Substituted alkane diacid compound as well as composition and application thereof

Abstract

The invention provides a novel compound or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or prodrug or a composition thereof. Meanwhile, the compound is used for inhibiting ATP citrate lyase (ACLY) or increasing the HDL level or reducing the LDL level.

Description

Cross-references to related applications

[0001] This application claims priority to international patent application PCT / CN2023 / 088528, filed on April 14, 2023, with the China National Intellectual Property Administration as the receiving office. Technical Field

[0002] This invention relates to a novel compound or its stereoisomers, geometric isomers, tautomers, etc. N - Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or combinations thereof; also relating to the inhibition of ATP citrate lyase (ACLY); increasing high-density lipoprotein (HDL) levels or decreasing low-density lipoprotein (LDL) levels; or the prevention, control, treatment or relief of the following diseases: aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein metabolism disorders, hypertension, erectile dysfunction, inflammation, insulin resistance, bile... Applications include lipid clearance disorders, obesity, cholecystosteroid clearance disorders, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, bile phospholipid clearance disorders, kidney diseases, sepsis, Syndrome X, thrombotic diseases, C-reactive protein regulation, and bile production promotion; as well as the following liver diseases: hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, and acute fatty liver of pregnancy. Background Technology

[0003] ATP citrate lyase (ACLY) is a homotetrameric enzyme that catalyzes an ATP-dependent reaction, cleaving citrate into acetyl-CoA and oxaloacetate (OAA). Acetyl-CoA is not only an important cellular metabolite but also functions as a second messenger; therefore, the enzymatic activity of ATP citrate lyase (ACLY) occupies a central position in intermediate metabolism. The formation of acetyl-CoA begins with phosphorylation at histidine 760 (His760) in ACLY. This modification triggers an enzymatic reaction: first, citrate phosphate is formed, followed by the formation of the citrate-CoA intermediate under CoA attack. Finally, the citrate-CoA intermediate cleaves, releasing acetyl-CoA and oxaloacetate (OAA). Acetyl-CoA, catalyzed by ACLY, participates in cholesterol synthesis via the mevalonate pathway as a carbon source and in de novo lipogenesis (DNL) as a fatty acid (FA). It also serves as an essential substrate for protein acetylation, thus establishing a crucial link between cellular metabolism, epigenetic regulation, and gene expression. Therefore, acetyl-CoA production, as a key regulatory node in cellular metabolism, coordinates cellular metabolic activities according to nutritional status and plays a central role in the synthesis of sterols and lipids in various tissues. Consequently, directly inhibiting the activity of ATP citrate lyase (ACLY) may have significant clinical implications for the treatment of various diseases, including hypercholesterolemia, cardiovascular disease (CVD), obesity, diabetes, insulin resistance, fatty liver, metabolic syndrome, and cancer.

[0004] Fatty liver disorders, also known as fatty liver disease (FLD), are a pathological condition characterized by the accumulation of large amounts of triglyceride-rich fat vesicles within liver cells. Early-stage FLD is often mild and may be reversible, but it can progress to more severe conditions. FLD can be divided into two distinct types: alcoholic fatty liver disease (also known as alcoholic steatosis, at least partially caused by alcohol abuse) and non-alcoholic fatty liver disease (NAFLD, unrelated to alcohol abuse). Both types typically exhibit microvesicular and macrovesicular steatosis at different stages of the disease. Fat accumulation may also be accompanied by progressive liver inflammation (i.e., hepatitis), a condition known as steatohepatitis. Steatohepatitis can be further classified into alcoholic steatohepatitis and non-alcoholic steatohepatitis (NASH). Nonalcoholic fatty liver disease-related cirrhosis is the most severe stage of the disease, characterized by liver inflammation leading to scarring of the liver tissue.

[0005] Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common causes of chronic liver disease in adults and are also important risk factors for progression to cirrhosis, hepatocellular carcinoma, and liver failure. Experts estimate that approximately two-thirds of obese adults and half of obese children may have fatty liver disease. The rising incidence of NAFLD and NASH in the United States may be related to the country's continued increase in obesity rates.

[0006] Hepatocellular carcinoma (HCC) is one of the most common primary malignant tumors of the liver. Patients with chronic liver diseases (such as cirrhosis and liver fibrosis) have a significantly increased risk of developing HCC. Therefore, patients with chronic liver diseases should be closely monitored for the development of HCC. Risk factors for HCC include: cirrhosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic alcoholism, hepatitis B, hepatitis C, type IIb hyperlipidemia, mixed dyslipidemia, obesity, and type 2 diabetes.

[0007] Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) are the main cholesterol transport carrier proteins in the body. The primary physiological function of LDL is to transport cholesterol from the liver to peripheral tissues. This cholesterol can originate from liver synthesis or dietary absorption. "Cholesterol reverse transport" refers to the transport of cholesterol from peripheral tissues to the liver, where it is metabolized and excreted. Current research indicates that plasma HDL particles play a crucial role in cholesterol reverse transport, primarily clearing cholesterol from peripheral tissues. Furthermore, HDL also has the function of clearing non-cholesterol lipids, oxidized cholesterol, and other oxidation products from the blood. For example, atherosclerosis is a chronic, progressive disease characterized by cholesterol deposition in the arterial walls. Sufficient evidence suggests that the lipids deposited in atherosclerotic lesions mainly originate from plasma lipoproteins containing apolipoprotein B (apo B), including chylomicrons, VLDL, DDL, and LDL. Lipoproteins containing apolipoprotein B (apo B), especially low-density lipoprotein (LDL), are commonly referred to as "bad cholesterol." Conversely, serum high-density lipoprotein (HDL) levels are negatively correlated with the incidence of coronary heart disease. In fact, high serum HDL levels are considered a protective factor against cardiovascular disease. It is speculated that high levels of HDL in plasma not only have a protective effect against coronary artery disease but may even promote the regression of atherosclerotic plaques (see: Badimon et al., 1992, Circulation 86: (Supplement 111) 86-94; Dansky and Fisher, 1999, Circulation 100: 1762-3). Therefore, HDL is commonly referred to as "good" cholesterol. Summary of the Invention

[0008] This invention relates to a compound or its stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or compositions comprising the compound. The compound or its compositions possess excellent pharmacodynamic and pharmacokinetic properties, and can be used to inhibit ATP citrate lyase or activate AMP-activated protein kinase, and can increase high-density lipoprotein (HDL) levels or decrease low-density lipoprotein (LDL) levels. These novel compounds or combinations thereof are effective in treating the following diseases: aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein metabolism disorders, hypertension, erectile dysfunction, inflammation, insulin resistance, bile lipid clearance disorders, obesity, bile oxysterol clearance disorders, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, bile phospholipid clearance disorders, kidney disease, sepsis, Syndrome X, thrombotic diseases, C-reactive protein regulation, and bile production promotion; and the following liver diseases: hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, and acute fatty liver of pregnancy; particularly hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, and cirrhosis.

[0009] On the one hand, the present invention provides a compound having the structure of Formula I, I Or its stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs. Among them, R 1 R 2 R 3 and R 4 Each of these can be independently H, D, amino, nitro, hydroxyl, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylamino, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, (C1-C9)heteroaryl, (C3-C7)cycloalkyl-(C1-C6)alkyl, (C2-C6)heterocyclic-(C1-C6)alkyl, (C6-C10)aryl-(C1-C6)alkyl, or (C1-C9)heteroaryl-(C1-C6)alkyl; or R on the same atom. 1 and R 2Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on the same atom 3 and R 4 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on different atoms 1 and R 2 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R on different atoms 3 and R 4 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R 1 and its adjacent R 2 Together with the atoms they are attached to, they form double bonds; or R 3 and its adjacent R 4 Together with the atoms they are attached to, they form double bonds; R on different atoms 1 and R 2 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; R 1 R 2 R 3 and R 4 Each of them may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen or cyano; n and m are each independently 4, 5, 6, 7, 8, 9 or 10; R is H, D, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, or (C1-C9)heteroaryl; R is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, or cyano; G is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, or (C1-C9)heteroaryl; G is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, or cyano. Or G is Or one or more deuterium-substituted ; Or G is H, and at the same time, at least one R 1 Independently, it is a hydroxyl group; Y 1 and Y 2Each can be independently -OH, -(C1-C6)alkylene-OH, -C(=O)-OH, -C(=O)H, or -C(=O)OR. 5 -S(=O)2OH or -S(=O)2NH2 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; or Y 1 and Y 2 One of them is ; R 5 It is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, (C1-C9)heteroaryl, (C3-C7)cycloalkyl-(C1-C6)alkyl, (C2-C6)heterocyclic-(C1-C6)alkyl, (C6-C10)aryl-(C1-C6)alkyl, or (C1-C9)heteroaryl-(C1-C6)alkyl; R 5 Optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, cyano, (C1-C6)alkoxy or (C1-C6) haloalkoxy; R 6 and R 7 Each is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)ynyl; R 6 and R 7Optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, cyano, (C1-C6)alkoxy or phenyl.

[0010] On the other hand, the present invention also provides compounds including the present invention's stereoisomers, geometric isomers, tautomers, and other isomers thereof. N - A pharmaceutical composition comprising oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs and pharmaceutically acceptable carriers, excipients or diluents.

[0011] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N - Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising compounds of the present invention for the prevention, control, treatment or relief of diseases associated with ATP citrate lyase or AMP-activated protein kinase or combinations thereof.

[0012] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions including compounds of the present invention are used to prevent, control, treat or alleviate disease by increasing HDL levels.

[0013] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions including compounds of the present invention are used to prevent, control, treat or alleviate disease by lowering LDL levels.

[0014] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N- Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising said compounds, for the prevention, control, treatment or relief of aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein metabolism disorders, hypertension, erectile dysfunction, inflammation, insulin resistance, bile lipid clearance disorders, obesity, bile oxysterol clearance disorders, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, bile phospholipid clearance disorders, kidney disease, sepsis, Syndrome X, thrombotic diseases, C-reactive protein regulation, bile production promotion; and the following liver diseases: hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, and acute fatty liver of pregnancy.

[0015] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N - The use of oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising compounds of the present invention in the preparation of a medicament for the prevention, control, treatment or relief of diseases associated with ATP citrate lyase or AMP-activated protein kinase or combinations thereof.

[0016] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N - The use of oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising compounds of the present invention in the preparation of a medicament for the prevention, control, treatment or relief of related diseases by increasing HDL levels.

[0017] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N - The use of oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising compounds of the present invention in the preparation of a medicament for the prevention, control, treatment or relief of related diseases by lowering LDL levels.

[0018] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N- Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising said compounds, for the preparation of medicaments for the prevention, control, treatment or relief of aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein metabolism disorders, hypertension, erectile dysfunction, inflammation, insulin resistance, bile lipid clearance disorders, obesity, bile oxysterol clearance disorders, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, bile phospholipid clearance disorders, kidney disease, sepsis, syndrome X, thrombotic diseases, C-reactive protein regulation, bile production promotion; and the following liver diseases: hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, and acute fatty liver of pregnancy.

[0019] On the other hand, the present invention also provides a method for preventing, controlling, treating, or alleviating diseases associated with ATP citrate lyase (ACLY) or AMP-activated protein kinase (AMPK) or combinations thereof, comprising administering a therapeutically effective amount of the compound of the present invention or its stereoisomers, geometric isomers, tautomers, or derivatives to a mammal in need. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions containing said compounds.

[0020] On the other hand, the present invention also provides a method for preventing, controlling, treating, or alleviating disease by increasing HDL levels, comprising administering a therapeutically effective amount of the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc., to a mammal in need. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions containing said compounds.

[0021] On the other hand, the present invention also provides a method for preventing, controlling, treating, or alleviating disease by lowering LDL levels, comprising administering a therapeutically effective amount of the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc., to a mammal in need. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions containing said compounds.

[0022] On the other hand, the present invention also provides a method for preventing, controlling, treating, or alleviating aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein metabolism disorders, hypertension, erectile dysfunction, inflammation, insulin resistance, bile lipid clearance disorders, obesity, bile oxysterol clearance disorders, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, bile phospholipid clearance disorders, kidney disease, sepsis, Syndrome X, thrombotic diseases, C-reactive protein regulation, and bile production promotion. Methods for treating or preventing liver diseases including hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, and acute fatty liver of pregnancy, comprising administering to a patient in need of treatment or prevention a therapeutically or preventively effective amount of the compound of the present invention or its stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising said compound.

[0023] This invention covers all combinations of the specific embodiments described herein, as if each combination has been individually and exhaustively listed.

[0024] This invention covers all combinations of the specific embodiments described herein. Detailed Implementation

[0025] To better understand the present invention and demonstrate its embodiments, the following description, in conjunction with the accompanying drawings, will provide an exemplary account. It should be specifically noted that the details illustrated in the drawings are solely for illustrative purposes to demonstrate and explain the core principles and concepts of the preferred embodiments of the present invention, aiming to provide the clearest and most understandable technical solution description, but should not be construed as any limitation on the scope of protection of the invention.

[0026] definition To facilitate understanding of this invention, some terms and phrases are defined below.

[0027] Unless the context otherwise requires, throughout the entire scope of this disclosure and the claims, "comprising" and its variations shall be understood to have an open-ended, inclusive meaning, that is, "including but not limited to".

[0028] In this specification, references to "one embodiment" or "a particular embodiment" refer to specific features, structures, or characteristics described that are included in at least one embodiment of this disclosure. Therefore, the expressions "in one embodiment" or "in a particular embodiment" appearing throughout this specification do not necessarily refer to the same embodiment. Furthermore, these specific features, structures, or characteristics can be combined in any suitable manner in one or more embodiments.

[0029] The terms "optional" or "optionally" in this specification mean that the event or situation described below may or may not occur, and the description should be understood to include both the occurrence and non-occurrence of the event / situation. For example, "optionally substituted heterocyclic group" means that the heterocyclic group may or may not be substituted, and this statement includes both substituted and unsubstituted heterocyclic groups.

[0030] When the term "independently" is used to describe substituents, it means that when a group is replaced by multiple substituents, these substituents can be the same or different from each other. Similarly, if multiple atoms or groups are "independently selected" from a specified group, the term "independently selected" or "independently is" means that each atom / group on the substituent can be the same as or different from the other atoms / groups. Furthermore, if a group can be replaced by multiple substituents, the term "independently selected" means that each substituent can be the same as or different from the other substituents.

[0031] As used herein, “a” or “an” means “one or more” and includes the plural form unless the context otherwise requires.

[0032] The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts can be formed by reacting the basic compounds of the present invention with inorganic or organic acids, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonates. Pharmaceutically acceptable salts can also be formed by reacting the acidic compounds of the present invention with inorganic or organic bases, such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ammonia, isopropylamine, and trimethylamine. Those skilled in the art will understand that pharmaceutically acceptable salts of the compounds of the present invention can be prepared by reacting the compound with a suitable inorganic acid, organic acid, inorganic base, or organic base.

[0033] The term "solvent" refers to a solvated complex formed by the binding of solute and solvent molecules through intermolecular forces. Solvents can be formed through solvation (a combination of solvent molecules and molecules or ions of the compounds of this invention), or they may be aggregates containing solute ions or molecules or solvent molecules. When the solvent is water, the resulting solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, and hexahydrates. Solvents can be formed through hydration, including through hygroscopic action. Pharmaceutically acceptable salts may also exist simultaneously as solvates. When a solvate is obtained by solvent crystallization, the solvent used can be an alcohol (such as methanol or ethanol), an aldehyde, a ketone (such as acetone), or an ester (such as ethyl acetate).

[0034] The compounds of this invention may contain one or more asymmetric centers, and therefore may exist as enantiomers, racemates, diastereomers, other stereoisomers, and mixtures thereof. The compounds of this invention include all possible isomers (including geometric isomers), as well as their racemic and optically pure forms, whether or not these forms are specifically described herein. Optically active isomers, (+) / (-), (R) / (S), or (D) / (L) isomers, can be synthesized using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing or separating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds of this invention contain an olefinic double bond or another geometrically asymmetric center, unless otherwise stated, the compounds of this invention include E and Z geometric isomers. Similarly, the compounds of this invention include all tautomeric forms.

[0035] As used herein, the term "stereoisomer" refers to a compound composed of identical atoms linked by the same bonds, but having different three-dimensional structures that are not interchangeable. This invention covers a variety of stereoisomers and mixtures thereof, including "enantiomers"—two stereoisomers whose molecular structures are non-overlapping mirror images of each other. In any embodiment disclosed herein, the disclosed compound may exist in its stereoisomer form.

[0036] The term “geometric isomer” as used in this article refers to diastereomers resulting from hindered double bond rotation. According to the Cahn-Ingold-Prelog rule, these configurations are distinguished by the prefixes “cis” and “trans”, or “Z” and “E”, which indicate whether the groups in the molecule are on the same side or opposite sides of the double bond.

[0037] The term "tautomer" as used in this article refers to a dynamic equilibrium between two or more structural isomers that readily interconvert. This transformation process involves the migration of hydrogen atoms and the conversion of adjacent conjugated double bonds. Tautomers coexist in solutions as mixed systems. In the solid state, one configuration usually predominates. In solutions where tautomerism is possible, all configurations eventually reach chemical equilibrium. The specific proportions of tautomers depend on various factors, including temperature, solvent, and pH. The phenomenon of interconversion between tautomers through tautomerism is called tautomerism.

[0038] The compounds of this invention can exist in the form of nitride oxides, i.e., at least one nitrogen atom in the compound is oxidized. This invention covers all such possible nitride oxide forms.

[0039] As used herein, “metabolite” refers to the metabolite of the compound of the present invention or its pharmaceutically acceptable salt, solvate, diastereomer and polymorph, and the metabolite exhibits similar activity in vivo to the compound of the present invention or its pharmaceutically acceptable salt, solvate, diastereomer and polymorph.

[0040] As used herein, "prodrug" refers to derivatives of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, diastereomers, and polymorphs, formed by covalently linking one or more precursor groups (such as amino acid groups or other water-soluble groups). The compounds of the present invention or their pharmaceutically acceptable salts, solvates, diastereomers, and polymorphs can be released from the precursor groups via hydrolysis, oxidation, and / or enzymatic decomposition mechanisms. In some embodiments, the prodrug compositions of the present invention have additional advantages such as enhanced water solubility, improved stability, and optimized pharmacokinetic characteristics. The desired prodrug properties can be obtained by selecting the precursor group. For example, the precursor group can be selected based on solubility, stability, bioavailability, and / or in vivo delivery or uptake, such as an amino acid moiety or other water-soluble moiety, such as a phosphate in R4. Examples of prodrugs include, but are not limited to, esters with hydroxyl functional groups (such as acetates, dialkylaminoacetic acids, formate esters, phosphates, sulfates, and benzoate derivatives) and carbamates (such as... N,N esters with a dimethylaminocarbonyl group (-dimethylaminocarbonyl), a carboxyl functional group, such as ethyl esters and morpholinoethanol esters. N -acyl derivatives (such as N -acetyl) N - Mannich bases, Schiff bases with amino functional groups and enamine ketones, oximes, acetals, ketals and enol esters with ketal and aldehyde functional groups, see Bundegaard, H., Drug Design, pp. 1-92, Elesevier, New York Oxford (1985).

[0041] The stereoisomers of the compounds of this invention can be prepared by synthesis from commercially available starting materials containing asymmetric or stereocenters, or by preparing racemic mixtures and then using resolution methods well known to those skilled in the art. Examples of such resolution methods include (1) attaching an enantiomer mixture to a chiral auxiliary agent, separating the resulting diastereomer mixture by recrystallization or chromatography, and releasing the optically pure product from the auxiliary agent; (2) forming a salt using an optically active resolving agent; or (3) directly separating the optically enantiomer mixture on a chiral chromatographic column. The stereoisomer mixture can also be resolved into its single components by methods known in the art, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallizing the compound into a chiral salt complex, or crystallizing the compound in a chiral solvent. The stereoisomers can also be prepared by asymmetric synthesis methods known in the art from stereochemically pure intermediates, reagents, and catalysts.

[0042] This invention also includes isotopically labeled compounds of the compounds of this invention, which are identical to the compounds described herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, […]. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl.

[0043] "Effective dose" or "therapeutic effective dose" means the amount of a compound according to the embodiments disclosed herein that, when administered to a patient in need, is sufficient to produce a therapeutic effect on the disease state, symptom, or disorder disclosed herein. This dose should be sufficient to elicit the biological or medical response in the tissue system or patient as desired by the researcher or clinician. The therapeutic effective dose of the compounds in the embodiments of the invention may vary due to a variety of factors, including the compound itself and its biological activity characteristics, the formulation composition used for administration, the time and route of administration, the excretion rate of the compound, the duration of treatment, the type and severity of the disease state or symptom being treated, other drugs used in combination with or concurrently with the compounds of the embodiments of the invention, the patient's age, weight, general health status, sex, and diet. Those skilled in the art can determine the therapeutic effective dose based on their expertise, the level of prior art, and the content of this disclosure.

[0044] "Subject" refers to a human or non-human mammal, such as a cow, horse, cat, dog, rodent, or non-human primate. The human subject may be male or female, including children, adolescents, or adults. The female subject may be an individual before or after menarche.

[0045] “Mammals” include humans, domesticated animals such as laboratory animals (e.g., mice, rats, rabbits, monkeys, dogs, etc.) and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits) as well as non-domesticated wild animals.

[0046] As used herein, the term "treatment" refers to the administration of a compound or composition according to embodiments disclosed in this invention to alleviate or eliminate one or more symptoms of HIV infection and / or reduce the viral load in a patient. In some embodiments, the term "treatment" further includes administration of the compound or composition disclosed in this invention after an individual has been exposed to the virus but before the onset of disease symptoms, and / or before the virus is detected in the blood, to prevent the onset of disease symptoms; and / or to prevent the virus from reaching detectable levels in the blood; and to prevent mother-to-child vertical transmission of HIV by administering the medication to the mother before delivery; and to administer the medication to the infant within days of birth. The term "treatment" also includes administration of the compound or composition disclosed in this invention before an individual is exposed to the virus (also known as pre-exposure prophylaxis or PrEP) to achieve one or more of the following preventive effects: prevention of HIV infection if the individual is exposed to the virus; prevention of permanent infection; prevention of the onset of disease symptoms; and prevention of the virus from reaching detectable levels in the blood. The term "treatment" also includes administration of the compound or composition disclosed in this invention both before and after an individual is exposed to the virus.

[0047] As used herein, the term "prevention" refers to the administration of a compound, composition, or pharmaceutically acceptable salt described in this disclosure before or after human exposure to a virus (but before the onset of disease symptoms and / or before the virus is detected in the blood). These terms also refer to the prevention of the onset of disease symptoms and / or the prevention of the virus from reaching detectable levels in the blood. These terms include pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), and event-driven or "on-demand" prophylaxis. These terms also refer to the prevention of HIV transmission from mother to infant during the perinatal period by administering medication to the mother before delivery and to the infant within days after birth. These terms also refer to the prevention of HIV transmission through blood transfusion.

[0048] Unless otherwise stated, all weight percentages (i.e., “weight%”, “wt.%”, and w / w) cited herein are relative to the total weight of the mixture or composition, as applicable.

[0049] "Alkyl" refers to a fully saturated straight-chain or branched hydrocarbon chain having 1 to 12 carbon atoms, linked by single bonds. Alkyl groups with 1 to 12 carbon atoms are all included. Alkyl groups with 1 to 12 carbon atoms are C1-C12 alkyl groups, alkyl groups with 1 to 10 carbon atoms are C1-C10 alkyl groups, alkyl groups with 1 to 6 carbon atoms are C1-C6 alkyl groups, and alkyl groups with 1 to 5 carbon atoms are C1-C5 alkyl groups. C1-C5 alkyl groups include: C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl groups include all C1-C5 alkyl groups described above, and also include C6 alkyl groups. C1-C10 alkyl groups include all C1-C5 and C1-C6 alkyl groups described above, and also include C7, C8, C9, and C10 alkyl groups. Similarly, C1-C12 alkyl groups include all the above alkyl types, and also include C11 and C12 alkyl groups. Non-limiting examples of C1-C12 alkyl groups include: methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise stated, the alkyl group may be unsubstituted or substituted with the substituents disclosed herein.

[0050] "alkylene" refers to a fully saturated straight-chain or branched divalent hydrocarbon group having 1 to 12 carbon atoms. Non-limiting examples of C1-C12 alkylenes include methylene, ethylene, propylene, n-butylene, etc. Each end of an alkylene group is connected to an atom by a single bond. The linking point of the alkylene chain can be one or two atoms. Unless otherwise stated, the alkylene chain can be unsubstituted or substituted with the substituents disclosed herein.

[0051] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 12 carbon atoms and containing one or more carbon-carbon double bonds. Each alkenyl group is connected to an atom by a single bond. Alkenyl groups with 2 to 12 carbon atoms are all included. Alkenyl groups with 2 to 12 carbon atoms are C2-C12 alkenyl groups, alkenyl groups with 2 to 10 carbon atoms are C2-C10 alkenyl groups, alkenyl groups with 2 to 6 carbon atoms are C2-C6 alkenyl groups, and alkenyl groups with 2 to 5 carbon atoms are C2-C5 alkenyl groups. C2-C5 alkenyl groups include C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl groups. C2-C6 alkenyl groups include all C2-C5 alkenyl groups described above, and also include C6 alkenyl groups. C2-C10 alkenyl groups include all C2-C5 alkenyl groups and C2-C6 alkenyl groups described above, and also include C7, C8, C9, and C10 alkenyl groups. Similarly, C2-C12 alkenyl groups include all the alkenyl types mentioned above, and also include C11 and C12 alkenyl groups. Non-limiting examples of C2-C12 alkenyl groups include: vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl. 6-Nonenyl, 7-Nonenyl, 8-Nonenyl, 1-Decenyl, 2-Decenyl, 3-Decenyl, 4-Decenyl, 5-Decenyl, 6-Decenyl, 7-Decenyl, 8-Decenyl, 9-Decenyl, 1-Undecenyl, 2-Undecenyl, 3-Undecenyl, 4-Undecenyl, 5-Undecenyl, 6-Undecenyl, 7-Undecenyl, 8-Undecenyl, 9-Undecenyl, 10-Undecenyl, 1-Dodecenyl, 2-Dodecenyl, 3-Dodecenyl, 4-Dodecenyl, 5-Dodecenyl, 6-Dodecenyl, 7-Dodecenyl, 8-Dodecenyl, 9-Dodecenyl, 10-Dodecenyl, and 11-Dodecenyl. Unless otherwise stated, the alkenyl group may be unsubstituted or substituted with the substituents disclosed herein.

