Aspartic acid derivatives and their use in the treatment of metabolic diseases such as liver fibrosis and non-alcoholic hepatitis - Patents.com

Abstract

The present invention relates to compounds of formula I and formula II and their use in the treatment of metabolic diseases such as liver fibrosis and non-alcoholic hepatitis. x -A' (Formula I); A1-(L1) x -A1' (Formula II) in the preparation of a drug or reagent for use in conjunction with at least one of the compounds as shown, and their pharma- ceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms and metabolite forms, or any combination or mixture thereof, are provided.

Description

[Technical field]

[0001] The present invention relates to the field of biopharmaceuticals, specifically to aspartic acid derivatives and their use in the treatment of liver fibrosis, non-alcoholic inflammation and other metabolic diseases. [Background technology]

[0002] Fibrosis can occur in various tissues and organs, but its main pathological changes are an increase in fibrous connective tissue and a decrease in parenchymal cells in organ tissues, and its continued progression can cause structural damage and functional decline or even failure of organs, thereby seriously threatening human health and life. Around the world, tissue fibrosis is the leading cause of disability and death in many diseases. According to relevant statistics in the United States, nearly 45% of patients who die from various diseases in the United States may be due to diseases related to tissue fibrosis. Liver fibrosis is especially prevalent in patients with tissue fibrosis. Liver fibrosis is a reversible pathological phenomenon in which excessive fibrous connective tissue is deposited in liver tissue during the body's repair process after liver injury. There are many causes of liver fibrosis. Patients with various chronic viral liver diseases are at high risk of developing liver fibrosis and cirrhosis. Alcoholics or long-term drinkers may develop fatty liver early and liver fibrosis and cirrhosis late, and other fatty livers caused by non-alcoholic factors such as obesity may also develop liver fibrosis and cirrhosis. In addition, repeated infection with schistosomiasis can easily cause portal hepatic fibrosis, chronic cholestasis can lead to biliary hepatic fibrosis, hepatocyte degeneration and hemoglobin deposition can lead to metabolic hepatic fibrosis, various toxic substances can cause toxic hepatic fibrosis, people who prefer low-protein diets and fatty fried foods can develop malnutrition-induced hepatic fibrosis, and patients with chronic congestive heart failure can develop cardiogenic hepatic fibrosis. In addition, liver fibrosis is also an important pathological diagnostic indicator of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

[0003] The mechanisms of the development and progression of liver fibrosis are very complex. Current research mainly focuses on the activation and transformation of hepatic stellate cells. Possible pathways include activation of signaling pathways through transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), tumor necrosis factor-α (TNF-α), etc., by various chronic stimuli, as well as activation of hepatic stellate cells by prostaglandin cyclooxygenase-2 (COX-2), diffuse extracellular matrix (ECM) and oxidative stress, which results in the transformation of hepatic stellate cells into myofibroblasts and fibroblasts, increased secretion or decreased degradation of extracellular matrix, and the formation of liver fibrosis. Because the mechanisms of the development and progression of liver fibrosis are still unclear, drug development for treating liver fibrosis is relatively slow. At present, in the clinical treatment of liver fibrosis or cirrhosis caused by viral hepatitis (mainly hepatitis B or C), nucleoside (acid) analogues or interferon are mainly used for antiviral treatment. Inhibiting viral replication controls the response of inflammatory factors, slowing the progression of liver fibrosis or cirrhosis. However, there is no effective treatment for liver fibrosis or cirrhosis caused by other factors such as alcohol, metabolism, and drugs, and it is mainly supplemented with traditional Chinese medicine or ready-made traditional Chinese medicine.

[0004] By using subtractive hybridization inhibition and bioinformatics methods, NS3TP1 (HCV nonstructural protein 3-transactivated protein 1, NS3TP1) was first screened and cloned, which is also called ASNSD1 (asparagine synthetase domain containing 1, ASNSD1), has the GenBank accession number AY11696, and is located on human chromosome 2q32.2. The full length of the coding sequence of this gene is 1,932 nucleotides, and the coding product consists of 643 amino acid residues. NS3TP1 is widely distributed in the body, mainly distributed in hepatocytes and gallbladder gland epithelial cells in the liver. Janine Meienberg et al. found by MLPA analysis that hemizygous complete deletion of COL3A1 (encoding collagen III, the main component of hepatic fibrosis extracellular matrix deposition) affected the expression of ASNSD1, and showed that the expression of ASNSD1 could interact with COL3A1. Therefore, the development of NS3TP1 modulators could be a direction for the development of new drugs for NAFLD. Summary of the Invention

[0005] The purpose of the present invention is to obtain a compound that has a regulatory effect on NS3TP1, and to obtain a compound that has a therapeutic effect on liver fibrosis and non-alcoholic fatty liver disease.Through creative research, the inventors have found that the aspartic acid derivatives of the present invention have a therapeutic effect on liver fibrosis and non-alcoholic fatty liver disease, and these molecules have good pharmaceutical properties (such as solubility, AUC and / or oral bioavailability and other properties) and safety.

[0006] For this purpose, in a first aspect, the present invention provides a method for producing a method for treating a cancer cell comprising the steps of: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression In the manufacture of a medicine or medicament for use in at least one of the following: A-(L 1 ) x -A' (Formula I) In the formula, A is [ka] and A' is [ka] where A and A' are the same or different; Where: x is selected from the group consisting of 0, 1 and 2; 1) If x is 0 and A' does not exist; for A, R 1 and R 2 are each independently C1-C6 alkyl, -OR a1 , -NR a2 R a3 selected from the group consisting of: R 3 and R 4 are each independently hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -C(R h ) 2 -R d1 , -(CO)-(L) n -R d2 , -(CO)O-(L) n -R d3 , -(SO 2 )-(L) n -R d4 , -P(O)(OR e ) 2 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-OR b2 , -(C1-C6 alkyl) n -O-(CO)-R b3 , -(C1-C6 alkyl) n -O-(CO)-OR b4 , -(C1-C6 alkyl) n -(CO)-NR b5 R b6 , -(C1-C6 alkyl) n -NR b7 -(CO)-R b8 , -(C1-C6 alkyl) n -NR b9 -(CO)-OR b10 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 are each independently hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-ORc1 , -(C1-C6 alkyl) n -O-(CO)-R c2 , -(C1-C6 alkyl) n -O-(CO)-OR c3 wherein said alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, and C6-C10 aryl; R c1 , R c2 , and R c3 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; L is independent of each other: absent, O, NR d5 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; R e are each independently selected from the group consisting of hydrogen, deuterium, Na, K, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; R h are each independently C1-C6 alkyl, -NHC(O)R g1 , -OC(O)R g2 , -OP(O)(ONa) 2 , -NHC(O)OR d6 , -OC(O)OR d7 , -OC(O)NHR d8 selected from the group consisting of; R d1 , R d2 , R d3 , R d4 , R d5 , Rd6 , R d7 , R d8 are each independently selected from the group consisting of hydrogen, deuterium, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are each independently selected from the group consisting of one or more R f may be optionally substituted with a group; R f are each independently a halogen, a C1-C6 alkyl, a halogenated C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C6-C10 aryl, a halogenated C6-C10 aryl, a C3-C7 cycloalkyl, a 3- to 15-membered heterocyclyl, -NR g3 R g4 , -OR g5 , -NHC(O)R g6 , -OC(O)R g7 selected from the group consisting of; R g1 , R g2 , R g3 , R g4 , R g5 , R g6 , and R g7 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from the group consisting of hydrogen, amino; Y is C or S; y is an integer equal to or greater than 0; or y is selected from the group consisting of 0, 1, 2, and 3; or y is 0 or 1; n is 0 or 1; 2) When x is 1 or 2, and A and A' are the same or different, R in Unit A 1 , R 2 , R 3 , and R4 One of the adjacent units A' is R 1 ', R 2 ', R 3 ', and R 4 ' and L 1 Connected via; Each L 1 are independently selected from the group consisting of absent, O, S, carbonyl, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-), cycloalkyl (or C3-C7 cycloalkyl), heteroalkyl (or 3-7 membered heteroalkyl; for example, -O-alkyl-O- (or -O-C1-C6 alkyl-O-)), wherein the alkyl, cycloalkyl, and heteroalkyl are optionally substituted with one or more groups independently selected from the group consisting of Z; Z is independently selected from the group consisting of halogen, amino, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), haloalkyl (or halogenated C1-C6 alkyl), cycloalkyl (or C3-C7 cycloalkyl), aryl (or C6-C12 aryl), and heterocyclyl; Or L 1 is selected from the group consisting of absent, -CR'R'', where R' and R'' are each independently H, C1-C6 alkyl (or C1-C3 alkyl); Or L 1 , absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 selected from the group consisting of; Regarding A, R 1 and R 2 are each independently C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 selected from the group consisting of; R 3 and R 4 are each independently hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -C(R h ) 2 -R d1 , -(CO)-(L) n -R d2 , -(CO)O-(L) n -R d3 , -(SO 2 )-(L) n -R d4 , -P(O)(OR e ) 2 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-OR b2 , -(C1-C6 alkyl) n -O-(CO)-R b3 , -(C1-C6 alkyl) n -O-(CO)-OR b4 , -(C1-C6 alkyl) n -(CO)-NR b5 R b6 , -(C1-C6 alkyl) n -NR b7 -(CO)-R b8 , -(C1-C6 alkyl) n -NR b9 -(CO)-ORb10 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 are each independently hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-OR c1 , -(C1-C6 alkyl) n -O-(CO)-R c2 , -(C1-C6 alkyl) n -O-(CO)-OR c3 wherein said alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, and C6-C10 aryl; R c1 , R c2 , and R c3 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; L is independent of each other: absent, O, NR d5 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; R eare each independently selected from the group consisting of hydrogen, deuterium, Na, K, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; R h are each independently C1-C6 alkyl, -NHC(O)R g1 , -OC(O)R g2 , -OP(O)(ONa) 2 , -NHC(O)OR d6 , -OC(O)OR d7 , -OC(O)NHR d8 selected from the group consisting of; R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 are each independently selected from the group consisting of hydrogen, deuterium, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are each independently selected from the group consisting of one or more R f may be optionally substituted with a group; R f are each independently a halogen, a C1-C6 alkyl, a halogenated C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C6-C10 aryl, a halogenated C6-C10 aryl, a C3-C7 cycloalkyl, a 3- to 15-membered heterocyclyl, -NR g3 R g4 , -OR g5 , -NHC(O)R g6 , -OC(O)R g7 selected from the group consisting of; R g1 , R g2 , Rg3 , R g4 , R g5 , R g6 , and R g7 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from the group consisting of hydrogen, amino; Y is C or S; y is an integer equal to or greater than 0; or y is selected from the group consisting of 0, 1, 2, and 3; or y is 0 or 1; n is 0 or 1; Regarding A', R 1 ' and R 2 ' are each independently C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 selected from the group consisting of; R 3 ' and R 4 ' are each independently hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -C(R h ) 2 -R d1 , -(CO)-(L) n -R d2 , -(CO)O-(L) n -R d3 , -(SO 2 )-(L) n -R d4 , -P(O)(OR e ) 2wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-OR b2 , -(C1-C6 alkyl) n -O-(CO)-R b3 , -(C1-C6 alkyl) n -O-(CO)-OR b4 , -(C1-C6 alkyl) n -(CO)-NR b5 R b6 , -(C1-C6 alkyl) n -NR b7 -(CO)-R b8 , -(C1-C6 alkyl) n -NR b9 -(CO)-OR b10 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9, R b10 are each independently hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-OR c1 , -(C1-C6 alkyl) n -O-(CO)-R c2 , -(C1-C6 alkyl) n -O-(CO)-OR c3 wherein said alkyl, cycloalkyl, aryl, heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, C6-C10 aryl; R c1 , R c2 , and R c3 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; L is independent of each other: absent, O, NR d5 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; R e are each independently selected from the group consisting of hydrogen, deuterium, Na, K, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; R h are each independently C1-C6 alkyl, -NHC(O)R g1 , -OC(O)R g2 , -OP(O)(ONa) 2 , -NHC(O)OR d6, -OC(O)OR d7 , -OC(O)NHR d8 selected from the group consisting of; R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 are each independently one or more R selected from the group consisting of hydrogen, deuterium, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl. f may be optionally substituted with a group; R f are each independently a halogen, a C1-C6 alkyl, a halogenated C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C6-C10 aryl, a halogenated C6-C10 aryl, a C3-C7 cycloalkyl, a 3- to 15-membered heterocyclyl, -NR g3 R g4 , -OR g5 , -NHC(O)R g6 , -OC(O)R g7 selected from the group consisting of; R g1 , R g2 , R g3 , R g4 , R g5 , R g6 , and R g7 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from the group consisting of hydrogen and amino; Y' is C or S; y' is an integer equal to or greater than 0; or y' is selected from the group consisting of 0, 1, 2, and 3; or y' is 0 or 1; n is 0 or 1; Alternatively, formula I is [ka] or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystal form, metabolite form, or any combination or mixture thereof.

[0007] In some embodiments, in the above formula I, when x is 0 and A' is absent; with respect to A, R 1 and R 2 are independent of each other, C1-C6 alkyl, -OR a1 , where R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-OR b2 , -(C1-C6 alkyl) n -O-(CO)-R b3 , -(C1-C6 alkyl) n -O-(CO)-OR b4 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); -NR a2 R a3 , where R a2 and Ra3 are each independently hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-OR b2 , -(C1-C6 alkyl) n -O-(CO)-R b3 , -(C1-C6 alkyl) n -O-(CO)-OR b4 , -(C1-C6 alkyl) n -(CO)-NR b5 R b6 wherein the alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R b1 , R b2 , R b3 , R b4 , R b5 and R b6 are each independently hydrogen, hydroxyl, amino, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-OR c1 , -(C1-C6 alkyl) n -O-(CO)-R c2 , -(C1-C6 alkyl) n -O-(CO)-OR c3 wherein said alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, and C6-C10 aryl; R c1 , R c2 and R c3are each independently selected from the group consisting of hydrogen, hydroxyl, amino, C1-C6 alkyl, and C3-C7 cycloalkyl; is selected from the group consisting of:

[0008] In some embodiments, in the above formula I, when x is 0 and A' is absent; with respect to A, R 1 and R 2 are independent of each other, Hydroxyl, C1-C6 alkyl, -OR a1 , where R a1 is C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, -(C1-C6 alkyl) n -O-(CO)-OR b4 which may be further substituted with one or more C6-C10 aryl groups; R b4 is selected from the group consisting of C1-C6 alkyl, and n is 1; -NR a2 R a3 , where R a2 and R a3 are independent of each other, hydrogen, C1-C6 alkyl, where the C1-C6 alkyl may be optionally further substituted with one or more C6-C10 aryl groups; -(C1-C6 alkyl) n -O-(CO)-R b3 , where R b3 is C1-C6 alkyl further substituted with C6-C10 aryl; -(C1-C6 alkyl) n -(CO)-R b1 , where R b1 is hydroxyl, n or 1; -(C1-C6 alkyl) n -(CO)-NR b5 R b6 , where n is 1 and R b5 and R b6are each independently hydrogen or a 3- to 15-membered heterocyclyl, said heterocyclic ring being further substituted with one or more C1-C6 alkyl groups; -(C1-C6 alkyl) n -(CO)-OR b2 wherein the alkyl is substituted with one or more C6-C10 aryl groups, n is 1, and R b2 is C1-C6 alkyl or -(C1-C6 alkyl) n -O-(CO)-OR c and R c is C1-C6 alkyl; Selected from the group consisting of: is selected from the group consisting of:

[0009] In some embodiments, in the above formula I, when x is 0 and A' is absent; for A, R 3 and R 4 are each independently hydrogen, hydroxyl, C1-C6 alkyl, -(CO)-(L) n -R d2 , -(CO)O-(L) n -R d3 wherein said alkyl, aryl and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; Each L is absent, O, NR d5 , C1-C6 alkyl; R d5 , R d2 and R d3 are each independently selected from the group consisting of hydrogen, amino, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, and heterocyclyl are each independently selected from the group consisting of one or more R f may be optionally substituted with a group; R fare each independently selected from the group consisting of amino, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C6-C10 aryl, halogenated C6-C10 aryl, C3-C7 cycloalkyl, and 3-15 membered heterocyclyl.

[0010] In some embodiments, in the above formula I, when x is 0 and A' is absent; with respect to A, R 3 and R 4 are independent of each other, hydrogen, Hydroxyl, C1-C6 alkyl, -(CO)-(L) n -R d2 , where (L) n and R d2 The combination options are the following: 1) L does not exist, and R d2 is an R of 1 or more. f is a C1-C6 alkyl further substituted with a R f is amino; 2) L does not exist, and R d2 is H; 3) L does not exist, and R d2 is C1-C6 alkyl; 4) L does not exist, and R d2 is an R of 1 or more. f is a C1-C6 alkyl further substituted with a R f is selected from the group consisting of C1-C6 alkyl and amino; 5) L does not exist, and R d2 is 3- to 15-membered heterocyclyl; 6) L is NR d5 and R d5 is C1-C6 alkyl, n is 1, and R d2 is H; selected from the group consisting of; -(CO)O-(L) n -R d3 ;where (L) n and R d3 The combination options are: L does not exist, Rd3 is an arbitrary R greater than or equal to 1. f and R is a C1-C6 alkyl group optionally further substituted with a group. f is selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, polycyclic aromatic hydrocarbonyl (e.g., fluorenyl); is selected from the group consisting of:

[0011] In some embodiments, in formula I above, when x is 1 or 2 and A is the same as or different from A', Regarding A, R 1 and R 2 are each independently C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 selected from the group consisting of; R 3 and R 4 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from the group consisting of hydrogen, amino; or R 5 is selected from the group consisting of hydrogen; Y is C; y is selected from the group consisting of 0, 1, 2, 3; or y is 0 or 1.

[0012] In some embodiments, in formula I above, when x is 1 or 2 (or x is 1) and A is the same as or different from A', Regarding A', R 1 ' and R 2 ' are each independently C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 selected from the group consisting of; R 3 ' and R 4' are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogen, C1-C6 alkyl, aryl (or C6-C12 aryl), or heterocyclyl; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from the group consisting of hydrogen, amino; or R 5 is selected from the group consisting of hydrogen; Y' is C; y' is selected from the group consisting of 0, 1, 2, 3; or y is 0 or 1.

[0013] In some embodiments, in the above formula I, when x is 0 and A' is absent; with respect to A, R 1 teeth, C1-C6 alkyl, -OR a1 , where R a1is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl) n -O-(CO)-R b3 wherein the alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); -NR a2 R a3 , where R a2 and R a3 are each independently hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -O-(CO)-R b3 wherein the alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R b1 and R b3 are each independently selected from the group consisting of hydrogen, hydroxyl, amino, C1-C6 alkyl, and C6-C10 aryl, wherein the alkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, and C6-C10 aryl.

[0014] In some embodiments, in the above formula I, when x is 0 and A' is absent; with respect to A, R 1 teeth, Hydroxyl, C1-C6 alkyl, -OR a , where R a1 is C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, -(C1-C6 alkyl) n -O-(CO)-OR b4 and R b4 is selected from the group consisting of C1-C6 alkyl, and n is 1; -NR a2 R a3 , where R a2 and R a3 are each independently hydrogen; C1-C6 alkyl optionally further substituted with one or more C6-C10 aryl groups; -(C1-C6 alkyl) n -O-(CO)-R b3 , R b3 is C1-C6 alkyl further substituted with C6-C10 aryl; -(C1-C6 alkyl) n -(CO)-R b1 , R b1 is hydroxyl and n is 1; is selected from the group consisting of:

[0015] In some embodiments, in the above formula I, when x is 0 and A' is absent; with respect to A, R 1 is hydroxyl, methoxy, -OCH 2 CH=CH 2 , ethoxy, -OC(CH 3 ) 3 , -OCH 2 C 6 H 5 , -OC 6 H 11 , Trt-NH-, [ka] , C.H.3 -NH-, HOCOCH 2 NH-, -OCH(CH 3 ) 2 , -CH 3 , [ka] where Trt represents trityl.

[0016] In some embodiments, in the above formula I, when x is 0 and A' is absent; with respect to A, R 2 teeth, C1-C6 alkyl, -OR a1 , where R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C6-C10 aryl, -(C1-C6 alkyl) n -O-(CO)-OR b4 wherein said alkyl, alkenyl, and aryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, and -(C1-C6 alkyl)-(C6-C10 aryl); -NR a2 R a3 , where R a2 and R a3 are each independently hydrogen, C1-C6 alkyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-OR b2 , -(C1-C6 alkyl) n -(CO)-NR b5 R b6 and 3-15 membered heterocyclyl, wherein the alkyl and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, and C1-C6 alkyl; selected from the group consisting of; R b1 , Rb2 , R b4 , R b5 and R b6 are each independently hydrogen, hydroxyl, C1-C6 alkyl, C3-C7 cycloalkyl, -(C1-C6 alkyl) n -O-(CO)-OR c3 wherein said cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, C6-C10 aryl; R c3 are each independently selected from the group consisting of hydrogen, hydroxyl, amino, C1-C6 alkyl, and C3-C7 cycloalkyl.

[0017] In some embodiments, in the above formula I, when x is 0 and A' is absent; with respect to A, R 2 teeth, Hydroxyl, -OR a1 , where R a1 is C1-C6 alkyl, C2-C6 alkenyl, -(C1-C6 alkyl) n -O-(CO)-OR b4 which may be optionally further substituted with one or more C6-C10 aryl groups; R b4 is selected from the group consisting of C1-C6 alkyl, and n is 1; -NR a2 R a3 , R a2 and R a3 are each independently hydrogen; -(C1-C6 alkyl) n -(CO)-NR b5 R b6 , n is 1, and R b5 and R b6 are each independently hydrogen or a 3- to 15-membered heterocyclyl, said heterocyclyl being further substituted with one or more C1-C6 alkyl groups; -(C1-C6 alkyl) n -(CO)-R b1 , n is 1, and R b1is hydroxyl; -(C1-C6 alkyl) n -(CO)-OR b2 wherein the alkyl is substituted with one or more C6-C10 aryl groups, n is 1, and R b2 is C1-C6 alkyl or -(C1-C6 alkyl) n -O-(CO)-OR c3 and R c3 is C1-C6 alkyl; is selected from the group consisting of:

[0018] In some embodiments, in the above formula I, when x is 0 and A' is absent; with respect to A, R 2 is hydroxyl, methoxy, -OCH 2 CH=CH 2 , ethoxy, -OC(CH 3 ) 3 , -OCH 2 C 6 H 5 , [ka] , -OCH(CH 3 ) 2 , [ka] selected from the group consisting of; R 3 and R 4 are each independently hydrogen, hydroxyl, Boc, Cbz, -CH 3 , Fmoc, -COOCH 2 C 6 H 5 , -COCH 2 NH 2 , -CHO, -COCH 3 , [ka] , -COCH 2 CH 3 , -COCH(CH 3 )2 , -COCH(CH 2 ) 2 , -COOCH 3 , -CON(CH 3 ) 2 , -COCH(CH 3 )(NH 2 wherein Boc represents tert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, and Fmoc represents fluorenylmethoxycarbonyl.

[0019] In some embodiments, in formula I above, when x is 1 and A is the same as or different from A', Regarding A, R 1 is -O-, C1-C6 alkyl, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 1 is -O-, hydroxyl, -OR a R a is C1-C6 alkyl; or R 1 is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; Y is C; y is 0; R 2 is -O-, C1-C6 alkyl, -OR a1 wherein R a1is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 2 is hydroxyl, -O-, -OR a R a is C1-C6 alkyl; or R 2 is selected from the group consisting of hydroxyl, -O-, and methoxy; R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 and R 4 are each independently hydrogen; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from the group consisting of hydrogen, amino; or R 5 is selected from the group consisting of hydrogen.

[0020] In some embodiments, in formula I above, when x is 1 and A is the same as or different from A', Regarding A', R 1 ' is -O-, C1-C6 alkyl, -OR a1 wherein R a1is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 1 is -O-, hydroxyl, -OR a R a is C1-C6 alkyl; or R 1 ' is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; Y' is C; y' is 0; R 2 ' is -O-, C1-C6 alkyl, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 2 ' is hydroxyl, -O-, -OR a R a is C1-C6 alkyl; or R 2 ' is selected from the group consisting of hydroxyl, -O-, methoxy; R 3 ' and R 4 ' are independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 ' and R 4 ' are each independently hydrogen; R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 ' is selected from the group consisting of hydrogen and amino; or R 5 ' is selected from the group consisting of hydrogen.

[0021] In some embodiments, in formula I above, when x is 2 and A is the same as or different from A', R in Unit A 1 , R 2 , R 3 , and R 4 One of the adjacent units A' is R 1 ', R 2 ', R 3 ', and R 4 ' and L 1 Connected via; Each L 1 are independently selected from the group consisting of absent, O, S, carbonyl, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-), cycloalkyl (or C3-C7 cycloalkyl), heteroalkyl (or 3-7 membered heteroalkyl; for example, -O-alkyl-O- (or -O-C1-C6 alkyl-O-)), wherein the alkyl, cycloalkyl, and heteroalkyl are optionally substituted with one or more groups independently selected from the group consisting of Z; Z is independently selected from the group consisting of halogen, amino, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), haloalkyl (or halogenated C1-C6 alkyl), cycloalkyl (or C3-C7 cycloalkyl), aryl (or C6-C12 aryl), and heterocyclyl; Or L 1 is selected from the group consisting of absent, -CR'R'', where R' and R'' are each independently H, C1-C6 alkyl (or C1-C3 alkyl); Or L 1 , absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 selected from the group consisting of; Or L 1 -CH 2 - is selected from the group consisting of

[0022] In some embodiments, in formula I above, when x is 2 and A is the same as or different from A', Regarding A, R 1 is -O-, C1-C6 alkyl, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 1 is -O-, hydroxyl, -OR a R a is C1-C6 alkyl; or R1 is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; or R 1 is selected from the group consisting of methoxy; Y is C; y is 0; R 2 is -O-, C1-C6 alkyl, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 2 is hydroxyl, -O-, -OR a R a is C1-C6 alkyl; or R 2 is selected from the group consisting of hydroxyl, -O-, and methoxy; or R 2 is selected from the group consisting of -O-; R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 and R 4 are each independently hydrogen; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from the group consisting of hydrogen, amino; or R 5 is selected from the group consisting of hydrogen.

[0023] In some embodiments, in formula I above, when x is 2 and A is the same as or different from A', Regarding A', R 1 ' is -O-, C1-C6 alkyl, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 1 is -O-, hydroxyl, -OR a R a is C1-C6 alkyl; or R 1 ' is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; or R 1 ' is selected from the group consisting of methoxy; Y' is C; y' is 0; R 2 ' is -O-, C1-C6 alkyl, -OR a1 wherein R a1is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 2 ' is hydroxyl, -O-, -OR a R a is C1-C6 alkyl; or R 2 ' is selected from the group consisting of hydroxyl, -O-, methoxy; Furthermore, R 2 ' is selected from the group consisting of -O-; R 3 ' and R 4 ' are independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 ' and R 4 ' are each independently hydrogen; R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 ' is selected from the group consisting of hydrogen and amino; or R 5 ' is selected from the group consisting of hydrogen.

[0024] In some embodiments, the present invention provides a method for the preparation of a method for the treatment of a disease comprising the steps of: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression In the manufacture of a medicine or medicament for use in at least one of the following: A-(L 1 ) x -A' (Formula I) In the formula, A is [ka] and A' is [ka] where A and A' are the same or different; Where: x is selected from the group consisting of 0, 1, and 2; 1) x is 0 and A' does not exist; Regarding A, R 1 and R 2 are independent of each other, -OR a1 , -NR a2 R a3 selected from the group consisting of; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; 2) When x is 1 or 2, and A and A' are the same or different, R in Unit A 1 and R 2 Either of the R of the adjacent unit A' 1 ' and R 2 ' and L 1 Connected via; Each L 1are independently a unit connecting group selected from the group consisting of absent, O, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkyl-O- (or -O-C1-C6 alkyl-O-), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-); Regarding A, R 1 and R 2 are independent of each other, -OR a1 , -NR a2 R a3 selected from the group consisting of; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; Regarding A', R 1 ' and R 2 ' are independent of each other, -OR a1 , -NR a2 R a3 selected from the group consisting of; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystal form, metabolite form, or any combination or mixture thereof.

