KR20240019753A - Compounds useful in treating liver disease - Google Patents

Abstract

The present invention provides, for example, compounds of formula (A)-(H) and (J)-(AA) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof. The present invention further provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier or vehicle. The compounds and compositions disclosed herein are useful for treating a variety of diseases and conditions, including liver diseases such as liver fibrosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), and kidney diseases such as It is useful in treating or preventing acute kidney injury (AKI).

Description

Compounds useful in treating liver disease

1. Cross-reference to related applications

This application claims the benefit of U.S. Application No. 17/195,334, filed March 8, 2021, and U.S. Application No. 17/219,058, filed March 31, 2021, the contents of each of which are incorporated herein in their entirety incorporated by reference.

2. Field of invention

The present invention relates to novel compounds, for example compounds of formula (A)-(H) and (J)-(AA) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, such as 2-(4 -(3-Hydroxy-3-(4-(methylthio)phenyl)prop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (“Compound I”) , 3-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3,5-dimethylphenyl)-1-(4-(methylthio)phenyl)prop-2-ene -1-one (“Compound II”) and 3-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3,5-dimethylphenyl)-1-(4-(methyl Thio)phenyl)prop-2-en-1-ol (“Compound III”) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof are provided. The present invention relates to novel compounds described herein, e.g. compounds of formulas (A)-(H) and (J)-(AA) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof, such as compounds A pharmaceutical composition comprising I, Compound II or Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and a pharmaceutically acceptable carrier or vehicle is further provided. The compounds and compositions disclosed herein are useful for treating or preventing conditions, e.g., liver diseases such as liver fibrosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH).

3. Background

Elevated levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides are associated with mixed dyslipidemia. Type IIb hyperlipidemia, a type of mixed dyslipidemia, is characterized by elevated levels of apolipoprotein B, very low-density lipoprotein cholesterol (VLDL-C), intermediate-density lipoprotein cholesterol (IDL), and small-density low-density lipoprotein cholesterol, in addition to elevated levels of LDL-C and triglycerides. It is characterized by an increase in (LDL) levels.

Liver diseases, such as non-alcoholic fatty liver disease (NAFLD), encompass a variety of conditions ranging from the relatively benign steatosis to the more severe non-alcoholic steatohepatitis (NASH), the latter of which, if untreated, leads to fibrosis. , which can lead to cirrhosis, liver failure, or hepatocellular carcinoma. NAFLD and NASH can be caused by overproduction and accumulation of hepatic triglycerides. NAFLD is strongly associated with features of obesity, diabetes, dyslipidemia, hyperlipidemia, and metabolic syndrome, such as obesity, insulin resistance, type 2 diabetes, and dyslipidemia. NASH can cause the liver to swell, become inflamed, fibrotic, damaged, and ultimately become less functional. NASH tends to occur in people who are overweight or obese or have diabetes, mixed dyslipidemia, high cholesterol or high triglycerides, or inflammatory conditions. NASH is marked by hepatocyte ballooning and liver inflammation, which can lead to liver damage and progress to scarring and irreversible changes, similar to damage caused by excessive alcohol use.

Hepatic steatosis and fibrosis can also be caused by drugs such as amiodarone, valproate, tamoxifen, methotrexate, and some chemotherapy agents and antiretrovirals (Amacher, D.E., et al. Semin. Liver Dis., 2014, 34 , 205). Drug-induced hepatic steatosis can be reversible and can involve drug accumulation in the liver.

NAFLD, NASH, fatty liver, or drug-induced hepatic steatosis can lead to metabolic complications such as elevations of liver enzymes, fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. Liver failure is life-threatening, so there is a need to develop therapies that delay the development of fatty liver, prevent its formation, or reverse the condition.

Peroxisome proliferator-activated receptor (PPAR) has been identified as a target for the treatment of cardiometabolic diseases such as diabetes, insulin resistance, dyslipidemia and liver diseases such as NAFLD and NASH. There are three types of PPARs: PPARα, PPARγ and PPARδ. Several PPAR agonists have been marketed, including fenofibrate (PPARα agonist), bezafibrate (PPAR pan-agonist), pioglitazone (PPARγ agonist), and rosiglitazone (PPARγ agonist). Recently, PPAR agonists such as seladelpar (PPARδ agonist), ranifibranor (pan-agonist) and elafibranor (dual PPARα/δ agonist) have been shown to treat NASH and primary biliary cholangitis (PBC). studied for treatment. However, several clinical trials involving these PPAR agonists have failed due to toxicity or failure to meet primary endpoints. For example, in a phase 3 trial in adults with NASH and fibrosis, elafibranor failed to demonstrate a statistically significant effect on the primary endpoint of resolution of NASH without worsening fibrosis (ir.genfit.com/news -releases/news-release-details/genfit-announces-results-interim-analysis-resolve-it-phase-3).

PPARδ agonists have also been proposed as a treatment for acute kidney injury (AKI). See, for example, WO 2018/067857. AKI is common in ICU patients, with an estimated incidence of >50% (Hoste et al., 2015, Intensive Care Med; 41:1411-1423). Additionally, increased AKI severity is associated with increased mortality. Sepsis is the leading cause of AKI, accounting for 45% to 70% of cases, and approximately 25% of sepsis is of intra-abdominal origin (Seymour et al., 2016, JAMA, 315:762-774; Bagshaw et al., 2007 , Clin J Am Soc Nephrol, 2:431-439). Ischemia/reperfusion injury (IRI) can also cause AKI and is a common complication in subjects receiving organ transplants, with an incidence of 50-75% after lung and heart transplantation (Gueler et al., 2014, Transplantation 98:337-338 ). The PPARδ agonist ASP1128 (also known as MA-0217) (Astellas) is being studied as a possible treatment for AKI following coronary artery bypass graft surgery and/or valve surgery (ClinicalTrials.gov identifier NCT03941483). However, to date, no PPARδ agonist has been approved and marketed as a treatment for AKI.

There remains a need for new prevention and treatments for liver disorders, kidney disorders, and other conditions associated with PPAR.

4. Contents of the invention

The present invention provides novel compounds and their use for treating various disorders, such as liver disorders such as NASH, kidney disorders such as AKI and other conditions associated with PPAR. Without wishing to be bound by theory, the inventors believe that the clinical utility of PPAR agonists, such as elafibranor, is limited by their toxicity, so that doses often cannot be increased sufficiently to reach effective doses. The present invention provides novel compounds, including derivatives of elafibranor and related compounds, and derivatives of PPAR modulators described in WO 2011/020001, WO 2017/06246, WO 2017/180818 and WO 2018/067857. Without wishing to be bound by theory, the inventors believe that the compounds described herein have PPAR efficacy properties that result in improved bioavailability and/or half-life and/or safety and/or efficacy and/or improved therapeutic index after administration. It is believed that they may act as prodrugs and/or PPAR agonist prodrugs. In particular, the compounds may have a correspondingly improved therapeutic index. The therapeutic index (TI) is a ratio comparing the dose at which a compound becomes toxic to the dose at which it is effective. One common measure of TI is TD ₅₀ /ED ₅₀ , where TD ₅₀ and ED ₅₀ are the toxic and effective doses, respectively, for 50% of the population. The larger the TI, the safer the compound. Compounds with low TIs can be difficult to use in clinical practice and often require monitoring of plasma concentrations to prevent toxicity. One or more advantageous properties of the compounds of the present disclosure (known PPAR agonists such as elafibranor, or WO 2011/020001, WO 2011/020001, WO 2017/06246, WO 2017/180818 and/or WO 2018/ 067857), for example, better solubility at pharmaceutically effective doses, better kinetics, better absorption, better PPAR receptor selectivity, cytochrome P450 or other enzymes such as Reduc This may include reduced drug metabolism by other enzymes, reduced glucuronidation, reduced toxicity, or combinations thereof.

In various aspects, the present invention provides compounds of formula (A)-(H) and (J)-(AA) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.

In one aspect, the invention provides compounds of formula (A) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof:

here

Each R ¹ and R ² is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl; or alternatively, R ¹ and R ² together with the carbon atoms to which R ¹ and R ² are attached form a C _3- C ₇ cycloalkyl group;

X is -CH ₂ OH, -COOH, -COH, -COOR ³ , -COOCH ₂ CONR ⁴ R ⁵ , -SO ₃ H,

이고;

ego;

R ³ is -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl;

Each R ⁴ and R ⁵ is independently alkyl, aryl or heteroaryl; or alternatively, R ⁴ and R ⁵ together with the carbon atoms to which R ⁴ and R ⁵ are attached form a heterocycle;

Each R ⁶ and R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl;

n is 0, 1, 2, 3 or 4.

