Quinolinamine compounds, processes for their preparation and their use in medicine

Abstract

The application relates to quinolinamine compounds, a preparation method thereof and medical applications thereof. Specifically, the application relates to a quinolinamine compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and the use of the compound as a therapeutic agent, in particular, the use as an miRNA regulator and the use in preparing a medicine for treating a disease or a condition improved by regulating an miRNA level.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a quinolinamine compound, its preparation method, and its pharmaceutical application. In particular, this disclosure relates to quinolinamine compounds of general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use as therapeutic agents, especially as miRNA modulators and in the preparation of medicaments for treating diseases or conditions improved by regulating miRNA levels. Background 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 transition of activated macrophages to microglia, 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 are decreased. Overexpression of miR-124 exerts its 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 significantly 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, the Nakamachi team found 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 inflammation 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, but it is known that an abnormal inflammatory response caused by the intestinal mucosal immune system plays a crucial role in its pathogenesis. Environmental, genetic, infectious, and immune factors can all contribute to the disease. IBD typically refers to ulcerative colitis (UC) and Crohn's disease (CD). Ulcerative colitis is a continuous inflammation of the colonic mucosa and submucosa, usually starting in the rectum 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 is typically characterized by 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 published 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:

[0008]

[0009] in:

[0010] Ring A is a cycloalkyl or heterocyclic group;

[0011] G is an N atom or CR 2a ;

[0012] Each R 1 The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, oxo, hydroxyalkyl, cycloalkyloxy, heterocyclic oxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR 5 R 6 -NHC(O)R 7 -C(O)R 8 -C(O)(CH2) q NR 9 R 10 , cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0013] Each R 2 They may be the same or different, and each is independently selected from hydrogen, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino;

[0014] Each R 3 They 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;

[0015] Or two adjacent R 3 The carbon atoms on the connected benzene ring form cycloalkyl or heterocyclic groups, each of which is independently and optionally substituted by one or more identical or different substituents selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano.

[0016] R 4The group is selected from hydrogen atoms, alkyl, cycloalkyl and heterocyclic groups; wherein each of the alkyl, cycloalkyl and heterocyclic groups is independently and optionally substituted by one or more identical or different substituents selected from halogen, hydroxy, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, amino and cyano.

[0017] R 5 and R 6 Whether the groups are the same or different, they are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, amino groups, cycloalkyl groups, and heterocyclic groups;

[0018] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

[0019] R 8 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups;

[0020] R 9 and R 10 Whether the groups are the same or different, they are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, amino groups, cycloalkyl groups, and heterocyclic groups;

[0021] R 2a Selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino;

[0022] n can be 0, 1, 2, 3, or 4;

[0023] m is 0, 1, or 2;

[0024] p is 1, 2, 3 or 4;

[0025] q can be 0, 1, 2 or 3.

[0026] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0027] Ring A is a cycloalkyl or heterocyclic group;

[0028] G is an N atom or CR 2a ;

[0029] Each R 1 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, oxo, hydroxyalkyl, cycloalkyloxy, heterocyclic oxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR 5 R 6 -NHC(O)R 7 -C(O)R 8 -C(O)(CH2)q NR 9 R 10 , cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, wherein each of the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0030] Each R 2 They may be the same or different, and each is independently selected from hydrogen, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino;

[0031] Each R 3 They 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;

[0032] Or two adjacent R 3 The carbon atoms on the connected benzene ring form cycloalkyl or heterocyclic groups, each of which is independently and optionally substituted by one or more identical or different substituents selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano.

[0033] R 4 The group is selected from hydrogen atoms, alkyl, cycloalkyl and heterocyclic groups; wherein each of the alkyl, cycloalkyl and heterocyclic groups is independently and optionally substituted by one or more identical or different substituents selected from halogen, hydroxy, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, amino and cyano.

[0034] R 5 and R 6 Whether the groups are the same or different, they are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, amino groups, cycloalkyl groups, and heterocyclic groups;

[0035] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

[0036] R 8 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, cycloalkyl groups, and heterocyclic groups;

[0037] R 9 and R 10 Whether the groups are the same or different, they are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, amino groups, cycloalkyl groups, and heterocyclic groups;

[0038] R 2a Selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and amino;

[0039] n can be 0, 1, 2, 3, or 4;

[0040] m is 0, 1, or 2;

[0041] p is 1, 2, 3, or 4; and

[0042] q can be 0, 1, 2 or 3.

[0043] 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 (IC) or a pharmaceutically acceptable salt thereof:

[0044]

[0045] in:

[0046] Rings A, G, R 1 To R 3 , n, m and p are as defined in general formula (I).

[0047] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (IC), or pharmaceutically acceptable salts thereof, wherein Not for

[0048] 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 (I-1) or general formula (I-2) or a pharmaceutically acceptable salt thereof:

[0049]

[0050] in:

[0051] Rings A, G, R 1 To R 3 , n, m and p are as defined in general formula (I).

[0052] 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 (I-3) or general formula (I-4) or a pharmaceutically acceptable salt thereof:

[0053]

[0054] in:

[0055] Ring B is a cycloalkyl or heterocyclic group; wherein each of the cycloalkyl or heterocyclic groups is independently and optionally substituted by one or more identical or different substituents selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano.

[0056] Each R 3a They may be the same or different, and each is independently selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano;

[0057] r is 0, 1, or 2;

[0058] Rings A, G, R 1 R 2 R 4 , n and m are as defined in general formula (I).

[0059] 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 (I-3C) or general formula (I-4C) or a pharmaceutically acceptable salt thereof:

[0060]

[0061] in:

[0062] Ring A, Ring B, G, R 1 R 2 R 3a , n, r and m are as defined in general formula (I-3) or general formula (I-4).

[0063] 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.

[0064] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt thereof 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) is 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.

[0065] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of general formulas (I), (I-1), (I-2), (I-3), (I-3C), (I-4), (I-4C), or (IC) are wherein: each R1 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and -C(O)R atoms. 8 C 1-6 Alkyl, C 1-6 Alkyl groups and oxo groups; preferably selected from hydrogen atoms, deuterium atoms, halogens, and -C(O)R. 8 and C 1-6 Alkyl; R 8 As defined in general formula (I).

[0066] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-2), (I-3), (I-3C), (I-4), (I-4C), or (IC) are used, wherein each R 1 They may be the same or different, and each is independently selected from hydrogen, deuterium, fluorine, acetyl, methyl and oxo groups.

[0067] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of general formulas (I), (I-1), (I-2), (I-3), (I-3C), (I-4), (I-4C), or (IC) are wherein: each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and -C(O)R. 8 C 1-6 Alkyl, C 1-6 Alkoxy and oxo groups; R 8 As defined in general formula (I).

[0068] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt thereof 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), wherein: R 8 Selected from hydrogen atoms, C 1-6 Alkyl and Halogenated C 1-6 Alkyl; preferably, R 8 C 1-6 Alkyl; more preferably, R 8 It is a methyl group.

[0069] 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:

[0070]

[0071] in:

[0072] G1 G 2 and G 3 They may be the same or different, and each is independently selected from O atoms, S atoms, and NR atoms. 1a and CR 1b R 1c ;

[0073] R 1a Selected from hydrogen atoms, alkyl groups, and -C(O)R 8 -C(O)(CH2) q NR 9 R 10 , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0074] R 1b and R 1c They may be the same or different, and each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclic oxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR 5 R 6 -NHC(O)R 7 -C(O)R 8 -C(O)(CH2) q NR 9 R 10 cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, or R 1b and R 1c Together they form an oxo group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally substituted by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl groups.

[0075] G, R 2 To R 10 m, p and q are as defined in general formula (I).

[0076] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0077] G 1 G 2 and G 3 They may be the same or different, and each is independently selected from O atoms, S atoms, and NR atoms. 1a and CR1b R 1c ;

[0078] R 1a Selected from hydrogen atoms, alkyl groups, and -C(O)R 8 -C(O)(CH2) q NR 9 R 10 , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0079] R 1b and R 1c The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclic alkyloxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR 5 R 6 -NHC(O)R 7 -C(O)R 8 -C(O)(CH2) q NR 9 R 10 cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, or R 1b and R 1c Together they form an oxo group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally substituted by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl groups.

[0080] G, R 2 To R 10 m, p and q are as defined in general formula (I).

[0081] 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:

[0082]

[0083] in:

[0084] G, G 1 G 2 G 3 R 2 R 3m and p are as defined in general formula (II).

[0085] 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:

[0086]

[0087] in:

[0088] G, G 1 G 2 G 3 R 2 R 3 m and p are as defined in general formula (II).

[0089] In some embodiments of this disclosure, the compounds represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2), or their pharmaceutically acceptable salts, wherein G 1 and G 2 They may be the same or different, and each is independently selected from O atoms, S atoms, and NR atoms. 1a and CR 1b R 1c G 3 For CR 1b R 1c ;R 1a R 1b and R 1c As defined in general formula (II).

[0090] In some embodiments of this disclosure, the compounds represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2), or their pharmaceutically acceptable salts, wherein G 1 For O atoms or NR 1a G 2 and G 3 Each independently for CR 1b R 1c ;R 1a R 1b and R 1c As defined in general formula (II).

[0091] In some embodiments of this disclosure, the compounds represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2), or their pharmaceutically acceptable salts, wherein G 2 For O atoms or NR 1a G 1 and G 3Each independently for CR 1b R 1c ;R 1a R 1b and R 1c As defined in general formula (II).

[0092] In some embodiments of this disclosure, the compounds represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2), or their pharmaceutically acceptable salts, wherein G 1 and G 2 All are O atoms; G 3 For CR 1b R 1c ;R 1b and R 1c As defined in general formula (II).

[0093] 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 a pharmaceutically acceptable salt thereof, wherein G 1 G 2 and G 3 Each independently for CR 1b R 1c ;R 1b and R 1c As defined in general formula (II).

[0094] In some embodiments of this disclosure, the compounds represented by general formula (II), general formula (IIC), general formula (IID-1) or general formula (IID-2), or their pharmaceutically acceptable salts, wherein for G 1 and G 2 Whether the atoms are the same or different, and each is independently selected from O atoms and NR atoms. 1a and CR 1b R 1c R 1a R 1b and R 1c As defined in general formula (II); preferably, Selected from R 1a R 1b and R 1c As defined in general formula (II); more preferably, Selected from

[0095] 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 (III) or a pharmaceutically acceptable salt thereof:

[0096]

[0097] in:

[0098] L 1 L 2 L 3 and L 4 They may be the same or different, and each is independently selected from O atoms, S atoms, and NR atoms. 1d and CR 1e R 1f ;

[0099] R 1d Selected from hydrogen atoms, alkyl groups, and -C(O)R 8 -C(O)(CH2) q NR 9 R 10 , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0100] R 1e and R 1f They may be the same or different, and each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclic oxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR 5 R 6 -NHC(O)R 7 -C(O)R 8 -C(O)(CH2) q NR 9 R 10 cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, or R 1e and R 1f Together they form an oxo group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally substituted by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl groups.

[0101] G, R 2 To R 10 m, p and q are as defined in general formula (I).

[0102] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein:

[0103] L 1 L 2 L 3 and L 4 They may be the same or different, and each is independently selected from O atoms, S atoms, and NR atoms. 1d and CR 1e R 1f ;

[0104] R 1d Selected from hydrogen atoms, alkyl groups, and -C(O)R 8 -C(O)(CH2) q NR 9 R 10 , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0105] R 1e and R 1f The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, cycloalkyloxy, heterocyclic alkyloxy, alkenyl, alkynyl, hydroxyl, cyano, nitro, -NR 5 R 6 -NHC(O)R 7 -C(O)R 8 -C(O)(CH2) q NR 9 R 10 cycloalkyl, heterocyclic, aryloxy, heteroaryloxy, aryl and heteroaryl, or R 1e and R 1f Together they form an oxo group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally substituted by one or more identical or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, amino, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl groups.

[0106] G, R 2 To R 10 m, p and q are as defined in general formula (I).

[0107] 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:

[0108]

[0109] in:

[0110] G, L 1 L 2 L 3 L 4 R 2 R 3 m and p are as defined in general formula (III).

[0111] 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:

[0112]

[0113] in:

[0114] G, L 1 L 2 L 3 L 4 R 2 R 3 m and p are as defined in general formula (III).

[0115] In some embodiments of this disclosure, the compounds represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2), or their pharmaceutically acceptable salts, wherein L 1 and L 2 They may be the same or different, and each is independently selected from O atoms, S atoms, and NR atoms. 1d and CR 1e R 1f L 3 and L 4 Each independently for CR 1e R 1f ;R 1d R 1e and R 1f As defined in general formula (III).

[0116] In some embodiments of this disclosure, the compounds represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2), or their pharmaceutically acceptable salts, wherein L 1For O atoms or NR 1d L 2 L 3 and L 4 Each independently for CR 1e R 1f ;R 1d R 1e and R 1f As defined in general formula (III).

[0117] In some embodiments of this disclosure, the compounds represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2), or their pharmaceutically acceptable salts, wherein L 2 For O atoms or NR 1d L 1 L 3 and L 4 Each independently for CR 1e R 1f ;R 1d R 1e and R 1f As defined in general formula (III).

[0118] In some embodiments of this disclosure, the compounds represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2), or their pharmaceutically acceptable salts, wherein L 3 For O atoms or NR 1d L 1 L 2 and L 4 Each independently for CR 1e R 1f ;R 1d R 1e and R 1f As defined in general formula (III).

[0119] In some embodiments of this disclosure, the compounds represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2), or their pharmaceutically acceptable salts, wherein L 4 For O atoms or NR 1d L 1 L 2 and L 3 Each independently for CR 1e R 1f ;R 1d R 1e and R 1f As defined in general formula (III).

[0120] In some embodiments of this disclosure, the compounds represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2), or their pharmaceutically acceptable salts, wherein L 1 and L 2 All are O atoms; L 3 and L 4 Each independently for CR 1e R 1f ;R 1e and R 1f As defined in general formula (III).

[0121] In some embodiments of this disclosure, the compounds represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2), or their pharmaceutically acceptable salts, wherein L 1 L 2 L 3 and L 4 Each independently for CR 1e R 1f ;R 1e and R 1f As defined in general formula (III).

[0122] In some embodiments of this disclosure, the compounds represented by general formula (III), general formula (IIIC), general formula (IIID-1) or general formula (IIID-2), or their pharmaceutically acceptable salts, wherein for L 1 and L 2 Whether the atoms are the same or different, and each is independently an O atom or a CR atom. 1e R 1f R 1e and R 1f As defined in general formula (III); preferably, for R 1e and R 1f As defined in general formula (III); more preferably, Selected from

[0123] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the 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 (IIID-2) are described, wherein each R 2They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; preferably, R 2 It is a hydrogen atom.