[0025] In some embodiments, in the above formula I, when x is 0 and A' is absent; with respect to A, R 1 are independent of each other, -OR a1, -NR a2 R a3 selected from the group consisting of; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; or R 1 are each independently -OH, -O-(C1-C3 alkyl), -O-(C1-C3 alkenyl), -NH 2 , -NH(C1-C3 alkyl), -N(C1-C3 alkyl) 2 selected from the group consisting of; or R 1 are each independently -OH, methoxy, ethoxy, -OCH(CH 3 ) 2 , -NH 2 selected from the group consisting of; R 2 are independent of each other, -OR a1 , -NR a2 R a3 selected from the group consisting of; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; or R 2 are each independently -OH, -O-(C1-C3 alkyl), -O-(C1-C3 alkenyl), -NH 2 , -NH(C1-C3 alkyl), -N(C1-C3 alkyl) 2 selected from the group consisting of; or R 2 are each independently -OH, methoxy, ethoxy, -OCH(CH 3 ) 2 , -NH 2 selected from the group consisting of;

[0026] In some embodiments, in formula I above, when x is 1 and A is the same as or different from A', R in Unit A 1 and R 2 Either of the R of the adjacent unit A' 1 ' and R 2 ' or L 1 Connected via; Each L 1 are independently a unit connecting group selected from the group consisting of absent, O, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkyl-O- (or -O-C1-C6 alkyl-O-), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-); Or L 1 is selected from the group consisting of absent, alkyl (or C1-C3 alkyl), alkenyl (or C2-C3 alkenyl); Or L 1 , absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 selected from the group consisting of; Or L 1 -CH 2 - is selected from the group consisting of

[0027] In some embodiments, in formula I above, when x is 1 and A is the same as or different from A', Regarding A, R 1 -O-, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; or R 1 is selected from the group consisting of -O-, hydroxyl, -O-(C1-C3 alkyl); or R 1is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; R 2 -O-, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; or R 2 is selected from the group consisting of -O-, hydroxyl, -O-(C1-C3 alkyl); or R 2 is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 is selected from the group consisting of:

[0028] In some embodiments, in formula I above, when x is 1 and A is the same as or different from A', Regarding A', R 1 -O-, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; or R 1 is selected from the group consisting of -O-, hydroxyl, -O-(C1-C3 alkyl); or R 1 is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; R 2 -O-, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; or R 2is selected from the group consisting of -O-, hydroxyl, -O-(C1-C3 alkyl); or R 2 is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 is selected from the group consisting of:

[0029] In some embodiments, in formula I above, when x is 2 and A is the same as or different from A', R in Unit A 1 and R 2 Either of the R of the adjacent unit A' 1 ' and R 2 ' and L 1 Connected via; Each L 1 are independently a unit connecting group selected from the group consisting of absent, O, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkyl-O- (or -O-C1-C6 alkyl-O-), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-); Or L 1 is selected from the group consisting of absent, alkyl (or C1-C3 alkyl), alkenyl (or C2-C3 alkenyl); Or L 1 , absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 selected from the group consisting of; Or L 1 -CH 2 - is selected from the group consisting of

[0030] In some embodiments, in formula I above, when x is 2 and A is the same as or different from A', Regarding A, R 1 -O-, -OR a1 wherein R a1is selected from the group consisting of hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; or R 1 is selected from the group consisting of -O-, hydroxyl, -O-(C1-C3 alkyl); or R 1 is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; R 2 -O-, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; or R 2 is selected from the group consisting of -O-, hydroxyl, -O-(C1-C3 alkyl); or R 2 is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 is selected from the group consisting of:

[0031] In some embodiments, in formula I above, when x is 2 and A is the same as or different from A', Regarding A', R 1 -O-, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; or R 1 is selected from the group consisting of -O-, hydroxyl, -O-(C1-C3 alkyl); or R 1 is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; R2 -O-, -OR a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; or R 2 is selected from the group consisting of -O-, hydroxyl, -O-(C1-C3 alkyl); or R 2 is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 is selected from the group consisting of:

[0032] In a second aspect of the present invention, the present invention provides a method for producing a composition comprising the steps of: below: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression In the manufacture of a medicine or medicament for use in at least one of the following, [ka] I-4 During the ceremony, Rn 1 and Rn 2 are each independently C1-C6 alkyl, -OR a4 , -OL 2 -OR a4 , -NR a5 R a6 selected from the group consisting of; Each R a4is hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, C6-C10 aryl, C6-C10 aryl-C1-C6 alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclyl-C1-C6 alkyl, C1-C6 alkoxyacyl, -(O=)C-CH 2 -CH(NH 2 )-COOR m , -(O=)C-CH(NH 2 )-CH 2 -COOR m , Ph-CH 2 -CH(NH 2 )-C(=O)-, NH 2 -CH 2 -C(=O)-, CH 3 -CH(NH 2 )-C(=O)-, R m OOC-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, -C(=O)-(CH 2 ) 2 -CH(NH 2 )-COOR m , R m OOC-CH(NH 2 )-CH 2 -SS-CH 2 -CH(NH 2 )-C(=O)-, H 2 N-CO-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, * N=CH-NH-CH= * C-CH 2 -CH(NH 2 )-C(=O)-(or [ka] ), HO-p-Ph-CH 2 -CH(NH 2 )-C(=O)-, HO-CH 2 -CH(NH 2 )-C(=O)-, CH3 -S-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(NH 2 )-C(=O)-, (CH 3 ) 2 CH-CH 2 -CH(NH 2 )-C(=O)-; where Ph represents phenyl, such as HO-p-Ph-CH 2 -CH(NH 2 )-C(=O)- represents p-hydroxybenzylaminomethylcarbonyl; R a5 and R a6 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclylaminoacyl-C1-C6 alkyl, Ph-CH 2 -CH(COOR m )-, -CH 2 -COOR m , -CH(COOR m )-CH 2 -COOR m , -CH(CH 3 )-COOR m , R m OOC-(CH 2 ) 2 -CH(COOR m )-, -CH(COOR m )-CH 2 -SS-CH 2 -CH(NH 2 )-COOR m , H 2 N-CO-(CH 2 ) 2 -CH(COOR m )-, * N=CH-NH-CH= * C-CH 2 -CH(COOR m )-(or [ka] ), HO-p-Ph-CH 2 -CH(COOR m )-, HO-CH 2 -CH(COOR m )-, CH 3 -S-(CH 2 ) 2 -CH(COOR m )-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(COOR m )-, (CH 3 ) 2 CH-CH 2 -CH(COOR m )- selected from the group consisting of; Each R m is hydrogen, C1-C6 alkyl, C1-C6 alkoxyacyl-OL 3 - independently selected from the group consisting of; L 2 and L 3 are each independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and 3- to 7-membered heteroalkyl; L 2 and L 3 is optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, and hydroxyl; Rn 3 and Rn 4 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, H(C=O)-, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, aminoacyl, C1-C6 alkylacyl, C1-C6 alkoxyacyl, C1-C6 alkylaminoacyl, amino-C1-C6 alkanoyl, 3-15 membered heterocyclyl acyl, C3-C7 cycloalkylacyl, C6-C10 aryl-C1-C6 alkoxyacyl; Y is C or S; y is 0, 1, 2 or 3; or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystal form, metabolite form, or any combination or mixture thereof.

[0033] In some embodiments, in formula I-4, Rn 1 and Rn 2 are each independently C1-C6 alkyl, -OR a4 , -OL 2 -OR a4 , -NR a5 R a6 selected from the group consisting of; Each R a4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, C6-C10 aryl, C6-C10 aryl-C1-C6 alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclyl-C1-C6 alkyl, C1-C6 alkoxyacyl, -(O=)C-CH 2 -CH(NH 2 )-COOR m , Ph-CH 2 -CH(NH 2 )-C(=O)-, NH 2 -CH 2 -C(=O)-, CH 3 -CH(NH 2 )-C(=O)-, R m OOC-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, R m OOC-CH(NH 2 )-CH 2 -SS-CH 2 -CH(NH 2 )-C(=O)-, H 2 N-CO-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, * N=CH-NH-CH= * C-CH 2-CH(NH 2 )-C(=O)-(or [ka] ), HO-p-Ph-CH 2 -CH(NH 2 )-C(=O)-, HO-CH 2 -CH(NH 2 )-C(=O)-, CH 3 -S-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(NH 2 )-C(=O)-, (CH 3 ) 2 CH-CH 2 -CH(NH 2 )—C(═O)—; R a5 and R a6 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclylaminoacyl-C1-C6 alkyl, Ph-CH 2 -CH(COOR m )-, -CH 2 -COOR m , -CH(COOR m )-CH 2 -COOR m , -CH(CH 3 )-COOR m , R m OOC-(CH 2 ) 2 -CH(COOR m )-, -CH(COOR m )-CH 2 -SS-CH 2 -CH(NH 2 )-COOR m , H 2 N-CO-(CH 2 ) 2 -CH(COOR m)-, * N=CH-NH-CH= * C-CH 2 -CH(COOR m )-(or [ka] ), HO-p-Ph-CH 2 -CH(COOR m )-, HO-CH 2 -CH(COOR m )-, CH 3 -S-(CH 2 ) 2 -CH(COOR m )-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(COOR m )-, (CH 3 ) 2 CH-CH 2 -CH(COOR m )- selected from the group consisting of; Each R m is hydrogen, C1-C6 alkyl, C1-C6 alkoxyacyl-OL 3 - independently selected from the group consisting of; L 2 and L 3 are each independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, and 3- to 7-membered heteroalkyl; L 2 and L 3 each may be optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, and hydroxyl; Rn 3 and Rn 4are each independently selected from the group consisting of hydrogen, hydroxyl, H(C=O)-, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, aminoacyl, C1-C6 alkylacyl, C1-C6 alkoxyacyl, C1-C6 alkylaminoacyl, amino-C1-C6 alkanoyl, 3-15 membered heterocyclyl acyl, C3-C7 cycloalkylacyl, C6-C10 aryl-C1-C6 alkoxyacyl; Y is C; y is 0, 1 or 2.

[0034] In some embodiments, in formula I, -4, Rn 1 and Rn 2 are each independently C1-C6 alkyl, -OR a4 , -O-L2-OR a4 , -NR a5 R a6 selected from the group consisting of; Each R a4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, C6-C10 aryl-C1-C6 alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclyl-C1-C6 alkyl, -(O=)C-CH 2 -CH(NH 2 )-COOR m , Ph-CH 2 -CH(NH 2 )-C(=O)-, NH 2 -CH 2 -C(=O)-, CH 3 -CH(NH 2 )-C(=O)-, R m OOC-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, R m OOC-CH(NH 2 )-CH 2 -SS-CH 2 -CH(NH 2 )-C(=O)-, H 2 N-CO-(CH 2 )2 -CH(NH 2 )-C(=O)-, * N=CH-NH-CH= * C-CH 2 -CH(NH 2 )-C(=O)-(or [ka] ), HO-p-Ph-CH 2 -CH(NH 2 )-C(=O)-, HO-CH 2 -CH(NH 2 )-C(=O)-, CH 3 -S-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(NH 2 )-C(=O)-, (CH 3 ) 2 CH-CH 2 -CH(NH 2 )—C(═O)—; R a5 and R a6 are each independently hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclylaminoacyl-C1-C6 alkyl, Ph-CH 2 -CH(COOR m )-, -CH 2 -COOR m , -CH(COOR m )-CH 2 -COOR m , -CH(CH 3 )-COOR m , R m OOC-(CH 2 ) 2 -CH(COOR m )-, -CH(COOR m )-CH 2 -SS-CH 2 -CH(NH 2 )-COORm , H 2 N-CO-(CH 2 ) 2 -CH(COOR m )-, * N=CH-NH-CH= * C-CH 2 -CH(COOR m )-(or [ka] ), HO-p-Ph-CH 2 -CH(COOR m )-, HO-CH 2 -CH(COOR m )-, CH 3 -S-(CH 2 ) 2 -CH(COOR m )-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(COOR m )-, (CH 3 ) 2 CH-CH 2 -CH(COOR m )- selected from the group consisting of; Each R m is hydrogen, C1-C6 alkyl, C1-C6 alkoxyacyl-OL 3 - independently selected from the group consisting of; L 2 and L 3 are each independently selected from the group consisting of C1-C6 alkyl; L 2 and L 3 each may be optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, and hydroxyl; Rn 3 and Rn 4are each independently selected from the group consisting of hydrogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, aminoacyl, C1-C6 alkylacyl, C1-C6 alkoxyacyl, C1-C6 alkylaminoacyl, amino-C1-C6 alkanoyl, 3-15 membered heterocyclyl acyl, C3-C7 cycloalkyl acyl, C6-C10 aryl-C1-C6 alkoxyacyl; Y is C; y is 0, 1 or 2.

[0035] In some embodiments of the first and second aspects of the invention, the compound represented by formula I, or I-1, I-2, I-3, or I-4 is: [ka] [ka] [ka] is selected from the group consisting of:

[0036] In some embodiments of the first and second aspects of the invention, the compound represented by formula I, or I-1, I-2, I-3, or I-4 is: [ka] is selected from the group consisting of:

[0037] In a third aspect of the present invention, the present invention provides a method for the preparation of a medicament for the treatment of a cancer, comprising: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression Use of a peptide containing 2 to 10 or 2 to 3 amino acids, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystal form, metabolite form, or any combination or mixture thereof, in the manufacture of a medicine or medicament for use in at least one of the following: In the peptide, at least one amino acid is aspartic acid, and when the aspartic acid has a free carboxyl group, the free carboxyl group may optionally be esterified with a C1-C6 alkyl-OH; Optionally, the amino acid is aspartic acid, phenylalanine, glycine, alanine, glutamic acid, cystine, glutamine, histidine, tyrosine, serine, methionine, arginic acid, or leucine; or the free amino acid located at one end of said peptide is aspartic acid, and optionally, the free carboxyl group of said free aspartic acid is optionally esterified with C1-C6 alkyl-OH; Optionally, the remaining amino acids are aspartic acid, phenylalanine, glycine, alanine, glutamic acid, cystine, glutamine, histidine, tyrosine, serine, methionine, arginine, or leucine. Provide use.

[0038] In a fourth aspect of the present invention, the present invention provides a method for the preparation of ... medicament for use in a pharmaceutical composition comprising: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression or a compound represented by the above formula I-4 or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof, which is used for at least one of the above. Alternatively, a peptide containing 2 to 10 or 2 to 3 amino acids as described in the above third aspect, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof, is provided.

[0039] In a fifth aspect of the present invention, the present invention provides the following advantages: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression The present invention provides a method for obtaining a compound represented by formula I above, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula I above, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof, or a compound represented by formula I-4 above, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof, or a peptide containing 2 to 10 or 2 to 3 amino acids as described in the third aspect above, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof.

[0040] In the above first to fifth aspects of the present invention, in some embodiments, liver fibrosis includes, but is not limited to, liver fibrosis caused by chronic viral liver disease, liver fibrosis caused by alcoholism or long-term drinking, liver fibrosis caused by non-alcoholic factors such as obesity, portal hepatic fibrosis caused by repeated infection with schistosomiasis, biliary hepatic fibrosis caused by chronic cholestasis, metabolic hepatic fibrosis caused by hepatocyte degeneration and hemoglobin deposition, toxic hepatic fibrosis caused by various harmful substances, malnutrition hepatic fibrosis caused by a low protein diet and a preference for fatty fried foods, and cardiogenic hepatic fibrosis caused by chronic congestive heart failure.

[0041] In a sixth aspect of the present invention, the present invention relates to the use of a pharmaceutical composition in the manufacture of a medicament, the pharmaceutical composition comprising a compound represented by formula I above, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystalline form, metabolite form, or any combination or mixture thereof, or a compound represented by formula I-4 above, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvent, isotopic compound, crystalline form, metabolite form, or any combination or mixture thereof, or a peptide containing 2-10 or 2-3 amino acids, as described in the third aspect above, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystalline form, metabolite form, or any combination or mixture thereof, and the medicament comprises one of the following: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression The present invention provides a method for the use of the present invention, the method being used for at least one of the following:

[0042] In a seventh aspect of the present invention, the present invention provides a method for the preparation of a medicament for the treatment of a cancer, comprising: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression The pharmaceutical composition is used for at least one of the above, comprising a compound represented by the above formula I, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof; or a compound represented by the above formula I-4, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvent, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof; or a peptide containing 2 to 10 or 2 to 3 amino acids as described in the above third aspect, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof.

[0043] In an eighth aspect of the present invention, the present invention has the following advantages: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression The present invention provides a method for obtaining a compound represented by formula I above, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula I above, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof, or a compound represented by formula I-4 above, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof, or a peptide containing 2 to 10 or 2 to 3 amino acids as described in the third aspect above, or a pharma- ceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope compound, crystalline form, metabolite form, or any combination or mixture thereof.

[0044] In the above-mentioned sixth to eighth aspects of the present invention, in some embodiments, liver fibrosis includes, but is not limited to, liver fibrosis caused by chronic viral liver disease, liver fibrosis caused by alcoholism or long-term alcohol consumption, liver fibrosis caused by non-alcoholic factors such as obesity, portal hepatic fibrosis caused by repeated infections with schistosomiasis, biliary hepatic fibrosis caused by chronic cholestasis, metabolic hepatic fibrosis caused by hepatocyte degeneration and hemoglobin deposition, toxic hepatic fibrosis caused by various harmful substances, malnutrition hepatic fibrosis caused by a low protein diet and a preference for fatty fried foods, and cardiogenic hepatic fibrosis caused by chronic congestive heart failure.

[0045] In some embodiments, the pharmaceutical composition contains additional active ingredients, such as: other amino acids for improving liver function (including but not limited to alanine, glutamic acid, cystine, glutamine, glycine, histidine, tyrosine, serine, methionine, arginine, leucine), cholesterol absorption inhibitors (e.g., ezetimibe), HSC activation and proliferation inhibitors (e.g., pirfenidone, fluorophenidone, pegbelfermin), PCSK9 inhibitors, PPAR agonists (e.g., gemfibrozil, fenofibrate, clofibrate, bezafibrate, pemafibrate, elafibranor), ACE inhibitors, CC inhibitors, R2 / 5 inhibitors, TLR4 inhibitors, LOXL2 inhibitors, TIMP-1 inhibitors, FXR agonists, AT1R blockers, NOX inhibitors, calcium channel blockers, ARBs, diuretics, renin, GLP-1 or its synthetic variants, insulin or its synthetic variants, metformin, sulfonylurea compounds, thiazolidinediones (TZDs), SGLT2 inhibitors, DPP-IV inhibitors, HMGCoA reductase inhibitors, proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors, gemcabene (CI-1027), ACC inhibitors, ApoC-III inhibitors, ACL inhibitors (e.g., bepedic acid acid), prescription fish oils, CETP inhibitors, ursodeoxycholic acid, obeticholic acid, polyene phosphatidylcholine, glucocorticoids, silymarin, glycyrrhizic acid preparations (e.g., magnesium isoglycyrrhizinate injection and diammonium isoglycyrrhizinate enteric coated capsules), and combinations thereof. In some embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition is a solid formulation, an injectable formulation, a topical formulation, a spray formulation, a liquid formulation, or a compound formulation.

[0046] In a ninth aspect of the present invention, the present invention provides a compound of formula II: A 1 -(L 1 ) x -A 1 'Formula II In the formula, A 1teeth, [ka] And A 1 'teeth, [ka] And A 1 and A 1 'same or different; x is selected from the group consisting of 0, 1 and 2; 1) If x is 0 and A' does not exist; A 1 Regarding R 1 and R 2 teeth, [ka] , -OR a are independently selected from the group consisting of: R a are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-OR b2 , -(C1-C6 alkyl) n -O-(CO)-R b3 , -(C1-C6 alkyl) n -NR b4 -(CO)-R b5 , -(C1-C6 alkyl) n -NR b6 -(CO)-OR b7wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl; R 3 and R 4 is -COCH(CH 3 )(NH 2 ), hydrogen, -COCH 2 CH 3 , deuterium, and C1-C6 alkyl, wherein said alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl, and heterocyclyl; And if "x is 0 and A' does not exist", then A 1 meets the following conditions (1), (2), (3) or (4): (1)R 1 and R 2 At least one of [ka] or [ka] is; (2)R 3 and R 4 At least one of -COCH(CH 3)(NH 2 ) or -COCH 2 CH 3 is; (3)R 1 and R 2 but, [ka] , hydroxyl, and methoxy, while R 3 and R 4 is hydrogen, -COCH 2 CH 3 and -COCH(CH 3 )(NH 2 ), A 1 satisfies the following conditions: R 1 and R 2 When one of R is hydroxyl or methoxy, R 1 and R 2 The other is [ka] or [ka] or R 3 and R 4 One is -COCH(CH 3 )(NH 2 ) is; (4)R 1 but [ka] , hydroxyl, and methoxy; R 2 but [ka] , hydroxyl, [ka] , methoxy, and R3 and R 4 is hydrogen, -COCH 2 CH 3 and -COCH(CH 3 )(NH 2 When independently selected from the group consisting of A 1 satisfies the following conditions: R 1 When R is hydroxyl or methoxy, 2 teeth [ka] or [ka] or R 3 and R 4 One is -COCH(CH 3 )(NH 2 ) or R 2 When R is hydroxyl or methoxy, 1 teeth [ka] or R 3 and R 4 One of them is -COCH(CH 3 )(NH 2 ) is; 2) x is 1 and A 1 and A 1 ' are the same or different, Unit A 1 R 1 , R 2 , R 3 , and R 4 One of the adjacent units A 1 'R 1 ', R 2 ', R 3 ' and R 4 'L in one of 1 Connected via; Each L 1are independently selected from the group consisting of absent, O, S, carbonyl, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkyl-O- (or -O-C1-C6 alkyl-O-), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-), cycloalkyl (or C3-C7 cycloalkyl), and heteroalkyl (or 3-7 membered heteroalkyl), and the alkyl, cycloalkyl, and heteroalkyl may be optionally substituted with one or more groups independently selected from the group consisting of Z; Z is independently selected from the group consisting of halogen, amino, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), haloalkyl (or halogenated C1-C6 alkyl), cycloalkyl (or C3-C7 cycloalkyl), aryl (or C6-C12 aryl), and heterocyclyl; Or L 1 is selected from the group consisting of absent, -CR'R'', where R' and R'' are each independently H, C1-C6 alkyl (or C1-C3 alkyl); Or L 1 , absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 selected from the group consisting of; A 1 Regarding R 1 and R 2 are each independently C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 selected from the group consisting of; R 3 and R 4are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 1 is -O-, C1-C6 alkyl, -OR a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl) n -O-(CO)-R b1 wherein the alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 is -O-, hydroxyl, -ORa R a is C1-C6 alkyl; or R 1 is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; or R 2 is -O-, C1-C6 alkyl, -OR a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl) n -O-(CO)-R b1 wherein the alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2 is hydroxyl, -O-, -OR a R a is C1-C6 alkyl; or R 2 is selected from the group consisting of hydroxyl, -O-, and methoxy; R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 and R 4 are, independently of each other, hydrogen; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 is selected from the group consisting of hydrogen and amino; or R 5 is selected from the group consisting of hydrogen; Y is C; y is selected from the group consisting of 0, 1, 2, 3; or y is 0 or 1; or y is 0; A 1 Regarding ' R 1 ' and R 2 ' are each independently C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 selected from the group consisting of; R 3 ' and R 4 ' are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), or heterocyclyl; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 1 ' is -O-, C1-C6 alkyl, -OR a1 wherein R a1is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl) n -O-(CO)-R b1 wherein the alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 ' is -O-, hydroxyl, -OR a R a is C1-C6 alkyl; or R 1 ' is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; or R 2 ' is -O-, C1-C6 alkyl, -OR a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl) n -O-(CO)-R b1 wherein the alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2 ' is hydroxyl, -O-, -OR a R a is C1-C6 alkyl; or R2 ' is selected from the group consisting of hydroxyl, -O-, methoxy; R 3 ' and R 4 ' are independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 ' and R 4 ' are, independently of each other, hydrogen; R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 ' is selected from the group consisting of hydrogen and amino; or R 5 ' is selected from the group consisting of hydrogen; Y' is C; y' is selected from the group consisting of 0, 1, 2, 3; or y is 0 or 1; or y' is 0; 3) x is 2 and A 1 and A 1 ' are the same or different, Unit A 1 R 1 , R 2 , R 3 and R 4 One of the adjacent units A 1 'R 1 ', R 2 ', R 3 ' and R 4 ' and L 1 Connected via; Each L 1are independently selected from the group consisting of absent, O, S, carbonyl, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkyl-O- (or -O-C1-C6 alkyl-O-), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-), cycloalkyl (or C3-C7 cycloalkyl), and heteroalkyl (or 3-7 membered heteroalkyl), and the alkyl, cycloalkyl, and heteroalkyl may be optionally substituted with one or more groups independently selected from the group consisting of Z; Z is independently selected from the group consisting of halogen, amino, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), haloalkyl (or halogenated C1-C6 alkyl), cycloalkyl (or C3-C7 cycloalkyl), aryl (or C6-C12 aryl), and heterocyclyl; Or L 1 is selected from the group consisting of absent, -CR'R'', where R' and R'' are each independently H, C1-C6 alkyl (or C1-C3 alkyl); Or L 1 , absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 selected from the group consisting of; Or L 1 is -CH 2 - selected from the group consisting of; A 1 Regarding R 1 and R 2 are each independently C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 selected from the group consisting of; R 3 and R 4are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 1 is -O-, C1-C6 alkyl, -OR a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl) n -O-(CO)-R b1 wherein the alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 is -O-, hydroxyl, -ORa R a is C1-C6 alkyl; or R 1 is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; or R 1 is selected from the group consisting of methoxy; or R 2 is -O-, C1-C6 alkyl, -OR a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl) n -O-(CO)-R b1 wherein the alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2 is hydroxyl, -O-, -OR a R a is C1-C6 alkyl; or R 2 is selected from the group consisting of hydroxyl, -O-, and methoxy; or R 2 is selected from the group consisting of -O-; R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 and R 4 are, independently of each other, hydrogen; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 is selected from the group consisting of hydrogen and amino; or R 5 is selected from the group consisting of hydrogen; Y is C; y is selected from the group consisting of 0, 1, 2, 3; or y is 0 or 1; or y is 0; A 1 Regarding ' R 1 ' and R 2 ' are each independently C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 selected from the group consisting of; R 3 ' and R 4 ' are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3-15 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3-15 membered heterocyclyl); or R 1 ' is -O-, C1-C6 alkyl, -ORa1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl) n -O-(CO)-R b1 wherein the alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 ' is -O-, hydroxyl, -OR a R a is C1-C6 alkyl; or R 1 ' is -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 selected from the group consisting of; or R 1 ' is selected from the group consisting of methoxy; or R 2 ' is -O-, C1-C6 alkyl, -OR a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1-C6 alkyl) n -O-(CO)-R b1 wherein the alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2' is hydroxyl, -O-, -OR a R a is C1-C6 alkyl; or R 2 ' is selected from the group consisting of hydroxyl, -O-, methoxy; or R 2 ' is selected from the group consisting of -O-; R 3 ' and R 4 ' are independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 ' and R 4 ' are, independently of each other, hydrogen; R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 ' is selected from the group consisting of hydrogen and amino; or R 5 ' is selected from the group consisting of hydrogen; Y is C; y' is selected from the group consisting of 0, 1, 2, 3; or y is 0 or 1; or y' is 0; Alternatively, formula II is [ka] That is, and pharma- ceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, and metabolic forms thereof.

[0047] In some embodiments, the compound represented by formula II or II-1, II-2, II-3 is: [ka] is selected from the group consisting of:

[0048] In a tenth aspect of the present invention, the present invention provides a pharmaceutical composition comprising a compound represented by formula II above, its pharma- ceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, and solvates, crystalline forms, metabolite forms, or any combination or mixture thereof.

[0049] In an eleventh aspect of the present invention, the present invention provides a method for the preparation of a medicament for the treatment of a cancer, comprising: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression The present invention provides use of a compound represented by formula II above, a pharma- ceutically acceptable salt, prodrug, stereoisomer, hydrate, solvate, crystalline form, metabolic form, or any combination or mixture thereof, in the manufacture of a medicament or pharmaceutical agent for use in at least one of the following:

[0050] In a twelfth aspect of the present invention, the present invention provides a method for the preparation of a medicament for the treatment of a pulmonary artery disease comprising: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression The present invention provides use of a pharmaceutical composition in the manufacture of a medicament or drug for use in at least one of the following:

[0051] In a thirteenth aspect of the present invention, the present invention provides a method for the preparation of a medicament for the treatment of a cancer, comprising: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression or a pharmaceutical composition comprising a compound represented by the above formula II, a pharma- ceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form, a metabolic product form, or any combination or mixture thereof, for use in at least one of the following purposes:

[0052] In a fourteenth aspect of the present invention, the present invention provides the following effects: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of stellate cell activation; 4) Regulation of NS3TP1 expression The present invention provides a method for obtaining a compound represented by formula II, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula II above, a pharma- ceutically acceptable salt, prodrug, stereoisomer, hydrate, solvate, crystalline form, metabolic form, or any combination or mixture thereof, or a pharmaceutical composition comprising a compound represented by formula II, a pharma- ceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystalline form, metabolic form, or any combination or mixture thereof.

