WO2023083291A1 - 天冬氨酸的衍生物及其在肝纤维化、非酒精性肝炎等代谢等疾病的治疗的应用 - Google Patents
天冬氨酸的衍生物及其在肝纤维化、非酒精性肝炎等代谢等疾病的治疗的应用 Download PDFInfo
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- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
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- 230000008717 functional decline Effects 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
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- 231100000234 hepatic damage Toxicity 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 238000007914 intraventricular administration Methods 0.000 description 1
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
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- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
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- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- 239000002547 new drug Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
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- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
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- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
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- 159000000000 sodium salts Chemical class 0.000 description 1
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- 239000003765 sweetening agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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- 239000003871 white petrolatum Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/08—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of an acyclic unsaturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
Definitions
- the invention relates to the field of biomedicine, in particular to aspartic acid derivatives and their application in the treatment of liver fibrosis, non-alcoholic hepatitis and other metabolic diseases.
- Fibrosis can occur in a variety of tissues and organs.
- the main pathological changes are the increase of fibrous connective tissue and the reduction of parenchymal cells in organ tissues. Continuous progress can lead to organ structural damage, functional decline, and even failure, which seriously threaten human health and life.
- tissue fibrosis is the main cause of disability and death in many diseases. According to relevant statistics in the United States, nearly 45% of the patients who died of various diseases in the United States can be attributed to tissue fibroproliferative diseases.
- Liver fibrosis is especially common in patients with tissue fibrosis. It is a reversible pathological phenomenon in which fibrous connective tissue is excessively deposited in liver tissue during the repair process of the body after liver damage. There are many causes of liver fibrosis. Patients with various chronic viral liver diseases are the most likely high-risk groups for liver fibrosis and cirrhosis. Alcoholics or long-term alcohol drinkers develop fatty liver in the early stage, and can develop into liver fibrosis in the later stage.
- liver cirrhosis, and fatty liver caused by other non-alcoholic factors such as obesity can also develop into liver fibrosis and liver cirrhosis; in addition, repeated infection with schistosomiasis can easily cause portal liver fibrosis; chronic cholestasis can produce biliary liver disease Fibrosis; hepatolenticular degeneration and hemochromatosis can produce metabolic liver fibrosis; various toxic substances can cause toxic liver fibrosis; people who prefer low-protein diets and fatty fried foods can produce malnourished liver Fibrosis; patients with chronic congestive heart failure can develop cardiogenic liver fibrosis.
- liver fibrosis is also an important pathological diagnostic index of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
- NAFLD nonalcoholic fatty liver disease
- NASH nonalcoholic steatohepatitis
- hepatic fibrosis The occurrence and development mechanism of hepatic fibrosis is very complicated.
- the current research mainly focuses on the activation and transformation of hepatic stellate cells.
- Signal transduction pathways mediated by platelet-derived growth factor (PDGF), tumor necrosis factor ⁇ (Tumour necrosis factor ⁇ , TNF- ⁇ ) and prostaglandin oxidoreductase (cyclooxygenase-2, COX-2 ), diffuse extracellular matrix (extracellular matrix, ECM) and oxidative stress activate hepatic stellate cells to convert them into myofibroblasts and fibroblasts, resulting in increased secretion or decreased degradation of extracellular matrix, and then the formation of hepatic fibroblasts etc. Since the mechanism of occurrence and development of liver fibrosis has not been clarified, the development of drugs for the treatment of liver fibrosis has been slow.
- nucleoside (acid) analogs or interferon are mainly used for antiviral treatment.
- nucleoside (acid) analogs or interferon are mainly used for antiviral treatment.
- By inhibiting virus replication Control the response of inflammatory factors and slow down the progression of liver fibrosis or cirrhosis.
- Traditional Chinese medicine or Chinese patent medicine is mainly used as adjuvant treatment.
- NS3TP1 HCV nonstructural protein 3-transactivated protein 1, NS3TP1
- ASNSD1 asparagine synthetase domain containing 1, ANSSD1
- the purpose of the present invention is to obtain the compound with regulating effect on NS3TP1 and obtain the compound with therapeutic effect on liver fibrosis and non-alcoholic fatty liver disease.
- the inventors have found through creative research 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 better druggability (such as solubility, AUC and/or oral biological properties such as availability) and security.
- the present invention provides the compound represented by the following formula I, or its pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotope Use of compounds, crystal forms, their metabolite forms, or any combination or mixture thereof in the preparation of medicines or reagents for at least one of the following:
- liver diseases such as NAFLD, NASH, liver fibrosis
- A is A' for A is the same as or different from A';
- x is selected from 0, 1 and 2;
- R 1 and R 2 are each independently selected from the following groups: C1-C6 alkyl, -OR a1 , -NR a2 R a3 ;
- R3 and R4 are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl , 3-15 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 , the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl are optionally replaced by one or more A group independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-OR b2 , -(C1-C6 alkyl base) 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 b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, amino, C1-C6 alkane Base, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 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 , the alkyl, cycloalkyl, aromatic
- the group and the heterocycle are optionally substituted by one or more groups independently selected
- R c1 , R c2 , and R c3 are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group;
- Each L is independently selected from the following groups: absent, O, NR d5 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
- R e are each independently selected from hydrogen, deuterium, Na, K, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered hetero Cyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle are optionally replaced by one or more independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl group substitution;
- R h are each independently selected from the following groups: 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 ;
- R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , and R d8 are each independently selected from the following groups: hydrogen, deuterium, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic optionally replaced by one or more R f ;
- R f is independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, halogenated C6-C10 aryl, C3- C7 cycloalkyl, 3-15 membered heterocyclyl, -NR g3 R g4 , -OR g5 , -NHC(O)R g6 , -OC(O)R g7 ;
- R g1 , R g2 , R g3 , R g4 , R g5 , R g6 , and R g7 are independently selected from the following groups: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3 -C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group;
- R is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R is selected from hydrogen, amino;
- Y is C or S
- y is an integer of 0 or more; or y is selected from 0, 1, 2, 3; or y is 0 or 1;
- n 0 or 1
- R 1 , R 2 , R 3 , R 4 of a unit A is connected to any one of R 1 ′, R 2 ′, R 3 ′, R 4 ′ of the adjacent unit A’ through L 1 ;
- Each L is independently selected from the group consisting of unit linking groups: 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 heteroalkyl; for example, -O-alkyl-O- (or -O-C1-C6 alkyl -O-)), wherein alkyl, cycloalkyl, heteroalkyl are optionally substituted by one or more groups independently selected from Z;
- Z is independently selected from the following groups: 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), heterocycle;
- L is selected from: absent, -CR'R", wherein R' and R" are each independently H, C1-C6 alkyl (or C1-C3 alkyl);
- L 1 is selected from: absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 ;
- R 1 and R 2 are each independently selected from the following groups: C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 ;
- R3 and R4 are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl , 3-15 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 , the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl are optionally replaced by one or more A group independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-OR b2 , -(C1-C6 alkyl base) 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 b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, amino, C1-C6 alkane Base, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 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 , the alkyl, cycloalkyl, aromatic
- the group and the heterocyclic group are optionally substituted by one or more groups
- R c1 , R c2 , and R c3 are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group;
- Each L is independently selected from the following groups: absent, O, NR d5 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
- R e are each independently selected from hydrogen, deuterium, Na, K, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered hetero Cyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle are optionally replaced by one or more independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl group substitution;
- R h are each independently selected from the following groups: 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 ;
- R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , and R d8 are each independently selected from the following groups: hydrogen, deuterium, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic optionally replaced by one or more R f ;
- R f is independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, halogenated C6-C10 aryl, C3- C7 cycloalkyl, 3-15 membered heterocyclyl, -NR g3 R g4 , -OR g5 , -NHC(O)R g6 , -OC(O)R g7 ;
- R g1 , R g2 , R g3 , R g4 , R g5 , R g6 , and R g7 are independently selected from the following groups: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3 -C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group;
- R is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R is selected from hydrogen, amino;
- Y is C or S
- y is an integer of 0 or more; or y is selected from 0, 1, 2, 3; or y is 0 or 1;
- n 0 or 1
- R 1 ' and R 2 ' are each independently selected from the following groups: C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 ;
- R 3 ' and R 4 ' are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 Aryl, 3-15 membered heterocyclic group, -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 , the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl are optionally replaced by one Or multiple substitutions independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group, -(C1-C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -(CO)-OR b2 , -(C1-C6 alkyl base) 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 b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, amino, C1-C6 alkane Base, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 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 , the alkyl, cycloalkyl, aromatic
- the group and the heterocycle are optionally substituted by one or more groups independently selected
- R c1 , R c2 , and R c3 are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group;
- Each L is independently selected from the following groups: absent, O, NR d5 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
- R e are each independently selected from hydrogen, deuterium, Na, K, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered hetero Cyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle are optionally replaced by one or more independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl group substitution;
- R h are each independently selected from the following groups: 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 ;
- R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 , and R d8 are each independently selected from the following groups: hydrogen, deuterium, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic optionally replaced by one or more R f ;
- R f is independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, halogenated C6-C10 aryl, C3- C7 cycloalkyl, 3-15 membered heterocyclyl, -NR g3 R g4 , -OR g5 , -NHC(O)R g6 , -OC(O)R g7 ;
- R g1 , R g2 , R g3 , R g4 , R g5 , R g6 , and R g7 are independently selected from the following groups: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3 -C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group;
- R 5 ' is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from hydrogen, amino;
- Y' is C or S
- y' is an integer of 0 or more; or y' is selected from 0, 1, 2, 3; or y' is 0 or 1;
- n 0 or 1
- R 1 and R 2 are each independently selected from the following groups:
- R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocycle base, -(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 , the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl are optionally replaced by one Or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10
- R a2 and R a3 are each independently selected from: hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 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 , the alkyl, cycloalkyl, aryl,
- the heterocycle is optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C
- R b1 , R b2 , R b3 , R b4 , R b5 , and R b6 are each independently selected from the following groups: hydrogen, hydroxyl, amino, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl , 3-15 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 , said alkyl, cycloalkyl, aryl, heterocycle are optionally selected from one or more independently selected from halogen, amino, hydroxyl, carboxyl, C1-C6 Alkyl, C6-C10 aryl group substitution;
- R c1 , R c2 , and R c3 are each independently selected from the following groups: hydrogen, hydroxyl, amino, C1-C6 alkyl, and C3-C7 cycloalkyl.
- R 1 and R 2 are each independently selected from the following groups:
- R a1 is selected from: C1-C6 alkyl optionally further substituted by one or more C6-C10 aryl, C3-C7 cycloalkyl, C2-C6 alkenyl, -(C1- C6 alkyl) n -O-(CO)-OR b4 , wherein R b4 is selected from C1-C6 alkyl, n is 1;
- R a2 and R a3 are each independently selected from:
- C1-C6 alkyl wherein C1-C6 alkyl is optionally further substituted by one or more C6-C10 aryl;
- R b3 is C1-C6 alkyl, which is further substituted by C6-C10 aryl;
- R b1 is hydroxyl, n or 1;
- n is 1, R b5 and R b6 are each independently hydrogen, or a 3-15 membered heterocyclic group, the heterocyclic ring is further surrounded by one or Multiple C1-C6 alkyl substitutions;
- R 3 and R 4 are each independently selected from: hydrogen, hydroxyl, C1-C6 alkyl, -(CO)-(L) n -R d2 , -(CO)O-(L) n -R d3 , the Alkyl, aryl, and heterocycle are optionally replaced by one or more groups independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), heterocycle group replacement;
- Each L is independently selected from the following groups: non-existent, O, NR d5 , C1-C6 alkyl;
- R d5 , R d2 , and R d3 are each independently selected from the following groups: hydrogen, amino, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group, said Alkyl, cycloalkyl, aryl, heterocyclic are optionally substituted by one or more R ;
- R f is independently selected from amino, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C6-C10 aryl, halogenated C6-C10 aryl, C3-C7 cycloalkyl, 3-15 membered hetero Ring base.
- R 3 and R 4 are each independently selected from: hydrogen,
- R d2 is C1-C6 alkyl, further substituted by one or more R f , R f is amino;
- L is absent, and R d2 is C1-C6 alkyl
- R d2 is C1-C6 alkyl, further substituted by one or more R f , R f is selected from C1-C6 alkyl, amino;
- L is absent, and R d2 is a 3-15 membered heterocyclic group
- L is NR d5 , R d5 is C1-C6 alkyl, n is 1, R d2 is H;
- R 1 and R 2 are each independently selected from the following groups: C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 ;
- R3 and R4 are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl , 3-15 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, C1-C6 alkyl, halogen C1-C6 alkyl, aryl (or C6-C12 aryl), heterocyclic group substitution;
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle are optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 Alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic base) group substitution;
- R 5 is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from hydrogen, amino; or R 5 is selected from hydrogen;
- Y is C
- y is selected from 0, 1, 2, 3; or y is 0 or 1.
- R 1 ' and R 2 ' are each independently selected from the following groups: C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 ;
- R 3 ' and R 4 ' are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 Aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, C1-C6 alkyl , halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), heterocyclic group substitution;
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle are optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 Alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic base) group substitution;
- R 5 ' is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from hydrogen, amino; or R 5 is selected from hydrogen;
- Y' is C
- y' is selected from 0, 1, 2, 3; or y is 0 or 1.
- R1 is selected from:
- R a1 is selected from: 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 , the alkyl, alkenyl, cycloalkyl, aryl, heterocycle are optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1 -C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 member Heterocyclyl) group substitution;
- R a2 and R a3 are each independently selected from: hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl, -(C1 -C6 alkyl) n -(CO)-R b1 , -(C1-C6 alkyl) n -O-(CO)-R b3 , the alkyl, cycloalkyl, aryl, heterocycle optionally By one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl) , -(C1-C6 alkyl)-(3-15 membered heterocyclyl) group substitution;
- R b1 and R b3 are each independently selected from the following groups: hydrogen, hydroxyl, amino, C1-C6 alkyl, C6-C10 aryl, and the alkyl, aryl, and heterocycle are optionally replaced by one or more Substituted by a group independently selected from halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, C6-C10 aryl.
- R 1 is selected from: hydroxyl
- R a1 is selected from: C1-C6 alkyl optionally further substituted by one or more C6-C10 aryl, C3-C7 cycloalkyl, C2-C6 alkenyl, -(C1- C6 alkyl) n -O-(CO)-OR b4 , wherein R b4 is selected from C1-C6 alkyl, n is 1;
- R a2 and R a3 are each independently selected from: hydrogen; C1-C6 alkyl, which is optionally further substituted by one or more C6-C10 aryl groups; -(C1-C6 alkyl ) n -O-(CO)-R b3 , R b3 is C1-C6 alkyl, which is further substituted by C6-C10 aryl; -(C1-C6 alkyl) n -(CO)-R b1 , R b1 is a hydroxyl group, and n is 1.
- R2 is selected from:
- R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C6-C10 aryl, -(C1-C6 alkyl) n -O-(CO)-OR b4 ,
- the alkyl, alkenyl, and aryl are optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, -(C1-C6 alkyl)-(C6 -C10 aryl) group substitution;
- R a2 and R a3 are each independently selected from: 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 , 3-15 membered heterocyclic groups, the alkyl and heterocyclic groups are optionally replaced by one Or multiple substitutions independently selected from halogen, amino, hydroxyl, C1-C6 alkyl;
- R b1 , R b2 , R b4 , R b5 , and R b6 are independently selected from the following groups: hydrogen, hydroxyl, C1-C6 alkyl, C3-C7 cycloalkyl, -(C1-C6 alkyl) n - O-(CO)-OR c3 , the cycloalkyl is optionally substituted by one or more groups independently selected from halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, C6-C10 aryl;
- Each R c3 is independently selected from the following groups: hydrogen, hydroxyl, amino, C1-C6 alkyl, C3-C7 cycloalkyl.
- R2 is selected from: hydroxyl
- R a1 is selected from: C1-C6 alkyl optionally further substituted by one or more C6-C10 aryl, C2-C6 alkenyl, -(C1-C6 alkyl) n -O -(CO)-OR b4 , wherein R b4 is selected from C1-C6 alkyl, n is 1;
- R a2 and R a3 are each independently selected from: hydrogen; -(C1-C6 alkyl) n -(CO)-NR b5 R b6 , n is 1, R b5 and R b6 are each independently hydrogen , or a 3-15 membered heterocyclic group, the heterocyclic ring is further substituted by one or more C1-C6 alkyl groups; -(C1-C6 alkyl) n -(CO)-R b1 , n is 1, R b1 is hydroxyl; -(C1-C6 alkyl) n -(CO)-OR b2 , said alkyl is substituted by one or more C6-C10 aryl groups, n is 1, R b2 is C1-C6 alkyl or- (C1-C6 alkyl) n -O-(CO)-OR c3 , R c3 is C1-C
- R 3 and R 4 are each independently selected from: hydrogen, hydroxyl, Boc, Cbz, -CH 3 , Fmoc, -COOCH 2 C 6 H 5 , -COCH 2 NH 2 , -CHO, -COCH 3 , -COCH 2 CH 3 , -COCH(CH 3 ) 2 , -COCH(CH 2 ) 2 , -COOCH 3 , -CON(CH 3 ) 2 , -COCH(CH 3 )(NH 2 ); where, Boc represents tertiary Butoxycarbonyl, Cbz means benzyloxycarbonyl, and Fmoc means fluorenylmethyloxycarbonyl.
- R 1 is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 Aryl, 3-15 membered heterocyclic group, said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclic are optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl , C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group) group substitution;
- R 1 is selected from: -O-, hydroxyl, -OR a : R a is C1-C6 alkyl;
- R 1 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- Y is C
- R 2 is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 Aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkane Base, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group ) group substitution;
- R 2 is selected from: hydroxyl, -O-, -OR a : R a is C1-C6 alkyl;
- R is selected from: hydroxyl, -O-, methoxy
- R 3 and R 4 are each independently selected from: hydrogen, hydroxyl, C1-C6 alkyl;
- R3 and R4 are each independently hydrogen
- R 5 is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from hydrogen, amino; or R 5 is selected from hydrogen.
- R 1 ' is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6- C10 aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, cycloalkyl, aryl, heterocycle are optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkane Base, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group ) group substitution;
- R 1 is selected from: -O-, hydroxyl, -OR a : R a is C1-C6 alkyl;
- R 1 ' is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- Y' is C
- y' is 0
- R 2 ' is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6- C10 aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, cycloalkyl, aryl, heterocycle are optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkane Base, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group ) group substitution;
- R 2 ' is selected from: hydroxyl, -O-, -OR a : R a is C1-C6 alkyl;
- R 2 ' is selected from: hydroxyl, -O-, methoxy
- R 3 ' and R 4 ' are each independently selected from: hydrogen, hydroxyl, C1-C6 alkyl;
- R 3 ' and R 4 ' are each independently hydrogen;
- R 5 ' is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino;
- R 5 ' is selected from hydrogen, amino
- R5 ' is selected from hydrogen.
- R 1 , R 2 , R 3 , R 4 of a unit A is connected to any one of R 1 ′, R 2 ′, R 3 ′, R 4 ′ of the adjacent unit A’ through L 1 ;
- Each L is independently selected from the group consisting of unit linking groups: 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 heteroalkyl; for example, -O-alkyl-O- (or -O-C1-C6 alkyl -O-)), wherein alkyl, cycloalkyl, heteroalkyl are optionally substituted by one or more groups independently selected from Z;
- Z is independently selected from the following groups: 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), heterocycle;
- L is selected from: absent, -CR'R", wherein R' and R" are each independently H, C1-C6 alkyl (or C1-C3 alkyl);
- L 1 is selected from: absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 ;
- L 1 is selected from: -CH 2 -.
- R 1 is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 Aryl, 3-15 membered heterocyclic group, said alkyl, alkenyl, cycloalkyl, aryl, and heterocyclic are optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl , C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group) group substitution;
- R 1 is selected from: -O-, hydroxyl, -OR a : R a is C1-C6 alkyl;
- R 1 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 1 is selected from: methoxy
- Y is C
- R 2 is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 Aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkane Base, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group ) group substitution;
- R 2 is selected from: hydroxyl, -O-, -OR a : R a is C1-C6 alkyl;
- R is selected from: hydroxyl, -O-, methoxy
- R 2 is selected from: -O-;
- R 3 and R 4 are each independently selected from: hydrogen, hydroxyl, C1-C6 alkyl;
- R3 and R4 are each independently hydrogen
- R 5 is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino; or R 5 is selected from hydrogen, amino; or R 5 is selected from hydrogen.
- R 1 ' is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6- C10 aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, cycloalkyl, aryl, heterocycle are optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkane Base, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group ) group substitution;
- R 1 is selected from: -O-, hydroxyl, -OR a : R a is C1-C6 alkyl;
- R 1 ' is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 1 ' is selected from: methoxy
- Y' is C
- y' is 0
- R 2 ' is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6- C10 aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, cycloalkyl, aryl, heterocycle are optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkane Base, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group ) group substitution;
- R 2 ' is selected from: hydroxyl, -O-, -OR a : R a is C1-C6 alkyl;
- R 2 ' is selected from: hydroxyl, -O-, methoxy
- R 2 ' is selected from: -O-;
- R 3 ' and R 4 ' are each independently selected from: hydrogen, hydroxyl, C1-C6 alkyl;
- R 3 ' and R 4 ' are each independently hydrogen;
- R 5 ' is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino;
- R 5 ' is selected from hydrogen, amino
- R5 ' is selected from hydrogen.
- the present invention provides a compound represented by the following formula I, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystal form,
- a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystal form The use of their metabolite forms, or any combination or mixture thereof in the preparation of medicines or reagents, the medicines are used for at least one of the following:
- liver-related diseases such as NAFLD, NASH, liver fibrosis
- A is A' for A is the same as or different from A';
- x is selected from 0, 1, 2;
- R 1 and R 2 are each independently selected from the following groups: -OR a1 , -NR a2 R a3 ;
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group;
- R 1 and R 2 of a unit A is connected to any one of R 1 ′ and R 2 ′ of the adjacent unit A’ through L 1 ;
- Each L is independently selected from the unit linking group of the following group: absent, O, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 Alkynyl), -O-alkyl-O-(or -O-C1-C6alkyl-O-), -O-alkenyl-O-(or -O-C2-C6alkenyl-O-), -O-alkynyl-O-(or -O-C2-C6alkynyl-O-);
- R 1 and R 2 are each independently selected from the following groups: -OR a1 , -NR a2 R a3 ;
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group;
- R 1 ' and R 2 ' are each independently selected from the following groups: -OR a1 , -NR a2 R a3 ;
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group;
- Each R 1 is independently selected from the following groups: -OR a1 , -NR a2 R a3 ;
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group;
- each R 1 is independently selected from the group consisting of -OH, -O-(C1-C3 alkyl), -O-(C1-C3 alkenyl), -NH 2 , -NH(C1-C3 alkyl ), -N(C1-C3 alkyl) 2 ;
- each R 1 is independently selected from the following groups: -OH, methoxy, ethoxy, -OCH(CH 3 ) 2 , -NH 2 ;
- Each R 2 is independently selected from the following groups: -OR a1 , -NR a2 R a3 ;
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group;
- each R 2 is independently selected from the following groups: -OH, -O-(C1-C3 alkyl), -O-(C1-C3 alkenyl), -NH 2 , -NH(C1-C3 alkyl ), -N(C1-C3 alkyl) 2 ;
- each R 2 is independently selected from the following groups: -OH, methoxy, ethoxy, -OCH(CH 3 ) 2 , -NH 2 ;
- R 1 and R 2 of a unit A is connected to any one of R 1 ′ and R 2 ′ of the adjacent unit A’ through L 1 ;
- Each L is independently selected from the unit linking group of the following group: absent, O, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 Alkynyl), -O-alkyl-O-(or -O-C1-C6alkyl-O-), -O-alkenyl-O-(or -O-C2-C6alkenyl-O-), -O-alkynyl-O-(or -O-C2-C6alkynyl-O-);
- Or L is selected from: absent, alkyl (or C1-C3 alkyl), alkenyl (or C2-C3 alkenyl);
- L 1 is selected from: absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 ;
- L 1 is selected from: -CH 2 -.
- R 1 is selected from: -O-, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl;
- R is selected from: -O-, hydroxyl, -O-(C1-C3 alkyl);
- R 1 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 2 is selected from: -O-, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl;
- R is selected from: -O-, hydroxyl, -O-(C1-C3 alkyl);
- R 2 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 1 is selected from: -O-, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl;
- R is selected from: -O-, hydroxyl, -O-(C1-C3 alkyl);
- R 1 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 2 is selected from: -O-, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl;
- R is selected from: -O-, hydroxyl, -O-(C1-C3 alkyl);
- R 2 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 1 and R 2 of a unit A is connected to any one of R 1 ′ and R 2 ′ of the adjacent unit A’ through L 1 ;
- Each L is independently selected from the unit linking group of the following group: absent, O, alkyl (or C1-C6 alkyl), alkenyl (or C2-C6 alkenyl), alkynyl (or C2-C6 Alkynyl), -O-alkyl-O-(or -O-C1-C6alkyl-O-), -O-alkenyl-O-(or -O-C2-C6alkenyl-O-), -O-alkynyl-O-(or -O-C2-C6alkynyl-O-);
- Or L is selected from: absent, alkyl (or C1-C3 alkyl), alkenyl (or C2-C3 alkenyl);
- L 1 is selected from: absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 ;
- L 1 is selected from: -CH 2 -.
- R 1 is selected from: -O-, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl;
- R is selected from: -O-, hydroxyl, -O-(C1-C3 alkyl);
- R 1 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 2 is selected from: -O-, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl;
- R is selected from: -O-, hydroxyl, -O-(C1-C3 alkyl);
- R 2 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 1 is selected from: -O-, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl;
- R is selected from: -O-, hydroxyl, -O-(C1-C3 alkyl);
- R 1 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 2 is selected from: -O-, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl;
- R is selected from: -O-, hydroxyl, -O-(C1-C3 alkyl);
- R 2 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 .
- the present invention provides the compound represented by the following formula I-4, or its pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound , crystal forms, their metabolite forms, or any combination or mixture thereof in the preparation of medicines or reagents, the medicine is used for at least one of the following:
- liver diseases such as NAFLD, NASH, liver fibrosis
- Rn 1 and Rn 2 are each independently selected from the following groups: C1-C6 alkyl, -OR a4 , -O-L2-OR a4 , -NR a5 R a6 ;
- Each Rm is independently selected from the following groups: hydrogen, C1-C6 alkyl, C1-C6 alkoxyacyl-O-L3-;
- L2 and L3 are each independently selected from the following groups: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 3-7 membered heteroalkyl, L2 and L3 each Optionally substituted by one or more groups independently selected from halogen, amino, hydroxyl;
- Y is C or S
- y 0, 1, 2 or 3.
- Rn 1 and Rn 2 are each independently selected from the following groups: C1-C6 alkyl, -OR a4 , -O-L2-OR a4 , -NR a5 R a6 ;
- Each Rm is independently selected from the following groups: hydrogen, C1-C6 alkyl, C1-C6 alkoxyacyl-O-L3-;
- L2 and L3 are each independently selected from the following groups: C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, 3-7 membered heteroalkyl, L2 and L3 are each optionally replaced by one or Substituted by multiple groups independently selected from halogen, amino, and hydroxyl;
- Y is C
- y 0, 1 or 2.
- Rn 1 and Rn 2 are each independently selected from the following groups: C1-C6 alkyl, -OR a4 , -O-L2-OR a4 , -NR a5 R a6 ;
- Each Rm is independently selected from the following groups: hydrogen, C1-C6 alkyl, C1-C6 alkoxyacyl-O-L3-;
- L2 and L3 are each independently selected from the following groups: C1-C6 alkyl, each of L2 and L3 is optionally substituted by one or more groups independently selected from halogen, amino, and hydroxyl;
- Rn 3 and Rn 4 are each independently selected from the following groups: hydrogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group , aminoacyl, C1-C6 alkylacyl, C1-C6 alkoxyacyl, C1-C6 alkylaminoacyl, aminoC1-C6 alkanoyl, 3-15 membered heterocyclic acyl, C3-C7 cycloalkylacyl, C6 -C10 aryl C1-C6 alkoxyacyl;
- Y is C
- y 0, 1 or 2.
- the compound represented by formula I or I-1, I-2, I-3 or I-4 is selected from the following:
- the compound represented by formula I or I-1, I-2, I-3 or I-4 is selected from the following:
- the present invention provides a peptide containing 2-10 or 2-3 amino acids, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate,
- solvates, isotopic compounds, crystal forms, their metabolite forms, or any combination or mixture thereof in the preparation of drugs or reagents
- the drug or reagent is used for at least one of the following:
- liver diseases such as NAFLD, NASH, liver fibrosis
- At least one amino acid is aspartic acid, and when the aspartic acid has a free carboxyl group, the free carboxyl group can arbitrarily form an ester with C1-C6 alkyl-OH;
- the amino acid is aspartic acid, phenylalanine, glycine, alanine, glutamic acid, cystine, glutamine, histidine, tyrosine, serine, methionine, arginine acid or leucine;
- the free amino acid on one side 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;
- amino acids are aspartic acid, phenylalanine, glycine, alanine, glutamic acid, cystine, glutamine, histidine, tyrosine, serine, methionine, arginine or leucine.
- the present invention provides the compound represented by the above formula I, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystal Types, their metabolite forms, or any combination or mixture thereof, or the compound shown in the above formula I-4, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvent Compounds, isotopic compounds, crystal forms, their metabolite forms, 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 its pharmaceutical Acceptable salts, esters, prodrugs, stereoisomers, hydrates, solvates, isotopic compounds, crystal forms, their metabolite forms, or any combination or mixture thereof,
- liver diseases such as NAFLD, NASH, liver fibrosis
- the present invention provides a method for obtaining the following effects:
- liver diseases such as NAFLD, NASH, liver fibrosis
- the liver fibrosis includes but is not limited to: liver fibrosis caused by chronic viral liver diseases, liver fibrosis caused by alcoholism or long-term drinking, liver fibrosis caused by non-alcoholic factors such as obesity , Portal liver fibrosis caused by repeated infection with schistosomiasis, biliary liver fibrosis caused by chronic cholestasis, metabolic liver fibrosis caused by hepatolenticular degeneration and hemochromatosis, and hepatic fibrosis caused by various toxic substances Toxic liver fibrosis, malnourished liver fibrosis caused by preference for low-protein diet and fatty fried food, and cardiogenic liver fibrosis caused by chronic congestive heart failure.
- the present invention provides the use of a pharmaceutical composition in the preparation of a drug, the pharmaceutical composition comprising the compound represented by the above formula I, or a pharmaceutically acceptable salt, ester, prodrug, Stereoisomers, hydrates, solvates, isotopic compounds, crystal forms, their metabolite forms, or any combination or mixture thereof, or the compound shown in the above formula I-4, or its pharmaceutically acceptable Salts, esters, prodrugs, stereoisomers, hydrates, solvates, isotopic compounds, crystal forms, their metabolite forms, or any combination or mixture thereof, or one of the above-mentioned third aspects containing Peptides of 2-10 or 2-3 amino acids, or pharmaceutically acceptable salts, esters, prodrugs, stereoisomers, hydrates, solvates, isotopic compounds, crystal forms, and their metabolite forms , or any combination or mixture thereof, the drug is used for at least one of the following:
- liver diseases such as NAFLD, NASH, liver fibrosis
- the present invention provides a pharmaceutical composition for at least one of the following:
- liver diseases such as NAFLD, NASH, liver fibrosis
- the pharmaceutical composition comprises the compound represented by the above formula I, or its pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, crystal form, and their metabolites form, or any combination or mixture thereof, or the compound shown in the above formula I-4, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, hydrate, solvate, isotopic compound, Crystal forms, their metabolite forms, 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 pharmaceutically acceptable salt thereof, Esters, prodrugs, stereoisomers, hydrates, solvates, isotopic compounds, crystal forms, metabolite forms thereof, or any combination or mixture thereof.
- the present invention provides a method for obtaining the following effects:
- liver diseases such as NAFLD, NASH, liver fibrosis
- the pharmaceutical composition comprising the compound represented by the above formula I, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer body, hydrate, solvate, isotopic compound, crystal form, their metabolite form, or any combination or mixture thereof, or the compound shown in the above formula I-4, or a pharmaceutically acceptable salt or ester thereof , prodrugs, stereoisomers, hydrates, solvates, isotopic compounds, crystal forms, their metabolite forms, or any combination or mixture thereof, or one of the above-mentioned third aspects containing 2-10 or 2-3 amino acid peptides, or pharmaceutically acceptable salts, esters, prodrugs, stereoisomers, hydrates, solvates, isotopic compounds, crystal forms, their metabolite forms, or their any combination or mixture of .
- the liver fibrosis includes but is not limited to: liver fibrosis caused by chronic viral liver diseases, liver fibrosis caused by alcoholism or long-term drinking, liver fibrosis caused by non-alcoholic factors such as obesity , Portal liver fibrosis caused by repeated infection with schistosomiasis, biliary liver fibrosis caused by chronic cholestasis, metabolic liver fibrosis caused by hepatolenticular degeneration and hemochromatosis, and hepatic fibrosis caused by various toxic substances Toxic liver fibrosis, malnourished liver fibrosis caused by preference for low-protein diet and fatty fried food, and cardiogenic liver fibrosis caused by chronic congestive heart failure.
- the pharmaceutical composition further comprises 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 (such as ezetimibe), HSC activation and proliferation inhibitors (such as pirfenidone, flufenidone, Pegbelfermin) PCSK9 inhibitors, PPAR agonists (eg, gemfibrozil, fenofibrate, clofibrate, bezafibrate, pemafibrate, Elafibranor), ACE inhibitors, CCR2/5 inhibitors, TLR4 inhibition LOXL2 inhibitors, TIMP-1 inhibitors, FXR agonists, AT1R blockers, NOX inhibitors, calcium channel blockers, ARBs, diuretics, renin, GLP-1 or its synthetic variants, insulin
- the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
- the pharmaceutical composition is a solid preparation, an injection, an external preparation, a spray, a liquid preparation or a compound preparation.
