Quinolineamine compounds, methods for preparing the same, and their pharmaceutical 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] This disclosure belongs to the pharmaceutical field and relates to quinolineamine compounds, methods for preparing the same, and their pharmaceutical applications. In particular, this disclosure relates to quinolineamine compounds represented by general formula (I), methods for preparing the same, pharmaceutical compositions containing such compounds, and their uses as therapeutic agents, in particular as miRNA modulators, and in the preparation of agents for treating diseases or conditions that are improved by the regulation of miRNA levels. [Background technology]

[0002] MicroRNAs (miRNAs) are a type of non-coding single-chain RNA molecule, approximately 22 nucleotides long, encoded by endogenous genes, and are involved in the regulation of post-transcriptional gene expression in plants and animals. Each miRNA may have multiple target genes, but multiple miRNAs may also regulate the same gene. This complex network allows for precise regulation of target genes. miR-124 is widely expressed in all tissues throughout the body, and is particularly highly expressed in brain tissue. Studies have shown that overexpression of miR-124 can promote the conversion of activated macrophages to a quiescent state, thereby suppressing encephalomyelitis, an autoimmune disease (Ponomarev ED et al., Nat Med, 2011;17:67-70). Furthermore, miR-124 can promote the conversion of macrophages to the M2 type, exerting an anti-inflammatory effect (Veremeyko T, et al., Plos One, 2013;8:e81774). miR-124 also affects T cell differentiation; T cells treated with miR-124 show reduced levels of both IFN-γ and TNFα. Overexpression of miR-124 exerts an anti-inflammatory effect by downregulating the STAT3 protein, reducing the expression of the inflammatory cytokine IL-17, and inhibiting Th17 cell differentiation (Wei J et.al, Cancer Res, 2013;73:3913-3926). One statistical study reported that miR-124 levels in children with ulcerative colitis were significantly lower than in healthy individuals, suggesting that upregulating miR-124 may inhibit the intestinal inflammatory response (Koukos G, et.al, Gastroenterology, 2013;145:842-852). Furthermore, the Nakamachi team discovered that miR-124 in synovial cells of rheumatoid arthritis patients was significantly downregulated compared to patients with osteoarthritis (Nakamachi, Y, et.al, Arthritis Rheum, 2009;60:1294-1304).As is evident from the above research, upregulating miR-124 can lead to the development of novel small molecule drugs that can be used for the effective treatment of related inflammatory diseases.

[0003] Inflammation is the immune system's defensive response to local infection or tissue damage, and severe inflammatory responses can damage muscles. Common findings of an inflammatory response include pain, fever, redness, swelling, and loss of function. Inflammatory diseases encompass a wide range of conditions, including autoimmune inflammatory diseases, central nervous system (CNS) inflammatory diseases, joint inflammatory diseases, gastrointestinal inflammatory diseases, and skin inflammatory diseases. Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) are two of the most common and widely recognized inflammatory diseases.

[0004] Inflammatory bowel disease (IBD) is an idiopathic inflammatory bowel disease characterized by diarrhea, abdominal pain, and potentially bloody stools. While the etiology and pathogenesis of IBD are not yet fully understood, it is known that an inflammatory response due to an abnormal reaction of the intestinal mucosal immune system plays a crucial role in its development. Many factors, including environmental, genetic, infection, and immune factors, can contribute 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, typically affecting the rectum first and gradually spreading throughout the colon. Crohn's disease, on the other hand, 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. IBD is generally described as excessive infiltration of immune cells into the intestinal mucosa, an imbalance in T cell subsets including Th17, Th1, and Treg, and excessive activation of macrophages and dendritic cells. Currently available or clinically tested drugs include JAK inhibitors that reduce inflammatory responses, TNFα antibodies, IL-12 and IL-23 antibodies that inhibit Th1 and Th17 differentiation, and integrin α4β7 antibodies that block the infiltration of inflammatory cells.

[0005] Rheumatoid arthritis is a systemic inflammatory disease affecting the synovial tissue (articular tissue) of the joints, characterized by polyarticular, symmetrical, and invasive inflammation of the small joints of the hands and feet, often accompanied by lesions of extraarticular organs, and capable of causing joint malformations and loss of function. Inflammatory cytokines (e.g., tumor necrosis factor TNFα, interleukins IL-1 and IL-6) play a crucial role in the pathogenesis of rheumatoid arthritis (RA). Treatment usually involves biological agents such as disease-modifying antirheumatic drugs (DMARDs) and TNFα inhibitors to alleviate the disease. However, patients who respond to these drugs typically lose their response after several years of use. Therefore, there is a need to develop new therapies with novel mechanisms of action that are highly effective and safe for long-term use.

[0006] Related patent applications that have been published include WO2010143169A2, WO2015001518A1, WO2016009065A2, WO2017158201A1, and WO2020127843A1, among others. [Overview of the project]

[0007] This disclosure aims to provide compounds represented by general formula (I) or medicinal salts thereof: [ka] Eventually, Ring A is a cycloalkyl group or a heterocyclyl group, G is an N atom or CR 2a And, Each R 1 These are homologous or different, and each is independently a hydrogen atom, deuterium atom, halogen, alkyl group, alkoxy group, oxo group, hydroxyalkyl group, cycloalkyloxy group, heterocyclyloxy group, alkenyl group, alkynyl group, hydroxy group, cyano group, nitro group, -NR 5 R 6 ,-NHC(O)R 7 , -C(O)R 8 -C(O)(CH2) q NR 9 R10 , selected from a cycloalkyl group, a heterocyclyl group, an aryloxy group, a heteroaryloxy group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with one or more identical or different substituents selected from 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 is identical or different and each independently selected from a hydrogen atom, 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, Each R 3 is identical or different and each independently selected from 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, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, Alternatively, two adjacent Rs among them 3 form a cycloalkyl group or a heterocyclyl group with a carbon atom on the benzene ring to be linked, and the cycloalkyl group or heterocyclyl group is each independently optionally substituted with one or more identical or different substituents selected from 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, cycloalkyl group, and heterocyclyl group are each independently optionally substituted with one or more identical or different substituents selected from halogen, 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 6These are homologous or different, and each is independently selected from a hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, hydroxyl group, amino group, cycloalkyl group, and heterocyclyl group. R 7 It is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups and heterocyclyl groups. R 8 These are selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, cycloalkyl groups, and heterocyclyl groups. R 9 and R 10 These are homologous or different, and each is independently selected from a hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, hydroxyl group, amino group, cycloalkyl group, and heterocyclyl group. R 2a These are selected from hydrogen atoms, halogens, hydroxyl groups, carboxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, and amino groups. 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 this disclosure, a compound represented by the above general formula (I) or a medicinal salt thereof, among which, Ring A is a cycloalkyl group or a heterocyclyl group, G is an N atom or CR 2a And, Each R 1 These are homologous or different, and each is independently a hydrogen atom, halogen, alkyl group, alkoxy group, oxo group, hydroxyalkyl group, cycloalkyloxy group, heterocyclyloxy group, alkenyl group, alkynyl group, hydroxy group, cyano group, nitro group, -NR 5 R 6 ,-NHC(O)R 7 , -C(O)R 8 -C(O)(CH2)q NR 9 R 10 , selected from cycloalkyl groups, heterocyclyl groups, aryloxy groups, heteroaryloxy groups, aryl groups and heteroaryl groups, of which the alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups are each independently and optionally substituted with one or more homologous or heteroatomic substituents selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, nitro groups, amino groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups. Each R 2 These are homologous or homologous, and each is independently selected from hydrogen atoms, halogens, hydroxyl groups, carboxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, and amino groups. Each R 3 These are homologous or homologous, and each is independently selected from halogens, hydroxyl groups, carboxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. Alternatively, two adjacent R 3 The carbon atoms on the linked benzene ring form a cycloalkyl group or heterocyclyl group, and each of the cycloalkyl group or heterocyclyl group is independently and optionally substituted with one or more homologous or homologous substituents selected from halogens, hydroxyl groups, carboxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, and cyano groups. R 4 The group is selected from hydrogen atoms, alkyl groups, cycloalkyl groups, and heterocyclyl groups, and each of the alkyl groups, cycloalkyl groups, and heterocyclyl groups is independently and optionally substituted with one or more homologous or homologous substituents selected from halogens, hydroxyl groups, carboxyl groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, nitro groups, amino groups, and cyano groups. R5 and R 6 These are homologous or different, and each is independently selected from a hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, hydroxyl group, amino group, cycloalkyl group, and heterocyclyl group. R 7 It is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups and heterocyclyl groups. R 8 These are selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, cycloalkyl groups, and heterocyclyl groups. R 9 and R 10 These are homologous or different, and each is independently selected from a hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, hydroxyl group, amino group, cycloalkyl group, and heterocyclyl group. R 2a These are selected from hydrogen atoms, halogens, hydroxyl groups, carboxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, and amino groups. 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 this disclosure, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (IC) or a pharmaceutically acceptable salt thereof: [ka] Eventually, Ring A, G, R 1 ~R 3 n, m, and p are as defined in general formula (I).

[0010] In some embodiments of this disclosure, a compound represented by the above general formula (I), general formula (IC), or a pharmaceutically acceptable salt thereof, among which, [ka] teeth [ka] isn't it.

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

[0012] In some embodiments of this disclosure, the compound represented by the above general formula (I) or a medicinal salt thereof is a compound represented by the general formula (I-3) or general formula (I-4) or a medicinal salt thereof: [ka] Eventually, Ring B is a cycloalkyl group or a heterocyclyl group, and each of these cycloalkyl groups or heterocyclyl groups is independently and optionally substituted with one or more homologous or homologous substituents selected from halogens, hydroxyl groups, carboxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, and cyano groups. Each R 3a These are homologous or different, and each is independently selected from halogens, hydroxyl groups, carboxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, and cyano groups. r is 0, 1, or 2. Ring A, G, R 1 , R 2 , R 4n and m are as defined in general formula (I).

[0013] In some embodiments of this disclosure, the compound represented by the above general formula (I) or a medicinal salt thereof is a compound represented by the general formula (I-3C) or the general formula (I-4C) or a medicinal salt thereof: [ka] Eventually, 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, 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 pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group, and more preferably a cyclopentyl group.

[0015] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group.

[0016] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, among which each R 1These are homologous or different, and each is independently a hydrogen atom, a deuterium atom, a halogen, and -C(O)R 8 , C 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy groups and oxo groups, preferably a hydrogen atom, a deuterium atom, a halogen, and -C(O)R 8 and C 1-6 Selected from alkyl groups, R 8 This is as defined in general formula (I).

[0017] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, among which each R 1 These are homologous or homologous, and each is independently selected from a hydrogen atom, a deuterium atom, fluorine, an acetyl group, a methyl group, and an oxo group.

[0018] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, among which each R 1 These are homologous or different, and each is independently a hydrogen atom, a halogen, and -C(O)R 8 , C 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy groups and oxo groups, R 8 This is as defined in general formula (I).

[0019] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, among which R 8 C is a hydrogen atom. 1-6 Alkyl and halo C 1-6 Selected from alkyl groups, preferably R 8 is C1-6 is an alkyl group, more preferably, R 8 is a methyl group.

[0020] In some embodiments of the present disclosure, a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

Chemical formula

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

[0022] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) above, or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (IIC) or a pharmaceutically acceptable salt thereof: [ka] Eventually, 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 this disclosure, the compound represented by general formula (I) or general formula (II) above, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IID-1) or (IID-2), or a pharmaceutically acceptable salt thereof: [ka] Eventually, 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 this disclosure, a compound represented by the above general formula (II), general formula (IIC), general formula (IID-1), or general formula (IID-2), or a pharmaceutically acceptable salt thereof, among which G 1 and G 2 These are homologous or different, and each is independently an O atom, an S atom, and an NR atom. 1a and CR 1b R 1c Selected from, G 3 CR 1b R 1c And R 1a , R 1b and R 1c This is as defined in general formula (II).

[0025] In some embodiments of this disclosure, a compound represented by the above general formula (II), general formula (IIC), general formula (IID-1), or general formula (IID-2), or a pharmaceutically acceptable salt thereof, among which G 1 is an O atom or NR 1a G 2 and G 3 Each of them independently performs CR 1b R 1c And R 1a , R 1b and R 1c This is as defined in general formula (II).

[0026] In some embodiments of this disclosure, a compound represented by the above general formula (II), general formula (IIC), general formula (IID-1), or general formula (IID-2), or a pharmaceutically acceptable salt thereof, among which G 2 is an O atom or NR 1a G 1 and G 3 Each of them independently performs CR 1b R 1c And R 1a , R 1b and R 1c This is as defined in general formula (II).

[0027] In some embodiments of this disclosure, a compound represented by the above general formula (II), general formula (IIC), general formula (IID-1), or general formula (IID-2), or a pharmaceutically acceptable salt thereof, among which G 1 and G 2 Both are O atoms, G 3 CR 1b R 1c And R 1b and R 1c This is as defined in general formula (II).

[0028] In some embodiments of this disclosure, a compound represented by the above general formula (II), general formula (IIC), general formula (IID-1), or general formula (IID-2), or a pharmaceutically acceptable salt thereof, among which G 1 , G 2 and G 3 Each of them independently performs CR 1b R 1c And R 1b and R 1c This is as defined in general formula (II).

[0029] In some embodiments of this disclosure, a compound represented by the above general formula (II), general formula (IIC), general formula (IID-1), or general formula (IID-2), or a pharmaceutically acceptable salt thereof, among which, [ka] teeth [ka] G 1 and G 2 They are homologous or different, and each is independently an O atom, NR 1a and CR 1b R 1c Selected from, R 1a , R 1b and R 1c This is as defined in general formula (II), and preferably, [ka] teeth [ka] Selected from, R 1a , R 1b and R 1c This is as defined in general formula (II), and more preferably, [ka] teeth [ka] They are selected from among them.

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

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

[0032] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (III) above, or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (IIIC) or a pharmaceutically acceptable salt thereof: [ka] Eventually, 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 this disclosure, the compound represented by general formula (I) or general formula (III) above, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IIID-1) or general formula (IIID-2), or a pharmaceutically acceptable salt thereof: [ka] Eventually, 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, a compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1), or general formula (IIID-2), or a pharmaceutically acceptable salt thereof, among which L 1 and L 2 These are homologous or different, and each is independently an O atom, an S atom, and an NR atom. 1d and CR 1e R 1f Selected from, L 3 and L 4 Each of them independently performs CR 1e R 1f And R 1d , R 1e and R 1f This is as defined in general formula (III).

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

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

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

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

[0039] In some embodiments of the present disclosure, a compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1), or general formula (IIID-2), or a pharmaceutically acceptable salt thereof, among which L 1 and L 2 Both are O atoms, L 3 and L 4 Each of them independently performs CR 1e R 1f And R 1e and R 1f This is as defined in general formula (III).

[0040] In some embodiments of the present disclosure, a compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1), or general formula (IIID-2), or a pharmaceutically acceptable salt thereof, among which L 1 , L 2 , L 3 and L 4 Each of them independently performs CR 1e R 1f And R 1e and R 1f This is as defined in general formula (III).

[0041] In some embodiments of this disclosure, a compound represented by the above general formula (III), general formula (IIIC), general formula (IIID-1), or general formula (IIID-2), or a pharmaceutically acceptable salt thereof, among which, [ka] teeth [ka] And L 1 and L 2 They are homologous or different, and each is independently an O atom or CR atom. 1e R 1f And R 1e and R 1f This is as defined in general formula (III), and preferably, [ka] teeth [ka] And R 1e and R 1f This is as defined in general formula (III), and more preferably, [ka] teeth, [ka] They are selected from among them.

[0042] In some embodiments of the present disclosure, compounds represented by the above general formulas (I), (I-1), (I-2), (I-3), (I-4), (IC), (I-3C), (I-4C), (IIC), (IIIC), (II), (IID-1), (IID-2), (IIID-1), (IIID-2), and (III) or pharmaceutically active salts thereof, among which each R 2 They are homologous or different, and each is independently a hydrogen atom, a halogen, and C 1-6 Selected from alkyl groups, preferably R 2 It is a hydrogen atom.

[0043] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, among which each R 3 They are homologous or different, and each is independently a halogen or C 1-6 It is an alkyl group, preferably R 3 is a halogen, more preferably R 3 It is Cl.

[0044] In some embodiments of this disclosure, 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 pharmaceutically acceptable salt thereof, among which each R 3a They are homologous or different, and each is independently a halogen or C 1-6 It is an alkyl group, preferably R 3a is a halogen, more preferably R 3a It is Cl.