In another aspect, the invention also provides compounds of formula (B) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof:

here

Each R ¹ and R ² is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl; or alternatively, R ¹ and R ² together with the carbon atoms to which R ¹ and R ² are attached form a C _3- C ₇ cycloalkyl group;

X is -CH ₂ OH, -COH, -COOCH ₂ CONR ⁴ R ⁵ , -SO ₃ H,

이고;

ego;

R ³ is -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl;

Each R ⁴ and R ⁵ is independently alkyl, aryl or heteroaryl; or alternatively, R ⁴ and R ⁵ together with the carbon atoms to which R ⁴ and R ⁵ are attached form a heterocycle;

Each R ⁶ and R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl;

n is 0, 1, 2, 3 or 4.

The present invention relates to 2-(4-(3-hydroxy-3-(4-(methylthio)phenyl)prop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropane Provided are acids (“Compound I”) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, wherein Compound I has the structure:

The present invention also provides 3-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3,5-dimethylphenyl)-1-(4-(methylthio)phenyl)prop- Provided are 2-en-1-one (“Compound II”) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, wherein Compound II has the structure:

The present invention relates to 3-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3,5-dimethylphenyl)-1-(4-(methylthio)phenyl)prop-2 Further provided are -en-1-ol ("Compound III") and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, wherein Compound III has the structure:

In another aspect, the invention provides compounds of formula (C) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof:

here

R ¹ is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl, any of which is unsubstituted or C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy , C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;

R ² is C 1-8 substituted with C _2-8 alkyl, _{C 1-8} haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkyl alkyl, or C _1-6 alkyl substituted with phenyl, naphthyl or pyridyl, any of which is unsubstituted or C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy, C _{1- 8} substituted with haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;

A is oxygen, sulfur or NR ⁹ , where R ⁹ is hydrogen or C _1-8 alkyl;

X is a C _1-8 alkylene chain, which is unsubstituted or substituted with C _1-8 alkyl, C _1-8 alkoxy or hydroxyl and has 0 or 1 double bond;

Y is C(=O), C(=N-OR ¹⁰ ), CH(OR ¹¹ ), CH=CH, C≡C or C(=CH ₂ ), where each of R ¹⁰ and R ¹¹ is hydrogen or C _1-8 alkyl;

Each of R ³ , R ⁴ and R ⁵ is independently hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _{2 -8} alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl; optionally wherein at least one of R ³ , R ⁴ and R ⁵ is not hydrogen;

B is CH or nitrogen;

Z is oxygen or sulfur;

Each R ⁶ and R ⁷ is independently hydrogen, C _1-8 alkyl, or C _1-8 haloalkyl;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In another aspect, the invention provides compounds of formula (D)-(H) and (J)-(AA) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.

The present invention has a structure

를 갖는 화합물 ("화합물 IV") 및 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 및 전구약물을 추가로 제공한다.

Further provided are compounds having (“Compound IV”) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.

The present invention has a structure

를 갖는 화합물 ("화합물 V") 및 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 및 전구약물을 추가로 제공한다.

Further provided are compounds having (“Compound V”) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.

The present invention has a structure

를 갖는 화합물 ("화합물 Va") 및 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 및 전구약물을 추가로 제공한다.

Further provided are compounds having (“Compound Va”) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.

The present invention has a structure

를 갖는 화합물 ("화합물 Vb") 및 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 및 전구약물을 추가로 제공한다.

Further provided are compounds having (“Compound Vb”) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.

In a further aspect, the invention relates to compounds of formula (D)-(H) and (J)-(AA) and pharmaceutically acceptable salts, solvates thereof, for example as described in Section 5.2 (including subparts) , esters, amides and prodrugs.

The present invention has a structure

를 갖는 화합물 ("화합물 VI") 및 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 및 전구약물을 추가로 제공한다.

Further provided are compounds having (“Compound VI”) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.

The present invention has a structure

를 갖는 화합물 ("화합물 VII") 및 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 및 전구약물을 추가로 제공한다.

Further provided are compounds having (“Compound VII”) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.

The present invention has a structure

를 갖는 화합물 ("화합물 VIII") 및 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 및 전구약물을 추가로 제공한다.

Further provided are compounds having (“Compound VIII”) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.

Each compound of formula (A)-(H) and (J)-(AA), each compound of compounds I, II, III, IV, V, Va, Vb, VI, VII and VIII, and Section 5- Each compound described in Section 7 (including its subparts) or its pharmaceutically acceptable salts, solvates, esters, amides and prodrugs is a “compound of the invention”. Exemplary features of the compounds of the invention are described in Specific Embodiments 1 to 50 in Section 5.2 and Section 7.1 and in Specific Embodiments 1 to 209 in Section 7.2, below.

The invention also provides compositions comprising i) an effective amount of a compound of the invention and ii) a pharmaceutically acceptable carrier or vehicle (each composition being a “composition of the invention”). Exemplary features of the pharmaceutical compositions of the present disclosure are described in Specific Embodiments 51 to 54 in Section 5.3 and Section 7.1, and Specific Embodiments 210 to 213 in Section 7.2, below.

The present invention relates to liver disorders, dyslipidemia, dyslipoproteinemia, renal diseases, glucose metabolism disorders, lipid metabolism disorders, glucose metabolism disorders, cardiovascular diseases, vascular diseases, metabolic syndrome, complications associated with metabolic syndrome, PPAR-related disorders, bacteremia, Thrombotic disorders, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, cerebrovascular disease, disorders related to neovascularization, hypertension, cancer, inflammation, inflammatory diseases, neurodegenerative diseases, autoimmune diseases, 1. A method for treating or preventing neoplastic disease, muscular atrophy, cholestasis, mitochondrial dysfunction, eye disease, lysosomal storage disease, renal disease (e.g., acute kidney injury), or erectile dysfunction, in a subject in need thereof. A method comprising administering an effective amount of a compound of the invention or composition of the invention is further provided.

The present invention provides a method for treating or preventing hyperlipidemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, or dyslipidemia, by administering an effective amount of a compound of the present invention or a composition of the present invention to a subject in need thereof. It additionally provides a method including:

The present invention relates to abnormally high concentrations of high low density lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein (a) (Lp(a)), apolipoprotein (a) or very low density lipoprotein ( Further provided is a method of treating or preventing a subject having VLDL), comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

The present invention provides a method for treating or preventing a subject having an abnormally low concentration of high-density lipoprotein (HDL) in the subject's plasma or serum, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or of the present invention. A method comprising administering the composition is further provided.

The present invention provides a method for treating or preventing a subject having abnormally reduced or deficient lipoprotein lipase concentration or activity in the subject's plasma or serum, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or the present invention. A method comprising administering a composition is further provided.

The present invention provides a method for treating or preventing hypoalphalipoproteinemia, lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, lipoprotein abnormalities associated with Alzheimer's disease, or familial combined hyperlipidemia, wherein an effective amount of the compound of the present invention is administered to a subject in need thereof. Or a method comprising administering the composition of the present invention is provided.

The present invention provides triglycerides, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) (Lp( a)), a method for reducing abnormally high concentrations of apolipoprotein B, HDL/(VLDL+LDL) ratio, apolipoprotein C-II or apolipoprotein C-III, wherein an effective amount of the present invention is administered to a subject in need thereof. Methods comprising administering a compound or composition of the invention are further provided.

The present invention is a method for increasing abnormally low concentrations of high-density lipoprotein (HDL)-related protein, HDL-cholesterol, apolipoprotein A-I or apolipoprotein E in the plasma or serum of a subject, providing an effective amount of the present invention to a subject in need thereof. Methods comprising administering a compound or composition of the invention are further provided.

The invention further provides a method of promoting the clearance of triglycerides from the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention.

The present invention provides a method for increasing abnormally low glucose metabolism or abnormally low lipid metabolism in a subject, comprising administering to a subject in need thereof an effective amount of a compound or composition of the present invention. is additionally provided.

The present invention provides a method for treating or preventing one or more symptoms of inflammation, systemic lupus erythematosus, lupus nephritis or arthritis, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention. Additional methods are provided.

The present invention further provides a method for reducing the fat content of meat in livestock, comprising administering to the livestock an effective amount of a compound of the invention or a composition of the invention.