[0124] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-2), (IC), (IIC), (IIIC), (II), (IID-1), (IID-2), (IIID-1), (IIID-2), or (III) are described, wherein each R 3 They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl; preferably, R 3 Halogen; more preferably, R 3 It is Cl.

[0125] In some embodiments of this disclosure, the compounds represented by general formulas (I-3), (I-4), (I-3C), or (I-4C) or their pharmaceutically acceptable salts, wherein each R 3a They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl; preferably, R 3a Halogen; more preferably, R 3a It is Cl.

[0126] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-2), (IC), (IIC), (IIIC), (II), (IID-1), (IID-2), (IIID-1), (IIID-2), or (III) are described, wherein each R 3 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkyl and cyano groups.

[0127] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (I-1), (I-2), (IC), (IIC), (IIIC), (II), (IID-1), (IID-2), (IIID-1), (IIID-2), or (III) are described, wherein each R 3 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic and cyano groups; preferably, each R 3They may be the same or different, and each is independently selected from Cl, Br, methyl, methoxy, cyano, cyclopropyl, tetrahydropyranyl, and dihydropyranyl; more preferably, each R 3 They may be the same or different, and each is independently selected from Cl, methyl, methoxy, cyano, cyclopropyl and tetrahydropyranyl.

[0128] In some embodiments of this disclosure, the compounds represented by general formulas (I-3), (I-4), (I-3C), or (I-4C) or their pharmaceutically acceptable salts, wherein each R 3a They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkyl and cyano groups.

[0129] In some embodiments of this disclosure, 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) is used, wherein p is 2, 3, or 4; and wherein two adjacent R 3 The carbon atom on the connected benzene ring forms a cycloalkyl or heterocyclic group, each of which is independently and optionally substituted by one or more identical or different substituents selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cyano; preferably, p is 3.

[0130] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt thereof 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) is used, wherein m is 0.

[0131] In some embodiments of this disclosure, 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) is used, wherein p is 1 or 2.

[0132] In some embodiments of this disclosure, 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) is used, wherein p is 3.

[0133] 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.

[0134] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts represented by general formulas (I), (IC), (I-1), (I-2), (II), (IIC), (IID-1), (IID-2), (III), (IIIC), (IIID-1), and (IIID-2) are used, wherein for R 3v R 3w R 3x and R 3y They may be the same or different, and each is independently selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl, or R 3v R 3w R 3x and R 3y Two adjacent carbon atoms together form a cycloalkyl or heterocyclic group, each of which is independently and optionally substituted by one or more identical or different substituents selected from halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, and cyano, provided that R 3v R 3w R 3x and R 3y Not both being hydrogen atoms; preferably, for R 3v For halogens, R 3w R 3x and R 3y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups, or R 3wR 3x Together with the attached carbon atom, it forms a 3- to 8-membered cycloalkyl group; more preferably, for R 3v For halogens, R 3w R 3x and R 3y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups.

[0135] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts represented by general formulas (I), (IC), (I-1), (I-2), (II), (IIC), (IID-1), (IID-2), (III), (IIIC), (IIID-1), and (IIID-2), when for At that time, R 3v It is Cl.

[0136] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts represented by general formulas (I), (IC), (I-1), (I-2), (II), (IIC), (IID-1), (IID-2), (III), (IIIC), (IIID-1), and (IIID-2), when for At that time, R 3w R 3x and R 3y They may be the same or different, and each is independently selected from hydrogen atom, Cl, Br, methyl, methoxy, cyano, cyclopropyl, tetrahydropyranyl, and dihydropyranyl; more preferably, R 3w R 3x and R 3y They may be the same or different, and each is independently selected from hydrogen, Cl, methyl, methoxy, cyano, cyclopropyl and tetrahydropyranyl.

[0137] 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:

[0138]

[0139] in:

[0140] G, R 3 R 4 G 1 G 2 R 1b and R 1c As defined in general formula (II).

[0141] 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:

[0142]

[0143] in:

[0144] G, G 1 G 2 R 3 R 1b and R 1c As defined in general formula (II-1);

[0145] In some embodiments of this disclosure, the compound represented by general formula (II-1) or (II-1C) or a pharmaceutically acceptable salt thereof, wherein G 1 and G 2 Whether the atoms are the same or different, and each is independently selected from O atoms and NR atoms. 1a and CR 1b R 1c ;R 1a R 1b and R 1c As defined in general formula (II).

[0146] In some embodiments of this disclosure, the compound represented by general formula (II-1) or (II-1C) or a pharmaceutically acceptable salt thereof, wherein G 1 For O atoms or NR 1a G 2 For CR 1b R 1c ; or ; G 2 For O atoms or NR 1a G 1 For CR 1b R 1c ;R 1a R 1b and R 1c As defined in general formula (II).

[0147] In some embodiments of this disclosure, the compound represented by general formula (II-1) or (II-1C) or a pharmaceutically acceptable salt thereof, wherein G1 and G 2 All are O atoms.

[0148] 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 (III-1) or a pharmaceutically acceptable salt thereof:

[0149]

[0150] in:

[0151] G, R 3 R 4 L 1 L 2 R 1e and R 1f As defined in general formula (III).

[0152] 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:

[0153]

[0154] in:

[0155] G, L 1 L 2 R 3 R 1e and R 1f As defined in general formula (III-1).

[0156] 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 L 1 and L 2 Whether the atoms are the same or different, and each is independently selected from O atoms and NR atoms. 1d and CR 1e R 1f ;R 1d R 1e and R 1f As defined in general formula (III).

[0157] 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 L 1 For O atoms or NR 1d L 2 For CR 1e R 1f; or ; L 2 For O atoms or NR 1d L 1 For CR 1e R 1f ;R 1d R 1e and R 1f As defined in general formula (III).

[0158] 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 L 1 and L 2 All are O atoms.

[0159] 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 R 3 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkyl and cyano groups.

[0160] 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 R 3 Halogen or C 1-6 Alkyl; preferably, R 3 It is a halogen; more preferably, it is Cl.

[0161] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt of the 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), wherein R 4 It 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 identical or different substituents selected from hydroxyl and carboxyl groups; preferably, R 4 for

[0162] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt of the 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), wherein R 4 It is a hydrogen atom.

[0163] In some embodiments of this disclosure, the compounds 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 pharmaceutically acceptable salts thereof, wherein R 1a or R 1d Selected from hydrogen atoms, C 1-6 Alkyl and -C(O)R 8 R 8 C 1-6 Alkyl; preferably, R 1a and R 1d They may be the same or different, and each is independently either methyl or acetyl.

[0164] In some embodiments of this disclosure, the compounds 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 pharmaceutically acceptable salts thereof, wherein R 1b With R 1c Or R 1e With R 1f They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl; preferably, R 1b With R 1c Or R 1e With R 1f They may be the same or different, and each is independently selected from hydrogen, deuterium, fluorine and methyl atoms.

[0165] In some embodiments of this disclosure, the compounds 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 pharmaceutically acceptable salts thereof, wherein R 1b With R 1c Or R 1e With R 1f They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; preferably, R 1e It is a hydrogen atom or a halogen; R 1f It can be a hydrogen atom or a halogen.

[0166] In some embodiments of this disclosure, the compounds represented by 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-1), or (III-1C), or pharmaceutically acceptable salts thereof, wherein G is CR 2a ;R 2a As defined in general formula (I).

[0167] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the 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-1), or (III-1C) are used, wherein R 2a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R 2a It is a hydrogen atom.

[0168] In some embodiments of this disclosure, 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 CR 2a ;R 2a Selected from hydrogen atoms, halogens and C 1-6 Alkyl groups; each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and -C(O)R atoms. 8 C 1-6 Alkyl, C 1-6 Alkoxy and oxo groups; R 8 C 1-6 Alkyl group; n is 0 (i.e., R) 1 (for hydrogen atoms), 1, 2, 3, or 4; each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; m is 0 (i.e., R) 2 (for hydrogen atoms), 1 or 2; each R 3 They may be the same or different, and each is independently selected from halogens, C 1-6Alkyl, C 1-6 Alkoxy and cyano groups; p is 1, 2, or 3; R 4 It 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 identical or different substituents selected from hydroxyl and carboxyl groups.

[0169] In some embodiments of this disclosure, 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 a CR 2a ;R 2a For hydrogen atoms; each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and -C(O)R atoms. 8 C 1-6 Alkyl and C 1-6 Alkoxy; R 8 C 1-6 Alkyl group; n is 0 (i.e., R) 1 (for hydrogen atoms), 1, 2, 3, or 4; each R 2 For hydrogen atoms; each R 3 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy and cyano groups; p is 1, 2, or 3; R 4 It 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 identical or different substituents selected from hydroxyl and carboxyl groups.

[0170] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein Selected from R 1a Selected from hydrogen atoms, C 1-6 Alkyl and -C(O)R 8 R 8 C 1-6 Alkyl; R 1b and R 1c They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl group; G is an N atom or CR 2a ;R 2a For hydrogen atoms; m is 0; for R 3v For halogens, R 3w R 3x and R 3y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups, or R 3w R 3x Together with the attached carbon atom, it forms a 3- to 8-membered cycloalkyl group; R 4 It 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 identical or different substituents selected from hydroxyl and carboxyl groups.

[0171] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein for R 1e and R 1f They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl group; G is an N atom or CR 2a ;R 2a For hydrogen atoms; m is 0; for R 3v For halogens, R 3w R 3x and R 3y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; R 4 It 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 identical or different substituents selected from hydroxyl and carboxyl groups.

[0172] In some embodiments of this disclosure, 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; and G is a CR 2a ;R 2a For hydrogen atoms; each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and -C(O)R atoms. 8 C 1-6 Alkyl and C 1-6 Alkoxy; R 8 C 1-6 Alkyl group; n is 0 (i.e., R) 1 (for hydrogen atoms), 1, 2, 3, or 4; R 2 For hydrogen atoms; each R 3aThey may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy and cyano groups, where r is 0, 1, or 2; R 4 It 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 identical or different substituents selected from hydroxyl and carboxyl groups.

[0173] Table A lists typical compounds disclosed herein, including but not limited to:

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180] Another aspect of this disclosure relates to compounds or salts thereof represented by general formula (I-1C) or (I-2C):

[0181]

[0182] in:

[0183] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0184] Rings A, G, R 1 To R 3 m, n and p are as defined in general formula (I).

[0185] Another aspect of this disclosure relates to compounds or salts thereof represented by general formula (IID-1A) or (IID-2A):

[0186]

[0187] in:

[0188] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0189] Rings A, G, G 1 G 2 G 3 R 2 R 3 m and p are as defined in general formula (II).

[0190] Another aspect of this disclosure relates to compounds of general formula (IIID-1A) or (IIID-2A) or salts thereof:

[0191]

[0192] in:

[0193] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0194] Rings A, G, L 1 L 2 L 3 L 4 R 2 R 3 m and p are as defined in general formula (III).

[0195] In some embodiments of this disclosure, the compounds represented by general formulas (I-1C), (I-2C), (IID-1A), (IID-2A), (IIID-1A), or (IIID-2A), or their pharmaceutically acceptable salts, wherein R is C 1-6 Alkyl; preferably, R is methyl.

[0196] In some embodiments of this disclosure, the compounds represented by general formulas (I-1C), (I-2C), (IID-1A), (IID-2A), (IIID-1A), or (IIID-2A), or pharmaceutically acceptable salts thereof, wherein R 11 C 1-6 Alkyl; preferably, R 11 It is a methyl group.

[0197] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0198]

[0199]

[0200]

[0201] 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:

[0202]

[0203] Compounds of general formula (IC) or their pharmaceutically acceptable salts with R 4’ -Y compound reacts, then R is removed 4’ The protecting group on the compound yields a compound of general formula (I) or a pharmaceutically usable salt thereof;

[0204] in:

[0205] Y is a halogen; preferably a Br atom.

[0206] R 4’ for

[0207] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0208] R 4 for

[0209] Rings A, G, R 1 To R 3 m, n and p are as defined in general formula (I).

[0210] 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:

[0211]

[0212] 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;

[0213] in:

[0214] X is a halogen; preferably a Cl atom.

[0215] Rings A, G, R 1 To R 3 m, n and p are as defined in general formula (IC).

[0216] 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:

[0217]

[0218] Compounds of general formula (I-1C) or their salts undergo ester hydrolysis to yield compounds of general formula (I-1) or their pharmaceutically usable salts;

[0219] in:

[0220] R and R 11 As defined in general formula (I-1C);

[0221] Rings A, G, R 1 To R 3 m, n and p are defined as in general formula (I-1).

[0222] 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:

[0223]

[0224] Compounds of general formula (I-2C) or their salts undergo ester hydrolysis to yield compounds of general formula (I-2) or their pharmaceutically usable salts;

[0225] in:

[0226] R and R 11 As defined in general formula (I-2C);

[0227] Rings A, G, R 1 To R 3 m, n and p are defined as in general formula (I-2).

[0228] 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:

[0229]

[0230] Compounds of general formula (I-3C) or their pharmaceutically acceptable salts with R 4’ -Y compound reacts, then R is removed 4’ The protecting group on the compound yields a compound of general formula (I-3) or a pharmaceutically usable salt thereof;

[0231] in:

[0232] Y is a halogen; preferably a Br atom.

[0233] R 4’ for

[0234] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C1-6 Alkyl; R 11 C 1-6 alkyl;

[0235] R 4 for

[0236] Ring A, Ring B, G, R 1 R 2 R 3a m, n and r are defined as in general formula (I-3).

[0237] 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:

[0238]

[0239] 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;

[0240] in:

[0241] X is a halogen; preferably a Cl atom.

[0242] Ring A, Ring B, G, R 1 R 2 R 3a m, n and r are as defined in general formula (I-3C).

[0243] 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:

[0244]

[0245] Compounds of general formula (I-4C) or their pharmaceutically acceptable salts with R 4’ -Y compound reacts, then R is removed 4’ The protecting group on the compound yields a compound of general formula (I-4) or a pharmaceutically usable salt thereof;

[0246] in:

[0247] Y is a halogen; preferably a Br atom.

[0248] R 4’ for

[0249] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C1-6 alkyl;

[0250] R 4 for

[0251] Ring A, Ring B, G, R 1 R 2 R 3a m, n and r are defined as in general formula (I-4).