[0045] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, among which each R 3 They are homologous or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 The group is selected from either an alkoxy group or a cyano group.

[0046] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, among which each R 3 They are homologous or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy groups, 3-8 membered cycloalkyl groups, 3-8 membered heterocyclyl groups, and cyano groups, preferably each R 3 These are homologous or homologous, and each is independently selected from Cl, Br, methyl group, methoxy group, cyano group, cyclopropyl group, tetrahydropyranyl group and dihydropyranyl group, more preferably each R 3 These groups are homologous or distinct, and each is 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 this disclosure, 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 pharmaceutically acceptable salt thereof, among which each R 3a They are homologous or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 The group is selected from either an alkoxy group or a cyano group.

[0048] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, wherein p is 2, 3, or 4, and two adjacent R 3 The carbon atoms on the linked benzene ring form a cycloalkyl group or heterocyclyl group, and each of the cycloalkyl group or heterocyclyl group is independently and optionally substituted with one or more homologous or homologous substituents selected from halogens, hydroxyl groups, carboxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, and cyano groups, preferably p is 3.

[0049] In some embodiments of the present disclosure, 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), or general formula (III), or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0050] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

[0051] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, wherein p is 3.

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

[0053] In some embodiments of this disclosure, compounds represented by the above general formulas (I), (IC), (I-1), (I-2), (II), (IIC), (IID-1), (IID-2), (III), (IIIC), (IIID-1), and (IIID-2), or pharmaceutically active salts thereof, among which, [ka] teeth [ka] And R 3v , R 3w , R 3x and R 3y R is homologous or homologous, and each is independently selected from hydrogen atoms, halogens, hydroxyl groups, carboxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, or 3v , R 3w , R 3x and R 3yTwo of these adjacent carbon atoms form a cycloalkyl or heterocyclyl group with the linked carbon atom, and each of these cycloalkyl or heterocyclyl groups is independently and optionally substituted with one or more homologous or homologous substituents selected from halogens, hydroxyl groups, carboxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, and cyano groups, and the condition is R 3v , R 3w , R 3x and R 3y In different cases, is a hydrogen atom, preferably, [ka] teeth [ka] And R 3v is a halogen, and R 3w , R 3x and R 3y They are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Selected from haloalkoxy groups, cyano groups, 3-8 membered cycloalkyl groups and 3-8 membered heterocyclyl groups, or R 3w , R 3x It forms a 3- to 8-membered cycloalkyl group with linked carbon atoms, more preferably, [ka] teeth [ka] And R 3v is a halogen, and R 3w , R 3x and R 3y They are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C1-6 Selected from haloalkoxy groups, cyano groups, 3-6 membered cycloalkyl groups, and 3-6 membered heterocyclyl groups.

[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 pharmaceutically acceptable salt thereof, [ka] but [ka] If R 3v It 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 pharmaceutically acceptable salt thereof, [ka] but [ka] If R 3w , R 3x and R 3y These are homologous or homologous and each is independently selected from a hydrogen atom, Cl, Br, methyl group, methoxy group, cyano group, cyclopropyl group, tetrahydropyranyl group and dihydropyranyl group, more preferably R 3w , R 3x and R 3yThese are homologous or homologous, and each is independently selected from a hydrogen atom, Cl, methyl group, methoxy group, cyano group, cyclopropyl group, and tetrahydropyranyl group.

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

[0057] In some embodiments of this disclosure, a compound represented by general formula (I), general formula (II), or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein it is a compound represented by general formula (II-1C) or a pharmaceutically acceptable salt thereof: [ka] Eventually, G, G 1 , G 2 , R 3 , R 1b and R 1c This is as defined in general formula (II-1), In some embodiments of this disclosure, a compound represented by the general formula (II-1) or (II-1C) above, or a medicinal salt thereof, among which G 1 and G 2 They are homologous or different, and each is independently an O atom, NR 1a and CR 1b R 1c Selected from, R 1a , R 1b and R 1c This is as defined in general formula (II).

[0058] In some embodiments of this disclosure, a compound represented by the general formula (II-1) or (II-1C) above, or a medicinal salt thereof, among which G 1 is an O atom or NR 1a G 2 CR 1b R 1c And, or, G 2 is an O atom or NR 1a G 1 CR 1b R 1c And R 1a , R 1b and R 1c This is as defined in general formula (II).

[0059] In some embodiments of this disclosure, a compound represented by the general formula (II-1) or (II-1C) above, or a medicinal salt thereof, among which G 1 and G 2 These are all oxygen atoms.

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

[0061] In some embodiments of this disclosure, a compound represented by general formula (I), general formula (III), or general formula (III-1) or a pharmaceutically acceptable salt thereof, wherein it is a compound represented by general formula (III-1C) or a pharmaceutically acceptable salt thereof: [ka] Eventually, G, L 1 , L 2 , R 3 , R 1e and R 1f This is as defined in general formula (III-1).

[0062] In some embodiments of this disclosure, a compound represented by the above general formula (III-1) or general formula (III-1C) or a pharmaceutically acceptable salt thereof, among which L 1 and L 2 They are homologous or different, and each is independently an O atom, NR 1d and CR 1e R 1f Selected from, R 1d , R 1e and R 1f This is as defined in general formula (III).

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

[0064] In some embodiments of this disclosure, a compound represented by the above general formula (III-1) or general formula (III-1C) or a pharmaceutically acceptable salt thereof, among which L 1 and L 2 These are all oxygen atoms.

[0065] In some embodiments of this disclosure, 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 pharmaceutically acceptable salt thereof, among which R 3 is halogen, C 1-6 Alkyl alkyl group, C 1-6 The group is selected from either an alkoxy group or a cyano group.

[0066] In some embodiments of this disclosure, 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 pharmaceutically acceptable salt thereof, among which R 3 is halogen or C 1-6 It is an alkyl group, preferably R 3 It is a halogen, and more preferably Cl.

[0067] In some embodiments of the present disclosure, a 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 pharmaceutically acceptable salt thereof, among which R 4 is a hydrogen atom or a 3-8 membered heterocyclyl group, and the above 3-8 membered heterocyclyl group is substituted with one or more homologous or homologous substituents selected from a hydroxyl group and a carboxyl group, preferably R 4 teeth [ka] or [ka] That is the case.

[0068] In some embodiments of the present disclosure, a 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 pharmaceutically acceptable salt thereof, among which R 4 It is a hydrogen atom.

[0069] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, among which R 1a or R 1d C is a hydrogen atom. 1-6 Alkyl and -C(O)R 8 Selected from, R 8 is C 1-6 It is an alkyl group, preferably R 1a and R 1d These are homologous or different, and each is independently a methyl group or an acetyl group.

[0070] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, among which R 1b and R 1c or R 1e and R 1f They are homologous or different, and each is independently a hydrogen atom, a deuterium atom, a halogen, and C 1-6 Selected from alkyl groups, preferably R 1b and R 1c or R 1e and R 1f These are homologous or homologous, and each is independently selected from a hydrogen atom, a deuterium atom, a fluorine atom, and a methyl group.

[0071] In some embodiments of the present disclosure, 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 pharmaceutically acceptable salt thereof, among which R 1b and R 1c or R 1e and R 1f They are homologous or different, and each is independently a hydrogen atom, a halogen, and C 1-6 Selected from alkyl groups, preferably R 1e R is a hydrogen atom or a halogen, 1f is a hydrogen atom or a halogen.

[0072] 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 (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 pharmaceutically acceptable salt thereof, wherein G is CR 2a And R 2a This is as defined in general formula (I).

[0073] 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 (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 pharmaceutically acceptable salt thereof, among which R 2ais a hydrogen atom, halogen and C 1-6 Selected from alkyl groups, preferably R 2a It is a hydrogen atom.

[0074] In some embodiments of this disclosure, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycline group, and G is an N atom or CR 2a And R 2a is a hydrogen atom, halogen and C 1-6 Selected from alkyl groups, each R 1 These are homologous or different, and each is independently a hydrogen atom, a deuterium atom, a halogen, and -C(O)R 8 , C 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy groups and oxo groups, R 8 is C 1-6 It is an alkyl group, and n is 0 (i.e., R 1 ( is a hydrogen atom), 1, 2, 3 or 4, and each R 2 They are homologous or different, and each is independently a hydrogen atom, a halogen, and C 1-6 Selected from alkyl groups, m is 0 (i.e., R 2 ( is a hydrogen atom), 1 or 2, and each R 3 They are homologous or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Selected from an alkoxy group and a cyano group, p is 1, 2, or 3, R 4 This is a hydrogen atom or a 3-8 membered heterocyclyl group, and the 3-8 membered heterocyclyl group is substituted with one or more homologous or homologous substituents selected from hydroxyl groups and carboxyl groups.

[0075] In some embodiments of this disclosure, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered or 6-membered cycloalkyl group or a 5-membered or 6-membered heterocyclyl group, and G is a CR 2a And R 2a Each R is a hydrogen atom, 1These are homologous or different, and each is independently a hydrogen atom, a deuterium atom, a halogen, and -C(O)R 8 , C 1-6 Alkyl and C 1-6 Selected from alkoxy groups, R 8 is C 1-6 It is an alkyl group, and n is 0 (i.e., R 1 ( is a hydrogen atom), 1, 2, 3 or 4, and each R 2 Each R is a hydrogen atom, 3 They are homologous or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Selected from an alkoxy group and a cyano group, p is 1, 2, or 3, R 4 This is a hydrogen atom or a 3- to 8-membered heterocyclyl group, of which the 3- to 8-membered heterocyclyl group is substituted with one or more homologous or homologous substituents selected from hydroxyl groups and carboxyl groups.

[0076] In some embodiments of this disclosure, a compound represented by the above general formula (II) or a medicinal salt thereof, among which, [ka] teeth [ka] Selected from, R 1a C is a hydrogen atom. 1-6 Alkyl and -C(O)R 8 Selected from, R 8 is C 1-6 It is an alkyl group, R 1b and R 1c They are homologous or different, and each is independently a hydrogen atom, a deuterium atom, a halogen, and C 1-6 Selected from alkyl groups, G is an N atom or CR 2a And R 2a m is a hydrogen atom, and m is 0. [ka] teeth [ka] And R 3v is a halogen, and R 3w , R 3x and R 3y They are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Selected from haloalkoxy groups, cyano groups, 3-8 membered cycloalkyl groups and 3-8 membered heterocyclyl groups, or R 3w , R 3x It forms a 3-8 membered cycloalkyl group with the linked carbon atoms, R 4 This is a hydrogen atom or a 3-8 membered heterocyclyl group, and the 3-8 membered heterocyclyl group is substituted with one or more homologous or homologous substituents selected from hydroxyl groups and carboxyl groups.

[0077] In some embodiments of this disclosure, a compound represented by the above general formula (III) or a medicinal salt thereof, among which, [ka] teeth [ka] And R 1e and R 1f They are homologous or different, and each is independently a hydrogen atom, a deuterium atom, a halogen, and C 1-6 Selected from alkyl groups, G is an N atom or CR 2a And R 2a m is a hydrogen atom, and m is 0. [ka] teeth [ka] And R 3v is a halogen, and R 3w , R 3x and R3y They are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Selected from haloalkoxy groups, cyano groups, 3-6 membered cycloalkyl groups, and 3-6 membered heterocyclyl groups, R 4 This is a hydrogen atom or a 3-8 membered heterocyclyl group, and the 3-8 membered heterocyclyl group is substituted with one or more homologous or homologous substituents selected from hydroxyl groups and carboxyl groups.

[0078] In some embodiments of this disclosure, a compound represented by the above general formula (I-3) or general formula (I-4) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocycline group, ring A is a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocycline group, and G is CR 2a And R 2a Each R is a hydrogen atom, 1 These are homologous or different, and each is independently a hydrogen atom, a deuterium atom, a halogen, and -C(O)R 8 , C 1-6 Alkyl and C 1-6 Selected from alkoxy groups, R 8 is C 1-6 It is an alkyl group, and n is 0 (i.e., R 1 ( is a hydrogen atom), 1, 2, 3 or 4, R 2 Each R is a hydrogen atom, 3a They are homologous or different, and each is independently a halogen, C 1-6 Alkyl alkyl group, C 1-6 Selected from an alkoxy group and a cyano group, r is 0, 1 or 2, R 4 This is a hydrogen atom or a 3- to 8-membered heterocyclyl group, of which the 3- to 8-membered heterocyclyl group is substituted with one or more homologous or homologous substituents selected from hydroxyl groups and carboxyl groups.

[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 this disclosure relates to compounds represented by general formulas (I-1C) or (I-2C) or salts thereof: [ka] Eventually, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 this disclosure relates to compounds represented by general formulas (IID-1A) or (IID-2A) or salts thereof: [ka] Eventually, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6It is an alkyl group, R 11 is C 1-6 It 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 this disclosure relates to compounds represented by general formula (IIID-1A) or (IIID-2A) or salts thereof: [ka] Eventually, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 this disclosure, a compound represented by the above general formula (I-1C), (I-2C), (IID-1A), (IID-2A), (IIID-1A), or (IIID-2A), or a pharmaceutically acceptable salt thereof, wherein R is C 1-6 It is an alkyl group, preferably R is a methyl group.

[0084] In some embodiments of this disclosure, a compound represented by the general formula (I-1C), (I-2C), (IID-1A), (IID-2A), (IIID-1A), or (IIID-2A), or a pharmaceutically acceptable salt thereof, among which R 11 is C 1-6 It is an alkyl group, preferably R 11It is a methyl group.

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

[0086] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (I) or a medicinal salt thereof, the method being: [ka] A compound of general formula (IC) or a pharmaceutically acceptable salt thereof is R 4’ - After reacting with compound Y, R 4’ This involves removing the protecting group above to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof. Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 this disclosure relates to a method for preparing a compound represented by general formula (IC) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes 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 pharmaceutically acceptable salt thereof. Eventually, X is a halogen, preferably a Cl atom. Ring A, G, R 1 ~R 3 m, n, and p are as defined in the general formula (IC).

[0088] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves esterifying a compound of general formula (I-1C) or a salt thereof to obtain a compound of general formula (I-1) or a pharmaceutically usable salt thereof. Eventually, R and R 11 This 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 this disclosure relates to a method for preparing a compound represented by general formula (I-2) or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves esterifying a compound of general formula (I-2C) or a salt thereof to obtain a compound of general formula (I-2) or a pharmaceutically usable salt thereof. Eventually, R and R 11 This is as defined in the 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 this disclosure relates to a method for preparing a compound represented by general formula (I-3) or a pharmaceutically acceptable salt thereof, the method being: [ka] A compound of general formula (I-3C) or a pharmaceutically acceptable salt thereof is R 4’ - After reacting with compound Y, R 4’ This involves removing the protecting group above to obtain a compound of general formula (I-3) or a pharmaceutically acceptable salt thereof. Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 defined as in the general formula (I-3).

[0091] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (I-3C) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes 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 pharmaceutically acceptable salt thereof. Eventually, X is a halogen, preferably a Cl atom. Ring A, Ring B, G, R 1 , R 2 , R 3a m, n, and r are defined as in the general formula (I-3C).

[0092] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (I-4) or a pharmaceutically acceptable salt thereof, the method being: [ka] Compounds of general formula (I-4C) or their pharmaceutically acceptable salts are R 4’ - After reacting with compound Y, R 4’ This involves removing the protecting group above to obtain a compound of general formula (I-4) or a pharmaceutically acceptable salt thereof. Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 defined as in the general formula (I-4).

[0093] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (I-4C) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes 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 pharmaceutically usable salt thereof. Eventually, X is a halogen, preferably a Cl atom. Ring A, Ring B, G, R 1 , R 2 , R 3a m, n, and r are defined as in the general formula (I-4C).

[0094] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method being: [ka] Compounds of general formula (IIC) or their pharmaceutically acceptable salts are R 4’ - After reacting with compound Y, R 4’ This involves removing the protecting group above to obtain a compound of general formula (II) or a pharmaceutically usable salt thereof, Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 this disclosure relates to a method for preparing a compound represented by general formula (IIC) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes 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 pharmaceutically acceptable salt thereof. Eventually, 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 the general formula (IIC).

[0096] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (IID-1) or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves esterifying a compound of general formula (IID-1A) or a salt thereof to obtain a compound of general formula (IID-1) or a pharmaceutically usable salt thereof. Eventually, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It is an alkyl group, G, G 1 , G 2 , G 3 , R 2 , R 3 m and p are as defined in the general formula (IID-1).