- the present invention provides the compound represented by formula II, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form, their metabolism object form,
- a 1 is A 1 ' for A 1 and A 1 ' are the same or different;
- x is selected from 0, 1 and 2;
- R and R are independently selected from: -OR a ,
- R a is independently selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 member 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 b7 , the alkane Base, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle can be optionally
- R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , and R b7 are independently selected from the following groups: hydrogen, deuterium, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2 -C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclyl;
- R 3 and R 4 are independently selected from: -COCH(CH 3 )(NH 2 ), hydrogen, -COCH 2 CH 3 , deuterium, C1-C6 alkyl, which may be selected independently by one or more Substituted by halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, aryl, heterocyclic group;
- At least one of R1 and R2 is
- R 3 and R 4 is -COCH(CH 3 )(NH 2 ) or -COCH 2 CH 3 ;
- R 1 and R 2 are independently selected from: hydroxy, methoxy,
- R 3 and R 4 are independently selected from: hydrogen, -COCH 2 CH 3 and -COCH(CH 3 )(NH 2 ),
- R 1 and R 2 When one of R 1 and R 2 is hydroxyl or methoxy, the other of R 1 and R 2 is Or one of R 3 and R 4 is -COCH(CH 3 )(NH 2 );
- R is selected from: hydroxy, methoxy,
- R2 is selected from: hydroxyl, Methoxy,
- R 3 and R 4 are independently selected from: hydrogen, -COCH 2 CH 3 and -COCH(CH 3 )(NH 2 ),
- R 1 is hydroxy or methoxy
- R 2 is Or one of R 3 and R 4 is -COCH(CH 3 )(NH 2 );
- R 1 is Or one of R 3 and R 4 is -COCH(CH 3 )(NH 2 );
- Any one of R 1 , R 2 , R 3 , R 4 of one unit A 1 passes through L 1 and any one of R 1 ′, R 2 ′, R 3 ′, R 4 ′ of adjacent unit A 1 ′ connected;
- Each L is independently selected from the group consisting of unit linking groups: 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), heteroalkyl (or 3-7 membered hetero Alkyl), wherein alkyl, cycloalkyl, heteroalkyl are optionally substituted by one or more groups independently selected from Z;
- Z is independently selected from the following groups: 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), heterocycle;
- L is selected from: absent, -CR'R", wherein R' and R" are each independently H, C1-C6 alkyl (or C1-C3 alkyl);
- L 1 is selected from: absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 ;
- R 1 and R 2 are each independently selected from the following groups: C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 ;
- R3 and R4 are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl , 3-15 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, C1-C6 alkyl, halogen C1-C6 alkyl, aryl (or C6-C12 aryl), heterocyclic group substitution;
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1- C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic Cyclic group) group substitution;
- R 1 is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6 -C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl) n -O-(CO)-R b1 , the alkyl, alkenyl, cycloalkyl, aryl, heterocyclic Optionally selected by one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 Aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclyl) group substitution;
- R 1 is selected from: -O-, hydroxyl, -OR a : R a is C1-C6 alkyl;
- R 1 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 2 is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6 -C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl) n -O-(CO)-R b1 , the alkyl, alkenyl, cycloalkyl, aryl, heterocyclic Optionally selected by one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 Aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclyl) group substitution;
- R 2 is selected from: hydroxyl, -O-, -OR a : R a is C1-C6 alkyl;
- R 2 is selected from: hydroxyl, -O-, methoxy,
- R 3 and R 4 are each independently selected from: hydrogen, hydroxyl, C1-C6 alkyl;
- R3 and R4 are each independently hydrogen
- R is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino;
- R is selected from hydrogen, amino
- R is selected from hydrogen
- Y is C
- y is selected from 0, 1, 2, 3; or y is 0 or 1; or y is 0;
- R 1 ' and R 2 ' are each independently selected from the following groups: C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 ;
- R 3 ' and R 4 ' are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 Aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, C1-C6 alkyl , halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), heterocyclic group substitution;
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1- C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic Cyclic group) group substitution;
- R 1 ' is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl) n -O-(CO)-R b1 , said alkyl, alkenyl, cycloalkyl, aryl, heterocyclic
- the group is optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6- C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group) group substitution;
- R 1 ' is selected from: -O-, hydroxyl, -OR a : R a is C1-C6 alkyl;
- R 1 ' is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 2 ' is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl) n -O-(CO)-R b1 , said alkyl, alkenyl, cycloalkyl, aryl, heterocyclic
- the group is optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6- C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group) group substitution;
- R 2 ' is selected from: hydroxyl, -O-, -OR a : R a is C1-C6 alkyl;
- R 2 ' is selected from: hydroxyl, -O-, methoxy
- R 3 ' and R 4 ' are each independently selected from: hydrogen, hydroxyl, C1-C6 alkyl;
- R 3 ' and R 4 ' are each independently hydrogen;
- R 5 ' is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino;
- R 5 ' is selected from hydrogen, amino
- R 5 ' is selected from hydrogen
- Y' is C
- y' is selected from 0, 1, 2, 3; or y is 0 or 1; or y' is 0;
- Any one of R 1 , R 2 , R 3 , R 4 of one unit A 1 passes through L 1 and any one of R 1 ′, R 2 ′, R 3 ′, R 4 ′ of adjacent unit A 1 ′ connected;
- Each L is independently selected from the group consisting of unit linking groups: 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), heteroalkyl (or 3-7 membered hetero Alkyl), wherein alkyl, cycloalkyl, heteroalkyl are optionally substituted by one or more groups independently selected from Z;
- Z is independently selected from the following groups: 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), heterocycle;
- L is selected from: absent, -CR'R", wherein R' and R" are each independently H, C1-C6 alkyl (or C1-C3 alkyl);
- L 1 is selected from: absent, -CH 2 -, -CH(CH 3 )-, -C-(CH 3 ) 2 ;
- L 1 is selected from: -CH 2 -;
- R 1 and R 2 are each independently selected from the following groups: C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 ;
- R3 and R4 are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aryl , 3-15 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, C1-C6 alkyl, halogen C1-C6 alkyl, aryl (or C6-C12 aryl), heterocyclic group substitution;
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1- C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic Cyclic group) group substitution;
- R 1 is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6 -C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl) n -O-(CO)-R b1 , the alkyl, alkenyl, cycloalkyl, aryl, heterocyclic Optionally selected by one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 Aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclyl) group substitution;
- R 1 is selected from: -O-, hydroxyl, -OR a : R a is C1-C6 alkyl;
- R 1 is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 1 is selected from: methoxy
- R 2 is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6 -C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl) n -O-(CO)-R b1 , the alkyl, alkenyl, cycloalkyl, aryl, heterocyclic Optionally selected by one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 Aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclyl) group substitution;
- R 2 is selected from: hydroxyl, -O-, -OR a : R a is C1-C6 alkyl;
- R 2 is selected from: hydroxyl, -O-, methoxy,
- R 2 is selected from: -O-;
- R 3 and R 4 are each independently selected from: hydrogen, hydroxyl, C1-C6 alkyl;
- R3 and R4 are each independently hydrogen
- R is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino;
- R is selected from hydrogen, amino
- R is selected from hydrogen
- Y is C
- y is selected from 0, 1, 2, 3; or y is 0 or 1; or y is 0;
- R 1 ' and R 2 ' are each independently selected from the following groups: C1-C6 alkyl, -O-, -OR a1 , -NR a2 R a3 ;
- R 3 ' and R 4 ' are each independently selected from the following groups: hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 Aryl, 3-15 membered heterocyclic group, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, C1-C6 alkyl , halogenated C1-C6 alkyl, aryl (or C6-C12 aryl), heterocyclic group substitution;
- R a1 , R a2 , and R a3 are each independently selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C10 aromatic Base, 3-15 membered heterocyclic group, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group is optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1- C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic Cyclic group) group substitution;
- R 1 ' is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl) n -O-(CO)-R b1 , said alkyl, alkenyl, cycloalkyl, aryl, heterocyclic
- the group is optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6- C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group) group substitution;
- R 1 ' is selected from: -O-, hydroxyl, -OR a : R a is C1-C6 alkyl;
- R 1 ' is selected from: -O-, hydroxyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ;
- R 1 ' is selected from: methoxy
- R 2 ' is selected from: -O-, C1-C6 alkyl, -OR a1 , wherein, R a1 is selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl) n -O-(CO)-R b1 , said alkyl, alkenyl, cycloalkyl, aryl, heterocyclic
- the group is optionally selected from one or more independently selected from halogen, amino, hydroxyl, C1-C6 alkyl, C6-C10 aryl, 3-15 membered heterocyclic group, -(C1-C6 alkyl)-(C6- C10 aryl), -(C1-C6 alkyl)-(3-15 membered heterocyclic group) group substitution;
- R 2 ' is selected from: hydroxyl, -O-, -OR a : R a is C1-C6 alkyl;
- R 2 ' is selected from: hydroxyl, -O-, methoxy
- R 2 ' is selected from: -O-;
- R 3 ' and R 4 ' are each independently selected from: hydrogen, hydroxyl, C1-C6 alkyl;
- R 3 ' and R 4 ' are each independently hydrogen;
- R 5 ' is selected from the following groups: hydrogen, deuterium, C1-C6 alkyl, halogen, amino;
- R 5 ' is selected from hydrogen, amino
- R 5 ' is selected from hydrogen
- Y' is C
- y' is selected from 0, 1, 2, 3; or y is 0 or 1; or y' is 0;
- the compound shown in formula II or II-1, II-2, II-3 is selected from the following:
- the present invention provides a pharmaceutical composition, which comprises the compound represented by the above formula II, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate , crystal forms, their metabolite forms, or any combination or mixture thereof.
- the present invention provides the compound represented by the above formula II, its pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, solvate, crystal form, their metabolism drug form, or any combination or mixture thereof, in the preparation of medicines or reagents, the medicine is used for at least one of the following:
- liver diseases such as NAFLD, NASH, liver fibrosis
- the present invention provides the use of the pharmaceutical composition in the preparation of medicines or reagents, and the medicines are used for at least one of the following:
- liver diseases such as NAFLD, NASH, liver fibrosis
- the pharmaceutical composition comprises the compound represented by the above formula II, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form, their metabolite form, or their any combination or mixture of .
- the present invention provides the compound represented by the above-mentioned formula II, its pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, solvate, crystal form, their metabolism substance form, or any combination or mixture thereof, or the above-mentioned compound represented by formula II, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form, their A pharmaceutical composition in the form of metabolites, or any combination or mixture thereof, for at least one of the following:
- liver diseases such as NAFLD, NASH, liver fibrosis
- the present invention provides a method for obtaining the following effects:
- liver diseases such as NAFLD, NASH, liver fibrosis
- It includes administering to a subject in need a therapeutically effective amount of the compound represented by the above formula II, its pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, solvate, crystal form, and their metabolism substance form, or any combination or mixture thereof, or the above-mentioned compound represented by formula II, its pharmaceutically acceptable salt or ester, prodrug, stereoisomer, hydrate, solvate, crystal form, their A pharmaceutical composition in the form of metabolites, or any combination or mixture thereof.
- the liver fibrosis includes but is not limited to: liver fibrosis caused by chronic viral liver diseases, liver fibrosis caused by alcoholism or long-term drinking, liver fibrosis caused by non-alcoholic factors such as obesity , Portal liver fibrosis caused by repeated infection with schistosomiasis, biliary liver fibrosis caused by chronic cholestasis, metabolic liver fibrosis caused by hepatolenticular degeneration and hemochromatosis, and hepatic fibrosis caused by various toxic substances Toxic liver fibrosis, malnourished liver fibrosis caused by preference for low-protein diet and fatty fried food, and cardiogenic liver fibrosis caused by chronic congestive heart failure.
- the pharmaceutical composition further comprises 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 (such as ezetimibe), HSC activation and proliferation inhibitors (such as pirfenidone, flufenidone, Pegbelfermin) PCSK9 inhibitors, PPAR agonists (eg, gemfibrozil, fenofibrate, clofibrate, bezafibrate, pemafibrate, Elafibranor), ACE inhibitors, CCR2/5 inhibitors, TLR4 inhibition LOXL2 inhibitors, TIMP-1 inhibitors, FXR agonists, AT1R blockers, NOX inhibitors, calcium channel blockers, ARBs, diuretics, renin, GLP-1 or its synthetic variants, insulin
- the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
- the pharmaceutical composition is a solid preparation, an injection, an external preparation, a spray, a liquid preparation or a compound preparation.
- C1-C6 alkyl and “C1-C6 alkyl” in various compound groups related to “C1-C6 alkyl” can be replaced by "C1- C20 alkyl", “C1-C12 alkyl", “C1-C10 alkyl", “C1-C8 alkyl", “C1-C4 alkyl", "C1-C3 alkyl” or "C1-C2 alkyl base";
- C2-C6 alkenyl and “C2-C6 alkenyl” in various composite groups involving “C2-C6 alkenyl” can be replaced by "C2-C12 alkenyl", “C2-C8 alkenyl” or "C2-C4 alkenyl”;
- C2-C6 alkynyl and “C2-C6 alkynyl” in various composite groups involving “C2-C6 alkynyl” can be replaced by "C2-C12 alkynyl", “C2-C8 alkynyl” or "C2-C4 alkynyl”;
- C3-C7 cycloalkyl and “C3-C8 cycloalkyl” in various composite groups involving “C3-C8 cycloalkyl” can be replaced by "C3-C20 cycloalkyl", “C3-C12 Cycloalkyl” or "C3-C10 cycloalkyl”;
- C1-C6 alkoxy and “C1-C6 alkoxy” in various complex groups related to it can be replaced by "C1-C20 alkoxy", “C1-C12 alkoxy” or "C1 -C10 alkoxy”;
- Figure 1 shows the inhibitory effects of compound 6, compound 47, and compound 54 on the expression of collagen I and collagen III proteins; GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was used as a control.
- Figure 2 shows the inhibitory effect of Compound 4, Compound 6, Compound 41, Compound 47, Compound 48, and Compound 52 on the expression of ⁇ -SMA protein; GAPDH was used as a control.
- con means the control well
- P1 means the positive control well (oxynidone)
- ASP-50 means the concentration of aspartic acid is 50 ⁇ M; other numbers are in the form of compound number-concentration ( ⁇ M).
- Figure 3 shows the inhibitory effect of compound 50, compound 52 and compound 54 on the expression of FN protein; GAPDH was used as a control.
- con means the control well
- P1 means the positive control well (oxynidone)
- ASP-50 means the concentration of aspartic acid is 50 ⁇ M; other numbers are in the form of compound number-concentration ( ⁇ M).
- Figure 4 shows the inhibitory effect of Compound 54, Compound 77a, and Compound 78a on the expression of Collagen I protein and ⁇ -SMA protein in LX2 cells stimulated by TGF ⁇ ; GAPDH was used as a control.
- Figure 5 shows the decrease of NS3TP1 expression in the liver tissue of the mouse model of liver injury and the regulatory effect of different doses of compound 6 on the expression of NS3TP1 in the liver tissue of the mouse model of liver injury, "mpk” in the figure means “mg per kg” .
- Figure 6 shows the Masson stained section of mouse liver tissue after intraperitoneal injection of carbon tetrachloride and treatment with Compound 4, Compound 6, Compound 47, and Compound 54.
- Fig. 7 shows the Masson stained section of mouse liver tissue after intraperitoneal injection of carbon tetrachloride and different doses of Compound 6 treatment.
- Figure 8 shows the concentration of compound 6 in rats after oral administration and injection of compound 6 (upper left), the concentration of aspartic acid in rats after oral administration and injection of compound 6 (upper right), and the concentration of aspartic acid in rats after injection of normal saline. Concentration of compound 6 (lower left), aspartic acid concentration in rats after injection of saline (lower right).
- Figure 9 shows H&E stained sections of liver tissue of mice treated with different doses of Compound 6 after being fed with HFD diet.
- Figure 10 shows the H&E stained sections of mouse liver tissue after being fed with CHOL diet and treated with different doses of Compound 6.
- the term "effective amount” or “therapeutically effective amount” refers to an amount sufficient to treat or prevent a patient's disease but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
- a therapeutically effective amount of a compound will depend on the particular compound selected (e.g., taking into account the potency, effectiveness, and half-life of the compound), the route of administration selected, the disease being treated, the severity of the disease being treated, the condition of the patient being treated, Factors such as age, size, weight and physical ailments, medical history of the patient being treated, duration of treatment, nature of concurrent therapy, desired therapeutic effect, etc. vary but can still be routinely determined by one skilled in the art.
- the term "mammal” refers to a warm-blooded animal suffering from or at risk of developing the diseases described herein, including but not limited to guinea pigs, dogs, cats, rats, mice, hamsters and primates, including people.
- the pharmaceutically acceptable salts of the compounds represented by formula I or formula I-4 or formula II of the present invention include their inorganic or organic acid salts, and inorganic or organic alkali salts, and the present invention relates to all forms of the above salts. These include, but are not limited to: sodium salts, potassium salts, calcium salts, lithium salts, meglumine salts, hydrochlorides, hydrochlorates, hydroiodes, nitrates, sulfates, bisulfates, phosphates, Hydrogen Phosphate, Acetate, Propionate, Butyrate, Oxalate, Trimethylacetate, Adipate, Alginate, Lactate, Citrate, Tartrate, Succinate , maleate, fumarate, picrate, aspartate, gluconate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonic acid salt and pamoate etc.
- the pharmaceutical composition involved in the present invention may include a pharmaceutically acceptable carrier, and the carrier includes, but is not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate , 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 oxidation Silicon, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, macrogol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin.
- the carrier includes, but is not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate , glycerin, sorbic acid
- the pharmaceutical composition of the present invention can be prepared in various forms according to different administration routes.
- the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal cavity administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
- oral administration spray inhalation, rectal administration, nasal cavity administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
- parenteral administration such as subcutaneous, intravenous, intramuscular , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
- oral, intraperitoneal or intravenous administration is preferred.
- Orally acceptable preparation forms include, but are not limited to, tablets, capsules, aqueous solutions or suspensions.
- the generally used carrier of tablet comprises lactose and cornstarch, also can add lubricating agent such as magnesium stearate in addition.
- Diluents commonly used in capsule formulations include lactose and dried cornstarch.
- Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral preparation forms.
- the compound represented by formula I or formula I-4 or formula II, its stereoisomer or its pharmaceutically acceptable salt and/or its solvate and/or its hydrate can generally be made into Suppository form, which is prepared by mixing the drug with a suitable non-irritating excipient.
- the excipient is solid at room temperature and melts at rectal temperature to release the drug.
- excipients include cocoa butter, beeswax and polyethylene glycols.
- the compound shown in the formula I or formula I-4 or formula II, its stereoisomer When used locally, especially for the treatment of affected areas or organs that are easily accessible by local external application, such as eyes, skin or lower intestinal neuropathy, the compound shown in the formula I or formula I-4 or formula II, its stereoisomer
- the conformer or its pharmaceutically acceptable salt and/or its solvate and/or its hydrate can be made into different forms of topical preparations according to different affected areas or organs, specifically as follows:
- the compound represented by formula I or formula I-4 or formula II, its stereoisomer or its pharmaceutically acceptable salt and/or its solvate and/or its hydrate can be formulated
- the carrier used is isotonic sterile saline at a certain pH with or without preservatives such as benzyl alkoxide chloride.
- the compounds may also be formulated in the form of ointments such as petrolatum ointment.
- the compound represented by formula I or formula I-4 or formula II, its stereoisomer or its pharmaceutically acceptable salt and/or its solvate and/or its hydrate can be made into Suitable ointment, lotion or cream formulations 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, polyethylene oxide, polypropylene oxide, 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 esters wax, cetyl aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the compound represented by formula I or formula I-4 or formula II, its stereoisomer or its pharmaceutically acceptable salt and/or its solvate and/or its hydrate can be prepared in the form of a rectal suppository formulation or a suitable enema formulation as described above, alternatively a topical transdermal patch may be used.
- the compound represented by formula I or formula I-4 or formula II, its stereoisomer or its pharmaceutically acceptable salt and/or its solvate and/or its hydrate can also be administered in the form of sterile injection preparation, These include sterile injectable aqueous or oleaginous suspensions, or sterile injectable solutions.
- sterile injectable vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils, such as mono- or diglycerides can be employed as a solvent or suspending medium.
- C1-C6 alkyl specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl, or "C1-C4 alkyl", or "C1- C3 alkyl”.
- the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R containing an asymmetric center , S configuration, (Z), (E) isomer of the double bond, and (Z), (E) conformational isomer.
- R containing an asymmetric center , S configuration for example, R containing an asymmetric center , S configuration, (Z), (E) isomer of the double bond, and (Z), (E) conformational isomer.
- the single stereochemical isomer of the compound of the present invention or its enantiomer Mixtures of isomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.
- any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, eg, in the (R), (S) or (R,S) configuration.
- each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess in the (R) or (S) configuration Enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
- prodrug used in the present invention means that a compound is transformed into a compound represented by formula (I) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure.
- Prodrug compounds of the present invention can be esters, and esters can be used as prodrugs in the existing inventions with phenyl esters, aliphatic (C1 24) esters, acyloxymethyl esters, carbonates, amino Formic acid esters and amino acid esters.
- Metal refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.
- a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
- Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol.
- hydrate refers to an association of solvent molecules with water.
- halogen and “halo” are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
- alkyl used in the present invention includes 1-20 carbon atoms saturated linear or branched monovalent hydrocarbon groups (C1-C20 alkyl), wherein the alkyl group can be independently and optionally described by one or more of the present invention replaced by substituents.
- the alkyl group contains 1-12 carbon atoms (C1-C12 alkyl); in other embodiments, the alkyl group contains 1-10 carbon atoms (C1-C10 alkyl); Some other embodiments are that the alkyl group contains 1-8 carbon atoms (C1-C8 alkyl); some other embodiments are that the alkyl group contains 1-6 carbon atoms (C1-C6 alkyl); Some other embodiments are that the alkyl group contains 1-4 carbon atoms (C1-C4 alkyl); some other embodiments are that the alkyl group contains 1-3 carbon atoms (C1-C3 alkyl); In other embodiments, the alkyl group contains 1-2 carbon atoms (C1-C2 alkyl).
- alkyl groups 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 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-
- C1-C6 alkyl refers to any alkyl group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl, etc.
- C2-C6 alkenyl refers to any alkenyl group containing 2-6 carbon atoms and at least one double bond, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butane Alkenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl and the like.
- alkynyl means 2-12 carbon atoms (C2-C12 alkynyl), or 2-8 carbon atoms (C2-C8 alkynyl), or 2-6 carbon atoms (C2-C6 alkynyl) , or a linear or branched monovalent hydrocarbon group of 2-4 carbon atoms (C2-C4 alkynyl), wherein at least one position of CC is a 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-ynylbutyl (-CH 2 CH 2 C ⁇ CH), 2- Alkynyl (-CH 2 C ⁇ CCH 3 ), 3-alkynyl (-C ⁇ CCH 2 CH 3 ), and the like.
- C2-C6 alkynyl refers to any alkynyl group containing 2-6 carbon atoms and at least one triple bond, such as ethynyl, 2-propynyl, 4-pentynyl and the like.
- alkoxy denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein. Unless specified otherwise, the alkoxy group contains 1-12 carbon atoms and may be represented as a C1-C12 alkoxy group.
- the alkoxy group contains 1-8 carbon atoms, which can be expressed as C1-C8 alkoxy; in other embodiments, the alkoxy group contains 1-6 carbon atoms, which can be Represented as C1-C6 alkoxy; In other embodiments, alkoxy groups contain 1-4 carbon atoms and may be represented as C1-C4 alkoxy; In still other embodiments, alkoxy groups The group contains 1-3 carbon atoms and can be expressed as a C1-C3 alkoxy group.
- 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 2 CH 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-butane Oxygen (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 ),
- alkylamino or “alkylamino” includes “N-alkylamino” and "N,N-dialkylamino", wherein the amino groups are independently substituted by one or two alkyl groups, Wherein the alkyl group has the meaning as described in the present invention.
- Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- -Diethylamino and the like.
- the alkylamino group is optionally substituted with one or more substituents described herein.
- haloalkoxy means that an alkoxy group is substituted by one or more halogen atoms, wherein the alkoxy group has the meaning as described in the present invention, such examples include, but are 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 and the like.
- the C1-C6 haloalkoxy group contains a fluorine-substituted C1-C6 alkoxy group; in another embodiment, the C1-C4 haloalkoxy group contains a fluorine-substituted C1-C4 alkoxy group; in yet another In an embodiment, the C1-C2 haloalkoxy group comprises a fluorine substituted C1-C2 alkoxy group.
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring contains 3 to 20 carbon atoms (ie “C3-C20 cycloalkyl”), preferably contains 3 to 12 carbon atoms (i.e. "C3-C12 cycloalkyl”), more preferably 3 to 10 carbon atoms (i.e. "C3-C10 cycloalkyl”), most preferably 3 to 7 carbon atoms (i.e. "C3 -C8 cycloalkyl”).
- Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexyl Dienyl, cycloheptyl, cycloheptatrienyl, etc.; polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl.
- halogenated C1-C6 alkyl refers to a group in which the C1-C6 alkyl skeleton is substituted by one or more halogens, for example, monofluoromethyl, difluoroethyl, trifluoromethyl, etc.
- halogen refers to fluorine, chlorine, bromine, iodine.
- C6-C12 aryl refers to a group of a carbocyclic aromatic system having 6-12 carbon atoms.
- C6-C10 aryl refers to a carbocyclic aromatic system group having 6-10 carbon atoms, such as phenyl, naphthyl and the like.
- heteroalkyl refers to a straight chain or branched chain alkyl group (preferably an alkyl group having 2 to 14 or 3 to 7 carbons) in which one or more carbons are independently selected from S, O, P or A heteroatom substitution of N (ie "2-14 membered heteroalkyl” or "3-7 membered heteroalkyl”).
- exemplary heteroalkyl groups include alkyl ethers, alkylamines, secondary alkylamines, thioethers, and the like.
- heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms (i.e. "3-20 membered heterocyclyl”), wherein one or more ring Atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
- Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
- Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
- 3-15 membered heterocyclyl refers to 3-, 4-, 5-, 6- and 7-membered up to 15 membered saturated or partially unsaturated carbocyclic rings, wherein one or more carbon atoms are replaced by heteroatoms such as Nitrogen, oxygen and sulfur substitution.
- “3-15 membered heterocyclic group” includes, for example, "3-7 membered heterocyclic group", non-limiting examples thereof, such as thietanyl, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, Pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine, morpholine, morpholinyl, tetrahydropyrrolyl, thiomorpholine Base etc.
- polycyclic aromatic hydrocarbon group refers to a group formed by condensing 1-2 C5-C6 aromatic rings and 1-2 aromatic rings or non-aromatic rings, non-limiting examples thereof, such as indenyl, naphthalene Base, phenanthrenyl, fluorenyl, etc.
- C1-C6 alkyl such as methyl, ethyl
- Peptide The amino group of one amino acid is condensed with the carboxyl group of another amino acid to form a peptide; for example: C # OOH-CH(N # H2 ) -CH2 - C# OOH, which can be marked by one, two or three # signs Atoms form peptide bonds with other amino acids.
- Isotopically enriched compounds have structures depicted by the general formulas given herein, except that one or more atoms are replaced by atoms 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, such as 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.
- Trt Trityl
- Embodiment 1 the synthesis of compound 35
- Embodiment 2 the synthesis of compound 36
- Embodiment 3 the synthesis of compound 37
- Step 1 Synthesis of 1-benzyl 4-(((isopropoxycarbonyl)oxy)methyl)(tert-butoxycarbonyl)-L-aspartic acid
- Step 2 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-4-(((isopropoxycarbonyl)oxy)methoxy)-4-oxobutanoic acid
- Embodiment 4 the synthesis of compound 49
- Embodiment 5 the synthesis of compound 50
- Embodiment 6 the synthesis of compound 51
- Step 1 Synthesis of 4-benzyl 1-(((isopropoxycarbonyl)oxy)methyl)(tert-butoxycarbonyl)-L-aspartic acid
- Step 2 Synthesis of (S)-3-((tert-butoxycarbonyl)amino)-4-(((isopropoxycarbonyl)oxy)methoxy)-4-oxobutanoic acid
- Embodiment 7 the synthesis of compound 52
- Embodiment 8 the synthesis of compound 53
- Step 1 Synthesis of ((isopropoxycarbonyl)oxy)methyl(tert-butoxycarbonyl)-L-phenylalanine
- Step 3 Synthesis of (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-1-(((isopropoxycarbonyl)oxy)methoxy)-1- Oxo-3-phenylpropan-2-yl)amino)-4-oxobutanoic acid tert-butyl ester
- Step 4 Synthesis of (S)-3-amino-4-(((S)-1-(((isopropoxycarbonyl)oxy)methoxy)-1-oxo-3-phenylpropane- 2-yl)amino)-4-oxobutyrate hydrochloride
- Embodiment 9 the synthesis of compound 54
- Step 2 Synthesis of 4-dimethyl O'1,O1-methylene(2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate)
- Embodiment 10 the synthesis of compound 56
- Embodiment 11 the synthesis of compound 57
- Step 1 Synthesis of 1-(chloromethyl)4-n-butyl(tert-butoxycarbonyl)-L-aspartic acid
- Step 2 Synthesis of 4-di-n-butyl O'1,O1-methylene(2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate)
- Step 3 Synthesis of (3S,3'S)-4,4'-(methylenebis(oxy))bis(3-amino-4-oxobutanoic acid) hydrochloride
- Embodiment 12 the synthesis of compound 55
- Embodiment 13 the synthesis of compound 58
- Embodiment 14 the synthesis of compound 59
- Embodiment 15 the synthesis of compound 60
- Embodiment 16 the synthesis of compound 61
- Embodiment 17 the synthesis of compound 62
- Embodiment 18 the synthesis of compound 63
- Embodiment 19 the synthesis of compound 64
- Embodiment 20 the synthesis of compound 65
- Embodiment 21 the synthesis of compound 66
- Embodiment 22 the synthesis of compound 67
- Step 1 Synthesis of 1-benzyl 4-methyl(tert-butoxycarbonyl)-L-alanyl-L-aspartic acid
- Embodiment 23 the synthesis of compound 68
- Step 3 Synthesis of O'1,O1-(ethane-1,1-diyl)4-dimethyl(2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate)
- Step 4 Synthesis of O'1,O1-(ethane-1,1-diyl)4-dimethyl(2S,2'S)-bis(2-aminosuccinate) hydrochloride
- Embodiment 24 the synthesis of compound 69
- Step 1 Synthesis of 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
- Embodiment 25 the synthesis of compound 70
- Step 3 Synthesis of 1-((((S)-2-((tert-butylcarbonyl)amino)-4-ethoxy-4-oxobutyryl)oxy)methyl)4-methyl(tert- Butoxycarbonyl)-L-Aspartic Acid
- Step 4 Synthesis of 1-((((S)-2-amino-4-ethoxy-4-oxobutyryl)oxy)methyl)4-methyl L-aspartic acid hydrochloride
- Embodiment 26 the synthesis of compound 71
- Step 2 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutanoic acid
- Step 3 Synthesis of 1-((((S)-2-((tert-butoxycarbonyl)amino)-4-isopropoxy-4-oxobutanoyl)oxy)methyl)4-methyl (tert-butoxycarbonyl)-L-aspartic acid
- Step 4 Synthesis of 1-((((S)-2-amino-4-isopropoxy-4-oxobutanoyl)oxy)methyl)4-methyl L-aspartic acid hydrochloride
- Embodiment 27 the synthesis of compound 72
- Step 1 Synthesis of 1-(chloromethyl)4-ethyl(tert-butoxycarbonyl)-L-aspartic acid
- Step 2 Synthesis of 4-diethyl O'1,O1-methylene(2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)succinate)
- Embodiment 28 the synthesis of compound 73
- Step 1 Synthesis of 1-(chloromethyl)4-isopropyl(tert-butoxycarbonyl)-L-aspartic acid
- Step 2 Synthesis 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
- Embodiment 29 Synthesis of Compound 74
- 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 (0.3g, 4.84mmol), S-2-(tert-butoxycarbonyl)amino-4-methoxy-4-oxobutanoic acid (2.5g, 10.16mmol), EDCI (2.32g, 12.1 mmol), DIPEA (3.12g, 24.2mmol) were dissolved in DMF (20mL), and the reaction solution was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was complete, an appropriate amount of ice water and ethyl acetate were added to separate the organic phase.
- Step 2 Synthesis of O'1,O1-(ethane-1,2-diyl)4-dimethyl(2S,2'S)-bis(2-aminosuccinate) hydrochloride
- Step 1 Synthesis of 1-(2-bromoethyl) 4-methyl(tert-butoxycarbonyl)-L-aspartic acid
- Step 2 Synthesis of 4-(2-((S)-2-(tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutanoyl)oxy)ethyl)1-methyl(tert- Butoxycarbonyl)-L-Aspartic Acid
- Step 3 Synthesis of 4-(2-(S)-2-amino-4-methoxy-4-oxobutanoyl)ethyl)1-methyl L-aspartate hydrochloride
- Ultra-clean workbench is irradiated with ultraviolet lamp for 30 minutes in advance; water bath is preheated at 37°C; complete medium is preheated at 37°C;
- LX2 cells were larger in size, and after adherence, the cells were pleomorphic, and mainly spindle-shaped. The refraction of the cells was better under the microscope, and the cell proliferation was obvious on the 2nd to 3rd day. According to the density and state of LX2 cells in the culture dish, replace the fresh cell culture medium. Note: Before changing the medium, put the fresh complete medium in a 37°C water bath and preheat it for 10-15 minutes. The negative pressure suction device sucks up the old medium, washes the cells twice with 4mL of 1 ⁇ PBS buffer, and then replaces with the preheated complete medium. Place in a 37°C incubator to continue culturing.
- Cell subculture When the cell confluence reaches about 90%, the cell subculture can be carried out.
- Digestion suck up the old medium with negative pressure suction device, wash the cells twice with 4mL of 1 ⁇ PBS buffer. Add 1mL of trypsin, shake the cell culture dish gently, so that the cells are completely infiltrated by the digestive solution;
- Termination of digestion Observe the cell shape under an inverted microscope. When the cells gradually become round from the spindle shape and the intercellular space gradually becomes obvious, quickly add 1 mL of DMEM complete medium containing 10% fetal bovine serum to terminate the digestion. Gently pipette the cells to dislodge all the cells from the cell culture plate. After blowing into a single-cell suspension, transfer to a 5mL glass flow tube, close the lid tightly, and centrifuge at 800rpm for 5min;
- Resuspension Discard the culture medium in the glass flow tube, lightly flick the flow tube with your fingers, after the cells pop up, add 2 mL of DMEM complete medium containing 10% fetal bovine serum to resuspend the cells, and gently pipette the tip of the pipette single cell suspension. According to 1:2 passaging or 5 ⁇ 10 5 /mL cell density plate, placed in the incubator to continue culturing.
- Each cell culture plate requires a total of 12 mL of medium, so 125 ⁇ L complete medium per well for a 96-well plate, 250 ⁇ L complete medium per well for a 48-well plate, 500 ⁇ L complete medium per well for a 24-well plate, and 1 mL per well for a 12-well plate Complete culture medium, 2mL complete culture medium per well of 6-well plate. Gently shake the cell culture plate with the conventional "cross" method to ensure that the cells are evenly spread on the cell culture plate;
- Protein denaturation Take 100 ⁇ g samples respectively, make up the volume of each sample with protein lysate, add 1/3 of the total volume of 4 ⁇ loading buffer, mix well, denature at 99°C for 10 minutes, centrifuge and store at -80°C.
- Electrotransfer activate the PVDF membrane by immersing it in anhydrous methanol for 1 min; put the transfer clip with the black side down, and place the sea surface-filter paper-PAGE glue-PVDF membrane-filter paper-sponge in order from bottom to top, and carefully drive out the glue/membrane and Bubbles between the filter papers, fasten the transfer clip, put it into the transfer tank, the PAGE glue faces the negative electrode, and the PVDF membrane faces the positive electrode; put it into the ice box, pour the pre-cooled 1 ⁇ electrotransfer solution; adjust the power to 100V, Transfer to membrane for 1 ⁇ 1.5h.
- Membrane washing Recover the secondary antibody, take out the PVDF membrane, put it in 1 ⁇ TBST, and wash the membrane three times on a shaker, 10 minutes each time; when detecting phosphorylated proteins, the number of membrane washings and the washing time should be appropriately reduced.
- the test compound was added to LX-2 cells, and the total RNA in the cells was extracted after 48 hours. This experiment was carried out in strict accordance with the instructions of the Total RNA Kit kit. gun head):
- step 6) Repeat step 6) once, centrifuge at 4°C, 12000g, 90sec, discard the waste liquid after centrifugation, and keep the collection column;
- the obtained product is cDNA, which can be directly used for subsequent Q-PCR experiments or stored at -20°C.