[0052] "Alkenyl" refers to a straight-chain or branched divalent hydrocarbon group having 2 to 12 carbon atoms and containing one or more carbon-carbon double bonds. Non-limiting examples of C2-C12 alkenyl groups include vinylidene, propenylidene, butenylidene, etc. Each end of an alkenyl group is connected to an atom by a single bond. The connection point of the alkenyl chain can be one or two atoms. Unless otherwise stated, the alkenyl chain can be unsubstituted or substituted with the substituents disclosed herein.

[0053] "Alynyl" refers to a straight-chain or branched hydrocarbon group having 2 to 12 carbon atoms and containing one or more carbon-carbon triple bonds. Each alkynyl group is connected to an atom by a single bond. Alynyl groups with 2 to 12 carbon atoms are all included. Alynyl groups with 2 to 12 carbon atoms are C2-C12 alkynyl groups, those with 2 to 10 carbon atoms are C2-C10 alkynyl groups, those with 2 to 6 carbon atoms are C2-C6 alkynyl groups, and those with 2 to 5 carbon atoms are C2-C5 alkynyl groups. C2-C5 alkynyl groups include C5, C4, C3, and C2 alkynyl groups. C2-C6 alkynyl groups include all C2-C5 alkynyl groups described above, and also include C6 alkynyl groups. C2-C10 alkynyl groups include all C2-C5 and C2-C6 alkynyl groups described above, and also include C7, C8, C9, and C10 alkynyl groups. Similarly, C2-C12 ynyl groups encompass all the ynyl groups described above, and also include C11 and C12 ynyl groups. Non-limiting examples of C2-C12 ynyl groups include ethynyl, propynyl, butynyl, pentyyn, etc. Unless otherwise stated, the ynyl group may be unsubstituted or substituted with the substituents disclosed herein.

[0054] "Idynyl" refers to a straight-chain or branched divalent hydrocarbon group having 2 to 12 carbon atoms and containing one or more carbon-carbon triple bonds. Non-limiting examples of C2-C12 yndynyl groups include ethynylene, propynylene, and butynylene. Each end of an yndynyl group is connected to an atom by a single bond. The linking point of the yndynyl chain can be one or two atoms. Unless otherwise stated, the yndynyl chain can be unsubstituted or substituted with the substituents disclosed herein.

[0055] "Alkoxy" indicates -OR a The group shown, wherein R a Alkyl groups are defined herein. Unless otherwise stated, an alkoxy group may be unsubstituted or substituted with the substituents disclosed herein. In some embodiments, "alkoxy" is a (C1-C6)alkoxy group. In some embodiments, "alkoxy" is a (C1-C4)alkoxy group. In some embodiments, "alkoxy" is a methoxy or ethoxy group.

[0056] "Alkylamino" formula — NHR a Or —NR a R b The group shown, wherein R a Or R bAlkyl, alkenyl, or alkynyl groups are defined herein. Unless otherwise stated, the alkylamino group may be unsubstituted or substituted with the substituents disclosed herein. In some embodiments, "alkylamino" is (C1-C6)alkylamino; in some embodiments, "alkylamino" is (C1-C4)alkylamino; in some embodiments, "alkylamino" is methylamino or dimethylamino.

[0057] "Alkylthio" index — SR a The group shown, wherein R a Alkyl, alkenyl, or alkynyl groups as defined herein. Unless otherwise stated, the alkathioyl group may be unsubstituted or substituted with the substituents disclosed herein. In some embodiments, "alkathioyl" is (C1-C6)alkathioyl; in some embodiments, "alkathioyl" is (C1-C4)alkathioyl; in some embodiments, "alkathioyl" is methylthioyl or ethylthioyl.

[0058] "Aryl" refers to a hydrocarbon ring system group comprising 6 to 18 carbon atoms and at least one aromatic ring. In some embodiments, "aryl" comprises 6 to 10 carbon atoms, i.e., C6-C10 aryl. The aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, and may comprise a fused ring or a bridged ring system. Aryl groups include, but are not limited to, the following groups: acenaphthenyl, acenaphthenyl, acetanthenyl, anthracene, azulel, phenanthrene, fluorenyl, asymmetric-dihydroacenaphthenyl, symmetric-dihydroacenaphthenyl, indenyl, indenyl, naphthyl, phenanthrene, phenanthrene, phenyl, lavany, pyrene, and triphenylene. Unless otherwise stated, the aryl group may be unsubstituted or substituted with the substituents disclosed herein.

[0059] “Cycloalkyl” refers to a non-aromatic monocyclic or polycyclic fully saturated hydrocarbon group composed of carbon and hydrogen atoms, which may contain fused rings or bridged ring systems, having 3 to 20 carbon atoms (preferably 3 to 10 carbon atoms) and linked to atoms by single bonds. In some embodiments, “cycloalkyl” contains 3 to 7 carbon atoms, i.e., C3-C7 cycloalkyl. In some embodiments, “cycloalkyl” is C3-C6 cycloalkyl. Monocyclic cycloalkyl includes, but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl includes, but is not limited to: adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, etc. Unless otherwise stated, cycloalkyl may be unsubstituted or substituted with the substituents disclosed herein.

[0060] "Aryloxy group" refers to a group represented by the formula -O (aryl), wherein the aryl group is as defined herein. Aryloxy groups include, but are not limited to, phenoxy groups (-O phenyl). Unless otherwise stated, aryloxy groups may be unsubstituted or substituted with the substituents disclosed herein.

[0061] "Cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon group composed of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds. Cycloalkenyl groups may comprise fused or bridged ring systems, having 3 to 20 carbon atoms, and in some embodiments 3 to 10 carbon atoms. The cycloalkenyl group is linked to atoms by single bonds. Monocyclic cycloalkenyl groups include, but are not limited to: cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyl groups include, but are not limited to: bicyclic [2.2.1]hept-2-enyl, etc. Unless otherwise stated, the cycloalkenyl group may be unsubstituted or substituted with the substituents disclosed herein.

[0062] "Cycloynyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, and may comprise a fused ring or bridged ring system. It has 5 to 20 carbon atoms (5 to 10 carbon atoms in some embodiments) and is linked to the rest of the molecule by single bonds. Monocyclic cycloynyl groups include, for example, cycloheptynyl, cyclooctyynyl, etc. Unless otherwise stated, the cycloynyl group may be unsubstituted or substituted with the substituents disclosed herein.

[0063] "Heterocyclic group" refers to a 3- to 20-membered non-aromatic, partially unsaturated, or aromatic cyclic group comprising 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, or sulfur. Heterocyclic groups include heteroaryl groups as defined herein. Unless otherwise stated, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, and can comprise fused rings, bridged rings, and spirocyclic systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic group may optionally be oxidized, the nitrogen atom may optionally be quaternized, and the heterocyclic group may be partially or fully saturated. In some embodiments, the "heterocyclic group" comprises 2 to 6 carbon atoms, i.e., a C2-C6 heterocyclic group. Examples of heterocyclic groups include, but are not limited to, dioxolane, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thio-morpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise stated, heterocyclic groups may be unsubstituted or substituted with the substituents disclosed herein.

[0064] In some embodiments, "heteroaryl" refers to a 5- to 20-membered cyclic group comprising a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, and having at least one aromatic ring. The heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, and may contain fused or bridged ring structures; the nitrogen, carbon, or sulfur atom in the heteroaryl may optionally be oxidized; the nitrogen atom may optionally be quaternized. Examples of heteroaryl groups include, but are not limited to: aziridine, acridine, benzimidazolyl, benzotriazolyl, benzoindolyl, benzodioxacyclopentyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazolyl, 1,4-benzodioxacyclohexyl, benzonaphthofuranyl, benzooxazolyl, benzodioxacyclopentyl, benzodioxacyclohexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiopheneyl, benzo[b][1,4]dioxazolyl, 1,4-benzodioxacyclohexyl, benzonaphthofuranyl, benzo[b][1,4]dioxazol ... Triazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanoneyl, isothiazolyl, imidazoyl, indazole, indoleyl, isoindoleyl, dihydroindoleyl, isodihydroindoleyl, isoquinolinyl, indoleazinyl, isoxazolyl, naphridyl, oxadiazolyl, 2-oxoazapyridine, oxazolyl, ethylene oxide, 1-pyridyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1 H -Pyrroloyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridinyl, purineyl, pyrroloyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. Unless otherwise stated, heteroaryl groups may be unsubstituted or substituted. In some embodiments, the "heteroaryl" has 1-9 carbon atoms, i.e., C1-C9 heteroaryl; in other embodiments, the "heteroaryl" has 1-5 carbon atoms, i.e., C1-C5 heteroaryl.

[0065] “Cycloalkylalkyl” refers to a group with the structural formula —Rb—Rd, where Rb is an alkylene group as defined herein, and Rd is a cycloalkyl group as defined herein. For example, (C3-C7)cycloalkyl-(C1-C6)alkyl. Unless otherwise stated, cycloalkylalkyl groups may be unsubstituted or substituted with the substituents disclosed herein.

[0066] “Arylalkyl” refers to a group with the structural formula —Rb—Rc, where Rb is an alkylene group as defined herein, and Rc is an aryl group as defined herein, such as (C6-C10)aryl-(C1-C6)alkyl, including but not limited to benzyl, diphenylmethyl, etc. Unless otherwise stated, arylalkyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0067] “Heterocyclic alkyl” refers to a group with the structural formula —Rb—Rd, where Rb is an alkylene group as defined herein, and Rd is a heterocyclic group as defined herein. For example, (C2-C6)heterocyclic-(C1-C6)alkyl. Unless otherwise stated, heterocyclic alkyl groups may be unsubstituted or substituted with the substituents disclosed herein.

[0068] “Heteroarylalkyl” refers to a group with the structural formula —Rb—Rd, where Rb is an alkylene group as defined herein, and Rd is a heteroaryl group as defined herein. For example, (C1-C9)heteroaryl-(C1-C6)alkyl. Unless otherwise stated, heteroarylalkyl groups may be unsubstituted or substituted with the substituents disclosed herein.

[0069] Halogenated, halogenated, or halogenated refers to Br, Cl, F, or I.

[0070] The amino group refers to -NH2.

[0071] The nitro group refers to -NO2.

[0072] The hydroxyl group refers to -OH.

[0073] The cyano group refers to -CN.

[0074] When used herein, the term "substitution" means that one or more hydrogen atoms on a specified atom are replaced by a group selected from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom and the resulting compound is stable. When the substituent is a ketone group (=O), two hydrogen atoms on that atom are substituted. Aromatic ring structures do not contain ketone substitutions. An intracyclic double bond, as used herein, refers to a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). A stable compound / stable structure is a compound that can be isolated from the reaction mixture with effective purity and can be formulated into a pharmaceutical preparation with therapeutic efficacy.

[0075] If a substituent bond spans the bonds between atoms within the ring, then the substituent can be attached to any atom on the ring. When the atom to which the substituent is attached is not specified, it can be attached to any bondable atom in the molecular formula. Combinations of substituents and / or variables are permitted, provided that these combinations can form a stable compound.

[0076] When any variable (such as R) 0 When a group appears multiple times in any composition or molecular formula of a compound, its definition for each occurrence is independent of the definition for any other position. For example, if a group shows 0-2 R... 0 If a substituent is used, the group can optionally be replaced by up to two R groups. 0 Substituent substitution, and each R 0 The occurrence of each is independently selected from R 0The definition of scope. It must be emphasized again that the combination of substituents and / or variables must be able to form a stable compound to be permitted.

[0077] Compounds of the present invention On the one hand, the present invention provides a compound having the structure of Formula I: I; Its stereoisomers, geometric isomers, tautomers, N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs Among them, R 1 R 2 R 3 and R 4 Each of these can be independently H, D, amino, nitro, hydroxyl, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylamino, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, (C1-C9)heteroaryl, (C3-C7)cycloalkyl-(C1-C6)alkyl, (C2-C6)heterocyclic-(C1-C6)alkyl, (C6-C10)aryl-(C1-C6)alkyl, or (C1-C9)heteroaryl-(C1-C6)alkyl; or R on the same atom. 1 and R 2 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on the same atom 3 and R 4 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on different atoms 1 and R 2 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R on different atoms 3 and R 4 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R 1 and its adjacent R 2 Together with the atoms they are attached to, they form double bonds; or R 3 and its adjacent R 4 Together with the atoms they are attached to, they form double bonds; or R 1 and R 3 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; R 1 R 2 R3 and R 4 Each of them may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen or cyano; n and m are each independently 4, 5, 6, 7, 8, 9 or 10; R is H, D, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, or (C1-C9)heteroaryl; R is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, or cyano; G is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, or (C1-C9)heteroaryl; G is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, or cyano. Or G is Or one or more deuterium-substituted ; Or G is H, and at the same time, at least one R 1 Independently, it is a hydroxyl group; Y 1 and Y 2 Each can be independently -OH, -(C1-C6)alkylene-OH, -C(=O)-OH, -C(=O)H, or -C(=O)OR. 5 -S(=O)2OH or -S(=O)2NH2 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R 5 It is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, (C1-C9)heteroaryl, (C3-C7)cycloalkyl-(C1-C6)alkyl, (C2-C6)heterocyclic-(C1-C6)alkyl, (C6-C10)aryl-(C1-C6)alkyl, or (C1-C9)heteroaryl-(C1-C6)alkyl; R 5 Optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, cyano, (C1-C6)alkoxy or (C1-C6) haloalkoxy; R 6 and R 7 Each is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)ynyl; R 6 and R 7 Optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, cyano, (C1-C6)alkoxy or phenyl.

[0078] In some embodiments, G is methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxetyl, aziryl, tetrahydrofuranyl, pyrrolyl, 1,4-dioxanecyclol, morpholinyl, piperidinyl, piperazine, phenyl, or pyridinyl; wherein G is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, or cyano.

[0079] In some embodiments, G is methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; wherein G is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, or cyano.

[0080] In some embodiments, G is methyl, ethyl, or cyclopropyl; wherein G is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, or cyano.

[0081] In some implementations, Y 1 and Y 2Each can be independently -OH, -(C1-C6)alkyl-OH, -C(=O)-OH, -C(=O)H, or -C(=O)OR. 5 -S(=O)2OH or -S(=O)2NH2; R 5 It is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, (C1-C9)heteroaryl, (C3-C7)cycloalkyl-(C1-C6)alkyl, (C2-C6)heterocyclic-(C1-C6)alkyl, (C6-C10)aryl-(C1-C6)alkyl, or (C1-C9)heteroaryl-(C1-C6)alkyl; R 5 Optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, cyano, (C1-C6)alkoxy or (C1-C6)haloalkoxy.

[0082] In some implementations, Y 1 and Y 2 Each can be independently -OH, -CH2CH2-OH, -C(=O)-OH, -C(=O)H, or -C(=O)OR 5 ; R 5 The following are compounds: methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxetane, azirane, tetrahydrofuranyl, pyrrolidinyl, 1,4-dioxanecyclol, morpholinyl, piperidinyl, piperazine, phenyl, or pyridinyl; R 5 It may optionally and independently be substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, cyano, methoxy, difluoromethoxy or trifluoromethoxy.

[0083] In some implementations, Y 1 and Y 2 Each can be independently -OH, -CH2-OH, -C(=O)-OH, -C(=O)H, or -C(=O)OR 5 ; R 5 The following are compounds: methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxetane, azirane, tetrahydrofuranyl, pyrrolidinyl, 1,4-dioxanecyclol, morpholinyl, piperidinyl, piperazine, phenyl, or pyridinyl; R 5It may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, cyano, methoxy, difluoromethoxy or trifluoromethoxy.

[0084] In some implementations, Y 1 and Y 2 Each can be independently -CH2-OH, -C(=O)-OH, or -C(=O)OR 5 ; R 5 It is methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, or allyl; R 5 It may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, cyano, methoxy, difluoromethoxy or trifluoromethoxy.

[0085] In some implementations, R 1 R 2 R 3 and R 4 Each of these groups can be independently H, D, amino, nitro, hydroxyl, halogen, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylamino, (C1-C4)alkylthio, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (C2-C5) heterocyclic, phenyl, (C3-C6)cycloalkylmethyl, (C3-C6)cycloalkylethyl, (C2-C6) heterocyclic methyl, (C2-C6) heterocyclic ethyl or benzyl; or R on the same atom. 1 and R 2 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on the same atom 3 and R 4 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on different atoms 1 and R 2 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R on different atoms 3 and R 4 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R 1 and its adjacent R 2 Together with the atoms they are attached to, they form double bonds; or R 3 and its adjacent R 4 Together with the atoms they are attached to, they form double bonds; or R 1 and R 3Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; R 1 R 2 R 3 and R 4 Each of them may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine or cyano; n and m are each independently 4, 5, 6, 7, 8, 9 or 10.

[0086] In some implementations, R 1 R 2 R 3 and R 4 Each of these groups independently represents H, D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylamino, (C1-C4)alkylthio, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (C2-C5) heterocyclic, phenyl, (C3-C6)cycloalkylmethyl, (C3-C6)cycloalkylethyl, (C2-C6) heterocyclic methyl, (C2-C6) heterocyclic ethyl or benzyl; or R on the same atom. 1 and R 2 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on the same atom 3 and R 4 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on different atoms 1 and R 2 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R on different atoms 3 and R 4 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R 1 and its adjacent R 2 Together with the atoms they are attached to, they form double bonds; or R 3 and its adjacent R 4 Together with the atoms they are attached to, they form double bonds; or R 1 and R 3 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; R 1 R 2 R 3 and R 4Each of them may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine or cyano; n and m are each independently 4, 5, 6, 7, 8 or 9.

[0087] In some implementations, R 1 R 2 R 3 and R 4 Each can be independently H, D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, fluorine, chlorine, bromine, methyl, ethyl, methoxy, or ethoxy; or R on the same atom. 1 and R 2 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on the same atom 3 and R 4 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on different atoms 1 and R 2 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R on different atoms 3 and R 4 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R 1 and its adjacent R 2 Together with the atoms they are attached to, they form double bonds; or R 3 and its adjacent R 4 Together with the atoms they are attached to, they form double bonds; or R 1 and R 3 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; R 1 R 2 R 3 and R 4 Each of them may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine or cyano; In some implementations, when R on different atoms 1 and R 2 When R groups are formed together with the atoms between them to form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups, "R on different atoms" 1 and R 2 " refers to R 1 With R 2 There are 2, 3 or 4 atoms between them.

[0088] In some implementations, when R on different atoms 3 and R 4 When R groups are formed together with the atoms between them to form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups, "R on different atoms" 3 and R 4 " refers to R 3 With R 4 There are 2, 3 or 4 atoms between them.

[0089] In some implementations, when R on different atoms 1 and R 3 When R forms (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups together with the atoms between them, 1 With R 3 The number of atoms between them is 3 or 4.

[0090] n and m are each independently 4, 5, 6, 7, 8 or 9.

[0091] In some embodiments, R is H, D, F, Cl, Br, cyano, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, (C2-C5)heterocyclic, (C6-C10)aryl, or (C1-C9)heteroaryl; R is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, or cyano.

[0092] In some embodiments, R is H, D, F, Cl, Br, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, monodeuterated methyl, dideuterated methyl, or trideuterated methyl.

[0093] In some embodiments, the compounds of the present invention have a structure of Formula II, or a stereoisomer, geometric isomer, tautomer, or other such structure. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs II; Among them, k, g, j and v are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0094] In some embodiments, the compounds of the present invention have a structure of Formula III, or a stereoisomer, geometric isomer, tautomer, or other equivalent. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs III; Among them, g1 and j1 are each independently 3, 4, 5, 6 or 7.

[0095] In some embodiments, the compounds of the present invention have the structures of formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or their stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs. IV-1, IV-2, IV-3, IV-4, IV-5, IV-6 IV-7 IV-8, IV-9 IV-10 or IV-11.

[0096] In some embodiments, the compounds of the present invention have structures of formula V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, or stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof. V-1, V-2, V-3 V-4 V-5 V-6 V-7 or V-8.

[0097] In some embodiments, the compounds of the present invention have structures of formulas VI, VII, and VIII, or their stereoisomers, geometric isomers, tautomers, etc. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs VI. VII or VIII.

[0098] In some embodiments, the compounds of the present invention have the structures of formulas IX, X, XI, or their stereoisomers, geometric isomers, tautomers, etc. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs IX X or XI.

[0099] In some embodiments, the compounds of the present invention have the following structures, or stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0100] Pharmaceutical Composition On the other hand, the present invention also provides compounds including the present invention's stereoisomers, geometric isomers, tautomers, and other isomers thereof. N - A pharmaceutical composition comprising oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs and pharmaceutically acceptable carriers, excipients or diluents.

[0101] This invention provides a pharmaceutical composition comprising a carboxy-cyclopropylundecanool compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition preferably comprises a therapeutically effective amount of one or more of the carboxy-cyclopropylundecanool compounds described herein or a pharmaceutically acceptable salt thereof, and is formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. As detailed below, the pharmaceutical compositions of the present invention can be specifically formulated into solid or liquid forms for administration, including formulations suitable for the following routes of administration: (1) oral administration, such as oral enemas (aqueous or non-aqueous solutions or suspensions), tablets (such as tablets for oral, sublingual and / or systemic absorption), pills, powders, granules, tongue pastes; (2) parenteral administration, such as by subcutaneous, intramuscular, intravenous or epidural injection, in the form of sterile solutions or suspensions, or sustained-release formulations; (3) topical administration, such as as creams, ointments, or controlled-release patches or sprays for use on the skin; (4) vaginal or rectal administration, such as as vaginal suppositories, creams or foams; (5) sublingual administration; (6) ophthalmic administration; (7) transdermal administration; or (8) nasal administration.

[0102] As used herein, the term "therapeuticly effective amount" refers to the amount of a compound, material, or composition comprising a compound of the present invention, which is sufficient to produce the desired therapeutic effect on at least a subset of cell populations at a reasonable benefit / risk ratio applicable to any medical treatment. In some embodiments, the cell populations are present in an animal. In some embodiments, the cell populations are present in a human.

[0103] As used in this document, "pharmaceutically acceptable" means that compounds, materials, compositions, and / or dosage forms are suitable for use in human and animal tissues within a reasonable medical judgment, without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, while maintaining a reasonable benefit / risk ratio.

[0104] The pharmaceutical composition may also contain wetting agents, emulsifiers and lubricants, such as sodium dodecyl sulfate and magnesium stearate, as well as colorants, releasing agents, coating agents, sweeteners, flavoring agents, preservatives and antioxidants.

[0105] Examples of pharmaceutical antioxidants: (1) Water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc. (2) Oil-soluble antioxidants, such as ascorbate palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc. (3) Metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0106] The pharmaceutical formulations provided by this invention are suitable for oral, nasal, topical (including oral and sublingual), rectal, vaginal, and / or parenteral administration. The formulations are preferably in unit dose form and can be prepared by any method known in the pharmaceutical field. When the active ingredient and carrier material are combined to form a unit dose, the dosage will vary depending on the treatment target and the specific route of administration.

[0107] Typically, this dosage should be the amount of the compound that produces the therapeutic effect. The content of the active ingredient, as a percentage of the total ingredients, is typically from about 0.1% to 99%, preferably from about 5% to 70%, and more preferably from about 10% to 30%.

[0108] In some embodiments, the formulations of the present invention comprise excipients selected from the group consisting of cyclodextrins, cellulose compounds, liposomes, micelle forming agents (e.g., bile acids), and polymer carriers (e.g., polyesters and polyanhydrides); and the compounds of the present invention. In some embodiments, the above formulations enable the compounds of the present invention to have oral bioavailability.

[0109] Methods for preparing these formulations or compositions include the step of combining the compounds of the present invention with a carrier and optionally one or more auxiliary components. Typically, the formulations of the present invention are prepared by uniformly mixing the active compound with a liquid carrier, a finely powdered solid carrier, or both, followed by molding if necessary.

[0110] Formulations suitable for oral administration may be in the following forms: capsules, tablets, pills, tablets, lozenges (made with a flavoring matrix such as sucrose and gum arabic or tragacanth), powders, granules, aqueous or non-aqueous solutions or suspensions, oil-in-water or water-in-oil liquid emulsions, elixirs, syrups, soft lozenges (made with an inert matrix such as gelatin and glycerin or sucrose and gum arabic), and / or mouthwashes, etc., all of which contain a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present invention may also be administered in the form of large pills, licks, or pastes.

[0111] In solid dosage forms (including capsules, tablets, pills, sugar-coated pills, powders, granules, lozenges, etc.) for oral administration, the active ingredient may be mixed with one or more of the following pharmaceutical carriers: sodium citrate, calcium hydrogen phosphate, and / or any of the following excipients: (1) fillers or diluents: such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders: such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants: such as glycerin; (4) disintegrants: such as agar, calcium carbonate, potato starch or cassava starch, (5) Sustained-release agents: such as paraffin; (6) Absorption enhancers: such as quaternary ammonium compounds and surfactants (including poloxamer and sodium lauryl sulfate); (7) Wetting agents: such as cetyl alcohol, glyceryl monostearate and nonionic surfactants; (8) Adsorbents: such as kaolin and bentonite; (9) Lubricants: including talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid and mixtures thereof; (10) Coloring agents; (11) Controlled-release agents: such as crospovidone or ethyl cellulose. For capsules, tablets and pills, the pharmaceutical composition may also contain a buffer. Similar solid compositions may also be used as fillers for soft capsules and hard capsules, with excipients including lactose and other lactose-like substances and high molecular weight polyethylene glycol.

[0112] Tablets can be prepared by compression or molding, with one or more excipients selectively added during preparation. Compressed tablets may use the following excipients: binders (such as gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch-hydroxyacetate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by compression molding: a mixture of powdered compounds wetted with an inert liquid diluent is molded in suitable equipment.

