Quinoline amine compounds, preparation method and medical use thereof

Abstract

This disclosure relates to quinolinamine compounds, their preparation methods, and their pharmaceutical applications. Specifically, this disclosure relates to a quinolinamine compound of general formula (I), its preparation method, pharmaceutical compositions containing such compounds, and its use as a therapeutic agent, particularly as a miRNA regulator, and its use in the preparation of medicaments for treating diseases or conditions improved by regulating miRNA levels.

Description

[Technical Field]

[0001] This disclosure pertains to the pharmaceutical field and relates to a quinolinamine compound, its preparation method, and its pharmaceutical applications. Specifically, this disclosure relates to quinolinamine compounds of general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use as therapeutic agents, particularly as miRNA regulators and in the preparation of medicaments for treating diseases or conditions improved by regulating miRNA levels. [Previous Technology]

[0002] MicroRNAs (miRNAs) are a class of non-coding single-stranded RNA molecules, approximately 22 nucleotides in length, encoded by endogenous genes. They participate in post-transcriptional gene expression regulation in animals and plants. Each miRNA can have multiple target genes, and several miRNAs can regulate the same gene. This complex network allows for precise regulation of target genes. miR-124 is widely expressed in various tissues throughout the body, especially in brain tissue. Studies have shown that overexpression of miR-124 can promote the transformation of activated macrophages-microglia to a quiescent state, thereby inhibiting the autoimmune disease encephalomyelitis (Ponomarev ED et al., Nat Med, 2011; 17: 67-70). In addition, miR-124 can promote the transformation of macrophages to the M2 type, thereby exerting an anti-inflammatory effect (Veremeyko T, et al., Plos One, 2013; 8: e81774). miR-124 also affects T cell differentiation; the levels of IFN-γ and TNFα in T cells treated with miR-124 decreased. Overexpression of miR-124 exerts an anti-inflammatory effect by downregulating STAT3 protein, thereby reducing the expression of the inflammatory cytokine IL-17 and inhibiting Th17 cell differentiation (Wei J et al., Cancer Res, 2013; 73: 3913-3926). Statistical studies have reported that miR-124 levels in children with ulcerative colitis are much lower than in healthy individuals, suggesting that upregulating miR-124 may suppress intestinal inflammatory responses (Koukos G, et al., Gastroenterology, 2013; 145: 842-852). Furthermore, Nakamachi's team discovered that miR-124 was significantly downregulated in synovial cells of rheumatoid arthritis patients compared to osteoarthritis patients (Nakamachi, Y, et al., Arthritis Rheum, 2009; 60: 1294-1304). These studies suggest that developing a novel small-molecule drug that upregulates miR-124 could be used to effectively treat related inflammatory diseases.

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

[0004] Inflammatory bowel disease (IBD) is an idiopathic inflammatory bowel disease, clinically manifested as diarrhea, abdominal pain, and even bloody stools. The etiology and pathogenesis of IBD are not fully understood. It is known that the inflammatory response caused by abnormal reactions of the intestinal mucosal immune system plays an important role in the pathogenesis of IBD. Environmental, genetic, infectious, and immune factors can all contribute to the disease. IBD usually refers to ulcerative colitis (UC) and Crohn's disease (CD). Ulcerative colitis is a continuous inflammation of the colonic mucosa and submucosa, usually affecting the rectum first and gradually spreading to the entire colon. Crohn's disease can affect the entire digestive tract, presenting as a discontinuous, full-thickness inflammation, most commonly affecting the terminal ileum, colon, and perianal region. IBD typically manifests as excessive immune cell invasion of the intestinal mucosa, an imbalance of T cell subsets including Th17, Th1, and Treg, and overactivated macrophages and dendritic cells. Currently marketed or clinically tested drugs include JAK inhibitors and TNFα antibodies that reduce inflammatory responses, antibodies against IL-12 and IL-23 that inhibit Th1 and Th17 differentiation, and integrin α4β7 antibodies that block inflammatory cell infiltration.

[0005] Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting the endothelial tissue of joints (called the synovium). It is characterized by polyarticular, symmetrical, and invasive joint inflammation of the small joints of the hands and feet, often accompanied by extra-articular organ involvement, leading to joint deformities and loss of function. Inflammatory cytokines (such as tumor necrosis factor-α, interleukins IL-1 and IL-6) play important roles in the pathogenesis of RA. Treatment typically involves disease-modifying small molecule antirheumatic drugs (DMARDs) or biologics such as TNF-α inhibitors. However, patients who initially respond to these drugs often become unresponsive after several years of use. Therefore, there is a need to develop treatments with novel mechanisms of action that are effective and safe for long-term use.

[0006] The disclosed related patent applications include WO2010143169A2, WO2015001518A1, WO2016009065A2, WO2017158201A1 and WO2020127843A1, etc. [Summary of the Invention]

[0007] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0007] Among them,

[0007] Ring A is a cycloalkyl or heterocyclic group;

[0007] G represents an N atom or CR2a;

[0008] Each R1 may be the same or different, and each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, sideoxy, hydroxyalkyl, cycloalkyloxy, heterocyclicoxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR5R6, -NHC(O)R7, -C(O)R8, -C(O)(CH2)qNR9R10, cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, wherein each alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl is independently substituted as needed by one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0009] Each R2 may be the same or different, and each is independently selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino groups;

[0010] Each R3 may be the same or different, and each is independently selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0011] Or two adjacent R3s and carbon atoms on the connected benzene ring form a cycloalkyl or heterocyclic group, each of which is independently substituted as needed by one or more identical or different substituents selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano.

[0012] R4 is selected from hydrogen atom, alkyl, cycloalkyl and heterocyclic group; wherein each of the alkyl, cycloalkyl and heterocyclic group is independently substituted as needed by one or more identical or different substituents selected from halogen, hydroxy, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, amino and cyano;

[0013] R5 and R6 may be the same or different, and each is independently selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, hydroxyl, amino, cycloalkyl and heterocyclic groups;

[0014] R7 is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

[0015] R8 is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups;

[0016] R9 and R10 may be the same or different, and are each independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, hydroxyl, amino, cycloalkyl and heterocyclic groups;

[0017] R2a is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino groups;

[0017] n is 0, 1, 2, 3 or 4;

[0017] m is 0, 1, or 2;

[0017] p is 1, 2, 3 or 4;

[0017] q is 0, 1, 2 or 3.

[0018] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0018] Ring A is a cycloalkyl or heterocyclic group;

[0018] G represents an N atom or CR2a;

[0019] Each R1 may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, sideoxy, hydroxyalkyl, cycloalkyloxy, heterocyclicoxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR5R6, -NHC(O)R7, -C(O)R8, -C(O)(CH2)qNR9R10, cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, wherein each alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl is independently substituted as needed by one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0020] Each R2 may be the same or different, and each is independently selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino groups;

[0021] Each R3 may be the same or different, and each is independently selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0022] Or two adjacent R3s and carbon atoms on the connected benzene ring form a cycloalkyl or heterocyclic group, each of which is independently substituted as needed by one or more identical or different substituents selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano.

[0023] R4 is selected from hydrogen atom, alkyl, cycloalkyl and heterocyclic group; wherein each of the alkyl, cycloalkyl and heterocyclic group is independently substituted as needed by one or more identical or different substituents selected from halogen, hydroxy, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, amino and cyano;

[0024] R5 and R6 may be the same or different, and each is independently selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, hydroxyl, amino, cycloalkyl and heterocyclic groups;

[0025] R7 is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

[0026] R8 is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups;

[0027] R9 and R10 may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, hydroxyl, amino, cycloalkyl and heterocyclic groups;

[0028] R2a is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino groups;

[0028] n is 0, 1, 2, 3 or 4;

[0028] m is 0, 1, or 2;

[0028] p is 1, 2, 3, or 4; and

[0028] q is 0, 1, 2 or 3.

[0029] In some embodiments disclosed herein, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IC) or a pharmaceutically acceptable salt thereof:

[0029]

[0029] Among them,

[0029] Rings A, G, R1 to R3, n, m and p are as defined in general formula (I).

[0030] In some embodiments disclosed herein, the compound represented by general formula (I), general formula (IC), or a pharmaceutically acceptable salt thereof, wherein it is not...

[0031] In some embodiments disclosed herein, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (I-1) or general formula (I-2) or a pharmaceutically acceptable salt thereof:

[0031]

[0031] Among them,

[0031] Rings A, G, R1 to R3, n, m and p are as defined in general formula (I).

[0032] In some embodiments disclosed herein, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (I-3) or general formula (I-4) or a pharmaceutically acceptable salt thereof:

[0032]

[0032] Among them,

[0032] Ring B is a cycloalkyl or heterocyclic group; wherein each of the cycloalkyl or heterocyclic group is independently substituted as needed by one or more identical or different substituents selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano;

[0032] Each R3a may be the same or different, and each is independently selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano;

[0032] r is 0, 1, or 2;

[0032] Rings A, G, R1, R2, R4, n and m are as defined in general formula (I).

[0033] In some embodiments disclosed herein, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (I-3C) or general formula (I-4C) or a pharmaceutically acceptable salt thereof:

[0033]

[0033] Among them,

[0033] Rings A, B, G, R1, R2, R3a, n, r and m are as defined in general formula (I-3) or general formula (I-4).

[0034] In some embodiments of this disclosure, the compound represented by 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 or a 3 to 8-membered heterocyclic group; preferably, ring B is a 5 or 6-membered cycloalkyl or a 5 or 6-membered heterocyclic group; more preferably, ring B is cyclopentyl.

[0035] In some embodiments of this disclosure, the compound represented by 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 or a 3 to 8-membered heterocyclic group; preferably, ring A is a 5 or 6-membered cycloalkyl or a 5 or 6-membered heterocyclic group.

[0036] In some embodiments disclosed herein, the compound represented by 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 each R1 is the same or different and is independently selected from hydrogen atom, deuterium atom, halogen, -C(O)R8, C1-6 alkyl, C1-6 alkoxy and septoxy groups; preferably selected from hydrogen atom, deuterium atom, halogen, -C(O)R8 and C1-6 alkyl; R8 is as defined in general formula (I).

[0037] In some embodiments disclosed herein, the compound represented by 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 its pharmaceutically acceptable salt, wherein each R1 is the same or different and is independently selected from hydrogen atom, deuterium atom, fluorine, acetyl, methyl and side oxygen.

[0038] In some embodiments disclosed herein, the compound represented by 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 each R1 is the same or different and is independently selected from hydrogen atom, halogen, -C(O)R8, C1-6 alkyl, C1-6 alkoxy and lateral oxygen; R8 is as defined in general formula (I).

[0039] In some embodiments of this disclosure, the compound represented by 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 R8 is selected from hydrogen atoms, C1-6 alkyl and halogenated C1-6 alkyl; preferably, R8 is a C1-6 alkyl; more preferably, R8 is methyl.

[0040] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0040]

[0040] Among them,

[0040] G1, G2 and G3 may be the same or different, and each is independently selected from O atoms, S atoms, NR1a and CR1bR1c;

[0041] R1a is selected from hydrogen atom, alkyl, -C(O)R8, -C(O)(CH2)qNR9R10, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl is independently substituted as needed by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0042] R1b and R1c may be the same or different, and each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclicoxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR5R6, -NHC(O)R7, -C(O)R8, -C(O)(CH2)qNR9R10, cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, or R1b and R1c together form a side oxygen group, wherein each alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl is independently substituted as needed by one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0042] G, R2 to R10, m, p and q are as defined in general formula (I).

[0043] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein,

[0043] G1, G2 and G3 may be the same or different, and each is independently selected from O atoms, S atoms, NR1a and CR1bR1c;

[0044] R1a is selected from hydrogen atom, alkyl, -C(O)R8, -C(O)(CH2)qNR9R10, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl is independently substituted as needed by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0045] R1b and R1c may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclicoxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR5R6, -NHC(O)R7, -C(O)R8, -C(O)(CH2)qNR9R10, cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, or R1b and R1c together form a side oxygen group, wherein each alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl is independently substituted as needed by one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0045] G, R2 to R10, m, p and q are as defined in general formula (I).

[0046] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IIC) or a pharmaceutically acceptable salt thereof:

[0046]

[0046] Among them,

[0046] G, G1, G2, G3, R2, R3, m and p are as defined in general formula (II).

[0047] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IID-1) or (IID-2) or a pharmaceutically acceptable salt thereof:

[0047]

[0047] Among them,

[0047] G, G1, G2, G3, R2, R3, m and p are as defined in general formula (II).

[0048] In some embodiments disclosed herein, the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or its pharmaceutically acceptable salt thereof, wherein G1 and G2 are the same or different and are each independently selected from O atoms, S atoms, NR1a and CR1bR1c; G3 is CR1bR1c; R1a, R1b and R1c are as defined in general formula (II).

[0049] In some embodiments of this disclosure, the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or its pharmaceutically acceptable salt, wherein G1 is an O atom or NR1a; G2 and G3 are each independently CR1bR1c; R1a, R1b and R1c are as defined in general formula (II).

[0050] In some embodiments disclosed herein, the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or its pharmaceutically acceptable salt thereof, wherein G2 is an O atom or NR1a; G1 and G3 are each independently CR1bR1c; R1a, R1b and R1c are as defined in general formula (II).

[0051] In some embodiments disclosed herein, the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or its pharmaceutically acceptable salt thereof, wherein G1 and G2 are both O atoms; G3 is CR1bR1c; R1b and R1c are as defined in general formula (II).

[0052] In some embodiments disclosed herein, the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or a pharmaceutically acceptable salt thereof, wherein G1, G2 and G3 are each independently CR1bR1c; R1b and R1c are as defined in general formula (II).

[0053] In some embodiments of this disclosure, the compound represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2) or its pharmaceutically acceptable salt, wherein G1 and G2 are the same or different and are each independently selected from O atom, NR1a and CR1bR1c, R1a, R1b and R1c as defined in general formula (II); preferably, selected from , , , and , R1a, R1b and R1c as defined in general formula (II); more preferably, selected from , , , ,

[0054] In some embodiments disclosed herein, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0054]

[0054] Among them,

[0054] L1, L2, L3 and L4 may be the same or different, and each is independently selected from O atom, S atom, NR1d and CR1eR1f;

[0055] R1d is selected from hydrogen atom, alkyl, -C(O)R8, -C(O)(CH2)qNR9R10, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl is independently substituted as needed by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0056] R1e and R1f may be the same or different, and each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclicoxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR5R6, -NHC(O)R7, -C(O)R8, -C(O)(CH2)qNR9R10, cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, or R1e and R1f together form a side oxygen group, wherein each alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl is independently substituted as needed by one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0056] G, R2 to R10, m, p and q are as defined in general formula (I).

[0057] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein,

[0057] L1, L2, L3 and L4 may be the same or different, and each is independently selected from O atom, S atom, NR1d and CR1eR1f;

[0058] R1d is selected from hydrogen atom, alkyl, -C(O)R8, -C(O)(CH2)qNR9R10, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl is independently substituted as needed by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0059] R1e and R1f may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclicoxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR5R6, -NHC(O)R7, -C(O)R8, -C(O)(CH2)qNR9R10, cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, or R1e and R1f together form a side oxygen group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted as needed by one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0059] G, R2 to R10, m, p and q are as defined in general formula (I).

[0060] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (III), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IIIC) or a pharmaceutically acceptable salt thereof:

[0060]

[0060] Among them,

[0060] G, L1, L2, L3, L4, R2, R3, m and p are as defined in general formula (III).

[0061] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (III) 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:

[0061]

[0061] Among them,

[0061] G, L1, L2, L3, L4, R2, R3, m and p are as defined in general formula (III).

[0062] In some embodiments disclosed herein, the compound represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or its pharmaceutically acceptable salt thereof, wherein L1 and L2 are the same or different and are each independently selected from O atom, S atom, NR1d and CR1eR1f; L3 and L4 are each independently CR1eR1f; R1d, R1e and R1f are as defined in general formula (III).

[0063] In some embodiments disclosed herein, the compound represented by formula (III), formula (IIIC), formula (IIID-1) or formula (IIID-2) or its pharmaceutically acceptable salt thereof, wherein L1 is an O atom or NR1d; L2, L3 and L4 are each independently CR1eR1f; R1d, R1e and R1f are as defined in formula (III).

[0064] In some embodiments of this disclosure, the compound represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or its pharmaceutically acceptable salt thereof, wherein L2 is an O atom or NR1d; L1, L3 and L4 are each independently CR1eR1f; R1d, R1e and R1f are as defined in general formula (III).

[0065] In some embodiments of this disclosure, the compound represented by formula (III), formula (IIIC), formula (IIID-1) or formula (IIID-2) or its pharmaceutically acceptable salt thereof, wherein L3 is an O atom or NR1d; L1, L2 and L4 are each independently CR1eR1f; R1d, R1e and R1f are as defined in formula (III).

[0066] In some embodiments of this disclosure, the compound represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or its pharmaceutically acceptable salt thereof, wherein L4 is an O atom or NR1d; L1, L2 and L3 are each independently CR1eR1f; R1d, R1e and R1f are as defined in general formula (III).

[0067] In some embodiments disclosed herein, the compound represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or its pharmaceutically usable salt thereof, wherein L1 and L2 are both O atoms; L3 and L4 are each independently CR1eR1f; R1e and R1f are as defined in general formula (III).

[0068] In some embodiments disclosed herein, the compound represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or a pharmaceutically acceptable salt thereof, wherein L1, L2, L3 and L4 are each independently CR1eR1f; R1e and R1f are as defined in general formula (III).

[0069] In some embodiments of this disclosure, the compound represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2) or its pharmaceutically acceptable salt, wherein L1 and L2 are the same or different and are each independently an O atom or CR1eR1f, R1e and R1f as defined in general formula (III); preferably, or, R1e and R1f as defined in general formula (III); more preferably, selected from,

[0070] In some embodiments disclosed herein, the compounds represented by 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) are pharmaceutically acceptable salts thereof, wherein each R2 is the same or different and is independently selected from hydrogen atoms, halogens, and C1-6 alkyl groups; preferably, R2 is a hydrogen atom.

[0071] In some embodiments disclosed herein, the compound or pharmaceutically acceptable salt thereof represented by 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) may have the same or different R3s, and each may be independently a halogen or a C1-6 alkyl group; preferably, R3 is a halogen; more preferably, R3 is Cl.

[0072] In some embodiments of this disclosure, the compound represented by general formula (I-3), general formula (I-4), general formula (I-3C) or general formula (I-4C) or its pharmaceutically usable salt, wherein each R3a is the same or different and is independently halogenated or C1-6 alkyl; preferably, R3a is halogenated; more preferably, R3a is Cl.

[0073] In some embodiments disclosed herein, the compound represented by 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 each R3 is the same or different, and each is independently selected from halogen, C1-6 alkyl, C1-6 alkoxy and cyano.

[0074] In some embodiments disclosed herein, the compound represented by 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 each R3 is the same or different and is independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic and cyano; preferably, each R3 is the same or different and is independently selected from Cl, Br, methyl, methoxy, cyano, cyclopropyl, tetrahydropyranyl and dihydropyranyl; more preferably, each R3 is the same or different and is independently selected from Cl, methyl, methoxy, cyano, cyclopropyl and tetrahydropyranyl.