The invention further provides a method for reducing the cholesterol content of poultry eggs, comprising administering to the poultry species an effective amount of a compound of the invention or a composition of the invention.

Exemplary uses of the compounds and compositions of the present disclosure are described in Specific Embodiments 55 to 163 in Section 7.1 and Specific Embodiments 214 to 322 in Section 7.2, below.

5. Detailed description of the invention

5.1. Justice

The term "about" when immediately preceding a numerical value means ± up to 20% of the numerical value. For example, “about” a numerical value is ± up to 20% of the numerical value, in some embodiments, ± up to 19%, ± up to 18%, ± up to 17%, ± up to 16%, ± up to 15%, ± up to 14%, ± max 13%, ± max 12%, ± max 11%, ± max 10%, ± max 9%, ± max 8%, ± max 7%, ± max 6%, ± max 5%, ± max means up to 4%, ± up to 3%, ± up to 2%, ± up to 1%, up to ± up to 1% or any other value or range of values therein.

Throughout this specification, numerical ranges are provided for specific quantities. These scopes include all subranges within them. Thus, the range “50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Additionally, any value within a given range may be an endpoint for the range encompassed by it (e.g., the range 50-80 includes ranges with endpoints, such as 55-80, 50-75, etc.).

The term “pharmaceutically acceptable salt” includes both acid and base addition salts. Pharmaceutically acceptable salts are prepared by reacting the compounds of the present invention, which function as bases, with inorganic or organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, It can be obtained by forming salts of hydrobromide acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Pharmaceutically acceptable salts may also be obtained by reacting the compounds of the invention, which function as acids, with inorganic or organic bases to form salts such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum. , can be obtained by forming salts of ammonia, isopropylamine, trimethylamine, choline, betaine, etc. Inorganic bases may include, but are not limited to, calcium hydroxide, potassium hydroxide, sodium hydroxide, and sodium carbonate. Organic bases include primary amines, secondary amines, tertiary amines, substituted amines such as naturally-occurring substituted amines and cyclic amines such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine. , ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, N-ethyl. It may include piperidine, but is not limited thereto. Those skilled in the art will further recognize that pharmaceutically acceptable salts may be prepared by reacting the compounds of the invention with an appropriate inorganic or organic acid or base via any of a number of known methods.

The term “solvate” refers to a solvated complex. Solvates may be formed by solvation (combination of solvent molecules with molecules or ions of a compound of the invention) or solvates may be aggregates comprising solute ions or molecules or solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, etc. Solvates can be formed through hydration, including absorption of water. Pharmaceutically acceptable salts may also be solvates. When the solvate is obtained through crystallization from a solvent, the solvent may be an alcohol, such as methanol or ethanol; aldehyde; Ketones such as acetone; or esters such as ethyl acetate.

The compounds of the invention may have one or more asymmetric centers and therefore may be enantiomers, racemates, diastereomers, other stereoisomers, and mixtures thereof. The compounds of the invention include all such possible isomers (including geometric isomers), as well as their racemic and optically pure forms, whether or not specifically shown herein. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral monomers or chiral reagents or by conventional techniques, e.g. It can be resolved using, for example, chromatography and fractional crystallization. Conventional techniques for the preparation or isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Likewise, the compounds of the present invention include all tautomeric forms.

The phrase “substantially free of its corresponding opposite enantiomer” refers to at most about 10 mol%, in another embodiment at most about 5 mol%, in another embodiment at most about 2 mol%, in another embodiment at most about 1 mol%. means having at most mol%, in another embodiment at most about 0.5 mol%, in another embodiment at most about 0.1 mol% of its corresponding opposite enantiomer.

The phrase “substantially free of its corresponding opposite stereoisomer” refers to at most about 10 mol%, in another embodiment at most about 5 mol%, in another embodiment at most about 2 mol%, in another embodiment at most about 1 mol%. means having at most mol%, in another embodiment at most about 0.5 mol%, in another embodiment at most about 0.1 mol% of its corresponding opposite stereoisomer.

The phrase “substantially free of its corresponding other olefinic configuration” refers to at most about 10 mol%, in another embodiment at most about 5 mol%, in another embodiment at most about 2 mol%, in another embodiment at most about 1 mol%. means having at most mol%, in another embodiment at most about 0.5 mol%, in another embodiment at most about 0.1 mol% of its corresponding other olefin coordination.

“Effective amount” when used in relation to a compound of the invention refers to the amount of a compound of the invention that is effective, either alone or in combination with another pharmaceutically active agent, to treat or prevent a disorder or condition disclosed herein when administered to a subject. it means.

“Effective amount” when used in connection with another pharmaceutically active agent means the amount of that other pharmaceutically active agent, alone or in combination with a compound of the invention, that is effective in treating or preventing the disorder or condition disclosed herein.

A “subject” is a human or non-human mammal, such as a cow, horse, cat, dog, rodent, or non-human primate. A human may be male or female, child, adolescent or adult. Women may be premenarchal or postmenarchal.

“Mammal” includes humans, domestic animals, such as laboratory animals (e.g., mice, rats, rabbits, monkeys, dogs, etc.) and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, etc.) horses, rabbits) and non-domestic wild animals.

All weight percentages (i.e., “weight percent” and “wt. %” and w/w) referred to herein are relative to the total weight of the mixture or composition, as the case may be, unless otherwise indicated.

“Alkyl” refers to a fully saturated, straight or branched hydrocarbon chain having 1 to 12 carbon atoms, which are attached to the atoms by single bonds. Alkyls having a number of carbon atoms ranging from 1 to 12 are included. Alkyl groups having 1 to 12 carbon atoms are C ₁ -C ₁₂ alkyl (alternatively referred to as C _1-12 alkyl), and alkyl groups having 1 to 10 carbon atoms are C ₁ -C ₁₀ alkyl (alternatively referred to as C 1-12 alkyl). C _1-10 alkyl), and an alkyl group having 1 to 6 carbon atoms is C ₁ -C ₆ alkyl (alternatively referred to as C _1-6 alkyl), and an alkyl group having 1 to 5 carbon atoms is C ₁ -C ₅ alkyl (alternatively referred to as C _1-5 alkyl), and the like. C ₁ -C ₅ alkyl includes C ₅ alkyl, C ₄ alkyl, C ₃ alkyl, C ₂ alkyl and C ₁ alkyl (ie, methyl). C ₁ -C ₆ alkyl includes all moieties described above for C ₁ -C ₅ alkyl but also includes C ₆ alkyl. C ₁ -C ₁₀ alkyl includes all moieties described above for C ₁ -C ₅ alkyl and C ₁ -C ₆ alkyl, but also includes C ₇ , C ₈ , C ₉ and C ₁₀ alkyl. Similarly, C ₁ -C ₁₂ alkyl includes all of the above moieties but also includes C ₁₁ and C ₁₂ alkyl. Non-limiting examples of C ₁ -C ₁₂ alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl. , n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Unless otherwise stated, alkyl groups may be unsubstituted or substituted with substituents disclosed herein. In some embodiments, an alkyl group is unsubstituted.

“Alkoxy” refers to RO where R is alkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is attached to an atom by a single bond. Alkenyl groups having a number of carbon atoms ranging from 2 to 12 are included. Alkenyl groups having 2 to 12 carbon atoms are C ₂ -C ₁₂ alkenyl (alternatively referred to as C _2-12 alkenyl), and alkenyl groups having 2 to 10 carbon atoms are C ₂ -C ₁₀ alkenyl. kenyl (alternatively represented as C _2-10 alkenyl), and an alkenyl group having 2 to 6 carbon atoms is C ₂ -C ₆ alkenyl (alternatively represented as C _2-6 alkenyl), and 2 Alkenyl groups having from 5 to 5 carbon atoms are C ₂ -C ₅ alkenyl (alternatively denoted C _2-5 alkenyl), and the like. C ₂ -C ₅ alkenyl includes C ₅ alkenyl, C ₄ alkenyl, C ₃ alkenyl and C ₂ alkenyl. C ₂ -C ₆ alkenyl includes all moieties described above for C ₂ -C ₅ alkenyl, but also includes C ₆ alkenyl. C ₂ -C ₁₀ alkenyl not only includes all moieties described above for C ₂ -C ₅ alkenyl and C ₂ -C ₆ alkenyl, but also includes C ₇ , C ₈ , C ₉ and C ₁₀ alkenyl. Includes. Similarly, C ₂ -C ₁₂ alkenyl includes all of the above moieties but also includes C ₁₁ and C ₁₂ alkenyl. Non-limiting examples of C ₂ -C ₁₂ alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 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-undecenyl, 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, Includes 10-dodecenyl and 11-dodecenyl. Unless otherwise stated, alkyl groups may be unsubstituted or substituted with substituents disclosed herein. In some embodiments, an alkenyl group is unsubstituted.