[0113] The tablets and other solid dosage forms (including sugar-coated pills, capsules, pellets, and granules, etc.) of the pharmaceutical compositions of the present invention may optionally be prepared with scored or encapsulated coatings and shells, such as enteric coatings and other coating materials known in the field of pharmaceutical formulations. Sustained or controlled release of the active ingredient can also be achieved by adjusting release characteristics using different ratios of hydroxypropyl methylcellulose, applying other polymer matrix systems, or using liposomes and / or microsphere carrier technologies. The formulations of the present invention may also be designed for immediate release, for example, by freeze-drying. For example, they may be sterilized by filtration through a bacterial trap or by incorporating a sterilizing agent in the form of a sterile solid composition that is immediately soluble in sterile water or other sterile injection media before use. These compositions may also optionally contain a light-blocking agent, and their formulation may be designed to release the active ingredient only (or preferentially at that site) in a specific location in the gastrointestinal tract, or optionally employ a delayed release approach. Examples of usable encapsulation compositions include polymers and waxes. Where appropriate, the active ingredient may also be formulated into microcapsules and used in combination with one or more of the excipients described above.

[0114] Liquid dosage forms for oral administration of the compounds of this invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, these liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, specifically including: ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, sorbitan fatty acid esters, and mixtures thereof.

[0115] In addition to inert diluents, oral compositions may also contain various excipients, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, flavoring agents, and preservatives.

[0116] In addition to the active ingredient, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, and mixtures thereof.

[0117] The pharmaceutical compositions of the present invention can be formulated into suppositories for rectal or vaginal administration by mixing one or more of the compounds of the present invention with one or more suitable non-irritating excipients or carriers. The excipients or carriers include, but are not limited to, cocoa butter, polyethylene glycol, suppository waxes, or salicylates. Such matrices are solid at room temperature but liquefy at body temperature, thereby melting and releasing the active ingredient within the rectal or vaginal cavity.

[0118] The present invention also applies to vaginal administration formulations including vaginal suppositories, tampons, creams, gels, pastes, foams, or sprays, which contain carriers recognized in the art as suitable for use.

[0119] The topical or transdermal dosage forms of the compounds of this invention include: powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient can be mixed with a pharmaceutically acceptable carrier under aseptic conditions, and excipients such as preservatives, buffers, or propellants can be added as needed.

[0120] In addition to the active ingredients, the ointments, pastes, creams, and gels of the present invention may also contain the following excipients: animal and vegetable oils, waxes, paraffin wax, starch, tragacanth gum, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0121] In addition to the compounds of this invention, powders and sprays may also contain the following excipients: lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Sprays may also additionally contain conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (e.g., butane and propane).

[0122] Transdermal patches offer the advantage of controlled release of the compounds of this invention. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Furthermore, absorption enhancers can be used to increase the rate of transdermal penetration of the compounds. This penetration rate can be controlled by using controlled-release membranes, dispersing the compounds in a polymer matrix or gel.

[0123] The scope of this invention also includes ophthalmic preparations, such as ophthalmic ointments, ophthalmic powders, and ophthalmic solutions.

[0124] This invention relates to pharmaceutical compositions suitable for parenteral administration comprising: one or more compounds of this invention, in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersants, suspensions, or emulsions; or sterile powders that can be reconstituted with sterile water for injection or dispersants prior to use. The formulations may contain: sugars, alcohols, antioxidants, buffers, antibacterial agents, solutes that enable isotonicity between the formulation and the recipient's blood, or suspending / thickening agents.

[0125] Examples of aqueous and non-aqueous carriers suitable for the pharmaceutical compositions of the present invention include: water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof; vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). For example, appropriate flowability can be maintained by using coating materials (such as lecithin); maintaining the desired particle size for dispersion systems; and using surfactants.

[0126] These compositions may also contain excipients such as preservatives, wetting agents, emulsifiers, and dispersants. To prevent microbial action on the target compound, various antimicrobial and antifungal agents may be added, such as parabens, chlorobutanol, phenol, and sorbic acid. Adding isotonic agents (such as sugars and sodium chloride) to the formulation may also be desirable. Furthermore, the absorption time of injectable drugs can be prolonged by adding sustained-release agents such as aluminum monostearate and gelatin.

[0127] In some cases, to prolong the duration of drug action, it is necessary to slow down the absorption rate of the drug after subcutaneous or intramuscular injection. This can be achieved by using suspensions of poorly water-soluble crystalline or amorphous substances. In this case, the absorption rate of the drug depends on its dissolution rate, which may be affected by crystal size and crystal form. Another approach is to achieve sustained-release in injectable dosage forms by dissolving or suspending the drug in an oily carrier.

[0128] Long-acting injectable formulations can be prepared by forming microcapsule matrices with biodegradable polymers such as polylactic-co-glycolic acid copolymers. The drug release rate can be controlled by adjusting the drug-to-polymer ratio and leveraging the properties of the specific polymer used. Other examples of biodegradable polymers include polyorthoesters and polyanhydrides. Sustained-release injectable formulations can also be prepared by encapsulating the drug in tissue-compatible liposomes or microemulsion systems.

[0129] When the compounds of the present invention are administered as drugs to humans or animals, they can be used alone or in combination with pharmaceutically acceptable carriers to form a pharmaceutical composition; the content of the active ingredient in the composition is, for example, 0.1% to 99% (preferably 10% to 30%).

[0130] The formulations of the present invention can be administered orally, by injection, topically, or rectally. Of course, the appropriate dosage form must be used according to each route of administration. For example, they can be administered in tablet or capsule form, or by injection, inhalation, eye cream, ointment, suppository, etc. Administration can be via injection, infusion, or inhalation; topical lotion or ointment; or rectal suppository. Oral administration is preferred.

[0131] The terms "parenteral administration" and "transfer via parenteral administration" as used in this document refer to administration methods other than intestinal and local administration, which are usually administered by injection, including but not limited to: intravenous injection, intramuscular injection, arterial injection, intrathecal injection, intra-articular injection, intraorbital injection, intracardiac injection, intradermal injection, intraperitoneal injection, intratracheal injection, subcutaneous injection, subcortical injection, intra-articular injection, subcapsular injection, subarachnoid injection, intraspinal injection, and intrasternal injection.

[0132] The terms “systemic administration,” “administered via the system,” “peripheral administration,” and “via the peripheral” used in this document refer to a route of administration of a compound, drug, or other substance that does not directly enter the central nervous system but allows the drug to enter the patient’s circulatory system and participate in metabolism and other similar physiological processes (e.g., subcutaneous administration).

[0133] These compounds can be administered to humans and other animals via any suitable route of administration, including: oral administration; nasal administration (e.g., spray); rectal administration; vaginal administration; parenteral administration; cerebellomedullary cistern administration; and topical administration (e.g., powder, ointment, or drops), as well as oral and sublingual administration.

[0134] Regardless of the chosen route of administration, the compounds of the present invention (which may be in a suitable hydrated form) and / or pharmaceutical compositions can be prepared into pharmaceutically acceptable dosage forms using conventional methods well known to those skilled in the art.

[0135] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be adjusted to obtain an active ingredient content that is effective for specific patients, compositions and administration methods, achieves the expected therapeutic response, and is non-toxic to patients.

[0136] The specific dosage level depends on a variety of factors, including but not limited to: the activity of the specific compound of the present invention or its ester, salt or amide, the route of administration, the time of administration, the excretion or metabolic rate of the specific compound used, the rate and extent of absorption, the duration of treatment, other drugs / compounds / substances used in combination with the specific compound used, the patient's age, sex, weight, physical condition, overall health and medical history, and similar factors recognized in the medical field.

[0137] Physicians or veterinarians with standard skills in the field can easily determine and prescribe an effective dose of the required drug composition. For example, a physician or veterinarian can administer an initial dose lower than the level required to achieve the desired therapeutic effect, and then gradually increase the dose until the ideal therapeutic effect is achieved.

[0138] Generally, the appropriate daily dose of the compounds of the present invention should be the lowest effective dose that produces a therapeutic effect. This effective dose typically depends on the factors described above. Preferably, the dosage of the compound is about 0.01 mg / kg to 200 mg / kg; more preferably about 0.1 mg / kg to 100 mg / kg; and even more preferably about 0.5 mg / kg to 50 mg / kg. When the compounds described herein are used in combination with other drugs (such as sensitizers), their effective dose may be lower than the dose when the drug is used alone.

[0139] If necessary, the daily effective dose of the active compound can be divided into two, three, four, five, six or more fractions, administered at appropriate intervals throughout the day in unit dosage form. The preferred dosing regimen is once daily.

[0140] Medical reagent kit Another aspect of the present invention provides a kit for treating a disease. The kit comprises: i) instructions for treating a liver disease (such as non-alcoholic steatohepatitis); ii) a carboxycyclopropyl undecanoyl alcohol compound or a pharmaceutically acceptable salt thereof (e.g., compound A). The kit may comprise one or more unit dosage forms wherein the dose of the carboxycyclopropyl undecanoyl alcohol compound or a pharmaceutically acceptable salt thereof is effective in treating said liver disease.

[0141] The foregoing has detailed various aspects and embodiments of the invention, including methods of using carboxycyclopropyl undecanoyl alcohol compounds or pharmaceutically acceptable salts thereof, compositions comprising the compound or pharmaceutically acceptable salts thereof, and kits. This patent application explicitly covers all combinations and arrangements of all aspects and embodiments.

[0142] Invention Implementation Method On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising compounds of the present invention for use in inhibiting ATP citrate lyase or activating AMP-activated protein kinase.

[0143] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N - Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising compounds of the present invention for the prevention, control, treatment or relief of diseases associated with ATP citrate lyase or AMP-activated protein kinase or combinations thereof.

[0144] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions including compounds of the present invention are used to prevent, control, treat or alleviate disease by increasing HDL levels.

[0145] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N-Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions including compounds of the present invention are used to prevent, control, treat or alleviate disease by lowering LDL levels.

[0146] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N - Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising said compounds, for the prevention, control, treatment or relief of aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein metabolism disorders, hypertension, erectile dysfunction, inflammation, insulin resistance, bile lipid clearance disorders, obesity, bile oxysterol clearance disorders, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, bile phospholipid clearance disorders, kidney disease, sepsis, Syndrome X, thrombotic diseases, C-reactive protein regulation, bile production promotion; and the following liver diseases: hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, and acute fatty liver of pregnancy.

[0147] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N - The use of oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising compounds of the present invention in the preparation of a medicament for the prevention, control, treatment or relief of diseases associated with ATP citrate lyase or AMP-activated protein kinase or combinations thereof.

[0148] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N - The use of oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising compounds of the present invention in the preparation of a medicament for the prevention, control, treatment or relief of related diseases by increasing HDL levels.

[0149] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N - The use of oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising compounds of the present invention in the preparation of a medicament for the prevention, control, treatment or relief of related diseases by lowering LDL levels.

[0150] On the other hand, the present invention also provides the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc. N - Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising said compounds, for the preparation of medicaments for the prevention, control, treatment or relief of aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein metabolism disorders, hypertension, erectile dysfunction, inflammation, insulin resistance, bile lipid clearance disorders, obesity, bile oxysterol clearance disorders, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, bile phospholipid clearance disorders, kidney disease, sepsis, syndrome X, thrombotic diseases, C-reactive protein regulation, bile production promotion; and the following liver diseases: hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, and acute fatty liver of pregnancy.

[0151] On the other hand, the present invention also provides a method for preventing, controlling, treating, or alleviating diseases associated with ATP citrate lyase (ACLY) or AMP-activated protein kinase (AMPK) or combinations thereof, comprising administering a therapeutically effective amount of the compound of the present invention or its stereoisomers, geometric isomers, tautomers, or derivatives to a mammal in need. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions containing said compounds.

[0152] On the other hand, the present invention also provides a method for preventing, controlling, treating, or alleviating disease by increasing HDL levels, comprising administering a therapeutically effective amount of the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc., to a mammal in need. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions containing said compounds.

[0153] On the other hand, the present invention also provides a method for preventing, controlling, treating, or alleviating disease by lowering LDL levels, comprising administering a therapeutically effective amount of the compound of the present invention or its stereoisomers, geometric isomers, tautomers, etc., to a mammal in need. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions containing said compounds.

[0154] On the other hand, the present invention also provides a method for preventing, controlling, treating, or alleviating aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein metabolism disorders, hypertension, erectile dysfunction, inflammation, insulin resistance, bile lipid clearance disorders, obesity, bile oxysterol clearance disorders, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, bile phospholipid clearance disorders, kidney disease, sepsis, Syndrome X, thrombotic diseases, C-reactive protein regulation, and bile production promotion. Methods for treating or preventing liver diseases including hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, and acute fatty liver of pregnancy, comprising administering to a patient in need of treatment or prevention a therapeutically or preventively effective amount of the compound of the present invention or its stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions comprising said compound.

[0155] In some embodiments of the method of the present invention, the dosage range of the compound of the present invention administered to a subject in need is about 1 mg to 1000 mg, or any dosage value between these ranges. In some embodiments of the present invention, the dosage range of the compound of the present invention administered to a subject in need is: about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, or about 1 mg to about 300 mg.

[0156] In some embodiments of the method of the present invention, the daily dose of the compound of the present invention administered to a subject in need ranges from about 1 mg to 1000 mg, or any dose value within this range. In some embodiments of the present invention, the daily dose of the compound of the present invention administered to a subject in need may be: about 1000 mg, about 950 mg, about 900 mg, about 850 mg, about 800 mg, about 750 mg, about 700 mg, about 650 mg, about 600 mg, about 550 mg, about 500 mg, about 450 mg, about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.

[0157] In some embodiments of the method of the present invention, the dose of the compound of the present invention administered to the subject in need is about 1 mg to 1000 mg, or any dose value within that range, once daily.

[0158] In some embodiments of the method of the present invention, the compound of the present invention is administered twice daily to a subject in need, with each dose being approximately 1 mg to 500 mg, or any dose value within that range. In some embodiments of the present invention, the compound of the present invention is administered twice daily to a subject in need, with each dose being approximately: 500 mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg, 80 mg, 60 mg, 40 mg, 20 mg, 10 mg, 5 mg, or 1 mg.

[0159] In some embodiments of the method of the present invention, the compound of the present invention is administered to a subject in need three times daily, with each dose ranging from about 1 mg to 400 mg, or any dose value within that range. In some embodiments of the present invention, the compound of the present invention is administered to a subject in need three times daily, with each dose being: about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.

[0160] In some embodiments of the method of the present invention, the method further includes administering an effective dose of another pharmaceutically active agent. In some embodiments of the present invention, the other pharmaceutically active agent is administered simultaneously with or sequentially with the administration of the compound or composition of the present invention (administered earlier or later). In some embodiments of the present invention, the other pharmaceutically active agent is a statin, a thiazolidinedione or fibrates, bile acid conjugating resin, niacin, anti-obesity drugs, hormones, tyrosine phosphorylation inhibitors, sulfonylureas, biguanides, α-glucosidase inhibitors, apolipoprotein AI agonists, apolipoprotein E agonists, phosphodiesterase type 5 inhibitors, cardiovascular drugs, high-density lipoprotein-enhancing drugs, high-density lipoprotein enhancers, apolipoprotein AI gene modulators, apolipoprotein A-IV gene modulators, apolipoprotein gene modulators, ATP citrate lyase modulators, ATP citrate lyase allosteric inhibitors, acetyl-CoA carboxylase modulators, or acetyl-CoA carboxylase allosteric inhibitors. In some embodiments of the present invention, the other pharmaceutically active agent is lovastatin. In some embodiments of the present invention, the other pharmaceutical active agents are sorafenib; paclitaxel; carlotuximab; pembrolizumab; lenvatinib; avelumab; durvalumab; trimemumab; nivolumab; tazesta; cimiprimab; ABX196; T-cell receptor (TCR) immunotherapy agents; IBI-302; namodenosine; MM-310; oncolytic viruses or genetically modified oncolytic viruses for tumor injection (e.g., but not limited to: telomeresin and imligen); or immunomodulatory gene therapy agents (such as MDA-7 / IL-24, GLIPR1 / RTVP-1, and REIC / Dkk-3).

[0161] In some embodiments of the method of the present invention, the method further includes administering two or more other pharmaceutically active agents. In some embodiments of the present invention, the method comprises administering two or more other pharmaceutically active agents, optionally in combination. In some embodiments of the present invention, the two or more other pharmaceutically active agents are oncolytic agents, such as, but not limited to, nanatinostat and valganciclovir. In other embodiments, the method of the present invention comprises oral administration of the compound of the present invention, and further comprises administering an oncolytic therapeutic agent for tumor injection. In some embodiments of the present invention, the composition is administered orally.

[0162] In some embodiments of the present invention, the other pharmaceutical active agents are cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, nivolumab, firsocostat, apararenone, metformin, leucine-metformin-sildenafil combination preparation (NS-0200), IMM-124E, RG-125, and vitamin E. E), cysteamine, selonsertib, losartan, R05093151, pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid acid), cilofexor, tropifexor, EDP-305, INT-767, galactarabinogalacturonic acid polysaccharide, liraglutide, semaglutide, exenatide, ND-L02-s0201 / BMS-986263, volixibat, ammexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipeluk AST, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Nalmafene, Pentamidine, Berberine, L-Carnitine, EYP001a, Silymarin, Miricorilant, Ursodeoxycholic Acid, Metadoxine, Ezetimibe, Cysadane, L-Alanine, Saroglitazar Magnesium, Volixibat, Solitromycin, Technetium [99mTc] Mebrofennin (99m Technetium-mebrofenin, tropifexor, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, or seladelpar.

[0163] In some embodiments of the methods disclosed in this invention, the method for treating or preventing disease includes administering an effective amount of (a) the compound of this invention and (b) another pharmaceutically active agent, which may be sorafenib, taxol, lenvatinib, tazemetostat, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, leucine-metformin-sildenafil combination, or vitamin E. E), cysteamine, selonsertib, losartan, R05093151, pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acidacid), cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, teprexa tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Nalmafene, Pentamidine, Berberine, L-Carnitine, EYP001a, Silymarin, Miricorilant, Ursodeoxycholic acidacid), metadoxine, ezetimibe, cystadane, L-alanine, saroglitazarmagnesium, volixibat, elafibranor, nalmefene, solitromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib. SF1126, Anlotinib, P1101, Varlitinib, SHR-1210, SHR6390, Capmatinib, Dabrafenib, Trametinib, Sapanisertib, Meclizine, Enzalutamide, H3B-6527, OBI-3424, Brivanib, Tipotinib (tepotinib), temsirolimus, epacadostat, R07119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, R07070179, axitinib, sunitinib, or zotiraciclib citrate.

[0164] In some embodiments of the methods disclosed herein, the method for treating or preventing disease includes administering an effective amount of (a) the compound of the present invention and (b) another pharmaceutically active agent selected from: sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, T-cell receptor (TCR) immunotherapy agents, IBI-302, namodenoson, MM-310, intratumorally injected oncolytic viruses, genetically modified oncolytic viruses, or immunomodulatory gene therapy agents.

[0165] In some embodiments of the method of the present invention, the method further includes administering radiation therapy to the subject. In some embodiments, the radiation therapy is gamma-ray radiation therapy or X-ray radiation therapy. In some embodiments, the radiation therapy is administered using a gamma-ray or X-ray radiation device.

[0166] In some embodiments, the radiotherapy is performed simultaneously with, before, or after the administration of the compound or composition of the present invention. In some embodiments, the radiotherapy is performed before or after the administration of the compound or composition of the present invention.

[0167] Synthesis Examples All reactions were carried out under an inert atmosphere of nitrogen or argon (unless otherwise specified). DMF, DMSO, THF, DCM, DMAc, and MeOH (99.9%, ultra-dry grade) were used directly without treatment. Other reagents were commercially available and used directly without purification (unless otherwise specified). NMR spectra were determined using a Bruker spectrometer. ¹H NMR (400 MHz) chemical shifts were calibrated against the internal standard tetramethylsilane (TMS, δ = 0.00 ppm) or residual protonated solvent. Data are presented in the following format: chemical shift (ppm), peak type (s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, m = multiplet, br = broad peak), coupling constant J (Hz), and integral value.

[0168] Method A: Agilent 1260-6125B, Waters CORTECS C18+ column (4.6 mm × 30 mm, 2.7 µm), mobile phase A: water containing 0.01% TFA (containing 10% ACN); mobile phase B: ACN containing 0.01% TFA; flow rate: 3.0 mL / min; gradient: 5-95%B (0.0-1.1 min), 95%B (1.1-1.52 min), 95-5%B (1.52-2.00 min), afterrun time: 0.5 min.

[0169] Method B: Shimadzu LCMS-2020, Waters CORTECS C18+ column (4.6 mm × 30 mm, 2.7 µm), mobile phase A: water containing 0.05% TFA (containing 10% ACN); mobile phase B: ACN containing 0.05% TFA; flow rate: 3.0 mL / min; gradient 5-95%B (0.0-1.1 min), 95%B (1.1-1.50 min), 95-5%B (1.50-1.52 min), 5%B (1.52-2.00 min).

[0170] Synthesis of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate (M1) Step 1: Synthesis of ethyl 7-bromo-2,2-dimethylheptanoate Under nitrogen protection and at -40 °C, LDA (18.08 mL, 36.16 mmol) was added to an anhydrous THF solution of ethyl 2-methylpropionate (4.2 g, 36.16 mmol) (40 mL). The reaction mixture was stirred at -40 °C for 1 hour, followed by the addition of 1,5-dibromopropane (11.64 g, 50.62 mmol). The reaction mixture was stirred at -40 °C for 0.5 hours, then at 25 °C overnight. The reaction mixture was poured into an ice-water mixture (20 mL). The aqueous layer was extracted with EA (50 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1). A yellow oily product (4.6 g, 48%) was obtained.

[0171] 1 HNMR (CHLOROFORM-d ) δ: 4.11 (q, J= 7.1 Hz, 2H), 3.37-3.43 (m, 2H),1.79-1.92 (m,2H), 1.49-1.55 (m, 2H), 1.37-1.46(m, 2H), 1.25 (t, J= 7.1 Hz (5H), 1.16 (s, 6H).

[0172] Step 2: Synthesis of diethyl 8-cyano-2,2,14,14-tetramethyl-8-p-toluenesulfonylpentadecanedioate Under nitrogen protection at 0 °C, sodium hydride (0.79 g, 19.80 mmol) was added to a DMSO (50 mL) solution of TosMIC (1.29 g, 6.60 mmol) and Bu4NI (0.24 g, 0.66 mmol). The reaction mixture was stirred at 25 °C for 30 min, followed by the addition of ethyl 7-bromo-2,2-dimethylheptanoate (3.5 g, 13.20 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched by adding an ice-water mixture (40 mL) to the reaction system at 0 °C. The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with 10% NH4Cl (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1). A yellow oily product was obtained (3.07 g, 41%).

[0173] 1 HNMR (400 MHz, CHLOROFORM- d ) δ = 7.85 (d, J = 8.3 Hz, 2H), 7.41 (d, J =8.0Hz, 2H), 4.14 - 4.10 (m, 4H), 2.49 (s, 3H), 2.02 - 1.84 (m, 4H), 1.59 -1.41 (m, 8H), 1.28 - 1.23 (m, 12H), 1.17 - 1.13 (m, 12H).

[0174] Step 3: Synthesis of 1-ethyl 1-ethyl 1-methyl 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid Hydrochloric acid (15 mL) was added to a solution of diethyl 8-cyano-2,2,14,14-tetramethyl-8-p-toluenesulfonylpentadecanedioate (3.0 g, 5.32 mmol) in dichloromethane (40 mL) at room temperature. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was diluted with water (30 mL). The aqueous layer was extracted with DCM (40 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1). A colorless oily product (1.90 g, 89%) was given.

[0175] 1 HNMR (CHLOROFORM- d ) δ: 4.11 (q, J= 7.1 Hz, 4H), 2.37 (t, J= 7.4 Hz, 4H), 1.52 (td, J= 15.5, 7.1 Hz, 8H), 1.18-1.31 (m, 14H), 1.15 (s, 12H).

[0176] Step 4: Synthesis of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate Under nitrogen protection at 0°C, sodium borohydride (NaBH4, 0.18 g, 4.77 mmol) was added to an anhydrous methanol (MeOH, 20 mL) solution of 1-ethyl 15-methyl 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid (1.9 g, 4.77 mmol). The reaction mixture was stirred at 0°C for 4 hours. The reaction mixture was poured into an ice-water mixture (20 mL). The aqueous layer was extracted with EA (30 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1). A colorless oily product (1.90 g, 99%) was given.

[0177] 1 HNMR (400 MHz, CHLOROFORM-d) δ = 4.15 - 4.07 (m, 4H), 3.56 (br s,1H), 1.54 - 1.47 (m, 4H), 1.47 - 1.32 (m, 8H), 1.29 - 1.20 (m, 14H), 1.15 (s,12H).

[0178] Synthesis of bepidinic acid To a methanol (8 mL) solution of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate (1.00 g, 2.50 mmol), 20% KOH aqueous solution (2 mL) was added. The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 3 / 2). A white solid product (750 mg, 87%) was given.

[0179] MS(ESI, pos.ion) m / z: 345.3 [M+1] + .

[0180] 1 HNMR (DMSO- d 6 ) δ: 11.99 (br s, 2H), 4.20 (br d, J= 5.0 Hz, 1H), 1.38-1.47 (m, 4H) 1.12-1.37 (m, 16H), 1.06 (s, 12H).

[0181] Example 1: Synthesis of 8-methoxy-2,2,14,14-tetramethylpentadecanedioic acid (0004) Step 1: Synthesis of diethyl 8-methoxy-2,2,14,14-tetramethylpentadecanedioate To a solution of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate (200 mg, 0.50 mmol) in dichloromethane (DCM, 2 mL), CF3SO3Me (0.08 mL, 0.75 mmol) and 2,6-di-tert-butylpyridine (0.22 mL, 1.00 mmol) were added. The reaction mixture was stirred at 40°C for 18 hours. The mixture was diluted with dichloromethane (20 mL), washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (150 mg, 75%).

[0182] Step 2: Synthesis of 8-methoxy-2,2,14,14-tetramethylpentadecanedioic acid To a methanol (4 mL) solution of diethyl 8-methoxy-2,2,14,14-tetramethylpentadecanedioate (150 mg, 0.36 mmol), 1 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (110 mg, 85%).

[0183] MS(ESI, pos.ion) m / z: 359.1 [M+1] + .