[0075] In some embodiments of this disclosure, the compound represented by general formula (I-3), general formula (I-4), general formula (I-3C) or general formula (I-4C) or its pharmaceutically acceptable salt, wherein each R3a is the same or different and is independently selected from halogen, C1-6 alkyl, C1-6 alkoxy and cyano.

[0076] In some embodiments disclosed herein, the compound or pharmaceutically acceptable salt thereof represented by formula (I), formula (I-1), formula (I-2), formula (IC), formula (IIC), formula (IIIC), formula (II), formula (IID-1), formula (IID-2), formula (IIID-1), formula (IIID-2), or formula (III) is 2, 3, or 4; and wherein two adjacent R3s and carbon atoms on the connected benzene ring form a cycloalkyl or heterocyclic group, each of which is independently and as desired substituted with one or more identical or different substituents selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, and cyano; preferably, p is 3.

[0077] In some embodiments disclosed herein, the compound represented by 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.

[0078] In some embodiments disclosed herein, the compound represented by 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.

[0079] In some embodiments disclosed herein, the compound represented by 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.

[0080] In some embodiments of this disclosure, the compound represented by 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.

[0081] In some embodiments disclosed herein, the compounds represented by general formulas (I), (IC), (I-1), (I-2), (II), (IIC), (IID-1), (IID-2), (III), (IIIC), (IIID-1), and (IIID-2) or their pharmaceutically acceptable salts, wherein R3v, R3w, R3x, and R3y are the same or different, 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, heterocyclic groups, aryl groups, and heteroaryl groups, or two adjacent R3v, R3w, R3x, and R3y, together with the attached carbon atoms, form a cycloalkyl or heterocyclic group, each of which is independently selected as needed from halogens, hydroxyl groups, carboxyl groups, etc. The carbon atoms R3v, R3w, R3x, and R3y are substituted with one or more identical or different substituents selected from alkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, and cyano, provided that R3v, R3w, R3x, and R3y are not simultaneously hydrogen atoms; preferably, R3v is a halogen, and R3w, R3x, and R3y are identical or different and are each independently selected from hydrogen atoms, halogens, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, 3 to 8-membered cycloalkyl, and 3 to 8-membered heterocyclic groups, or R3w and R3x together with the attached carbon atoms form 3 to 8-membered cycloalkyl groups; more preferably, R3v is a halogen, and R3w, R3x, and R3y are identical or different and are each independently selected from hydrogen atoms, halogens, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, 3 to 6-membered cycloalkyl, and 3 to 6-membered heterocyclic groups.

[0082] In some embodiments disclosed herein, the compound represented by 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), and general formula (IIID-2), or a pharmaceutically usable salt thereof, wherein R3v is Cl when the expression is true.

[0083] In some embodiments disclosed herein, the compounds represented by general formulas (I), (IC), (I-1), (I-2), (II), (IIC), (IID-1), (IID-2), (III), (IIIC), (IIID-1), and (IIID-2), or pharmaceutically acceptable salts thereof, wherein R3w, R3x, and R3y are the same or different, and each is independently selected from hydrogen atom, Cl, Br, methyl, methoxy, cyano, cyclopropyl, tetrahydropyranyl, and dihydropyranyl; more preferably, R3w, R3x, and R3y are the same or different, and each is independently selected from hydrogen atom, Cl, methyl, methoxy, cyano, cyclopropyl, and tetrahydropyranyl.

[0084] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof:

[0084]

[0084] Among them,

[0084] G, R3, R4, G1, G2, R1b and R1c are as defined in general formula (II).

[0085] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (II), or general formula (II-1), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (II-1C) or a pharmaceutically acceptable salt thereof:

[0085]

[0085] Among them,

[0085] G, G1, G2, R3, R1b and R1c are as defined in general formula (II-1);

[0086] In some embodiments of this disclosure, the compound represented by general formula (II-1) or (II-1C) or its pharmaceutically acceptable salt, wherein G1 and G2 are the same or different and are each independently selected from O atoms, NR1a and CR1bR1c; R1a, R1b and R1c are as defined in general formula (II).

[0087] In some embodiments of this disclosure, the compound represented by general formula (II-1) or (II-1C) or its pharmaceutically acceptable salt, wherein G1 is an O atom or NR1a; G2 is CR1bR1c; or; G2 is an O atom or NR1a; G1 is CR1bR1c; R1a, R1b and R1c are as defined in general formula (II).

[0088] In some embodiments disclosed herein, the compound represented by general formula (II-1) or (II-1C) or its pharmaceutically acceptable salt thereof, wherein G1 and G2 are both O atoms.

[0089] In some embodiments disclosed herein, the compound represented by general formula (I) or general formula (III), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof:

[0089]

[0089] Among them,

[0089] G, R3, R4, L1, L2, R1e and R1f are as defined in general formula (III).

[0090] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (III), or general formula (III-1), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III-1C) or a pharmaceutically acceptable salt thereof:

[0090]

[0090] Among them,

[0090] G, L1, L2, R3, R1e and R1f are as defined in general formula (III-1).

[0091] In some embodiments disclosed herein, the compound represented by general formula (III-1) or general formula (III-1C) or its pharmaceutically acceptable salt, wherein L1 and L2 are the same or different and are each independently selected from O atoms, NR1d and CR1eR1f; R1d, R1e and R1f are as defined in general formula (III).

[0092] In some embodiments of this disclosure, the compound represented by general formula (III-1) or general formula (III-1C) or its pharmaceutically acceptable salt, wherein L1 is an O atom or NR1d; L2 is CR1eR1f; or; L2 is an O atom or NR1d; L1 is CR1eR1f; R1d, R1e and R1f are as defined in general formula (III).

[0093] In some embodiments disclosed herein, the compound represented by general formula (III-1) or general formula (III-1C) or its pharmaceutically usable salt, wherein L1 and L2 are both O atoms.

[0094] In some embodiments of this disclosure, the compound represented by general formula (II-1), general formula (II-1C), general formula (III-1) or general formula (III-1C) or a pharmaceutically acceptable salt thereof, wherein R3 is selected from halogens, C1-6 alkyl, C1-6 alkoxy and cyano.

[0095] In some embodiments of this disclosure, the compound represented by general formula (II-1), general formula (II-1C), general formula (III-1) or general formula (III-1C) or a pharmaceutically acceptable salt thereof, wherein R3 is a halogen or a C1-6 alkyl group; preferably, R3 is a halogen; more preferably, it is C1.

[0096] In some embodiments of this disclosure, the compound represented by 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, wherein R4 is a hydrogen atom or a 3- to 8-membered heterocyclic group, the 3- to 8-membered heterocyclic group being substituted by one or more identical or different substituents selected from hydroxyl and carboxyl groups; preferably, R4 is...

[0097] In some embodiments disclosed herein, the compound represented by 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, wherein R4 is a hydrogen atom.

[0098] In some embodiments disclosed herein, the compound represented by 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 R1a or R1d is selected from hydrogen atoms, C1-6 alkyl and -C(O)R8, where R8 is a C1-6 alkyl; preferably, R1a and R1d are the same or different, and each is independently methyl or acetyl.

[0099] In some embodiments disclosed herein, the compound or pharmaceutically acceptable salt thereof represented by 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) wherein R1b is the same as or different from R1c or R1e is different from R1f and is independently selected from hydrogen, deuterium, halogen and C1-6 alkyl; preferably, R1b is the same as or different from R1c or R1e is different from R1f and is independently selected from hydrogen, deuterium, fluorine and methyl.

[0100] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt thereof represented by 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) is wherein R1b and R1c or R1e and R1f are the same or different, and each is independently selected from hydrogen atoms, halogens and C1-6 alkyl groups; preferably, R1e is a hydrogen atom or a halogen; R1f is a hydrogen atom or a halogen.

[0101] In some embodiments disclosed herein, the compound 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-1) or general formula (III-1C), or a pharmaceutically acceptable salt thereof, wherein G is CR2a; R2a is as defined in general formula (I).

[0102] In some embodiments disclosed herein, the compound 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-1) or general formula (III-1C), or a pharmaceutically acceptable salt thereof, wherein R2a is selected from hydrogen atoms, halogens and C1-6 alkyl groups; preferably, R2a is a hydrogen atom.

[0103] In some embodiments disclosed herein, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group; G is an N atom or CR2a; R2a is selected from hydrogen, halogens, and C1-6 alkyl; each R1 may be the same or different, and each is independently selected from hydrogen, deuterium, halogens, -C(O)R8, C1-6 alkyl, C1-6 alkoxy, and sideoxy groups; R8 is a C1-6 alkyl; n is 0 (i.e., ... R1 is a hydrogen atom, 1, 2, 3, or 4; each R2 may be the same or different and is independently selected from hydrogen, halogen, and C1-6 alkyl; m is 0 (i.e., R2 is a hydrogen atom), 1, or 2; each R3 may be the same or different and is independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, and cyano; p is 1, 2, or 3; R4 is a hydrogen atom or a 3 to 8-membered heterocyclic group substituted by one or more of the same or different substituents selected from hydroxyl and carboxyl groups.

[0104] In some embodiments disclosed herein, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclic group; G is CR2a; R2a is a hydrogen atom; each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -C(O)R8, C1-6 alkyl, and C1-6 alkoxy; R8 is a C1-6 alkyl; n is 0 (i.e., R1 is a hydrogen atom), 1, 2, 3, or 4; each R2 is a hydrogen atom; each R3 is the same or different and is independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, and cyano; p is 1, 2, or 3; R4 is a hydrogen atom or a 3- to 8-membered heterocyclic group; wherein the 3- to 8-membered heterocyclic group is substituted by one or more of the same or different substituents selected from hydroxyl and carboxyl groups.

[0105] In some embodiments disclosed herein, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof is selected from , , , and , R1a is selected from hydrogen atom, C1-6 alkyl and -C(O)R8, R8 is C1-6 alkyl; R1b and R1c are the same or different, and are each independently selected from hydrogen atom, deuterium atom, halogen and C1-6 alkyl; G is N atom or CR2a; R2a is hydrogen atom; m is O; is , R3v is halogen, R3w R3x and R3y may be the same or different, and each is independently selected from hydrogen atoms, halogens, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic groups, or R3w and R3x together with the attached carbon atom form 3 to 8-membered cycloalkyl; R4 is a hydrogen atom or a 3 to 8-membered heterocyclic group, which is substituted by one or more of the same or different substituents selected from hydroxyl and carboxyl groups.

[0106] In some embodiments disclosed herein, the compound represented by general formula (III) or its pharmaceutically acceptable salt, wherein R1e and R1f are the same or different and are each independently selected from hydrogen, deuterium, halogen and C1-6 alkyl; G is N or CR2a; R2a is hydrogen; m is O; R3v is halogen; R3w, R3x and R3y are the same or different and are each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, 3 to 6 member cycloalkyl and 3 to 6 member heterocyclic group; R4 is hydrogen or 3 to 8 member heterocyclic group, which is substituted by one or more of the same or different substituents selected from hydroxyl and carboxyl groups.

[0107] In some embodiments disclosed herein, the compound represented by general formula (I-3) or general formula (I-4) or its pharmaceutically acceptable salt, wherein ring B is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group; ring A is a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclic group; G is CR2a; R2a is a hydrogen atom; each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen, -C(O)R8, C1-6 alkyl, and C1-6 alkoxy; R8 is a C1-6 alkyl; n is 0 (i.e., R1 is a hydrogen atom), 1, 2, 3, or 4; R2 is a hydrogen atom; each R3a is the same or different and is independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, and cyano; r is 0, 1, or 2; R4 is a hydrogen atom or a 3- to 8-membered heterocyclic group; wherein the 3- to 8-membered heterocyclic group is substituted by one or more of the same or different substituents selected from hydroxyl and carboxyl groups.

[0108] Table A contains typical compounds including, but not limited to:

[0108]

[0108]

[0108]

[0108]

[0108]

[0109] Another aspect of this disclosure relates to compounds or salts thereof represented by general formula (I-1C) or (I-2C):

[0109]

[0109] Among them,

[0109] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0109] Rings A, G, R1 to R3, m, n and p are as defined in general formula (I).

[0110] Another aspect of this disclosure relates to compounds or salts thereof represented by general formula (IID-1A) or (IID-2A):

[0110]

[0110] Among them,

[0110] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0110] Rings A, G, G1, G2, G3, R2, R3, m and p are as defined in general formula (II).

[0111] Another aspect of this disclosure relates to compounds or salts thereof represented by general formula (IIID-1A) or (IIID-2A):

[0111]

[0111] Among them,

[0111] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0111] Rings A, G, L1, L2, L3, L4, R2, R3, m and p are as defined in general formula (III).

[0112] In some embodiments of this disclosure, the compound represented by general formula (I-1C), (I-2C), (IID-1A), (IID-2A), (IIID-1A), or (IIID-2A) or a pharmaceutically acceptable salt thereof, wherein R is a C1-6 alkyl group; preferably, R is a methyl group.

[0113] In some embodiments of this disclosure, the 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, wherein R11 is a C1-6 alkyl group; preferably, R11 is a methyl group.

[0114] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0114]

[0115] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0115]

[0115] A compound of general formula (IC) or a pharmaceutically usable salt thereof is reacted with a compound of R4'-Y, and then the protecting group on R4' is removed to obtain a compound of general formula (I) or a pharmaceutically usable salt thereof;

[0115] Among them,

[0115] Y is a halogen; preferably a Br atom;

[0115] R4' is OR;

[0115] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0115] R4 is OR;

[0115] Rings A, G, R1 to R3, m, n and p are as defined in general formula (I).

[0116] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IC) or a pharmaceutically acceptable salt thereof, the method comprising:

[0116]

[0116] A compound of general formula (IA) or a salt thereof reacts with a compound of general formula (IB) or a salt thereof to give a compound of general formula (IC) or a pharmaceutically usable salt thereof;

[0116] Among them,

[0116] X is a halogen; preferably a Cl atom;

[0116] Rings A, G, R1 to R3, m, n and p are as defined in general formula (IC).

[0117] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0117]

[0117] A compound of general formula (I-1C) or its salt undergoes an ester hydrolysis reaction to give a compound of general formula (I-1) or its pharmaceutically usable salt;

[0117] Among them,

[0117] R and R11 are as defined in general formula (I-1C);

[0117] Rings A, G, R1 to R3, m, n and p are as defined in general formula (I-1).

[0118] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0118]

[0118] A compound of general formula (I-2C) or its salt undergoes an ester hydrolysis reaction to give a compound of general formula (I-2) or its pharmaceutically usable salt;

[0118] Among them,

[0118] R and R11 are as defined in general formula (I-2C);

[0118] Rings A, G, R1 to R3, m, n and p are as defined in general formula (I-2).

[0119] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-3) or a pharmaceutically acceptable salt thereof, the method comprising:

[0119]

[0119] A compound of general formula (I-3C) or a pharmaceutically usable salt thereof is reacted with a compound of R4'-Y, and then the protecting group on R4' is removed to obtain a compound of general formula (I-3) or a pharmaceutically usable salt thereof;

[0119] Among them,

[0119] Y is a halogen; preferably a Br atom;

[0119] R4' is OR;

[0120] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0120] R4 is OR;

[0120] Rings A, B, G, R1, R2, R3a, m, n and r are as defined in general formula (I-3).

[0121] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-3C) or a pharmaceutically acceptable salt thereof, the method comprising:

[0121]

[0121] A compound of general formula (I-3A) or a salt thereof reacts with a compound of general formula (IB) or a salt thereof to give a compound of general formula (I-3C) or a pharmaceutically usable salt thereof;

[0121] Among them,

[0121] X is a halogen; preferably a Cl atom;

[0121] Rings A, B, G, R1, R2, R3a, m, n and r are as defined in general formula (I-3C).

[0122] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-4) or a pharmaceutically acceptable salt thereof, the method comprising:

[0122]

[0123] A compound of general formula (I-4C) or a pharmaceutically usable salt thereof is reacted with a compound of R4'-Y, and then the protecting group on R4' is removed to obtain a compound of general formula (I-4) or a pharmaceutically usable salt thereof;

[0123] Among them,

[0123] Y is a halogen; preferably a Br atom;

[0123] R4' is OR;

[0123] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0123] R4 is OR;

[0123] Rings A, B, G, R1, R2, R3a, m, n and r are as defined in general formula (I-4).

[0124] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-4C) or a pharmaceutically acceptable salt thereof, the method comprising:

[0124]

[0124] A compound of general formula (I-4A) or a salt thereof reacts with a compound of general formula (IB) or a salt thereof to give a compound of general formula (I-4C) or a pharmaceutically usable salt thereof;

[0124] Among them,

[0124] X is a halogen; preferably a Cl atom;

[0124] Rings A, B, G, R1, R2, R3a, m, n and r are as defined in general formula (I-4C).

[0125] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0125]

[0125] A compound of general formula (IIC) or a pharmaceutically usable salt thereof is reacted with a compound of R4'-Y, and then the protecting group on R4' is removed to obtain a compound of general formula (II) or a pharmaceutically usable salt thereof;

[0125] Among them,

[0125] Y is a halogen; preferably a Br atom;

[0125] R4' is OR;

[0125] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0125] R4 is OR;

[0125] G, G1, G2, G3, R2, R3, m and p are as defined in general formula (II).

[0126] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIC) or a pharmaceutically acceptable salt thereof, the method comprising:

[0126]

[0126] A compound of general formula (IA) or a salt thereof reacts with a compound of general formula (IIB) or a salt thereof to give a compound of general formula (IIC) or a pharmaceutically usable salt thereof;

[0126] Among them,

[0126] X is a halogen; preferably a Cl atom;

[0126] G, G1, G2, G3, R2, R3, m and p are as defined in general formula (IIC).

[0127] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IID-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0127]

[0127] A compound of general formula (IID-1A) or a salt thereof undergoes an ester hydrolysis reaction to give a compound of general formula (IID-1) or a pharmaceutically usable salt thereof;

[0127] Among them,

[0127] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0127] G, G1, G2, G3, R2, R3, m and p are as defined in general formula (IID-1).

[0128] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IID-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0128]

[0128] A compound of general formula (IID-2A) or a salt thereof undergoes an ester hydrolysis reaction to give a compound of general formula (IID-2) or a pharmaceutically usable salt thereof;

[0128] Among them,

[0128] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0128] G, G1, G2, G3, R2, R3, m and p are as defined in general formula (IID-2).

[0129] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0129]

[0129] A compound of general formula (II-1C) or a pharmaceutically usable salt thereof is reacted with a compound of R4'-Y, and then the protecting group on R4' is removed to obtain a compound of general formula (II-1) or a pharmaceutically usable salt thereof;

[0129] Among them,

[0129] Y is a halogen; preferably a Br atom;

[0129] R4' is OR;

[0130] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0130] R4 is OR;

[0130] G, G1, G2, R1b, R1c and R3 are as defined in general formula (II-1); preferably, R3 is a halogen.

[0131] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1C) or a pharmaceutically acceptable salt thereof, the method comprising:

[0131]

[0131] A compound of general formula (II-1A) or a salt thereof reacts with a compound of general formula (II-1B) or a salt thereof to give a compound of general formula (II-1C) or a pharmaceutically usable salt thereof;

[0131] Among them,

[0131] X is a halogen; preferably a Cl atom;

[0131] G, G1, G2, R1b, R1c and R3 are as defined in general formula (II-1C); preferably, R3 is a halogen.

