Use of compounds in the treatment of fatty liver disease and related diseases

Abstract

The present application relates to the use of compounds in the treatment of fatty liver disease and related diseases, in particular, the present application provides the use of a compound represented by formula O or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof in the preparation of a drug for treating and / or preventing fatty liver disease and related diseases,

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to the use of compounds in the treatment of fatty liver disease and related diseases. Background Technology

[0002] Nonalcoholic fatty liver disease (NAFLD) refers to an excessive deposition of lipids in the liver of patients without a history of alcohol abuse or other secondary causes of hepatic steatosis. It is a major indication for liver transplantation in both developed and developing countries, including: hepatic steatosis (NAFL, the progression-free stage of NAFLD) and nonalcoholic steatohepatitis (NASH, the progressive stage of NAFLD). NASH is a key factor in the progression of NAFLD; 25% of NAFL patients may progress to NASH, accompanied by hepatocellular steatosis, ballooning degeneration, inflammation, and fibrosis. 35%-50% of NASH patients will progress to liver cancer. Furthermore, NAFLD is closely associated with metabolic diseases such as insulin resistance, hypertension, dyslipidemia, and obesity, thus its development can promote the gradual progression of various metabolic syndromes, including diabetes. It is estimated that the global prevalence of NAFLD is approximately 25%, while the number of NAFLD patients in China has increased dramatically from 18% to nearly 30% in the past 10 years, and is projected to exceed 300 million by 2030.

[0003] Given the high incidence and associated morbidity of NASH, it is currently believed that there is no identified therapy capable of slowing, stopping, or reversing the progression of NASH and NAFLD, thus highlighting a lack of medical need. Although several drugs are currently being used for treatment, none have been approved by the U.S. Food and Drug Administration (FDA), therefore, further research is needed to discover safe and effective drugs for the treatment of NAFLD. Summary of the Invention

[0004] The purpose of this invention is to at least partially solve the problems existing in the prior art.

[0005] The inventors of this application have discovered that the compounds of this invention can significantly inhibit lipid accumulation in hepatocytes without obvious toxic side effects. Moreover, oral administration of the compounds of this invention can effectively alleviate non-alcoholic fatty liver disease.

[0006] Therefore, in a first aspect, the present invention provides the use of compounds of formula O or their stereoisomers, their prodrugs, their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates in the preparation of medicaments for treating and / or preventing fatty liver disease and related diseases.

[0007] Alternatively, a compound of formula O or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate are provided for the treatment and / or prevention of fatty liver disease and related conditions.

[0008] Alternatively, methods for treating and / or preventing fatty liver disease and related conditions are provided, comprising administering to a subject in need an effective amount of a compound of formula O or a stereoisomer thereof, its prodrug, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate.

[0009]

[0010] in:

[0011] A is Furthermore, position 1 is connected to a carbonyl group, and position 2 is connected to a phenyl group;

[0012] n is selected from 0, 1, and 2;

[0013] R a R b Each is independently selected from H and C1-C6 alkyl groups;

[0014] R 1a R 1b Each is independently selected from H, aryl, and alkyl, wherein the aryl and alkyl groups are optionally substituted with groups selected from halogen, alkyl, haloalkyl, alkoxy, and aryl; or, R 1a R 1b Together with the N atoms attached to them, they form heterocyclic groups, which are optionally substituted with alkyl groups;

[0015] R 2a R 2b Each is independently selected from H, alkyl, cycloalkyl, aryl, benzyl, and adamantyl, wherein the alkyl, cycloalkyl, aryl, benzyl, and adamantyl groups are optionally substituted with halogens; or, R 2a R 2b Together with the N atoms attached to them, they form heterocyclic groups, which are optionally substituted with alkyl groups;

[0016] Y is selected from

[0017] R 3 The group is selected from alkyl, cycloalkyl, aryl, benzyl, and heteroaryl groups, wherein the alkyl, cycloalkyl, aryl, benzyl, and heteroaryl groups are optionally substituted by groups selected from halogens and alkyl groups;

[0018] Optionally, the drug may further comprise one or more pharmaceutically acceptable carriers or excipients.

[0019] In some implementations, n is selected from 1 or 2.

[0020] In some implementation schemes, R a R b Each is independently selected from H and methyl.

[0021] In some implementation schemes, Y is selected from

[0022] In some implementation schemes, R 1a R 1b Each group is independently selected from H, C6-C10 aryl, and C1-C6 alkyl, wherein the C6-C10 aryl and C1-C6 alkyl groups are optionally substituted with groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and phenyl groups; or, R 1a R 1b Together with the N atoms attached to them, they form 6-10 membered heterocyclic groups, which are optionally substituted with C1-C6 alkyl groups.

[0023] In some implementation schemes, R 1a R 1b Each is selected independently from:

[0024] 1) H, C1-C6 alkyl groups;

[0025] 2) Among them, L 1 Selected from direct key, -CR m R n -;

[0026] R m R n Each is independently selected from H and C1-C4 alkyl groups;

[0027] Preferably, R m R n Each is independently selected from H and methyl;

[0028] More preferably, R m R n In this case, one of them is H, and the other is methyl;

[0029] R 4 R 5 R 6 R 7 R 8 Each is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0030] Preferably, R 4 R 5 R6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The radicals are selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, with the remaining four being H.

[0031] More preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The first four are selected from F, methyl, trifluoromethyl, and methoxy, while the remaining four are all H.

[0032] 3) Naphthyl group, wherein the naphthyl group is optionally substituted with a C1-C6 alkyl group;

[0033] Or, R 1a R 1b Together with the N atoms attached to them, they form 6-10 membered heterocyclic groups, which are optionally substituted with C1-C6 alkyl groups.

[0034] In some implementation schemes, R 1a R 1b In the given text, one of them is H, and the other is selected from:

[0035] 1) C1-C6 alkyl groups;

[0036] 2) Among them, L 1 Selected from direct key, -CR m R n -;

[0037] R m R n Each is independently selected from H and C1-C4 alkyl groups;

[0038] Preferably, R m R n Each is independently selected from H and methyl;

[0039] More preferably, R m R n In this case, one of them is H, and the other is methyl;

[0040] R 4 R 5 R 6 R 7 R8 Each is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0041] Preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The radicals are selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, with the remaining four being H.

[0042] More preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The first four are selected from F, methyl, trifluoromethyl, and methoxy, while the remaining four are all H.

[0043] 3) Naphthyl group, wherein the naphthyl group is optionally substituted with a C1-C6 alkyl group;

[0044] Or, R 1a R 1b Together with the N atoms attached to them, they form 9-10 membered heterocyclic groups, preferably forming... More preferably formed

[0045] In some implementation schemes, R 1a R 1b In the given text, one of them is H, and the other is selected from:

[0046] 1) Among them, L 1 Selected from direct key, -CR m R n -;

[0047] R m R n Each is independently selected from H and C1-C4 alkyl groups;

[0048] Preferably, R m R n Each is independently selected from H and methyl;

[0049] More preferably, R m R nIn this case, one of them is H, and the other is methyl;

[0050] R 4 R 5 R 6 R 7 R 8 Each is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0051] Preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The radicals are selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, with the remaining four being H.

[0052] More preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The first four are selected from F, methyl, trifluoromethyl, and methoxy, while the remaining four are all H.

[0053] 2) Naphthyl;

[0054] Or, R 1a R 1b Together with the N atoms bonded to them, they form Preferred Formation

[0055] In some implementation schemes, R 1a R 1b In the given information, one of them is H, and the other is selected from... Or, R 1a R 1b Together with the N atoms bonded to them, they form

[0056] In some implementation schemes, R 2a R 2bEach is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, and adamantyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, and adamantyl are optionally substituted with halogens; or, R 2a R 2b Together with the N atoms attached to them, they form 5-10 membered heterocyclic groups, which are optionally substituted with C1-C6 alkyl groups.

[0057] In some implementation schemes, R 2a R 2b Each is selected independently from:

[0058] 1) H, C1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

[0059] 2) Among them, L 2 Selected from direct bond, methylene;

[0060] R 9 R 10 R 11 R 12 R 13 Each is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups;

[0061] Preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0062] More preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H, F, Cl, Br, and I, while the last four are H.

[0063] Most preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H and F, while the other four are all H.

[0064] Or, R 2a R 2bTogether with the N atoms attached to them, they form 5-10 membered heterocyclic groups, which are optionally substituted with C1-C6 alkyl groups.

[0065] In some implementation schemes, R 2a R 2b In the given text, any one of them is H, and the other is selected from:

[0066] 1) C1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

[0067] 2) Among them, L 2 Selected from direct bond, methylene;

[0068] R 9 R 10 R 11 R 12 R 13 Each is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups;

[0069] Preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0070] More preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H, F, Cl, Br, and I, while the last four are H.

[0071] Most preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H and F, while the other four are all H.

[0072] Or, R 2a R 2b Together with the N atoms attached to them, they form 5-10 membered heterocyclic groups, preferably forming... More preferably formed

[0073] In some implementation schemes, R 2aR 2b In the given text, any one of them is H, and the other is selected from:

[0074] 1) Cycloheptyl, adamantyl;

[0075] 2) Among them, L 2 Selected from direct bond, methylene;

[0076] R 9 R 10 R 11 R 12 R 13 Each is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups;

[0077] Preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0078] More preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H, F, Cl, Br, and I, while the last four are H.

[0079] Most preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H and F, while the other four are all H.

[0080] Or, R 2a R 2b Together with the N atoms bonded to them, they form Preferred Formation

[0081] In some implementation schemes, R 2a R 2b In the given information, one of them is H, and the other is selected from... Or, R 2a R 2b Together with the N atoms bonded to them, they form

[0082] In some implementation schemes, R 3 The group is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, benzyl, and 5-10 heteroaryl groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, benzyl, and 5-10 heteroaryl groups are optionally substituted by groups selected from halogens and C1-C6 alkyl groups.

[0083] In some implementation schemes, R 3 Selected from:

[0084] 1) Among them, L 3 Selected from direct bond, methylene, and ethylene, preferably selected from direct bond and methylene;

[0085] R 14 R 15 R 16 R 17 R 18 Each is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups;

[0086] Preferably, R 14 R 15 R 16 R 17 R 18 In, any one (such as R) 16 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0087] More preferably, R 14 R 15 R 16 R 17 R 18 In, any one (such as R) 16 The first four are selected from H, F, Cl, and methyl, while the remaining four are all H.

[0088] 2) C3-C6 cycloalkyl, 9-10 heteroaryl, wherein the C3-C6 cycloalkyl, 9-10 heteroaryl are optionally replaced by C1-C6 alkyl.

[0089] In some implementation schemes, R 3 Selected from:

[0090] 1) Among them, L 3 Selected from direct bond, methylene, and ethylene, preferably selected from direct bond and methylene;

[0091] R 14 R 15 R 16R 17 R 18 Each is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups;

[0092] Preferably, R 14 R 15 R 16 R 17 R 18 In, any one (such as R) 16 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0093] More preferably, R 14 R 15 R 16 R 17 R 18 In, any one (such as R) 16 The first four are selected from H, F, Cl, and methyl, while the remaining four are all H.

[0094] 2) C3-C6 cycloalkyl, indole (preferred) ).