[0252] 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:

[0253]

[0254] 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;

[0255] in:

[0256] X is a halogen; preferably a Cl atom.

[0257] Ring A, Ring B, G, R 1 R 2 R 3a m, n and r are as defined in general formula (I-4C).

[0258] 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:

[0259]

[0260] Compounds of general formula (IIC) or their pharmaceutically acceptable salts with R 4’ -Y compound reacts, then R is removed 4’ The protecting group on the compound yields a compound of general formula (II) or a pharmaceutically usable salt thereof;

[0261] in:

[0262] Y is a halogen; preferably a Br atom.

[0263] R 4’ for

[0264] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0265] R 4 for

[0266] G, G 1 G 2 G 3 R 2 R 3 m and p are as defined in general formula (II).

[0267] 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:

[0268]

[0269] 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;

[0270] in:

[0271] X is a halogen; preferably a Cl atom.

[0272] G, G 1 G 2 G 3 R 2 R 3 m and p are defined as in the general formula (IIC).

[0273] 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:

[0274]

[0275] Compounds of general formula (IID-1A) or their salts undergo ester hydrolysis to yield compounds of general formula (IID-1) or their pharmaceutically usable salts;

[0276] in:

[0277] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0278] G, G 1 G 2 G 3 R 2 R 3 m and p are defined as in general formula (IID-1).

[0279] 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:

[0280]

[0281] Compounds of general formula (IID-2A) or their salts undergo ester hydrolysis to yield compounds of general formula (IID-2) or their pharmaceutically usable salts;

[0282] in:

[0283] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0284] G, G 1 G 2 G 3 R 2 R 3 m and p are as defined in general formula (IID-2).

[0285] 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:

[0286]

[0287] Compounds of general formula (II-1C) or their pharmaceutically acceptable salts with R 4’ -Y compound reacts, then R is removed 4’ By removing the protecting group on the compound, a compound of general formula (II-1) or its pharmaceutically usable salt is obtained;

[0288] in:

[0289] Y is a halogen; preferably a Br atom.

[0290] R 4’ for

[0291] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0292] R 4 for

[0293] G, G1 G 2 R 1b R 1c and R 3 As defined in general formula (II-1); preferably, R 3 It is a halogen.

[0294] 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:

[0295]

[0296] 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;

[0297] in:

[0298] X is a halogen; preferably a Cl atom.

[0299] G, G 1 G 2 R 1b R 1c and R 3 As defined in general formula (II-1C); preferably, R 3 It is a halogen.

[0300] 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:

[0301]

[0302] Compounds of general formula (IIIC) or their pharmaceutically acceptable salts with R 4’ -Y compound reacts, then R is removed 4’ The protecting group on the compound yields a compound of general formula (III) or a pharmaceutically usable salt thereof;

[0303] in:

[0304] Y is a halogen; preferably a Br atom.

[0305] R 4’ for

[0306] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0307] R4 for

[0308] G, L 1 L 2 L 3 L 4 R 2 R 3 m and p are as defined in general formula (III).

[0309] 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:

[0310]

[0311] 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;

[0312] in:

[0313] X is a halogen; preferably a Cl atom.

[0314] G, L 1 L 2 L 3 L 4 R 2 R 3 m and p are as defined in general formula (IIIC).

[0315] 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:

[0316]

[0317] Compounds of general formula (IIID-1A) or their salts undergo ester hydrolysis to yield compounds of general formula (IIID-1) or their pharmaceutically usable salts;

[0318] in:

[0319] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0320] G, L 1 L 2 L 3 L 4 R 2 R3 m and p are as defined in general formula (IIID-1).

[0321] 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:

[0322]

[0323] Compounds of general formula (IIID-2A) or their salts undergo ester hydrolysis to yield compounds of general formula (IIID-2) or their pharmaceutically usable salts;

[0324] in:

[0325] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0326] G, L 1 L 2 L 3 L 4 R 2 R 3 m and p are as defined in general formula (IIID-2).

[0327] 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:

[0328]

[0329] Compounds of general formula (III-1C) or their pharmaceutically acceptable salts with R 4’ -Y compound reacts, then R is removed 4’ The protecting group on the compound yields a compound of general formula (III-1) or a pharmaceutically usable salt thereof;

[0330] in:

[0331] Y is a halogen; preferably a Br atom.

[0332] R 4’ for

[0333] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0334] R 4 for

[0335] G, L 1 L 2 R 1e R 1f and R 3 As defined in general formula (III-1); preferably, R 3 It is a halogen.

[0336] 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:

[0337]

[0338] 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;

[0339] in:

[0340] X is a halogen; preferably a Cl atom.

[0341] G, L 1 L 2 R 1e R 1f and R 3 As defined in general formula (III-1C); preferably, R 3 It is a halogen.

[0342] Another aspect of this disclosure relates to a pharmaceutical composition comprising 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 the compounds shown in Table A, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0343] This disclosure further relates to the use of compounds 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 compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for regulating miRNA levels; preferably, the miRNA is miR-124.

[0344] This disclosure further relates to the use of compounds 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 compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for treating a disease or condition that is improved by regulating miRNA levels.

[0345] This disclosure further relates to the use of compounds 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 compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for treating and / or preventing diseases or conditions selected from viral infections, inflammation, and cancer.

[0346] This disclosure further relates to the use of compounds 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 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).

[0347] This disclosure further relates to the use of compounds of 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 them, in the preparation of medicaments for treating and / or preventing diseases or conditions, said diseases or conditions being inflammation 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 of epithelial cells, cancer-related inflammation, irritation-related inflammation, and injury-related inflammation.

[0348] This disclosure further relates to general formulas (I), (IC), (I-1), (I-2), (I-3), (I-3C), (I-4), (I-4C), (II), (IIC), (II-1), (II-1C), (III), (IID-1), (IID-2), (IIID-1), (IIID-2), (IIIC), (III-1C), (III-1), and Table A. The compound shown or its pharmaceutically usable salt, or a pharmaceutical composition comprising the compound, is used as a medicine for treating and / or preventing diseases or conditions, wherein the diseases or conditions are 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.

[0349] 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 a medicament for treating and / or preventing a disease or condition, said disease or condition being cancer, selected from leukemia. Blood diseases, 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.

[0350] This disclosure further relates to a method for regulating miRNA levels, 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 formula (III-1) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof; preferably, the miRNA is miR-124.

[0351] 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), and (IIID-2). The compounds of general formula (IIIC), general formula (III-1C), general formula (III-1), and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the thereof, wherein the disease or condition is selected from viral infections, inflammation, and cancer; wherein the inflammation is preferably 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.

[0352] This disclosure further relates to general formulas (I), (IC), (I-1), (I-2), (I-3), (I-3C), (I-4), (I-4C), (II), (IIC), (II-1), (II-1C), (III), (IID-1), (IID-2), (IIID-1), (IIID-2), (IIIC), (III-1C), (III-1), and Table A. The compound shown or its pharmaceutically usable salt, or a pharmaceutical composition comprising the compound, is used as a medicine for treating and / or preventing diseases or conditions, wherein the diseases or conditions are 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.

[0353] 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 the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, wherein the disease or condition is selected from viral infections, inflammation, and cancer; The cancers mentioned are 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.

[0354] 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 the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, wherein the disease or condition is selected from AIDS or AIDS-related conditions and human immunodeficiency virus (HIV).

[0355] 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 the thereof, which is used as a medicament.

[0356] 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.

[0357] 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 (II I-1) and 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 diseases or conditions are selected from viral infections, inflammation, and cancer; wherein the inflammation is preferably 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.

[0358] This disclosure further relates to general formulas (I), (IC), (I-1), (I-2), (I-3), (I-3C), (I-4), (I-4C), (II), (IIC), (II-1), (II-1C), (III), (IID-1), (IID-2), (IIID-1), (IIID-2), (IIIC), (III-1C), (III-1), and Table A. The compound shown or its pharmaceutically usable salt, or pharmaceutical composition comprising the compound, is intended for the treatment and / or prevention of a disease or condition, 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.

[0359] 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, wherein the disease or condition is 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).

[0360] 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 those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases or conditions, wherein said diseases or conditions are selected from viral infections, inflammation, and cancer; said 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, 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 tumor, and myeloma.

[0361] 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 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 AIDS or AIDS-related conditions or human immunodeficiency virus (HIV).

[0362] The diseases or conditions described in this disclosure are treated and / or prevented by regulating miRNA levels; preferably, the miRNA is miR-124.

[0363] Preferably, the viral infection described in this disclosure is a retroviral infection.

[0364] Preferably, the inflammatory bowel disease described in this disclosure is ulcerative colitis (UC) or Crohn's disease (CD).

[0365] Preferably, the lymphoma described in this disclosure is Hodgkin's disease or non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma); the liver cancer is preferably hepatocellular carcinoma; the lung cancer (also 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 cell tumor; the leukemia is selected from chronic lymphocytic leukemia (CLL). LL), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML); skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma, and angiosarcoma; myeloma is preferably multiple myeloma; colorectal cancer is preferably colon cancer or rectal cancer; glioma (i.e., glioma or glioblastoma) is preferably selected from glioblastoma, astrocytoma, and oligodendroglioma.

[0366] The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through 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 blow-through administration. 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.

[0367] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

[0368] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: 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.

[0369] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients 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, thus providing sustained release over a longer period.

[0370] Oral formulations can 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.

[0371] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0372] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0373] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. 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.

[0374] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. 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 via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. 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.

[0375] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0376] 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.

[0377] The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. 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.

[0378] 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 validated based on conventional treatment protocols.

[0379] Terminology Explanation

[0380] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0381] 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 an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups containing 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups. Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl 2-Methylpentyl, 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. The alkyl group can be substituted or unsubstituted; when substituted, it can be substituted at any usable linking point. The substituent is preferably selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0382] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived from a parent alkane by removing two hydrogen atoms from the same carbon atom or two different carbon atoms. It 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., C64). 1-12 Alkylenes, more preferably alkylenes containing 1 to 6 carbon atoms (i.e., C16-64 ... 1-6Alkylenes. Non-limiting examples of alkylenes include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are preferably independently selected independently 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 oxo.

[0383] 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, alkenyl compounds contain 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), more preferably alkenyl compounds containing 2 to 6 carbon atoms (i.e., C14, C24, C34, C44, C54, C64, C7 ... 2-6 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, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0384] 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, the alkynyl group (i.e., C14) contains 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12). 2-12 Alkyne group), more preferably an alkyne group containing 2 to 6 carbon atoms (i.e., C12-C64 ... 2-6 (Alkyne group). 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, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0385] 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), 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.

[0386] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintiles, sharing a single carbon atom (called a spiro atom) between the rings, and may contain one or more double bonds. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles (e.g., 7, 8, 9, or 10 quintiles). Spirocycloalkyl groups are classified as monospirocycloalkyl or polyspirocycloalkyl (such as bispirocycloalkyl) based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl being preferred. More preferably, it is a 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, 5 / 6, 6 / 4, 6 / 5, or 6 / 6 monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

[0387]

[0388] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon 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. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, and other polycyclic fused-ring alkyl groups, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, 6 / 6-membered, 6 / 7-membered, 7 / 5-membered, or 7 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused-ring alkyl groups include:

[0389]

[0390] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Based on the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic, and other polycyclic bridged cycloalkyl groups, with bicyclic, tricyclic, or tetracyclic bridged cycloalkyl groups being preferred, and bicyclic or tricyclic bridged cycloalkyl groups being more preferred. Non-limiting examples of bridged cycloalkyl groups include:

[0391]

[0392] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; preferred

[0393] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can 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, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0394] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, 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.

[0395] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but does not include the ring moiety 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, wherein 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), wherein 1 to 3 are heteroatoms (e.g., 1, 2, and 3) (i.e., 3 to 8-membered heterocyclic groups); even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms (i.e., 3 to 6-membered heterocyclic groups); most preferably, it comprises 5 or 6 ring atoms, wherein 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.

[0396] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom) between the rings, wherein the one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic groups or polyspirocyclic groups (such as bispirocyclic groups) according to the number of shared spiro atoms between the rings, preferably monospirocyclic and bispirocyclic groups. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, 5 / 6-membered, or 6 / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0397]

[0398] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which 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, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Based on the number of constituent rings, multi-ring fused heterocyclic groups can be classified into bicyclic, tricyclic, and tetracyclic groups, with bicyclic or tricyclic groups being preferred. More preferably, they are 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0399]

[0400] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, etc., with bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups being preferred, and bicyclic or tricyclic bridged heterocyclic groups being more preferred. Non-limiting examples of bridged heterocyclic groups include:

[0401]

[0402] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0403] wait.

[0404] The heterocyclic group can be substituted or unsubstituted. When substituted, it can 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.

[0405] The term "aryl" refers to a 6- to 14-membered 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-membered, 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:

[0406]

[0407] The aryl group can be substituted or unsubstituted. When substituted, it can 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.

[0408] 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-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, 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:

[0409]

[0410]

[0411] The heteroaryl group can be substituted or unsubstituted. When substituted, it can 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.

[0412] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups 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".

[0413] The term "amino protecting group" refers to the protection of the amino group by an easily removable group to ensure that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl. These groups may optionally be substituted with 1-3 substituents selected from halogens, alkoxy groups, and nitro groups.

[0414] The term "hydroxyl protecting group" refers to a hydroxyl derivative that is typically used to block or protect the 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, formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0415] The term "cycloalkyloxy" refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0416] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0417] The term "aryloxy group" refers to aryl-O-, where the aryl group is as defined above.

[0418] The term “heteroaryloxy” refers to heteroaryl-O-, where the heteroaryl group is as defined above.

[0419] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0420] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0421] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0422] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0423] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0424] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0425] The term "hydroxyl group" refers to -OH.

[0426] The term "thiol" refers to -SH.

[0427] The term "amino" refers to -NH2.

[0428] The term "cyano" refers to -CN.

[0429] The term "nitro" refers to -NO2.

[0430] The term "oxo" or "oxo" refers to "=O".

[0431] The term "carbonyl" refers to C=O.

[0432] The term "carboxyl group" refers to -C(O)OH.

[0433] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0434] 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, using "deuterium" or "tritium" instead of hydrogen, or using... 18 F-fluorine labeling ( 18 F isotopes) can be used instead of fluorine, or... 11 C-、 13 C- or 14 C-enriched carbon ( 11 C-、 13 C- or 14 C-carbon labeling; 11 C-、 13 C- or 14Compounds in which carbon atoms are replaced by C-isotopes are within the scope of this disclosure. Such compounds can be used 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, 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 with reference to relevant literature. Commercially available deuteration starting materials can be used in the preparation of the deuterated form of the compound, or they can be synthesized using conventional techniques with deuteration reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to undeuterated compounds, and better metabolic stability can be achieved when deuterated at certain specific sites, thus providing certain 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 may be independently replaced by a deuterium atom, wherein deuterium substitution may be partial or complete, with partial deuterium substitution referring to at least one hydrogen atom being replaced by at least one deuterium atom. When a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance at least 1000 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.