- the 7500 system uses the following two-step standard amplification procedure:
- mice in the carbon tetrachloride group intraperitoneally inject the total amount of carbon tetrachloride 0.5 ⁇ L/g, diluted with corn oil to 10 ⁇ L/g, 3 times/week. After 4 weeks of modeling, the carbon tetrachloride group was randomly divided into groups, plus the negative control group:
- 1Mice in the negative control group intraperitoneally injected with corn oil solution, 10 ⁇ L/g, 3 times/week; at the same time, 200 ⁇ L of drinking water was administered orally.
- mice in the carbon tetrachloride group intraperitoneally inject 0.5 ⁇ L/g of total carbon tetrachloride, 10 ⁇ L/g diluted with corn oil, 3 times/week; orally with 200 ⁇ L normal saline.
- 4Treatment group mice intraperitoneal injection of 0.5 ⁇ L/g of carbon tetrachloride in total, 10 ⁇ L/g diluted with corn oil, 3 times/week; different doses of the compound of the present invention were gavaged.
- HFD 50% high fat
- CHOL 50% high fat + 1.25% cholesterol
- the blood was collected by picking the eyeballs, and about 1 mL of whole blood was collected in an anticoagulant tube, and immediately placed on ice. 4°C, 3000rpm, centrifuge for 15min. Take about 0.4ml of the supernatant into an EP tube, be careful not to absorb the lower liquid, and then store it in a -80°C refrigerator to detect biochemical indicators such as blood lipids and transaminases. Mice were euthanized, and fresh liver tissues were taken and weighed.
- One part was placed in a cryopreservation tube and stored in liquid nitrogen for later use; the other part was fixed in 4% paraformaldehyde solution for 16h to 24h, and histological HE staining and oil red O Staining to determine the severity of fatty liver.
- 3Transparency Put the dehydrated tissue into 50% xylene (equal volume of xylene and ethanol), 100% xylene, and 100% xylene for 20 minutes each for transparency treatment;
- Wax immersion put the transparent tissue into paraffin at 60°C, change the paraffin every 1 hour, a total of four times, pay attention to use new paraffin;
- H&E staining hematoxylin eosin staining
- 4Staining cell nuclei put the rehydrated tissue slices into the hematoxylin solution and stain for about 3-5 minutes, the specific time depends on the observation under the microscope; wash the slices in tap water twice, each tens of seconds;
- 5Differentiation put the slice into 1% hydrochloric acid ethanol solution (70% ethanol preparation) to differentiate for tens of seconds, and control the time under the microscope until the nucleus staining is clear;
- 10Seal the slide add an appropriate amount of neutral gum to the tissue, cover the slide with a cover glass, and avoid air bubbles.
- Masson staining is one of the classic and authoritative staining methods in collagen fiber staining. Collagen fibers appear red. The staining steps are as follows:
- Routine baking, dewaxing (the steps are the same as before); oxidation of potassium permanganate solution for 5 minutes, washing with water; dyeing with Masson dye solution for 5 minutes; 0.2% acetic acid solution for 2-3 seconds; 5% phosphotungstic acid solution for 5 minutes; aniline blue solution for 7 minutes; Washed 3 times with % acetic acid solution; conventional dehydration, permeable sealing, sealing, drying naturally, and storing at room temperature.
- Use the imaging system to collect images on tissue stained sections use the analysis software to automatically read the tissue measurement area, calculate the positive area and tissue area in the measurement area, and calculate the proportion of the positive area.
- the mouse serum was taken, and the relevant levels of ALT and AST in the serum were detected.
- the resulting product is cDNA, which can be directly used for subsequent Q-PCR experiments or stored at -20°C.
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Abstract
涉及式I以及式II的化合物及其在肝纤维化、非酒精性肝炎等代谢等疾病的治疗的应用;具体提供了所示的化合物,其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物在制备药物或试剂中的用途,所述药物用于以下的至少一种: A-(L1)x-A' (式I) A1-(L1)x-A1' (式II)。
Description
本发明涉及生物医药领域,具体涉及天冬氨酸的衍生物及其在肝纤维化、非酒精性肝炎等代谢等疾病的治疗的应用。
纤维化(fibrosis)可发生于多种组织器官,主要病理改变为器官组织内纤维结缔组织增多,实质细胞减少,持续进展可致器官结构破坏和功能减退,乃至衰竭,严重威胁人类健康和生命。在全世界范围内,组织纤维化是许多疾病致残、致死的主要原因,据美国有关统计资料证明,美国因各种疾病而致死的病人中,接近45%可以归于组织纤维增生疾病。
肝纤维化在组织纤维化患者中尤其常见,它是肝脏受损后,机体在修复过程中纤维结缔组织在肝组织中过度沉积的一种可逆性病理现象。肝纤维化的诱因有多种,各种慢性病毒性肝类疾病患者,都是肝纤维化、肝硬化最易发生的高危人群;酗酒或长期饮酒者初期发生脂肪肝,后期可发展为肝纤维化、肝硬化,其他如肥胖等非酒精性因素导致的脂肪肝,也可以发展为肝纤维化、肝硬化;另外,反复感染血吸虫容易引起门脉性肝纤维化;慢性胆汁淤积可产生胆汁性肝纤维化;肝豆状核变性和血色素沉积可产生代谢性肝纤维化;各种有毒物质可引起中毒性肝纤维化;喜好低蛋白饮食和偏爱肥肉煎炸食品的人可产生营养不良性肝纤维化;慢性充血性心衰患者可产生心源性肝纤维化。此外,肝纤维化也是非酒精性脂肪肝病(Nonalcoholic fatty liver disease,NAFLD)及非酒精性脂肪性肝炎(Nonalcoholic Steatohepatitis,NASH)的重要病理诊断指标。
肝纤维化的发生和发展机制十分复杂,目前研究主要围绕肝星状细胞的激活和转化,其可能途径是各种慢性刺激激活转化生长因子-β(Transforming growth factor beta,TGF-β)、血小板衍生生长因子(Platelet-derived growth factor,PDGF)、肿瘤坏死因子α(Tumour necrosis factor α,TNF-α)等介导的信号转导通路及前列腺素内氧化还原酶(cyclooxygenase-2,COX-2)、弥漫性细胞外基质(extracellular matrix,ECM)和氧化应激等激活肝星状细胞,使其转化为肌成纤维细胞和成纤维细胞导致细胞外基质分泌增多或降解减少,进而形成肝纤维化等。由于肝纤维化的发生和发展机制尚未明确,因此,治疗肝纤维化的药物开发进展比较缓慢。
目前临床对于病毒性肝炎(乙型肝炎或丙型肝炎为主)引起的肝纤维化或肝硬化的治疗,主要使用核苷(酸)类似物或者干扰素进行抗病毒治疗,通过抑制病毒复制,控制炎症因子的反应,减缓肝纤维化或肝硬化进展。但对于酒精性、代谢性、药物性等其他诱因引起的肝纤维化或肝硬化,尚无有效治疗手段,主要以中药或中成药进行辅助治疗。
通过抑制消减杂交和生物信息学方法,首次筛选并克隆了NS3TP1(HCV nonstructural protein 3-transactivated protein 1,NS3TP1),也被命名为ASNSD1(asparagine synthetase domain containing 1,ASNSD1),在GenBank中注册号为AY11696,位于人类2q32.2染色体上。该基因编码序列总长度为1,932个核苷酸,编码产物由643个氨基酸残基组成。NS3TP1广泛分布于体内,在肝内主要分布在肝细胞和胆囊腺上皮细胞中。Janine Meienberg等人通过MLPA分析发现完全COL3A1(编码collagen Ⅲ,主要肝纤维化细胞外基质沉积成分)半合子缺失会影响ASNSD1的表达,说明ASNSD1的表达可能与COL3A1相互作用。因此,NS3TP1调节剂的开发可作为NAFLD新药研发方向。
发明内容
本发明目的是:获得对NS3TP1有调节作用的化合物,获得对肝纤维化、非酒精性脂肪肝病有治疗效果的化合物。发明人通过创造性的研究发现,本发明的天冬氨酸衍生物对肝纤维化、非酒精性脂肪肝病有治疗效果,且这些分子具有较好的成药性(例如溶解度、AUC和/或口服生物利用度等性质)和安全性。
为此,在本发明的第一方面,本发明提供了下式I所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物在制备药物或试剂中的用途,所述药物用于以下的至少一种:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、或炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达;
A-(L
1)
x-A’ (式I)
其中:
x选自0、1和2;
1)当x为0时,A’不存在;对于A,其中:
R
1和R
2各自独立选自下组基团:C1-C6烷基、-O-R
a1、-NR
a2R
a3;
R
3和R
4各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-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,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环基的基团取代;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)
n-(CO)-R
b1、-(C1-C6烷基)
n-(CO)-O-R
b2、-(C1-C6烷基)
n-O-(CO)-R
b3、-(C1-C6烷基)
n-O-(CO)-O-R
b4、-(C1-C6烷基)
n-(CO)-NR
b5R
b6、-(C1-C6烷基)
n-NR
b7-(CO)-R
b8、-(C1-C6烷基)
n-NR
b9-(CO)-O-R
b10,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
R
b1、R
b2、R
b3、R
b4、R
b5、R
b6、R
b7、R
b8、R
b9、R
b10各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)
n-(CO)-O-R
c1、-(C1-C6烷基)
n-O-(CO)-R
c2、-(C1-C6烷基)
n-O-(CO)-O-R
c3,所述烷基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代;
R
c1、R
c2、R
c3各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
L各自独立选自下组基团:不存在、O、NR
d5、C1-C6烷基、C2-C6烯基、C2-C6炔基;
R
e各自独立选自氢、氘、Na、K、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7 环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基的基团取代;
R
h各自独立选自下组基团:C1-C6烷基、-NHC(O)R
g1、-OC(O)R
g2、-OP(O)(ONa)
2、-NHC(O)OR
d6、-OC(O)OR
d7、-OC(O)NHR
d8;
R
d1、R
d2、R
d3、R
d4、R
d5、R
d6、R
d7、R
d8各自独立选自下组基团:氢、氘、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个R
f取代;
R
f各自独立选自卤素、C1-C6烷基、卤代C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、卤代C6-C10芳基、C3-C7环烷基、3-15元杂环基、-NR
g3R
g4、-OR
g5、-NHC(O)R
g6、-OC(O)R
g7;
R
g1、R
g2、R
g3、R
g4、R
g5、R
g6、R
g7各自独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
R
5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R
5选自氢、氨基;
Y为C或S;
y为0及0以上的整数;或者y选自0、1、2、3;再或者y为0或1;
n为0或1;
2)当x为1或者2时,A与A’相同或者不同,其中:
一个单元A的R
1、R
2、R
3、R
4中的任意一个通过L
1与相邻单元A’的R
1’、R
2’、R
3’、R
4’中的任意一个相连;
各L
1独立地选自下组的单元连接基团组成:不存在、O、S、羰基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-)、环烷基(或者C3-C7环烷基)、杂烷基(或者3-7元杂烷基;例如,-O-烷基-O-(或者-O-C1-C6烷基-O-)),其中烷基、环烷基、杂烷基任选地被一个或多个独立选自Z的基团取代;
Z各自独立选自下组基团:卤素、氨基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、卤代烷基(或者卤代C1-C6烷基)、环烷基(或者C3-C7环烷基)、芳基(或者C6-C12芳基)、杂环;
或者L
1选自:不存在、-CR’R”,其中R’和R”各自独立地为H、C1-C6烷基(或者C1-C3烷基);
再或者L
1选自:不存在、-CH
2-、-CH(CH
3)-、-C-(CH
3)
2;
对于A,其中:
R
1和R
2各自独立选自下组基团:C1-C6烷基、-O-、-O-R
a1、-NR
a2R
a3;
R
3和R
4各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-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,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)
n-(CO)-R
b1、-(C1-C6烷基)
n-(CO)-O-R
b2、-(C1-C6烷基)
n-O-(CO)-R
b3、-(C1-C6烷基)
n-O-(CO)-O-R
b4、-(C1-C6烷基)
n-(CO)-NR
b5R
b6、-(C1-C6烷基)
n-NR
b7-(CO)-R
b8、-(C1-C6烷基)
n-NR
b9-(CO)-O-R
b10,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
R
b1、R
b2、R
b3、R
b4、R
b5、R
b6、R
b7、R
b8、R
b9、R
b10各自独立选自下组基团:氢、 氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)
n-(CO)-O-R
c1、-(C1-C6烷基)
n-O-(CO)-R
c2、-(C1-C6烷基)
n-O-(CO)-O-R
c3,所述烷基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代;
R
c1、R
c2、R
c3各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
L各自独立选自下组基团:不存在、O、NR
d5、C1-C6烷基、C2-C6烯基、C2-C6炔基;
R
e各自独立选自氢、氘、Na、K、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基的基团取代;
R
h各自独立选自下组基团:C1-C6烷基、-NHC(O)R
g1、-OC(O)R
g2、-OP(O)(ONa)
2、-NHC(O)OR
d6、-OC(O)OR
d7、-OC(O)NHR
d8;
R
d1、R
d2、R
d3、R
d4、R
d5、R
d6、R
d7、R
d8各自独立选自下组基团:氢、氘、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个R
f取代;
R
f各自独立选自卤素、C1-C6烷基、卤代C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、卤代C6-C10芳基、C3-C7环烷基、3-15元杂环基、-NR
g3R
g4、-OR
g5、-NHC(O)R
g6、-OC(O)R
g7;
R
g1、R
g2、R
g3、R
g4、R
g5、R
g6、R
g7各自独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
R
5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R
5选自氢、氨基;
Y为C或S;
y为0及0以上的整数;或者y选自0、1、2、3;再或者y为0或1;
n为0或1;
对于A’,其中:
R
1’和R
2’各自独立选自下组基团:C1-C6烷基、-O-、-O-R
a1、-NR
a2R
a3;
R
3’和R
4’各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-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,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)
n-(CO)-R
b1、-(C1-C6烷基)
n-(CO)-O-R
b2、-(C1-C6烷基)
n-O-(CO)-R
b3、-(C1-C6烷基)
n-O-(CO)-O-R
b4、-(C1-C6烷基)
n-(CO)-NR
b5R
b6、-(C1-C6烷基)
n-NR
b7-(CO)-R
b8、-(C1-C6烷基)
n-NR
b9-(CO)-O-R
b10,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
R
b1、R
b2、R
b3、R
b4、R
b5、R
b6、R
b7、R
b8、R
b9、R
b10各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)
n-(CO)-O-R
c1、-(C1-C6烷基)
n-O-(CO)-R
c2、-(C1-C6烷基)
n-O-(CO)-O-R
c3,所述烷基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代;
R
c1、R
c2、R
c3各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6 烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
L各自独立选自下组基团:不存在、O、NR
d5、C1-C6烷基、C2-C6烯基、C2-C6炔基;
R
e各自独立选自氢、氘、Na、K、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基的基团取代;
R
h各自独立选自下组基团:C1-C6烷基、-NHC(O)R
g1、-OC(O)R
g2、-OP(O)(ONa)
2、-NHC(O)OR
d6、-OC(O)OR
d7、-OC(O)NHR
d8;
R
d1、R
d2、R
d3、R
d4、R
d5、R
d6、R
d7、R
d8各自独立选自下组基团:氢、氘、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个R
f取代;
R
f各自独立选自卤素、C1-C6烷基、卤代C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、卤代C6-C10芳基、C3-C7环烷基、3-15元杂环基、-NR
g3R
g4、-OR
g5、-NHC(O)R
g6、-OC(O)R
g7;
R
g1、R
g2、R
g3、R
g4、R
g5、R
g6、R
g7各自独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
R
5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R
5选自氢、氨基;
Y’为C或S;
y’为0及0以上的整数;或者y’选自0、1、2、3;再或者y’为0或1;
n为0或1;
或者式I为:
在一些实施方案中,在上述式I中,当x为0时,A’不存在;对于A,其中:
R
1和R
2各自独立选自下组基团:
C1-C6烷基,
-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)
n-(CO)-R
b1、-(C1-C6烷基)
n-(CO)-O-R
b2、-(C1-C6烷基)
n-O-(CO)-R
b3、-(C1-C6烷基)
n-O-(CO)-O-R
b4,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
-NR
a2R
a3,其中,R
a2、R
a3各自独立选自:氢、C1-C6烷基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基)
n-(CO)-R
b1、-(C1-C6烷基)
n-(CO)-O-R
b2、-(C1-C6烷基)
n-O-(CO)-R
b3、-(C1-C6烷基)
n-O-(CO)-O-R
b4、-(C1-C6烷基)
n-(CO)-NR
b5R
b6,所述烷基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
R
b1、R
b2、R
b3、R
b4、R
b5、R
b6各自独立选自下组基团:氢、羟基、氨基、C1-C6烷基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)
n-(CO)-O-R
c1、-(C1-C6烷基)
n-O-(CO)-R
c2、-(C1-C6烷基)
n-O-(CO)-O-R
c3,所述烷基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代;
R
c1、R
c2、R
c3各自独立选自下组基团:氢、羟基、氨基、C1-C6烷基、C3-C7环烷基。
在一些实施方案中,在上述式I中,当x为0时,A’不存在;对于A,其中:
R
1和R
2各自独立选自下组基团:
羟基,
C1-C6烷基,
-O-R
a1,其中,R
a1选自:任选地进一步被一个或多个C6-C10芳基取代的C1-C6烷基,C3-C7环烷基,C2-C6烯基,-(C1-C6烷基)
n-O-(CO)-O-R
b4,其中R
b4选自C1-C6烷基,n为1;
-NR
a2R
a3,其中,R
a2、R
a3各自独立选自:
氢,
C1-C6烷基,其中C1-C6烷基任选地进一步被一个或多个C6-C10芳基取代;
-(C1-C6烷基)
n-O-(CO)-R
b3,R
b3为C1-C6烷基,其进一步被C6-C10芳基取代;
-(C1-C6烷基)
n-(CO)-R
b1,R
b1为羟基,n或1;
-(C1-C6烷基)
n-(CO)-NR
b5R
b6,n为1,R
b5、R
b6各自独立为氢,或3-15元杂环基, 所述杂环进一步被一个或多个C1-C6烷基取代;
-(C1-C6烷基)
n-(CO)-O-R
b2,烷基被一个或多个C6-C10芳基取代,n为1,R
b2为C1-C6烷基或-(C1-C6烷基)
n-O-(CO)-O-R
c,R
c为C1-C6烷基。
在一些实施方案中,在上述式I中,当x为0时,A’不存在;对于A,其中:
R
3与R
4各自独立地选自:氢、羟基、C1-C6烷基、-(CO)-(L)
n-R
d2、-(CO)O-(L)
n-R
d3,所述烷基、芳基、杂环任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;
L各自独立选自下组基团:不存在、O、NR
d5、C1-C6烷基;
R
d5、R
d2、R
d3各自独立选自下组基团:氢、氨基、C1-C6烷基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、环烷基、芳基、杂环任选地被一个或多个R
f取代;
R
f各自独立选自氨基、卤素、C1-C6烷基、卤代C1-C6烷基、C6-C10芳基、卤代C6-C10芳基、C3-C7环烷基、3-15元杂环基。
在一些实施方案中,在上述式I中,当x为0时,A’不存在;对于A,其中:
R
3与R
4各自独立地选自:氢,
羟基,
C1-C6烷基,
-(CO)-(L)
n-R
d2:其中,(L)
n与R
d2的组合选项分别选自以下组合:
1)L为不存在,R
d2为C1-C6烷基,进一步被一个或多个R
f取代,R
f为氨基;
2)L为不存在,R
d2为H;
3)L为不存在,R
d2为C1-C6烷基;
4)L为不存在,R
d2为C1-C6烷基,进一步被一个或多个R
f取代,R
f选自C1-C6烷基、氨基;
5)L为不存在,R
d2为3-15元杂环基;
6)L为NR
d5,R
d5为C1-C6烷基,n为1,R
d2为H;
-(CO)O-(L)
n-R
d3:其中,(L)
n与R
d3的组合选项选自:L为不存在,R
d3为C1-C6烷基,其任选地进一步被一个或多个R
f取代,R
f选自C1-C6烷基、C6-C10芳基、多环芳香烃基(例如,芴基)。
在一些实施方案中,在上述式I中,当x为1或者2时,A与A’相同或者不同,其中
对于A,其中:
R
1和R
2各自独立选自下组基团:C1-C6烷基、-O-、-O-R
a1、-NR
a2R
a3;
R
3和R
4各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
R
5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R
5选自氢、氨基;再或者R
5选自氢;
Y为C;
y选自0、1、2、3;或者y为0或1。
在一些实施方案中,在上述式I中,当x为1或者2(或者x为1)时,A与A’相同或者不同,其中
对于A’,其中:
R
1’和R
2’各自独立选自下组基团:C1-C6烷基、-O-、-O-R
a1、-NR
a2R
a3;
R
3’和R
4’各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
R
5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R
5选自氢、氨基;再或者R
5选自氢;
Y’为C;
y’选自0、1、2、3;或者y为0或1。
在一些实施方案中,在上述式I中,当x为0时,A’不存在;对于A,其中:
R
1选自:
C1-C6烷基,
-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基)
n-O-(CO)-R
b3,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
-NR
a2R
a3,其中,R
a2、R
a3各自独立选自:氢、C1-C6烷基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基)
n-(CO)-R
b1、-(C1-C6烷基)
n-O-(CO)-R
b3,所述烷基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
R
b1、R
b3各自独立选自下组基团:氢、羟基、氨基、C1-C6烷基、C6-C10芳基,所述烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代。
在一些实施方案中,在上述式I中,当x为0时,A’不存在;对于A,其中:
R
1选自:羟基,
C1-C6烷基,
-O-R
a,其中,R
a1选自:任选地进一步被一个或多个C6-C10芳基取代的C1-C6烷基,C3-C7环烷基,C2-C6烯基,-(C1-C6烷基)
n-O-(CO)-O-R
b4,其中R
b4选自C1-C6烷基,n为1;
-NR
a2R
a3,其中,R
a2、R
a3各自独立选自:氢;C1-C6烷基,其任选地进一步被一个或多个C6-C10芳基取代;-(C1-C6烷基)
n-O-(CO)-R
b3,R
b3为C1-C6烷基,其进一步被C6-C10芳基取代;-(C1-C6烷基)
n-(CO)-R
b1,R
b1为羟基,n为1。
在一些实施方案中,在上述式I中,当x为0时,A’不存在;对于A,其中:
R
1选自:羟基、甲氧基、-OCH
2CH=CH
2、乙氧基、-OC(CH
3)
3、-OCH
2C
6H
5、- OC
6H
11、Trt-NH-、
CH
3-NH-、HOCOCH
2NH-、-OCH(CH
3)
2、-CH
3、
其中,Trt表示三苯甲基。
在一些实施方案中,在上述式I中,当x为0时,A’不存在;对于A,其中:
R
2选自:
C1-C6烷基,
-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C6-C10芳基,-(C1-C6烷基)
n-O-(CO)-O-R
b4,所述烷基、烯基、芳基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、-(C1-C6烷基)-(C6-C10芳基)的基团取代;
-NR
a2R
a3,其中,R
a2、R
a3各自独立选自:氢、C1-C6烷基、-(C1-C6烷基)
n-(CO)-R
b1、-(C1-C6烷基)
n-(CO)-O-R
b2、-(C1-C6烷基)
n-(CO)-NR
b5R
b6、3-15元杂环基,所述烷基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基的基团取代;
R
b1、R
b2、R
b4、R
b5、R
b6各自独立选自下组基团:氢、羟基、C1-C6烷基、C3-C7环烷基、-(C1-C6烷基)
n-O-(CO)-O-R
c3,所述环烷基任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代;
R
c3各自独立选自下组基团:氢、羟基、氨基、C1-C6烷基、C3-C7环烷基。
在一些实施方案中,在上述式I中,当x为0时,A’不存在;对于A,其中:
R
2选自:羟基,
-O-R
a1:其中,R
a1选自:任选地进一步被一个或多个C6-C10芳基取代的C1-C6烷基,C2-C6烯基,-(C1-C6烷基)
n-O-(CO)-O-R
b4,其中R
b4选自C1-C6烷基,n为1;
-NR
a2R
a3:R
a2、R
a3各自独立选自:氢;-(C1-C6烷基)
n-(CO)-NR
b5R
b6,n为1,R
b5、R
b6各自独立为氢,或3-15元杂环基,所述杂环进一步被一个或多个C1-C6烷基取代;-(C1-C6烷基)
n-(CO)-R
b1,n为1,R
b1为羟基;-(C1-C6烷基)
n-(CO)-O-R
b2,所述烷基被一个或多个C6-C10芳基取代,n为1,R
b2为C1-C6烷基或-(C1-C6烷基)
n-O-(CO)-O-R
c3,R
c3为C1-C6烷基。
在一些实施方案中,在上述式I中,当x为0时,A’不存在;对于A,其中:
R
3与R
4各自独立地选自:氢、羟基、Boc、Cbz、-CH
3、Fmoc、-COOCH
2C
6H
5、- COCH
2NH
2、-CHO、-COCH
3、
-COCH
2CH
3、-COCH(CH
3)
2、-COCH(CH
2)
2、-COOCH
3、-CON(CH
3)
2、-COCH(CH
3)(NH
2);其中,Boc表示叔丁氧羰基,Cbz表示苄氧羰基,Fmoc表示芴甲氧羰基。
在一些实施方案中,在上述式I中,当x为1时,A与A’相同或者不同,其中
对于A,其中:
R
1选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
1选自:-O-,羟基,-O-R
a:R
a为C1-C6烷基;
再或者,R
1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
Y为C;
y为0;
R
2选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
2选自:羟基,-O-,-O-R
a:R
a为C1-C6烷基;
再或者,R
2选自:羟基、-O-、甲氧基;
R
3与R
4各自独立地选自:氢、羟基、C1-C6烷基;
或者,R
3和R
4各自独立地为氢;
R
5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R
5选自氢、氨基;再或者R
5选自氢。
在一些实施方案中,在上述式I中,当x为1时,A与A’相同或者不同,其中
对于A’,其中:
R
1’选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
1选自:-O-,羟基,-O-R
a:R
a为C1-C6烷基;
再或者,R
1’选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
Y’为C;
y’为0;
R
2’选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
2’选自:羟基,-O-,-O-R
a:R
a为C1-C6烷基;
再或者,R
2’选自:羟基、-O-、甲氧基;
R
3’与R
4’各自独立地选自:氢、羟基、C1-C6烷基;
或者,R
3’和R
4’各自独立地为氢;
R
5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;
或者R
5’选自氢、氨基;
再或者R
5’选自氢。
在一些实施方案中,在上述式I中,当x为2时,A与A’相同或者不同,其中
一个单元A的R
1、R
2、R
3、R
4中的任意一个通过L
1与相邻单元A’的R
1’、R
2’、R
3’、R
4’中的任意一个相连;
各L
1独立地选自下组的单元连接基团组成:不存在、O、S、羰基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-)、环烷基(或者C3-C7环烷基)、杂烷基(或者3-7元杂烷基;例如,-O-烷基-O-(或者-O-C1-C6烷基-O-)),其中烷基、环烷基、杂烷基任选地被一个或多个独立选自Z的基团取代;
Z各自独立选自下组基团:卤素、氨基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、卤代烷基(或者卤代C1-C6烷基)、环烷基(或者C3-C7环烷基)、芳基(或者C6-C12芳基)、杂环;
或者L
1选自:不存在、-CR’R”,其中R’和R”各自独立地为H、C1-C6烷基(或者C1-C3烷基);
再或者L
1选自:不存在、-CH
2-、-CH(CH
3)-、-C-(CH
3)
2;
进而再或者,L
1选自:-CH
2-。
在一些实施方案中,在上述式I中,当x为2时,A与A’相同或者不同,其中
对于A,其中:
R
1选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
1选自:-O-,羟基,-O-R
a:R
a为C1-C6烷基;
再或者,R
1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
再进一步或者,R
1选自:甲氧基;
Y为C;
y为0;
R
2选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
2选自:羟基,-O-,-O-R
a:R
a为C1-C6烷基;
再或者,R
2选自:羟基、-O-、甲氧基;
再进一步或者,R
2选自:-O-;
R
3与R
4各自独立地选自:氢、羟基、C1-C6烷基;
或者,R
3和R
4各自独立地为氢;
R
5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R
5选自氢、氨基;再或者R
5选自氢。
在一些实施方案中,在上述式I中,当x为2时,A与A’相同或者不同,其中
对于A’,其中:
R
1’选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
1选自:-O-,羟基,-O-R
a:R
a为C1-C6烷基;
再或者,R
1’选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
再进一步或者,R
1’选自:甲氧基;
Y’为C;
y’为0;
R
2’选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
2’选自:羟基,-O-,-O-R
a:R
a为C1-C6烷基;
再或者,R
2’选自:羟基、-O-、甲氧基;
再进一步或者,R
2’选自:-O-;
R
3’与R
4’各自独立地选自:氢、羟基、C1-C6烷基;
或者,R
3’和R
4’各自独立地为氢;
R
5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;
或者R
5’选自氢、氨基;
再或者R
5’选自氢。
在一些实施方案中,本发明提供了下式I所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物在制备药物或试剂中的用途,所述药物用于以下的至少一种:
1)治疗、改善、或预防肝脏相关疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、或炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达;
A-(L
1)
x-A’ (式I)
其中:
x选自0、1、2;
1)当x为0时,A’不存在;
对于A,其中:
R
1和R
2各自独立选自下组基团:-O-R
a1、-NR
a2R
a3;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
2)当x为1或者2时,A与A’相同或者不同,其中:
一个单元A的R
1、R
2中的任意一个通过L
1与相邻单元A’的R
1’、R
2’中的任意一个相连;
各L
1独立地选自下组的单元连接基团组成:不存在、O、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烷基-O-(或者-O-C1-C6烷基-O-)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-);
对于A,其中:
R
1和R
2各自独立选自下组基团:-O-R
a1、-NR
a2R
a3;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
对于A’,其中:
R
1’和R
2’各自独立选自下组基团:-O-R
a1、-NR
a2R
a3;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
在一些实施方案中,在上述式I中,当x为0时,A’不存在;对于A,其中:
R
1各自独立选自下组基团:-O-R
a1、-NR
a2R
a3;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
或者,R
1各自独立选自下组基团:-OH、-O-(C1-C3烷基)、-O-(C1-C3烯基)、-NH