[0097] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (IID-2) or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves esterifying a compound of general formula (IID-2A) or a salt thereof to obtain a compound of general formula (IID-2) or a pharmaceutically usable salt thereof. Eventually, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It is an alkyl group, G, G 1 , G 2 , G 3 , R 2 , R 3 m and p are as defined in the general formula (IID-2).

[0098] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method being: [ka] A compound of general formula (II-1C) or a pharmaceutically acceptable salt thereof is R 4’ - After reacting with compound Y, R 4’ This involves removing the protecting group above to obtain a compound of general formula (II-1) or a pharmaceutically acceptable salt thereof. Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It is an alkyl group, R 4 teeth [ka] And, G, G 1 , G 2 , R 1b , R 1c and R 3 This is as defined in general formula (II-1), and preferably R 3 It is a halogen.

[0099] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (II-1C) or a pharmaceutically usable salt thereof, the method being: [ka] This method involves 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 pharmaceutically acceptable salt thereof. Eventually, X is a halogen, preferably a Cl atom. G, G 1 , G 2 , R 1b , R 1c and R 3 This is as defined in general formula (II-1C), and preferably R 3 It is a halogen.

[0100] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method being: [ka] A compound of general formula (IIIC) or a pharmaceutically acceptable salt thereof is R 4’- After reacting with compound Y, R 4’ This involves removing the protecting group above to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof. Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 this disclosure relates to a method for preparing a compound represented by general formula (IIIC) or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes 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 pharmaceutically acceptable salt thereof. Eventually, X is a halogen, preferably a Cl atom. G, L 1 , L 2 , L 3 , L 4 , R 2 , R 3m and p are as defined in general formula (IIIC).

[0102] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (IIID-1) or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves esterifying a compound of general formula (IIID-1A) or a salt thereof to obtain a compound of general formula (IIID-1) or a pharmaceutically usable salt thereof. Eventually, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 this disclosure relates to a method for preparing a compound represented by general formula (IIID-2) or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves esterifying a compound of general formula (IIID-2A) or a salt thereof to obtain a compound of general formula (IIID-2) or a pharmaceutically usable salt thereof. Eventually, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 this disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method being: [ka] A compound of general formula (III-1C) or a pharmaceutically acceptable salt thereof is R 4’ - After reacting with compound Y, R 4’ This involves removing the protecting group above to obtain a compound of general formula (III-1) or a pharmaceutically usable salt thereof. Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It is an alkyl group, R 4 teeth [ka] And, G, L 1 , L 2 , R 1e , R 1f and R 3 This is as defined by general formula (III-1), and preferably R 3 It is a halogen.

[0105] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (III-1C) or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves 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 pharmaceutically acceptable salt thereof. Eventually, X is a halogen, preferably a Cl atom. G, L 1 , L 2 , R 1e , R 1f and R 3 This is as defined in general formula (III-1C), and preferably R 3 It is a halogen.

[0106] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of the compounds represented by 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 the compounds shown in Table A or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable vectors, diluents or excipients.

[0107] This disclosure further relates to the use of compounds represented by 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 general formula (III-1) shown in Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing them, wherein the miRNA is preferably miR-124.

[0108] This disclosure further relates to the use of compounds represented by 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 general formula (III-1) shown in Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for treating diseases or conditions that can be improved by regulation of miRNA levels.

[0109] This disclosure further relates to the use of compounds represented by 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 general formula (III-1) shown in Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for treating and / or preventing diseases or conditions, wherein the diseases or conditions are selected from viral infections, inflammation and cancer.

[0110] This disclosure further relates to the uses of compounds represented by 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 general formula (III-1) shown in Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for treating and / or preventing AIDS or AIDS-related conditions or human immunodeficiency virus (HIV).

[0111] This disclosure further relates to the preparation of agents for treating and / or preventing diseases or medical conditions, using general formulas (I), (IC), (I-1), (I-2), (I-3), (I-3C), (I-4), (I-4C), (II), (IIC), (II-1), (II-1C), (III), (IID-1), (IID-2), (IIID-1), (IIID-2), and (IIIC). With regard to the use of compounds shown in general formula (III-1C), general formula (III-1), and Table A, or their medicinal salts, or pharmaceutical compositions containing them, the above disease or condition is inflammation, and the inflammation is selected from autoimmune inflammatory diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the skin, other inflammatory diseases related to epithelial cells, cancer-related inflammation, irritation-related inflammation, and injury-related inflammation.

[0112] This disclosure further relates to the following general formulas used as agents for treating and / or preventing diseases or medical conditions: 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 the compounds shown in Table A or their medicinal salts, or pharmaceutical compositions containing them, wherein the above disease or condition is selected from viral infection, inflammation and cancer, and the above 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, Sjögren's syndrome, bronchitis, asthma and colon cancer, and preferably the above inflammation is inflammatory bowel disease.

[0113] This disclosure further relates to the use of compounds represented by 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 general formula (III-1) shown in Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for treating and / or preventing diseases or conditions. The disease is cancer, and the cancers listed above are 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 carcinoma, medullary carcinoma, bronchial cancer, liver cancer, bile duct cancer, choriocarcinoma, seminomas, embryonic carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pineal glandoma, hemangioblastoma, acoustic neuroma, schwannoma, 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 tumors, thyroid cancer, osteoma, neuroblastoma, brain tumors, and myeloma.

[0114] This disclosure further relates to a method for modulating miRNA levels, which comprises administering to a patient in need a therapeutically effective dose of a compound of formula (I), formula (IC), formula (I-1), formula (I-2), formula (I-3), formula (I-3C), formula (I-4), formula (I-4C), formula (II), formula (IIC), formula (II-1), formula (II-1C), formula (III), formula (IID-1), formula (IID-2), formula (IIID-1), formula (IIID-2), formula (IIIC), formula (III-1C), formula (III-1) and a compound shown in Table A, or a pharmaceutically usable salt thereof, or a pharmaceutical composition containing the same, preferably the miRNA being miR-124.

[0115] This disclosure further relates to a method for treating and / or preventing a disease or medical condition, wherein it provides to a patient in need a therapeutically effective amount 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) The treatment involves administering a compound shown in General Formula (III-1) and Table A, or a pharmaceutically usable salt thereof, or a pharmaceutical composition containing the same, wherein the disease or condition is preferably selected from viral infection, inflammation, and cancer, and the inflammation is preferably selected from autoimmune inflammatory diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the skin, other inflammatory diseases related to epithelial cells, cancer-related inflammation, irritation-related inflammation, and injury-related inflammation.

[0116] This disclosure further relates to the following general formulas used as agents for treating and / or preventing diseases or medical conditions: 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 the compounds shown in Table A or their medicinal salts, or pharmaceutical compositions containing them, wherein the above disease or condition is selected from viral infection, inflammation and cancer, and the above 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, Sjögren's syndrome, bronchitis, asthma and colon cancer, and preferably the above inflammation is inflammatory bowel disease.

[0117] This disclosure further relates to a method for treating and / or preventing a disease or medical condition, which includes administering to a patient in need a therapeutically effective amount of the compounds shown in Table A, or a pharmaceutically usable salt thereof, or a pharmaceutical composition containing the same, among which the above disease Alternatively, the medical condition may be selected from viral infection, inflammation, and cancer, and the cancers listed above include 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 carcinoma, medullary carcinoma, bronchial cancer, liver cancer, bile duct cancer, choriocarcinoma, seminomas, embryonic carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, The selection is made from bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pineal glandoma, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, head and neck cancer, colorectal cancer, rectal cancer, small intestine cancer, gallbladder cancer, pediatric tumors, urothelial carcinoma, ureteral tumors, thyroid cancer, osteoma, neuroblastoma, brain tumors, and myeloma.

[0118] This disclosure further relates to a method for treating and / or preventing a disease or medical condition, which includes administering to a patient in need a therapeutically effective dose of a compound of formula (I), formula (IC), formula (I-1), formula (I-2), formula (I-3), formula (I-3C), formula (I-4), formula (I-4C), formula (II), formula (IIC), formula (II-1), formula (II-1C), formula (III), formula (IID-1), formula (IID-2), formula (IIID-1), formula (IIID-2), formula (IIIC), formula (III-1C), formula (III-1) and a compound shown in Table A or a pharmaceutically usable salt thereof, or a pharmaceutical composition containing the same, wherein the disease or medical condition is selected from AIDS or AIDS-related medical conditions and human immunodeficiency virus (HIV).

[0119] This disclosure further relates to pharmaceuticals using the 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), and the compounds shown in Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing them.

[0120] This 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), and general formula (III-1) shown in Table A, or pharmaceutically usable salts thereof, or pharmaceutical compositions containing the same, wherein the miRNA is preferably miR-124.

[0121] This disclosure further relates to general formulas (I), (IC), (I-1), (I-2), (I-3), (I-3C), (I-4), (I-4C), (II), (IIC), (II-1), (II-1C), (III), (IID-1), (IID-2), (IIID-1), (IIID-2), (IIIC), (III-1C), used for purposes of treating and / or preventing diseases or medical conditions. The present invention relates to a compound represented by general formula (III-1) and Table A, or a medicinal salt thereof, or a pharmaceutical composition containing the same, wherein the disease or condition is preferably selected from viral infection, inflammation, and cancer, and the inflammation is preferably selected from autoimmune inflammatory diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the skin, other inflammatory diseases related to epithelial cells, inflammation related to cancer, inflammation related to irritation, and inflammation related to injury.

[0122] This disclosure further relates to general formulas (I), (IC), (I-1), (I-2), (I-3), (I-3C), (I-4), (I-4C), (II), (IIC), (II-1), (II-1C), (III), (IID-1), (IID-2), (IIID-1), (IIID-2), (IIIC), (III-1C), and (III-1) used for treating and / or preventing diseases or medical conditions. The invention relates to the compounds shown in Table A or their medicinal salts, or pharmaceutical compositions containing them, wherein the disease or condition is selected from viral infection, inflammation and cancer, and 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, Sjögren's syndrome, bronchitis, asthma and colon cancer, and preferably the inflammation is inflammatory bowel disease.

[0123] This disclosure further relates to general formulas (I), (IC), (I-1), (I-2), (I-3), (I-3C), (I-4), (I-4C), (II), (IIC), (II-1), (II-1C), (III), (IID-1), (IID-2), and (I) used for purposes of treating and / or preventing diseases or medical conditions. The present invention relates to compounds represented by IID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1), and general formula (III-1) shown in Table A, or their medicinal salts, or pharmaceutical compositions containing them, wherein the disease or condition is selected from viral infection, inflammation, and cancer, and the inflammation is inflammatory bowel disease, and the inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).

[0124] This disclosure further relates to pharmaceutical compositions containing the compounds shown in Table A, or pharmaceutically usable salts thereof, used for the treatment and / or prevention of diseases or conditions, wherein the diseases or conditions are viral infections. The cancers are selected from inflammation and cancer, and include 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 carcinoma, medullary carcinoma, bronchial cancer, liver cancer, bile duct cancer, choriocarcinoma, seminomas, embryonic carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, bladder cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal glandoma, hemangioblastoma, acoustic neuroma, schwannoma, 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 tumors, thyroid cancer, osteoma, neuroblastoma, brain tumors, and myeloma.

[0125] This disclosure further relates to pharmaceutical compositions containing the compounds shown in Table A, or pharmaceutically usable salts thereof, for use in treating and / or preventing AIDS or AIDS-related conditions or human immunodeficiency virus (HIV), with 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), or pharmaceutically usable salts thereof.

[0126] The diseases or conditions described herein are diseases or conditions that are treated and / or prevented by regulation of miRNA levels, preferably the miRNA being miR-124.

[0127] Preferably, the viral infection described herein is a retroviral infection.

[0128] Preferably, the inflammatory bowel disease described herein is ulcerative colitis (UC) or Crohn's disease (CD).

[0129] Preferably, the lymphoma described in this disclosure is Hodgkin's disease or non-Hodgkin 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), liver cancer is preferably hepatocellular carcinoma, lung cancer (also called bronchopulmonary cancer) is selected from non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma) and small cell lung cancer (SCLC), kidney cancer is selected from renal cell carcinoma, clear cell and renal eosinophilic granuloma, and leukemia is chronic Lymphocytic leukemia (CLL), chronic granulocytic leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), and acute osteomyelopathy (AML) are selected from these. Skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma, and angiosarcoma. Multiple myeloma is preferred for myeloma, colon cancer or rectal cancer is preferred for colorectal cancer, and glioblastoma (i.e., glioma or cavernous cell tumor) is preferred from glioblastoma, astrocytoma, and oligodendroglioma.

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

[0131] As a general guideline, the active compound is preferably in the form of a unit dose or in a form that the patient can administer to themselves as a monotherapy. The unit dose of the compound or composition relating to this disclosure may be expressed as a tablet, capsule, cachet, bottled solution, drug powder, granules, topical tablet, suppository, regenerated powder, or liquid formulation. A preferred unit dose may be 0.1 to 1000 mg.

[0132] The pharmaceutical composition relating to this 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. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0133] The tablets comprise an active ingredient and a non-toxic, medicinal excipient suitable for mixing in the preparation of the tablets. These excipients may be inert excipients, granulators, disintegrants, binders, and lubricants. These tablets may be uncoated or coated by known techniques that mask the taste of the drug or slow its disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a long period.

[0134] An oral formulation may be provided in the form of a soft gelatin capsule containing the active ingredient and an inert solid diluent, or the active ingredient and a water-soluble vector or oily solvent.

[0135] The aqueous suspension comprises an active substance and an excipient suitable for mixing in the preparation of the aqueous suspension. Such an excipient is a suspending agent, a dispersing agent, or a wetting agent. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners.

[0136] An oil suspension can be prepared by suspending the active ingredient in vegetable oil or mineral oil. The oil suspension may contain a thickening agent. Sweeteners and flavoring agents may be added to provide a palatable formulation. These compositions can be preserved by adding antioxidants.

[0137] The pharmaceutical compositions relating to this disclosure may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. A suitable emulsifier may be a naturally occurring phospholipid, and the emulsion may contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain mitigating agents, preservatives, colorants, and antioxidants.

[0138] The pharmaceutical compositions relating to this disclosure may be in the form of sterile aqueous solutions for injection. Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injection formulation may also be a sterile oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection solution or microemulsion can be injected into the patient's bloodstream by local injection in large quantities. Alternatively, it is preferable to administer the solution and microemulsion in a manner that can maintain a constant cycle concentration of the compound relating to this disclosure. A continuous intravenous infusion device can be used to maintain such a constant concentration. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0139] The pharmaceutical compositions relating to this disclosure may be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. Such suspensions can be prepared using the appropriate dispersants or wetting agents and suspending agents described above, according to known techniques. The sterile injection formulation may also be a sterile injection solution or suspension prepared in a parenterally acceptable, non-toxic diluent or solvent. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. For this purpose, any compounding fixative oil can be used. Fatty acids can also be used to prepare injection formulations.

[0140] The compounds relating to this 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 dissolves in the rectum to release the drug.

[0141] The compounds according to this disclosure can be administered by adding water to prepare aqueous suspensions of dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant, a 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, weight, physical condition, behavior, diet, administration time, method of administration, excretion rate, drug composition, and disease severity. Furthermore, the optimal treatment method, such as the mode of treatment, the daily dose of the compound, or the type of medicinal salt, can be determined according to conventional treatment plans.

[0143] Explanation of terms Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0144] The term "alkyl group" refers to a saturated linear or branched aliphatic hydrocarbon group which is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12). 1-12 It is an alkyl group, more preferably an alkyl group containing 1 to 6 carbon atoms (i.e., C 1-6Alkyl groups are non-limiting examples of alkyl groups: methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methyl 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, The group includes 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof. The alkyl group may be substituted or not, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is one or more selected from deuterium atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, oxo groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0145] The term "alkylene group" refers to a saturated linear or branched aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a linear or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) (i.e., C 1-12 an alkylene group), more preferably an alkylene group containing 1 to 6 carbon atoms (i.e., C 1-6 This refers to an alkylene group. Non-restrictive examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-). The alkylene group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is independently and selectively one or more selected from alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkyloxy groups, heterocyclyloxy groups, cycloalkylthio groups, heterocyclylthio groups, and oxo groups.