[0132] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0132]

[0132] A compound of general formula (IIIC) or a pharmaceutically usable salt thereof is reacted with a compound of R4'-Y, and then the protecting group on R4' is removed to obtain a compound of general formula (III) or a pharmaceutically usable salt thereof;

[0132] Among them,

[0132] Y is a halogen; preferably a Br atom;

[0132] R4' is OR;

[0132] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0132] R4 is OR;

[0132] G, L1, L2, L3, L4, R2, R3, m and p are as defined in general formula (III).

[0133] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIIC) or a pharmaceutically acceptable salt thereof, the method comprising:

[0133]

[0133] A compound of general formula (IA) or a salt thereof reacts with a compound of general formula (IIIB) or a salt thereof to give a compound of general formula (IIIC) or a pharmaceutically usable salt thereof;

[0133] Among them,

[0133] X is a halogen; preferably a Cl atom;

[0133] G, L1, L2, L3, L4, R2, R3, m and p are as defined in general formula (IIIC).

[0134] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIID-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0134]

[0134] A compound of general formula (IIID-1A) or a salt thereof undergoes an ester hydrolysis reaction to give a compound of general formula (IIID-1) or a pharmaceutically usable salt thereof;

[0134] Among them,

[0134] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0134] G, L1, L2, L3, L4, R2, R3, m and p are as defined in general formula (IIID-1).

[0135] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIID-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0135]

[0135] A compound of general formula (IIID-2A) or a salt thereof undergoes an ester hydrolysis reaction to give a compound of general formula (IIID-2) or a pharmaceutically usable salt thereof;

[0135] Among them,

[0135] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0135] G, L1, L2, L3, L4, R2, R3, m and p are as defined in general formula (IIID-2).

[0136] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0136]

[0136] A compound of general formula (III-1C) or a pharmaceutically usable salt thereof is reacted with a compound of R4'-Y, and then the protecting group on R4' is removed to obtain a compound of general formula (III-1) or a pharmaceutically usable salt thereof;

[0136] Among them,

[0136] Y is a halogen; preferably a Br atom;

[0136] R4' is OR;

[0136] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0136] R4 is OR;

[0136] G, L1, L2, R1e, R1f and R3 are as defined in general formula (III-1); preferably, R3 is a halogen.

[0137] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1C) or a pharmaceutically acceptable salt thereof, the method comprising:

[0137]

[0137] A compound of general formula (II-1A) or a salt thereof reacts with a compound of general formula (III-1B) or a salt thereof to give a compound of general formula (III-1C) or a pharmaceutically usable salt thereof;

[0137] Among them,

[0137] X is a halogen; preferably a Cl atom;

[0137] G, L1, L2, R1e, R1f and R3 are as defined in general formula (III-1C); preferably, R3 is a halogen.

[0138] Another aspect of this disclosure relates to a pharmaceutical composition containing a therapeutically effective amount of 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 Table A, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0139] This disclosure further relates to the use of 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 acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for regulating miRNA levels; preferably, the miRNA is miR-124.

[0140] This disclosure further relates to the use of 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 acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for treating diseases or conditions improved by regulating miRNA levels.

[0141] This disclosure further relates to the use of 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 Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions selected from viral infections, inflammation, and cancer.

[0142] This disclosure further relates to the use of 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 acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of AIDS or AIDS-related conditions or human immunodeficiency virus (HIV).

[0143] 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), and (III-1) C) Use of compounds of general formula (III-1) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions of inflammation selected from autoimmune inflammatory diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory diseases of the digestive tract, inflammatory diseases of the skin, other inflammatory diseases of the epithelial cells, cancer-related inflammation, irritation-related inflammation, and injury-related inflammation.

[0144] This disclosure further relates to a 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 pharmaceutically usable salts, or pharmaceutical compositions comprising them, used as medicines for the treatment and / or prevention of diseases or conditions, wherein the disease or condition is selected from viral infections, inflammation, and cancer; wherein the inflammation is selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma, and inflammation associated with colon cancer; preferably, the inflammation is inflammatory bowel disease.

[0145] This disclosure further relates to the use of compounds of 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), (III-1), and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of a disease or condition, namely cancer, selected from... Leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, cystadenoma, medullary carcinoma, bronchial cancer, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal carcinoma, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small bowel cancer, gallbladder cancer, pediatric tumors, urothelial carcinoma, ureteral tumors, thyroid cancer, osteoma, neuroblastoma, brain tumor, and myeloma.

[0146] This disclosure further relates to a method for regulating miRNA levels, comprising administering to a desired patient a therapeutically effective amount 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 formula (III-1) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the miRNA is miR-124.

[0147] This disclosure further relates to a method for treating and / or preventing a disease or condition, comprising administering to a patient a therapeutically effective amount of the following 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), (III... D-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and the compounds shown in Table A, or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, wherein the disease or condition is selected from viral infections, inflammation, and cancer; 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 digestive tract, inflammatory diseases of the skin, other inflammatory diseases of the epithelial cells, cancer-related inflammation, irritation-related inflammation, and injury-related inflammation.

[0148] This disclosure further relates to a 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 pharmaceutically usable salts, or pharmaceutical compositions comprising them, used as medicines for the treatment and / or prevention of diseases or conditions, wherein the disease or condition is selected from viral infections, inflammation, and cancer; wherein the inflammation is selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma, and inflammation associated with colon cancer; preferably, the inflammation is inflammatory bowel disease.

[0149] This disclosure further relates to a method of treating and / or preventing a disease or condition, comprising administering to a desired patient a therapeutically effective amount 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 formula (III-1) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, wherein the disease or condition is selected from viral infections, inflammation, and Cancer; this cancer is selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, cystadenoma, medullary carcinoma, bronchial cancer, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal carcinoma, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, rectal cancer, small bowel cancer, gallbladder cancer, pediatric tumors, urothelial carcinoma, ureteral tumors, thyroid cancer, osteoma, neuroblastoma, brain tumor, and myeloma.

[0150] This disclosure further relates to a method of treating and / or preventing a disease or condition comprising administering to a patient a therapeutically effective amount 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 the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, wherein the disease or condition is selected from AIDS or AIDS-related conditions and human immunodeficiency virus (HIV).

[0151] This disclosure further relates to a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1), and the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicine.

[0152] This disclosure further relates to 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 the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, for regulating miRNA; preferably, the miRNA is miR-124.

[0153] 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), and (III-1C). The compounds of general formula (III-1) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, are used for the treatment and / or prevention of diseases or conditions selected from viral infections, inflammation, and cancer; 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 digestive tract, inflammatory diseases of the skin, other inflammatory diseases of the epithelial cells, cancer-related inflammation, irritation-related inflammation, and injury-related inflammation.

[0154] This disclosure further relates to a 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 use of the compounds shown in Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, for the treatment and / or prevention of diseases or conditions, wherein the disease or condition is selected from viral infections, inflammation, and cancer; wherein the inflammation is selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma, and inflammation associated with colon cancer; preferably, the inflammation is inflammatory bowel disease.

[0155] This disclosure further relates to the use 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 the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, for the treatment and / or prevention of a disease or condition selected from viral infections, inflammation, and cancer; wherein the inflammation is inflammatory bowel disease; and wherein the inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).

[0156] This disclosure further relates to the use of a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1), and a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, for the treatment and / or prevention of a disease or condition selected from viral infections, inflammation, and cancer; the cancer selected from... Leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, cystadenoma, medullary carcinoma, bronchial cancer, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, bladder cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal carcinoma, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small bowel cancer, gallbladder cancer, pediatric tumors, urothelial carcinoma, ureteral tumors, thyroid cancer, osteoma, neuroblastoma, brain tumors, and myeloma.

[0157] This disclosure further relates to the use of a compound of general formula (I), general formula (IC), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3C), general formula (I-4), general formula (I-4C), general formula (II), general formula (IIC), general formula (II-1), general formula (II-1C), general formula (III), general formula (IID-1), general formula (IID-2), general formula (IIID-1), general formula (IIID-2), general formula (IIIC), general formula (III-1C), general formula (III-1) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and / or prevention of AIDS or AIDS-related conditions or human immunodeficiency virus (HIV).

[0158] The diseases or conditions described in this disclosure are those that are treated and / or prevented by regulating miRNA levels; preferably, the miRNA is miR-124.

[0159] Preferably, the viral infection described in this disclosure is a retroviral infection.

[0160] Preferably, the inflammatory bowel disease described in this disclosure is ulcerative colitis (UC) or Crohn's disease (CD).

[0161] Preferably, the lymphomas described in this disclosure are Hodgkin's disease or non-Hodgkin's lymphomas (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma); the liver cancer is preferably hepatocellular carcinoma; the lung cancer (also known as bronchogenic carcinoma) is selected from non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma) and small cell lung cancer (SCLC); the kidney cancer is selected from renal cell carcinoma, clear cell renal cell carcinoma, and renal eosinophilic tumor; the leukemia is selected from chronic lymphocytic leukemia. Diseases (CLL), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML); skin cancers selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma, and angiosarcoma; multiple myeloma is preferred for myeloma; colorectal cancer is preferred for colon cancer or rectal cancer; gliomas (i.e., gliomas or glioblastomas) are preferred for glioblastoma, astrocytoma, and oligodendroglioma.

[0162] The active compounds can be formulated into forms suitable for administration by any appropriate route of delivery, using one or more pharmaceutically acceptable carriers via conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of this disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0163] As a general guideline, active compounds are preferably expressed in unit dose form, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compounds or components may be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. Suitable unit doses may range from 0.1 to 1000 mg.

[0164] In addition to the active compound, the pharmaceutical composition disclosed herein may contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0165] The tablets contain an active ingredient and a non-toxic, pharmaceutically acceptable excipient suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over a longer period of time.

[0166] Oral formulations may also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0167] The aqueous suspension contains an active substance and excipients suitable for preparing the aqueous suspension for mixing. Such excipients are suspending agents, dispersing agents, or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0168] Oil suspensions can be prepared by suspending the active ingredients in vegetable or mineral oil. Oil suspensions may contain thickeners. The aforementioned sweeteners and flavoring agents may be added to provide palatable formulations. These components may be preserved by adding antioxidants.

[0169] The pharmaceutical composition disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0170] The pharmaceutical composition disclosed herein may be in the form of a sterile injectable aqueous solution. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream by local mass injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0171] The pharmaceutical composition disclosed herein can be in the form of a sterile injectable aqueous or oil suspension for intramuscular and subcutaneous administration. This suspension can be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulation can also be a sterile injectable solution or suspension prepared in a parenteral-acceptable, non-toxic diluent or solvent. Furthermore, a sterile fixative oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixative oil can be used. Additionally, fatty acids can also be used to prepare injectable formulations.

[0172] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0173] The compounds disclosed herein can be prepared by adding water to form water-soluble dispersible powders and particles. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0174] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be verified based on conventional treatment protocols.

[0174] [Terminology Explanation]

[0175] Unless otherwise stated, the terms used in the specification and the claims have the following meanings.

[0176] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C1-12 alkyl), and more preferably containing 1 to 6 carbon atoms (i.e., C1-6 alkyl). Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tributyl, dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl 2,3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. The substituents are preferably selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, lateral oxy, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0177] The term “alkylene” refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, and is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e. C1-12 alkylene), more preferably containing 1 to 6 carbon atoms (i.e. C1-6 alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-epenylethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-epenylpropylene (-CH2CH(CH3)-), 1,3-epenylpropylene (-CH2CH2CH2-), 1,4-epenylbutylene (-CH2CH2CH2CH2-), etc. Alkylene groups may be substituted or unsubstituted, and when substituted, they may be substituted at any usable linking point. The substituents are preferably selected independently, as needed, from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyloxy, heterocyclic oxy, cycloalkylthio, heterocyclic thio, and side oxy groups.

[0178] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Preferably, an alkenyl group contains 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), more preferably an alkenyl group containing 2 to 6 carbon atoms (i.e., C2-6 alkenyl). The alkenyl group can be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, septyloxy, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0179] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. Preferably, it is 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., C2-12 alkynyl), more preferably an alkynyl group containing 2 to 6 carbon atoms (i.e., C2-6 alkynyl). The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0180] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., 3 to 12-membered cycloalkyl), more preferably 3 to 8 carbon atoms (i.e., 3 to 8-membered cycloalkyl), even more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl), and most preferably 5 or 6 carbon atoms (i.e., 5 or 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0181] The term "spirocycloalkyl" refers to a polycyclic group with 5 to 20 rings sharing a single carbon atom (called a spiro atom) between the rings, and may contain one or more double bonds. Preferred are 6 to 14 rings, more preferably 7 to 10 rings (e.g., 7, 8, 9, or 10 rings). Spirocycloalkyl groups are classified as monospirocycloalkyl or polyspirocycloalkyl (such as bispirocycloalkyl) according to the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl being more preferred. More preferably are 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, 5 / 6, 6 / 4, 6 / 5, or 6 / 6 monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0181]

[0182] The term "fused-ring alkyl" refers to a 5 to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferred are 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of constituent rings, fused-ring alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, etc., preferably bicyclic or tricyclic, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 bicyclic alkyl groups. Non-limiting examples of fused-ring alkyl groups include:

[0182]

[0183] The term "bridged cycloalkyl" refers to a polycyclic carbon group with 5 to 20 rings, in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferred are 6 to 14 rings, more preferably 7 to 10 rings (e.g., 7, 8, 9, or 10 rings). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, etc., with bicyclic, tricyclic, or tetracyclic bridged cycloalkyl being preferred, and bicyclic or tricyclic bridged cycloalkyl being even more preferred. Non-limiting examples of bridged cycloalkyl groups include:

[0183]

[0184] The cycloalkyl ring includes cycloalkyl groups (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include, etc.; preferably, and.

[0185] The cycloalkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, lateral oxy, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0186] The term "alkoxy" refers to -O-(alkyl), wherein the definition of alkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted as desired, and when substituted, the substituents are preferably selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0187] The term “heterocyclic group” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, which may be oxidized as needed (i.e., to form sulfonium or sulfonium), but does not include the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms (i.e., 3 to 12-membered heterocyclic groups); more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 are heteroatoms (e.g., 1, 2, and 3) (i.e., 3 to 8-membered heterocyclic groups); more preferably, it comprises 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 3 to 6-membered heterocyclic groups); most preferably, it comprises 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 5 or 6-membered heterocyclic groups). Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0188] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 rings sharing a single atom (called a spiro atom) between the rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur being oxidized as needed (i.e., forming a sulphine or sulphine), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it has 6 to 14 rings, more preferably 7 to 10 rings (e.g., 7, 8, 9, or 10 rings). Spiroheterocyclic groups are classified as monospirocyclic or polyspirocyclic (e.g., bispirocyclic) groups according to the number of shared spiro atoms between the rings, with monospirocyclic and bispirocyclic groups being more preferred. More preferably, they are 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, 5 / 6, or 6 / 6 monospirocyclic groups. Non-limiting examples of spirocyclic groups include:

[0188]

[0189] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, wherein each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be oxidized as needed (i.e., form sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-member / 4-member, 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 3-member, 5-member / 4-member, 5-member / 5-member, 5-member / 6-member, 5-member / 7-member, 6-member / 3-member, 6-member / 4-member, 6-member / 5-member, 6-member / 6-member, 6-member / 7-member, 7-member / 5-member or 7-member / 6-member bicyclic fused heterocyclic groups. Non-limiting examples of the fused heterocyclic group include:

[0189]

[0190] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 14 members, wherein any two rings share two non-directly connected atoms, which may contain one or more double bonds, one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be oxidized as needed (i.e., form sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of the bridged heterocyclic group include:

[0190]

[0191] The heterocyclic ring includes the heterocyclic groups (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:

[0191] , etc.

[0192] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available connection point, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

[0193] The term "aryl" refers to a 6- to 14-member all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6 to 10 members, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0193]

[0194] The aryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0195] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4) and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members (e.g., 5, 6, 7, 8, 9, or 10 members), more preferably 5 or 6 members, such as furanyl, thiophene, pyridinyl, pyrrolithyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0195]

[0195]

[0196] The heteroaryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0197] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, namely “divalent cycloalkyl”, “divalent heterocyclic”, “aryl”, and “heteroaryl”.

[0198] The term "amine protecting group" refers to the protection of an amine group by a group that is easily removed, so that the amine group remains unchanged when other parts of the molecule undergo reactions. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, etc. These groups may be substituted with 1 to 3 substituents selected from halogens, alkoxy groups, and nitro groups as needed.

[0199] The term "hydroxyl protecting group" refers to a hydroxyl derivative that is typically used to block or protect a hydroxyl group in a reaction on other functional groups of a compound. Preferably, the hydroxyl protecting group can be, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, methyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0199] The term “cycloalkyloxy” refers to cycloalkyl-O-, wherein the cycloalkyl group is as defined above.

[0199] The term “heterocyclic oxygen group” refers to the heterocyclic group -O-, wherein the heterocyclic group is as defined above.

[0199] The term “aryloxy group” refers to aryl-O-, where the aryl group is as defined above.

[0199] The term “heteroaryloxy” refers to heteroaryl-O-, wherein the heteroaryl group is as defined above.

[0199] The term “alkylthio” refers to alkyl-S-, wherein the alkyl group is as defined above.

[0199] The term “haloalkyl” means an alkyl group that is substituted with one or more halogens, wherein the alkyl group is as defined above.

[0199] The term “haloalkoxy” refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0199] The term “deuterated alkyl” means that an alkyl group is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0199] The term “hydroxyalkyl” means an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0199] The term “halogen” refers to fluorine, chlorine, bromine or iodine.

[0199] The term “hydroxyl” refers to -OH.

[0199] The term "mercapto" refers to -SH.

[0199] The term "amino" refers to -NH2.

[0199] The term "cyano" refers to -CN.

[0199] The term "nitro" refers to -NO2.

[0199] The term "oxo" or "oxo group" refers to "=O".

[0199] The term "carbonyl" refers to C=O.

[0199] The term "carboxyl" refers to -C(O)OH.

[0199] The term "carboxylate group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0200] The compounds disclosed herein include their isotopic derivatives. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure disclosed herein, in which hydrogen is replaced by "deuterium" or "tritium," or fluorine is replaced by 18F-fluorine labeling (18F isotope), or carbon atoms are replaced by 11C-, 13C-, or 14C-enriched carbon (11C-, 13C-, or 14C-carbon labeling; 11C-, 13C-, or 14C-isotope), are within the scope of this disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. In the deuterated form of the compound, each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare deuterated compounds, or they can be synthesized using conventional techniques with deuterating reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds typically retain activity comparable to their undeuterated counterparts, and deuteration at certain sites can result in better metabolic stability, leading to therapeutic advantages. Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, where deuteration substitution can be partial or complete; partial deuteration substitution refers to at least one hydrogen atom being replaced by at least one deuterium atom. When a position is specifically designated as deuterium (D), the position should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation).The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0201] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, trans-block isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. For all carbon-carbon double bonds, even if only one configuration is named, both Z-type and E-type are included. 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. This disclosure discloses an isomer of a certain compound that can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of a diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0202] The compounds disclosed herein can exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The term "tautomer" or "tautomer form" refers to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. It includes all possible tautomers, i.e., existing as a single isomer or as a mixture of such tautomers in any proportion. Non-limiting examples include: keto-enol, imine-enamine, endo-endoimine, etc. An example of an endo-endoimine equilibrium is shown below:

[0202]

[0203] When referring to the pyrazol group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0203]

[0204] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0205] In the chemical structure of the compound disclosed herein, the bond “” indicates that the configuration is not specified. That is, if there is a chiral isomer in the chemical structure, the bond “” can be “” or “”, or it can contain both “” and “” configurations at the same time.