[0095] In some implementation schemes, R 3 Selected from

[0096] In a second aspect, the present invention provides the use of compounds of Formula I or their stereoisomers, their prodrugs, their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates in the preparation of medicaments for the treatment and / or prevention of fatty liver disease and related diseases.

[0097] Alternatively, a compound of Formula I or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate are provided for the treatment and / or prevention of fatty liver disease and related conditions.

[0098] Alternatively, methods for treating and / or preventing fatty liver disease and related conditions are provided, comprising administering to a subject in need an effective amount of a compound of formula I or a stereoisomer thereof, its prodrug, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate.

[0099]

[0100] in:

[0101] R 1a R 1b Each is independently selected from H, aryl, and alkyl, wherein the aryl and alkyl groups are optionally substituted with groups selected from halogen, alkyl, haloalkyl, alkoxy, and aryl; or, R1a R 1b Together with the N atoms attached to them, they form heterocyclic groups, which are optionally substituted with alkyl groups;

[0102] Preferably, R 1a R 1b Each group is independently selected from H, C6-C10 aryl, and C1-C6 alkyl, wherein the C6-C10 aryl and C1-C6 alkyl groups are optionally substituted with groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and phenyl groups; or, R 1a R 1b Together with the N atoms attached to them, they form 6-10 membered heterocyclic groups, which are optionally substituted with C1-C6 alkyl groups;

[0103] More preferably, R 1a R 1b Each is selected independently from:

[0104] 1) H, C1-C6 alkyl groups;

[0105] 2) Among them, L 1 Selected from direct key, -CR m R n -;

[0106] R m R n Each is independently selected from H and C1-C4 alkyl groups;

[0107] Preferably, R m R n Each is independently selected from H and methyl;

[0108] More preferably, R m R n In this case, one of them is H, and the other is methyl;

[0109] R 4 R 5 R 6 R 7 R 8 Each is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0110] Preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R6 The radicals are selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, with the remaining four being H.

[0111] More preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The first four are selected from F, methyl, trifluoromethyl, and methoxy, while the remaining four are all H.

[0112] 3) Naphthyl group, wherein the naphthyl group is optionally substituted with a C1-C6 alkyl group;

[0113] Or, R 1a R 1b Together with the N atoms attached to them, they form 6-10 membered heterocyclic groups, which are optionally substituted with C1-C6 alkyl groups;

[0114] More preferably, R 1a R 1b In the given text, one of them is H, and the other is selected from:

[0115] 1) C1-C6 alkyl groups;

[0116] 2) Among them, L 1 Selected from direct key, -CR m R n -;

[0117] R m R n Each is independently selected from H and C1-C4 alkyl groups;

[0118] Preferably, R m R n Each is independently selected from H and methyl;

[0119] More preferably, R m R n In this case, one of them is H, and the other is methyl;

[0120] R 4 R 5 R 6 R 7 R 8 Each is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0121] Preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The radicals are selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, with the remaining four being H.

[0122] More preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The first four are selected from F, methyl, trifluoromethyl, and methoxy, while the remaining four are all H.

[0123] 3) Naphthyl group, wherein the naphthyl group is optionally substituted with a C1-C6 alkyl group;

[0124] Or, R 1a R 1b Together with the N atoms attached to them, they form 9-10 membered heterocyclic groups, preferably forming... More preferably formed

[0125] More preferably, R 1a R 1b In the given text, one of them is H, and the other is selected from:

[0126] 1) Among them, L 1 Selected from direct key, -CR m R n -;

[0127] R m R n Each is independently selected from H and C1-C4 alkyl groups;

[0128] Preferably, R m R n Each is independently selected from H and methyl;

[0129] More preferably, R m R n In this case, one of them is H, and the other is methyl;

[0130] R 4 R 5 R 6 R7 R 8 Each is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

[0131] Preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The radicals are selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, with the remaining four being H.

[0132] More preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The first four are selected from F, methyl, trifluoromethyl, and methoxy, while the remaining four are all H.

[0133] 2) Naphthyl;

[0134] Or, R 1a R 1b Together with the N atoms bonded to them, they form Preferred Formation

[0135] Most preferably, R 1a R 1b In the given information, one of them is H, and the other is selected from... Or, R 1a R 1b Together with the N atoms bonded to them, they form

[0136] R 2a R 2b Each is independently selected from H, alkyl, cycloalkyl, aryl, benzyl, and adamantyl, wherein the alkyl, cycloalkyl, aryl, benzyl, and adamantyl groups are optionally substituted with halogens; or, R 2a R 2b Together with the N atoms attached to them, they form heterocyclic groups, which are optionally substituted with alkyl groups;

[0137] Preferably, R 2a R 2bEach is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, and adamantyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, and adamantyl are optionally substituted with halogens; or, R 2a R 2b Together with the N atoms attached to them, they form 5-10 membered heterocyclic groups, which are optionally substituted with C1-C6 alkyl groups;

[0138] More preferably, R 2a R 2b Each is selected independently from:

[0139] 1) H, C1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

[0140] 2) Among them, L 2 Selected from direct bond, methylene;

[0141] R 9 R 10 R 11 R 12 R 13 Each is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups;

[0142] Preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0143] More preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H, F, Cl, Br, and I, while the last four are H.

[0144] Most preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H and F, while the other four are all H.

[0145] Or, R 2a R 2bTogether with the N atoms attached to them, they form 5-10 membered heterocyclic groups, which are optionally substituted with C1-C6 alkyl groups;

[0146] More preferably, R 2a R 2b In the given text, any one of them is H, and the other is selected from:

[0147] 1) C1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

[0148] 2) Among them, L 2 Selected from direct bond, methylene;

[0149] R 9 R 10 R 11 R 12 R 13 Each is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups;

[0150] Preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0151] More preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H, F, Cl, Br, and I, while the last four are H.

[0152] Most preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H and F, while the other four are all H.

[0153] Or, R 2a R 2b Together with the N atoms attached to them, they form 5-10 membered heterocyclic groups, preferably forming... More preferably formed

[0154] More preferably, R 2a R2b In the given text, one of them is H, and the other is selected from:

[0155] 1) Cycloheptyl, adamantyl;

[0156] 2) Among them, L 2 Selected from direct bond, methylene;

[0157] R 9 R 10 R 11 R 12 R 13 Each is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups;

[0158] Preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0159] More preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H, F, Cl, Br, and I, while the last four are H.

[0160] Most preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from H and F, while the other four are all H.

[0161] Or, R 2a R 2b Together with the N atoms bonded to them, they form Preferred Formation

[0162] Most preferably, R 2a R 2b In the given information, one of them is H, and the other is selected from... Or, R 2a R 2b Together with the N atoms bonded to them, they form

[0163] Y is selected from

[0164] Preferably, Y is selected from

[0165] R 3 The group is selected from alkyl, cycloalkyl, aryl, benzyl, and heteroaryl groups, wherein the alkyl, cycloalkyl, aryl, benzyl, and heteroaryl groups are optionally substituted by groups selected from halogens and alkyl groups;

[0166] Preferably, R 3 The group is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, benzyl, and 5-10 heteroaryl groups, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, benzyl, and 5-10 heteroaryl groups are optionally substituted by groups selected from halogens and C1-C6 alkyl groups;

[0167] More preferably, R 3 Selected from:

[0168] 1) Among them, L 3 Selected from direct bond, methylene, and ethylene, preferably selected from direct bond and methylene;

[0169] R 14 R 15 R 16 R 17 R 18 Each is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups;

[0170] Preferably, R 14 R 15 R 16 R 17 R 18 In, any one (such as R) 16 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0171] More preferably, R 14 R 15 R 16 R 17 R 18 In, any one (such as R) 16 The first four are selected from H, F, Cl, and methyl, while the remaining four are all H.

[0172] 2) C3-C6 cycloalkyl, 9-10 heteroaryl, wherein the C3-C6 cycloalkyl, 9-10 heteroaryl are optionally replaced by C1-C6 alkyl;

[0173] More preferably, R 3 Selected from:

[0174] 1) Among them, L 3 Selected from direct bond, methylene, and ethylene, preferably selected from direct bond and methylene;

[0175] R 14 R 15 R 16 R 17 R 18 Each is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups;

[0176] Preferably, R 14 R 15 R 16 R 17 R 18 In, any one (such as R) 16 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0177] More preferably, R 14 R 15 R 16 R 17 R 18 In, any one (such as R) 16 The first four are selected from H, F, Cl, and methyl, while the remaining four are all H.

[0178] 2) C3-C6 cycloalkyl, indole (preferred) );

[0179] Most preferably, R 3 Selected from

[0180] Optionally, the drug may further comprise one or more pharmaceutically acceptable carriers or excipients.

[0181] In a third aspect, the present invention provides the use of compounds of Formula II or their stereoisomers, their prodrugs, their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates in the preparation of medicaments for the treatment and / or prevention of fatty liver disease and related diseases.

[0182] Alternatively, a compound of Formula II or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate are provided for the treatment and / or prevention of fatty liver disease and related conditions.

[0183] Alternatively, methods for treating and / or preventing fatty liver disease and related conditions are provided, comprising administering to a subject in need an effective amount of a compound of formula II or a stereoisomer thereof, its prodrug, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate.

[0184]

[0185] in:

[0186] R a R b Each is independently selected from H and C1-C6 alkyl groups;

[0187] Preferably, R a R b Each is independently selected from H and methyl;

[0188] More preferably, R a R b Each is independently selected from H and methyl, and R a R b Not both methyl;

[0189] R 1a R 1b Each is selected independently from:

[0190] 1) H, C1-C6 alkyl groups;

[0191] 2) in,

[0192] R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The radicals are selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, with the remaining four being H.

[0193] Preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The first four are selected from F, methyl, trifluoromethyl, and methoxy, while the remaining four are all H.

[0194] 3) Naphthyl group, wherein the naphthyl group is optionally substituted with a C1-C6 alkyl group;

[0195] Or, R 1a R 1b Together with the N atoms attached to them, they form 6-10 membered heterocyclic groups, which are optionally substituted with C1-C6 alkyl groups;

[0196] Preferably, R 1a R 1b In the given text, one of them is H, and the other is selected from:

[0197] 1) C1-C6 alkyl groups;

[0198] 2) in,

[0199] R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The radicals are selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, with the remaining four being H.

[0200] Preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 4 R 5 Or R 6 The first four are selected from F, methyl, trifluoromethyl, and methoxy, while the remaining four are all H.

[0201] More preferably, R 1a R 1b In the above, one is H, and the other is... in,

[0202] R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 5 The four alkyl groups are selected from C1-C6 haloalkyl groups, and the remaining four are all H;

[0203] Preferably, R 4 R 5 R 6 R 7 R 8 In, any one (such as R) 5 ) is trifluoromethyl, and the other four are all H;

[0204] Most preferably, R 1a R 1b In the above, one is H, and the other is...

[0205] R 2a R 2b Each is selected independently from:

[0206] 1) H, C1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

[0207] 2) Among them, L 2 Selected from direct bonds and methylene groups, preferably methylene groups;

[0208] R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0209] Preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from F, Cl, Br, and I, while the remaining four are all H.

[0210] More preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first one is F, and the other four are H;

[0211] Or, R 2a R 2b Together with the N atoms attached to them, they form 5-10 membered heterocyclic groups, which are optionally substituted with C1-C6 alkyl groups;

[0212] Preferably, R 2a R 2b In the given text, any one of them is H, and the other is selected from:

[0213] 1) C1-C6 alkyl groups;

[0214] 2) Among them, L 2Selected from direct bonds and methylene groups, preferably methylene groups;

[0215] R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0216] Preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from F, Cl, Br, and I, while the remaining four are all H.