[0053] In the above ninth to fourteenth aspects of the present invention, in some embodiments, liver fibrosis includes, but is not limited to, liver fibrosis caused by chronic viral liver disease, liver fibrosis caused by alcoholism or long-term alcohol consumption, liver fibrosis caused by non-alcoholic factors such as obesity, portal hepatic fibrosis caused by repeated infection with schistosomiasis, biliary hepatic fibrosis caused by chronic cholestasis, metabolic hepatic fibrosis caused by hepatocyte degeneration and hemoglobin deposition, toxic hepatic fibrosis caused by various harmful substances, malnutrition hepatic fibrosis caused by a low protein diet and a preference for fatty fried foods, and cardiogenic hepatic fibrosis caused by chronic congestive heart failure.

[0054] In some embodiments, the pharmaceutical composition contains additional active ingredients, such as: other amino acids for improving liver function (including but not limited to alanine, glutamic acid, cystine, glutamine, glycine, histidine, tyrosine, serine, methionine, arginine, leucine), cholesterol absorption inhibitors (e.g., ezetimibe), HSC activation and proliferation inhibitors (e.g., pirfenidone, fluorophenidone, pegbelfermin), PCSK9 inhibitors, PPAR agonists (e.g., gemfibrozil, fenofibrate, clofibrate, bezafibrate, pemafibrate, elafibranor), ACE inhibitors, CC inhibitors, R2 / 5 inhibitors, TLR4 inhibitors, LOXL2 inhibitors, TIMP-1 inhibitors, FXR agonists, AT1R blockers, NOX inhibitors, calcium channel blockers, ARBs, diuretics, renin, GLP-1 or its synthetic variants, insulin or its synthetic variants, metformin, sulfonylurea compounds, thiazolidinediones (TZDs), SGLT2 inhibitors, DPP-IV inhibitors, HMGCoA reductase inhibitors, proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors, gemcabene (CI-1027), ACC inhibitors, ApoC-III inhibitors, ACL inhibitors (e.g., bepedic acid acid), prescription fish oils, CETP inhibitors, ursodeoxycholic acid, obeticholic acid, polyene phosphatidylcholine, glucocorticoids, silymarin, glycyrrhizic acid preparations (e.g., magnesium isoglycyrrhizinate injection and diammonium isoglycyrrhizinate enteric coated capsules), and combinations thereof. In some embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition is a solid formulation, an injectable formulation, a topical formulation, a spray formulation, a liquid formulation, or a compound formulation.

[0055] In the above aspects of the invention and in these embodiments, "C1-C6 alkyl" and various hybrid groups including "C1-C6 alkyl" (e.g., "halogenated C1-C6 alkyl") can be substituted with "C1-C20 alkyl", "C1-C12 alkyl", "C1-C10 alkyl", "C1-C8 alkyl", "C1-C4 alkyl", "C1-C3 alkyl" or "C1-C2 alkyl"; "C2-C6 alkenyl" and various hybrid groups including "C2-C6 alkenyl" can be substituted with "C2-C12 alkenyl", "C2-C8 alkenyl" or "C2-C4 alkenyl"; "C2-C6 alkynyl" and various hybrid groups including "C2-C6 alkynyl" can be substituted with "C2-C12 alkynyl", "C2-C8 alkynyl" or "C2-C4 alkynyl"; "C3-C7 cycloalkyl" and various hybrid groups including "C3-C7 cycloalkyl" can be substituted with "C3-C20 cycloalkyl", "C3-C12 cycloalkyl" or "C3-C10 cycloalkyl"; "C1-C6 alkoxy" and various hybrid groups including "C1-C6 alkoxy" can be substituted with "C1-C20 alkoxy", "C1-C12 alkoxy" or "C1-C10 alkoxy"; "C6-C10 aryl" and various hybrid groups including "C6-C10 aryl" can be substituted with "C6-C12 aryl"; "3- to 7-membered heteroalkyl" and various hybrid groups containing it can be substituted with "2- to 14-membered heteroalkyl"; The "3- to 15-membered heterocyclyl" and various hybrid groups containing it can be substituted with "3- to 20-membered heterocyclyl" or "3- to 12-membered heterocyclyl" or "3- to 10-membered heterocyclyl". [Brief description of the drawings]

[0056] [Figure 1] FIG. 1 shows the inhibitory effects of compound 6, compound 47, and compound 54 on the protein expression of collagen I and collagen III, and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was used as a control. In the figure, "con" represents the control well, "P1" represents the positive control well (hydronidone), "ASP-50" represents that the aspartic acid concentration was 50 μM, and the remaining numbers are all in the form of compound number-concentration (μM), where "6-50" represents that the concentration of compound 6 was 50 μM, "6-100" represents that the concentration of compound 6 was 100 μM, "6-200" represents that the concentration of compound 6 was 200 μM, and "47 "-50" represents that the concentration of compound 47 was 50 μM, "47-100" represents that the concentration of compound 47 was 100 μM, "47-200" represents that the concentration of compound 47 was 200 μM, "54-50" represents that the concentration of compound 54 was 50 μM, "54-100" represents that the concentration of compound 54 was 100 μM, and "54-200" represents that the concentration of compound 54 was 200 μM. [Diagram 2] Figure 2 shows the inhibitory effects of Compound 4, Compound 6, Compound 41, Compound 47, Compound 48, and Compound 52 on α-SMA protein expression, with GAPDH used as a control. In the figure, "con" represents the control well, "P1" represents the positive control well (hydronidone), "ASP-50" represents the aspartic acid concentration was 50 μM, and the remaining numbers are all in the form of compound number-concentration (μM). [Diagram 3] Figure 3 shows the inhibitory effects of compound 50, compound 52, and compound 54 on FN protein expression, with GAPDH used as a control. In the figure, "con" represents the control well, "P1" represents the positive control well (hydronidone), "ASP-50" represents the aspartic acid concentration was 50 μM, and all remaining numbers are in the form of compound number-concentration (μM). [Figure 4]FIG. 4 shows the inhibitory effects of compound 54, compound 77a, and compound 78a on the expression of collagen I protein and α-SMA protein in LX2 cells stimulated by TGFβ, and GAPDH was used as a control. [Diagram 5] FIG. 5 shows the reduction of NS3TP1 expression in liver tissue of a mouse model of liver injury, and the regulatory effect of various doses of compound 6 on NS3TP1 expression in liver tissue of a mouse model of liver injury, in which "mpk" stands for "mg / kg." [Figure 6] 6 shows Masson stained sections of mouse liver tissue after intraperitoneal injection of carbon tetrachloride and treatment with Compound 4, Compound 6, Compound 47, and Compound 54. In the figure, "40x" means that the microscope magnification was 40x, and "100x" means that the microscope magnification was 100x. [Figure 7] 7 shows Masson-stained sections of mouse liver tissue after intraperitoneal injection of carbon tetrachloride and treatment with various doses of compound 6. In the figure, "40x" means that the microscope magnification was 40x, and "100x" means that the microscope magnification was 100x. [Figure 8] FIG. 8 shows the concentration of compound 6 in rats after oral administration and injection of compound 6 (top left), the concentration of aspartic acid in rats after oral administration and injection of compound 6 (top right), the concentration of compound 6 in rats after injection of saline (bottom left), and the concentration of aspartic acid in rats after injection of saline (bottom right). [Figure 9] Figure 9 shows H&E stained sections of mouse liver tissue after feeding HFD diet and treatment with various doses of Compound 6. In the figure, "100x" means that the microscope magnification was 100x, and "200x" means that the microscope magnification was 200x. [Figure 10] Figure 10 shows H&E stained sections of mouse liver tissue after CHOL feeding and treatment with various doses of Compound 6. In the figure, "100x" means that the microscope magnification was 100x, and "200x" means that the microscope magnification was 200x. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] Specific Models for Implementing the Invention The embodiments of the present invention are described in detail below. The embodiments described below are illustrative and are intended to illustrate the present invention, but should not be construed as limiting the present invention. As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount that is sufficient to treat or prevent a patient's disease, within the scope of reasonable medical judgment, but low enough (at a reasonable benefit / risk ratio) to avoid serious side effects. The therapeutically effective amount of a compound will vary depending on the particular compound selected (e.g., taking into account the potency, efficacy, and half-life of the compound), the selected route of administration, the disease being treated, the severity of the disease being treated, factors of the patient being treated, such as age, size, weight, and medical disease, medical history of the patient being treated, duration of treatment, nature of concurrent therapy, desired therapeutic effect, etc., but can also be routinely determined by one of ordinary skill in the art. As used herein, the term "mammal" refers to warm-blooded animals, such as, but not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans, that are suffering from or at risk of developing a disease as described herein. Furthermore, it should be noted that the specific dose and method of use of the compound represented by formula I or formula I-4 or formula II, its stereoisomer or its pharma- ceutically acceptable salt and / or solvate and / or hydrate are determined by many factors, including the patient's age, body weight, sex, general health condition, nutritional state, drug activity, administration time, metabolic rate, disease severity, and the physician's subjective judgment. The preferred dose used herein is 0.001-1000 mg / kg body weight / day.

[0058] The pharma- ceutically acceptable salts of the compounds of formula I, formula I-4 or formula II of the present invention include inorganic or organic acid salts and inorganic or organic alkali salts thereof. The present invention relates to all forms of the above salts, including, but not limited to, sodium salt, potassium salt, calcium salt, lithium salt, meglumine salt, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, propionate, butyrate, oxalate, trimethylacetate, adipate, alginate, lactate, citrate, tartrate, succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. The pharmaceutical composition of the present invention may contain a pharma- ceutically acceptable carrier, which includes, but is not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human albumin, and buffer substances such as phosphates, glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, and lanolin.

[0059] The pharmaceutical composition of the present invention can be prepared in various forms according to various administration routes. According to the invention, the pharmaceutical compositions can be administered by any of the following methods: oral administration, aerosol inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or administration by means of an implanted reservoir, with oral, intraperitoneal or intravenous administration being preferred. When used for oral administration, the compound represented by formula I or formula I-4 or formula II, its stereoisomer, or its pharma- ceutical acceptable salt and / or solvate and / or hydrate thereof can be in any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions. Here, carriers commonly used for tablets include lactose and corn starch, and lubricants such as magnesium stearate can also be added. Diluents commonly used for capsule formulations include lactose and dried corn starch. Aqueous suspension formulations usually consist of the active ingredient mixed with suitable emulsifiers and suspending agents. If desired, sweeteners, flavorings or colorings can be added to the above oral dosage forms. When used for rectal administration, the compound represented by formula I or formula I-4 or formula II, its stereoisomer, or its pharma- ceutical acceptable salt and / or solvate and / or hydrate can generally be in the form of a suppository, which is prepared by mixing the drug with a suitable non-irritating excipient, which is solid at room temperature and melts at rectal temperature to release the drug. Such excipients include cocoa butter, beeswax, and polyethylene glycol.

[0060] When used for local administration, particularly when treating diseased surfaces or organs that are easily accessible by topical application, such as eye, skin, or lower enteric nervous disorders, the compounds of formula I, formula I-4, or formula II, their stereoisomers, or their pharma- ceutically acceptable salts and / or their solvates and / or their hydrates can be made into different topical dosage forms according to the different diseased surfaces or organs. Specific methods of use are as follows: When used for topical administration to the eye, the compound of formula I or formula I-4 or formula II, its stereoisomer or its pharma- ceutically acceptable salt and / or solvate and / or hydrate can be formulated in the form of a fine suspension or solution, and the carrier used is an isotonic, sterile saline solution having a certain pH, with or without the addition of a preservative such as chlorobenzyl alkoxide.Furthermore, for ophthalmic use, the compound can be formulated in the form of an ointment, such as petrolatum jelly. When used for topical administration to the skin, the compound of formula I or formula I-4 or formula II, its stereoisomer or its pharma- ceutically acceptable salt and / or solvate and / or hydrate can be formulated in the form of a suitable ointment, lotion or cream in which the active ingredient is suspended or dissolved in one or more carriers.Carriers that can be used for ointments include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water;Carriers that can be used for lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecene aromatic alcohol, 2-octyl dodecanol, benzyl alcohol and water. When used for local administration to the lower intestine, the compounds of Formula I or Formula I-4 or Formula II, their stereoisomers or their pharma- ceutically acceptable salts and / or solvates and / or hydrates may be formulated in the form of a rectal suppository or a suitable enema preparation as described above, or a topical transdermal patch may also be used.

[0061] The compound represented by formula I or formula I-4 or formula II, its stereoisomer or its pharma- ceutically acceptable salt and / or solvate and / or hydrate thereof can also be administered in the form of a sterile injectable aqueous or oily suspension or a sterile injectable preparation, including a sterile injectable solution.Here, the carriers and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution.Alternatively, sterile non-volatile oils such as monoglycerides or diglycerides can also be used as a solvent or suspension medium. The various dosage forms of the drugs mentioned above can be prepared according to conventional methods in the pharmaceutical field.

[0062] At various points in the present specification, the substituents of the compounds disclosed herein are disclosed by group types or ranges. In particular, the present invention includes any and all individual subcombinations of the individual members of these group types and ranges. For example, the term "C1-C6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl, or "C1-C4 alkyl", or "C1-C3 alkyl", which are disclosed independently. Furthermore, it should be noted that the phrase "independently selected from the group consisting of" used throughout this specification should be understood broadly unless otherwise expressly stated, which indicates that the specific options represented by different symbols do not affect each other and may be the same or different. "Optionally" means that the stated condition may or may not be present. For example, if a structure is described as being "optionally" substituted with a group, it means that the "substitution" may or may not be present.

[0063] Unless otherwise indicated, the structural formulae depicted in the present invention include all isomeric forms of the enantiomers, diastereomers, and geometric (or conformational) isomers of the compounds of the present invention: for example, R, S configurations, (Z), (E) double bond isomers, and (Z), (E) conformational isomers, which contain asymmetric centers. Thus, all individual stereochemical isomers, diastereomers, or mixtures of geometric (or conformational) isomers are within the scope of the present invention. Any asymmetric atom of the compounds disclosed herein (e.g., carbon, etc.) may be present in racemic or enantioenriched form, such as the (R), (S) or (R,S) configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) or (S) configuration.

[0064] The term "prodrug" as used herein refers to a compound that is converted in vivo to a compound represented by formula (I). Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion of the prodrug to its parent structure in blood or tissue. The prodrug compound of the present invention may be an ester. Esters that can be used as prodrugs in the present invention include phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbonate esters, carbamic acid esters and amino acid esters. "Metabolite" refers to a product obtained by metabolism of a particular compound or salt thereof in the body. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized by the assays described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of an administered compound. Thus, the present invention includes the compounds of the present invention, including the metabolic products produced by contacting a compound of the present invention with a mammal for a sufficient period of time. "Solvate" as used herein refers to an association complex of one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association complex formed with water as the solvent molecule.

[0065] The terms "halogen" and "halo" are used interchangeably herein and refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). The term "alkyl" as used herein refers to a saturated linear or branched monovalent hydrocarbonyl (C1-C20 alkyl) containing 1 to 20 carbon atoms, which may be optionally substituted independently with one or more substituents as described herein. In some embodiments, the alkyl contains 1 to 12 carbon atoms (C1-C12 alkyl); in other embodiments, the alkyl contains 1 to 10 carbon atoms (C1-C10 alkyl); in other embodiments, the alkyl contains 1 to 8 carbon atoms (C1-C8 alkyl); in other embodiments, the alkyl contains 1 to 6 carbon atoms (C1-C6 alkyl); in other embodiments, the alkyl contains 1 to 4 carbon atoms (C1-C4 alkyl); in other embodiments, the alkyl contains 1 to 3 carbon atoms (C1-C3 alkyl); in other embodiments, the alkyl contains 1 to 2 carbon atoms (C1-C2 alkyl). Further examples of alkyl include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-Butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-Butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 )2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, and n-octyl. The term "C1-C6 alkyl" refers to any alkyl containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl, and the like.

[0066] The term "alkenyl" refers to a straight or branched monovalent hydrocarbonyl containing 2 to 12 carbon atoms (C2-C12 alkenyl), or 2 to 8 carbon atoms (C2-C8 alkenyl), or 2 to 6 carbon atoms (C2-C6 alkenyl), or 2 to 4 carbon atoms (C2-C4 alkenyl), where at least one position of CC is an sp2 double bond, including "cis", "trans" or "Z", "E" isomers. Specific examples include, but are not limited to, vinyl (-CH=CH 2 ), propenyl (-CH=CHCH 3 ), allyl (-CH 2 CH=CH 2 ) etc. The term "C2-C6 alkenyl" refers to any alkenyl containing from 2 to 6 carbon atoms and containing at least one double bond, examples of which include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl, and the like.

[0067] The term "alkynyl" refers to a linear or branched monovalent hydrocarbonyl containing 2 to 12 carbon atoms (C2-C12 alkynyl), or 2 to 8 carbon atoms (C2-C8 alkynyl), or 2 to 6 carbon atoms (C2-C6 alkynyl), or 2 to 4 carbon atoms (C2-C4 alkynyl), in which at least one position of CC is an sp triple bond. Specific examples include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH 2 C≡CH), propynyl (-C≡C-CH 3 ), 1-butynyl (-CH 2 CH 2 C≡CH), 2-butynyl (-CH 2 C≡CCH 3 ), 3-butynyl (-C≡CCH 2 CH 3 ) etc. The term "C2-C6 alkynyl" refers to any alkynyl containing from 2 to 6 carbon atoms and containing at least one triple bond, such as ethynyl, 2-propynyl, 4-pentynyl, and the like.

[0068] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom, said alkyl group having the meaning described herein. Unless otherwise specified, an alkoxy group contains 1-12 carbon atoms and can be represented as C1-C12 alkoxy. In some embodiments, an alkoxy group contains 1-8 carbon atoms and can be represented as C1-C8 alkoxy; in other embodiments, an alkoxy group contains 1-6 carbon atoms and can be represented as C1-C6 alkoxy; in other embodiments, an alkoxy group contains 1-4 carbon atoms and can be represented as C1-C4 alkoxy; and in still other embodiments, an alkoxy group contains 1-3 carbon atoms and can be represented as C1-C3 alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy (-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyloxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-l-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-l-butoxy (-OCH 2 CH(CH 3 ))CH 2 CH 3 ) etc. The term "alkylamino" or "alkylamino group" includes "N-alkylamino" and "N,N-dialkylamino", where the amino group is substituted, independently of each other, with one or two alkyl groups, said alkyl having the meaning as described herein. Suitable alkylamino may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, etc. The alkylamino may be optionally substituted with one or more substituents as described herein.

[0069] The term "haloalkoxy" means that an alkoxy is substituted with one or more halogen atoms, said alkoxy having the meaning as described herein, including, but not limited to, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCHFCH 3 , -OCH 2 CH 2 F, -OCF 2 CH 3 , -OCH 2 CF 2 CHF 2 In one embodiment, C1-C6 haloalkoxy comprises fluorine-substituted C1-C6 alkoxy; in another embodiment, C1-C4 haloalkoxy comprises fluorine-substituted C1-C4 alkoxy; in yet another embodiment, C1-C2 haloalkoxy comprises fluorine-substituted C1-C2 alkoxy. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains from 3 to 20 carbon atoms (i.e., "C3-C20 cycloalkyl"), preferably from 3 to 12 carbon atoms (i.e., "C3-C12 cycloalkyl"), more preferably from 3 to 10 carbon atoms (i.e., "C3-C10 cycloalkyl"), and most preferably from 3 to 7 carbon atoms (i.e., "C3-C7 cycloalkyl"). Non-limiting examples of monocyclic cycloalkyls (e.g., "C3-C7 cycloalkyl") include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and the like, and polycyclic cycloalkyls include spiro-, fused-, and bridged-cycloalkyls.

[0070] The term "halogenated C1-C6 alkyl" refers to groups in which the C1-C6 alkyl backbone is substituted with one or more halogens, such as monofluoromethyl, difluoroethyl, trifluoromethyl, and the like. The term "halogen" refers to fluorine, chlorine, bromine, and iodine. The term "C6-C12 aryl" refers to a carbocyclic aromatic radical having from 6 to 12 carbon atoms. The term "C6-C10 aryl" refers to a carbocyclic aromatic group having from 6 to 10 carbon atoms, such as phenyl, naphthyl, and the like.

[0071] The term "heteroalkyl" refers to a linear or branched alkyl (preferably having 2 to 14 or 3 to 7 carbon atoms) in which one or more carbon atoms are independently replaced with a heteroatom selected from the group consisting of S, O, P, and N (i.e., a "2-14 membered heteroalkyl" or a "3-7 membered heteroalkyl"). Exemplary heteroalkyl groups include alkyl ethers, alkyl amines, secondary alkyl amines, thioethers, and the like. The term "heterocyclyl" refers to a heterocyclyl group in which one or more ring atoms are nitrogen, oxygen, and S(O) m(where m is an integer from 0 to 2), but not including the ring moieties -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon atoms (i.e., "3-20 membered heterocyclyl"). Preferably, the heterocyclyl contains 3 to 15 ring atoms (i.e., "3-15 membered heterocyclyl") or 3 to 12 ring atoms (i.e., "3-12 membered heterocyclyl"), of which 1 to 4 are heteroatoms; more preferably, the heterocyclyl contains 3 to 10 ring atoms (i.e., "3-10 membered heterocyclyl"). Non-limiting examples of monocyclic heterocyclyls (e.g., 3-7 membered heterocyclyls) include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl includes spiro-, fused- and bridged-heterocyclyl. The term "3- to 15-membered heterocyclyl" refers to a 3-, 4-, 5-, 6-, and 7-membered to 15-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced with a heteroatom such as nitrogen, oxygen, and sulfur. "3- to 15-membered heterocyclyl" includes, for example, "3- to 7-membered heterocyclyl", non-limiting examples of which include thiacyclobutyl, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine, morpholine, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, and the like.

[0072] The term "polycyclic aromatic hydrocarbonyl" refers to a group formed by fusing one to two C5-C6 aromatic rings with one to two aromatic or non-aromatic rings, non-limiting examples of which include indenyl, naphthalenyl, phenanthrenyl, fluorenyl, and the like. "-(C1-C6 alkyl) n -O-(CO)-R b3" and other hybrid structures are those in which any n C1-C6 alkyl groups (e.g., methyl, ethyl) as described above are connected to R via oxygen (-O-) and carbonyl (-(C=O)-). b3 The meaning of other similar hybrid structures can be understood by reference to the above.

[0073] Peptide: The amino group of one amino acid condenses with the carboxyl group of another amino acid to form a peptide; e.g., C # OOH-CH(N # H 2 )-CH 2 -C # OOH, which can form a peptide bond with other amino acids through one, two, or three atoms marked with #. The structural formulae shown herein are also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures shown in the general formulae of the invention, except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I can be mentioned. * N=CH-NH-CH= * C-CH 2 -CH(NH 2 )-C(=O)-, N and C are * Marked with * indicates that the two atoms marked are connected by a single bond.

[0074] Abbreviation Boc: tert-butoxycarbonyl Cbz: benzyloxycarbonyl Ph: Phenyl Fmoc: fluorenylmethoxycarbonyl Trt: Trityl HO-p-Ph-CH 2 -CH(NH 2 )-C(=O)-: p-hydroxybenzylaminomethylcarbonyl EXAMPLES

[0075] The present invention is illustrated and described below with reference to specific examples. [Table 1]

[0076] Synthesis Example Example 1: Synthesis of Compound 35 [ka] Step 1: Synthesis of 1-benzyl 4-ethyl (tert-butoxycarbonyl)-L-aspartic acid ester (S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyric acid (1 g, 3.096 mmol) was dissolved in dichloromethane (10 mL), acetyl chloride (490 mg, 6.19 mmol) was added dropwise to the reaction system, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated, then diluted with dichloromethane, and the above solution was added dropwise to absolute ethanol (10 ml), and the reaction solution was stirred at room temperature for 1 hour. After that, the completion of the reaction was detected, and the reaction solution was washed with water, and the organic phase was separated, dried, and concentrated to obtain 900 mg of 1-benzyl 4-ethyl(tert-butoxycarbonyl)-L-aspartic acid ester. MS m / z(ESI): 352 [M+H] + . Step 2: Synthesis of 1-benzyl 4-ethyl L-aspartate 1-benzyl 4-ethyl (tert-butoxycarbonyl)-L-aspartate (900 mg, 2.56 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, and hydrogen chloride solution (2 M) (7.7 ml, 15.38 mmol) in ethyl acetate was added to the reaction system, and the reaction solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction by TLCA, the reaction solution was concentrated to obtain 600 mg of 1-benzyl 4-ethyl L-aspartate. MS m / z (ESI): 252 [M+H] + . Step 3: Synthesis of 4-ethyl L-aspartate 1-Benzyl 4-ethyl L-aspartate (600 mg, 2.39 mmol) was dissolved in ethanol (5 mL), palladium on carbon (120 mg) was added, stirred and reacted at room temperature under hydrogen atmosphere for 16 hours. After monitoring for reaction completion, the palladium on carbon was filtered off using diatomaceous earth and the filtrate was concentrated to give 200 mg of 4-ethyl L-aspartate (compound 35). MS m / z (ESI): 162 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.92(s,1H),8.49(s,2H),4.17(t,J=5.6Hz,1H),4.13-4.06(m,2H),2.98-2.86(m,2H),1.18(t,J=7.1Hz,3H).

[0077] Example 2: Synthesis of Compound 36 [ka] Step 1: Synthesis of 1-benzyl 4-isopropyl (tert-butoxycarbonyl)-L-aspartic acid ester (S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyric acid (1 g, 3.096 mmol) was dissolved in dichloromethane (10 mL), acetyl chloride (490 mg, 6.19 mmol) was added dropwise to the reaction system, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated and diluted with dichloromethane. The above solution was added dropwise to isopropanol (10 ml), and the reaction solution was stirred at room temperature for 1 hour. After the completion of the reaction was detected by TLC, the reaction solution was washed with water, and the organic phase was separated, dried, and concentrated to obtain 850 mg of 1-benzyl 4-isopropyl (tert-butoxycarbonyl)-L-aspartic acid ester. MS m / z(ESI): 366 [M+H] + . Step 2: Synthesis of 1-benzyl 4-isopropyl L-aspartate 1-Benzyl 4-isopropyl (tert-butoxycarbonyl)-L-aspartate (860 mg, 2.35 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, then hydrogen chloride solution (2 M) in ethyl acetate (7.07 ml, 14.14 mmol) was added, and the solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction by TLC, the reaction solution was concentrated to give 500 mg of 1-benzyl 4-isopropyl L-aspartate. MS m / z (ESI): 266 [M+H] + . Step 3: Synthesis of 4-isopropyl L-aspartate 1-Benzyl 4-isopropyl L-aspartate (500 mg, 1.88 mmol) was dissolved in ethanol (5 mL), palladium on carbon (100 mg) was added, stirred and reacted at room temperature under hydrogen atmosphere for 16 hours. After monitoring for reaction completion, the palladium on carbon was filtered off using diatomaceous earth and the filtrate was concentrated to give 200 mg of 4-isopropyl L-aspartate (compound 36). MS m / z (ESI): 176 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.90(s,2H),4.99-4.93(m,1H),4.17(t,J=5.2Hz,1H),2.92-2.89(m,2H),1.18(dd,J=6.2,1.5Hz,6H).

[0078] Example 3: Synthesis of Compound 37 [ka] Step 1: Synthesis of 1-benzyl 4-(((isopropoxycarbonyl)oxy)methyl) (tert-butoxycarbonyl)-L-aspartic acid ester (S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyric acid (2 g, 6.19 mmol), chloromethyl isopropyl carbonate (1.47 g, 9.29 mmol) and potassium carbonate (1.7 g, 12.38 mmol) were dissolved in DMF (10 mL) and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, water was added to dilute the reaction solution, extracted with ethyl acetate, and then the reaction solution was washed with brine, and the organic phase was separated, dried and concentrated to give 900 mg of 1-benzyl 4-(((isopropoxycarbonyl)oxy)methyl) (tert-butoxycarbonyl)-L-aspartic acid ester. MS m / z(ESI): 440 [M+H] + . Step 2: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-4-(((isopropoxycarbonyl)oxy)methoxy)-4-oxobutyric acid 1-Benzyl 4-(((isopropoxycarbonyl)oxy)methyl) (tert-butoxycarbonyl)-L-aspartate (900 mg, 2.05 mmol) was dissolved in methanol (5 mL) and palladium on carbon (180 mg) was added, stirred and reacted at room temperature under hydrogen atmosphere for 16 hours. After completion of the reaction was monitored by TLC, the palladium on carbon was filtered off using diatomaceous earth and the filtrate was concentrated to give 500 mg of (S)-2-((tert-butoxycarbonyl)amino)-4-(((isopropoxycarbonyl)oxy)methoxy)-4-oxobutyric acid. MS m / z(ESI): 350 [M+H] + . Step 3: Synthesis of 4-(((isopropoxycarbonyl)oxy)methyl)-L-aspartic acid (S)-2-((tert-butoxycarbonyl)amino)-4-(((isopropoxycarbonyl)oxy)methoxy)-4-oxobutyric acid (500 mg, 1.43 mmol) was dissolved in ethyl acetate (5 mL), and hydrogen chloride solution (2 M) in ethyl acetate (4.3 ml, 8.6 mmol) was added, and the solution was reacted at room temperature for 1 hour. After the completion of the reaction was monitored by TLC, the reaction solution was concentrated, water was added to dilute the reaction solution, and sodium bicarbonate was added to adjust the pH of the solution to neutral. The mixture was extracted with ethyl acetate, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 100 mg of 4-(((isopropoxycarbonyl)oxy)methyl)-L-aspartic acid (compound 37). 1 H NMR(300MHz,DMSO-d6)δ13.93(s,1H),8.66(s,2H),5.69(d,J=12.8Hz,2H),4 .79(h,J=6.2Hz,1H),4.18(s,1H),3.16-2.94(m,2H),1.23(d,J=6.2Hz,6H). MS m / z(ESI):250[M+H] + .