2、-NH(C1-C3烷基)、-N(C1-C3烷基)
2;
再或者,R
1各自独立选自下组基团:-OH、甲氧基、乙氧基、-OCH(CH
3)
2、-NH
2;
R
2各自独立选自下组基团:-O-R
a1、-NR
a2R
a3;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C3烷基、C2-C4烯基、C2-C4炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
或者,R
2各自独立选自下组基团:-OH、-O-(C1-C3烷基)、-O-(C1-C3烯基)、-NH
2、-NH(C1-C3烷基)、-N(C1-C3烷基)
2;
再或者,R
2各自独立选自下组基团:-OH、甲氧基、乙氧基、-OCH(CH
3)
2、-NH
2;
在一些实施方案中,在上述式I中,当x为1时,A与A’相同或者不同,其中:
一个单元A的R
1、R
2中的任意一个通过L
1与相邻单元A’的R
1’、R
2’中的任意一个相连;
各L
1独立地选自下组的单元连接基团组成:不存在、O、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烷基-O-(或者-O-C1-C6烷基-O-)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-);
或者L
1选自:不存在、烷基(或者C1-C3烷基)、烯基(或者C2-C3烯基);
再或者L
1选自:不存在、-CH
2-、-CH(CH
3)-、-C-(CH
3)
2;
进而再或者,L
1选自:-CH
2-。
在一些实施方案中,在上述式I中,当x为1时,A与A’相同或者不同,其中:
对于A,其中:
R
1选自:-O-,-O-R
a1,其中,R
a1选自:氢、C1-C3烷基、C2-C4烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
或者,R
1选自:-O-,羟基,-O-(C1-C3烷基);
再或者,R
1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
R
2选自:-O-,-O-R
a1,其中,R
a1选自:氢、C1-C3烷基、C2-C4烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
或者,R
2选自:-O-,羟基,-O-(C1-C3烷基);
再或者,R
2选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
在一些实施方案中,在上述式I中,当x为1时,A与A’相同或者不同,其中:
对于A’,其中:
R
1选自:-O-,-O-R
a1,其中,R
a1选自:氢、C1-C3烷基、C2-C4烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
或者,R
1选自:-O-,羟基,-O-(C1-C3烷基);
再或者,R
1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
R
2选自:-O-,-O-R
a1,其中,R
a1选自:氢、C1-C3烷基、C2-C4烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
或者,R
2选自:-O-,羟基,-O-(C1-C3烷基);
再或者,R
2选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
在一些实施方案中,在上述式I中,当x为2时,A与A’相同或者不同,其中:
一个单元A的R
1、R
2中的任意一个通过L
1与相邻单元A’的R
1’、R
2’中的任意一个相连;
各L
1独立地选自下组的单元连接基团组成:不存在、O、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烷基-O-(或者-O-C1-C6烷基-O-)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-);
或者L
1选自:不存在、烷基(或者C1-C3烷基)、烯基(或者C2-C3烯基);
再或者L
1选自:不存在、-CH
2-、-CH(CH
3)-、-C-(CH
3)
2;
进而再或者,L
1选自:-CH
2-。
在一些实施方案中,在上述式I中,当x为2时,A与A’相同或者不同,其中:
对于A,其中:
R
1选自:-O-,-O-R
a1,其中,R
a1选自:氢、C1-C3烷基、C2-C4烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
或者,R
1选自:-O-,羟基,-O-(C1-C3烷基);
再或者,R
1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
R
2选自:-O-,-O-R
a1,其中,R
a1选自:氢、C1-C3烷基、C2-C4烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
或者,R
2选自:-O-,羟基,-O-(C1-C3烷基);
再或者,R
2选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
在一些实施方案中,在上述式I中,当x为2时,A与A’相同或者不同,其中:
对于A’,其中:
R
1选自:-O-,-O-R
a1,其中,R
a1选自:氢、C1-C3烷基、C2-C4烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
或者,R
1选自:-O-,羟基,-O-(C1-C3烷基);
再或者,R
1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
R
2选自:-O-,-O-R
a1,其中,R
a1选自:氢、C1-C3烷基、C2-C4烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
或者,R
2选自:-O-,羟基,-O-(C1-C3烷基);
再或者,R
2选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2。
在本发明的第二方面,本发明提供了下式I-4所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物在制备药物或试剂中的用途,所述药物用于以下的至少一种:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、或炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达;
其中:
Rn
1和Rn
2各自独立选自下组基团:C1-C6烷基、-O-R
a4、-O-L2-O-R
a4、-NR
a5R
a6;
各R
a4独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C3-C7环烷基C1-C6烷基、C6-C10芳基、C6-C10芳基C1-C6烷基、3-15元杂环基、3-15元杂环基C1-C6烷基、C1-C6烷氧酰基、-(O=)C-CH
2-CH(NH
2)-COORm、-(O=)C-CH(NH
2)-CH
2-COORm、Ph-CH
2-CH(NH
2)-C(=O)-、NH
2-CH
2-C(=O)-、CH
3-CH(NH
2)-C(=O)-、RmOOC-(CH
2)
2-CH(NH
2)-C(=O)-、-C(=O)-(CH
2)
2-CH(NH
2)-COORm、RmOOC-CH(NH
2)-CH
2-S-S-CH
2-CH(NH
2)-C(=O)-、H
2N-CO-(CH
2)
2-CH(NH
2)-C(=O)-、*N=CH-NH-CH=*C-CH
2-CH(NH
2)-C(=O)-(或者
)、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)
2CH-CH
2-CH(NH
2)-C(=O)-;其中,Ph表示苯基,HO-p-Ph-CH
2-CH(NH
2)-C(=O)-表示对羟基苯甲基氨基甲基羰基;
R
a5和R
a6各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、3-15元杂环基氨酰基C1-C6烷基、Ph-CH
2-CH(COORm)-、-CH
2-COORm、-CH(COORm)-CH
2-COORm、-CH(CH
3)-COORm、RmOOC-(CH
2)
2-CH(COORm)-、-CH(COORm)-CH
2-S-S-CH
2-CH(NH
2)-COORm、H
2N-CO-(CH
2)
2-CH(COORm)-、*N=CH-NH-CH=*C-CH
2-CH(COORm)-(或者
)、HO-p-Ph-CH
2-CH(COORm)-、HO-CH
2-CH(COORm)-、CH
3-S-(CH
2)
2-CH(COORm)-、HN=C(NH
2)-NH-(CH
2)
3-CH(COORm)-、(CH
3)
2CH-CH
2-CH(COORm)-;
各Rm独立选自下组基团:氢、C1-C6烷基、C1-C6烷氧酰基-O-L3-;
L2和L3各自独立的选自下组基团:C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、3-7元杂烷基,L2和L3各自任选的被一个或多个独立选自卤素、氨基、羟基的基团取代;
Rn
3和Rn
4各自独立选自下组基团:氢、氘、羟基、H(C=O)-,C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、氨基酰基、C1-C6烷基酰基、C1-C6烷氧酰基、C1-C6烷氨基酰基,氨基C1-C6烷酰基、3-15元杂环基酰基、C3-C7环烷基酰基、C6-C10芳基C1-C6烷氧基酰基;
Y为C或S;
y为0、1、2或3。
在一些实施方案中,在上述式I-4中,Rn
1和Rn
2各自独立选自下组基团:C1-C6烷基、-O-R
a4、-O-L2-O-R
a4、-NR
a5R
a6;
各R
a4独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C3-C7环烷基C1-C6烷基、C6-C10芳基、C6-C10芳基C1-C6烷基、3-15元杂环基、3-15元杂环 基C1-C6烷基、C1-C6烷氧酰基、-(O=)C-CH
2-CH(NH
2)-COORm、Ph-CH
2-CH(NH
2)-C(=O)-、NH
2-CH
2-C(=O)-、CH
3-CH(NH
2)-C(=O)-、RmOOC-(CH
2)
2-CH(NH
2)-C(=O)-、RmOOC-CH(NH
2)-CH
2-S-S-CH
2-CH(NH
2)-C(=O)-、H
2N-CO-(CH
2)
2-CH(NH
2)-C(=O)-、*N=CH-NH-CH=*C-CH
2-CH(NH
2)-C(=O)-(或者
)、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)
2CH-CH
2-CH(NH
2)-C(=O)-;
R
a5和R
a6各自独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、3-15元杂环基氨酰基C1-C6烷基、Ph-CH
2-CH(COORm)-、-CH
2-COORm、-CH(COORm)-CH
2-COORm、-CH(CH
3)-COORm、RmOOC-(CH
2)
2-CH(COORm)-、-CH(COORm)-CH
2-S-S-CH
2-CH(NH
2)-COORm、H
2N-CO-(CH
2)
2-CH(COORm)-、*N=CH-NH-CH=*C-CH
2-CH(COORm)-(或者
)、HO-p-Ph-CH
2-CH(COORm)-、HO-CH
2-CH(COORm)-、CH
3-S-(CH
2)
2-CH(COORm)-、HN=C(NH
2)-NH-(CH
2)
3-CH(COORm)-、(CH
3)
2CH-CH
2-CH(COORm)-;
各Rm独立选自下组基团:氢、C1-C6烷基、C1-C6烷氧酰基-O-L3-;
L2和L3各自独立的选自下组基团:C1-C6烷基、C2-C6烯基、C3-C7环烷基、3-7元杂烷基,L2和L3各自任选的被一个或多个独立选自卤素、氨基、羟基的基团取代;
Rn
3和Rn
4各自独立选自下组基团:氢、羟基、H(C=O)-,C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、氨基酰基、C1-C6烷基酰基、C1-C6烷氧酰基、C1-C6烷氨基酰基,氨基C1-C6烷酰基、3-15元杂环基酰基、C3-C7环烷基酰基、C6-C10芳基C1-C6烷氧基酰基;
Y为C;
y为0、1或2。
在一些实施方案中,在上述式I-4中,Rn
1和Rn
2各自独立选自下组基团:C1-C6烷基、-O-R
a4、-O-L2-O-R
a4、-NR
a5R
a6;
各R
a4独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、C6-C10芳基C1-C6烷基、3-15元杂环基、3-15元杂环基C1-C6烷基、-(O=)C-CH
2-CH(NH
2)-COORm、Ph-CH
2-CH(NH
2)-C(=O)-、NH
2-CH
2-C(=O)-、CH
3-CH(NH
2)-C(=O)-、RmOOC-(CH
2)
2-CH(NH
2)-C(=O)-、RmOOC-CH(NH
2)-CH
2-S-S-CH
2-CH(NH
2)-C(=O)-、H
2N-CO-(CH
2)
2-CH(NH
2)-C(=O)-、*N=CH-NH-CH=*C-CH
2-CH(NH
2)-C(=O)-(或者
)、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)
2CH-CH
2-CH(NH
2)-C(=O)-;
R
a5和R
a6各自独立选自下组基团:氢、C1-C6烷基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、3-15元杂环基氨酰基C1-C6烷基、Ph-CH
2-CH(COORm)-、-CH
2-COORm、-CH(COORm)-CH
2-COORm、-CH(CH
3)-COORm、RmOOC-(CH
2)
2-CH(COORm)-、-CH(COORm)-CH
2-S-S-CH
2-CH(NH
2)-COORm、H
2N-CO-(CH
2)
2- CH(COORm)-、*N=CH-NH-CH=*C-CH
2-CH(COORm)-(或者
)、HO-p-Ph-CH
2-CH(COORm)-、HO-CH
2-CH(COORm)-、CH
3-S-(CH
2)
2-CH(COORm)-、HN=C(NH
2)-NH-(CH
2)
3-CH(COORm)-、(CH
3)
2CH-CH
2-CH(COORm)-;
各Rm独立选自下组基团:氢、C1-C6烷基、C1-C6烷氧酰基-O-L3-;
L2和L3各自独立的选自下组基团:C1-C6烷基,L2和L3各自任选的被一个或多个独立选自卤素、氨基、羟基的基团取代;
Rn
3和Rn
4各自独立选自下组基团:氢、羟基、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、氨基酰基、C1-C6烷基酰基、C1-C6烷氧酰基、C1-C6烷氨基酰基,氨基C1-C6烷酰基、3-15元杂环基酰基、C3-C7环烷基酰基、C6-C10芳基C1-C6烷氧基酰基;
Y为C;
y为0、1或2。
在本发明的第一方面和第二方面的一些实施方案中,式I或I-1、I-2、I-3或I-4所示的化合物选自以下:
在本发明的第一方面和第二方面的一些实施方案中,式I或I-1、I-2、I-3或I-4所示的化合物选自以下:
在本发明的第三方面,本发明提供了一种含有2-10个或者2-3个氨基酸的肽,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物在制备药物或试剂中的用途,
所述药物或试剂用于以下的至少一种:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、或炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达;
在所述肽中,至少一个氨基酸为天冬氨酸,当天冬氨酸具有游离羧基时,所述游离羧基任意的与C1-C6烷基-OH成酯;
任选的,所述氨基酸为天冬氨酸,苯丙氨酸、甘氨酸,丙氨酸、谷氨酸、胱氨酸、谷氨酰胺、组氨酸、酪氨酸、丝氨酸、蛋氨酸、精氨酸或亮氨酸;
或者,位于肽一侧的游离氨基酸为天冬氨酸,且任选地,该游离天冬氨酸的游离羧基任意的与C1-C6烷基-OH成酯;
任选的,其余氨基酸为天冬氨酸,苯丙氨酸、甘氨酸,丙氨酸、谷氨酸、胱氨酸、谷氨酰胺、组氨酸、酪氨酸、丝氨酸、蛋氨酸、精氨酸或亮氨酸。
在本发明的第四方面,本发明提供了上述式I所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或上述式I-4所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或上述第三方面所述的一种含有2-10个或者2-3个氨基酸的肽,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,
其用于以下的至少一种:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达。
在本发明的第五方面,本发明提供了获得以下效应的方法:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达;
其包括给予有需要的受试者治疗有效量的上述式I所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或上述式I-4所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或上述第三方面所述的一种含有2-10个或者2-3个氨基酸的肽,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、 同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物。
在本发明的上述第一方面至第五方面,
在一些实施方案中,所述肝纤维化包括不限于:慢性病毒性肝类疾病引起导致的肝纤维化、酗酒或长期饮酒引起导致的肝纤维化、肥胖等非酒精性因素引起导致的肝纤维化、反复感染血吸虫引起导致的门脉性肝纤维化、慢性胆汁淤积引起导致的胆汁性肝纤维化、肝豆状核变性和血色素沉积引起导致的代谢性肝纤维化、各种有毒物质引起导致的中毒性肝纤维化、喜好低蛋白饮食和偏爱肥肉煎炸食品导致的营养不良性肝纤维化、慢性充血性心衰导致的心源性肝纤维化。
在本发明的第六方面,本发明提供了药物组合物在制备药物中的用途,所述药物组合物包含上述式I所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或上述式I-4所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或上述第三方面所述的一种含有2-10个或者2-3个氨基酸的肽,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,所述药物用于以下的至少一种:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达。
在本发明的第七方面,本发明提供了药物组合物,其用于以下的至少一种:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达;
所述药物组合物包含上述式I所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或上述式I-4所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或上述第三方面所述的一种含有2-10个或者2-3个氨基酸的肽,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物。
在本发明的第八方面,本发明提供了获得以下效应的方法:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达;
其包括给予有需要的受试者治疗有效量的所述药物组合物,所述药物组合物包含上述式I所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或上述式I-4所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或上述第三方面所述的一种含有2-10个或者2-3个氨基酸的肽,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它 们的任意组合或混合物。
在本发明的上述第六方面至第八方面,
在一些实施方案中,所述肝纤维化包括不限于:慢性病毒性肝类疾病引起导致的肝纤维化、酗酒或长期饮酒引起导致的肝纤维化、肥胖等非酒精性因素引起导致的肝纤维化、反复感染血吸虫引起导致的门脉性肝纤维化、慢性胆汁淤积引起导致的胆汁性肝纤维化、肝豆状核变性和血色素沉积引起导致的代谢性肝纤维化、各种有毒物质引起导致的中毒性肝纤维化、喜好低蛋白饮食和偏爱肥肉煎炸食品导致的营养不良性肝纤维化、慢性充血性心衰导致的心源性肝纤维化。
在一些实施方案中,所述药物组合物还包含另外的活性成分:其他用于改善肝功能作用的氨基酸(包括但不限于丙氨酸、谷氨酸、胱氨酸、谷氨酰胺、甘氨酸、组氨酸、酪氨酸、丝氨酸、蛋氨酸、精氨酸、亮氨酸)、胆固醇吸收抑制剂(如依替米贝)、HSC活化增殖抑制剂(如吡非尼酮、氟非尼酮、Pegbelfermin)PCSK9抑制剂、PPAR激动剂(如吉非罗齐、非诺贝特、氯贝特、苯扎贝特、培马贝特、Elafibranor)、ACE抑制剂、CCR2/5抑制剂、TLR4抑制剂、LOXL2抑制剂、TIMP-1抑制剂、FXR激动剂、AT1R阻滞剂、NOX抑制剂、钙离子通道阻断剂、ARBs、利尿剂、肾素、GLP-1或其合成变体、胰岛素或其合成变体、二甲双胍、磺酰脲化合物、噻唑烷二酮(TZD)、SGLT2抑制剂、DPP-IV抑制剂、HMGCoA还原酶的抑制剂、前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(PCSK9)的抑制剂、吉卡宾(CI-1027)、ACC抑制剂、ApoC-III抑制剂、ACL-抑制剂(如贝派地酸)、处方鱼油、CETP抑制剂、熊去氧胆酸、奥贝胆酸、多烯磷脂酰胆碱、糖皮质激素、水飞蓟素、甘草酸类制剂(如异甘草酸镁注射液和甘草酸二铵肠溶胶囊)以及它们的组合。
在一些实施方案中,所述药物组合物还包含药学上可接受的载体或辅料。
在一些实施方案中,所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂或复方制剂。
在本发明的第九方面,本发明提供了式II所示的化合物,其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式,
A
1-(L
1)
x-A
1’
式II
x选自0、1和2;
1)当x为0时,A’不存在;对于A
1,其中:
R
a各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)
n-(CO)-R
b1、-(C1-C6烷基)
n- (CO)-O-R
b2、-(C1-C6烷基)
n-O-(CO)-R
b3、-(C1-C6烷基)
n-NR
b4-(CO)-R
b5、-(C1-C6烷基)
n-NR
b6-(CO)-O-R
b7,所述烷基、烯基、炔基、环烷基、芳基、杂环可选被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
R
b1、R
b2、R
b3、R
b4、R
b5、R
b6、R
b7各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;
R
3和R
4独立地选自:-COCH(CH
3)(NH
2)、氢、-COCH
2CH
3、氘、C1-C6烷基,所述烷基可选被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基、杂环的基团取代;
且满足以下条件:
或者R
3和R
4中至少之一为-COCH(CH
3)(NH
2)或-COCH
2CH
3;
R
3和R
4独立地选自:氢、-COCH
2CH
3和-COCH(CH
3)(NH
2),
且满足以下条件:
R
3和R
4独立地选自:氢、-COCH
2CH
3和-COCH(CH
3)(NH
2),
且满足以下条件:
2)当x为1时,A
1与A
1’相同或者不同,其中
一个单元A
1的R
1、R
2、R
3、R
4中的任意一个通过L
1与相邻单元A
1’的R
1’、R
2’、R
3’、R
4’中的任意一个相连;
各L
1独立地选自下组的单元连接基团组成:不存在、O、S、羰基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烷基-O-(或者-O-C1-C6烷基-O-)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-)、环烷基(或者C3-C7环烷基)、杂烷基(或者3-7元杂烷基),其中烷基、环烷基、杂烷基任选地被一个或多个独立选自Z的基团取代;
Z各自独立选自下组基团:卤素、氨基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、卤代烷基(或者卤代C1-C6烷基)、环烷基(或者C3-C7环烷基)、芳基(或者C6-C12芳基)、杂环;
或者L
1选自:不存在、-CR’R”,其中R’和R”各自独立地为H、C1-C6烷基(或者C1-C3烷基);
再或者L
1选自:不存在、-CH
2-、-CH(CH
3)-、-C-(CH
3)
2;
对于A
1,其中:
R
1和R
2各自独立选自下组基团:C1-C6烷基、-O-、-O-R
a1、-NR
a2R
a3;
R
3和R
4各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
1选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基)
n-O-(CO)-R
b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
再或者,R
1选自:-O-,羟基,-O-R
a:R
a为C1-C6烷基;
进而再或者,R
1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
或者,R
2选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基)
n-O-(CO)-R
b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
再或者,R
2选自:羟基,-O-,-O-R
a:R
a为C1-C6烷基;
进而再或者,R
2选自:羟基、-O-、甲氧基,
R
3与R
4各自独立地选自:氢、羟基、C1-C6烷基;
或者,R
3和R
4各自独立地为氢;
R
5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;
或者R
5选自氢、氨基;
再或者R
5选自氢;
Y为C;
y选自0、1、2、3;或者y为0或1;再或者y为0;
对于A
1’,其中:
R
1’和R
2’各自独立选自下组基团:C1-C6烷基、-O-、-O-R
a1、-NR
a2R
a3;
R
3’和R
4’各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
1’选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基)
n-O-(CO)-R
b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
再或者,R
1’选自:-O-,羟基,-O-R
a:R
a为C1-C6烷基;
进而再或者,R
1’选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
或者,R
2’选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基)
n-O-(CO)-R
b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
再或者,R
2’选自:羟基,-O-,-O-R
a:R
a为C1-C6烷基;
进而再或者,R
2’选自:羟基、-O-、甲氧基;
R
3’与R
4’各自独立地选自:氢、羟基、C1-C6烷基;
或者,R
3’和R
4’各自独立地为氢;
R
5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;
或者R
5’选自氢、氨基;
再或者R
5’选自氢;
Y’为C;
y’选自0、1、2、3;或者y为0或1;再或者y’为0;
3)当x为2时,A
1与A
1’相同或者不同,其中
一个单元A
1的R
1、R
2、R
3、R
4中的任意一个通过L
1与相邻单元A
1’的R
1’、R
2’、R
3’、R
4’中的任意一个相连;
各L
1独立地选自下组的单元连接基团组成:不存在、O、S、羰基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烷基-O-(或者-O-C1-C6烷基-O-)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-)、环烷基(或者C3-C7环烷基)、杂烷基(或者3-7元杂烷基),其中烷基、环烷基、杂烷基任选地被一个或多个独立选自Z的基团取代;
Z各自独立选自下组基团:卤素、氨基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、卤代烷基(或者卤代C1-C6烷基)、环烷基(或者C3-C7环烷基)、芳基(或者C6-C12芳基)、杂环;
或者L
1选自:不存在、-CR’R”,其中R’和R”各自独立地为H、C1-C6烷基(或者C1-C3烷基);
再或者L
1选自:不存在、-CH
2-、-CH(CH
3)-、-C-(CH
3)
2;
进而再或者,L
1选自:-CH
2-;
对于A
1,其中:
R
1和R
2各自独立选自下组基团:C1-C6烷基、-O-、-O-R
a1、-NR
a2R
a3;
R
3和R
4各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
1选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基)
n-O-(CO)-R
b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
再或者,R
1选自:-O-,羟基,-O-R
a:R
a为C1-C6烷基;
进而再或者,R
1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
再进一步或者,R
1选自:甲氧基;
或者,R
2选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基)
n-O-(CO)-R
b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
再或者,R
2选自:羟基,-O-,-O-R
a:R
a为C1-C6烷基;
进而再或者,R
2选自:羟基、-O-、甲氧基,
再进一步或者,R
2选自:-O-;
R
3与R
4各自独立地选自:氢、羟基、C1-C6烷基;
或者,R
3和R
4各自独立地为氢;
R
5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;
或者R
5选自氢、氨基;
再或者R
5选自氢;
Y为C;
y选自0、1、2、3;或者y为0或1;再或者y为0;
对于A
1’,其中:
R
1’和R
2’各自独立选自下组基团:C1-C6烷基、-O-、-O-R
a1、-NR
a2R
a3;
R
3’和R
4’各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;
R
a1、R
a2、R
a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
或者,R
1’选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基)
n-O-(CO)-R
b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;
再或者,R
1’选自:-O-,羟基,-O-R
a:R
a为C1-C6烷基;
进而再或者,R
1’选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH
3)
2;
再进一步或者,R
1’选自:甲氧基;
或者,R
2’选自:-O-,C1-C6烷基,-O-R
a1,其中,R
a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基)
n-O-(CO)-R
b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷 基)-(3-15元杂环基)的基团取代;
再或者,R
2’选自:羟基,-O-,-O-R
a:R
a为C1-C6烷基;
进而再或者,R
2’选自:羟基、-O-、甲氧基;
再进一步或者,R
2’选自:-O-;
R
3’与R
4’各自独立地选自:氢、羟基、C1-C6烷基;
或者,R
3’和R
4’各自独立地为氢;
R
5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;
或者R
5’选自氢、氨基;
再或者R
5’选自氢;
Y’为C;
y’选自0、1、2、3;或者y为0或1;再或者y’为0;
或者式II为:
在一些实施方案中,式II或II-1、II-2、II-3所示的化合物选自以下:
在本发明的第十方面,本发明提供了药物组合物,其包含上述式II所示的化合物,其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物。
在本发明的第十一方面,本发明提供了上述式II所示的化合物,其药学上可接受的盐、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,在制备药物或试剂中的用途,所述药物用于以下的至少一种:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、或炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达。
在本发明的第十二方面,本发明提供了药物组合物在制备药物或试剂中的用途,所述药物用于以下的至少一种:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、或炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达;
所述药物组合物包含上述式II所示的化合物,其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物。
在本发明的第十三方面,本发明提供了上述式II所示的化合物,其药学上可接受的盐、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物或上述包含式II所示的化合物,其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物的药物组合物,其用于以下的至少一种:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达。
在本发明的第十四方面,本发明提供了获得以下效应的方法:
1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);
2)减轻哺乳动物肝纤维化、肝脏脂肪变性、炎症;
3)抑制星状细胞的激活;
4)调节NS3TP1的表达;
其包括给予有需要的受试者治疗有效量的上述式II所示的化合物,其药学上可接受的盐、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或上述包含式II所示的化合物,其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物的药物组合物。
在本发明的上述第九方面至第十四方面,
在一些实施方案中,所述肝纤维化包括不限于:慢性病毒性肝类疾病引起导致的肝纤维化、酗酒或长期饮酒引起导致的肝纤维化、肥胖等非酒精性因素引起导致的肝纤维化、反复感染血吸虫引起导致的门脉性肝纤维化、慢性胆汁淤积引起导致的胆汁性肝纤维化、肝豆状核变性和血色素沉积引起导致的代谢性肝纤维化、各种有毒物质引起导致的中毒性肝纤维化、喜好低蛋白饮食和偏爱肥肉煎炸食品导致的营养不良性肝纤维化、慢性充血性心衰导致的心源性肝纤维化。
在一些实施方案中,所述药物组合物还包含另外的活性成分:其他用于改善肝功能作用的氨基酸(包括但不限于丙氨酸、谷氨酸、胱氨酸、谷氨酰胺、甘氨酸、组氨酸、酪氨酸、丝氨酸、蛋氨酸、精氨酸、亮氨酸)、胆固醇吸收抑制剂(如依替米贝)、HSC活化增殖抑制剂(如吡非尼酮、氟非尼酮、Pegbelfermin)PCSK9抑制剂、PPAR激动剂(如吉非罗齐、非诺贝特、氯贝特、苯扎贝特、培马贝特、Elafibranor)、ACE抑制剂、CCR2/5抑制剂、TLR4抑制剂、LOXL2抑制剂、TIMP-1抑制剂、FXR激动剂、AT1R阻滞剂、NOX抑制剂、钙离子通道阻断剂、ARBs、利尿剂、肾素、GLP-1或其合成变体、胰岛素或其合成变体、二甲双胍、磺酰脲化合物、噻唑烷二酮(TZD)、SGLT2抑制剂、DPP-IV抑制剂、HMGCoA还原酶的抑制剂、前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(PCSK9)的抑制剂、吉卡宾(CI-1027)、ACC抑制剂、ApoC-III抑制剂、ACL-抑制剂(如贝派地酸)、处方鱼油、CETP抑制剂、熊去氧胆酸、奥贝胆酸、多烯磷脂酰胆碱、糖皮质激素、水飞蓟素、甘草酸类制剂(如异甘草酸镁注射液和甘草酸二铵肠溶胶囊)以及它们的组合。
在一些实施方案中,所述药物组合物还包含药学上可接受的载体或辅料。
在一些实施方案中,所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂或复方制剂。
在本发明的以上各个方面及其实施方式中,
“C1-C6烷基”以及各种涉及“C1-C6烷基”的复合基团(例如,“卤代C1-C6烷基”)中的“C1-C6烷基”可以替换为“C1-C20烷基”、“C1-C12烷基”、“C1-C10烷基”、“C1-C8烷基”、“C1-C4烷基”、“C1-C3烷基”或“C1-C2烷基”;
“C2-C6烯基”以及各种涉及“C2-C6烯基”的复合基团中的“C2-C6烯基”可以替换为“C2-C12烯基”、“C2-C8烯基”或“C2-C4烯基”;
“C2-C6炔基”以及各种涉及“C2-C6炔基”的复合基团中的“C2-C6炔基”可以替换为“C2-C12炔基”、“C2-C8炔基”或“C2-C4炔基”;
“C3-C7环烷基”以及各种涉及“C3-C8环烷基”的复合基团中的“C3-C8环烷基”可以替换为“C3-C20环烷基”、“C3-C12环烷基”或“C3-C10环烷基”;
“C1-C6烷氧基”以及各种涉及其的复合基团中的“C1-C6烷氧基”可以替换为“C1-C20烷氧基”、“C1-C12烷氧基”或“C1-C10烷氧基”;
“C6-C10芳基”以及各种涉及其的复合基团中的“C6-C10芳基”可以替换为“C6-C12芳基”;
“3-7元杂烷基”以及各种涉及其的复合基团中的“3-7元杂烷基”可以替换为“2-14元杂烷基”;
“3-15元杂环基”以及各种涉及其的复合基团中的“3-15元杂环基”可以替换为“3-20元杂环基”、“3-12元杂环基”或“3-10元杂环基”。
图1显示化合物6、化合物47、化合物54对collagen Ⅰ和collagen Ⅲ蛋白表达的抑制作用;GAPDH(甘油醛-3-磷酸脱氢酶)作为对照。
其中,“con”表示对照孔,“P1”表示阳性对照孔(羟尼酮),“ASP-50”表示天冬氨酸 浓度为50μM;其余编号均为化合物编号-浓度(μM)的形式:“6-50”表示化合物6浓度为50μM,“6-100”表示化合物6浓度为100μM,“6-200”表示化合物6浓度为200μM;“47-50”表示化合物47浓度为50μM,“47-100”表示化合物47浓度为100μM,“47-200”表示化合物47浓度为200μM;“54-50”表示化合物54浓度为50μM,“54-100”表示化合物54浓度为100μM,“54-200”表示化合物54浓度为200μM。
图2显示化合物4、化合物6、化合物41、化合物47、化合物48、化合物52对α-SMA蛋白表达的抑制作用;GAPDH作为对照。
其中,“con”表示对照孔,“P1”表示阳性对照孔(羟尼酮),“ASP-50”表示天冬氨酸浓度为50μM;其余编号均为化合物编号-浓度(μM)的形式。
图3显示化合物50、化合物52、化合物54对FN蛋白表达的抑制作用;GAPDH作为对照。
其中,“con”表示对照孔,“P1”表示阳性对照孔(羟尼酮),“ASP-50”表示天冬氨酸浓度为50μM;其余编号均为化合物编号-浓度(μM)的形式。
图4显示化合物54、化合物77a、化合物78a对给予TGFβ刺激的LX2细胞的Collagen Ⅰ蛋白和α-SMA蛋白表达的抑制作用;GAPDH作为对照。
图5显示肝损伤小鼠模型的肝组织中NS3TP1表达的下降及不同剂量的化合物6对于肝损伤小鼠模型的肝组织中NS3TP1表达的调节作用,图中的“mpk”表示“mg per kg”。
图6显示腹腔注射四氯化碳后,给予化合物4、化合物6、化合物47、化合物54治疗后,小鼠肝组织的马松染色切片。
其中,“40×”表示显微镜放大倍数为40倍,“100×”表示显微镜放大倍数为100倍。
图7显示腹腔注射四氯化碳后,给予不同剂量的化合物6治疗后,小鼠肝组织的马松染色切片。
其中,“40×”表示显微镜放大倍数为40倍,“100×”表示显微镜放大倍数为100倍。
图8显示口服和注射化合物6后大鼠体内的化合物6浓度(上左)、口服和注射化合物6后大鼠体内的天冬氨酸的浓度(上右)、注射生理盐水后大鼠体内的化合物6的浓度(下左)、注射生理盐水后大鼠体内的天冬氨酸的浓度(下右)。
图9显示给予HFD饮食饲喂后,不同剂量的化合物6治疗后,小鼠肝组织的H&E染色切片。
其中,“100×”表示显微镜放大倍数为100倍,“200×”表示显微镜放大倍数为200倍。
图10显示给予CHOL饮食饲喂后,不同剂量的化合物6治疗后,小鼠肝组织的H&E染色切片。
其中,“100×”表示显微镜放大倍数为100倍,“200×”表示显微镜放大倍数为200倍。
下面详细描述本发明的实施例,下面描述的实施例是示例性的,旨在用于解释本发明,而不能理解为对本发明的限制。
本发明中,术语“有效量”或“治疗有效量”是指在合理的医学判断范围内,足以治疗或预防患者疾病但足够低地避免严重副作用(在合理的利益/风险比)的量。化合物的治疗有效量将根据所选择的具体化合物(例如考虑化合物的效力、有效性和半衰期)、所选择的给药途径、所治疗的疾病、所治疗的疾病的严重性、所治疗的患者的年龄、大小、体重和身体疾病、所治疗的患者的医疗史、治疗持续时间、并行疗法的性质、所需的治疗效果等因素发生变化,但仍可以由本领域技术人员常规确定。
本发明中,术语“哺乳动物”是指患有或有风险发生本文所述疾病的温血动物,包括但不限于豚鼠、狗、猫、大鼠、小鼠、仓鼠和灵长类动物,包括人。