[0217] More preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first one is F, and the other four are H;

[0218] Or, R 2a R 2b Together with the N atoms attached to them, they form 5-6 membered heterocyclic groups;

[0219] More preferably, R 2a R 2b In the above, one is H, and the other is... Among them, L 2 Selected from direct bonds and methylene groups, preferably methylene groups;

[0220] R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0221] Preferably, R 9 R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first four are selected from F, Cl, Br, and I, while the remaining four are all H.

[0222] More preferably, R 9R 10 R 11 R 12 R 13 In, any one (such as R) 11 The first one is F, and the other four are H;

[0223] Or, R 2a R 2b Together with the N atoms bonded to them, they form Preferred

[0224] Most preferably, R 2a R 2b In the above, one is H, and the other is... Or, R 2a R 2b Together with the N atoms bonded to them, they form

[0225] R 3 Selected from:

[0226] 1) Among them, L 3 Selected from direct bond, methylene, ethylene, preferably selected from direct bond, methylene, more preferably direct bond;

[0227] R 14 R 15 R 16 R 17 R 18 In, any one (such as R) 16 The molecule is selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with the other four being H.

[0228] Preferably, R 14 R 15 R 16 R 17 R 18 In, any one (such as R) 16 The first four are selected from H, F, Cl, and methyl, while the remaining four are all H.

[0229] 2) C3-C6 cycloalkyl, 9-10 heteroaryl, wherein the C3-C6 cycloalkyl, 9-10 heteroaryl are optionally replaced by C1-C6 alkyl;

[0230] Preferably, R 3 for Among them, L 3 Selected from direct bond, methylene, ethylene, preferably selected from direct bond, methylene, more preferably direct bond;

[0231] R14 R 15 R 16 R 17 R 18 In, any one (such as R) 16 The first four are selected from H and C1-C6 alkyl groups, while the remaining four are all H.

[0232] Preferably, R 14 R 15 R 16 R 17 R 18 All are H;

[0233] More preferably, R 3 for

[0234] Optionally, the drug may further comprise one or more pharmaceutically acceptable carriers or excipients.

[0235] In some embodiments, the compound is selected from the following:

[0236]

[0237]

[0238]

[0239]

[0240]

[0241] In some implementations, the fatty liver disease is non-alcoholic fatty liver disease.

[0242] In some implementations, the fatty liver disease is simple steatosis.

[0243] In some implementations, the fatty liver disease is non-alcoholic steatohepatitis.

[0244] In some implementations, the fatty liver disease is liver fibrosis.

[0245] In some implementations, the fatty liver disease is cirrhosis.

[0246] In some implementations, the fatty liver disease is liver cancer.

[0247] In some implementations, the fatty liver disease is diet-induced non-alcoholic fatty liver disease.

[0248] In some implementations, the fatty liver disease is non-alcoholic fatty liver disease induced by a high-fat, high-cholesterol diet.

[0249] In some implementations, the fatty liver-related disease is diabetes.

[0250] In some implementations, the fatty liver-related disease is obesity.

[0251] In some implementations, the fatty liver-related disease is hyperlipidemia.

[0252] In some implementations, the fatty liver-related disease is insulin resistance.

[0253] In a fourth aspect, the present invention provides the following compounds or their stereoisomers, their prodrugs, their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates.

[0254]

[0255]

[0256]

[0257]

[0258] In a fifth aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, optionally further comprising one or more pharmaceutically acceptable carriers or excipients.

[0259] Terminology Definition

[0260] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. Additionally, unless otherwise specified, the groups and substituents of this invention have their general meanings in the field of organic chemistry.

[0261] The substituents in the compounds of this invention are disclosed according to the type or range of groups. In particular, this invention includes every independent sub-combination of the members of these types and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0262] The term "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably "C1-C4 alkyl", more preferably "C1-C3 alkyl", and most preferably "C1-C2 alkyl". Examples of "C1-C6 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). Examples of "C1-C4 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, isobutyl, tert-butyl). Examples of "C1-C3 alkyl" include methyl, ethyl, and propyl (e.g., n-propyl, isopropyl). Examples of "C1-C2 alkyl" include methyl and ethyl.

[0263] The term "C1-C6 haloalkyl" refers to a group obtained by replacing one or more (e.g., 2, 3 or 4) hydrogen atoms of any of the above C1-C6 alkyl groups with a halogen (preferably fluorine), examples of which include monofluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, etc., preferably trifluoromethyl.

[0264] The term “C1-C6 alkoxy” refers to any of the above C1-C6 alkyl groups that are attached to the rest of the molecule by an oxygen atom (-O-), examples of which include methoxy, ethoxy, isopropoxy, etc.

[0265] The term "C3-C8 cycloalkyl" refers to hydrocarbons with a 3-8 member monocyclic system having a saturated ring, such as cycloheptyl, preferably "C3-C6 cycloalkyl", such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0266] The term "heterocyclic group" refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered (preferably 5-10-, 6-10-, or 9-10-membered) saturated or unsaturated monocyclic, bicyclic, or polycyclic carbocyclic group, wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur, and when it is bicyclic or polycyclic, at least one ring in the bicyclic or polycyclic group does not constitute an aromatic system, and at least one carbon atom in the ring that does not constitute an aromatic system is replaced by a heteroatom such as nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclic groups include, for example, pyranyl, pyrrolylyl, pyrrololinyl, imidazolinyl, imidazolinyl, pyrazolealkyl, pyrazolelinyl, thiazolinyl, thiazolinyl, dihydrofuranyl, tetrahydrofuranyl, 1,3-dioxolanecycloyl, piperidinyl, piperazineyl, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, etc. etc., preferred

[0267] The term "aryl" refers to the fact that all carbon atoms in each carbon ring have conjugated p orbitals, preferably "C6-C10 aryl", such as phenyl or naphthyl.

[0268] The term "heteroaryl" refers to an aromatic monocyclic, bicyclic, tricyclic, or more cyclic group comprising 5-, 6-, 7-, 8-, 9-, or 10-membered (preferably 9- or 10-membered) rings having at least one heteroatom (N, O, or S), optionally further comprising one, two, or three heteroatoms selected from N, O, or S. For a heteroaryl group to be bicyclic, tricyclic, or polycyclic, each ring must constitute an aromatic system. Non-limiting examples of said heteroaryl groups include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thiazolyl, pyrroleyl, phenyl-pyrroleyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiophene, benzofuranyl, benzothiophene, benzimidazolyl, indazole, quinolinyl, isoquinolinyl, etc.

[0269] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0270] The term "heteroatoms" refers to N, O, or S.

[0271] The term "benzyl" refers to

[0272] The term "adamantyl" refers to

[0273] In this invention, unless otherwise explicitly stated, the descriptive phrase “...each independently selected” used throughout this document can mean either that the specific options expressed by the same or different symbols in different groups do not affect each other, or that the specific options expressed by the same or different symbols in the same group do not affect each other.

[0274] In this invention, "substituted" or "replaced by" means that any hydrogen atom or group is selectively replaced by a specified group, provided that the replacement does not exceed the normal valence state of the specified atom.

[0275] In this invention, "optionally" means that it can be selected or not.

[0276] In this invention, by way of example, "R" 1a R 1bEach group is independently selected from H, C6-C10 aryl, and C1-C6 alkyl, wherein the C6-C10 aryl and C1-C6 alkyl groups are optionally substituted with groups selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, and phenyl groups. The phrase "optionally" indicates that the C6-C10 aryl and C1-C6 alkyl groups may be unsubstituted or substituted with groups selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, and phenyl groups. Furthermore, when the C6-C10 aryl and C1-C6 alkyl groups are substituted, the substituents do not affect each other and may be the same or different. Other similar definitions in this invention should be understood with reference to the foregoing content.

[0277] In this invention, by way of example, if in formula O, "R" 1a R 1b Together with the N atoms bonded to them, they form The structural formula of O then becomes For other similar definitions in this invention, please refer to the foregoing content for understanding.

[0278] In this invention, "direct bond" means that the groups on both sides are directly connected. For example, if in formula O, R 1a for Then when L 1 When it is a direct key, R 1a Become The structural formula of formula O becomes For other similar definitions in this invention, please refer to the foregoing content for understanding.

[0279] The term "pharmaceutically acceptable salt" refers to a salt formed by a basic functional group present in the compounds provided by this invention and a suitable inorganic or organic anion (acid), including but not limited to: hydrohalides, such as hydrofluoric acid, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkyl sulfonates, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.; aryl sulfonates, such as benzenesulfonates, p-benzenesulfonates, etc.; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, etc.; amino acid salts, such as glycinates, trimethylglycinates, arginines, ornithines, glutamates, aspartates, etc.; or the salts of this invention. The compounds provided by Ming contain salts formed by acidic functional groups and suitable inorganic or organic cations (bases), including but not limited to: alkali metal salts, such as sodium, potassium, and lithium salts; alkaline earth metal salts, such as calcium and magnesium salts; other metal salts, such as aluminum, iron, zinc, copper, nickel, and cobalt salts; inorganic base salts, such as ammonium salts; and organic base salts, such as tert-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycine alkyl ester, ethylenediamine, N-methylglucosamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzyl-phenylethylamine, piperazine, tetramethylamine, and tris(hydroxymethyl)aminomethane.

[0280] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0281] The term "solvent" refers to a pharmaceutically usable solvate formed by the compound of the present invention with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile, isopropanol, DMSO, and ethyl acetate.

[0282] The term "stereoisomer" refers to compounds with the same molecular formula in which atoms or substituents are connected in the same order but arranged in different spaces. It is a phenomenon of isomerism in organic chemistry.

[0283] The term "prodrug" refers to a derivative of the compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compound of the present invention. Prodrugs become active compounds only after undergoing the reaction under biological conditions, or they are inactive in their unreacted forms. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

[0284] The term "carrier" refers to a system that can alter the way drugs enter the body and their distribution within the body, control the rate of drug release, and deliver drugs to target organs. Drug carrier release and targeting systems can reduce drug degradation and loss, decrease side effects, and improve bioavailability. For example, high-molecular-weight surfactants, due to their unique amphiphilic structure, can self-assemble to form various forms of aggregates, preferably such as micelles, microemulsions, gels, liquid crystals, and vesicles. These aggregates have the ability to encapsulate drug molecules while also exhibiting good membrane permeability, making them excellent drug carriers.

[0285] The term "excipient" refers to any additive in a pharmaceutical preparation other than the active pharmaceutical ingredient. Excipients include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycerol, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, lanolin, etc.

[0286] The term "treatment" generally refers to achieving a desired pharmacological and / or physiological effect. This effect can be preventative, based on the complete or partial prevention of the disease or its symptoms; and / or therapeutic, based on the partial or complete stabilization or cure of the disease and / or side effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) prevention of disease or symptoms occurring in a patient who is susceptible to the disease or its symptoms but has not yet been diagnosed with the disease; (b) suppression of the symptoms of the disease, i.e., prevention of its progression; or (c) relief of the symptoms of the disease, i.e., causing the disease or its symptoms to regress.