“Alkynyl” refers to a straight or branched hydrocarbon chain radical having 2 to 12 carbon atoms and having at least one carbon-carbon triple bond. Each alkynyl group is attached to an atom by a single bond. Alkynyl groups having a number of carbon atoms ranging from 2 to 12 are included. An alkynyl group having 2 to 12 carbon atoms is C ₂ -C ₁₂ alkynyl (alternatively referred to as C _2-12 alkynyl), and an alkynyl group having 2 to 10 carbon atoms is C ₂ -C ₁₀ alkyl. Nyl (alternatively represented as C _2-10 alkynyl), and an alkynyl group having 2 to 6 carbon atoms is C ₂ -C ₆ alkynyl (alternatively represented as C _2-6 alkynyl), 2 An alkynyl group having from 5 to 5 carbon atoms is C ₂ -C ₅ alkynyl (alternatively denoted C _2-5 alkynyl). C ₂ -C ₅ alkynyl includes C ₅ alkynyl, C ₄ alkynyl, C ₃ alkynyl and C ₂ alkynyl. C ₂ -C ₆ alkynyl includes all moieties described above for C ₂ -C ₅ alkynyl, but also includes C ₆ alkynyl. C ₂ -C ₁₀ alkynyl includes all moieties described above for C ₂ -C ₅ alkynyl and C ₂ -C ₆ alkynyl, but also includes C ₇ , C ₈ , C ₉ and C ₁₀ alkynyl. Includes. Similarly, C ₂ -C ₁₂ alkynyl includes all of the above moieties but also includes C ₁₁ and C ₁₂ alkynyl. Non-limiting examples of C ₂ -C ₁₂ alkenyl include ethynyl, propynyl, butynyl, pentynyl, and the like. Unless otherwise stated, alkyl groups may be unsubstituted or substituted with substituents disclosed herein. In some embodiments, an alkynyl group is unsubstituted.

“Aryl” refers to a hydrocarbon ring radical containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. Aryl radicals may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, and may include fused or bridged ring systems. The aryl radical is aceanthrylenyl, acenaphthylenyl, acephenanthrylenyl, anthracenyl, azulenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl , naphthalenyl, phenalenyl, phenanthrenyl, phenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless otherwise stated, aryl may be unsubstituted or substituted with a substituent disclosed herein. In some embodiments, the aryl group is unsubstituted.

“Cycloalkyl” refers to a non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting of carbon and hydrogen atoms, which may contain a fused or bridged ring system, and preferably from 3 to 20 carbon atoms, It has 3 to 10 carbon atoms, attached to the atoms by single bonds. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated, cycloalkyl groups may be unsubstituted or substituted with substituents disclosed herein. In some embodiments, a cycloalkyl group is unsubstituted.

“Halo” or “halogen” refers to chloro, fluoro, bromo or iodo.

“Haloalkyl” refers to an alkyl group in which one or more hydrogen atoms have been replaced by halogen. Examples of haloalkyl groups are trifluoromethyl (CF ₃ ), difluoromethyl (CF ₂ H), monofluoromethyl (CH ₂ F), pentafluoroethyl (CF ₂ CF ₃ ), tetrafluoroethyl. (CHFCF ₃ ), monofluoroethyl (CH ₂ CH ₂ F), trifluoroethyl (CH ₂ CF ₃ ), tetrafluorotrifluoromethylethyl (CF(CF ₃ ) ₂ ).

“Haloalkoxy” refers to RO where R is a haloalkyl group.

“Heteroaryl” refers to a 5- to 20-membered ring radical comprising a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 nitrogen, oxygen or sulfur heteroatoms and at least one aromatic ring. Heteroaryl radicals may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused or bridged ring systems; The nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; The nitrogen atom may be optionally quaternized. Examples of heteroaryls include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b ][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxynyl, benzopyranyl, benzopyranonyl, benzofuranyl , benzofuranonyl, benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, Benzothiophene, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl , naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl , 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrida. Includes zinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thienyl. It is not limited to this. Unless otherwise stated, heteroaryl groups may be unsubstituted or substituted. In some embodiments, heteroaryl groups are unsubstituted.

“Heterocyclyl” refers to a 3- to 20-membered non-aromatic, partially unsaturated or aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 nitrogen, oxygen or sulfur heteroatoms. Heterocyclyl includes heteroaryl as defined herein. Unless otherwise stated, heterocyclyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused, bridged, and helical ring systems; The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; The nitrogen atom may be optionally quaternized; Heterocyclyl radicals may be partially or fully saturated. Examples of heterocyclyl radicals include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, and morpholinyl. , octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, Pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1, Including, but not limited to, 1-dioxo-thiomorpholinyl. Unless otherwise stated, heterocyclyl groups may be unsubstituted or substituted with substituents disclosed herein. In some embodiments, a heterocyclyl group is unsubstituted.

("부착 지점 결합")는 2개의 화학 엔티티 사이의 부착 지점인 결합을 나타내며, 이들 중 하나는 부착 지점 결합에 부착된 것으로 도시되고, 다른 하나는 부착 지점 결합에 부착된 것으로 도시되지 않는다. 예를 들어,

는 화학 엔티티 "XY"가 부착 지점 결합을 통해 또 다른 화학 엔티티에 결합된 것을 나타낸다.Symbols used herein

(“Point of attachment bond”) refers to a bond that is the point of attachment between two chemical entities, one of which is shown attached to the point of attachment bond and the other is not shown to be attached to the point of attachment bond. for example,

indicates that the chemical entity “XY” is bound to another chemical entity through a point of attachment bond.

5.2. Compounds of the invention

5.2.1. Compounds of formula (A)

In some embodiments, the compound of the invention is a compound of Formula (A): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof:

here

Each R ¹ and R ² is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl; or alternatively, R ¹ and R ² together with the carbon atoms to which R ¹ and R ² are attached form a C _3- C ₇ cycloalkyl group;

X is -CH ₂ OH, -COOH, -COH, -COOR ³ , -COOCH ₂ CONR ⁴ R ⁵ , -SO ₃ H,

이고;

ego;

R ³ is -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl;

Each R ⁴ and R ⁵ is independently alkyl, aryl or heteroaryl; or alternatively, R ⁴ and R ⁵ together with the carbon atoms to which R ⁴ and R ⁵ are attached form a heterocycle;

Each R ⁶ and R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl;

n is 0, 1, 2, 3 or 4.

In some embodiments, the compound of Formula (A) is a racemate or a mixture of enantiomers or diastereomers. In some embodiments, the compound of Formula (A) has the olefinic isomeric configuration of (Z) or (E). In some embodiments, the hydroxyl-bearing allylic carbon atom of a compound of Formula (A) has (R)- or (S)-stereochemistry.

In some embodiments, the compound of Formula (A) is the (Z)-isomer (or cis) and has the structure:

일부 실시양태에서, 화학식 ((Z)-A)의 화합물은 그의 상응하는 다른 올레핀 배위 (즉, (E)-이성질체)를 실질적으로 갖지 않는다.

In some embodiments, a compound of formula ((Z)-A) is substantially free of its corresponding other olefinic configuration (i.e., (E)-isomer).

In some embodiments, the compound of formula (A) is the (E)-isomer (or trans) and has the structure:

일부 실시양태에서, 화학식 ((E)-A)의 화합물은 그의 상응하는 다른 올레핀 배위 (즉, (Z)-이성질체)를 실질적으로 갖지 않는다.

In some embodiments, a compound of formula ((E)-A) is substantially free of its corresponding other olefinic configuration (i.e., (Z)-isomer).

In some embodiments, the compound of Formula (A) has a hydroxyl-bearing allylic carbon atom with (R)-stereochemistry and has the structure:

일부 실시양태에서, 화학식 ((R)-A)의 화합물은 그의 상응하는 반대 입체이성질체, 즉 그의 히드록실-보유 알릴 탄소 원자가 (S)-입체화학을 갖는 것인 화학식 (A)의 화합물을 실질적으로 갖지 않는다.