[0146] The term "alkenyl group" refers to an alkyl group compound that contains at least one carbon-carbon double bond in its molecule, the definition of an alkyl group as described above. Preferably, it is an alkenyl group containing 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12), and more preferably, an alkenyl group containing 2 to 6 carbon atoms (i.e., C 2-6The alkenyl group is an alkenyl group. The alkenyl group may or may not be substituted. If substituted, the substituent is preferably one or more selected from an alkoxy group, halogen, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, oxo group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0147] The term "alkynyl group" refers to an alkyl group compound that contains at least one carbon-carbon triple bond in its molecule, the definition of an alkyl group as described above. Preferably, an alkynyl group containing 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) (i.e., C 2-12 An alkynyl group) and more preferably an alkynyl group containing 2 to 6 carbon atoms (i.e., C 2-6 The alkynyl group is an alkynyl group. The alkynyl group may or may not be substituted. If substituted, the substituent is preferably one or more selected from an alkoxy group, halogen, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

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

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

[0150] The term "condensed cycloalkyl group" refers to a 5-20 membered, all-carbon polycyclic group in which each ring in the system shares one pair of adjacent carbon atoms with the other rings in the system, and one or more of these rings may contain one or more double bonds. Preferably, they are 6-14 membered, and more preferably 7-10 membered (e.g., 7, 8, 9, or 10 membered). Depending on the number of constituent rings, they can be classified into polycyclic condensed cycloalkyl groups such as bicyclic, tricyclic, and tetracyclic, preferably bicyclic or tricyclic, and more preferably 3-4 membered, 3-5 membered, 3-6 membered, 4-4 membered, 4-5 membered, 4-6 membered, 5-4 membered, 5-5 membered, 5-6 membered, 6-3 membered, 6-4 membered, 6-5 membered, 6-6 membered, 6-7 membered, 7-5 membered, or 7-6 membered bicyclic alkyl groups. Non-limiting examples of condensed cycloalkyl groups are: [ka] Includes.

[0151] The term "crosslinked cycloalkyl group" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, and which may contain one or more double bonds. Preferably, it is 6-14 membered, and more preferably 7-10 membered (e.g., 7, 8, 9, or 10 membered). Depending on the number of rings, it can be classified into polycyclic crosslinked cycloalkyl groups such as bicyclic, tricyclic, and tetracyclic, preferably bicyclic, tricyclic, or tetracyclic crosslinked cycloalkyl groups, and more preferably bicyclic or tricyclic crosslinked cycloalkyl groups. Non-limiting examples of crosslinked cycloalkyl groups are: [ka] The above cycloalkyl rings include those in which the above cycloalkyl groups (including monocyclic, spirocyclic, fused, and crosslinked rings) are fused to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, and among these, the ring linked to the parent structure is a cycloalkyl group, and non-limiting examples thereof are: [ka] This includes, preferably [ka] That is the case.

[0152] The cycloalkyl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is one or more selected from halogen, alkyl, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, oxo group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0153] The term "alkoxy group" refers to an -O-(alkyl group), and the definition of an alkyl group is as described above. Non-exclusive examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups. Alkoxy groups may be optionally substituted or left unsubstituted. If substituted, the substituent is preferably one or more selected from deuterium, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0154] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, of 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., forming a sulfoxide or sulfone), but without the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12), 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 ring atoms (e.g., 3, 4, 5, 6, 7 and 8), 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-exclusive examples of monocyclic heterocyclyl groups include pyrrolidinyl groups, tetrahydropyranyl groups, 1,2,3,6-tetrahydropyridyl groups, piperidinyl groups, piperazinyl groups, morpholinyl groups, thiomorpholinyl groups, and homopiperazinyl groups. Polycyclic heterocyclyl groups include spiroheterocyclyl groups, condensed heterocyclyl groups, and cross-linked heterocyclyl groups.

[0155] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which monocyclic rings share one atom (called a spiro atom), one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, and the sulfur may optionally be 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. Preferably, it has 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), preferably a monospiroheterocyclyl group or a bisspiroheterocyclyl group. More preferably, a 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, 5-member / 6-member or 6-member / 6-member monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

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

[0158] The above heterocyclyl rings include those in which the above heterocyclyl group (including monocycles, spiroheterocycles, fused heterocycles, and bridged heterocycles) is fused to an aryl group, a heteroaryl group, or a cycloalkyl ring, and among these, the ring linked to the parent structure is a heterocyclyl group, and non-limiting examples thereof are: [ka] This includes, among others.

[0159] The heterocyclyl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is 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 a 6-14 member all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring that shares adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6-10 member, such as a phenyl group and a naphthyl group. The above aryl rings include those in which the above aryl ring is fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl ring, where the ring linked to the parent structure is an aryl ring, and non-limiting examples include: [ka] Includes.

[0161] The aryl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is one or more selected from halogens, alkyl groups, 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.

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

[0163] The heteroaryl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is 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-mentioned cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom, or residues derived by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, 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 an easily detachable group so that it is not altered when other parts of the molecule react. Non-exclusive examples include (trimethylsilicon)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl groups. These groups can be optionally substituted with 1 to 3 substituents selected from halogens, alkoxy groups, and nitro groups.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0181] The term "nitro group" refers to -NO2.

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

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

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

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

[0186] The compounds relating to this disclosure include their isotopic derivatives. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotope-rich atoms. For example, a compound having the structure relating to this disclosure, in which hydrogen is replaced by "deuterium" or "tritium," or fluorine is 18 F-Fluorine label ( 18 Replaced by the F isotope, or carbon atoms 11 C-, 13 C-, or 14 C- rich carbon ( 11 C-, 13 C- or 14 C-carbon label, 11 C-, 13 C- or 14Compounds substituted with 1C isotopes are within the scope of this 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 diseases, or as tracers in pharmacodynamic, pharmacokinetic, or receptor studies. Among these, the deuterated forms of compounds are those in which each available hydrogen atom bonded to a carbon atom can be independently substituted with a deuterium atom. Those skilled in the art can synthesize the deuterated forms of compounds by referring to relevant literature. When preparing the deuterated forms of compounds, commercially available deuterated starting materials may be used, or they may be synthesized by deuterating reagents using conventional techniques, including, but not limited to, deuterated borane, trihydrobolanetetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds can generally maintain activity equivalent to that of non-deuterated compounds, and when deuteration is located at a specific site, they can obtain better metabolic stability and several therapeutic advantages. Compared to non-deuterated drugs, deuterated drugs offer advantages such as reduced toxicity and side effects, increased drug stability, improved therapeutic efficacy, and extended biological half-life. All isotopic transformations of the compounds relating to this disclosure, whether radioactive or non-radioactive, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom may be independently substituted with a deuterium atom, the deuterium substitution may be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium. Where a position is specifically designated as deuterium(D), that position should be understood to be deuterium with an abundance at least 1000 times higher than the natural abundance of deuterium (0.015%) (i.e., incorporating at least 15% deuterium).Having a higher abundance of deuterium in the example compound than the natural abundance of deuterium means that the compound has at least 1000 times the abundance of deuterium (i.e., at least 15% deuterium incorporated), at least 2000 times the abundance of deuterium (i.e., at least 30% deuterium incorporated), at least 3000 times the abundance of deuterium (i.e., at least 45% deuterium incorporated), at least 3340 times the abundance of deuterium (i.e., at least 50.1% deuterium incorporated), at least 3500 times the abundance of deuterium (i.e., at least 52.5% deuterium incorporated), at least 4000 times the abundance of deuterium (i.e., at least 60% deuterium incorporated), and at least 4500 times the abundance of deuterium (i.e., at least 67.5% deuterium incorporated). Deuterium may be present in an abundance of at least 5000 times (i.e., at least 75% deuterium), at least 5500 times (i.e., at least 82.5% deuterium), at least 6000 times (i.e., at least 90% deuterium), at least 6333.3 times (i.e., at least 95% deuterium), at least 6466.7 times (i.e., at least 97% deuterium), at least 6600 times (i.e., at least 99% deuterium), at least 6633.3 times (i.e., at least 99.5% deuterium), or even greater than that.

[0187] The compounds relating to this disclosure may exist in the form of specific stereoisomers. The term “stereoisomer” refers to isomers that have the same structure but differ in the spatial arrangement of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, atropisomers, conformational isomers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in the compounds relating to this disclosure may include other chiral atoms. All such stereoisomers and mixtures thereof are within the scope of this disclosure. Any carbon-carbon double bond, even if only one configuration is named, may include both the Z and E configurations. 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. One isomer of a compound in this disclosure can be prepared by asymmetric synthesis or by inductive action with a chiral auxiliary, or, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer can be formed with a suitable optically active acid or base, and the diastereomer can be resolved by conventional methods known in the art to obtain a pure product of the isomer. Furthermore, the separation of enantiomers and diastereomers is generally completed by chromatography.

[0188] The compounds relating to this disclosure may exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms “tautomer” or “tautomer form” refer to structural isomers that exist in equilibrium and whose isomer forms are readily convertible from one to the other. This includes all possible tautomers, i.e., they exist in the form of single isomers or mixtures of the above tautomers in any ratio. Non-limiting examples include keto-enols, imine-enamines, lactam-lactims, etc. An example of lactam-lactim equilibrium is as follows: [ka]

[0189] For example, when referring to a pyrazolyl group, it should be understood that it includes one or a mixture of either of the following two structures: [ka]

[0190] All tautomer forms are within the scope of this disclosure, and the naming of the compounds does not exclude any of the tautomers.

[0191] In the chemical structure of the compounds described in this disclosure, [ka] This type of bond indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, [ka] The combination is [ka] It may be so, or [ka] It is also acceptable to include both of these arrangements simultaneously.

[0192] "Optionally" or "optionally" means that the event or situation described thereafter may or may not occur, and this description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "C where C is optionally substituted with a halogen or cyano group." 1-6 The term "alkyl group" means 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] "Substituting" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3, are substituted with a number of substituents that correspond to each other independently. Those skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) with little effort. For example, an amino or hydroxyl group with free hydrogen can become unstable when bonded to a carbon atom with an unsaturated (e.g., olefin) bond.

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

[0195] "Medicinal salt" refers to a salt of the compound relating to this disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in the body of a mammal and possess the desired biological activity. Salts may be prepared individually during the final separation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. Generally, bases for forming pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. Generally, acids for forming pharmaceutically acceptable salts include inorganic acids and organic acids.

[0196] With respect to drugs or pharmacological agents, the term "therapeutic effective dose" refers to a dose of the drug or agent sufficient to produce, or at least partially produce, the desired effect. The effective dose is determined by the individual, depending on the subject's age and general condition, and also on the specific active substance. A suitable effective dose for an individual can be determined by a person skilled in the art through ordinary testing.

[0197] As used herein, the term “pharmaceutically acceptable” means that these compounds, materials, compositions and / or dosage forms are, within reasonable medical judgment, free from excessive toxicity, irritation, allergic reactions or other problems or complications, applicable to patient tissues, have a reasonable profit-benefit ratio, and are effective for the desired use.

[0198] As used herein, the singular forms "one," "one type," and "the said" include multiple quotations, and vice versa, unless otherwise specified in the context.

[0199] The term "approximately," when used with parameters such as pH, concentration, and temperature, indicates that the parameter may vary within ±10%, and in some cases, more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, the number is generally given simply for illustrative purposes, not as a limitation.

[0200] Synthesis method of the compound related to this disclosure To achieve the objectives of this disclosure, this disclosure adopts the following technical proposals.

[0201] Technical proposal 1 A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof relating to this disclosure, is provided, [ka] A compound of general formula (IC) or a pharmaceutically acceptable salt thereof is R 4’ -Y compound is subjected to a nucleophilic substitution reaction under basic conditions, followed by R under basic conditions. 4’ The process includes the step of removing the protecting group to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof, Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 method for preparing a compound represented by the general formula (IC) relating to this disclosure or a pharmaceutically acceptable salt thereof, wherein the method is: [ka] The process includes the step of optionally reacting a compound of general formula (IA) or a salt thereof with a compound of general formula (IB) or a salt thereof in an aromatic nucleophilic substitution reaction under basic or acidic conditions, or optionally carrying out a coupling reaction under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (IC) or a medicinal salt thereof. Eventually, X is a halogen, preferably a Cl atom. Ring A, G, R 1 ~R 3 m, n, and p are as defined in the general formula (IC).

[0203] Technical proposal 3 A method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof relating to this disclosure, is provided, [ka] The process includes the step of esterifying a compound of general formula (I-1C) or a salt thereof under basic conditions to obtain a compound of general formula (I-1) or a pharmaceutically usable salt thereof. Eventually, R and R 11 This 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 represented by general formula (I-2) or a pharmaceutically acceptable salt thereof, relating to this disclosure, is provided, [ka] The process includes the step of esterifying a compound of general formula (I-2C) or a salt thereof under basic conditions to obtain a compound of general formula (I-2) or a pharmaceutically usable salt thereof. Eventually, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, or heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 represented by general formula (I-3) or a pharmaceutically acceptable salt thereof, relating to this disclosure, [ka] A compound of general formula (I-3C) or a pharmaceutically acceptable salt thereof is R 4’ -Y compound is subjected to a nucleophilic substitution reaction under basic conditions, followed by R under basic conditions. 4’ The process includes the step of removing the protecting group to obtain a compound of general formula (I-3) or a pharmaceutically acceptable salt thereof, Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 defined as in the general formula (I-3).

[0206] Technical proposal 6 A method for preparing a compound represented by the general formula (I-3C) or a pharmaceutically acceptable salt thereof, relating to this disclosure, [ka] The process includes the step of optionally reacting a compound of general formula (I-3A) or a salt thereof with a compound of general formula (IB) or a salt thereof in a nucleophilic substitution reaction under basic or acidic conditions, or optionally carrying out a coupling reaction under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (I-3C) or a pharmaceutically usable salt thereof. Eventually, X is a halogen, preferably a Cl atom. Ring A, Ring B, G, R 1 , R 2 , R 3a n, m, and r are defined as in the general formula (I-3C).

[0207] Technical proposal 7 A method for preparing a compound represented by general formula (I-4) or a pharmaceutically acceptable salt thereof relating to this disclosure, is provided, [ka] Compounds of general formula (I-4C) or their pharmaceutically acceptable salts are R 4’ -Y compound is subjected to a nucleophilic substitution reaction under basic conditions, followed by R under basic conditions. 4’ The process includes the step of removing the protecting group to obtain a compound of general formula (I-4) or a pharmaceutically usable salt thereof, Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 defined as in the general formula (I-4).

[0208] Technical proposal 8 A method for preparing a compound represented by the general formula (I-4C) or a pharmaceutically acceptable salt thereof, relating to the present disclosure, is provided, [ka] The process includes the step of optionally reacting a compound of general formula (I-4A) or a salt thereof with a compound of general formula (IB) or a salt thereof in a nucleophilic substitution reaction under basic or acidic conditions, or optionally carrying out a coupling reaction under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (I-4C) or a pharmaceutically usable salt thereof. Eventually, 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 the general formula (I-4C).

[0209] Technical proposal 9 A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof as relating to this disclosure, wherein the method is: [ka] Compounds of general formula (IIC) or their pharmaceutically acceptable salts are R 4’ -Y compound is subjected to a nucleophilic substitution reaction under basic conditions, followed by R under basic conditions. 4’ The process includes the step of removing the protecting group to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof, Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 method for preparing a compound represented by the general formula (IIC) relating to this disclosure or a pharmaceutically acceptable salt thereof, wherein the method is: [ka] The process includes the step of optionally reacting a compound of general formula (IA) or a salt thereof with a compound of general formula (IIB) or a salt thereof in a nucleophilic substitution reaction under basic or acidic conditions, or optionally carrying out a coupling reaction under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (IIC) or a pharmaceutically usable salt thereof. Eventually, 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 the general formula (IIC).

[0211] Technical proposal 11 A method for preparing a compound represented by the general formula (IID-1) relating to this disclosure or a pharmaceutically acceptable salt thereof, wherein the method is as follows: [ka] The process includes the step of esterifying a compound of general formula (IID-1A) or a salt thereof under basic conditions to obtain a compound of general formula (IID-1) or a pharmaceutically usable salt thereof. Eventually, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It is an alkyl group, G, G 1 , G 2 , G 3 , R 2 , R 3 m and p are as defined in the general formula (IID-1).

[0212] Technical proposal 12 A method for preparing a compound represented by the general formula (IID-2) relating to this disclosure or a pharmaceutically acceptable salt thereof, wherein the method is as follows: [ka] The process includes the step of esterifying a compound of general formula (IID-2A) or a salt thereof under basic conditions to obtain a compound of general formula (IID-2) or a pharmaceutically usable salt thereof. Eventually, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It is an alkyl group, G, G 1 , G 2 , G 3 , R 2 , R 3 m and p are as defined in the general formula (IID-2).