[0287] The term "subject" includes humans or non-human animals. Exemplary human subjects include people with a disease (such as the disease described herein) (referred to as patients) or normal individuals. The term "non-human animal" in this invention includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0288] The term "effective amount" refers to the amount that effectively achieves the desired therapeutic or preventative effect at the necessary dose and time. The "therapeutic effective amount" of the compounds of this invention may vary depending on factors such as an individual's disease state, age, sex, weight, and the compound's ability to elicit the desired response in the individual. Therapeutic effective amount also encompasses the amount in which the beneficial therapeutic effect of the compound outweighs any toxic or harmful consequences. "Preventative effective amount" refers to the amount that effectively achieves the desired preventative effect at the necessary dose and time. Typically, but not necessarily, the preventative effective amount will be lower than the therapeutic effective amount because the preventative dose is administered to the subject before or in the early stages of the disease. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; shrink tumor volume; inhibit (i.e., slow down, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down, preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent.

[0289] Beneficial effects

[0290] 1. The compounds of the present invention, such as all specific compounds in series A, B, C, D, and E, can significantly inhibit lipid accumulation in hepatocytes without obvious toxic side effects.

[0291] 2. Oral administration of the compounds of the present invention, such as all specific compounds in series A, B, C, D, and E, can effectively alleviate fatty liver disease and related diseases (e.g., non-alcoholic fatty liver disease, specifically non-alcoholic fatty liver disease induced by a high-fat, high-cholesterol diet). Attached Figure Description

[0292] Figure 1 , Figure 2 Images show BODIPY staining and imaging analysis of hepatocytes after treatment with different compounds. *, **, ***: P < 0.05 for each treatment group compared to the PO group; ****: P < 0.0001 for each treatment group compared to the PO group.

[0293] Figure 3 The results show the liver weight and liver weight / body weight ratio of different groups of mice.

[0294] Figure 4 The results of liver tissue pathological examination in different groups of mice are shown. Detailed Implementation

[0295] The embodiments of the present invention will now be described in detail with reference to the accompanying drawings and examples. However, those skilled in the art will understand that the following drawings and examples are for illustrative purposes only and are not intended to limit the scope of the invention. Various objects and advantages of the present invention will become apparent to those skilled in the art from the following detailed description of the drawings and preferred embodiments.

[0296] General synthesis scheme

[0297] The compounds of the present invention can be prepared by the following reaction process, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, using standard synthetic methods and processes known to those skilled in the art. It should be understood that while typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other preparation conditions may also be used unless otherwise stated. Reaction conditions may vary depending on the specific reactants or solvents used. Those skilled in the art will recognize that the nature and sequence of the provided synthetic steps can be varied to optimize the formation of the compounds described herein.

[0298] The prepared compound can be identified using any suitable method known in the art. For example, it can be identified by nuclear magnetic resonance spectroscopy (e.g., nuclear magnetic resonance spectroscopy). 1 H or 13 C) Monitoring product formation by infrared spectroscopy, spectrophotometry, mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC).

[0299] The following routes, including those mentioned in the examples and preparations, illustrate methods for synthesizing the compounds of the present invention. Those skilled in the art will understand that the compounds and intermediates thereof can be prepared by methods other than those specifically described herein. Therefore, those skilled in the art can modify the methods described herein using synthetic methods known in the art.

[0300] When a solvent ratio is given, it is in volume.

[0301] Those skilled in the art will understand that the experimental conditions listed in the following scheme describe suitable conditions for achieving the shown transformations, and that it may be necessary or desirable to change the precise conditions used to prepare the compounds of the present invention.

[0302] Synthesis process of series A compounds

[0303]

[0304]

[0305]

[0306] Synthesis process of series B compounds

[0307]

[0308]

[0309] Synthesis process of series C compounds

[0310]

[0311]

[0312] Synthesis process of series D compounds

[0313]

[0314]

[0315] Synthesis process of series E compounds

[0316]

[0317]

[0318] The following examples illustrate the synthesis of various compounds of the present invention. The synthesis of these compounds is merely exemplary and is not intended to limit the scope of the invention. Other compounds within the scope of the invention may be prepared alone or in combination with techniques generally known in the art using the methods illustrated in these examples.

[0319] abbreviation

[0320] In the examples and preparations listed below and in the foregoing schemes, the following abbreviations or their English expressions may be used, as well as other abbreviations commonly used in the art. Standard IUPAC nomenclature is used.

[0321] AcOH: Acetic acid;

[0322] Boc is tert-butoxycarbonyl;

[0323] ℃ is degrees Celsius;

[0324] CDCl3: Deuterated chloroform;

[0325] (COCl)2: Oxaloyl chloride;

[0326] (COCl2)3: Triphosgene;

[0327] δ: Chemical shift;

[0328] d: Double peak;

[0329] DCM: Dichloromethane;

[0330] DMF: N,N-dimethylformamide;

[0331] DMSO: Dimethyl sulfoxide;

[0332] DIPEA: N,N-diisopropylethylamine;

[0333] eq: equivalent;

[0334] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

[0335] EtOAc: Ethyl acetate;

[0336] EtOH: Ethanol;

[0337] g: gram;

[0338] H2O: water;

[0339] HCl: hydrochloric acid;

[0340] HPLC: High Performance Liquid Chromatography;

[0341] 1 H-NMR: 1H NMR spectrum

[0342] HOBT: 1-Hydroxybenzotriazole;

[0343] HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; KOH: potassium hydroxide;

[0344] K2CO3: Potassium carbonate;

[0345] K2CO3: Potassium carbonate;

[0346] LC-MS: Liquid Chromatography-Mass Spectrometry;

[0347] m: multiple peak;

[0348] M: mole;

[0349] MeOH: Methanol;

[0350] mg: milliliter;

[0351] g: gram;

[0352] MgSO4: Magnesium sulfate;

[0353] MHz: Megahertz;

[0354] min: minutes;

[0355] mL: milliliters;

[0356] mmol: millimole;

[0357] mol: mole;

[0358] MS m / z: mass spectrum peak;

[0359] Na2CO3: Sodium carbonate;

[0360] NaOH: Sodium hydroxide;

[0361] Na2SO4: Sodium sulfate;

[0362] NMR stands for nuclear magnetic resonance.

[0363] pH: acidity or alkalinity;

[0364] ppm: parts per million;

[0365] prep-TLC: a preparative thin-layer chromatography method;

[0366] Py: Pyridine;

[0367] q: Four-peaked peak;

[0368] Rf: Displacement value;

[0369] RT: Retention time;

[0370] s: unimodal;

[0371] sat. means saturated.

[0372] THF: Tetrahydrofuran;

[0373] TEA: Triethylamine;

[0374] TFA: Trifluoroacetic acid;

[0375] TLC: Thin-layer chromatography;

[0376] Zn: Zinc powder

[0377] Characteristic chemical shift (δ) from a low magnetic field (for tetramethylsilane) 1 For H-NMR, conventional abbreviations are used for naming major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. The following abbreviations are used for common solvents: CDCl3, deuterated chloroform; DMSO-d6, deuterated dimethyl sulfoxide; and MeOH-d4, deuterated methanol. When appropriate, NMR data for tautomers can be recorded; and some exchangeable protons may be invisible.

[0378] Mass spectrometry (MS / z) was recorded using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI).

[0379] In cases where preparative TLC or silica gel chromatography has already been used, those skilled in the art can choose any combination of solvents to purify the desired compound.

[0380] Typically, the reaction is followed by thin-layer chromatography and / or liquid chromatography-mass spectrometry, and post-processing when appropriate. Those skilled in the art will recognize that purification can be varied between experiments; generally, the adsorbent, solvent, and solvent ratio used for the eluent / gradient are selected to provide a suitable Rf or retention time. Those skilled in the art will also recognize that HPLC purification can be performed in a variety of ways, including using forward-reverse stationary phases, chiral stationary phases, and supercritical eluents. Those skilled in the art will recognize the appropriate selection of chromatographic and HPLC purification conditions.

[0381] Example 1: Preparation of Compounds 1-2

[0382]

[0383] Compound 1-1 (20 g, 1 eq) was dissolved in THF (300 mL), and EDCI (24.85 g, 1.2 eq) and HOBT (17.52 g, 1.2 eq) were added. The mixture was stirred at 20 °C for 0.5 h. Then, compound 1a (9.2 g, 1 eq) and DIPEA (57 mL, 3 eq) were added. The mixture was stirred at 20 °C for 12 h. After the reaction was confirmed to be complete by LC-MS, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with 1 M hydrochloric acid (100 mL × 2) and saturated sodium bicarbonate solution (100 mL × 2). After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to give crude compound 1-2: a yellow oil (27.3 g, yield: 99%).

[0384] Example 2 Preparation of compounds 1-3

[0385]

[0386] Compounds 1-2 (25.3 g, 1 eq) were dissolved in DMF (300 mL), and potassium carbonate (27.73 g, 2 eq) and compound 1b (20 g, 1 eq) were added. The mixture was stirred at 70 °C for 12 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with water (100 mL × 2). After drying with anhydrous sodium sulfate, the mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 / 60:40) to give compound 1-3: a yellow solid (34 g, yield: 79%, purity: 92%).

[0387] Example 3 Preparation of compounds 1-4

[0388]

[0389] Compound 1-3 (3 g, 1 eq) was dissolved in DCM (40 mL), and TFA (10 mL) was added. The mixture was stirred at 20 °C for 12 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated under reduced pressure to obtain crude compound 1-4: a yellow oily substance (2.3 g, yield: 99%).

[0390] Example 4 Preparation of compounds 1-5

[0391]

[0392] Compound 1c (1.12 g, 1 eq) was dissolved in DCM (20 mL), cooled to 0 °C, and triphosgene (0.7 g, 0.34 eq) was added. After stirring at 0 °C for 10 minutes, TEA (1 mL, 1 eq) was added. The mixture was naturally heated to 20 °C and stirred for 2 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was cooled to 0 °C, and compounds 1-4 (2.3 g, 1 eq) and TEA (5 mL, 5 eq) were added. The mixture was stirred at 20 °C for 12 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was poured into water (20 mL), extracted with ethyl acetate (30 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 / 18:82) to give compounds 1-5: a yellow oil (3 g, yield: 83%, purity: 93%).

[0393] Example 5 Preparation of Compound 1

[0394]

[0395] Compounds 1-5 (3 g, 1 eq) were dissolved in MeOH (50 mL), cooled to 0 °C, and zinc powder (1.89 g, 5 eq) and acetic acid (1.65 mL, 5 eq) were added. The mixture was stirred at 70 °C for 12 hours. After the reaction was confirmed to be complete by LC-MS, ethyl acetate (30 mL) was added and the mixture was filtered through diatomaceous earth. The filtrate was adjusted to pH 8 with 1 M sodium hydroxide aqueous solution, filtered through diatomaceous earth, extracted with ethyl acetate (30 mL × 2), dried, and concentrated under reduced pressure to give compound 1: a pale yellow solid (2.7 g, yield: 95%, MS m / z: M+H). + =490.1).

[0396] Example 6 Preparation of compounds A-1 to A-7

[0397]

[0398] Taking the synthesis of compound A-1 as an example: Compound 1 (57.2 mg, 1 eq) was dissolved in THF (3 mL), and EDCI (94 mg, 1.2 eq) and HOBT (66.24 mg, 1.2 eq) were added. The mixture was stirred at 20 °C for 0.5 hours. Then, compound 9 (200 mg, 1 eq) and DIPEA (214 μL, 3 eq) were added. The mixture was stirred at 20 °C for 12 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with 1M hydrochloric acid aqueous solution (10 mL × 2) and saturated sodium bicarbonate solution (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was prepared by reverse phase reaction (20%-65% acetonitrile, 0.1% TFA) to give compound A-1: ​​white solid (120 mg, yield: 50%, purity: 96.13%, MS m / z: M+H). + =612.3).

