogen atom, C 1-6 Alkyl groups and -C(O)R 8 Selected from R 8 is C 1-6 is an alkyl group, R 1b and R 1c are identical or different, and each independently represents a hydrogen atom, a deuterium atom, a halogen atom, and C 1-6 alkyl group, G is a N atom or CR 2a and R 2a is a hydrogen atom, m is 0, [ka] teeth [ka] and R 3v is a halogen, and R 3w , R 3x and R 3y are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 haloalkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl groups, or R 3w , R 3x forms a 3- to 8-membered cycloalkyl group together with the carbon atom to which it is linked, and R 4 is a hydrogen atom or a 3- to 8-membered heterocyclyl group, and the 3- to 8-membered heterocyclyl group is substituted with one or more identical or different substituents selected from a hydroxy group and a carboxy group.

[0077] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (III) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 1e and R 1f are identical or different, and each independently represents a hydrogen atom, a deuterium atom, a halogen atom, and C 1-6 alkyl group, G is a N atom or CR 2a and R 2a is a hydrogen atom, m is 0, [ka] teeth [ka] and R 3v is a halogen, and R 3w , R 3x and R3y are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 R is selected from a haloalkoxy group, a cyano group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group; 4 is a hydrogen atom or a 3- to 8-membered heterocyclyl group, and the 3- to 8-membered heterocyclyl group is substituted with one or more identical or different substituents selected from a hydroxy group and a carboxy group.

[0078] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I-3) or general formula (I-4) or a medicamentable salt thereof, wherein ring B is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclyl group, ring A is a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group, and G is CR 2a and R 2a is a hydrogen atom, and each R 1 are identical or different and each independently represents a hydrogen atom, a deuterium atom, a halogen, -C(O)R 8 , C 1-6 Alkyl groups and C 1-6 alkoxy groups, R 8 is C 1-6 is an alkyl group, n is 0 (i.e., R 1 is a hydrogen atom), 1, 2, 3 or 4; R 2 is a hydrogen atom, and each R 3a are the same or different, and each independently represents a halogen, C 1-6 Alkyl group, C 1-6 alkoxy and cyano, r is 0, 1 or 2, R 4 is a hydrogen atom or a 3- to 8-membered heterocyclyl group, and the 3- to 8-membered heterocyclyl group is substituted with one or more identical or different substituents selected from a hydroxy group and a carboxy group.

[0079] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0080] Another aspect of the present disclosure relates to a compound represented by the general formula (I-1C) or (I-2C) or a salt thereof: [ka] Among them, R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, Ring A, G, R 1 ~R 3 , m, n and p are as defined in general formula (I).

[0081] Another aspect of the present disclosure relates to a compound represented by general formula (IID-1A) or (IID-2A) or a salt thereof: [ka] Among them, R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6is an alkyl group, R 11 is C 1-6 is an alkyl group, Ring A, G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (II).

[0082] Another aspect of the present disclosure relates to a compound represented by general formula (IIID-1A) or (IIID-2A) or a salt thereof: [ka] Among them, R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, Rings A, G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (III).

[0083] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I-1C), (I-2C), (IID-1A), (IID-2A), (IIID-1A) or (IIID-2A) or a medicamentable salt thereof, wherein R is C 1-6 R is an alkyl group, preferably R is a methyl group.

[0084] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I-1C), (I-2C), (IID-1A), (IID-2A), (IIID-1A) or (IIID-2A) or a medicamentable salt thereof, wherein R 11 is C 1-6 is an alkyl group, preferably R 11is a methyl group.

[0085] [Table 2-1] [Table 2-2]

[0086] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I) or a medicamentable salt thereof, the method comprising: [ka] The compound of formula (IC) or a medicamentous salt thereof is represented by R 4’ After reacting with the -Y compound, R 4’ removing said protecting group to obtain a compound of general formula (I) or a medicamentable salt thereof, Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and Ring A, G, R 1 ~R 3 , m, n and p are as defined in general formula (I).

[0087] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IC) or a medicamentable salt thereof, the method comprising: [ka] reacting a compound of general formula (IA) or a salt thereof with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (IC) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; Ring A, G, R 1 ~R 3 , m, n and p are as defined in general formula (IC).

[0088] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a medicamentable salt thereof, the method comprising: [ka] The method comprises subjecting a compound of general formula (I-1C) or a salt thereof to an ester hydrolysis reaction to obtain a compound of general formula (I-1) or a medicamentable salt thereof, Among them, R and R 11 is as defined in general formula (I-1C), Ring A, G, R 1 ~R 3 , m, n and p are as defined in general formula (I-1).

[0089] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-2) or a medicamentable salt thereof, the method comprising: [ka] The method comprises subjecting a compound of general formula (I-2C) or a salt thereof to an ester hydrolysis reaction to obtain a compound of general formula (I-2) or a medicamentable salt thereof, Among them, R and R 11 is as defined in general formula (I-2C), Ring A, G, R 1 ~R 3 , m, n and p are as defined in general formula (I-2).

[0090] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-3) or a medicamentable salt thereof, the method comprising: [ka] The compound of formula (I-3C) or a medicamentous salt thereof is represented by R 4’ After reacting with the -Y compound, R 4’ and removing the protecting group to obtain a compound of general formula (I-3) or a medicamentable salt thereof, Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and Ring A, Ring B, G, R 1 , R 2 , R 3a , m, n and r are as defined in general formula (I-3).

[0091] Another aspect of the present disclosure relates to a method for preparing a compound of formula (I-3C) or a medicamentable salt thereof, the method comprising: [ka] reacting a compound of general formula (I-3A) or a salt thereof with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (I-3C) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; Ring A, Ring B, G, R 1 , R 2 , R 3a , m, n and r are as defined in general formula (I-3C).

[0092] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-4) or a medicamentable salt thereof, the method comprising: [ka] The compound of formula (I-4C) or a medicamentous salt thereof is represented by R 4’ After reacting with the -Y compound, R 4’ and removing the protecting group to obtain a compound of general formula (I-4) or a medicamentable salt thereof, Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and Ring A, Ring B, G, R 1 , R 2 , R 3a , m, n and r are as defined in general formula (I-4).

[0093] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I-4C) or a medicamentable salt thereof, the method comprising: [ka] reacting a compound of general formula (I-4A) or a salt thereof with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (I-4C) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; Ring A, Ring B, G, R 1 , R 2 , R 3a , m, n and r are as defined in general formula (I-4C).

[0094] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (II) or a medicamentable salt thereof, the method comprising: [ka] The compound of formula (IIC) or a medicamentous salt thereof is represented by R 4’ After reacting with the -Y compound, R 4’ removing the protecting group above to obtain a compound of general formula (II) or a medicamentable salt thereof, Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and G, G 1 , G 2 , G3 , R 2 , R 3 , m and p are as defined in general formula (II).

[0095] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IIC) or a medicamentable salt thereof, the method comprising: [ka] reacting a compound of general formula (IA) or a salt thereof with a compound of general formula (IIB) or a salt thereof to obtain a compound of general formula (IIC) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (IIC).

[0096] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IID-1) or a medicamentable salt thereof, the method comprising: [ka] The method comprises subjecting a compound of general formula (IID-1A) or a salt thereof to an ester hydrolysis reaction to obtain a compound of general formula (IID-1) or a medicamentable salt thereof, Among them, R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (IID-1).

[0097] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IID-2) or a medicamentable salt thereof, the method comprising: [ka] The method comprises subjecting a compound of general formula (IID-2A) or a salt thereof to an ester hydrolysis reaction to obtain a compound of general formula (IID-2) or a medicamentable salt thereof, Among them, R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (IID-2).

[0098] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a medicamentable salt thereof, the method comprising: [ka] The compound of formula (II-1C) or a medicamentous salt thereof is represented by R 4’ After reacting with the -Y compound, R 4’ removing the protecting group to obtain a compound of general formula (II-1) or a medicamentable salt thereof; Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and G, G 1 , G 2 , R 1b , R 1c and R 3 is as defined in general formula (II-1), preferably R 3 is a halogen.

[0099] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1C) or a medicamentable salt thereof, the method comprising: [ka] reacting a compound of general formula (II-1A) or a salt thereof with a compound of general formula (II-1B) or a salt thereof to obtain a compound of general formula (II-1C) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; G, G 1 , G 2 , R 1b , R 1c and R 3 is as defined in general formula (II-1C), preferably R 3 is a halogen.

[0100] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (III) or a medicamentable salt thereof, the method comprising: [ka] The compound of formula (IIIC) or a medicamentous salt thereof is represented by R 4’After reacting with the -Y compound, R 4’ removing the protecting group above to obtain a compound of general formula (III) or a medicamentable salt thereof, Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (III).

[0101] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IIIC) or a medicamentable salt thereof, the method comprising: [ka] reacting a compound of general formula (IA) or a salt thereof with a compound of general formula (IIIB) or a salt thereof to obtain a compound of general formula (IIIC) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3, m and p are as defined in general formula (IIIC).

[0102] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IIID-1) or a medicamentable salt thereof, the method comprising: [ka] The method comprises subjecting a compound of general formula (IIID-1A) or a salt thereof to an ester hydrolysis reaction to obtain a compound of general formula (IIID-1) or a medicamentable salt thereof, Among them, R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (IIID-1).

[0103] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IIID-2) or a medicamentable salt thereof, the method comprising: [ka] The method comprises subjecting a compound of general formula (IIID-2A) or a salt thereof to an ester hydrolysis reaction to obtain a compound of general formula (IIID-2) or a medicamentable salt thereof, Among them, R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, G, L 1 , L 2, L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (IIID-2).

[0104] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (III-1) or a medicamentable salt thereof, the method comprising: [ka] The compound of general formula (III-1C) or a medicamentous salt thereof is represented by R 4’ After reacting with the -Y compound, R 4’ removing the protecting group to obtain a compound of general formula (III-1) or a medicamentable salt thereof, Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and G, L 1 , L 2 , R 1e , R 1f and R 3 is as defined in general formula (III-1), preferably R 3 is a halogen.

[0105] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (III-1C) or a medicamentable salt thereof, the method comprising: [ka] reacting a compound of general formula (II-1A) or a salt thereof with a compound of general formula (III-1B) or a salt thereof to obtain a compound of general formula (III-1C) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; G, L 1 , L 2 , R 1e , R 1f and R 3 is as defined in general formula (III-1C), preferably R 3 is a halogen.

[0106] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure as set forth in general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicamentable salt thereof, and one or more pharma- ceutically acceptable vectors, diluents or excipients.

[0107] The present disclosure further relates to the use of a compound as set forth in general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicament salt thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament for modulating miRNA levels, preferably wherein said miRNA is miR-124.

[0108] The present disclosure further relates to the use of a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament for treating a disease or condition ameliorated by modulation of miRNA levels.

[0109] The present disclosure further relates to the use of a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicament salt thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament for treating and / or preventing a disease or condition, wherein said disease or condition is selected from viral infection, inflammation and cancer.

[0110] The present disclosure further relates to the use of a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament for treating and / or preventing AIDS or a condition related to AIDS or human immunodeficiency virus (HIV).

[0111] The present disclosure further relates to the use of a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (IIID-3), general formula (IIID-4), general formula (IIID-5), general formula (IIID-6), general formula (IIID-7), general formula (IIID-8), general formula (IIID-9), general formula (IIID-10), general formula (IIID-11), general formula (IIID-12), general formula (IIID-13), general formula (IIID-14), general formula (IIID-15), general formula (IIID-16), general formula (IIID-17), general formula (IIID-18), general formula (IIID-19), general formula (IIID-21), general formula (IIID-22), general formula (IIID-23), general formula (IIID-24), general formula (IIID-25), general formula (IIID-26), general formula (IIID-27), general formula (IIID-28), general formula (IIID-29 ... In the present invention, the use of the compound of formula (III-1C), formula (III-1) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is inflammation, and the inflammation is selected from inflammatory diseases associated with autoimmunity, inflammatory diseases in the central nervous system (CNS), inflammatory diseases in the joints, inflammatory diseases in the gastrointestinal tract, inflammatory diseases in the skin, other inflammatory diseases associated with epithelial cells, inflammation associated with cancer, inflammation associated with irritation, and inflammation associated with injury.

[0112] The present disclosure further relates to compounds of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1 ... ) and a compound shown in Table A or a medicament salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is selected from viral infection, inflammation and cancer, wherein the inflammation is selected from inflammation associated with inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma, and colon cancer, preferably the inflammation is inflammatory bowel disease.

[0113] The present disclosure further relates to the use of a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicament comprising the same, in the preparation of a medicament for treating and / or preventing a disease or condition, The condition is cancer, and the cancer is selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, neurilemmoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, childhood tumors, urothelial carcinoma, ureteral tumor, thyroid cancer, osteoma, neuroblastoma, brain tumor, and myeloma.

[0114] The present disclosure further relates to a method of modulating miRNA levels comprising administering to a patient in need thereof a therapeutically effective amount of a compound as set forth in general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising same, wherein preferably said miRNA is miR-124.

[0115] The present disclosure further relates to a method of treating and / or preventing a disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III- 1C), comprising administering a compound of formula (III-1) and shown in Table A or a medicamentous salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is selected from viral infection, inflammation and cancer, and the inflammation is preferably selected from autoimmune-related inflammatory diseases, inflammatory diseases in the central nervous system (CNS), inflammatory diseases in the joints, inflammatory diseases in the gastrointestinal tract, inflammatory diseases in the skin, other inflammatory diseases associated with epithelial cells, cancer-related inflammation, irritation-related inflammation, and injury-related inflammation.

[0116] The present disclosure further relates to compounds of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1 ... ) and a compound shown in Table A or a medicament salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is selected from viral infection, inflammation and cancer, wherein the inflammation is selected from inflammation associated with inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma, and colon cancer, preferably the inflammation is inflammatory bowel disease.

[0117] The present disclosure further relates to a method for treating and / or preventing a disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising same, wherein the method is for treating and / or preventing a disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3C), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a pharmaceutical salt thereof, or a pharmaceutical composition comprising same, Or the disease state is selected from viral infection, inflammation and cancer, and the cancer is selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, The cancer is selected from bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, rectal cancer, small intestine cancer, gallbladder cancer, childhood tumors, urothelial carcinoma, ureteral tumor, thyroid cancer, osteoma, neuroblastoma, brain tumor and myeloma.

[0118] The present disclosure further relates to a method for treating and / or preventing a disease or condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising same, wherein said disease or condition is selected from AIDS or AIDS-related conditions and human immunodeficiency virus (HIV).

[0119] The present disclosure further relates to a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising same, for use as a medicament.

[0120] The present disclosure further relates to a compound as set forth in general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising the same, for use in regulating miRNA, preferably said miRNA is miR-124.

[0121] The present disclosure further relates to compounds of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (IIIC ... The present invention relates to a compound of general formula (III-1) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is selected from viral infection, inflammation and cancer, and the inflammation is preferably selected from autoimmune-related inflammatory diseases, inflammatory diseases in the central nervous system (CNS), inflammatory diseases in the joints, inflammatory diseases in the gastrointestinal tract, inflammatory diseases in the skin, other inflammatory diseases associated with epithelial cells, cancer-related inflammation, irritation-related inflammation, and injury-related inflammation.

[0122] The present disclosure further relates to compounds of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1), general formula (III-2), general formula (III-1 ... and a compound as set forth in Table A or a medicament salt thereof, or a pharmaceutical composition comprising same, wherein the disease or condition is selected from viral infection, inflammation and cancer, wherein the inflammation is selected from inflammation associated with inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma, and colon cancer, preferably the inflammation is inflammatory bowel disease.

[0123] The present disclosure further relates to compounds of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IID-3), general formula (IID-4), general formula (IID-5), general formula (IID-6), general formula (IID-7), general formula (IID-8), general formula (IID-9), general formula (IID-10), general formula (IID-11), general formula (IID-12), general formula (IID-13), general formula (IID-14), general formula (IID-15), general formula (IID-16), general formula (IID-17), general formula (IID-18), general formula (IID-19), general formula (IID-20), general formula (IID-21), general formula (IID-22), general formula (IID-23), general formula (IID-24), general formula (IID-25), general formula (IID-26), general formula (IID-27), general formula (IID-28), general formula (IID-29), general formula (IID-30), general formula (IID-31), general formula (IID-32), general formula (IID-33), general formula (IID-34), general formula (IID-35), general formula (IID-36), general formula (IID-37), general formula (IID-38), general formula (IID-39), general formula (IID-39), general formula (IID-39), general formula (IID-31), general formula (IID-32), general formula (IID-33), general formula (IID-34), general formula (IID-35), general formula (IID-35), general formula (I The present invention relates to a compound as set forth in formula (IID-1), formula (IIID-2), formula (IIIC), formula (III-1C), formula (III-1) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition containing the same, wherein the disease or condition is selected from viral infection, inflammation and cancer, wherein the inflammation is inflammatory bowel disease, wherein the inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).

[0124] The present disclosure further relates to a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing a disease or condition, wherein the disease or condition is selected from the group consisting of a viral infection, The cancer is selected from inflammation and cancer, the cancer being selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, bladder cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, neurilemmoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, childhood tumors, urothelial carcinoma, ureteral tumor, thyroid cancer, osteoma, neuroblastoma, brain tumor and myeloma.

[0125] The present disclosure further relates to a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising same, for use in treating and / or preventing AIDS or a condition related to AIDS or human immunodeficiency virus (HIV).

[0126] The disease or condition according to the present disclosure is a disease or condition that is treated and / or prevented by modulating miRNA levels, preferably said miRNA is miR-124.

[0127] Preferably, the viral infection according to the present disclosure is a retroviral infection.

[0128] Preferably, the inflammatory bowel disease according to the present disclosure is ulcerative colitis (UC) or Crohn's disease (CD).

[0129] Preferably, the lymphoma described in the present disclosure is Hodgkin's disease or non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma), the liver cancer is preferably hepatocellular carcinoma, the lung cancer (also called bronchiolocardiac cancer) is selected from non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma) and small cell lung cancer (SCLC), the kidney cancer is selected from renal cell carcinoma, clear cell and renal eosinophilic granular cell tumor, and the leukemia is selected from chronic leukemia, chronic myeloid ... The cancer is preferably selected from lymphocytic leukemia (CLL), chronic granulocytic leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML); the skin cancer is preferably selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma; the myeloma is preferably multiple myeloma; the colorectal cancer is preferably colon cancer or rectal cancer; and the glioma (i.e. glioma or spongioblastoma) is preferably selected from glioblastoma, astrocytoma and oligodendroglioma.