[0184] 1 HNMR (DMSO- d 6 ) δ: 11.14-12.65 (m, 2H), 3.19 (s, 3H), 3.08 (m, 1H), 1.32-1.46 (m, 8H), 1.15-1.29 (m, 12H), 1.07 (s, 12H).

[0185] Example 2: Synthesis of 8-ethoxy-2,2,14,14-tetramethylpentadecanedioic acid (0010) Step 1: Synthesis of diethyl 8-ethoxy-2,2,14,14-tetramethylpentadecanedioate To a solution of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate (150 mg, 0.37 mmol) in dichloromethane (2 mL), 2,6-di-tert-butylpyridine (107.46 mg, 0.56 mmol) and ethyl trifluoromethanesulfonate (133.40 mg, 0.75 mmol) were added. The reaction mixture was stirred at 40 °C for 18 hours. The mixture was diluted with dichloromethane (20 mL), washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography, eluting with PE:EA = 20:1 to give a yellow oily liquid of diethyl 8-ethoxy-2,2,14,14-tetramethylpentadecanedioate (162 mg, 0.34 mmol, 91%).

[0186] 1 HNMR (400 MHz, CHLOROFORM- d ) δ = 4.17 - 4.06 (m, 4H), 3.51 - 3.41(m, 2H), 3.23 - 3.12 (m, 1H), 1.53 - 1.47 (m, 4H), 1.46 - 1.39 (m, 4H), 1.33(br d, J = 14.4 Hz, 18H), 1.20 - 1.17 (m, 3H), 1.17 - 1.13 (m, 12H).

[0187] Step 2: Synthesis of 8-ethoxy-2,2,14,14-tetramethylpentadecanedioic acid To a methanol (1.6 mL) solution of diethyl 8-ethoxy-2,2,14,14-tetramethylpentadecanedioic acid (162 mg, 0.38 mmol), KOH (0.4 mL, 20% H₂O solution) was added. The reaction mixture was stirred overnight at 70 °C. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography, eluting with PE:EA = 4:1 to obtain a yellow oily liquid of 8-ethoxy-2,2,14,14-tetramethylpentadecanedioic acid (110 mg, 0.30 mmol, 78%).

[0188] MS(ESI, pos.ion) m / z: 373.1 [M+1] + .

[0189] 1HNMR (400 MHz, DMSO-d 6 ) δ = 12.22 - 11.77 (m, 2H), 3.42 - 3.36 (m,2H), 3.20 - 3.14 (m, 1H), 1.46 - 1.39 (m, 4H), 1.38 - 1.31 (m, 4H), 1.28 -1.13 (m, 12H), 1.10 - 1.02 (m, 15H).

[0190] Example 3: Synthesis of 8-methoxy-2,2,14,14-tetramethylpentadecanedioic acid-7,7,9,9-d4 (0011) Step 1: Synthesis of diethyl 2,2,14,14-tetramethyl-8-oxopentadecanoic acid-7,7,9,9-d4 (0011) Add 1,3,4,6,7,8-hexahydro-2-diethyl 2,2,14,14-tetramethyl-8-oxopentadecanoic acid diethyl ester (500 mg, 1.25 mmol) to a deuterated chloroform (3 mL) solution. H -Pyrimidino[1,2-a]pyrimidine (18 mg, 0.13 mmol). The reaction mixture was stirred for 48 hours. The reaction mixture was diluted with dichloromethane (20 mL). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was used directly in the next step of the reaction (460 mg, 91%).

[0191] Step 2: Synthesis of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate-7,7,9,9-d4 Under nitrogen protection at 0 °C, sodium borohydride (19 mg, 0.05 mmol) was added to an anhydrous methanol (2 mL) solution of ethyl 2,2,14,14-tetramethyl-8-oxopentadecanoate-7,7,9,9-d4 (200 mg, 0.50 mmol). The reaction mixture was stirred at 0 °C for 4 hours and then poured into an ice-water mixture (10 mL). The aqueous layer was extracted with EA (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (170 mg, 84%).

[0192] Step 3: Synthesis of diethyl 8-methoxy-2,2,14,14-tetramethylpentadecanedioate-7,7,9,9-d4 To a solution of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate-7,7,9,9-d4 (170 mg, 0.42 mmol) in dichloromethane (2 mL), CF3SO3Me (138 mg, 0.84 mmol) and 2,6-di-tert-butylpyridine (121 mg, 0.63 mmol) were added. The reaction mixture was stirred at 40 °C for 18 hours and then diluted with dichloromethane (20 mL). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (130 mg, 74%).

[0193] Step 4: Synthesis of 8-methoxy-2,2,14,14-tetramethylpentadecanedioic acid-7,7,9,9-d4 To a methanol (4 mL) solution of diethyl 8-methoxy-2,2,14,14-tetramethylpentadecanedioic acid-7,7,9,9-d4 (130 mg, 0.31 mmol), 1 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (45 mg, 40%).

[0194] MS(ESI, pos.ion) m / z: 363.3 [M+1] + .

[0195] 1 HNMR (400 MHz, DMSO-d6) δ = 12.00 (br s, 2H), 3.18 (s, 3H), 3.06 (d,J = 4.8 Hz, 1H), 1.46 - 1.38 (m, 4H), 1.22 -1.27 (m, 12H), 1.06 (s, 12H).

[0196] Example 4: Synthesis of 8-methoxy-2,2,14,14-tetramethylpentadecanedioic acid-7,7,8,9,9-d5 (0012) Step 1: Synthesis of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate-7,7,8,9,9-d5 Under nitrogen protection at 0°C, NaBD4 (24 mg, 0.57 mmol) was added to an anhydrous methanol (2 mL) solution of ethyl 2,2,14,14-tetramethyl-8-oxo-pentadecanedioate-7,7,8,9,9-d5 (230 mg, 0.57 mmol). The reaction mixture was stirred at 0°C for 4 hours and then poured into an ice-water mixture (10 mL). The aqueous layer was extracted with EA (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (220 mg, 95%).

[0197] Step 2: Synthesis of diethyl 8-methoxy-2,2,14,14-tetramethylpentadecanedioate-7,7,8,9,9-d5 To a solution of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate-7,7,8,9,9-d5 (220 mg, 0.57 mmol) in dichloromethane (2 mL), CF3SO3Me (187 mg, 1.14 mmol) and 2,6-di-tert-butylpyridine (164 mg, 0.85 mmol) were added. The reaction mixture was stirred at 40 °C for 18 hours and then diluted with dichloromethane (20 mL). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (170 mg, 71%).

[0198] Step 3: Synthesis of 8-methoxy-2,2,14,14-tetramethylpentadecanedioic acid-7,7,8,9,9-d5 To a methanol (4 mL) solution of diethyl 8-methoxy-2,2,14,14-tetramethylpentadecanedioic acid-7,7,8,9,9-d5 (170 mg, 0.41 mmol), 1 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (70 mg, 47%).

[0199] MS(ESI, pos.ion) m / z: 364.2 [M+1] + .

[0200] 1 HNMR (400 MHz, DMSO-d6) δ = 12.11 - 11.89 (m, 2H), 3.18 (s, 3H), 1.46 - 1.39 (m, 4H), 1.22 ~1.27 (m, 12H), 1.06 (s, 12H).

[0201] Example 5: Synthesis of 8-methoxy-2,2,14,14-tetramethylpentadecanedioic acid-8-d(0013) Step 1: Synthesis of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate-8-d Under nitrogen protection at 0 °C, NaBD4 (21 mg, 0.50 mmol) was added to a methanol (2 mL) solution of ethyl 2,2,14,14-tetramethyl-8-oxopentadecanoate (200 mg, 0.50 mmol). The reaction mixture was stirred at 0 °C for 4 hours and then poured into an ice-water mixture (10 mL). The aqueous layer was extracted with EA (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA(v / v) = 5 / 1) to give a colorless oily product (190 mg, 94%).

[0202] Step 2: Synthesis of diethyl 8-methoxy-2,2,14,14-tetramethylpentadecanedioate-8-d To a solution of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate-8-d (160 mg, 0.40 mmol) in dichloromethane (2 mL), CF3SO3Me (130 mg, 0.80 mmol) and 2,6-di-tert-butylpyridine (114 mg, 0.60 mmol) were added. The reaction mixture was stirred at 40 °C for 18 hours and then diluted with dichloromethane (20 mL). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (130 mg, 78%).

[0203] Step 3: Synthesis of 8-methoxy-2,2,14,14-tetramethylpentadecanedioic acid-8-d To a methanol (4 mL) solution of diethyl 8-methoxy-2,2,14,14-tetramethylpentadecanedioic acid (130 mg, 0.31 mmol), 1 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (70 mg, 47%).

[0204] 1 HNMR (400 MHz, DMSO-d6) δ = 11.99 (s, 2H), 3.18 (s, 3H), 1.45 - 1.32 (m, 8H), 1.28 - 1.13 (m, 12H), 1.06 (s, 12H).

[0205] Example 6: Synthesis of 8-(methoxy-d3)-2,2,14,14-tetramethylpentadecanedioic acid (0014) Step 1: Synthesis of diethyl 8-(methoxy-d3)-2,2,14,14-tetramethylpentadecanedioate Sodium hydride (39.94 mg, 1.00 mmol) and... N,N Diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate (100 mg, 0.25 mmol) was added to a 2 mL mixture of dimethylformamide at 0°C. After stirring the reaction mixture for 10 min, CD3I (0.06 mL, 1.00 mmol) was added. The reaction mixture was stirred at 70 °C for 18 h. The reaction mixture was quenched with 10 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layers were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA(v / v) = 20 / 1) to give a colorless oil (40 mg, 38.37%).

[0206] Step 2: Synthesis of 8-(methoxy-d3)-2,2,14,14-tetramethylpentadecanedioic acid To a methanol (4 mL) solution of diethyl 8-(methoxy-d3)-2,2,14,14-tetramethylpentadecanedioic acid (40 mg, 0.10 mmol), 1 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (24 mg, 69%).

[0207] MS(ESI, pos.ion) m / z: 362.1 [M+1] + .

[0208] 1 HNMR (400 MHz, DMSO- d 6 ) δ: 12.00 (br s, 2H), 3.07 (t, J= 5.5 Hz, 1H), 1.32-1.46 (m, 8H), 1.15-1.26 (m, 12H), 1.06 (s, 12H).

[0209] Example 7: Synthesis of 8-cyclopropoxy-2,2,14,14-tetramethylpentadecanedioic acid (0015) Step 1: Synthesis of diethyl 2,2,14,14-tetramethyl-8-ethyleneoxypentadecanedioate Under nitrogen atmosphere, 1,10-phenanthroline (77 mg, 0.42 mmol) and Pd(OAc)₂ (95 mg, 0.42 mmol) were added to a solution of diethyl ethyl ether of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate (340 mg, 0.85 mmol) (5 mL). The reaction mixture was stirred overnight at 45 °C and then diluted with ethyl acetate (20 mL). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 20 / 1) to give a colorless oil (110 mg, 30%).

[0210] Step 2: Synthesis of diethyl 8-cyclopropoxy-2,2,14,14-tetramethylpentadecanedioate Under a nitrogen atmosphere, diethylzinc (0.72 mL, 0.72 mmol) was added to a solution of diethyl 2,2,14,14-tetramethyl-8-(ethoxy)pentadecanedioic acid (75 mg, 0.18 mmol) and diiodomethane (193 mg, 0.72 mmol) in dichloromethane (2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 4 hours, then quenched with saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (20 mL × 2). The combined organic layers were washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (40 mg, 51%).

[0211] Step 3: Synthesis of 8-cyclopropoxy-2,2,14,14-tetramethylpentadecanedioic acid To a methanol (4 mL) solution of diethyl 8-cyclopropoxy-2,2,14,14-tetramethylpentadecanedioate (40 mg, 0.09 mmol), 1 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (29 mg, 83%).

[0212] MS(ESI, pos.ion) m / z: 384.1 [M+1] + .

[0213] 1 HNMR (DMSO- d 6 ) δ: 12.00 (br d, J= 2.9 Hz, 2H), 3.22-3.29 (m, 2H), 1.33-1.47 (m, 8H), 1.16-1.27 (m, 12H), 1.06 (s, 12H), 0.36-0.44 (m, 4H).

[0214] Example 8: Synthesis of 2,2,14,14-Tetramethyl-8-(trifluoromethoxy)pentadecanedioic acid (0016) Step 1: Synthesis of diethyl 2,2,14,14-tetramethyl-8-(trifluoromethoxy)pentadecanedioic acid Under a nitrogen atmosphere, 1-trifluoromethyl-1,2-benzoiodocyclopentane-3(1 H (OTf)₂Zn (45 mg, 0.12 mmol) and diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate (500 mg, 1.25 mmol) were added to a CDCl₃ solution (0.15 M, 3 mL) of 143 mg, 0.45 mmol, 3-ketone. The reaction mixture was stirred for 3 days. Thin-layer chromatography (petroleum ether:ethyl acetate = 10:1) showed that the starting material was not completely consumed, but new spots were detected. The reaction mixture was diluted with dichloromethane (20 mL). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 20 / 1) to give a colorless oily product (17 mg, 3%).

[0215] Step 2: Synthesis of 2,2,14,14-Tetramethyl-8-(trifluoromethoxy)pentadecanedioic acid To a methanol (4 mL) solution of diethyl 2,2,14,14-tetramethyl-8-(trifluoromethoxy)pentadecanedioic acid (17 mg, 0.04 mmol), 1 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (10 mL × 2). The organic layer was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (13 mg, 87%).

[0216] MS(ESI, pos.ion) m / z: 413.2 [M+1] + .

[0217] 1 HNMR (400 MHz, DMSO- d 6 ) δ = 12.29 - 11.73 (m, 2H), 4.34 - 4.27 (m,1H), 1.64 - 1.51 (m, 4H), 1.46 - 1.38 (m, 4H), 1.30 - 1.15 (m, 12H), 1.07 (s,12H).

[0218] Example 9: Synthesis of 8-methoxy-2,2,14,14-tetramethylpentadecanediol-1,15-diol (0017) To a solution of ethyl 15-ethoxy-8-methoxy-2,2,14,14-tetramethyl-15-oxopentadecanoate (120 mg, 0.29 mmol) in anhydrous tetrahydrofuran (1.5 mL), LiAlH4 (44 mg, 1.16 mmol) was added at 0°C. The reaction mixture was stirred overnight at 20°C. The reaction was quenched by slow addition of ice water, and the mixture was then extracted with dichloromethane (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography, eluting with PE:EA = 6:1 to give a colorless oily liquid of 8-methoxy-2,2,14,14-tetramethylpentadecane-1,15-diol (74 mg, 0.22 mmol, 77%).

[0219] MS(ESI, pos.ion) m / z: 331.2 [M+1] + .

[0220] 1 HNMR (400 MHz, DMSO-d 6 )δ: 4.38 (t, J= 5.3 Hz, 2H), 3.19 (s, 3H), 3.03-3.12 (m, 5H), 1.33-1.43 (m, 4H), 1.10-1.30 (m, 16H), 0.76 (s, 12H).

[0221] Example 10: Synthesis of 8-(methoxy-d3)-2,2,14,14-tetramethylpentadecanedioic acid-8-d(0018) Step 1: Synthesis of diethyl 8-(methoxy-d3)-2,2,14,14-tetramethylpentadecanedioate-8-d Sodium hydride (120 mg, 2.99 mmol) and... N,N In a 3 mL mixture of dimethylformamide, diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid-8-d (300 mg, 0.75 mmol) was added at 0°C. After stirring the reaction mixture for 10 min, CD3I (433 mg, 2.99 mmol) was added. The reaction mixture was stirred at 70 °C for 18 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1). A colorless oily product (140 mg, 45%) was given.

[0222] Step 2: Synthesis of 8-(methoxy-d3)-2,2,14,14-tetramethylpentadecanedioic acid-8-d To a methanol (4 mL) solution of 8-(methoxy-d3)-2,2,14,14-tetramethylpentadecanedioic acid diethyl ester-8-d (140 mg, 0.33 mmol), 1 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (70 mg, 58%).

[0223] MS(ESI, pos.ion) m / z: 359.1 [M+1] + .

[0224] 1 HNMR (400 MHz, DMSO-d6) δ = 12.00 (br s, 2H), 2.07 (s, 1H), 1.47 -1.39 (m, 4H), 1.35 (br s, 4H), 1.28 - 1.13 (m, 12H), 1.07 (s, 12H).

[0225] Example 11: Synthesis of 1,1'-(6-methoxyundecane-1,11-diyl)bis(cyclopropane-1-carboxylic acid) (0019) Step 1: Synthesis of diethyl 8-(methoxy-d3)-2,2,14,14-tetramethylpentadecanedioate-8-d At -40°C, tert-butyl cyclopropane-1-carboxylate (5000 mg, 35.16 mmol) was slowly added to a 50 mL solution of LDA (17.58 mL, 35.16 mmol) in THF, and the mixture was stirred for 30 minutes. Then, 1-bromo-5-chloropentane (9783 mg, 52.74 mmol) was added to the mixture. After the addition was complete, the reaction mixture was heated to -5°C and stirred for 4 hours. The solution was then cooled to 0°C, and the reaction was quenched with an aqueous solution of ammonium chloride (50 mL). Extraction was performed with ethyl acetate (80 mL × 2). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography, eluting with PE to obtain a colorless oily liquid of tert-butyl 1-(5-chloropentyl)cyclopropane-1-carboxylate (2900 mg, 11.75 mmol, 33%).

[0226] 1 HNMR (400 MHz, CHLOROFORM-d) δ = 3.58 - 3.50 (m, 2H), 1.83 - 1.74(m, 2H), 1.56 - 1.44 (m, 6H), 1.44 - 1.37 (m, 9H), 1.15 - 1.06 (m, 2H), 0.65(br s, 2H).

[0227] Step 2: Synthesis of tert-butyl 1-(5-iodopentyl)cyclopropane-1-carboxylate Sodium iodide (2429 mg, 16.21 mmol) was added to a solution of 2-methylpropyl-2-yl-1-(5-chloropentyl)cyclopropane-1-carboxylate (2000 mg, 8.10 mmol) in 2-butanone (25 mL). The reaction mixture was stirred at 80 °C for 12 hours. It was then diluted with ethyl acetate (40 mL), washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product tert-butyl 1-(5-iodopentyl)cyclopropane-1-carboxylate (2150 mg, 6.36 mmol, yield 78%).

[0228] 1HNMR (400 MHz, CHLOROFORM-d) δ = 3.23 - 3.17 (m, 2H), 1.83 (quin, J= 7.1 Hz, 2H), 1.51 - 1.46 (m, 4H), 1.43 (s, 9H), 1.41 (br s, 2H), 1.14 -1.09 (m, 2H), 0.64 - 0.56 (m, 2H).

[0229] Step 3: Synthesis of 1,11-bis(1-tert-butoxycarbonylcyclopropyl)-6-oxoundecane t-BuOK (504 mg, 4.50 mmol) was added to a DMAC (30 mL) solution of TosMIC (820 mg, 4.2 mmol). After stirring the mixture at 0 °C for 0.5 h, tert-butyl 1-(5-iodopentyl)cyclopropane-1-carboxylate (1.50 g, 4.43 mmol) was added. The reaction mixture was heated to room temperature and stirred for 1 h, then cooled again to 0 °C and t-BuOK (450 mg, 4.50 mmol) was added. After 0.5 h, tert-butyl 1-(5-iodopentyl)cyclopropane-1-carboxylate (1.61 g, 4.76 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h, then cooled to 0 °C and quenched with ice water (30 mL), followed by extraction with dichloromethane (30 mL). Concentrated hydrochloric acid (10 mL) was added dropwise to the organic layer, and the mixture was stirred for 2 h. The reaction mixture was diluted with dichloromethane (20 mL), washed successively with NaHCO3 (30 mL) aqueous solution (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography, eluting with PE:EA = 20:1 to obtain 1,11-bis(1-tert-butoxycarbonylcyclopropyl)-6-oxoundecane (840 mg, 20%).

[0230] 1 HNMR (400 MHz, CHLOROFORM-d) δ = 2.45 - 2.32 (m, 4H), 1.59 - 1.53(m, 4H), 1.49 - 1.44 (m, 8H), 1.42 (s, 18H), 1.31 - 1.22 (m, 4H), 1.16 - 1.03 (m, 4H), 0.64 - 0.53 (m, 4H).

[0231] Step 4: Synthesis of 1,11-bis(1-tert-butoxycarbonylcyclopropyl)-6-hydroxyundecane At 0 °C, NaBH4 (64 mg, 1.69 mmol) was slowly added to a methanol (10 mL) solution of 1,11-bis(1-tert-butoxycarbonylcyclopropyl)-6-oxoundecane (380 mg, 0.84 mmol). The mixture was stirred at 0 °C for 2 hours, followed by quenching with 0.5 mL of 1 M hydrochloric acid. After dilution with water (20 mL), the mixture was extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography, eluting with PE:EA to obtain 1,11-bis(1-tert-butoxycarbonylcyclopropyl)-6-hydroxyundecane (330 mg, 0.73 mmol, 86%).

[0232] 1 HNMR (400 MHz, CHLOROFORM-d) δ = 3.63 - 3.54 (m, 1H), 1.61 - 1.49(m, 8H), 1.44 - 1.40 (m, 22H), 1.39 (br s, 8H), 1.13 - 1.06 (m, 4H), 0.63 -0.55 (m, 4H).

[0233] Step 5: Synthesis of 1,11-bis(1-tert-butoxycarbonylcyclopropyl)-6-methoxyundecane To a DCM solution of 1,11-bis(1-tert-butoxycarbonylcyclopropyl)-6-hydroxyundecane (280 mg, 0.62 mmol) and 2,6-di-tert-butylpyridine (177 mg, 0.93 mmol) in 3 mL, CF3SO2OMe (15 mg, 0.09 mmol) was added. The reaction mixture was stirred overnight at 40 °C. The mixture was diluted with dichloromethane (20 mL), washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography, eluting with PE:EA = 20:1 to give a yellow oily substance, 1,11-bis(1-tert-butoxycarbonylcyclopropyl)-6-methoxyundecane (200 mg, 0.43 mmol, 69%).

[0234] 1HNMR (400 MHz, CHLOROFORM-d) δ = 3.35 - 3.29 (m, 3H), 3.15 - 3.08(m, 1H), 1.51 - 1.45 (m, 8H), 1.43 (s, 18H), 1.39 (br d, J = 7.8 Hz, 12H), 1.13 - 1.07 (m, 4H), 0.62 - 0.54 (m, 4H).

[0235] Step 6: Synthesis of 1,1'-(6-methoxyundecane-1,11-diyl)bis(cyclopropane-1-carboxylic acid) CF3COOH (1.5 mL) was added to a DCM (3 mL) solution of 1,11-bis(1-tert-butoxycarbonylcyclopropyl)-6-methoxyundecane (200 mg, 0.43 mmol). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was concentrated to give the crude product. The crude product was purified by silica gel column chromatography, eluting with PE:EA = 4:1 to give a yellow oily substance 1,1'-(6-methoxyundecane-1,11-diyl)bis(cyclopropane-1-carboxylic acid) (130 mg, 89%).

[0236] MS(ESI, pos.ion) m / z: 355.2 [M+1] + .

[0237] 1 HNMR (400 MHz, DMSO-d6) δ = 11.96 (s, 2H), 3.21 - 3.16 (m, 3H), 3.11- 3.04 (m, 1H), 2.07 (s, 1H), 1.47 - 1.33 (m, 12H), 1.27 - 1.15 (m, 8H), 1.03- 0.96 (m, 4H), 0.68 - 0.62 (m, 4H).

[0238] Example 11: Synthesis of 7-methoxy-2,2,12,12-tetramethyltridecanoic acid (0020) Step 1: Synthesis of ethyl 6-bromo-2,2-dimethylhexanoate Under a nitrogen atmosphere at -40 °C, LDA (21.52 mL, 43.04 mmol, 1.0 eq) was added dropwise to a THF (50 mL) solution of ethyl isobutyrate (5.00 g, 43.04 mmol, 1.0 eq). After the addition was complete, the reaction mixture was stirred at -40 °C for 30 min. Then, 1,4-dibromobutane (11.15 g, 51.65 mmol, 1.2 eq) was slowly added, and the reaction mixture was heated to room temperature and stirred for 2 h. After the reaction was complete, the reaction was quenched with ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (3.30 g, 30%).

[0239] Step 2: Synthesis of diethyl 7-isocyano-2,2,12,12-tetramethyl-7-p-toluenesulfonyltridecanoate At room temperature, NaH (455 mg, 11.37 mmol, 3.0 eq) was slowly added to a DMSO (20 mL) solution of TBAI (140 mg, 0.38 mmol, 0.1 eq) and TosMIC (740 mg, 3.79 mmol, 1.0 eq). After 30 minutes, ethyl 6-bromo-2,2-dimethylhexanoate (1.99 g, 7.96 mmol, 2.0 eq) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was quenched with an aqueous solution of NH4Cl (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1). A colorless oily product (1.30 g, 64%) was given.

[0240] Step 3: Synthesis of diethyl 2,2,12,12-tetramethyl-7-oxotridecanoic acid At 0 °C, concentrated hydrochloric acid (5 mL) was added to a solution of diethyl 7-isocyano-2,2,12,12-tetramethyl-7-p-toluenesulfonyltridecanoate (1.2 g, 2.24 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at 25 °C for 4 hours. The solution was then cooled to 0 °C, and the reaction was quenched with an aqueous solution of NaHCO3 (30 mL). Extraction was performed using DCM (30 mL × 2). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1). A colorless oily product (700 mg, 84%) was obtained.

[0241] Step 4: Synthesis of diethyl 7-hydroxy-2,2,12,12-tetramethyltridecanoate At 0 °C, NaBH4 (143 mg, 3.78 mmol, 2.0 eq) was added to a methanol (10 mL) solution of diethyl 2,2,12,12-tetramethyl-7-oxotridecanoic acid (700 mg, 1.89 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 1N HCl aqueous solution (0.5 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 4 / 1) to give a colorless oily product (600 mg, 85%).

[0242] Step 5: Synthesis of diethyl 7-methoxy-2,2,12,12-tetramethyltridecanoate At 0 °C, 2,6-di-tert-butylpyridine (0.27 mL, 1.21 mmol, 1.5 eq) and CF3SO2OMe (159 mg, 0.97 mmol, 1.2 eq) were added to a DCM (2 mL) solution of diethyl 7-hydroxy-2,2,12,12-tetramethyltridecanoate (300 mg, 0.81 mmol, 1.0 eq). The reaction mixture was stirred overnight at 40 °C. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oil (200 mg, 64%).