[0206] “as needed” or “as needed” means that the event or environment subsequently described may but does not have to occur, and this description includes the possibility or absence of the event or environment. For example, “C1-6 alkyl group substituted with halogen or cyano group as needed” means that halogen or cyano group may but does not have to be present, and this description includes cases where the alkyl group is substituted with halogen or cyano group and cases where the alkyl group is not substituted with halogen or cyano group.

[0207] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (by experiment or theory). For example, an amino group or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0208] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0209] "Pharmaceutical-grade salt" refers to the salt of the disclosed compounds, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. Salts can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as amines. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0210] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as on the specific active substance. The appropriate effective amount in a case can be determined by a person of ordinary knowledge in the relevant technical field based on routine testing.

[0211] As used herein, the term “pharmaceutically acceptable” means that such compounds, materials, components and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio and are effective for their intended use.

[0212] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0213] When the term “about” is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by one of ordinary skill in the art, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0214] The method for synthesizing the compounds disclosed herein

[0214] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0214] [Option 1]

[0215] This disclosure includes a method for preparing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0215]

[0215] A compound of general formula (IC) or a pharmaceutically acceptable salt thereof undergoes a nucleophilic substitution reaction with a compound of R4'-Y under basic conditions, and then the protecting group on R4' is removed under basic conditions to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof;

[0215] Among them,

[0215] Y is a halogen; preferably a Br atom;

[0215] R4' is OR;

[0215] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0215] R4 is OR;

[0215] Rings A, G, R1 to R3, m, n and p are as defined in general formula (I).

[0215] [Option Two]

[0216] This disclosure discloses a method for preparing a compound of general formula (IC) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0216]

[0216] A compound of general formula (IA) or a salt thereof undergoes an aromatic nucleophilic substitution reaction with a compound of general formula (IB) or a salt thereof, as needed, under basic or acidic conditions; or, as needed, a coupling reaction occurs under basic conditions and in the presence of a catalyst, to give a compound of general formula (IC) or a pharmaceutically usable salt thereof;

[0216] Among them,

[0216] X is a halogen; preferably a Cl atom;

[0216] Rings A, G, R1 to R3, m, n and p are as defined in general formula (IC).

[0216] [Option 3]

[0217] This disclosure discloses a method for preparing the compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0217]

[0217] A compound of general formula (I-1C) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to give a compound of general formula (I-1) or its pharmaceutically usable salt;

[0217] Among them,

[0217] R and R11 are as defined in general formula (I-1C);

[0217] Rings A, G, R1 to R3, m, n and p are as defined in general formula (I-1).

[0217] [Option Four]

[0218] This disclosure discloses a method for preparing the compound represented by general formula (I-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0218]

[0218] A compound of general formula (I-2C) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to give a compound of general formula (I-2) or its pharmaceutically usable salt;

[0218] Among them,

[0218] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl or heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0218] Rings A, G, R1 to R3, m, n and p are as defined in general formula (I-2).

[0218] [Option Five]

[0219] This disclosure discloses a method for preparing the compound represented by general formula (I-3) or its pharmaceutically acceptable salt, comprising the following steps:

[0219]

[0219] A compound of general formula (I-3C) or a pharmaceutically acceptable salt thereof undergoes a nucleophilic substitution reaction with a compound of R4'-Y under basic conditions, and then the protecting group on R4' is removed under basic conditions to obtain a compound of general formula (I-3) or a pharmaceutically acceptable salt thereof;

[0219] Among them,

[0219] Y is a halogen; preferably a Br atom;

[0219] R4' is OR;

[0220] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0220] R4 is OR;

[0220] Rings A, B, G, R1, R2, R3a, n, m and r are as defined in general formula (I-3).

[0220] [Option Six]

[0221] This disclosure discloses a method for preparing the compound represented by general formula (I-3C) or its pharmaceutically acceptable salt, comprising the following steps:

[0221] A compound of general formula (I-3A) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IB) or a salt thereof, as needed, under basic or acidic conditions; or, as needed, undergoes a coupling reaction under basic conditions and in the presence of a catalyst, to give a compound of general formula (I-3C) or a pharmaceutically usable salt thereof;

[0221] Among them,

[0221] X is a halogen; preferably a Cl atom;

[0221] Rings A, B, G, R1, R2, R3a, n, m and r are as defined in general formula (I-3C).

[0221] [Option Seven]

[0222] This disclosure discloses a method for preparing the compound represented by general formula (I-4) or its pharmaceutically acceptable salt, comprising the following steps:

[0222]

[0223] A compound of general formula (I-4C) or a pharmaceutically acceptable salt thereof undergoes a nucleophilic substitution reaction with a compound of R4'-Y under basic conditions, and then the protecting group on R4' is removed under basic conditions to obtain a compound of general formula (I-4) or a pharmaceutically acceptable salt thereof;

[0223] Among them,

[0223] Y is a halogen; preferably a Br atom;

[0223] R4' is OR;

[0223] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0223] R4 is OR;

[0223] Rings A, B, G, R1, R2, R3a, n, m and r are as defined in general formula (I-4).

[0223] [Option Eight]

[0224] This disclosure discloses a method for preparing compounds of general formula (I-4C) or pharmaceutically acceptable salts thereof, comprising the following steps:

[0224]

[0224] A compound of general formula (I-4A) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IB) or a salt thereof, as needed, under basic or acidic conditions; or, as needed, undergoes a coupling reaction under basic conditions and in the presence of a catalyst, to give a compound of general formula (I-4C) or a pharmaceutically usable salt thereof;

[0224] Among them,

[0224] X is a halogen; preferably a Cl atom;

[0224] Rings A, B, G, R1, R2, R3a, n, m and r are as defined in general formula (I-4C).

[0224] [Option Nine]

[0225] This disclosure discloses a method for preparing the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0225]

[0225] A compound of general formula (IIC) or a pharmaceutically acceptable salt thereof undergoes a nucleophilic substitution reaction with a compound of R4'-Y under basic conditions, and then the protecting group on R4' is removed under basic conditions to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof;

[0225] Among them,

[0225] Y is a halogen; preferably a Br atom;

[0225] R4' is OR;

[0225] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0225] R4 is OR;

[0225] G, G1, G2, G3, R2, R3, m and p are as defined in general formula (II).

[0225] [Option Ten]

[0226] This disclosure discloses a method for preparing compounds of general formula (IIC) or pharmaceutically acceptable salts thereof, comprising the following steps:

[0226]

[0227] A compound of general formula (IA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IIB) or a salt thereof, as needed, under basic or acidic conditions; or, as needed, undergoes a coupling reaction under basic conditions and in the presence of a catalyst, to give a compound of general formula (IIC) or a pharmaceutically usable salt thereof.

[0227] Among them,

[0227] X is a halogen; preferably a Cl atom;

[0227] G, G1, G2, G3, R2, R3, m and p are as defined in general formula (IIC).

[0227] [Option Eleven]

[0228] This disclosure discloses a method for preparing the compound represented by general formula (IID-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0228]

[0229] A compound of general formula (IID-1A) or its salt undergoes ester hydrolysis under alkaline conditions to give a compound of general formula (IID-1) or its pharmaceutically usable salt;

[0229] Among them,

[0229] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0229] G, G1, G2, G3, R2, R3, m and p are as defined in general formula (IID-1).

[0229] [Option Twelve]

[0230] This disclosure discloses a method for preparing the compound represented by general formula (IID-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0230]

[0231] A compound of general formula (IID-2A) or its salt undergoes ester hydrolysis under alkaline conditions to give a compound of general formula (IID-2) or its pharmaceutically usable salt;

[0231] Among them,

[0231] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0231] G, G1, G2, G3, R2, R3, m and p are as defined in general formula (IID-2).

[0231] [Option Thirteen]

[0232] This disclosure discloses a method for preparing the compound of general formula (II-1) or its pharmaceutically acceptable salt, comprising the following steps:

[0232]

[0233] A compound of general formula (II-1C) or a pharmaceutically acceptable salt thereof undergoes a nucleophilic substitution reaction with a compound of R4'-Y under basic conditions, and then the protecting group on R4' is removed under basic conditions to obtain a compound of general formula (II-1) or a pharmaceutically acceptable salt thereof;

[0233] Among them,

[0233] Y is a halogen; preferably a Br atom;

[0233] R4' is OR;

[0233] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0233] R4 is OR;

[0233] G, G1, G2, R1b, R1c and R3 are as defined in general formula (II-1); preferably, R3 is a halogen.

[0233] [Option Fourteen]

[0234] This disclosure discloses a method for preparing a compound of general formula (II-1C) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0234]

[0235] A compound of general formula (II-1A) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (II-1B) or a salt thereof, as needed, under basic or acidic conditions; or, as needed, undergoes a coupling reaction under basic conditions and in the presence of a catalyst, to give a compound of general formula (II-1C) or a pharmaceutically usable salt thereof;

[0235] Among them,

[0235] X is a halogen; preferably a Cl atom;

[0235] G, G1, G2, R1b, R1c and R3 are as defined in general formula (II-1C); preferably, R3 is a halogen.

[0235] [Option Fifteen]

[0236] This disclosure includes a method for preparing the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0236]

[0237] A compound of general formula (IIIC) or a pharmaceutically acceptable salt thereof undergoes a nucleophilic substitution reaction with a compound of R4'-Y under basic conditions, and then the protecting group on R4' is removed under basic conditions to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof;

[0237] Among them,

[0237] Y is a halogen; preferably a Br atom;

[0237] R4' is OR;

[0237] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0237] R4 is OR;

[0237] G, L1, L2, L3, L4, R2, R3, m and p are as defined in general formula (III).

[0237] [Option Sixteen]

[0238] This disclosure discloses a method for preparing a compound of general formula (IIIC) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0238]

[0239] A compound of general formula (IA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IIIB) or a salt thereof, as needed, under basic or acidic conditions; or, as needed, undergoes a coupling reaction under basic conditions and in the presence of a catalyst, to give a compound of general formula (IIIC) or a pharmaceutically usable salt thereof.

[0239] Among them,

[0239] X is a halogen; preferably a Cl atom;

[0239] G, L1, L2, L3, L4, R2, R3, m and p are as defined in general formula (IIIC).

[0239] [Option Seventeen]

[0240] This disclosure discloses a method for preparing the compound represented by general formula (IIID-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0240]

[0241] A compound of general formula (IIID-1A) or its salt undergoes ester hydrolysis under alkaline conditions to give a compound of general formula (IIID-1) or its pharmaceutically usable salt.

[0241] Among them,

[0241] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0241] G, L1, L2, L3, L4, R2, R3, m and p are as defined in general formula (IIID-1).

[0241] [Option 18]

[0241]

[0242] A compound of general formula (IIID-2A) or its salt undergoes ester hydrolysis under alkaline conditions to give a compound of general formula (IIID-2) or its pharmaceutically usable salt;

[0242] Among them,

[0242] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0242] G, L1, L2, L3, L4, R2, R3, m and p are as defined in general formula (IIID-2).

[0242] [Option Nineteen]

[0243] This disclosure discloses a method for preparing the compound represented by general formula (III-1) or its pharmaceutically usable salt, comprising the following steps:

[0243]

[0244] A compound of general formula (III-1C) or a pharmaceutically acceptable salt thereof undergoes a nucleophilic substitution reaction with a compound of R4'-Y under basic conditions, and then the protecting group on R4' is removed under basic conditions to obtain a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof;

[0244] Among them,

[0244] Y is a halogen; preferably a Br atom;

[0244] R4' is OR;

[0244] R and R11 may be the same or different, and each is independently selected from alkyl, cycloalkyl and heterocyclic groups; preferably, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group;

[0244] R4 is OR;

[0244] G, L1, L2, R1e, R1f and R3 are as defined in general formula (III-1); preferably, R3 is a halogen.

[0244] [Option Twenty]

[0245] This disclosure discloses a method for preparing the compound represented by general formula (III-1C) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0245]

[0246] A compound of general formula (II-1A) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (III-1B) or a salt thereof, as needed, under basic or acidic conditions; or, as needed, undergoes a coupling reaction under basic conditions and in the presence of a catalyst, to give a compound of general formula (III-1C) or a pharmaceutically usable salt thereof;

[0246] Among them,

[0246] X is a halogen; preferably a Cl atom;

[0246] G, L1, L2, R1e, R1f and R3 are as defined in general formula (III-1C); preferably, R3 is a halogen.

[0247] The reagents providing the basic conditions in the above synthetic schemes include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, sodium acetate, potassium acetate, sodium terbutoxide, potassium terbutoxide, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, cadmium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide. Preferably, the reagent providing the basic conditions is selected from lithium hydroxide monohydrate, potassium carbonate, cesium carbonate, and cadmium carbonate. In Schemes 2, 6, 8, 10, 14, 16, and 20, the reagent providing the basic conditions is more preferably potassium carbonate or cesium carbonate. In Schemes 1, 5, 7, 9, 13, 15, and 19, the reagent providing the basic conditions in the nucleophilic substitution reaction is more preferably cadmium carbonate.

[0248] In Schemes 3, 4, 11-12, 17 and 18, the reagent for the alkaline conditions is preferably lithium hydroxide monohydrate, and more preferably lithium hydroxide monohydrate and hydrogen peroxide.

[0249] In Schemes 1, 5, 7, 9, 13, 15 and 19, the reagent that provides basic conditions in the reaction of removing the protecting group on R4' is preferably lithium hydroxide monohydrate, and more preferably lithium hydroxide monohydrate and hydrogen peroxide.

[0250] The reagents providing the acidic conditions in the above synthesis scheme include, but are not limited to, phenylhexacarboxylic acid, nitrothiocarboxylic acid, trichloroacetic acid, trinitrobenzenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid; preferably, the reagent providing the acidic conditions is trifluoroacetic acid.

[0251] The ester hydrolysis reaction involved in the above synthesis scheme is preferably carried out under the conditions of lithium hydroxide monohydrate and hydrogen peroxide.

[0252] The catalyst in the above synthesis scheme includes, but is not limited to, tetra(triphenylphosphine)palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), 1,1'-bis(dibenzylphosphine)dichloroferrocene palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloride, [1,1'-bis(diphenylphosphine) [Ferrocene] Palladium dichloride dichloromethane complex, tris(dibenzylacetone)dipalladium and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene; preferably, the catalyst is selected from methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), tris(dibenzylacetone)dipalladium and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene.

[0253] The above steps are preferably carried out in a solvent, including but 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. [Simplified Explanation of the Diagram]

[0254] Figure 1: Effect of compound 1 disclosed herein on body weight of UC mice induced by sodium sulfate dextran (DSS). Wherein, #P<0.05 indicates a significant difference between the model group and the normal control group, ##P<0.01 indicates a highly significant difference between the model group and the normal control group, ###P<0.001 indicates an extremely highly 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 highly significant difference between the treatment group and the model group, and ***P<0.001 indicates an extremely highly significant difference between the treatment group and the model group.

[0254] Figure 2: Effect of compound 1 disclosed in this study on colon length in UC mice induced by sodium sulfate dextran (DSS). Wherein, #P<0.05 indicates a significant difference between the model group and the normal control group, ##P<0.01 indicates a highly significant difference between the model group and the normal control group, ###P<0.001 indicates an extremely highly 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 highly significant difference between the treatment group and the model group, and ***P<0.001 indicates an extremely highly significant difference between the treatment group and the model group.

Implementation Method

[0255] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0255] Example

[0256] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl monoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0257] MS determination was performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

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

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

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

[0261] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0262] The CombiFlash rapid preparation instrument uses the CombiFlash Rf200 (TELEDYNE ISCO).

[0263] The thin-layer chromatography silica gel plates used are Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for thin-layer chromatography (TLC) have a size of 0.15mm~0.2mm, and the silica gel plates used for thin-layer chromatography separation and purification products have a size of 0.4mm~0.5mm.

[0264] Silicone column chromatography generally uses Yantai Huanghai silicone 200~300 mesh silicone as the carrier.

[0265] The average inhibition rate and IC50 value of the kinase were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0266] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

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

[0268] Argon atmosphere or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a volume of about 1L.

[0269] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0270] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HG2-SS hydrogenator.

[0271] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and the operation is repeated 3 times.

[0272] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0273] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0274] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0275] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography extraction solvent system used to purify the compound, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0275] Example 1

[0275] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)quinoline-2-amine

[0275]

[0276] 2,8-Dichloroquinoline 1a (100 mg, 0.51 mmol, Bio-Tech Pharmaceuticals) and 5-amino-2,2-difluoro-1,3-benzo[1,3]dioxane 1b (105 mg, 0.61 mmol, Shanghai Haohong) were dissolved in isopropanol (1 mL) and heated to 90 °C for 12 hours. After cooling to room temperature, the reaction solution was filtered and purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 0.1% formic acid aqueous solution and acetonitrile, acetonitrile gradient: 65%-85%, flow rate: 30 mL / min) to obtain title compound 1 (150 mg, yield 89%).

[0276] MS m / z (ESI): 335.0 [M+1].

[0276] 1H NMR(500MHz,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).

[0276] Example 2

[0276] (2S,3S,4S,5R,6R)-6-((8-chloroquinoline-2-yl)(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 2

[0276]

[0276] [Step 1]

[0276] (2R,3R,4S,5S,6S)-2-((8-chloroquinoline-2-yl)(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate 2b

[0277] Compound 1 (500 mg, 1.49 mmol) was dissolved in toluene (30 mL), and cadmium carbonate (155 mg, 0.90 mmol) was added. The mixture was heated to 140 °C and reacted to remove water for 12 hours. Then, methyl 1-bromo-1-deoxy-2,3,4-tris-O-acetylglucuronide 2a (1.05 g, 2.64 mmol, Shaoyuan Chemical Technology) was added, and the mixture was reacted to remove water at 140 °C for 24 hours. After cooling to room temperature, toluene was removed by concentration under reduced pressure. The mixture was purified by column chromatography using extraction solvent system B to give the title compound 2b (340 mg, 35% yield).

[0277] MS m / z (ESI): 651.0 [M+1].

[0277] [Step Two]

[0277] (2S,3S,4S,5R,6R)-6-((8-chloroquinoline-2-yl)(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 2

[0278] Lithium hydroxide monohydrate (450 mg, 10.74 mmol) was dissolved in water (5 mL), and hydrogen peroxide (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 2b (340 mg, 0.52 mmol), and the mixture was stirred at room temperature for 2 hours. After quenching with saturated sodium thiosulfate solution (20 mL), the pH was adjusted to 3 with 1 N hydrochloric acid solution. The mixture was extracted with ethyl acetate (50 mL × 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 chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 25%-45%, flow rate: 30 mL / min) to obtain title compound 2 (95 mg, yield 36%).

[0278] MS m / z (EST): 511.0 [M+1].

[0278] 1H NMR(500MHz,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,2 H),6.60(d,1H),6.30(d,1H),5.05-4.82(m,2H),3.55-3.36(m,4H),2.98(t,1H).