In some embodiments, the compound of formula ((R)-A) is substantially identical to its corresponding opposite stereoisomer, i.e., a compound of formula (A) wherein its hydroxyl-bearing allylic carbon atom has (S)-stereochemistry. do not have it

In some embodiments, the hydroxyl-bearing allylic carbon atom of a compound of Formula (A) has (S)-stereochemistry and has the structure:

일부 실시양태에서, 화학식 ((S)-A)의 화합물은 그의 상응하는 반대 입체이성질체, 즉 그의 히드록실-보유 알릴 탄소 원자가 (R)-입체화학을 갖는 것인 화학식 (A)의 화합물을 실질적으로 갖지 않는다.

In some embodiments, the compound of formula ((S)-A) is substantially identical to its corresponding opposite stereoisomer, i.e., a compound of formula (A) wherein its hydroxyl-bearing allylic carbon atom has (R)-stereochemistry. do not have it

In some embodiments, the compound of Formula (A) is the (Z)-isomer (or cis), has a hydroxyl-bearing allylic carbon atom with (R)-stereochemistry, and has the structure:

In some embodiments, a compound of formula ((Z)-(R)-A) is a compound of formula ((Z)-(S)-A), ((E)-(R)-A), or ((E)- It is substantially free of the compound of (S)-A).

In some embodiments, the compound of Formula (A) is the (Z)-isomer (or cis), has a hydroxyl-bearing allylic carbon atom with (S)-stereochemistry, and has the structure:

일부 실시양태에서, 화학식 ((Z)-(S)-A)의 화합물은 화학식 ((Z)-(R)-A), ((Z)-(R)-A) 또는 ((Z)-(S)-A)의 화합물을 실질적으로 갖지 않는다.

In some embodiments, the compound of formula ((Z)-(S)-A) is of formula ((Z)-(R)-A), ((Z)-(R)-A), or ((Z)- It is substantially free of the compound of (S)-A).

In some embodiments, the compound of Formula (A) is the (E)-isomer (or cis), has a hydroxyl-bearing allylic carbon atom with (R)-stereochemistry, and has the structure:

일부 실시양태에서, 화학식 ((E)-(R)-A)의 화합물은 화학식 ((E)-(S)-A), ((Z)-(R)-A) 또는 ((Z)-(S)-A)의 화합물을 실질적으로 갖지 않는다.

In some embodiments, a compound of formula ((E)-(R)-A) is a compound of formula ((E)-(S)-A), ((Z)-(R)-A), or ((Z)- It is substantially free of the compound of (S)-A).

In some embodiments, the compound of Formula (A) is the (E)-isomer (or cis), has a hydroxyl-bearing allylic carbon atom with (S)-stereochemistry, and has the structure:

일부 실시양태에서, 화학식 ((E)-(S)-A)의 화합물은 화학식 ((E)-(R)-A), ((Z)-(R)-A) 또는 ((Z)-(S)-A)의 화합물을 실질적으로 갖지 않는다.

In some embodiments, the compound of formula ((E)-(S)-A) is of formula ((E)-(R)-A), ((Z)-(R)-A), or ((Z)- It is substantially free of the compound of (S)-A).

Formula (A), ((Z)-A), ((E)-A), ((R)-A), ((S)-A), ((E)-(R)-A), ( In some embodiments of compounds of (E)-(S)-A), ((Z)-(R)-A) or ((Z)-(S)-A), each of R ¹ and R ² is Independently -C _1- C ₆ alkyl. In some embodiments, each R ¹ and R ² is independently —C _1- C ₃ alkyl. In some embodiments, each R ¹ and R ² is independently methyl.

Formula (A), ((Z)-A), ((E)-A), ((R)-A), ((S)-A), ((E)-(R)-A), ( In some embodiments of compounds of (E)-(S)-A), ((Z)-(R)-A) or ((Z)-(S)-A), X is -CH ₂ OH, - COOH, -COH or -COOR ³ or -COOCH ₂ CONR ⁴ R ⁵ . In some embodiments, X is -CH ₂ OH, -COOH, -COOR ³ , -COOCH ₂ CONR ⁴ R ⁵ . In some embodiments, X is -CH ₂ OH or -COOH.

Formula (A), ((Z)-A), ((E)-A), ((R)-A), ((S)-A), ((E)-(R)-A), ( In some embodiments of compounds of (E)-(S)-A), ((Z)-(R)-A) or ((Z)-(S)-A), R ³ is -C _1- C ₆ It is alkyl. In some embodiments, R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, or t-butyl.

Formula (A), ((Z)-A), ((E)-A), ((R)-A), ((S)-A), ((E)-(R)-A), ( In some embodiments of compounds of (E)-(S)-A), ((Z)-(R)-A) or ((Z)-(S)-A), n is 0, 1, 2 or It is 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.

5.2.1.1. Compound I

In some embodiments, the compounds of the invention have the structure:

를 갖는 화합물 I 또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물이다.

Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

In some embodiments, Compound I is a racemate or a mixture of enantiomers. In some embodiments, Compound I has the olefin isomeric configuration of (Z) or (E). In some embodiments, Compound I has a hydroxyl-bearing allyl carbon atom with (R)- or (S)-stereochemistry.

In some embodiments, Compound I is the (Z)-isomer (or cis) and has the structure:

일부 실시양태에서, 화합물 I은 (Z)-이성질체이고, 그의 상응하는 다른 올레핀 배위 (즉, (E)-이성질체)를 실질적으로 갖지 않는다.

In some embodiments, Compound I is a (Z)-isomer and is substantially free of its corresponding other olefinic configuration (i.e., (E)-isomer).

In some embodiments, Compound I is the (E)-isomer (or trans) and has the structure:

일부 실시양태에서, 화합물 I은 (E)-이성질체이고, 그의 상응하는 다른 올레핀 배위 (즉, (Z)-이성질체)를 실질적으로 갖지 않는다.

In some embodiments, Compound I is the (E)-isomer and is substantially free of its corresponding other olefinic configuration (i.e., (Z)-isomer).

In some embodiments, Compound I has a hydroxyl-bearing allylic carbon atom that is (R)-enantiomeric and has the structure:

일부 실시양태에서, 화합물 I은 (R)-거울상이성질체를 갖는 히드록실-보유 알릴 탄소 원자를 갖고, 그의 상응하는 반대 거울상이성질체 (즉, (S)-거울상이성질체)를 실질적으로 갖지 않는다.

In some embodiments, Compound I has a hydroxyl-bearing allylic carbon atom with the (R)-enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., the (S)-enantiomer).

In some embodiments, Compound I has a hydroxyl-bearing allylic carbon atom with (S)-enantiomers and has the structure:

일부 실시양태에서, 화합물 I은 (S)-거울상이성질체를 갖는 히드록실-보유 알릴 탄소 원자를 갖고, 그의 상응하는 반대 거울상이성질체 (즉, (R)-거울상이성질체)를 실질적으로 갖지 않는다. 일부 실시양태에서, 화합물 I은 그의 (R)-거울상이성질체 및 (S)-거울상이성질체의 비-라세미 혼합물이다. 일부 실시양태에서, 비-라세미 혼합물은 (S)-거울상이성질체에 비해 과량의 (R)-거울상이성질체를 갖는다. 일부 실시양태에서, 비-라세미 혼합물은 (R)-거울상이성질체에 비해 과량의 (S)-거울상이성질체를 갖는다.

In some embodiments, Compound I has a hydroxyl-bearing allylic carbon atom with the (S)-enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., the (R)-enantiomer). In some embodiments, Compound I is a non-racemic mixture of its (R)-enantiomers and (S)-enantiomers. In some embodiments, the non-racemic mixture has an excess of the (R)-enantiomer relative to the (S)-enantiomer. In some embodiments, the non-racemic mixture has an excess of the (S)-enantiomer relative to the (R)-enantiomer.

In some embodiments, Compound I is the (Z)-isomer (or cis), has a hydroxyl-bearing allylic carbon atom with the (R)-enantiomer, and has the structure:

일부 실시양태에서, 화합물 ((Z)-(R)-I)은 화합물 ((Z)-(S)-I), ((E)-(R)-I) 또는 ((E)-(S)-I)을 실질적으로 갖지 않는다.

In some embodiments, compound ((Z)-(R)-I) is compound ((Z)-(S)-I), ((E)-(R)-I) or ((E)-(S )-I) does not have substantially.