[0079] Example 4: Synthesis of Compound 49 [ka] Synthesis of (S)-3-amino-4-methoxy-4-oxobutyric acid hydrochloride (S)-3-amino-4-methoxy-4-oxobutyric acid (100 mg, 0.68 mmol) was dissolved in tetrahydrofuran (3 ml), hydrogen chloride solution in ethyl acetate (0.34 ml, 0.68 mmol) was added, stirred at room temperature for 30 minutes, and then a solid precipitate could be obtained. The mixture was filtered to obtain a filtration residue, and the filtration residue was dried to obtain 80 mg of (S)-3-amino-4-methoxy-4-oxobutyric acid hydrochloride (compound 49). 1 H NMR (300MHz, DMSO-d6) δ9.60 (s, 1H), 4.23 (t, J = 5.2Hz, 1H), 3.70 (s, 3H), 2.94 (d, J = 5.2Hz, 2H). MS m / z(ESI):184[M+H] + .

[0080] Example 5: Synthesis of Compound 50 [ka] Step 1: Synthesis of 4-benzyl 1-isopropyl (tert-butoxycarbonyl)-L-aspartic acid ester (S)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutyric acid (1 g, 3.096 mmol) was dissolved in dichloromethane (10 mL), acetyl chloride (490 mg, 6.19 mmol) was added dropwise to the reaction system, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated, diluted with dichloromethane, and the above solution was added dropwise to isopropanol (10 ml), and the reaction solution was stirred at room temperature for 1 hour. The completion of the reaction was detected by TLC, and the reaction solution was washed with water, and the organic phase was separated, dried, and concentrated to obtain 840 mg of 4-benzyl 1-isopropyl (tert-butoxycarbonyl)-L-aspartic acid ester. MS m / z(ESI): 366 [M+H] + . Step 2: Synthesis of (S)-3-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutyric acid 4-Benzyl 1-isopropyl (tert-butoxycarbonyl)-L-aspartate (840 mg, 2.3 mmol) was dissolved in ethanol (5 mL), palladium on carbon (160 mg) was added, stirred and reacted at room temperature under hydrogen atmosphere for 16 hours. After monitoring for reaction completion, the palladium on carbon was filtered off using diatomaceous earth and the filtrate was concentrated to give 300 mg of (S)-3-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutyric acid. MS m / z(ESI): 276[M+H] + . Step 3: Synthesis of 1-isopropyl L-aspartate hydrochloride (S)-3-((Tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutyric acid (300 mg, 1.1 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, and hydrogen chloride solution (2 M) in ethyl acetate (3.3 ml, 6.55 mmol) was added to the reaction system, and the solution was reacted at room temperature for 1 hour. After the completion of the reaction was monitored by TLC, the reaction solution was concentrated to give 130 mg of 1-isopropyl L-aspartate hydrochloride (compound 50). 1 H NMR(300MHz,DMSO-d6)δ13.00(s,1H),8.58(s,2H),4.97(p,J=6.3Hz,1H),4.1 9(t,J=5.2Hz,1H),2.90(dd,J=5.2,1.8Hz,2H),1.20(dd,J=10.2,6.2Hz,6H). MS m / z(ESI):212[M+H] + .

[0081] Example 6: Synthesis of Compound 51 [ka] Step 1: Synthesis of 4-benzyl 1-(((isopropoxycarbonyl)oxy)methyl) (tert-butoxycarbonyl)-L-aspartic acid ester (S)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutyric acid (10 g, 30.96 mmol), chloromethyl isopropyl carbonate (5.65 g, 37.15 mmol) and potassium carbonate (8.54 g, 61.92 mmol) were dissolved in DMF (100 mL) and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, water was added to dilute the reaction solution, extracted with ethyl acetate, washed with brine, and the organic phase was separated, dried and concentrated to give 4.2 g of 4-benzyl 1-(((isopropoxycarbonyl)oxy)methyl) (tert-butoxycarbonyl)-L-aspartic acid ester. MS m / z(ESI): 440 [M+H] + . Step 2: Synthesis of (S)-3-((tert-butoxycarbonyl)amino)-4-(((isopropoxycarbonyl)oxy)methoxy)-4-oxobutyric acid 4-Benzyl 1-(((isopropoxycarbonyl)oxy)methyl) (tert-butoxycarbonyl)-L-aspartate (4.2 g, 9.57 mmol) was dissolved in methanol (50 mL) and palladium on carbon (810 mg) was added, stirred and reacted at room temperature under hydrogen atmosphere for 16 hours. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth and the filtrate was concentrated to give 3 g of (S)-3-((tert-butoxycarbonyl)amino)-4-(((isopropoxycarbonyl)oxy)methoxymethyl)-4-oxobutyric acid. MS m / z(ESI): 350 [M+H] + . Step 3: Synthesis of 1-(((isopropoxycarbonyl)oxy)methyl) L-aspartic acid ester hydrochloride At room temperature, (S)-3-((tert-butoxycarbonyl)amino)-4-(((isopropoxycarbonyl)oxy)methoxy)-4-oxobutyric acid (3 g, 8.60 mmol) was dissolved in ethyl acetate (30 mL), and a solution of hydrogen chloride in ethyl acetate (2 M) (25.8 ml, 51.58 mmol) was added, and the solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction by TLC, the reaction solution was concentrated to give 1.2 g of 1-(((isopropoxycarbonyl)oxy)methyl) L-aspartic acid ester hydrochloride (compound 51). 1 H NMR (400MHz, DMSO-d6) δ8.80(s, 2H), 5.79-5.68(m, 2H), 4.80(p, J=6.2Hz, 1H), 4.34(s, 1H), 2.97(d, J=5.1 Hz, 2H), 1.23(d, J=6.2Hz, 6H). MS m / z(ESI):286[M+H] + .

[0082] Example 7: Synthesis of Compound 52 [ka] Synthesis of 4-(((isopropoxycarbonyl)oxy)methyl) L-aspartic acid ester hydrochloride (S)-2-((Tert-butoxycarbonyl)amino)-4-(((isopropoxycarbonyl)oxy)methoxy)-4-oxobutyric acid (500 mg, 1.43 mmol) was dissolved in ethyl acetate (5 mL) and dissolved in hydrogen chloride solution (2 M) in ethyl acetate (4.3 ml, 8.6 mmol), and the solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction by TLC, the reaction solution was concentrated to give 130 mg of 4-(((isopropoxycarbonyl)oxy)methyl) L-aspartic acid ester hydrochloride (compound 52). 1 H NMR(300MHz,DMSO-d6)δ13.93(s,1H),8.66(s,2H),5.69(d,J=12.8Hz,2H),4 .79(h,J=6.2Hz,1H),4.18(s,1H),3.16-2.94(m,2H),1.23(d,J=6.2Hz,6H). MS m / z(ESI):286[M+H]+ .

[0083] Example 8: Synthesis of Compound 53 [ka] Step 1: Synthesis of ((isopropoxycarbonyl)oxy)methyl ester (tert-butoxycarbonyl)-L-phenylalanine (tert-Butoxycarbonyl)-L-phenylalanine (2 g, 7.55 mmol), chloromethyl isopropyl carbonate (1.38 g, 9.06 mmol) and potassium carbonate (2.08 g, 15.09 mmol) were dissolved in DMF (10 mL) and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, water was added to dilute the reaction solution, extracted with ethyl acetate, and then the reaction solution was washed with brine, and the organic phase was separated, dried and concentrated to give 550 mg of ((isopropoxycarbonyl)oxy)methyl ester (tert-butoxycarbonyl)-L-phenylalanine. MS m / z (ESI): 382 [M+H] + . Step 2: Synthesis of ((isopropoxycarbonyl)oxy)methyl ester L-phenylalanine hydrochloride ((isopropoxycarbonyl)oxy)methyl ester (tert-butoxycarbonyl)-L-phenylalanine (550 mg, 1.44 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, then hydrogen chloride solution (2 M) in ethyl acetate (4.33 ml, 8.66 mmol) was added, and the reaction solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction by TLC, the reaction solution was concentrated to obtain 416 mg of ((isopropoxycarbonyl)oxy)methyl ester L-phenylalanine hydrochloride. MS m / z (ESI): 318 [M+H] + . Step 3: Synthesis of tert-butyl (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-1-(((isopropoxycarbonyl)oxy)methoxy)-1-oxo-3-phenylprop-2-yl)amino)-4-oxobutyrate ((isopropoxycarbonyl)oxy)methyl ester L-phenylalanine hydrochloride (416 mg, 1.3 mmol), (S)-4-(tert-butoxy)-2-((tert-butyloxycarbonyl)amino)-4-oxobutyric acid (416 mg, 1.44 mmol), HATU (994 mg, 2.62 mmol) and DMAP (16 mg, 0.13 mmol) were dissolved in DMF (5 mL), DIPEA (506 mg, 3.9 mmol) was added dropwise, stirred and reacted at room temperature for 2 hours. After the completion of the reaction was monitored by TLC, water was added to dilute the reaction solution and ethyl acetate (5 mL) was added. * 2) and separated to obtain an organic phase. The organic phase was dried, concentrated, and purified by column chromatography to obtain 500 mg of tert-butyl (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-1-(((isopropoxycarbonyl)oxy)methoxy)-1-oxo-3-phenylpropan-2-yl)amino)-4-oxobutyrate. MS m / z(ESI): 553[M+H] + . Step 4: Synthesis of (S)-3-amino-4-(((S)-1-(((isopropoxycarbonyl)oxy)methoxy)-1-oxo-3-phenylpropan-2-yl)amino)-4-oxobutyric acid hydrochloride (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-1-(((isopropoxycarbonyl)oxy)methoxy)-1-oxo-3-phenylpropan-2-yl)amino)-4-oxobutyric acid tert-butyl (500 mg, 0.91 mmol) was dissolved in ethyl acetate (5 mL), and hydrogen chloride solution (2M) in ethyl acetate (2.72 ml, 5.43 mmol) was added, and the reaction solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction by TLC, the reaction solution was concentrated to obtain 320 mg of (S)-3-amino-4-(((S)-1-(((isopropoxycarbonyl)oxy)methoxy)-1-oxo-3-phenylpropan-2-yl)amino)-4-oxobutyric acid hydrochloride (compound 53). 1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),9.17(d,J=7.3Hz,1H),8.31(s,2H),7.31-7.22(m,5H),5.74-5.63(m,2H),4.81(hept,J= 6.2Hz,1H), 4.56(ddd,J=8.6,7.3,5.6Hz,1H),4.10-4.03(m,1H),3.09-2.95(m,2H),2.89-2.69(m,2H),1.24(d,J=6.2Hz,6H). MS m / z(ESI):433[M+H] + .

[0084] Example 9: Synthesis of Compound 54 [ka] Step 1: Synthesis of 1-(chloromethyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester Boc-L-aspartic acid 4-methyl ester (1.2 g, 5.0 mmol) and tetrabutylammonium bisulfate (84.0 mg, 0.3 mmol) were dissolved in dichloromethane (5 mL), placed in an ice bath, stirred, and cooled to 0° C. A solution of potassium carbonate (2.7 g, 20.0 mmol) in water (5 mL) and a solution of chloromethyl chlorosulfonate (1.0 g, 6.0 mmol) in dichloromethane (5 mL) were added dropwise to the above reaction, stirred, slowly warmed to room temperature, and stirred overnight. After the reaction was complete by TLC, 5 mL of dichloromethane was added, washed with water three times, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EA / PE gradient elution, 20:1 to 5:1) to give 1.1 g of 1-(chloromethyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester (colorless oil, 83% yield). Step 2: Synthesis of 4-dimethyl O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) Sodium iodide (174 mg, 1.1 mmol) and potassium carbonate (276 mg, 2.0 mmol) were dissolved in DMF (1.5 mL), placed in an ice bath, stirred, and cooled to 0 ° C. Boc-L-aspartic acid 4-methyl ester (296.7 mg, 1.2 mmol) was dissolved in DMF (1.0 mL), added dropwise to the above reaction system, placed in an ice bath, and stirred for 30 minutes. 1-(Chloromethyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester (295.7 mg, 1.0 mmol) was dissolved in DMF (1.0 mL), added dropwise to the reaction system, stirred, slowly warmed to room temperature, stirred for about overnight, and the reaction was monitored by TLC. After the reaction of the raw material was completed, 10 mL of water was added, extracted with ethyl acetate three times, and washed with water three times. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EA / PE gradient elution, 10:1 to 3:1) to give 60 mg of 4-dimethyl O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) (white solid, 12% yield). Step 3: Synthesis of 4-dimethyl O'1,O1-methylene (2S,2'S)-bis(2-aminosuccinic acid) hydrochloride 4-Dimethyl O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) (1.0 g, 2.0 mmol) was dissolved in dichloromethane (6 mL), placed in an ice bath, stirred, cooled to 0° C., 2N hydrochloric acid solution in ethyl acetate (12 mL) was added dropwise, stirred, warmed slowly to room temperature, and then stirred for about 2 hours. After the reaction was monitored to be complete by HPLC, the reaction solution was filtered by suction, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to give 530 mg of 4-dimethyl O'1,O1-methylene (2S,2'S)-bis(2-aminosuccinate) hydrochloride (compound 54) (white solid, 60% yield). 1 H NMR (400MHz, CD3OD), δ5.99 (s, 2H), 4.52 (t, J=6Hz, 2H), 3.77 (s, 6H), 3.10 (m, 4H). MS m / z(ESI):343[M+H] + .

[0085] Example 10: Synthesis of Compound 56 [ka] The synthesis method of the title compound was the same as that of Compound 54 in Example 9 of the present application. In Steps 1 and 2, Boc-L-aspartic acid 4-methyl ester was replaced with N-tert-butoxycarbonyl-L-aspartic acid 1-methyl ester to give 1-dimethyl O'4,O4-methylene (2S,2'S)-bis(2-aminosuccinate) hydrochloride (Compound 56) in a 46% yield as a white solid. 1 H NMR (400MHz, CD3OD), δ5.88 (s, 2H), 4.45 (t, J=8Hz, 2H), 3.85 (s, 6H), 3.02 (m, 4H). MS m / z(ESI):343[M+H] + .

[0086] Example 11: Synthesis of Compound 57 [ka] Step 1: Synthesis of 1-(chloromethyl) 4-n-butyl (tert-butoxycarbonyl)-L-aspartic acid ester tert-Butoxycarbonyl-L-aspartic acid 4-tert-butyl ester (2.3 g, 8.0 mmol) and tetrabutylammonium bisulfate (136 mg, 0.4 mmol) were dissolved in dichloromethane (8 mL), stirred in an ice bath, and cooled to 0° C. A solution of potassium carbonate (4.4 g, 32 mmol) in water (8 mL) and a solution of chloromethyl chlorosulfonate (1.7 g, 10.0 mmol) in dichloromethane (8 mL) were added dropwise to the reaction, stirred, and allowed to slowly warm to room temperature overnight. After the reaction was complete as monitored by TLC, 8 mL of dichloromethane was added, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EA / PE gradient elution, 20:1 to 5:1) to give 1.4 g of 1-(chloromethyl) 4-n-butyl (tert-butoxycarbonyl)-L-aspartic acid ester (colorless oil, 53% yield). Step 2: Synthesis of 4-di(n-butyl) O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) Sodium iodide (349 mg, 2.1 mmol) and potassium carbonate (552 mg, 4.0 mmol) were dissolved in DMF (2 mL), placed in an ice bath, stirred, and cooled to 0° C. 1-(Chloromethyl) 4-n-butyl (tert-butoxycarbonyl)-L-aspartic acid ester (694.0 mg, 2.4 mmol) was dissolved in DMF (2 mL), added dropwise to the above reaction system, placed in an ice bath, and stirred for 30 minutes. 1-(Chloromethyl) 4-n-butyl (tert-butoxycarbonyl)-L-aspartic acid ester (676.0 mg, 2.0 mmol) was dissolved in DMF (2 mL), added dropwise to the reaction system, stirred, slowly warmed to room temperature, and stirred for about overnight. After the reaction was completed by monitoring by TLC, 10 mL of water was added and extracted with ethyl acetate three times, then the organic phase was separated, washed with water, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by chromatography column (EA / PE gradient elution, 10:1 to 3:1) to give 619 mg of 4-di(n-butyl) O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) (white solid, 52% yield). Step 3: Synthesis of (3S,3'S)-4,4'-(methylenebis(oxy))bis(3-amino-4-oxobutyric acid) hydrochloride 4-Di(n-butyl) O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) (295.0 mg, 0.5 mmol) was dissolved in dichloromethane (2 mL), placed in an ice bath, stirred, cooled to 0° C., and 2N hydrochloric acid solution in ethyl acetate (6 mL) was added dropwise, stirred, slowly warmed to room temperature, and stirred for about 2 hours. After the reaction was monitored to be complete by HPLC, the reaction solution was filtered by suction, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to give 95 mg of (3S,3'S)-4,4'-(methylenebis(oxy))bis(3-amino-4-oxobutyric acid) hydrochloride (compound 57) (white solid, 61% yield). 1H NMR (400MHz, CD3OD), δ5.99 (s, 2H), 4.16 (t, J=4Hz, 2H), 3.05 (m, 4H). MS m / z(ESI):315[M+H] + .

[0087] Example 12: Synthesis of Compound 55 [ka] The synthesis method of the title compound was the same as that of compound 57 in Example 11 of the present application. In steps 1 and 2, tert-butoxycarbonyl-L-aspartic acid 4-tert-butyl ester was replaced with N-tert-butoxycarbonyl-L-aspartic acid 1-tert-butyl ester to obtain (2S,2'S)-4,4'-(methylenebis(oxy)) bis(2-amino-4-oxobutyric acid) hydrochloride (compound 55) (yield 54%, white solid). 1 H NMR(400MHz,CD3OD),δ5.89(s,2H),4.36(dd,J 1 =8Hz,J 2 =4Hz,2H),3.12(m,4H). MS m / z(ESI):315[M+H] + .

[0088] Example 13: Synthesis of Compound 58 [ka] Step 1: Synthesis of dibenzyl propionyl-L-aspartate L-Aspartic acid dibenzyl ester (1g, 3.19mmol) and propionyl chloride (353mg, 3.83mmol) were dissolved in dichloromethane (10mL) and triethylamine (0.88mL, 6.39ml) and added dropwise to the reaction system, and the reaction solution was stirred at room temperature for 2 hours. An appropriate amount of water was added to the reaction solution, and the solution was extracted with dichloromethane. The organic phase was separated. The organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain 980mg of dibenzyl propionyl-L-aspartic acid ester. MS m / z(ESI): 370[M+H] +. Step 2: Synthesis of propionyl-L-aspartic acid Dibenzyl propionyl-L-aspartate (200 mg, 0.54 mmol) and palladium on carbon (40 mg) were dissolved in tetrahydrofuran (3 mL), 2 drops of concentrated hydrochloric acid were added, and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 16 h. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth, and the organic phase was concentrated to give 80 mg of propionyl-L-aspartate (compound 58). 1 H NMR(500MHz,DMSO-d6)δ12.48(s,2H),8.07(d,J=8.0Hz,1H),4.51(td,J=7.5 ,5.7Hz,1H),2.69-2.51(m,2H),2.09(q,J=7.6Hz,2H),0.96(t,J=7.6Hz,3H). MS m / z(ESI):190[M+H] + .

[0089] Example 14: Synthesis of Compound 59 [ka] Step 1: Synthesis of dibenzyl isobutyryl-L-aspartate L-Aspartic acid dibenzyl ester (1g, 3.19mmol) and isobutyryl chloride (406mg, 3.83mmol) were dissolved in dichloromethane (10mL), then triethylamine (0.88mL, 6.39ml) was added dropwise, and the reaction solution was stirred at room temperature for 2 hours. An appropriate amount of water was added to the reaction solution, and it was extracted with dichloromethane. The organic phase was separated. The organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain 960mg of dibenzyl isobutyryl-L-aspartic acid ester. MS m / z(ESI):384[M+H] + . Step 2: Synthesis of isobutyryl-L-aspartic acid Dibenzyl isobutyryl-L-aspartate (200 mg, 0.52 mmol) and palladium on carbon (40 mg) were dissolved in tetrahydrofuran (3 mL), 2 drops of concentrated hydrochloric acid were added, and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 16 hours. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth, and the organic phase was concentrated to give 85 mg of isobutyryl-L-aspartate (compound 59). 1 H NMR(500MHz,DMSO-d6)δ12.47(s,2H),8.02(d,J=8.0Hz,1H),4.50(td,J=7.6 ,5.7Hz,1H),2.70-2.51(m,2H),2.40(p,J=6.8Hz,1H),0.97(t,J=6.5Hz,6H). MS m / z(ESI):204[M+H] + .

[0090] Example 15: Synthesis of Compound 60 [ka] Step 1: Synthesis of dibenzyl (cyclopropylcarbonyl)-L-aspartic acid ester L-Aspartic acid dibenzyl ester (1g, 3.19mmol) and cyclopropylformyl chloride (398mg, 3.83mmol) were dissolved in dichloromethane (10mL), then triethylamine (0.88mL, 6.39ml) was added dropwise, and the reaction solution was stirred at room temperature for 2 hours. An appropriate amount of water was added to the reaction solution, and it was extracted with dichloromethane. The organic phase was separated. The organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain 480mg of dibenzyl (cyclopropylcarbonyl)-L-aspartic acid ester. MS m / z(ESI):382[M+H] + . Step 2: Synthesis of (cyclopropylcarbonyl)-L-aspartic acid Dibenzyl (cyclopropylcarbonyl)-L-aspartate (200 mg, 0.52 mmol) and palladium on carbon (40 mg) were dissolved in tetrahydrofuran (3 mL), then 2 drops of concentrated hydrochloric acid were added and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 16 hours. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth and the organic phase was concentrated to give 90 mg of (cyclopropylcarbonyl)-L-aspartic acid (compound 60). 1 H NMR(500MHz,DMSO-d6)δ12.51(s,2H),8.39(d,J=8.0Hz,1H),4.53(td,J=7.4,5.6Hz,1H),2.70-2.52(m,2H),1.66-1.59(m, 1H),0.68-0.61(m,4H). MS m / z(ESI):202[M+H] + .

[0091] Example 16: Synthesis of Compound 61 [ka] Step 1: Synthesis of dibenzyl (methoxycarbonyl)-L-aspartic acid ester L-Aspartic acid dibenzyl ester (1g, 3.19mmol) and methyl chloroformate (360mg, 3.83mmol) were dissolved in dichloromethane (10mL), then triethylamine (0.88mL, 6.39ml) was added dropwise, and the reaction solution was stirred at room temperature for 2 hours. An appropriate amount of water was added to the reaction solution, and it was extracted with dichloromethane. The organic phase was separated. The organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain 600mg of dibenzyl (methoxycarbonyl)-L-aspartic acid ester. MS m / z(ESI):372[M+H] + . Step 2: Synthesis of (methoxycarbonyl)-L-aspartic acid Dibenzyl (methoxycarbonyl)-L-aspartate (500 mg, 1.35 mmol) and palladium on carbon (100 mg) were dissolved in tetrahydrofuran (5 mL), then 2 drops of concentrated hydrochloric acid were added and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 16 hours. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth and the organic phase was concentrated to give 130 mg of (methoxycarbonyl)-L-aspartic acid (compound 61). 1 H NMR (500MHz, DMSO-d6) δ12.55(s,2H),7.43(d,J=8.4Hz,1H),4.30(td,J=8.2,5.4Hz,1H),3.53(s,3H),2.73-2.51(m,2H). MS m / z(ESI):192[M+H] + .

[0092] Example 17: Synthesis of Compound 62 [ka] Step 1: Synthesis of dibenzyl (dimethylcarbamoyl)-L-aspartic acid ester L-Aspartic acid dibenzyl ester (1g, 3.19mmol) and dimethylcarbamoyl chloride (411mg, 3.83mmol) were dissolved in dichloromethane (10mL), then triethylamine (0.88mL, 6.39ml) was added dropwise, and the reaction solution was stirred at room temperature for 2 hours. An appropriate amount of water was added to the reaction solution, and it was extracted with dichloromethane. The organic phase was separated. The organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain 940mg of dibenzyl (methylcarbamoyl)-L-aspartic acid ester. MS m / z(ESI):385[M+H] + . Step 2: Synthesis of (dimethylcarbamoyl)-L-aspartic acid Dibenzyl (dimethylcarbamoyl)-L-aspartic acid ester (500 mg, 1.30 mmol) and palladium on carbon (100 mg) were dissolved in tetrahydrofuran (5 mL), then 2 drops of concentrated hydrochloric acid were added and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 16 hours. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth and the organic phase was concentrated to give 120 mg of (dimethylcarbamoyl)-L-aspartic acid (compound 62). 1 H NMR (500MHz, DMSO-d6) δ12.38(s,2H),6.47(d,J=8.1Hz,1H),4.39(td,J=7.6,5.7Hz,1H),2.77(s,6H),2.73-2.53(m,2H). MS m / z(ESI):205[M+H] + .

[0093] Example 18: Synthesis of Compound 63 [ka] Step 1: Synthesis of 1-benzyl 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester (S)-2-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyric acid (9 g, 36.44 mmol), benzyl bromide (7.47 g, 43.72 mmol) and potassium carbonate (10.06 g, 72.87 mmol) were dissolved in DMF (10 mL) and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, water was added to dilute the reaction solution, extracted with ethyl acetate, the reaction solution was washed with brine, the organic phase was dried and concentrated to give 9 g of 1-benzyl 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester. MS m / z(ESI): 338 [M+H] + . Step 2: Synthesis of 1-benzyl 4-methyl L-aspartate 1-Benzyl 4-methyl (tert-butoxycarbonyl)-L-aspartate (9 g, 26.71 mmol) was dissolved in dichloromethane (20 mL) at room temperature, then hydrogen chloride solution (2 M) in ethyl acetate (80 ml, 160.24 mmol) was added and the solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction, the precipitated solid was filtered to obtain 6 g of 1-benzyl 4-methyl L-aspartate. MS m / z (ESI): 238 [M+H] + . Step 3: Synthesis of 1-benzyl 4-methyl acetyl-L-aspartate 1-Benzyl 4-methyl L-aspartate (1g, 4.22mmol) and acetyl chloride (397mg, 5.06mmol) were dissolved in dichloromethane (10mL), then triethylamine (1.17mL, 8.44ml) was added dropwise, and the reaction solution was stirred at room temperature for 2 hours. An appropriate amount of water was added to the reaction solution, and it was extracted with dichloromethane. The organic phase was separated. The organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain 900mg of 1-benzyl 4-methyl acetyl-L-aspartate. MS m / z(ESI):280[M+H] + . Step 4: Synthesis of 4-methyl acetyl-L-aspartic acid ester 1-Benzyl 4-methyl acetyl-L-aspartate (900 mg, 3.23 mmol) and palladium on carbon (180 mg) were dissolved in tetrahydrofuran (5 mL), 2 drops of concentrated hydrochloric acid were added, and the reaction solution was stirred at room temperature under hydrogen atmosphere for 16 h. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth, and the organic phase was concentrated and purified by column chromatography to give 50 mg of 4-methyl acetyl-L-aspartate (compound 63). 1H NMR (400MHz, DMSO-d6) δ12.68(s,1H),8.22(d,J=8.0Hz,1H),4.54(ddd,J=8.0,7.3,5.9Hz,1H),3.59(s,3H),2.78-2.59(m,2H),1.82(s,3H). MS m / z(ESI):190[M+H] + .