[0130] The active compound can be prepared in a suitable form for administration by any suitable route, and the composition of the present disclosure can be prepared by one or more pharma- ceutically acceptable vectors in a conventional manner.Accordingly, the active compound of the present disclosure can be prepared in various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration.The compound of the present disclosure can be prepared in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injection solutions, dispersible powders or granules, suppositories, tablets or syrups.

[0131] As a general guideline, it is preferred that the active compound be in a unit dose form or in a form that the patient can self-administer as a single agent. The unit dose of the compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled liquid, drug powder, granule, topical tablet, suppository, reconstituted powder or liquid formulation. A suitable unit dose may be 0.1 to 1000 mg.

[0132] The pharmaceutical composition according to the present disclosure may contain one or more additives in addition to the active compound, and the additives are selected from components such as fillers (diluents), binders, wetting agents, disintegrants, or excipients. The composition may contain 0.1 to 99% by weight of the active compound, depending on the method of administration.

[0133] The tablets contain the active ingredient and non-toxic medicamentous excipients suitable for mixing in the preparation of tablets. These excipients may be inert diluents, granulating agents, disintegrating agents, binding agents and lubricants. The tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over an extended period of time.

[0134] Oral formulations may be provided by soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or with a water-soluble vector or oil-based solvent.

[0135] Aqueous suspensions contain the active substances and mixing excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0136] Oil suspensions can be prepared by suspending the active ingredient in vegetable oil or mineral oil.Oil suspensions can also contain thickening agents.In order to provide a palatable preparation, the above-mentioned sweeteners and flavorings can also be added.These compositions can be preserved by adding antioxidants.

[0137] The pharmaceutical compositions according to the present disclosure may be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may contain sweeteners, flavoring agents, preservatives and antioxidants. Such formulations may also contain demulcents, preservatives, coloring agents and antioxidants.

[0138] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or vehicles that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injectable solution or microemulsion can be injected into the patient's bloodstream by local injection of large amounts. Alternatively, it is preferable to administer the solutions and microemulsions in a manner that allows a constant cyclic concentration of the compounds of the present disclosure to be maintained. A continuous intravenous administration device can be used to maintain such a constant concentration. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

[0139] The pharmaceutical composition according to the present disclosure may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be prepared according to known techniques using the above-mentioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension prepared in a non-toxic diluent or solvent that is parenterally acceptable. Sterile fixed oils may also be conveniently used as a solvent or suspension medium. Any fixed oil for formulation may be used for this purpose. Fatty acids may also be used to prepare an injectable.

[0140] The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum, and therefore melts in the rectum to release the drug.

[0141] The compounds of the present disclosure can be administered by adding water to prepare dispersible powders and granules in aqueous suspension. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, and one or more preservatives.

[0142] As is well known to those skilled in the art, the dosage of a drug depends on many factors, including but not limited to the activity of the specific compound used, the patient's age, the patient's weight, the patient's physical condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the composition of the drug, the severity of the disease, etc., and the optimal treatment method, such as the treatment mode, the daily dosage of the compound or the type of medicinal salt, can be verified according to conventional treatment plans.

[0143] Explanation of terms Unless specifically stated to the contrary, terms used in the specification and claims have the following meanings.

[0144] The term "alkyl group" refers to a saturated, straight or branched chain aliphatic hydrocarbon group that is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 1-12 alkyl group), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 7-methylhexyl, 8-methylhexyl, 9-methylhexyl, 10-methylhexyl, 11-methylhexyl, 12-methylhexyl, 13-methylhexyl, 14-methylhexyl, 15-methylhexyl, 16-methylhexyl, 17-methylhexyl, 18-methylhexyl, 19-methylhexyl, 20-methylhexyl, 21-methylhexyl, 22-methylhexyl, 23-methylhexyl, 24-methylhexyl, 25-methylhexyl, 26-methylhexyl, 27-methylhexyl, 28-methylhexyl, 29-methylhexyl, 30-methylhexyl, 31-methylhexyl, 32-methylhexyl, 33-methylhexyl, 34-methylhexyl, 35-methylhexyl, 36-methylhexyl, 37-methylhexyl, 38-methylhexyl, 39-methylhexyl, 40-methylhexyl, 41-methylhexyl, 42-methylhexyl, 43 hexyl group, 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, Examples of the alkyl group include 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available attachment point, and the substituent is preferably one or more selected from a deuterium atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxy group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0145] The term "alkylene group" refers to a saturated, straight or branched chain aliphatic hydrocarbon group, the residue derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane, and is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably containing from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 1-12 alkylene group), more preferably an alkylene group containing 1 to 6 carbon atoms (i.e., C 1-6 Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH)-, 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCHCH-), 1,4-butylene (-CHCHCHCHCH-), and the like. An alkylene group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and the substituents are preferably independently and optionally one or more selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo.

[0146] The term "alkenyl group" refers to an alkyl group compound containing at least one carbon-carbon double bond in the molecule, of which the definition of alkyl group is as above. The alkenyl group preferably contains 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably contains 2 to 6 carbon atoms (i.e., C 2-6The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more selected from an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxy group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0147] The term "alkynyl group" refers to an alkyl group compound containing at least one carbon-carbon triple bond in the molecule, of which alkyl group is defined as above. Preferably, the alkynyl group contains 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12 alkynyl groups), more preferably alkynyl groups containing 2 to 6 carbon atoms (i.e., C 2-6 The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more selected from an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxy 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.

[0148] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., 3 to 12-membered cycloalkyl group), preferably 3 to 8 carbon atoms (i.e., 3 to 8-membered cycloalkyl group), more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl group), and most preferably 5 or 6 carbon atoms (i.e., 5- or 6-membered cycloalkyl group). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, and polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups.

[0149] The term "spirocycloalkyl group" refers to a polycyclic group having 5 to 20 members, in which the monocyclic rings share one carbon atom (referred to as a spiro atom), which may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of spiro atoms shared between the rings, the spirocycloalkyl group is divided into a monospirocycloalkyl group or a polyspirocycloalkyl group (e.g., a bisspirocycloalkyl group), and is preferably a monospirocycloalkyl group and a bisspirocycloalkyl group. More preferably, it is a 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 4-membered, 6-membered / 5-membered or 6-membered / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes.

[0150] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares a pair of adjacent carbon atoms with another ring in the system, in which one or more rings may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of rings that constitute it, it can be divided into polycyclic fused cycloalkyl groups such as bicyclic, tricyclic and tetracyclic, and is preferably bicyclic or tricyclic, and more preferably 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 / 4-membered, 5-membered / 5-membered, 5-membered / 6-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 alkyl groups. Non-limiting examples of fused cycloalkyl groups are: [ka] Includes.

[0151] The term "bridged cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of rings that constitute it, it can be divided into polycyclic bridged cycloalkyl groups such as bicyclic, tricyclic and tetracyclic bridged cycloalkyl groups, and is preferably a bicyclic, tricyclic or tetracyclic bridged cycloalkyl group, and more preferably a bicyclic or tricyclic bridged cycloalkyl group. Non-limiting examples of bridged cycloalkyl groups are: [ka] The cycloalkyl rings include the above cycloalkyl groups (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, in which the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which are: [ka] and the like, preferably [ka] It is.

[0152] The cycloalkyl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and the substituents are preferably one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

[0153] The term "alkoxy group" refers to -O-(alkyl group), where alkyl group is defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy and butoxy groups. An alkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more selected from deuterium atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0154] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent containing 3 to 20 ring atoms, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be substituted with an oxo group (i.e., to form a sulfoxide or sulfone), but does not contain -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon. Preferably it contains 3 to 12 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g. 1, 2, 3, and 4) are heteroatoms (i.e. a 3- to 12-membered heterocyclyl group), more preferably it contains 3 to 8 (e.g. 3, 4, 5, 6, 7, and 8) ring atoms, of which 1 to 3 (e.g. 1, 2, and 3) are heteroatoms (i.e. a 3- to 8-membered heterocyclyl group), more preferably it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (i.e. a 3- to 6-membered heterocyclyl group), and most preferably it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e. a 5- or 6-membered heterocyclyl group). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyl groups include spiroheterocyclyl groups, fused heterocyclyl groups, and bridged heterocyclyl groups.

[0155] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which the monocyclic rings share one atom (called a spiro atom), in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of spiro atoms shared between the rings, the spiroheterocyclyl group is divided into a monospiroheterocyclyl group or a polyspiroheterocyclyl group (e.g., a bisspiroheterocyclyl group), and preferably a monospiroheterocyclyl group and a bisspiroheterocyclyl group. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, 5 / 6-membered or 6 / 6-membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

[0156] The term "fused heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more of the rings optionally containing one or more double bonds, in which one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon, preferably having 6 to 14 members, more preferably having 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of rings, the heterocyclyl group may be divided into polycyclic fused heterocyclyl groups such as bicyclic, tricyclic, and tetracyclic, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes.

[0157] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 14 members, in which any two rings share two atoms that are not directly connected, and may contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of rings that constitute it, it can be divided into polycyclic bridged heterocyclyl groups such as bicyclic, tricyclic and tetracyclic bridged heterocyclyl groups, and is preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclyl group, and more preferably a bicyclic or tricyclic bridged heterocyclyl group. Non-limiting examples of bridged heterocyclyl groups are: [ka] Includes.

[0158] The heterocyclyl rings include the above heterocyclyl groups (including monocyclic, spiro, fused and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring, in which the ring connected to the parent structure is a heterocyclyl group, non-limiting examples of which are: [ka] etc.

[0159] The heterocyclyl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and the substituents are preferably one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

[0160] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic (fused polycyclic rings are rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6-14 members, such as phenyl and naphthyl groups. The aryl rings include those fused to a heteroaryl, heterocyclyl or cycloalkyl ring, in which the ring connected to the parent structure is an aryl ring, non-limiting examples of which are: [ka] Includes.

[0161] The aryl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and the substituents are preferably one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

[0162] The term "heteroaryl group" refers to a heteroaromatic system containing 1-4 (e.g. 1, 2, 3, and 4) heteroatoms and 5-14 ring atoms, of which the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5-10 membered (e.g. 5, 6, 7, 8, 9, or 10 membered), more preferably 5 or 6 membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes the above heteroaryl group fused to an aryl group, heterocyclyl group, or cycloalkyl ring, of which the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which are: [ka] Includes.

[0163] The heteroaryl group may be substituted or unsubstituted and, if substituted, may be substituted at any available attachment point, and the substituents are preferably one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

[0164] The above cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom, or two hydrogen atoms from the same parent ring atom or two different ring atoms, i.e., "divalent cycloalkyl groups," "divalent heterocyclyl groups," "arylene groups," and "heteroarylene groups."

[0165] The term "amino-protecting group" refers to a group that protects an amino group with a group that is easily removable so that the amino group is not altered when other parts of the molecule react. Non-limiting examples include (trimethylsilicon)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl. These groups can be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, and nitro groups.

[0166] The term "hydroxy protecting group" refers to a hydroxy derivative that is commonly used to block or protect a hydroxy group, which reacts with other functional groups of a compound. By way of example, the hydroxy protecting group may preferably be a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilane group (TBS), a tert-butyldiphenylsilyl group, a methyl group, a tert-butyl group, an allyl group, a benzyl group, a methoxymethyl group (MOM), an ethoxyethyl group, a formyl group, a acetyl group, a benzoyl group, a p-nitrobenzoyl group, etc.

[0167] The term "cycloalkyloxy" refers to a cycloalkyl-O- group, in which the cycloalkyl group is as defined above.

[0168] The term "heterocyclyloxy" refers to a heterocyclyl-O- group, in which the heterocyclyl group is as defined above.

[0169] The term "aryloxy group" refers to an aryl-O- group, in which the aryl group is defined above.

[0170] The term "heteroaryloxy group" refers to a heteroaryl-O- group, in which the heteroaryl group is as defined above.

[0171] The term "alkylthio group" refers to an alkyl-S- group, in which the alkyl group is as defined above.

[0172] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0173] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0174] The term "deuterated alkyl group" refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

[0175] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined above.

[0176] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0177] The term "hydroxy group" refers to --OH.

[0178] The term "mercapto" refers to -SH.

[0179] The term "amino group" refers to -NH2.

[0180] The term "cyano" refers to -CN.

[0181] The term "nitro group" refers to --NO.sub.2.

[0182] The term "oxo group" or "oxo" refers to "=O".

[0183] The term "carbonyl group" refers to C=O.

[0184] The term "carboxy" refers to -C(O)OH.

[0185] The term "carboxylic acid ester group" refers to a -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are defined above.

[0186] The compounds of the present disclosure include their isotopic derivatives. The term "isotopic derivative" refers to a compound having a structure according to the present disclosure that differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure according to the present disclosure in which hydrogen has been replaced by "deuterium" or "tritium" or fluorine has been replaced by 18 F-fluorine labeling ( 18 F isotope) or carbon atoms are replaced by 11 C-, 13 C-, or 14 C-rich carbon ( 11 C-, 13 C- or 14 C-carbon label, 11 C-, 13 C- or 14Compounds in which the hydrogen atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds may be used, for example, as analytical tools or probes in biological measurements, or as imaging tracers for in vivo diagnosis of disease, or as tracers in pharmacodynamic, pharmacokinetic, or receptor studies. In the deuterated form of the compound, each available hydrogen atom connected to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound by referring to the relevant literature. The deuterated form of the compound may be prepared using commercially available deuterated starting materials, or may be synthesized by conventional techniques with deuterated reagents, including, but not limited to, deuterated borane, tritium borane tetrahydrofuran solution, lithium aluminum deuteride, deuterated iodoethane, deuterated iodomethane, and the like. Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuteration is at a certain site, may obtain better metabolic stability and some therapeutic advantages. Compared to non-deuterated drugs, deuterated drugs have the advantages of reducing toxicity and side effects, increasing drug stability, improving therapeutic efficacy, and extending the biological half-life of drugs. All isotopic variations of the compounds according to the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom may be independently replaced with a deuterium atom, where the deuterium replacement may be partial or complete, with partial deuterium replacement meaning that at least one hydrogen is replaced with at least one deuterium. When a position is specifically designated as deuterium (D), it should be understood that the position is deuterium (i.e., at least 15% deuterium incorporated) having an abundance at least 1000 times higher than the natural abundance of deuterium (which is 0.015%).In the examples, a compound having an abundance greater than the natural abundance of deuterium includes at least 1000 times the abundance of deuterium (i.e., at least 15% of deuterium is incorporated), at least 2000 times the abundance of deuterium (i.e., at least 30% of deuterium is incorporated), at least 3000 times the abundance of deuterium (i.e., at least 45% of deuterium is incorporated), at least 3340 times the abundance of deuterium (i.e., at least 50.1% of deuterium is incorporated), at least 3500 times the abundance of deuterium (i.e., at least 52.5% of deuterium is incorporated), at least 4000 times the abundance of deuterium (i.e., at least 60% of deuterium is incorporated), at least 4500 times the abundance of deuterium (i.e., at least 67.5% of deuterium is incorporated), and the like. deuterium may be at least 5000 times abundant (i.e., at least 75% of the deuterium are incorporated), at least 5500 times abundant (i.e., at least 82.5% of the deuterium are incorporated), at least 6000 times abundant (i.e., at least 90% of the deuterium are incorporated), at least 6333.3 times abundant (i.e., at least 95% of the deuterium are incorporated), at least 6466.7 times abundant (i.e., at least 97% of the deuterium are incorporated), at least 6600 times abundant (i.e., at least 99% of the deuterium are incorporated), at least 6633.3 times abundant (i.e., at least 99.5% of the deuterium are incorporated) or more abundant.

[0187] The compounds of the present disclosure may have specific stereoisomeric forms. The term "stereoisomer" refers to isomers that have the same structure but differ in the spatial arrangement of atoms. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in the compounds of the present disclosure may have other asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of the present disclosure. Both Z and E configurations are included for any carbon-carbon double bond, even if only one configuration is named. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. Single isomers of certain compounds of the present disclosure can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, or, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxy) functional group, by forming a diastereomeric salt with an appropriate optically active acid or base, and then performing diastereomeric resolution by conventional methods known in the art to obtain pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0188] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and in which the isomeric form is easily converted from one to the other. It includes all possible tautomers, i.e., exists in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include keto-enol, imine-enamine, lactam-lactim, etc. An example of a lactam-lactim equilibrium is as follows: [ka]

[0189] For example, reference to a pyrazolyl group should be understood to include any one or a mixture of the two tautomers of the following two structures: [ka]

[0190] All tautomeric forms are within the scope of the disclosure, and the naming of a compound does not exclude any tautomeric form.

[0191] In the chemical structures of the compounds described in this disclosure, [ka] indicates that the configuration is not specified, i.e., if chiral isomers are present in the chemical structure, [ka] The bond [ka] or [ka] The above two types of arrangements may be included at the same time.

[0192] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not. For example, "C optionally substituted with a halogen or cyano group" 1-6 By "alkyl group" is meant that a halogen or cyano group may or may not be present, and this description 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.

[0193] "Substituted" refers to one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in a group being independently replaced with a corresponding number of substituents. A person skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having a free hydrogen may be unstable if it is attached to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0194] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or their medicamentous salts or prodrugs with other chemical components, and other components such as pharmaceutical acceptable vectors and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredient to further exert biological activity.

[0195] "Pharmaceutical salt" refers to a salt of a compound according to the present disclosure, which may be selected from inorganic salts or organic salts. Such salts have the desired biological activity while being safe and effective when used in a mammalian body. The salts may be prepared separately during the final isolation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. In general, bases for forming pharmaceutical acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. In general, acids for forming pharmaceutical acceptable salts include inorganic acids and organic acids.

[0196] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a dose of the drug or agent sufficient to obtain or at least partially obtain a desired effect. The effective amount is determined by the person and depends on the age and general condition of the subject, and also on the specific active agent, and the appropriate effective amount for an individual can be determined by one skilled in the art through routine experimentation.

[0197] As used herein, the term "pharmacologically acceptable" means that these compounds, materials, compositions and / or dosage forms are, within the scope of reasonable medical judgment, applicable to contact with the tissues of a patient without undue toxicity, irritation, allergic response or other problem or complication, and are effective for the desired use, with a reasonable benefit / risk ratio.

[0198] As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly indicates otherwise.

[0199] The term "about" when applied to parameters such as pH, concentration, temperature, etc., indicates that the parameter may be varied within ±10%, and in some cases more preferably ±5%. As will be appreciated by those skilled in the art, when a parameter is not critical, generally numbers are given merely for illustration, not limitation.