[0399] 1 H NMR (400MHz, DMSO) δ10.21 (s, 1H), 8.67 (s, 1H), 8.08-7.98 (m, 3H), 7.81 (d, J = 7.8Hz, 1H),7.68(d,J=8.4Hz,1H),7.55(s,1H),7.47(t,J=7.9Hz,1H),7.37(t,J=8.6Hz,2H) ,7.27(d,J=7.3Hz,1H),7.11(d,J=8.8Hz,1H),3.86(s,1H),3.60(d,J=31.1Hz,4H),3 .28(s,4H),3.10(d,J=22.5Hz,3H),1.79(s,2H),1.54(s,2H),1.31(d,J=32.7Hz,4H).

[0400] The synthesis of A-2 to A-7 is the same as that of A-1.

[0401] Compound A-2: white solid (130 mg, yield 50%, purity 99.6%).

[0402] 1H NMR (400MHz, DMSO) δ10.27(s,1H),8.67(s,1H),8.07-7.95(m,3H),7.81(d,J= 7.7Hz,1H),7.69(d,J=8.0Hz,1H),7.64-7.53(m,3H),7.47(t,J=7.8Hz,1H),7. 27(d,J=7.2Hz,1H),7.11(d,J=8.7Hz,1H),3.86(s,1H),3.60(d,J=31.3Hz,4H ),3.28(s,4H),3.10(d,J=29.3Hz,3H),1.80(s,2H),1.53(s,2H),1.34(s,4H).

[0403] Compound A-3: white solid (140 mg, yield 56%, purity 98.5%).

[0404] 1 H NMR (400MHz, DMSO) δ10.12(s,1H),8.67(s,1H),8.01(d,J=9.7Hz,1H),7.87(d,J=7.9Hz,2H),7. 82(d,J=8.1Hz,1H),7.71(dd,J=8.7,1.9Hz,1H),7.57(d,J=2.0Hz,1H),7.47(t,J=7.9Hz,1H),7. 33(d,J=7.9Hz,2H),7.27(d,J=7.6Hz,1H),7.10(d,J=8.8Hz,1H),3.86(s,1H),3.60(d,J=30.1H z,4H),3.27(s,4H),3.09(d,J=17.1Hz,3H),2.38(s,3H),1.80(s,2H),1.53(s,2H),1.34(s,4H).

[0405] Compound A-4: white solid (130 mg, yield 51%, purity 95.8%).

[0406] 1H NMR (400MHz, DMSO) δ10.09(s,1H),8.65(s,1H),8.01(s,1H),7.80(d,J=7.8Hz,1H),7.47(d,J=6.7Hz,2H),7.40(s,1H),7.24(dd,J=20.6,7.5Hz,3H) ,7.13(d,J=7.4Hz,2H),7.06(d,J=8.7Hz,1H),3.82(s,1H),3.58(d,J=26. 1Hz,6H),3.28-2.98(m,7H),2.27(s,3H),1.78(s,2H),1.54-1.20(m,6H).

[0407] Compound A-5: white solid (135 mg, yield 55%, purity 99.8%).

[0408] 1 H NMR (400MHz, DMSO) δ9.75 (s, 1H), 8.65 (s, 1H), 8.01 (s, 1H), 7.80 (d, J = 8.2Hz ,1H),7.50-7.41(m,3H),7.26(d,J=7.7Hz,1H),7.04(d,J=8.8Hz,1H),3.82(s ,1H),3.61(s,4H),3.19(d,J=23.9Hz,4H),3.03(s,3H),2.27(dd,J=15.6,7. 3Hz,1H),1.75(t,J=12.1Hz,6H),1.64(d,J=10.3Hz,1H),1.55-1.16(m,11H).

[0409] Compound A-6: white solid (140 mg, yield 54%, purity 96.9%, MS m / z: M+H+=633.3).

[0410] 1H NMR(400MHz,DMSO)δ11.42(s,1H),10.09(s,1H),8.67(s,1H),8.27(s,1H),8.02(s,1 H),7.82(d,J=8.4Hz,1H),7.74(dd,J=8.6,1.8Hz,2H),7.62(d,J=2.5Hz,1H),7.51-7 .45(m,3H),7.27(d,J=7.6Hz,1H),7.11(d,J=8.9Hz,1H),6.59(s,1H),3.87(s,1H),3 .61(d,J=26.2Hz,4H),3.27(s,4H),3.08(s,3H),1.80(s,2H),1.43(d,J=73.9Hz,6H).

[0411] Compound A-7: White solid (0.458 g, yield 61%, purity 96.33%, MS m / z: M+H) + =594.1).

[0412] 1 H NMR: (400MHz, DMSO) δ10.20(s,1H),8.66(s,1H),8.01(s,1H),7.98-7.92(m,2H),7.81(d, J=8.4Hz,1H),7.70(dd,J=8.9,2.5Hz,1H),7.62-7.50(m,4H),7.47(t,J=8.0Hz,1H),7.27( d,J=7.7Hz,1H),7.11(d,J=8.9Hz,1H),3.87(d,J=13.1Hz,1H),3.70-3.50(m,4H),3.32-3. 20(m,4H),3.16-2.99(m,3H),1.89-1.72(m,2H),1.54(d,J=7.3Hz,2H),1.36-1.33(m,4H).

[0413] Example 7 Preparation of Compound 2-1

[0414]

[0415] At room temperature, zinc powder (6.25 g, 4.0 eq) and acetic acid (5.85 g, 4.0 eq) were added to a MeOH (250 mL) solution of compound 1-3 (10.0 g, 1.0 eq). The reaction solution was heated to 65 °C and stirred under reflux overnight. The reaction progress was monitored by LC-MS. After the reaction was completed, the reaction solution was filtered under reduced pressure. The filter cake was washed with MeOH (100 mL), filtered again, and the filtrates were combined and concentrated under reduced pressure. After dilution with ethyl acetate (200 mL), saturated sodium bicarbonate solution (200 mL) was added. The aqueous phase was extracted three times with ethyl acetate (100 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, crude compound 2-1 was obtained: a yellow oily substance (11.0 g, yield: 98%, MS m / z: M+H). + =403.26).

[0416] Example 8 Preparation of compound 2-2

[0417]

[0418] At room temperature, a7 (0.61 g, 1.0 eq), EDCI (1.43 g, 1.5 eq), HOBT (0.81 g, 1.2 eq), DIPEA (1.9 g, 3.0 eq), and THF (50 mL) were added sequentially to a flask. After stirring for half an hour until the solution was clear, compound 2-1 (2.01 g, 1.0 eq) was added. The reaction mixture was stirred overnight at room temperature. The reaction progress was monitored by LC-MS. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), and then saturated sodium bicarbonate solution (50 mL) was added. The aqueous phase was extracted three times with ethyl acetate (50 mL). The liquid and liquid phases were separated, combined, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 / 3:1). Compound 2-2 was obtained as a yellow solid (2.4 g, yield: 94.8%, purity: 95%, MS m / z: M+H). + =507.29).

[0419] Example 9 Preparation of Compound 2

[0420]

[0421] Compound 2-2 (2.4 g, 1.0 eq), DCM (30 mL), and TFA (10 mL) were added sequentially to a flask at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and the reaction progress was monitored by LC-MS. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous phase was extracted three times with ethyl acetate (50 mL), and the liquid and liquid phases were separated. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 2: a yellow solid (2.0 g, yield: 96.3%, MS m / z: M+H). + =407.24).

[0422] Example 10 Preparation of compounds B-1 to B-6

[0423]

[0424] Taking the synthesis of compound B-1 as an example: Compound B1 (60 mg, 1.0 eq) and DCM (5 mL) were added sequentially to a flask at room temperature, stirred until dissolved, and then cooled to 0°C under nitrogen protection. Triphosgene (50 mg, 0.17 mmol, 0.33 eq) was dissolved in DCM (2 mL) and added dropwise to the reaction solution. After stirring for 20 minutes, TEA (50 mg) was added dropwise to the reaction solution. The reaction temperature was maintained at 0°C, and the reaction was monitored by TLC. After the starting materials were consumed and new spots were formed, compound 2 (200 mg, 0.497 mmol, 1.0 eq) was dissolved in DCM (2 mL) and added dropwise to the reaction solution. The reaction temperature was maintained at 0°C. The pH of the reaction solution was adjusted to 8–9 with TEA, and the reaction system was brought to room temperature and reacted for 2 hours. LC-MS was used to monitor the reaction progress. After compound 2 was completely consumed, the reaction solution was concentrated under reduced pressure to obtain a crude product. This crude product was then purified by reverse synthesis (20%–78% acetonitrile, 0.1% TFA) to obtain compound B-1: a pale yellow solid (50 mg, yield: 18.5%, purity: 95.9%, MS m / z: M+H). + =556.28).

[0425] 1H NMR (400MHz, DMSO) δ10.20(s,1H),8.16(s,1H),7.98-7.91(m,2H),7.69(dd,J=8.8,2.6Hz,1H),7.62-7.50(m,4H),7.40-7.34(m,2H),7.10(d, J=8.9Hz,1H),6.87-6.76(m,2H),3.70(s,3H),3.62-3.53(m,4H),3.28 -3.03(m,8H),1.90-1.71(m,2H),1.64-1.54(m,2H),1.54-1.34(m,4H).

[0426] The synthesis of B-2 to B-6 is the same as that of B-1.

[0427] Compound B-2: White solid (32 mg, yield: 12.1%, purity: 95.8%, MS m / z: M+H) + =544.3)

[0428] 1 H NMR (400MHz, DMSO) δ10.21(s,1H),8.09(s,1H),8.00-7.90(m,2H),7.70(dd,J=8.9,2.6Hz,1H),7.63-7.51(m,4H),7.50-7.42(m,1H),7.25-7.16( m,1H),7.16-7.06(m,3H),3.59-3.54(m,6H),3.30-3.24(m,2H),3.19(d, J=8.5Hz,2H),3.14-3.08(m,2H),1.82(s,2H),1.53(s,4H),1.37(s,2H).

[0429] Compound B-3: Pale yellow solid (35 mg, yield: 13.3%, purity: 96.4%, MS m / z: M+H) + =540.3)

[0430] 1H NMR (400MHz, DMSO) δ10.20(s,1H),8.22(s,1H),8.01-7.85(m,2H),7.69(dd,J=8.9,2.6Hz,1H ),7.62-7.46(m,4H),7.34(s,1H),7.29(d,J=8.0Hz,1H),7.17-7.03(m,2H),6.75(d,J=7.5Hz, 1H),4.09-4.00(m,2H),3.64-3.59(m,2H),3.59-3.50(m,2H),3.26(t,J=4.9Hz,2H),3.17(d,J =3.1Hz,2H),3.08(t,J=4.8Hz,2H),2.25(s,3H),1.87-1.69(m,2H),1.50(s,4H),1.33(s,2H).