[0094] Example 19: Synthesis of Compound 64 [ka] Step 1: Synthesis of 1-benzyl 4-methyl propionyl-L-aspartate 1-Benzyl 4-methyl L-aspartate (1g, 4.22mmol) and propionyl chloride (468mg, 5.06mmol) were dissolved in dichloromethane (10mL), then triethylamine (1.17mL, 8.44ml) was added dropwise, and the reaction solution was stirred at room temperature for 2 hours. An appropriate amount of water was added to the reaction solution, and it was extracted with dichloromethane. The organic phase was separated. The organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain 860mg of 1-benzyl 4-methyl propionyl-L-aspartate. MS m / z(ESI):294[M+H] + . Step 2: Synthesis of 4-methyl propionyl-L-aspartic acid ester 1-Benzyl 4-methylpropionyl-L-aspartate (860 mg, 2.93 mmol) and palladium on carbon (180 mg) were dissolved in tetrahydrofuran (5 mL), 2 drops of concentrated hydrochloric acid were added, and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 16 h. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth, and the organic phase was concentrated and purified by column chromatography to give 65 mg of 4-methylpropionyl-L-aspartate (compound 64). 1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),8.12(d,J=8.0Hz,1H),4.55(td,J=7.6,6.0Hz ,1H),3.59(s,3H),2.79-2.58(m,2H),2.09(q,J=7.6Hz,2H),0.96(t,J=7.6Hz,3H). MS m / z(ESI):204[M+H] + .

[0095] Example 20: Synthesis of Compound 65 [ka] Step 1: Synthesis of 4-benzyl 1-methyl (tert-butoxycarbonyl)-L-aspartic acid ester (S)-2-((tert-butoxycarbonyl)amino)-1-methoxy-1-oxobutyric acid (9 g, 36.44 mmol), benzyl bromide (7.47 g, 43.72 mmol) and potassium carbonate (10.06 g, 72.87 mmol) were dissolved in DMF (10 mL) and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, water was added to dilute the reaction solution, extracted with ethyl acetate, the reaction solution was washed with brine, and the organic phase was separated, dried and concentrated to give 12 g of 4-benzyl 1-methyl (tert-butoxycarbonyl)-L-aspartic acid ester. MS m / z(ESI): 338 [M+H] + . Step 2: Synthesis of 4-benzyl 1-methyl L-aspartate 4-Benzyl 1-methyl(tert-butoxycarbonyl)-L-aspartate (12 g, 35.6 mmol) was dissolved in dichloromethane (50 mL) at room temperature, then hydrogen chloride solution (2 M) in ethyl acetate (106 ml, 213.65 mmol) was added and the solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction, the precipitated solid was filtered to obtain 9 g of 4-benzyl 1-methyl L-aspartate. MS m / z(ESI): 238 [M+H] + . Step 3: Synthesis of 4-benzyl 1-methyl acetyl-L-aspartate 4-benzyl 1-methyl L-aspartate (1g, 4.22mmol) and acetyl chloride (397mg, 5.06mmol) were dissolved in dichloromethane (10mL), then triethylamine (1.17mL, 8.44ml) was added dropwise, and the reaction solution was stirred at room temperature for 2 hours. An appropriate amount of water was added to the reaction solution, and it was extracted with dichloromethane. The organic phase was separated. The organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain 600mg of 4-benzyl 1-methyl acetyl-L-aspartate. MS m / z(ESI):280[M+H] + . Step 4: Synthesis of 1-methyl acetyl-L-aspartic acid ester 4-Benzyl 1-methyl acetyl-L-aspartate (600 mg, 2.15 mmol) and palladium on carbon (120 mg) were dissolved in tetrahydrofuran (5 mL), 2 drops of concentrated hydrochloric acid were added, and the reaction solution was stirred at room temperature under hydrogen atmosphere for 16 h. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth, and the organic phase was concentrated and purified by column chromatography to give 40 mg of 1-methyl acetyl-L-aspartate (compound 65). 1 H NMR (400MHz, DMSO-d6) δ12.43(s,1H),8.31(d,J=7.8Hz,1H),4.56(td,J=7.4,5.6Hz,1H),3.60(s,3H),2.72-2.53(m,2H),1.82(s,3H). MS m / z(ESI):190[M+H] + .

[0096] Example 21: Synthesis of Compound 66 [ka] Step 1: Synthesis of 4-benzyl 1-methyl propionyl-L-aspartate 4-benzyl 1-methyl L-aspartate (1g, 4.22mmol) and propionyl chloride (468mg, 5.06mmol) were dissolved in dichloromethane (10mL), then triethylamine (1.17mL, 8.44ml) was added dropwise, and the reaction solution was stirred at room temperature for 2 hours. An appropriate amount of water was added to the reaction solution, and it was extracted with dichloromethane. The organic phase was separated. The organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain 650mg of 4-benzyl 1-methyl propionyl-L-aspartate. MS m / z(ESI):294[M+H] + . Step 2: Synthesis of 1-methyl propionyl-L-aspartic acid ester 4-Benzyl 1-methylpropionyl-L-aspartate (650 mg, 2.22 mmol) and palladium on carbon (130 mg) were dissolved in tetrahydrofuran (5 mL), 2 drops of concentrated hydrochloric acid were added, and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 16 h. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth, and the organic phase was concentrated and purified by column chromatography to give 37 mg of 1-methylpropionyl-L-aspartate (compound 66). 1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.21(d,J=7.8Hz,1H),4.57(td,J=7.5,5.8Hz ,1H),3.60(s,3H),2.72-2.54(m,2H),2.10(q,J=7.6Hz,2H),0.97(t,J=7.6Hz,3H). MS m / z(ESI):204[M+H] + .

[0097] Example 22: Synthesis of Compound 67 [ka] Step 1: Synthesis of 1-benzyl 4-methyl (tert-butoxycarbonyl)-L-alanyl-L-aspartate 1-Benzyl 4-methyl L-aspartate (500 mg, 2.11 mmol), (tert-butoxycarbonyl)-L-alanine (479 mg, 2.5 mmol), HATU (962 mg, 2.53 mmol) and DMAP (26 mg, 0.21 mmol) were dissolved in DMF (5 mL), DIPEA (506 mg, 3.9 mmol) was added dropwise, and then the mixture was stirred and reacted at room temperature for 2 hours. After monitoring the completion of the reaction, water was added to dilute the reaction solution and ethyl acetate (5 mL) was added. * 2), and the organic phase was washed with water, dried, concentrated, and purified by column chromatography to give 400 mg of 1-benzyl 4-methyl (tert-butoxycarbonyl)-L-alanyl-L-aspartic acid ester. MS m / z(ESI): 409[M+H] + . Step 2: Synthesis of 1-benzyl 4-methyl L-alanyl-L-aspartate 1-Benzyl 4-methyl (tert-butoxycarbonyl)-L-alanyl-L-aspartate (400 mg, 0.98 mmol) was dissolved in dichloromethane (5 mL), and hydrogen chloride solution (2 M) in ethyl acetate (2.9 ml, 5.88 mmol) was added to the reaction system, and the solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction, the reaction solution was concentrated to obtain 100 mg of 1-benzyl 4-methyl L-alanyl-L-aspartate. MS m / z (ESI): 309 [M+H] + . Step 3: Synthesis of (S)-2-((S)-2-aminopropionamido)-4-methoxy-4-oxobutyric acid hydrochloride 1-Benzyl 4-methyl L-alanyl-L-aspartate (100 mg, 0.32 mmol) and palladium on carbon (50 mg) were dissolved in tetrahydrofuran (3 mL), one drop of concentrated hydrochloric acid was added, and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 16 h. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth, and the organic phase was concentrated and purified by column chromatography to give 20 mg of (S)-2-((S)-2-aminopropionamido)-4-methoxy-4-oxobutyric acid hydrochloride (compound 67). 1 H NMR(400MHz,DMSO-d6)δ12.60(s,1H),8.94(d,J=8.0Hz,1H),8.35(s,2H),4.62-4.55(m,1H),3.84(dd,MS m / z(ESI):255[M+H] + .

[0098] Example 23: Synthesis of Compound 68 [ka] Step 1: Synthesis of 1-chloroethylsulfonyl chloride To a solution of 1-chloroethyl chloroformate (3.02 mL, 28.0 mmol) in anhydrous dichloromethane (40 mL) was slowly added chlorosulfonic acid (3.72 mL, 56.0 mmol) within 10 min at 0° C. The mixture was stirred at 0° C. for 4 h under nitrogen atmosphere. Ice water was added to the reaction to quench the reaction, and dichloromethane (200 mL) was added for extraction. The organic layer was separated, washed with brine solution, dried over anhydrous sodium sulfate, and concentrated to give 4.0 g of 1-chloroethylsulfonyl chloride as a pale yellow liquid. Step 2: Synthesis of 1-(1-chloroethyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester (S)-2-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyric acid and tetrabutylammonium bisulfate were dissolved in dichloromethane, stirred and cooled to 0° C. in an ice bath. Aqueous potassium carbonate and a dichloromethane solution of 1-chloroethylsulfonyl chloride were successively added dropwise to the reaction, stirred, slowly heated to room temperature and stirred overnight. After the reaction was completed as monitored by TLC, dichloromethane was added, washed with water three times and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EA / PE gradient elution, 20:1 to 5:1) to give 1.0 g of 1-(1-chloroethyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester as a colorless oil. Step 3: Synthesis of O'1,O1-(ethane-1,1-diyl)4-dimethyl(2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) Sodium iodide and potassium carbonate were dissolved in DMF, placed in an ice bath, stirred, and cooled to 0°C. Boc-L-aspartic acid 4-methyl ester was dissolved in DMF, added dropwise to the above reaction system, placed in an ice bath, and stirred for 30 minutes. 1-(1-chloroethyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester was dissolved in DMF, added dropwise to the reaction system, stirred, slowly warmed to room temperature, stirred for about overnight, and the reaction was monitored by TLC. After the reaction of the raw material was completed, 10 mL of water was added, and extraction was performed three times with ethyl acetate, and washing was performed three times with water. The organic phases were separated and combined, then dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EA / PE gradient elution, 10:1 to 3:1) to give 200 mg of O′1,O1-(ethane-1,1-diyl) 4-dimethyl (2S,2′S)-bis(2-((tert-butoxycarbonyl)amino)succinate) as a white solid. Step 4: Synthesis of O'1,O1-(ethane-1,1-diyl) 4-dimethyl (2S,2'S)-bis(2-aminosuccinate) hydrochloride O'1,O1-(ethane-1,1-diyl) 4-dimethyl (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) was dissolved in dichloromethane, placed in an ice bath, stirred, cooled to 0°C, then 2N hydrochloric acid solution in ethyl acetate was added dropwise, stirred, warmed slowly to room temperature, and stirred for about 2 hours. After the reaction was monitored to be complete by HPLC, the reaction solution was filtered by suction, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to obtain 105 mg of O'1,O1-(ethane-1,1-diyl) 4-dimethyl (2S,2'S)-bis(2-aminosuccinate) hydrochloride (compound 68) as a white solid. MS m / z(ESI): 357[M+H] + .

[0099] Example 24: Synthesis of Compound 69 [ka] Step 1: Synthesis of 4-dimethyl O'1,O1-(propane-2,2-diyl) (2S,2'S)-bis(2-(((benzyloxy)carbonyl)amino)succinate) (S)-2-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyric acid and 2,2-dibromopropane were dissolved in acetonitrile, DIPEA was added dropwise, stirred and reacted at room temperature for 2 hours. After monitoring that the reaction was completed, water was added to dilute the reaction solution, the reaction solution was extracted with ethyl acetate, the organic phase was separated, washed with water, then dried, concentrated and purified by column chromatography to obtain 4-dimethyl O'1,O1-(propane-2,2-diyl) (2S,2'S)-bis(2-((((benzyloxy)carbonyl)amino)succinate). Step 2: Synthesis of 4-dimethyl O'1,O1-(propane-2,2-diyl) (2S,2'S)-bis(2-aminosuccinate) hydrochloride 4-Dimethyl O'1,O1-(propane-2,2-diyl) (2S,2'S)-bis(2-(((benzyloxy)carbonyl)amino)succinate) and palladium on carbon were dissolved in tetrahydrofuran, one drop of concentrated hydrochloric acid was added, and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 16 hours. After monitoring for reaction completion, the palladium on carbon was filtered off using diatomaceous earth, and the organic phase was concentrated and purified by column chromatography to give 4-dimethyl O'1,O1-(propane-2,2-diyl) (2S,2'S)-bis(2-aminosuccinate) hydrochloride (compound 69). MS m / z(ESI): 371 [M+H] + .

[0100] Example 25: Synthesis of Compound 70 [ka] Step 1: Synthesis of 1-benzyl 4-ethyl (tert-butoxycarbonyl)-L-aspartic acid ester (S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyric acid (5 g), EDCI, triethylamine, DMAP and ethanol were added to dichloromethane and stirred at room temperature, and the reaction was monitored by TLC. After monitoring that the reaction was complete, saturated sodium bicarbonate solution was added to the reaction solution and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain 4.8 g of 1-benzyl 4-ethyl (tert-butoxycarbonyl)-L-aspartic acid ester. Step 2: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-4-ethoxy-4-oxobutyric acid 1-Benzyl 4-ethyl (tert-butoxycarbonyl)-L-aspartate (4.8 g) and palladium on carbon were dissolved in tetrahydrofuran, one drop of concentrated hydrochloric acid was added, and the reaction solution was stirred at room temperature under hydrogen atmosphere for 16 hours. After monitoring the reaction to be complete, the palladium on carbon was filtered off using diatomaceous earth, and the organic phase was concentrated and purified by column chromatography to give 3.2 g of (S)-2-((tert-butoxycarbonyl)amino)-4-ethoxy-4-oxobutyric acid. Step 3: Synthesis of 1-((((S)-2-((tert-butylcarbonyl)amino)-4-ethoxy-4-oxobutyryl)oxy)methyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester Sodium iodide and potassium carbonate were dissolved in DMF, placed in an ice bath, stirred, and cooled to 0°C. (S)-2-((tert-butoxycarbonyl)amino)-4-ethoxy-4-oxobutyric acid (1.2 g) was dissolved in DMF, added dropwise to the above reaction system, placed in an ice bath, and stirred for 30 minutes. 1-(chloromethyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester was dissolved in DMF, added dropwise to the reaction system, stirred, slowly warmed to room temperature, and stirred for about overnight. The reaction was monitored by TLC. After the reaction of the raw material was completed, water was added, extracted with ethyl acetate three times, and washed with water three times. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 720 mg of 1-((((S)-2-((tert-butylcarbonyl)amino)-4-ethoxy-4-oxobutyryl)oxy)methyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester. Step 4: Synthesis of 1-((((S)-2-amino-4-ethoxy-4-oxobutyryl)oxy)methyl) 4-methyl L-aspartate hydrochloride 1-((((S)-2-((tert-butylcarbonyl)amino)-4-ethoxy-4-oxobutyryl)oxy)methyl) 4-methyl (tert-butoxycarbonyl)-L-aspartate (720 mg) was dissolved in dichloromethane, stirred in an ice bath, cooled to 0° C., and then 2N hydrochloric acid solution in ethyl acetate was added dropwise, stirred, slowly warmed to room temperature, and stirred for about 2 hours. After the reaction was monitored to be complete by HPLC, the reaction solution was filtered by suction, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to obtain 225 mg of 1-((((S)-2-amino-4-ethoxy-4-oxobutyryl)oxy)methyl) 4-methyl L-aspartate hydrochloride (compound 70). MS m / z(ESI): 357[M+H] + .

[0101] Example 26: Synthesis of Compound 71 [ka] Step 1: Synthesis of 1-benzyl 4-isopropyl (tert-butoxycarbonyl)-L-aspartic acid ester (S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyric acid (10 g), EDCI, triethylamine, DMAP and isopropanol alcohol were added to dichloromethane and stirred at room temperature, and the reaction was monitored by TLC. After monitoring that the reaction was complete, saturated sodium bicarbonate solution was added to the reaction solution, the organic layer was separated, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified to obtain 1-benzyl 4-isopropyl (tert-butoxycarbonyl)-L-aspartic acid ester (8.8 g). Step 2: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutyric acid 1-Benzyl 4-isopropyl (tert-butoxycarbonyl)-L-aspartate (8.8 g) and palladium on carbon were dissolved in tetrahydrofuran, one drop of concentrated hydrochloric acid was added, and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 16 hours. After monitoring for completion of the reaction, the palladium on carbon was filtered off using diatomaceous earth, and the organic phase was concentrated and purified by column chromatography to give 6.0 g of (S)-2-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxybutyric acid. Step 3: Synthesis of 1-((((S)-2-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutyryl)oxy)methyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester Sodium iodide and potassium carbonate were dissolved in DMF, placed in an ice bath, stirred, and cooled to 0° C. (S)-2-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutyric acid (1.6 g) was dissolved in DMF, added dropwise to the above reaction system, placed in an ice bath, and stirred for 30 minutes. 1-(chloromethyl) 4-methyl (tert-butoxycarbonyl)-L-aspartate was dissolved in DMF, added dropwise to the reaction system, stirred, slowly warmed to room temperature, and stirred for about overnight. The reaction was monitored by TLC. After the reaction of the raw materials was completed, water was added, extracted with ethyl acetate three times, washed with water three times, and the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by chromatography to obtain 870 mg of 1-((((S)-2-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutyryl)oxy)methyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester. Step 4: Synthesis of 1-((((S)-2-amino-4-isopropoxy-4-oxobutyryl)oxy)methyl) 4-methyl L-aspartate hydrochloride 1-((((S)-2-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutyryl)oxy)methyl) 4-methyl (tert-butoxycarbonyl)-L-aspartate (570 mg) was dissolved in dichloromethane, placed in an ice bath, stirred, cooled to 0° C., 2N hydrochloric acid solution in ethyl acetate was added dropwise, stirred, slowly heated to room temperature, and stirred for about 2 hours. The reaction was monitored for completion by HPLC, the reaction solution was filtered by suction, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to give 140 mg of 1-((((S)-2-amino-4-isopropoxy-4-oxobutyryl)oxy)methyl) 4-methyl L-aspartate hydrochloride (compound 71). MS m / z(ESI): 371[M+H] + .

[0102] Example 27: Synthesis of Compound 72 [ka] Step 1: Synthesis of 1-(chloromethyl) 4-ethyl (tert-butoxycarbonyl)-L-aspartic acid ester (S)-2-((tert-butoxycarbonyl)amino)-4-ethoxy-4-oxobutyric acid (3.2 g) and tetrabutylammonium bisulfate were dissolved in dichloromethane, placed in an ice bath, stirred, and cooled to 0° C. An aqueous solution of potassium carbonate and a solution of 1-chloromethylsulfonyl chloride in dichloromethane were successively added dropwise to the reaction, stirred, slowly warmed to room temperature, and stirred overnight. After the reaction was completed by monitoring by TLC, dichloromethane was added, washed three times with water, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1.6 g of 1-(chloromethyl) 4-ethyl (tert-butyloxycarbonyl)-L-aspartic acid ester. Step 2: Synthesis of 4-diethyl O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) Sodium iodide and potassium carbonate were dissolved in DMF, placed in an ice bath, stirred, and cooled to 0°C. (S)-2-((tert-butoxycarbonyl)amino)-4-ethoxy-4-oxobutyric acid was dissolved in DMF, added dropwise to the above reaction system, placed in an ice bath, and stirred for 30 minutes. 1-(chloromethyl) 4-ethyl (tert-butoxycarbonyl)-L-aspartic acid ester (1.6 g) was dissolved in DMF, added dropwise to the reaction system, stirred, slowly warmed to room temperature, and stirred for about overnight. The reaction was monitored by TLC. After the reaction of the raw material was completed, water was added, extracted with ethyl acetate three times, and washed with water three times. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 850 mg of 4-diethyl O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate). Step 3: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyric acid hydrochloride 4-Diethyl O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) (850 mg) was dissolved in dichloromethane, placed in an ice bath, stirred, cooled to 0°C, then 2N hydrochloric acid solution in ethyl acetate was added dropwise, stirred, warmed slowly to room temperature, and stirred for about 2 hours. The reaction was monitored for completion by HPLC, the reaction solution was filtered by suction, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to give 174 mg of (S)-2-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyric acid hydrochloride (compound 72). MS m / z(ESI): 371 [M+H] + .

[0103] Example 28: Synthesis of Compound 73 [ka] Step 1: Synthesis of 1-(chloromethyl) 4-isopropyl (tert-butoxycarbonyl)-L-aspartic acid ester (S)-2-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutyric acid (4.0 g) and tetrabutylammonium bisulfate were dissolved in dichloromethane, placed in an ice bath, stirred, and cooled to 0° C. An aqueous solution of potassium carbonate and a solution of 1-chloromethylsulfonyl chloride in dichloromethane were successively added dropwise to the reaction, stirred, slowly warmed to room temperature, and stirred overnight. After the reaction was completed by monitoring by TLC, dichloromethane was added, washed three times with water, the organic phase was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 4.0 g of 1-(chloromethyl) 4-isopropyl (tert-butoxycarbonyl)-L-aspartic acid ester. Step 2: Synthesis of 4-diisopropyl O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) Sodium iodide and potassium carbonate were dissolved in DMF, placed in an ice bath, stirred, and cooled to 0°C. (S)-2-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutyric acid was dissolved in DMF, added dropwise to the above reaction system, placed in an ice bath, and stirred for 30 minutes. 1-(Chloromethyl) 4-isopropyl (tert-butoxycarbonyl)-L-aspartic acid ester (2.5 g) was added to DMF, added dropwise to the reaction system, stirred, slowly warmed to room temperature, and stirred for about overnight. The reaction was monitored by TLC. After the reaction of the raw material was completed, water was added, extracted with ethyl acetate three times, and washed with water three times. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by chromatography to give 1.3 g of 4-diisopropyl O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate). Step 3: Synthesis of 4-diisopropyl O'1,O1-methylene (2S,2'S)-bis(2-aminosuccinate) hydrochloride 4-Diisopropyl O'1,O1-methylene (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate) (0.8 g) was dissolved in dichloromethane, placed in an ice bath, stirred, cooled to 0°C, 2N hydrochloric acid solution in ethyl acetate was added dropwise, stirred, warmed slowly to room temperature, and stirred for about 2 hours. The reaction was monitored for completion by HPLC, the reaction solution was filtered by suction, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to give 270 mg of 4-diisopropyl O'1,O1-methylene (2S,2'S)-bis(2-aminosuccinate) hydrochloride (compound 73). MS m / z(ESI): 399 [M+H] + .

[0104] Example 29: Synthesis of Compound 74 [ka] The synthesis method of the title compound was as described in Example 9 of the present application. In step 2, Boc-L-aspartic acid 4-methyl ester was replaced with N-tert-butoxycarbonyl-L-aspartic acid 1-methyl ester to obtain 4-((((S)-2-amino-4-methoxy-4-oxobutyryl)oxy)methyl) 1-methyl L-aspartic acid ester hydrochloride (compound 74) as a white solid. MS m / z (ESI): 343 [M+H] + .

[0105] Example 30: Synthesis of compound 77a Step 1: Synthesis of O'1,O1-(ethane-1,2-diyl) 4-dimethyl (2S,2'S)-bis(2-(tert-butoxycarbonyl)amino)succinic acid) Ethylene glycol (0.3 g, 4.84 mmol), S-2-(tert-butoxycarbonyl)amino-4-methoxy-4-oxobutyric acid (2.5 g, 10.16 mmol), EDCI (2.32 g, 12.1 mmol) and DIPEA (3.12 g, 24.2 mmol) were dissolved in DMF (20 mL) and the reaction solution was stirred at room temperature under nitrogen atmosphere for 2 hours. After the reaction was completed, an appropriate amount of ice water and ethyl acetate were added and the organic phase was separated. The organic phase was washed with water, dried and purified by column chromatography (PE:EA=3:1) to obtain 1.5 g of O'1,O1-(ethane-1,2-diyl) 4-dimethyl (2S,2'S)-bis(2-(tert-butoxycarbonyl)amino)succinic acid). MS(ESI): C 22 H 36 N 2 O 12 Theoretical mass 520.2 m / z Measured mass 521.2 [M+H] + . Step 2: Synthesis of O'1,O1-(ethane-1,2-diyl) 4-dimethyl (2S,2'S)-bis(2-aminosuccinate) hydrochloride At room temperature, O'1,O1-(ethane-1,2-diyl) 4-dimethyl (2S,2'S)-bis(2-(tert-butoxycarbonyl)amino)succinate) (1.5 g, 2.88 mmol) was dissolved in dichloromethane (20 mL), then a solution of hydrochloric acid (17.29 mL, 2 M, 34.58 mmol) in ethyl acetate was added under ice bath, and the solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction, the supernatant was discarded and the solid was dried to obtain 800 mg of O'1,O1-(ethane-1,2-diyl) 4-dimethyl (2S,2'S)-bis(2-aminosuccinate) hydrochloride. MS(ESI): C 12 H 20 N 2 O 8 Theoretical mass as +2HCl: 320.1 m / z Measured mass: 321.1 [M+H] + . 1 H NMR (DMSO-d6) δ: 8.88 (br s, 6H), 4.32-4.42 (m, 6H), 3.66 (s, 6H), 3.00-3.12 (m, 4H).

[0106] Example 31: Synthesis of compound 78a [ka] Step 1: Synthesis of 1-(2-bromoethyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester S-2-(tert-butoxycarbonyl)amino-4-methoxy-4-oxobutyric acid (1.9 g, 7.68 mmol), 2-bromoethanol (1.06 g, 8.45 mmol), EDCI (2.21 g, 11.53 mmol) and DIPEA (3.82 ml, 23.05 mmol) were dissolved in DMF (20 mL) and the reaction solution was stirred at room temperature under nitrogen atmosphere for 2 hours. After the reaction was completed, an appropriate amount of ice water and ethyl acetate were added and the organic phase was separated. The organic phase was washed with water, dried and purified by column chromatography (PE:EA=4:1) to obtain 1.1 g of 1-(2-bromoethyl) 4-methyl (tert-butoxycarbonyl)-L-aspartic acid ester. MS(ESI):C 12 H 20 BrNO 6 Theoretical mass 353.0 m / z Measured mass 354.0 [M+H] + . Step 2: Synthesis of 4-(2-((S)-2-(tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyryl)oxy)ethyl) 1-methyl (tert-butoxycarbonyl)-L-aspartic acid ester 1-(2-Bromoethyl) 4-methyl (tert-butoxycarbonyl)-L-aspartate (1g, 2.82mmol), (S)-3-(tert-butoxycarbonyl)amino-4-methoxy-4-oxobutyric acid (837mg, 3.39mmol), potassium iodide (938mg, 5.65mmol), and potassium carbonate (780mg, 5.65mmol) were dissolved in DMF (20mL), and the reaction solution was stirred at room temperature under nitrogen atmosphere for 2 hours. After the reaction was completed, an appropriate amount of ice water and ethyl acetate were added, and the organic phase was separated. The organic phase was washed with water, dried and purified by column chromatography (PE:EA=3:1) to give 460 mg of 4-(2-((S)-2-(tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyryl)oxy)ethyl) 1-methyl (tert-butoxycarbonyl)-L-aspartic acid ester. MS(ESI):C 22 H 36 N 2 O 12 Theoretical mass 520.2 m / z Measured mass 521.2 [M+ H] + . Step 3: Synthesis of 4-(2-(S)-2-amino-4-methoxy-4-oxobutyryl)ethyl) 1-methyl L-aspartate hydrochloride At room temperature, 4-(2-((S)-2-(tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyryl)oxy)ethyl) 1-methyl (tert-butoxycarbonyl)-L-aspartate (460 mg, 0.88 mmol) was dissolved in dichloromethane (10 mL), and a solution of hydrochloric acid in ethyl acetate (5.3 mL, 2 M, 10.6 mmol) was added to the reaction system under ice bath, and the solution was reacted at room temperature for 1 hour. After monitoring the completion of the reaction, the supernatant was poured off and the solid was dried to obtain 180 mg of 4-(2-(S)-2-amino-4-methoxy-4-oxobutyryl)ethyl) 1-methyl L-aspartate hydrochloride. MS(ESI):C 12 H 20 N 2 O 8 Theoretical mass as +2HCl: 320.1 m / z Measured mass: 321.1 [M+H]+ . 1 H NMR(DMSO-d6)δ:8.87(brs,6H),4.33-4.42(m,4H),4.26-4.32(m,2H),3.74(s,3H),3.66(s,3H),2.98-3.14(m,4H).

[0107] Activity Test Examples Test Method (a) In vitro pharmacodynamic evaluation of compounds 1. Harvesting LX2 cells: Preparation: The ultraclean workbench was pre-irradiated with an ultraviolet lamp for 30 minutes, the water bath was pre-heated to 37°C, and the complete culture medium was pre-heated to 37°C. After completing the UV disinfection of the ultraclean workbench, turn on the ventilation switch and wipe the surface with a 75% alcohol cotton ball. Prepare a 10 cm cell culture dish, add 7 mL of complete culture medium containing 10% fetal bovine serum, and cover for later use. After the operating temperature of the water bath reached 37°C, the tube containing the frozen LX2 cells was removed from the liquid nitrogen tank and quickly transferred to the water bath. The cryopreservation tube was shaken at high frequency and low amplitude to ensure that the cryopreservation solution was melted quickly and to reduce damage to the cells. Once it was confirmed that the cryopreservation solution was almost completely melted, the cryopreservation tube was quickly removed, the surface moisture was wiped off, the cryopreservation tube was disinfected with 75% alcohol, the alcohol remaining on the sealing film of the cryopreservation tube was wiped off, and the sealing film was peeled off. The cryopreservation solution was quickly and gently sucked up with a pipette and transferred to the prepared cell culture dish. The cell culture dish was gently shaken using the "cross" method to ensure that the cells were evenly spread on the cell culture dish. The culture dish was placed in a 37°C, 5% CO2 incubator. The culture dish was kept in a CO 2 The specimen was placed as close to the inside as possible to reduce fluctuations in temperature.