[0278] Example 3

[0278] 8-Chloro-N-(2,3-dihydrobenzofuran-5-yl)quinoline-2-amine

[0278]

[0279] Compound 1a (100 mg, 0.51 mmol, Bio-Tech Pharmaceuticals), 5-amino-2,3-dihydrobenzofuran 3a (105 mg, 0.61 mmol, Bio-Tech Pharmaceuticals), 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 solution was filtered and purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 0.1% formic acid aqueous solution and acetonitrile, acetonitrile gradient: 45%-65%, flow rate: 30 mL / min) to obtain title compound 3 (115 mg, yield 77%).

[0279] MS m / z (ESI): 297.0 [M+1].

[0279] 1H NMR(500MHz,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).

[0279] Example 4

[0279] 8-Chloro-N-(2,3-dihydro-1H-inden-5-yl)quinoline-2-amine

[0279]

[0280] 5-Aminoindane 4a (168 mg, 1.26 mmol, TCI), compound 1a (100 mg, 0.51 mmol, Shanghai Haohong), and trifluoroacetic acid (173 mg, 1.51 mmol) were dissolved in isopropanol (3 mL). The reaction was heated to 100 °C and reacted for 12 hours. After cooling to room temperature, the reaction solution was filtered and purified by high performance liquid preparative chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 65%-85%, flow rate: 30 mL / min) to give title compound 4 (129 mg, yield: 87%).

[0280] MS m / z (ESI): 295.1 [M+1].

[0280] 1H NMR (500MHz, 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).

[0280] Example 5

[0280] 1-(5-((8-chloroquinolin-2-yl)amino)indololin-1-yl)ethane-1-one 5

[0280]

[0280]

[0280] [Step 1]

[0280] 1-(5-nitroindoline-1-yl)ethane-1-one 5b

[0281] 5-Nitrodihydroindole 5a (2.0 g, 12.19 mmol, Bioder Pharmaceuticals) 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 slowly added at 0 °C. The mixture was then allowed to rise naturally to room temperature and reacted for another 2 hours. 30 mL of water was added to the mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 5b (1.8 g, yield: 72%).

[0281] MS m / z (ESI): 207.1 [M+1].

[0281] [Step Two]

[0281] 1-(5-aminoindololin-1-yl)ethane-1-one 5c

[0282] Compound 5b (0.8 g, 3.88 mmol) was added to 10 mL of methanol, and palladium on carbon (10%, 0.2 g) was added. The mixture was purged three times with hydrogen gas, and the reaction was carried out under a hydrogen atmosphere for 2 hours. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain crude title compound 5c (0.5 g). The crude product was used directly in the next reaction.

[0282] MS m / z (ESI): 177.1 [M+1].

[0282] [Step 3]

[0282] 1-(5-((8-chloroquinoline-2-yl)amino)indololin-1-yl)ethane-1-one 5

[0283] Compound 5c (100 mg, 0.57 mmol), 2,8-dichloroquinoline 1a (112 mg, 0.57 mmol, Bio-Pharmaceutical), and trifluoroacetic acid (64.72 mg, 0.57 mmol) were dissolved in isopropanol (1 mL), and then heated to 90 °C for 12 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to remove the solvent. The residue was purified by thin-layer chromatography (TLC) with developing solvent system B to give the title product 5 (48 mg, yield: 25%).

[0283] MS m / z (ESI): 338.1 [M+1].

[0283] 1H NMR(400MHz,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).

[0283] Example 6

[0283] 8-Chloro-N-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)quinoline-2-amine

[0283]

[0284] 6-amino-1,4-benzodioxane 6a (95 mg, 0.63 mmol, TCI) and 2,8-dichloroquinoline 1a (50 mg, 0.25 mmol, Bio-Pharmaceutical) were dissolved in isopropanol (3 mL). The reaction solution was heated to 100 °C and reacted for 12 hours. After cooling to room temperature, the reaction solution was filtered and purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 58%-78%, flow rate: 30 mL / min) to obtain title compound 6 (63 mg, yield: 80%).

[0284] MS m / z (ESI): 313.1 [M+1].

[0284] 1H NMR(500MHz, 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).

[0284] Example 7

[0284] 8-Chloro-N-(5,6,7,8-tetrahydronaphth-2-yl)quinoline-2-amine 7

[0284]

[0285] 5,6,7,8-Tetrahydro-2-naphthylamine 7a (147 mg, 0.51 mmol, TCI), 2,8-dichloroquinoline 1a (100 mg, 0.51 mmol, Bio-Tech Pharmaceuticals), and trifluoroacetic acid (173 mg, 1.51 mmol) were dissolved in isopropanol (3 mL). The reaction was heated to 100 °C and reacted for 12 hours. After cooling to room temperature, the reaction solution was filtered and purified by high performance liquid preparative chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 60%-80%, flow rate: 30 mL / min) to give title compound 7 (136 mg, yield: 87%).

[0285] MS m / z (ESI): 309.1 [M+1].

[0285] 1H NMR(500MHz, 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).

[0285] Example 8

[0285] 8-Chloro-N-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)quinoline-2-amine

[0285]

[0285] [Step 1]

[0285] 1-(2-bromo-1,1,2,2-tetrafluoroethoxy)-2-methoxy-4-nitrobenzene 8c

[0286] 2-Methoxy-4-nitrophenol 8a (2.0 g, 11.82 mmol, Bio-Tech Pharmaceuticals), cesium carbonate (5.8 g, 17.74 mmol), 1,2-dibromotetrafluoroethane 8b (6.2 g, 23.65 mmol, Shanghai Titan Technology), and 1-propanethiol (0.45 g, 5.91 mmol, TCI) were dissolved in 30 mL of dimethyl sulfoxide and reacted at 100 °C for 12 hours. After cooling to room temperature, 50 mL of 2N sodium hydroxide solution was added, and the mixture was extracted with diethyl ether (50 mL × 3). The organic phases were combined, washed with 2N sodium hydroxide solution (50 mL × 3), washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 8c (2.6 g, yield: 64%).

[0286] [Step Two]

[0286] 2-(2-bromo-1,1,2,2-tetrafluoroethoxy)-5-nitrophenol 8d

[0287] Compound 8c (2.6 g, 7.56 mmol) was added to 46 mL of acetic acid, followed by 19 mL of hydrobromic acid solution (40% by mass). The mixture was heated to 120 °C and reacted for 30 hours. After cooling to room temperature, 50 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 8d (2.0 g, yield: 79%).

[0287] MS m / z (ESI): 331.9 [M-1].

[0287] [Step 3]

[0287] 2,2,3,3-Tetrafluoro-6-nitro-2,3-dihydrobenzo[b][1,4]dioxane 8e

[0288] Compound 8d (200 mg, 0.60 mmol) was dissolved in methanol, followed by the addition of potassium hydroxide (37 mg, 0.66 mmol), and the reaction was allowed to proceed for 1 hour. The solvent was removed under reduced pressure, and 4 mL of cyclobutane was added. 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 × 3), washed with saturated sodium chloride solution (50 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 8e (98 mg, yield: 65%).

[0288] [Step 4]

[0288] 2,2,3,3-Tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxane-6-amine 8f

[0289] Compound 8e (95 mg, 0.38 mmol) was dissolved in 3 mL of methanol, followed by the addition of platinum dioxide. The mixture was purged three times with hydrogen gas, and the reaction was carried out under a hydrogen atmosphere for 4 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 8f (60 mg, yield: 72%).

[0289] MS m / z (ESI): 224.0 [M+1].

[0289] [Step 5]

[0289] 8-Chloro-N-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)quinoline-2-amine

[0290] Compound 8f (60 mg, 0.27 mmol), 2,8-dichloroquinoline 1a (50 mg, 0.25 mmol, Bio-Pharmaceutical), potassium carbonate (32 mg, 0.30 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (52 mg, 0.1 mmol) and tris(dibenzylacetone)dipalladium (28 mg, 0.03 mmol) were dissolved in 3 mL of 1,4-dioxane, and the reaction solution was heated to 100 °C and reacted for 12 hours. The reaction mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 80%-95%, flow rate: 30 mL / min) to give title compound 8 (23 mg, yield: 24%).

[0290] MS m / z (ESI): 385.0 [M+1].

[0290] 1H NMR (500MHz, 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).

[0290] Example 9

[0290] N-(8-chloroquinoline-2-yl)-[1,3]dioxacyclopenta[4,5-b]pyridine-6-amine 9

[0290]

[0290]

[0290] [Step 1]

[0290] 6-Bromo-[1,3]dioxanepenta[4,5-b]pyridine 9b

[0291] 2,3-Dihydroxy-5-bromopyridine 9a (2.0 g, 10.53 mmol, Bio-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 solution was poured into 30 mL of water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 9b (300 mg, yield: 14%).

[0291] MS m / z (ESI): 201.9[M+1], 203.9[M+3].

[0291] [Step Two]

[0291] [1,3]dioxanepenta[4,5-b]pyridine-6-ylaminocarbamate tert-butyl 9c

[0292] Compound 9b (100 mg, 0.49 mmol) and tributyl carbamate (104 mg, 0.89 mmol) were dissolved in 8 mL of 1,4-dioxane. Tris(dibenzylacetone)dipalladium (45 mg, 0.049 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (47 mg, 0.098 mmol), and sodium tributoxide (85 mg, 0.89 mmol) were added under a nitrogen atmosphere. The mixture was heated to 105 °C and reacted for 20 hours. The reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The solution was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 9c (50 mg, yield: 42%).

[0292] MS m / z (ESI): 239.1 [M+1].

[0292] [Step 3]

[0292] [1,3]dioxanepenta[4,5-b]pyridine-6-amine hydrochloride 9d

[0293] Compound 9c (50 mg, 0.21 mmol) was dissolved in 5 mL of dichloromethane, and a solution of 4N hydrogen chloride in dioxane (425 μL, 1.7 mmol) was added dropwise under ice bath. After the addition was complete, the mixture was allowed to rise to room temperature and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 9d (36 mg), which was used directly in the next reaction step.

[0293] MS m / z (ESI): 139.0 [M+1].

[0293] [Step 4]

[0293] N-(8-chloroquinoline-2-yl)-[1,3]dioxacyclopenta[4,5-b]pyridine-6-amine 9

[0294] Compound 9d (36 mg, 0.21 mmol), 2,8-dichloroquinoline 1a (30 mg, 0.15 mmol, Bio-Pharmaceutical), cesium carbonate (148 mg, 0.45 mmol), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg, 0.02 mmol) were dissolved in 5 mL of 1,4-dioxane, and the reaction solution was heated to 100 °C and reacted for 12 hours. Cool to room temperature, add 30 mL of water, extract with ethyl acetate (50 mL × 3), wash with saturated sodium chloride solution (50 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 1 / 1000 aqueous trifluoroacetic acid solution and acetonitrile, acetonitrile gradient: 50%-95%, flow rate: 30 mL / min) to obtain title compound 9 (12 mg, yield: 26%).

[0294] MS m / z (ESI): 300.0 [M+1].

[0294] 1H NMR(500MHz, 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).

[0294] Example 10

[0294] N-(benzo[d][1,3]dioxacyclopenten-5-yl)-8-chloroquinoline-2-amine 10

[0294]

[0295] The compounds benzo[d][1,3]dioxane-5-amine 10a (693 mg, 5.05 mmol, Bio-D Pharmaceutical), 1a (1.0 g, 5.05 mmol), cesium carbonate (2.64 g, 8.10 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (584 mg, 1.01 mmol), and tris(dibenzylacetone)dipalladium (462 mg, 0.50 mol) were dissolved in 30 mL of 1,4-dioxane, and the reaction solution was heated to 105 °C and reacted for 12 hours. The reaction solution was cooled to room temperature, 25 mL of water was added, 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. The residue was purified by high performance liquid chromatography (Waters-2545, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 10%-26%, flow rate: 30 mL / min) to obtain target compound 10 (750 mg, yield: 50%).

[0295] MS m / z (ESI): 299.0 [M+1].

[0295] 1H NMR(500MHz,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).

[0295] Example 11

[0295] N-(benzo[d][1,3]dioxacyclopenten-5-yl-2,2-dideuterium)-8-chloroquinoline-2-amine 11

[0295]

[0296] The following compounds were prepared: benzo[d][1,3]dioxane-2,2-dideuterium-5-amine 11a (170 mg, 1.21 mmol, prepared by the method disclosed in the intermediate synthesis method 2 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-bis(diphenylphosphine-9,9-dimethyloxanthracene) (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 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 × 3), washed with saturated sodium chloride solution (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2767 Autopurification, extraction system: 1 / 1000 formic acid aqueous solution and acetonitrile, acetonitrile gradient: 45%-95%, flow rate: 30 mL / min) to obtain target compound 11 (100 mg, yield: 27%).

[0296] MS m / z (ESI): 300.9 [M+1].

[0296] 1H NMR (500MHz, 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).

[0296] Example 12

[0296] 8-Chloro-N-(2,2-dimethylbenzo[d][1,3]dioxacyclopenten-5-yl)quinoline-2-amine 12

[0296]

[0297] Compound 2,2-dimethylbenzo[d][1,3]dioxane-5-amine 12a (141 mg, 0.85 mmol, Shanghai Haohong Biopharmaceutical), compound 1a (146 mg, 0.74 mmol), cesium carbonate (362 mg, 1.11 mmol), tris(dibenzylacetone)dipalladium (68 mg, 0.074 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (86 mg, 0.15 mmol) were dissolved in 5 mL of 1,4-dioxane, and the reaction was heated to 105 °C for 12 hours. The reaction mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then purified by high performance liquid chromatography (Waters-2545, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 60%-95%, flow rate: 30 mL / min) to obtain the target compound 12 (132 mg, yield: 55%).

[0297] MS m / z (ESI): 327.1 [M+1].

[0297] 1H NMR(500MHz,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).

[0297] Example 13

[0297] 8-Chloro-N-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)quinoline-2-amine 13

[0297]

[0298] Compound 2,2-dimethyl-2,3-dihydrobenzofuran-5-amine 13a (59 mg, 0.36 mmol, prepared 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 heated to 90 °C for 12 hours. The reaction solution was cooled to room temperature, 15 mL of water was added, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The solution 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. The residue was purified by high performance liquid chromatography (Waters-2767 Autopurification, extraction system: 1 / 1000 formic acid aqueous solution and methanol, methanol gradient: 60%-95%, flow rate: 30 mL / min) to obtain target compound 13 (55 mg, yield: 56%).

[0298] MS m / z (ESI): 325.1 [M+1].

[0298] 1H NMR(500MHz,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).

[0298] Example 14

[0298] 5-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-8,9-dihydro-7H-cyclopenten[f]quinoline-3-amine 14

[0298]

[0298] [Step 1]

[0298] 6-Chloro-2,3-dihydro-1H-inden-5-amine 14b

[0299] 50 mL of dichloromethane, (6-chloro-2,3-dihydro-1H-inden-5-yl)aminocarbamate tributyl ester 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 sequentially to a 100 mL single-necked flask. The reaction was carried out at room temperature for 3 hours. The solvent was removed by concentration under reduced pressure, diluted with 100 mL of dichloromethane, washed with saturated sodium bicarbonate solution (50 mL × 2), washed with saturated sodium chloride solution (50 mL × 2), 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%). The crude product was used directly in the next reaction.

[0299] MS m / z (ESI): 168.1 [M+1].

[0299] [Step Two]

[0299] N-(6-chloro-2,3-dihydro-1H-inden-5-yl)-3,3-dimethoxypropionic acid 14d

[0300] To 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, methyl methacrylate) were added sequentially. Then, sodium bis(trimethylsilyl)amino (2 M tetrahydrofuran solution, 6.96 mL, 13.92 mmol) was slowly added dropwise at 0 °C. The reaction was allowed to rise naturally to room temperature for 12 hours. The reaction was quenched by adding 50 mL of saturated ammonium bicarbonate solution to the system under ice bath conditions, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 3), dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 14d (950 mg, yield: 36%).

[0300] [Step 3]

[0300] 5-Chloro-4,7,8,9-Tetrahydro-3H-cyclopenten[f]quinolin-3-one 14e

[0301] 10 mL of dichloromethane and compound 14d (800 mg, 2.83 mmol) were added sequentially to a 50 mL single-necked flask. Concentrated sulfuric acid (2.27 mL, 42.40 mmol) was slowly added dropwise to the system at 0 °C. After the addition was complete, the mixture was reacted at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure. The residue was added dropwise to ice water to precipitate a solid. The solid was filtered and dried to give the title compound 14e (500 mg, yield: 81%).

[0301] MS m / z (ESI): 220.0 [M+1].

[0301] [Step 4]

[0301] 3,5-Dichloro-8,9-dihydro-7H-cyclopenten[f]quinoline 14f

[0302] Add 2 mL of N,N-dimethylformamide and compound 14e (300 mg, 1.37 mmol) sequentially to a 50 mL single-necked flask. Raise the temperature to 95 °C and slowly add phosphorus oxychloride (0.1 mL, 1.10 mmol), continuing the reaction for 30 minutes. Concentrate under reduced pressure to remove phosphorus oxychloride, dilute with 20 mL of ethyl acetate, and wash with 0.2 N sodium hydroxide solution (30 mL × 2) and saturated sodium chloride solution (30 mL × 3). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound 14f (0.25 g, yield: 78%), which was used directly in the next reaction step.

[0302] MS m / z (ESI): 238.0 [M+1].

[0302] [Step 5]

[0302] 5-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-8,9-dihydro-7H-cyclopenten[f]quinoline-3-amine 14

[0303] To a 25 mL single-necked 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 sequentially. The temperature was then raised to 85 °C and the reaction was carried out for 16 hours. The solvent was removed under reduced pressure, and the mixture was diluted with 1 mL of methanol. The solution was purified by thin-layer chromatography (TLC) using solvent system B to obtain the title compound 14 (78 mg, yield: 49%).

[0303] MS m / z (ESI): 375.0 [M+1].

[0303] 1H NMR(400MHz,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).

[0303] Example 15

[0303] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-7-methylquinoline-2-amine 15

[0303]

[0303]

[0303] Step 1

[0303] N-(2-chloro-3-methylphenyl)-3,3-dimethoxypropionic acid 15b

[0304] 25 mL of tetrahydrofuran, 2-chloro-3-methylaniline 15a (1.5 g, 10.59 mmol, Bio-Pharmaceutical), and compound 14c (1.88 g, 11.69 mmol) were added sequentially to a 100 mL three-necked flask. After the system temperature was lowered to 0 °C, sodium bis(trimethylsilyl)amino (2 M tetrahydrofuran solution, 10.57 mL, 21.14 mmol) was slowly added dropwise. The system was then brought to room temperature and the reaction was allowed to proceed for 24 hours. 50 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction. The reaction solution was concentrated under reduced pressure to remove most of the organic phase. The solution was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 15b (2.70 g, yield: 98%). The crude product was used directly in the next reaction step.

[0304] [Step Two]

[0304] 8-Chloro-7-methylquinoline-2(1H)-one 15c

[0305] 15 mL of dichloromethane and compound 15b (2.70 g, 10.48 mmol) were added sequentially to a 100 mL single-necked flask. Concentrated sulfuric acid (8.37 mL, 157.11 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the ice bath was removed, and the reaction was continued for 16 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to ice water to precipitate a solid. The solid was filtered and dried to give the title compound 15c (1.8 g, yield: 89%).

[0305] MS m / z (ESI): 194.0 [M+1].