[0200] Methods for synthesizing compounds according to the present disclosure In order to achieve the objectives of the present disclosure, the present disclosure adopts the following technical solutions:

[0201] Technical proposal 1 A process for preparing a compound of general formula (I) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The compound of formula (IC) or a medicamentous salt thereof is represented by R 4’ -Y compound and nucleophilic substitution reaction under basic conditions, followed by R 4’ removing said protecting group to obtain a compound of general formula (I) or a medicamentable salt thereof, Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and Ring A, G, R 1 ~R 3 , m, n and p are as defined in general formula (I).

[0202] Technical proposal 2 A process for preparing a compound of general formula (IC) or a medicamentable salt thereof according to the present disclosure, comprising: [ka] Aromatic nucleophilic substitution reaction of a compound of general formula (IA) or a salt thereof with a compound of general formula (IB) or a salt thereof, optionally under basic or acidic conditions, or a coupling reaction, optionally under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (IC) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; Ring A, G, R 1 ~R 3 , m, n and p are as defined in general formula (IC).

[0203] Technical proposal 3 A method for preparing a compound of general formula (I-1) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method includes the step of subjecting a compound of general formula (I-1C) or a salt thereof to an ester hydrolysis reaction under basic conditions to obtain a compound of general formula (I-1) or a medicamentable salt thereof, Among them, R and R 11 is as defined in general formula (I-1C), Ring A, G, R 1 ~R 3 , m, n and p are as defined in general formula (I-1).

[0204] Technical proposal 4 A method for preparing a compound of general formula (I-2) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method includes the step of subjecting a compound of general formula (I-2C) or a salt thereof to an ester hydrolysis reaction under basic conditions to obtain a compound of general formula (I-2) or a medicamentable salt thereof, Among them, R and R 11 are identical or different and are each independently selected from an alkyl group, a cycloalkyl group, or a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, Ring A, G, R 1 ~R 3 , m, n and p are as defined in general formula (I-2).

[0205] Technical proposal 5 A method for preparing a compound of general formula (I-3) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The compound of formula (I-3C) or a medicamentous salt thereof is represented by R 4’ -Y compound and nucleophilic substitution reaction under basic conditions, followed by R 4’ removing the protecting group above to obtain a compound of general formula (I-3) or a medicamentable salt thereof, Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and Ring A, Ring B, G, R 1 , R 2 , R 3a , n, m and r are as defined in general formula (I-3).

[0206] Technical plan 6 A method for preparing a compound of the present disclosure having general formula (I-3C) or a medicamentable salt thereof, comprising: [ka] A nucleophilic substitution reaction of a compound of general formula (I-3A) or a salt thereof with a compound of general formula (IB) or a salt thereof, optionally under basic or acidic conditions, or a coupling reaction, optionally under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (I-3C) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; Ring A, Ring B, G, R 1 , R 2 , R 3a , n, m and r are as defined in general formula (I-3C).

[0207] Technical proposal 7 A method for preparing a compound of general formula (I-4) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The compound of formula (I-4C) or a medicamentous salt thereof is represented by R 4’ -Y compound and nucleophilic substitution reaction under basic conditions, followed by R 4’ removing the protecting group above to obtain a compound of general formula (I-4) or a medicamentable salt thereof, Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and Ring A, Ring B, G, R 1 , R 2 , R 3a , n, m and r are as defined in general formula (I-4).

[0208] Technical proposal 8 A method for preparing a compound of the present disclosure having general formula (I-4C) or a medicamentable salt thereof, comprising: [ka] A nucleophilic substitution reaction of a compound of general formula (I-4A) or a salt thereof with a compound of general formula (IB) or a salt thereof, optionally under basic or acidic conditions, or a coupling reaction, optionally under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (I-4C) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; Ring A, Ring B, G, R 1 , R 2 , R 3a , n, m and r are as defined in general formula (I-4C).

[0209] Technical proposal 9 A method for preparing a compound of general formula (II) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The compound of formula (IIC) or a medicamentous salt thereof is represented by R 4’ -Y compound and nucleophilic substitution reaction under basic conditions, followed by R 4’ removing said protecting group to obtain a compound of general formula (II) or a medicamentable salt thereof, Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (II).

[0210] Technical proposal 10 A process for preparing a compound of general formula (IIC) or a medicamentable salt thereof according to the present disclosure, comprising: [ka] nucleophilic substitution reaction of a compound of general formula (IA) or a salt thereof with a compound of general formula (IIB) or a salt thereof, optionally under basic or acidic conditions, or a coupling reaction, optionally under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (IIC) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (IIC).

[0211] Technical proposal 11 A method for preparing a compound of general formula (IID-1) or a medicamentable salt thereof according to the present disclosure, comprising: [ka] The method comprises the steps of subjecting a compound of general formula (IID-1A) or a salt thereof to an ester hydrolysis reaction under basic conditions to obtain a compound of general formula (IID-1) or a medicamentable salt thereof, Among them, R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (IID-1).

[0212] Technical proposal 12 A method for preparing a compound of general formula (IID-2) or a medicamentable salt thereof according to the present disclosure, comprising: [ka] The method comprises the steps of subjecting a compound of general formula (IID-2A) or a salt thereof to an ester hydrolysis reaction under basic conditions to obtain a compound of general formula (IID-2) or a medicamentable salt thereof, Among them, R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, G, G 1 , G 2 , G 3 , R 2 , R 3 , m and p are as defined in general formula (IID-2).

[0213] Technical proposal 13 A method for preparing a compound of general formula (II-1) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The compound of formula (II-1C) or a medicamentous salt thereof is represented by R 4’ -Y compound and nucleophilic substitution reaction under basic conditions, followed by R 4’ removing the protecting group to obtain a compound of general formula (II-1) or a medicamentable salt thereof; Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and G, G 1 , G 2 , R 1b , R 1c and R 3 is as defined in general formula (II-1), preferably R 3 is a halogen.

[0214] Technical proposal 14 A method for preparing a compound of general formula (II-1C) or a medicamentable salt thereof according to the present disclosure, comprising: [ka] The method comprises the steps of subjecting a compound of general formula (II-1A) or a salt thereof to a nucleophilic substitution reaction, optionally under basic or acidic conditions, with a compound of general formula (II-1B) or a salt thereof, or a coupling reaction, optionally under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (II-1C) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; G, G 1 , G 2 , R 1b , R 1c and R 3 is as defined in general formula (II-1C), preferably R 3 is a halogen.

[0215] Technical proposal 15 A process for preparing a compound of general formula (III) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The compound of formula (IIIC) or a medicamentous salt thereof is represented by R 4’ -Y compound and nucleophilic substitution reaction under basic conditions, followed by R 4’ removing said protecting group to obtain a compound of general formula (III) or a medicamentable salt thereof, Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (III).

[0216] Technical proposal 16 A process for preparing a compound of general formula (IIIC) or a medicamentable salt thereof according to the present disclosure, comprising: [ka] A method for the preparation of a compound of general formula (IA) or a salt thereof, comprising the steps of: subjecting a compound of general formula (IA) or a salt thereof to a nucleophilic substitution reaction, optionally under basic or acidic conditions, or a coupling reaction, optionally under basic conditions and in the presence of a catalyst, with a compound of general formula (IIIB) or a salt thereof, to obtain a compound of general formula (IIIC) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (IIIC).

[0217] Technical proposal 17 A method for preparing a compound of general formula (IIID-1) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method includes the step of subjecting a compound of general formula (IIID-1A) or a salt thereof to an ester hydrolysis reaction under basic conditions to obtain a compound of general formula (IIID-1) or a medicamentable salt thereof, Among them, R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (IIID-1).

[0218] Technical proposal 18 [ka] The method comprises the steps of subjecting a compound of general formula (IIID-2A) or a salt thereof to an ester hydrolysis reaction under basic conditions to obtain a compound of general formula (IIID-2) or a medicamentable salt thereof, Among them, R and R 11are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , m and p are as defined in general formula (IIID-2).

[0219] Technical proposal 19 A method for preparing a compound of general formula (III-1) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The compound of general formula (III-1C) or a medicamentous salt thereof is represented by R 4’ -Y compound and nucleophilic substitution reaction under basic conditions, followed by R 4’ removing the protecting group to obtain a compound of general formula (III-1) or a medicamentable salt thereof; Among them, Y is a halogen atom, preferably a Br atom; R 4’ teeth [ka] and R and R 11 are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C 1-6 is an alkyl group, R 11 is C 1-6 is an alkyl group, R 4 teeth [ka] and G, L 1 , L 2, R 1e , R 1f and R 3 is as defined in general formula (III-1), preferably R 3 is a halogen.

[0220] Technical proposal 20 A method for preparing a compound of general formula (III-1C) or a medicamentable salt thereof according to the present disclosure, comprising: [ka] The method comprises the steps of subjecting a compound of general formula (II-1A) or a salt thereof to a nucleophilic substitution reaction, optionally under basic or acidic conditions, or a coupling reaction, optionally under basic conditions and in the presence of a catalyst, with a compound of general formula (III-1B) or a salt thereof to obtain a compound of general formula (III-1C) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; G, L 1 , L 2 , R 1e , R 1f and R 3 is as defined in general formula (III-1C), preferably R 3 is a halogen.

[0221] In the above synthesis technical solution, the reagents for providing the basic condition include organic bases and inorganic bases, the organic bases include, but are not limited to, triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, cadmium carbonate, potassium ... The reagent for providing basic conditions for the nucleophilic substitution reaction may include, but is not limited to, lithium hydroxide monohydrate, potassium carbonate, cesium carbonate, and cadmium carbonate, preferably, the reagent for providing basic conditions for the nucleophilic substitution reaction is selected from lithium hydroxide monohydrate, potassium carbonate, cesium carbonate, and cadmium carbonate, and in technical schemes 2, 6, 8, 10, 14, 16, and 20, the reagent for providing basic conditions for the nucleophilic substitution reaction is more preferably potassium carbonate or cesium carbonate, and in technical schemes 1, 5, 7, 9, 13, 15, and 19, the reagent for providing basic conditions for the nucleophilic substitution reaction is more preferably cadmium carbonate.

[0222] In the technical proposals 3, 4, 11, 12, 17 and 18, the reagent for the basic condition is preferably lithium hydroxide monohydrate, more preferably lithium hydroxide monohydrate and hydrogen peroxide.

[0223] In technical proposals 1, 5, 7, 9, 13, 15 and 19, 4’ The reagent providing basic conditions for the reaction to remove the above protecting group is preferably lithium hydroxide monohydrate, more preferably lithium hydroxide monohydrate and hydrogen peroxide.

[0224] In the above synthesis technique, the reagent for providing the acidic condition includes, but is not limited to, mellitic acid, nitrogen sulfosquaric acid, trichloroacetic acid, trinitrobenzenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid, and preferably, the reagent for providing the acidic condition is trifluoroacetic acid.

[0225] The ester hydrolysis reaction in the above synthesis scheme is preferably carried out under the conditions of lithium hydroxide monohydrate and hydrogen peroxide.

[0226] The catalysts described in the above synthesis technical proposal include tetrakis(triphenylphosphino)palladium, dichloropalladium, palladium acetate, methanesulfonate (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II), 1,1'-bis(diphenylphosphino)dichloroferrocene palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, Preferably, the catalyst is selected from (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, tris(dibenzylideneacetone)dipalladium and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, including but not limited to radium dichloromethane complex, tris(dibenzylideneacetone)dipalladium and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0227] The reaction of the above steps is preferably carried out in a solvent, and the solvents used include, but are not limited to, pyridine, 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. [Brief description of the drawings]

[0228] [Figure 1]The effect of Compound 1 of the present disclosure on the body weight of UC mice induced by dextran sulfate sodium (DSS), where #P<0.05 indicates that the model group has a significant difference compared to the normal control group, ##P<0.01 indicates that the model group has a large significant difference compared to the normal control group, ###P<0.001 indicates that the model group has a very large significant difference compared to the normal control group, *P<0.05 indicates that the administration group has a significant difference compared to the model group, **P<0.01 indicates that the administration group has a large significant difference compared to the model group, and ***P<0.001 indicates that the administration group has a very large significant difference compared to the model group. [Diagram 2] The effect of Compound 1 of the present disclosure on the colon length of UC mice induced by dextran sulfate sodium (DSS), where #P<0.05 indicates that the model group has a significant difference compared to the normal control group, ##P<0.01 indicates that the model group has a large significant difference compared to the normal control group, ###P<0.001 indicates that the model group has a very large significant difference compared to the normal control group, *P<0.05 indicates that the treatment group has a significant difference compared to the model group, **P<0.01 indicates that the treatment group has a large significant difference compared to the model group, and ***P<0.001 indicates that the treatment group has a very large significant difference compared to the model group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0229] 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.

[0230] Working Example The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are within the range of 10 -6The units are shown in ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer was used for the NMR measurements, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0231] For MS measurements, liquid chromatograph mass spectrometers Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (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), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q Exactive) were used.

[0232] For high performance liquid chromatography (HPLC) analysis, high performance liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 were used.

[0233] For chiral HPLC analysis, a high performance liquid chromatograph Agilent 1260 DAD was used.

[0234] For preparative high performance liquid chromatography, preparative chromatographs Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 were used.

[0235] For chiral separation, a preparative chromatograph Shimadzu LC-20AP was used.

[0236] Combiflash Rf200 (TELEDYNE ISCO) was used as the CombiFlash high-speed preparative chromatograph.

[0237] As the silica gel plate for thin layer chromatography, Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate is used, the specification of the silica gel plate used for thin layer chromatography (TLC) is 0.15-0.2 mm, and the specification for separating and purifying the product by thin layer chromatography is 0.4-0.5 mm.

[0238] For silica gel column chromatography, 200-300 mesh silica gel manufactured by Yantai Huanghai Silica Gel was generally used as the vector.

[0239] Kinase mean inhibition rate and IC 50 The values ​​were measured using a plate reader NovoStar (BMG, Germany).

[0240] Known starting materials according to the present disclosure may be synthesized by employing or following methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), Darui Chemical, etc.

[0241] In the examples, unless otherwise stated, all reactions can be carried out in an argon or nitrogen atmosphere.

[0242] An argon or nitrogen atmosphere refers to an argon or nitrogen balloon of approximately 1 L volume connected to the reaction flask.

[0243] Hydrogen atmosphere refers to a hydrogen balloon of approximately 1 L volume attached to the reaction flask.

[0244] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenation apparatus and a Seiran QL-500 hydrogen generator or an HC2-SS hydrogenation apparatus were used.

[0245] The hydrogenation reaction was generally carried out by repeating the process of evacuating and refilling with hydrogen three times.

[0246] A CEM Discover-S 908860 microwave reactor was used for microwave reactions.

[0247] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0248] In the examples, unless otherwise specified, the reaction temperature is room temperature, 20 to 30°C.

[0249] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The developing solvent used in the reaction, the eluent system of column chromatography for purifying the compound, and the developing solvent system of thin layer chromatography included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and the volume ratio of the solvents may be adjusted according to the polarity of the compound, or may be adjusted by adding a small amount of basic or acidic reagent such as triethylamine and acetic acid.

[0250] Example 1 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine 1 [ka] 2,8-Dichloroquinoline 1a (100mg, 0.51mmol, BiDe Pharmaceutical) and 5-amino-2,2-difluoro-1,3-benzo[1,3]dioxolane 1b (105mg, 0.61mmol, Shanghai Haohong) were dissolved in isopropanol (1mL), heated to 90℃ and reacted for 12 hours. After cooling to room temperature and filtering the reaction solution, it was separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 0.1% formic acid aqueous solution and acetonitrile, acetonitrile gradient: 65% to 85%, flow rate: 30mL / min) to obtain the title compound 1 (150mg, yield 89%). MS m / z (ESI): 335.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.88 (d, 1H), 8.17 (d, 1H), 7.81 (dd, 1H), 7.77 (dd, 1H), 7.50 (dd, 1H), 7.39 (d, 1H), 7.32 (t, 1H), 7.14 (d, 1H).

[0251] Example 2 (2S,3S,4S,5R,6R)-6-((8-chloroquinolin-2-yl)(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 2 [ka]

[0252] Step 1 (2R,3R,4S,5S,6S)-2-((8-chloroquinolin-2-yl)(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate 2b Compound 1 (500mg, 1.49mmol) was dissolved in toluene (30mL), cadmium carbonate (155mg, 0.90mmol) was added, and the mixture was heated to 140℃ and reacted with water for 12 hours. 1-Bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucuronic acid methyl ester 2a (1.05g, 2.64mmol, Shaoyuan Chemical Technology) was added, and the mixture was reacted with water for 24 hours at 140℃. The mixture was cooled to room temperature, concentrated under reduced pressure to remove toluene, and purified by column chromatography using eluent system B to obtain the title compound 2b (340mg, 35% yield). MS m / z (ESI): 651.0 [M+1].

[0253] Step 2 (2S,3S,4S,5R,6R)-6-((8-chloroquinolin-2-yl)(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 2 Lithium hydroxide monohydrate (450 mg, 10.74 mmol) was dissolved in water (5 mL), hydrogen peroxide (1 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The solution was added to a tetrahydrofuran solution (15 mL) of compound 2b (340 mg, 0.52 mmol), and the mixture was stirred at room temperature for 2 hours. After quenching with saturated sodium thiosulfate solution (20 mL), the pH was adjusted to 3 with 1N hydrochloric acid solution, extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (100 mL), and the organic phase was concentrated under reduced pressure. The mixture was then separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 25% to 45%, flow rate: 30 mL / min), and the title compound 2 (95 mg, yield 36%) was obtained. MS m / z (ESI): 511.0 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 8.06 (d, 1H), 7.79 (d, 1H), 7.75 (d, 1H), 7.58 (d, 1H), 7.42 (d, 1H), 7.34-7.22 (m, 2H), 6.60 (d, 1H), 6.30 (d, 1H), 5.05-4.82 (m, 2H), 3.55-3.36 (m, 4H), 2.98 (t, 1H).

[0254] Example 3 8-Chloro-N-(2,3-dihydrobenzofuran-5-yl)quinolin-2-amine 3 [ka] Compound 1a (100 mg, 0.51 mmol, Bi De Pharmaceutical), 5-amino-2,3-dihydrobenzofuran 3a (105 mg, 0.61 mmol, Bi De Pharmaceutical), trifluoroacetic acid (0.15 mL, 2.0 mmol) were added to isopropanol (1 mL), heated to 90 ° C., and reacted for 12 hours. After cooling to room temperature and filtering the reaction solution, it was separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 0.1% formic acid aqueous solution and acetonitrile, acetonitrile gradient: 45% to 65%, flow rate: 30 mL / min) to obtain the title compound 3 (115 mg, yield 77%). MS m / z (ESI): 297.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.20 (d, 1H), 8.05 (d, 1H), 7.80-7.65 (m, 3H), 7.23 (t, 1H), 7.07 (d, 1H), 6.75 (d, 1H), 4.52 (t, 2H), 3.22 (t, 2H).