[0108] 2. Cell medium replacement: After the cells were collected, the complete medium was replaced depending on the cell growth status, the degree of adhesion, and the color of the medium. The LX2 cells were large in size. After adhesion, the cells were polymorphic and mostly spindle-shaped. These cells had a good refractive index under a microscope, and the cells proliferated significantly on the 2nd to 3rd day. The replacement with fresh medium was performed depending on the density and condition of the LX2 cells in the culture dish. Note: Before medium replacement, fresh complete medium should be placed in a 37°C water bath and pre-warmed for 10 to 15 minutes. The old culture medium was aspirated using a negative pressure suction device, and the cells were washed twice with 4 mL of 1x PBS buffer, after which the pre-warmed complete culture medium was used for replacement. The cells were placed in a 37°C incubator and cultured continuously.

[0109] 3. Subculture of cells: When the cells reach about 90% confluency, they can be subcultured. Digestion: After the old culture medium was aspirated with a negative pressure suction device, the cells were washed twice with 4 mL of 1x PBS buffer, 1 mL of trypsin was then added, and the cell culture dish was gently shaken so that the cells were completely immersed in the digestion solution. End of digestion: The morphology of the cells was observed under an inverted microscope. When the cells slowly changed from spindle to round shape and the gaps between the cells gradually became clear, 1 mL of DMEM complete medium containing 10% fetal bovine serum was quickly added to stop the digestion. The cells were gently pipetted to ensure that all the cells fell off the cell culture plate. After pipetting to a single cell suspension, the cells were transferred to a 5 mL glass flow cytometry tube, sealed with a lid, and centrifuged at 800 rpm for 5 min. Resuspension: After discarding the culture medium in the flow cytometry tube, gently tap the flow cytometry tube to move the cells, then add 2 mL of DMEM complete medium containing 10% fetal bovine serum to resuspend the cells and gently pipette with a pipette tip to form a single cell suspension. Passage according to 1:2 or 5 × 10 5Plate splitting was performed at a cell density of 10000000 cells / mL, and then the cells were placed in an incubator to continue culturing. NOTE: A total of 12 mL of medium was required for each cell culture plate, so 125 µL of complete culture medium per well for 96-well plates, 250 µL of complete culture medium per well for 48-well plates, 500 µL of complete culture medium per well for 24-well plates, 1 mL of complete culture medium per well for 12-well plates, and 2 mL of complete culture medium per well for 6-well plates. To ensure that the cells were evenly spread on the cell culture plates, the cell culture plates were gently shaken in the traditional "cross" method.

[0110] 4. Detection of Protein Expression Levels by Western Blotting 4.1 Extraction of total cell protein: Take out the cells, discard the original culture medium, add 1-2mL of 1xPBS, wash twice, then perform trypsin digestion, discard the supernatant, gently tap to move the cells at the bottom of the tube, add 1mL of PBS again to wash the cells twice, centrifuge at 1200rpm for 5 minutes, discard the supernatant completely, tap to mix well the cells at the bottom of the tube. Depending on the amount of cells, add 50-100μL of protein lysis buffer containing protease inhibitors and phosphatase inhibitors, mix the cells thoroughly by pipetting, place on ice to lyse for 30 minutes, then centrifuge at 12,000rcf for 15 minutes at 4℃, pipette the supernatant and transfer to a new EP tube to obtain total cell protein, which can be used as is for the next protein concentration determination or stored at -80℃. 4.2 Determination of protein concentration by BCA method: BCA reagent solution A and solution B were mixed well in a ratio of 50:1 to prepare a working solution. 5μL of the test sample was taken and added to 95μL of deionized water, mixed, and diluted 20 times. 20μL of the diluted test sample was taken and added to a 96-well plate, and after adding 200μL of working solution, the 96-well plate was placed in a 37℃ incubator and incubated for 30 minutes, and then tested by the test machine.

[0111] 4.3 Protein denaturation: 100 μg of each sample was taken, and protein dissolution buffer was added to each sample volume, followed by addition of 1 / 3 of the total volume of 4× loading buffer, mixing thoroughly, denaturing at 99°C for 10 minutes, centrifuging, and storing at -80°C. 4.4 Protein electrophoresis: The precast gel was installed in the electrophoresis tank, 1×MOPS electrophoresis solution was added, the comb on the top of the precast gel was removed, the loading well was gently pipetted to remove the residual gel in the well, the pre-stained protein sample of the same quality as the protein manufacturer was carefully added to the gel well, and the voltage was adjusted to 60V-80V. After 30 minutes, the voltage was adjusted to 110V-120V. When the bromophenol blue reached the groove at the bottom of the gel, the power was turned off to terminate the electrophoresis, and the whole electrophoresis process took about 2 hours to 2.5 hours. 4.5 Electrochemical transfer: Activate the PVDF membrane by immersing it in anhydrous methanol for 1 minute, place the transfer clamp with the black side down, and place the following order from bottom to top: sponge-filter paper-PAGE gel-PVDF membrane-filter paper-sponge. Carefully remove any air bubbles between the glue / membrane and the filter paper, then fix the transfer clamp, place the PAGE gel toward the negative electrode and the PVDF membrane toward the positive electrode in the transfer tank, place this in an ice box, pour in the pre-cooled 1x electrochemical transfer solution, adjust the power supply to 100V, and transfer the membrane for 1-1.5 hours.

[0112] 4.6 Blocking: After the membrane transfer was completed, the PVDF membrane was taken out and washed several times with 1×TBST. After removing the residual electrolyte on the membrane, the membrane was immersed in 5% skim milk and blocked at room temperature for 2 hours or at 4°C overnight. 4.7 Primary antibody incubation: The primary antibodies GAPDH and HCBP6 were diluted to 1 / 1000, and the PVDF membrane and the above antibodies at the corresponding positions according to the molecular weight of the protein were sealed in a hybridization bag and incubated at 4°C overnight. 4.8 Membrane washing: The hybridization bag was cut to retrieve the primary antibody, and the PVDF membrane was taken out and placed in 1×TBST and washed three times on a shaker for 10 min each. 4.9 Secondary antibody incubation: The secondary antibody was diluted at a ratio of 1 / 5,000 to 1 / 10,000, and the PVDF membrane was immersed in the corresponding secondary antibody, placed on a shaker, and incubated at room temperature for 45 to 60 minutes. 4.10 Membrane washing: The secondary antibody was withdrawn, the PVDF membrane was taken out, placed in 1×TBST, and washed 3 times for 10 min each on a shaker. If phosphorylated proteins were detected, the number of washes and washing time needed to be reduced accordingly. 4.11 Exposure and development: The membrane was placed in the dark box of the Fusion Solo imager and developed by adding a drop of ECL exposure solution.

[0113] 5. Q-PCR Detection of Target Gene Expression 5.1 Extraction of total cellular RNA Test compounds were added to LX-2 cells, and total RNA was extracted from the cells 48 hours later. This test was carried out strictly according to the instructions of Total RNA Kit. The procedure was as follows (Note: This test was carried out on ice throughout the entire process, and RNase-free dedicated tips were used throughout the entire process). 1) Remove the 12-well cell culture plate from the incubator, discard the cell culture medium, wash the cells twice with 1 mL of 1x PBS, and completely remove the PBS using a negative pressure suction device. 2) Prepare 350 μL of TRK lysis buffer mixture / well as needed (mixture preparation method: 1 mL TRK lysis buffer + 20 μL β-mercaptoethanol), vortex and mix well. Add 350 μL to each well of a 12-well cell culture plate and leave at room temperature for 5 minutes to completely lyse the cells. 3) Prepare 70% ethanol / well as needed, vortex and mix well. Add 350 μL to each well of a 12-well cell culture plate, shake to mix well and transfer to spin column (spin column + collection tube assembled).

[0114] 4) Centrifugation was carried out at 12,000 g for 60 seconds at 4° C. After centrifugation, the waste liquid was discarded and the spin column was retained. 5) 500 μL of RNA Wash Buffer I was added, and the mixture was centrifuged at 4° C. and 12,000 g for 60 seconds. The waste liquid after centrifugation was discarded, and the collection column was retained. 6) 500 μL of RNA Wash Buffer II (confirm that ethanol has been added) was added, and the mixture was centrifuged at 4° C. and 12,000 g for 60 seconds. The waste liquid after centrifugation was discarded, and the collection column was retained. 7) Step 6) was repeated once more, and the mixture was centrifuged at 4°C, 12,000 g, and 90 seconds. The waste liquid after centrifugation was discarded, and the collection column was retained. 8) Centrifuge at 12,000 g for 120 seconds at 4° C. to completely dry the spin column. 9) The dried spin column was inserted into a new 1.5 mL EP tube, and 30 μL of DEPC water was added to the membrane in the center of the spin column. In this step, be careful not to touch the lid of the EP tube. Leave it at room temperature for 5 minutes and confirm that the RNA is completely dissolved in the DEPC water. Centrifuge at 4°C and 12000g for 60 seconds, and keep the EP tube. 10) RNA concentration was detected using a NanoDrop ultra-microspectrophotometer.

[0115] 5.2 Reverse transcription of RNA to cDNA: According to the instructions of the PrimeScript™ RT reagent kit (Perfect Real Time), the specific test procedure was as follows: 5.2.1 Preparation of reverse transcription reaction system (operate on ice): [Table 2] 5.2.2 The reverse transcription reaction conditions for the device were as follows: [Table 3]

[0116] 5.2.3 The resulting product is cDNA and can be used directly for subsequent Q-PCR testing or stored at -20°C. 5.3 Q-PCR detection of target gene expression: According to the instructions of Power SYBR® Green PCR Master Mix, the specific operations are as follows: 5.3.1 The Q-PCR reaction system was prepared according to the manufacturer's instructions as follows: [Table 4]

[0117] 5.3.2 The following two-step standard amplification procedure was employed using the ABI PRISM® 7500 system. [Table 5] After the reaction is complete, the Q-PCR amplification curve and lysis curve are checked and the relative quantification method (2 -ΔΔC T The test results were analyzed using the FTIR method.

[0118] 5.3.3 The primer sequences used were as follows: [Table 6]

[0119] (b) In vivo pharmacodynamic evaluation of compounds 1. Establishment and treatment of carbon tetrachloride-induced liver fibrosis model in mice Carbon tetrachloride (CCl 4 Chronic intraperitoneal injection of ) induces reversible liver fibrosis, which is commonly used to screen and evaluate anti-liver fibrosis drugs. C57BL / 6 wild-type mice were randomly divided into control, carbon tetrachloride, and treatment groups. Treatments were as follows: Mice in carbon tetrachloride group: Animals were intraperitoneally injected with carbon tetrachloride in a total amount of 0.5μL / g diluted with corn oil to 10μL / g, 3 times a week. After 4 weeks of model establishment, the carbon tetrachloride group was randomly divided into the following groups and the negative control group: (1) Mice in the negative control group: the animals were intraperitoneally injected with 10 μL / g of corn oil solution three times a week, and simultaneously received 200 μL of drinking water by oral gavage. (2) Mice in the carbon tetrachloride group: the animals were injected intraperitoneally with a total amount of 0.5 μL / g of carbon tetrachloride diluted in corn oil to 10 μL / g three times a week, and 200 μL of saline was administered by oral gavage. (3) Mice in the aspartic acid group: the animals were injected intraperitoneally with a total amount of 0.5 μL / g of carbon tetrachloride diluted in corn oil to 10 μL / g three times a week, and 30 mg / kg of aspartic acid was administered by oral gavage. (4) Treatment group of mice: the animals were injected intraperitoneally with a total amount of 0.5 μL / g of carbon tetrachloride diluted with corn oil to 10 μL / g three times a week, and various doses of the compounds of the present invention were administered by oral gavage. The animals were treated for 4 weeks, and blood was taken from the eyeball 48 hours after the last injection of carbon tetrachloride. Approximately 1 mL of whole blood per animal was collected in an anticoagulant tube, immediately placed on ice, and left to stand for 1 hour. Centrifugation was performed at 4°C and 3000 rpm for 15 minutes. Approximately 0.4 mL of the supernatant was collected and added to an EP tube, taking care not to suck up the substratum with a pipette, and then stored in a freezer at -80°C. The mice were euthanized, and fresh liver tissue was collected, a portion of which was placed in a cryopreservation tube and stored in liquid nitrogen for later use, and another portion was fixed in 4% paraformaldehyde solution for 16 to 24 hours for subsequent testing.

[0120] 2. Establishment and treatment of mouse NAFLD model induced by HFD or CHOL (1) 6-8 week-old C57BL / 6J male mice were selected and randomly divided into a normal feed group (n=10) and an HFD or CHOL group. The changes in the body weight of the mice were recorded during the model establishment. The model establishment took 8 weeks (CHOL) or 10 weeks (HFD). After that, the mice in the HFD or CHOL group were randomly divided into the following groups and a negative control group according to their body weight, for a total of 5 groups. (2) Negative control group of mice (n=10): The animals were fed with normal chow twice a day and administered 200 μL of drinking water by oral gavage. Mice in the HFD or CHOL group (n=10): The animals were fed HFD or CHOL twice a day, and at the same time, 200 μL of saline was administered by oral gavage. (Note: HFD (60% high fat) feed (Whitby Technology Development (Beijing) Co., Ltd.) (D12492), CHOL (40% high fat + 1.25% cholesterol) feed (Whitby Technology Development (Beijing) Co., Ltd.) (D12108C)) (3) Compound 6-low dose group of mice (n=10): The animals were fed HFD or CHOL diet twice a day, and simultaneously administered Compound 6 at a dose of 10 mg / kg by oral gavage. (4) Compound 6-medium dose group of mice (n=10): The animals were fed HFD or CHOL twice a day, and simultaneously administered Compound 6 at a dose of 50 mg / kg by oral gavage. (5) Compound 6-high dose group of mice (n=10): The animals were fed HFD or CHOL diet twice a day, and simultaneously administered Compound 6 by oral gavage at a dose of 150 mg / kg. After 8 weeks of administration, blood was collected by enucleation. Approximately 1 mL of whole blood per mouse was collected in an anticoagulant tube and immediately placed on ice. Centrifugation was performed at 4°C and 3000 rpm for 15 minutes. 0.4 mL of the supernatant was collected and added to an EP tube, taking care not to aspirate the sublayer with a pipette, and stored in a freezer at -80°C to detect biochemical indicators such as blood lipids and transaminases. Mice were euthanized, and fresh liver tissue was collected and weighed, a portion of which was placed in a cryopreservation tube and stored in liquid nitrogen for later use, and another portion was fixed in 4% paraformaldehyde solution for 16 to 24 hours, and histological HE staining and Oil Red O staining were performed to determine the severity of fatty liver.

[0121] 3. Liver Histological Analysis (1) Paraffin embedding (1 Fixation: Mice were treated following standard procedures, and tissues were harvested and placed in 4% paraformaldehyde and fixed for 24 hours. (2) Dehydration: Fixed tissues were placed in 70% ethanol overnight, then dehydrated stepwise in 85%, 95%, 95%, 95%, 100%, and 100% ethanol for 1 hour each. (3) Permeabilization: Dehydrated tissues were permeabilized by sequentially placing them in 50% xylene (xylene and ethanol in the same volume), 100% xylene, and 100% xylene for 20 min each. (4) Wax immersion: The permeabilized tissue was placed in paraffin at 60°C and the paraffin was renewed every hour for a total of four times. Be sure to use fresh paraffin when renewing. (5) Embedding: Add molten paraffin (60°C) to a small iron trough, take out the paraffin-soaked tissue, place it in it, turn over the embedding box with the label attached, and add molten paraffin again. Be careful not to introduce air bubbles during this procedure. ( 6 ) The paraffin-embedded tissues were placed on the ice table of the automatic embedding machine. After the paraffin solidified, they were placed in a −20°C freezer for further cooling.

[0122] (2) Serial sectioning (1) The wax block with the embedded tissue was placed in the corresponding position on the microtome. (2) The thickness of the sections was adjusted to the thickness required for the test. Generally, 3 to 4 μm sections are used. (3) Serial tissue sections were gently placed and expanded in a water bath expander at 55°C. (4) Serial tissue sections were gently separated with forceps. (5) Wax sections that were fully extended and had no wrinkles in the tissue were selected and collected using adhesive slides to ensure that the sections adhered to the slide. (6) The slide was pre-dried by placing it horizontally on a slide dryer at 70°C, and then baked in an oven at 70°C for approximately 1 hour.

[0123] (3) H&E staining (hematoxylin and eosin staining, H&E) (1) Bake sections: Place tissue sections in a 70°C oven for 1 hour. (2) Degreasing: The specimen was degreased by immersing in xylene (I) → xylene (II) → xylene (III) for 10 minutes each; (3) Rehydration: The delipidated tissue sections were washed in the following order: 100% ethanol for 2 min → 100% ethanol for 2 min → 95% ethanol for 2 min → 85% ethanol for 2 min → 70% ethanol for 2 min → distilled water for 3 min. (4) Staining of cell nuclei: Rehydrated tissue sections were stained with hematoxylin solution for about 3 to 5 minutes. The specific time was determined by observation under a microscope. The sections were washed twice with tap water for several tens of seconds each time. (5 Differentiation: The sections were placed in a 1% hydrochloric acid ethanol solution (prepared with 70% ethanol) for several tens of seconds, and the time was adjusted until the nuclei were clearly stained by observation under a microscope. (6) Turn blue: Rinse the sections in running water for approximately 15-30 minutes until the sections turn blue, then briefly rinse the tissue sections in distilled water. (7) The sections were placed in the eosin solution and stained for about 30 seconds. The time was adjusted by observing under a microscope. If staining was difficult, adding 1-2 drops of glacial acetic acid to the staining solution made it easier to stain the tissue sections and less likely to destain. (8) Dehydration: Tissue sections were sequentially placed in 70% ethanol for 2 min → 85% ethanol for 2 min → 95% ethanol for 2 min → 100% ethanol for 2 min → 100% ethanol for 2 min. (9) Permeabilization: The sections were placed in xylene (I), xylene (II), and xylene (III) for 10 min each. (10) Mounting of sections: An appropriate amount of neutral gum was dropped onto the tissue, covered with a cover glass, and the sections were mounted without allowing any air bubbles to get in.

[0124] (4) Masson staining Masson staining is one of the classic and reliable staining methods for collagen fibers. Collagen fibers appear red. The staining procedure was as follows: Conventional baking and degreasing (same procedure as above); oxidation with potassium permanganate solution for 5 min, washing with water, staining with Masson's staining solution for 5 min, 0.2% acetic acid solution for 2-3 s, 5% phosphotungstic acid solution for 5 min, aniline blue solution for 7 min, washing three times with 0.2% acetic acid solution, dehydration, permeabilization of the sections, mounting of the sections, air drying, and storage at room temperature were performed in the usual manner. Images of stained tissue on the sections were collected using an imaging system, and analysis software was used to automatically read the tissue measurement area, calculate the positive area and tissue area within the measurement area, and calculate the percentage of the positive area. 4. Liver function index test Mouse serum was collected to detect the relevant levels of ALT and AST in serum.

[0125] 5. Q-PCR Detection of Target Gene Expression in Mouse Liver Tissue (1) Extraction of total tissue RNA (1) 10 mg of tissue was collected, weighed, placed in a grinder, liquid nitrogen was added, and the tissue was thoroughly ground with a grinding rod. During the grinding process, care was taken to add liquid nitrogen at any time to prevent melting of the tissue, which may result in degradation of RNA. (2) The ground tissue was placed in a 1.5 mL EP tube, 1 mL of Trizol dissolving solution was added, and mixed well. (3) The sample was placed in a thermostatic mixer and shaken at room temperature for approximately 3–5 h until the tissue was completely dissolved. (4) 200 mL of chloroform was added, the mixture was shaken vigorously for several tens of seconds, and then allowed to stand at room temperature for 5 to 10 minutes. (5) The mixture was centrifuged at 12,000 rcf for 15 minutes at 4°C, and 75% alcohol (prepared in DEPC water) was prepared during centrifugation and stored at -20°C for later use. (6) After centrifugation, the supernatant was collected and placed in a new EP tube. The same amount of isopropanol was added, the tube was turned upside down 10 times, and the tube was left to stand at room temperature for 10 minutes. (7) Centrifuge at 4°C and 12,000 rcf for 15 to 20 minutes. (8) The supernatant was discarded, the precipitate was retained, and 1 mL of pre-chilled 75% ethanol was added to wash out the isopropanol, followed by centrifugation at 4°C and 12,000 rcf for 10 min. This step was repeated once, and then the precipitate was air-dried. (9 Depending on the amount of precipitate, 30 to 100 μL of DEPC water was added to dissolve the precipitate, and this was used as extracted tissue RNA. (10) Extracted RNA was measured using a UV spectrophotometer to determine the concentration and purity and stored at -80°C.

[0126] (2) Reverse transcription of RNA to cDNA: According to the instructions for the PrimeScript™ RT reagent kit (Perfect Real Time), the specific test steps were as follows: (1) Preparation of reverse transcription reaction system (operate on ice): [Table 7] (2) The reverse transcription reaction conditions were as follows: [Table 8] The resulting product is cDNA and can be used directly for subsequent Q-PCR testing or stored at -20°C.

[0127] (3) Q-PCR detection of target gene expression: According to the instructions for Power SYBR (registered trademark) Green PCR Master Mix, the specific operations were as follows. (1) The Q-PCR reaction system was prepared as follows according to the manufacturer's instructions. [Table 9]

[0128] (2) The following two-step standard amplification procedure was employed using the ABI PRISM® 7500 system. [Table 10] After the reaction is complete, the Q-PCR amplification curve and lysis curve are checked and the relative quantification method (2 -ΔΔC T The test results were analyzed using the FTIR method.

[0129] (3) The primer sequences used were as follows: [Table 11]

[0130] (c) Thermodynamic solubility test of compounds The drug was taken in several portions and used to prepare a series of solutions ranging from unsaturated to saturated solutions. The solutions were then vibrated until equilibrium was reached under constant temperature conditions, filtered through a membrane, and the filtrate was collected and analyzed to determine the actual concentration S of the drug in the solution. A graph was then drawn of the concentration c of the prepared solutions, and the turning point A of the curve on the graph was determined as the equilibrium solubility of the drug. Thermodynamic solubilities were measured using the shake flask method (pH = 7.4) and analyzed using high performance liquid chromatography-diode array detector (HPLC-DAD) or high performance liquid chromatography-tandem mass spectrometry (LC / MS / MS).

[0131] (d) Pharmacokinetic studies 1. Research purpose: Rats were used as test animals to investigate the pharmacokinetic behavior of the following compounds in rat plasma. 2. Test Protocol: 2.1 Test Drugs: The drug was made in-house according to the examples of the present invention. 2.2 Test animals: SD rats, 6-8 weeks old, 3 males for each administration method / example. 2.3 Feeding conditions: The animals were fasted overnight and were allowed to eat food 8 hours after drug intake and had free access to water. 2.4 Sample Collection Blood samples were collected before administration and 5, 15, and 30 minutes, 1, 2, 4, 8, and 24 hours after administration. 2.5 Sample processing Blood was placed on wet ice and centrifuged (2000 g, 5 min at 4°C) to obtain plasma samples. 2.6 Analysis by liquid chromatography The blood drug concentration was measured using LC-MS / MS. The HPLC conditions were mobile phase A:H 2 O-0.5% FA, mobile phase B: ACN-0.5% FA. 3. Test results and analysis The WinNonlin 8.2 non-compartmental model was used to estimate pharmacokinetic parameters (PK parameters including but not limited to peak concentration (Cmax), time to peak (Tmax), terminal elimination rate (Ke), terminal elimination half-life (T1 / 2), area under the drug-time curve (AUC), clearance rate (CL), apparent volume of distribution (Vd), mean residence time (MRT), and bioavailability (F)).

[0132] Test results: (a) Regulation of NS3TP1 in semi-activated LX2 cells - qPCR LX2 cells were routinely subcultured and seeded. After 12 hours of adherent growth, 200 μM of test compounds were added. After 48 hours, cells were harvested, total RNA was extracted, and NS3TP1 gene expression was detected using Q-PCR. The results (Table 1) show that the compounds of the present invention can upregulate the expression level of mRNA. [Table 12] NOTE: Compared with the control group, NA indicates no obvious upregulation; C represents that the upregulation was 1-20%; B represents that the upregulation was 20-40%; A represents that the upregulation was 40% or more; "-" indicates that no results were obtained; * Compounds marked with " were tested at a concentration of 12.5 μM; **Compounds marked with " were tested at a concentration of 10 mM.

[0133] (b) In vitro drug efficacy evaluation in semi-activated LX2 cells - qPCR LX2 cells were subcultured and seeded as normal. After 12 hours of adherent growth, 50 μM of test compounds were added. After 48 hours, cells were harvested, total RNA was extracted, and changes in the expression levels of mRNA of liver fibrosis-related genes (ACTA2 encoding α-SMA, COL1A1 and COL1A2 encoding collagen I, COL3A1 encoding collagen III, SMAD3 encoding Smad3) and inflammation-related genes (IL1B encoding IL-1β, TNFa encoding TNFα) were detected using Q-PCR (for specific methods, see 5. Q-PCR detection of target gene expression as described above). α-SMA was a marker of hepatic stellate cell activation, and collagen I and collagen III were the main components of extracellular matrix deposition.

[0134] The results (Table 2) showed that the compounds of the present invention can inhibit the expression level of mRNA of liver fibrosis-related genes. Among them, Compound 2, Compound 4, Compound 6, Compound 8, Compound 10, Compound 12, Compound 14, Compound 15, Compound 18, Compound 19, Compound 21, Compound 22, Compound 26, Compound 28, Compound 30, Compound 33, Compound 35, Compound 38, Compound 40, Compound 42, Compound 44, Compound 47, Compound 48, Compound 50, Compound 52, Compound 53, Compound 54, Compound 59, Compound 61, Compound 63, Compound 66, Compound 70, Compound 71, Compound 72, Compound 7 Compound 4, Compound 6, Compound 26, Compound 28, Compound 33, Compound 53, Compound 54, Compound 68, Compound 70, Compound 73, etc. can inhibit the expression of α-SMA at the mRNA level; Compound 1, Compound 4, Compound 6, Compound 9, Compound 12, Compound 15, Compound 22, Compound 26, and Compound 28 can inhibit the expression of Smad3 at the mRNA level. Overall, Compound 4, Compound 6, Compound 12, Compound 26, Compound 47, Compound 48, Compound 52, and Compound 54 had a stronger effect on inhibiting the expression level of the mRNA of liver fibrosis-related genes. [Table 13] TIFF2024546039000081.tif173153 NOTE: Compared with the control group, NA indicates that no obvious inhibitory effect was observed; E represents that the inhibition rate was 1%-10%; D represents that the inhibition rate was 10%-25%; C represents that the inhibition rate was 25%-50% or more; B represents that the inhibition rate was 50%-75%; A represents that the inhibition rate was 75%-100%; "-" indicates that no results were obtained; * Compounds marked with " were tested at a concentration of 12.5 μM; ** Compounds marked with " were tested at a concentration of 25 μM; *** Compounds with a " test concentration was 100 μM.

[0135] (c) Evaluation of drug efficacy in an in-vitro liver fibrosis model using activated LX2 cells - qPCR LX2 cells were routinely subcultured and seeded. After 12 hours of adhesion growth, cells were activated by administration of TGFβ1 (5 ng / mL) and test compounds were added at a concentration of 25 μM. After 24 hours, cells were harvested, total RNA was extracted, and real-time PCR was used to detect the expression levels of liver fibrosis- and inflammation-related genes. α-SMA was a marker of hepatic stellate cell activation, and collagen 1 and collagen 3 were the main components of extracellular matrix deposition. [Table 14] NOTE: Compared with the control group, NA indicates that no obvious inhibitory effect was observed; C represents that the inhibition rate was 1%-10%; B represents that the inhibition rate was 10%-25%; A represents that the inhibition rate was more than 25%; "-" indicates that no results were obtained. These results indicated that the compounds of the present invention could inhibit the expression levels of mRNA of hepatic fibrosis-related genes in this test.