[0435] 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-blocked 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 compound, which can be prepared by asymmetric synthesis or by 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 the 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 performed by chromatography.

[0436] The compounds disclosed herein can exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. An example of a lactam-lactamimide in equilibrium is shown below:

[0437]

[0438] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0439]

[0440] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0441] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or simultaneously include and Two configurations.

[0442] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0443] "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 (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0444] "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 a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0445] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, 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. The salt 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 ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0446] 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 the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine testing.

[0447] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, 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.

[0448] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0449] 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 those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0450] The method for synthesizing the compounds disclosed herein

[0451] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0452] Option 1

[0453] The method for preparing the compound of formula (I) or its pharmaceutically acceptable salt thereof includes the following steps:

[0454]

[0455] Compounds of general formula (IC) or their pharmaceutically acceptable salts with R 4’ The -Y compound undergoes a nucleophilic substitution reaction under basic conditions, followed by the removal of R under basic conditions. 4’ The protecting group on the compound yields a compound of general formula (I) or a pharmaceutically usable salt thereof;

[0456] in:

[0457] Y is a halogen; preferably a Br atom.

[0458] R 4’ for

[0459] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0460] R 4 for

[0461] Rings A, G, R 1 To R3 m, n and p are as defined in general formula (I).

[0462] Option 2

[0463] The preparation method of the compound represented by the general formula (IC) of this disclosure or a pharmaceutically acceptable salt thereof includes the following steps:

[0464]

[0465] A compound of general formula (IA) or a salt thereof may optionally undergo an aromatic nucleophilic substitution reaction with a compound of general formula (IB) or a salt thereof under basic or acidic conditions; or optionally undergo a coupling reaction under basic conditions and in the presence of a catalyst to give a compound of general formula (IC) or a pharmaceutically usable salt thereof.

[0466] in:

[0467] X is a halogen; preferably a Cl atom.

[0468] Rings A, G, R 1 To R 3 m, n and p are as defined in general formula (IC).

[0469] Option 3

[0470] The method for preparing the compound of formula (I-1) or its pharmaceutically acceptable salt thereof includes the following steps:

[0471]

[0472] Compounds of general formula (I-1C) or their salts undergo ester hydrolysis under alkaline conditions to yield compounds of general formula (I-1) or their pharmaceutically usable salts.

[0473] in:

[0474] R and R 11 As defined in general formula (I-1C);

[0475] Rings A, G, R 1 To R 3 m, n and p are defined as in general formula (I-1).

[0476] Option 4

[0477] The present disclosure discloses a method for preparing the compound of formula (I-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0478]

[0479] Compounds of general formula (I-2C) or their salts undergo ester hydrolysis under alkaline conditions to yield compounds of general formula (I-2) or their pharmaceutically usable salts.

[0480] in:

[0481] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, or heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0482] Rings A, G, R 1 To R 3 m, n and p are defined as in general formula (I-2).

[0483] Option 5

[0484] The method for preparing the compound of formula (I-3) or its pharmaceutically acceptable salt thereof includes the following steps:

[0485]

[0486] Compounds of general formula (I-3C) or their pharmaceutically acceptable salts with R 4’ The -Y compound undergoes a nucleophilic substitution reaction under basic conditions, followed by the removal of R under basic conditions. 4’ The protecting group on the compound yields a compound of general formula (I-3) or a pharmaceutically usable salt thereof;

[0487] in:

[0488] Y is a halogen; preferably a Br atom.

[0489] R 4’ for

[0490] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0491] R 4 for

[0492] Ring A, Ring B, G, R 1 R 2 R 3a , n, m and r are as defined in general formula (I-3).

[0493] Option Six

[0494] The method for preparing the compound of general formula (I-3C) or its pharmaceutically acceptable salt thereof includes the following steps:

[0495]

[0496] A compound of general formula (I-3A) or a salt thereof may be reacted with a compound of general formula (IB) or a salt thereof under either basic or acidic conditions by a nucleophilic substitution reaction; or by a coupling reaction under either basic conditions and in the presence of a catalyst, to give a compound of general formula (I-3C) or a pharmaceutically usable salt thereof.

[0497] in:

[0498] X is a halogen; preferably a Cl atom.

[0499] Ring A, Ring B, G, R 1 R 2 R 3a , n, m and r are as defined in general formula (I-3C).

[0500] Option 7

[0501] The method for preparing the compound of formula (I-4) or its pharmaceutically acceptable salt thereof includes the following steps:

[0502]

[0503] Compounds of general formula (I-4C) or their pharmaceutically acceptable salts with R 4’ The -Y compound undergoes a nucleophilic substitution reaction under basic conditions, followed by the removal of R under basic conditions. 4’ The protecting group on the compound yields a compound of general formula (I-4) or a pharmaceutically usable salt thereof;

[0504] in:

[0505] Y is a halogen; preferably a Br atom.

[0506] R 4’ for

[0507] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0508] R 4 for

[0509] Ring A, Ring B, G, R 1 R 2 R 3a , n, m and r are as defined in general formula (I-4).

[0510] Option 8

[0511] The method for preparing the compound represented by general formula (I-4C) or its pharmaceutically acceptable salt thereof includes the following steps:

[0512]

[0513] A compound of general formula (I-4A) or a salt thereof may optionally undergo a nucleophilic substitution reaction with a compound of general formula (IB) or a salt thereof under basic or acidic conditions; or optionally undergo 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.

[0514] in:

[0515] X is a halogen; preferably a Cl atom.

[0516] Ring A, Ring B, G, R 1 R 2 R 3a , n, m and r are as defined in general formula (I-4C).

[0517] Option Nine

[0518] The method for preparing the compound of formula (II) or its pharmaceutically acceptable salt thereof includes the following steps:

[0519]

[0520] Compounds of general formula (IIC) or their pharmaceutically acceptable salts with R 4’ The -Y compound undergoes a nucleophilic substitution reaction under basic conditions, followed by the removal of R under basic conditions. 4’ The protecting group on the compound yields a compound of general formula (II) or a pharmaceutically usable salt thereof;

[0521] in:

[0522] Y is a halogen; preferably a Br atom.

[0523] R 4’ for

[0524] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0525] R 4 for

[0526] G, G 1 G 2 G 3R 2 R 3 m and p are as defined in general formula (II).

[0527] Option 10

[0528] The method for preparing the compound represented by the general formula (IIC) of this disclosure or a pharmaceutically acceptable salt thereof includes the following steps:

[0529]

[0530] A compound of general formula (IA) or a salt thereof may optionally undergo a nucleophilic substitution reaction with a compound of general formula (IIB) or a salt thereof under basic or acidic conditions; or optionally undergo 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.

[0531] in:

[0532] X is a halogen; preferably a Cl atom.

[0533] G, G 1 G 2 G 3 R 2 R 3 m and p are defined as in the general formula (IIC).

[0534] Option 11

[0535] The method for preparing the compound of general formula (IID-1) or its pharmaceutically acceptable salt thereof includes the following steps:

[0536]

[0537] Compounds of general formula (IID-1A) or their salts undergo ester hydrolysis under alkaline conditions to yield compounds of general formula (IID-1) or their pharmaceutically usable salts.

[0538] in:

[0539] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0540] G, G 1 G 2 G 3 R 2 R 3 m and p are defined as in general formula (IID-1).

[0541] Option Twelve

[0542] The preparation method of the compound represented by general formula (IID-2) or its pharmaceutically acceptable salt thereof includes the following steps:

[0543]

[0544] Compounds of general formula (IID-2A) or their salts undergo ester hydrolysis under alkaline conditions to yield compounds of general formula (IID-2) or their pharmaceutically usable salts.

[0545] in:

[0546] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0547] G, G 1 G 2 G 3 R 2 R 3 m and p are as defined in general formula (IID-2).

[0548] Option Thirteen

[0549] The method for preparing the compound of formula (II-1) or its pharmaceutically acceptable salt thereof includes the following steps:

[0550]

[0551] Compounds of general formula (II-1C) or their pharmaceutically acceptable salts with R 4’ The -Y compound undergoes a nucleophilic substitution reaction under basic conditions, followed by the removal of R under basic conditions. 4’ By removing the protecting group on the compound, a compound of general formula (II-1) or its pharmaceutically usable salt is obtained;

[0552] in:

[0553] Y is a halogen; preferably a Br atom.

[0554] R 4’ for

[0555] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0556] R 4for

[0557] G, G 1 G 2 R 1b R 1c and R 3 As defined in general formula (II-1); preferably, R 3 It is a halogen.

[0558] Option Fourteen

[0559] The method for preparing the compound of general formula (II-1C) or its pharmaceutically acceptable salt thereof includes the following steps:

[0560]

[0561] A compound of general formula (II-1A) or a salt thereof may be reacted with a compound of general formula (II-1B) or a salt thereof under either basic or acidic conditions to undergo a nucleophilic substitution reaction; or, optionally, a coupling reaction may be carried out 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.

[0562] in:

[0563] X is a halogen; preferably a Cl atom.

[0564] G, G 1 G 2 R 1b R 1c and R 3 As defined in general formula (II-1C); preferably, R 3 It is a halogen.

[0565] Option Fifteen

[0566] The method for preparing the compound of formula (III) or its pharmaceutically acceptable salt thereof includes the following steps:

[0567]

[0568] Compounds of general formula (IIIC) or their pharmaceutically acceptable salts with R 4’ The -Y compound undergoes a nucleophilic substitution reaction under basic conditions, followed by the removal of R under basic conditions. 4’ The protecting group on the compound yields a compound of general formula (III) or a pharmaceutically usable salt thereof;

[0569] in:

[0570] Y is a halogen; preferably a Br atom.

[0571] R 4’ for

[0572] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0573] R 4 for

[0574] G, L 1 L 2 L 3 L 4 R 2 R 3 m and p are as defined in general formula (III).

[0575] Option Sixteen

[0576] The method for preparing the compound of formula (IIIC) or its pharmaceutically acceptable salt thereof includes the following steps:

[0577]

[0578] A compound of general formula (IA) or a salt thereof may optionally undergo a nucleophilic substitution reaction with a compound of general formula (IIIB) or a salt thereof under basic or acidic conditions; or optionally undergo 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.

[0579] in:

[0580] X is a halogen; preferably a Cl atom.

[0581] G, L 1 L 2 L 3 L 4 R 2 R 3 m and p are as defined in general formula (IIIC).

[0582] Option 17

[0583] The method for preparing the compound of general formula (IIID-1) or its pharmaceutically acceptable salt thereof includes the following steps:

[0584]

[0585] Compounds of general formula (IIID-1A) or their salts undergo ester hydrolysis under alkaline conditions to yield compounds of general formula (IIID-1) or their pharmaceutically usable salts.

[0586] in:

[0587] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0588] G, L 1 L 2 L 3 L 4 R 2 R 3 m and p are as defined in general formula (IIID-1).

[0589] Option 18

[0590]

[0591] Compounds of general formula (IIID-2A) or their salts undergo ester hydrolysis under alkaline conditions to yield compounds of general formula (IIID-2) or their pharmaceutically usable salts.

[0592] in:

[0593] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0594] G, L 1 L 2 L 3 L 4 R 2 R 3 m and p are as defined in general formula (IIID-2).

[0595] Option 19

[0596] The method for preparing the compound of formula (III-1) or its pharmaceutically acceptable salt thereof includes the following steps:

[0597]

[0598] Compounds of general formula (III-1C) or their pharmaceutically acceptable salts with R 4’ The -Y compound undergoes a nucleophilic substitution reaction under basic conditions, followed by the removal of R under basic conditions. 4’ The protecting group on the compound yields a compound of general formula (III-1) or a pharmaceutically usable salt thereof;

[0599] in:

[0600] Y is a halogen; preferably a Br atom.

[0601] R 4’ for

[0602] R and R 11 They may be the same or different, and each is independently selected from alkyl, cycloalkyl, and heterocyclic groups; preferably, R is C 1-6 Alkyl; R 11 C 1-6 alkyl;

[0603] R 4 for

[0604] G, L 1 L 2 R 1e R 1f and R 3 As defined in general formula (III-1); preferably, R 3 It is a halogen.

[0605] Option 20

[0606] The method for preparing the compound of general formula (III-1C) or its pharmaceutically acceptable salt thereof includes the following steps:

[0607]

[0608] A compound of general formula (II-1A) or a salt thereof may be subjected to a nucleophilic substitution reaction with a compound of general formula (III-1B) or a salt thereof, optionally under basic or acidic conditions; or optionally 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.

[0609] in:

[0610] X is a halogen; preferably a Cl atom.

[0611] G, L 1 L 2 R 1e R 1f and R 3 As defined in general formula (III-1C); preferably, R 3 It is a halogen.

[0612] The reagents providing the basic conditions in the above synthetic schemes include organic 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 tert-butoxide, potassium tert-butoxide, 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 reagents providing the basic conditions are selected from lithium hydroxide monohydrate, potassium carbonate, cesium carbonate, and cadmium carbonate. In schemes two, six, eight, ten, fourteen, sixteen, and twenty, the reagents providing the basic conditions are more preferably potassium carbonate or cesium carbonate. In schemes one, five, seven, nine, thirteen, fifteen, and nineteen, the reagents providing the basic conditions in the nucleophilic substitution reaction are more preferably cadmium carbonate.

[0613] The reagents for alkaline conditions described in Schemes 3, 4, 11, 12, 17 and 18 are preferably lithium hydroxide monohydrate, and more preferably lithium hydroxide monohydrate and hydrogen peroxide.

[0614] The removal of R described in schemes 1, 5, 7, 9, 13, 15, and 19 4’ The reagent that provides alkaline conditions in the reaction of the protecting group is preferably lithium hydroxide monohydrate, more preferably lithium hydroxide monohydrate and hydrogen peroxide.

[0615] 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.

[0616] The ester hydrolysis reaction involved in the above synthesis scheme is preferably carried out under the conditions of lithium hydroxide monohydrate and hydrogen peroxide.

[0617] The catalysts described in the above synthesis schemes include, but are 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)dichloroferrocene]palladium dichloride, and [1,1'-bis(diphenylphosphine)dichloroferrocene]dichloride palladium. [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.