[0255] Example 4 8-Chloro-N-(2,3-dihydro-1H-inden-5-yl)quinolin-2-amine [ka] 5-Aminoindan 4a (168 mg, 1.26 mmol, TCI), compound 1a (100 mg, 0.51 mmol, Shanghai Haohong) and trifluoroacetic acid (173 mg, 1.51 mmol) were dissolved in isopropanol (3 mL). The reaction was heated to 100 °C and reacted for 12 hours. After cooling to room temperature, the reaction solution was filtered and separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 65% to 85%, flow rate: 30 mL / min) to give the title compound 4 (129 mg, yield: 87%). MS m / z (ESI): 295.1 [M+1]. 1 H NMR (500 MHz, CDCl3) 7.90 (d, 1H), 7.69 (dd, 1H), 7.63 (s, 1H), 7.57 dd, 1H), 7.34 (d, 1H), 7.25 (d, 1H), 7.21 (t, 1H), 7.01 (d, 1H), 6.96 (s, 1H), 3.04-2.90 (m, 4H), 2.17-2.09 (m, 2H).

[0256] Example 5 1-(5-((8-chloroquinolin-2-yl)amino)indolin-1-yl)ethan-1-one 5 [ka]

[0257] Step 1 1-(5-Nitroindolin-1-yl)ethan-1-one 5b 5-Nitrodihydroindole 5a (2.0 g, 12.19 mmol, Bi De Pharmaceutical) and triethylamine (1.6 g, 15.85 mmol) were added to 40 mL of dichloromethane, and acetyl chloride (1.24 g, 15.85 mmol) was added slowly at 0 ° C. Then, the temperature was naturally raised to room temperature and the reaction was continued for 2 hours. 30 mL of water was added to the system, and it was extracted with dichloromethane (50 mL × 3), and the organic phase was combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5b (1.8 g, yield: 72%). MS m / z (ESI): 207.1 [M+1].

[0258] Step 2 1-(5-aminoindolin-1-yl)ethan-1-one 5c Compound 5b (0.8 g, 3.88 mmol) was added to 10 mL of methanol, palladium carbon (10%, 0.2 g) was added, and the mixture was replaced with hydrogen gas three times to remove air, and the mixture was reacted in a hydrogen atmosphere for 2 hours. The palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product, the title compound 5c (0.5 g), which was used directly in the next reaction. MS m / z (ESI): 177.1 [M+1].

[0259] Step 3 1-(5-((8-chloroquinolin-2-yl)amino)indolin-1-yl)ethan-1-one 5 Compound 5c (100 mg, 0.57 mmol), 2,8-dichloroquinoline 1a (112 mg, 0.57 mmol, BiDe Pharmaceutical), and trifluoroacetic acid (64.72 mg, 0.57 mmol) were dissolved in isopropanol (1 mL), and then heated to 90° C. and reacted for 12 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by thin layer chromatography (TLC) using developing solvent system B to obtain the title product 5 (48 mg, yield: 25%). MS m / z (ESI): 338.1 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.27 (s, 1H), 8.10 (d, 1H), 8.01 (d, 1H), 7.89-7.65 (m, 3H), 7.26 (t, 1H), 7.12 (d, 1H), 4.11 (t, 2H), 3.19 (t, 2H), 2.15 (s, 3H).

[0260] Example 6 8-Chloro-N-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)quinolin-2-amine 6 [ka] 6-Amino-1,4-benzodioxane 6a (95 mg, 0.63 mmol, TCI) and 2,8-dichloroquinoline 1a (50 mg, 0.25 mmol, Bi De Pharmaceutical) were dissolved in isopropanol (3 mL). The reaction solution was heated to 100 ° C. and reacted for 12 hours. After cooling to room temperature and filtering the reaction solution, it was separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 58% to 78%, flow rate: 30 mL / min) to obtain the title compound 6 (63 mg, yield: 80%). MS m / z (ESI): 313.1 [M+1]. 1 H NMR (500 MHz, CDCl3) 7.90 (d, 1H), 7.73 (dd, 1H), 7.57 (dd, 1H), 7.40 (s, 1H), 7.21 (t, 1H), 7.04 (dd, 1H), 6.96 (d, 1H), 6.90 (d, 1H), 6.83 (s, 1H), 4.35-4.26 (m, 4H).

[0261] Example 7 8-Chloro-N-(5,6,7,8-tetrahydronaphthalen-2-yl)quinolin-2-amine 7 [ka] 5,6,7,8-Tetrahydro-2-naphthylamine 7a (147 mg, 0.51 mmol, TCI), 2,8-dichloroquinoline 1a (100 mg, 0.51 mmol, BiDe Pharmaceutical) and trifluoroacetic acid (173 mg, 1.51 mmol) were dissolved in isopropanol (3 mL). The reaction was heated to 100 °C and reacted for 12 hours. After cooling to room temperature, the reaction solution was filtered and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 60% to 80%, flow rate: 30 mL / min) to obtain the title compound 7 (136 mg, yield: 87%). MS m / z (ESI): 309.1 [M+1]. 1 H NMR (500 MHz, CDCl3) 7.88 (d, 1H), 7.70 (d, 1H), 7.60-7.47 (m, 2H), 7.29 (dd, 1H), 7.18 (t, 1H), 7.07 (d, 1H), 6.96 (d, 1H), 6.86 (s, 1H), 2.88-2.68 (m, 4H), 1.90-1.74 (m, 4H).

[0262] Example 8 8-Chloro-N-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)quinolin-2-amine 8 [ka]

[0263] Step 1 1-(2-Bromo-1,1,2,2-tetrafluoroethoxy)-2-methoxy-4-nitrobenzene 8c 2-Methoxy-4-nitrophenol 8a (2.0 g, 11.82 mmol, BiDe Pharmaceutical), cesium carbonate (5.8 g, 17.74 mmol), 1,2-dibromotetrafluoroethane 8b (6.2 g, 23.65 mmol, Shanghai Taitan Science & Technology) and 1-propanethiol (0.45 g, 5.91 mmol, TCI) were dissolved in 30 mL of dimethyl sulfoxide, heated to 100° C., and reacted for 12 hours. Cool to room temperature, add 50mL of 2N sodium hydroxide solution, extract with diethyl ether (50mL×3), combine the organic phases, then wash with 2N sodium hydroxide solution (50mL×3), wash with saturated sodium chloride solution (50mL×2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title compound 8c (2.6g, yield: 64%).

[0264] Step 2 2-(2-Bromo-1,1,2,2-tetrafluoroethoxy)-5-nitrophenol 8d Compound 8c (2.6 g, 7.56 mmol) was placed in 46 mL of acetic acid, hydrogen bromide solution (40% mass fraction, 19 mL) was added, and the mixture was heated to 120° C. and reacted for 30 hours. After cooling to room temperature, 50 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 8d (2.0 g, yield: 79%). MS m / z (ESI): 331.9 [M-1].

[0265] Step 3 2,2,3,3-Tetrafluoro-6-nitro-2,3-dihydrobenzo[b][1,4]dioxane 8e Compound 8d (200 mg, 0.60 mmol) was dissolved in methanol, and then potassium hydroxide (37 mg, 0.66 mmol) was added and reacted for 1 hour. The solvent was removed under reduced pressure, 4 mL of sulfolane was added, and the mixture was heated to 140° C. and reacted for 8 hours. After cooling to room temperature, 20 mL of water was added to the reaction, which was extracted with ethyl acetate (50 mL×3), washed with saturated sodium chloride solution (50 mL×2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 8e (98 mg, yield: 65%).

[0266] Step 4 2,2,3,3-Tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxan-6-amine 8f Compound 8e (95 mg, 0.38 mmol) was dissolved in 3 mL of methanol, platinum dioxide was added, and the mixture was replaced with hydrogen gas three times to remove air, and reacted in a hydrogen atmosphere for 4 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 8f (60 mg, yield: 72%). MS m / z (ESI): 224.0 [M+1].

[0267] Step 5 8-Chloro-N-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)quinolin-2-amine 8 Compound 8f (60 mg, 0.27 mmol), 2,8-dichloroquinoline 1a (50 mg, 0.25 mmol, BiDe Pharmaceutical), potassium carbonate (32 mg, 0.30 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (52 mg, 0.1 mmol) and tris(dibenzylideneacetone)dipalladium (28 mg, 0.03 mmol) were dissolved in 3 mL of 1,4-dioxane, and the reaction solution was heated to 100° C. and reacted for 12 hours. The reaction was cooled to room temperature, 30 mL of water was added, extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 80% to 95%, flow rate: 30 mL / min) to give the title compound 8 (23 mg, yield: 24%). MS m / z (ESI): 385.0 [M+1]. 1 H NMR (500 MHz, CDCl3) 8.34 (s, 1H), 7.93 (d, 1H), 7.75 (d, 1H), 7.57 (d, 1H), 7.34 (dd, 1H), 7.25 (t, 1H), 7.09 (d, 1H), 6.96-6.76 (m, 2H).

[0268] Example 9 N-(8-chloroquinolin-2-yl)-[1,3]dioxolo[4,5-b]pyridin-6-amine 9 [ka]

[0269] Step 1 6-Bromo-[1,3]dioxolo[4,5-b]pyridine 9b 2,3-Dihydroxy-5-bromopyridine 9a (2.0 g, 10.53 mmol, Bi De Pharmaceutical), anhydrous potassium carbonate (4.36 g, 31.55 mmol), dibromomethane (2.2 g, 12.65 mmol) were dissolved in 30 mL of N-methylpyrrolidone, and the mixture was heated to 100 ° C. and reacted for 12 hours. The mixture was cooled to room temperature, poured into 30 mL of water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 9b (300 mg, yield: 14%). MS m / z (ESI): 201.9 [M+1], 203.9 [M+3].

[0270] Step 2 [1,3]Dioxolo[4,5-b]pyridin-6-ylcarbamic acid tert-butyl ester 9c Compound 9b (100 mg, 0.49 mmol) and tert-butyl carbamate (104 mg, 0.89 mmol) were dissolved in 8 mL of 1,4-dioxane, and tris(dibenzylideneacetone)dipalladium (45 mg, 0.049 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (47 mg, 0.098 mmol) and sodium tert-butoxide (85 mg, 0.89 mmol) were added under a nitrogen atmosphere. The mixture was heated to 105°C and reacted for 20 hours. The reaction mixture was cooled to room temperature, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title compound 9c (50 mg, yield: 42%). MS m / z (ESI): 239.1 [M+1].

[0271] Step 3 [1,3]Dioxolo[4,5-b]pyridin-6-amine hydrochloride 9d Compound 9c (50 mg, 0.21 mmol) was dissolved in 5 mL of dichloromethane, and 4N hydrogen chloride in dioxane solution (425 μL, 1.7 mmol) was added dropwise under ice bath. After the addition was completed, the temperature was naturally raised to room temperature and the reaction was carried out at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 9d (36 mg), which was used as it was in the next reaction. MS m / z (ESI): 139.0 [M+1].

[0272] Step 4 N-(8-chloroquinolin-2-yl)-[1,3]dioxolo[4,5-b]pyridin-6-amine 9 Compound 9d (36 mg, 0.21 mmol), 2,8-dichloroquinoline 1a (30 mg, 0.15 mmol, BiDe Pharmaceutical), cesium carbonate (148 mg, 0.45 mmol), methanesulfonate (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (20 mg, 0.02 mmol) were dissolved in 5 mL of 1,4-dioxane, and the reaction solution was heated to 100°C and reacted for 12 hours. The mixture was cooled to room temperature, 30 mL of water was added, extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 1‰ aqueous trifluoroacetic acid solution and acetonitrile, acetonitrile gradient: 50% to 95%, flow rate: 30 mL / min) to obtain the title compound 9 (12 mg, yield: 26%). MS m / z (ESI): 300.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) 9.80 (s, 1H), 8.46 (d, 1H), 8.18 (d, 1H), 8.13 (d, 1H), 7.78 (d, 1H), 7.74 (d, 1H), 7.28 (t, 1H), 7.10(d, 1H), 6.14 (s, 2H).

[0273] Example 10 N-(benzo[d][1,3]dioxolan-5-yl)-8-chloroquinolin-2-amine 10 [ka] Compound benzo[d][1,3]dioxolane-5-amine 10a (693 mg, 5.05 mmol, BiDe Pharmaceutical), compound 1a (1.0 g, 5.05 mmol), cesium carbonate (2.64 g, 8.10 mmol), 4,5-diphenylphosphino-9,9-dimethylxanthene (584 mg, 1.01 mmol), tris(dibenzylideneacetone)dipalladium (462 mg, 0.50 mol) were dissolved in 30 mL of 1,4-dioxane, and the reaction solution was heated to 105 ° C. and reacted for 12 hours. The reaction solution was cooled to room temperature, 25 mL of water was added, extracted with ethyl acetate (25 mL x 3), washed with saturated sodium chloride solution (25 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 10% to 26%, flow rate: 30 mL / min) to obtain the target compound 10 (750 mg, yield: 50%). MS m / z (ESI): 299.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) 9.64 (s, 1H), 8.30 (d, 1H), 8.08 (d, 1H), 7.75 (dd, 1H), 7.70 (dd, 1H), 7.28 (dd, 1H), 7.25 (t, 1H), 7.07(d, 1H), 6.90(d, 1H), 5.99 (s, 2H).

[0274] Example 11 N-(benzo[d][1,3]dioxolan-5-yl-2,2-dideutero)-8-chloroquinolin-2-amine 11 [ka] Compound benzo[d][1,3]dioxolane-2,2-dideutero-5-amine 11a (170 mg, 1.21 mmol, obtained by preparation according to the method disclosed in patent application "WO2012037351A1, page 41 of the specification, synthesis method 2 of intermediates"), compound 1a (240 mg, 1.21 mmol), cesium carbonate (636 mg, 1.95 mmol), 4,5-diphenylphosphino-9,9-dimethylxanthene (141 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (111 mg, 0.12 mol) were dissolved in 10 mL of 1,4-dioxane, and the reaction was heated to 105 °C and reacted for 12 hours. The reaction was cooled to room temperature, 25 mL of water was added, extracted with ethyl acetate (25 mL × 3), washed with saturated sodium chloride solution (25 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by high-performance liquid preparative chromatography (Waters-2767 Autopurification, elution system: 1‰ aqueous formic acid and acetonitrile, acetonitrile gradient: 45% to 95%, flow rate: 30 mL / min) to give the target compound 11 (100 mg, yield: 27%). MS m / z (ESI): 300.9 [M+1]. 1 H NMR (500 MHz, DMSO-d6) 9.64 (s, 1H), 8.29 (d, 1H), 8.08 (d, 1H), 7.75 (dd, 1H), 7.71 (dd, 1H), 7.32-7.18 (m, 2H), 7.07 (d, 1H), 6.89 (d, 1H).

[0275] Example 12 8-Chloro-N-(2,2-dimethylbenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine 12 [ka] Compound 2,2-dimethylbenzo[d][1,3]dioxolane-5-amine 12a (141 mg, 0.85 mmol, Shanghai Haohong Biological Pharmaceuticals), compound 1a (146 mg, 0.74 mmol), cesium carbonate (362 mg, 1.11 mmol), tris(dibenzylideneacetone)dipalladium (68 mg, 0.074 mmol), and 4,5-diphenylphosphino-9,9-dimethylxanthene (86 mg, 0.15 mmol) were dissolved in 5 mL of 1,4-dioxane and the reaction was heated to 105 °C and allowed to react for 12 h. The reaction was cooled to room temperature, 30 mL of water was added, extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by high-performance liquid preparative chromatography (Waters-2545, elution system: 10 mmol / L aqueous ammonium bicarbonate and acetonitrile, acetonitrile gradient: 60% to 95%, flow rate: 30 mL / min) to give the target compound 12 (132 mg, yield: 55%). MS m / z (ESI): 327.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.18 (d, 1H), 8.06 (d, 1H), 7.74 (dd, 1H), 7.69 (dd, 1H), 7.30-7.17 (m, 2H), 7.06 (d, 1H), 6.79 (d, 1H), 1.65 (s, 6H).

[0276] Example 13 8-Chloro-N-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)quinolin-2-amine 13 [ka] Compound 2,2-dimethyl-2,3-dihydrobenzofuran-5-amine 13a (59 mg, 0.36 mmol, obtained by preparation according to the method disclosed in patent application "WO2014169845, Example 13, page 72 of the specification"), compound 1a (60 mg, 0.30 mmol), trifluoroacetic acid (62 mg, 0.54 mmol) and 2 mL of isopropanol were placed in a 25 mL sealed tube, and the reaction was heated to 90° C. for 12 hours. The reaction solution was cooled to room temperature, 15 mL of water was added, and the pH was adjusted to about 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (25 mL x 3), washed with saturated sodium chloride solution (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by high-performance liquid preparative chromatography (Waters-2767 Autopurification, elution system: 1‰ aqueous formic acid and methanol, methanol gradient: 60% to 95%, flow rate: 30 mL / min) to obtain the target compound 13 (55 mg, yield: 56%). MS m / z (ESI): 325.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) 9.47 (s, 1H), 8.18 (s, 1H), 8.04 (dd, 1H), 7.78-7.60 (m, 3H), 7.22 (td, 1H), 7.05 (dd, 1H), 6.67 (dd, 1H), 3.03 (s, 2H), 1.42 (s, 6H).

[0277] Example 14 5-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-8,9-dihydro-7H-cyclopenta[f]quinolin-3-amine 14 [ka]

[0278] Step 1 6-Chloro-2,3-dihydro-1H-inden-5-amine 14b In a 100 mL single-neck flask, 50 mL of dichloromethane, (6-chloro-2,3-dihydro-1H-inden-5-yl) tert-butyl carbamate 14a (3.4 g, 12.73 mmol, obtained by preparing using a known method "ACS Catalysis, 2018, 8, 4783-4788"), and 10 mL of trifluoroacetic acid were added in sequence and reacted at room temperature for 3 hours. The mixture was concentrated under reduced pressure to remove the solvent, diluted with 100 mL of dichloromethane, washed with saturated sodium bicarbonate solution (50 mL x 2), washed with saturated sodium chloride solution (50 mL x 2), dried the organic phase over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, the title compound 14b (1.55 g, yield: 73%), which was used as is in the next reaction. MS m / z (ESI): 168.1 [M+1].