[0305] [Step 3]

[0305] 2,8-Dichloro-7-methylquinoline 15d

[0306] Compound 15c (800 mg, 4.67 mmol) and phosphorus oxychloride (3.16 g, 20.66 mmol) were added sequentially to a 50 mL single-necked flask. 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, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 15d (620 mg, yield: 71%).

[0306] MS m / z (ESI): 211.9 [M+1].

[0306] [Step 4]

[0306] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-7-methylquinoline-2-amine 15

[0307] 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 sequentially to a 25 mL sealed tube. The reaction was then heated to 95 °C and reacted for 16 hours. The solvent was removed under reduced pressure, diluted with 100 mL of ethyl acetate, and washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated sodium chloride solution (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Waters-2767 Autopurification, extraction system: 1 / 1000 formic acid aqueous solution and methanol, methanol gradient: 65%-95%, flow rate: 30 mL / min) to give title compound 15 (300 mg, yield: 73%).

[0307] MS m / z (ESI): 349.1 [M+1].

[0307] 1H NMR(500MHz,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).

[0307] Example 16

[0307] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-7-methoxyquinoline-2-amine 16

[0307]

[0307] [Step 1]

[0307] N-(2-chloro-3-methoxyphenyl)-3,3-dimethoxypropionic acid 16b

[0308] 25 mL of tetrahydrofuran, 2-chloro-3-methoxyaniline 16a (1.5 g, 9.51 mmol, Bio-Pharmaceutical), and compound 14c (1.69 g, 11.40 mmol) were added sequentially to a 100 mL three-necked flask. Bis(trimethylsilyl)aminosodium (2 M tetrahydrofuran solution, 9.51 mL, 19.03 mmol) was slowly added dropwise at 0 °C. The mixture was allowed to rise naturally to room temperature and reacted for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure to remove most of the organic phase. Extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 16b (2.50 g, yield: 96%). The crude product was used directly in the next reaction step.

[0308] [Step Two]

[0308] 8-Chloro-7-methoxyquinoline-2(1H)-one 16c

[0309] 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 slowly added dropwise at 0 °C. The ice bath was removed, and the reaction was continued for 16 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to ice water to precipitate a solid. The solid was filtered and dried to give the title compound 16c (1.6 g, yield: 84%).

[0309] MS m / z (ESI): 210.0 [M+1].

[0309] [Step 3]

[0309] 2,8-Dichloro-7-methoxyquinoline 16d

[0310] To a 50 mL single-necked flask, add 8 mL of toluene, compound 16c (800 mg, 3.81 mmol), and phosphorus oxychloride (1.17 g, 7.63 mmol) sequentially. The system temperature is raised to 100 °C and reacted for 3 hours. After cooling to room temperature, add 20 mL of ice water and adjust the pH to approximately 8 with saturated sodium bicarbonate. Extract with ethyl acetate (50 mL × 3). Wash the organic phase with saturated sodium chloride solution (50 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and purify the residue using silicone column chromatography with extraction solvent B to give the title compound 16d (680 mg, yield: 78%).

[0310] MS m / z (ESI): 227.9 [M+1].

[0310] [Step 4]

[0310] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-7-methoxyquinoline-2-amine 16

[0311] To a 25 mL sealed tube, add 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) sequentially. Then, raise the temperature to 95 °C and react for 16 hours. The solvent is removed by vacuum concentration, diluted with 100 mL of ethyl acetate, and washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated sodium chloride solution (50 mL × 2). The organic phase is dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is purified by silica gel column chromatography using extraction system B to obtain the target product 16 (280 mg, yield: 70%).

[0311] MS m / z (ESI): 365.1 [M+1].

[0311] 1H NMR(400MHz,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).

[0311] Example 17

[0311] 7,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-quinoline-2-amine 17

[0311]

[0311] [Step 1]

[0311] N-((2,3-dichlorophenyl)-3,3-dimethoxypropionic acid 17b

[0312] 25 mL of tetrahydrofuran, 2,3-dichloroaniline 17a (1.5 g, 9.26 mmol, Bailingwei), and compound 14c (1.65 g, 11.11 mmol) were added sequentially to a 100 mL three-necked flask. Bis(trimethylsilyl)aminosodium (2 M tetrahydrofuran solution, 9.30 mL, 18.60 mmol) was slowly added dropwise at 0 °C. The system was then brought to room temperature and the reaction was allowed to proceed for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate aqueous solution. The reaction solution was concentrated under reduced pressure to remove most of the organic phase. Extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 17b (2.50 g, yield: 97%). The crude product was used directly in the next reaction step.

[0312] [Step Two]

[0312] 7,8-Dichloroquinoline-2(1H)-one 17c

[0313] 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 slowly added dropwise at 0 °C. The ice bath was then removed, and the reaction was continued for 16 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to ice water to precipitate a solid. The solid was filtered and dried to give the title compound 17c (1.70 g, yield: 89%).

[0313] MS m / z (ESI): 214.0 [M+1].

[0313] [Step 3]

[0313] 2,7,8-Trichloroquine 17d

[0314] 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-necked flask. 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, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate. 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 residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 17d (950 mg, yield: 87%).

[0314] MS m / z (ESI): 231.9 [M+1].

[0314] [Step Four]

[0314] 7,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-quinoline-2-amine 17

[0315] 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 sequentially to a 25 mL sealed reaction flask. The temperature was then raised to 95 °C and reacted for 16 hours. The solvent was removed under reduced pressure, diluted with 100 mL of ethyl acetate, and washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated sodium chloride solution (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography using extraction solvent system A to obtain the target product 17 (300 mg, yield: 63%).

[0315] MS m / z (ESI): 369.0 [M+1].

[0315] 1H NMR (400MHz, 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).

[0315] Example 18

[0315] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-6-methylquinoline-2-amine 18

[0315]

[0315]

[0315] [Step 1]

[0315] N-(2-chloro-4-methylphenyl)-3,3-dimethoxypropionic acid 18b

[0316] 25 mL of tetrahydrofuran, 2-chloro-4-methylaniline 18a (1 g, 7.06 mmol, Bio-Pharmaceutical), and compound 14c (1.26 g, 8.47 mmol) were added sequentially to a 100 mL three-necked flask. Bis(trimethylsilyl)amino sodium (2 M tetrahydrofuran solution, 5.30 mL, 10.60 mmol) was slowly added dropwise at 0 °C. The system was then brought to room temperature and the reaction was allowed to proceed for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate aqueous solution. The reaction solution was concentrated under reduced pressure to remove most of the organic phase. Extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 18b (1.50 g, yield: 82%).

[0316] [Step Two]

[0316] 8-Chloro-6-methylquinoline-2(1H)-one 18c

[0317] 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 slowly added dropwise at 0 °C. The ice bath was then removed, and the reaction was continued for 4 hours. The solvent was removed by concentration under reduced pressure. The residue was added dropwise to ice water to precipitate a solid. The solid was filtered and dried to give the title compound 18c (0.8 g, yield: 71%).

[0317] MS m / z (ESI): 194.0 [M+1].

[0317] [Step 3]

[0317] 2,8-Dichloro-6-methylquinoline 18d

[0318] Compound 18c (0.5 g, 2.58 mmol) and phosphorus oxychloride (2 mL) were added sequentially to a 50 mL single-necked flask. 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, 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 residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 18d (0.3 g, yield: 55%).

[0318] MS m / z (ESI): 212.0 [M+1].

[0318] [Step 4]

[0318] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-6-methylquinoline-2-amine 18

[0319] To 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 sequentially. The temperature was then raised to 95 °C and the reaction was carried out 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), and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 70%-90%, flow rate: 30 mL / min) to give title compound 18 (55 mg, yield: 67%).

[0319] MS m / z (ESI): 349.1 [M+1].

[0319] 1H NMR(500MHz, 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).

[0319] Example 19

[0319] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-6-methoxyquinoline-2-amine 19

[0319]

[0319] [Step 1]

[0319] N-(2-chloro-4-methoxyphenyl)-3,3-dimethoxypropionic acid 19b

[0320] 25 mL of tetrahydrofuran, 2-chloro-4-methoxyaniline 19a (1 g, 6.35 mmol, Bio-Pharmaceutical), and compound 14c (1.13 g, 7.61 mmol) were added sequentially to a 100 mL three-necked flask. Bis(trimethylsilyl)amino sodium (2 M tetrahydrofuran solution, 4.76 mL, 9.52 mmol) was slowly added dropwise at 0 °C. The system was then brought to room temperature and the reaction was allowed to proceed for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate aqueous solution. The reaction solution was concentrated under reduced pressure to remove most of the organic phase. Extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 19b (1.20 g, yield: 69%).

[0320] [Step Two]

[0320] 8-Chloro-6-methoxyquinoline-2(1H)-one 19c

[0321] 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 slowly added dropwise at 0 °C. The ice bath was then removed, 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 a solid. The solid was filtered and dried to give the title compound 19c (0.6 g, yield: 65%).

[0321] MS m / z (ESI): 210.0 [M+1].

[0321] [Step 3]

[0321] 2,8-Dichloro-6-methoxyquinoline 19d

[0322] Compound 19c (500 mg, 2.39 mmol) and phosphorus oxychloride (2.5 mL) were added sequentially to a 50 mL single-necked flask. The system temperature was raised to 95 °C and reacted for 90 minutes. After removing phosphorus oxychloride under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 19d (75 mg, yield: 14%).

[0322] MS m / z (ESI): 228.0 [M+1].

[0322] [Step 4]

[0322] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-6-methoxyquinoline-2-amine 19

[0323] To a 25 mL sealed 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 sequentially. The temperature was then raised to 95 °C and the reaction was carried out 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), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 65%-85%, flow rate: 30 mL / min) to give title compound 19 (55 mg, yield: 67%).

[0323] MS m / z (ESI): 365.1 [M+1].

[0323] 1H NMR (500MHz, 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).

[0323] Example 20

[0323] 6,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)quinoline-2-amine 20

[0323]

[0323]

[0323] [Step 1]

[0323] N-(2,4-dichlorophenyl)-3,3-dimethoxypropionic acid 20b

[0324] 25 mL of tetrahydrofuran, 2,4-dichloroaniline 20a (1.0 g, 6.17 mmol, basil), and compound 14c (1.10 g, 7.41 mmol) were added sequentially to a 100 mL three-necked flask. Bis(trimethylsilyl)aminosodium (2 M tetrahydrofuran solution, 4.63 mL, 9.26 mmol) was slowly added dropwise at 0 °C. The system was then brought to room temperature and the reaction was allowed to proceed for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate aqueous solution. The reaction solution was concentrated under reduced pressure to remove most of the organic phase. Extraction was performed with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 20b (1.40 g, yield: 82%).

[0324] [Step Two]

[0324] 6,8-Dichloroquinoline-2(1H)-one 20c

[0325] 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 slowly added dropwise at 0 °C. The ice bath was then removed, and 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 a solid. The solid was filtered and dried to give the title compound 20c (0.5 g, yield: 54%).

[0325] MS m / z (ESI): 213.9 [M+1].

[0325] [Step 3]

[0325] 2,6,8-Trichloroquine 20d

[0326] Compound 20c (300 mg, 1.40 mmol) and phosphorus oxychloride (2 mL) were added sequentially to a 50 mL single-necked flask. 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, 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 residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 20d (240 mg, yield: 74%).

[0326] MS m / z (ESI): 231.9 [M+1].

[0326] [Step Four]

[0326] 6,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)quinoline-2-amine 20

[0327] To 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 sequentially. The temperature was then raised to 95 °C and the reaction was carried out 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), and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 80%-95%, flow rate: 30 mL / min) to give title compound 20 (55 mg, yield: 63%).

[0327] MS m / z (ESI): 369.0 [M+1].

[0327] 1H NMR (500MHz, 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).

[0327] Example 21

[0327] (2S,3S,4S,5R,6R)-6-(benzo[d][1,3]dioxacyclopenten-5-yl(8-chloroquinoline-2-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 21

[0327]

[0327] [Step 1]

[0327] (2R,3R,4S,5S,6S)-2-(benzo[d][1,3]dioxacyclopenten-5-yl)(8-chloroquinoline-2-yl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate 21a

[0328] Compound 10 (380 mg, 1.27 mmol) was dissolved in toluene (15 mL), and cadmium carbonate (131 mg, 0.76 mmol) was added. The mixture was heated to 145 °C and reacted to remove water for 12 hours. Then, compound 2a (606 mg, 1.53 mmol) was added, and the mixture was reacted to remove water at 145 °C for 24 hours. The mixture was cooled to room temperature, and toluene was removed by concentration under reduced pressure. The residue was purified by column chromatography using extraction solvent B to give the title compound 21a (450 mg, 58% yield).

[0328] MS m / z (ESI): 615.0 [M+1].

[0328] [Step Two]

[0328] (2S,3S,4S,5R,6R)-6-(benzo[d][1,3]dioxacyclopenten-5-yl(8-chloroquinoline-2-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 21

[0329] 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 the mixture was stirred at room temperature for 16 hours. After quenching with saturated sodium thiosulfate solution (20 mL), the pH was adjusted to 4 with 1N hydrochloric acid solution. The mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride solution (100 mL), and the organic phase was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 15%-95%, flow rate: 30 mL / min) to give title compound 21 (85 mg, yield 35%).

[0329] MS m / z (ESI): 475.1 [M+1].

[0329] 1H NMR(500MHz,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).

[0329] Example 22

[0329] (2S,3S,4S,5R,6R)-6-((8-chloroquinoline-2-yl)(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 22

[0329]

[0329] [Step 1]

[0329] (2R,3R,4S,5S,6S)-2-((8-chloroquinoline-2-yl)(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate 22a

[0330] Compound 6 (500 mg, 1.60 mmol) was dissolved in toluene (30 mL), and cadmium carbonate (165 mg, 0.96 mmol) was added. The mixture was heated to 140 °C and reacted to remove water for 12 hours. Then, compound 2a (1.90 g, 4.80 mmol) was added, and the mixture was reacted to remove water at 140 °C for 24 hours. The mixture was cooled to room temperature, and toluene was removed by concentration under reduced pressure. The residue was purified by column chromatography using extraction solvent B to give the title compound 22a (400 mg, 40% yield).

[0330] MS m / z (ESI): 629.0 [M+1].

[0330] [Step Two]

[0330] (2S,3S,4S,5R,6R)-6-((8-chloroquinoline-2-yl)(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 22

[0331] 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 then 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 1N hydrochloric acid solution. The mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride solution (100 mL), and the organic phase was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 20%-65%, flow rate: 30 mL / min) to give title compound 22 (95 mg, yield 36%).

[0331] MS m / z (ESI): 489.1 [M+1].

[0331] 1H NMR(500MHz,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),6.3 3(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).

[0331] Example 23

[0331] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-5-methylquinoline-2-amine

[0331]

[0331]

[0331] [Step 1]

[0331] N-(2-chloro-5-methylphenyl)-3,3-diethoxypropionic acid 23c

[0332] Add 5 mL of N,N-dimethylformamide, 2-chloro-5-methylaniline 23a (0.5 g, 3.53 mmol, Bio-Pharmaceutical), and 3,3-diethoxypropionic acid 23b (0.63 g, 3.88 mmol, Bailingwei) sequentially to a 100 mL three-necked flask. Slowly add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.01 g, 5.29 mmol) and N,N-diisopropylethylamine (0.91 g, 7.06 mmol) at 0 °C. Then, raise the system to room temperature and react for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate solution to the system, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL × 3). The organic phases were dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 23c (1.0 g, yield: 99%). The crude product was used directly in the next reaction.

[0332] [Step Two]

[0332] 8-Chloro-5-methylquinoline-2(1H)-one 23d

[0333] 2 mL of dichloromethane and compound 23c (1.00 g, 3.5 mmol) were added sequentially to a 100 mL single-necked flask. Concentrated sulfuric acid (3.35 mL, 62.98 mmol) was slowly added dropwise at 0 °C. The ice bath was then removed, and the reaction was continued for 4 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to 50 mL of ice water. The residue was extracted with ethyl acetate (50 mL × 5). The organic phases were combined and washed with saturated sodium chloride solution (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 23d (0.26 g, yield: 38%).

[0333] MS m / z (ESI): 194.0 [M+1].

[0333] [Step 3]

[0333] 2,8-Dichloro-5-methylquinoline 23e

[0334] Compound 23d (0.26 g, 1.34 mmol) and phosphorus oxychloride (2 mL) were added sequentially to a 50 mL single-necked flask. The system temperature was raised to 95 °C and reacted for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, ice water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, title compound 23e (0.28 g, yield: 99%). The crude product was used directly in the next reaction.

[0334] MS m / z (ESI): 212.0 [M+1].

[0334] [Step Four]

[0334] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-5-methylquinoline-2-amine 23

[0335] To 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 sequentially. The temperature was then raised to 95 °C and the reaction was carried out 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), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 70%-90%, flow rate: 30 mL / min) to give title compound 23 (80 mg, yield: 48%).

[0335] MS m / z (ESI): 349.1 [M+1].

[0335] 1H NMR (500MHz, 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).

[0335] Example 24

[0335] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-5-methoxyquinoline-2-amine 24

[0335]

[0335] [Step 1]

[0335] N-(2-chloro-5-methoxyphenyl)-3,3-diethoxypropionic acid 24b

[0336] Add 5 mL of N,N-dimethylformamide, 2-chloro-5-methoxyaniline 24a (0.5 g, 3.17 mmol, Bio-Pharmaceutical), and compound 23b (0.63 g, 3.88 mmol) sequentially to a 100 mL three-necked flask. Slowly add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.01 g, 5.29 mmol) and N,N-diisopropylethylamine (0.91 g, 7.06 mmol) at 0 °C. Then, raise the system to room temperature and react for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate solution to the system, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL × 2). The organic phases were dried with 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%). The crude product was used directly in the next reaction.

[0336] [Step Two]

[0336] 8-Chloro-5-methoxyquinoline-2(1H)-one 24c

[0337] 2 mL of dichloromethane and compound 24b (0.95 g, 3.14 mmol) were added sequentially to a 100 mL single-necked flask. Concentrated sulfuric acid (2.52 mL, 47.22 mmol) was slowly added dropwise at 0 °C. The ice bath was then removed, and the reaction was continued for 4 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to 50 mL of ice water. The residue was extracted with ethyl acetate (50 mL × 5). The organic phases were combined and washed with saturated sodium chloride solution (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 24c (0.26 g, yield: 40%).

[0337] MS m / z (ESI): 210.0 [M+1].

[0337] [Step 3]

[0337] 2,8-Dichloro-5-methoxyquinoline 24d

[0338] Compound 24c (365 mg, 1.26 mmol) and phosphorus oxychloride (2.5 mL) were added sequentially to a 50 mL single-necked flask. The system temperature was raised to 95 °C and the reaction was carried out for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, title compound 24d (288 mg, yield: 99%). The crude product was used directly in the next reaction.

[0338] MS m / z (ESI): 228.0 [M+1].

[0338] [Step Four]

[0338] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-5-methoxyquinoline-2-amine 24

[0339] To 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 sequentially. The temperature was then raised to 95 °C and the reaction was carried out 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), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 65%-85%, flow rate: 30 mL / min) to give title compound 24 (230 mg, yield: 49%).

[0339] MS m / z (ESI): 365.1 [M+1].

[0339] 1H NMR(400MHz,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).