[0243] Step 6: Synthesis of diethyl 7-methoxy-2,2,12,12-tetramethyltridecanoate To a methanol (3 mL) solution of diethyl 7-methoxy-2,2,12,12-tetramethyltridecanoic acid (200 mg, 0.52 mmol, 1.0 eq), 1 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred overnight at 80 °C. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 4 / 1). A colorless oily product (69 mg, 40%) was given.

[0244] MS(ESI, neg.ion) m / z: 329.0 [M-1] + .

[0245] 1 HNMR (400 MHz, DMSO- d 6) δ = 11.99 (br s, 2H), 3.20-3.17 (s, 3H), 3.06(t, J = 5.5Hz, 1H), 1.48-1.40 (m, 4H), 1.40 - 1.33 (m, 4H), 1.25-1.14 (m, 8H), 1.09-1.03 (s, 12H).

[0246] Example 12: Synthesis of 1-(12-carboxylic acid-6-methoxy-12-methyltridecyl)cyclopropane-1-carboxylic acid (0021) Step 1: Synthesis of ethyl 8-cyano-2,2-dimethyl-8-p-toluenesulfonyl octanoate Under N2 protection, TosMIC (1.00 g, 5.12 mmol), Bu4NI (0.19 g, 0.51 mmol), and K2CO3 (1.06 g, 7.68 mmol) were added to a DMF (10 mL) solution of ethyl 9-bromo-2,2-dimethylnonanoate (2.04 g, 7.68 mmol). The reaction mixture was stirred at 25 °C for 5 days. The reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1) to give a colorless oily product (1.05 g, 54%).

[0247] Step 2: Synthesis of tert-butyl 1-(6-cyano-13-ethoxy-12,12-dimethyl-13-oxo-6-toluenesulfonyltridecyl)cyclopropane-1-carboxylate Under a nitrogen atmosphere at 0 °C, a solution of 2.4 mL of DMA (800 mg, 2.11 mmol) in t-BuOK (355 mg, 3.16 mmol) was added dropwise over 20 minutes to a solution of 2.4 mL of DMA (800 mg, 2.11 mmol). Subsequently, a solution of 2.4 mL of DMA (713 mg, 2.11 mmol) in 1-(5-iodopentyl)cyclopropane-1-carboxylic acid tert-butyl ester was slowly added dropwise over 10 minutes at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. A saturated aqueous solution of NH4Cl (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL × 3). The combined organic layers were washed with water (20 mL × 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was used directly in the next reaction to give a yellow oily crude product (1.10 g, 88%).

[0248] Step 3: Synthesis of tert-butyl 1-(13-ethoxy-12,12-dimethyl-6,13-dioxotridecyl)cyclopropane-1-carboxylate At room temperature, concentrated hydrochloric acid (0.88 mL) was added to a solution of 1-(6-cyano-13-ethoxy-12,12-dimethyl-13-oxo-6-toluenesulfonyltridecyl)cyclopropane-1-carboxylic acid tert-butyl ester (1100 mg, 1.86 mmol) in dichloromethane (6.6 mL). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with H₂O (20 mL) and DCM (30 mL). The aqueous layer was extracted with DCM (20 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 20 / 1) to give a colorless oily product (460 mg, 58%).

[0249] Step 4: Synthesis of tert-butyl 1-(13-ethoxy-6-hydroxy-12,12-dimethyl-13-oxotridecyl)cyclopropane-1-carboxylate Under nitrogen protection at 0°C, NaBH4 (41 mg, 1.08 mmol) was added to a methanol (5 mL) solution of 1-(13-ethoxy-12,12-dimethyl-6,13-dioxotridecyl)cyclopropane-1-carboxylic acid tert-butyl ester (460 mg, 1.08 mmol). The reaction mixture was stirred at 0°C for 4 hours. The reaction mixture was poured into an ice-water mixture (10 mL). The aqueous layer was extracted with EA (30 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (380 mg, 82%).

[0250] Step 5: Synthesis of 1-(13-ethoxy-6-methoxy-12,12-dimethyl-13-oxotridecyl)cyclopropane-1-carboxylic acid To a solution of 1-(13-ethoxy-6-hydroxy-12,12-dimethyl-13-oxotridecyl)cyclopropane-1-carboxylic acid tert-butyl ester (380 mg, 0.89 mmol) in dichloromethane (4 mL), CF3SO3Me (293 mg, 1.78 mmol) and 2,6-di-tert-butylpyridine (0.85 mg, 1.34 mmol) were added. The reaction mixture was stirred at 40 °C for 18 hours. The reaction mixture was diluted with dichloromethane (20 mL). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1) to give a colorless oily product (100 mg, 29%).

[0251] Step 6: Synthesis of 1-(12-carboxylic acid-6-methoxy-12-methyltridecyl)cyclopropane-1-carboxylic acid A 20% KOH aqueous solution (1 mL) was added to a methanol (4 mL) solution of 1-(13-ethoxy-6-methoxy-12,12-dimethyl-13-oxotridecyl)cyclopropane-1-carboxylic acid (100 mg, 0.26 mmol). The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (60 mg, 59%).

[0252] MS(ESI, pos.ion) m / z: 357.3 [M+1] + .

[0253] 1 HNMR (400 MHz, DMSO- d 6 ) δ = 12.00 (br s, 2H), 3.19 (s, 3H), 3.14 -3.02 (m, 1H), 1.45 - 1.32 (m, 10H), 1.29 - 1.15 (m, 10H), 1.07 (s, 6H), 1.03- 0.98 (m, 2H), 0.85 (br d, J = 6.6 Hz, 1H), 0.72 - 0.61 (m, 2H).

[0254] Example 13: (8) R 9R )-8,9-dimethoxy-2,2,15,15-tetramethylhexadecanoic acid (0022-a) and (8 S 9 S Synthesis of 8,9-dimethoxy-2,2,15,15-tetramethylhexadecanoic acid (0022-b) Step 1: 2-((hept-6-yn-1-yl)oxy)tetrahydro-2 H Synthesis of pyran To a solution of hexano-6-yn-1-ol (5.00 g, 44.58 mmol, 1.0 eq) in DCM (50 mL), PPTS (12.32 g, 49.03 mmol, 1.1 eq) and DHP (4.50 g, 53.49 mmol, 1.2 eq) were added. The reaction mixture was stirred overnight at 25 °C. The reaction mixture was concentrated under reduced pressure. The residue was diluted with a mixture of DCM (40 mL) and MTBE (50 mL) and stirred for 1 hour. The reaction mixture was filtered and concentrated to give a crude product, which was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1) to give a yellow oily product (7.00 g, 80%).

[0255] Step 2: 2-((5-bromopentyl)oxy)tetrahydro-2 H Synthesis of pyran PPTS (7.45 g, 29.63 mmol, 1.1 eq) and DHP (3.17 g, 37.71 mmol, 1.2 eq) were added to a DCM (60 mL) solution of 5-bromopentan-1-ol (5.00 g, 26.94 mmol). The reaction mixture was stirred overnight at 25 °C. The reaction mixture was concentrated under reduced pressure. The residue was diluted with a mixture of DCM (15 mL) and MTBE (80 mL) and stirred for 1 hour. The reaction mixture was filtered and concentrated to give a crude product, which was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1) to give a yellow oily product (5.47 g, 80%).

[0256] Step 3: 1,12-bis((tetrahydro-2) H Synthesis of pyran-2-yl)oxy)dodecane-6-yne Under a N2 atmosphere at -40 °C, 2-((hexane-6-yn-1-yl)oxy)tetrahydro-2 H n-BuLi (392 mg, 6.11 mmol, 1.0 eq) was added dropwise to a THF (20 mL) solution of pyran (1.20 g, 6.11 mmol, 1.0 eq). After the addition was complete, HMPA (5 mL) was added. The reaction mixture was stirred at -40 °C for 1 hour, and then 2-((5-bromopentyl)oxy)tetrahydro-2- H -Pyran (1.61 g, 6.42 mmol, 1.05 eq). The reaction mixture was stirred at -40 °C for 1 hour, then stirred overnight at 25 °C. The reaction was quenched with NH4Cl aqueous solution (30 mL), followed by extraction with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (1.320 g, 58%).

[0257] Step 4: ( E )-1,12-bis((tetrahydro-2 H Synthesis of pyran-2-yl)oxy)dodecane-6-ene Under a nitrogen atmosphere at 25°C, 1,12-bis((tetrahydro-2-dimethyl ether)) was added to a 20 mL solution of LAH (942 mg, 24.83 mmol, 8.0 eq) in diethylene glycol dimethyl ether. H 1,300 mg (3.55 mmol, 1.0 eq) pyran-2-yl)oxo)dodecane-6-yne. The reaction mixture was stirred at 140 °C for 12 hours. The reaction mixture was cooled to 0 °C, and then water (0.9 mL), 15% NaOH aqueous solution (0.9 mL), and water (2.7 mL) were added. The reaction mixture was stirred for 15 minutes, Na2SO4 was added, and the mixture was filtered and concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (1000 mg, 77%).

[0258] Step 5: ( E Synthesis of 1,12-dodecane-6-ene-1,12-diol Towards( E )-1,12-bis((tetrahydro-2 H1,2-pyran-2-yl)oxy)dodecane-6-ene (1000 mg, 2.71 mmol, 1.0 eq) was reacted with PTSA (98 mg, 0.52 mmol, 0.20 eq) in a mixture of MeOH (10 mL) and H₂O (1 mL). The reaction mixture was stirred overnight at 25 °C. The mixture was diluted with EA (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 1 / 1) to give a white solid product (250 mg, 46%).

[0259] Step 6: ( E Synthesis of 1,12-dibromododecane-6-ene At 0 °C, under a protected N2 atmosphere, towards ( E PPh3 (982 mg, 3.74 mmol, 3.0 eq) was added to a DCM (8 mL) solution of 1,12-dodecane-6-ene-1,12-diol (250 mg, 1.25 mmol, 1.0 eq) and CBr4 (1242 mg, 3.74 mmol, 3.0 eq). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1) to give a white solid product (340 mg, 84%).

[0260] Step 7: ( E Synthesis of diethyl 2,2,15,15-tetramethylhexadecane-8-enediacid Under a nitrogen atmosphere at -40 °C, LDA (446 mg, 4.16 mmol, 4.0 eq) was added dropwise to a THF (4 mL) solution of ethyl 2-methylpropionate (483 mg, 4.16 mmol, 4.0 eq). After stirring the reaction mixture for 1 hour, (… E 1,12-Dibromododecane-6-ene (340 mg, 1.04 mmol, 1.0 eq). The reaction mixture was stirred at -40 °C for 0.5 hours, followed by stirring at 25 °C for 18 hours. The reaction was quenched with an ice-water solution (10 mL), followed by extraction with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a yellow oil (300 mg, 73%).

[0261] Step 8: (8) R 9R )-8,9-dihydroxy-2,2,15,15-tetramethylhexadecanoic acid diethyl ester and (8 S 9 S Synthesis of diethyl 8,9-dihydroxy-2,2,15,15-tetramethylhexadecanoic acid At 0 ℃, towards ( E Diethyl 2,2,15,15-tetramethylhexadecane-8-enedioic acid (300 mg, 0.76 mmol, 1.0 eq) and NMO (222 mg, 1.89 mmol, 2.5 eq) were added to a mixture of THF (5 mL) and H2O (5 mL) with OsO4 (4 mg, 0.02 mmol, 0.02 eq). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with an aqueous solution of Na2SO3 (20 mL) and then extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give two colorless oily products (220 mg, 68%).

[0262] Step 9: (8) R 9 R )-8,9-dimethoxy-2,2,15,15-tetramethylhexadecanoic acid diethyl ester and (8 S 9 S Synthesis of diethyl 8,9-dimethoxy-2,2,15,15-tetramethylhexadecanoic acid To (8) R 9 R )-8,9-dihydroxy-2,2,15,15-tetramethylhexadecanoic acid diethyl ester and (8 S 9 S CF3SO3Me (0.18 mL, 1.58 mmol, 4.0 eq) and 2,6-di-tert-butylpyridine (0.27 mL, 1.18 mmol, 3.0 eq) were added to a solution of diethyl 8,9-dihydroxy-2,2,15,15-tetramethylhexadecanoate (170 mg, 0.39 mmol, 1.0 eq) in dichloromethane (3 mL). The reaction mixture was stirred at 40 °C for 18 hours. The mixture was diluted with DCM (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give two products (80 mg, 44%) as a colorless oil.

[0263] Step 10: (8) R 9 R )-8,9-dimethoxy-2,2,15,15-tetramethylhexadecanoic acid and (8 S 9 S Synthesis of 8,9-dimethoxy-2,2,15,15-tetramethylhexadecanoic acid To (8) R 9 R )-8,9-dimethoxy-2,2,15,15-tetramethylhexadecanoic acid diethyl ester and (8 S 9 S Diethyl hexadecanoate (80 mg, 0.17 mmol, 1.0 eq) in methanol (4 mL) was added to a 20% KOH aqueous solution (1 mL). The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M HCl solution, and then extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give two colorless oily products (30 mg, 43%).

[0264] MS(ESI, neg.ion) m / z: 401.1 [M-1] + .

[0265] 1 HNMR (400 MHz, DMSO-d6) δ = 11.97 (br d, J = 1.1 Hz, 2H), 3.28 (s, 6H), 3.15 (br s, 2H), 1.31-1.47 (m, 8H), 1.14-1.29 (m, 12H), 1.07 (s, 12H).

[0266] Example 14: Synthesis of 10-methoxy-2,2,18,18-tetramethylnonadecanedioic acid (0023) Step 1: Synthesis of ethyl 9-bromo-2,2-dimethylnonanoate Under a nitrogen atmosphere at -40 °C, LDA (17.20 mL, 34.44 mmol) was added to a THF (40 mL) solution of ethyl 2-methylpropionate (4.00 g, 34.44 mmol). After stirring the reaction mixture for 1 hour, 1,7-dibromoheptane (12.40 g, 48.21 mmol) was added. The reaction mixture was stirred at -40 °C for 0.5 hours, and then at 25 °C for 1 hour. The reaction mixture was then poured into an ice-water mixture (20 mL). The aqueous layer was extracted with EA (50 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1). A yellow oily product (5.00 g, 49%) was obtained.

[0267] Step 2: Synthesis of diethyl 10-cyano-2,2,18,18-tetramethyl-10-toluenesulfonylnonadecanedioate Under nitrogen protection at 0°C, sodium hydride (0.92 g, 23.02 mmol) was added to a DMSO (45 mL) solution of TosMIC (1.50 g, 7.67 mmol) and Bu4NI (0.28 g, 0.77 mmol). The reaction mixture was stirred at 25°C for 30 min, followed by the addition of ethyl 9-bromo-2,2-dimethylnonanoate (4.5 g, 15.35 mmol). The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was quenched with water (40 mL) at 0°C. The mixture was extracted with EA (50 mL × 2). The combined organic layers were washed with 10% HCl (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1). A yellow oily product (4.10 g, 43%) was obtained.

[0268] Step 3: Synthesis of diethyl 2,2,18,18-tetramethyl-10-oxononadecanedioate At room temperature, concentrated hydrochloric acid (18 mL) was added to a solution of diethyl 10-cyano-2,2,18,18-tetramethyl-10-toluenesulfonylnonadecanedioate (3.60 g, 5.81 mmol) in dichloromethane (47 mL). The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was diluted with water (30 mL). The aqueous layer was extracted with DCM (40 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (2.50 g, 95%).

[0269] Step 4: Synthesis of diethyl 10-hydroxy-2,2,18,18-tetramethylnonadecanedioate Under nitrogen protection at 0°C, NaBH4 (0.22 g, 5.94 mmol) was added to a methanol (30 mL) solution of diethyl 2,2,18,18-tetramethyl-10-oxononadecanedioate (2.70 g, 5.94 mmol). The reaction mixture was stirred at 0°C for 4 hours. The reaction mixture was poured into an ice-water mixture (20 mL). The aqueous layer was extracted with EA (30 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (2.60 g, 96%).

[0270] Step 5: Synthesis of diethyl 10-methoxy-2,2,18,18-tetramethylnonadecanedioate To a solution of diethyl 10-hydroxy-2,2,18,18-tetramethylnonadecanedioate (300 mg, 0.66 mmol) in dichloromethane (3 mL), CF3SO3Me (0.15 mL, 1.31 mmol) and 2,6-di-tert-butylpyridine (0.22 mL, 0.99 mmol) were added. The reaction mixture was stirred at 40 °C for 18 hours. The reaction mixture was diluted with dichloromethane (20 mL). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (120 mg, 38%).

[0271] Step 6: Synthesis of 10-methoxy-2,2,18,18-tetramethylnonadecanedioic acid To a methanol (4 mL) solution of diethyl 10-methoxy-2,2,18,18-tetramethylnonadecanedioate (120 mg, 0.25 mmol), 1 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1). A colorless oily product (70 mg, 66%) was given.

[0272] MS(ESI, pos.ion) m / z: 415.1 [M+1] + .

[0273] 1 HNMR (400 MHz, DMSO-d6) δ = 12.00 (br s, 2H), 3.19 (s, 3H), 3.08 (brd, J = 5. Hz, 1H), 1.46 - 1.33 (m, 8H), 1.30 - 1.17 (m, 20H), 1.07 (s, 12H).

[0274] Example 15: (9) R 10 R )-9,10-dimethoxy-2,2,17,17-tetramethyloctadecanoic acid (0045-a) and (9 S 10 S Synthesis of 9,10-dimethoxy-2,2,17,17-tetramethyloctadecanoic acid (0045-b) Step 1: (9) R 10 R )-9,10-dihydroxy-2,2,17,17-tetramethyloctadecanoic acid diethyl ester and (9 S 10 S Synthesis of diethyl 9,10-dihydroxy-2,2,17,17-tetramethylhexadecanoic acid At 0 ℃, towards ( EDiethyl 2,2,17,17-tetramethyloctadecane-9-enedioic acid (400 mg, 0.94 mmol, 1.0 eq) and NMO (276 mg, 2.35 mmol, 2.5 eq) were added to a mixture of THF (5 mL) and H2O (5 mL) with OsO4 (5 mg, 0.02 mmol, 0.02 eq). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with an aqueous solution of Na2SO3 (20 mL) and then extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1). Two products (280 mg, 65%) were given as a colorless oil.

[0275] Step 2: (9) R 10 R )-9,10-dimethoxy-2,2,17,17-tetramethyloctadecanoic acid diethyl ester and (9 S 10 S Synthesis of diethyl 9,10-dimethoxy-2,2,17,17-tetramethylhexadecanoic acid To 9 R 10 R )-9,10-dihydroxy-2,2,17,17-tetramethyloctadecanoic acid diethyl ester and (9 S 10 S CF3SO3Me (0.20 mL, 1.74 mmol, 4.0 eq) and 2,6-di-tert-butylpyridine (0.29 mL, 1.31 mmol, 3.0 eq) were added to a solution of diethyl 9,10-dihydroxy-2,2,17,17-tetramethylhexadecanoate (200 mg, 0.44 mmol, 1.0 eq) in dichloromethane (3 mL). The reaction mixture was stirred at 40 °C for 18 hours. The mixture was diluted with DCM (20 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give two products (40 mg, 19%) as a colorless oil.

[0276] Step 3: (9) R 10 R )-9,10-dimethoxy-2,2,17,17-tetramethyloctadecanoic acid and (9 S 10 S Synthesis of 9,10-dimethoxy-2,2,17,17-tetramethyloctadecanoic acid To (9) R 10 R )-9,10-dimethoxy-2,2,17,17-tetramethyloctadecanoic acid diethyl ester and (9 S 10 S Diethyl hexadecanoate (40 mg, 0.08 mmol, 1.0 eq) in methanol (4 mL) was added to a 20% KOH aqueous solution (1 mL). The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M HCl solution, and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1). Two products (20 mg, 57%) were given as a colorless oil.

[0277] MS(ESI, neg.ion) m / z: 429.1 [M-1] + .

[0278] 1 HNMR (400 MHz, DMSO- d 6) δ = 11.99 (br s, 2H), 3.28 (s, 6H), 3.15 (brs, 2H), 1.31-1.47 (m, 8H), 1.23 (br s, 16H), 1.06 (s, 12H).

[0279] Example 16: Synthesis of 8-(difluoromethoxy)-2,2,14,14-tetramethylpentadecanedioic acid (0046) Step 1: Synthesis of diethyl 8-(difluoromethoxy)-2,2,14,14-tetramethylpentadecanedioate At 0 °C, KHF2 (312 mg, 4.00 mmol) was added to a mixed solution of diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate (200 mg, 0.50 mmol) in H2O (0.3 mL) and DCM (0.1 mL). After dissolution of KHF2, TMS-CF2Br (406 mg, 2.00 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with an aqueous H2O solution (10 mL) and then extracted with DCM (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography and eluted with PE:EA = 10:1 to obtain a yellow oily liquid of 8-(difluoromethoxy)-2,2,14,14-tetramethylpentadecanedioic acid (120 mg, 0.27 mmol, 53%).

[0280] 1 HNMR (400 MHz, CHLOROFORM-d) δ = 6.42 - 5.99 (m, 1H), 4.18 - 4.08(m, 4H), 4.07 - 3.99 (m, 1H), 1.56 - 1.46 (m, 8H), 1.39 - 1.20 (m, 18H), 1.16(s, 12H).

[0281] Step 2: Synthesis of 8-(difluoromethoxy)-2,2,14,14-tetramethylpentadecanedioic acid To a methanol (0.8 mL) solution of diethyl 8-(difluoromethoxy)-2,2,14,14-tetramethylpentadecanedioic acid (100 mg, 0.22 mmol), 0.2 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred overnight at 70 °C. The pH of the reaction mixture was adjusted to 1 with 1M hydrochloric acid solution. The aqueous layer was extracted with EA (10 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography, eluting with PE:EA = 4:1 to obtain a yellow oily liquid of 8-(difluoromethoxy)-2,2,14,14-tetramethylpentadecanedioic acid (70 mg, 0.18 mmol, 80%).

[0282] MS(ESI, pos.ion) m / z: 395.2 [M+H] + , 417.2 [M+Na] + .

[0283] 1 HNMR (400 MHz, DMSO-d6) δ = 12.00 (s, 2H), 6.85 - 6.43 (m, 1H), 4.01 (s, 1H), 1.52 - 1.37 (m, 8H), 1.32 - 1.16 (m, 12H), 1.06 (s, 12H).

[0284] Example 17: Synthesis of 6,6'-(2-methoxycyclohexane-1,3-diyl)bis(2,2-dimethylhexanoic acid) (0047) Step 1: Synthesis of 6,6'-(2-oxocyclohexane-1,3-diyl)bis(2,2-dimethylhexanoate diethyl ester) Potassium tert-butoxide (285 mg, 2.55 mmol, 2.5 eq) was slowly added to a toluene (5 mL) solution of cyclohexanone (100 mg, 1.02 mmol, 1.0 eq) at 0 °C. The reaction mixture was stirred at the same temperature for 30 min, followed by the addition of ethyl 6-bromo-2,2-dimethylhexanoate (589 mg, 2.34 mmol, 2.3 eq). The reaction mixture was heated to room temperature and stirred overnight. The reaction was quenched with 10 mL of aqueous NH4Cl solution and then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1) to give a colorless oil (200 mg, 45%).

[0285] Step 2: Synthesis of 6,6'-(2-hydroxycyclohexane-1,3-diyl)bis(2,2-dimethylhexanoate diethyl ester) At 0 °C, NaBH4 (35 mg, 0.92 mmol, 2.0 eq) was added to a methanol (2 mL) solution of 6,6'-(2-oxocyclohexane-1,3-diyl)bis(2,2-dimethylhexanoate) (200 mg, 0.46 mmol, 1.0 eq). The reaction mixture was brought to room temperature and stirred for 2 hours. The reaction mixture was quenched with 1N HCl (0.5 mL) aqueous solution and extracted with ethyl acetate (5 mL × 2). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 4 / 1) to give a colorless oil (190 mg, 94%).

[0286] Step 3: Synthesis of 6,6'-(2-methoxycyclohexane-1,3-diyl)bis(diethyl 2,2-dimethylhexanoate) At 0 °C, 2,6-di-tert-butylpyridine (0.15 mL, 0.68 mmol, 1.5 eq) and CF3SO2OMe (97 mg, 0.59 mmol, 1.3 eq) were added to a solution of 6,6'-(2-hydroxycyclohexane-1,3-diyl)bis(2,2-dimethylhexanoate) (200 mg, 0.45 mmol, 1.0 eq) in DCM (2 mL). The reaction mixture was stirred overnight at 40 °C. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oil (178 mg, 86%).

[0287] Step 4: Synthesis of 6,6'-(2-methoxycyclohexane-1,3-diyl)bis(2,2-dimethylhexanoic acid) To a methanol (3 mL) solution of 6,6'-(2-methoxycyclohexane-1,3-diyl)bis(2,2-dimethylhexanoate) (100 mg, 0.22 mmol, 1.0 eq), 1 mL of 20% KOH aqueous solution was added. The reaction mixture was stirred overnight at 80 °C. The pH of the reaction mixture was adjusted to 1 with 1N hydrochloric acid solution. The aqueous layer was extracted with EA (10 mL × 2). The organic layer was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 4 / 1) to give a colorless oily product (70 mg, 79%).

[0288] MS(ESI,neg.ion) m / z: 397.1 [M-1] + .

[0289] 1 HNMR (400 MHz, DMSO- d 6) δ = 11.99 (s, 2H), 3.19 (s, 3H), 2.92 - 2.87 (m, 1H), 1.54 - 1.40 (m, 6H), 1.35 - 1.08 (m, 18H), 1.06 (s, 12H).

[0290] Example 18: 8-Methoxy-2,2,14,14-Tetra(methyl- d 3 )Synthesis of Pentadecanedioic acid-8-d (0027) Step 1: Synthesis of ethyl 7-(formyloxy)heptaate At 0 °C, TEA (7.31 mL, 52.71 mmol) was added to a solution of ethyl 7-bromoheptaate (5.00 g, 21.08 mmol) in formic acid (2.00 mL, 52.71 mmol). The reaction mixture was stirred at 50 °C for 24 hours. After the reaction was complete, the mixture was diluted with EA (50 mL), washed successively with 1 M HCl (20 mL), saturated NaHCO3 solution (20 mL), and saturated saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (3.9 g, 91%).