[0279] Step 2 N-(6-chloro-2,3-dihydro-1H-inden-5-yl)-3,3-dimethoxypropanamide 14d In a 100 mL three-neck flask, 16 mL of tetrahydrofuran, compound 14b (1.55 g, 9.28 mmol), and methyl 3,3-dimethoxypropionate 14c (1.65 g, 11.14 mmol, J&K) were added in sequence, and then sodium bis(trimethylsilyl)amide (2 M tetrahydrofuran solution, 6.96 mL, 13.92 mmol) was slowly added dropwise at 0°C. The reaction was allowed to warm to room temperature naturally and reacted for 12 hours. The reaction was quenched by adding 50 mL of saturated ammonium bicarbonate solution to the system under ice bath, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL x 3), the organic phase was dried, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 14d (950 mg, yield: 36%).

[0280] Step 3 5-Chloro-4,7,8,9-tetrahydro-3H-cyclopenta[f]quinolin-3-one 14e 10 mL of dichloromethane and compound 14d (800 mg, 2.83 mmol) were added in sequence to a 50 mL single-neck flask, concentrated sulfuric acid (2.27 mL, 42.40 mmol) was slowly added dropwise to the system at 0° C., and after the addition was completed, the mixture was reacted at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was added dropwise to ice water to precipitate a solid, which was then filtered and dried to obtain the title compound 14e (500 mg, yield: 81%). MS m / z (ESI): 220.0 [M+1].

[0281] Step 4 3,5-Dichloro-8,9-dihydro-7H-cyclopenta[f]quinoline 14f 2mL of N,N-dimethylformamide and compound 14e (300mg, 1.37mmol) were added in sequence to a 50mL single-neck flask, and the temperature of the system was raised to 95°C. Then, phosphorus oxychloride (0.1mL, 1.10mmol) was gradually added dropwise and the reaction was continued for 30 minutes. The mixture was concentrated under reduced pressure to remove phosphorus oxychloride, diluted with 20mL of ethyl acetate, washed with 0.2N sodium hydroxide solution (30mL x 2) and saturated sodium chloride solution (30mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 14f (0.25g, yield: 78%), which was used directly in the next reaction. MS m / z (ESI): 238.0 [M+1].

[0282] Step 5 5-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-8,9-dihydro-7H-cyclopenta[f]quinolin-3-amine 14 2 mL of isopropanol, compound 14f (100 mg, 0.42 mmol), trifluoroacetic acid (47.89 mg, 0.42 mmol), and compound 1b (73 mg, 0.42 mmol) were added in this order to a 25 mL single-neck flask, and then the temperature was raised to 85° C. and reacted for 16 hours. The solvent was removed under reduced pressure, and the mixture was diluted with 1 mL of methanol and purified by thin layer chromatography (TLC) using developing solvent system B to obtain the title compound 14 (78 mg, yield: 49%). MS m / z (ESI): 375.0 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.89 (d, 1H), 8.08 (d, 1H), 7.72 (s, 1H), 7.48-7.45 (m, 1H), 7.37 (d, 1H), 7.13 (d, 1H), 3.15 (t, 2H), 3.02 (t, 2H), 2.12-2.14 (m, 2H).

[0283] Example 15 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-7-methylquinolin-2-amine 15 [ka]

[0284] Step 1 N-(2-chloro-3-methylphenyl)-3,3-dimethoxypropanamide 15b Into a 100 mL three-neck flask, 25 mL of tetrahydrofuran, 2-chloro-3-methylaniline 15a (1.5 g, 10.59 mmol, BiDe Pharmaceutical), and compound 14c (1.88 g, 11.69 mmol) were added in that order, and the temperature of the system was lowered to 0°C. Then, sodium bis(trimethylsilyl)amide (2 M tetrahydrofuran solution, 10.57 mL, 21.14 mmol) was gradually added dropwise, and the system was then warmed to room temperature and reacted for 24 hours. The reaction was quenched by adding 50 mL of saturated aqueous sodium bicarbonate solution to the system, the reaction solution was concentrated under reduced pressure to remove most of the organic phase, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 15b (2.70 g, yield: 98%). The crude product was used directly in the next reaction.

[0285] Step 2 8-Chloro-7-methylquinolin-2(1H)-one 15c In a 100 mL single-neck flask, 15 mL of dichloromethane and compound 15b (2.70 g, 10.48 mmol) were added in that order, and concentrated sulfuric acid (8.37 mL, 157.11 mmol) was gradually added dropwise at 0° C. After completion of the addition, the ice bath was removed and the reaction was continued for 16 hours. The solvent was removed under reduced pressure, and the residue was dropped into ice water to precipitate a solid, which was then filtered and dried to obtain the title compound 15c (1.8 g, yield: 89%). MS m / z (ESI): 194.0 [M+1].

[0286] Step 3 2,8-Dichloro-7-methylquinoline 15d Compound 15c (800 mg, 4.67 mmol) and phosphorus oxychloride (3.16 g, 20.66 mmol) were added in order to a 50 mL single-neck flask, and the temperature of the system was raised to 95 ° C. and reacted for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, the pH was adjusted to about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 15d (620 mg, yield: 71%). MS m / z (ESI): 211.9 [M+1].

[0287] Step 4 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-7-methylquinolin-2-amine 15 In a 25 mL sealed tube, 8 mL of isopropanol, compound 15d (300 mg, 1.29 mmol), compound 1b (268 mg, 1.54 mmol), and trifluoroacetic acid (260 mg, 2.28 mmol) were added in that order. The reaction was then heated to 95 °C and reacted for 16 hours. The solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added to dilute the mixture, washed with saturated sodium bicarbonate solution (50 mL x 2), and washed with saturated sodium chloride solution (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid preparative chromatography (Waters-2767 Autopurification, elution system: 1‰ aqueous formic acid and methanol, methanol gradient: 65% to 95%, flow rate: 30 mL / min) to obtain the title compound 15 (300 mg, yield: 73%). MS m / z (ESI): 349.1 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.90 (s, 1H), 8.11 (d, 1H), 7.65 (d, 1H), 7.49 (d, 1H), 7.37 (d, 1H), 7.30 (d, 1H), 7.07 (d, 1H), 2.55 (s, 3H).

[0288] Example 16 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-7-methoxyquinolin-2-amine 16 [ka]

[0289] Step 1 N-(2-chloro-3-methoxyphenyl)-3,3-dimethoxypropanamide 16b In a 100mL three-neck flask, 25mL of tetrahydrofuran, 2-chloro-3-methoxyaniline 16a (1.5g, 9.51mmol, BiDe Pharmaceutical), and compound 14c (1.69g, 11.40mmol) were added in sequence, and sodium bis(trimethylsilyl)amide (2M tetrahydrofuran solution, 9.51mL, 19.03mmol) was gradually added dropwise at 0°C, and the mixture was allowed to naturally warm to room temperature and react for 24 hours. The reaction was quenched by adding 50mL of saturated sodium bicarbonate solution to the system, and the reaction solution was concentrated under reduced pressure to remove most of the organic phase, extracted with ethyl acetate (50mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 16b (2.50g, yield: 96%), which was used as is in the next reaction.

[0290] Step 2 8-Chloro-7-methoxyquinolin-2(1H)-one 16c In a 100 mL single-neck flask, 10 mL of dichloromethane and compound 16b (2.50 g, 9.13 mmol) were added in that order, concentrated sulfuric acid (7.29 mL, 136.93 mmol) was slowly added dropwise at 0° C., the ice bath was removed, and the reaction was continued for 16 hours. The solvent was removed under reduced pressure, and the residue was dropped into ice water to precipitate a solid, which was then filtered and dried to obtain the title compound 16c (1.6 g, yield: 84%). MS m / z (ESI): 210.0 [M+1].

[0291] Step 3 2,8-Dichloro-7-methoxyquinoline 16d 8 mL of toluene, compound 16c (800 mg, 3.81 mmol), and phosphorus oxychloride (1.17 g, 7.63 mmol) were added in order to a 50 mL single-neck flask, and the temperature of the system was raised to 100 ° C. and reacted for 3 hours. The reaction was cooled to room temperature, 20 mL of ice water was added, the pH was adjusted to about 8 with saturated sodium bicarbonate, extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 16d (680 mg, yield: 78%). MS m / z (ESI): 227.9 [M+1].

[0292] Step 4 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-7-methoxyquinolin-2-amine 16 In a 25 mL sealed tube, 4 mL of isopropanol, compound 16d (250 mg, 1.09 mmol), compound 1b (227 mg, 1.31 mmol), and trifluoroacetic acid (224 mg, 1.96 mmol) were added in sequence, and the temperature was raised to 95 ° C. and reacted for 16 hours. The mixture was concentrated under reduced pressure to remove the solvent, diluted with 100 mL of ethyl acetate, washed with saturated sodium bicarbonate solution (50 mL x 2) and saturated sodium chloride solution (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the target product 16 (280 mg, yield: 70%). MS m / z (ESI): 365.1 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.92 (s, 1H), 8.09 (d, 1H), 7.76 (d, 1H), 7.49 (d, 1H), 7.38 (d, 1H), 7.31 (d, 1H), 6.97 (d, 1H), 4.00 (s, 3H).

[0293] Example 17 7,8-Dichloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-quinolin-2-amine 17 [ka]

[0294] Step 1 N-((2,3-dichlorophenyl)-3,3-dimethoxypropanamide 17b 25mL of tetrahydrofuran, 2,3-dichloroaniline 17a (1.5g, 9.26mmol, J&K), and compound 14c (1.65g, 11.11mmol) were added in sequence to a 100mL three-neck flask, and sodium bis(trimethylsilyl)amide (2M tetrahydrofuran solution, 9.30mL, 18.60mmol) was slowly added dropwise at 0°C, after which the system was warmed to room temperature and reacted for 24 hours. 50mL of saturated aqueous sodium bicarbonate was added to the system to quench the reaction, the reaction solution was concentrated under reduced pressure to remove most of the organic phase, extracted with ethyl acetate (50mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 17b (2.50g, yield: 97%), which was used as is in the next reaction.

[0295] Step 2 7,8-Dichloroquinolin-2(1H)-one 17c 15 mL of dichloromethane and compound 17b (2.50 g, 8.99 mmol) were added in sequence to a 100 mL single-neck flask, and concentrated sulfuric acid (7.18 mL, 134.79 mmol) was slowly added dropwise at 0° C., after which the ice bath was removed and the reaction was continued for 16 hours. The solvent was removed under reduced pressure, and the residue was dropped into ice water to precipitate a solid, which was then filtered and dried to obtain the title compound 17c (1.70 g, yield: 89%). MS m / z (ESI): 214.0 [M+1].

[0296] Step 3 2,7,8-Trichloroquinoline 17d Compound 17c (1.0 g, 4.67 mmol) and phosphorus oxychloride (3.58 g, 23.36 mmol) were added in order to a 50 mL single-neck flask, and the temperature of the system was raised to 95 ° C. and reacted for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, the pH was adjusted to about 8 with saturated sodium bicarbonate, extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 17d (950 mg, yield: 87%). MS m / z (ESI): 231.9 [M+1].

[0297] Step 4 7,8-Dichloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-quinolin-2-amine 17 In a 25 mL sealed tube reaction flask, 8 mL of isopropanol, compound 17d (300 mg, 1.29 mmol), compound 1b (268 mg, 1.54 mmol), and trifluoroacetic acid (260 mg, 2.28 mmol) were added in sequence, and the temperature was raised to 95 °C for 16 hours. The solvent was removed under reduced pressure, and the mixture was diluted with 100 mL of ethyl acetate, washed with saturated sodium bicarbonate solution (50 mL x 2), and washed with saturated sodium chloride solution (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the target product 17 (300 mg, yield: 63%). MS m / z (ESI): 369.0 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.76 (s, 1H), 8.16 (d, 1H), 7.76 (d, 1H), 7.54-7.45 (m, 2H), 7.38 (d, 1H), 7.12 (d, 1H).

[0298] Example 18 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-6-methylquinolin-2-amine 18 [ka]

[0299] Step 1 N-(2-chloro-4-methylphenyl)-3,3-dimethoxypropanamide 18b 25mL of tetrahydrofuran, 2-chloro-4-methylaniline 18a (1g, 7.06mmol, BiDe Pharmaceutical), and compound 14c (1.26g, 8.47mmol) were added in sequence to a 100mL three-neck flask, and sodium bis(trimethylsilyl)amide (2M tetrahydrofuran solution, 5.30mL, 10.60mmol) was slowly added dropwise at 0°C, after which the system was warmed to room temperature and reacted for 24 hours. 50mL of saturated aqueous sodium bicarbonate was added to the system to quench the reaction, the reaction solution was concentrated under reduced pressure to remove most of the organic phase, extracted with ethyl acetate (50mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (50mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 18b (1.50g, yield: 82%).

[0300] Step 2 8-Chloro-6-methylquinolin-2(1H)-one 18c 2 mL of dichloromethane and compound 18b (1.50 g, 5.82 mmol) were added to a 100 mL single-neck flask in that order, and concentrated sulfuric acid (4.7 mL, 87.31 mmol) was slowly added dropwise at 0° C., after which the ice bath was removed and the reaction was continued for 4 hours. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was dropped into ice water to precipitate a solid, which was then filtered and dried to obtain the title compound 18c (0.8 g, yield: 71%). MS m / z (ESI): 194.0 [M+1].

[0301] Step 3 2,8-Dichloro-6-methylquinoline 18d Compound 18c (0.5 g, 2.58 mmol) and 2 mL of phosphorus oxychloride were added in a 50 mL single-neck flask, and the temperature of the system was raised to 95° C. and reacted for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 18d (0.3 g, yield: 55%). MS m / z (ESI): 212.0 [M+1].

[0302] Step 4 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-6-methylquinolin-2-amine 18 In a 25 mL sealed tube, 3 mL of isopropanol, compound 18d (50 mg, 0.24 mmol), compound 1b (102 mg, 0.59 mmol), and trifluoroacetic acid (67 mg, 0.59 mmol) were added in sequence, and the temperature was raised to 95 ° C. and reacted for 16 hours. The reaction was cooled to room temperature, 25 mL of water was added, extracted with ethyl acetate (25 mL × 3), washed with saturated sodium chloride solution (25 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 70% to 90%, flow rate: 30 mL / min) to give the title compound 18 (55 mg, yield: 67%). MS m / z (ESI): 349.1 [M+1]. 1 H NMR (500 MHz, CDCl3) 8.26 (s, 1H), 7.87 (d, 1H), 7.60 (s, 1H), 7.35 (s, 1H), 7.14 (m, 1H), 7.02 (d, 1H), 6.85 (d, 1H), 6.79 (s, 1H), 2.46 (s, 3H).

[0303] Example 19 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-6-methoxyquinolin-2-amine 19 [ka]

[0304] Step 1 N-(2-chloro-4-methoxyphenyl)-3,3-dimethoxypropanamide 19b 25mL of tetrahydrofuran, 2-chloro-4-methoxyaniline 19a (1g, 6.35mmol, BiDe Pharmaceutical), and compound 14c (1.13g, 7.61mmol) were added in sequence to a 100mL three-neck flask, and sodium bis(trimethylsilyl)amide (2M tetrahydrofuran solution, 4.76mL, 9.52mmol) was slowly added dropwise at 0°C, after which the system was warmed to room temperature and reacted for 24 hours. 50mL of saturated aqueous sodium bicarbonate was added to the system to quench the reaction, the reaction solution was concentrated under reduced pressure to remove most of the organic phase, extracted with ethyl acetate (50mL x 3), the organic phase was combined and washed with saturated sodium chloride solution (50mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 19b (1.20g, yield: 69%).

[0305] Step 2 8-Chloro-6-methoxyquinolin-2(1H)-one 19c 2 mL of dichloromethane and compound 19b (1.20 g, 4.38 mmol) were added in sequence to a 100 mL single-neck flask, and concentrated sulfuric acid (3.52 mL, 65.76 mmol) was slowly added dropwise at 0° C., after which the ice bath was removed and the reaction was continued for 4 hours. The solvent was removed under reduced pressure, and the residue was dropped into ice water to precipitate a solid, which was then filtered and dried to obtain the title compound 19c (0.6 g, yield: 65%). MS m / z (ESI): 210.0 [M+1].

[0306] Step 3 2,8-Dichloro-6-methoxyquinoline 19d Compound 19c (500 mg, 2.39 mmol) and 2.5 mL of phosphorus oxychloride were added in order to a 50 mL single-neck flask, and the temperature of the system was raised to 95° C. and reacted for 90 minutes. After removing phosphorus oxychloride under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 19d (75 mg, yield: 14%). MS m / z (ESI): 228.0 [M+1].

[0307] Step 4 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-6-methoxyquinolin-2-amine 19 In a 25 mL sealed tube reaction flask, 3 mL of isopropanol, compound 19d (75 mg, 0.33 mmol), compound 1b (142 mg, 0.82 mmol), and trifluoroacetic acid (94 mg, 0.82 mmol) were added in sequence, and the temperature was raised to 95 °C and then reacted for 16 hours. The reaction was cooled to room temperature, 25 mL of water was added, extracted with ethyl acetate (25 mL x 3), washed with saturated sodium chloride solution (25 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 65% to 85%, flow rate: 30 mL / min) to give the title compound 19 (55 mg, yield: 67%). MS m / z (ESI): 365.1 [M+1]. 1H NMR (500 MHz, CDCl3) 8.22 (s, 1H), 7.85 (d, 1H), 7.45 (s, 1H), 7.11 (s, 1H), 7.00 (d, 1H), 6.94 (s, 1H), 6.85 (d, 1H), 6.73 (s, 1H), 3.89 (s, 3H).

[0308] Example 20 6,8-Dichloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine 20 [ka]

[0309] Step 1 N-(2,4-dichlorophenyl)-3,3-dimethoxypropanamide 20b 25mL of tetrahydrofuran, 2,4-dichloroaniline 20a (1.0g, 6.17mmol, J&K), and compound 14c (1.10g, 7.41mmol) were added in sequence to a 100mL three-neck flask, and sodium bis(trimethylsilyl)amide (2M tetrahydrofuran solution, 4.63mL, 9.26mmol) was slowly added dropwise at 0°C, after which the system was warmed to room temperature and reacted for 24 hours. 50mL of saturated aqueous sodium bicarbonate was added to the system to quench the reaction, the reaction solution was concentrated under reduced pressure to remove most of the organic phase, extracted with ethyl acetate (50mL x 3), the organic phase was combined and washed with saturated sodium chloride solution (50mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 20b (1.40g, yield: 82%).