[0339] Example 25

[0339] 5,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)quinoline-2-amine 25

[0339]

[0339]

[0339] [Step 1]

[0339] N-(2,5-dichlorophenyl)-3,3-diethoxypropionic acid 25b

[0340] Add 5 mL of N,N-dimethylformamide, 2,5-dichloroaniline 25a (0.5 g, 3.08 mmol, Bio-Pharmaceutical), and compound 23b (0.50 g, 3.39 mmol) sequentially to a 100 mL three-necked flask. Slowly add 2-(7-azabenzotriquinone)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.01 g, 5.29 mmol) and N,N-diisopropylethylamine (0.91 g, 7.06 mmol) at 0 °C. Then raise the system to room temperature and react for 24 hours. The reaction was quenched by adding 50 mL of saturated sodium bicarbonate aqueous solution to the system, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL × 2). The organic phases were dried with 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%). The crude product was used directly in the next reaction.

[0340] [Step Two]

[0340] 5,8-Dichloroquinoline-2(1H)-one 25c

[0341] 2 mL of dichloromethane and compound 25b (0.51 g, 1.67 mmol) were added sequentially to a 100 mL single-necked flask. Concentrated sulfuric acid (1.33 mL, 25.05 mmol) was slowly added dropwise at 0 °C. The ice bath was then removed, and the reaction was continued for 4 hours. The solvent was removed under reduced pressure, and the reaction solution was added dropwise to 50 mL of ice water. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed with saturated sodium chloride solution (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 25c (0.21 g, yield: 56%).

[0341] MS m / z (ESI): 214.1 [M+1].

[0341] [Step 3]

[0341] 2,5,8-Trichloroquine 25d

[0342] Compound 25c (213 mg, 0.99 mmol) and phosphorus oxychloride (2 mL) were added sequentially to a 50 mL single-necked flask. 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, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, title compound 25d (230 mg, yield: 99%). The crude product was used directly in the next reaction step.

[0342] MS m / z (ESI): 231.9 [M+1].

[0342] [Step Four]

[0342] 5,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopenten-5-yl)quinoline-2-amine 25

[0343] 3 mL of isopropanol, compound 25d (234 mg, 1.01 mmol), compound 1b (174 mg, 1.01 mmol), and trifluoroacetic acid (344 mg, 3.02 mmol) were added sequentially to a 25 mL sealed tube. The temperature was then 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 preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 80%-95%, flow rate: 30 mL / min) to give title compound 25 (230 mg, yield: 59%).

[0343] MS m / z (ESI): 369.0 [M+1].

[0343] 1H NMR (400MHz, 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).

[0343] Example 26

[0343] 8-Chloro-2-((2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)amino)quinoline-6-nitrile 26

[0343]

[0343] [Step 1]

[0343] N-(4-bromo-2-chlorophenyl)-3,3-dimethoxypropionic acid 26b

[0344] 25 mL of tetrahydrofuran, 4-bromo-2-chloroaniline 26a (3.0 g, 14.53 mmol, basil), and compound 14c (2.36 g, 15.98 mmol) were added sequentially to a 100 mL three-necked flask. Bis(trimethylsilyl)aminosodium (2 M tetrahydrofuran solution, 10.89 mL, 21.79 mmol) was slowly added dropwise at 0 °C. The system was then brought to room temperature and the reaction was allowed to proceed for 24 hours. The reaction was quenched by adding 50 mL of saturated ammonium chloride solution. The solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL × 2), 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%). The crude product was used directly in the next reaction step.

[0344] [Step Two]

[0344] 6-Bromo-8-chloroquinoline-2(1H)-one 26c

[0345] 5 mL of dichloromethane and compound 26b (4.60 g, 14.25 mmol) were added sequentially to a 100 mL single-necked flask. Concentrated sulfuric acid (11.40 mL, 213.89 mmol) was slowly added dropwise at 0 °C. The ice bath was then removed, and the mixture was heated to 90 °C and reacted for another 2 hours. The solvent was removed under reduced pressure, and the residue was added dropwise to 50 mL of ice water. The mixture was extracted with ethyl acetate (50 mL × 5). The combined organic phases were washed with saturated sodium chloride solution (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 26c (0.46 g, yield: 12%).

[0345] MS m / z (ESI): 257.9 [M+1].

[0345] [Step 3]

[0345] 6-Bromo-2,8-Dichloroquinoline 26d

[0346] Compound 26c (460 mg, 1.78 mmol) and phosphorus oxychloride (2 mL) were added sequentially to a 50 mL single-necked flask. 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, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, title compound 26d (440 mg, yield: 89%). The crude product was used directly in the next reaction.

[0346] [Step Four]

[0346] 6-Bromo-8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)quinoline-2-amine 26e

[0347] To 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 sequentially, and the temperature was raised to 95 °C and reacted for 16 hours. The reaction was cooled to room temperature, and 25 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (25 mL × 3). The organic phase was washed with saturated sodium chloride solution (25 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using extraction solvent system B to give title compound 26e (260 mg, yield: 62%).

[0347] MS m / z (ESI): 412.9 [M+1].

[0347] Step 5

[0347] 8-Chloro-2-((2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)amino)quinoline-6-nitrile 26

[0348] Add 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(dibenzylacetone)palladium (36 mg, 0.04 mmol), and 1,1'-bis(diphenylphosphine)ferrocene (46 mg, 0.08 mmol) sequentially to a 25 mL three-necked flask. Heat to 135 °C and react for 3 hours. Cool the reaction to room temperature, add 25 mL of water, extract with ethyl acetate (25 mL × 3), wash with saturated sodium chloride solution (25 mL × 2), and dry with 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, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 80%-95%, flow rate: 30 mL / min) to give title compound 26 (55 mg, yield: 63%).

[0348] MS m / z (ESI): 360.1 [M+1].

[0348] 1H NMR (400MHz, 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).

[0348] Example 27

[0348] 8-Chloro-6-cyclopropyl-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)quinoline-2-amine 27

[0348]

[0349] Compound 26e (165 mg, 0.40 mmol) was dissolved in 7.5 mL of 1,4-dioxane and water (V / V = 4:1), and cyclopropylboronic acid 27a (41 mg, 0.48 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), sodium carbonate (127 mg, 1.20 mmol), and dichloro[1,1'-bis(di-tert-butylphosphine)ferrocenepalladium(II)] (39 mg, 0.06 mmol, Bio-Pharmaceutical) were added. After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 3 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate solution (25 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 75%-95%, flow rate: 30 mL / min) to give title compound 27 (20 mg, yield: 13%).

[0349] MS m / z (ESI): 375.1 [M+1].

[0349] 1H NMR(400MHz,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).

[0349] Example 28

[0349] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-6-(tetrahydro-2H-pyran-4-yl)quinoline-2-amine 28

[0349]

[0349] [Step 1]

[0349] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-6-(3,6-dihydro-2H-pyran-4-yl)quinoline-2-amine 28b

[0350] 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-boronate pinacol ester 28a (92 mg, 0.44 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), sodium carbonate (140 mg, 1.31 mmol), and dichloro[1,1'-bis(di-tert-butylphosphine)ferrocenepalladium(II)) (29 mg, 0.044 mmol) were added. After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 3 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate solution (25 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silicone column chromatography using extraction system B to give title compound 28b (140 mg, yield: 77%).

[0350] MS m / z (ESI): 417.0 [M+1].

[0350] [Step Two]

[0350] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-6-(tetrahydro-2H-pyran-4-yl)quinoline-2-amine 28

[0351] Compound 28b (140 mg, 0.34 mmol) was dissolved in 10 mL of ethyl acetate, and 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 and reacted under a hydrogen atmosphere for 24 hours. The reaction solution was filtered with diatomaceous earth, the solvent was removed under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 70%-95%, flow rate: 30 mL / min) to give title compound 28 (70 mg, yield: 50%).

[0351] MS m / z (ESI): 419.0 [M+1].

[0351] 1H NMR(400MHz,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).

[0351] Example 29

[0351] 8-Chloro-7-cyclopropyl-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)quinoline-2-amine 29

[0351]

[0351]

[0351] [Step 1]

[0351] N-(3-bromo-2-chlorophenyl)-3,3-dimethoxypropionic acid 29b

[0352] 3-Bromo-2-chloro-aniline 29a (2.0 g, 9.72 mmol, Bio-Tech Pharmaceuticals) was dissolved in 15 mL of tetrahydrofuran, and compound 14c (1.58 g, 10.68 mmol) was added. The reaction was cooled to 0 °C, and sodium bis(trimethylsilyl)amino (2 M tetrahydrofuran solution, 5.4 mL, 10.7 mmol) was added dropwise. The system was then warmed to room temperature and reacted for 16 hours. A saturated ammonium chloride solution (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3), washed with saturated sodium chloride solution (100 mL × 2), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried under vacuum to obtain the crude product, title compound 29b (3.1 g, yield: 99%). The crude product was used directly in the next reaction without purification.

[0352] MS m / z (ESI): 321.9 [M+1].

[0352] [Step Two]

[0352] 7-Bromo-8-chloroquinoline-2(1H)-one 29c

[0353] Compound 29b (3.1 g, 9.61 mmol) was dissolved in 3 mL of dichloromethane, cooled to 0 °C, and concentrated sulfuric acid (7.7 mL, 144 mmol) was added. The ice bath was then removed, and the mixture was heated to 90 °C and reacted for another 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. The mixture was extracted with ethyl acetate (50 mL × 5), and the combined organic phases were washed with saturated sodium chloride solution (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using extraction system B to give the title compound 29c (0.56 g, yield: 23%).

[0353] MS m / z (ESI): 257.9 [M+1].

[0353] [Step 3]

[0353] 7-Bromo-2,8-Dichloroquinoline 29d

[0354] Compound 29c (560 mg, 2.17 mmol) and phosphorus oxychloride (3 mL) were added sequentially to a 50 mL single-necked flask. 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, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, title compound 29d (599 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0354] [Step Four]

[0354] 7-Bromo-8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)quinoline-2-amine 29e

[0355] To 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 sequentially. The temperature was then raised to 95 °C and the reaction was carried out for 16 hours. The reaction was cooled to room temperature, and 25 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (25 mL × 3). The organic phase was washed with saturated sodium chloride solution (25 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system B to give the title compound 29e (554 mg, yield: 62%).

[0355] MS m / z (ESI): 412.9 [M+1].

[0355] [Step 5]

[0355] 8-Chloro-7-cyclopropyl-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)quinoline-2-amine 29

[0356] 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(di-tert-butylphosphine)ferrocene-palladium(II) (33.0 mg, 0.051 mmol) were added. After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 3 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate solution (25 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (50 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 55%-95%, flow rate: 30 mL / min) to give title compound 29 (30 mg, yield: 23%).

[0356] MS m / z (ESI): 375.4 [M+1].

[0356] 1H NMR(400MHz,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).

[0356] Example 30

[0356] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-amine 30

[0356]

[0356]

[0356] [Step 1]

[0356] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-7-(3,6-dihydro-2H-pyran-4-yl)quinoline-2-amine 30a

[0357] 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(di-tert-butylphosphine)ferrocene-palladium(II) (16 mg, 0.025 mmol) were added. After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 3 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate solution (25 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (50 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography using extraction system B to give the title compound 30a (70 mg, yield: 41%).

[0357] MS m / z (ESI): 417.0 [M+1].

[0357] [Step Two]

[0357] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-amine 30

[0358] Compound 30a (70 mg, 0.17 mmol) was dissolved in 5 mL of ethyl acetate, and platinum carbon (35 mg, 5% Wt., 50-70% water content, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added. The mixture was purged three times with hydrogen and reacted under a hydrogen atmosphere for 24 hours. The reaction solution was filtered with diatomaceous earth, and the solvent was removed under reduced pressure. The residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and methanol, methanol gradient: 75%-95%, flow rate: 30 mL / min) to give title compound 30 (10 mg, yield: 14%).

[0358] MS m / z (ESI): 419.1 [M+1].

[0358] 1H NMR (400MHz, 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,2 H),7.08(d,1H),4.01(dd,2H),3.54(td,2H),2.04-1.95(m,1H),1.87-1.69(m,4H).

[0358] Example 31

[0358] 5-((8-chloroquinoline-2-yl)amino)-3-methylbenzo[d]oxazol-2(3H)-one 31

[0358]

[0359] 5-amino-3-methyl-1,3-benzoquinoline-2(3H)-one 31a (123 mg, 0.75 mmol, Bio-D Pharmaceutical), compound 1a (135 mg, 0.68 mmol), cesium carbonate (333 mg, 1.02 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (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 for 12 hours. The reaction mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, extraction system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 45%-95%, flow rate: 30 mL / min) to give title compound 31 (74 mg, yield: 33%).

[0359] MS m / z (ESI): 324.1 [M-1].

[0359] 1H NMR (500MHz, 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).

[0360] Biological Evaluation

[0360] Explanation of abbreviations appearing in the following content:

[0360] p.o.: Oral administration

[0360] bid: Twice a day

[0360] qd: Once a day

[0360] MC: Sodium carboxymethyl cellulose

[0361] Test Example 1: Preventive and therapeutic effects of the disclosed compounds on ulcerative colitis (UC) in mice

[0361] 1. Abstract

[0362] In this experiment, female C57BL / 6 mice from Vital River were used 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 (Compound 90 in WO2015001518A1) and the disclosed Compound 1 on DSS-induced ulcerative colitis were evaluated.<>

[0362]

[0362] 2. Experimental methods and materials

[0362] 2.1. Experimental animals and feeding conditions

[0363] Female C57BL / 6 mice were used in the experiment. They were purchased from Vital River Laboratory Animal Co., Ltd. (Production License No.: SCXK(Zhe)2019-No.0001, Animal Qualification Certificate No.: 20210401Abzz0619000795). Their body weight was 20-22 g when purchased. They were housed in separate SPF spaces at 5 mice per cage, with a 12 / 12-hour light / dark cycle, a constant temperature of 23±1°C, and a humidity of 50-60%. They had free access to food and water. After the animals were purchased, they were adaptively fed for at least 1 week before the experiment began.

[0363] 2.2. Experimental reagents and instruments

[0364] Dextran sulfate sodium salt (DSS): MP Biomedicals, product number 160110, batch number S5036. Prepared with sterile water, filtered, not autoclaved, and replaced every two days.

[0365] Ethanol: Shanghai Baxter Medical Supplies Co., Ltd., batch number S2001050.

[0366] Olive oil: Sinopharm Chemical Reagent Co., Ltd., product number 30189828, batch number 20180104.

[0367] Methylcellulose M450: Sinopharm Chemical Reagent Co., Ltd., Product No. 69016460, Batch No. 20170308.

[0368] ELISA reader: Manufacturer: BMGlabtech, Model: PHERAstar Fs.

[0369] Tabletop low-speed centrifuge: Manufacturer: Eppendorf, Model: 5417R.

[0370] Electronic balance: Mettler Toledo Instruments Ltd., model AL204.

[0370] 2.3. Experimental Design and Methods

[0370] 2.3.1. Animal grouping:

[0371] After acclimatization, the mice were grouped as follows:

[0371]

[0371] 2.3.2. Drug preparation:

[0371] DSS preparation method: 25g DSS + 1L ultrapure water, sterile filter, store at 4℃.

[0372] Preparation method for 50mg / kg ABX-464: 100mg ABX-464 + 20mL 0.5%MC, grind, store at 4℃. Prepare twice.

[0373] 50mg / kg Preparation method of compound 1 disclosed herein: 100mg of compound 1 disclosed herein + 20mL of 0.5%MC, grind, and store at 4℃.

[0373] 2.3.3. Experimental Methods:

[0374] Mice were randomly divided into 5 groups according to their body weight: normal control group (Naïve group), model group (DSS group), ABX-464 (50 mg / kg, po, qd), ABX-464 (50 mg / kg, po, bid), and compound 1 disclosed herein (50 mg / kg, po, bid). After acclimatization, mice were fed 2.5% DSS starting on day 0. After 7 days of DSS feeding, the mice were fed normal water until day 10. From day 0 to day 10, the mice were administered the corresponding solvent and drug by gavage for 10 consecutive days. The weight changes of the mice were observed daily from day 0 to day 10. On day 10, the colon length of the mice was measured after weighing.

[0374] 2.4. Data Presentation and Statistical Processing

[0375] Experimental data are expressed as mean ± standard error (SEM). Statistical comparisons were performed using an Excel t-test. Data from the model group and the normal control group were analyzed and compared. #P<0.05 indicates a significant difference between the model group and the normal control group; ##P<0.01 indicates a highly significant difference; ###P<0.001 indicates an extremely highly significant difference. *P<0.05 indicates a significant difference between the treatment group and the model group; **P<0.01 indicates a highly significant difference; ***P<0.001 indicates an extremely highly significant difference.

[0375] 3. Results

[0375] 3.1 The effect of compound 1 disclosed herein on body weight of DSS-induced UC mice

[0376] The results of the weight loss experiment (Figure 1) showed that compared with the normal control group, the DSS model group mice experienced a significant decrease in weight starting from day 4, with the rate of weight loss gradually increasing, reaching 30.0% on day 10 (P<0.001). Compared with the DSS model group, all treatment groups showed a significant recovery in weight starting from day 7. On day 10, the weight loss of ABX-464 (qd), ABX-464 (bid), and compound 1 disclosed herein (bid) decreased to 14.1% (P<0.001), 10.3% (P<0.001), and 0.4% (P<0.001), respectively. At the experimental endpoint, the rate of weight recovery from strongest to weakest was: compound 1 disclosed herein 50mg / kg (bid) > ABX-464 50mg / kg (bid) > ABX-464 50mg / kg (qd).

[0376] 3.2 The effect of compound 1 disclosed herein on colon length in DSS-induced UC mice

[0377] The colon length results (Figure 2) showed that compared with the normal control group, the colon length of the DSS model group was significantly shortened (P<0.001), only 75.4% of that of the normal control group; compared with the DSS model group, the colon length of all treatment groups was significantly increased. The colon lengths of ABX-464 (qd), ABX-464 (bid), and compound 1 disclosed herein (bid) were 85.5% (P<0.05), 89.3% (P<0.05), and 91.9% (P<0.01) of the normal control group, respectively. The colon length from longest to shortest was: compound 1 disclosed herein 50mg / kg (bid) > ABX-464 50mg / kg (bid) > ABX-464 50mg / kg (qd).

[0377] 4. Conclusion

[0378] The DSS model serves as an animal model for ulcerative colitis (UC) induced by IBD. The molecular weight (36,000-50,000), batch number, storage configuration, mouse housing environment, and strain of DSS all affect the model's effectiveness. This modeling was relatively successful, with significant changes in mouse body weight and colon length. Results showed that compound 1, as disclosed herein, exhibited superior efficacy compared to the positive control drug ABX-464 in terms of body weight and colon length. Therefore, both 50 mg / kg ABX-464 and compound 1 disclosed herein have certain preventative and therapeutic effects on DSS-induced UC, with compound 1 showing the strongest efficacy, exceeding that of the same dose of ABX-464.

[0379] Test Example 2. Upregulation of miR-124 by the disclosed compound

[0379] I. Abstract

[0380] This experiment was used to evaluate the upregulation effect of the disclosed compound on miR-124.