[0618] The reactions described above are preferably carried out in a solvent, which may include, but is 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. Attached Figure Description

[0619] Figure 1 The effect of compound 1 disclosed herein on the body weight of DSS-induced UC mice. 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 treated group and the model group, **P<0.01 indicates a highly significant difference between the treated group and the model group, and ***P<0.001 indicates an extremely highly significant difference between the treated group and the model group.

[0620] Figure 2This disclosure pertains to the effect of compound 1 on colon length in DSS-induced UC mice. The values ​​are as follows: #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 treated group and the model group; **P<0.01 indicates a highly significant difference between the treated group and the model group; ***P<0.001 indicates an extremely highly significant difference between the treated group and the model group. Detailed Implementation

[0621] 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.

[0622] Example

[0623] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0624] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC-MS 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).

[0625] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0626] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0627] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0628] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0629] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0630] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0631] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0632] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0633] 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, AccelaChemBio Inc, and Darui Chemicals.

[0634] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0635] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0636] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0637] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0638] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0639] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0640] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0641] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0642] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, 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 compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0643] Example 1

[0644] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)quinoline-2-amine

[0645]

[0646] 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 reacted at 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, elution 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%).

[0647] MS m / z (ESI): 335.0 [M+1].

[0648] 1 H NMR (500MHz, DMSO-d6) δ9.99(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).

[0649] Example 2

[0650] (2S,3S,4S,5R,6R)-6-((8-chloroquinoline-2-yl)(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 2

[0651]

[0652]

[0653] first step

[0654] (2R,3R,4S,5S,6S)-2-((8-chloroquinoline-2-yl)(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate 2b

[0655] 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-acetyl-α-D-glucuronide 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, the toluene was removed by concentration under reduced pressure, and the mixture was purified by column chromatography using eluent system B to give the title compound 2b (340 mg, 35% yield).

[0656] MS m / z (ESI): 651.0 [M+1].

[0657] Step 2

[0658] (2S,3S,4S,5R,6R)-6-((8-chloroquinoline-2-yl)(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 2

[0659] 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 then added to a tetrahydrofuran solution (15 mL) of compound 2b (340 mg, 0.52 mmol), and stirred at room temperature for 2 hours. After quenching with saturated sodium thiosulfate solution (20 mL), the solution was adjusted to pH 3 with 1 N hydrochloric acid solution, 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 Detecor 2, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 25%-45%, flow rate: 30 mL / min) to give title compound 2 (95 mg, yield 36%).

[0660] MS m / z (ESI): 511.0 [M+1].

[0661] 1 H NMR(500MHz,DMSO-d6)δ8.06(d,1H),7.79(d,1H),7.75(d,1H),7.58(d,1H),7.42(d,1H),7.3 4-7.22(m,2H),6.60(d,1H),6.30(d,1H),5.05-4.82(m,2H),3.55-3.36(m,4H),2.98(t,1H).

[0662] Example 3

[0663] 8-Chloro-N-(2,3-dihydrobenzofuran-5-yl)quinoline-2-amine

[0664]

[0665] 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 (HPLC) (Waters 2767-SQDetecor2, elution 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%).

[0666] MS m / z (ESI): 297.0 [M+1].

[0667] 1 H NMR(500MHz,DMSO-d6)δ9.51(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).

[0668] Example 4

[0669] 8-Chloro-N-(2,3-dihydro-1H-inden-5-yl)quinoline-2-amine

[0670]

[0671] 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 preparative high-performance liquid chromatography (Waters 2767-SQ Detecor2, elution 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%).

[0672] MS m / z (ESI): 295.1 [M+1].

[0673] 1 H NMR(500MHz, CDCl3)7.90(d,1H),7.69(dd,1H),7.63(s,1H),7.57dd,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).

[0674] Example 5

[0675] 1-(5-((8-chloroquinolin-2-yl)amino)indoline-1-yl)ethane-1-one 5

[0676]

[0677] first step

[0678] 1-(5-nitroindoline-1-yl)ethane-1-one 5b

[0679] 5-Nitrodihydroindole 5a (2.0 g, 12.19 mmol, Bio-Pharmaceutical) and triethylamine (1.6 g, 15.85 mmol) were added to 40 mL of dichloromethane, and acetyl chloride (1.24 g, 15.85 mmol) was 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 eluent system B to give the title compound 5b (1.8 g, yield: 72%).

[0680] MS m / z (ESI): 207.1 [M+1].

[0681] Step 2

[0682] 1-(5-aminoindoline-1-yl)ethane-1-one 5c

[0683] Compound 5b (0.8 g, 3.88 mmol) was added to 10 mL of methanol, followed by palladium on carbon (10%, 0.2 g). The mixture was purged three times with hydrogen gas, and the reaction proceeded for 2 hours under a hydrogen atmosphere. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5c (0.5 g). The crude product was used directly in the next reaction step.

[0684] MS m / z (ESI): 177.1 [M+1].

[0685] Step 3

[0686] 1-(5-((8-chloroquinolin-2-yl)amino)indoline-1-yl)ethane-1-one 5

[0687] 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 the mixture was heated to 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by thin-layer chromatography (TLC) using solvent system B to give the title product 5 (48 mg, yield: 25%).

[0688] MS m / z (ESI): 338.1 [M+1].

[0689] 1 H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.27(s,1H),8.10(d,1H),8.01(d,1H),7.8 9-7.65(m,3H),7.26(t,1H),7.12(d,1H),4.11(t,2H),3.19(t,2H),2.15(s,3H).

[0690] Example 6

[0691] 8-Chloro-N-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)quinoline-2-amine

[0692]

[0693] 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 mixture was heated to 100 °C and reacted for 12 hours. After cooling to room temperature, the reaction mixture was filtered and purified by high-performance liquid chromatography (HPLC) (Waters 2767-SQ Detecor2, elution 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%).

[0694] MS m / z (ESI): 313.1 [M+1].

[0695] 1 H 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).

[0696] Example 7

[0697] 8-Chloro-N-(5,6,7,8-tetrahydronaphth-2-yl)quinoline-2-amine

[0698]

[0699]

[0700] 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 mixture was heated to 100 °C and reacted for 12 hours. After cooling to room temperature, the reaction mixture was filtered and purified by preparative high-performance liquid chromatography (Waters 2767-SQDetecor2, elution 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%).

[0701] MS m / z (ESI): 309.1 [M+1].

[0702] 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).

[0703] Example 8

[0704] 8-Chloro-N-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)quinoline-2-amine

[0705]

[0706] first step

[0707] 1-(2-Bromo-1,1,2,2-Tetrafluoroethoxy)-2-methoxy-4-nitrobenzene 8c

[0708] 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 eluent system B to give the title compound 8c (2.6 g, yield: 64%).

[0709] Step 2

[0710] 2-(2-bromo-1,1,2,2-tetrafluoroethoxy)-5-nitrophenol 8d

[0711] 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 eluent system B to give the title compound 8d (2.0 g, yield: 79%).

[0712] MS m / z (ESI): 331.9 [M-1].

[0713] Step 3

[0714] 2,2,3,3-Tetrafluoro-6-nitro-2,3-dihydrobenzo[b][1,4]dioxane 8e

[0715] 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 sulfolane 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 eluent system B to give the title compound 8e (98 mg, yield: 65%).

[0716] Step 4

[0717] 2,2,3,3-Tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxane-6-amine 8f

[0718] 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 to remove air, and reacted for 4 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 8f (60 mg, yield: 72%).

[0719] MS m / z (ESI): 224.0 [M+1].

[0720] Step 5

[0721] 8-Chloro-N-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)quinoline-2-amine

[0722] 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)palladium (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, elution 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%).

[0723] MS m / z (ESI): 385.0 [M+1].

[0724] 1 H 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).

[0725] Example 9

[0726] N-(8-chloroquinolin-2-yl)-[1,3]dioxapentano[4,5-b]pyridine-6-amine 9

[0727]

[0728] first step

[0729] 6-Bromo-[1,3]dioxapentane[4,5-b]pyridine 9b

[0730] 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 eluent system B to give the title compound 9b (300 mg, yield: 14%).

[0731] MS m / z(ESI): 201.9[M+1], 203.9[M+3].

[0732] Step 2

[0733] [1,3]dioxapentane[4,5-b]pyridin-6-ylcarbamate tert-butyl ester 9c

[0734] Compound 9b (100 mg, 0.49 mmol) and tert-butyl carbamate (104 mg, 0.89 mmol) were dissolved in 8 mL of 1,4-dioxane. Tris(dibenzylacetone)dipalladium (45 mg, 0.049 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (47 mg, 0.098 mmol), and sodium tert-butoxide (85 mg, 0.89 mmol) were added under a nitrogen atmosphere. The mixture was heated to 105 °C and reacted for 20 hours. The reaction solution was cooled to room temperature, and 20 mL of water was added. The mixture was extracted with ethyl acetate (20 mL × 3), 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 eluent system B to give the title compound 9c (50 mg, yield: 42%).

[0735] MS m / z (ESI): 239.1 [M+1].

[0736] Step 3

[0737] [1,3]dioxapentane[4,5-b]pyridine-6-amine hydrochloride 9d

[0738] Compound 9c (50 mg, 0.21 mmol) was dissolved in 5 mL of dichloromethane. A solution of dioxane in 4N hydrogen chloride (425 μL, 1.7 mmol) was added dropwise under ice bath conditions. 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.

[0739] MS m / z (ESI): 139.0 [M+1].

[0740] Step 4

[0741] N-(8-chloroquinolin-2-yl)-[1,3]dioxapentano[4,5-b]pyridine-6-amine 9

[0742] 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. 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, elution system: 1 / 1000 aqueous trifluoroacetic acid solution and acetonitrile, acetonitrile gradient: 50%-95%, flow rate: 30 mL / min) to give title compound 9 (12 mg, yield: 26%).

[0743] MS m / z (ESI): 300.0 [M+1].

[0744] 1 H 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).

[0745] Example 10

[0746] N-(benzo[d][1,3]dioxacyclopentan-5-yl)-8-chloroquinoline-2-amine 10

[0747]

[0748] Compounds benzo[d][1,3]dioxane-5-amine 10a (693 mg, 5.05 mmol, Bio-Pharmaceutical), compound 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(dibenzylideneacetone)dipalladium (462 mg, 0.50 mol) were dissolved in 30 mL of 1,4-dioxane. 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, elution 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%).

[0749] MS m / z (ESI): 299.0 [M+1].

[0750] 1 H 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).

[0751] Example 11

[0752] N-(benzo[d][1,3]dioxacyclopentan-5-yl-2,2-dideuterium)-8-chloroquinoline-2-amine 11

[0753]

[0754] Compound benzo[d][1,3]dioxacyclopentane-2,2-dideuter-5-amine 11a (170 mg, 1.21 mmol, prepared by the method disclosed in the intermediate synthesis method 2 on page 41 of 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 separated and purified by high performance liquid chromatography (Waters-2767 Autopurification, elution 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%).

[0755] MS m / z (ESI): 300.9 [M+1].

[0756] 1 H 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).

[0757] Example 12

[0758] 8-Chloro-N-(2,2-Dimethylbenzo[d][1,3]dioxacyclopentan-5-yl)quinoline-2-amine 12

[0759]

[0760]

[0761] Compound 2,2-dimethylbenzo[d][1,3]dioxacyclopentane-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, elution 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%).

[0762] MS m / z (ESI): 327.1 [M+1].

[0763] 1 H NMR(500MHz,DMSO-d6)δ9.59(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).

[0764] Example 13

[0765] 8-Chloro-N-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)quinoline-2-amine 13

[0766]

[0767] 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 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, elution 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%).

[0768] MS m / z (ESI): 325.1 [M+1].

[0769] 1 H 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).

[0770] Example 14

[0771] 5-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-8,9-dihydro-7H-cyclopentano[f]quinoline-3-amine 14

[0772]

[0773] first step

[0774] 6-Chloro-2,3-dihydro-1H-inden-5-amine 14b

[0775] 50 mL of dichloromethane, 10 mL of (6-chloro-2,3-dihydro-1H-inden-5-yl)carbamate tert-butyl 14a (3.4 g, 12.73 mmol, prepared by the known method "ACS Catalysis, 2018, 8, 4783–4788"), and 10 mL of trifluoroacetic acid were added 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, 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 to obtain the crude product, title compound 14b (1.55 g, yield: 73%). The crude product was used directly in the next reaction step.

[0776] MS m / z (ESI): 168.1 [M+1].

[0777] Step 2

[0778] N-(6-chloro-2,3-dihydro-1H-inden-5-yl)-3,3-dimethoxypropionamide 14d

[0779] 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 eluent system B to give the title compound 14d (950 mg, yield: 36%).

[0780] Step 3

[0781] 5-Chloro-4,7,8,9-Tetrahydro-3H-cyclopentano[f]quinoline-3-one 14e

[0782] 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%).

[0783] MS m / z (ESI): 220.0 [M+1].

[0784] Step 4

[0785] 3,5-Dichloro-8,9-dihydro-7H-cyclopentano[f]quinoline 14f

[0786] 2 mL of N,N-dimethylformamide and compound 14e (300 mg, 1.37 mmol) were added sequentially to a 50 mL single-necked flask. The system temperature was raised to 95 °C, and phosphorus oxychloride (0.1 mL, 1.10 mmol) was slowly added dropwise. The reaction was continued for 30 minutes. The phosphorus oxychloride was removed by concentration under reduced pressure, diluted with 20 mL of ethyl acetate, and washed with 0.2 N sodium hydroxide solution (30 mL × 2) and saturated sodium chloride solution (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 14f (0.25 g, yield: 78%), which was used directly in the next reaction.

[0787] MS m / z (ESI): 238.0 [M+1].

[0788] Step 5

[0789] 5-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-8,9-dihydro-7H-cyclopentano[f]quinoline-3-amine 14

[0790] 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 mixture was then heated to 85 °C and reacted for 16 hours. The solvent was removed under reduced pressure, and the mixture was diluted with 1 mL of methanol. The solution was purified by thin-layer chromatography (TLC) using solvent system B to obtain the title compound 14 (78 mg, yield: 49%).

[0791] MS m / z (ESI): 375.0 [M+1].

[0792] 1 H NMR(400MHz,DMSO-d6)δ9.90(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).

[0793] Example 15

[0794] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-7-methylquinoline-2-amine 15

[0795]

[0796]

[0797] first step

[0798] N-(2-chloro-3-methylphenyl)-3,3-dimethoxypropionamide 15b

[0799] To a 100 mL three-necked flask, 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. The system temperature was lowered to 0 °C, and then 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. 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 and washed with 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 to obtain the crude title compound 15b (2.70 g, yield: 98%). The crude product was used directly in the next reaction step.