[0310] Step 2 6,8-Dichloroquinolin-2(1H)-one 20c 2 mL of dichloromethane and compound 20b (1.20 g, 4.31 mmol) were added in sequence to a 100 mL single-neck flask, and concentrated sulfuric acid (3.52 mL, 65.76 mmol) was slowly added dropwise at 0° C., after which the ice bath was removed and the mixture was heated to 90° C. and reacted for 4 hours. The solvent was removed under reduced pressure, and the residue was dropped into ice water to precipitate a solid, which was then filtered and dried to obtain the title compound 20c (0.5 g, yield: 54%). MS m / z (ESI): 213.9 [M+1].

[0311] Step 3 2,6,8-Trichloroquinoline 20d Compound 20c (300 mg, 1.40 mmol) and 2 mL of phosphorus oxychloride were added in a 50 mL single-neck flask, and the temperature of the system was raised to 95° C. and reacted for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 20d (240 mg, yield: 74%). MS m / z (ESI): 231.9 [M+1].

[0312] Step 4 6,8-Dichloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine 20 3 mL of isopropanol, compound 20d (100 mg, 0.43 mmol), compound 1b (82 mg, 0.47 mmol), and trifluoroacetic acid (123 mg, 1.08 mmol) were added in sequence to a 25 mL sealed tube, and the temperature was raised to 95 °C and reacted for 16 hours. The reaction was cooled to room temperature, 25 mL of water was added, extracted with ethyl acetate (25 mL x 3), washed with saturated sodium chloride solution (25 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 80% to 95%, flow rate: 30 mL / min) to give the title compound 20 (55 mg, yield: 63%). MS m / z (ESI): 369.0 [M+1]. 1 H NMR (500 MHz, CDCl3) 8.23 ​​(s, 1H), 7.86 (d, 1H), 7.72 (s, 1H), 7.56 (s, 1H), 7.14 (d, 1H), 7.03 (s, 1H), 6.94-6.72 (m, 2H).

[0313] Example 21 (2S,3S,4S,5R,6R)-6-(benzo[d][1,3]dioxolan-5-yl(8-chloroquinolin-2-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 21 [ka]

[0314] Step 1 (2R,3R,4S,5S,6S)-2-(benzo[d][1,3]dioxolan-5-yl)(8-chloroquinolin-2-yl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate 21a Compound 10 (380 mg, 1.27 mmol) was dissolved in toluene (15 mL), cadmium carbonate (131 mg, 0.76 mmol) was added, and the mixture was heated to 145° C. and reacted with water for 12 hours. Compound 2a (606 mg, 1.53 mmol) was added and reacted with water for 24 hours at 145° C. The mixture was cooled to room temperature and concentrated under reduced pressure to remove toluene. The residue was purified by column chromatography using eluent system B to obtain the title compound 21a (450 mg, 58% yield). MS m / z (ESI): 615.0 [M+1].

[0315] Step 2 (2S,3S,4S,5R,6R)-6-(benzo[d][1,3]dioxolan-5-yl(8-chloroquinolin-2-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 21 Lithium hydroxide monohydrate (645 mg, 15.35 mmol) was dissolved in water (4 mL), 30% hydrogen peroxide solution (1.83 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The solution was added to a tetrahydrofuran solution (16 mL) of compound 21a (450 mg, 0.51 mmol), and the mixture was stirred at room temperature for 16 hours. After quenching with saturated sodium thiosulfate solution (20 mL), the pH was adjusted to 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (100 mL), and the organic phase was concentrated under reduced pressure, and then purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 15% to 95%, flow rate: 30 mL / min) to obtain the title compound 21 (85 mg, yield 35%). MS m / z (ESI): 475.1 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 8.03 (d, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.26 (t, 1H), 7.06 (d, 1H), 7.00-6.86 (m, 2H), 6.50 (d, 1H), 6.34 (d, 1H), 6.13 (d, 2H), 5.08-4.82 (m, 2H), 3.51 (d, 1H), 3.40-3.25 (m, 2H), 3.06 (t, 1H), 2.98-2.82 (m, 1H).

[0316] Example 22 (2S,3S,4S,5R,6R)-6-((8-chloroquinolin-2-yl)(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 22 [ka]

[0317] Step 1 (2R,3R,4S,5S,6S)-2-((8-chloroquinolin-2-yl)(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate 22a Compound 6 (500 mg, 1.60 mmol) was dissolved in toluene (30 mL), cadmium carbonate (165 mg, 0.96 mmol) was added, and the mixture was heated to 140° C. and reacted with water for 12 hours. Compound 2a (1.90 g, 4.80 mmol) was added and reacted with water for 24 hours at 140° C. The mixture was cooled to room temperature and concentrated under reduced pressure to remove toluene. The residue was purified by column chromatography using eluent system B to obtain the title compound 22a (400 mg, 40% yield). MS m / z (ESI): 629.0 [M+1].

[0318] Step 2 (2S,3S,4S,5R,6R)-6-((8-chloroquinolin-2-yl)(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 22 Lithium hydroxide monohydrate (534 mg, 12.72 mmol) was dissolved in water (5 mL), 30% hydrogen peroxide solution (1.1 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The solution was added to a tetrahydrofuran solution (15 mL) of compound 22a (400 mg, 0.64 mmol), and the mixture was stirred at room temperature for 2 hours. After quenching with saturated sodium thiosulfate solution (20 mL), the pH was adjusted to 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (100 mL), and the organic phase was concentrated under reduced pressure. The mixture was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 20% to 65%, flow rate: 30 mL / min) to obtain the title compound 22 (95 mg, yield 36%). MS m / z (ESI): 489.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 8.01 (d, 1H), 7.77 (dd, 1H), 7.70 (dd, 1H), 7.25 (t, 1H), 6.99 (d, 1H), 6.94 (d, 1H), 6.89 (dd, 1H), 6.46 (d, 1H), 6.33 (d, 1H), 5.03-4.83 (m, 2H), 4.40-4.20 (m, 4H), 3.54 (d, 1H), 3.43-3.36 (m, 2H), 3.08 (t, 1H), 2.97-2.81 (m, 1H).

[0319] Example 23 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-5-methylquinolin-2-amine 23 [ka]

[0320] Step 1 N-(2-chloro-5-methylphenyl)-3,3-diethoxypropanamide 23c Into a 100 mL three-neck flask, 5 mL of N,N-dimethylformamide, 2-chloro-5-methylaniline 23a (0.5 g, 3.53 mmol, BiDe Pharmaceutical), and 3,3-diethoxypropionic acid 23b (0.63 g, 3.88 mmol, J&K) were added in that order, and 2-(7-azabenzotriazazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.01 g, 5.29 mmol) and N,N-diisopropylethylamine (0.91 g, 7.06 mmol) were gradually added at 0°C. The system was then warmed to room temperature and reacted for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate solution to the system, extracted with ethyl acetate (50 mL x 3), the organic phases were combined and washed with saturated sodium chloride solution (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 23c (1.0 g, yield: 99%), which was used directly in the next reaction.

[0321] Step 2 8-Chloro-5-methylquinolin-2(1H)-one 23d 2mL of dichloromethane and compound 23c (1.00g, 3.5mmol) were added in a 100mL single-neck flask in that order, concentrated sulfuric acid (3.35mL, 62.98mmol) was slowly added dropwise at 0°C, the ice bath was removed, and the reaction was continued for 4 hours. The solvent was removed under reduced pressure, the residue was added dropwise to 50mL of ice water, extracted with ethyl acetate (50mL x 5), the organic phases were combined, washed with saturated sodium chloride solution (50mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 23d (0.26g, yield: 38%). MS m / z (ESI): 194.0 [M+1].

[0322] Step 3 2,8-Dichloro-5-methylquinoline 23e Compound 23d (0.26 g, 1.34 mmol) and phosphorus oxychloride (2 mL) were added in this order to a 50 mL single-neck flask, and the temperature of the system was raised to 95° C. and reacted for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, ice water (50 mL) was added, and extraction was performed with ethyl acetate (50 mL×3). The organic phase was washed with a saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, title compound 23e (0.28 g, yield: 99%), which was used as it was in the next reaction. MS m / z (ESI): 212.0 [M+1].

[0323] Step 4 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-5-methylquinolin-2-amine 23 3 mL of isopropanol, compound 23e (100 mg, 0.47 mmol), compound 1b (97 mg, 0.56 mmol), and trifluoroacetic acid (161 mg, 1.41 mmol) were added in sequence to a 25 mL sealed tube, and the temperature was raised to 95 °C and reacted for 16 hours. The reaction was cooled to room temperature, 25 mL of water was added, extracted with ethyl acetate (25 mL x 3), washed with saturated sodium chloride solution (25 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 70% to 90%, flow rate: 30 mL / min) to give the title compound 23 (80 mg, yield: 48%). MS m / z (ESI): 349.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.88 (d, 1H), 8.27 (d, 1H), 7.69 (d, 1H), 7.48 (dd, 1H), 7.37 (d, 1H), 7.19-7.12 (m, 2H), 2.57 (s, 3H).

[0324] Example 24 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-5-methoxyquinolin-2-amine 24 [ka]

[0325] Step 1 N-(2-chloro-5-methoxyphenyl)-3,3-diethoxypropanamide 24b In a 100 mL three-neck flask, 5 mL of N,N-dimethylformamide, 2-chloro-5-methoxyaniline 24a (0.5 g, 3.17 mmol, BiDe Pharmaceutical), and compound 23b (0.63 g, 3.88 mmol) were added in that order, and 2-(7-azabenzotriazazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.01 g, 5.29 mmol) and N,N-diisopropylethylamine (0.91 g, 7.06 mmol) were gradually added at 0°C. The system was then warmed to room temperature and reacted for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate solution to the system, extracted with ethyl acetate (50 mL x 3), the organic phases were combined and washed with saturated sodium chloride solution (50 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product title compound 24b (0.95 g, yield: 99%), which was used directly in the next reaction.

[0326] Step 2 8-Chloro-5-methoxyquinolin-2(1H)-one 24c 2mL of dichloromethane and compound 24b (0.95g, 3.14mmol) were added in a 100mL single-neck flask in that order, and concentrated sulfuric acid (2.52mL, 47.22mmol) was gradually added dropwise at 0°C, and then the ice bath was removed and the reaction was continued for 4 hours. The solvent was removed under reduced pressure, the residue was dropped into 50mL of ice water, extracted with ethyl acetate (50mL x 5), the organic phases were combined, washed with saturated sodium chloride solution (50mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 24c (0.26g, yield: 40%). MS m / z (ESI): 210.0 [M+1].

[0327] Step 3 2,8-Dichloro-5-methoxyquinoline 24d Compound 24c (365 mg, 1.26 mmol) and 2.5 mL of phosphorus oxychloride were added in a 50 mL single-neck flask, and the temperature of the system was raised to 95° C. and reacted for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was washed with a saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, title compound 24d (288 mg, yield: 99%), which was used as it was in the next reaction. MS m / z (ESI): 228.0 [M+1].

[0328] Step 4 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-5-methoxyquinolin-2-amine 24 In a 25 mL sealed tube, 3 mL of isopropanol, compound 24d (288 mg, 1.26 mmol), compound 1b (218 mg, 1.26 mmol), and trifluoroacetic acid (431 mg, 3.78 mmol) were added in sequence, and the temperature was raised to 95 ° C. and reacted for 16 hours. The reaction was cooled to room temperature, 25 mL of water was added, extracted with ethyl acetate (25 mL × 3), washed with saturated sodium chloride solution (25 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 65% to 85%, flow rate: 30 mL / min) to give the title compound 24 (230 mg, yield: 49%). MS m / z (ESI): 365.1 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.87 (s, 1H), 8.31 (d, 1H), 7.72 (d, 1H), 7.48 (d, 1H), 7.37 (d, 1H), 7.09 (d, 1H), 6.83 (d, 1H), 3.95 (s, 3H).

[0329] Example 25 5,8-Dichloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine 25 [ka]

[0330] Step 1 N-(2,5-dichlorophenyl)-3,3-diethoxypropanamide 25b Into a 100 mL three-neck flask, 5 mL of N,N-dimethylformamide, 2,5-dichloroaniline 25a (0.5 g, 3.08 mmol, BiDe Pharmaceutical), and compound 23b (0.50 g, 3.39 mmol) were added in that order, and 2-(7-azabenzotriazazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.01 g, 5.29 mmol) and N,N-diisopropylethylamine (0.91 g, 7.06 mmol) were gradually added at 0°C. The system was then warmed to room temperature and reacted for 24 hours. The reaction was quenched by adding 50 mL of saturated aqueous sodium bicarbonate solution to the system, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 25b (0.94 g, yield: 99%), which was used directly in the next reaction.

[0331] Step 2 5,8-Dichloroquinolin-2(1H)-one 25c 2mL of dichloromethane and compound 25b (0.51g, 1.67mmol) were added to a 100mL single-neck flask in that order, concentrated sulfuric acid (1.33mL, 25.05mmol) was slowly added dropwise at 0°C, the ice bath was removed, and the reaction was continued for 4 hours. The solvent was removed under reduced pressure, the reaction solution was added dropwise to 50mL of ice water, extracted with ethyl acetate (50mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 25c (0.21g, yield: 56%). MS m / z (ESI): 214.1 [M+1].

[0332] Step 3 2,5,8-Trichloroquinoline 25d Compound 25c (213 mg, 0.99 mmol) and 2 mL of phosphorus oxychloride were added in a 50 mL single-neck flask, and the temperature of the system was raised to 95° C. and reacted for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was washed with a saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, title compound 25d (230 mg, yield: 99%), which was used as it was in the next reaction. MS m / z (ESI): 231.9 [M+1].

[0333] Step 4 5,8-Dichloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine 25 3 mL of isopropanol, compound 25d (234 mg, 1.01 mmol), compound 1b (174 mg, 1.01 mmol), and trifluoroacetic acid (344 mg, 3.02 mmol) were added in sequence to a 25 mL sealed tube, and the temperature was raised to 95 ° C. and reacted for 16 hours. The reaction was cooled to room temperature, 25 mL of water was added, extracted with ethyl acetate (25 mL × 3), washed with saturated sodium chloride solution (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 80% to 95%, flow rate: 30 mL / min) to give the title compound 25 (230 mg, yield: 59%). MS m / z (ESI): 369.0 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.79 (d, 1H), 8.35 (d, 1H), 7.81 (d, 1H), 7.51 (dd, 1H), 7.46 (d, 1H), 7.40 (d, 1H), 7.27 (d, 1H).

[0334] Example 26 8-Chloro-2-((2,2-difluorobenzo[d][1,3]dioxolan-5-yl)amino)quinoline-6-carbonitrile 26 [ka]

[0335] Step 1 N-(4-bromo-2-chlorophenyl)-3,3-dimethoxypropanamide 26b 25mL of tetrahydrofuran, 4-bromo-2-chloroaniline 26a (3.0g, 14.53mmol, J&K), and compound 14c (2.36g, 15.98mmol) were added in sequence to a 100mL three-neck flask, and sodium bis(trimethylsilyl)amide (2M tetrahydrofuran solution, 10.89mL, 21.79mmol) was gradually added dropwise at 0°C, after which the system was warmed to room temperature and reacted for 24 hours. 50mL of saturated ammonium chloride solution was added to the system to quench the reaction, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (50mL x 3), the organic phase was combined and washed with saturated sodium chloride solution (50mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 26b (4.60g, yield: 98%), which was used as is in the next reaction.

[0336] Step 2 6-Bromo-8-chloroquinolin-2(1H)-one 26c 5mL of dichloromethane and compound 26b (4.60g, 14.25mmol) were added in a 100mL single-neck flask in that order, and concentrated sulfuric acid (11.40mL, 213.89mmol) was slowly added dropwise at 0°C, and then the ice bath was removed and the reaction was continued for 2 hours by heating to 90°C. The solvent was removed under reduced pressure, the residue was dropped into 50mL of ice water, extracted with ethyl acetate (50mL x 5), the combined organic phase was washed with saturated sodium chloride solution (50mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 26c (0.46g, yield: 12%). MS m / z (ESI): 257.9 [M+1].

[0337] Step 3 6-Bromo-2,8-dichloroquinoline 26d Compound 26c (460 mg, 1.78 mmol) and 2 mL of phosphorus oxychloride were added in a 50 mL single-neck flask, and the temperature of the system was raised to 95° C. and reacted for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, title compound 26d (440 mg, yield: 89%), which was used as it was in the next reaction.

[0338] Step 4 6-Bromo-8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine 26e In a 25 mL sealed tube, 3 mL of isopropanol, compound 26d (280 mg, 1.01 mmol), compound 1b (175 mg, 1.01 mmol), and trifluoroacetic acid (345 mg, 3.03 mmol) were added in sequence, and the temperature was raised to 95° C. and reacted for 16 hours. The reaction was cooled to room temperature, 25 mL of saturated sodium bicarbonate solution was added, and extracted with ethyl acetate (25 mL×3). The organic phase was washed with saturated sodium chloride solution (25 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 26e (260 mg, yield: 62%). MS m / z (ESI): 412.9 [M+1].

[0339] Step 5 8-Chloro-2-((2,2-difluorobenzo[d][1,3]dioxolan-5-yl)amino)quinoline-6-carbonitrile 26 In a 25 mL three-neck flask, 3 mL of N,N-dimethylacetamide, compound 26e (150 mg, 0.36 mmol), zinc cyanide (126 mg, 1.01 mmol), zinc dust (3.50 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (46 mg, 0.08 mmol) were added in that order, heated to 135 °C, and reacted for 3 h. The reaction was cooled to room temperature, 25 mL of water was added, extracted with ethyl acetate (25 mL x 3), washed with saturated sodium chloride solution (25 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 80% to 95%, flow rate: 30 mL / min) to obtain the title compound 26 (55 mg, yield: 63%). MS m / z (ESI): 360.1 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.74 (s, 1H), 8.36 (s, 1H), 8.22-8.12 (m, 2H), 7.53 (d, 1H), 7.41 (d, 1H), 7.22 (d, 1H).

[0340] Example 27 8-Chloro-6-cyclopropyl-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine 27 [ka] Compound 26e (165 mg, 0.40 mmol) was dissolved in 7.5 mL of 1,4-dioxane and water (V / V=4:1), and cyclopropylboronic acid 27a (41 mg, 0.48 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), sodium carbonate (127 mg, 1.20 mmol), and dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene palladium(II) (39 mg, 0.06 mmol, BiDe Pharmaceutical) were added. After purging with nitrogen gas three times, the temperature was raised to 100 ° C. and the reaction was carried out for 3 hours. The reaction was cooled to room temperature, and saturated sodium bicarbonate solution (25 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 75% to 95%, flow rate: 30 mL / min) to obtain the title compound 27 (20 mg, yield: 13%). MS m / z (ESI): 375.1 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.85 (d, 1H), 8.05 (d, 1H), 7.55 (d, 1H), 7.48-7.44 (m, 2H), 7.36 (d, 1H), 7.09 (d, 1H), 2.08-2.03 (m, 1H), 1.06-0.97 (m, 2H), 0.81-0.75 (m, 2H).