[0431] Compound B-4: White solid (49 mg, yield: 18.2%, purity: 97.2%, MS m / z: M+H) + =554.3)

[0432] 1 H NMR (400MHz, DMSO) δ10.20 (s, 1H), 8.03-7.85 (m, 2H), 7.69 (dd, J = 8.9, 2.6Hz, 1H), 7.6 2-7.50(m,4H),7.34-7.25(m,6H),7.22-7.15(m,1H),7.06(d,J=8.9Hz,1H),6.59(d,J =8.0Hz,1H),4.87(p,J=7.1Hz,1H),3.47(dd,J=14.4,8.4Hz,4H),3.19(s,2H),3.10(d ,J=5.0Hz,4H),1.76(s,2H),1.55(s,4H),1.37(d,J=7.1Hz,5H),1.29(d,J=7.0Hz,2H).

[0433] Compound B-5: White solid (50 mg, yield: 17.8%, purity: 98.9%, MS m / z: M+H) + =576.3)

[0434] 1H NMR (400MHz, DMSO) δ10.20(s,1H),8.54(s,1H),8.07(d,J=1.8Hz,1H),7.94(dd,J=5.3,3.2Hz,2H ),7.79(dd,J=8.5,2.7Hz,2H),7.74(d,J=8.0Hz,1H),7.69-7.66(m,2H),7.62-7.49(m,4H),7.46- 7.39(m,1H),7.37-7.31(m,1H),7.12(d,J=8.9Hz,1H),3.72-3.65(m,3H),3.65-3.59(m,2H),3.33 -3.27(m,2H),3.26-3.14(m,2H),3.13-3.04(m,2H),1.84(s,2H),1.47(s,4H),1.35-1.23(m,3H).

[0435] Compound B-6: Pale yellow solid (20 mg, yield: 7.2%, purity: 95.0%, MS m / z: M+H) + =566.3)

[0436] 1 H NMR (400MHz, DMSO) δ10.19 (s, 1H), 7.97-7.90 (m, 2H), 7.69 (dd, J = 8.9, 2.6Hz, 1H), 7.62- 7.57(m,1H),7.54-7.51(m,3H),7.19-7.13(m,4H),7.09(d,J=8.9Hz,1H),4.28(s,2H),4. 05-4.01(m,2H),3.44(s,4H),3.40-3.33(m,2H),3.30-3.23(m,2H),3.16(t,J=7.6Hz,2H ),3.06(s,2H),2.86(t,J=5.5Hz,2H),1.85-1.82(m,2H),1.50(s,2H),1.44-1.28(m,4H).

[0437] Example 11 Preparation of compound 3-1

[0438]

[0439] Compound 1c (5 g, 1 eq) was dissolved in DCM (100 mL), cooled to 0 °C, and triphosgene (3.13 g, 0.34 eq) was added. After stirring at 0 °C for 10 minutes, TEA (3 g, 1 eq) was added. The mixture was naturally heated to 20 °C and stirred for 2 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was cooled to 0 °C, and compound 1b (6.21 g, 1 eq) and TEA (15.6 g, 5 eq) were added. The mixture was stirred at room temperature for 12 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was poured into water (200 mL), extracted with DCM (50 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 / 1:1) to give compound 3-1: a yellow oil (10 g, yield: 83.3%, purity: 90%).

[0440] Example 12 Preparation of compound 3-2

[0441]

[0442] Compound 3-1 (10 g, 1 eq) was dissolved in DCM (70 mL), cooled to 0 °C, and TFA (30 mL) was added. The mixture was naturally heated to 20 °C and stirred for 2 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated under reduced pressure to obtain the TFA salt of compound 3-2: a brown oily substance (10 g, purity: 90%).

[0443] Example 13 Preparation of compound 3-3

[0444]

[0445] Compounds 3-2 (10 g, 1 eq) and 3a (5.2 g, 1 eq) were dissolved in DMF (150 mL) and cooled to 0 °C. Potassium carbonate (28.8 g, 8 eq) was added in portions. The mixture was stirred at 50 °C for 4 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, and the filtrate was poured into water (200 mL). The pH was adjusted to 7 with 6 M hydrochloric acid, and the solid was washed off. The solid was then filtered, and the filter cake was dried to give compound 3-3: a yellow solid (9 g, yield: 74%, purity: 92%).

[0446] Example 14 Preparation of compounds 3-4

[0447]

[0448] Under ice bath conditions, glacial acetic acid (5.8 g, 5 eq) was added to a MeOH (150 mL) solution of compound 3-3 (9 g, 1 eq), followed by the addition of zinc powder (5.7 g, 5 eq) in portions. The mixture was stirred at 70 °C for 4 hours under nitrogen protection. After LC-MS analysis to confirm the reaction was complete, the mixture was filtered, and the filtrate was poured into water (200 mL). The pH was adjusted to 8 with 1 M sodium hydroxide aqueous solution, and the mixture was extracted three times with ethyl acetate (100 mL). The combined organic phases were concentrated to give compound 3-4: a yellow solid (7 g, yield: 83%, purity: 90%).

[0449] Example 15 Preparation of compounds 3-5

[0450]

[0451] A THF solution of compound a7 (1.96 g, 1 eq), HATU (7.94 g, 1 eq), and DIPEA (4.2 g, 2 eq) in 100 mL was stirred at room temperature for 10 minutes. Compound 3-4 (7 g, 1 eq) was then added. The mixture was stirred at room temperature for 4 hours under nitrogen protection. After LC-MS analysis to confirm the reaction was complete, the mixture was poured into water (200 mL), the pH was adjusted to 6-7 with 1 M dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine (200 mL), concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 / 2:1) to give compound 3-5: a yellow solid (5 g, yield: 57%, purity: 90%).

[0452] Example 16 Preparation of Compound 3

[0453]

[0454] To a THF (50 mL) solution of compounds 3-5 (5 g, 1 eq), a solution of lithium hydroxide monohydrate (3.1 g, 8 eq) in water (25 mL) was added. The mixture was stirred at 50 °C for 4 hours under nitrogen protection. After LC-MS analysis to confirm the reaction was complete, the pH was adjusted to 6-7 with 6 M hydrochloric acid solution, filtered, and the filter cake was concentrated and dried to give compound 3: a white solid (3 g, yield: 61.6%, purity: 92%, MS m / z: M+H). + =527.1).

[0455] Example 17 Preparation of compounds C-1 to C-7

[0456]

[0457] Taking the synthesis of compound C-1 as an example: To a THF (2 mL) solution of compound 3 (0.1 g, 1 eq), HATU (94 mg, 1.3 eq) and DIPEA (49 mg, 2 eq) were added. The mixture was stirred at room temperature for 10 minutes under nitrogen protection. Then, compound C1 (16 mg, 1.2 eq) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was poured into water (5 mL), and the pH was adjusted to 6-7 with 1 M hydrochloric acid aqueous solution. The mixture was extracted three times with ethyl acetate (10 mL), and the crude product was concentrated. The crude product was purified by reverse-phase column chromatography (50%–90% acetonitrile, 0.1% TFA) to obtain compound C-1: a yellow solid (70 mg, yield 42%, purity 99.2%, MS m / z: M+H). + =580.3).

[0458] 1 H NMR (400MHz, DMSO) δ10.20(s,1H),8.67(s,1H),8.01(s,1H),7.94(d,J=7.1Hz,2H),7.81(d,J =8.2Hz,1H),7.68(dd,J=8.8,2.5Hz,1H),7.61(d,J=2.5Hz,1H),7.58(d,J=7.2Hz,1H),7.53(t ,J=7.3Hz,2H),7.47(t,J=8.0Hz,1H),7.27(d,J=7.7Hz,1H),7.11(d,J=8.9Hz,1H),3.67-3.5 4(m,4H),3.42(s,2H),3.25(d,J=24.2Hz,5H),2.91(d,J=10.1Hz,1H),1.73(d,J=39.4Hz,6H).

[0459] The synthesis of C-2 to C-6 is the same as that of C-1.

[0460] Compound C-2: Yellow solid (80 mg, yield 44%, purity 99.4%).

[0461] 1H NMR (400MHz, DMSO) δ10.23(d,J=6.3Hz,1H),8.57(d,J=13.5Hz,1H),7.97-7.89(m,3H),7.79-7.70(m,2H),7.64-7. 61(m,1H),7.58(d,J=7.2Hz,1H),7.53(t,J=7.3Hz,2H),7.41(q,J=7.8Hz,1H),7.26-7.21(m,1H),7.21-7.11(m,4H) ,7.02(dd,J=52.5,8.0Hz,1H),5.00-4.58(m,1H),4.45-4.24(m,1H),4.02-3.72(m,1H),3.67-3.40(m,4H),3.36-3. 13(m,4H),2.96(s,1H),2.88(t,J=6.8Hz,1H),2.72(t,J=5.6Hz,1H),1.79(d,J=4.9Hz,1H),1.60(d,J=64.3Hz,1H).

[0462] Compound C-3: Pale yellow solid (60 mg, yield 52.5%, purity 97.3%, MS m / z: M+H) + =602.3).

[0463] 1 H NMR (400MHz, DMSO) δ11.60(s,1H),10.36(s,1H),8.64(s,1H),8.16(d,J=2.6Hz,1H),8.05-7.9 0(m,4H),7.80(d,J=8.3Hz,1H),7.74(d,J=7.6Hz,2H),7.61(t,J=7.3Hz,1H),7.55(t,J=7.2Hz, 2H),7.47(t,J=7.9Hz,1H),7.36(d,J=8.8Hz,1H),7.33-7.23(m,3H),7.05(t,J=7.3Hz,1H),3.7 7-3.68(m,2H),3.63(t,J=5.7Hz,2H),3.24-3.17(m,2H),1.97-1.87(m,2H),1.30-1.20(m,2H).

[0464] Compound C-4: Yellow solid (52 mg, yield 41.5%, purity 97.2%, MS m / z: M+H) + =660.3.

[0465] 1H NMR (400MHz, DMSO) δ10.33(s,1H),9.48(s,1H),8.68(s,1H),8.11(d,J=2.7Hz,1H),8.02(s,1H) ,8.00-7.96(m,2H),7.93(dd,J=8.8,2.6Hz,1H),7.82(d,J=8.0Hz,1H),7.63-7.58(m,1H),7.57 -7.51(m,2H),7.47(t,J=8.1Hz,1H),7.32(d,J=8.8Hz,1H),7.28(d,J=7.6Hz,1H),3.75-3.62(m ,6H),3.36-3.27(m,2H),3.20-3.07(m,2H),2.04(s,6H),2.00(s,1H),1.95(s,4H),1.58(s,5H).

[0466] Compound C-5: Pale yellow solid (46 mg, yield 38.9%, purity 95.1%, MS m / z: M+H) + =622.3.

[0467] 1 H NMR (400MHz, DMSO) δ10.35(s,1H),9.73(d,J=7.8Hz,1H),8.69(s,1H),8.12(d,J=2.7Hz,1H),8 .05(s,1H),8.02-7.90(m,3H),7.84(d,J=8.7Hz,1H),7.63-7.57(m,1H),7.57-7.51(m,2H),7. 48(t,J=8.1Hz,1H),7.35(d,J=8.8Hz,1H),7.28(d,J=7.9Hz,1H),3.97-3.81(m,2H),3.73-3.6 8(m,4H),3.33(dd,J=8.8,4.6Hz,2H),3.21-3.09(m,2H),1.99-1.80(m,4H),1.59-1.32(m,9H).