[0213] Technical proposal 13 A method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof relating to this disclosure, is provided, [ka] A compound of general formula (II-1C) or a pharmaceutically acceptable salt thereof is R 4’ -Y compound is subjected to a nucleophilic substitution reaction under basic conditions, followed by R under basic conditions. 4’ The process includes the step of removing the protecting group to obtain a compound of general formula (II-1) or a pharmaceutically acceptable salt thereof, Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It is an alkyl group, R 4 teeth [ka] And, G, G 1 , G 2 , R 1b , R 1c and R 3 This is as defined in general formula (II-1), and preferably R 3 It is a halogen.

[0214] Technical proposal 14 A method for preparing a compound represented by the general formula (II-1C) relating to this disclosure or a pharmaceutically acceptable salt thereof, wherein the method is as follows: [ka] The process includes the step of optionally reacting a compound of general formula (II-1A) or a salt thereof with a compound of general formula (II-1B) or a salt thereof in a nucleophilic substitution reaction under basic or acidic conditions, or optionally reacting them in a coupling reaction under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (II-1C) or a pharmaceutically usable salt thereof. Eventually, X is a halogen, preferably a Cl atom. G, G 1 , G 2 , R 1b , R 1c and R 3 This is as defined in general formula (II-1C), and preferably R 3 It is a halogen.

[0215] Technical proposal 15 A method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof as relating to this disclosure, is provided, [ka] A compound of general formula (IIIC) or a pharmaceutically acceptable salt thereof is R 4’ -Y compound is subjected to a nucleophilic substitution reaction under basic conditions, followed by R under basic conditions. 4’ The process includes the step of removing the protecting group to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof, Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It 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 method for preparing a compound represented by general formula (IIIC) or a pharmaceutically acceptable salt thereof as disclosed herein, wherein the method is: [ka] The process includes the step of optionally reacting a compound of general formula (IA) or a salt thereof with a compound of general formula (IIIB) or a salt thereof in a nucleophilic substitution reaction under basic or acidic conditions, or optionally reacting them in a coupling reaction under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (IIIC) or a pharmaceutically usable 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 represented by general formula (IIID-1) according to the present disclosure or a pharmaceutically acceptable salt thereof, which comprises

Chemical formula

[0218] Technical proposal 18

Chemical formula

[0219] Technical proposal 19 A method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof relating to this disclosure, is provided, [ka] A compound of general formula (III-1C) or a pharmaceutically acceptable salt thereof is R 4’ -Y compound is subjected to a nucleophilic substitution reaction under basic conditions, followed by R under basic conditions. 4’ The process includes the step of removing the protecting group to obtain a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof, Eventually, Y is a halogen, preferably a Br atom. R 4’ teeth [ka] And, R and R 11 The groups are homologous or different and are independently selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, preferably R is C 1-6 It is an alkyl group, R 11 is C 1-6 It is an alkyl group, R 4 teeth [ka] And, G, L 1 , L 2, R 1e , R 1f and R 3 This is as defined by general formula (III-1), and preferably R 3 It is a halogen.

[0220] Technical proposal 20 A method for preparing a compound represented by the general formula (III-1C) or a pharmaceutically acceptable salt thereof, relating to the present disclosure, is provided, [ka] The process includes the step of optionally reacting a compound of general formula (II-1A) or a salt thereof with a compound of general formula (III-1B) or a salt thereof in a nucleophilic substitution reaction under basic or acidic conditions, or optionally reacting them in a coupling reaction under basic conditions and in the presence of a catalyst, to obtain a compound of general formula (III-1C) or a pharmaceutically usable salt thereof. Eventually, X is a halogen, preferably a Cl atom. G, L 1 , L 2 , R 1e , R 1f and R 3 This is as defined in general formula (III-1C), and preferably R 3 It is a halogen.

[0221] In the above-described synthesis technique, the reagents that provide the above basic conditions 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 sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, cadmium carbonate The reagents include, but are not limited to, um, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide. Preferably, the reagent that provides the basic conditions described above is selected from lithium hydroxide monohydrate, potassium carbonate, cesium carbonate, and cadmium carbonate. In Technical Proposals 2, 6, 8, 10, 14, 16, and 20, potassium carbonate or cesium carbonate is more preferred as the reagent that provides the basic conditions described above. In Technical Proposals 1, 5, 7, 9, 13, 15, and 19, cadmium carbonate is more preferred as the reagent that provides the basic conditions for the nucleophilic substitution reaction described above.

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

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

[0224] In the above-described synthesis technique, the reagent that provides the above-described acidic conditions includes, but is not limited to, meritol acid, nitrogen sulfosqualic acid, trichloroacetic acid, trinitrobenzenesulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid. Preferably, the reagent that provides the above-described acidic conditions is trifluoroacetic acid.

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

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

[0227] The reactions in the above steps are 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 explanation of the drawing]

[0228] [Figure 1]This shows the effect of compound 1 of the present disclosure on the body weight of UC mice induced by dextran sulfate sodium (DSS). Here, #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 an extremely 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 an extremely large significant difference compared to the model group. [Figure 2] This shows the effect of compound 1 of the present disclosure on colon length in UC mice induced by dextran sulfate sodium (DSS). Here, #P<0.05 indicates a significant difference between the model group and the normal control group, ##P<0.01 indicates a large significant difference between the model group and the normal control group, ###P<0.001 indicates an extremely large significant difference between the model group and the normal control group, *P<0.05 indicates a significant difference between the treatment group and the model group, **P<0.01 indicates a large significant difference between the treatment group and the model group, and ***P<0.001 indicates an extremely large significant difference between the treatment group and the model group. [Modes for carrying out the invention]

[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] Examples The structure of a compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6The values ​​are expressed in units of ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer is used for NMR measurements, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

[0231] For MS measurements, the following liquid chromatograph mass spectrometers were used: Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (Manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive).

[0232] High-performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489.

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

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

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

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

[0237] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications of the silica gel plates used for thin-layer chromatography (TLC) are 0.15 to 0.2 mm, and the specifications for separation and purification of products by thin-layer chromatography are 0.4 to 0.5 mm.

[0238] In silica gel column chromatography, silica gel of 200-300 mesh size, manufactured by Yantai Huanghai Silica Gel, was commonly used as a vector.

[0239] Kinase mean inhibition rate and IC 50 A plate reader, NovoStar (BMG GmbH, Germany), was used to measure the values.

[0240] The known starting materials relating to this disclosure may be synthesized by employing or in accordance with methods known in the art, or may be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., and Dalui Chemicals.

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

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

[0243] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1 liter.

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

[0245] The hydrogenation reaction typically involved repeating the process of evacuating the system and filling it with hydrogen three times.

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

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

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

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

[0250] Example 1 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinoline-2-amine 1 [ka] 2,8-Dichloroquinoline 1a (100 mg, 0.51 mmol, Bi De Pharmaceutical) and 5-amino-2,2-difluoro-1,3-benzo[1,3]dioxolane 1b (105 mg, 0.61 mmol, Shanghai Hao Hong) were dissolved in isopropanol (1 mL) and heated to 90°C and reacted for 12 hours. After cooling to room temperature, the reaction mixture was filtered and separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: 0.1% aqueous formic acid solution and acetonitrile, acetonitrile gradient: 65%~85%, flow rate: 30 mL / min) to obtain the title compound 1 (150 mg, 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-chloroquinoline-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-chloroquinoline-2-yl)(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate 2b Compound 1 (500 mg, 1.49 mmol) was dissolved in toluene (30 mL), cadmium carbonate (155 mg, 0.90 mmol) was added, and the mixture was heated to 140°C and reacted in water for 12 hours. Then, 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucuronate methyl ester 2a (1.05 g, 2.64 mmol, Shaoyuan Chemical Technology) was added, and the mixture was reacted in water for 24 hours at 140°C. The mixture was cooled to room temperature, concentrated under reduced pressure to remove toluene, and purified using eluent system B by column chromatography to obtain the title compound 2b (340 mg, yield 35%). MS m / z (ESI): 651.0 [M+1].

[0253] Step 2 (2S,3S,4S,5R,6R)-6-((8-chloroquinoline-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. This solution was added to a tetrahydrofuran solution (15 mL) of compound 2b (340 mg, 0.52 mmol) and stirred at room temperature for 2 hours. After quenching with saturated sodium thiosulfate solution (20 mL), the pH was adjusted to 3 with 1 N hydrochloric acid solution, and the mixture was extracted with ethyl acetate (50 mL x 3). After washing with saturated sodium chloride solution (100 mL), the organic phase was concentrated under reduced pressure and separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 25%~45%, flow rate: 30 mL / min) to obtain the title compound 2 (95 mg, yield 36%). 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)quinoline-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), and trifluoroacetic acid (0.15 mL, 2.0 mmol) were added to isopropanol (1 mL), and the mixture was heated to 90°C and reacted for 12 hours. After cooling to room temperature, the reaction mixture was filtered and then separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: 0.1% aqueous formic acid solution and acetonitrile, acetonitrile gradient: 45%~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)quinoline-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 allowed to proceed for 12 hours. After cooling to room temperature, the reaction mixture was filtered and separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 65%~85%, flow rate: 30 mL / min) to obtain 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-chloroquinoline-2-yl)amino)indoline-1-yl)ethane-1-one5 [ka]

[0257] Step 1 1-(5-nitroindoline-1-yl)ethane-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 gradually added at 0°C. The mixture was then allowed to rise naturally to room temperature and the reaction continued for 2 hours. 30 mL of water was added to the system, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, 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 resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 5b (1.8 g, yield: 72%). MS m / z (ESI): 207.1 [M+1].

[0258] Step 2 1-(5-aminoindoline-1-yl)ethane-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 purged three times with hydrogen gas to remove air. The mixture was then reacted under 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). This crude product was then used directly in the next reaction. MS m / z (ESI): 177.1 [M+1].

[0259] Step 3 1-(5-((8-chloroquinoline-2-yl)amino)indoline-1-yl)ethane-1-one5 Compound 5c (100 mg, 0.57 mmol), 2,8-dichloroquinoline 1a (112 mg, 0.57 mmol, Bi-de Pharmaceutical), and trifluoroacetic acid (64.72 mg, 0.57 mmol) were dissolved in isopropanol (1 mL), and the mixture was heated to 90°C and reacted for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by thin-layer chromatography (TLC) using 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)quinoline-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 mixture was heated to 100 °C and reacted for 12 hours. After cooling to room temperature, the reaction mixture was filtered and then separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 58%~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-tetrahydronaphthalene-2-yl)quinoline-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, Bi De Pharmaceutical), and trifluoroacetic acid (173 mg, 1.51 mmol) were dissolved in isopropanol (3 mL). The reaction was heated to 100 °C and allowed to proceed for 12 hours. After cooling to room temperature, the reaction mixture was filtered and separated and purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 60%~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)quinoline-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, Bi De Pharmaceutical), cesium carbonate (5.8 g, 17.74 mmol), 1,2-dibromotetrafluoroethane 8b (6.2 g, 23.65 mmol, Shanghai Taitan Technology), and 1-propanethol (0.45 g, 5.91 mmol, TCI) were dissolved in 30 mL of dimethyl sulfoxide and reacted at 100°C for 12 hours. The solution was cooled to room temperature, 50 mL of 2N sodium hydroxide solution was added, and the mixture was extracted with diethyl ether (50 mL x 3). The organic phases were combined, then washed with 2N sodium hydroxide solution (50 mL x 3), then with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 8c (2.6 g, 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 added to 46 mL of acetic acid, and hydrogen bromide solution (40% mass fraction, 19 mL) was added. The temperature was raised to 120°C and the reaction was allowed to proceed for 30 hours. After cooling to room temperature, 50 mL of water was added to the reaction and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system B by silica gel column chromatography to obtain 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, then potassium hydroxide (37 mg, 0.66 mmol) was added and the mixture was 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 mixture, and the mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (50 mL x 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 8e (98 mg, yield: 65%).

[0266] Step 4 2,2,3,3-Tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxane-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 purged three times with hydrogen gas to remove air. The reaction was then carried out under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using eluent system B by silica gel column chromatography 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)quinoline-2-amine 8 Compound 8f (60 mg, 0.27 mmol), 2,8-dichloroquinoline 1a (50 mg, 0.25 mmol, Bi-de Pharmaceutical), potassium carbonate (32 mg, 0.30 mmol), 4,5-bis(diphenylphosphin)-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 mixture was heated to 100°C and allowed to react for 12 hours. The reaction was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). It was then 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 purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 80%~95%, flow rate: 30 mL / min) to obtain 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-chloroquinoline-2-yl)-[1,3]dioxolo[4,5-b]pyridine-6-amine9 [ka]

[0269] Step 1 6-Bromo-[1,3]dioxolo[4,5-b]pyridine9b 2,3-Dihydroxy-5-bromopyridine 9a (2.0 g, 10.53 mmol, Bi-de Pharmaceutical), anhydrous potassium carbonate (4.36 g, 31.55 mmol), and dibromomethane (2.2 g, 12.65 mmol) were dissolved in 30 mL of N-methylpyrrolidone and reacted at 100°C for 12 hours. After cooling to room temperature, the mixture was poured into 30 mL of water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, 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 resulting residue was purified using eluent system B by silica gel column chromatography 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] pyridine-6-ylcarbamate tert-butyl9c 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. Under a nitrogen atmosphere, 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, and 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, and the mixture was extracted with ethyl acetate (20 mL x 3). It was then washed with saturated sodium chloride solution (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system B by silica gel column chromatography to obtain 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]pyridine-6-amine hydrochloride 9d Compound 9c (50 mg, 0.21 mmol) was dissolved in 5 mL of dichloromethane, and a 4N hydrogen chloride dioxane solution (425 μL, 1.7 mmol) was added dropwise under ice bath. After the addition was complete, the mixture was allowed to rise naturally to room temperature and reacted at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, the title compound 9d (36 mg), which was then used directly in the next reaction. MS m / z (ESI): 139.0 [M+1].

[0272] Step 4 N-(8-chloroquinoline-2-yl)-[1,3]dioxolo[4,5-b]pyridine-6-amine9 Compound 9d (36 mg, 0.21 mmol), 2,8-dichloroquinoline 1a (30 mg, 0.15 mmol, Bi-de Pharmaceutical), cesium carbonate (148 mg, 0.45 mmol), methanesulfonic acid (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 mixture was heated to 100°C and allowed to react for 12 hours. The solution was cooled to room temperature, 30 mL of water was added, and the solution was extracted with ethyl acetate (50 mL x 3). It was then 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 Detecor 2, eluent: 1‰ aqueous trifluoroacetic acid solution and acetonitrile, acetonitrile gradient: 50%~95%, flow rate: 30 mL / min) to obtain 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-chloroquinoline-2-amine10 [ka] Compound benzo[d][1,3]dioxolane-5-amine 10a (693 mg, 5.05 mmol, Bi-de Pharmaceutical), compound 1a (1.0 g, 5.05 mmol), cesium carbonate (2.64 g, 8.10 mmol), 4,5-diphenylphosphin-9,9-dimethylxanthene (584 mg, 1.01 mmol), and tris(dibenzylideneacetone)dipalladium (462 mg, 0.50 mol) were dissolved in 30 mL of 1,4-dioxane, and the reaction mixture was heated to 105 °C and allowed to react for 12 hours. The reaction mixture was cooled to room temperature, 25 mL of water was added, and the mixture was extracted with ethyl acetate (25 mL x 3). It was then 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 purified by high-performance liquid preparative chromatography (Waters-2545, eluent: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 10%~26%, flow rate: 30 mL / min) to obtain 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-didutero)-8-chloroquinoline-2-amine11 [ka] Compound benzo[d][1,3]dioxolane-2,2-didutero-5-amine 11a (170 mg, 1.21 mmol, obtained by the method disclosed in "method 2 for the synthesis of intermediates on page 41 of the specification in patent application WO2012037351A1"), compound 1a (240 mg, 1.21 mmol), cesium carbonate (636 mg, 1.95 mmol), 4,5-diphenylphosphin-9,9-dimethylxanthene (141 mg, 0.24 mmol), and 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 allowed to proceed for 12 hours. The reaction was cooled to room temperature, 25 mL of water was added, and the mixture was extracted with ethyl acetate (25 mL x 3). It was then 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, eluent: 1‰ aqueous formic acid solution and acetonitrile, acetonitrile gradient: 45%~95%, flow rate: 30 mL / min) to obtain 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)quinoline-2-amine 12 [ka] Compound 2,2-dimethylbenzo[d][1,3]dioxolane-5-amine 12a (141 mg, 0.85 mmol, Shanghai Haohong Biomedical), 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-diphenylphosphin-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 proceed for 12 hours. The reaction was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). It was then 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 mixture was separated and purified by high-performance liquid preparative chromatography (Waters-2545, eluent: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 60%~95%, flow rate: 30 mL / min) to obtain 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)quinoline-2-amine 13 [ka] Compound 2,2-dimethyl-2,3-dihydrobenzofuran-5-amine 13a (59 mg, 0.36 mmol, obtained by the method disclosed in Example 13 on page 72 of the specification in patent application "WO2014169845"), 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 carried out by heating to 90°C for 12 hours. The reaction mixture was cooled to room temperature, 15 mL of water was added, the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution, 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 separated and purified by high-performance liquid preparative chromatography (Waters-2767 Autopurification, eluent: 1‰ aqueous formic acid solution and methanol, methanol gradient: 60%~95%, flow rate: 30 mL / min) to obtain 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]quinoline-3-amine14 [ka]