[0341] Example 28 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-6-(tetrahydro-2H-pyran-4-yl)quinolin-2-amine 28 [ka]

[0342] Step 1 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-6-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-amine 28b Compound 26e (181 mg, 0.44 mmol) was dissolved in 7.5 mL of 1,4-dioxane and water (V / V=4:1), and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester 28a (92 mg, 0.44 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), sodium carbonate (140 mg, 1.31 mmol), and dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene palladium(II) (29 mg, 0.044 mmol) were added. After purging with nitrogen gas three times, the temperature was raised to 100 ° C. and the reaction was carried out for 3 hours. The reaction was cooled to room temperature, and saturated sodium bicarbonate solution (25 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 28b (140 mg, yield: 77%). MS m / z (ESI): 417.0 [M+1].

[0343] Step 2 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-6-(tetrahydro-2H-pyran-4-yl)quinolin-2-amine 28 Compound 28b (140 mg, 0.34 mmol) was dissolved in 10 mL of ethyl acetate, and platinum carbon (70 mg, 5% Wt., 50% to 70% water content, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, and the mixture was replaced with hydrogen gas three times and reacted in a hydrogen atmosphere for 24 hours. The reaction solution was filtered through diatomaceous earth, the solvent was removed under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 70% to 95%, flow rate: 30 mL / min) to obtain the title compound 28 (70 mg, yield: 50%). MS m / z (ESI): 419.0 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.86 (d, 1H), 8.11 (d, 1H), 7.74 (d, 1H), 7.61 (d, 1H), 7.47 (dd, 1H), 7.37 (d, 1H), 7.10 (d, 1H), 3.99 (dd, 2H), 3.46 (td, 2H), 2.93-2.85 (m, 1H), 1.83-1.68 (m, 4H).

[0344] Example 29 8-Chloro-7-cyclopropyl-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine 29 [ka]

[0345] Step 1 N-(3-bromo-2-chlorophenyl)-3,3-dimethoxypropanamide 29b 3-Bromo-2-chloro-aniline 29a (2.0 g, 9.72 mmol, BiDe Pharmaceutical) was dissolved in 15 mL of tetrahydrofuran, compound 14c (1.58 g, 10.68 mmol) was added, the reaction was cooled to 0°C, sodium bis(trimethylsilyl)amide (2M tetrahydrofuran solution, 5.4 mL, 10.7 mmol) was added dropwise, and the system was warmed to room temperature and reacted for 16 hours. Saturated ammonium chloride solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and dried under vacuum to obtain the crude product, title compound 29b (3.1 g, yield: 99%), which was used directly in the next reaction without purification. MS m / z (ESI): 321.9 [M+1].

[0346] Step 2 7-Bromo-8-chloroquinolin-2(1H)-one 29c Compound 29b (3.1 g, 9.61 mmol) was dissolved in 3 mL of dichloromethane, cooled to 0° C., and concentrated sulfuric acid (7.7 mL, 144 mmol) was added. The ice bath was then removed, and the mixture was heated to 90° C. and reacted for 2 hours. The reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, the residue was dropped into 50 mL of ice water, extracted with ethyl acetate (50 mL×5), the organic phase was combined and washed with saturated sodium chloride solution (50 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 29c (0.56 g, yield: 23%). MS m / z (ESI): 257.9 [M+1].

[0347] Step 3 7-Bromo-2,8-dichloroquinoline 29d Compound 29c (560 mg, 2.17 mmol) and 3 mL of phosphorus oxychloride were added in a 50 mL single-neck flask, and the temperature of the system was raised to 95° C. and reacted for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, title compound 29d (599 mg, yield: 99%), which was used in the next reaction without purification.

[0348] Step 4 7-Bromo-8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine 29e In a 25 mL sealed tube, 3 mL of isopropanol, compound 29d (600 mg, 2.17 mmol), compound 1b (319 mg, 1.84 mmol), and trifluoroacetic acid (741 mg, 6.50 mmol) were added in sequence, and the temperature was raised to 95° C. and reacted for 16 hours. The reaction was cooled to room temperature, 25 mL of saturated sodium bicarbonate solution was added, and extracted with ethyl acetate (25 mL×3). The organic phase was washed with saturated sodium chloride solution (25 mL×2) and dried over anhydrous sodium sulfate. After filtration, the filtrate was removed of the solvent under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 29e (554 mg, yield: 62%). MS m / z (ESI): 412.9 [M+1].

[0349] Step 5 8-Chloro-7-cyclopropyl-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinolin-2-amine 29 Compound 29e (140 mg, 0.34 mmol) was dissolved in 7.5 mL of 1,4-dioxane and water (V / V=4:1), and compound 27a (37.8 mg, 0.44 mmol), sodium carbonate (107.6 mg, 1.02 mmol), and dichloro[1,1'-bis(ditert-butylphosphino)ferrocenepalladium(II) (33.0 mg, 0.051 mmol) were added. After replacing with nitrogen gas three times, the temperature was raised to 100 ° C. and the reaction was carried out for 3 hours. The reaction was cooled to room temperature, and saturated sodium bicarbonate solution (25 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL × 2), and the organic phase was combined, and the organic phase was washed with saturated sodium chloride solution (50 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 55% to 95%, flow rate: 30 mL / min) to obtain the title compound 29 (30 mg, yield: 23%). MS m / z (ESI): 375.4 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.92 (d, 1H), 8.08 (d, 1H), 7.64 (d, 1H), 7.48 (dd, 1H), 7.37 (d, 1H), 7.05 (d, 1H), 6.90 (d, 1H), 2.50-2.42 (m, 1H), 1.15-1.10 (m, 2H), 0.86-0.81 (m, 2H).

[0350] Example 30 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-7-(tetrahydro-2H-pyran-4-yl)quinolin-2-amine 30 [ka]

[0351] Step 1 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-amine 30a Compound 29e (170 mg, 0.41 mmol) was dissolved in 7.5 mL of 1,4-dioxane and water (V / V=4:1), and compound 28a (104 mg, 0.49 mmol), sodium carbonate (131 mg, 1.23 mmol), and dichloro[1,1'-bis(ditert-butylphosphino)ferrocenepalladium(II) (16 mg, 0.025 mmol) were added. After replacing with nitrogen gas three times, the temperature was raised to 100 ° C. and the reaction was carried out for 3 hours. The reaction was cooled to room temperature, and saturated sodium bicarbonate solution (25 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL × 2), and the organic phase was combined, and the organic phase was washed with saturated sodium chloride solution (50 mL × 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was stripped of solvent under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to give the title compound 30a (70 mg, yield: 41%). MS m / z (ESI): 417.0 [M+1].

[0352] Step 2 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-7-(tetrahydro-2H-pyran-4-yl)quinolin-2-amine 30 Compound 30a (70 mg, 0.17 mmol) was dissolved in 5 mL of ethyl acetate, and platinum carbon (35 mg, 5% Wt., 50%-70% water content, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, and the mixture was replaced with hydrogen gas three times and reacted in a hydrogen atmosphere for 24 hours. The reaction solution was filtered through diatomaceous earth, the solvent was removed under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous ammonium bicarbonate solution and methanol, methanol gradient: 75%-95%, flow rate: 30 mL / min) to obtain the title compound 30 (10 mg, yield: 14%). MS m / z (ESI): 419.1 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.90 (d, 1H), 8.12 (d, 1H), 7.74 (d, 1H), 7.48 (dd, 1H), 7.40-7.35 (m, 2H), 7.08 (d, 1H), 4.01 (dd, 2H), 3.54 (td, 2H), 2.04-1.95 (m, 1H), 1.87-1.69 (m, 4H).

[0353] Example 31 5-((8-chloroquinolin-2-yl)amino)-3-methylbenzo[d]oxazol-2(3H)-one 31 [ka] 5-Amino-3-methyl-1,3-benzoxazol-2(3H)-one 31a (123 mg, 0.75 mmol, BiDe Pharmaceutical), compound 1a (135 mg, 0.68 mmol), cesium carbonate (333 mg, 1.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (78.9 mg, 0.14 mmol) and tris(dibenzylideneacetone)dipalladium (63 mg, 0.068 mmol) were dissolved in 5 mL of 1,4-dioxane and the reaction was heated to 100 °C and allowed to react for 12 h. The reaction was cooled to room temperature, 30 mL of water was added, extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 45% to 95%, flow rate: 30 mL / min) to give the title compound 31 (74 mg, yield: 33%). MS m / z (ESI): 324.1 [M-1]. 1 H NMR (500 MHz, CDCl3) δ 9.89 (s, 1H), 9.00 (d, 1H), 8.14 (d, 1H), 7.80 (d, 1H), 7.75 (d, 1H),7.33-7.22 (m, 3H), 7.14 (d, 1H), 3.39 (s, 3H).

[0354] Biological evaluation Explanation of the abbreviations used below: po: Oral administration Bid: twice a day qd: once a day MC: Sodium carboxymethylcellulose Test Example 1: Preventive and therapeutic effects of the compounds disclosed herein on ulcerative colitis (UC) in mice

[0355] 1. Summary In this experiment, female Vittoria C57BL / 6 mice were selected to establish a dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) model, and the preventive and therapeutic effects of the positive compound ABX-464 (see compound 90 in WO2015001518A1) and compound 1 of the present disclosure against DSS-induced ulcerative colitis were evaluated. [ka]

[0356] 2. Experimental methods and materials 2.1. Experimental animals and breeding conditions In the experiments, C57BL / 6 female mice from Weitong Lihua Laboratory Animal Co., Ltd. (Production License Number: SCXK (Zhejiang) 2019-0001, Animal Qualification Certificate Number: 20210401Abzz0619000795) were used, weighing 20-22 g at the time of purchase, and were housed in an independent SPF space with 5 mice / cage, regulated with a 12 / 12 h light / dark cycle, the temperature was kept at 23 ± 1 °C, humidity was 50%-60%, and food and water were available ad libitum. After purchasing the animals, they were kept for at least 1 week to adapt before starting the experiment.

[0357] 2.2. Experimental Reagents and Equipment Dextrane sulfate sodium salt (DSS): MP Biomedicals, product number 160110, lot number S5036. Prepared in sterile water, filtered, not autoclaved, and changed once every 2 days. Ethanol: Shanghai Baite Medical Supplies Co., Ltd., Lot No. S2001050. Olive oil: Sinopharm Group Chemical Reagents Co., Ltd., product number 30189828, lot number 20180104. Methylcellulose M450: Sinopharm Group Chemical Reagents Co., Ltd., product number 69016460, lot number 20170308. Plate reader: Manufacturer BMGlabtech, model number PHERAstar Fs. Benchtop low-speed centrifuge: Manufacturer Eppendorf, model number 5417R. Electronic balance: METTLER TOLEDO Instruments Co., Ltd., model number AL204.

[0358] 2.3. Experimental design and methods 2.3.1. Animal Grouping: Mice were adaptively housed and then divided into groups as follows:

[0359] [Table 3-1] [Table 3-2] Solvent: 0.5% MC suspension 2.3.2. Preparation of the drug: Preparation method of DSS: 25g DSS + 1L ultrapure water, sterile filtered and stored at 4℃. Method for preparation of 50 mg / kg ABX-464: 100 mg ABX-464 + 20 mL 0.5% MC, ground and stored at 4° C. Prepared in duplicate. Method for preparing 50 mg / kg of compound 1 according to the present disclosure: 100 mg of compound 1 according to the present disclosure + 20 mL of 0.5% MC, polished and stored at 4°C. 2.3.3 Experimental Method: Mice were randomly divided into five groups according to body weight: normal control group (Naive group), model group (DSS group), ABX-464 (50 mg / kg, po, qd), ABX-464 (50 mg / kg, po, bid), and compound 1 according to the present disclosure (50 mg / kg, po, bid). After adaptive breeding, the mice were fed 2.5% DSS from day 0, and fed with DSS for 7 days, and then fed with normal water until day 10. In addition, solvents and drugs corresponding to days 0 to 10 were administered intragastrically for 10 consecutive days, and the weight changes of the mice were observed every day between days 0 and 10. On day 10, the mice were weighed and the length of the colon was measured.

[0360] 2.4. Data Representation and Statistical Treatment The experimental data are shown as the mean ± standard error of the mean (SEM). Statistical comparison was performed by t-test using Excel software. When analyzing and comparing the data of the model group and the normal control group, #P<0.05 indicates that the model group has a significant difference compared to the normal control group, ##P<0.01 indicates that the model group has a large significant difference compared to the normal control group, and ###P<0.001 indicates that the model group has a very large significant difference compared to the normal control group. *P<0.05 indicates that the treatment group has a significant difference compared to the model group, **P<0.01 indicates that the treatment group has a large significant difference compared to the model group, and ***P<0.001 indicates that the treatment group has a very large significant difference compared to the model group.

[0361] 3.Results 3.1 Effect of Compound 1 of the Present Disclosure on Body Weight of DSS-Induced UC Mice According to the results of the body weight experiment (FIG. 1), compared with the normal control group, the mice in the DSS model group showed a clear decrease in body weight from day 4, and the weight loss gradually increased, with the weight loss reaching 30.0% (P<0.001) on day 10. Compared with the DSS model group, the weight of all the administration groups increased significantly from day 7, and on day 10, the weight loss of 50 mg / kg ABX-464 (qd), ABX-464 (bid), and compound 1 (bid) of the present disclosure was reduced to 14.1% (P<0.001), 10.3% (P<0.001), and 0.4% (P<0.001), respectively. At the end of the experiment, the weight recovery was strongest in the order of compound 1 of the present disclosure 50 mg / kg (bid)>ABX-464 50 mg / kg (bid)>ABX-464 50 mg / kg (qd).

[0362] 3.2 Effect of Compound 1 of the Present Disclosure on Colon Length in DSS-Induced UC Mice According to the results of colon length (Figure 2), compared with the normal control group, the DSS model group had a significantly shortened colon length of only 75.4% of the normal control group (P<0.001), and compared with the DSS model group, the entire administration group had a significantly longer colon length, with 50mg / kg ABX-464 (qd), ABX-464 (bid), and compound 1 (bid) of the present disclosure having a colon length of 85.5% (P<0.05), 89.3% (P<0.05), and 91.9% (P<0.01) of the normal control group, respectively. The order of colon length is compound 1 of the present disclosure 50mg / kg (bid)>ABX-464 50mg / kg (bid)>ABX-464 50mg / kg (qd).

[0363] 4. Conclusion DSS model is an animal model of UC simulating IBD disease. The molecular weight (36000-50000) of DSS, lot number, storage form, mouse breeding environment, strain, etc. all affect the effect of the model. The model construction was relatively successful, and there were significant changes in mouse body weight and colon length. The results showed that compound 1 of the present disclosure showed better efficacy than the positive drug ABX-464 in body weight and colon length. Therefore, 50 mg / kg of ABX-464 and compound 1 of the present disclosure have a certain preventive and therapeutic effect on DSS-induced UC, and compound 1 of the present disclosure has the strongest efficacy, higher than ABX-464 at the same dose.

[0364] Test Example 2. Upregulation effect of the compound according to the present disclosure on miR-124 Summary This study is to evaluate the upregulation effect of compounds of the present disclosure on miR-124.

[0365] II. Experimental materials and equipment 1. Human T-cell activator CD3 / CD28 magnetic beads (Dynabead Human T-Activator CD3 / CD28 for T Cell Expansion and Activation) (Gibco, 11131D) 2. Pan T Cell Isolation Kit, human (Miltenyi, 130-096-535) 3. Human Interleukin 2 (IL-2) (Peprotech, 200-02-100) 4. Small RNA extraction reagent kit (microRNA extraction reagent kit) (Qiagen, 217004) 5. Mini RNA Reverse Transcription Kit (miScript II RT Kit) (Qiagen, 218161) 6. Small RNA SYBR Green PCR Reagent Kit (miScript SYBR Green PCR Kit) (Qiagen, 218073) 7. Phosphate buffer PBS, pH 7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320) 8. Bovine serum albumin, BSA (Hekidonten, ST023) 9.EDTA (0.5 M), pH 8.0 (Invitrogen, AM9260G) 10. LS Columns (Miltenyi, 130-042-401) 11. 24-well cell culture plate (Corning, 3524) 12. 96-well plate (Corning, 3788) 13. Cell incubator (Thermo, Steri cycle i160) 14. Real-time fluorescent quantitative PCR device (Applied Biosystem, QuantStudio6 Flex) 15. PCR device (Applied biosystem, ProFlex) 16. 96-well clear PCR plate, 0.2 mL (Applied biosystems, N8010560) 17. RPMI 1640 medium (Gibco, 11875119) 18. Fetal bovine serum, FBS (Gibco, 10099-141) 19. Magnetic rack (Invitrogen, DynaMag TM -2) 20. 6-well cell culture plate (Thermo, 150239) 21.Spectrophotometer (IMPLEN, NP80) 22.Magnetic Bead Separator Rack (QuadroMACS Separator) (Miltenyi, 130-090-976) 23. miR124-3P-F primer (customized by GENEWIZ) 24. hsa-U6 detection primer (TIANGEN, CD201-0145)

[0366] III. Experimental Procedure The effect of compounds on miR-124 expression levels was detected in T cells after CD3 / CD28 antibody activation. After treating activated T cells with compounds, the total RNA of the cells was extracted, and the resulting cDNA was reverse transcribed as a template and quantified by SYBR green fluorescent quantitative PCR using specific miR-124 primers.

[0367] Isolation of T cells: Human peripheral blood mononuclear cells (PBMCs) obtained were purchased, counted, centrifuged, washed once with isolation buffer (PBS pH 7.4, containing 0.5% BSA and 2 mM EDTA), the supernatant was discarded, and 1 × 10 7 Each component was added to the cells in an amount of 40 μL of buffer and 10 μL of pan T Cell Biotin-Antibody Cocktail per cell, the precipitate was resuspended and mixed uniformly, and incubated in a refrigerator at 4 °C for 5 minutes. After incubation, 1 × 10 7 Each component was added in an amount of 30 μL of buffer and 20 μL of T cell separation magnetic beads (Pan T Cell MicroBeads Cocktail) per cell, mixed uniformly, and incubated in a refrigerator at 4°C for 10 minutes. The LS column was pre-rinsed with 3 mL of cell separation buffer, and the above cell suspension was applied to the column. After the cell suspension was applied to the column, the column was washed three times with 1 mL of cell separation buffer, and the flow-through cell solution was collected in a 15 mL centrifuge tube, i.e., enriched T cells. The cells were counted and found to be 1 x 106 The cells were cultured at a density of 10 cells / mL in RPMI1640 medium (complete medium) containing 10% FBS and 40 U / mL IL-2, and stored on ice until ready for use.