[0468] Compound C-6: White solid (49 mg, yield 40.7%, purity 98.3%, MS m / z: M+H+=634.3).

[0469] 1H NMR (400MHz, DMSO) δ10.33(s,1H),10.05(t,J=5.9Hz,1H),8.64(s,1H),8.12(d,J=2.7Hz,1H),8.03-7. 94(m,3H),7.91(dd,J=8.8,2.7Hz,1H),7.81(d,J=8.6Hz,1H),7.64-7.57(m,1H),7.57-7.51(m,2H),7.4 7(t,J=8.0Hz,1H),7.37(dd,J=8.7,5.6Hz,2H),7.32(d,J=8.8Hz,1H),7.30-7.26(m,1H),7.17-7.11(m, 2H), 4.46 (d, J = 5.8Hz, 2H), 3.63-3.56 (m, 4H), 3.23-3.17 (m, 2H), 3.15-3.08 (m, 2H), 1.85-1.76 (m, 2H).

[0470] Example 18 Preparation of Compound 4-1

[0471]

[0472] Compound 1-1 (10 g, 1 eq) was dissolved in THF (300 mL), and EDCI (12.4 g, 1.2 eq) and HOBT (8.86 g, 1.2 eq) were added. The mixture was stirred at 20 °C for 0.5 h. Then, compound c6 (6.76 g, 1 eq) and DIPEA (28.5 mL, 3 eq) were added. The mixture was stirred at room temperature for 12 h. After the reaction was confirmed to be complete by LC-MS, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with 1 M hydrochloric acid (100 mL × 2) and saturated sodium bicarbonate solution (100 mL × 2). After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to give crude compound 4-1: a yellow oil (15 g, yield: 95%).

[0473] Example 19 Preparation of Compound 4-2

[0474]

[0475] Compound 4-1 (10 g, 1 eq) and 1b (6.85 g, 1 eq) were dissolved in DMF (150 mL), cooled to 0 °C, and potassium carbonate (14.2 g, 3 eq) was added. The mixture was stirred at 50 °C for 4 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, and the filtrate was poured into water (200 mL). The pH was adjusted to 7 with 6 M hydrochloric acid, and the solid was washed off. The solid was filtered, and the filter cake was dried to give compound 4-2: a yellow solid (14 g, yield: 86.5%, purity: 92%).

[0476] Example 20 Preparation of Compounds 4-3

[0477]

[0478] Compound 4-2 (14 g, 1.0 eq), DCM (70 mL), and TFA (30 mL) were added sequentially to a single-necked flask at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and the reaction progress was monitored by LC-MS. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain the crude compound 4-3 TFA salt: a brown oily substance (13 g, MS m / z: M+H). + =373.1).

[0479] Example 21 Preparation of compound 4-4

[0480]

[0481] Taking R=3-CH3 as an example: Under ice bath conditions, triphosgene (0.46 g, 0.33 eq) was added to a DCM (10 mL) solution of m-methylaniline (0.5 g, 1.0 eq), and TEA (0.47 g, 1 eq) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 20 minutes, and the reaction was monitored by TLC. After the starting material was completely consumed, a DCM (5 mL) solution of compound 4-3 (1.74 g, 1.0 eq) was added dropwise to the reaction solution at 0 °C. TEA was added to adjust the pH of the reaction solution to 8-9, and the reaction system was brought to room temperature and reacted for 2 hours. The reaction progress was monitored by LC-MS. After compound 4-3 was completely consumed, the reaction solution was concentrated under reduced pressure to obtain a crude product. Compound 4-4 was purified by reverse preparation (20%-78% acetonitrile, 0.1% TFA): a pale yellow solid (1.2 g, yield: 50.8%, purity: 93%).

[0482] Other R-substituents refer to m-methylaniline.

[0483] Example 22 Preparation of Compound 4

[0484]

[0485] Taking R=3-CH3 as an example: To a MeOH (20 mL) solution of compound 4-4 (1.2 g, 1.0 eq), glacial acetic acid (0.57 g, 4 eq) was added, and zinc powder (0.62 g, 4 eq) was added in portions to the reaction solution. The mixture was stirred at 80 °C for 4 hours. The reaction was monitored by LC-MS. After the starting material was completely consumed and the product was formed, the mixture was filtered. The filtrate was poured into water (100 mL), and the pH was adjusted to 8 with 1 M sodium hydroxide aqueous solution. The mixture was extracted three times with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude compound 4: a yellow solid (0.8 g, yield: 70.8%, purity: 90%, MS m / z: M+H). + =476.1).

[0486] Other R-substituents refer to m-methylaniline.

[0487] Example 23 Preparation of compounds D-1 to D-4

[0488]

[0489] Taking the synthesis of compound D-1 as an example: To a DMF (10 mL) solution of compound a3 (0.23 g, 1.0 eq), HATU (1.09 g, 1.3 eq) and DIPEA (0.57 g, 2 eq) were added. After stirring at room temperature for 10 minutes, compound 4 (0.8 g, 1 eq) was added, and the mixture was stirred at room temperature for 4 hours. LC-MS analysis showed the disappearance of the starting material and the formation of the product. The reaction solution was poured into water (50 mL), and the pH was adjusted to 7 with 1 M hydrochloric acid solution. The mixture was extracted three times with ethyl acetate (50 mL), concentrated, and purified by reverse reaction (30%-90% acetonitrile, 0.1% trifluoroacetic acid) to obtain compound D-1: a yellow solid (0.65 g, yield: 65%, purity: 95%, MS m / z: M+H). + =594.3). 1 HNMR (400MHz, DMSO) δ10.24 (s, 1H), 10.10 (t, J = 5.9Hz, 1H), 8.21 (s, 1H), 8.12 (d, J=2.7Hz,1H),7.91(dd,J=11.6,5.4Hz,3H),7.42-7.33(m,4H),7.29(dd,J=10.5,7 .3Hz,3H),7.18-7.08(m,3H),6.77(d,J=7.5Hz,1H),4.46(d,J=5.8Hz,2H),3.58-3 .46(m,4H),3.10(dd,J=19.3,14.6Hz,4H),2.39(s,3H),2.25(s,3H),1.78(s,2H).

[0490] The synthesis of D-2 to D-4 is the same as that of D-1.

[0491] Compound D-2: White solid (70 mg, yield: 70%, purity: 96%, MS m / z: M+H) + =610.3.)

[0492] 1 H NMR (400MHz, DMSO) δ10.24 (s, 1H), 10.12 (t, J = 6.0Hz, 1H), 8.17-8.08 (m, 2H), 7. 94-7.87(m,3H),7.43-7.32(m,6H),7.29(d,J=8.8Hz,1H),7.20-7.12(m,2H),6. 85-6.80(m,2H),4.47(d,J=5.9Hz,2H),3.71(s,3H),3.57-3.52(m,2H),3.51-3. 46(m,2H),3.18-3.12(m,2H),3.11-3.06(m,2H),2.39(s,3H),1.79-1.76(m,2H).

[0493] Compound D-3: White solid (0.29 g, yield: 67%, purity: 97.1%, MS m / z: M+H) + =598.3)

[0494] 1 H NMR: (400MHz, DMSO) δ10.34(s,1H),10.09(t,J=5.9Hz,1H),8.21(s,1H),8.07(m,J=8.8 ,8.4,2.4Hz,3H),7.90(dd,J=8.8,2.7Hz,1H),7.42-7.35(m,4H),7.34-7.27(m,3H),7. 20-7.07(m,3H),6.77(d,J=7.4Hz,1H),4.47(d,J=5.8Hz,2H),3.55(d,J=5.1Hz,2H),3. 50(t,J=6.0Hz,2H),3.17(d,J=4.6Hz,2H),3.13-3.04(m,2H),2.25(s,3H),1.78(m,2H).

[0495] Compound D-4: White solid (49 mg, yield: 58.2%, purity: 97.2%, MS m / z: M+H) + =619.3)

[0496] 1H NMR (400MHz, DMSO) δ10.18(d,J=9.5Hz,1H),9.57-9.54(m,1H),7.69-7.59(m,2H),7.53-7.44(m,1H),7.41-7.02(m,12H),4.40(dd,J=23 .4,5.9Hz,2H),3.66-3.55(m,2H),3.23(t,J=5.7Hz,2H),3.16-3.05(m,2H),3.03-2.95(m,2H),2.34(d,J=2.9Hz,3H),1.84-1.53(m,2H).

[0497] Example 24 Preparation of Compound 5-1

[0498]

[0499] Compound 5a, using 4-tert-butyloxycarbonyl-2-methylpiperazine as an example: Triphosgene (0.6 g, 0.33 eq) was added to a DCM (10 mL) solution of compound 1c (1 g, 1.0 eq) under ice bath conditions. After stirring for 20 minutes, TEA (0.63 g, 1 eq) was added dropwise to the reaction solution, maintaining the reaction temperature at 0°C. The reaction was monitored by TLC. After the starting material was completely consumed and new spots were formed, a DCM (5 mL) solution of compound 5a (1.24 g, 1.0 eq) was added dropwise to the reaction solution, maintaining the reaction temperature at 0°C. The pH of the reaction solution was adjusted to 8-9 with TEA, and the reaction system was brought to room temperature and reacted for 2 hours. The reaction progress was monitored by TLC. After compound 1c was completely consumed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 / 2:1) to obtain compound 5-1: a pale yellow solid (1.8 g, yield: 75%, purity: 90%).

[0500] Example 25 Preparation of Compound 5-2

[0501]

[0502] With R a =CH3,R b =H example: Compound 5-1 (1.8 g, 1 eq) was dissolved in DCM (20 mL), and TFA (10 mL) was added. The mixture was stirred at 20 °C for 12 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetate of compound 5-2: a yellowish-brown oily substance (1.6 g, purity: 90%).

[0503] Other 5-1 substituents are synthesized in accordance with the method described above.

[0504] Example 26 Preparation of Compound 5-3

[0505]

[0506] With R a =CH3,R b =H example: Compound 5-2 (1.6 g, 1 eq) and 5b (1.1 g, 1 eq) were dissolved in DMF (50 mL), cooled to 0 °C, and potassium carbonate (6.15 g, 8 eq) was added in batches. The mixture was stirred at 50 °C for 4 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, and the filtrate was poured into water (100 mL). The pH was adjusted to 7 with 6 M hydrochloric acid, and the solid was washed off. The solid was then filtered, and the filter cake was dried to obtain compound 5-3: a yellow solid (1.54 g, yield: 59%, purity: 92%).

[0507] Other 5-2 substituents are synthesized with reference to this substituent.

[0508] Example 27 Preparation of Compounds 5-4

[0509]

[0510] With R a =CH3,R b For example, in an ice bath, glacial acetic acid (0.79 g, 4 eq) was added to a MeOH (30 mL) solution of compound 5-3 (1.54 g, 1 eq), followed by the addition of zinc powder (0.8 g, 4 eq) in batches. The mixture was stirred at 70 °C for 4 hours under nitrogen protection. After LC-MS analysis to confirm the reaction was complete, the mixture was filtered, washed with ethyl acetate (100 mL), and the filtrate was poured into water (200 mL). The pH was adjusted to 8 with 1 M sodium hydroxide aqueous solution, and the layers were separated. The aqueous layer was extracted three times with ethyl acetate (50 mL). The combined organic phases were concentrated to obtain compound 5-4: a yellow solid (1.2 g, yield: 84%, purity: 89%).

[0511] Other 5-3 substituents are synthesized according to the same method.