[0278] Step 1 6-Chloro-2,3-dihydro-1H-inden-5-amine 14b In a 100 mL single-necked flask, 50 mL of dichloromethane, tert-butyl (6-chloro-2,3-dihydro-1H-inden-5-yl)carbamate tert-butyl 14a (3.4 g, 12.73 mmol, prepared by the known method "ACS Catalysis, 2018, 8, 4783-4788"), and 10 mL of trifluoroacetic acid were added in sequence, and the mixture was 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), 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 14b (1.55 g, yield: 73%), which was then used directly 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-necked 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 sequentially. Then, sodium bis(trimethylsilyl)amide (2 M tetrahydrofuran solution, 6.96 mL, 13.92 mmol) was gradually added dropwise at 0°C. The reaction was allowed to proceed naturally to room temperature for 12 hours. The reaction was quenched by adding 50 mL of saturated ammonium bicarbonate solution to the system under an 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 phases were dried, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using 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]quinoline-3-one 14e 10 mL of dichloromethane and compound 14d (800 mg, 2.83 mmol) were sequentially added to a 50 mL single-necked flask. Concentrated sulfuric acid (2.27 mL, 42.40 mmol) was gradually added dropwise to the system at 0°C, and after the addition was complete, 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 the solid. The mixture was filtered, and the solid was 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 In a 50 mL single-necked flask, 2 mL of N,N-dimethylformamide and compound 14e (300 mg, 1.37 mmol) were added sequentially. After raising the temperature of the system to 95°C, phosphorus oxychloride (0.1 mL, 1.10 mmol) was gradually added dropwise, and the reaction was continued for 30 minutes. The mixture was concentrated under reduced pressure to remove the phosphorus oxychloride, diluted with 20 mL of ethyl acetate, washed with 0.2 N sodium hydroxide solution (30 mL x 2), and washed with saturated sodium chloride solution (30 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, the title compound 14f (0.25 g, yield: 78%), which was then 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]quinoline-3-amine14 In a 25 mL single-neck flask, 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 order. The temperature was then raised to 85 °C and the mixture was reacted for 16 hours. The solvent was removed under reduced pressure, the mixture was diluted with 1 mL of methanol, and purified by thin-layer chromatography (TLC) using 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-methylquinoline-2-amine 15 [ka]

[0284] Step 1 N-(2-chloro-3-methylphenyl)-3,3-dimethoxypropanamide 15b In a 100 mL three-necked flask, 25 mL of tetrahydrofuran, 2-chloro-3-methylaniline 15a (1.5 g, 10.59 mmol, Bi De Pharmaceutical), and compound 14c (1.88 g, 11.69 mmol) were added in sequence. After lowering the temperature of the system to 0°C, sodium bis(trimethylsilyl)amide (2 M tetrahydrofuran solution, 10.57 mL, 21.14 mmol) was gradually added dropwise, and the system was then raised to room temperature and reacted for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate aqueous solution to the system, and the reaction mixture was concentrated under reduced pressure to remove most of the organic phase. The organic phase was extracted with ethyl acetate (50 mL x 3), and 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%), which was then used directly in the next reaction.

[0285] Step 2 8-Chloro-7-methylquinoline-2(1H)-one 15c In a 100 mL single-necked flask, 15 mL of dichloromethane and compound 15b (2.70 g, 10.48 mmol) were added sequentially. Concentrated sulfuric acid (8.37 mL, 157.11 mmol) was gradually added dropwise at 0°C. After the addition was complete, the ice bath was removed and the reaction was allowed to continue for 16 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to ice water to precipitate the solid. The mixture was filtered, and the solid was 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 sequentially to a 50 mL single-neck flask, and the system temperature was raised to 95°C and reacted for 90 minutes. The phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was 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 resulting residue was purified using eluent system B by silica gel column chromatography 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-methylquinoline-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 sequence. The reaction was then carried out at 95°C for 16 hours. The solvent was removed under reduced pressure, and the mixture was diluted with 100 mL of ethyl acetate. The mixture was 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 the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid preparative chromatography (Waters-2767 Autopurification, eluent: 1‰ aqueous formic acid solution and methanol, methanol gradient: 65%~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-methoxyquinoline-2-amine16 [ka]

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

[0290] Step 2 8-Chloro-7-methoxyquinoline-2(1H)-one 16c 10 mL of dichloromethane and compound 16b (2.50 g, 9.13 mmol) were added sequentially to a 100 mL single-necked flask. Concentrated sulfuric acid (7.29 mL, 136.93 mmol) was gradually added dropwise at 0°C, the ice bath was removed, and the reaction was allowed to continue for 16 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to ice water to precipitate the solid. The mixture was filtered, and the solid was 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 In a 50 mL single-necked flask, 8 mL of toluene, compound 16c (800 mg, 3.81 mmol), and phosphorus oxychloride (1.17 g, 7.63 mmol) were added in sequence, and the temperature of the system was raised to 100 °C and the reaction was allowed to proceed for 3 hours. The reaction was cooled to room temperature, 20 mL of ice water was added, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (50 mL x 3), the organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified with eluent system B by silica gel column chromatography 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-methoxyquinoline-2-amine16 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. The temperature was then raised to 95°C and the reaction was allowed to proceed 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 then washed with saturated sodium chloride solution (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified using eluent system B by silica gel column chromatography to obtain 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)-quinoline-2-amine17 [ka]

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

[0295] Step 2 7,8-Dichloroquinoline-2(1H)-one 17c 15 mL of dichloromethane and compound 17b (2.50 g, 8.99 mmol) were added sequentially to a 100 mL single-necked flask. Concentrated sulfuric acid (7.18 mL, 134.79 mmol) was then gradually added dropwise at 0°C, after which the ice bath was removed and the reaction was allowed to continue for 16 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to ice water to precipitate the solid. The mixture was filtered, and the solid was 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 sequentially to a 50 mL single-neck flask, and the system temperature 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 approximately 8 with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified with eluent system B by silica gel column chromatography 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)-quinoline-2-amine17 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. The temperature was then raised to 95 °C and the reaction was allowed to proceed for 16 hours. The solvent was removed under reduced pressure, and the mixture was diluted with 100 mL of ethyl acetate. The mixture was then 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. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain 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-methylquinoline-2-amine18 [ka]

[0299] Step 1 N-(2-chloro-4-methylphenyl)-3,3-dimethoxypropanamide 18b In a 100 mL three-necked flask, 25 mL of tetrahydrofuran, 2-chloro-4-methylaniline 18a (1 g, 7.06 mmol, Bi De Pharmaceutical), and compound 14c (1.26 g, 8.47 mmol) were added in sequence. Sodium bis(trimethylsilyl)amide (2 M tetrahydrofuran solution, 5.30 mL, 10.60 mmol) was gradually added dropwise at 0°C, and the system was then heated to room temperature and reacted for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate aqueous solution to the system, and the reaction mixture was concentrated under reduced pressure to remove most of the organic phase. The mixture was 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. The resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 18b (1.50 g, yield: 82%).

[0300] Step 2 8-Chloro-6-methylquinoline-2(1H)-one 18c 2 mL of dichloromethane and compound 18b (1.50 g, 5.82 mmol) were added sequentially to a 100 mL single-necked flask. Concentrated sulfuric acid (4.7 mL, 87.31 mmol) was then gradually added dropwise at 0°C, after which the ice bath was removed and the reaction was allowed to continue for 4 hours. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was added dropwise to ice water to precipitate the solid. The mixture was filtered, and the solid was 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 sequentially to a 50 mL single-necked flask, and the system temperature was raised to 95°C and reacted for 90 minutes. The phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified using eluent system B by silica gel column chromatography 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-methylquinoline-2-amine18 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. The temperature was then raised to 95 °C and the reaction was allowed to proceed for 16 hours. The reaction was cooled to room temperature, 25 mL of water was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The mixture was washed with saturated sodium chloride solution (25 mL x 2) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 70%~90%, flow rate: 30 mL / min) to obtain 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-methoxyquinoline-2-amine19 [ka]

[0304] Step 1 N-(2-chloro-4-methoxyphenyl)-3,3-dimethoxypropanamide 19b In a 100 mL three-necked flask, 25 mL of tetrahydrofuran, 2-chloro-4-methoxyaniline 19a (1 g, 6.35 mmol, Bi De Pharmaceutical), and compound 14c (1.13 g, 7.61 mmol) were added in sequence. Sodium bis(trimethylsilyl)amide (2 M tetrahydrofuran solution, 4.76 mL, 9.52 mmol) was gradually added dropwise at 0°C, and the system was then heated to room temperature and reacted for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate aqueous solution to the system, and the reaction mixture was concentrated under reduced pressure to remove most of the organic phase. The mixture was 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. The resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 19b (1.20 g, yield: 69%).

[0305] Step 2 8-Chloro-6-methoxyquinoline-2(1H)-one 19c 2 mL of dichloromethane and compound 19b (1.20 g, 4.38 mmol) were added sequentially to a 100 mL single-necked flask. Concentrated sulfuric acid (3.52 mL, 65.76 mmol) was then gradually added dropwise at 0°C, after which the ice bath was removed and the reaction was allowed to continue for 4 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to ice water to precipitate the solid. The mixture was filtered, and the solid was 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 sequentially to a 50 mL single-necked flask, and the system temperature was raised to 95°C and reacted for 90 minutes. After removing the phosphorus oxychloride under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified using eluent system B by silica gel column chromatography 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-methoxyquinoline-2-amine19 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. The temperature was then raised to 95°C and the reaction was allowed to proceed for 16 hours. The reaction was cooled to room temperature, 25 mL of water was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The mixture was 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 Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 65%~85%, flow rate: 30 mL / min) to obtain 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)quinoline-2-amine 20 [ka]

[0309] Step 1 N-(2,4-dichlorophenyl)-3,3-dimethoxypropanamide 20b In a 100 mL three-necked flask, 25 mL of tetrahydrofuran, 2,4-dichloroaniline 20a (1.0 g, 6.17 mmol, J&K), and compound 14c (1.10 g, 7.41 mmol) were added in sequence. Sodium bis(trimethylsilyl)amide (2 M tetrahydrofuran solution, 4.63 mL, 9.26 mmol) was gradually added dropwise at 0°C, and the system was then heated to room temperature and reacted for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate aqueous solution to the system, and the reaction mixture was concentrated under reduced pressure to remove most of the organic phase. The mixture was 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. The resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 20b (1.40 g, yield: 82%).

[0310] Step 2 6,8-Dichloroquinoline-2(1H)-one 20c 2 mL of dichloromethane and compound 20b (1.20 g, 4.31 mmol) were added sequentially to a 100 mL single-necked flask. Concentrated sulfuric acid (3.52 mL, 65.76 mmol) was gradually added dropwise at 0°C. After removing the ice bath, the mixture was heated to 90°C and the reaction was continued for 4 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to ice water to precipitate the solid. The mixture was filtered, and the solid was 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 sequentially to a 50 mL single-neck flask, and the system temperature was raised to 95°C and reacted for 90 minutes. The phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified using eluent system B by silica gel column chromatography 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)quinoline-2-amine 20 In a 25 mL sealed tube, 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. The temperature was then raised to 95 °C and the reaction was allowed to proceed for 16 hours. The reaction was cooled to room temperature, 25 mL of water was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The mixture was washed with saturated sodium chloride solution (25 mL x 2) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 80%~95%, flow rate: 30 mL / min) to obtain 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-chloroquinoline-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-chloroquinoline-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 in water for 12 hours. Compound 2a (606 mg, 1.53 mmol) was then added, and the mixture was reacted in water at 145°C for 24 hours. The mixture was cooled to room temperature, concentrated under reduced pressure to remove toluene, and the residue was purified by column chromatography using eluent system B to obtain the title compound 21a (450 mg, yield 58%). 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-chloroquinoline-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), and 30% hydrogen peroxide solution (1.83 mL) was added. The mixture was stirred at room temperature for 10 minutes. This solution was added to a tetrahydrofuran solution (16 mL) of compound 21a (450 mg, 0.51 mmol) and stirred at room temperature for 16 hours. After quenching with saturated sodium thiosulfate solution (20 mL), the pH was adjusted to 4 with 1 N hydrochloric acid solution. The mixture was 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 purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 15%~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-chloroquinoline-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-chloroquinoline-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 in water for 12 hours. Compound 2a (1.90 g, 4.80 mmol) was then added, and the mixture was reacted in water at 140°C for 24 hours. The mixture was cooled to room temperature, concentrated under reduced pressure to remove toluene, and the residue was purified by column chromatography using eluent system B to obtain the title compound 22a (400 mg, yield 40%). MS m / z (ESI): 629.0 [M+1].

[0318] Step 2 (2S,3S,4S,5R,6R)-6-((8-chloroquinoline-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), and 30% hydrogen peroxide solution (1.1 mL) was added. The mixture was stirred at room temperature for 10 minutes. This solution was added to a tetrahydrofuran solution (15 mL) of compound 22a (400 mg, 0.64 mmol) and stirred at room temperature for 2 hours. After quenching with saturated sodium thiosulfate solution (20 mL), the pH was adjusted to 4 with 1 N hydrochloric acid solution. The mixture was 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 purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: 10 mmol / L aqueous ammonium bicarbonate solution and acetonitrile, acetonitrile gradient: 20%~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-methylquinoline-2-amine 23 [ka]

[0320] Step 1 N-(2-chloro-5-methylphenyl)-3,3-diethoxypropanamide 23c In a 100 mL three-necked flask, 5 mL of N,N-dimethylformamide, 2-chloro-5-methylaniline 23a (0.5 g, 3.53 mmol, Bi-De Pharmaceutical), and 3,3-diethoxypropionic acid 23b (0.63 g, 3.88 mmol, J&K) were added in sequence. At 0°C, 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, and the system was then heated 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), combined the organic phases, washed with saturated sodium chloride solution (50 mL x 3), dried the organic phases over anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure to obtain the crude product, title compound 23c (1.0 g, yield: 99%), which was then used directly in the next reaction.

[0321] Step 2 8-Chloro-5-methylquinoline-2(1H)-one 23d 2 mL of dichloromethane and compound 23c (1.00 g, 3.5 mmol) were sequentially added to a 100 mL single-necked flask. Concentrated sulfuric acid (3.35 mL, 62.98 mmol) was gradually added dropwise at 0°C, then the ice bath was removed and the reaction was allowed to continue for 4 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to 50 mL of ice water. Extraction was performed with ethyl acetate (50 mL x 5), the organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 23d (0.26 g, 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 sequentially to a 50 mL single-necked flask, and the system temperature was raised to 95 °C and reacted for 90 minutes. The phosphorus oxychloride was removed under reduced pressure, ice water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, the title compound 23e (0.28 g, yield: 99%), which was then used directly 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-methylquinoline-2-amine 23 In a 25 mL sealed tube, 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. The temperature was then raised to 95 °C and the reaction was allowed to proceed for 16 hours. The reaction was cooled to room temperature, 25 mL of water was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The mixture was 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 Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 70%~90%, flow rate: 30 mL / min) to obtain 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-methoxyquinoline-2-amine 24 [ka]

[0325] Step 1 N-(2-chloro-5-methoxyphenyl)-3,3-diethoxypropanamide 24b In a 100 mL three-necked flask, 5 mL of N,N-dimethylformamide, 2-chloro-5-methoxyaniline 24a (0.5 g, 3.17 mmol, Bi De Pharmaceutical), and compound 23b (0.63 g, 3.88 mmol) were added in sequence. At 0°C, 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, and the system was then heated 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 phases were 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 then used directly in the next reaction.