In some embodiments, Compound I is the (Z)-isomer, has a hydroxyl-bearing allylic carbon atom with the (S)-enantiomer, and has the structure:

일부 실시양태에서, 화합물 ((Z)-(S)-I)은 화합물 ((Z)-(R)-I), ((E)-(R)-I) 또는 ((E)-(S)-I)을 실질적으로 갖지 않는다.

In some embodiments, compound ((Z)-(S)-I) is compound ((Z)-(R)-I), ((E)-(R)-I) or ((E)-(S )-I) does not have substantially.

In some embodiments, Compound I is the (E)-isomer (or trans), has a hydroxyl-bearing allylic carbon atom with the (R)-enantiomer, and has the structure:

일부 실시양태에서, 화합물 ((E)-(R)-I)은 화합물 (E)-(S)-I), ((Z)-(R)-I) 또는 ((Z)-(S)-I)을 실질적으로 갖지 않는다.

In some embodiments, compound ((E)-(R)-I) is compound (E)-(S)-I), ((Z)-(R)-I) or ((Z)-(S) -I) is practically absent.

In some embodiments, Compound I is the (E)-isomer, has a hydroxyl-bearing allylic carbon atom with the (S)-enantiomer, and has the structure:

일부 실시양태에서, 화합물 ((E)-(S)-I)은 화합물 ((E)-(R)-I), ((Z)-(R)-I) 또는 ((Z)-(S)-I)을 실질적으로 갖지 않는다.

In some embodiments, compound ((E)-(S)-I) is compound ((E)-(R)-I), ((Z)-(R)-I) or ((Z)-(S )-I) does not have substantially.

5.2.1.2. Compound III

In some embodiments, the compounds of the invention have the structure:

를 갖는 화합물 III 또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물이다.

Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

In some embodiments, Compound III is a racemate or a mixture of enantiomers. In some embodiments, Compound III has the olefinic isomeric configuration of (Z) or (E). In some embodiments, Compound III has a hydroxyl-bearing allyl carbon atom with (R)- or (S)-stereochemistry.

In some embodiments, Compound III is the (Z)-isomer (or cis) and has the structure:

일부 실시양태에서, 화합물 III은 (Z)-이성질체이고, 그의 상응하는 다른 올레핀 배위 (즉, (E)-이성질체)를 실질적으로 갖지 않는다.

In some embodiments, Compound III is a (Z)-isomer and is substantially free of its corresponding other olefinic configuration (i.e., (E)-isomer).

In some embodiments, Compound III is the (E)-isomer (or trans) and has the structure:

일부 실시양태에서, 화합물 III은 (E)-이성질체이고, 그의 상응하는 다른 올레핀 배위 (즉, (Z)-이성질체)를 실질적으로 갖지 않는다.

In some embodiments, Compound III is the (E)-isomer and is substantially free of its corresponding other olefinic configuration (i.e., (Z)-isomer).

In some embodiments, Compound III has a hydroxyl-bearing allylic carbon atom with (R)-enantiomers and has the structure:

일부 실시양태에서, 화합물 III은 (R)-거울상이성질체를 갖는 히드록실-보유 알릴 탄소 원자를 갖고, 그의 상응하는 반대 거울상이성질체 (즉, (S)-거울상이성질체)를 실질적으로 갖지 않는다.

In some embodiments, Compound III has a hydroxyl-bearing allylic carbon atom with the (R)-enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., the (S)-enantiomer).

In some embodiments, Compound III has a hydroxyl-bearing allylic carbon atom with (S)-enantiomers and has the structure:

일부 실시양태에서, 화합물 III은 (S)-거울상이성질체를 갖는 히드록실-보유 알릴 탄소 원자를 갖고, 그의 상응하는 반대 거울상이성질체 (즉, (R)-거울상이성질체)를 실질적으로 갖지 않는다. 일부 실시양태에서, 화합물 III은 그의 (R)-거울상이성질체 및 (S)-거울상이성질체의 비-라세미 혼합물이다. 일부 실시양태에서, 비-라세미 혼합물은 (S)-거울상이성질체에 비해 과량의 (R)-거울상이성질체를 갖는다. 일부 실시양태에서, 비-라세미 혼합물은 (R)-거울상이성질체에 비해 과량의 (S)-거울상이성질체를 갖는다.

In some embodiments, Compound III has a hydroxyl-bearing allylic carbon atom with the (S)-enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., the (R)-enantiomer). In some embodiments, Compound III is a non-racemic mixture of its (R)-enantiomers and (S)-enantiomers. In some embodiments, the non-racemic mixture has an excess of the (R)-enantiomer relative to the (S)-enantiomer. In some embodiments, the non-racemic mixture has an excess of the (S)-enantiomer relative to the (R)-enantiomer.

In some embodiments, Compound III is the (Z)-isomer (or cis), has a hydroxyl-bearing allylic carbon atom with the (R)-enantiomer, and has the structure:

일부 실시양태에서, 화합물 ((Z)-(R)-III)은 화합물 ((Z)-(S)-III), ((E)-(R)-III) 또는 ((E)-(S)-III)을 실질적으로 갖지 않는다.

In some embodiments, compound ((Z)-(R)-III) is compound ((Z)-(S)-III), ((E)-(R)-III) or ((E)-(S )-III) is substantially absent.

In some embodiments, Compound III is the (Z)-isomer, has a hydroxyl-bearing allylic carbon atom with the (S)-enantiomer, and has the structure:

일부 실시양태에서, 화합물 ((Z)-(S)-III)은 화합물 ((Z)-(R)-III), ((E)-(R)-III) 또는 ((E)-(S)-III)을 실질적으로 갖지 않는다.

In some embodiments, compound ((Z)-(S)-III) is compound ((Z)-(R)-III), ((E)-(R)-III) or ((E)-(S )-III) is substantially absent.

In some embodiments, Compound I is the (E)-isomer (or trans), has a hydroxyl-bearing allylic carbon atom with the (R)-enantiomer, and has the structure:

일부 실시양태에서, 화합물 ((E)-(R)-III)은 화합물 ((E)-(S)-III), ((Z)-(R)-III) 또는 ((Z)-(S)-III)을 실질적으로 갖지 않는다.

In some embodiments, compound ((E)-(R)-III) is compound ((E)-(S)-III), ((Z)-(R)-III) or ((Z)-(S )-III) is substantially absent.

In some embodiments, Compound III is the (E)-isomer, has a hydroxyl-bearing allylic carbon atom with the (S)-enantiomer, and has the structure:

일부 실시양태에서, 화합물 ((E)-(S)-III)은 화합물 ((E)-(R)-III), ((Z)-(R)-III) 또는 ((Z)-(S)-III)을 실질적으로 갖지 않는다.

In some embodiments, compound ((E)-(S)-III) is compound ((E)-(R)-III), ((Z)-(R)-III) or ((Z)-(S )-III) is substantially absent.

5.2.2. Compounds of formula (B)

In some embodiments, the compound of the invention is a compound of Formula (B): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

Each R ¹ and R ² is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl; or alternatively, R ¹ and R ² together with the carbon atoms to which R ¹ and R ² are attached form a C _3- C ₇ cycloalkyl group;

X is -CH ₂ OH, -COH, -COOCH ₂ CONR ⁴ R ⁵ , -SO ₃ H,

이고;

ego;

R ³ is -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl;

Each R ⁴ and R ⁵ is independently alkyl, aryl or heteroaryl; or alternatively, R ⁴ and R ⁵ together with the carbon atoms to which R ⁴ and R ⁵ are attached form a heterocycle;

Each R ⁶ and R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl;

n is 0, 1, 2, 3 or 4.

In some embodiments, the compound of Formula (B) is a racemate or a mixture of enantiomers. In some embodiments, the compound of Formula (B) has the olefinic isomeric configuration of (Z) or (E).

In some embodiments, the compound of Formula (B) is the (Z)-isomer (or cis) and has the structure:

일부 실시양태에서, 화학식 (B)의 화합물은 (Z)-이성질체이고, 그의 상응하는 다른 올레핀 배위 (즉, (E)-이성질체)를 실질적으로 갖지 않는다.

In some embodiments, the compound of formula (B) is a (Z)-isomer and is substantially free of its corresponding other olefinic configuration (i.e., (E)-isomer).

In some embodiments, the compound of Formula (B) is the (E)-isomer (or trans) and has the structure:

일부 실시양태에서, 화학식 (B)의 화합물은 (E)-이성질체이고, 그의 상응하는 다른 올레핀 배위 (즉, (Z)-이성질체)를 실질적으로 갖지 않는다.