[0291] 1 HNMR (400 MHz, METHANOL- d 4) δ = 8.10 (s, 1H), 4.19 - 4.10 (m, 4H), 2.33 (t, J = 7.4 Hz, 2H), 1.73 - 1.60 (m, 4H), 1.47 - 1.35 (m, 4H), 1.26 (t, J =7.1 Hz, 3H).

[0292] Step 2: Synthesis of ethyl 7-hydroxyheptaate At 0 °C, K₂CO₃ (3.8 g, 27.69 mmol) was added to an ethanol (30 mL) solution of ethyl 7-(formyloxy)heptaate (2.80 g, 13.84 mmol). The reaction mixture was stirred at 25 °C for 18 hours. After the reaction was complete, the mixture was diluted with EA (50 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 3 / 1). A colorless oily product (2.3 g, 95%) was obtained.

[0293] 1 HNMR (400 MHz, DMSO- d 6) δ = 4.32 (t, J= 5.2 Hz, 1H), 4.08 - 4.02 (m,2H), 3.39 -3.34 (m, 2H), 2.26 (t, J = 7.4 Hz, 2H), 1.51 (br t, J = 7.3 Hz, 2H),1.44 - 1.35 (m, 2H), 1.26 (td, J = 3.3, 7.0 Hz, 4H), 1.17 (t, J = 7.1 Hz, 3H).

[0294] Step 3: 7-((tetrahydro-2) H Synthesis of ethyl pyran-2-yl)oxy)heptanate PPTS (2.90 g, 11.48 mmol) was added to a DCM (20 mL) solution of ethyl 7-hydroxyheptaate (2.00 g, 11.48 mmol) and DHP (1.06 g, 12.63 mmol). The reaction mixture was stirred at 25 °C for 18 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1) to give a colorless oily product (2.90 g, 97%).

[0295] Step 4: 2-((methyl- d 3 ))-7-((tetrahydro-2 H Synthesis of ethyl pyran-2-yl)oxy)heptanate Under a protective N2 atmosphere at -78 °C, 7-((tetrahydro-2) H LDA (4.84 mL, 9.68 mmol) was added dropwise to a THF (15 mL) solution of ethyl pyran-2-yl)oxy)heptanate (1.00 g, 3.87 mmol). After the addition was complete, the reaction mixture was stirred at -78 °C for 1 hour, followed by the addition of CD3I (1.40 g, 9.68 mmol). The reaction mixture was stirred at 25 °C for 18 hours. The reaction was quenched with saturated NH4Cl aqueous solution (20 mL) and then with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 25 / 1) to give a colorless oily product (430 mg, 40%).

[0296] 1 HNMR (400 MHz, DMSO- d6) δ = 4.54 - 4.50 (m, 1H), 4.09 - 4.01 (m, 2H), 3.72 (ddd, J = 3.0, 8.1, 11.2 Hz, 1H), 3.59 (td, J = 6.7, 9.6 Hz, 1H), 3.46 -3.37 (m, 1H), 3.31 - 3.26 (m, 1H), 2.36 (t, J = 6.8 Hz, 1H), 1.75 - 1.65 (m,1H), 1.60 - 1.35 (m, 9H), 1.34 - 1.23 (m, 4H), 1.17 (t, J = 7.1 Hz, 3H).

[0297] Step 5: 2,2-bis(methyl- d 3 )-7-((tetrahydro-2 H Synthesis of ethyl pyran-2-yl)oxy)heptanate Under a protective N2 atmosphere at -78 °C, 2-((methyl- d 3 ))-7-((tetrahydro-2 H LDA (5 mL, 9.99 mmol) was added dropwise to a THF (10 mL) solution of ethyl pyran-2-yl)oxy)heptanate (1100 mg, 3.99 mmol). After the addition was complete, the reaction mixture was stirred at -78 °C for 1 hour, followed by the addition of CD3I (1.45 g, 9.99 mmol). The reaction mixture was stirred at 25 °C for 18 hours. The reaction was quenched with saturated NH4Cl aqueous solution (20 mL) and then with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 25 / 1) to give a colorless oily product (790 mg, 67%).

[0298] 1 HNMR (400 MHz, DMSO- d 6) δ = 4.52 (t, J = 3.3 Hz, 1H), 4.04 (q, J = 7.1Hz, 2H), 3.72 (ddd, J = 2.9, 8.1, 11.1 Hz, 1H), 3.59 (td,J = 6.7, 9.6 Hz, 1H),3.46 - 3.37 (m, 1H), 3.31 - 3.25 (m, 1H), 1.78 - 1.66 (m, 1H), 1.65 - 1.55(m, 1H), 1.54 - 1.38 (m, 9H), 1.35 - 1.23 (m, 2H), 1.22 - 1.12 (m, 5H).

[0299] Step 6: 7-Hydroxy-2,2-bis(methyl- d 3 Synthesis of ethyl heptanoate To 2,2-bis(methyl- d 3 )-7-((tetrahydro-2 H Ethyl pyran-2-yl)oxy)heptanate (790 mg, 2.70 mmol) was added to a mixed solution of MeOH (10 mL) and H₂O (1 mL) with PTSA (80 mg, 0.42 mmol). The reaction mixture was stirred at 25 °C for 18 hours. After the reaction was complete, the mixture was diluted with EA (30 mL), washed successively with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 4 / 1). A colorless oily product (400 mg, 71%) was obtained.

[0300] 1 HNMR (400 MHz, DMSO- d 6) δ = 4.32 (t, J = 5.2 Hz, 1H), 4.04 (q, J = 7.1Hz, 2H), 3.39 - 3.33 (m, 2H), 1.48 - 1.35 (m, 4H), 1.26 -1.19 (m, 2H), 1.18 -1.09 (m, 5H).

[0301] Step 7: 7-Bromo-2,2-bis(methyl- d 3 Synthesis of ethyl heptanoate Under a protected N2 atmosphere, the 7-hydroxy-2,2-bis(methyl- d 3CBr4 (716 mg, 2.16 mmol) was added dropwise to a DCM (5 mL) solution of ethyl heptanoate (300 mg, 1.44 mmol). PPh3 (566 mg, 2.16 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1). A colorless oily product (350 mg, 86%) was obtained.

[0302] 1 HNMR (400 MHz, DMSO- d 6) δ = 4.05 (q, J = 7.1 Hz, 2H), 3.51 (t, J = 6.7Hz, 2H), 1.83 - 1.74 (m, 2H), 1.50 - 1.40 (m, 2H), 1.39 - 1.29 (m, 2H), 1.23- 1.12 (m, 5H).

[0303] Step 8: 8-Cyano-2,2,14,14-Tetra(methyl- d 3 Synthesis of diethyl 8-p-toluenesulfonylpentadecanedioate Under nitrogen protection at 25°C, sodium hydride (442 mg, 11.05 mmol) was added to a 20 mL solution of TosMIC (720 mg, 3.69 mmol) and Bu4NI (136 mg, 0.37 mmol) in DMSO. After stirring the reaction mixture at 25°C for 30 min, 7-bromo-2,2-di(methyl- d 3 Ethyl heptanoate (2.0 g, 7.37 mmol). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was quenched in an ice-water solution (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1) to give a yellow oily product (1.6 g, 37%).

[0304] Step 9: 2,2,14,14-Tetra(methyl- d 3 )-Synthesis of diethyl 8-oxopentadecanedioic acid At room temperature, 8-cyano-2,2,14,14-tetra(methyl- d 3 Hydrochloric acid (12 mL, 12 N) was added to a solution of diethyl 8-p-toluenesulfonylpentadecanedioate (1.8 g, 3.13 mmol) in dichloromethane (23 mL). The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1). A colorless oily product (1.1 g, 85%) was given.

[0305] Step 10: 8-Hydroxy-2,2,14,14-Tetra(methyl- d 3 Synthesis of 8-d-pentadecanedioic acid diethyl ester Under nitrogen protection and at 0°C, 2,2,14,14-tetra(methyl- d 3 NaBD4 (21 mg, 0.49 mmol) was added to a methanol (20 mL) solution of diethyl 8-oxopentadecanoate (200 mg, 0.49 mmol). The reaction mixture was stirred at 0 °C for 4 hours. After the reaction was complete, the reaction mixture was poured into an ice-water solution (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1). A colorless oily product (200 mg, 98%) was given.

[0306] Step 11: 8-Methoxy-2,2,14,14-Tetra(methyl- d 3 Synthesis of 8-d-pentadecanedioic acid diethyl ester To 8-hydroxy-2,2,14,14-tetra(methyl- d 3CF3SO3Me (164 mg, 0.97 mmol) and 2,6-di-tert-butylpyridine (138 mg, 0.73 mmol) were added to a solution of diethyl pentadecanoate-8-d (200 mg, 0.48 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at 40 °C for 18 hours. The mixture was diluted with dichloromethane (20 mL), washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (160 mg, 80%).

[0307] Step 12: 8-Methoxy-2,2,14,14-Tetra(methyl- d 3 )-Synthesis of pentadecanedioic acid-8-d To 8-methoxy-2,2,14,14-tetra(methyl- d 3 Diethyl pentadecanoate-8-d (160 mg, 0.37 mmol) was dissolved in methanol (4 mL) and 20% KOH aqueous solution (1 mL) was added. The reaction mixture was stirred at 70 °C for 18 hours. After the reaction was complete, the mixture was adjusted to pH 1 with 1 M HCl solution and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 3 / 2) to give a white solid product (100 mg, 72%).

[0308] MS (ESI, pos.ion) m / z: 372.2 [M+1] + .

[0309] 1 HNMR (400 MHz, DMSO- d 6) δ = 11.98 (s, 2H), 3.18 (s, 3H), 1.45 - 1.31 (m, 8H), 1.28 - 1.12 (m, 12H).

[0310] Example 19: (8) R 9 S Synthesis of 8,9-dimethoxy-2,2,15,15-tetramethylhexadecanoic acid (0028) Step 1: Synthesis of 7,7'-(ethylene oxide-2,3-diyl)bis(2,2-dimethylheptanoate diethyl ester) Towards( E m-CPBA (283 mg, 1.64 mmol, 1.0 eq) was added to a DCM (5 mL) solution of diethyl 2,2,15,15-tetramethylhexadec-8-enedioic acid (650 mg, 1.64 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with an aqueous solution of NaHCO3 (20 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1) to give a colorless oily product (550 mg, 81%).

[0311] Step 2: (8) R 9 S Synthesis of diethyl 8-hydroxy-9-methoxy-2,2,15,15-tetramethylhexadecanoic acid H₂SO₄ (0.1 mL) was added to a methanol (8 mL) solution of 7,7'-(ethylene oxide-2,3-diyl)bis(2,2-dimethylheptaate) (550 mg, 1.33 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 5 / 1) to give a colorless oil (500 mg, 87%).

[0312] Step 3: (8) R 9 S Synthesis of diethyl 8,9-dimethoxy-2,2,15,15-tetramethylhexadecanoic acid To (8) R 9 SCF3SO3Me (0.20 mL, 1.80 mmol, 4.0 eq) and 2,6-di-tert-butylpyridine (0.30 mL, 1.35 mmol, 3.0 eq) were added to a solution of diethyl 2,8-hydroxy-9-methoxy-2,2,15,15-tetramethylhexadecanoate (200 mg, 0.46 mmol, 1.0 eq) in dichloromethane (5 mL). The reaction mixture was stirred at 40 °C for 18 hours. The mixture was diluted with DCM (20 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (100 mg, 48%).

[0313] Step 4: (8) R 9 S Synthesis of 8,9-dimethoxy-2,2,15,15-tetramethylhexadecanoic acid To (8) R 9 S Diethyl hexadecanoate (100 mg, 0.22 mmol, 1.0 eq) in methanol (4 mL) was added to a 20% KOH aqueous solution (1 mL). The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M HCl solution, and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (30 mg, 34%).

[0314] MS(ESI, neg.ion) m / z: 401.1 [M-1] + . 1 HNMR (400 MHz, DMSO- d 6) δ = 11.65-12.32 (m, 2H), 3.27 (s, 6H), 3.13(br d, J = 5.4 Hz, 2H), 1.40-1.46 (m, 4H), 1.35 (br s, 5H), 1.14-1.28 (m, 11H), 1.06 (s, 12H).

[0315] Example 20: (9) R 10 SSynthesis of 9,10-dimethoxy-2,2,17,17-tetramethyloctadecanoic acid (0029) Step 1: Synthesis of 2-((oct-7-yn-1-yl)oxy)tetrahydro-2H-pyran To a solution of octano-7-yn-1-ol (8.00 g, 63.39 mmol) in DCM (80 mL), PPTS (17.52 g, 69.73 mmol) and DHP (6.40 g, 76.07 mmol) were added. The reaction mixture was stirred overnight at 25 °C. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was diluted with a mixture of DCM (15 mL) and MTBE (90 mL). The reaction mixture was stirred for 1 hour and then filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1). A yellow oily product (12.00 g, 90%) was given.

[0316] Step 2: Synthesis of 2-((6-bromohexyl)oxy)tetrahydro-2H-pyran To a solution of 6-bromohexane-1-ol (12.00 g, 66.27 mmol) in DCM (120 mL), PPTS (18.32 g, 72.90 mmol) and DHP (6.69 g, 79.53 mmol) were added. The reaction mixture was stirred overnight at 25 °C. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was diluted with a mixture of DCM (15 mL) and MTBE (90 mL). The reaction mixture was stirred for 1 hour and then filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1) to give a yellow oily product (15.00 g, 85%).

[0317] Step 3: Synthesis of 1,14-bis((tetrahydro-2H-pyran-2-yl)oxy)tetradecane-7-yne Under a protective N2 atmosphere at -40 °C, the 2-((oct-7-yn-1-yl)oxy)tetrahydro-2 Hn-BuLi (31.00, 49.93 mmol) was added dropwise to a THF (100 mL) solution of pyran (10.00 g, 47.55 mmol). After the addition was complete, HMPA (25 mL) was added. The reaction mixture was stirred at -40 °C for 1 h, and then 2-((6-bromohexyl)oxy)tetrahydro-2H-pyran (13.24 g, 49.92 mmol) was added dropwise at -40 °C. The reaction mixture was stirred at -40 °C for 1 hour, and then at 25 °C for 18 hours. After the reaction was complete, the reaction was quenched with NH4Cl (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (10.00 g, 53%).

[0318] Step 4: ( E )-1,14-bis((tetrahydro-2 H Synthesis of pyran-2-yl)oxy)tetradecane-7-ene Under a nitrogen atmosphere at 25°C, 1,14-bis(tetrahydro-2-dimethyl ether) solution of LAH (6.73 g, 177.39 mmol) was slowly added to 150 mL of diethylene glycol dimethyl ether. H 10 g (25.34 mmol) of pyran-2-yl)oxy)tetradecane-7-yne was added. The reaction mixture was stirred at 140 °C for 24 hours. After the reaction was complete, the reaction solution was cooled to 0 °C, and then water (7 mL), 15% NaOH aqueous solution (7 mL), and water (21 mL) were added. The reaction solution was stirred for 15 minutes, and then Na2SO4 was added. The mixture was filtered and concentrated. The crude product (10.00 g) was used directly in the next step of the reaction.

[0319] Step 5: ( E Synthesis of 1,14-tetradecane-7-ene-1,14-diol Towards( E )-1,14-bis((tetrahydro-2 H10.00 g of pyran-2-yl)oxy)tetradecane-7-ene was added to a mixed solution of MeOH (100 mL) and H₂O (10 mL) with PTSA (1 g). The reaction mixture was stirred at 25 °C for 18 h. After the reaction was complete, the reaction mixture was diluted with EA (100 mL), washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 1 / 1) to give a white solid product (4.10 g, 71%).

[0320] Step 6: ( E Synthesis of 1,14-dibromotetradec-7-ene At 0 °C, under a protected N2 atmosphere, towards ( E PPh3 (14.13 g, 53.86 mmol) was added to a DCM (40 mL) solution of tetradecane-7-ene-1,14-diol (4.10 g, 17.95 mmol) and CBr4 (17.86 g, 53.86 mmol). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1) to give a white solid product (3.40 g, 53%).

[0321] Step 7: ( E Synthesis of diethyl 2,2,17,17-tetramethyloctadec-9-enediol Under a N2 atmosphere at -40 °C, LDA (12.00 mL, 23.72 mmol) was added dropwise to a 20 mL THF solution of ethyl 2-methylpropionate (2.76 g, 23.72 mmol). After 1 hour, LDA was added dropwise to the reaction solution. E 1,14-Dibromotetradec-7-ene (2.10 g, 5.93 mmol). After addition, the reaction mixture was stirred at -40 °C for 0.5 h, then heated to 25 °C and stirred for 18 h. After the reaction was complete, it was quenched with an ice-water solution (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a yellow oily product (2.40 g, 95%).

[0322] Step 8: Synthesis of 8,8'-(ethylene oxide-2,3-diyl)bis(2,2-dimethyloctanoate diethyl ester) Towards(E m-CPBA (97 mg, 1.64 mmol) was added to a DCM (5 mL) solution of diethyl 2,2,17,17-tetramethyloctadec-9-enedioic acid (200 mg, 1.64 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (20 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL × 2). The combined organic layers were washed with an aqueous solution of NaHCO3 (20 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1) to give a colorless oily product (200 mg, 96%).

[0323] Step 9: (9) S 10 R Synthesis of diethyl 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoate H₂SO₄ (0.1 mL) was added to a methanol (5 mL) solution of 8,8'-(ethylene oxide-2,3-diyl)bis(2,2-dimethyloctanoate) (290 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) was added to the mixture and extracted with DCM (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 5 / 1) to give a colorless oily product (200 mg, 64%).

[0324] Step 10: (9) R 10 S Synthesis of diethyl 9,10-dimethoxy-2,2,17,17-tetramethyloctadecanoate To (9) S 10 RCF3SO3Me (0.10 mL, 1.80 mmol) and 2,6-di-tert-butylpyridine (0.14 mL, 0.63 mmol) were added to a solution of diethyl 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoate (200 mg, 0.42 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at 40 °C for 18 hours. After the reaction was complete, the mixture was diluted with DCM (20 mL), washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1). A colorless oily product (150 mg, 73%) was obtained.

[0325] Step 11: (9) R 10 S Synthesis of 9,10-dimethoxy-2,2,17,17-tetramethyloctadecanoic acid To (9) R 10 S A 20% KOH aqueous solution (1 mL) was added to a methanol (4 mL) solution of diethyl 9,10-dimethoxy-2,2,17,17-tetramethyloctadecanoate (150 mg, 0.31 mmol). The reaction mixture was stirred at 70 °C for 18 hours. After the reaction was complete, the mixture was adjusted to pH 1 with 1 M HCl solution and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1). A colorless oily product (80 mg, 60%) was obtained.

[0326] MS(ESI, pos.ion) m / z: 431.2 [M+1] + .

[0327] 1 HNMR (400 MHz, DMSO- d 6) δ = 12.00 (br s, 2H), 3.28 (s, 6H), 3.13 (brd, J = 5.5 Hz, 2H), 1.46 - 1.31 (m, 10H), 1.28 - 1.16 (m, 14H), 1.07 (s, 12H).

[0328] Example 21: Synthesis of 1-(12-carboxylic acid-6-methoxy-12-methyltridecyl)cyclopropane-1-carboxylic acid (0048) Step 1: Synthesis of diethyl 7-cyano-2,2,13,13-tetramethyl-7-toluenesulfonyltetradecanoate Under a nitrogen atmosphere at 0 °C, a solution of 8-cyano-2,2-dimethyl-8-toluenesulfonyl octanoate (800 mg, 2.11 mmol) in DMA (3 mL) was added dropwise to a solution of t-BuOK (355 mg, 3.16 mmol, 1.5 eq) in DMA (3 mL). After 30 minutes, a solution of 6-bromo-2,2-dimethylhexanoate (589 mg, 2.11 mmol, 1.0 eq) in DMA (3 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, a saturated aqueous solution of NH4Cl (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. A yellow oily crude product was given. The crude product (1.10 g) was used directly in the next reaction.

[0329] Step 2: Synthesis of diethyl 2,2,13,13-tetramethyl-7-oxotetradecanoic acid Hydrochloric acid (2 mL) was added to a solution of diethyl 7-cyano-2,2,13,13-tetramethyl-7-p-toluenesulfonyltetradecanoate (1100 mg, crude) in dichloromethane (15 mL) at room temperature. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA(v / v) = 20 / 1) to give a colorless oily product (460 mg, 57%).

[0330] Step 3: Synthesis of diethyl 7-hydroxy-2,2,13,13-tetramethyltetradecanoate Under nitrogen protection at 0°C, NaBH4 (43 mg, 1.20 mmol, 1.0 eq) was added to a methanol (5 mL) solution of 1-(13-ethoxy-12,12-dimethyl-6,13-dioxotridecyl)cyclopropane-1-carboxylic acid tert-butyl ester (460 mg, 1.20 mmol, 1.0 eq). The reaction mixture was stirred at 0°C for 4 hours. The reaction mixture was poured into an ice-water mixture (10 mL). The aqueous layer was extracted with EA (30 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (380 mg, 82%).

[0331] Step 4: Synthesis of diethyl 7-methoxy-2,2,13,13-tetramethyltetradecanoic acid To a solution of diethyl 7-hydroxy-2,2,13,13-tetramethyltetradecanoate (380 mg, 0.89 mmol, 1.0 eq) in dichloromethane (10 mL), CF3SO3Me (293 mg, 1.78 mmol, 2.0 eq) and 2,6-di-tert-butylpyridine (0.85 mL, 1.34 mmol, 1.5 eq) were added. The reaction mixture was stirred at 40 °C for 18 hours. The reaction mixture was diluted with dichloromethane (20 mL). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1). A colorless oily product (100 mg, 29%) was given.

[0332] Step 5: Synthesis of 7-methoxy-2,2,13,13-tetramethyltetradecanoic acid A 20% KOH aqueous solution (1 mL) was added to a methanol (4 mL) solution of diethyl 7-methoxy-2,2,13,13-tetramethyltetradecanoic acid (100 mg, 0.26 mmol, 1.0 eq). The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1N hydrochloric acid solution. The aqueous layer was extracted with EA (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA(v / v) = 5 / 1) to give a colorless oily product (60 mg, 59%).

[0333] MS(ESI, neg.ion) m / z: 343.1 [M-1]+ .

[0334] 1 HNMR (400 MHz, DMSO- d 6) δ = 12.00 (br s, 2H), 3.19 (s, 3H), 3.07(quin, J = 5.5 Hz, 1H), 1.48 - 1.31 (m, 8H), 1.28 - 1.13 (m, 10H), 1.06 (s, 12H).

[0335] Example 22: (9) S 10 S Synthesis of )-9,10-dihydroxy-2,2,17,17-tetramethyloctadecanedioic acid (0049) Step 1: (9) S 10 S Synthesis of diethyl 9,10-dihydroxy-2,2,17,17-tetramethyloctadecanoate At 0 °C, MeSO₂NH₂ (98 mg, 1.04 mmol) was added to a mixed solution of AD-mix-α (1520 mg) with t-BuOH (5 mL) and H₂O (5 mL). The reaction mixture was stirred at 0 °C for 10 min, and then (…) E Diethyl 2,2,17,17-tetramethyloctadec-9-enedioic acid (400 mg, 0.94 mmol). The reaction mixture was stirred at 25 °C for 24 h. After the reaction was complete, the reaction was quenched with saturated Na₂SO₃ aqueous solution and stirred for 1 h. The mixture was extracted with EA (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 2 / 1) to give the colorless oily target product (220 mg, 51%).

[0336] Step 2: (9) S 10 S Synthesis of )-9,10-dihydroxy-2,2,17,17-tetramethyloctadecanedioic acid To (9) S 10 SA 20% KOH aqueous solution (1 mL) was added to a methanol (4 mL) solution of diethyl 9,10-dihydroxy-2,2,17,17-tetramethyloctadecanoate (100 mg, 0.22 mmol). The reaction mixture was stirred at 70 °C for 18 hours. After the reaction was complete, the mixture was adjusted to pH 1 with 1 M HCl solution and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 2 / 1) to give a white solid product (33 mg, 37%).

[0337] MS(ESI, pos.ion) m / z:403.1 [M+1] + .

[0338] 1 HNMR (400 MHz, DMSO- d 6) δ = 11.96 (s, 2H), 4.13 (br s, 2H), 3.19 (brd, J = 4.0 Hz, 2H), 1.50 - 1.34 (m, 8H), 1.22 (br s, 16H), 1.06 (s, 12H).

[0339] Example 23: (9) R 10 R Synthesis of )-9,10-dihydroxy-2,2,17,17-tetramethyloctadecanedioic acid (0050) Step 1: (9) R 10 R Synthesis of diethyl 9,10-dihydroxy-2,2,17,17-tetramethyloctadecanoate At 0 °C, MeSO₂NH₂ (98 mg, 1.04 mmol) was added to a mixed solution of AD-mix-β (1520 mg) with t-BuOH (5 mL) and H₂O (5 mL). The reaction mixture was stirred at 0 °C for 10 min, and then (…) EDiethyl 2,2,17,17-tetramethyloctadec-9-enedioic acid (400 mg, 0.94 mmol). The reaction mixture was stirred at 25 °C for 24 hours. After the reaction was complete, the reaction was quenched with saturated Na₂SO₃ aqueous solution and stirred for 1 hour. The mixture was extracted with EA (20 mL × 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 2 / 1) to give the colorless oily target product (120 mg, 28%).

[0340] Step 2: (9) R 10 R Synthesis of )-9,10-dihydroxy-2,2,17,17-tetramethyloctadecanedioic acid To (9) R 10 R A 20% KOH aqueous solution (1 mL) was added to a methanol (4 mL) solution of diethyl 9,10-dihydroxy-2,2,17,17-tetramethyloctadecanoate (110 mg, 0.22 mmol). The reaction mixture was stirred at 70 °C for 18 hours. After the reaction was complete, the mixture was adjusted to pH 1 with 1 M HCl solution and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 2 / 1) to give a white solid product (28 mg, 37%).