[0326] Step 2 8-Chloro-5-methoxyquinoline-2(1H)-one 24c 2 mL of dichloromethane and compound 24b (0.95 g, 3.14 mmol) were sequentially added to a 100 mL single-necked flask. Concentrated sulfuric acid (2.52 mL, 47.22 mmol) was gradually added dropwise at 0°C, then the ice bath was removed and the reaction was allowed to continue for 4 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to 50 mL of ice water. Extraction was performed with ethyl acetate (50 mL x 5), the organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 24c (0.26 g, 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 sequentially to a 50 mL single-necked flask, and the system temperature was raised to 95°C and reacted for 90 minutes. The phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, the title compound 24d (288 mg, yield: 99%), which was then used directly 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-methoxyquinoline-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. The temperature was then raised to 95 °C and the reaction was allowed to proceed for 16 hours. The reaction was cooled to room temperature, 25 mL of water was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The mixture was 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 Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 65%~85%, flow rate: 30 mL / min) to obtain 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)quinoline-2-amine 25 [ka]

[0330] Step 1 N-(2,5-dichlorophenyl)-3,3-diethoxypropanamide 25b In a 100 mL three-necked flask, 5 mL of N,N-dimethylformamide, 2,5-dichloroaniline 25a (0.5 g, 3.08 mmol, Bi De Pharmaceutical), and compound 23b (0.50 g, 3.39 mmol) were added in sequence. At 0°C, 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, and the system was then heated to room temperature and reacted for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate aqueous 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 phases were 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 then used directly in the next reaction.

[0331] Step 2 5,8-Dichloroquinoline-2(1H)-one 25c 2 mL of dichloromethane and compound 25b (0.51 g, 1.67 mmol) were sequentially added to a 100 mL single-necked flask. Concentrated sulfuric acid (1.33 mL, 25.05 mmol) was gradually added dropwise at 0°C, then the ice bath was removed and the reaction was allowed to continue for 4 hours. The solvent was removed under reduced pressure, the reaction solution was added dropwise to 50 mL of ice water, 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 phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified with eluent system B by silica gel column chromatography to obtain the title compound 25c (0.21 g, 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 sequentially added 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, 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, concentrated, and the crude product, the title compound 25d (230 mg, yield: 99%), was obtained. The crude product was directly used 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 sequentially added to a 25 mL sealed tube. Then, 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, and the mixture was 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. The residue was purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor2, eluent system: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 80% - 95%, flow rate: 30 mL / min) to obtain 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-carbonitriel 26 [ka]

[0335] Step 1 N-(4-bromo-2-chlorophenyl)-3,3-dimethoxypropanamide 26b In a 100 mL three-necked flask, 25 mL of tetrahydrofuran, 4-bromo-2-chloroaniline 26a (3.0 g, 14.53 mmol, J&K), and compound 14c (2.36 g, 15.98 mmol) were added in sequence. Sodium bis(trimethylsilyl)amide (2 M tetrahydrofuran solution, 10.89 mL, 21.79 mmol) was gradually added dropwise at 0°C, and the system was raised to room temperature and reacted for 24 hours. The reaction was quenched by adding 50 mL of saturated ammonium chloride solution to the system, the solvent was removed under reduced pressure, and the mixture was 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 phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 26b (4.60 g, yield: 98%), which was then used directly in the next reaction.

[0336] Step 2 6-Bromo-8-chloroquinoline-2(1H)-one 26c 5 mL of dichloromethane and compound 26b (4.60 g, 14.25 mmol) were sequentially added to a 100 mL single-necked flask. Concentrated sulfuric acid (11.40 mL, 213.89 mmol) was gradually added dropwise at 0°C. After removing the ice bath, the mixture was heated to 90°C and the reaction was continued for 2 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to 50 mL of ice water and extracted with ethyl acetate (50 mL x 5). The organic phases were combined and washed with saturated sodium chloride solution (50 mL x 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system B by silica gel column chromatography to obtain the title compound 26c (0.46 g, 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 sequentially to a 50 mL single-neck flask, and the system temperature was raised to 95°C and reacted for 90 minutes. The phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, the title compound 26d (440 mg, yield: 89%), which was then used directly in the next reaction.

[0338] Step 4 6-Bromo-8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinoline-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. The temperature was then raised to 95°C and the reaction was allowed to proceed for 16 hours. The reaction was cooled to room temperature, 25 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phase was 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 resulting residue was purified using eluent system B by silica gel column chromatography to obtain 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-carbonitriel 26 In a 25 mL three-necked flask, 3 mL of N,N-dimethylacetamide, compound 26e (150 mg, 0.36 mmol), zinc cyanide (126 mg, 1.01 mmol), zinc powder (3.50 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol), and 1,1'-bis(diphenylphosphin)ferrocene (46 mg, 0.08 mmol) were added in order, and the mixture was heated to 135 °C and reacted for 3 hours. The reaction was cooled to room temperature, 25 mL of water was added, and the mixture was 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 Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 80%~95%, flow rate: 30 mL / min) to obtain 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)quinoline-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(ditert-butylphosphino)ferrocenepalladium(II) (39 mg, 0.06 mmol, Bi De Pharmaceuticals) were added. After substituting with nitrogen gas three times, the temperature was raised to 100°C and the reaction was allowed to proceed for 3 hours. The reaction was cooled to room temperature, saturated sodium bicarbonate solution (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). 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 Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 75%~95%, flow rate: 30 mL / min) to obtain 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)quinoline-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)quinoline-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(ditert-butylphosphino)ferrocene palladium(II) (29 mg, 0.044 mmol) were added. After substituting with nitrogen gas three times, the temperature was raised to 100°C and the reaction was allowed to proceed for 3 hours. The reaction was cooled to room temperature, saturated sodium bicarbonate solution (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with eluent system B by silica gel column chromatography to obtain 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)quinoline-2-amine 28 Compound 28b (140 mg, 0.34 mmol) was dissolved in 10 mL of ethyl acetate, platinum-carbon (70 mg, 5% wt., 50%-70% water content, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, the mixture was purged three times with hydrogen gas, and the reaction was carried out under 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 Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 70%-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)quinoline-2-amine 29 [ka]

[0345] Step 1 N-(3-bromo-2-chlorophenyl)-3,3-dimethoxypropanamide 29b 3-Bromo-2-chloroaniline 29a (2.0 g, 9.72 mmol, Bi-de Pharmaceuticals) 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 (2 M tetrahydrofuran solution, 5.4 mL, 10.7 mmol) was added dropwise, and the system was raised to room temperature and reacted for 16 hours. Saturated ammonium chloride solution (100 mL) was added to the reaction mixture, 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-chloroquinoline-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 allowed to react for 2 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was added dropwise to 50 mL of ice water and extracted with ethyl acetate (50 mL x 5). The organic phases were combined and washed with saturated sodium chloride solution (50 mL x 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified using eluent system B by silica gel column chromatography 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 sequentially to a 50 mL single-necked flask, and the system temperature was raised to 95°C and reacted for 90 minutes. The phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, the title compound 29d (599 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0348] Step 4 7-Bromo-8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)quinoline-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. The temperature was then raised to 95 °C and the reaction was allowed to proceed for 16 hours. The reaction was cooled to room temperature, 25 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phase was washed with saturated sodium chloride solution (25 mL x 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was purified using eluent system B by silica gel column chromatography to obtain 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)quinoline-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 substituting with nitrogen gas three times, the temperature was raised to 100°C and the reaction was allowed to proceed for 3 hours. The reaction was cooled to room temperature, saturated sodium bicarbonate solution (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, the organic phases were washed with saturated sodium chloride solution (50 mL x 2), and the mixture was 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, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 55%~95%, flow rate: 30 mL / min) to obtain 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)quinoline-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)quinoline-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 substituting with nitrogen gas three times, the temperature was raised to 100°C and the reaction was allowed to proceed for 3 hours. The reaction was cooled to room temperature, saturated sodium bicarbonate solution (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, the organic phases were washed with saturated sodium chloride solution (50 mL x 2), and the mixture was dried over anhydrous sodium sulfate. The filtrate was filtered, the solvent was removed under reduced pressure, and the resulting residue was purified with eluent system B by silica gel column chromatography to obtain 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)quinoline-2-amine 30 Compound 30a (70 mg, 0.17 mmol) was dissolved in 5 mL of ethyl acetate, platinum-carbon (35 mg, 5% Wt., 50%-70% water content, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, the mixture was purged three times with hydrogen gas, and the reaction was carried out 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 Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate 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-chloroquinoline-2-yl)amino)-3-methylbenzo[d]oxazole-2(3H)-one 31 [ka] 5-amino-3-methyl-1,3-benzoxazole-2(3H)-one 31a (123 mg, 0.75 mmol, Bi-de Pharmaceutical), compound 1a (135 mg, 0.68 mmol), cesium carbonate (333 mg, 1.02 mmol), 4,5-bis(diphenylphosphin)-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 proceed for 12 hours. The reaction was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). It was then 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 purified by high-performance liquid preparative chromatography (Waters 2767-SQ Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 45%~95%, flow rate: 30 mL / min) to obtain 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 abbreviations used below: po: Oral administration Bid: Twice a day qd: Once a day MC: Sodium Carboxymethylcellulose Test Example 1: Prophylactic and therapeutic effects of the compound relating to this disclosure on mouse ulcerative colitis (UC).

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

Chemical formula

[0356] 2. Experimental methods and materials 2.1. Experimental animals and breeding conditions In the experiment, female C57BL / 6 mice from Vital River Laboratory Animal Co., Ltd. (production license number: SCXK(Zhe)2019-0001, animal certificate number: 20210401Abzz0619000795) were used. Their body weight at the time of purchase was 20-22 g. They were housed in independent SPF spaces at 5 mice / cage, adjusted to a 12 / 12 hour light / dark cycle, with the temperature maintained at 23±1°C and the humidity at 50%-60%. They were allowed to freely consume food and water. After purchasing the animals, they were adaptively bred for at least one week before starting the experiment.

[0357] 2.2. Experimental reagents and equipment Dextran sulfate sodium salt (DSS): MP Biomedicals, product number 160110, lot number S5036. It was prepared with sterile water, filtered, and should not be sterilized under high pressure. It was replaced once every two days. Ethanol: Shanghai Baxter Medical Supplies Co., Ltd., lot number S2001050. Olive oil: Sinopharm Chemical Reagent Co., Ltd., product number 30189828, lot number 20180104. Methylcellulose M450: Sinopharm Chemical Reagent Co., Ltd., product number 69016460, lot number 20170308. Plate reader: Manufacturer BMGlabtech, model number PHERAstar Fs. Tabletop low-speed centrifugal separator: Manufacturer Eppendorf, model number 5417R. Electronic balance: METTLER TOLEDO Instruments Co., Ltd., model number AL204.

[0358] 2.3. Experimental Design and Method 2.3.1. Classification of animals: After selectively rearing the mice, they were divided into the following groups:

[0359] [Table 3-1] [Table 3-2] Solvent: 0.5% MC suspension 2.3.2. Preparation of medications: Preparation method for DSS: 25g of DSS was mixed with 1L of ultrapure water, sterile filtered, and stored at 4°C. Preparation method for 50 mg / kg of ABX-464: 100 mg of ABX-464 was polished with 20 mL of 0.5% MC and stored at 4°C. Two preparations were made. Preparation method for compound 1 of the present disclosure at 50 mg / kg: 100 mg of compound 1 of the present disclosure was polished with 20 mL of 0.5% MC and stored at 4°C. 2.3.3 Experimental Method: Mice were randomly divided into five groups based on body weight: a normal control group (Naive group), a model group (DSS group), ABX-464 (50 mg / kg, po, qd), ABX-464 (50 mg / kg, po, bid), and Compound 1 of the present disclosure (50 mg / kg, po, bid). After adaptive rearing, the mice were reared in 2.5% DSS from day 0, reared in DSS for 7 days, then reared in normal water until day 10. During days 0-10, the corresponding solvent and drug were administered intragastricly for 10 consecutive days, and the changes in the mice's body weight were observed daily. On day 10, the mice's body weight was weighed, and the length of the colon was measured.

[0360] 2.4. Data Representation and Statistical Processing The experimental data are presented as Mean ± Standard Error (SEM). Statistical comparisons were performed using t-tests in Excel software. When analyzing and comparing data from the model group and the normal control group, #P<0.05 indicates a significant difference between the model group and the normal control group, ##P<0.01 indicates a large significant difference between the model group and the normal control group, and ###P<0.001 indicates an extremely large significant difference between the model group and the normal control group. *P<0.05 indicates a significant difference between the treatment group and the model group, **P<0.01 indicates a large significant difference between the treatment group and the model group, and ***P<0.001 indicates an extremely large significant difference between the treatment group and the model group.

[0361] 3.Results 3.1 Effect of Compound 1 of this Disclosure on DSS-Inducible UC Mouse Body Weight According to the results of the weight experiment (Figure 1), compared to the normal control group, the weight of mice in the DSS model group clearly decreased from day 4, and the amount of weight loss gradually increased, reaching 30.0% (P<0.001) on day 10. Compared to the DSS model group, the weight of all administered groups clearly increased from day 7, and on day 10, the weight loss was reduced to 14.1% (P<0.001), 10.3% (P<0.001), and 0.4% (P<0.001) for 50 mg / kg ABX-464(qd), ABX-464(bid), and Compound 1 of the Disclosure (bid), respectively. At the experimental endpoint, the amount of weight recovery was strongest in the order of Compound 1 of the 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 this Disclosure on Colon Length in DSS-Inducible UC Mice According to the colon length results (Figure 2), the colon length in the DSS model group was significantly shorter than that of the normal control group, being only 75.4% (P<0.001). Compared to the DSS model group, the colon length in all treatment groups was significantly longer, with ABX-464(qd), ABX-464(bid), and Compound 1 of the Disclosure (bid) at 50 mg / kg each resulting in colon lengths of 85.5% (P<0.05), 89.3% (P<0.05), and 91.9% (P<0.01), respectively, compared to the normal control group. The colon lengths, in descending order, were Compound 1 of the Disclosure 50 mg / kg (bid) > ABX-464 50 mg / kg (bid) > ABX-464 50 mg / kg (qd).

[0363] 4. Conclusion The DSS model, used as an animal model of ulcerative colitis (UC) in IBD, shows that factors such as the molecular weight of DSS (36,000-50,000), lot number, storage form, mouse rearing environment, and strain all affect the model's effectiveness. The model construction in this study was relatively successful, with significant changes observed in both mouse body weight and colon length. The results showed that compound 1 of this disclosure exhibited superior efficacy compared to the positive drug ABX-464 in terms of body weight and colon length. Therefore, both 50 mg / kg of ABX-464 and compound 1 of this disclosure have a certain preventive and therapeutic effect on DSS-induced UC, with compound 1 exhibiting the strongest efficacy, surpassing that of ABX-464 at the same dose.

[0364] Test Example 2. Upregulation effect of the compound relating to this disclosure on miR-124. 1. Summary This study is intended to evaluate the upregulation effect of the compounds disclosed herein on miR-124.

[0365] 2. Experimental materials and equipment 1. Human T-cell activating CD3 / CD28 magnetic beads (Dynabead Human T-Activator CD3 / CD28 for T Cell Expansion and Activation) (Gibco, 11131D) 2. Human Total T Cell Isolation Reagent Kit (Pan T Cell Isolation Kit, human) (Miltenyi, 130-096-535) 3. Human Interleukin-2 (Human IL-2) (Peprotech, 200-02-100) 4. MicroRNA Extraction Reagent Kit (Qiagen, 217004) 5. Miniature RNA Reverse Transcription Reagent 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 (Aodonten, ST023) 9.EDTA (0.5 M), pH 8.0 (Invitrogen, AM9260G) 10. LS Isolation Columns (Miltenyi, 130-042-401) 11.24-well cell culture plate (Corning, 3524) 12.96-well plate (Corning, 3788) 13. Cell incubators (Thermo, Steri cycle i160) 14. Real-time fluorescence quantitative PCR instrument (Applied biosystem, QuantStudio6 Flex) 15. PCR device (Applied biosystem, ProFlex) 16.96-well transparent PCR plate, 0.2 mL (Applied Biosystems, N8010560) 17. RPMI1640 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 product from GENEWIZ) 24. hsa-U6 detection primer (TIANGEN, CD201-0145)

[0366] III. Experimental Procedure The effect of the compound on miR-124 expression levels was detected in T cells activated with CD3 / CD28 antibodies. After treating activated T cells with the compound, total cellular RNA was extracted, and the resulting cDNA was reverse transcribed using a template. Specific miR-124 primers were then quantified by SYBR green fluorescence quantitative PCR.