[0136] (d) In vitro drug efficacy evaluation in semi-activated LX2 cells - Western blot LX2 cells were subcultured and seeded as normal. After 12 hours of adhesion growth, test compounds were added at various concentrations (50 μM, 100 μM, 200 μM, 400 μM). After 48 hours, cells were harvested, proteins were extracted, and changes in the expression levels of proteins (α-SMA, collagen I, collagen III, FN) of liver fibrosis-related genes were detected using Western blot (for specific methods, see 4. Detection of protein expression levels by protein immunoblotting). α-SMA is a marker of hepatic stellate cell activation, collagen I and collagen III are the main components of extracellular matrix deposition, and fibronectin (FN) is an adhesive glycoprotein mainly involved in cell-cell adhesion interactions. These results showed that the compounds of the present invention can inhibit the expression level of mRNA of liver fibrosis-related genes. The results are not shown in full, con is the control well, P1 is the positive control well, "ASP-50" is 50μM aspartic acid, and all other numbers are in the form of compound number-concentration (μM). Among them, compound 6, compound 47, and compound 54 have stronger inhibitory effect on collagen I and collagen III protein expression than ASP (Figure 1); compound 4, compound 6, compound 41, compound 47, compound 48, and compound 52 have stronger inhibitory effect on α-SMA protein than ASP (Figure 2); compound 50, compound 52, and compound 54 have stronger inhibitory effect on FN protein expression than ASP (Figure 3).

[0137] (e) In vitro drug efficacy evaluation in activated LX2 cells - Western blot LX2 cells were subcultured and seeded as normal. After 12 hours of adherent growth, cells were activated by administration of TGFβ1 (5 ng / mL), and test compounds were added at various concentrations. After 24 hours, cells were harvested, proteins were extracted, and changes in the expression levels of proteins (α-SMA, collagen I) of liver fibrosis-related genes were detected using Western blot (for specific methods, see 4. Detection of protein expression levels by protein immunoblotting). α-SMA is a marker of hepatic stellate cell activation, and collagen I was the main component of extracellular matrix deposition. These results showed that after stimulation of LX2 cells with TGFβ, the expression of collagen I in the cells increased. After administration of compounds 54, 77a, and 78a, the expression of collagen I and α-SMA in the cells significantly decreased (FIG. 4). (f) Modulation effect of compounds on the NS3TP1 gene in an animal model of liver fibrosis After induction of CCl4, the expression of NS3TP1 in mouse liver tissue was significantly decreased, indicating a possible correlation between mouse liver fibrosis and abnormal expression of NS3TP1. After treatment with various doses of compound 6, the expression of NS3TP1 in mouse liver tissue was significantly increased in a dose-dependent manner compared with the untreated group (Figure 5).

[0138] (g) Efficacy of the compound in liver fibrosis model animals Observation of Masson-stained sections and computer analysis showed that collagen (blue) was CCl 4 After induction, collagen was clearly deposited in mouse liver tissue. After treatment with compound 4 (20 mg / kg / day), compound 6 (25 mg / kg / day), compound 47 (20 mg / kg / day), and compound 54 (40 mg / kg / day), collagen deposition in mouse liver tissue was reduced compared with the non-treatment group and aspartic acid group (30 mg / kg / day), indicating that the compounds of the present invention (e.g., compound 4, compound 6, compound 47, compound 54) can reduce collagen deposition and suppress liver fibrosis (Figure 6). Observation of Masson-stained sections and computer analysis showed that collagen (blue) was CCl 4 After induction, collagen was clearly deposited in mouse liver tissue. After treatment with compound 6 (10mg / kg / twice a day, 50mg / kg / twice a day, 150mg / kg / twice a day), collagen deposition in mouse liver tissue was reduced compared with that in the non-treated group, indicating that the compound of the present invention (e.g., compound 6) can reduce collagen deposition and suppress liver fibrosis (Figure 7). CCl 4 After induction, the levels of aminotransferase ALT and AST in mice are significantly increased, and obvious liver damage occurs.Compared with non-treated group, the ALT in mouse plasma is reduced after administration of the compound of the present invention, indicating that the compound of the present application has a protective effect on hepatocytes, can reduce liver damage, and improve liver function of mice.

[0139] The activity results revealed the following: 1. CCl 4In a mouse model of hepatic fibrosis induced by NS3TP1, the expression level of NS3TP1 in liver tissue was decreased, indicating that there may be a correlation between hepatic fibrosis and abnormal expression of NS3TP1 in mice. 2. From the activity characterization results, it can be seen that the compounds of the present invention have the effect of up-regulating the expression of NS3TP1 in cell assays and in vivo assays. 3. From the results of activity characterization, it can be seen that the compounds of the present invention also showed the effect of alleviating the symptoms of liver fibrosis in liver fibrosis models at the cellular and animal levels.

[0140] (h) Efficacy of the compound in NAFLD model animals Observation of H&E stained sections and computer analysis showed that after feeding HFD diet, a large number of lipid droplets accumulated in the liver tissue of mice, and the liver tissue showed soap-like diffuse fatty changes. After treatment with compound 6, compared with the non-treated group, the aggregation of lipid droplets in the liver tissue of mice was dose-dependently reduced, indicating that the compounds of the present invention (e.g., compound 6) can have the effect of suppressing the formation of fatty liver (Figure 9). Observation of H&E stained sections and computer analysis showed that after feeding CHOL diet, a large number of lipid droplets accumulated in the liver tissue of mice, and the liver tissue showed soap-like diffuse fatty changes.After treatment with compound 6, compared with the non-treated group, the aggregation of lipid droplets in the liver tissue of mice was dose-dependently reduced, indicating that the compound of the present invention (e.g., compound 6) can have the effect of suppressing the formation of fatty liver (Figure 10). (i) Solubility test Some compounds of the present invention showed good solubility, which was clearly better than that of aspartic acid.

[0141] (j) Pharmacokinetic testing of compounds These results showed that after the administration of saline to rats, the concentrations of compound 6 and aspartic acid in the rats varied between 1000 and 3000 ng / mL within 24 hours, suggesting that compound 6 and aspartic acid of the present invention are endogenous substances in rats. After administration of compound 6 to rats (IV 10 mg / kg, PO 40 mg / kg), the levels of compound 6 in the body were significantly increased (Cmax of 6100 ng / mL for IV 10 mg / kg and 22500 ng / mL for PO 40 mg / kg), but there was no significant increase in the levels of aspartic acid (Cmax of 3017 ng / mL for IV 10 mg / kg and 4020 ng / mL for PO 40 mg / kg), suggesting that compound 6 exerts its pharmacological action mainly in the prototypic form, rather than being metabolized to aspartic acid and exerting its pharmacological action after administration to rats. After administration of aspartic acid and compound 6 to rats (PO 20mg / kg), the Cmax and AUC of rats administered compound 6 were significantly higher than those of rats administered aspartic acid, suggesting that compound 6 has a significantly higher in vivo exposure than aspartic acid. At the same time, the Tmax of rats administered compound 6 was significantly smaller than that of rats administered aspartic acid, suggesting that compound 6 can reach the maximum concentration more quickly. [Table 15] These results showed that the compounds of the present invention have good pharmacokinetic parameters, perform better than aspartic acid in multiple pharmacokinetic parameters such as AUC, Cmax and / or bioavailability, and have better drug properties.

Claims

1. below: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of hepatic stellate cell activation; 4) Regulation of NS3TP1 expression In the manufacture of a medicine or medicament for use in at least one of the following: A-(L 1 ) x -A' (Formula I) In the formula, A is 【Chemistry 1】 and A' is 【Chemistry 2】 where A and A' are the same or different; where: x is selected from the group consisting of 0, 1 and 2; 1) if x is 0 and A' does not exist; for A, R 1 and R 2 are each independently C1-C6 alkyl, —O—R a1 , and -NR a2 R a3 selected from the group consisting of: R 3 and R 4 are each independently hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, —C(R h ) 2 -R d1 , -(CO)-(L) n -R d2 , -(CO)O-(L) n -R d3 , -(SO 2 ) - (L) n -R d4 , and -P(O)(OR e ) 2 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-O-R b2 , -(C1-C6 alkyl) n —O—(CO)—R b3 , -(C1-C6 alkyl) n -O-(CO)-OR b4 , -(C1-C6 alkyl) n -(CO)-NR b5 R b6 , -(C1-C6 alkyl) n -NR b7 -(CO)-R b8 , and —(C1-C6 alkyl) n -NR b9 -(CO)-O-R b10 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 are each independently hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-O-R c1 , -(C1-C6 alkyl) n —O—(CO)—R c2 , and —(C1-C6 alkyl) n -O-(CO)-OR c3 wherein said alkyl, cycloalkyl, aryl, heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, and C6-C10 aryl; R c1 , R c2 , and R c3 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl; L is independently absent, O, NR d5 , C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R e are each independently selected from the group consisting of hydrogen, deuterium, Na, K, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; R h are each independently C1-C6 alkyl, —NHC(O)R g1 , -OC(O)R g2 , -OP(O)(ONa) 2 , -NHC(O)OR d6 , -OC(O)OR d7 , and —OC(O)NHR d8 selected from the group consisting of: R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 are each independently selected from the group consisting of hydrogen, deuterium, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are each independently selected from the group consisting of one or more R f optionally substituted with a group; R f are each independently a halogen, a C1-C6 alkyl, a halogenated C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C6-C10 aryl, a halogenated C6-C10 aryl, a C3-C7 cycloalkyl, a 3- to 15-membered heterocyclyl, -NR g3 R g4 , -OR g5 , -NHC(O)R g6 , and -OC(O)R g7 selected from the group consisting of: R g1 , R g2 , R g3 , R g4 , R g5 , R g6 , and R g7 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 is selected from the group consisting of hydrogen and amino; Y is C or S; y is an integer greater than or equal to 0; or y is selected from the group consisting of 0, 1, 2, and 3; or y is 0 or 1; n is 0 or 1; 2) When x is 1 or 2, and A and A' are the same or different, Unit A R 1 , R 2 , R 3 , and R 4 Any one of the R of the adjacent unit A' 1 ', R 2 ', R 3 ', and R 4 ' and L 1 Connected via; Each L 1 are independently a unit bridging group selected from the group consisting of absent, O, S, carbonyl, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-), cycloalkyl (or C3-C7 cycloalkyl), and heteroalkyl (or 3- to 7-membered heteroalkyl; for example, -O-alkyl-O- (or -O-C1-C6 alkyl-O-)), wherein said alkyl, cycloalkyl, and heteroalkyl are optionally substituted with one or more groups independently selected from the group consisting of Z; Z is independently selected from the group consisting of halogen, amino, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), haloalkyl (or halogenated C1-C6 alkyl), cycloalkyl (or C3-C7 cycloalkyl), aryl (or C6-C12 aryl), and heterocyclyl; or L 1 is selected from the group consisting of absent and -CR'R'', where R' and R'' are each independently H, C1-C6 alkyl (or C1-C3 alkyl); or L 1 is absent, -CH 2 -, -CH(CH 3 )-, and -C-(CH 3 ) 2 selected from the group consisting of: Regarding A, R 1 and R 2 are each independently C1-C6 alkyl, —O—, —O—R a1 , and -NR a2 R a3 selected from the group consisting of: R 3 and R 4 are each independently hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, —C(R h ) 2 -R d1 , -(CO)-(L) n -R d2 , -(CO)O-(L) n -R d3 , -(SO 2 ) - (L) n -R d4 , and -P(O)(OR e ) 2 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-O-R b2 , -(C1-C6 alkyl) n —O—(CO)—R b3 , -(C1-C6 alkyl) n -O-(CO)-OR b4 , -(C1-C6 alkyl) n -(CO)-NR b5 R b6 , -(C1-C6 alkyl) n -NR b7 -(CO)-R b8 , and —(C1-C6 alkyl) n -NR b9 -(CO)-O-R b10 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 are each independently hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-O-R c1 , -(C1-C6 alkyl) n —O—(CO)—R c2 , and —(C1-C6 alkyl) n -O-(CO)-OR c3 wherein said alkyl, cycloalkyl, aryl, heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, and C6-C10 aryl; R c1 , R c2 , and R c3 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl; L is independently absent, O, NR d5 , C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R e are each independently selected from the group consisting of hydrogen, deuterium, Na, K, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; R h are each independently C1-C6 alkyl, —NHC(O)R g1 , -OC(O)R g2 , -OP(O)(ONa) 2 , -NHC(O)OR d6 , -OC(O)OR d7 , and —OC(O)NHR d8 selected from the group consisting of: R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 are each independently selected from the group consisting of hydrogen, deuterium, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are each independently selected from the group consisting of one or more R f optionally substituted with a group; R f are each independently a halogen, a C1-C6 alkyl, a halogenated C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C6-C10 aryl, a halogenated C6-C10 aryl, a C3-C7 cycloalkyl, a 3- to 15-membered heterocyclyl, -NR g3 R g4 , -OR g5 , -NHC(O)R g6 , and -OC(O)R g7 selected from the group consisting of: R g1 , R g2 , R g3 , R g4 , R g5 , R g6 , and R g7 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 is selected from the group consisting of hydrogen and amino; Y is C or S; y is an integer greater than or equal to 0; or y is selected from the group consisting of 0, 1, 2, and 3; or y is 0 or 1; n is 0 or 1; Regarding A', R 1 ' and R 2 ' are each independently C1-C6 alkyl, -O-, -O-R a1 , and -NR a2 R a3 selected from the group consisting of: R 3 ' and R 4 ' are each independently hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -C(R h ) 2 -R d1 , -(CO)-(L) n -R d2 , -(CO)O-(L) n -R d3 , -(SO 2 ) - (L) n -R d4 , and -P(O)(OR e ) 2 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-O-R b2 , -(C1-C6 alkyl) n —O—(CO)—R b3 , -(C1-C6 alkyl) n -O-(CO)-OR b4 , -(C1-C6 alkyl) n -(CO)-NR b5 R b6 , -(C1-C6 alkyl) n -NR b7 -(CO)-R b8 , and —(C1-C6 alkyl) n -NR b9 -(CO)-O-R b10 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 are each independently hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-O-R c1 , -(C1-C6 alkyl) n —O—(CO)—R c2 , and —(C1-C6 alkyl) n -O-(CO)-OR c3 wherein said alkyl, cycloalkyl, aryl, heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, and C6-C10 aryl; R c1 , R c2 , and R c3 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl; L is independently absent, O, NR d5 , C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R e are each independently selected from the group consisting of hydrogen, deuterium, Na, K, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl; R h are each independently C1-C6 alkyl, —NHC(O)R g1 , -OC(O)R g2 , -OP(O)(ONa) 2 , -NHC(O)OR d6 , -OC(O)OR d7 , and —OC(O)NHR d8 selected from the group consisting of: R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , R d8 are each independently selected from the group consisting of hydrogen, deuterium, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are each independently selected from the group consisting of one or more R f optionally substituted with a group; R f are each independently a halogen, a C1-C6 alkyl, a halogenated C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C6-C10 aryl, a halogenated C6-C10 aryl, a C3-C7 cycloalkyl, a 3- to 15-membered heterocyclyl, -NR g3 R g4 , -OR g5 , -NHC(O)R g6 , and -OC(O)R g7 selected from the group consisting of: R g1 , R g2 , R g3 , R g4 , R g5 , R g6 , and R g7 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl; R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 ' is selected from the group consisting of hydrogen and amino; Y' is C or S; y' is an integer greater than or equal to 0; or y' is selected from the group consisting of 0, 1, 2, and 3; or y' is 0 or 1; n is 0 or 1; Alternatively, Formula I is 【Transformation 3】 That is, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystalline form, metabolite form, or any combination or mixture thereof.

2. 1) if x is 0 and A' does not exist; for A, R 1 and R 2 are independent of each other, C1-C6 alkyl, -O-R a1 , where R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-O-R b2 , -(C1-C6 alkyl) n —O—(CO)—R b3 , and —(C1-C6 alkyl) n -O-(CO)-OR b4 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); and -NR a2 R a3 , where R a2 and R a3 are each independently hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-O-R b2 , -(C1-C6 alkyl) n —O—(CO)—R b3 , -(C1-C6 alkyl) n -O-(CO)-OR b4 , and —(C1-C6 alkyl) n -(CO)-NR b5 R b6 wherein said alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); selected from the group consisting of: R b1 , R b2 , R b3 , R b4 , R b5 and R b6 are each independently hydrogen, hydroxyl, amino, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-O-R c1 , -(C1-C6 alkyl) n —O—(CO)—R c2 , and —(C1-C6 alkyl) n -O-(CO)-OR c3 wherein said alkyl, cycloalkyl, aryl, heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, and C6-C10 aryl; R c1 , R c2 and R c3 are each independently selected from the group consisting of hydrogen, hydroxyl, amino, C1-C6 alkyl, and C3-C7 cycloalkyl; or R 1 and R 2 are independent of each other, hydroxyl, C1-C6 alkyl, -O-R a1 , where R a1 is C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and -(C1-C6 alkyl) n -O-(CO)-OR b4 which may be optionally further substituted with one or more C6-C10 aryl groups; R b4 is selected from the group consisting of C1-C6 alkyl, and n is 1; and -NR a2 R a3 , where R a2 and R a3 are independent of each other hydrogen, C1-C6 alkyl, wherein the C1-C6 alkyl may be optionally further substituted with one or more C6-C10 aryl groups; -(C1-C6 alkyl) n —O—(CO)—R b3 , where R b3 is a C1-C6 alkyl further substituted with a C6-C10 aryl; -(C1-C6 alkyl) n -(CO)-R b1 , where R b1 is hydroxyl and n is 1; -(C1-C6 alkyl) n -(CO)-NR b5 R b6 , where n is 1 and R b5 and R b6 are each independently hydrogen or a 3- to 15-membered heterocyclyl, said heterocyclic ring being further substituted with one or more C1-C6 alkyl groups; and -(C1-C6 alkyl) n -(CO)-O-R b2 wherein the alkyl is substituted with one or more C6-C10 aryl groups, n is 1, and R b2 is C1-C6 alkyl or -(C1-C6 alkyl) n -O-(CO)-OR c and R c is C1-C6 alkyl; selected from the group consisting of: selected from the group consisting of: R 3 and R 4 are each independently hydrogen, hydroxyl, C1-C6 alkyl, -(CO)-(L) n -R d2 , and -(CO)O-(L) n -R d3 wherein said alkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; L is independently absent, O, NR d5 and C1-C6 alkyl; R d5 , R d2 and R d3 are each independently selected from the group consisting of hydrogen, amino, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, and heterocyclyl are each independently selected from the group consisting of one or more R f optionally substituted with a group; R f are each independently selected from the group consisting of amino, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C6-C10 aryl, halogenated C6-C10 aryl, C3-C7 cycloalkyl, and 3- to 15-membered heterocyclyl; or R 3 and R 4 are independent of each other, hydrogen, hydroxyl, C1-C6 alkyl, -(CO)-(L) n -R d2 , where (L) n and R d2 The combination options are as follows: 1) L does not exist and R d2 is 1 or more R f C1-C6 alkyl further substituted with a group, R f is amino; 2) L does not exist and R d2 is H; 3) L does not exist and R d2 is C1-C6 alkyl; 4) L does not exist and R d2 is 1 or more R f C1-C6 alkyl further substituted with a group, R f is selected from the group consisting of C1-C6 alkyl and amino; 5) L does not exist and R d2 is a 3- to 15-membered heterocyclyl; and 6) L is NR d5 and R d5 is C1-C6 alkyl, n is 1, and R d2 is H; selected from the group consisting of: -(CO)O-(L) n -R d3 , where (L) n and R d3 The combination of options is that L does not exist and R d3 is 1 or more R f C1-C6 alkyl optionally further substituted with a group, and R f is selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, and polycyclic aromatic hydrocarbonyl (e.g., fluorenyl); selected from the group consisting of: 2) When x is 1 or 2 and A and A' are the same or different, then with respect to A: R 1 and R 2 are each independently C1-C6 alkyl, —O—, —O—R a1 , and -NR a2 R a3 selected from the group consisting of: R 3 and R 4 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 is selected from the group consisting of hydrogen and amino; or R 5 is selected from the group consisting of hydrogen; Y is C; y is selected from the group consisting of 0, 1, 2, and 3; or y is 0 or 1; Regarding A', R 1 ' and R 2 ' are each independently C1-C6 alkyl, -O-, -O-R a1 , and -NR a2 R a3 selected from the group consisting of: R 3 ' and R 4 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogen, C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 ' is selected from the group consisting of hydrogen and amino; or R 5 ' is selected from the group consisting of hydrogen; Y' is C; 2. The use of claim 1, wherein y' is selected from the group consisting of 0, 1, 2, and 3; or y' is 0 or 1.

3. 1) If x is 0 and A' does not exist, then for A, R 1 teeth, C1-C6 alkyl, -O-R a1 , where R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, and —(C1-C6 alkyl) n —O—(CO)—R b3 wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); and -NR a2 R a3 , where R a2 and R a3 are each independently hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , and —(C1-C6 alkyl) n —O—(CO)—R b3 wherein said alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); selected from the group consisting of: R b1 and R b3 are each independently selected from the group consisting of hydrogen, hydroxyl, amino, C1-C6 alkyl, and C6-C10 aryl, wherein the alkyl, aryl, and heterocyclyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, and C6-C10 aryl; or R 1 teeth, hydroxyl, C1-C6 alkyl, -O-Ra1, where R a1 is C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and -(C1-C6 alkyl) n -O-(CO)-OR b4 which may be optionally further substituted with one or more C6-C10 aryl groups; R b4 is selected from the group consisting of C1-C6 alkyl, and n is 1; and -NR a2 R a3 , where R a2 and R a3 are each independently hydrogen; C1-C6 alkyl optionally further substituted with one or more C6-C10 aryl groups; -(C1-C6 alkyl) n —O—(CO)—R b3 , R b3 is a C1-C6 alkyl further substituted with a C6-C10 aryl; and —(C1-C6 alkyl) n -(CO)-R b1 , R b1 is hydroxyl and n is 1; is selected from the group consisting of or R 1 is hydroxyl, methoxy, -OCH 2 CH=CH 2 , ethoxy, —OC(CH 3 ) 3 , -OCH 2 C 6 H 5 , -OC 6 H 11 , Trt-NH-, 【Chemistry 4】 , CH 3 -NH-, HOCOCH 2 NH-, -OCH(CH 3 ) 2 , -CH 3 , and 【Transformation 5】 wherein Trt represents trityl; R 2 teeth, C1-C6 alkyl, -O-R a1 , where R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C6-C10 aryl, and -(C1-C6 alkyl) n -O-(CO)-OR b4 wherein the alkyl, alkenyl, and aryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, and -(C1-C6 alkyl)-(C6-C10 aryl); and -NR a2 R a3 , where R a2 and R a3 are each independently hydrogen, C1-C6 alkyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-O-R b2 , -(C1-C6 alkyl) n -(CO)-NR b5 R b6 and 3- to 15-membered heterocyclyl, wherein said alkyl and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, and C1-C6 alkyl; selected from the group consisting of: R b1 , R b2 , R b4 , R b5 and R b6 are each independently hydrogen, hydroxyl, C1-C6 alkyl, C3-C7 cycloalkyl, and -(C1-C6 alkyl) n -O-(CO)-OR c3 wherein said cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, and C6-C10 aryl; R c3 are each independently selected from the group consisting of hydrogen, hydroxyl, amino, C1-C6 alkyl, and C3-C7 cycloalkyl; or R 2 teeth, Hydroxyl -O-R a1 , where R a1 is C1-C6 alkyl, C2-C6 alkenyl, and -(C1-C6 alkyl) n -O-(CO)-OR b4 which may be optionally further substituted with one or more C6-C10 aryl groups; R b4 is selected from the group consisting of C1-C6 alkyl, and n is 1; and -NR a2 R a3 , R a2 and R a3 are each independently hydrogen; -(C1-C6 alkyl) n -(CO)-NR b5 R b6 , n is 1, and R b5 and R b6 are each independently hydrogen or a 3- to 15-membered heterocyclyl, said heterocyclyl being further substituted with one or more C1-C6 alkyl groups; -(C1-C6 alkyl) n -(CO)-R b1 , n is 1, and R b1 is hydroxyl; and —(C1-C6 alkyl) n -(CO)-O-R b2 wherein the alkyl is substituted with one or more C6-C10 aryl groups, n is 1, and R b2 is C1-C6 alkyl or -(C1-C6 alkyl) n -O-(CO)-OR c3 and R c3 is C1-C6 alkyl; selected from the group consisting of: selected from the group consisting of: or R 2 is hydroxyl, methoxy, -OCH 2 CH=CH 2 , ethoxy, —OC(CH 3 ) 3 , -OCH 2 C 6 H 5 , 【Transformation 6】 ,-OCH(CH 3 ) 2 、 【Transformation 7】 , and 【Transformation 8】 selected from the group consisting of: R 3 and R 4 are independent of each other, Hydrogen, ヒドロキシル, Boc, Cbz, -CH 3 ,Fmoc,-COOCH 2 C 6 H 5 -COCH 2 NH 2 ,-CHO,-COCH 3 , 【Chemistry 9】 , -COCH 2 CH 3 , -COCH(CH 3 ) 2 , -COCH(CH 2 ) 2 , -COOCH 3 , -CON(CH 3 ) 2 , and -COCH(CH 3 ) (NH 2 wherein Boc represents tert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, and Fmoc represents fluorenylmethoxycarbonyl; 2) When x is 1 and A and A' are the same or different, Unit A R 1 , R 2 , R 3 , and R 4 Any one of the R of the adjacent unit A' 1 ', R 2 ', R 3 ', and R 4 ' and L 1 Connected via; L 1 are each independently a unit bridging group selected from the group consisting of absent, O, S, carbonyl, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-), cycloalkyl (or C3-C7 cycloalkyl), and heteroalkyl (or 3- to 7-membered heteroalkyl; for example, -O-alkyl-O- (or -O-C1-C6 alkyl-O-)), wherein the alkyl, cycloalkyl, and heteroalkyl are optionally substituted with one or more groups independently selected from the group consisting of Z; Z is independently selected from the group consisting of halogen, amino, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), haloalkyl (or halogenated C1-C6 alkyl), cycloalkyl (or C3-C7 cycloalkyl), aryl (or C6-C12 aryl), and heterocyclyl; or L 1 is selected from the group consisting of absent and -CR'R'', where R' and R'' are each independently H, C1-C6 alkyl (or C1-C3 alkyl); or L 1 is absent, -CH 2 -, -CH(CH 3 )-, and -C-(CH 3 ) 2 selected from the group consisting of: Regarding A, R 1 is —O—, C1-C6 alkyl, and —O—R a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 is selected from the group consisting of —O—, hydroxyl, and —O—R a1 , where R a1 is C1-C6 alkyl; or R 1 is —O—, hydroxyl, methoxy, ethoxy, and —OCH(CH 3 ) 2 selected from the group consisting of: Y is C; y is 0; R 2 is —O—, C1-C6 alkyl, and —O—R a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2 is selected from the group consisting of hydroxyl, —O—, and —O—R a1 , where R a1 is C1-C6 alkyl; or R 2 is selected from the group consisting of hydroxyl, —O—, and methoxy; R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 and R 4 are each independently hydrogen; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 is selected from the group consisting of hydrogen and amino; or R 5 is selected from the group consisting of hydrogen; Regarding A', R 1 ' is -O-, C1-C6 alkyl, and -O-R a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 ' is selected from the group consisting of -O-, hydroxyl, and -O-Ra1, where Ra1 is C1-C6 alkyl; or R 1 ' is -O-, hydroxyl, methoxy, ethoxy, and -OCH(CH 3 ) 2 selected from the group consisting of: Y' is C; y' is 0; R 2 ' is -O-, C1-C6 alkyl, and -O-R a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2 ' is selected from the group consisting of hydroxyl, -O-, and -O-Ra1, where Ra1 is C1-C6 alkyl; or R 2 ' is selected from the group consisting of hydroxyl, -O-, and methoxy; R 3 ' and R 4 ' are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 ' and R 4 ' are, independently of each other, hydrogen; R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 ' is selected from the group consisting of hydrogen and amino; or R 5 ' is selected from the group consisting of hydrogen; 3) When x is 2 and A and A' are the same or different, Unit A R 1 , R 2 , R 3 , and R 4 Any one of the R of the adjacent unit A' 1 ', R 2 ', R 3 ', and R 4 ' and L 1 Connected via; Each L 1 are independently a unit bridging group selected from the group consisting of absent, O, S, carbonyl, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-), cycloalkyl (or C3-C7 cycloalkyl), and heteroalkyl (or 3- to 7-membered heteroalkyl; for example, -O-alkyl-O- (or -O-C1-C6 alkyl-O-)), wherein the alkyl, cycloalkyl, and heteroalkyl are optionally substituted with one or more groups independently selected from the group consisting of Z; Z is independently selected from the group consisting of halogen, amino, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), haloalkyl (or halogenated C1-C6 alkyl), cycloalkyl (or C3-C7 cycloalkyl), aryl (or C6-C12 aryl), and heterocyclyl; or L 1 is selected from the group consisting of absent and -CR'R'', where R' and R'' are each independently H, C1-C6 alkyl (or C1-C3 alkyl); or L 1 is absent, -CH 2 -, -CH(CH 3 )-, and -C-(CH 3 ) 2 selected from the group consisting of: or L 1 is -CH 2 - selected from the group consisting of; Regarding A, R 1 is —O—, C1-C6 alkyl, and —O—R a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 is selected from the group consisting of —O—, hydroxyl, and —O—R a1 , where R a1 is C1-C6 alkyl; or R 1 is —O—, hydroxyl, methoxy, ethoxy, and —OCH(CH 3 ) 2 selected from the group consisting of: or R 1 is selected from the group consisting of methoxy; Y is C; y is 0; R 2 is —O—, C1-C6 alkyl, and —O—R a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2 is selected from the group consisting of hydroxyl, —O—, and —O—R a1 , where R a1 is C1-C6 alkyl; or R 2 is selected from the group consisting of hydroxyl, —O—, and methoxy; or R 2 is selected from the group consisting of —O—; R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 and R 4 are, independently of each other, hydrogen; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 is selected from the group consisting of hydrogen and amino; or R 5 is selected from the group consisting of hydrogen; Regarding A', R 1 ' is -O-, C1-C6 alkyl, and -O-R a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 ' is selected from the group consisting of -O-, hydroxyl, and -O-Ra1, where Ra1 is C1-C6 alkyl; or R 1 ' is -O-, hydroxyl, methoxy, ethoxy, and -OCH(CH 3 ) 2 selected from the group consisting of: or R 1 ' is selected from the group consisting of methoxy; Y' is C; y' is 0; R 2 ' is -O-, C1-C6 alkyl, and -O-R a1 wherein R a1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2 ' is selected from the group consisting of hydroxyl, -O-, and -O-Ra1, where Ra1 is C1-C6 alkyl; or R 2 ' is selected from the group consisting of hydroxyl, -O-, and methoxy; Furthermore, R 2 ' is selected from the group consisting of -O-; R 3 ' and R 4 ' are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 ' and R 4 ' are, independently of each other, hydrogen; R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 ' is selected from the group consisting of hydrogen and amino; or R 5 ' is selected from the group consisting of hydrogen, 2. The use according to claim 1.