[0341] MS(ESI, pos.ion) m / z:403.1 [M+1] + .

[0342] 1 HNMR (400 MHz, DMSO-d6) δ = 11.99 (br s, 2H), 4.13 (br s, 2H), 3.19(br s, 2H), 1.48 - 1.32 (m, 8H), 1.22 (br s, 16H), 1.07 (s, 12H).

[0343] Example 24: (9) S 10 S Synthesis of 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid (0034) Step 1: (9)S 10 S Synthesis of diethyl 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoate To (9) S 10 S CF3SO3Me (98 mg, 0.60 mmol) and 2,6-di-tert-butylpyridine (77 mg, 0.40 mmol) were added to a solution of diethyl 9,10-dihydroxy-2,2,17,17-tetramethyloctadecanoate (90 mg, 0.20 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at 40 °C for 18 hours. After the reaction was complete, the mixture was diluted with an aqueous solution (10 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (70 mg, 75%).

[0344] Step 2: (9) S 10 S Synthesis of 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid To (9) S 10 S A 20% KOH aqueous solution (1 mL) was added to a methanol (4 mL) solution of diethyl 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoate (70 mg, 0.15 mmol). The reaction mixture was stirred at 70 °C for 18 hours. After the reaction was complete, the mixture was adjusted to pH 1 with 1 M HCl solution and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (32 mg, 52%).

[0345] MS(ESI, pos.ion) m / z: 417.1 [M+1] + .

[0346] 1 HNMR (400 MHz, DMSO- d 6) δ = 11.99 (br s, 2H), 4.28 (br d, J= 4.0 Hz,1H), 3.48 - 3.39 (m, 1H), 3.27 (s, 3H), 3.00 -2.88 (m, 1H), 1.50 - 1.37 (m,6H), 1.30 - 1.11 (m, 18H), 1.06 (s, 12H).

[0347] Example 25: (9) R 10 R Synthesis of 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid (0035) Step 1: (9) R 10 R Synthesis of diethyl 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoate To (9) R 10 R CF3SO3Me (107 mg, 0.65 mmol) and 2,6-di-tert-butylpyridine (84 mg, 0.44 mmol) were added to a solution of diethyl 9,10-dihydroxy-2,2,17,17-tetramethyloctadecanoate (100 mg, 0.22 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at 40 °C for 18 hours. After the reaction was complete, the mixture was diluted with an aqueous solution (10 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (60 mg, 58%).

[0348] Step 2: (9) R 10 R Synthesis of 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid To (9) R 10 RA 20% KOH aqueous solution (1 mL) was added to a methanol (4 mL) solution of diethyl 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoate (60 mg, 0.15 mmol). The reaction mixture was stirred at 70 °C for 18 hours. After the reaction was complete, the mixture was adjusted to pH 1 with 1 M HCl solution and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1). A colorless oily product (28 mg, 53%) was given.

[0349] MS(ESI, pos.ion) m / z: 417.1 [M+1] + .

[0350] 1 HNMR (400 MHz, DMSO- d 6) δ= 11.99 (br s, 2H), 4.28 (br d, J = 5.0 Hz,1H), 3.49 - 3.39 (m, 1H), 3.27 (s, 3H), 2.94 (br d, J = 2.8 Hz, 1H), 1.50 -1.38 (m, 6H), 1.22 (br d, J = 7.3 Hz, 18H), 1.06 (s, 12H).

[0351] Example 26: (7) R 8 R Synthesis of 7,8-dimethoxy-2,2,14,14-tetramethylpentadecanedioic acid (0051) Step 1: 2-((hexane-5-yn-1-yl)oxy)tetrahydro-2 H Synthesis of pyran PPTS (67.60 g, 269.00 mmol) and DHP (28.80 g, 342.37 mmol) were added to a DCM (300 mL) solution of hexano-5-yn-1-ol (24.00 g, 244.55 mmol). The reaction mixture was stirred overnight at 25 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was diluted with a mixed solution of DCM (60 mL) and MTBE (200 mL), stirred for 1 hour, and filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1) to give a yellow oily product (44.00 g, 98%).

[0352] Step 2: 2-((5-bromopentyl)oxy)tetrahydro-2 H Synthesis of pyran To a solution of 5-bromopentan-1-ol (5.00 g, 26.94 mmol) in DCM (60 mL), PPTS (7.45 g, 29.63 mmol) and DHP (3.17 g, 37.71 mmol) were added. The reaction mixture was stirred overnight at 25 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was diluted with a mixture of DCM (10 mL) and MTBE (80 mL), stirred for 1 hour, and filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1). A yellow oily product (5.47 g, 80%) was given.

[0353] Step 3: Synthesis of 2,2'-(undec-5-yne-1,11-dimethylbis(oxy))bis(tetrahydro-2H-pyran) Under a N2 atmosphere at -40 °C, the 2-((hexane-5-yn-1-yl)oxy)tetrahydro-2 H2-((5-bromopentyl)oxy)tetrahydro-2H-pyran (20.5 g, 32.92 mmol) was added dropwise to a THF (60 mL) solution of 2-pyran (6.00 g, 32.92 mmol). Then HMPA (15 mL) was added. The reaction mixture was stirred at -40 °C for 1 h, followed by the dropwise addition of 2-((5-bromopentyl)oxy)tetrahydro-2H-pyran (8.68 g, 34.57 mmol). The reaction mixture was stirred at -40 °C for 1 hour, then heated to 25 °C and stirred for 18 hours. After the reaction was complete, the reaction was quenched with NH4Cl (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (9.20 g, 79%).

[0354] Step 4: ( E Synthesis of 2,2'-(undec-5-ene-1,11-diylbis(oxy))bis(tetrahydro-2H-pyran) Under a nitrogen atmosphere, 2,2'-(undeca-5-yne-1,11-dimethylbis(oxy))bis(tetrahydro-2H-pyran) (900 mg, 2.55 mmol) was added to a solution of LAH (678 mg, 17.87 mmol) in diethylene glycol dimethyl ether (20 mL). The reaction mixture was stirred at 140 °C for 12 hours. After the reaction was complete, the reaction solution was cooled to 0 °C, and then water (0.700 mL), 15% NaOH aqueous solution (0.700 mL), and water (2.1 mL) were added. The reaction solution was stirred for 15 minutes, Na2SO4 was added, and the mixture was filtered and concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (680 mg, 75%).

[0355] Step 5: ( E Synthesis of 5-undecane-5-ene-1,11-diol Towards( E600 mg, 1.69 mmol) of 2,2'-(undec-5-ene-1,11-diylbis(oxy))bis(tetrahydro-2H-pyran) (600 mg) was added to a mixed solution of MeOH (10 mL) and H₂O (1 mL) with PTSA (60 mg). The reaction mixture was stirred overnight at 25 °C. After the reaction was complete, the mixture was diluted with EA (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 1 / 1) to give a white solid product (300 mg, 95%).

[0356] Step 6: ( E Synthesis of 1,11-dibromoundecane-5-ene At 0 °C, under a protected N2 atmosphere, towards ( E PPh3 (844 mg, 3.22 mmol) was added to a DCM (8 mL) solution of undecane-5-ene-1,11-diol (200 mg, 1.07 mmol) and CBr4 (1068 mg, 3.22 mmol). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1) to give a white solid product (270 mg, 80%).

[0357] Step 7: ( E Synthesis of diethyl 2,2,14,14-tetramethylpentadecano-7-enediacid Under a nitrogen atmosphere at -40 °C, LDA (2.6 mL, 2.56 mmol) was added dropwise to a THF (4 mL) solution of ethyl 2-methylpropionate (297 mg, 2.56 mmol). After the addition was complete, the reaction mixture was stirred for 1 hour, and then (…) E 1,11-Dibromoundecane-5-ene (200 mg, 0.64 mmol). The reaction mixture was stirred at 25 °C for 18 hours. After the reaction was complete, the reaction was quenched with an ice-water solution (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a yellow oily product (120 mg, 49%).

[0358] Step 8: (7) R 8 R)-Synthesis of diethyl 7,8-dihydroxy-2,2,14,14-tetramethylpentadecanedioate At 0 °C, methanesulfonamide (219 mg, 2.30 mmol, 1.1 eq) was added to a mixed solution of AD-mix-β (3000 mg) with t-BuOH (14 mL) and H2O (14 mL). The reaction mixture was stirred at 0 °C for 10 minutes, and then ( E A mixture of tert-butanol (5 mL) and water (5 mL) of diethyl 2,2,14,14-tetramethylpentadecano-7-enedioic acid (800 mg, 2.09 mmol, 1.0 eq) was prepared. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was quenched with saturated aqueous Na₂SO₃ solution (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 1 / 1). A colorless oily product (240 mg, 27%) was given.

[0359] Step 9: (7) R 8 R Synthesis of diethyl 7,8-dimethoxy-2,2,14,14-tetramethylpentadecanedioate At 0 ℃, towards (7 R 8 R CF3SO3Me (0.13 mL, 1.15 mmol, 2.0 eq) and 2,6-di-tert-butylpyridine (0.19 mL, 0.86 mmol, 1.5 eq) were added to a solution of diethyl 7,8-dihydroxy-2,2,14,14-tetramethylpentadecanedioate (240 mg, 0.58 mmol, 1.0 eq) in dichloromethane (3 mL). The reaction mixture was stirred at 25 °C for 18 hours. After the reaction was complete, the mixture was diluted with DCM (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (70 mg, 27%).

[0360] Step 10: (7) R 8 R Synthesis of 7,8-dimethoxy-2,2,14,14-tetramethylpentadecanedioic acid To (7) R 8 RDiethyl 7,8-dimethoxy-2,2,14,14-tetramethylpentadecanedioate (70 mg, 0.16 mmol, 1.0 eq) was added to a methanol (4 mL) solution with 20% KOH aqueous solution (1 mL). The reaction mixture was stirred at 70 °C for 18 hours. After the reaction was complete, the mixture was adjusted to pH 1 with 1 M HCl solution and then extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (28 mg, 45%).

[0361] MS(ESI, pos.ion) m / z: 389.2 [M+1] + .

[0362] 1 HNMR (400 MHz, DMSO- d 6) δ = 11.99 (br s, 2H), 3.28 (s, 6H), 3.15 (brs, 2H), 1.48 - 1.33 (m, 8H), 1.29 - 1.16 (m, 10H), 1.07 (s, 12H).

[0363] Example 27: (7) S 8 S Synthesis of 7,8-dimethoxy-2,2,14,14-tetramethylpentadecanedioic acid (0052) Step 1: (7) S 8 S )-Synthesis of diethyl 7,8-dihydroxy-2,2,14,14-tetramethylpentadecanedioate At 0 °C, methanesulfonamide (219 mg, 2.30 mmol, 1.1 eq) was added to a mixed solution of AD-mix-β (3000 mg) with t-BuOH (14 mL) and H2O (14 mL). The reaction mixture was stirred for 10 minutes, and then ( EA mixture of tert-butanol (5 mL) and water (5 mL) of diethyl 2,2,14,14-tetramethylpentadecano-7-enedioic acid (800 mg, 2.09 mmol, 1.0 eq) was prepared. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was quenched with saturated aqueous Na₂SO₃ solution (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO₂, PE / EA (v / v) = 1 / 1) to give a colorless oily product (640 mg, 73%).

[0364] Step 2: Synthesis of diethyl (7S,8S)-7,8-dimethoxy-2,2,14,14-tetramethylpentadecanedioate At 0 ℃, towards (7 S 8 S A solution of diethyl 7,8-dihydroxy-2,2,14,14-tetramethylpentadecanedioate (400 mg, 0.96 mmol, 1.0 eq) in dichloromethane (5 mL) was mixed with CF3SO3Me (0.22 mL, 1.92 mmol, 2.0 eq) and 2,6-di-tert-butylpyridine (0.32 mL, 1.44 mmol, 1.5 eq). The reaction mixture was stirred at 25 °C for 18 hours. After the reaction was complete, the mixture was diluted with DCM (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1). A colorless oily product (190 mg, 44%) was obtained.

[0365] Step 3: (7) S 8 S Synthesis of 7,8-dimethoxy-2,2,14,14-tetramethylpentadecanedioic acid To (7) S 8 SDiethyl hexadecanoate (190 mg, 0.43 mmol, 1.0 eq) in methanol (4 mL) was added to a 20% KOH aqueous solution (2 mL). The reaction mixture was stirred at 70 °C for 18 hours. After the reaction was complete, the mixture was adjusted to pH 1 with 1 M HCl solution and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1). A colorless oily product (110 mg, 66%) was given.

[0366] MS(ESI, pos.ion) m / z: 389.2 [M+1] + .

[0367] 1 HNMR (400 MHz, DMSO- d 6) δ = 11.99 (br s, 2H), 3.28 (s, 6H), 3.15 (brs, 2H), 1.49 - 1.35 (m, 8H), 1.28 - 1.16 (m, 10H), 1.07 (s, 12H).

[0368] Example 28: Synthesis of (9S,10S)-9-((2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionyl)oxy)-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid (0040) Step 1: ( E Synthesis of di-tert-butyl 2,2,17,17-tetramethyloctadec-9-enediol Under a nitrogen atmosphere at 0 °C, LDA (4.52 mL, 9.04 mmol) was added dropwise to a 20 mL THF solution of tert-butyl isobutyrate (1302 mg, 9.04 mmol, 4.0 eq). After 1 hour, LDA was added dropwise to the reaction solution. EAfter the addition of 1,14-dibromotetradec-7-ene (800 mg, 2.26 mmol), the reaction mixture was stirred at 0 °C for 0.5 h, followed by stirring at 25 °C for another 18 h. After the reaction was complete, it was quenched with an ice-water solution (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a yellow oily product (850 mg, 78%).

[0369] Step 2: (9) S 10 S )-9,10-Dihydroxy-2,2,17,17-Tetramethyloctadecanedioic acid di-tert-butyl ester At 0 °C, MeSO₂NH₂ (109 mg, 1.14 mmol, 1.1 eq) was added to a mixed solution of AD-MIX-α (1900 mg) with t-BuOH (10 mL) and H₂O (10 mL). The reaction mixture was stirred at 0 °C for 10 min, and then (…) was added. E Di-tert-butyl 2,2,17,17-tetramethyloctadec-9-enedioic acid (500 mg, 1.04 mmol, 1.0 eq). The reaction mixture was stirred at RT for 18 hours. After the reaction was complete, the reaction mixture was quenched with an aqueous solution of Na2SO3 (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 2 / 1) to give a colorless oily product (480 mg, 89%).

[0370] Step 3: (9) S 10 S Synthesis of di-tert-butyl 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid At 0 ℃, towards (9 S 10 SNaH (47 mg, 1.17 mmol, 1.5 eq) was added to a THF (10 mL) solution of di-tert-butyl 9,10-dihydroxy-2,2,17,17-tetramethyloctadecanoate (400 mg, 0.78 mmol, 1.0 eq). The reaction mixture was stirred for 30 min, and then CH3I (166 mg, 1.17 mmol, 1.5 eq) was added. The reaction mixture was stirred at 25 °C for 3 h. After the reaction was complete, it was quenched with an aqueous solution (10 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1). A colorless oily product (200 mg, 48%) was obtained.

[0371] Step 4: (9) S 10 S Synthesis of di-tert-butyl 2-((2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionyl)oxy)-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid To (9) S 10 S A solution of di-tert-butyl 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoate (200 mg, 0.38 mmol, 1.0 eq) in THF (4 mL) was mixed with fenofibrate acid (145 mg, 0.45 mmol, 1.2 eq), DCC (117 mg, 0.57 mmol, 1.5 eq), and DMAP (9 mg, 0.08 mmol, 0.2 eq). The reaction mixture was stirred at 25 °C for 18 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1). A colorless oily product (90 mg, 28%) was given.

[0372] Step 5: (9) S 10 S Synthesis of 9-((2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionyl)oxy)-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid To (9) S 10 STFA (1 mL) was added to a solution of di-tert-butyl 2,2,17,17-tetramethyloctadecanoate (80 mg, 0.10 mmol, 1.0 eq) in DCM (5 mL). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 1 / 1) to give a yellow oily product (43 mg, 60%).

[0373] MS(ESI, pos.ion) m / z: 717.2 [M+1] + .

[0374] 1 HNMR (400 MHz, DMSO- d 6) δ = 12.10 - 11.68 (m, 2H), 7.71 (dd, J = 6.8,8.6 Hz, 4H), 7.65 - 7.58 (m, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.98 - 4.90 (m,1H), 3.26 (s, 3H), 3.17 - 3.10 (m, 1H), 1.63 (s, 6H), 1.55 - 1.31 (m, 6H), 1.12 (br s, 18H), 1.03 (d, J = 3.4 Hz, 12H).

[0375] Example 29: (9) S 10 R Synthesis of 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid (0042) Step 1: (9S, 10) R Synthesis of diethyl 2,2,17,17-tetramethyloctadecanoate (2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionyl)oxy)-10-methoxy-2,2,17,17-tetramethyloctadecanoate To a THF (5 mL) solution of diethyl 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoate (100 mg, 0.21 mmol, 1.0 eq), DCC (65 mg, 0.32 mmol, 1.5 eq), DMAP (3 mg, 0.02 mmol, 0.1 eq), and 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionic acid (80 mg, 0.25 mmol, 1.2 eq) were added. The reaction mixture was stirred overnight at room temperature. The mixture was filtered and concentrated. The crude product was purified by column chromatography (SiO2, PE / EA(v / v) = 5 / 1) and SFC to give a colorless oily product (50 mg, 31%).

[0376] SFC conditions: Analytical separation methods Instrument: Waters UPC2 analytical SFC (SFC-H) Column: ChiralPak AD, 50×4.6mm ID, 3µm Mobile phase: Phase A: carbon dioxide (CO2), Phase B: isopropanol (0.05% DEA) Gradient: B 5-40% Flow rate: 3 mL / min Back pressure: 100 bar Column pressure: 35℃ Wavelength: 220nm Preparation and separation methods Instrument: Waters 150 preparative SFC (SFC-26) Column: ChiralPak AD, 250×30mm ID, 10µm Mobile phases: Phase A: carbon dioxide (CO2), Phase B: isopropanol Gradient: B 15% Flow rate: 120 mL / min Back pressure: 100 bar Step 2: (9) S 10 R Synthesis of 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid To (9) S 10 R20% KOH aqueous solution (1 mL) was added to a MeOH solution of 50 mg (0.06 mmol, 1.0 eq) of diethyl 2,2,17,17-tetramethyloctadecanoate (4 mL). The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1 M HCl solution, and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (12 mg, 44%).

[0377] MS(ESI, neg.ion) m / z: 415.1 [M-1] + .

[0378] 1 HNMR (400 MHz, DMSO- d 6) δ = 12.00 (br s, 2H), 4.34 (br d, J = 5.4 Hz,1H), 3.41 – 3.36 (m,1H), 3.25 (s, 3H), 2.90 (br d, J = 4.8 Hz, 1H), 1.46 – 1.40 (m, 6H), 1.30 – 1.16 (m, 18H), 1.07 (s, 12H).

[0379] Example 30: (9) R 10 S Synthesis of 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid (0043) Step 1: (9) R Synthesis of diethyl 10-methoxy-2,2,17,17-tetramethyloctadecanoate (2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionyl)oxy)-10-methoxy-2,2,17,17-tetramethyloctadecanoate To a THF (5 mL) solution of diethyl 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoate (100 mg, 0.21 mmol, 1.0 eq), DCC (65 mg, 0.32 mmol, 1.5 eq), DMAP (3 mg, 0.02 mmol, 0.1 eq), and 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionic acid (80 mg, 0.25 mmol, 1.2 eq) were added. The reaction mixture was stirred overnight at room temperature. The mixture was filtered and concentrated. The crude product was purified by column chromatography (SiO2, PE / EA(v / v) = 5 / 1) and SFC to give a colorless oily product (50 mg, 31%).

[0380] SFC conditions: Analytical separation methods Instrument: Waters UPC2 analytical SFC (SFC-H) Column: ChiralPak AD, 50×4.6mm ID, 3µm Mobile phase: Phase A: carbon dioxide (CO2), Phase B: isopropanol (0.05% DEA) Gradient: B 5-40% Flow rate: 3 mL / min Back pressure: 100 bar Column pressure: 35℃ Wavelength: 220nm Preparation and separation methods Instrument: Waters 150 preparative SFC (SFC-26) Column: ChiralPak AD, 250×30mm ID, 10µm Mobile phases: Phase A: carbon dioxide (CO2), Phase B: isopropanol Gradient: B 15% Flow rate: 120 mL / min Back pressure: 100 bar Step 2: (9) R 10 S Synthesis of 9-hydroxy-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid To (9) R 10 SA solution of 20% KOH aqueous solution (1 mL) of 9-((2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionyl)oxy)-10-methoxy-2,2,17,17-tetramethyloctadecanoic acid diethyl ester (50 mg, 0.06 mmol, 1.0 eq) in MeOH (4 mL) was added. The reaction mixture was stirred at 70 °C for 18 hours. The pH of the reaction mixture was adjusted to 1 with 1M HCl solution, and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (10 mg, 36%).

[0381] 1 HNMR (400 MHz, DMSO-d6) δ = 11.99 (br s, 2H), 4.34 (d, J = 5.8 Hz, 1H),3.37 (br s, 1H), 3.31 - 3.20 (m, 3H), 2.90 (brd, J = 4.6 Hz, 1H), 1.46 - 1.36 (m, 8H), 1.29 (br s, 4H), 1.23 - 1.17 (m, 12H), 1.07 (s, 12H).

[0382] Example 31: Synthesis of 9-methoxy-2,2,16,16-tetramethylheptadecanoic acid (0044) Step 1: Synthesis of ethyl 8-bromo-2,2-dimethyloctanoate Under a nitrogen atmosphere at -40 °C, LDA (18.08 mL, 36.16 mmol, 1.05 eq) was added dropwise to a THF (40 mL) solution of ethyl 2-methylpropionate (4.00 g, 34.44 mmol, 1.0 eq). After 1 hour, 1,6-dibromohexane (10.92 g, 44.77 mmol, 1.3 eq) was added. After the addition was complete, the reaction mixture was stirred at -40 °C for 0.5 hours, then heated to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was poured into an ice-water solution (20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 50 / 1) to give a yellow oily product (3.30 g, 34%).

[0383] Step 2: Synthesis of diethyl 9-cyano-2,2,16,16-tetramethyl-9-toluenesulfonylheptadecanoate Under nitrogen protection, at 25°C, sodium hydride (0.71 g, 17.73 mmol, 3.0 eq) was added to a DMSO (50 mL) solution of TosMIC (1.15 g, 5.91 mmol, 1.0 eq) and Bu4NI (0.22 g, 0.59 mmol, 0.1 eq). The reaction mixture was stirred at 25°C for 30 min, followed by the addition of ethyl 8-bromo-2,2-dimethyloctanoate (3.30 g, 11.82 mmol, 2.0 eq). After 1 hour, the reaction was quenched at 0°C with an ice-water solution (40 mL), and then extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with 10% HCl (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 10 / 1) to give a yellow oily product (2.60 g, 37%).

[0384] Step 3: Synthesis of diethyl 2,2,16,16-tetramethyl-9-oxoheptadecanedioate At room temperature, concentrated hydrochloric acid (2 mL) was added to a solution of diethyl 9-cyano-2,2,16,16-tetramethyl-9-toluenesulfonylheptadecanoate (2.60 g, 4.39 mmol, 1.0 eq) in dichloromethane (30 mL). The reaction mixture was stirred at 25 °C for 4 hours. After the reaction was complete, the mixture was diluted with an aqueous solution (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (1.70 g, 91%).

[0385] Step 4: Synthesis of diethyl 9-hydroxy-2,2,16,16-tetramethylheptadecanoate Under nitrogen protection, at 0°C, NaBH4 (0.15 g, 3.98 mmol, 1.0 eq) was added to a methanol (20 mL) solution of diethyl 2,2,16,16-tetramethyl-9-oxoheptadecanedioate (1.70 g, 3.98 mmol, 1.0 eq). The reaction mixture was stirred at 0°C for 3 hours. After the reaction was complete, the reaction mixture was poured into an ice-water solution (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 5 / 1) to give a colorless oily product (1.40 g, 82%).

[0386] Step 5: Synthesis of diethyl 9-methoxy-2,2,16,16-tetramethylheptadecanoate To a solution of diethyl 9-hydroxy-2,2,16,16-tetramethylheptadecanoate (1400 mg, 3.27 mmol, 1.0 eq) in dichloromethane (20 mL), CF3SO3Me (0.74 mL, 6.53 mmol, 2.0 eq) and 2,6-di-tert-butylpyridine (1.10 mL, 4.90 mmol, 1.0 eq) were added. The reaction mixture was stirred at 40 °C for 18 hours. After the reaction was complete, the mixture was diluted with DCM (20 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 20 / 1) to give a colorless oily product (900 mg, 62%).

[0387] Step 5: Synthesis of 9-methoxy-2,2,16,16-tetramethylheptadecanoic acid To a methanol (8 mL) solution of diethyl 9-methoxy-2,2,16,16-tetramethylheptadecanoate (900 mg, 2.03 mmol, 1.0 eq), 20% KOH aqueous solution (2 mL) was added. The reaction mixture was stirred at 70 °C for 6 hours. After the reaction was complete, the mixture was adjusted to pH 1 with 1 M HCl solution and then extracted with ethyl acetate (20 mL × 2). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, PE / EA (v / v) = 3 / 2) to give a white solid product (500 mg, 63%).

[0388] MS(ESI, pos.ion) m / z: 387.2 [M+1] + .

[0389] 1 HNMR (400 MHz, DMSO- d 6) δ = 11.99 (br s, 2H), 3.19 (s, 3H), 3.08 (t, J = 5.6 Hz, 1H), 1.49 - 1.32 (m, 8H), 1.31 - 1.14 (m, 16H), 1.06 (s, 12H).

[0390] Biological testing Test 1: Effects of the example compound of this invention on sterol and fatty acid synthesis in male ICRCD-1 mouse hepatocytes 1. Compound dilution 1.1 Dissolve the compound in DMSO to prepare a 10 mM solution.

[0391] 1.2 The compound was diluted using a 4-fold serial dilution method to prepare a total of 7 concentration gradients. 10 µL of the compound DMSO solution was added to 190 µL of William's E medium to prepare an intermediate solution (diluted 20 times, containing 5% DMSO).