In some embodiments, the compound of formula (B) is the (E)-isomer and is substantially free of its corresponding other olefinic configuration (i.e., (Z)-isomer).

In some embodiments of compounds of Formula (B), each R ¹ and R ² is independently —C _1- C ₆ alkyl. In some embodiments, each R ¹ and R ² is independently —C _1- C ₃ alkyl. In some embodiments, each R ¹ and R ² is independently methyl.

In some embodiments of compounds of Formula (B), X is -CH ₂ OH, -COH, or -COOCH ₂ CONR ⁴ R ⁵ . In some embodiments, X is -CH ₂ OH.

In some embodiments of compounds of Formula (B), R ³ is -C _1- C ₆ alkyl. In some embodiments, R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, or t-butyl.

In some embodiments of compounds of Formula (B), n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.

5.2.2.1. Compound II

In some embodiments, the compounds of the invention have the structure:

를 갖는 화합물 II 또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물이다.

Compound II or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

In some embodiments, Compound II has the olefinic isomeric configuration of (Z) or (E).

In some embodiments, Compound II is the (Z)-isomer (or cis) and has the structure:

일부 실시양태에서, 화합물 II는 (Z)-이성질체이고, 그의 상응하는 다른 올레핀 배위 (즉, (E)-이성질체)를 실질적으로 갖지 않는다.

In some embodiments, Compound II is a (Z)-isomer and is substantially free of its corresponding other olefinic configuration (i.e., (E)-isomer).

In some embodiments, Compound II is the (E)-isomer (or trans) and has the structure:

일부 실시양태에서, 화합물 II는 (E)-이성질체이고, 그의 상응하는 다른 올레핀 배위 (즉, (Z)-이성질체)를 실질적으로 갖지 않는다.

In some embodiments, Compound II is the (E)-isomer and is substantially free of its corresponding other olefinic configuration (i.e., (Z)-isomer).

5.2.3. Compounds of formula (C)

In some embodiments, the compound of the invention is a compound of Formula (C): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

R ¹ is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl, any of which is unsubstituted or C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy , C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;

R ² is C 1-8 substituted with C _2-8 alkyl, _{C 1-8} haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkyl alkyl, or C _1-6 alkyl substituted with phenyl, naphthyl or pyridyl, any of which is unsubstituted or C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy, C _{1- 8} substituted with haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;

A is oxygen, sulfur or NR ⁹ , where R ⁹ is hydrogen or C _1-8 alkyl;

X is a C _1-8 alkylene chain, which is unsubstituted or substituted with C _1-8 alkyl, C _1-8 alkoxy or hydroxyl and has 0 or 1 double bond;

Y is C(=O), C(=N-OR ¹⁰ ), CH(OR ¹¹ ), CH=CH, C≡C or C(=CH ₂ ), where each of R ¹⁰ and R ¹¹ is hydrogen or C _1-8 alkyl;

Each of R ³ , R ⁴ and R ⁵ is independently hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _{2 -8} alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl; optionally wherein at least one of R ³ , R ⁴ and R ⁵ is not hydrogen;

B is CH or nitrogen;

Z is oxygen or sulfur;

Each R ⁶ and R ⁷ is independently hydrogen, C _1-8 alkyl, or C _1-8 haloalkyl;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In formula (C), examples of alkyl groups having 1 to 8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl.

Examples of alkyl groups with 1-8 carbon atoms and halogen substituents include methyl, ethyl, propyl, isopropyl, butyl and t-butyl substituted with 1-3 halogens such as fluorine, chlorine and bromine. . Examples include trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fluoroethyl.

Examples of alkoxy groups having 1-8 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and pentyloxy.

Examples of alkoxy groups having 1-8 carbon atoms and halogen substituents include methoxy, ethoxy, propoxy, isopropoxy, methyl group substituted with 1-3 halogen atoms such as fluorine atom, chlorine atom or bromine atom. Contains toxy and t-butoxy groups. Included are trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy and 2-fluoroethoxy.

Examples of alkenyl groups having 2-8 carbon atoms include vinyl and allyl.

Examples of alkynyl groups having 2-8 carbon atoms include propargyl.

Examples of 3-7 membered cycloalkyl groups include cyclohexyl and cyclopentyl.

Examples of alkyl groups having 1-8 carbon atoms and 3-7 membered cycloalkyl substituents include cyclohexylmethyl and cyclopentylmethyl.

Compounds of formula (C) may exist in the form of geometric isomers, such as cis and trans and optical isomers. These isomers are included in the compounds provided. Additionally, the provided compounds may be in the form of pharmaceutically acceptable salts, such as alkali metal salts, for example sodium or potassium salts.

^{In some} _{embodiments ,} ^R In other _embodiments , ^R

In some embodiments, the compound of Formula (C) is

,

,

or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

In some embodiments, the compound of Formula (C) is a compound shown in Table 1, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.

5.2.4. Compounds of formula (D)

In some embodiments, the compound of the invention is a compound of Formula (D): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

Each of R ¹ and R ² is independently hydrogen, halogen, nitro, C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl having 1 to 3 halogens, C having 1 to 3 halogens _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl, C _1-8 alkyl substituted with 3-7 membered cycloalkyl, optionally substituted C _6-10 aryl , an arylalkyl group with a C _6-10 aryl moiety and a C _1-8 alkyl moiety, a heterocyclic group or a heterocyclic-alkyl group with a C _1-8 alkyl group;

Each occurrence of R ³ , R ⁴ and R ⁵ is independently hydrogen or C _1-8 alkyl;

A is an oxygen atom, a sulfur atom, or NR ³ ;

^{Each of X 1} _, SO ₂ NH, CH=CH, C≡C or a combination;

Y is C _1-8 alkylene;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

Examples of halogen atoms for R ¹ and R ² include fluorine, chlorine, and bromine.

Examples of alkyl groups with 1-8 carbon atoms for R ¹ , R ² , R ³ , R ⁴ and R ⁵ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl. do.

Examples of alkoxy groups having 1-8 carbon atoms for R ¹ and R ² include methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, t-butyloxy and pentyloxy. .

Examples of alkyl groups having 1-8 carbon atoms with 1-3 halogen substituents for R ¹ and R ² are chloromethyl, fluoromethyl, bromomethyl, chloroethyl, 2-fluoroethyl and trifluoro. Contains rhomethyl.

Examples of alkoxy groups having 1-8 carbon atoms with 1-3 halogen substituents for R ¹ and R ² are chloromethoxy, fluoromethoxy, bromomethoxy, 2-chloroethoxy, 2-fluoro. Includes ethoxy and trifluoroethoxy.

Examples of alkenyl groups having 2-8 carbon atoms for R ¹ and R ² include vinyl or allyl. An alkynyl group having 2-8 carbon atoms may be, for example, propargyl. Cycloalkyl groups having 3-7 carbon atoms can be, for example, cyclohexyl or cyclopentyl. Alkyl groups with 3-7 membered cycloalkyl substituents can be, for example, cyclohexylmethyl or cyclopentylmethyl.

In the case of aryl groups optionally bearing substituents on R ¹ and R ² the aryl group may be, for example, phenyl or naphthyl.

Examples of arylalkyl groups optionally having substituents include benzyl and phenethyl.

For heterocyclic groups optionally bearing substituents, examples of heterocyclic groups include 5-7 membered cyclic groups with 1-4 ring-forming heteroatoms, such as nitrogen, oxygen and sulfur. For example, pyridyl, thienyl and furyl may be included. Additionally, a benzene ring condensed with a heterocyclic group may be included, such as quinolyl or benzothienyl.

For heterocyclic ring-alkyl groups optionally having substituents (the alkyl moiety has 1-8 carbon atoms) examples of heterocyclic groups may be the same as those described above for heterocyclic groups optionally having substituents. . Alkyl groups preferably have 1-3 carbon atoms.