4. below: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of hepatic stellate cell activation; 4) Regulation of NS3TP1 expression In the manufacture of a medicine or medicament for use in at least one of the following: 【Chemistry 10】 I-4 During the ceremony, Rn 1 and Rn 2 are each independently C1-C6 alkyl, —O—R a4 , -O-L 2 -O-R a4 , and -NR a5 R a6 selected from the group consisting of: Each R a4 is hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, C6-C10 aryl, C6-C10 aryl-C1-C6 alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclyl-C1-C6 alkyl, C1-C6 alkoxyacyl, -(O=)C-CH 2 -CH(NH 2 )-COOR m , -(O=)C-CH(NH 2 )-CH 2 -COOR m , Ph-CH 2 -CH(NH 2 )-C(=O)-, NH 2 -CH 2 -C(=O)-, CH 3 -CH(NH 2 )-C(=O)-, R m OOC-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, -C(=O)-(CH 2 ) 2 -CH(NH 2 )-COOR m , R m OOC-CH(NH 2 )-CH 2 -S-S-CH 2 -CH(NH 2 )-C(=O)-, H 2 N—CO—(CH 2 ) 2 -CH(NH 2 )-C(=O)-, * N=CH-NH-CH= * C-CH 2 -CH(NH 2 )-C(=O)-(or 【Chemistry 11】 ), HO-p-Ph-CH 2 -CH(NH 2 )-C(=O)-, HO-CH 2 -CH(NH 2 )-C(=O)-, CH 3 -S-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(NH 2 )—C(═O)—, and (CH 3 ) 2 CH-CH 2 -CH(NH 2 )—C(═O)—; where Ph represents phenyl, and HO-p-Ph-CH 2 -CH(NH 2 )-C(=O)- represents p-hydroxybenzylaminomethylcarbonyl; R a5 and R a6 are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclylaminoacyl-C1-C6 alkyl, Ph-CH 2 -CH(COOR m ) -, -CH 2 -COOR m , -CH(COOR m )-CH 2 -COOR m , -CH(CH 3 )-COOR m , R m OOC-(CH 2 ) 2 -CH(COOR m )-,-CH(COOR m )-CH 2 -S-S-CH 2 -CH(NH 2 )-COOR m , H 2 N—CO—(CH 2 ) 2 -CH(COOR m ) -, * N=CH-NH-CH= * C-CH 2 -CH(COOR m )-(or 【Chemistry 12】 ), HO-p-Ph-CH 2 -CH(COOR m )-, HO-CH 2 -CH(COOR m ) -, CH 3 -S-(CH 2 ) 2 -CH(COOR m )-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(COOR m ) - and (CH 3 ) 2 CH-CH 2 -CH(COOR m )-selected from the group consisting of; Each R m is hydrogen, C1-C6 alkyl, and C1-C6 alkoxyacyl-OL 3 - independently selected from the group consisting of; L 2 and L 3 are each independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and 3- to 7-membered heteroalkyl; L 2 and L 3 is optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, and hydroxyl; Rn 3 and Rn 4 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, H(C═O)—, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, aminoacyl, C1-C6 alkylacyl, C1-C6 alkoxyacyl, C1-C6 alkylaminoacyl, amino-C1-C6 alkanoyl, 3- to 15-membered heterocyclylacyl, C3-C7 cycloalkylacyl, and C6-C10 aryl-C1-C6 alkoxyacyl; Y is C or S; y is 0, 1, 2 or 3; or Rn 1 and Rn 2 are each independently C1-C6 alkyl, —O—R a4 , -O-L 2 -O-R a4 , and -NR a5 R a6 selected from the group consisting of: Each R a4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-C1-C6 alkyl, C6-C10 aryl, C6-C10 aryl-C1-C6 alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclyl-C1-C6 alkyl, C1-C6 alkoxyacyl, -(O=)C-CH 2 -CH(NH 2 )-COOR m , Ph-CH 2 -CH(NH 2 )-C(=O)-, NH 2 -CH 2 -C(=O)-, CH 3 -CH(NH 2 )-C(=O)-, R m OOC-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, R m OOC-CH(NH 2 )-CH 2 -S-S-CH 2 -CH(NH 2 )-C(=O)-, H 2 N—CO—(CH 2 ) 2 -CH(NH 2 )-C(=O)-, * N=CH-NH-CH= * C-CH 2 -CH(NH 2 )-C(=O)-(or 【Chemistry 13】 ), HO-p-Ph-CH 2 -CH(NH 2 )-C(=O)-, HO-CH 2 -CH(NH 2 )-C(=O)-, CH 3 -S-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(NH 2 )—C(═O)—, and (CH 3 ) 2 CH-CH 2 -CH(NH 2 )—C(═O)—; R a5 and R a6 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclylaminoacyl-C1-C6 alkyl, Ph-CH 2 -CH(COOR m ) -, -CH 2 -COOR m , -CH(COOR m )-CH 2 -COOR m , -CH(CH 3 )-COOR m , R m OOC-(CH 2 ) 2 -CH(COOR m )-,-CH(COOR m )-CH 2 -S-S-CH 2 -CH(NH 2 )-COOR m , H 2 N—CO—(CH 2 ) 2 -CH(COOR m ) -, * N=CH-NH-CH= * C-CH 2 -CH(COOR m )-(or 【Chemistry 14】 ), HO-p-Ph-CH 2 -CH(COOR m )-, HO-CH 2 -CH(COOR m ) -, CH 3 -S-(CH 2 ) 2 -CH(COOR m )-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(COOR m ) - and (CH 3 ) 2 CH-CH 2 -CH(COOR m )-selected from the group consisting of; Each R m is hydrogen, C1-C6 alkyl, and C1-C6 alkoxyacyl-OL 3 - independently selected from the group consisting of; L 2 and L 3 are each independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, and 3- to 7-membered heteroalkyl; L 2 and L 3 each optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, and hydroxyl; Rn 3 and Rn 4 are each independently selected from the group consisting of hydrogen, hydroxyl, H(C═O)—, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, aminoacyl, C1-C6 alkylacyl, C1-C6 alkoxyacyl, C1-C6 alkylaminoacyl, amino-C1-C6 alkanoyl, 3- to 15-membered heterocyclylacyl, C3-C7 cycloalkylacyl, and C6-C10 aryl-C1-C6 alkoxyacyl; Y is C; y is 0, 1 or 2; or Rn 1 and Rn 2 are each independently C1-C6 alkyl, —O—R a4 , -O-L2-O-R a4 , and -NR a5 R a6 selected from the group consisting of: Each R a4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, C6-C10 aryl-C1-C6 alkyl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclyl-C1-C6 alkyl, -(O=)C-CH 2 -CH(NH 2 )-COOR m , Ph-CH 2 -CH(NH 2 )-C(=O)-, NH 2 -CH 2 -C(=O)-, CH 3 -CH(NH 2 )-C(=O)-, R m OOC-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, R m OOC-CH(NH 2 )-CH 2 -S-S-CH 2 -CH(NH 2 )-C(=O)-, H 2 N—CO—(CH 2 ) 2 -CH(NH 2 )-C(=O)-, * N=CH-NH-CH= * C-CH 2 -CH(NH 2 )-C(=O)-(or 【Chemistry 15】 ), HO-p-Ph-CH 2 -CH(NH 2 )-C(=O)-, HO-CH 2 -CH(NH 2 )-C(=O)-, CH 3 -S-(CH 2 ) 2 -CH(NH 2 )-C(=O)-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(NH 2 )—C(═O)—, and (CH 3 ) 2 CH-CH 2 -CH(NH 2 )—C(═O)—; R a5 and R a6 are each independently hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, 3- to 15-membered heterocyclylaminoacyl-C1-C6 alkyl, Ph-CH 2 -CH(COOR m ) -, -CH 2 -COOR m , -CH(COOR m )-CH 2 -COOR m , -CH(CH 3 )-COOR m , R m OOC-(CH 2 ) 2 -CH(COOR m )-,-CH(COOR m )-CH 2 -S-S-CH 2 -CH(NH 2 )-COOR m , H 2 N—CO—(CH 2 ) 2 -CH(COOR m ) -, * N=CH-NH-CH= * C-CH 2 -CH(COOR m )-(or 【Chemistry 16】 ), HO-p-Ph-CH 2 -CH(COOR m )-, HO-CH 2 -CH(COOR m ) -, CH 3 -S-(CH 2 ) 2 -CH(COOR m )-, HN=C(NH 2 )-NH-(CH 2 ) 3 -CH(COOR m ) - and (CH 3 ) 2 CH-CH 2 -CH(COOR m )-selected from the group consisting of; Each R m is hydrogen, C1-C6 alkyl, and C1-C6 alkoxyacyl-OL 3 - independently selected from the group consisting of; L 2 and L 3 are each independently selected from the group consisting of C1-C6 alkyl; L 2 and L 3 each optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, and hydroxyl; Rn 3 and Rn 4 are each independently selected from the group consisting of hydrogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, aminoacyl, C1-C6 alkylacyl, C1-C6 alkoxyacyl, C1-C6 alkylaminoacyl, amino-C1-C6 alkanoyl, 3- to 15-membered heterocyclylacyl, C3-C7 cycloalkylacyl, and C6-C10 aryl-C1-C6 alkoxyacyl; Y is C; y is 0, 1 or 2; or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystalline form, metabolite form, or any combination or mixture thereof.

5. The compound represented by formula I or I-1, I-2, I-3, or I-4 is as follows: 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 The use according to claim 1, selected from the group consisting of:

6. The compound represented by formula I or I-1, I-2, I-3, or I-4 is as follows: 【Chemistry 20】 The use according to claim 1, selected from the group consisting of:

7. below: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of hepatic stellate cell activation; 4) Regulation of NS3TP1 expression 2. Use of a peptide containing 2 to 10 or 2 to 3 amino acids, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystalline form, metabolite form, or any combination or mixture thereof, in the manufacture of a medicine or medicament for use in at least one of the following: In the peptide, at least one amino acid is aspartic acid, and if the aspartic acid has a free carboxyl group, the free carboxyl group may optionally be esterified with C1-C6 alkyl-OH; Optionally, the amino acid is aspartic acid, phenylalanine, glycine, alanine, glutamic acid, cystine, glutamine, histidine, tyrosine, serine, methionine, arginine, or leucine; or the free amino acid located at one end of the peptide is aspartic acid, and optionally, the free carboxyl group of the free aspartic acid is optionally esterified with C1-C6 alkyl-OH; Optionally, the remaining amino acids are aspartic acid, phenylalanine, glycine, alanine, glutamic acid, cystine, glutamine, histidine, tyrosine, serine, methionine, arginine, or leucine. use.

8. 8. The use according to any one of claims 1 to 7, wherein the liver fibrosis includes, but is not limited to, liver fibrosis caused by chronic viral liver disease, liver fibrosis caused by alcoholism or long-term alcohol consumption, liver fibrosis caused by non-alcoholic factors such as obesity, portal hepatic fibrosis caused by repeated infection with schistosomiasis, biliary hepatic fibrosis caused by chronic cholestasis, metabolic hepatic fibrosis caused by hepatocyte degeneration and hemoglobin deposition, toxic hepatic fibrosis caused by various harmful substances, malnutrition hepatic fibrosis caused by a low-protein diet and a preference for fatty fried foods, and cardiogenic hepatic fibrosis caused by chronic congestive heart failure.

9. below: 1) Treating, ameliorating, or preventing liver disease (e.g., NAFLD, NASH, liver fibrosis); 2) alleviating mammalian liver fibrosis, fatty liver, or inflammation; 3) inhibition of hepatic stellate cell activation; 4) Regulation of NS3TP1 expression 10. Use of a pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystalline form, metabolite form, or any combination or mixture thereof, or a peptide according to claim 7, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystalline form, metabolite form, or any combination or mixture thereof, in the manufacture of a medicament for at least one of the following:

10. 10. The use of claim 9, wherein the liver fibrosis includes, but is not limited to, liver fibrosis caused by chronic viral liver disease, liver fibrosis caused by alcoholism or long-term alcohol consumption, liver fibrosis caused by non-alcoholic factors such as obesity, portal hepatic fibrosis caused by repeated schistosomiasis infection, biliary hepatic fibrosis caused by chronic cholestasis, metabolic hepatic fibrosis caused by hepatocyte degeneration and hemoglobin deposition, toxic hepatic fibrosis caused by various harmful substances, malnutrition hepatic fibrosis caused by a low-protein diet or a preference for fatty fried foods, and cardiogenic hepatic fibrosis caused by chronic congestive heart failure.

11. The pharmaceutical composition may further comprise an additional active ingredient: other amino acids for improving liver function (including but not limited to alanine, glutamic acid, cystine, glutamine, glycine, histidine, tyrosine, serine, methionine, arginine, leucine), cholesterol absorption inhibitors (e.g., ezetimibe), HSC activation and proliferation inhibitors (e.g., pirfenidone, fluorofenidone, pegbelfermin), PCSK9 inhibitors, PPAR agonists (e.g., gemfibrozil, fenofibrate, clofibrate, bezafibrate, pemafibrate, elafibranor), ACE inhibitors, CCR2 / 5 inhibitors, TLR4 inhibitors, LOXL2 inhibitors, TIMP-1 inhibitors, FXR agonists, AT1R blockers, NOX inhibitors, calcium channel blockers, ARBs, Further including diuretics, renin, GLP-1 or synthetic variants thereof, insulin or synthetic variants thereof, metformin, sulfonylureas, thiazolidinediones (TZDs), SGLT2 inhibitors, DPP-IV inhibitors, HMGCoA reductase inhibitors, proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors, gemcabene (CI-1027), ACC inhibitors, ApoC-III inhibitors, ACL inhibitors (e.g., bepedic acid), prescription fish oil, CETP inhibitors, ursodeoxycholic acid, obeticholic acid, polyene phosphatidylcholine, glucocorticoids, silymarin, glycyrrhizinic acid preparations (e.g., magnesium isoglycyrrhizinate injection and diammonium glycyrrhizinate enteric coated capsules), and combinations thereof; and further comprising a pharmaceutically acceptable carrier or excipient; Or the use according to claim 9, wherein the pharmaceutical composition is a solid formulation, an injection formulation, a topical formulation, a spray formulation, a liquid formulation or a compound formulation.

12. Formula II: A 1 -(L 1 ) x -A 1 ' of Formula II In the formula, A 1 teeth, 【Chemistry 21】 and A 1 'teeth, 【Chemistry 22】 and A 1 and A 1 ' is the same or different; x is selected from the group consisting of 0, 1 and 2; 1) If x is 0 and A' does not exist, then A 1 Regarding R 1 and R 2 teeth, 【Chemistry 23】 , and -O-R a are independently selected from the group consisting of: R a are each independently hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-O-R b2 , -(C1-C6 alkyl) n —O—(CO)—R b3 , -(C1-C6 alkyl) n -NR b4 -(CO)-R b5 , and —(C1-C6 alkyl) n -NR b6 -(CO)-O-R b7 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl; R 3 and R 4 is -COCH(CH 3 ) (NH 2 ), hydrogen, -COCH 2 CH 3 , deuterium, and C1-C6 alkyl, wherein said alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl, and heterocyclyl; And if "x is 0 and A' does not exist", then A 1 satisfies one of the following conditions (1), (2), (3) or (4): (1) R 1 and R 2 At least one of 【Chemistry 24】 , or 【Chemistry 25】 is; (2) R 3 and R 4 At least one of the groups is -COCH(CH 3 ) (NH 2 ) or -COCH 2 CH 3 is; (3) R 1 and R 2 but 【Chemistry 26】 , hydroxyl, and methoxy, while R 3 and R 4 is hydrogen, -COCH 2 CH 3 and -COCH(CH 3 ) (NH 2 ), when independently selected from the group consisting of: A 1 satisfies the following conditions: R 1 and R 2 is hydroxyl or methoxy, R 1 and R 2 The other side is 【Chemistry 27】 or 【Chemistry 28】 or R 3 and R 4 One of them is -COCH(CH 3 ) (NH 2 ) is; (4) R 1 but 【Chemistry 29】 , hydroxyl, and methoxy; R 2 but 【Transformation 30】 , hydroxyl, 【Chemistry 31】 , methoxy, and R 3 and R 4 is hydrogen, -COCH 2 CH 3 and -COCH(CH 3 ) (NH 2 ), when independently selected from the group consisting of: A 1 satisfies the following conditions: R 1 is hydroxyl or methoxy, R 2 teeth 【Chemistry 32】 or 【Transformation 33】 or R 3 and R 4 One of them is -COCH(CH 3 ) (NH 2 ) or R 2 is hydroxyl or methoxy, R 1 teeth 【Transformation 34】 or R 3 and R 4 One of them is -COCH(CH 3 ) (NH 2 ) is; 2) x is 1 and A 1 and A 1 ' are the same or different, Unit A 1 R 1 , R 2 , R 3 , and R 4 Any one of the adjacent units A 1 'R' 1 ', R 2 ', R 3 ' and R 4 ' and L 1 Connected via; Each L 1 are independently a unit bridging group selected from the group consisting of absent, O, S, carbonyl, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkyl-O- (or -O-C1-C6 alkyl-O-), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-), cycloalkyl (or C3-C7 cycloalkyl), and heteroalkyl (or 3- to 7-membered heteroalkyl), wherein said alkyl, cycloalkyl, heteroalkyl may be optionally substituted with one or more groups independently selected from the group consisting of Z; Z is independently selected from the group consisting of halogen, amino, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), haloalkyl (or halogenated C1-C6 alkyl), cycloalkyl (or C3-C7 cycloalkyl), aryl (or C6-C12 aryl), and heterocyclyl; or L 1 is selected from the group consisting of absent and -CR'R'', where R' and R'' are each independently H, C1-C6 alkyl (or C1-C3 alkyl); or L 1 is absent, -CH 2 -, -CH(CH 3 )-, and -C-(CH 3 ) 2 selected from the group consisting of: A 1 Regarding R 1 and R 2 are each independently C1-C6 alkyl, —O—, —O—R a1 , and -NR a2 R a3 selected from the group consisting of: R 3 and R 4 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 is —O—, C1-C6 alkyl, and —O—R a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, and —(C1-C6 alkyl) n —O—(CO)—R b1 wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 is selected from the group consisting of —O—, hydroxyl, and —O—R a1 , where R a1 is C1-C6 alkyl; or R 1 is —O—, hydroxyl, methoxy, ethoxy, and —OCH(CH 3 ) 2 selected from the group consisting of: or R 2 is —O—, C1-C6 alkyl, and —O—R a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, and —(C1-C6 alkyl) n —O—(CO)—R b1 wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2 is selected from the group consisting of hydroxyl, —O—, and —O—R a1 , where R a1 is C1-C6 alkyl; or R 2 is selected from the group consisting of hydroxyl, —O—, and methoxy; R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 and R 4 are each independently hydrogen; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 is selected from the group consisting of hydrogen and amino; or R 5 is selected from the group consisting of hydrogen; Y is C; y is selected from the group consisting of 0, 1, 2, and 3; or y is 0 or 1; or y is 0; A 1 Regarding ' R 1 ' and R 2 ' are each independently C1-C6 alkyl, -O-, -O-R a1 , and -NR a2 R a3 selected from the group consisting of: R 3 ' and R 4 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 ' is -O-, C1-C6 alkyl, and -O-R a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, and —(C1-C6 alkyl) n —O—(CO)—R b1 wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 ' is selected from the group consisting of -O-, hydroxyl, and -O-Ra1, where Ra1 is C1-C6 alkyl; or R 1 ' is -O-, hydroxyl, methoxy, ethoxy, and -OCH(CH 3 ) 2 selected from the group consisting of: or R 2 ' is -O-, C1-C6 alkyl, and -O-R a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, and —(C1-C6 alkyl) n —O—(CO)—R b1 wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2 ' is selected from the group consisting of hydroxyl, -O-, and -O-Ra1, where Ra1 is C1-C6 alkyl; or R 2 ' is selected from the group consisting of hydroxyl, -O-, and methoxy; R 3 ' and R 4 ' are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 ' and R 4 ' are, independently of each other, hydrogen; R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 ' is selected from the group consisting of hydrogen and amino; or R 5 ' is selected from the group consisting of hydrogen; Y' is C; y' is selected from the group consisting of 0, 1, 2, and 3; or y' is 0 or 1; or y' is 0; 3) x is 2 and A 1 and A 1 ' are the same or different, Unit A 1 R 1 , R 2 , R 3 and R 4 Any one of the adjacent units A 1 'R' 1 ', R 2 ', R 3 ' and R 4 ' and L 1 Connected via; Each L 1 are independently a unit bridging group selected from the group consisting of absent, O, S, carbonyl, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), -O-alkyl-O- (or -O-C1-C6 alkyl-O-), -O-alkenyl-O- (or -O-C2-C6 alkenyl-O-), -O-alkynyl-O- (or -O-C2-C6 alkynyl-O-), cycloalkyl (or C3-C7 cycloalkyl), and heteroalkyl (or 3- to 7-membered heteroalkyl), wherein said alkyl, cycloalkyl, and heteroalkyl are optionally substituted with one or more groups independently selected from the group consisting of Z; Z is independently selected from the group consisting of halogen, amino, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 alkynyl), haloalkyl (or halogenated C1-C6 alkyl), cycloalkyl (or C3-C7 cycloalkyl), aryl (or C6-C12 aryl), and heterocyclyl; or L 1 is selected from the group consisting of absent and -CR'R'', where R' and R'' are each independently H, C1-C6 alkyl (or C1-C3 alkyl); or L 1 is absent, -CH 2 -, -CH(CH 3 )-, and -C-(CH 3 ) 2 selected from the group consisting of: or L 1 is -CH 2 - selected from the group consisting of; A 1 Regarding R 1 and R 2 are each independently C1-C6 alkyl, —O—, —O—R a1 , and -NR a2 R a3 selected from the group consisting of: R 3 and R 4 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 is —O—, C1-C6 alkyl, and —O—R a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, and —(C1-C6 alkyl) n —O—(CO)—R b1 wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 is selected from the group consisting of —O—, hydroxyl, and —O—R a1 ; R a1 is C1-C6 alkyl; or R 1 is —O—, hydroxyl, methoxy, ethoxy, and —OCH(CH 3 ) 2 selected from the group consisting of: or R 1 is selected from the group consisting of methoxy; or R 2 is —O—, C1-C6 alkyl, and —O—R a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, and —(C1-C6 alkyl) n —O—(CO)—R b1 wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2 is selected from the group consisting of hydroxyl, —O—, and —O—R a1 ; R a1 is C1-C6 alkyl; or R 2 is selected from the group consisting of hydroxyl, —O—, and methoxy; or R 2 is selected from the group consisting of —O—; R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 and R 4 are, independently of each other, hydrogen; R 5 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 is selected from the group consisting of hydrogen and amino; or R 5 is selected from the group consisting of hydrogen; Y is C; y is selected from the group consisting of 0, 1, 2, and 3; or y is 0 or 1; or y is 0; A 1 Regarding ' R 1 ' and R 2 ' are each independently C1-C6 alkyl, -O-, -O-R a1 , and -NR a2 R a3 selected from the group consisting of: R 3 ' and R 4 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), and heterocyclyl; R a1 , R a2 , and R a3 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, and 3- to 15-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 ' is -O-, C1-C6 alkyl, and -O-R a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, and —(C1-C6 alkyl) n —O—(CO)—R b1 wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 1 ' is selected from the group consisting of -O-, hydroxyl, and -O-Ra1; Ra1 is C1-C6 alkyl; or R 1 ' is -O-, hydroxyl, methoxy, ethoxy, and -OCH(CH 3 ) 2 selected from the group consisting of: or R 1 ' is selected from the group consisting of methoxy; or R 2 ' is -O-, C1-C6 alkyl, and -O-R a1 wherein R a1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, and —(C1-C6 alkyl) n —O—(CO)—R b1 wherein said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3- to 15-membered heterocyclyl, -(C1-C6 alkyl)-(C6-C10 aryl), and -(C1-C6 alkyl)-(3- to 15-membered heterocyclyl); or R 2 ' is selected from the group consisting of hydroxyl, -O-, and -O-Ra1; Ra1 is C1-C6 alkyl; or R 2 ' is selected from the group consisting of hydroxyl, -O-, and methoxy; or R 2 ' is selected from the group consisting of -O-; R 3 ' and R 4 ' are each independently selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; or R 3 ' and R 4 ' are, independently of each other, hydrogen; R 5 ' is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, halogen, and amino; or R 5 ' is selected from the group consisting of hydrogen and amino; or R 5 ' is selected from the group consisting of hydrogen; Y' is C; y' is selected from the group consisting of 0, 1, 2, and 3; or y' is 0 or 1; or y' is 0; Alternatively, Formula II is 【Chemistry 35】 That is, or a pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystalline form, and metabolic form thereof.

13. The compound represented by formula II or II-1, II-2, or II-3 is 【Transformation 36】 【Chemistry 37】 13. The compound of claim 12 selected from the group consisting of:

14. The compound of formula II according to any one of claims 12 to 13, or a pharmaceutically acceptable salt or ester thereof, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystalline form, metabolite form, or any combination or mixture thereof, optionally further comprising a pharmaceutically acceptable carrier or excipient; Optionally, additional active ingredients: other amino acids for improving liver function (including but not limited to alanine, glutamic acid, cystine, glutamine, glycine, histidine, tyrosine, serine, methionine, arginine, leucine), cholesterol absorption inhibitors (e.g., ezetimibe), HSC activation and proliferation inhibitors (e.g., pirfenidone, fluorofenidone, pegbelfermin), PCSK9 inhibitors, PPAR agonists (e.g., gemfibrozil, fenofibrate, clofibrate, bezafibrate, pemafibrate, elafibranor), ACE inhibitors, CCR2 / 5 inhibitors, TLR4 inhibitors, LOXL2 inhibitors, TIMP-1 inhibitors, FXR agonists, AT1R blockers, NOX inhibitors, calcium channel blockers, ARBs, diuretics , renin, GLP-1 or synthetic variants thereof, insulin or synthetic variants thereof, metformin, sulfonylurea compounds, thiazolidinediones (TZDs), SGLT2 inhibitors, DPP-IV inhibitors, HMGCoA reductase inhibitors, proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors, gemcabene (CI-1027), ACC inhibitors, ApoC-III inhibitors, ACL inhibitors (e.g., bepedic acid), prescription fish oil, CETP inhibitors, ursodeoxycholic acid, obeticholic acid, polyene phosphatidylcholine, glucocorticoids, silymarin, glycyrrhizic acid preparations (e.g., magnesium isoglycyrrhizinate injection and diammonium isoglycyrrhizinate enteric coated capsules), and combinations thereof. A pharmaceutical composition, or a pharmaceutical composition that is a solid formulation, an injectable formulation, a topical formulation, a spray formulation, a liquid formulation, or a compound formulation.

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