[0512] Example 28 Preparation of compound 5-5

[0513]

[0514] With R a =CH3,R b=H example: A THF (20 mL) solution of compound a7 (0.34 g, 1 eq), HATU (1.34 g, 1.3 eq), and DIPEA (0.77 g, 2 eq) was stirred at room temperature for 10 minutes, and then compound 5-4 (1.2 g, 1 eq) was added. After stirring at room temperature for 4 hours under nitrogen protection, the reaction was confirmed to be complete by LC-MS. The solution was then poured into water (100 mL), the pH was adjusted to 6-7 with 1 M dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine (100 mL), concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 / 1:1) to obtain compound 5-5: a yellow solid (1.3 g, yield: 89%, purity: 95%).

[0515] Other 5-4 substituents are synthesized according to the same method.

[0516] Example 29 Preparation of Compound 5

[0517]

[0518] With R a =CH3,R b =H example: To a THF (10 mL) solution of compound 5-5 (1.3 g, 1 eq), a water solution of lithium hydroxide monohydrate (0.8 g, 8 eq) (5 mL) was added. The mixture was stirred at 50 °C for 4 hours under nitrogen protection. After LC-MS analysis to confirm the reaction was complete, the pH was adjusted to 6-7 with 6 M hydrochloric acid solution, filtered, and the filter cake was concentrated and dried to obtain compound 5: a white solid (1.26 g, yield: 98%, purity: 92%, MS m / z: M+H). + =527.1).

[0519] Other 5-5 substituents are synthesized in accordance with the method described above.

[0520] Example 30 Preparation of compound E-1

[0521]

[0522] Taking the synthesis of compound E-1 as an example: To a THF (2 mL) solution of compound 5 (0.1 g, 1 eq), HATU (94 mg, 1.3 eq) and DIPEA (49 mg, 2 eq) were added. The mixture was stirred at room temperature for 10 minutes under nitrogen protection. Then, compound 1a (19 mg, 1.2 eq) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was poured into water (5 mL), and the pH was adjusted to 6-7 with 1 M hydrochloric acid aqueous solution. The mixture was extracted three times with ethyl acetate (10 mL), and the crude product was concentrated. The crude product was purified by reverse-phase column chromatography (50%–90% acetonitrile, 0.1% TFA) to obtain compound E-1: a pale yellow solid (40 mg, yield: 35.5%, purity: 96%, MS m / z: M+H). + =594.1). 1 H NMR (400MHz, CDCl3) δ8.57(d,J=71.2Hz,1H),7.90(dt,J=4.9,3.2Hz,2H),7.87-7.69(m,3H),7.60-7.52(m,1H),7.48(dd,J= 11.4,4.4Hz,2H),7.40(t,J=7.7Hz,1H),7.23(dd,J=23.9,2.4Hz,1H),7.02(d,J=8.8Hz,1H),4.40(dd,J=124.4,9.3Hz,1H), 4.20-4.07(m,2H),3.65-3.30(m,1H),3.28-3.15(m,3H),3.13-3.05(m,1H),3.02(dd,J=14.1,6.9Hz,1H),2.95-2.82(m,1H) ,2.51(ddd,J=20.5,11.8,6.0Hz,1H),1.73-1.66(m,1H),1.57(dd,J=20.9,9.4Hz,3H),1.45-1.36(m,1H),1.31-1.22(m,4H).

[0523] The synthesis of E-2 to E-4 is the same as that of E-1.

[0524] Compound E-3: White solid (purity: 97%, MS m / z: M+H) + =580.2)

[0525] 2H NMR:1H NMR (400MHz, CDCl3) δ8.02(s,1H),7.90(d,J=7.3Hz,2H),7.87-7.82(m,1H),7.72(s,1H),7.66(s,1H),7.57(s,1H),7.53(d,J=7.8Hz ,2H),7.44(s,1H),7.06(d,J=12.9Hz,2H),3.75(d,J=41.3Hz,4H),3.48(s,2H),3.22(s,4H),2.86(s,2H),1.69(s,4H),1.28(s,4H).

[0526] Activity test example

[0527] 1. Laboratory animals and their care

[0528] Experimental animals: Male C57BL / 6 mice aged 8-10 weeks and weighing 22.0-26.0g were selected as experimental subjects.

[0529] Housing environment: SPF-grade laboratory animal center; SPF-grade mouse feed was purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0530] Feeding conditions: The room temperature should be between 22 and 24°C, the humidity between 40 and 70%, the light should be alternating between light and dark for 12 hours, and the animals should have free access to water and food.

[0531] 2. Experimental cells and protocol

[0532] Experimental cells: The human liver cell line L02 (normal human liver cells) was used as the experimental subject. The human liver cell line L02 was purchased from the National Center for Identification and Collection of Cell Cultures.

[0533] Culture of human hepatocyte line L02: cultured in DMEM high glucose medium (containing 10% fetal bovine serum + 1% penicillin and antibiotics, hereinafter referred to as medium) at 37°C and 5% CO2.

[0534] Experimental steps:

[0535] (1) Plating cells: Observe the cell state, select cells with good viability, digest, centrifuge and resuspend the cells, count the cells, dilute the cells at a density of 8000 cells / well and evenly plate them in high-content cell imaging microplates.

[0536] (2) Drug pretreatment: After the plated cells adhered and grew for 12 hours, 20 μM of the compound of the present invention was added to the culture medium (0.5% bovine serum albumin) to pretreat the cells.

[0537] (3) Palmitic acid (PA) / oleic acid (OA) induces lipid droplet accumulation: After drug pretreatment for 8 hours, palmitic acid and oleic acid are added to the culture medium, and the concentration of PA in the culture medium is 0.2 mM PA, the concentration of OA is 0.4 mM OA, and the concentration of the compound of the present invention is 20 μM. The cells are treated to induce the production of lipid droplets.

[0538] (4) Staining: After induction treatment for 18 h, discard the cell waste liquid, wash twice with PBS, fix with 4% paraformaldehyde at room temperature for 45 min, discard the fixative, wash twice with PBS, stain with BODIPY for 10 min, discard the staining solution, and wash twice with PBS.

[0539] (5) Use a high-content cell imaging system for on-machine detection.

[0540] (6) Analyze the data and plot it.

[0541] 3. Pathological examination

[0542] The main procedures for preparing paraffin-embedded specimen sections are as follows: trimming the liver → preparing the embedding frame → rinsing with running water → dehydration → clearing → embedding → sectioning → spreading → air-drying or baking for later use.

[0543] The main steps of hematoxylin-eosin (H&E) staining, CD11b staining, and Sirius red (PSR) staining used in the embodiments of the present invention are described below:

[0544] The main steps of hematoxylin-eosin (H&E) staining are as follows: take paraffin-embedded specimens, dewax them to water, stain cell nuclei with hematoxylin, stain cytoplasm with eosin, dehydrate and mount the slides, and examine them under a microscope, and acquire and analyze the images.

[0545] The main steps of CD11b staining are as follows: After baking, dewaxing, hydration, and repair of paraffin sections, mouse liver sections are first blocked with 10% goat serum. Then, they are incubated overnight at 4°C with primary antibody (Boster, BM3925). After incubation, they are washed with PBS. After completion, they are incubated at 37°C for 1 hour with secondary antibody (goat anti-rabbit IgG(H+L) cross-adsorbed secondary antibody (Thermo Fisher Scientific, A-11011, Massachusetts, USA)). Finally, the nuclei are stained with 4',6-diamidinyl-2-phenylindole (DAPI).

[0546] The main steps of Sirius Red (PSR) staining are as follows: take paraffin-embedded specimen sections, dewax them to water, drop Sirius Red staining solution on them, rinse slightly with running water to remove the staining solution from the surface of the sections, stain the cell nuclei with Mayer's hematoxylin staining solution, rinse with running water, and dehydrate and mount the sections.

[0547] Test Example 1: Effect of treatment with the compound of the present invention on fat accumulation in hepatocytes

[0548] Hepatocytes were divided into three groups: different compound treatment groups, a control solution group, and a BSA group. After 12 hours of cell adhesion, each compound treatment group was pretreated with 20 μM of a different compound in the culture medium for 8 hours, followed by treatment with 0.2 mM PA and 0.4 mM OA for 18 hours. The PA / OA treatment alone served as the control solution group; the group without PA / OA treatment was the BSA group. After treatment, BODIPY staining was performed using the Operetta CLS high-content analysis system.

[0549] Table 1. Experiments verifying the effect of the compound of the present invention on fat accumulation in hepatocytes.

[0550]

[0551]

[0552] Figure 1 , Figure 2 Images showing BODIPY staining and imaging analysis of hepatocytes after treatment with different compounds. Figure 1 , 2 Compared with the PA / OA group, the relative fluorescence intensity of lipid droplets A1, A2, A3, A4, A5, A6, A7, B3, B4, B5, B6, D1, D2, D3, C1, C2, C3, C4, C5, C6, E1, and E3 was significantly decreased, while the cell number remained essentially unchanged. This indicates that the compound of the present invention can significantly inhibit lipid accumulation in hepatocytes without obvious toxic side effects.

[0553] Test Example 2: Effect of the compounds of the present invention (such as A7) on non-alcoholic fatty liver disease induced by a high-fat, high-cholesterol diet.

[0554] Twenty-four C57 wild-type mice were divided into four groups of six each. The mice were fed a normal chow (NC) diet (protein: 19.2%, carbohydrates: 67.3%, fat: 4.3%; calorie percentage: protein: 20%, carbohydrates: 70%, fat: 10%; total calorie ratio: 3.85 kcal / g) and a high-fat / high-cholesterol diet (HFHC) diet (protein: 18.3%, carbohydrates: 20.8%, fat: 60.9%; total calorie ratio: 5.2 kcal / g), designated as the NC group and the HFHC group. After eight weeks of feeding, the NC-fed mice were administered 60 mg / kg A7 orally via gavage, while the other group was treated with a solvent. Similarly, the HFHC-fed mice were administered 60 mg / kg A7 orally via gavage, while the other group was treated with a solvent. Administration was once daily for eight weeks, during which time the mice continued to be fed either the NC or HFHC diet.

[0555] After 16 weeks, the mice were harvested to measure their body weight and liver weight, and the liver weight / body weight ratio was calculated. The liver tissue was then subjected to pathological examination.

[0556] Figure 3 The results showed that, compared with the NC group, HFHC feeding induced non-alcoholic fatty liver disease, manifested as increased body weight and liver weight-to-body weight ratio. The increase in body weight and liver weight-to-body weight ratio in mice orally administered A7 was reversed. Figure 4 The results showed that, compared with the NC group, the liver tissue of mice fed HFHC exhibited steatosis and vacuolation, increased inflammatory cell infiltration, and increased liver fibrosis. Oral administration of A7 to the NC group did not show significant changes, while under HFHC feeding conditions, steatosis, inflammatory cell infiltration, and fibrosis in the livers of mice fed A7 orally were inhibited, indicating that oral administration of A7 can alleviate HFHC diet-induced non-alcoholic fatty liver disease.

[0557] It should be understood that the invention described herein is not limited to specific methodologies, experimental protocols, or reagents, as these can vary. The discussions and examples provided herein are for illustrative purposes only and are not intended to limit the scope of the invention, which is defined solely by the claims.

Claims

1. Use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of non-alcoholic fatty liver disease, wherein, The compound is selected from the following: 。

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