另外需要指出,所述式I或式I-4或式II所示化合物、其立体异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物针对不同患者的特定使用剂量和使用方法决定于诸多因素,包括患者的年龄,体重,性别,自然健康状况,营养状况,药物的活性强度,服用时间,代谢速率,病症的严重程度以及诊治医师的主观判断。这里优选使用剂量介于0.001-1000mg/kg体重/天。
本发明式I或式I-4或式II所示化合物的药学上可接受的盐包括其无机或有机酸盐,以及无机或有机碱盐,本发明涉及上述盐的所有形式。其中包括但不限于:钠盐、钾盐、钙盐、锂盐、葡甲胺盐、盐酸盐,氢澳酸盐,氢腆酸盐,硝酸盐,硫酸盐,硫酸氢盐,磷酸盐,磷酸氢盐,乙酸盐,丙酸盐,丁酸盐,草酸盐,三甲基乙酸盐,己二酸盐,藻酸盐,乳酸盐,柠檬酸盐,酒石酸盐,琥珀酸盐,马来酸盐,富马酸盐,苦味酸盐,天冬氨酸盐,葡糖酸盐,苯甲酸盐,甲磺酸盐,乙磺酸盐,苯磺酸盐,对甲苯磺酸盐和双羟萘酸盐等。
本发明涉及的药物组合物可以包括药学上可接受的载体,载体包括但不限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血白蛋白,缓冲物质如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛脂。
本发明所述药物组合物可以根据不同给药途径而制备成各种形式。
根据本发明,所述的药物组合物可以以下面的任意方式施用:口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药、阴道用药、局部用药、非肠道用药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入、或借助一种外植储器用药。其中优选口服、腹膜内或静脉内用药方式。
当口服用药时,所述式I或式I-4或式II所示化合物、其立体异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物可制成任意口服可接受的制剂形式,包括但不限于片剂、胶囊、水溶液或水悬浮液。其中,片剂一般使用的载体包括乳糖和玉米淀粉,另外也可加入润滑剂如硬质酸镁。胶囊制剂一般使用的稀释剂包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要,以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当直肠用药时,所述式I或式I-4或式II所示化合物、其立体异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物一般可制成栓剂的形式,其通过将药物与一种适宜的非刺激性赋形剂混合而制得。该赋形剂在室温下呈现固体状态,而在直肠温度下熔化释出药物。该类赋形剂包括可可脂、蜂蜡和聚乙二醇。
当局部用药时,特别是治疗局部外敷容易达到的患面或器官,如眼睛、皮肤或下肠道神经性疾病时,所述式I或式I-4或式II所示化合物、其立体异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物可根据不同的患面或器官制成不同的局部用药制剂形式,具体说明如下:
当眼部局部施用时,所述式I或式I-4或式II所示化合物、其立体异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物可配制成一种微粉化悬浮液或溶液的制剂形式,所使用载体为等渗的一定pH的无菌盐水,其中可加入也可不加防腐剂如氯化苄基烷醇盐。此外对于眼用,也可将化合物制成膏剂形式如凡士林膏。
当皮肤局部施用时,所述式I或式I-4或式II所示化合物、其立体异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物可制成适当的软膏、洗剂或霜剂制剂形式,其中活性成分悬浮或溶解于一种或多种载体中。这里软膏即可使用的载体包括但不限于:矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水;洗剂或霜剂可使用的载体包括但不限于:矿物油、脱水山梨糖醇单硬脂酸酯、吐 温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
当下肠道局部施用时,所述式I或式I-4或式II所示化合物、其立体异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物可制成如上所述的直肠栓剂制剂或适宜的灌肠制剂形式,另外也可使用局部透皮贴剂。
所述式I或式I-4或式II所示化合物、其立体异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物还可以无菌注射制剂形式用药,包括无菌注射水或油悬浮液,或无菌注射溶液。其中,可使用的载体和溶剂包括水,林格氏溶液和等渗氯化钠溶液。另外,灭菌的非挥发油也可用作溶剂或悬浮介质,如单甘油酯或二甘油酯。
上述各种剂型的药物均可以按照药学领域的常规方法制备。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C1-C6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基,或者“C1-C4烷基”,或者“C1-C3烷基”。
另外,需要说明的是,除非以其他方式明确指出,在本文中通篇采用的描述方式“…各自独立选自”应做广义理解,其是指不同的符号之间所表达的具体选项之间互相不影响,可以相同,也可以不同。
“任选地”表示所提及的该情况可以为存在,也可以为不存在。例如,描述某一结构“任选地”被某些基团取代时,表示所述的“取代”可以存在,也可以不存在。
除非其他方面表明,本发明所描述的结构式包括所有的同分异构形式(如对映异构,非对映异构,和几何异构(或构象异构):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体,和(Z)、(E)的构象异构体。因此,本发明的化合物的单个立体化学异构体或其对映异构体,非对映异构体,或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明公开化合物的任何不对称原子(例如,碳等)都可以以外消旋或对映体富集的形式存在,例如(R)、(S)或(R,S)构型形式存在。在某些实施方案中,各不对称原子在(R)或(S)构型方面具有至少50%对映体过量,至少60%对映体过量,至少70%对映体过量,至少80%对映体过量,至少90%对映体过量,至少95%对映体过量,或至少99%对映体过量。
本发明所使用的术语“前药”,代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯,在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(C1 24)酯类,酰氧基甲基酯类,碳酸酯,氨基甲酸酯类和氨基酸酯类。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定,其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化、还原、水解、酰氨化、脱酰氨作用、酯化、脱脂作用、酶裂解等等方法得到。相应地,本发明包括化合物的代谢产物,包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括,但并不限于,水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸、氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
术语“卤素”和“卤代”在本发明中可互换使用,是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基(C1-C20烷基),其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是,烷基基团含有1-12个碳原子(C1-C12烷基);另外一些实施例是,烷基基团含有1-10个碳原子(C1-C10烷基);另外一些实施例是,烷基基团含有1-8个碳 原子(C1-C8烷基);另外一些实施例是,烷基基团含有1-6个碳原子(C1-C6烷基);另外一些实施例是,烷基基团含有1-4个碳原子(C1-C4烷基);另外一些实施例是,烷基基团含有1-3个碳原子(C1-C3烷基);另外一些实施例是,烷基基团含有1-2个碳原子(C1-C2烷基)。烷基基团更进一步的实例包括,但并不限于,甲基(Me,-CH
3)、乙基(Et,-CH
2CH
3)、正丙基(n-Pr,-CH
2CH
2CH
3)、异丙基(i-Pr,-CH(CH
3)
2)、正丁基(n-Bu,-CH
2CH
2CH
2CH
3)、2-甲基丙基或异丁基(i-Bu,-CH
2CH(CH
3)
2)、1-甲基丙基或仲丁基(s-Bu,-CH(CH
3)CH
2CH
3)、叔丁基(t-Bu,-C(CH
3)
3)、正戊基(-CH
2CH
2CH
2CH
2CH
3)、2-戊基(-CH(CH
3)CH
2CH
2CH
3)、3-戊基(-CH(CH
2CH
3)
2)、2-甲基-2-丁基(-C(CH
3)
2CH
2CH
3)、3-甲基-2-丁基(-CH(CH
3)CH(CH
3)
2)、3-甲基-1-丁基(-CH
2CH
2CH(CH
3)
2)、2-甲基-1-丁基(-CH
2CH(CH
3)CH
2CH
3)、正己基(-CH
2CH
2CH
2CH
2CH
2CH
3)、2-己基(-CH(CH
3)CH
2CH
2CH
2CH
3)、3-己基(-CH(CH
2CH
3)(CH
2CH
2CH
3))、2-甲基-2-戊基(-C(CH
3)
2CH
2CH
2CH
3)、3-甲基-2-戊基(-CH(CH
3)CH(CH
3)CH
2CH
3)、4-甲基-2-戊基(-CH(CH
3)CH
2CH(CH
3)
2)、3-甲基-3-戊基(-C(CH
3)(CH
2CH
3)
2)、2-甲基-3-戊基(-CH(CH
2CH
3)CH(CH
3)
2)、2,3-二甲基-2-丁基(-C(CH
3)
2CH(CH
3)
2)、3,3-二甲基-2-丁基(-CH(CH
3)C(CH
3)
3)、正庚基、正辛基,等等。
术语“C1-C6烷基”指的是任意的含有1-6个碳原子烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、叔戊基、正己基等。
术语“烯基”表示含有2-12个碳原子(C2-C12烯基),或2-8个碳原子(C2-C8烯基),或2-6个碳原子(C2-C6烯基),或2-4个碳原子(C2-C4烯基)的直链或支链的一价烃基,其中至少有一个位置的C-C为sp2双键,包括有“顺”、“反”或"Z"、"E"异构体,其中具体的实例包括,但并不限于,乙烯基(-CH=CH
2),丙烯基(-CH=CHCH
3)、烯丙基(-CH
2CH=CH
2)等等。
术语“C2-C6烯基”指的是任意的含有2-6个碳原子且含有至少一个双键的烯基,例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-戊烯基、1-己烯基等。
术语“炔基”表示含有2-12个碳原子(C2-C12炔基),或2-8个碳原子(C2-C8炔基),或2-6个碳原子(C2-C6炔基),或2-4个碳原子(C2-C4炔基)的直链或支链的一价烃基,其中至少有一个位置的C-C为sp三键,具体的实例包括,但并不限于,乙炔基(-C≡CH)、炔丙基(-CH
2C≡CH)、丙炔基(-C≡C-CH
3)、1-炔丁基(-CH
2CH
2C≡CH)、2-炔丁基(-CH
2C≡CCH
3)、3-炔丁基(-C≡CCH
2CH
3)等等。
术语“C2-C6炔基”指的是任意的含有2-6个碳原子且含有至少一个三键的炔基,例如乙炔基、2-丙炔基、4-戊炔基等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连,其中烷基基团具有如本发明所述的含义。除非另外详细说明,所述烷氧基基团含有1-12个碳原子,可以表示为C1-C12烷氧基。在一些实施方案中,烷氧基基团含有1-8个碳原子,可以表示为C1-C8烷氧基;在另一些实施方案中,烷氧基基团含有1-6个碳原子,可以表示为C1-C6烷氧基;在另一些实施方案中,烷氧基基团含有1-4个碳原子,可以表示为C1-C4烷氧基;在又一些实施方案中,烷氧基基团含有1-3个碳原子,可以表示为C1-C3烷氧基。烷氧基基团的实例包括,但并不限于,甲氧基(MeO、-OCH
3),乙氧基(EtO、-OCH
2CH
3),1-丙氧基(n-PrO、n-丙氧基、-OCH
2CH
2CH
3),2-丙氧基(i-PrO、i-丙氧基、-OCH(CH
3)
2),1-丁氧基(n-BuO、n-丁氧基、-OCH
2CH
2CH
2CH
3),2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH
2CH(CH
3)
2),2-丁氧基(s-BuO、s-丁氧基、-OCH(CH
3)CH
2CH
3),2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH
3)
3),1-戊氧基(n-戊氧基、-OCH
2CH
2CH
2CH
2CH
3),2-戊氧基(-OCH(CH
3)CH
2CH
2CH
3),3-戊氧基(-OCH(CH
2CH
3)
2),2-甲基-2-丁氧基(-OC(CH
3)
2CH
2CH
3),3-甲基-2-丁氧基(-OCH(CH
3)CH(CH
3)
2),3-甲基-l-丁氧基(-OCH
2CH
2CH(CH
3)
2),2-甲基-l-丁氧基(- OCH
2CH(CH
3)CH
2CH
3),等等。
术语“烷氨基”或“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”,其中氨基基团分别独立地被一个或两个烷基基团所取代,其中烷基基团具有如本发明所述的含义。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基,这样的实例包括,但并不限于,N-甲氨基,N-乙氨基,N,N-二甲氨基,N,N-二乙氨基等等。所述烷氨基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“卤代烷氧基”表示烷氧基基团被一个或多个卤素原子所取代,其中烷氧基基团具有如本发明所述的含义,这样的实例包含,但并不限于,-OCHF
2、-OCF
3、-OCHFCH
2F、-OCF
2CHF
2、-OCH
2CF
3、-OCHFCH
3、-OCH
2CH
2F、-OCF
2CH
3、-OCH
2CF
2CHF
2等。在一实施方案中,C1-C6卤代烷氧基包含氟取代的C1-C6烷氧基;在另一实施方案中,C1-C4卤代烷氧基包含氟取代的C1-C4烷氧基;在又一实施方案中,C1-C2卤代烷氧基包含氟取代的C1-C2烷氧基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子(即“C3-C20环烷基”),优选包含3至12个碳原子(即“C3-C12环烷基”),更优选包含3至10个碳原子(即“C3-C10环烷基”),最优选包含3至7个碳原子(即“C3-C8环烷基”)。单环环烷基(例如,“C3-C7环烷基”)的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基等;多环环烷基包括螺环、稠环和桥环的环烷基。
术语“卤代C1-C6烷基”是指C1-C6烷基骨架被一个或多个卤素取代所成的基团,例如,单氟甲基,二氟乙基,三氟甲基等。
术语“卤素”指的是氟、氯、溴、碘。
术语“C6-C12芳基”指的是具有6-12个碳原子的碳环芳族体系的基团。
术语“C6-C10芳基”指的是具有6-10个碳原子的碳环芳族体系的基团,例如苯基、萘基等。
术语“杂烷基”指的是直链或支链烷基(优选具有2至14个或者3至7个碳的烷基)中的一个或多个碳被独立选自S、O、P或N的杂原子替代(即“2-14元杂烷基”或“3-7元杂烷基”)。示例性杂烷基包括烷基醚、烷基胺、仲烷基胺、硫醚等。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子(即“3-20元杂环基”),其中一个或多个环原子为选自氮、氧或S(O)
m(其中
m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至15个环原子(即“3-15元杂环基”)或3至12个环原子(即“3-12元杂环基”),其中1~4个是杂原子;更优选环烷基环包含3至10个环原子(即“3-10元杂环基”)。单环杂环基(例如,3-7元杂环基)的非限制性实例包括吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“3-15元杂环基”指的是3-、4-、5-、6-和7-元直至15元饱和或部分不饱和碳环,其中一个或多个碳原子被杂原子例如氮、氧和硫替代。“3-15元杂环基”包括例如“3-7元杂环基”,其非限制性实例,例如硫杂环丁烷基、吡喃、吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、噻唑啉、噻唑烷、二氢呋喃、四氢呋喃、1,3-二氧戊环、哌啶、哌嗪、吗啉、吗啡啉基、四氢吡咯基、硫吗啉基等。
术语“多环芳香烃基”指的是1-2个C5-C6芳香环与1-2个芳香环或非芳香环稠合在一起形成的基团,其非限制性实例,例如茚基、萘基、菲基、芴基等。
复合结构如“-(C1-C6烷基)
n-O-(CO)-R
b3”,其指的是任意n个上述C1-C6烷基(如甲基、乙基)等,其通过氧(-O-)以及羰基(-(C=O)-)连接到R
b3。其他类似的复合结构的含义可以参照前述内容进行理解。
肽:一个氨基酸的氨基与另一个氨基酸的羧基缩合成肽;例如:C
#OOH-CH(N
#H
2)-CH
2-C
#OOH,可以通过一个、两个或三个#号标记的原子与其他氨基酸形成肽键。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构,除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,如
2H、
3H、
11C、
13C、
14C、
15N、
17O、
18O、
18F、
31P、
32P、
35S、
36Cl和
125I。
*N=CH-NH-CH=*C-CH
2-CH(NH
2)-C(=O)-中N与C有*号标记,表示的是*号标记的两个原子单键相连。
简写说明
Boc:叔丁氧羰基
Cbz:苄氧羰基
Ph:苯基
Fmoc:芴甲氧羰基
Trt:三苯甲基
HO-p-Ph-CH
2-CH(NH
2)-C(=O)-:对羟基苯甲基氨基甲基羰基
下面结合具体实施例对本发明进行进一步的解释说明。
部分已知化合物的购买来源
化合物 | CAS | 供应商 | 化合物 | CAS | 供应商 |
1 | 13726-67-5 | 毕得医药 | 24 | 7536-58-5 | 毕得医药 |
2 | 1152-61-0 | 毕得医药 | 25 | 4668-42-2 | 毕得医药 |
3 | 4226-18-0 | 毕得医药 | 26 | 98045-03-5 | 毕得医药 |
4 | 17812-32-7 | 毕得医药 | 27 | 132388-58-0 | 毕得医药 |
5 | 145038-52-4 | 毕得医药 | 28 | 4685-12-5 | 毕得医药 |
6 | 16856-13-6 | 毕得医药 | 29 | 19427-28-2 | 毕得医药 |
7 | 32213-95-9 | 毕得医药 | 30 | 997-55-7 | 毕得医药 |
8 | 59768-74-0 | 毕得医药 | 31 | 117833-18-8 | 毕得医药 |
9 | 145038-53-5 | 毕得医药 | 32 | 22839-61-8 | 毕得医药 |
10 | 144120-53-6 | 毕得医药 | 33 | 7175-34-0 | 毕得医药 |
11 | 146982-24-3 | 毕得医药 | 34 | 3790-52-1 | 毕得医药 |
12 | 16115-68-7 | 毕得医药 | 38 | 80863-62-3 | 京东 |
13 | 3057-74-7 | 毕得医药 | 39 | 13433-09-5 | 毕得医药 |
14 | 4125-93-3 | 毕得医药 | 40 | 85227-98-1 | 毕得医药 |
15 | 2673-19-0 | 毕得医药 | 41 | 1791-13-5 | 毕得医药 |
16 | 5545-52-8 | 毕得医药 | 42 | 52615-97-1 | 毕得医药 |
17 | 1676-90-0 | 毕得医药 | 43 | 23220-52-2 | 毕得医药 |
18 | 71989-14-5 | 毕得医药 | 44 | 34582-30-4 | 毕得医药 |
19 | 152548-66-8 | 毕得医药 | 45 | 6853-87-8 | 毕得医药 |
20 | 7362-93-8 | 毕得医药 | 46 | 207121-48-0 | 毕得医药 |
21 | 30925-18-9 | 毕得医药 | 47 | 56-86-0 | 毕得医药 |
22 | 2177-63-1 | 毕得医药 | 48 | 22839-47-0 | 毕得医药 |
23 | 112259-66-2 | 毕得医药 |
合成实施例
实施例1:化合物35的合成
步骤1:合成1-苄基4-乙基(叔丁氧基羰基)-L-天冬氨酸
将(S)-4-(苄氧基)-3-((叔丁氧基羰基)氨基)-4-氧代丁酸(1g,3.096mmol)溶解在二氯甲烷(10mL)中,向反应体系滴加乙酰氯(490mg,6.19mmol),反应液室温搅拌1小时。浓缩反应液,然后加二氯甲烷稀释,将上述液体滴加入无水乙醇(10ml),反应液室温搅拌1小时。检测反应完全后,水洗反应液,分离并干燥有机相,浓缩有机相得到1-苄基4-乙基(叔丁氧基羰基)-L-天冬氨酸900mg,MS m/z(ESI):352[M+H]
+。
步骤2:合成1-苄基4-乙基L-天冬氨酸
室温下,将1-苄基4-乙基(叔丁氧基羰基)-L-天冬氨酸(900mg,2.56mmol)溶解在乙酸乙酯(5mL)中,向反应体系加入氯化氢的乙酸乙酯溶液(2M)(7.7ml,15.38mmol),反应液在室温下反应1小时。TLC监测反应完全后,浓缩反应液得到1-苄基4-乙基L-天冬氨酸600mg。MS m/z(ESI):252[M+H]
+。
步骤3:合成4-乙基L-天冬氨酸
将1-苄基4-乙基L-天冬氨酸(600mg,2.39mmol)溶解在乙醇(5mL)中,加入钯碳(120mg),在氢气气氛下室温搅拌反应16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩滤液得到4-乙基L-天冬氨酸(化合物35)200mg。MS m/z(ESI):162[M+H]
+。
1H 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).
实施例2:化合物36的合成
步骤1:合成1-苄基4-异丙基(叔丁氧基羰基)-L-天冬氨酸
将(S)-4-(苄氧基)-3-((叔丁氧基羰基)氨基)-4-氧代丁酸(1g,3.096mmol)溶解在二氯甲烷(10mL)中,向反应体系滴加乙酰氯(490mg,6.19mmol),反应液室温搅拌1小时。浓缩反应液,加二氯甲烷稀释,将上述液体滴加至异丙醇(10ml),反应液室温搅拌1小时。TLC检测反应完全后,水洗反应液,分离并干燥有机相,浓缩有机相得到1-苄基4-异丙基(叔丁氧基羰基)-L-天冬氨酸850mg,MS m/z(ESI):366[M+H]
+。
步骤2:合成1-苄基4-异丙基L-天冬氨酸
室温下,将1-苄基4-异丙基(叔丁氧基羰基)-L-天冬氨酸(860mg,2.35mmol)溶解在乙酸乙酯(5mL)中,然后加入氯化氢的乙酸乙酯溶液(2M)(7.07ml,14.14mmol),该溶液在室温下反应1小时。TLC监测反应完全,浓缩反应液得到1-苄基4-异丙基L-天冬氨酸500mg。MS m/z(ESI):266[M+H]
+。
步骤3:合成4-异丙基L-天冬氨酸
将1-苄基4-异丙基L-天冬氨酸(500mg,1.88mmol)溶解在乙醇(5mL)中,加入钯碳(100mg),在氢气气氛下室温搅拌反应16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩滤液得到4-异丙基L-天冬氨酸(化合物36)200mg。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).
实施例3:化合物37的合成
步骤1:合成1-苄基4-(((异丙氧基羰基)氧基)甲基)(叔丁氧基羰基)-L-天冬氨酸
将(S)-4-(苄氧基)-3-((叔丁氧基羰基)氨基)-4-氧代丁酸(2g,6.19mmol),氯甲基异丙基碳酸酯(1.47g,9.29mmol)和碳酸钾(1.7g,12.38mmol)溶解在DMF(10mL)中,反应液室温搅拌16小时。反应完全后,加水稀释反应液,用乙酸乙酯萃取、盐水洗反应液,分离并干燥有机相,浓缩有机相得到1-苄基4-(((异丙氧基羰基)氧基)甲基)(叔丁氧基羰基)-L-天冬氨酸900mg。MS m/z(ESI):440[M+H]
+。
步骤2:合成(S)-2-((叔丁氧基羰基)氨基)-4-(((异丙氧基羰基)氧基)甲氧基)-4-氧代丁酸
将1-苄基4-(((异丙氧基羰基)氧基)甲基)(叔丁氧基羰基)-L-天冬氨酸(900mg,2.05mmol)溶解在甲醇(5mL)中,加入钯碳(180mg),在氢气气氛下室温搅拌反应16h。TLC监测反应完全后,用硅藻土过滤掉钯碳,浓缩滤液得到(S)-2-((叔丁氧基羰基)氨基)-4-(((异丙氧基羰基)氧基)甲氧基)-4-氧代丁酸500mg。MS m/z(ESI):350[M+H]
+。
步骤3:合成4-(((异丙氧基羰基)氧基)甲基)-L-天冬氨酸
室温下,将(S)-2-((叔丁氧基羰基)氨基)-4-(((异丙氧基羰基)氧基)甲氧基)-4-氧代丁酸(500mg,1.43mmol)溶解在乙酸乙酯(5mL)中,加入氯化氢的乙酸乙酯溶液(2M)(4.3ml,8.6mmol),该溶液在室温下反应1小时。TLC监测反应完全,浓缩反应液,加水稀释反应液,加入碳酸氢钠将溶液调节pH至中性。乙酸乙酯萃取混合物,分离有机相,有机相经无水硫酸钠干燥、减压浓缩得到4-(((异丙氧基羰基)氧基)甲基)-L-天冬氨酸(化合物37)100mg。
1H 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]
+.
实施例4:化合物49的合成
合成(S)-3-氨基-4-甲氧基-4-氧代丁酸盐酸盐
将(S)-3-氨基-4-甲氧基-4-氧代丁酸(100mg,0.68mmol)溶解于四氢呋喃(3ml)中,加入氯化氢的乙酸乙酯溶液(0.34ml,0.68mmol),室温搅拌30分钟后可见固体析出。过滤混合物取滤渣,干燥滤渣即得(S)-3-氨基-4-甲氧基-4-氧代丁酸盐酸盐(化合物49)80mg。
1H 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]
+.
实施例5:化合物50的合成
步骤1:合成4-苄基1-异丙基(叔丁氧羰基)-L-天冬氨酸
将(S)-4-(苄氧基)-2-((叔丁氧基羰基)氨基)-4-氧代丁酸(1g,3.096mmol)溶解在二氯甲烷(10mL)中,向反应体系滴加乙酰氯(490mg,6.19mmol),反应液室温搅拌1小时。浓缩反应液,加入二氯甲烷稀释,将上述液体滴加至异丙醇(10ml)中,反应液室温搅拌1小时。TLC检测反应完全后,水洗反应液,分离并干燥有机相,浓缩有机相得到4-苄基 1-异丙基(叔丁氧基羰基)-L-天冬氨酸840mg,MS m/z(ESI):366[M+H]
+。
步骤2:合成(S)-3-((叔丁氧基羰基)氨基)-4-异丙氧基-4-氧代丁酸
将4-苄基1-异丙基(叔丁氧基羰基)-L-天冬氨酸(840mg,2.3mmol)溶解在乙醇(5mL)中,加入钯碳(160mg),在氢气气氛下室温搅拌反应16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩滤液得到(S)-3-((叔丁氧基羰基)氨基)-4-异丙氧基-4-氧代丁酸300mg。MS m/z(ESI):276[M+H]
+。
步骤3:合成1-异丙基L-天冬氨酸盐酸盐
室温下,将(S)-3-((叔丁氧基羰基)氨基)-4-异丙氧基-4-氧代丁酸(300mg,1.1mmol)溶解在乙酸乙酯(5mL)中,向反应体系加入氯化氢的乙酸乙酯溶液(2M)(3.3ml,6.55mmol),该溶液在室温下反应1小时。TLC监测反应完全,浓缩反应液得到1-异丙基L-天冬氨酸盐酸盐(化合物50)130mg。
1H NMR(300MHz,DMSO-d6)δ13.00(s,1H),8.58(s,2H),4.97(p,J=6.3Hz,1H),4.19(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]
+.
实施例6:化合物51的合成
步骤1:合成4-苄基1-(((异丙氧基羰基)氧基)甲基)(叔丁氧基羰基)-L-天冬氨酸
将(S)-4-(苄氧基)-2-((叔丁氧基羰基)氨基)-4-氧代丁酸(10g,30.96mmol),氯甲基异丙基碳酸酯(5.65g,37.15mmol)和碳酸钾(8.54g,61.92mmol)溶解在DMF(100mL)中,反应液室温搅拌16小时。反应完全后,加水稀释反应液,用乙酸乙酯萃取、盐水洗涤反应液,分离并干燥有机相,浓缩有机相得到4-苄基1-(((异丙氧基羰基)氧基)甲基)(叔丁氧基羰基)-L-天冬氨酸4.2g。MS m/z(ESI):440[M+H]
+。
步骤2:合成(S)-3-((叔丁氧基羰基)氨基)-4-(((异丙氧基羰基)氧基)甲氧基)-4-氧代丁酸
将4-苄基1-(((异丙氧基羰基)氧基)甲基)(叔丁氧基羰基)-L-天冬氨酸(4.2g,9.57mmol)溶解在甲醇(50mL)中,加入钯碳(810mg),在氢气气氛下室温搅拌反应16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩滤液得到(S)-3-((叔丁氧基羰基)氨基)-4-(((异丙氧基羰基)氧基)甲氧基)-4-氧代丁酸3g。MS m/z(ESI):350[M+H]
+。
步骤3:合成1-(((异丙氧基羰基)氧基)甲基)L-天冬氨酸盐酸盐
室温下,将(S)-3-((叔丁氧基羰基)氨基)-4-(((异丙氧基羰基)氧基)甲氧基)-4-氧代丁酸(3g,8.60mmol)溶解在乙酸乙酯(30mL)中,加入氯化氢的乙酸乙酯溶液(2M)(25.8ml,51.58mmol),该溶液在室温下反应1小时。TLC监测反应完全,反应液浓缩,得到1-(((异丙氧基羰基)氧基)甲基)L-天冬氨酸盐酸盐(化合物51)1.2g。
1H 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=5.1Hz,2H),1.23(d,J=6.2Hz,6H).MS m/z(ESI):286[M+H]
+.
实施例7:化合物52的合成
合成4-(((异丙氧基羰基)氧基)甲基)-L-天冬氨酸盐酸盐
室温下,将(S)-2-((叔丁氧基羰基)氨基)-4-(((异丙氧基羰基)氧基)甲氧基)-4-氧代丁酸 (500mg,1.43mmol)溶解在乙酸乙酯(5mL)中,加入氯化氢的乙酸乙酯溶液(2M)(4.3ml,8.6mmol),该溶液在室温下反应1小时。TLC监测反应完全,浓缩反应液得到4-(((异丙氧基羰基)氧基)甲基)-L-天冬氨酸盐酸盐(化合物52)130mg。
1H 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]
+。
实施例8:化合物53的合成
步骤1:合成((异丙氧基羰基)氧基)甲基(叔丁氧基羰基)-L-苯丙氨酸
将(叔丁氧羰基)-L-苯丙氨酸(2g,7.55mmol)、氯甲基异丙基碳酸酯(1.38g,9.06mmol)和碳酸钾(2.08g,15.09mmol)溶解在DMF(10mL)中,反应液室温搅拌16小时。反应完全后,加水稀释反应液,用乙酸乙酯萃取、盐水洗反应液,分离并干燥有机相,浓缩得到((异丙氧基羰基)氧基)甲基(叔丁氧基羰基)-L-苯丙氨酸550mg。MS m/z(ESI):382[M+H]
+。
步骤2:合成((异丙氧基羰基)氧基)甲基L-苯丙氨酸盐酸盐
室温下,将((异丙氧基羰基)氧基)甲基(叔丁氧基羰基)-L-苯丙氨酸(550mg,1.44mmol)溶解在乙酸乙酯(5mL)中,然后加入氯化氢的乙酸乙酯溶液(2M)(4.33ml,8.66mmol),上述反应液在室温下反应1小时。TLC监测反应完全,反应液浓缩,得到((异丙氧基羰基)氧基)甲基L-苯丙氨酸盐酸盐416mg。MS m/z(ESI):318[M+H]
+。
步骤3:合成(S)-3-((叔丁氧基羰基)氨基)-4-(((S)-1-(((异丙氧基羰基)氧基)甲氧基)-1-氧代-3-苯基丙-2-基)氨基)-4-氧代丁酸叔丁酯
将((异丙氧基羰基)氧基)甲基L-苯丙氨酸盐酸盐(416mg,1.3mmol)、(S)-4-(叔丁氧基)-2-((叔丁氧基羰基)氨基)-4-氧代丁酸(416mg,1.44mmol)、HATU(994mg,2.62mmol)和DMAP(16mg,0.13mmol)溶解在DMF(5mL)中,滴加DIPEA(506mg,3.9mmol),室温搅拌反应2h。TLC监测反应完全后,加水稀释反应液,乙酸乙酯(5mL*2)萃取反应液,分离有机相,有机相经干燥、浓缩、色谱柱纯化得到(S)-3-((叔丁氧基羰基)氨基)-4-(((S)-1-(((异丙氧基羰基)氧基)甲氧基)-1-氧代-3-苯基丙-2-基)氨基)-4-氧代丁酸叔丁酯500mg。MS m/z(ESI):553[M+H]
+。
步骤4:合成(S)-3-氨基-4-(((S)-1-(((异丙氧基羰基)氧基)甲氧基)-1-氧代-3-苯基丙-2-基)氨基)-4-氧代丁酸盐酸盐
将(S)-3-((叔丁氧基羰基)氨基)-4-(((S)-1-(((异丙氧基羰基)氧基)甲氧基)-1-氧代-3-苯基丙-2-基)氨基)-4-氧代丁酸叔丁酯(500mg,0.91mmol)溶解在乙酸乙酯(5mL)中,加入氯化氢的乙酸乙酯溶液(2M)(2.72ml,5.43mmol),上述反应液在室温下反应1小时。TLC监测反应完全,浓缩反应液得到(S)-3-氨基-4-(((S)-1-(((异丙氧基羰基)氧基)甲氧基)-1-氧代-3-苯基丙-2-基)氨基)-4-氧代丁酸盐酸盐(化合物53)320mg。
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]
+.
实施例9:化合物54的合成
步骤1:合成1-(氯甲基)4-甲基(叔丁氧基羰基)-L-天冬氨酸
将Boc-L-天冬氨酸4-甲酯(1.2g,5.0mmol)及四丁基硫酸氢铵(84.0mg,0.3mmol)溶解于二氯甲烷(5mL)中,置于冰浴中搅拌冷却至0℃。按顺序向体系中滴加碳酸钾(2.7g,20.0mmol)的水(5mL)溶液和氯甲基氯磺酸酯(1.0g,6.0mmol)的二氯甲烷(5mL)溶液,搅拌并缓慢升温至室温搅拌过夜。TLC监测反应完成后,加入5mL二氯甲烷,水洗3次,分离有机相,有机相经无水硫酸钠干燥、过滤、浓缩、色谱柱纯化(EA/PE梯度洗脱,20:1~5:1)得到1-(氯甲基)4-甲基(叔丁氧基羰基)-L-天冬氨酸1.1g(无色油状物,产率83%)。
步骤2:合成4-二甲基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧羰基)氨基)琥珀酸酯)
将碘化钠(174mg,1.1mmol)、碳酸钾(276mg,2.0mmol)溶解于DMF(1.5mL)中,置于冰浴中搅拌冷却至0℃。将Boc-L-天冬氨酸4-甲酯(296.7mg,1.2mmol)溶解于DMF(1.0mL)中并滴入上述反应体系,置于冰浴中搅拌30分钟。将1-(氯甲基)4-甲基(叔丁氧基羰基)-L-天冬氨酸(295.7mg,1.0mmol)溶解于DMF(1.0mL)中并滴入反应体系,搅拌并缓慢升温至室温搅拌约过夜,TLC监测反应。原料反应完后,加入10mL水,用乙酸乙酯萃取3次后水洗3次,分离合并有机相,经无水硫酸钠干燥、过滤、浓缩、色谱柱纯化(EA/PE梯度洗脱,10:1~3:1)得到4-二甲基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧羰基)氨基)琥珀酸酯)60mg(白色固体,产率12%)。
步骤3:合成4-二甲基O'1,O1-亚甲基(2S,2'S)-双(2-氨基琥珀酸酯)盐酸盐
将4-二甲基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧羰基)氨基)琥珀酸酯)(1.0g,2.0mmol)溶解于二氯甲烷(6mL)中,置于冰浴中搅拌冷却至0℃,滴入2N盐酸乙酸乙酯溶液(12mL),搅拌并缓慢升温至室温搅拌约2小时,HPLC监测反应完成后,抽滤反应液,并用少量乙酸乙酯清洗滤饼,干燥滤饼得到4-二甲基O'1,O1-亚甲基(2S,2'S)-双(2-氨基琥珀酸酯)盐酸盐(化合物54)530mg(白色固体,产率60%)。
1H NMR(400MHz,CD
3OD),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]
+.
实施例10:化合物56的合成
其合成方法参照本文实施例9中化合物54的合成。将步骤1和步骤2中的Boc-L-天冬氨酸4-甲酯替换为N-叔丁氧羰基-L-天门冬氨酸1-甲酯可得到1-二甲基O'4,O4-亚甲基(2S,2'S)-双(2-氨基琥珀酸酯)盐酸盐(化合物56),收率46%,为白色固体。
1H NMR(400MHz,CD
3OD),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]
+.
实施例11:化合物57的合成
步骤1:合成1-(氯甲基)4-正丁基(叔丁氧基羰基)-L-天冬氨酸
将叔丁氧羰基-L-天冬氨酸-4-叔丁酯(2.3g,8.0mmol)以及四丁基硫酸氢铵(136mg,0.4mmol)溶解于二氯甲烷(8mL)中,置于冰浴中搅拌冷却至0℃。按顺序向反应体系中滴加碳酸钾(4.4g,32mmol)的水(8mL)溶液和氯甲基氯磺酸酯(1.7g,10.0.mmol)的二氯甲烷(8mL)溶液,搅拌并缓慢升温至室温搅拌过夜。TLC监测反应完成后,加入8mL二氯甲烷,水洗3次,分离有机相,有机相经无水硫酸钠干燥、过滤、浓缩、色谱柱纯化(EA/PE梯度洗脱,20:1~5:1)得到1-(氯甲基)4-正丁基(叔丁氧基羰基)-L-天冬氨酸1.4g(无色油状物,产率53%)。
步骤2:合成4-二正丁基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧羰基)氨基)琥珀酸酯)
将碘化钠(349mg,2.1mmol)、碳酸钾(552mg,4.0mmol)溶解于DMF(2mL)中,置于冰浴中搅拌冷却至0℃。将1-(氯甲基)4-正丁基(叔丁氧基羰基)-L-天冬氨酸(694.0mg,2.4mmol)溶解于DMF(2mL)中并滴入上述反应体系,置于冰浴中搅拌30分钟。将1-(氯甲基)4-正丁基(叔丁氧基羰基)-L-天冬氨酸(676.0mg,2.0mmo)溶解于DMF(2mL)中并滴入反应体系,搅拌并缓慢升温至室温搅拌约过夜。TLC监测反应完成后,加入10mL水,用乙酸乙酯萃取3次,分离并水洗有机相,有机相经合并、无水硫酸钠干燥、过滤、浓缩、色谱柱纯化(EA/PE梯度洗脱,10:1~3:1)得到4-二正丁基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧羰基)氨基)琥珀酸酯)619mg(白色固体,产率52%)。
步骤3:合成(3S,3'S)-4,4'-(亚甲基双(氧基))双(3-氨基-4-氧代丁酸)盐酸盐
将4-二正丁基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧羰基)氨基)琥珀酸酯)(295.0mg,0.5mmol)溶解于二氯甲烷(2mL)中,置于冰浴中搅拌冷却至0℃,滴入2N盐酸乙酸乙酯溶液(6mL),搅拌并缓慢升温至室温搅拌约2小时。HPLC监测反应完成后,抽滤反应液,用少量乙酸乙酯清洗滤饼,干燥滤饼,得到(3S,3'S)-4,4'-(亚甲基双(氧基))双(3-氨基-4-氧代丁酸)盐酸盐(化合物57)95mg(白色固体,产率61%)。
1H NMR(400MHz,CD
3OD),δ5.99(s,2H),4.16(t,J=4Hz,2H),3.05(m,4H).MS m/z(ESI):315[M+H]
+.
实施例12:化合物55的合成
其合成方法参照本文实施例11中化合物57的合成。将步骤1和步骤2中的叔丁氧羰基-L-天冬氨酸-4-叔丁酯替换为N-叔丁氧羰基-L-天冬氨酸1-叔丁酯可得到(2S,2'S)-4,4'-(亚甲基双(氧基))双(2-氨基-4-氧代丁酸)盐酸盐(化合物55),收率为54%,为白色固体。
1H NMR(400MHz,CD
3OD),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]
+.
实施例13:化合物58的合成
步骤1:合成二苄基丙酰-L-天冬氨酸
将L-天冬氨酸二苄酯(1g,3.19mmol)和丙酰氯(353mg,3.83mmol)溶解在二氯甲烷(10mL)中,向反应体系滴加三乙胺(0.88mL,6.39ml),反应液室温搅拌2h。向反应液中加适量水并用二氯甲烷萃取,分离有机相,有机相经水洗、干燥、浓缩、柱层析纯化得到二苄基丙酰-L-天冬氨酸980mg。MS m/z(ESI):370[M+H]
+。
步骤2:合成丙酰-L-天冬氨酸
将二苄基丙酰-L-天冬氨酸(200mg,0.54mmol)和钯碳(40mg)溶解在四氢呋喃(3mL)中,滴加两滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相得到丙酰-L-天冬氨酸(化合物58)80mg。
1H 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]
+.
实施例14:化合物59的合成
步骤1:合成二苄基异丁酰-L-天冬氨酸
将L-天冬氨酸二苄酯(1g,3.19mmol)和异丁酰氯(406mg,3.83mmol)溶解在二氯甲烷(10mL)中,然后滴加三乙胺(0.88mL,6.39ml),反应液室温搅拌2h。向反应液中加适量水并用二氯甲烷萃取,分离有机相,有机相经水洗、干燥、浓缩、柱层析纯化得到二苄基异丁酰-L-天冬氨酸960mg。MS m/z(ESI):384[M+H]
+。
步骤2:合成异丁酰-L-天冬氨酸
将二苄基异丁酰-L-天冬氨酸(200mg,0.52mmol)和钯碳(40mg)溶解在四氢呋喃(3mL)中,滴加两滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相得到异丁酰-L-天冬氨酸(化合物59)85mg。
1H 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]
+.
实施例15:化合物60的合成
步骤1:合成二苄基(环丙烷羰基)-L-天冬氨酸
将L-天冬氨酸二苄酯(1g,3.19mmol)和环丙基甲酰氯(398mg,3.83mmol)溶解在二氯甲烷(10mL)中,然后滴加三乙胺(0.88mL,6.39ml),反应液室温搅拌2h。向反应液中加适量水并用二氯甲烷萃取,分离有机相,有机相经水洗、干燥、浓缩、柱层析纯化得到二苄基(环丙烷羰基)-L-天冬氨酸480mg。MS m/z(ESI):382[M+H]
+。
步骤2:合成(环丙烷羰基)-L-天冬氨酸
将二苄基(环丙烷羰基)-L-天冬氨酸(200mg,0.52mmol)和钯碳(40mg)溶解在四氢呋喃(3mL)中,滴加两滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相得到(环丙烷羰基)-L-天冬氨酸(化合物60) 90mg。
1H 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]
+.