[0800] Step 2

[0801] 8-Chloro-7-methylquinoline-2(1H)-one 15c

[0802] 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%).

[0803] MS m / z (ESI): 194.0 [M+1].

[0804] Step 3

[0805] 2,8-Dichloro-7-methylquinoline 15d

[0806] 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 was heated 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 eluent system B to give the title compound 15d (620 mg, yield: 71%).

[0807] MS m / z (ESI): 211.9 [M+1].

[0808] Step 4

[0809] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-7-methylquinoline-2-amine 15

[0810] To a 25 mL sealed tube, 8 mL of isopropanol, compound 15d (300 mg, 1.29 mmol), compound 1b (268 mg, 1.54 mmol), and trifluoroacetic acid (260 mg, 2.28 mmol) were added sequentially. The reaction mixture 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, elution 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%).

[0811] MS m / z (ESI): 349.1 [M+1].

[0812] 1 H NMR (500MHz, DMSO-d6) δ9.93(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).

[0813] Example 16

[0814] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-7-methoxyquinoline-2-amine 16

[0815]

[0816] first step

[0817] N-(2-chloro-3-methoxyphenyl)-3,3-dimethoxypropionamide 16b

[0818] To a 100 mL three-necked flask, 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. Sodium bis(trimethylsilyl)amino (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 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 16b (2.50 g, yield: 96%). The crude product was used directly in the next reaction step.

[0819] Step 2

[0820] 8-Chloro-7-methoxyquinoline-2(1H)-one 16c

[0821] 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%).

[0822] MS m / z (ESI): 210.0 [M+1].

[0823] Step 3

[0824] 2,8-Dichloro-7-methoxyquinoline 16d

[0825] To a 50 mL single-necked flask, 8 mL of toluene, compound 16c (800 mg, 3.81 mmol), and phosphorus oxychloride (1.17 g, 7.63 mmol) were added sequentially. The system temperature was raised to 100 °C and the reaction was carried out for 3 hours. After cooling to room temperature, 20 mL of ice water was added, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated sodium chloride solution (50 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 16d (680 mg, yield: 78%).

[0826] MS m / z (ESI): 227.9 [M+1].

[0827] Step 4

[0828] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-7-methoxyquinoline-2-amine 16

[0829] To a 25 mL sealed tube, 4 mL of isopropanol, compound 16d (250 mg, 1.09 mmol), compound 1b (227 mg, 1.31 mmol), and trifluoroacetic acid (224 mg, 1.96 mmol) were added sequentially. The temperature was then raised to 95 °C and the reaction was carried out for 16 hours. The solvent was removed by concentration 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 eluent system B to give the target product 16 (280 mg, yield: 70%).

[0830] MS m / z (ESI): 365.1 [M+1].

[0831] 1 H NMR (400MHz, DMSO-d6) δ9.92(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).

[0832] Example 17

[0833] 7,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-quinoline-2-amine 17

[0834]

[0835]

[0836] first step

[0837] N-((2,3-dichlorophenyl)-3,3-dimethoxypropionamide 17b

[0838] To a 100 mL three-necked flask, 25 mL of tetrahydrofuran, 2,3-dichloroaniline 17a (1.5 g, 9.26 mmol, benzoyl peroxide), and compound 14c (1.65 g, 11.11 mmol) were added sequentially. Sodium bis(trimethylsilyl)amino (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 solution. The reaction mixture 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), 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.

[0839] Step 2

[0840] 7,8-Dichloroquinoline-2(1H)-one 17c

[0841] 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%).

[0842] MS m / z (ESI): 214.0 [M+1].

[0843] Step 3

[0844] 2,7,8-Trichloroquine 17d

[0845] 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 eluent system B to give the title compound 17d (950 mg, yield: 87%).

[0846] MS m / z (ESI): 231.9 [M+1].

[0847] Step 4

[0848] 7,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-quinoline-2-amine 17

[0849] To a 25 mL sealed reaction flask, add 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), and then react at 95 °C for 16 hours. Remove the solvent under reduced pressure, dilute with 100 mL of ethyl acetate, and wash with saturated sodium bicarbonate solution (50 mL × 2) and saturated sodium chloride solution (50 mL × 2). Dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography using eluent system A to give the target product 17 (300 mg, yield: 63%).

[0850] MS m / z (ESI): 369.0 [M+1].

[0851] 1 H NMR (400MHz, DMSO-d6) δ10.06(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).

[0852] Example 18

[0853] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-6-methylquinoline-2-amine 18

[0854]

[0855] first step

[0856] N-(2-chloro-4-methylphenyl)-3,3-dimethoxypropionamide 18b

[0857] To a 100 mL three-necked flask, 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. Sodium bis(trimethylsilyl)amino (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 solution. The reaction mixture 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 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 eluent system B to give the title compound 18b (1.50 g, yield: 82%).

[0858] Step 2

[0859] 8-Chloro-6-methylquinoline-2(1H)-one 18c

[0860] 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%).

[0861] MS m / z (ESI): 194.0 [M+1].

[0862] Step 3

[0863] 2,8-Dichloro-6-methylquinoline 18d

[0864] 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, and 50 mL of ice water was added. 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 eluent system B to give the title compound 18d (0.3 g, yield: 55%).

[0865] MS m / z (ESI): 212.0 [M+1].

[0866] Step 4

[0867] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-6-methylquinoline-2-amine 18

[0868] 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, and 25 mL of water was added. 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. The residue was purified by preparative high-performance liquid chromatography (Waters 2767-SQDetecor2, elution 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%).

[0869] MS m / z (ESI): 349.1 [M+1].

[0870] 1 H 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).

[0871] Example 19

[0872] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-6-methoxyquinoline-2-amine 19

[0873]

[0874]

[0875] first step

[0876] N-(2-chloro-4-methoxyphenyl)-3,3-dimethoxypropionamide 19b

[0877] To a 100 mL three-necked flask, 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. Sodium bis(trimethylsilyl)amino (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 solution. The reaction mixture 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 eluent system B to give the title compound 19b (1.20 g, yield: 69%).

[0878] Step 2

[0879] 8-Chloro-6-methoxyquinoline-2(1H)-one 19c

[0880] 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%).

[0881] MS m / z (ESI): 210.0 [M+1].

[0882] Step 3

[0883] 2,8-Dichloro-6-methoxyquinoline 19d

[0884] 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 eluent system B to give the title compound 19d (75 mg, yield: 14%).

[0885] MS m / z (ESI): 228.0 [M+1].

[0886] Step 4

[0887] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-6-methoxyquinoline-2-amine 19

[0888] 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 proceeded for 16 hours. After cooling 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 preparative high-performance liquid chromatography (Waters 2767-SQDetecor2, elution 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%).

[0889] MS m / z (ESI): 365.1 [M+1].

[0890] 1 H 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).

[0891] Example 20

[0892] 6,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)quinoline-2-amine 20

[0893]

[0894] first step

[0895] N-(2,4-dichlorophenyl)-3,3-dimethoxypropionamide 20b

[0896] To a 100 mL three-necked flask, 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. Sodium bis(trimethylsilyl)amino (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 solution. The reaction mixture 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 eluent system B to give the title compound 20b (1.40 g, yield: 82%).

[0897] Step 2

[0898] 6,8-Dichloroquinoline-2(1H)-one 20c

[0899] 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%).

[0900] MS m / z (ESI): 213.9 [M+1].

[0901] Step 3

[0902] 2,6,8-Trichloroquine 20d

[0903] 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, and 50 mL of ice water was added. 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 eluent system B to give the title compound 20d (240 mg, yield: 74%).

[0904] MS m / z (ESI): 231.9 [M+1].

[0905] Step 4

[0906] 6,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)quinoline-2-amine 20

[0907] 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, and 25 mL of water was added. 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. The residue was purified by preparative high-performance liquid chromatography (Waters 2767-SQDetecor2, elution 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%).

[0908] MS m / z (ESI): 369.0 [M+1].

[0909] 1 H 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).

[0910] Example 21

[0911] (2S,3S,4S,5R,6R)-6-(benzo[d][1,3]dioxacyclopentan-5-yl(8-chloroquinoline-2-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 21

[0912]

[0913]

[0914] first step

[0915] (2R,3R,4S,5S,6S)-2-(benzo[d][1,3]dioxacyclopentan-5-yl)(8-chloroquinoline-2-yl)amino)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate 21a

[0916] 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. After cooling to room temperature, the toluene was removed by concentration under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 21a (450 mg, 58% yield).

[0917] MS m / z (ESI): 615.0 [M+1].

[0918] Step 2

[0919] (2S,3S,4S,5R,6R)-6-(benzo[d][1,3]dioxacyclopentan-5-yl(8-chloroquinoline-2-yl)amino)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 21

[0920] 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 then added to a tetrahydrofuran solution (16 mL) of compound 21a (450 mg, 0.51 mmol), and stirred at room temperature for 16 hours. After quenching with saturated sodium thiosulfate solution (20 mL), the solution was adjusted to pH 4 with 1N hydrochloric acid solution, 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 Detecor 2, elution 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%).

[0921] MS m / z (ESI): 475.1 [M+1].

[0922] 1 H NMR(500MHz,DMSO-d6)δ8.03(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).

[0923] Example 22

[0924] (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

[0925]

[0926] first step

[0927] (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

[0928] 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 eluent system B to give the title compound 22a (400 mg, 40% yield).

[0929] MS m / z (ESI): 629.0 [M+1].

[0930] Step 2

[0931] (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

[0932] 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. The mixture was then purified by high performance liquid chromatography (Waters 2767-SQ Detecor 2, elution 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%).

[0933] MS m / z (ESI): 489.1 [M+1].

[0934] 1 H NMR(500MHz,DMSO-d6)δ8.01(d,1H),7.77(dd,1H),7.70(dd,1H),7.25(t,1H),6.99(d,1H),6.94(d,1H),6.89(dd,1H),6.46 (d,1H),6.33(d,1H),5.03-4.83(m,2H),4.40-4.20(m,4H),3.54(d,1H),3.43-3.36(m,2H),3.08(t,1H),2.97-2.81(m,1H).

[0935] Example 23

[0936] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-5-methylquinoline-2-amine 23

[0937]

[0938] first step

[0939] N-(2-chloro-5-methylphenyl)-3,3-diethoxypropionamide 23c

[0940] Add 5 mL of N,N-dimethylformamide, 2-chloro-5-methylaniline 23a (0.5 g, 3.53 mmol, Bio-Dexter Pharmaceuticals), and 3,3-diethoxypropionic acid 23b (0.63 g, 3.88 mmol, Bailingwei) sequentially to a 100 mL three-necked flask. Then, 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. The system is then brought to room temperature and the reaction is allowed to proceed 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.

[0941] Step 2

[0942] 8-Chloro-5-methylquinoline-2(1H)-one 23d

[0943] 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 eluent system B to give the title compound 23d (0.26 g, yield: 38%).

[0944] MS m / z (ESI): 194.0 [M+1].

[0945] Step 3

[0946] 2,8-Dichloro-5-methylquinoline 23e

[0947] 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 was heated to 95 °C and reacted for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, and ice water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated sodium chloride solution (50 mL × 2). The mixture was 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 step.

[0948] MS m / z (ESI): 212.0 [M+1].

[0949] Step 4

[0950] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-5-methylquinoline-2-amine 23

[0951] 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, and 25 mL of water was added. 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 preparative high-performance liquid chromatography (Waters 2767-SQ Detecor2, elution 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%).

[0952] MS m / z (ESI): 349.1 [M+1].

[0953] 1 H NMR (500MHz, DMSO-d6) δ9.96(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).

[0954] Example 24

[0955] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-5-methoxyquinoline-2-amine 24

[0956]

[0957]

[0958] first step

[0959] N-(2-chloro-5-methoxyphenyl)-3,3-diethoxypropionamide 24b

[0960] To a 100 mL three-necked flask, 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) were added sequentially. Then, 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) were slowly added 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 solution. 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 to obtain the crude product, title compound 24b (0.95 g, yield: 99%). The crude product was used directly in the next reaction step.

[0961] Step 2

[0962] 8-Chloro-5-methoxyquinoline-2(1H)-one 24c

[0963] 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), and the organic phases were combined and washed with 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 silica gel column chromatography using eluent system B to give the title compound 24c (0.26 g, yield: 40%).

[0964] MS m / z (ESI): 210.0 [M+1].

[0965] Step 3

[0966] 2,8-Dichloro-5-methoxyquinoline 24d

[0967] 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, and 50 mL of ice water was added. 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 step.

[0968] MS m / z (ESI): 228.0 [M+1].

[0969] Step 4

[0970] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-5-methoxyquinoline-2-amine 24

[0971] 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, and 25 mL of water was added. 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 preparative high-performance liquid chromatography (Waters 2767-SQ Detecor2, elution 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%).

[0972] MS m / z (ESI): 365.1 [M+1].

[0973] 1 H NMR (400MHz, DMSO-d6) δ9.97(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).

[0974] Example 25

[0975] 5,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)quinoline-2-amine 25

[0976]

[0977] first step

[0978] N-(2,5-Dichlorophenyl)-3,3-diethoxypropionamide 25b

[0979] To a 100 mL three-necked flask, 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) were added sequentially. Then, 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) were slowly added 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 solution. 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 to obtain the crude product, title compound 25b (0.94 g, yield: 99%). The crude product was used directly in the next reaction step.

[0980] Step 2

[0981] 5,8-Dichloroquinoline-2(1H)-one 25c

[0982] Add 2 mL of dichloromethane and compound 25b (0.51 g, 1.67 mmol) sequentially to a 100 mL single-necked flask. Slowly add concentrated sulfuric acid (1.33 mL, 25.05 mmol) at 0 °C, then remove the ice bath and continue the reaction for 4 hours. Remove the solvent under reduced pressure, add the reaction solution dropwise to 50 mL of ice water, and extract with ethyl acetate (50 mL × 3). Combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to give title compound 25c (0.21 g, yield: 56%).

[0983] MS m / z (ESI): 214.1 [M+1].

[0984] Step 3

[0985] 2,5,8-Trichloroquine 25d

[0986] 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 the reaction was carried out for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, and 50 mL of ice water was added. 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.

[0987] MS m / z (ESI): 231.9 [M+1].

[0988] Step 4

[0989] 5,8-Dichloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)quinoline-2-amine 25

[0990] To a 25 mL sealed tube, 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. The temperature was then raised to 95 °C and the reaction was carried out for 16 hours. After cooling 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, elution 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%).

[0991] MS m / z (ESI): 369.0 [M+1].