[0392] Add 50 µL of the intermediate compound solution to a 24-well plate, and then add 200 µL of culture medium (diluted 10 times, with a final DMSO concentration of 1%) to each well.

[0393] 2. Thaw the cells and inoculate them. 2.1 Preheat the test medium and thawed medium in a 37°C water bath for 20 minutes.

[0394] 2.2 Immediately immerse the cryovials of ICRCD-1 male mouse hepatocytes in a 37°C water bath. Gently agitate. This step should take 90-120 seconds.

[0395] 2.3 Once the contents have completely thawed, immediately remove the cryovials from the water bath and disinfect them by immersion or spraying with 70% ethanol.

[0396] 2.4 Transfer the solution in the cryopreservation tube to 45 mL of preheated thawing medium.

[0397] 2.5 Centrifuge the ICRCD-1 male mouse hepatocyte suspension at 100 × g for 5 minutes in a room temperature centrifuge.

[0398] 2.6 Resuspend the cell pellet in 1 mL of test medium and mix well, then add 4 mL of test medium for cell counting.

[0399] 3. Lyse cells according to standard procedures. 3.1 Prepare a 24-well plate, add 200 μL of Williams' E medium and 50 μL of diluted compound solution to each well.

[0400] 3.2 Inoculate ICRCD-1 male mouse hepatocytes into 24-well plates (2 × 10⁻⁶ cells / well). 5 Cells / well / 250 μL), and cultured in a humidified incubator at 37°C and 5% CO2.

[0401] 3.3 Add 2 μCi of [2-14C]-acetate to each well and incubate at 37°C in a 5% CO2 humidifier for 3.5 hours.

[0402] 3.4 Transfer the culture medium to 15 mL centrifuge tubes, add 0.5 mL of 0.1 M sodium hydroxide solution to each well, and incubate at room temperature to lyse the cell monolayer. Then transfer the cell lysate to the corresponding 15 mL centrifuge tubes.

[0403] 3.5 Add 1.0 mL of ethanol and 0.17 mL of 50% potassium hydroxide solution to each tube and incubate in a 90°C water bath for 1 hour.

[0404] 3.6 Cool to room temperature, add 5 mL of petroleum ether to each tube, shake vigorously, centrifuge at 1500 rpm for 3 minutes, and transfer 4 mL of the petroleum ether layer to a glass tube (18×180 mm).

[0405] 3.7 Repeat step 3.6.

[0406] 3.8 Add 1 mL of concentrated hydrochloric acid to each tube to acidify the aqueous phase. Randomly test the pH of 1-2 extracts to ensure the pH is below 1.

[0407] 3.9 Add 5 mL of petroleum ether to each tube, shake vigorously, centrifuge at 1500 rpm for 3 minutes, and transfer 4 mL of the petroleum ether layer to a new glass tube (18×180 mm).

[0408] 3.10 Repeat step 3.9.

[0409] 3.11 Evaporate the combined extracts to dryness in a 64°C water bath (30 minutes).

[0410] 3.12 Dissolve fatty acids in 400 μL of chloroform-n-hexane (1:1) solution.

[0411] 3.13 Add 50 μL to an Isoplate-96 microplate, add 200 μL of UltimaGold scintillation solution, incubate for 5 minutes, and then detect using a MicroBeta liquid scintillation analyzer.

[0412] 4. Testing Principle 4.1 Compound screening was performed using the de novo lipid synthesis (DNL) assay. Cells were seeded in sterile culture wells, and the test compound and D-[U-] were added. 14 C] Glucose, enabling cells to take up extracellular D-[U-] in the presence of receptor compounds. 14 C] Glucose, and use it as a raw material to synthesize [C] glucose, which contains 14 C-labeled fatty acids are finally extracted from cells. 14 C-labeled fatty acids. 14 C-labeled fatty acids react with a scintillation fluid that can induce chemiluminescence, and the luminescence signal is detected using a MicroBeta liquid scintillation analyzer. The intensity of the luminescence signal is positively correlated with the ability of adipocytes to synthesize new lipids.

[0413] EC 50 The values ​​are shown in Table 1.

[0414] Table 1. Effects of example compounds on sterol and fatty acid synthesis in hepatocytes of male ICRCD-1 mice.

[0415] A indicates EC50 ≤ 1 μM, B indicates 1 μM ≤ EC50 ≤ 5 μM, C indicates 5 μM ≤ EC50 ≤ 10 μM, and D indicates EC50 ≥ 10 μM.

[0416] Test 2: Study on the stability of liver microsomes 1. The mother liquor was prepared according to the method shown in Table 2.

[0417] Table 2. Preparation of Mother Liquor

[0418] 2. Two independent experiments were conducted according to the following protocols: a) NADPH-containing group: 10 μL of 20 mg / mL liver microsomes and 40 μL of 10 mM NADPH solution were added to the incubation system. The final concentrations were 0.5 mg / mL (microsomes) and 1 mM (NADPH), respectively. b) NADPH-free group: 10 μL of 20 mg / mL liver microsomes and 40 μL of ultrapure water were added to the incubation system. The final concentration of microsomes was 0.5 mg / mL.

[0419] 3. Add 4 μL of 100 μM test compound solution or control compound solution (final concentration 1 μM) to start the reaction and carry out the reaction at 37°C.

[0420] 4. At 0, 15, 30, 45, and 60 minutes, respectively, take 50 µL of sample from the reaction system and immediately add 4 volumes of cold acetonitrile containing internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 µM ketoprofen) to terminate the reaction. Centrifuge the sample at 3220 g for 40 minutes. Mix 100 µL of the supernatant with 100 µL of ultrapure water and perform LC-MS / MS analysis.

[0421] 5. Data Analysis: All calculations were performed using Microsoft Excel.

[0422] Peak areas were determined from the extracted ion chromatogram. The slope was determined by linear regression of the natural logarithm of the remaining percentage of drug substance against the incubation time curve.

[0423] in vitro half-life (t) 1 / 2 Calculated based on the slope value: , Where: k is the rate constant (k = -slope value) The in vitro half-life (t) 1 / 2 When converting protein (in minutes) to in vitro intrinsic clearance (in vitro CLint, in µL / min / mg protein), the following formula is used (the result is the mean of two parallel measurements): The results are shown in Table 3.

[0424] Table 3. Summary of Compound Hepatic Microsomal Stability Data

[0425] Test 3: Plasma pharmacokinetic characteristics of the compound after a single dose in male CD1 mice 1. Materials The compound of this invention.

[0426] 2. Animals Male CD1 mice were purchased from Si Bei Fu Laboratory Animal Technology Co., Ltd. Animals were 6-8 weeks old and weighed 20-30 grams on the day of administration. Animals were housed in a 12-hour light / dark cycle. All animals administered intravenously (IV) and orally (PO) were fasted overnight and resumed eating 4 hours after sampling.

[0427] 3. Preparation of Dosage Solution 3.1 Intravenous (IV) administration solution: Prepare a clear solution (final pH 7.0~8.0) using PBS as solvent, and add 2 equivalents of NaOH to a concentration of 4 mg / mL.

[0428] 3.2 Oral administration solution: Using ultrapure water as solvent, containing 1.5% (w / v) carboxymethyl cellulose and 0.2% Tween 20, add 2 eq NaOH to achieve a concentration of 2 mg / mL.

[0429] 3.3 If the measured concentration value deviates from the nominal value within 20%, the nominal dose value shall be used to calculate the pharmacokinetic parameters.

[0430] 4. In vivo experimental procedure Six mice were administered the drugs according to the protocol in Table 4: three were administered intravenously via tail vein bolus (IV), and three were administered orally via gavage (PO). Blood was collected via the orbital sinus into K2EDTA anticoagulant tubes before administration (PO group only), and at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, and 48 hours after administration. Blood samples (approximately 0.03 mL at each time point, with 0.3 mL collected via cardiac puncture at the final time point) were centrifuged at 4000 g for 5 minutes in a refrigerated centrifuge (4°C), and plasma was collected and stored at -80°C for analysis.

[0431] Table 4. Dosage Information

[0432] A: PBS buffer (final pH 7.0~8.0) (add 2 eq NaOH) B: An ultrapure aqueous solution of 1.5% (w / v) carboxymethyl cellulose and 0.2% Tween 20 (with 2 eq NaOH added). 5. Plasma sample analysis 5.1 Compound Standard Stock Solutions: A 1 mg / mL solution was prepared using DMSO. Working standard solutions with concentrations of 10, 20, 50, 100, 200, 500, 1000, 5000, and 10000 ng / mL were prepared by serially diluting the standard stock solution (DMSO as the diluent). Quality control (QC) working solutions with concentrations of 20, 50, 500, and 8000 ng / mL were prepared by serially diluting the standard stock solution using 50% acetonitrile aqueous solution. All QC samples were prepared on the day of analysis using the same method as the standard curve.

[0433] 5.2 Plasma Sample Pretreatment: 30 μL of blank plasma from male CD1 mice was collected, and 3 μL of standard working solutions of various concentrations (10-10000 ng / mL) were added to prepare standard curve samples with a total volume of 33 μL and a concentration range of 1-1000 ng / mL (1, 2, 5, 10, 20, 50, 100, 500, 1000 ng / mL). Four quality control samples were also prepared independently from blank plasma at concentrations of 2 ng / mL (low concentration 1), 5 ng / mL (low concentration 2), 50 ng / mL (medium concentration), and 800 ng / mL (high concentration). All quality control samples were prepared on the day of analysis using the same method as the standard curve.

[0434] 5.3 Take 33 μL of standard curve sample, 33 μL of quality control sample, or 33 μL of test sample (30 μL plasma sample + 3 μL DMSO), and add 200 μL of acetonitrile solution containing internal standard (dexamethasone 50 ng / mL) to precipitate proteins. Vortex mix for 30 seconds. Centrifuge at 4000 rpm, 4°C for 15 minutes, and dilute the supernatant with ultrapure water at a 1:2 volume ratio. Take 10 μL of the diluted plasma sample supernatant for LC-MS / MS quantitative analysis.

[0435] 6. LC-MS / MS Analysis Conditions 6.1 The liquid chromatography-mass spectrometry (LC-MS) system included: a Shimadzu LC-30 AD liquid chromatograph, a DGU-20A5R degasser, a CBM-20A communication bus module, a SIL-30AC autosampler, a Shimadzu Rack Changer II sample rack switching system, and a Shimadzu LCMS-8060 mass spectrometer. Chromatographic separation was performed at room temperature using a Raptor Biphenyl 2.7μm 50×2.1mm column (analyte 0010). The mobile phase composition was: Phase A was a 5% acetonitrile aqueous solution containing 0.1% formic acid; Phase B was a 95% acetonitrile aqueous solution containing 0.1% formic acid. The mobile phase flow rate was 0.6 mL / min. The injection volume was 10 µL.

[0436] 6.2 Protonated ions of analyte 0010 and internal standard dexamethasone were obtained using a positive ion mode electrospray ionization (ESI) source. The optimized monitoring ion pair was: analyte 0010 m / z 373.15→309.15, and dexamethasone internal standard m / z 393.30→373.15.

[0437] 7. Validation Standards for Bioanalytical Methods 7.1 The standard curve was determined using two parallel measurements at nine concentration points. The deviations of the measured concentration values ​​from the nominal values ​​at all standard points and the lower limit of quantitation (LLOQ) were within ±20%. The signal-to-noise ratio of the lower limit of quantitation (LLOQ) was not less than 3. Each analytical batch included two parallel quality control samples at three concentration levels (low, medium, and high concentrations): the low concentration quality control sample (low QC) was no more than three times the LLOQ, the medium concentration quality control sample (mid QC) was located in the middle of the curve, and the high concentration quality control sample (high QC) was close to the upper limit of quantitation (ULOQ), reaching at least 80% but no more than 100% of the highest standard concentration.

[0438] 7.2 The deviation between the mean and theoretical value of the quality control samples must be within ±20%. Quality control results are used as the basis for determining whether an analytical batch is acceptable. The measured values ​​of each concentration quality control sample must be within ±20% of its nominal value. A 1 / x² weighted linear regression model is used as the simplest model to describe the concentration-response relationship.

[0439] The results are shown in Tables 5, 6, 7 and 8.

[0440] Table 5. Summary of mean pharmacokinetic parameters of the compounds in mouse plasma (intravenous injection)

[0441] Table 6. Summary of mean pharmacokinetic parameters of compounds in mouse plasma (oral administration)

[0442] Table 7. Summary of plasma pharmacokinetic parameters of compound 0040 after intravenous injection

[0443] Table 8. Summary of plasma pharmacokinetic parameters of compound 0040 in mice after oral administration.

[0444] The scope of this invention should not be limited to the specific embodiments disclosed in the examples, which are merely intended to illustrate certain aspects of the invention. Any functionally equivalent embodiments are within the scope of this invention. In fact, those skilled in the art will readily recognize various modifications to this invention beyond what is shown and described herein, and all such modifications fall within the scope of the appended claims.

Claims

1. A compound having formula I, I Or its stereoisomers, geometric isomers, tautomers, N- Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, in, R 1 R 2 R 3 and R 4 Each of these can be independently H, D, amino, nitro, hydroxyl, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylamino, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, (C1-C9)heteroaryl, (C3-C7)cycloalkyl-(C1-C6)alkyl, (C2-C6)heterocyclic-(C1-C6)alkyl, (C6-C10)aryl-(C1-C6)alkyl, or (C1-C9)heteroaryl-(C1-C6)alkyl; or R on the same atom. 1 and R 2 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on the same atom 3 and R 4 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on different atoms 1 and R 2 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R on different atoms 3 and R 4 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R 1 and its adjacent R 2 Together with the atoms they are attached to, they form double bonds; or R 3 and its adjacent R 4 Together with the atoms they are attached to, they form double bonds; R 1 and R 3 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; R 1 R 2 R 3 and R 4 Each of them may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen or cyano; n and m are each independently 4, 5, 6, 7, 8, 9 or 10; R is H, D, halogen, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, or (C1-C9)heteroaryl; R is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, or cyano; G is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C7)cycloalkyl, (C2-C6) heterocyclic, (C6-C10) aryl, or (C1-C9) heteroaryl; G is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, or cyano. Or G is Or one or more deuterium-substituted ; Or G is H, and at the same time, at least one R 1 Independently, it is a hydroxyl group; Y 1 and Y 2 Each can be independently -OH, -(C1-C6)alkylene-OH, -C(=O)-OH, -C(=O)H, or -C(=O)OR. 5 -S(=O)2OH or -S(=O)2NH2 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; or Y 1 and Y 2 One of them is ; R 5 It is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, (C1-C9)heteroaryl, (C3-C7)cycloalkyl-(C1-C6)alkyl, (C2-C6)heterocyclic-(C1-C6)alkyl, (C6-C10)aryl-(C1-C6)alkyl, or (C1-C9)heteroaryl-(C1-C6)alkyl; R 5 Optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, cyano, (C1-C6)alkoxy or (C1-C6) haloalkoxy; R 6 and R 7 Each is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)ynyl; R 6 and R 7 Optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, cyano, (C1-C6)alkoxy or phenyl.

2. The compound according to claim 1, wherein, G is methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxetane, azirane, tetrahydrofuranyl, pyrrolyl, 1,4-dioxane, morpholinyl, piperidinyl, piperazine, phenyl, or pyridinyl; wherein G is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, or cyano.

3. The compound according to claim 1, wherein, G is methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; wherein G is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, or cyano.

4. The compound according to claim 1, wherein, G is methyl, ethyl, or cyclopropyl; wherein G is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, or cyano.

5. The compound according to claim 1, wherein, Y 1 and Y 2 Each can be independently -OH, -(C1-C6)alkyl-OH, -C(=O)-OH, -C(=O)H, or -C(=O)OR. 5 -S(=O)2OH or -S(=O)2NH2; R 5 It is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C7)cycloalkyl, (C2-C6)heterocyclic, (C6-C10)aryl, (C1-C9)heteroaryl, (C3-C7)cycloalkyl-(C1-C6)alkyl, (C2-C6)heterocyclic-(C1-C6)alkyl, (C6-C10)aryl-(C1-C6)alkyl, or (C1-C9)heteroaryl-(C1-C6)alkyl; R 5 Optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, cyano, (C1-C6)alkoxy or (C1-C6)haloalkoxy.

6. The compound according to claim 1, wherein, Y 1 and Y 2 Each can be independently -OH, -CH2-OH, -CH2CH2-OH, -C(=O)-OH, -C(=O)H, or -C(=O)OR 5 ; R 5 The following are compounds: methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxetane, azirane, tetrahydrofuranyl, pyrrolidinyl, 1,4-dioxanecyclol, morpholinyl, piperidinyl, piperazine, phenyl, or pyridinyl; R 5 It may optionally and independently be substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, cyano, methoxy, difluoromethoxy or trifluoromethoxy.

7. The compound according to claim 1, wherein, Y 1 and Y 2 Each can be independently -OH, -CH2-OH, -C(=O)-OH, -C(=O)H, or -C(=O)OR 5 ; R 5 The following are compounds: methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxetane, azirane, tetrahydrofuranyl, pyrrolidinyl, 1,4-dioxanecyclol, morpholinyl, piperidinyl, piperazine, phenyl, or pyridinyl; R 5 It may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, cyano, methoxy, difluoromethoxy or trifluoromethoxy.

8. The compound according to claim 1, wherein, Y 1 and Y 2 Each can be independently -CH2-OH, -C(=O)-OH, or -C(=O)OR 5 ; R 5 It is methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, or allyl; R 5 It may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, cyano, methoxy, difluoromethoxy or trifluoromethoxy.

9. The compound according to claim 1, wherein, R 1 R 2 R 3 and R 4 Each of these groups can be independently H, D, amino, nitro, hydroxyl, halogen, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylamino, (C1-C4)alkylthio, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (C2-C5) heterocyclic, phenyl, (C3-C6)cycloalkylmethyl, (C3-C6)cycloalkylethyl, (C2-C6) heterocyclic methyl, (C2-C6) heterocyclic ethyl or benzyl; or R on the same atom. 1 and R 2 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on the same atom 3 and R 4 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on different atoms 1 and R 2 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R on different atoms 3 and R 4 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R 1 and its adjacent R 2 Together with the atoms they are attached to, they form double bonds; or R 3 and its adjacent R 4 Together with the atoms they are attached to, they form double bonds; or R 1 and R 3 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; R 1 R 2 R 3 and R 4 Each of them may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine or cyano; n and m are each independently 4, 5, 6, 7, 8, 9 or 10.

10. The compound according to claim 1, wherein, R 1 R 2 R 3 and R 4 Each of these groups independently represents H, D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylamino, (C1-C4)alkylthio, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (C2-C5) heterocyclic, phenyl, (C3-C6)cycloalkylmethyl, (C3-C6)cycloalkylethyl, (C2-C6) heterocyclic methyl, (C2-C6) heterocyclic ethyl or benzyl; or R on the same atom. 1 and R 2 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on the same atom 3 and R 4 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on different atoms 1 and R 2 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R on different atoms 3 and R 4 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R 1 and its adjacent R 2 Together with the atoms they are attached to, they form double bonds; or R 3 and its adjacent R 4 Together with the atoms they are attached to, they form double bonds; or R 1 and R 3 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; R 1 R 2 R 3 and R 4 Each of them may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine or cyano; n and m are each independently 4, 5, 6, 7, 8 or 9.

11. The compound according to claim 1, wherein, R 1 R 2 R 3 and R 4 Each can be independently H, D, amino, nitro, hydroxyl, fluorine, chlorine, bromine, fluorine, chlorine, bromine, methyl, ethyl, methoxy, or ethoxy; or R on the same atom. 1 and R 2 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on the same atom 3 and R 4 Together with the atoms attached to them, they form C=O, C=S, (C3-C7) cycloalkyl, or (C2-C6) heterocyclic groups; or R on different atoms 1 and R 2 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R on different atoms 3 and R 4 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; or R 1 and its adjacent R 2 Together with the atoms they are attached to, they form double bonds; or R 3 and its adjacent R 4 Together with the atoms they are attached to, they form double bonds; or R 1 and R 3 Together with the atoms between them, they form (C3-C7) cycloalkyl or (C2-C6) heterocyclic groups; R 1 R 2 R 3 and R 4 Each of them may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from D, amino, nitro, hydroxyl, fluorine, chlorine, bromine or cyano; n and m are each independently 4, 5, 6, 7, 8 or 9.

12. The compound according to claim 1, wherein, R is H, D, F, Cl, Br, cyano, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, (C2-C5)heterocyclic, (C6-C10)aryl, or (C1-C9)heteroaryl; R is optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from D, amino, nitro, hydroxyl, halogen, or cyano.

13. The compound according to claim 1, wherein, R can be H, D, F, Cl, Br, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, monodeuterated methyl, dideuterated methyl, or trideuterated methyl.

14. The compound according to any one of claims 1 to 13 has a structure of formula II, or a stereoisomer, geometric isomer, tautomer, or thereof. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs II; in, k, g, j, and v are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

15. The compound according to any one of claims 1 to 13 has a structure of formula III, or a stereoisomer, geometric isomer, tautomer, or thereof. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs III; in, g1 and j1 are each independently 3, 4, 5, 6 or 7.

16. The compound according to claim 15 having the structures of formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9, or their stereoisomers, geometric isomers, tautomers, or other such structures. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs IV-1、 IV-2、 IV-3、 IV-4、 IV-5、 IV-6、 IV-7, IV-8, IV-9 IV-10 or IV-11.

17. The compound according to claim 15 having the structures of formula V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, or their stereoisomers, geometric isomers, tautomers, etc. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs V-1、 V-2、 V-3、 V-4、 V-5、 V-6、 V-7、 V-8。 18. The compound according to any one of claims 1 to 17 has a structure of formula VI, VII, or VIII, or a stereoisomer, geometric isomer, or tautomer thereof. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs WE, VII or VIII。 19. The compound according to any one of claims 1 to 17 has the structure of formula IX, X, XI, or a stereoisomer, geometric isomer, tautomer, or other such structure. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs IX X or XI.

20. The compound according to any one of claims 1 to 19 has the following structure, or a stereoisomer, geometric isomer, tautomer, or other such structure. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or 。 21. A pharmaceutical composition comprising the compound of any one of claims 1 to 20, or a stereoisomer, geometric isomer, tautomer thereof. N - A pharmaceutical composition comprising oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs and pharmaceutically acceptable carriers, excipients or diluents.

22. The compound according to any one of claims 1-20, or its stereoisomers, geometric isomers, tautomers, etc. N - Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 21, for the prevention, control, treatment or relief of diseases associated with ATP citrate lyase or AMP-activated protein kinase or combinations thereof.

23. The compound according to any one of claims 1-20, or its stereoisomers, geometric isomers, tautomers, N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 21, prevent, control, treat or alleviate disease by increasing HDL levels.

24. The compound according to any one of claims 1-20, or its stereoisomers, geometric isomers, tautomers, N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 21, prevent, control, treat or alleviate disease by lowering LDL levels.

25. The compound according to any one of claims 1-20, or its stereoisomers, geometric isomers, tautomers, etc. N - Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 21, for the prevention, control, treatment or relief of aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein metabolism disorders, hypertension, erectile dysfunction, inflammation, insulin resistance, bile lipid clearance disorders, obesity, bile oxysterol clearance disorders, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, bile phospholipid clearance disorders, kidney disease, sepsis, syndrome X, thrombotic diseases, C-reactive protein regulation, bile production promotion; and the following liver diseases: hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, and acute fatty liver of pregnancy.

26. The compound according to any one of claims 1-20, or its stereoisomers, geometric isomers, tautomers, N - Use of an oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition of claim 21 in the preparation of a medicament for the prevention, control, treatment or relief of diseases associated with ATP citrate lyase or AMP-activated protein kinase or combinations thereof.

27. The compound according to any one of claims 1-20, or its stereoisomers, geometric isomers, tautomers, etc. N - The use of an oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition of claim 21 in the preparation of a medicament for preventing, controlling, treating or alleviating related diseases by increasing HDL levels.

28. The compound according to any one of claims 1-20, or its stereoisomers, geometric isomers, tautomers, N - The use of an oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition of claim 21 in the preparation of a medicament for preventing, controlling, treating or alleviating related diseases by lowering LDL levels.

29. The compound according to any one of claims 1-20, or its stereoisomers, geometric isomers, tautomers, N - The use of an oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of claim 21, in the preparation of a medicament for the prevention, control, treatment or relief of aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein metabolism disorders, hypertension, erectile dysfunction, inflammation, insulin resistance, bile lipid clearance disorders, obesity, bile oxysterol clearance disorders, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, bile phospholipid clearance disorders, kidney disease, sepsis, syndrome X, thrombotic diseases, C-reactive protein regulation, bile production promotion; and the following liver diseases: hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, and acute fatty liver of pregnancy.

30. A method for preventing, controlling, treating, or alleviating diseases associated with ATP citrate lyase (ACLY) or AMP-activated protein kinase (AMPK) or combinations thereof, comprising administering to a mammal in need a therapeutically effective amount of the compound of any one of claims 1-20 or a stereoisomer, geometric isomer, tautomer, or other similar compound. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 21.

31. A method for preventing, controlling, treating, or alleviating disease by increasing HDL levels, comprising administering to a mammal in need a therapeutically effective amount of the compound of any one of claims 1-20 or a stereoisomer, geometric isomer, tautomer, or other similar compound. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 21.

32. A method for preventing, controlling, treating, or alleviating disease by lowering LDL levels, comprising administering to a mammal in need a therapeutically effective amount of the compound of any one of claims 1-20 or a stereoisomer, geometric isomer, tautomer, or other similar compound. N -Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 21.

33. A method for preventing, controlling, treating, or alleviating aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein metabolism disorders, hypertension, erectile dysfunction, inflammation, insulin resistance, bile lipid clearance disorders, obesity, bile oxysterol clearance disorders, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-related diseases, bile phospholipid clearance disorders, kidney disease, sepsis, syndrome X, thrombotic diseases, C-reactive protein regulation, bile production promotion; and the following liver diseases. Methods for treating hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, steatohepatitis, alcoholic liver disease, fatty liver, hepatic steatosis, cirrhosis, and acute fatty liver of pregnancy, comprising administering to a patient requiring treatment or prevention a therapeutically or preventively effective amount of the compound of any one of claims 1-20 or its stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 21.

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