实施例16:化合物61的合成
步骤1:合成二苄基(甲氧基羰基)-L-天冬氨酸
将L-天冬氨酸二苄酯(1g,3.19mmol)和氯甲酸甲酯(360mg,3.83mmol)溶解在二氯甲烷(10mL)中,然后滴加三乙胺(0.88mL,6.39ml),反应液室温搅拌2h。向反应液中加适量水并用二氯甲烷萃取,分离有机相,有机相经水洗、干燥、浓缩、柱层析纯化二苄基(甲氧基羰基)-L-天冬氨酸600mg。MS m/z(ESI):372[M+H]
+。
步骤2:合成(甲氧基羰基)-L-天冬氨酸
将二苄基(甲氧基羰基)-L-天冬氨酸(500mg,1.35mmol)和钯碳(100mg)溶解在四氢呋喃(5mL)中,滴加两滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相得到(甲氧基羰基)-L-天冬氨酸(化合物61)130mg。
1H 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]
+.
实施例17:化合物62的合成
步骤1:合成二苄基(二甲氨基甲酰基)-L-天冬氨酸
将L-天冬氨酸二苄酯(1g,3.19mmol)和二甲氨基甲酰氯(411mg,3.83mmol)溶解在二氯甲烷(10mL)中,然后滴加三乙胺(0.88mL,6.39ml),反应液室温搅拌2h。向反应液中加适量水并用二氯甲烷萃取,分离有机相,有机相经水洗、干燥、浓缩、柱层析纯化得到二苄基(甲基氨基甲酰基)-L-天冬氨酸940mg。MS m/z(ESI):385[M+H]
+。
步骤2:合成(二甲基氨基甲酰基)-L-天冬氨酸
将二苄基(二甲基氨基甲酰基)-L-天冬氨酸(500mg,1.30mmol)和钯碳(100mg)溶解在四氢呋喃(5mL)中,滴加两滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相得到(二甲基氨基甲酰基)-L-天冬氨酸(化合物62)120mg。
1H 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]
+.
实施例18:化合物63的合成
步骤1:合成1-苄基4-甲基(叔丁氧羰基)-L-天冬氨酸
将(S)-2-((叔丁氧基羰基)氨基)-4-甲氧基-4-氧代丁酸(9g,36.44mmol),苄溴(7.47g,43.72mmol)和碳酸钾(10.06g,72.87mmol)溶解在DMF(10mL)中,反应液室温搅拌 16小时。反应完全后,加水稀释反应液,用乙酸乙酯萃取、盐水洗反应液,分离有机相,有机相经干燥、浓缩得到1-苄基4-甲基(叔丁氧羰基)-L-天冬氨酸9g。MS m/z(ESI):338[M+H]
+。
步骤2:合成1-苄基4-甲基L-天冬氨酸
室温下,将1-苄基4-甲基(叔丁氧羰基)-L-天冬氨酸(9g,26.71mmol)溶解在二氯甲烷(20mL)中,然后加入氯化氢的乙酸乙酯溶液(2M)(80ml,160.24mmol),该溶液在室温下反应1小时。监测反应完全,过滤收集析出固体得到1-苄基4-甲基L-天冬氨酸6g。MS m/z(ESI):238[M+H]
+。
步骤3:合成1-苄基4-甲基乙酰-L-天冬氨酸
将1-苄基4-甲基L-天冬氨酸(1g,4.22mmol)和乙酰氯(397mg,5.06mmol)溶解在二氯甲烷(10mL)中,然后滴加三乙胺(1.17mL,8.44ml),反应液室温搅拌2h。向反应液中加适量水并用二氯甲烷萃取,分离有机相,有机相经水洗、干燥、浓缩、柱层析纯化得到1-苄基4-甲基乙酰-L-天冬氨酸900mg。MS m/z(ESI):280[M+H]
+。
步骤4:合成4-甲基乙酰-L-天冬氨酸
将1-苄基4-甲基乙酰-L-天冬氨酸(900mg,3.23mmol)和钯碳(180mg)溶解在四氢呋喃(5mL)中,滴加两滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相,经柱层析纯化得到4-甲基乙酰-L-天冬氨酸(化合物63)50mg。
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]
+.
实施例19:化合物64的合成
步骤1:合成1-苄基4-甲基丙酰-L-天冬氨酸
将1-苄基4-甲基L-天冬氨酸(1g,4.22mmol)和丙酰氯(468mg,5.06mmol)溶解在二氯甲烷(10mL)中,然后滴加三乙胺(1.17mL,8.44ml),反应液室温搅拌2h。向反应液中加适量水并用二氯甲烷萃取,分离有机相,有机相经水洗、干燥、浓缩、柱层析纯化得到1-苄基4-甲基丙酰-L-天冬氨酸860mg。MS m/z(ESI):294[M+H]
+。
步骤2:合成4-甲基丙酰-L-天冬氨酸
将1-苄基4-甲基丙酰-L-天冬氨酸(860mg,2.93mmol)和钯碳(180mg)溶解在四氢呋喃(5mL)中,滴加两滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相,经柱层析纯化得到4-甲基丙酰-L-天冬氨酸(化合物64)65mg。
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]
+.
实施例20:化合物65的合成
步骤1:合成4-苄基1-甲基(叔丁氧羰基)-L-天冬氨酸
将(S)-2-((叔丁氧基羰基)氨基)-1-甲氧基-1-氧代丁酸(9g,36.44mmol),苄溴(7.47g, 43.72mmol)和碳酸钾(10.06g,72.87mmol)溶解在DMF(10mL)中,反应液室温搅拌16小时。反应完全后,加水稀释反应液,用乙酸乙酯萃取、盐水洗反应液,分离有机相,有机相经干燥、浓缩得到4-苄基1-甲基(叔丁氧羰基)-L-天冬氨酸12g。MS m/z(ESI):338[M+H]
+。
步骤2:合成4-苄基1-甲基L-天冬氨酸
室温下,将4-苄基1-甲基(叔丁氧羰基)-L-天冬氨酸(12g,35.6mmol)溶解在二氯甲烷(50mL)中,然后加入氯化氢的乙酸乙酯溶液(2M)(106ml,213.65mmol),该溶液在室温下反应1小时。监测反应完全,过滤收集析出固体得到4-苄基1-甲基L-天冬氨酸9g。MS m/z(ESI):238[M+H]
+。
步骤3:合成4-苄基1-甲基乙酰-L-天冬氨酸
将4-苄基1-甲基L-天冬氨酸(1g,4.22mmol)和乙酰氯(397mg,5.06mmol)溶解在二氯甲烷(10mL)中,然后滴加三乙胺(1.17mL,8.44ml),反应液室温搅拌2h。向反应液中加适量水并用二氯甲烷萃取,分离有机相,有机相经水洗、干燥、浓缩、柱层析纯化得到4-苄基1-甲基乙酰-L-天冬氨酸600mg。MS m/z(ESI):280[M+H]
+。
步骤4:合成1-甲基乙酰-L-天冬氨酸
将4-苄基1-甲基乙酰-L-天冬氨酸(600mg,2.15mmol)和钯碳(120mg)溶解在四氢呋喃(5mL)中,滴加两滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相,经柱层析纯化得到1-甲基乙酰-L-天冬氨酸(化合物65)40mg。
1H 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]
+.
实施例21:化合物66的合成
步骤1:合成4-苄基1-甲基丙酰-L-天冬氨酸
将4-苄基1-甲基L-天冬氨酸(1g,4.22mmol)和丙酰氯(468mg,5.06mmol)溶解在二氯甲烷(10mL)中,然后滴加三乙胺(1.17mL,8.44ml),反应液室温搅拌2h。向反应液中加适量水并用二氯甲烷萃取,分离有机相,有机相经水洗、干燥、浓缩、柱层析纯化得到4-苄基1-甲基丙酰-L-天冬氨酸650mg。MS m/z(ESI):294[M+H]
+。
步骤2:合成1-甲基丙酰-L-天冬氨酸
将4-苄基1-甲基丙酰-L-天冬氨酸(650mg,2.22mmol)和钯碳(130mg)溶解在四氢呋喃(5mL)中,滴加两滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相,经柱层析纯化得到1-甲基丙酰-L-天冬氨酸(化合物66)37mg。
1H 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]
+.
实施例22:化合物67的合成
步骤1:合成1-苄基4-甲基(叔丁氧羰基)-L-丙氨酰-L-天冬氨酸
将1-苄基4-甲基L-天冬氨酸(500mg,2.11mmol)、(叔丁氧羰基)-L-丙氨酸(479mg,2.5mmol)、HATU(962mg,2.53mmol)和DMAP(26mg,0.21mmol)溶解在DMF(5mL) 中,滴加DIPEA(506mg,3.9mmol)然后室温搅拌反应2h。监测反应完全后,加水稀释反应液,用乙酸乙酯(5mL*2)萃取反应液,有机相经水洗、干燥、浓缩、柱层析纯化得到1-苄基4-甲基(叔丁氧羰基)-L-丙氨酰-L-天冬氨酸400mg。MS m/z(ESI):409[M+H]
+。
步骤2:合成1-苄基4-甲基L-丙氨酰-L-天冬氨酸
将1-苄基4-甲基(叔丁氧羰基)-L-丙氨酰-L-天冬氨酸(400mg,0.98mmol)溶解在二氯甲烷(5mL)中,向反应体系中加入氯化氢的乙酸乙酯溶液(2M)(2.9ml,5.88mmol),该溶液在室温下反应1小时。监测反应完全,浓缩反应液得到1-苄基4-甲基L-丙氨酰-L-天冬氨酸100mg。MS m/z(ESI):309[M+H]
+
步骤3:合成(S)-2-((S)-2-氨基丙酰胺基)-4-甲氧基-4-氧代丁酸盐酸盐
将1-苄基4-甲基L-丙氨酰-L-天冬氨酸(100mg,0.32mmol)和钯碳(50mg)溶解在四氢呋喃(3mL)中,滴加一滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相,经柱层析纯化得到(S)-2-((S)-2-氨基丙酰胺基)-4-甲氧基-4-氧代丁酸盐酸盐(化合物67)20mg。
1H 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,J=7.0,2.9Hz,1H),3.59(d,J=8.2Hz,3H),2.83–2.69(m,2H),1.35(d,J=7.0Hz,3H).MS m/z(ESI):255[M+H]
+.
实施例23:化合物68的合成
步骤1:合成1-氯乙基磺酰氯
0℃下,10分钟内向氯甲酸1-氯乙酯(3.02mL,28.0mmol)的无水二氯甲烷(40mL)中的溶液中缓慢加入氯磺酸(3.72mL,56.0mmol)。将混合物在0℃的氮气氛围下搅拌4小时。向反应体系中加入冰水淬灭反应,用二氯甲烷(200mL)萃取。分离有机层,有机层经盐水溶液洗涤、无水硫酸钠干燥、浓缩得到1-氯乙基磺酰氯4.0g,为淡黄色液体。
步骤2:合成1-(1-氯乙基)4-甲基(叔丁氧基羰基)-L-天冬氨酸
将(S)-2-((叔丁氧羰基)氨基)-4-甲氧基-4-氧代丁酸、四丁基硫酸氢铵溶解于二氯甲烷中,置于冰浴中搅拌冷却至0℃。按顺序向反应体系中滴加碳酸钾的水溶液和1-氯乙基磺酰氯的二氯甲烷溶液,搅拌并缓慢升温至室温搅拌过夜。TLC监测反应完成后,加入二氯甲烷,水洗3次,分离有机相,有机相经无水硫酸钠干燥、过滤、浓缩、色谱柱纯化(EA/PE梯度洗脱,20:1~5:1)得到1-(1-氯乙基)4-甲基(叔丁氧基羰基)-L-天冬氨酸1.0g,为无色油状物。
步骤3:合成O'1,O1-(乙烷-1,1-二基)4-二甲基(2S,2'S)-双(2-((叔丁氧基羰基)氨基)琥珀酸酯)
将碘化钠、碳酸钾溶解于DMF中,置于冰浴中搅拌冷却至0℃。将Boc-L-天冬氨酸4-甲酯溶解于DMF中并滴入上述反应体系,置于冰浴中搅拌30分钟。将1-(1-氯乙基)4-甲基(叔丁氧基羰基)-L-天冬氨酸溶解于DMF中并滴入反应体系,搅拌并缓慢升温至室温搅拌约过夜,TLC监测反应。原料反应完后,加入10mL水,用乙酸乙酯萃取3次后水洗3次,分离合并有机相,经无水硫酸钠干燥、过滤、浓缩、色谱柱纯化(EA/PE梯 度洗脱,10:1~3:1)得到O'1,O1-(乙烷-1,1-二基)4-二甲基(2S,2'S)-双(2-((叔丁氧基羰基)氨基)琥珀酸酯)200mg,为白色固体。
步骤4:合成O'1,O1-(乙烷-1,1-二基)4-二甲基(2S,2'S)-双(2-氨基琥珀酸酯)盐酸盐
将O'1,O1-(乙烷-1,1-二基)4-二甲基(2S,2'S)-双(2-((叔丁氧基羰基)氨基)琥珀酸酯)溶解于二氯甲烷中,置于冰浴中搅拌冷却至0℃,滴入2N盐酸乙酸乙酯溶液,搅拌并缓慢升温至室温搅拌约2小时,HPLC监测反应完成后,抽滤反应液,并用少量乙酸乙酯清洗滤饼,干燥滤饼得到O'1,O1-(乙烷-1,1-二基)4-二甲基(2S,2'S)-双(2-氨基琥珀酸酯)盐酸盐(化合物68)105mg,为白色固体。MS m/z(ESI):357[M+H]
+.
实施例24:化合物69的合成
步骤1:合成4-二甲基O'1,O1-(丙烷-2,2-二基)(2S,2'S)-双(2-((((苄氧基)羰基)氨基)琥珀酸酯)
将(S)-2-(((苄氧基)羰基)氨基)-4-甲氧基-4-氧代丁酸、2,2-二溴丙烷溶解在乙腈中,滴加DIPEA,室温搅拌反应2h。监测反应完全后,加水稀释反应液,用乙酸乙酯萃取反应液,分离有机相,有机相经水洗、干燥、浓缩、柱层析纯化得到4-二甲基O'1,O1-(丙烷-2,2-二基)(2S,2'S)-双(2-((((苄氧基)羰基)氨基)琥珀酸酯)。
步骤2:合成4-二甲基O'1,O1-(丙烷-2,2-二基)(2S,2'S)-双(2-氨基琥珀酸酯)盐酸盐
将4-二甲基O'1,O1-(丙烷-2,2-二基)(2S,2'S)-双(2-((((苄氧基)羰基)氨基)琥珀酸酯)和钯碳溶解在四氢呋喃中,滴加一滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相,经柱层析纯化得到4-二甲基O'1,O1-(丙烷-2,2-二基)(2S,2'S)-双(2-氨基琥珀酸酯)盐酸盐(化合物69)。MS m/z(ESI):371[M+H]
+.
实施例25:化合物70的合成
步骤1:合成1-苄基4-乙基(叔丁氧基羰基)-L-天冬氨酸
将(S)-4-(苄氧基)-3-((叔丁氧基羰基)氨基)-4-氧代丁酸(5g)、EDCI、三乙胺、DMAP及乙醇加入二氯甲烷中,室温搅拌,TLC检测反应。检测反应完全后,向反应液中加入饱和碳酸氢钠溶液,分离有机层,有机层经无水硫酸钠干燥、过滤、浓缩、柱层析纯化得到1-苄基4-乙基(叔丁氧基羰基)-L-天冬氨酸4.8g。
步骤2:合成(S)-2-((叔丁氧羰基)氨基)-4-乙氧基-4-氧代丁酸
将1-苄基4-乙基(叔丁氧基羰基)-L-天冬氨酸(4.8g)和钯碳溶解在四氢呋喃中,滴加一滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相,经柱层析纯化得到(S)-2-((叔丁氧羰基)氨基)-4-乙氧基-4-氧代丁酸3.2g。
步骤3:合成1-((((S)-2-((叔丁基羰基)氨基)-4-乙氧基-4-氧代丁酰)氧基)甲基)4-甲基(叔丁氧羰基)-L-天冬氨酸
将碘化钠、碳酸钾溶解于DMF中,置于冰浴中搅拌冷却至0℃。将(S)-2-((叔丁氧羰基)氨基)-4-乙氧基-4-氧代丁酸(1.2g)溶解于DMF中并滴入上述反应体系,置于冰浴中 搅拌30分钟。将1-(氯甲基)4-甲基(叔丁氧基羰基)-L-天冬氨酸溶解于DMF中并滴入反应体系,搅拌并缓慢升温至室温搅拌约过夜,TLC监测反应。原料反应完后,加入水,用乙酸乙酯萃取3次后水洗3次,分离合并有机相,经无水硫酸钠干燥、过滤、浓缩、色谱柱纯化得到1-((((S)-2-((叔丁基羰基)氨基)-4-乙氧基-4-氧代丁酰)氧基)甲基)4-甲基(叔丁氧羰基)-L-天冬氨酸720mg。
步骤4:合成1-((((S)-2-氨基-4-乙氧基-4-氧代丁酰)氧基)甲基)4-甲基L-天冬氨酸盐酸盐
将1-((((S)-2-((叔丁基羰基)氨基)-4-乙氧基-4-氧代丁酰)氧基)甲基)4-甲基(叔丁氧羰基)-L-天冬氨酸(720mg)溶解于二氯甲烷中,置于冰浴中搅拌冷却至0℃,滴入2N盐酸乙酸乙酯溶液,搅拌并缓慢升温至室温搅拌约2小时,HPLC监测反应完成后,抽滤反应液,并用少量乙酸乙酯清洗滤饼,干燥滤饼得到1-((((S)-2-氨基-4-乙氧基-4-氧代丁酰)氧基)甲基)4-甲基L-天冬氨酸盐酸盐(化合物70)225mg。MS m/z(ESI):357[M+H]
+.
实施例26:化合物71的合成
步骤1:合成1-苄基4-异丙基(叔丁氧基羰基)-L-天冬氨酸
将(S)-4-(苄氧基)-3-((叔丁氧基羰基)氨基)-4-氧代丁酸(10g)、EDCI、三乙胺、DMAP及异丙醇加入二氯甲烷中,室温搅拌,TLC检测反应。检测反应完全后,向反应液中加入饱和碳酸氢钠溶液,分离有机层,有机层经无水硫酸钠干燥、过滤、浓缩、纯化得到1-苄基4-异丙基(叔丁氧基羰基)-L-天冬氨酸(8.8g)。
步骤2:合成(S)-2-((叔丁氧基羰基)氨基)-4-异丙氧基-4-氧代丁酸
将1-苄基4-异丙基(叔丁氧基羰基)-L-天冬氨酸(8.8g)和钯碳溶解在四氢呋喃中,滴加一滴浓盐酸,反应液在氢气气氛下室温搅拌16h。监测反应完全后,用硅藻土过滤掉钯碳,浓缩有机相,经柱层析纯化得到(S)-2-((叔丁氧羰基)氨基)-4-异丙氧基-4-氧代丁酸6.0g。
步骤3:合成1-((((S)-2-((叔丁氧基羰基)氨基)-4-异丙氧基-4-氧代丁酰基)氧基)甲基)4-甲基(叔丁氧基羰基)-L-天冬氨酸
将碘化钠、碳酸钾溶解于DMF中,置于冰浴中搅拌冷却至0℃。将(S)-2-((叔丁氧羰基)氨基)-4-异丙氧基-4-氧代丁酸(1.6g)溶解于DMF中并滴入上述反应体系,置于冰浴中搅拌30分钟。将1-(氯甲基)4-甲基(叔丁氧基羰基)-L-天冬氨酸溶解于DMF中并滴入反应体系,搅拌并缓慢升温至室温搅拌约过夜,TLC监测反应。原料反应完后,加入水,用乙酸乙酯萃取3次后水洗3次,分离合并有机相,经无水硫酸钠干燥、过滤、浓缩、色谱柱纯化得到1-((((S)-2-((叔丁氧基羰基)氨基)-4-异丙氧基-4-氧代丁酰基)氧基)甲基)4-甲基(叔丁氧基羰基)-L-天冬氨酸870mg。
步骤4:合成1-((((S)-2-氨基-4-异丙氧基-4-氧代丁酰基)氧基)甲基)4-甲基L-天冬氨酸盐酸盐
将1-((((S)-2-((叔丁氧基羰基)氨基)-4-异丙氧基-4-氧代丁酰基)氧基)甲基)4-甲基(叔丁氧基羰基)-L-天冬氨酸(570mg)溶解于二氯甲烷中,置于冰浴中搅拌冷却至0℃,滴入2N盐酸乙酸乙酯溶液,搅拌并缓慢升温至室温搅拌约2小时,HPLC监测反应完成后,抽滤反应液,并用少量乙酸乙酯清洗滤饼,干燥滤饼得到1-((((S)-2-氨基-4-异丙氧基-4-氧代丁酰基)氧基)甲基)4-甲基L-天冬氨酸盐酸盐(化合物71)140mg。MS m/z(ESI):371[M+H]
+.
实施例27:化合物72的合成
步骤1:合成1-(氯甲基)4-乙基(叔丁氧基羰基)-L-天冬氨酸
将(S)-2-((叔丁氧羰基)氨基)-4-乙氧基-4-氧代丁酸(3.2g)以及四丁基硫酸氢铵溶解于二氯甲烷中,置于冰浴中搅拌冷却至0℃。按顺序向反应体系中滴加碳酸钾的水溶液和1-氯甲基磺酰氯的二氯甲烷溶液,搅拌并缓慢升温至室温搅拌过夜。TLC监测反应完成后,加入二氯甲烷,水洗3次,分离有机相,有机相经无水硫酸钠干燥、过滤、浓缩、色谱柱纯化得到1-(氯甲基)4-乙基(叔丁氧基羰基)-L-天冬氨酸1.6g。
步骤2:合成4-二乙基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧基羰基)氨基)琥珀酸酯)
将碘化钠、碳酸钾溶解于DMF中,置于冰浴中搅拌冷却至0℃。将(S)-2-((叔丁氧羰基)氨基)-4-乙氧基-4-氧代丁酸溶解于DMF中并滴入上述反应体系,置于冰浴中搅拌30分钟。将1-(氯甲基)4-乙基(叔丁氧基羰基)-L-天冬氨酸(1.6g)溶解于DMF中并滴入反应体系,搅拌并缓慢升温至室温搅拌约过夜,TLC监测反应。原料反应完后,加入水,用乙酸乙酯萃取3次后水洗3次,分离合并有机相,经无水硫酸钠干燥、过滤、浓缩、色谱柱纯化得到4-二乙基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧基羰基)氨基)琥珀酸酯)850mg。
步骤3:合成(S)-2-((叔丁氧基羰基)氨基)-4-甲氧基-4-氧代丁酸盐酸盐
将4-二乙基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧基羰基)氨基)琥珀酸酯)(850mg)溶解于二氯甲烷中,置于冰浴中搅拌冷却至0℃,滴入2N盐酸乙酸乙酯溶液,搅拌并缓慢升温至室温搅拌约2小时,HPLC监测反应完成后,抽滤反应液,并用少量乙酸乙酯清洗滤饼,干燥滤饼得到(S)-2-((叔丁氧基羰基)氨基)-4-甲氧基-4-氧代丁酸盐酸盐(化合物72)174mg。MS m/z(ESI):371[M+H]
+.
实施例28:化合物73的合成
步骤1:合成1-(氯甲基)4-异丙基(叔丁氧基羰基)-L-天冬氨酸
将(S)-2-((叔丁氧羰基)氨基)-4-异丙氧基-4-氧代丁酸(4.0g)以及四丁基硫酸氢铵溶解于二氯甲烷中,置于冰浴中搅拌冷却至0℃。按顺序向反应体系中滴加碳酸钾的水溶液和1-氯甲基磺酰氯的二氯甲烷溶液,搅拌并缓慢升温至室温搅拌过夜。TLC监测反应完成后,加入二氯甲烷,水洗3次,分离有机相,有机相经无水硫酸钠干燥、过滤、浓缩、色谱柱纯化得到1-(氯甲基)4-异丙基(叔丁氧基羰基)-L-天冬氨酸4.0g。
步骤2:合成4-二异丙基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧基羰基)氨基)琥珀酸酯)
将碘化钠、碳酸钾溶解于DMF中,置于冰浴中搅拌冷却至0℃。将(S)-2-((叔丁氧羰 基)氨基)-4-异丙氧基-4-氧代丁酸溶解于DMF中并滴入上述反应体系,置于冰浴中搅拌30分钟。将1-(氯甲基)4-异丙基(叔丁氧基羰基)-L-天冬氨酸(2.5g)溶解于DMF中并滴入反应体系,搅拌并缓慢升温至室温搅拌约过夜,TLC监测反应。原料反应完后,加入水,用乙酸乙酯萃取3次后水洗3次,分离合并有机相,经无水硫酸钠干燥、过滤、浓缩、色谱柱纯化得到4-二异丙基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧基羰基)氨基)琥珀酸酯)1.3g。
步骤3:合成4-二异丙基O'1,O1-亚甲基(2S,2'S)-双(2-氨基琥珀酸酯)盐酸盐
将4-二异丙基O'1,O1-亚甲基(2S,2'S)-双(2-((叔丁氧基羰基)氨基)琥珀酸酯)(0.8g)溶解于二氯甲烷中,置于冰浴中搅拌冷却至0℃,滴入2N盐酸乙酸乙酯溶液,搅拌并缓慢升温至室温搅拌约2小时,HPLC监测反应完成后,抽滤反应液,并用少量乙酸乙酯清洗滤饼,干燥滤饼得到4-二异丙基O'1,O1-亚甲基(2S,2'S)-双(2-氨基琥珀酸酯)盐酸盐(化合物73)270mg。MS m/z(ESI):399[M+H]
+.
实施例29:化合物74的合成
其合成方法参照本文实施例9中化合物54的合成。将和步骤2中的Boc-L-天冬氨酸4-甲酯替换为N-叔丁氧羰基-L-天门冬氨酸1-甲酯可得到4-((((S)-2-氨基-4-甲氧基-4-氧代丁酰基)氧基)甲基)1-甲基L-天冬氨酸盐酸盐(化合物74),为白色固体。MS m/z(ESI):343[M+H]
+.