[0992] 1 H NMR (400MHz, DMSO-d6) δ10.18(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).

[0993] Example 26

[0994] 8-Chloro-2-((2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)amino)quinoline-6-nitrile 26

[0995]

[0996]

[0997] first step

[0998] N-(4-bromo-2-chlorophenyl)-3,3-dimethoxypropionamide 26b

[0999] To a 100 mL three-necked flask, 25 mL of tetrahydrofuran, 4-bromo-2-chloroaniline 26a (3.0 g, 14.53 mmol, benzoyl peroxide), and compound 14c (2.36 g, 15.98 mmol) were added sequentially. Sodium bis(trimethylsilyl)amino (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.

[1000] Step 2

[1001] 6-Bromo-8-chloroquinoline-2(1H)-one 26c

[1002] Add 5 mL of dichloromethane and compound 26b (4.60 g, 14.25 mmol) sequentially to a 100 mL single-necked flask. Slowly add concentrated sulfuric acid (11.40 mL, 213.89 mmol) at 0 °C. Remove the ice bath and heat to 90 °C for 2 hours. Remove the solvent under reduced pressure. Add the residue to 50 mL of ice water and extract with ethyl acetate (50 mL × 5). Combine the organic phases and wash with saturated sodium chloride solution (50 mL × 2). Dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to give title compound 26c (0.46 g, yield: 12%).

[1003] MS m / z (ESI): 257.9 [M+1].

[1004] Step 3

[1005] 6-Bromo-2,8-Dichloroquinoline 26d

[1006] 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 the reaction was carried out for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, and 50 mL of ice water was added. 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 step.

[1007] Step 4

[1008] 6-Bromo-8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)quinoline-2-amine 26e

[1009] 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. 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 solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give title compound 26e (260 mg, yield: 62%).

[1010] MS m / z (ESI): 412.9 [M+1].

[1011] Step 5

[1012] 8-Chloro-2-((2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)amino)quinoline-6-nitrile 26

[1013] To a 25 mL three-necked flask, 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)dipalladium (36 mg, 0.04 mmol), and 1,1'-bis(diphenylphosphine)ferrocene (46 mg, 0.08 mmol). Heat to 135 °C and react for 3 hours. After cooling 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 chromatography (Waters 2767-SQ Detecor2, elution 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%).

[1014] MS m / z (ESI): 360.1 [M+1].

[1015] 1H NMR (400MHz, DMSO-d6) δ10.33(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).

[1016] Example 27

[1017] 8-Chloro-6-cyclopropyl-N-(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)quinoline-2-amine 27

[1018]

[1019] Compound 26e (165 mg, 0.40 mmol) was dissolved in 7.5 mL of 1,4-dioxane and water (V / V = 4:1). 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 chromatography (Waters 2767-SQ Detecor 2, elution 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%).

[1020] MS m / z (ESI): 375.1 [M+1].

[1021] 1 H NMR(400MHz,DMSO-d6)δ9.90(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).

[1022] Example 28

[1023] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-6-(tetrahydro-2H-pyran-4-yl)quinoline-2-amine 28

[1024]

[1025] first step

[1026] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-6-(3,6-dihydro-2H-pyran-4-yl)quinoline-2-amine 28b

[1027] 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 reaction was heated to 100 °C for 3 hours. The reaction 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 silica gel column chromatography with eluent system B to give title compound 28b (140 mg, yield: 77%).

[1028] MS m / z (ESI): 417.0 [M+1].

[1029] Step 2

[1030] 8-Chloro-N-(2,2-Difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-6-(tetrahydro-2H-pyran-4-yl)quinoline-2-amine 28

[1031] 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 through diatomaceous earth, the solvent was removed under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters 2767-SQDetecor2, elution 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%).

[1032] MS m / z (ESI): 419.0 [M+1].

[1033] 1H NMR(400MHz,DMSO-d6)δ9.92(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).

[1034] Example 29

[1035] 8-Chloro-7-cyclopropyl-N-(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)quinoline-2-amine 29

[1036]

[1037] first step

[1038] N-(3-bromo-2-chlorophenyl)-3,3-dimethoxypropionamide 29b

[1039] 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 mixture 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 mixture, 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.

[1040] MS m / z (ESI): 321.9 [M+1].

[1041] Step 2

[1042] 7-Bromo-8-chloroquinoline-2(1H)-one 29c

[1043] 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 for 2 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was added dropwise to 50 mL of ice water. Extraction was performed 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 eluent system B to give the title compound 29c (0.56 g, yield: 23%).

[1044] MS m / z (ESI): 257.9 [M+1].

[1045] Step 3

[1046] 7-Bromo-2,8-Dichloroquinoline 29d

[1047] 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 the reaction was carried out for 90 minutes. Phosphorus oxychloride was removed under reduced pressure, and 50 mL of ice water was added. 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.

[1048] Step 4

[1049] 7-Bromo-8-chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)quinoline-2-amine 29e

[1050] 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 eluent system B to give the title compound 29e (554 mg, yield: 62%).

[1051] MS m / z (ESI): 412.9 [M+1].

[1052] Step 5

[1053] 8-Chloro-7-cyclopropyl-N-(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)quinoline-2-amine 29

[1054] 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)ferrocenepalladium(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 chromatography (Waters 2767-SQ Detecor2, elution 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%).

[1055] MS m / z (ESI): 375.4 [M+1].

[1056] 1 H NMR(400MHz,DMSO-d6)δ9.92(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).

[1057] Example 30

[1058] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-amine 30

[1059]

[1060] first step

[1061] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-7-(3,6-dihydro-2H-pyran-4-yl)quinoline-2-amine 30a

[1062] 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)ferrocenepalladium(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 with eluent system B to give title compound 30a (70 mg, yield: 41%).

[1063] MS m / z (ESI): 417.0 [M+1].

[1064] Step 2

[1065] 8-Chloro-N-(2,2-difluorobenzo[d][1,3]dioxacyclopentan-5-yl)-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-amine 30

[1066] 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 through diatomaceous earth, and the solvent was removed under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Waters 2767-SQ Detecor 2, elution 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%).

[1067] MS m / z (ESI): 419.1 [M+1].

[1068] 1 H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.90(d,1H),8.12(d,1H),7.74(d,1H),7.48(dd,1H),7.4 0-7.35(m,2H),7.08(d,1H),4.01(dd,2H),3.54(td,2H),2.04-1.95(m,1H),1.87-1.69(m,4H).

[1069] Example 31

[1070] 5-((8-chloroquinoline-2-yl)amino)-3-methylbenzo[d]oxazol-2(3H)-one 31

[1071]

[1072] 5-Amino-3-methyl-1,3-benzoxazol-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(dibenzylacetone)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, elution 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%).

[1073] MS m / z (ESI): 324.1 [M-1].

[1074] 1 H NMR (500MHz, CDCl3) δ9.89(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).

[1075] Biological evaluation

[1076] Explanation of abbreviations appearing below:

[1077] po: oral

[1078] bid: twice a day

[1079] qd: once a day

[1080] MC: Sodium carboxymethyl cellulose

[1081] Test Example 1: The preventive and therapeutic effects of the disclosed compound on ulcerative colitis (UC) in mice.

[1082] 1. Abstract

[1083] 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 (see Compound 90 in WO2015001518A1) and Compound 1 of the present disclosure on DSS-induced ulcerative colitis were evaluated.

[1084]

[1085] 2. Experimental methods and materials

[1086] 2.1. Experimental animals and feeding conditions

[1087] Female C57BL / 6 mice were used in the experiment. They were from Vital River Laboratory Animal Co., Ltd. (Production License Number: SCXK(Zhe)2019-0001, Animal Certificate Number: 20210401Abzz0619000795). When purchased, their body weight was 20-22 g. They were housed at 5 per cage in an independent SPF space, with a 12 / 12-hour light / dark cycle adjustment, 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.

[1088] 2.2. Experimental reagents and instruments

[1089] Dextran sulfate sodium salt (DSS): MP Biomedicals, Catalog Number 160110, Batch Number S5036. Prepared with sterile water, filtered, not autoclaved, and changed every two days.

[1090] Ethyl alcohol: Shanghai Baxter Medical Supplies Co., Ltd., Batch Number S2001050.

[1091] Olive oil: Sinopharm Chemical Reagent Co., Ltd., Catalog Number 30189828, Batch Number 20180104.

[1092] Methyl cellulose M450: Sinopharm Chemical Reagent Co., Ltd., Catalog Number 69016460, Batch Number 20170308.

[1093] Microplate reader: Manufacturer BMGlabtech, Model PHERAstar Fs.

[1094] Desktop low-speed centrifuge: Manufacturer Eppendorf, Model 5417R.

[1095] Electronic balance: Mettler Toledo Instruments Co., Ltd., Model AL204.

[1096] 2.3. Experimental Design and Methods

[1097] 2.3.1. Animal grouping:

[1098] After acclimatization, the mice were divided into the following groups:

[1099]

[1100]

[1101] Solvent: 0.5% MC suspension

[1102] 2.3.2. Drug preparation:

[1103] DSS preparation method: 25g DSS + 1L ultrapure water, aseptically filtered, stored at 4℃.

[1104] Preparation method for 50mg / kg ABX-464: 100mg ABX-464 + 20mL 0.5% MC, grind, and store at 4℃. Prepare twice.

[1105] Preparation method of compound 1 disclosed in this invention (50 mg / kg): 100 mg of compound 1 disclosed in this invention + 20 mL of 0.5% MC, grind, and store at 4°C.

[1106] 2.3.3. Experimental Methods:

[1107] Mice were randomly divided into 5 groups according to their body weight: normal control group ( The mice were fed a combination of two groups: a control group (DSS group), a 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 via gavage for 10 consecutive days. Body weight was observed daily from day 0 to day 10. Colon length was measured after weighing the mice on day 10.

[1108] 2.4. Data Presentation and Statistical Processing

[1109] Experimental data are expressed as mean ± standard error (SEM). Statistical comparisons were performed using the t-test in Excel software. Data from the model group and the normal control group were analyzed and compared. #P < 0.05 indicated a statistically significant difference between the model group and the normal control group; ##P < 0.01 indicated a highly statistically significant difference; ###P < 0.001 indicated an extremely highly statistically significant difference. *P < 0.05 indicated a statistically significant difference between the treatment group and the model group; **P < 0.01 indicated a highly statistically significant difference; and ***P < 0.001 indicated an extremely highly statistically significant difference.

[1110] 3. Results

[1111] 3.1 Effect of compound 1 disclosed herein on body weight of DSS-induced UC mice

[1112] The results of the weight test showed that ( Figure 1 Compared with the normal control group, mice in the DSS model group experienced a significant decrease in body weight starting from day 4, with the rate of weight loss gradually increasing, reaching 30.0% by day 10 (P<0.001). Compared with the DSS model group, all treatment groups showed a significant recovery in body weight starting from day 7. By day 10, the weight loss rates for ABX-464 (qd), ABX-464 (bid), and compound 1 (bid) disclosed in this publication were reduced 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 (50 mg / kg, bid) > ABX-464 (50 mg / kg, bid) > ABX-464 (50 mg / kg, qd).

[1113] 3.2 Effect of Compound 1 of this disclosure on colon length in DSS-induced UC mice

[1114] The colon length results showed ( Figure 2Compared with the normal control group, the colon length in the DSS model group was significantly shortened (P<0.001), only 75.4% of that in the normal control group. Compared with the DSS model group, the colon length in all treatment groups was significantly increased. The colon lengths of ABX-464 (qd), ABX-464 (bid), and compound 1 of this disclosure (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 of this disclosure 50 mg / kg (bid) > ABX-464 50 mg / kg (bid) > ABX-464 50 mg / kg (qd).

[1115] 4. Conclusion

[1116] The DSS model serves as a culprit-like animal model for ulcerative colitis (UC) induced by IBD. Factors affecting the model's effectiveness include the molecular weight (36,000-50,000), batch number, storage configuration, mouse housing environment, and strain of the DSS. This modeling attempt was relatively successful, showing significant changes in mouse body weight and colon length. Results showed that compound 1 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 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.

[1117] Test Example 2. Upregulation of miR-124 by the disclosed compounds

[1118] I. Abstract

[1119] This experiment was used to evaluate the upregulation effect of the disclosed compounds on miR-124.

[1120] II. Experimental Materials and Instruments

[1121] 1. Dynabead Human T-Activator CD3 / CD28 for TCell Expansion and Activation (Gibco, 11131D)

[1122] 2. Pan T Cell Isolation Kit (human) (Miltenyi, 130-096-535)

[1123] 3. Human interleukin-2 (Peprotech, 200-02-100)

[1124] 4. MicroRNA Extraction Kit (Qiagen, 217004)

[1125] 5. Small RNA Reverse Transcription Kit (miScript II RT Kit) (Qiagen, 218161)

[1126] 6. Small RNA SYBR Green PCR Kit (miScript SYBR Green PCR Kit) (Qiagen, 218073)

[1127] 7. Phosphate-buffered saline (PBS), pH 7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320)

[1128] 8. Bovine serum albumin (BSA) (Beyotime, ST023)

[1129] 9.EDTA (0.5M), pH 8.0 (Invitrogen, AM9260G)

[1130] 10. LS Separation Columns (Miltenyi, 130-042-401)

[1131] 11. 24-well cell culture plate (Corning, 3524)

[1132] 12. 96-well plate (Corning, 3788)

[1133] 13. Cell incubator (Thermo, Steri cycle i160)

[1134] 14. Real-time quantitative PCR instrument (Applied biosystem, QuantStudio6 Flex)

[1135] 15.PCR instrument (Applied biosystem, ProFlex)

[1136] 16. 96-well clear PCR plate, 0.2 mL (Applied biosystems, N8010560)

[1137] 17. RPMI 1640 medium (Gibco, 11875119)

[1138] 18. Fetal bovine serum, FBS (Gibco, 10099-141)

[1139] 19. Magnetic rack (Invitrogen, DynaMag) TM -2)

[1140] 20. Six-well cell culture plate (Thermo, 150239)

[1141] 21. Spectrophotometer (IMPLEN, NP80)

[1142] 22. QuadroMACS Separator (Meitianni, 130-090-976)

[1143] 23. miR124-3P-F primers (custom-made by Genewiz)

[1144] 24. HSA-U6 detection primers (Tiangen, CD201-0145)

[1145] III. Experimental Procedure

[1146] 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 from reverse transcription was used as a template. Quantification was performed using SYBR Green real-time PCR with specific miR-124 primers.