[0380] II. Experimental Materials and Instruments

[0380] 1. Dynabead Human T-Activator CD3 / CD28 for T Coll Expansion and Activation (Gibco, 11131D)

[0380] 2. Pan T Cell Isolation Kit (human) (Miltenyi, 130-096-535)

[0380] 3. Human interleukin-2 (Peprotech, 200-02-100)

[0380] 4. MicroRNA Extraction Kit (Qiagen, 217004)

[0380] 5. Small RNA Reverse Transcription Kit (miScript II RT Kit) (Qiagen, 218161)

[0380] 6. Small RNA SYBR Green PCR Kit (miScript SYBR Green PCR Kit) (Qiagen, 218073)

[0380] 7. Phosphate-buffered saline (PBS), pH 7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320)

[0380] 8. Bovine serum albumin, BSA (Beyotime, ST023)

[0380] 9. EDTA (0.5M), pH 8.0 (Invitrogen, AM9260G)

[0380] 10. LS Separation Columns (Miltenyi, 130-042-401)

[0380] 11. 24-well cell culture plate (Corning, 3524)

[0380] 12. 96-well plate (Corning, 3788)

[0380] 13. Cell incubator (Thermo, Steri cycle i160)

[0380] 14. Real-time quantitative PCR instrument (Applied biosystem, QuantStudio6 Flex)

[0380] 15. PCR instrument (Applied biosystem, ProFlex)

[0380] 16. 96-well clear PCR plate, 0.2 mL (Applied biosystems, N8010560)

[0380] 17. RPMI 1640 medium (Gibco, 11875119)

[0380] 18. Fetal bovine serum, FBS (Gibco, 10099-141)

[0380] 19. Magnetic rack (Invitrogen, DynaMagTM-2)

[0380] 20. Six-well cell culture plate (Thermo, 150239)

[0380] 21. Spectrophotometer (IMPLEN, NP80)

[0380] 22. QuadroMACS Separator (Meitianni, 130-090-976)

[0380] 23. miR124-3P-F primer (custom-made by Genewiz)

[0380] 24. HSA-U6 detection primer (Tiangen, CD201-0145)

[0380] III. Experimental Procedure

[0381] The effect of the compound on miR-124 expression levels was detected in T cells activated by CD3 / CD28 antibody. After treatment with the compound, total RNA was extracted from the activated T cells, and the cDNA obtained by reverse transcription was used as a template. The expression level was quantified using SYBR Green fluorescence quantitative PCR with a specific miR-124 primer.

[0382] T cell isolation: Purchased human peripheral blood mononuclear cells (PBMCs) were counted and centrifuged, then washed once with separation buffer (PBS pH 7.4, containing 0.5% BSA and 2mM EDTA). The supernatant was discarded. 40 μL of buffer and 10 μL of pan T cell biotinylated antibody (pan T Cell Biotin-Antibody Cocktail) were added per 1×10⁷ cells to resuspend the precipitate and mix well. The mixture was incubated at 4°C for 5 minutes. After incubation, 30 μL of buffer and 20 μL of pan T cell microbeads (pan T Cell MicroBeads Cocktail) were added per 1×10⁷ cells. The mixture was then incubated at 4°C for 10 minutes. Rinse the separation column (LS column) with 3 mL of cell separation buffer beforehand. Pass the cell suspension through the column, and then wash the column three times with 1 mL of cell separation buffer. Collect the eluent in a 15 mL centrifuge tube; this is the enriched T cells. Count the cells and add RPMI 1640 medium (complete medium) containing 10% FBS and 40 U / mL IL-2 at a density of 1 × 10⁶ cells / mL. Store on ice for later use.

[0383] T cell activation: Add 25 μL of activation magnetic beads per 1 × 10⁶ cells. Take the corresponding amount of T cell activation CD3 / CD28 magnetic beads and place them in a 1.5 mL centrifuge tube. Shake the tube for approximately 30 seconds before aspirating. Wash the activation magnetic beads three times with culture medium at a volume ratio greater than 1:1. Remove all washings on the last wash and resuspend the activation magnetic beads in an equal volume of complete culture medium. Add the washed activation magnetic beads to the cell resuspension and mix thoroughly. Add 3 mL of cells to each well of a six-well plate and incubate at 37°C in a 5% CO₂ incubator for 2 days.

[0384] Compound Treatment: The compound stock solution was 20 mM, diluted to 200 μM with DMSO, and then diluted 4-fold with complete culture medium to 50 μM (50×). Mix well and set aside. A 4-fold dilution with DMSO (25% DMSO) served as a negative control well. T cells activated for two days were pipetted and resuspended in a magnetic rack with 1.5 mL centrifuge tubes. The activation beads were removed, and the cell suspension was collected. After cell counting, the cells were centrifuged at 300 xg for 10 min, the supernatant was discarded, and the cells were resuspended to 1.02 × 10⁶ / mL. 980 μL of cell suspension and 20 μL of 50× compound were added to each 24-well plate, resulting in a final compound concentration of 1 μM. The cells were cultured at 37°C in a 5% CO₂ incubator for 3 days.

[0385] RNA Extraction: Collect T cells by centrifugation at 1500 rpm for 3 minutes, wash once with PBS, and discard the supernatant after centrifugation. Extract total RNA from cells using a small RNA extraction kit according to the manufacturer's instructions. Add 700 μL of Trizol cell lysis buffer to the cell pellet, mix well by pipetting, and incubate at room temperature for 5 minutes. Add 140 μL of chloroform, vortex to mix, and incubate at room temperature for 3 minutes. Centrifuge the chloroform-cell lysis buffer mixture at 12000 xg for 15 minutes at 4°C. Transfer the supernatant to a new RNase-free centrifuge tube, add 1.5 volumes of anhydrous ethanol, and mix several times by pipetting. Transfer the solution to an RNA adsorption column and centrifuge at 8000 xg for 15 seconds. Wash the centrifuge column once with 700 μL of RWT solution, centrifuge at 8000 xg for 15 seconds, add 500 μL of RPE solution, wash twice, and centrifuge at 8000 xg for 2 minutes. Transfer the adsorption column to a new 2 mL centrifuge tube and centrifuge at 12000 xg for 1 min to remove residual washings. Transfer the adsorption column to a new 1.5 mL centrifuge tube, add 30-50 μL of RNase-free water, centrifuge at 12000 xg for 2 min, and collect the RNA solution. Measure the RNA concentration using a spectrophotometer. Store the RNA solution at -80°C.

[0386] Reverse Transcription: Place the extracted RNA template on ice. Take out the small RNA reverse transcription kit and thaw some components (including 5×miScript HiSpec Buffer, 10×miScript nucleics Mix, and RNase-free water) at room temperature. Thaw the miScript Reverse Transcriptase mix component on ice. Each reaction (10 μL) consists of: 5×miScript HiSpec Buffer (2 μL), 10×miScript nucleics Mix (1 μL), miScript Reverse Transcriptase mix (1 μL), RNase-free water (2 μL), and RNA template (4 μL). Prepare the above reactions on ice. Place the samples in a PCR instrument and set the program as follows: 37℃, 60 minutes; 95℃, 5 minutes; store at 4℃. The completed reaction sample is a cDNA sample.

[0387] Quantitative Fluorescence PCR: The transcriptional level of miR-124 was detected using SYBR Green staining, while the transcriptional level of the housekeeping gene U6 was detected as an internal control. Thaw all reagents required for the small RNA SYBR Green PCR kit to room temperature. Dilute each cDNA sample template 10-fold with RNase-free water, then dilute 5-fold. Prepare the reaction mixture according to Table 1 below, and add the reaction mixture to a 96-well PCR plate. Seal the plate with sealing film and centrifuge. Perform the PCR reaction on a quantitative fluorescence PCR instrument according to the steps in Table 2.

[0388] Table 1: Components of Fluorescence Quantitative PCR Reaction

[0389] Table 2 Fluorescence Quantitative PCR Procedure

[0390] Table 3 Primer list for quantitative PCR detection using fluorescence.

[0391] Data Analysis: Based on the CT values ​​calculated by the software, the ratio of miR-124 expression level to internal reference U6 expression level for each sample was calculated, i.e., ΔCT(test compound) = CTmiRNA-124(test compound) - CTU6(test compound). The relative expression level was calculated using the following formula: Relative expression level (test compound) = 2(-[ΔCT(test compound) - ΔCT(DMSO)]).

[0392] Table 4: Activity of the disclosed compounds on miR-124 upregulation

[0393] Conclusion: The compound disclosed in this study has good activity in promoting the upregulation of miR124.

[0394] Test Example 3: Pharmacokinetic Test of the Compounds Disclosed herein

[0394] 1. Abstract

[0395] Using rats as test animals, the plasma drug concentrations at different time points after oral gavage and intravenous injection of the compound of Example 2 and comparative compound A (see compound (1) of Example 3 in WO2016135052A1) were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in rats was studied to evaluate its pharmacokinetic characteristics.

[0395]

[0395] 2. Test Plan

[0395] 2.1 Test Drugs

[0395] Compound of Example 2, Comparative Compound A.

[0395] 2.2 Experimental Animals

[0396] Sixteen healthy adult SD rats, half male and half female, were randomly divided into four groups and purchased from Vital River Laboratory Animal Technology Co., Ltd.

[0396] 2.3 Drug Preparation

[0397] Weigh a certain amount of the drug and add 5% DMSO, 5% Tween 80 and 90% physiological saline to prepare a clear solution.

[0397] 2.4 Administration

[0398] Gavage group: SD rats were fasted overnight and then administered the drug by gavage. The dosage was 2 mg / kg and the administration volume was 10.0 mL / kg.

[0399] Intravenous group: SD rats were fasted overnight and then administered the drug intravenously at a dose of 1 mg / kg and a volume of 5.0 mL / kg.

[0399] 3. Operation

[0400] Gavage group: Rats were administered compound 2 and comparative compound A via gavage. Blood samples of 0.1 mL were collected from the orbital cavity 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 samples were placed in EDTA-K2 anticoagulant tubes, centrifuged at 10,000 rpm for 1 minute at 4°C, and the plasma was separated within 1 hour and stored at -20°C for analysis. The blood collection and centrifugation process was performed under ice bath conditions. Rats were fed 2 hours after administration.

[0401] Intravenous group: Rats were intravenously injected with compound 2 of Example 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. The treatment was the same as that of the gavage group.

[0402] Determination of the content of the target compound in rat plasma after administration of different concentrations of the drug by gavage and intravenous injection: Take 20 μL of rat plasma at each time point after administration, add 50 μL of internal standard solution (camptothecin 100 ng / mL) and 200 μL of acetonitrile, vortex mix for 5 minutes, centrifuge for 10 minutes (3700-4000 rpm), and take 1.0-2.0 μL of the supernatant of the plasma sample for LC / MS / MS analysis.

[0402] 4. Results of pharmacokinetic parameters

[0403] Table 5. Pharmacokinetic parameters of the compounds disclosed herein after oral administration

[0404] Table 6: Pharmacokinetic parameters of the compounds disclosed herein after intravenous administration

[0404] 【(0405) Conclusion: As shown in Tables 5 and 6, compared with Comparative Compound A, the compound of Example 2 disclosed in this paper has good drug metabolism and absorption, and has obvious pharmacokinetic advantages. [Sequence List]

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, 1. Among them, Ring A is a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclic group; G is an N atom or CR2a; each R1 may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, hydroxyl, and -C(O)R8; each R2 may be the same or different, and each is independently selected from hydrogen, halogen, and C1-6 alkyl; each R3 may be the same or different, and each is independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 hydroxyalkyl. R3 is a cyano group, a 3- to 6-membered cycloalkyl group, or a 5- or 6-membered heterocyclic group; or two adjacent R3 groups and carbon atoms on the connected benzene ring form a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclic group; R4 is a hydrogen atom or a 3- to 8-membered heterocyclic group; wherein the 3- to 8-membered heterocyclic group is substituted as needed by one or more identical or different substituents selected from hydroxyl and carboxyl groups; R8 is selected from hydrogen atom, C1-6 alkyl group, and C1-6 haloalkyl group; R2a is selected from hydrogen atom, halogen, and C1-6 alkyl group; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is 1, 2, 3, or 4.

2. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, 2. Among them, Ring A is a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclic group; G is an N atom or CR2a; each R1 may be the same or different, and each is independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, syloxy, C1-6 hydroxyalkyl, hydroxyl, and -C(O)R8; each R2 may be the same or different, and each is independently selected from hydrogen, halogen, and C1-6 alkyl; each R3 may be the same or different, and each is independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 hydroxyalkyl. R3 is a cyano group, a 3- to 6-membered cycloalkyl group, or a 5- or 6-membered heterocyclic group; or two adjacent R3 groups and carbon atoms on the connected benzene ring form a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclic group; R4 is a hydrogen atom or a 3- to 8-membered heterocyclic group; wherein the 3- to 8-membered heterocyclic group is substituted as needed by one or more identical or different substituents selected from hydroxyl and carboxyl groups; R8 is selected from hydrogen atom, C1-6 alkyl group, and C1-6 haloalkyl group; R2a is selected from hydrogen atom, halogen, and C1-6 alkyl group; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; p is 1, 2, 3, or 4.

3. A compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IC) or a pharmaceutically acceptable salt thereof:

3. Among them, rings A, G, R1 to R3, n, m and p are as defined in request item 1 or 2.

4. A compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof:

4. Among them, rings A, G, R1 to R3, n, m and p are as defined in request item 1 or 2.

5. A compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-3) or formula (I-4) or a pharmaceutically acceptable salt thereof:

5. Among them, Ring B is a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclic group; each R3a may be the same or different and is independently selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl and cyano; r is 0, 1 or 2; rings A, G, R1, R2, R4, n and m are as defined in claim 1 or 2.

6. A compound of formula (I) as claimed in claim 5, or a pharmaceutically acceptable salt thereof, wherein, Cycle B is cyclopentyl.

7. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, Each R1 may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, -C(O)R8, C1-6 alkyl and C1-6 alkoxy; R8 is as defined in claim 1.

8. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, Each R1 may be the same or different, and each is independently selected from hydrogen, deuterium, fluorine, acetyl, and methyl.

9. A compound of formula (I) as claimed in claim 2, or a pharmaceutically acceptable salt thereof, wherein, Each R1 may be the same or different, and each is independently selected from hydrogen, halogen, -C(O)R8, C1-6 alkyl, C1-6 alkoxy and lateral oxygen; R8 is as defined in claim 2.

10. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (II) or a pharmaceutically acceptable salt thereof is:

10. Among them, G1, G2, and G3 may be the same or different, and each is independently selected from O atoms, NR1a, and CR1bR1c; R1a is selected from hydrogen atoms, C1-6 alkyl groups, and -C(O)R8; R1b and R1c may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, C1-6 alkyl groups, and C1-6 alkoxy groups, or R1b and R1c together form a side oxygen group; G, R2 to R4, R8, m, and p are as defined in claim 1.

11. A compound of formula (I) as claimed in claim 10, or a pharmaceutically acceptable salt thereof, wherein, G1 and G2 may be the same or different, and each is independently selected from O atoms, NR1a and CR1bR1c; G3 is CR1bR1c; R1a, R1b and R1c are as defined in claim 10.

12. A compound of formula (I) as claimed in claim 10, or a pharmaceutically acceptable salt thereof, wherein, Selected from, , , and, R1a, R1b and R1c as defined in request item 10.

13. A compound of formula (I) as claimed in claim 10, or a pharmaceutically acceptable salt thereof, wherein, Selected from , , , , , , and.

14. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (III) is a compound of formula (III) or a pharmaceutically acceptable salt thereof:

14. Wherein, L1, L2, L3 and L4 may be the same or different, and each is independently selected from O atom, NR1d and CR1eR1f; R1d is selected from hydrogen atom, C1-6 alkyl and -C(O)R8; R1e and R1f may be the same or different, and each is independently selected from hydrogen atom, deuterium atom, halogen, C1-6 alkyl and C1-6 alkoxy; G, R2 to R4, R8, m and p are as defined in claim 1.

15. A compound of formula (I) as claimed in claim 14, or a pharmaceutically acceptable salt thereof, wherein, L1 and L2 may be the same or different, and each is independently selected from O atoms, NR1d and CR1eR1f; L3 and L4 are each independently CR1eR1f; R1d, R1e and R1f are as defined in claim 14.

16. A compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R2 is a hydrogen atom.

17. A compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R2a is a hydrogen atom.

18. A compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R8 is a C1-6 alkyl group.

19. A compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, Each R3 may be the same or different, and each is independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, 3-membered cycloalkyl, 6-membered heterocyclic and cyano groups.

20. A compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R3 is a halogen.

21. A compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R4 is a hydrogen atom, or...

22. A compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R4 is OR.

23. A compound or a pharmaceutically acceptable salt thereof, selected from any of the following compounds or pharmaceutically acceptable salts thereof:

24. A compound or a salt thereof represented by general formula (I-1C) or (I-2C), 24. Among them, R is a C1-6 alkyl group; R11 is a C1-6 alkyl group; and the rings A, G, R1 to R3, m, n and p are as defined in claim 1 or 2.

25. The compound or a salt thereof as claimed in claim 24, wherein the compound is:

26. A method for preparing a compound of general formula (IC) or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

26. A compound of general formula (IA) or a salt thereof reacts with a compound of general formula (IB) or a salt thereof to give a compound of general formula (IC) or a pharmaceutically usable salt thereof; wherein, X is a halogen; rings A, G, R1 to R3, m, n and p are as defined in request item 3.

27. The method as described in claim 26, wherein X is a Cl atom.

28. A method for preparing a compound of formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

28. A compound of general formula (IC) or a pharmaceutically acceptable salt thereof reacts with a compound of R4'-Y, and then the protecting group on R4' is removed to give a compound of general formula (I) or a pharmaceutically acceptable salt thereof; wherein, Y is a halogen; R4' is OR; R is a C1-6 alkyl; R11 is a C1-6 alkyl; R4 is OR; rings A, G, R1 to R3, m, n and p are as defined in claim 1 or 2.

29. The method as described in claim 28, wherein Y is a Br atom.

30. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as described in any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

31. Use of a compound of general formula (I) as described in any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 30, in the preparation of a medicament for regulating miRNA levels.

32. Use of a compound of general formula (I) as described in any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 30, in the preparation of a medicament for treating a disease or condition selected from viral infections, inflammation, and cancer.

33. The use as described in claim 32, wherein the inflammation is selected from autoimmune-related inflammatory diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory diseases of the digestive tract, inflammatory diseases of the skin, other inflammatory diseases related to epithelial cells, cancer-related inflammation, irritation-related inflammation, and injury-related inflammation.

34. The use as described in claim 32, wherein the inflammation is selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, systemic lupus erythematosus, Sjogren's syndrome, bronchitis, asthma, and inflammation associated with colon cancer.

35. The use as described in claim 32, wherein the inflammation is inflammatory bowel disease.

36. The use as described in claim 35, wherein the inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).

37. The use as described in claim 32, wherein the cancer is selected from leukemia, lymphoma, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, cystadenoma, medullary carcinoma, bronchial carcinoma, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, uterine cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, skin cancer, kidney cancer, nasopharyngeal carcinoma, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, gallbladder cancer, pediatric tumors, urothelial carcinoma, ureteral tumors, thyroid cancer, osteoma, neuroblastoma, brain tumor, and myeloma.

38. The use as described in claim 37, wherein the lymphoma is macroglobulinemia; the uterine cancer is cervical cancer; the skin cancer is melanoma; and the colorectal cancer is small bowel cancer.

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