[0368] T cell activation: 1×10 6 Add 25μL of activated magnetic beads per cell, take out the corresponding T cell activated CD3 / CD28 magnetic beads and place them in a 1.5mL centrifuge tube, shake for 30s on a shaker before aspirating. Wash the activated magnetic beads three times with culture medium at a volume ratio of more than 1:1 in the centrifuge tube, remove all washing solution in the final time, and add an equal amount of complete medium to the initial volume to resuspend the activated magnetic beads. Add the washed activated magnetic beads to the cell resuspension and mix evenly. Take out the 6-well plate, add cells in a volume of 3mL per well, and culture in a cell incubator at 37℃, 5%CO2 for 2 days.

[0369] Treatment with compounds: Compound stock solution 20 mM was diluted with DMSO to 200 μM, further diluted 4-fold with complete medium to 50 μM (50x), mixed uniformly and prepared for use. 4-fold dilution with DMSO (25% DMSO) was used as a negative control. T cells were activated for 2 days, the cells were pipetted uniformly, a 1.5 mL centrifuge tube was attached using a magnetic rack, the activated magnetic beads were removed, and the cell suspension was collected. After counting the cells, they were centrifuged at 300xg for 10 min to discard the supernatant, and the cells were collected at 1.02 x 10 6 980 μL of cell suspension and 20 μL of 50× compound were added to each 24-well plate to give a final compound concentration of 1 μM. The cells were kept in a 37°C, 5% CO2 cell incubator and cultured for 3 days.

[0370] RNA extraction: T cells were collected by centrifugation, centrifuged at 1500 rpm for 3 minutes, washed once with PBS, centrifuged, and the supernatant was discarded. Total RNA of cells was extracted using a small RNA extraction reagent kit according to the instruction manual. 700 μL of Trizol cell lysis solution was added to the cell pellet, pipetted evenly with a pipette head, and left to stand at room temperature for 5 minutes. 140 μL of chloroform was added, mixed evenly by shaking, and left to stand at room temperature for 3 minutes. The chloroform-cell lysis solution mixture was centrifuged at 12000 x g for 15 minutes at 4 °C. The upper layer solution was transferred to a new RNA enzyme-free (RNase-free) centrifuge tube, 1.5-fold volume of absolute ethanol was added, and pipetted several times with a pipette head. The solution was transferred to an RNA adsorption column and centrifuged at 8000 x g for 15 s. The centrifugation column was washed once with 700 μL of RWT solution and centrifuged at 8000 x g for 15 s, and washed twice by adding 500 μL of RPE solution and centrifuged at 8000 x g for 2 min. The adsorption column was placed in a new 2 mL centrifuge tube and centrifuged at 12000 x g for 1 min to remove residual washing solution. The adsorption column was placed in a new 1.5 mL centrifuge tube, 30 to 50 μL of RNA enzyme-free water was added, and centrifuged at 12000 x g for 2 min. The collected solution was used as the RNA solution, and the RNA concentration was measured using a spectrophotometer. The RNA solution was stored in a refrigerator at -80 °C.

[0371] Reverse transcription: Place the extracted RNA template on ice, take out the small RNA reverse transcription reagent kit, thaw some components (including 5x miScript HiSpec Buffer, 10x miScript nucleic mix and RNA enzyme-free water) at room temperature, and thaw the miScript Reverse Transcriptase mix components on ice. Each reaction (10μL) components were 5x miScript HiSpec Buffer (2μL), 10x miScript nucleic mix (1μL), miScript Reverse Transcriptase mix (1μL), RNA enzyme-free water (2μL), and RNA template (4μL), and the above reaction was prepared on ice. The sample was placed in a PCR machine and the program was set as follows: 37℃ for 60 minutes, 95℃ for 5 minutes, and stored at 4℃. The sample that completed the reaction became a cDNA sample.

[0372] Fluorescent quantitative PCR: The transcription level of miR-124 was detected by SYBR green staining, and the transcription level of the housekeeping gene U6 was detected as an internal standard. All the reagents required for the small RNA SYBR green PCR reagent kit were thawed at room temperature, and each cDNA sample template was diluted 10-fold with RNA enzyme-free water, and then further diluted 5-fold. The reaction mixture was prepared according to Table 1 below, and the reaction mixture was placed in a 96-well PCR plate, the plate was blocked with a blocking film, and centrifuged. The PCR reaction was performed using a fluorescent quantitative PCR device according to the steps in Table 2.

[0373] [Table 4]

[0374] [Table 5]

[0375] [Table 6] Data analysis: The ratio of the expression level of miR-124 in each sample to the internal standard U6 was calculated by the C value calculated by the software, i.e., ΔC (test compound) = C miRNA-124 (Test Compound)-CT U6 (test compound) was calculated. The relative expression level was calculated as follows: Relative expression level (test compound) = 2 (-[ΔCT(試験化合物)-ΔCT(DMSO)]) It was calculated by the formula:

[0376] [Table 7-1] [Table 7-2] Conclusion: The compounds according to the present disclosure have good activity in promoting the upregulation of miR124.

[0377] Test Example 3: Pharmacokinetic test of the compound according to the present disclosure 1. Summary Using rats as test animals, the compound of Example 2 and Comparative Compound A were administered intragastrically and intravenously to rats (see Compound (1) of Example 3 of WO2016135052A1), and the plasma drug concentrations at different time points were measured by LC / MS / MS. The pharmacokinetic behavior of the compound according to the present disclosure in the rat body was studied, and its pharmacokinetic characteristics were evaluated. [ka]

[0378] 2. Test plan 2.1 Study Drugs Compound of Example 2, Comparative Compound A. 2.2 Test animals Sixteen healthy adult SD rats, half male and half female, were equally divided into four groups and purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd. 2.3 Drug Preparation A certain amount of drug was weighed out and prepared into a clear solution by adding 5% DMSO, 5% Tween® 80 and 90% saline. 2.4 Administration Intragastric administration group: SD rats were fasted overnight and then intragastric administration was performed. The dose was 2 mg / kg, and the administration volume was 10.0 mL / kg in both cases. Intravenous group: SD rats were fasted overnight and then intravenously administered with a dose of 1 mg / kg and an administration volume of 5.0 mL / kg.

[0379] 3, operation Intragastric administration group: The compound of Example 2 and Comparative Compound A were administered intragastrically to rats, and 0.1 mL of blood was collected from the orbit before and after administration at 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, 11.0 hours, and 24.0 hours, and placed in an EDTA-K2 anticoagulant test tube and centrifuged at 10,000 rpm at 4°C for 1 minute. Plasma was separated within 1 hour and stored at -20°C for measurement. The process from blood collection to centrifugation was carried out under ice bath conditions. The rats were fed 2 h after administration.

[0380] Intravenous group: The compound of Example 2 and comparative compound A were intravenously injected into rats, and blood samples were taken before administration and at 5 minutes, 15 minutes, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 8.0 hours, 11.0 hours, and 24.0 hours after administration, and treated in the same manner as the intragastric administration group.

[0381] The content of compounds to be measured in rat plasma after various concentrations of drugs were administered intragastrically and intravenously was measured: 20 μL of rat plasma was collected at each time point after administration, 50 μL of internal standard solution (camptothecin 100 ng / mL) and 200 μL of acetonitrile were added, mixed by vortex for 5 minutes, and centrifuged for 10 minutes (3700-4000 rpm). 1.0-2.0 μL of the supernatant was taken from the plasma sample and subjected to LC / MS / MS analysis.

[0382] 4. Pharmacokinetic parameters

[0383] [Table 8]

[0384] [Table 9] Conclusion: As can be seen from Tables 5 and 6, compared with Comparative Compound A, the compound of Example 2 according to the present disclosure has better pharmacokinetic absorption and significant advantages in pharmacokinetics.

Claims

1. A compound represented by the general formula (I) or a medicamentous salt thereof, 【Chemistry 1】 Among them, Ring A is a cycloalkyl group or a heterocyclyl group; G is a N atom or CR ２ａ and Each R １ are identical or different and each independently represent a hydrogen atom, a deuterium atom, a halogen atom, an alkyl group, an alkoxy group, an oxo group, a hydroxyalkyl group, a cycloalkyloxy group, a heterocyclyloxy group, an alkenyl group, an alkynyl group, a hydroxy group, a cyano group, a nitro group, -NR ５ R ６ , -NHC(O)R ７ , -C(O)R ８ , -C(O)(CH ２ ) ｑ N.R. ９ R １０ , a cycloalkyl group, a heterocyclyl group, an aryloxy group, a heteroaryloxy group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a nitro group, an amino group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; Each R ２ are identical or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyano group and an amino group; Each R ３ are identical or different and are each independently selected from a halogen, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; Or, two adjacent R ３ form a cycloalkyl group or a heterocyclyl group together with a carbon atom on the benzene ring to which it is linked, and the cycloalkyl group or the heterocyclyl group is each independently optionally substituted with one or more identical or different substituents selected from a halogen, a hydroxy group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyano group; R ４ is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group and the heterocyclyl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen atom, a hydroxy group, a carboxy group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a nitro group, an amino group and a cyano group; R ５ and R ６ are identical or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxy group, an amino group, a cycloalkyl group and a heterocyclyl group; R ７ is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group; R ８ is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, a cycloalkyl group and a heterocyclyl group; R ９ and R １０ are identical or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxy group, an amino group, a cycloalkyl group and a heterocyclyl group; R ２ａ is selected from a hydrogen atom, a halogen, a hydroxy group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, and an amino group; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; p is 1, 2, 3 or 4, and q is 0, 1, 2 or 3; A compound represented by the general formula (I) or a medicamentable salt thereof.

2. Each R １ are identical or different and each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an oxo group, a hydroxyalkyl group, a cycloalkyloxy group, a heterocyclyloxy group, an alkenyl group, an alkynyl group, a hydroxy group, a cyano group, a nitro group, -NR ５ R ６ , -NHC(O)R ７ , -C(O)R ８ , -C(O)(CH ２ ) ｑ N.R. ９ R １０ , a cycloalkyl group, a heterocyclyl group, an aryloxy group, a heteroaryloxy group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a nitro group, an amino group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R ５ ~R １０ and q are as defined in claim 1; A compound of formula (I) according to claim 1 or a medicamentable salt thereof.

3. A compound represented by general formula (IC), general formula (I-1) or general formula (I-2) or a medicamentable salt thereof, i.e. 【Chemistry 2】 Among them, Ring A, G, R １ ~R ３ , n, m and p are as defined in claim 1; A compound of formula (I) according to claim 1 or a medicamentable salt thereof.

4. A compound represented by general formula (I-3) or general formula (I-4) or a medicamentable salt thereof, namely: 【Chemistry 3】 Among them, Ring B is a cycloalkyl group or a heterocyclyl group, wherein the cycloalkyl group or the heterocyclyl group is each independently and optionally substituted with one or more identical or different substituents selected from halogen, hydroxyl group, carboxy group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group and cyano group, preferably, Ring B is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclyl group, more preferably, Ring B is a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group; Each R ３ａ are identical or different and are each independently selected from a halogen, a hydroxy group, a carboxy group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyano group; r is 0, 1 or 2; Ring A, G, R １ , R ２ , R ４ , n and m are as defined in claim 1; A compound of formula (I) according to claim 1 or a medicamentable salt thereof.

5. Ring A is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably Ring A is a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group; and / or each R 1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -C(O)R 8 , C 1-6 alkyl, C 1-6 alkoxy and oxo, R 8 being as defined in claim 1; A compound of formula (I) according to claim 1 or a medicamentable salt thereof.

6. A compound represented by the general formula (II) or a medicamentable salt thereof, namely: 【Chemistry 4】 Among them, G １ , G ２ and G ３ are identical or different, and each independently represents an O atom, a S atom, or an NR １ａ and C.R. １ｂ R １ｃ Preferably, G 1 and G 2 are the same or different and each independently selected from an O atom, an S atom, NR 1a and CR 1b R 1c , and G 3 is CR 1b R 1c ; R １ａ represents a hydrogen atom, an alkyl group, or -C(O)R ８ , -C(O)(CH ２ ) ｑ N.R. ９ R １０ , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a nitro group, an amino group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R １ｂ and R １ｃ are identical or different and each independently represent a hydrogen atom, a deuterium atom, a halogen atom, an alkyl group, an alkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, an alkenyl group, an alkynyl group, a hydroxy group, a cyano group, a nitro group, -NR ５ R ６ , -NHC(O)R ７ , -C(O)R ８ , -C(O)(CH ２ ) ｑ N.R. ９ R １０ , a cycloalkyl group, a heterocyclyl group, an aryloxy group, a heteroaryloxy group, an aryl group and a heteroaryl group, or R １ｂ and R １ｃ together form an oxo group, in which the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; G, R ２ ~R １０ , m, p and q are as defined in claim 1; A compound of formula (I) according to claim 1 or a medicamentable salt thereof.

7. A compound represented by the general formula (III) or a medicamentable salt thereof, namely: 【Chemistry 5】 Among them, L １ , L ２ , L ３ and L ４ are identical or different, and each independently represents an O atom, a S atom, or an NR １ｄ and C.R. １ｅ R １ｆ Preferably, L 1 and L 2 are the same or different and each independently selected from an O atom, an S atom, NR 1d and CR 1e R 1f , and L 3 and L 4 are each independently CR 1e R 1f ; R １ｄ represents a hydrogen atom, an alkyl group, or -C(O)R ８ , -C(O)(CH ２ ) ｑ N.R. ９ R １０ , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a nitro group, an amino group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R １ｅ and R １ｆ are identical or different and each independently represent a hydrogen atom, a deuterium atom, a halogen atom, an alkyl group, an alkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, an alkenyl group, an alkynyl group, a hydroxy group, a cyano group, a nitro group, -NR ５ R ６ , -NHC(O)R ７ , -C(O)R ８ , -C(O)(CH ２ ) ｑ N.R. ９ R １０ , a cycloalkyl group, a heterocyclyl group, an aryloxy group, a heteroaryloxy group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a nitro group, an amino group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; G, R ２ ~R １０ , m, p and q are as defined in claim 1; A compound of formula (I) according to claim 1 or a medicamentable salt thereof.

8. Each R ２ are the same or different, and each independently represents a hydrogen atom, a halogen atom, and C １－６ alkyl group, preferably R ２ is a hydrogen atom, and / or each R 3 is the same or different and is independently selected from halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group and a cyano group, preferably R 3 is halogen; and / or R 4 is a hydrogen atom or a 3- to 8-membered heterocyclyl group, and the 3- to 8-membered heterocyclyl group is substituted with one or more identical or different substituents selected from a hydroxy group and a carboxy group; A compound of formula (I) according to claim 1 or a medicamentable salt thereof.

9. R ４ is a hydrogen atom, or 【Chemistry 6】 That is, A compound of formula (I) according to claim 1 or a medicamentable salt thereof.

10. 【Chemical 7】 【Chemistry 8】 Any one of the compounds selected from A compound of formula (I) according to any one of claims 1 to 9, or a medicamentable salt thereof.

11. A compound represented by formula (I-1C) or (I-2C) or a salt thereof, 【Chemistry 9】 Among them, R and R １１ are the same or different and are each independently selected from an alkyl group, a cycloalkyl group and a heterocyclyl group, preferably R is C １－６ is an alkyl group, R １１ is C １－６ is an alkyl group, Ring A, G, R １ ~R ３ , m, n and p are as defined in claim 1; A compound represented by formula (I-1C) or (I-2C) or a salt thereof.

12. 【Catalog 10】 This is a compound called The compound or salt thereof according to claim 11.

13. A process for preparing a compound of general formula (IC) or a medicamentable salt thereof as claimed in claim 3, comprising the steps of: 【Chemistry 11】 reacting a compound of general formula (IA) or a salt thereof with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (IC) or a medicamentable salt thereof, Among them, X is a halogen, preferably a Cl atom; Ring A, G, R １ ~R ３ , m, n and p are as defined in claim 3; method.

14. A method for preparing a compound of general formula (I) or a medicamentous salt thereof according to claim 1, comprising the steps of: 【Chemistry 12】 The compound of formula (IC) or a medicamentous salt thereof is ４’ After reacting with the —Y compound, R ４’ removing said protecting group to obtain a compound of general formula (I) or a medicamentable salt thereof, Among them, Y is a halogen, preferably a Br atom; R ４’ teeth 【Chemistry 13】 and R and R １１ are identical or different and are each independently selected from an alkyl group, a cycloalkyl group, and a heterocyclyl group; R ４ teeth 【Chemistry 14】 and Ring A, G, R １ ~R ３ , m, n and p are as defined in claim 1; method.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I) according to any one of claims 1 to 10 or a medicamentable salt thereof, and one or more pharma- ceutically acceptable vectors, diluents or excipients.

16. A compound of general formula (I) as defined in any one of claims 1 to 10 or a medicament salt thereof or a pharmaceutical composition as defined in claim 15 for use in modulating miRNA levels.

17. A compound of general formula (I) as defined in any one of claims 1 to 10 or a medicament salt thereof or a pharmaceutical composition as defined in claim 15 for use in treating and / or preventing a disease or condition, wherein the disease or condition is selected from viral infection, inflammation and cancer.

18. A compound of general formula (I) as defined in any one of claims 1 to 10 or a medicament salt thereof or a pharmaceutical composition as defined in claim 15 for use in treating and / or preventing AIDS or conditions associated with AIDS or human immunodeficiency virus (HIV).

19. The inflammation is selected from autoimmune-associated inflammatory diseases, inflammatory diseases in the central nervous system (CNS), inflammatory diseases in the joints, inflammatory diseases in the gastrointestinal tract, inflammatory diseases in the skin, other inflammatory diseases associated with epithelial cells, inflammation associated with cancer, inflammation associated with irritation, and inflammation associated with injury; and / or 18. The compound of claim 17, wherein the cancer is selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, neurilemmoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric tumors, urothelial carcinoma, ureteral tumor, thyroid cancer, osteoma, neuroblastoma, brain tumor, and myeloma.

20. 18. The compound of claim 17, wherein the inflammation is selected from inflammation associated with inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma, and colon cancer, preferably the inflammation is inflammatory bowel disease, preferably the inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).

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