[0367] T cell isolation: Purchase the obtained human peripheral blood mononuclear cells (PBMCs), count them, and centrifuge them. Wash once with isolation buffer (PBS pH 7.4, containing 0.5% BSA and 2 mM EDTA), discard the supernatant, and divide into 1 × 10⁶ cells. 7 Each cell was mixed with 40 μL of buffer and 10 μL of pan T Cell Biotin-Antibody Cocktail. The precipitate was resuspended and mixed uniformly, then incubated at 4°C for 5 minutes. After incubation, 1 × 10⁶ cells were collected. 7 Each component was added in amounts of 30 μL buffer and 20 μL of T cell isolation magnetic beads (Pan T Cell MicroBeads Cocktail) per cell, and after homogeneous mixing, the mixture was incubated at 4°C for 10 minutes. The LS column was pre-rinsed with 3 mL of cell isolation buffer and separated, and the cell suspension was passed over the column. After passing the cell suspension over the column, the column was washed three times with 1 mL of cell isolation buffer, and the resulting cell saturation was collected in a 15 mL centrifuge tube, i.e., enriched T cells. The cells were counted, and 1 × 10⁶ cells were obtained.6 RPMI1640 medium (complete medium) containing 10% FBS and 40 U / mL of IL-2 at a density of cells / mL was added and stored on ice for use.

[0368] T cell activation: 1 × 10 6 25 μL of activated magnetic beads were added per cell, and the corresponding T cell-activated CD3 / CD28 magnetic beads were removed and placed in a 1.5 mL centrifuge tube. The tube was shaken for approximately 30 seconds before aspiration. The activated magnetic beads were washed three times in the centrifuge tube with culture medium at a volume ratio greater than 1:1. In the final wash, all washing solution was removed, and the activated magnetic beads were resuspended in an equal volume of complete medium to the initial volume. The washed activated magnetic beads were added to the cell resuspension and mixed uniformly. A 6-well plate was removed, cells were added at a rate of 3 mL per well, and the cells were cultured in a cell incubator at 37°C and 5% CO2 for 2 days.

[0369] Compound treatment: A 20 mM stock solution of the compound was diluted to 200 μM with DMSO, and then further diluted fourfold with complete medium to 50 μM (50 ×), and the mixture was homogeneously prepared for use. A four-fold dilution with DMSO (25% DMSO) was used as a negative control well. T cells were activated for 2 days, and the cells were uniformly pipetted. A 1.5 mL centrifuge tube was attached using a magnetic rack, the activation magnetic beads were removed, and the cell suspension was collected. After counting the cells, the cells were centrifuged at 300 x g for 10 min, the supernatant was discarded, and the cells were counted to 1.02 × 10⁶. 6 The cells were resuspended in 1 / mL, and 980 μL of cell suspension and 20 μL of 50× compound were added to each 24-well plate to a final compound concentration of 1 μM. The cells were cultured in a 37°C, 5% CO2 cell incubator for 3 days.

[0370] RNA extraction: T cells were collected by centrifugation, centrifuged at 1500 rpm for 3 minutes, washed once with PBS, and then centrifuged again, discarding the supernatant. Total RNA from the cells was extracted using a miniature RNA extraction reagent kit according to the instructions. 700 μL of Trizol cell lysate was added to the cell precipitate, pipetted uniformly with a pipette head, and allowed to stand at room temperature for 5 minutes. 140 μL of chloroform was added, shaken to mix uniformly, and allowed to stand at room temperature for 3 minutes. The chloroform-cell lysate mixture was centrifuged at 12000 xg for 15 minutes at 4°C. The upper solution was transferred to a new RNA enzyme-free (RNase-free) centrifuge tube, 1.5 times the volume of anhydrous ethanol was added, and pipetted several times with a pipette head. The solution was transferred to an RNA adsorption column and centrifuged at 8000 xg for 15 seconds. The centrifugation column was washed once with 700 μL of RWT solution, centrifuged at 8000xg for 15s, washed twice with 500 μL of RPE solution, and centrifuged at 8000xg for 2 minutes. The adsorption column was placed in a new 2 mL centrifuge tube and centrifuged at 12000xg for 1 minute to remove residual washing solution. The adsorption column was placed in a new 1.5 mL centrifuge tube, 30-50 μL of RNA enzyme-free water (RNase-free water) was added, and centrifuged at 12000xg for 2 minutes. 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: The extracted RNA template was placed on ice, the miniature RNA reverse transcription reagent kit was removed, some components (including 5×miScript HiSpec Buffer, 10×miScript nucleics Mix, and RNA enzyme-free water) were thawed at room temperature, and the miScript Reverse Transcriptase mix components were thawed on ice. Each reaction (10 μL) consisted of 5×miScript HiSpec Buffer (2 μL), 10×miScript nucleics Mix (1 μL), miScript Reverse Transcriptase mix (1 μL), RNA enzyme-free water (2 μL), and RNA template (4 μL), and the above reactions were prepared on ice. The samples were placed in a PCR instrument and the program was set as follows: 60 minutes at 37°C, 5 minutes at 95°C, and stored at 4°C. The samples that completed the reaction became cDNA samples.

[0372] Fluorescence quantitative PCR: The transcription level of miR-124 was detected using the SYBR green staining method, and the transcription level of the housekeeping gene U6 was detected as an internal reference. All 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 mixtures were prepared according to Table 1 below, and the reaction mixtures were placed in 96-well PCR plates, the plates were blocked with blocking film, and the plates were centrifuged. The PCR reaction was performed using a fluorescence quantitative PCR instrument according to the steps in Table 2.

[0373] [Table 4]

[0374] [Table 5]

[0375] [Table 6] Data Analysis: The CT value calculated by the software determines the ratio of the expression levels of miR-124 and the internal reference U6 for each sample, i.e., ΔCT(test compound) = CT miRNA-124 (Test compound)-CT U6 The (test compound) was calculated. The relative expression level is: relative expression level (test compound) = 2 (-[ΔCT(試験化合物)-ΔCT(DMSO)]) It was calculated using the following formula.

[0376] [Table 7-1] [Table 7-2] Conclusion: The compounds described herein have good activity to promote the upregulation of miR124.

[0377] Test Example 3: Pharmacokinetic study of the compound relating to this disclosure 1. Summary Using rats as test animals, the drug concentrations in plasma were measured at different time points after intragastric and intravenous administration of the compound of Example 2 and comparative compound A to rats by LC / MS / MS (see compound (1) of Example 3 in WO2016135052A1). The pharmacokinetic behavior of the compounds of this disclosure in rats was studied, and their pharmacokinetic characteristics were evaluated. [ka]

[0378] 2. Test Plan 2.1 Test reagent Compound of Example 2, comparative compound A. 2.2 Test animals Sixteen healthy adult SD rats, with an equal number of males and females, were divided into four groups and purchased from Victoria Experimental Animal Technology Co., Ltd. 2.3 Preparation of drugs A certain amount of the drug was weighed out, and a clear solution was prepared by adding 5% DMSO, 5% Tween® 80, and 90% physiological saline. 2.4 Administration Intragastric administration group: SD rats were fasted overnight before intragastric administration. The dose was 2 mg / kg, and the volume of administration was 10.0 mL / kg in all cases. Intravenous group: SD rats were fasted overnight and then administered intravenously. The dose was 1 mg / kg, and the volume of administration was 5.0 mL / kg in all cases.

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

[0380] Intravenous group: Rats were intravenously injected with the compound from Example 2 and comparative compound A. Blood samples were collected 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 processed in the same manner as the intragastric administration group.

[0381] The content of compounds awaiting measurement was measured in rat plasma after intragastric and intravenous administration of drugs at various concentrations: 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, the mixture was vortexed for 5 minutes, and the mixture was centrifuged for 10 minutes (3700-4000 rpm). 1.0-2.0 μL of the supernatant was taken from the plasma sample and analyzed by LC / MS / MS.

[0382] 4. Results of pharmacokinetic parameters

[0383] [Table 8]

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

Claims

1. A compound represented by general formula (I) or a medicinal salt thereof, 【Chemistry 1】 Eventually, Ring A is a 5-membered or 6-membered cycloalkyl group or a 5-membered or 6-membered heterocyclyl group. G is an N atom or CR ２ａ And, Each R １ These are homologous or homologous, and each is independently selected from the group consisting of hydrogen atoms, deuterium atoms, halogens, C1-6 alkyl groups, C1-6 alkoxy groups, C1-6 hydroxyalkyl groups, hydroxyl groups, cyano groups, and -C(O)R8. Each R ２ These are homologous or homologous, and each is independently selected from the group consisting of hydrogen atoms, halogens, and C1-6 alkyl groups. Each R ３ These are homologous or different, and each is independently selected from the group consisting of halogens, hydroxyl groups, C1-6 alkyl groups, C1-6 haloalkyl groups, C1-6 alkoxy groups, C1-6 haloalkoxy groups, C1-6 hydroxyalkyl groups, cyano groups, 3-6 membered cycloalkyl groups, and 3-6 membered heterocyclyl groups. Alternatively, two adjacent R ３ It forms a five-membered or six-membered cycloalkyl group or a five-membered or six-membered heterocyclyl group with the carbon atoms on the linked benzene ring, R ４ The group is selected from the group consisting of hydrogen atoms and 3- to 8-membered heterocyclyl groups, and each of the 3- to 8-membered heterocyclyl groups is independently and optionally substituted with one or more homologous or homologous substituents selected from the group consisting of hydroxyl groups and carboxyl groups. R ８ This is selected from the group consisting of hydrogen atoms, C1-6 alkyl groups, and C1-6 haloalkyl groups. R ２ａ This is selected from the group consisting of hydrogen atoms, halogens, and C1-6 alkyl groups. n is 0, 1, 2, 3 or 4, m is 0, 1 or 2, and p is 1, 2, 3, or 4. A compound represented by general formula (I) or a medicinal salt thereof.

2. Each R １ is the same or different and each independently is selected from the group consisting of a hydrogen atom, a halogen, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, a hydroxy group, and -C(O)R8, where R8 is as defined in claim 1 A compound represented by general formula (I) as described in claim 1, or a medicinal salt thereof.

3. A compound represented by general formula (IC), general formula (I-1), or general formula (I-2), or a pharmaceutically acceptable salt thereof, that is, 【Chemistry 2】 Eventually, Ring A, G, R １ ~R ３ n, m, and p are as defined in claim 1. A compound represented by general formula (I) as described in claim 1, or a medicinal salt thereof.

4. A compound represented by general formula (I-3) or general formula (I-4) or a pharmaceutically acceptable salt thereof, that is, 【Transformation 3】 Eventually, Ring B is a 5-membered or 6-membered cycloalkyl group or a 5-membered or 6-membered heterocyclyl group. Each R ３ａ These are homologous or homologous, and each is independently selected from the group consisting of halogens, hydroxyl groups, C1-6 alkyl groups, C1-6 haloalkyl groups, C1-6 alkoxy groups, C1-6 haloalkoxy groups, C1-6 hydroxyalkyl groups, and cyano groups. 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 represented by general formula (I) as described in claim 1, or a medicinal salt thereof.

5. Ring A is a 5-membered or 6-membered heterocyclyl group, and / or Each R １ These are homologous or different, and each is independently a hydrogen atom, a deuterium atom, a halogen, and -C(O)R. ８ , C １－６ Alkyl groups, and C １－６ Selected from the group consisting of alkoxy groups, R ８ This is as defined in claim 1, A compound represented by general formula (I) as described in claim 1, or a medicinal salt thereof.

6. A compound represented by general formula (II) or a medicinal salt thereof, that is, 【Chemistry 4】 Eventually, G １ G ２ and G ３ They are homologous or different, and each is independently an O atom, an S atom, and an NR １ａ , and CR １ｂ R １ｃ Selected from a group consisting of, R １ａ This is selected from the group consisting of hydrogen atoms, C1-6 alkyl groups, and -C(O)R8. R １ｂ and R １ｃ They are homologous or homologous, and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a C1-6 alkyl group, and a C1-6 alkoxy group, or R １ｂ and R １ｃ They form an oxo group together, G, R ２ ~R4, R8, m, and p are as defined in claim 1. A compound or a medicinal salt thereof.

7. A compound represented by general formula (II) as described in claim 6, or a pharmaceutically acceptable salt thereof, wherein G1 and G2 are homologous or homologous and each is independently selected from the group consisting of an O atom, an S atom, NR1a, and CR1bR1c, G3 is CR1bR1c, and R1a, R1b, and R1c are as defined in claim 6.

8. A compound represented by general formula (III) or a medicinal salt thereof, that is, 【Transformation 5】 Eventually, L １ and L ２ They are homologous or different, and each is independently an O atom, an S atom, and an NR １ｄ , and CR １ｅ R １ｆ Selected from the group consisting of L ３ and L ４ Each is independently CR １ｅ R １ｆ And, R １ｄ This is selected from the group consisting of hydrogen atoms, C1-6 alkyl groups, and -C(O)R8. R １ｅ and R １ｆ These are homologous or homologous, and each is independently selected from the group consisting of hydrogen atoms, deuterium atoms, halogens, C1-6 alkyl groups, and C1-6 alkoxy groups. G, R ２ ~R4, R8, m, and p are as defined in claim 1, A compound represented by general formula (I) as described in claim 1, or a medicinal salt thereof.

9. R ２ is a hydrogen atom, and / or Each R ３ They are homologous or different, and each is independently a halogen, C １－６ alkyl group, C １－６ Selected from the group consisting of alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered heterocyclyl groups, and cyano groups, A compound represented by general formula (I) as described in claim 1, or a medicinal salt thereof.

10. R 2a is a hydrogen atom, and / or R 8 is a C 1-6 alkyl group, A compound represented by general formula (I) as described in claim 1, or a medicinal salt thereof.

11. R ４ is a hydrogen atom, or 【Transformation 6】 That is, A compound represented by general formula (I) as described in claim 1, or a medicinal salt thereof. 【Request Item 12】 【Chemistry 7】 【Transformation 8】 A compound or a medicinal salt thereof, which is any one compound selected from the above.

13. A compound represented by the general formula (I-1C) or (I-2C) or a salt thereof, 【Chemistry 9】 Eventually, R is C １－６ It is an alkyl group, R １１ is C １－６ It 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 the general formula (I-1C) or (I-2C), or a salt thereof. 【Request Item 14】 【Chemistry 10】 Selected from the group consisting of the following compounds: The compound or salt thereof according to claim 13.

15. A method for preparing a compound represented by the general formula (IC) described in claim 3 or a pharmaceutically acceptable salt thereof, 【Chemistry 11】 The process includes the step of 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 pharmaceutically acceptable salt thereof. Eventually, X is a halogen, Ring A, G, R １ ~R ３ m, n, and p are as defined in claim 3. method.

16. A method for preparing a compound represented by general formula (I) as described in claim 1 or a medicinal salt thereof, 【Chemistry 12】 A compound of general formula (IC) or a pharmaceutically acceptable salt thereof is R ４’ - After reacting with compound Y, R ４’ The process includes the step of removing the protecting group to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof, Eventually, Y is a halogen, R ４’ teeth 【Chemistry 13】 And, R and R １１ These are homologous or different, and each is independently a C1-6 alkyl 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.

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

18. A pharmaceutical composition according to claim 17 for regulating miRNA levels.

19. A pharmaceutical composition for treating and / or preventing a disease or medical condition, wherein the disease or medical condition is selected from the group consisting of viral infection, inflammation, and cancer, according to claim 17.

20. The pharmaceutical composition according to claim 17 for treating and / or preventing AIDS or AIDS-related conditions or human immunodeficiency virus (HIV).

21. The inflammation is selected from the group consisting of autoimmune inflammatory diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the skin, other inflammatory diseases related to epithelial cells, cancer-related inflammation, irritation-related inflammation, and injury-related inflammation, and / or The pharmaceutical composition according to claim 19, wherein the cancer is selected from the group consisting of 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 carcinoma, medullary carcinoma, bronchial cancer, liver cancer, bile duct cancer, choriocarcinoma, seminomas, embryonic carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pineal glandoma, hemangioblastoma, acoustic neuroma, schwannoma, 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 tumors, thyroid cancer, osteoma, neuroblastoma, brain tumors, and myeloma.

22. The pharmaceutical composition according to claim 19, wherein the inflammation is selected from the group consisting of 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, Sjögren's syndrome, bronchitis, asthma, and colon cancer.

23. The pharmaceutical composition according to claim 22, wherein the inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).

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