[1147] T cell isolation: Purchased human peripheral blood mononuclear cells (PBMCs), counted and centrifuged, washed once with separation buffer (PBS pH 7.4, containing 0.5% BSA and 2mM EDTA), discarded the supernatant, and divided into 1×10⁻⁶ cells per cell. 7 Add 40 μL of buffer and 10 μL of pan T cell biotinylated antibody (pan T Cell Biotin-Antibody Cocktail) to each cell, resuspend the precipitate, mix well, and incubate at 4°C for 5 minutes. After incubation, repeat the process at 1 × 10⁻⁶ cells / cell. 7 Add 30 μL of buffer and 20 μL of Pan T Cell MicroBeads Cocktail to each cell, mix well, and incubate at 4°C for 10 minutes. Pre-wash the separation column (LS column) with 3 mL of cell separation buffer, then pass the cell suspension through the column. After passing the cell suspension through the column, wash the column three times with 1 mL of cell separation buffer. Collect the eluent cell solution in a 15 mL centrifuge tube; this is the enriched T cells. Count the cells at a ratio of 1 × 10⁻⁶ cells / mL. 6 Add cells at a density of 10% FBS and 40 U / mL IL-2 to RPMI 1640 medium (complete medium) and store on ice for later use.

[1148] T cell activation: per 1×10 6Add 25 μL of activating magnetic beads to each cell. Take the corresponding amount of activated CD3 / CD28 magnetic beads for T cell activation and place them in a 1.5 mL centrifuge tube. Shake the tube for approximately 30 seconds before aspirating. Wash the activated 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 activated magnetic beads in an equal volume of complete culture medium. Add the washed activated 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.

[1149] Compound preparation: The stock solution of the compound 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 25% DMSO served as a negative control. T cells activated for two days were pipetted and placed on 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 x g for 10 min, the supernatant was discarded, and the cells were resuspended to 1.02 × 10⁻⁶. 6 Add 980 μL of cell suspension and 20 μL of 50× compound to each well of a 24-well plate, bringing the final compound concentration to 1 μM. Incubate the cells at 37°C in a 5% CO2 cell culture incubator for 3 days.

[1150] 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 column once with 700 μL of RWT solution, centrifuge at 8000 xg for 15 seconds, wash twice with 500 μL of RPE solution, and centrifuge at 8000 xg for 2 minutes. Transfer the adsorption column to a new 2 mL centrifuge tube and centrifuge at 12000 x g for 1 min to remove residual washing buffer. Transfer the adsorption column to a new 1.5 mL centrifuge tube, add 30-50 μL of RNase-free water, centrifuge at 12000 x g for 2 min, and collect the RNA solution. Measure the RNA concentration using a spectrophotometer. Store the RNA solution at -80°C.

[1151] Reverse transcription: Place the extracted RNA template on ice. Remove the small RNA reverse transcription kit and thaw a portion of its components (containing 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 reaction 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 the cDNA sample.

[1152] Quantitative real-time 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 real-time PCR instrument according to the steps in Table 2.

[1153] Table 1. Components of Real-Time PCR Reaction

[1154]

[1155] Table 2. Steps for Real-Time PCR

[1156]

[1157]

[1158] Table 3 Primer list for quantitative real-time PCR detection

[1159]

[1160] Data Analysis: Based on the CT values ​​calculated by the software, the ratio of miR-124 expression level to the internal reference U6 expression level for each sample was calculated, i.e., ΔCT (test compound) = CT. miRNA-124 (Test Compound)-CT U6 (Test compound). The relative expression level is calculated using the following formula: Relative expression level (test compound) = 2 (-[ΔCT(测试化合物)-ΔCT(DMSO)]).

[1161] Table 4. Activity of the disclosed compounds against miR-124 upregulation

[1162] compound miR-124 increased (by a factor) DMSO 1.0 1 3.9 2 1.2 3 5.2 4 5.4 5 1.4 6 2.7 7 5.2 8 5.4 9 2.4 10 2.1 11 2.4 12 1.8 13 2.8 14 1.5 15 5.7 16 3.9 17 5.9 18 2.7 20 5.0 21 1.9 22 1.7 23 2.3 24 3.0

[1163] 25 6.7 26 2.4

[1164] Conclusion: The compound disclosed herein exhibits good activity in promoting miR124 upregulation.

[1165] Test Example 3: Pharmacokinetic Test of the Compounds Disclosed

[1166] 1. Abstract

[1167] 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 compounds in rats was studied to evaluate their pharmacokinetic characteristics.

[1168]

[1169] 2. Test Plan

[1170] 2.1 Test Drugs

[1171] Compound of Example 2, Comparative Compound A.

[1172] 2.2 Experimental Animals

[1173] 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.

[1174] 2.3 Drug Preparation

[1175] Weigh a certain amount of the drug and add 5% DMSO, 5% Tween 80 and 90% physiological saline to prepare a clear solution.

[1176] 2.4 Administration

[1177] Gavage group: SD rats were fasted overnight and then administered the drug by gavage at a dose of 2 mg / kg and a volume of 10.0 mL / kg.

[1178] 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.

[1179] 3. Operation

[1180] 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 processes were performed under ice bath conditions. Rats were fed 2 hours after administration.

[1181] 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.

[1182] To determine the content of the target compound in rat plasma after administration of different concentrations of the drug via 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.

[1183] 4. Pharmacokinetic Parameter Results

[1184] Table 5. Pharmacokinetic parameters of the compounds disclosed herein after oral administration.

[1185]

[1186] Table 6. Pharmacokinetic parameters of the disclosed compounds after intravenous administration.

[1187]

[1188] Conclusion: As shown in Tables 5 and 6, compared with comparative compound A, the compound of Example 2 of this disclosure has good pharmacokinetic absorption and obvious pharmacokinetic advantages. sequence list <110> Jiangsu Hengrui Medicine Co., Ltd. Shanghai Hengrui Medicine Co., Ltd. <120> Quinolinamine compounds, their preparation methods and their pharmaceutical applications <130> 722060CPCT <150> 202110606803.1 <151> 2021-05-27 <150> 202110976020.2 <151> 2021-08-24 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 20 <212> DNA <213> Artificial sequence <220> <223> Primer miR124-3p-F <400> 1 taaggcacgc ggtgaatgcc 20

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: ； in: Ring A is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclic group; G is an N atom or CR 2a ; Each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy and -C(O)R 8 ; Each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl; Each R 3 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl and cyano groups; Or two adjacent R 3 It forms a 5- or 6-membered cycloalkyl group with the carbon atom on the connected benzene ring; R 4 It is a hydrogen atom or a 3 to 8-membered heterocyclic group, wherein the 3 to 8-membered heterocyclic group is optionally substituted by one or more identical or different substituents selected from hydroxyl and carboxyl groups; R 8 C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2a Selected from hydrogen atoms, halogens and C 1-6 alkyl; n is 0, 1, 2, 3 or 4; m is 0, 1, or 2; p can be 1, 2, 3 or 4.

2. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: ； in: Ring A is a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclic group; G is an N atom or CR 2a ; Each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, oxo, and -C(O)R 8 ; Each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl; Each R 3 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl and cyano groups; Or two adjacent R 3 It forms a 5- or 6-membered cycloalkyl group with the carbon atom on the connected benzene ring; R 4 It is a hydrogen atom or a 3 to 8-membered heterocyclic group, wherein the 3 to 8-membered heterocyclic group is optionally substituted by one or more identical or different substituents selected from hydroxyl and carboxyl groups; R 8 C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 2a Selected from hydrogen atoms, halogens and C 1-6 alkyl; n is 0, 1, 2, 3 or 4; m is 0, 1, or 2; p can be 1, 2, 3 or 4.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (IC) or a pharmaceutically acceptable salt thereof: ； in: Rings A, G, R 1 To R 3 n, m and p are as defined in claim 1.

4. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (IC) or a pharmaceutically acceptable salt thereof: ； in: Rings A, G, R 1 To R 3 n, m and p are as defined in claim 2.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of general formula (I-1) or general formula (I-2), or a pharmaceutically acceptable salt thereof: or ; in: Rings A, G, R 1 To R 3 n, m and p are as defined in claim 1.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound is a compound or a pharmaceutically acceptable salt thereof represented by general formula (I-1) or general formula (I-2): or ; in: Rings A, G, R 1 To R 3 n, m and p are as defined in claim 2.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is a compound or a pharmaceutically acceptable salt thereof represented by general formula (I-3) or general formula (I-4): or ; in: Ring B is a 5- or 6-membered cycloalkyl group; Each R 3a They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl and cyano groups; r is 0, 1, or 2; Rings A, G, R 1 R 2 R 4 , n and m are as defined in claim 1.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound is a compound or a pharmaceutically acceptable salt thereof represented by general formula (I-3) or general formula (I-4): or ; in: Ring B is a 5- or 6-membered cycloalkyl group; Each R 3a They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl and cyano groups; r is 0, 1, or 2; Rings A, G, R 1 R 2 R 4 , n and m are as defined in claim 2.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein: Cycle B is cyclopentyl.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein ring A is a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclic group.

11. The compound according to any one of claims 1, 3, 5 and 7, or a pharmaceutically acceptable salt thereof, wherein: Each R 1 They may be the same or different, and each is independently selected from hydrogen, deuterium, fluorine, acetyl, and methyl.

12. A compound of general formula (II) or a pharmaceutically acceptable salt thereof: ； in: G 1 G 2 and G 3 Whether the atoms are the same or different, and each is independently selected from O atoms and NR atoms. 1a and CR 1b R 1c ; R 1a Selected from hydrogen atoms, C 1-6 Alkyl and -C(O)R 8 ; R 1b and R 1c They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 alkoxy, or R 1b and R 1c Together they form an oxygen group; G, R 2 To R 4 R 8 m and p are as defined in claim 1.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein: G 1 and G 2 Whether the atoms are the same or different, and each is independently selected from O atoms and NR atoms. 1a and CR 1b R 1c ; G 3 is CR 1b R 1c ; R 1a R 1b and R 1c As defined in claim 12.

14. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein: Selected from , , , and R 1a R 1b and R 1c As defined in claim 12.

15. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein: Selected from , , , , , , , and .

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (III) or a pharmaceutically acceptable salt thereof: ； in: L 1 L 2 L 3 and L 4 Whether the atoms are the same or different, and each is independently selected from O atoms and NR atoms. 1d and CR 1e R 1f ; R 1d Selected from hydrogen atoms, C 1-6 Alkyl and -C(O)R 8 ; R 1e and R 1f They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy; G, R 2 To R 4 R 8 m and p are as defined in claim 1.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein: L 1 and L 2 Whether the atoms are the same or different, and each is independently selected from O atoms and NR atoms. 1d and CR 1e R 1f L 3 and L 4 Each independently for CR 1e R 1f ; R 1d R 1e and R 1f As defined in claim 16.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, 12 to 17, wherein: R 2 It is a hydrogen atom.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, 12 to 17, wherein: R 2a It is a hydrogen atom.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, 12 to 14, 16, 17, wherein: R 8 C 1-6 alkyl.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, 12 to 17, wherein: Each R 3 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkyl and cyano groups.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, 12 to 17, wherein: R 3 It is a halogen.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 7, 8, 12 to 17, wherein: R 4 It is a hydrogen atom, or R 4 for or .

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 7, 8, 12 to 17, wherein: R 4 for or .

25. A compound or a pharmaceutically acceptable salt thereof, selected from any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

26. A compound of general formula (I-1C) or (I-2C) or a salt thereof: or ; in: R is C 1-6 Alkyl; R 11 C 1-6 alkyl; Rings A, G, R 1 To R 3 m, n and p are as defined in claim 1.

27. A compound of general formula (I-1C) or (I-2C) or a salt thereof: or ; in: R is C 1-6 Alkyl; R 11 C 1-6 alkyl; Rings A, G, R 1 To R 3 m, n and p are as defined in claim 2.

28. A compound or a salt thereof, wherein the compound is one of the following: , , , , and .

29. A method for preparing a compound of formula (IC) according to claim 3 or a pharmaceutically acceptable salt thereof, the method comprising the steps of: ； 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; in: X is a halogen; Rings A, G, R 1 To R 3 m, n and p are as defined in claim 3.

30. A method for preparing a compound of formula (IC) according to claim 4 or a pharmaceutically acceptable salt thereof, the method comprising the steps of: ； 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; in: X is a halogen; Rings A, G, R 1 To R 3 m, n and p are as defined in claim 4.

31. The method according to claim 29 or 30, wherein X is a Cl atom.

32. A method for preparing a compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, the method comprising the following steps: ； Compounds of general formula (IC) or their pharmaceutically acceptable salts with R 4’ -Y compound reacts, then R is removed 4’ The protecting group on the compound yields a compound of general formula (I) or a pharmaceutically usable salt thereof; in: Y represents a halogen; R 4’ for or ; R and R 11 The same or different, and each independently is C. 1-6 alkyl; R 4 for or ; Rings A, G, R 1 To R 3 m, n and p are as defined in claim 1.

33. A method for preparing a compound of general formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, the method comprising the following steps: ； Compounds of general formula (IC) or their pharmaceutically acceptable salts with R 4’ -Y compound reacts, then R is removed 4’ The protecting group on the compound yields a compound of general formula (I) or a pharmaceutically usable salt thereof; in: Y represents a halogen; R 4’ for or ; R and R 11 The same or different, and each independently is C. 1-6 alkyl; R 4 for or ; Rings A, G, R 1 To R 3 m, n and p are as defined in claim 2.

34. The method according to claim 32 or 33, wherein Y is a Br atom.

35. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, and one or more pharmaceutically acceptable carriers, diluents or excipients.

36. Use of the compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 35, in the preparation of a medicament for regulating miRNA levels.

37. Use of the compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 35 in the preparation of a medicament for treating and / or preventing a disease or condition selected from viral infections, inflammation, and cancer.

38. Use of the compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 35 in the preparation of a medicament for the treatment and / or prevention of AIDS or human immunodeficiency virus (HIV).

39. The use according to claim 37, 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, and asthma.

40. The use according to claim 37, wherein the inflammation is inflammatory bowel disease.

41. The use according to claim 39, wherein the inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).

42. The use according to claim 37, wherein the cancer is selected from leukemia, macroglobulinemia, heavy chain disease, sarcoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, cervical cancer, uterine cancer, testicular cancer, lung cancer, bladder cancer, skin cancer, kidney cancer, nasopharyngeal carcinoma, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small bowel cancer, gallbladder cancer, urothelial carcinoma, and thyroid cancer.

43. The use according to claim 37, wherein the cancer is selected from lymphoma, Wilms' tumor, glioma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, pediatric tumors, ureteral tumors, osteoma, neuroblastoma, brain tumors, and myeloma.

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