实施例30:化合物77a的合成
步骤1:合成O'1,O1-(乙烷-1,2-二基)4-二甲基(2S,2'S)-双(2-(叔丁氧羰基)氨基)丁二酸)
将乙二醇(0.3g,4.84mmol)、S-2-(叔丁氧羰基)氨基-4-甲氧基-4-氧代丁酸(2.5g,10.16mmol)、EDCI(2.32g,12.1mmol)、DIPEA(3.12g,24.2mmol)溶解在DMF(20mL)中,反应液在氮气气氛下室温搅拌2小时,反应完全后加入适量冰水和乙酸乙酯,分离出有机相,有机相经水洗、干燥、柱层析后(PE:EA=3:1)得到O'1,O1-(乙烷-1,2-二基)4-二甲基(2S,2'S)-双(2-(叔丁氧羰基)氨基)丁二酸)1.5g,MS(ESI):mass calcd.For C
22H
36N
2O
12 520.2m/z found 521.2[M+H]
+。
步骤2:合成O'1,O1-(乙烷-1,2-二基)4-二甲基(2S,2'S)-双(2-氨基琥珀酸酯)盐酸盐
室温下,将O'1,O1-(乙烷-1,2-二基)4-二甲基(2S,2'S)-双(2-(叔丁氧羰基)氨基)丁二酸)(1.5g,2.88mmol)溶解在二氯甲烷(20mL)中,然后冰浴下加入盐酸乙酸乙酯溶液(17.29mL,2M,34.58mmol),该溶液在室温下反应1小时,监测反应完全,倒掉上清液,固体干燥后得到O'1,O1-(乙烷-1,2-二基)4-二甲基(2S,2'S)-双(2-氨基琥珀酸酯)盐酸盐800mg,MS(ESI):mass calcd.For C
12H
20N
2O
8+2HCl,320.1m/z found 321.1[M+H]+。1H 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)。
实施例31:化合物78a的合成
步骤1:合成1-(2-溴乙基)4-甲基(叔丁氧羰基)-L-天冬氨酸
将S-2-(叔丁氧羰基)氨基-4-甲氧基-4-氧代丁酸(1.9g,7.68mmol)、2-溴乙醇(1.06g,8.45mmol)、EDCI(2.21g,11.53mmol)、DIPEA(3.82ml,23.05mmol)溶解在DMF(20mL)中,反应液在氮气气氛下室温搅拌2小时,反应完全后加入适量冰水和乙酸乙酯,分离出有机相,有机相经水洗、干燥、柱层析后(PE:EA=4:1)得到1-(2-溴乙基)4-甲基(叔丁氧羰基)-L-天冬氨酸1.1g,MS(ESI):mass calcd.For C
12H
20BrNO
6 353.0m/z found 354.0[M+H]
+。
步骤2:合成4-(2-((S)-2-(叔丁氧羰基)氨基)-4-甲氧基-4-氧代丁酰基)氧基)乙基)1-甲基(叔丁氧羰基)-L-天冬氨酸
将1-(2-溴乙基)4-甲基(叔丁氧羰基)-L-天冬氨酸(1g,2.82mmol)、(S)-3-(叔丁氧羰基)氨基-4-甲氧基-4-氧代丁酸(837mg,3.39mmol)、碘化钾(938mg,5.65mmol)、碳酸钾(780mg,5.65mmol)溶解在DMF(20mL)中,反应液在氮气气氛下室温搅拌2小时,反应完全后加入适量冰水和乙酸乙酯,分离出有机相。有机相经水洗、干燥、柱层析(PE:EA=3:1)后得到4-(2-((S)-2-(叔丁氧羰基)氨基)-4-甲氧基-4-氧代丁酰基)氧基)乙基)1-甲基(叔丁氧羰基)-L-天冬氨酸460mg,MS(ESI):mass calcd.For C
22H
36N
2O
12 520.2m/z found 521.2[M+H]
+。
步骤3:合成4-(2-(S)-2-氨基-4-甲氧基-4-氧代丁酰基)乙基)1-甲基L-天冬氨酸酯盐酸盐
室温下,将4-(2-((S)-2-(叔丁氧羰基)氨基)-4-甲氧基-4-氧代丁酰基)氧基)乙基)1-甲基(叔丁氧羰基)-L-天冬氨酸(460mg,0.88mmol)溶解在二氯甲烷(10mL)中,冰浴下向反应体系中加入盐酸乙酸乙酯溶液(5.3mL,2M,10.6mmol),该溶液在室温下反应1小时,监测反应完全,倒掉上清液,固体干燥后得到4-(2-(S)-2-氨基-4-甲氧基-4-氧代丁酰基)乙基)1-甲基L-天冬氨酸酯盐酸盐180mg,MS(ESI):mass calcd.For C
12H
20N
2O
8+2HCl,320.1m/z found 321.1[M+H]
+。
1H NMR(DMSO-d6)δ:8.87(br s,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)。
活性试验例
测试方法
(a)化合物的体外药效评价
1.LX2细胞复苏:
准备:超净工作台提前紫外线灯管照射30min;水浴锅37℃预热;完全培养基37℃预热;
超净工作台紫外消毒结束后,打开通风开关,用75%酒精棉球擦拭台面。准备10cm细胞培养皿,加入含10%胎牛血清的完全培养基7mL,盖上盖子备用;
等待水浴锅工作温度达到37℃后,从液氮罐中取出一支冻存的LX2细胞,快速转移至水浴锅中。高频度、低幅度摇晃冻存管,以确保冻存液快速融化,从而降低对细胞的损伤。观察冻存液接近完全融化时,快速取出冻存管,擦拭表面水分,用75%酒精消毒冻存管,擦拭干净冻存管封口膜处残存酒精,撕开封口膜。快速、轻柔吸出冻存液放入准备好的细胞培养皿中。“十”字法轻柔晃动细胞培养皿,确保细胞均匀铺于细胞培养皿。将培养皿置于37℃,5%CO
2孵箱。尽量靠近内部放置培养皿,以减少CO
2和温度波动。
2.细胞换液:
细胞复苏后,根据细胞生长状态、贴壁程度以及培养基的颜色,更换完全培养基。LX2细胞体积较大,贴壁后细胞呈多形性,且以梭形为主,显微镜下细胞折光性较好,第2~3天细胞增殖明显。根据培养皿中LX2细胞的密度、状态,更换新鲜细胞培养基。注意:换液前需要将新鲜完全培养基置于37℃水浴锅,预热10~15min。负压吸引装置吸干净旧培养基,1×PBS缓冲液4mL,清洗细胞2遍,之后换上预热好的完全培养基。 置于37℃孵箱,继续培养。
3.细胞传代:当细胞融合度达到90%左右时,即可进行细胞传代培养。
消化:负压吸引装置吸干净旧培养基,1×PBS缓冲液4mL,清洗细胞2遍。加入胰酶1mL,轻柔晃动细胞培养皿,从而使细胞被消化液完全浸润;
终止消化:倒置显微镜下观察细胞形态,当细胞慢慢从梭形开始变圆,细胞间隙逐渐变明显,迅速加入1mL含10%胎牛血清的DMEM完全培养基,以中止消化。轻轻吹打细胞,使细胞全部从细胞培养板脱落。吹打成单细胞悬液后,转移至5mL玻璃流式管,盖紧盖子,800rpm,5min离心;
重悬:弃去玻璃流式管中培养液,手指轻弹流式管,将细胞弹起后,加入2mL含10%胎牛血清的DMEM完全培养基重悬细胞,枪头轻柔吹打成后单细胞悬液。按1:2传代或5×10
5个/mL细胞密度分板,置于孵箱中继续培养。注意:每个细胞培养板共需要培养基12mL,因此96孔板每孔125μL完全培养基,48孔板每孔250μL完全培养基,24孔板每孔500μL完全培养基,12孔板每孔1mL完全培养液,6孔板每孔2mL完全培养液。常规“十字”法轻柔晃动细胞培养板,确保细胞均匀铺于细胞培养板;
4.蛋白免疫印迹检测蛋白水平表达
4.1细胞总蛋白提取:取出细胞,弃去原培养基,加入1~2mL 1×PBS,清洗两次,胰酶消化,弃去上清,轻轻弹起管底细胞,再次加入1mL PBS洗涤细胞两次,1200rpm,离心5min,完全弃去上清,弹匀管底细胞,根据细胞量,加入50~100μL含有蛋白酶抑制剂和磷酸酶抑制剂的蛋白裂解液,充分吹打混匀细胞,置于冰上裂解30min后,4℃,12,000rcf,离心15min,吸取上清放入新的EP管中,所得即为细胞总蛋白。可直接进行后续蛋白浓度的测定或-80℃保存。
4.2BCA法测蛋白浓度:将BCA试剂A液与B液按照50:1的比例混匀,制备工作液;取5μL待测样本,加入95μL去离子水混匀,稀释20倍,取20μL稀释后的待测样本加入到96孔板中;加入200μL工作液后,将96孔板置于37℃孵箱,孵育30min,上机检测。
4.3蛋白变性:分别取100μg样品,用蛋白裂解液将各样本体积补齐,加入1/3总体积的4×loading buffer,充分混匀,99℃变性10min,离心后-80℃保存。
4.4蛋白电泳:将预制胶安装入电泳槽中,加入1×MOPS电泳液,拔掉预制胶顶层梳子,轻轻吹打上样孔,去除孔内残余凝胶;将预染蛋白Maker及等质量的蛋白样品小心加入凝胶孔中;将电压调至60V~80V,30min后,调整电压为110V~120V,当溴酚蓝跑至凝胶底部凹槽处,断开电源,停止电泳,整个电泳过程约2h~2.5h。
4.5电转印:将PVDF膜浸入无水甲醇中激活1min;将转膜夹黑色面朝下,由下向上依次放置海面-滤纸-PAGE胶-PVDF膜-滤纸-海绵,小心赶出胶/膜和滤纸之间的气泡,扣紧转膜夹,放入转膜槽中,PAGE胶朝向负极,PVDF膜朝向正极;放入冰盒,倒入预冷的1×电转液;将电源调至100V,转膜1~1.5h。
4.6封闭:转膜结束后,取出PVDF膜,放入1×TBST清洗数次,去除膜上残留的电转液后,浸入5%脱脂牛奶中封闭,室温2h,或4℃过夜。
4.7孵育一抗:按照1/1000稀释一抗GAPDH,HCBP6;按照蛋白分子量的大小,将相应位置的PVDF膜与上述抗体封闭于杂交袋中,4℃孵育过夜。
4.8洗膜:剪开杂交袋,回收一抗,取出PVDF膜,放入1×TBST中,置于摇床上洗膜三次,每次10min。
4.9孵育二抗:按照1/5,000~1/10,000的比例稀释二抗,将上述PVDF膜浸入相应二抗中,置于摇床上,室温孵育45-60min。
4.10洗膜:回收二抗,取出PVDF膜,放入1×TBST中,置于摇床上洗膜三次,每次10min;检测磷酸化蛋白时,需适当减少洗膜次数和洗膜时间。
4.11曝光显色:将膜置于Fusion Solo成像仪暗箱中,滴加ECL曝光液,进行显 影。
5.Q-PCR检测目的基因表达
5.1细胞总RNA提取
LX-2细胞分别加入受测化合物,48h后提取细胞中的总RNA,本实验严格按照Total RNA Kit试剂盒说明书进行,步骤如下(注意:本实验全程冰上进行,全程使用无RNA酶的专用枪头):
1)从孵箱中取出12孔细胞培养板,弃去细胞培养液,1×PBS 1mL清洗细胞2次,负压吸引装置吸干净PBS;
2)根据需要配制350μL TRK Lysis Buffer混合液/孔(混合液配制方法:1mL TRKLysis Buffer+20μLβ-巯基乙醇),涡旋混匀。12孔细胞培养板每孔分别加入350μL,室温静置5min,使细胞充分裂解;
3)根据需要配制70%乙醇/孔,涡旋混匀。12孔细胞培养板每孔分别加入350μL,摇晃混匀,转移至离心柱(离心柱+收集管组装好)内;
4)4℃离心机,12000g,60sec,离心后弃废液,保留离心柱;
5)加入500μL RNA Wash Buffer Ⅰ,4℃离心机,12000g,60sec,离心后弃废液,保留收集柱;
6)加入500μL RNA Wash BufferⅡ(确认已加乙醇),4℃离心机,12000g,60sec,离心后弃废液,保留收集柱;
7)重复步骤6)一遍,4℃离心机,12000g,90sec,离心后弃废液,保留收集柱;
8)4℃离心机,12000g,120sec,以保证离心柱充分干燥;
9)干燥后的离心柱插入新的1.5mL EP管中,在离心柱中心的膜上加入30μL DEPC水。注意该步骤不要触碰到EP管盖子。室温静置5min,以确保RNA被DEPC水充分溶解。4℃离心机,12000g,60sec,保留EP管;
10)NanoDrop超微量分光光度计检测RNA浓度;
5.2RNA逆转录为cDNA:按照PrimeScript
TM RT reagent Kit(Perfect Real Time)说明书,具体实验步骤如下:
5.2.1配制逆转录反应体系(冰上操作):
表1-10逆转录反应体系
5.2.2逆转录上机反应条件如下:
表1-11逆转录反应条件
5.2.3所得产物即为cDNA,可直接用于后续Q-PCR实验或者-20℃保存。
5.3.1根据说明书配制Q-PCR反应体系如下:
表1-12 Q-PCR反应体系
表1-13 Q-PCR反应条件
反应结束后,确认Q-PCR的扩增曲线和溶解曲线,采用相对定量法(2
-ΔΔC
T法)对实验结果进行数据分析。
5.3.3所用引物序列如下:
表1-14 Q-PCR实验所用引物序列
(b)化合物的体内药效评价
1.四氯化碳诱导小鼠肝纤维化模型的建立与治疗
长期腹腔注射四氯化碳(carbon tetrachloride,CCl
4)诱发可逆性肝纤维化,通常用于筛选和评估抗肝纤维化药物。C57BL/6野生型小鼠随机分为对照组,四氯化碳组及治疗组,处理如下:
四氯化碳组小鼠:腹腔注射四氯化碳总量0.5μL/g,以玉米油稀释后10μL/g,3次/周。造模满4周后,四氯化碳组随机分组,加上阴性对照组:
①阴性对照组小鼠:腹腔注射玉米油溶液,10μL/g,3次/周;同时饮用水200μL灌胃。
②四氯化碳组小鼠:腹腔注射四氯化碳总量0.5μL/g,以玉米油稀释后10μL/g,3次/周;200μL生理盐水灌胃。
③天冬氨酸组小鼠:腹腔注射四氯化碳总量0.5μL/g,以玉米油稀释后10μL/g,3次/周;30mg/kg天冬氨酸灌胃。
④治疗组小鼠:腹腔注射四氯化碳总量0.5μL/g,以玉米油稀释后10μL/g,3次/周;不同剂量的本发明化合物灌胃。
治疗4周,最后一次四氯化碳注射48h后,进行眼球取血。抗凝管收集全血约1mL/只,立即于冰上静置1h。4℃、3000rpm,离心15min。取上清约0.4mL于EP管中,注意不要吸取到下层液体,之后-80℃冰箱保存。小鼠安乐死,取新鲜肝脏组织,一部分置于冻存管,液氮中保存备用;另一部分置于4%多聚甲醛溶液中固定16h~24h,以备后续实验。
2.HFD或CHOL诱导小鼠NAFLD模型的建立与治疗
①选取6~8周龄C57BL/6J雄性小鼠,随机分为正常饮食组(n=10)和HFD或CHOL组;造模期间记录小鼠体重变化,造模8周(CHOL)或10周(HFD)后,根据小鼠体重,将HFD或CHOL组小鼠随机分组,加上阴性对照组共5组:
②阴性对照组小鼠(n=10):正常饮食饲喂,同时饮用水200μL灌胃,bid。
HFD或CHOL组小鼠(n=10):HFD或CHOL饮食饲喂,同时生理盐水200μL灌胃,bid。(注:HFD(60%高脂)饲料(惠特比科技发展(北京)有限公司)(D12492)、CHOL(40%高脂+1.25%胆固醇)饲料(惠特比科技发展(北京)有限公司)(D12108C))
③化合物6-低组小鼠(n=10):HFD或CHOL饮食饲喂,同时化合物6 10mg/kg灌胃,bid。
④化合物6-中组小鼠(n=10):HFD或CHOL饮食饲喂,同时化合物6 50mg/kg灌胃,bid。
⑤化合物6-高组小鼠(n=10):HFD或CHOL饮食饲喂,同时化合物6 150mg/kg灌胃,bid。
给药8周后,通过摘眼球取血,抗凝管收集全血约1mL/只,立即于冰上静置。4℃、3000rpm,离心15min。取上清约0.4ml于EP管中,注意不要吸取到下层液体,之后-80℃冰箱保存,检测血脂和转氨酶等生化指标。小鼠安乐死,取新鲜肝脏组织,称重,一部分置于冻存管,液氮中保存备用;另一部分置于4%多聚甲醛溶液中固定16h~24h,进行组织学HE染色和油红O染色,判定脂肪肝严重程度。
3.肝脏的组织学分析
(1)石蜡包埋
①固定:将小鼠按照标准操作,取出组织,将组织放入4%多聚甲醛中固定24h;
②脱水:将固定好的组织放入70%乙醇中过夜,然后依次放入85%、95%、95%、95%、100%、100%的乙醇中各1h,进行逐级脱水;
③透明:将经过脱水的组织依次放入50%二甲苯(二甲苯与乙醇等体积)、100%二甲苯中、100%二甲苯中各20min,进行透明处理;
④浸蜡:将透明好的组织放入60℃的石蜡中,每隔1h换一次石蜡,一共四次,注意使用新的石蜡;
⑤包埋:向小铁槽内加入已经融化的石蜡(60℃),夹取浸好石蜡的组织放入其中,扣上带有标记一侧的包埋盒,再次加入融化的石蜡,操作过程中注意去除气泡;
⑥将用石蜡包埋好的组织置于自动包埋机的冰台之上,待石蜡凝固后,放入-20℃冰箱中,进一步冷却。
(2)连续切片
①将包埋好的组织蜡块放置于切片机的相应位置上;
②调整切片厚度至实验所需的厚度,一般选用3~4μM进行切片;
③将6~8个连续的组织切片轻轻放置于55℃水浴展片机中,使其充分舒展;
④用镊子轻轻将连续的组织切片分开;
⑤选取完全舒展、组织无褶皱的蜡片,用黏附载玻片将其取出,使切片附着与载玻片上;
⑥将载玻片水平放置于70℃烘片机上,进行初步烘干,然后将其放入70℃烤箱中烤片约1h。
(3)H&E染色(hematoxylin eosin staining,H&E)
①烤片:将组织切片放置于70℃烤箱中1h;
②脱蜡:将组织切片依次放入二甲苯(Ⅰ)→二甲苯(Ⅱ)→二甲苯(Ⅲ)中各10min,进行脱蜡;
③复水:将脱蜡后的组织切片依次放入100%乙醇2min→100%乙醇2min→95%的乙醇2min→85%乙醇2min→70%乙醇2min→蒸馏水洗3min;
④染细胞核:将复水后的组织切片放入苏木素溶液中染色约3~5min,具体时间根据显微镜下观察情况而定;将切片放入自来水中清洗两次,每次数十秒;
⑤分化:将切片放入l%盐酸乙醇溶液(70%乙醇配制)中分化数十秒,显微镜下控制时间,直至细胞核染色清晰;
⑥反蓝:流水冲洗,直至切片变蓝,约15~30min;将组织切片放入蒸馏水中短洗;
⑦将切片放入伊红溶液中,染色约30s,显微镜下观察调整时间,若着色困难,可在染液中加入1~2滴冰醋酸,使组织切片更易着色,且不易脱色;
⑧脱水:将组织切片依次放入70%乙醇2min→85%乙醇2min→95%乙醇2min→100%的乙醇2min→100%乙醇2min;
⑨透明:将切片一次放入二甲苯(Ⅰ)→二甲苯(Ⅱ)→二甲苯(Ⅲ)中各10min;
⑩封片:向组织上滴加适量中性树胶,盖上盖玻片封片,避免产生气泡。
(4)马松染色
马松(Masson)染色是胶原纤维染色中经典且权威的染色方法之一。胶原纤维显红色。染色步骤如下:
常规烤片、脱蜡(步骤同前);高锰酸钾溶液氧化5min,水洗;Masson染液染色5min;0.2%醋酸溶液2~3s;5%磷钨酸溶液5min;苯胺蓝溶液7min;0.2%醋酸溶液洗3次;常规脱水、透封片,封片,自然晾干,室温保存。
使用成像系统采集组织染色切片上的图像,利用分析软件自动读取组织测量区域,计算测量区域中的阳性面积以及组织面积,并计算出阳性面积占比。
4.肝功能指标检测
取小鼠血清,检测血清中ALT、AST的相关水平。
5.Q-PCR检测小鼠肝组织中目的基因表达
(1)组织总RNA的提取
①称取10mg组织放入研磨器中,加入液氮,用研磨棒充分研磨,研磨过程中,注意随时加入液氮,防止组织融化,导致RNA降解;
②将研磨后的组织放入1.5mL EP中,加入1mL Trizol裂解液,混匀;
③将样品置于恒温混匀器上,室温震荡,至组织完全溶解,约3~5h;
④加入200mL三氯甲烷,剧烈震荡数十秒,室温静置5~10min;
⑤4℃,12,000rcf,离心15min;离心时配制75%酒精(DEPC水配制),-20℃保存备用;
⑥取离心后的上清,置于新的EP管中,加入同体积的异丙醇,上下颠倒10次,室温静置10min;
⑦4℃,12,000rcf,离心15-20min;
⑧弃去上清,留下沉淀,加入1mL提前预冷的75%乙醇,洗去异丙醇,4℃,12,000rcf,离心10min;重复该步骤一次,晾干;
⑨根据沉淀量,加入30-100μL DEPC水,溶解沉淀,即为所提组织RNA。
⑩用紫外分光光度计测定所提RNA浓度和纯度,-80℃保存。
(2)RNA逆转录为cDNA:
按照PrimeScript
TM RT reagent Kit(Perfect Real Time)说明书,具体实验步骤如下:
①配制逆转录反应体系(冰上操作):
表3-1逆转录反应体系
②逆转录上机反应条件如下:
表3-2逆转录反应条件
所得产物即为cDNA,可直接用于后续Q-PCR实验或者-20℃保存。
(3)Q-PCR检测目的基因表达:
①根据说明书配制Q-PCR反应体系如下:
表3-3 Q-PCR反应体系
表3-4 Q-PCR反应条件
反应结束后,确认Q-PCR的扩增曲线和溶解曲线,采用相对定量法(2
-ΔΔC
T法)对实验结果进行数据分析。
③所用引物序列如下:
表3-5 Q-PCR实验所用引物序列
(c)化合物的热力学溶解度测试
取数份药物,配制从不饱和溶液到饱和溶液的系列溶液,置恒温条件下振荡至平衡,经滤膜过滤,取滤液分析,测定药物在溶液中的实际浓度S,并对配制溶液浓度c作图,图中曲线的转折点A,即为该药物的平衡溶解度。
热力学溶解度的测定采用的是摇瓶法(pH=7.4),并用高效液相-二极管阵列检测器(HPLC-DAD)或高效液相-串联质谱(LC/MS/MS)进行分析。
(d)药代动力学测试
1.研究目的:
以大鼠为受试动物,研究以下化合物在大鼠体内血浆的药代动力学行为。
2.试验方案:
2.1试验药品:
本发明实施例,自制。
2.2试验动物:
SD大鼠,6-8周龄,每种给药方式3只/实施例,雄性。
2.3进食状态:
禁食一晚,服药后8小时进食,自由饮水。
2.4样品收集:
在给药前、给药后5min、15min、30min、1hr、2hr、4hr、8hr和24hr采集血液。
2.5样品处理:
将血液置于湿冰上离心获得血浆标本(2000g,4℃下5min)。
2.6液相分析
采用LC-MS/MS法测定血药浓度,HPLC条件为流动相A:H
2O-0.5%FA;流动相B:ACN-0.5%FA;
3.试验结果与分析
采用WinNonlin 8.2非室型模型估算药代动力学参数(PK parameter,包括但不限于药峰浓度(Cmax)、达峰时间(Tmax)、末端消除速率(Ke)、末端消除半衰期(T1/2)、药时曲线下面积(AUC)、清除率(CL)、表观分布容积(Vd)、平均驻留时间(MRT)、生物利用度(F)等)。
测试结果:
(a)半活化LX2细胞中的对NS3TP1的调控情况-qPCR
LX2细胞正常传代分板,贴壁生长12小时后,加入200μM的待测化合物,48小时后收集细胞,提取总RNA,应用Q-PCR方法检测NS3TP1基因的表达。
结果(表1)显示,本发明的化合物可上调的mRNA表达水平。
表1对LX-2细胞中NS3TP1表达的上调情况
实施例 | NS3TP1上调作用 |
4** | B |
6 | A |
54 | A |
77a | C |
78a* | C |
注:与对照组相比,未见明显上调作用为NA;上调1~20%评级为C;上调20~40%评级为B;上调40%及以上评级为A;“-”表示未提供结果;“*”标记的化合物测试浓度为12.5μM;“**”标记的化合物测试浓度为10mM。
(b)半活化LX2细胞中的体外药效评价-qPCR
LX2细胞正常传代分板,贴壁生长12小时后,加入50μM的待测化合物,48小时后收集细胞,提取总RNA,应用Q-PCR方法检测肝纤维化相关基因(编码α-SMA的ACTA2、编码collagen Ⅰ的COL1A1和COL1A2、编码collagen Ⅲ的COL3A1、编码Smad3的SMAD3)和炎症相关基因(编码IL-1β的IL1B、编码TNFα的TNFa)mRNA表达水平的变化(具体方法参见前述5.Q-PCR检测目的基因表达)。α-SMA是肝星状细胞激活标志,collagen Ⅰ、collagen Ⅲ为主要细胞外基质沉积成分。
结果(表2)显示,本发明的化合物可抑制肝纤维化相关基因的mRNA表达水平。其中,化合物2、化合物4、化合物6、化合物8、化合物10、化合物12、化合物14、化合物15、化合物18、化合物19、化合物21、化合物22、化合物26、化合物28、化合物30、化合物33、化合物35、化合物38、化合物40、化合物42、化合物44、化合物47、化合物48、化合物50、化合物52、化合物53、化合物54、化合物59、化合物61、化合物63、化合物66、化合物70、化合物71、化合物72、化合物74等在mRNA水平上抑制collagen I和collagen III的表达;化合物4、化合物6、化合物26、化合物28、化合物33、化合物53、化合物54、化合物68、化合物70、化合物73等在mRNA水平上抑制α-SMA的表达;化合物1、化合物4、化合物6、化合物9、化合物12、化合物15、化合物22、化合物26、化合物28、在mRNA水平上抑制Smad3的表达。整体来说,化合物4、化合物6、化合物12、化合物26、化合物47、化合物48、化合物52、化合物54抑制肝纤维化相关基因的mRNA表达水平的效果较强。
表2
实施例 | COL1A1 | COL1A2 | COL3A1 | α-SMA | Smad3 | IL-1β | TNF-α |
1 | E | NA | NA | E | D | NA | E |
2 | C | E | D | E | E | E | D |
3* | C | E | E | NA | E | E | E |
4 | C | E | C | C | C | E | C |
5 | NA | NA | NA | NA | NA | E | NA |
6 | C | E | C | D | C | E | D |
7** | NA | NA | NA | NA | NA | E | NA |
8 | D | NA | D | NA | E | E | NA |
9 | NA | NA | NA | E | D | C | NA |
10 | E | E | D | E | E | E | D |
11 | NA | NA | NA | NA | E | C | E |
12 | C | E | C | E | D | E | D |
13 | NA | E | NA | E | NA | E | E |
14 | D | NA | E | NA | NA | NA | E |
15 | D | NA | D | E | D | NA | E |
16 | E | NA | NA | NA | NA | NA | E |
17 | E | NA | NA | E | E | NA | D |
18 | D | E | E | NA | NA | NA | NA |
19 | D | D | D | NA | NA | NA | NA |
20* | E | NA | E | E | E | NA | NA |
21 | E | NA | D | E | E | NA | NA |
22 | D | NA | E | NA | D | E | E |
23 | E | E | E | NA | E | E | E |
24 | E | NA | E | NA | NA | NA | NA |
25 | E | NA | NA | E | NA | NA | NA |
26 | C | E | C | D | D | NA | D |
27 | NA | NA | NA | NA | E | NA | NA |
28 | D | E | D | D | D | D | E |
29 | E | E | NA | E | NA | NA | NA |
30 | C | E | NA | E | NA | D | NA |
31 | E | NA | NA | E | NA | E | NA |
32 | D | NA | E | E | NA | NA | NA |
33 | C | E | E | C | E | E | NA |
34 | NA | NA | E | E | E | E | E |
35 | D | NA | E | NA | NA | NA | NA |
36 | NA | NA | E | E | E | NA | E |
38 | C | NA | E | NA | NA | NA | NA |
39 | NA | E | E | NA | NA | NA | E |
40 | C | NA | C | NA | E | E | E |
41 | NA | NA | E | NA | NA | E | NA |
42 | C | NA | E | NA | E | E | D |
43 | NA | NA | E | E | E | NA | NA |
44 | D | NA | E | NA | NA | E | NA |
45** | E | E | E | E | E | E | E |
46** | NA | E | NA | NA | NA | NA | NA |
47 | C | NA | D | NA | E | E | D |
48 | C | NA | D | NA | NA | NA | E |
50 | C | NA | E | NA | NA | NA | NA |
51 | NA | NA | NA | E | NA | NA | NA |
52 | C | E | C | NA | NA | NA | NA |
53 | D | E | D | D | NA | NA | NA |
54 | C | NA | D | NA | NA | NA | E |
55** | E | E | E | E | NA | E | NA |
57** | NA | NA | NA | NA | E | NA | NA |
58 | NA | E | E | E | NA | E | NA |
59 | D | NA | NA | E | NA | NA | E |
60 | NA | NA | NA | E | E | NA | NA |
61 | C | E | E | NA | E | E | E |
62 | E | NA | NA | E | E | E | E |
63 | NA | - | D | E | - | - | - |
65* | D | - | E | E | - | - | - |
66 | C | - | NA | NA | - | - | - |
67 | NA | - | E | NA | - | - | - |
68*** | E | - | E | C | - | - | - |
70*** | E | - | D | B | - | - | - |
71* | D | - | E | NA | - | - | - |
72** | C | - | C | NA | - | - | - |
73* | NA | - | NA | D | - | - | - |
74*** | C | - | C | C | - | - | - |
注:与对照组相比,未见明显抑制作用为NA;抑制1~10%评级为E;抑制10~25%评级为D;抑制25%~50%评级为C;抑制50%~75%评级为B;抑制75%~100%评级为A;“-”表示未提供结果;“*”标记的化合物测试浓度为12.5μM;“**”标记的化合物测试浓度为25μM;“***”标记的化合物测试浓度为100μM。
(c)活化LX2细胞中的体外肝纤维化模型的药效评价-qPCR
LX2细胞正常传代分板,贴壁生长12小时后,给予TGFβ1(5ng/mL)激活,加入25μM浓度的待测化合物,24小时后收集细胞,提取总RNA,应用real-time PCR方法检测肝纤维化相关基因和炎症相关基因的表达水平。α-SMA是肝星状细胞激活标志,collagen1、collagen 3为主要细胞外基质沉积成分。
表3对活化LX-2细胞中肝纤维化相关基因表达的调节情况
实施例 | collagen 1 | collagen 3 | α-SMA |
4 | A | A | B |
6 | B | A | A |
注:与对照组相比,未见明显抑制作用为NA;抑制1~10%评级为C;抑制10~25%评级为B;抑制25%以上评级为A;“-”表示未提供结果。
结果显示,在此项测试中,本发明的化合物可抑制肝纤维化相关基因的mRNA表达水平。
(d)半活化LX2细胞中的体外药效评价-Western blot
LX2细胞正常传代分板,贴壁生长12小时后,加入不同浓度(50μM、100μM、200μM、400μM)的待测化合物,48小时后收集细胞,提取蛋白,应用Western blot方法检测肝纤维化相关基因的蛋白(α-SMA、collagen Ⅰ、collagen Ⅲ、FN)表达水平变化(具体方法参见前述4蛋白免疫印迹检测蛋白水平表达)。α-SMA是肝星状细胞激活标志,collagen Ⅰ、collagen Ⅲ为主要细胞外基质沉积成分,纤维连接蛋白(Fibronectin,FN)是一种主要参与细胞黏附相互作用的黏附糖蛋白。
结果显示,本发明的化合物可抑制肝纤维化相关基因的mRNA表达水平,结果未展 示完全(con为对照孔,P1为阳性对照孔,“ASP-50”为50μM天冬氨酸,其余编号均为化合物编号-浓度(μM)的形式)。其中化合物6、化合物47、化合物54对collagen Ⅰ和collagen Ⅲ蛋白表达的(图1)抑制作用强于ASP;化合物4、化合物6、化合物41、化合物47、化合物48、化合物52对α-SMA蛋白表达的(图2)抑制作用强于ASP;化合物50、化合物52、化合物54对FN蛋白表达的(图3)抑制作用强于ASP。
(e)活化LX2细胞中的体外药效评价-Western blot
LX2细胞正常传代分板,贴壁生长12小时后,给予TGFβ1(5ng/mL)激活,加入不同浓度的待测化合物,24小时后收集细胞,提取蛋白,应用Western blot方法检测肝纤维化相关基因的蛋白(α-SMA、collagen Ⅰ)表达水平变化(具体方法参见前述4蛋白免疫印迹检测蛋白水平表达)。α-SMA是肝星状细胞激活标志,collagen Ⅰ为主要细胞外基质沉积成分。
结果显示,LX2细胞给予TGFβ刺激后,细胞中Collagen Ⅰ表达增多,给予化合物54、77a、78a后,细胞中Collagen Ⅰ和α-SMA表达量明显减少(图4)。
(f)化合物对肝纤维化动物模型中NS3TP1基因的调节效果
CCl4诱导后,小鼠肝组织中的小鼠肝组织中NS3TP1表达明显下降,说明小鼠肝纤维化和NS3TP1表达异常可能存在相关性。给予不同剂量的化合物6治疗后,与未治疗组相比,小鼠肝组织中NS3TP1表达逐渐升高,且呈剂量依赖性(图5)。
(g)化合物对肝纤维化模型动物的药效
观察及计算机分析马松染色切片情况,可见CCl
4诱导后,鼠肝脏组织中胶原(蓝色)明显沉积。给予化合物4(20mg/kg/d)、化合物6(25mg/kg/d)、化合物47(20mg/kg/d)、化合物54(40mg/kg/d)治疗后,与未治疗组和天冬氨酸组(30mg/kg/d)相比,小鼠肝组织中胶原沉积减少,说明本发明的化合物(如化合物4、化合物6、化合物47、化合物54)可能具有减少胶原沉积,抑制肝纤维化的作用(图6)。
观察及计算机分析马松染色切片情况,可见CCl
4诱导后,鼠肝脏组织中胶原(蓝色)明显沉积。给予化合物6(10mg/kg/bid、50mg/kg/bid、150mg/kg/bid)治疗后,与未治疗组相比,小鼠肝组织中胶原沉积减少,说明本发明的化合物(如化合物6)可能具有减少胶原沉积,抑制肝纤维化的作用(图7)。
CCl
4诱导后,小鼠转氨酶ALT、AST水平明显升高,出现明显肝脏损伤,给予本发明的化合物后,与未治疗组相比,小鼠血浆中ALT下降,说明本申请的化合物对肝细胞具有保护作用,可以减轻小鼠肝脏损伤,改善肝功能。
从活性结果可知,
1.CCl
4诱导的肝纤维化小鼠模型中,肝组织中的NS3TP1表达水平下降,说明小鼠肝纤维化和NS3TP1表达异常可能存在相关性。
2.从活性表征结果可知,本发明中的化合物在细胞实验和体内实验中有上调NS3TP1表达的作用。
3.从活性表征结果可知,本发明中的化合物在细胞层面和动物层面的肝纤维化模型中也表现出减轻肝纤维化症状的作用。
(h)化合物对NAFLD模型动物的药效
观察及计算机分析H&E染色切片情况,可见给予HFD饮食饲喂后,小鼠肝组织中可见大量脂滴积聚,肝组织呈皂状弥漫性脂肪变。给予化合物6治疗后,与未治疗组相比,小鼠肝组织中脂滴聚集减少,且呈剂量依赖性,说明本发明的化合物(如化合物6)可能具有抑制脂肪肝的形成的作用(图9)。
观察及计算机分析H&E染色切片情况,可见给予CHOL饮食饲喂后,小鼠肝组织中可见大量脂滴积聚,肝组织呈皂状弥漫性脂肪变。给予化合物6治疗后,与未治疗组相比,小鼠肝组织中脂滴聚集减少,且呈剂量依赖性,说明本发明的化合物(如化合物6)可能具有抑制脂肪肝的形成的作用(图10)。
(i)溶解度测试
本发明部分化合物表现出良好的溶解度,明显优于天冬氨酸。
(j)化合物的药代动力学测试
结果显示,向大鼠给予生理盐水后,24小时内大鼠体内的化合物6和天冬氨酸浓度在1000~3000ng/mL之间波动,提示本发明的化合物6和天冬氨酸为大鼠的内源性物质;
向大鼠给予化合物6后(IV 10mg/kg,PO 40mg/kg),体内的化合物6水平显著提升(IV 10mg/kg的Cmax为6100ng/mL、PO 40mg/kg的Cmax为22500ng/mL),但未见天冬氨酸水平显著提升(IV 10mg/kg的Cmax为3017ng/mL、PO 40mg/kg的Cmax为4020ng/mL),提示给予化合物6之后在大鼠体内主要以原型形式发挥药理作用,而不是代谢为天冬氨酸发挥药理作用。
向大鼠分别给予天冬氨酸及化合物6后(PO 20mg/kg),可见给予化合物6的大鼠的Cmax和AUC显著高于给予天冬氨酸的大鼠,提示化合物6较天冬氨酸在体内暴露量上有明显提升。同时可见给予化合物6的大鼠的Tmax显著小于给予天冬氨酸的大鼠,提示化合物6能够更快地达到最高浓度。
表4化合物在大鼠体内的药代动力学参数
天冬氨酸 | 化合物6 | |
Tmax(hr) | 24 | 0.5 |
Cmax(ng/mL) | 1960 | 14800 |
AUClast(hr*ng/mL) | 26671.815 | 71261.16 |
结果表明,本发明的化合物具有良好的药代动力学参数,在例如:AUC、Cmax和/或生物利用度等多个药代动力学参数表现均优于天冬氨酸,具有更佳的成药性。
Claims (14)
- 下式I所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物在制备药物或试剂中的用途,所述药物用于以下的至少一种:1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);2)减轻哺乳动物肝纤维化、肝脏脂肪变性、或炎症;3)抑制星状细胞的激活;4)调节NS3TP1的表达;A-(L 1) x-A’ (式I)其中:x选自0、1和2;1)当x为0时,A’不存在;对于A,其中:R 1和R 2各自独立选自下组基团:C1-C6烷基、-O-R a1、-NR a2R a3;R 3和R 4各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-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,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环基的基团取代;R a1、R a2、R a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基) n-(CO)-R b1、-(C1-C6烷基) n-(CO)-O-R b2、-(C1-C6烷基) n-O-(CO)-R b3、-(C1-C6烷基) n-O-(CO)-O-R b4、-(C1-C6烷基) n-(CO)-NR b5R b6、-(C1-C6烷基) n-NR b7-(CO)-R b8、-(C1-C6烷基) n-NR b9-(CO)-O-R b10,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;R b1、R b2、R b3、R b4、R b5、R b6、R b7、R b8、R b9、R b10各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基) n-(CO)-O-R c1、-(C1-C6烷基) n-O-(CO)-R c2、-(C1-C6烷基) n-O-(CO)-O-R c3,所述烷基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代;R c1、R c2、R c3各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;L各自独立选自下组基团:不存在、O、NR d5、C1-C6烷基、C2-C6烯基、C2-C6炔基;R e各自独立选自氢、氘、Na、K、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基的基团取代;R h各自独立选自下组基团:C1-C6烷基、-NHC(O)R g1、-OC(O)R g2、-OP(O)(ONa) 2、-NHC(O)OR d6、-OC(O)OR d7、-OC(O)NHR d8;R d1、R d2、R d3、R d4、R d5、R d6、R d7、R d8各自独立选自下组基团:氢、氘、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个R f取代;R f各自独立选自卤素、C1-C6烷基、卤代C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、卤代C6-C10芳基、C3-C7环烷基、3-15元杂环基、-NR g3R g4、-OR g5、-NHC(O)R g6、-OC(O)R g7;R g1、R g2、R g3、R g4、R g5、R g6、R g7各自独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;R 5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5选自氢、氨基;Y为C或S;y为0及0以上的整数;或者y选自0、1、2、3;再或者y为0或1;n为0或1;2)当x为1或者2时,A与A’相同或者不同,其中:一个单元A的R 1、R 2、R 3、R 4中的任意一个通过L 1与相邻单元A’的R 1’、R 2’、R 3’、R 4’中的任意一个相连;各L 1独立地选自下组的单元连接基团组成:不存在、O、S、羰基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-)、环烷基(或者C3-C7环烷基)、杂烷基(或者3-7元杂烷基;例如,-O-烷基-O-(或者-O-C1-C6烷基-O-)),其中烷基、环烷基、杂烷基任选地被一个或多个独立选自Z的基团取代;Z各自独立选自下组基团:卤素、氨基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、卤代烷基(或者卤代C1-C6烷基)、环烷基(或者C3-C7环烷基)、芳基(或者C6-C12芳基)、杂环;或者L 1选自:不存在、-CR’R”,其中R’和R”各自独立地为H、C1-C6烷基(或者C1-C3烷基);再或者L 1选自:不存在、-CH 2-、-CH(CH 3)-、-C-(CH 3) 2;对于A,其中:R 1和R 2各自独立选自下组基团:C1-C6烷基、-O-、-O-R a1、-NR a2R a3;R 3和R 4各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-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,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;R a1、R a2、R a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基) n-(CO)-R b1、-(C1-C6烷基) n-(CO)-O-R b2、-(C1-C6烷基) n-O-(CO)-R b3、-(C1-C6烷基) n-O-(CO)-O-R b4、-(C1-C6烷基) n-(CO)-NR b5R b6、-(C1-C6烷基) n-NR b7-(CO)-R b8、-(C1-C6烷基) n-NR b9-(CO)-O-R b10,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;R b1、R b2、R b3、R b4、R b5、R b6、R b7、R b8、R b9、R b10各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基) n-(CO)-O-R c1、-(C1-C6烷基) n-O-(CO)-R c2、-(C1-C6烷基) n-O-(CO)-O-R c3,所述烷基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代;R c1、R c2、R c3各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;L各自独立选自下组基团:不存在、O、NR d5、C1-C6烷基、C2-C6烯基、C2-C6炔基;R e各自独立选自氢、氘、Na、K、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基的基团取代;R h各自独立选自下组基团:C1-C6烷基、-NHC(O)R g1、-OC(O)R g2、-OP(O)(ONa) 2、-NHC(O)OR d6、-OC(O)OR d7、-OC(O)NHR d8;R d1、R d2、R d3、R d4、R d5、R d6、R d7、R d8各自独立选自下组基团:氢、氘、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个R f取代;R f各自独立选自卤素、C1-C6烷基、卤代C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、卤代C6-C10芳基、C3-C7环烷基、3-15元杂环基、-NR g3R g4、-OR g5、-NHC(O)R g6、-OC(O)R g7;R g1、R g2、R g3、R g4、R g5、R g6、R g7各自独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;R 5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5选自氢、氨基;Y为C或S;y为0及0以上的整数;或者y选自0、1、2、3;再或者y为0或1;n为0或1;对于A’,其中:R 1’和R 2’各自独立选自下组基团:C1-C6烷基、-O-、-O-R a1、-NR a2R a3;R 3’和R 4’各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-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,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;R a1、R a2、R a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基) n-(CO)-R b1、-(C1-C6烷基) n-(CO)-O-R b2、-(C1-C6烷基) n-O-(CO)-R b3、-(C1-C6烷基) n-O-(CO)-O-R b4、-(C1-C6烷基) n-(CO)-NR b5R b6、-(C1-C6烷基) n-NR b7-(CO)-R b8、-(C1-C6烷基) n-NR b9-(CO)-O-R b10,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;R b1、R b2、R b3、R b4、R b5、R b6、R b7、R b8、R b9、R b10各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基) n-(CO)-O-R c1、-(C1-C6烷基) n-O-(CO)-R c2、-(C1-C6烷基) n-O-(CO)-O-R c3,所述烷基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代;R c1、R c2、R c3各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;L各自独立选自下组基团:不存在、O、NR d5、C1-C6烷基、C2-C6烯基、C2-C6炔基;R e各自独立选自氢、氘、Na、K、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7 环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基的基团取代;R h各自独立选自下组基团:C1-C6烷基、-NHC(O)R g1、-OC(O)R g2、-OP(O)(ONa) 2、-NHC(O)OR d6、-OC(O)OR d7、-OC(O)NHR d8;R d1、R d2、R d3、R d4、R d5、R d6、R d7、R d8各自独立选自下组基团:氢、氘、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个R f取代;R f各自独立选自卤素、C1-C6烷基、卤代C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、卤代C6-C10芳基、C3-C7环烷基、3-15元杂环基、-NR g3R g4、-OR g5、-NHC(O)R g6、-OC(O)R g7;R g1、R g2、R g3、R g4、R g5、R g6、R g7各自独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;R 5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5选自氢、氨基;Y’为C或S;y’为0及0以上的整数;或者y’选自0、1、2、3;再或者y’为0或1;n为0或1;或者式I为:
- 权利要求1的用途,其中,1)当x为0时,A’不存在;对于A,其中:R 1和R 2各自独立选自下组基团:C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基) n-(CO)-R b1、-(C1-C6烷基) n-(CO)-O-R b2、-(C1-C6烷基) n-O-(CO)-R b3、-(C1-C6烷基) n-O-(CO)-O-R b4,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;-NR a2R a3,其中,R a2、R a3各自独立选自:氢、C1-C6烷基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基) n-(CO)-R b1、-(C1-C6烷基) n-(CO)-O-R b2、-(C1-C6烷基) n-O-(CO)-R b3、-(C1-C6烷基) n-O-(CO)-O-R b4、-(C1-C6烷基) n-(CO)-NR b5R b6,所述烷基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;R b1、R b2、R b3、R b4、R b5、R b6各自独立选自下组基团:氢、羟基、氨基、C1-C6烷基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基) n-(CO)-O-R c1、-(C1-C6烷基) n-O-(CO)-R c2、-(C1-C6烷基) n-O-(CO)-O-R c3,所述烷基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代;R c1、R c2、R c3各自独立选自下组基团:氢、羟基、氨基、C1-C6烷基、C3-C7环烷基;或者,R 1和R 2各自独立选自下组基团:羟基,C1-C6烷基,-O-R a1,其中,R a1选自:任选地进一步被一个或多个C6-C10芳基取代的C1-C6烷基,C3-C7环烷基,C2-C6烯基,-(C1-C6烷基) n-O-(CO)-O-R b4,其中R b4选自C1-C6烷基,n为1;-NR a2R a3,其中,R a2、R a3各自独立选自:氢,C1-C6烷基,其中C1-C6烷基任选地进一步被一个或多个C6-C10芳基取代;-(C1-C6烷基) n-O-(CO)-R b3,R b3为C1-C6烷基,其进一步被C6-C10芳基取代;-(C1-C6烷基) n-(CO)-R b1,R b1为羟基,n或1;-(C1-C6烷基) n-(CO)-NR b5R b6,n为1,R b5、R b6各自独立为氢,或3-15元杂环基,所述杂环进一步被一个或多个C1-C6烷基取代;-(C1-C6烷基) n-(CO)-O-R b2,烷基被一个或多个C6-C10芳基取代,n为1,R b2为C1-C6烷基或-(C1-C6烷基) n-O-(CO)-O-R c,R c为C1-C6烷基;R 3与R 4各自独立地选自:氢、羟基、C1-C6烷基、-(CO)-(L) n-R d2、-(CO)O-(L) n-R d3,所述烷基、芳基、杂环任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;L各自独立选自下组基团:不存在、O、NR d5、C1-C6烷基;R d5、R d2、R d3各自独立选自下组基团:氢、氨基、C1-C6烷基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、环烷基、芳基、杂环任选地被一个或多个R f取代;R f各自独立选自氨基、卤素、C1-C6烷基、卤代C1-C6烷基、C6-C10芳基、卤代C6-C10芳基、C3-C7环烷基、3-15元杂环基;或者,R 3与R 4各自独立地选自:氢,羟基,C1-C6烷基,-(CO)-(L) n-R d2:其中,(L) n与R d2的组合选项分别选自以下组合:1)L为不存在,R d2为C1-C6烷基,进一步被一个或多个R f取代,R f为氨基;2)L为不存在,R d2为H;3)L为不存在,R d2为C1-C6烷基;4)L为不存在,R d2为C1-C6烷基,进一步被一个或多个R f取代,R f选自C1-C6烷基、氨基;5)L为不存在,R d2为3-15元杂环基;6)L为NR d5,R d5为C1-C6烷基,n为1,R d2为H;-(CO)O-(L) n-R d3:其中,(L) n与R d3的组合选项选自:L为不存在,R d3为C1-C6烷基,其任选地进一步被一个或多个R f取代,R f选自C1-C6烷基、C6-C10芳基、多环芳香烃基(例如,芴基);2)当x为1或者2时,A与A’相同或者不同,其中对于A,其中:R 1和R 2各自独立选自下组基团:C1-C6烷基、-O-、-O-R a1、-NR a2R a3;R 3和R 4各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;R a1、R a2、R a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;R 5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5选自氢、氨基;再或者R 5选自氢;Y为C;y选自0、1、2、3;或者y为0或1;对于A’,其中:R 1’和R 2’各自独立选自下组基团:C1-C6烷基、-O-、-O-R a1、-NR a2R a3;R 3’和R 4’各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;R a1、R a2、R a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;R 5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5选自氢、氨基;再或者R 5选自氢;Y’为C;y’选自0、1、2、3;或者y为0或1。
- 权利要求1或2的用途,其中,1)当x为0时,A’不存在;对于A,其中:R 1选自:C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基) n-O-(CO)-R b3,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;-NR a2R a3,其中,R a2、R a3各自独立选自:氢、C1-C6烷基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基) n-(CO)-R b1、-(C1-C6烷基) n-O-(CO)-R b3,所述烷基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;R b1、R b3各自独立选自下组基团:氢、羟基、氨基、C1-C6烷基、C6-C10芳基,所述烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代;或者,R 1选自:羟基,C1-C6烷基,-O-R a,其中,R a1选自:任选地进一步被一个或多个C6-C10芳基取代的C1-C6烷基,C3-C7环烷基,C2-C6烯基,-(C1-C6烷基) n-O-(CO)-O-R b4,其中R b4选自C1-C6烷基,n为1;-NR a2R a3,其中,R a2、R a3各自独立选自:氢;C1-C6烷基,其任选地进一步被一个或多个C6-C10芳基取代;-(C1-C6烷基) n-O-(CO)-R b3,R b3为C1-C6烷基,其进一步被C6-C10芳基取代;-(C1-C6烷基) n-(CO)-R b1,R b1为羟基,n为1;再或者,R 1选自:羟基、甲氧基、-OCH 2CH=CH 2、乙氧基、-OC(CH 3) 3、-OCH 2C 6H 5、-OC 6H 11、Trt-NH-、 CH 3-NH-、HOCOCH 2NH-、-OCH(CH 3) 2、 -CH 3、 其中,Trt表示三苯甲基;R 2选自:C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C6-C10芳基,-(C1-C6烷基) n-O-(CO)-O-R b4,所述烷基、烯基、芳基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、-(C1-C6烷基)-(C6-C10芳基)的基团取代;-NR a2R a3,其中,R a2、R a3各自独立选自:氢、C1-C6烷基、-(C1-C6烷基) n-(CO)-R b1、-(C1-C6烷基) n-(CO)-O-R b2、-(C1-C6烷基) n-(CO)-NR b5R b6、3-15元杂环基,所述烷基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基的基团取代;R b1、R b2、R b4、R b5、R b6各自独立选自下组基团:氢、羟基、C1-C6烷基、C3-C7环烷基、-(C1-C6烷基) n-O-(CO)-O-R c3,所述环烷基任选地被一个或多个独立选自卤素、氨基、羟基、羧基、C1-C6烷基、C6-C10芳基的基团取代;R c3各自独立选自下组基团:氢、羟基、氨基、C1-C6烷基、C3-C7环烷基;或者,R 2选自:羟基,-O-R a1:其中,R a1选自:任选地进一步被一个或多个C6-C10芳基取代的C1-C6烷基,C2-C6烯基,-(C1-C6烷基) n-O-(CO)-O-R b4,其中R b4选自C1-C6烷基,n为1;-NR a2R a3:R a2、R a3各自独立选自:氢;-(C1-C6烷基) n-(CO)-NR b5R b6,n为1,R b5、R b6各自独立为氢,或3-15元杂环基,所述杂环进一步被一个或多个C1-C6烷基取代;-(C1-C6烷基) n-(CO)-R b1,n为1,R b1为羟基;-(C1-C6烷基) n-(CO)-O-R b2,所述烷基被一个或多个C6-C10芳基取代,n为1,R b2为C1-C6烷基或-(C1-C6烷基) n-O-(CO)-O-R c3,R c3为C1-C6烷基;R 3与R 4各自独立地选自:氢、羟基、Boc、Cbz、-CH 3、Fmoc、-COOCH 2C 6H 5、-COCH 2NH 2、-CHO、-COCH 3、 -COCH 2CH 3、-COCH(CH 3) 2、-COCH(CH 2) 2、-COOCH 3、-CON(CH 3) 2、-COCH(CH 3)(NH 2);其中,Boc表示叔丁氧羰基,Cbz表示苄氧羰基,Fmoc表示芴甲氧羰基;2)当x为1时,A与A’相同或者不同,其中一个单元A的R 1、R 2、R 3、R 4中的任意一个通过L 1与相邻单元A’的R 1’、R 2’、R 3’、 R 4’中的任意一个相连;各L 1独立地选自下组的单元连接基团组成:不存在、O、S、羰基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-)、环烷基(或者C3-C7环烷基)、杂烷基(或者3-7元杂烷基;例如,-O-烷基-O-(或者-O-C1-C6烷基-O-)),其中烷基、环烷基、杂烷基任选地被一个或多个独立选自Z的基团取代;Z各自独立选自下组基团:卤素、氨基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、卤代烷基(或者卤代C1-C6烷基)、环烷基(或者C3-C7环烷基)、芳基(或者C6-C12芳基)、杂环;或者L 1选自:不存在、-CR’R”,其中R’和R”各自独立地为H、C1-C6烷基(或者C1-C3烷基);再或者L 1选自:不存在、-CH 2-、-CH(CH 3)-、-C-(CH 3) 2;对于A,其中:R 1选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 1选自:-O-,羟基,-O-R a:R a为C1-C6烷基;再或者,R 1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH 3) 2;Y为C;y为0;R 2选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 2选自:羟基,-O-,-O-R a:R a为C1-C6烷基;再或者,R 2选自:羟基、-O-、甲氧基;R 3与R 4各自独立地选自:氢、羟基、C1-C6烷基;或者,R 3和R 4各自独立地为氢;R 5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5选自氢、氨基;再或者R 5选自氢;对于A’,其中:R 1’选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 1选自:-O-,羟基,-O-R a:R a为C1-C6烷基;再或者,R 1’选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH 3) 2;Y’为C;y’为0;R 2’选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 2’选自:羟基,-O-,-O-R a:R a为C1-C6烷基;再或者,R 2’选自:羟基、-O-、甲氧基;R 3’与R 4’各自独立地选自:氢、羟基、C1-C6烷基;或者,R 3’和R 4’各自独立地为氢;R 5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5’选自氢、氨基;再或者R 5’选自氢;3)当x为2时,A与A’相同或者不同,其中一个单元A的R 1、R 2、R 3、R 4中的任意一个通过L 1与相邻单元A’的R 1’、R 2’、R 3’、R 4’中的任意一个相连;各L 1独立地选自下组的单元连接基团组成:不存在、O、S、羰基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-)、环烷基(或者C3-C7环烷基)、杂烷基(或者3-7元杂烷基;例如,-O-烷基-O-(或者-O-C1-C6烷基-O-)),其中烷基、环烷基、杂烷基任选地被一个或多个独立选自Z的基团取代;Z各自独立选自下组基团:卤素、氨基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、卤代烷基(或者卤代C1-C6烷基)、环烷基(或者C3-C7环烷基)、芳基(或者C6-C12芳基)、杂环;或者L 1选自:不存在、-CR’R”,其中R’和R”各自独立地为H、C1-C6烷基(或者C1-C3烷基);再或者L 1选自:不存在、-CH 2-、-CH(CH 3)-、-C-(CH 3) 2;进而再或者,L 1选自:-CH 2-;对于A,其中:R 1选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 1选自:-O-,羟基,-O-R a:R a为C1-C6烷基;再或者,R 1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH 3) 2;再进一步或者,R 1选自:甲氧基;Y为C;y为0;R 2选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 2选自:羟基,-O-,-O-R a:R a为C1-C6烷基;再或者,R 2选自:羟基、-O-、甲氧基;再进一步或者,R 2选自:-O-;R 3与R 4各自独立地选自:氢、羟基、C1-C6烷基;或者,R 3和R 4各自独立地为氢;R 5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5选自氢、氨基;再或者R 5选自氢;对于A’,其中:R 1’选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯 基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 1选自:-O-,羟基,-O-R a:R a为C1-C6烷基;再或者,R 1’选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH 3) 2;再进一步或者,R 1’选自:甲氧基;Y’为C;y’为0;R 2’选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、环烷基、芳基、杂环任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 2’选自:羟基,-O-,-O-R a:R a为C1-C6烷基;再或者,R 2’选自:羟基、-O-、甲氧基;再进一步或者,R 2’选自:-O-;R 3’与R 4’各自独立地选自:氢、羟基、C1-C6烷基;或者,R 3’和R 4’各自独立地为氢;R 5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5’选自氢、氨基;再或者R 5’选自氢。
- 下式I-4所示的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物在制备药物或试剂中的用途,所述药物用于以下的至少一种:1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);2)减轻哺乳动物肝纤维化、肝脏脂肪变性、或炎症;3)抑制星状细胞的激活;4)调节NS3TP1的表达;其中:Rn 1和Rn 2各自独立选自下组基团:C1-C6烷基、-O-R a4、-O-L2-O-R a4、-NR a5R a6;各R a4独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C3-C7环烷基C1-C6烷基、C6-C10芳基、C6-C10芳基C1-C6烷基、3-15元杂环基、3-15元杂环基C1-C6烷基、C1-C6烷氧酰基、-(O=)C-CH 2-CH(NH 2)-COORm、-(O=)C-CH(NH 2)-CH 2-COORm、Ph-CH 2-CH(NH 2)-C(=O)-、NH 2-CH 2-C(=O)-、CH 3-CH(NH 2)-C(=O)-、RmOOC-(CH 2) 2-CH(NH 2)-C(=O)-、-C(=O)-(CH 2) 2-CH(NH 2)-COORm、RmOOC-CH(NH 2)-CH 2-S-S-CH 2-CH(NH 2)-C(=O)-、H 2N-CO-(CH 2) 2-CH(NH 2)-C(=O)-、 *N=CH-NH-CH=*C-CH 2-CH(NH 2)-C(=O)-(或者 )、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) 2CH-CH 2-CH(NH 2)-C(=O)-;其中,Ph表示苯基,HO-p-Ph-CH 2-CH(NH 2)-C(=O)-表示对羟基苯甲基氨基甲基羰基;R a5和R a6各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、3-15元杂环基氨酰基C1-C6烷基、Ph-CH 2-CH(COORm)-、-CH 2-COORm、-CH(COORm)-CH 2-COORm、-CH(CH 3)-COORm、RmOOC-(CH 2) 2-CH(COORm)-、-CH(COORm)-CH 2-S-S-CH 2-CH(NH 2)-COORm、H 2N-CO-(CH 2) 2-CH(COORm)-、*N=CH-NH-CH=*C-CH 2-CH(COORm)-(或者 )、HO-p-Ph-CH 2-CH(COORm)-、HO-CH 2-CH(COORm)-、CH 3-S-(CH 2) 2-CH(COORm)-、HN=C(NH 2)-NH-(CH 2) 3-CH(COORm)-、(CH 3) 2CH-CH 2-CH(COORm)-;各Rm独立选自下组基团:氢、C1-C6烷基、C1-C6烷氧酰基-O-L3-;L2和L3各自独立的选自下组基团:C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、3-7元杂烷基,L2和L3各自任选的被一个或多个独立选自卤素、氨基、羟基的基团取代;Rn 3和Rn 4各自独立选自下组基团:氢、氘、羟基、H(C=O)-,C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、氨基酰基、C1-C6烷基酰基、C1-C6烷氧酰基、C1-C6烷氨基酰基,氨基C1-C6烷酰基、3-15元杂环基酰基、C3-C7环烷基酰基、C6-C10芳基C1-C6烷氧基酰基;Y为C或S;y为0、1、2或3;或者Rn 1和Rn 2各自独立选自下组基团:C1-C6烷基、-O-R a4、-O-L2-O-R a4、-NR a5R a6;各R a4独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C3-C7环烷基C1-C6烷基、C6-C10芳基、C6-C10芳基C1-C6烷基、3-15元杂环基、3-15元杂环基C1-C6烷基、C1-C6烷氧酰基、-(O=)C-CH 2-CH(NH 2)-COORm、Ph-CH 2-CH(NH 2)-C(=O)-、NH 2-CH 2-C(=O)-、CH 3-CH(NH 2)-C(=O)-、RmOOC-(CH 2) 2-CH(NH 2)-C(=O)-、RmOOC-CH(NH 2)-CH 2-S-S-CH 2-CH(NH 2)-C(=O)-、H 2N-CO-(CH 2) 2-CH(NH 2)-C(=O)-、*N=CH-NH-CH=*C-CH 2-CH(NH 2)-C(=O)-(或者 )、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) 2CH-CH 2-CH(NH 2)-C(=O)-;R a5和R a6各自独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、 C6-C10芳基、3-15元杂环基、3-15元杂环基氨酰基C1-C6烷基、Ph-CH 2-CH(COORm)-、-CH 2-COORm、-CH(COORm)-CH 2-COORm、-CH(CH 3)-COORm、RmOOC-(CH 2) 2-CH(COORm)-、-CH(COORm)-CH 2-S-S-CH 2-CH(NH 2)-COORm、H 2N-CO-(CH 2) 2-CH(COORm)-、*N=CH-NH-CH=*C--CH 2-CH(COORm)-(或者 )、HO-p-Ph-CH 2-CH(COORm)-、HO-CH 2-CH(COORm)-、CH 3-S-(CH 2) 2-CH(COORm)-、HN=C(NH 2)-NH-(CH 2) 3-CH(COORm)-、(CH 3) 2CH-CH 2-CH(COORm)-;各Rm独立选自下组基团:氢、C1-C6烷基、C1-C6烷氧酰基-O-L3-;L2和L3各自独立的选自下组基团:C1-C6烷基、C2-C6烯基、C3-C7环烷基、3-7元杂烷基,L2和L3各自任选的被一个或多个独立选自卤素、氨基、羟基的基团取代;Rn 3和Rn 4各自独立选自下组基团:氢、羟基、H(C=O)-,C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、氨基酰基、C1-C6烷基酰基、C1-C6烷氧酰基、C1-C6烷氨基酰基,氨基C1-C6烷酰基、3-15元杂环基酰基、C3-C7环烷基酰基、C6-C10芳基C1-C6烷氧基酰基;Y为C;y为0、1或2;再或者Rn 1和Rn 2各自独立选自下组基团:C1-C6烷基、-O-R a4、-O-L2-O-R a4、-NR a5R a6;各R a4独立选自下组基团:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、C6-C10芳基C1-C6烷基、3-15元杂环基、3-15元杂环基C1-C6烷基、-(O=)C-CH 2-CH(NH 2)-COORm、Ph-CH 2-CH(NH 2)-C(=O)-、NH 2-CH 2-C(=O)-、CH 3-CH(NH 2)-C(=O)-、RmOOC-(CH2) 2-CH(NH 2)-C(=O)-、RmOOC-CH(NH 2)-CH 2-S-S-CH 2-CH(NH 2)-C(=O)-、H 2N-CO-(CH 2) 2-CH(NH 2)-C(=O)-、*N=CH-NH-CH=*C-CH 2-CH(NH 2)-C(=O)-(或者 )、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) 2CH-CH 2-CH(NH 2)-C(=O)-;R a5和R a6各自独立选自下组基团:氢、C1-C6烷基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、3-15元杂环基氨酰基C1-C6烷基、Ph-CH 2-CH(COORm)-、-CH 2-COORm、-CH(COORm)-CH 2-COORm、-CH(CH 3)-COORm、RmOOC-(CH 2) 2-CH(COORm)-、-CH(COORm)-CH 2-S-S-CH 2-CH(NH 2)-COORm、H 2N-CO-(CH 2) 2-CH(COORm)-、*N=CH-NH-CH=*C--CH 2-CH(COORm)-(或者 )、HO-p-Ph-CH 2-CH(COORm)-、HO-CH 2-CH(COORm)-、CH 3-S-(CH 2) 2-CH(COORm)-、HN=C(NH 2)-NH-(CH 2) 3-CH(COORm)-、(CH 3) 2CH-CH 2-CH(COORm)-;各Rm独立选自下组基团:氢、C1-C6烷基、C1-C6烷氧酰基-O-L3-;L2和L3各自独立的选自下组基团:C1-C6烷基,L2和L3各自任选的被一个或多个独立选自卤素、氨基、羟基的基团取代;Rn 3和Rn 4各自独立选自下组基团:氢、羟基、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、氨基酰基、C1-C6烷基酰基、C1-C6烷氧酰基、C1-C6烷氨基酰基,氨基C1-C6烷酰基、3-15元杂环基酰基、C3-C7环烷基酰基、C6-C10芳基C1-C6烷氧基酰基;Y为C;y为0、1或2。
- 一种含有2-10个或者2-3个氨基酸的肽,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任 意组合或混合物在制备药物或试剂中的用途,所述药物或试剂用于以下的至少一种:1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);2)减轻哺乳动物肝纤维化、肝脏脂肪变性、或炎症;3)抑制星状细胞的激活;4)调节NS3TP1的表达;在所述肽中,至少一个氨基酸为天冬氨酸,当天冬氨酸具有游离羧基时,所述游离羧基任意的与C1-C6烷基-OH成酯;任选的,所述氨基酸为天冬氨酸,苯丙氨酸、甘氨酸,丙氨酸、谷氨酸、胱氨酸、谷氨酰胺、组氨酸、酪氨酸、丝氨酸、蛋氨酸、精氨酸或亮氨酸;或者,位于肽一侧的游离氨基酸为天冬氨酸,且任选地,该游离天冬氨酸的游离羧基任意的与C1-C6烷基-OH成酯;任选的,其余氨基酸为天冬氨酸,苯丙氨酸、甘氨酸,丙氨酸、谷氨酸、胱氨酸、谷氨酰胺、组氨酸、酪氨酸、丝氨酸、蛋氨酸、精氨酸或亮氨酸。
- 权利要求1-7任一项的用途,其中,所述肝纤维化包括不限于:慢性病毒性肝类疾病引起导致的肝纤维化、酗酒或长期饮酒引起导致的肝纤维化、肥胖等非酒精性因素引起导致的肝纤维化、反复感染血吸虫引起导致的门脉性肝纤维化、慢性胆汁淤积引起导致的胆汁性肝纤维化、肝豆状核变性和血色素沉积引起导致的代谢性肝纤维化、各种有毒物质引起导致的中毒性肝纤维化、喜好低蛋白饮食和偏爱肥肉煎炸食品导致的营养不良性肝纤维化、慢性充血性心衰导致的心源性肝纤维化。
- 药物组合物在制备药物中的用途,所述药物组合物包含权利要求1-6任一项所限定的化合物,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,或者权利要求7所限定的肽,或其药学上可接受的盐、酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物,所述药物用于以下的至少一种:1)治疗、改善、或预防肝脏疾病(如NAFLD、NASH、肝纤维化);2)减轻哺乳动物肝纤维化、肝脏脂肪变性或炎症;3)抑制星状细胞的激活;4)调节NS3TP1的表达。
- 权利要求9的用途,其中,所述肝纤维化包括不限于:慢性病毒性肝类疾病引起导致的肝纤维化、酗酒或长期饮酒引起导致的肝纤维化、肥胖等非酒精性因素引起导致的肝纤维化、反复感染血吸虫引起导致的门脉性肝纤维化、慢性胆汁淤积引起导致的胆汁性肝纤维化、肝豆状核变性和血色素沉积引起导致的代谢性肝纤维化、各种有毒物质引起导致的中毒性肝纤维化、喜好低蛋白饮食和偏爱肥肉煎炸食品导致的营养不良性肝纤维化、慢性充血性心衰导致的心源性肝纤维化。
- 权利要求9的用途,其中,所述药物组合物还包含另外的活性成分:其他用于改善肝功能作用的氨基酸(包括但不限于丙氨酸、谷氨酸、胱氨酸、谷氨酰胺、甘氨酸、组氨酸、酪氨酸、丝氨酸、蛋氨酸、精氨酸、亮氨酸)、胆固醇吸收抑制剂(如依替米贝)、HSC活化增殖抑制剂(如吡非尼酮、氟非尼酮、Pegbelfermin)PCSK9抑制剂、PPAR激动剂(如吉非罗齐、非诺贝特、氯贝特、苯扎贝特、培马贝特、Elafibranor)、ACE抑制剂、CCR2/5抑制剂、TLR4抑制剂、LOXL2抑制剂、TIMP-1抑制剂、FXR激动剂、AT1R阻滞剂、NOX抑制剂、钙离子通道阻断剂、ARBs、利尿剂、肾素、GLP -1或其合成变体、胰岛素或其合成变体、二甲双胍、磺酰脲化合物、噻唑烷二酮(TZD)、SGLT2抑制剂、DPP-IV抑制剂、HMGCoA还原酶的抑制剂、前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(PCSK9)的抑制剂、吉卡宾(CI-1027)、ACC抑制剂、ApoC-III抑制剂、ACL-抑制剂(如贝派地酸)、处方鱼油、CETP抑制剂、熊去氧胆酸、奥贝胆酸、多烯磷脂酰胆碱、糖皮质激素、水飞蓟素、甘草酸类制剂(如异甘草酸镁注射液和甘草酸二铵肠溶胶囊)以及它们的组合;还包含药学上可接受的载体或辅料;或者,所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂或复方制剂。
- 式II所示的化合物,其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式,A 1-(L 1) x-A 1’式IIx选自0、1和2;1)当x为0时,A’不存在;对于A 1,其中:R a各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基) n-(CO)-R b1、-(C1-C6烷基) n-(CO)-O-R b2、-(C1-C6烷基) n-O-(CO)-R b3、-(C1-C6烷基) n-NR b4-(CO)-R b5、-(C1-C6烷基) n-NR b6-(CO)-O-R b7,所述烷基、烯基、炔基、环烷基、芳基、杂环可选被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;R b1、R b2、R b3、R b4、R b5、R b6、R b7各自独立选自下组基团:氢、氘、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基;R 3和R 4独立地选自:-COCH(CH 3)(NH 2)、氢、-COCH 2CH 3、氘、C1-C6烷基,所述烷基可选被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基、杂环的基团取代;且满足以下条件:或者R 3和R 4中至少之一为-COCH(CH 3)(NH 2)或-COCH 2CH 3;R 3和R 4独立地选自:氢、-COCH 2CH 3和-COCH(CH 3)(NH 2),且满足以下条件:R 3和R 4独立地选自:氢、-COCH 2CH 3和-COCH(CH 3)(NH 2),且满足以下条件:2)当x为1时,A 1与A 1’相同或者不同,其中一个单元A 1的R 1、R 2、R 3、R 4中的任意一个通过L 1与相邻单元A 1’的R 1’、R 2’、R 3’、R 4’中的任意一个相连;各L 1独立地选自下组的单元连接基团组成:不存在、O、S、羰基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烷基-O-(或者-O-C1-C6烷基-O-)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-)、环烷基(或者C3-C7环烷基)、杂烷基(或者3-7元杂烷基),其中烷基、环烷 基、杂烷基任选地被一个或多个独立选自Z的基团取代;Z各自独立选自下组基团:卤素、氨基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、卤代烷基(或者卤代C1-C6烷基)、环烷基(或者C3-C7环烷基)、芳基(或者C6-C12芳基)、杂环;或者L 1选自:不存在、-CR’R”,其中R’和R”各自独立地为H、C1-C6烷基(或者C1-C3烷基);再或者L 1选自:不存在、-CH 2-、-CH(CH 3)-、-C-(CH 3) 2;对于A 1,其中:R 1和R 2各自独立选自下组基团:C1-C6烷基、-O-、-O-R a1、-NR a2R a3;R 3和R 4各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;R a1、R a2、R a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 1选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基) n-O-(CO)-R b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;再或者,R 1选自:-O-,羟基,-O-R a:R a为C1-C6烷基;进而再或者,R 1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH 3) 2;或者,R 2选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基) n-O-(CO)-R b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;再或者,R 2选自:羟基,-O-,-O-R a:R a为C1-C6烷基;进而再或者,R 2选自:羟基、-O-、甲氧基,R 3与R 4各自独立地选自:氢、羟基、C1-C6烷基;或者,R 3和R 4各自独立地为氢;R 5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5选自氢、氨基;再或者R 5选自氢;Y为C;y选自0、1、2、3;或者y为0或1;再或者y为0;对于A 1’,其中:R 1’和R 2’各自独立选自下组基团:C1-C6烷基、-O-、-O-R a1、-NR a2R a3;R 3’和R 4’各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;R a1、R a2、R a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 1’选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基) n-O-(CO)-R b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;再或者,R 1’选自:-O-,羟基,-O-R a:R a为C1-C6烷基;进而再或者,R 1’选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH 3) 2;或者,R 2’选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基) n-O-(CO)-R b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;再或者,R 2’选自:羟基,-O-,-O-R a:R a为C1-C6烷基;进而再或者,R 2’选自:羟基、-O-、甲氧基;R 3’与R 4’各自独立地选自:氢、羟基、C1-C6烷基;或者,R 3’和R 4’各自独立地为氢;R 5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5’选自氢、氨基;再或者R 5’选自氢;Y’为C;y’选自0、1、2、3;或者y为0或1;再或者y’为0;3)当x为2时,A 1与A 1’相同或者不同,其中一个单元A 1的R 1、R 2、R 3、R 4中的任意一个通过L 1与相邻单元A 1’的R 1’、R 2’、R 3’、R 4’中的任意一个相连;各L 1独立地选自下组的单元连接基团组成:不存在、O、S、羰基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、-O-烷基-O-(或者-O-C1-C6烷基-O-)、-O-烯基-O-(或者-O-C2-C6烯基-O-)、-O-炔基-O-(或者-O-C2-C6炔基-O-)、环烷基(或者C3-C7环烷基)、杂烷基(或者3-7元杂烷基),其中烷基、环烷 基、杂烷基任选地被一个或多个独立选自Z的基团取代;Z各自独立选自下组基团:卤素、氨基、烷基(或者C1-C6烷基)、烯基(或者C2-C6烯基)、炔基(或者C2-C6炔基)、卤代烷基(或者卤代C1-C6烷基)、环烷基(或者C3-C7环烷基)、芳基(或者C6-C12芳基)、杂环;或者L 1选自:不存在、-CR’R”,其中R’和R”各自独立地为H、C1-C6烷基(或者C1-C3烷基);再或者L 1选自:不存在、-CH 2-、-CH(CH 3)-、-C-(CH 3) 2;进而再或者,L 1选自:-CH 2-;对于A 1,其中:R 1和R 2各自独立选自下组基团:C1-C6烷基、-O-、-O-R a1、-NR a2R a3;R 3和R 4各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;R a1、R a2、R a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 1选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基) n-O-(CO)-R b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;再或者,R 1选自:-O-,羟基,-O-R a:R a为C1-C6烷基;进而再或者,R 1选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH 3) 2;再进一步或者,R 1选自:甲氧基;或者,R 2选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基) n-O-(CO)-R b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;再或者,R 2选自:羟基,-O-,-O-R a:R a为C1-C6烷基;进而再或者,R 2选自:羟基、-O-、甲氧基,再进一步或者,R 2选自:-O-;R 3与R 4各自独立地选自:氢、羟基、C1-C6烷基;或者,R 3和R 4各自独立地为氢;R 5选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5选自氢、氨基;再或者R 5选自氢;Y为C;y选自0、1、2、3;或者y为0或1;再或者y为0;对于A 1’,其中:R 1’和R 2’各自独立选自下组基团:C1-C6烷基、-O-、-O-R a1、-NR a2R a3;R 3’和R 4’各自独立选自下组基团:氢、氘、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、C1-C6烷基、卤代C1-C6烷基、芳基(或者C6-C12芳基)、杂环的基团取代;R a1、R a2、R a3各自独立选自下组基团:氢、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,所述烷基、烯基、炔基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;或者,R 1’选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基) n-O-(CO)-R b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;再或者,R 1’选自:-O-,羟基,-O-R a:R a为C1-C6烷基;进而再或者,R 1’选自:-O-、羟基、甲氧基、乙氧基、-OCH(CH 3) 2;再进一步或者,R 1’选自:甲氧基;或者,R 2’选自:-O-,C1-C6烷基,-O-R a1,其中,R a1选自:氢、C1-C6烷基、C2-C6烯基、C3-C7环烷基、C6-C10芳基、3-15元杂环基,-(C1-C6烷基) n-O-(CO)-R b1,所述烷基、烯基、环烷基、芳基、杂环基任选地被一个或多个独立选自卤素、氨基、羟基、C1-C6烷基、C6-C10芳基、3-15元杂环基、-(C1-C6烷基)-(C6-C10芳基)、-(C1-C6烷基)-(3-15元杂环基)的基团取代;再或者,R 2’选自:羟基,-O-,-O-R a:R a为C1-C6烷基;进而再或者,R 2’选自:羟基、-O-、甲氧基;再进一步或者,R 2’选自:-O-;R 3’与R 4’各自独立地选自:氢、羟基、C1-C6烷基;或者,R 3’和R 4’各自独立地为氢;R 5’选自下组基团:氢、氘、C1-C6烷基、卤素、氨基;或者R 5’选自氢、氨基;再或者R 5’选自氢;Y’为C;y’选自0、1、2、3;或者y为0或1;再或者y’为0;或者式II为:
- 药物组合物,其包含权利要求12-13任一项所述的式II所示的化合物,其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、同位素化合物、晶型、它们的代谢物形式、或它们的任意组合或混合物;任选地,所述药物组合物还包含药学上可接受的载体或辅料;任选地,所述药物组合物还包含另外的活性成分:其他用于改善肝功能作用的氨基酸(包括但不限于丙氨酸、谷氨酸、胱氨酸、谷氨酰胺、甘氨酸、组氨酸、酪氨酸、丝氨酸、蛋氨酸、精氨酸、亮氨酸)、胆固醇吸收抑制剂(如依替米贝)、HSC活化增殖抑制剂(如吡非尼酮、氟非尼酮、Pegbelfermin)PCSK9抑制剂、PPAR激动剂(如吉非 罗齐、非诺贝特、氯贝特、苯扎贝特、培马贝特、Elafibranor)、ACE抑制剂、CCR2/5抑制剂、TLR4抑制剂、LOXL2抑制剂、TIMP-1抑制剂、FXR激动剂、AT1R阻滞剂、NOX抑制剂、钙离子通道阻断剂、ARBs、利尿剂、肾素、GLP-1或其合成变体、胰岛素或其合成变体、二甲双胍、磺酰脲化合物、噻唑烷二酮(TZD)、SGLT2抑制剂、DPP-IV抑制剂、HMGCoA还原酶的抑制剂、前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(PCSK9)的抑制剂、吉卡宾(CI-1027)、ACC抑制剂、ApoC-III抑制剂、ACL-抑制剂(如贝派地酸)、处方鱼油、CETP抑制剂、熊去氧胆酸、奥贝胆酸、多烯磷脂酰胆碱、糖皮质激素、水飞蓟素、甘草酸类制剂(如异甘草酸镁注射液和甘草酸二铵肠溶胶囊)以及它们的组合;任选地,所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂或复方制剂。
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