Aryl groups, optionally having substituents, arylalkyl groups, optionally having substituents (aryl moieties have 6-10 carbon atoms and alkyl moieties have 1-8 carbon atoms), heterocyclic groups optionally having substituents. and in the case of substituents of heterocyclic ring-alkyl groups (the alkyl moiety has 1-8 carbon atoms) optionally having substituents, the substituents are halogen atoms such as chlorine, bromine or fluorine, nitro, hydroxyl, amino. , alkylamino groups having 1-8 carbon atoms, such as methylamino or ethylamino, dialkylamino groups having 2-10 carbon atoms, such as dimethylamino, alkyl groups having 1-8 carbon atoms, such as methyl. , ethyl, propyl, isopropyl or butyl, alkoxy groups having 1-8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy, having 1-8 carbon atoms and 1-3 Alkyl groups with halogen substituents, such as chloromethyl, fluoromethyl, bromomethyl, 2-chloroethyl, 2-fluoroethyl or trifluoromethyl, have 1-8 carbon atoms and 1-3 halogen substituents. an alkoxy group having, such as chloromethoxy, fluoromethoxy, bromomethoxy, 2-chloroethoxy, 2-fluoroethoxy or trifluoromethoxy, an alkenyl group having 2-8 carbon atoms, such as vinyl or Allyl, an alkynyl group having 2-8 carbon atoms, such as propargyl, a cycloalkyl group having 3-7 carbon atoms, such as cyclohexyl or cyclopentyl, an alkyl group having 3-7 carbon atoms. groups such as cyclohexylmethyl or cyclopentylmethyl, phenyl or pyridyl.

In some embodiments, the compound of Formula (D) is a compound shown in Table 2, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.

5.2.5. Compounds of formula (E)

In some embodiments, the compound of the invention is a compound of Formula (E): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

Each R ¹¹ and R ¹² is independently hydrogen, halogen, nitro, hydroxyl, amino, C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl group having 1 to 3 halogens, 1 to C _1-8 haloalkoxy group with 3 halogens, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl, C _1-8 alkyl with 3-7 membered cycloalkyl substituent, or a phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl group, which optionally has a halogen atom, nitro, hydroxyl, amino, C _1-8 alkyl, C _1-8 Alkoxy, C _1-8 haloalkyl with 1 to 3 halogens, C _1-8 haloalkoxy with 1 to 3 halogens, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl group, a C _1-8 alkyl group with a 3-7 membered cycloalkyl substituent, a phenyl or pyridyl substituent;

^{Each of _ _} _{_ _} NH, CH=CH, C≡C or a bond, where each R ¹⁴ and R ¹⁵ is hydrogen or C _1-8 alkyl;

Y ¹ is C _1-8 alkylene;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In some embodiments, a halogen atom for R ¹¹ and R ¹² , an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms having 1-3 halogen substituents, 1-3 halogen Alkoxy groups having 1-8 carbon atoms with substituents, alkenyl groups having 2-8 carbon atoms, alkynyl groups having 2-8 carbon atoms, cycloalkyl groups having 3-7 carbon atoms, An alkyl group having 1-8 carbon atoms with a cycloalkyl group of 3-7 carbon atoms has a halogen atom, an alkoxy group, a halogen substituent for R ¹ and R ² of formula (D). alkyl groups having 1-8 carbon atoms, alkoxy groups having 1-8 carbon atoms having halogen substituents, alkenyl, alkynyl, cycloalkyl groups and cycloalkyl groups having 3-7 carbon atoms. It may be written about.

In some embodiments, the alkyl groups having 1-8 carbon atoms for R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are as described for R ¹ , R ² , R ³ , R ⁴ and R ⁵ of Formula (D) It may be an alkyl group.

When R ¹¹ or R ¹² is phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl, these rings are in some embodiments a halogen atom such as chlorine, bromine or fluorine, nitro, hydroxyl, amino, alkylamino groups having 1-8 carbon atoms such as methylamino or ethylamino, dialkylamino groups having 2-10 carbon atoms such as dimethylamino, 1-8 carbon atoms Alkyl groups with carbon atoms, such as methyl, ethyl, propyl, isopropyl or butyl, alkoxy groups with 1-8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy, 1-3 An alkyl group having 1-8 carbon atoms with halogen substituents, such as chloromethyl, fluoromethyl, bromomethyl, 2-chloroethyl, 2-fluoroethyl or trifluoromethyl, with 1-3 halogen substituents. an alkoxy group having 1-8 carbon atoms, such as chloromethoxy, fluoromethoxy, bromomethoxy, 2-chloroethoxy, 2-fluoroethoxy or trifluoromethoxy, 2-8 carbon atoms Alkenyl groups having, such as vinyl or allyl, alkynyl groups having 2-8 carbon atoms, such as propargyl, cycloalkyl groups having 3-7 carbon atoms, such as cyclohexyl or cyclopentyl, 3-7 Alkyl groups with cycloalkyl groups of two carbon atoms may have such substituents, such as cyclohexylmethyl or cyclopentylmethyl, phenyl or pyridyl.

Provided compounds may be stereoisomers, such as cis or trans or optical isomers. These isomers are encompassed by the present invention.

Provided compounds include pharmaceutically acceptable salts, such as alkali metal salts, for example sodium salts or potassium salts. Additionally, the provided compounds may be in the form of pharmaceutically acceptable salts, such as alkali metal salts, for example sodium salts and potassium salts.

In some embodiments, the compound of Formula (E) is a compound shown in Table 3, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.

5.2.6. Compounds of formula (F)

In some embodiments, the compound of the invention is a compound of Formula (F): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

A is O, S or NR ⁷ , where R ⁷ is hydrogen or C _1-8 alkyl;

B ¹ is CW or N, where W is hydrogen or a bond; B ² is O, S or NR ⁸ , where R ⁸ is hydrogen or C _1-8 alkyl;

^Each of ^{X 1 and} , wherein each R ⁹ and R ¹⁰ is hydrogen or C _1-8 alkyl;

Y is C _1-8 alkylene, which is unsubstituted or substituted with C _1-8 alkyl or C _1-8 haloalkyl with 1-3 halogens;

Z is NH, O or S;

R ¹ is unsubstituted or aryl substituted with C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl with 1-3 halogens, hydroxyl, nitro, amino, phenyl, pyridyl or halogen. , or a heterocyclic group having a 5- to 8-membered ring, each of which is independently nitrogen, oxygen or sulfur, and the other atom is carbon, optionally wherein the benzene ring is condensed with the heterocyclic ring and ;

R ² is C _2-8 alkyl, C _1-8 haloalkyl with 1-3 halogens, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, unsubstituted or C _{1 -8} alkyl, C _1-8 alkoxy, C _1-8 haloalkyl with 1-3 halogens, C _1-4 alkyl substituted with hydroxyl, nitro, amino, phenyl, pyridyl or aryl substituted with halogen, or C _1-4 alkyl substituted with a heterocyclic group having a 5 to 8 membered ring having 1 to 3 heteroatoms each independently being nitrogen, oxygen or sulfur;

R ³ is halogen, trifluoromethyl, C _1-8 alkyl, C _2-8 alkenyl or C _2-8 alkynyl;

each of R ⁴ and R ⁵ is hydrogen, C _1-8 alkyl or C _1-8 haloalkyl with 1-3 halogens;

Each of Z and R ³ is attached to a benzene ring and X ² is not attached to a benzene ring;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In formula (F), substituents on alkylene chains of R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , Y, substituents on aryl and heterocyclic groups of R ³ , The substituents of the aryl-substituted alkyl group of R ² and the substituents of the heterocyclic group of R ² may in some embodiments be alkyl groups having 1-8 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

In some embodiments, R ² can be an alkyl group having 2-8 carbon atoms. Examples of alkyl groups include ethyl, propyl, iso-propyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

In some embodiments, a substituent on an alkylene chain of R ² , R ⁴ , R ⁵ , Y, a substituent on an aryl or heterocyclic group on R ¹ , a substituent on an aryl substituted alkyl group on R ² , and a substituent on a heterocyclic group on R ² The substituent of an alkyl group substituted with a cyclic group may be an alkyl group having 1-8 carbon atoms substituted with 1-3 halogens. Examples of haloalkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl substituted with 1-3 halogens such as fluorine, chlorine and bromine. In some embodiments, the group is trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl, or 2-fluoroethyl.

In some embodiments, R ² and R ³ can be an alkenyl group having 2-8 carbon atoms. Examples of alkenyl groups include vinyl and allyl. R ² and R ³ may be an alkynyl group having 2-8 carbon atoms. Examples of alkynyl groups include propargyl.

In some embodiments, R ³ can be a halogen atom. Examples of halogen atoms include fluorine, chlorine, and bromine.

In some embodiments, R ² can be a cycloalkyl group having 3-7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, and cyclohexyl.

In some embodiments, the substituent on the aryl or heterocyclic group of R ¹ , the substituent on the aryl-substituted alkyl group of R ² and the substituent of the alkyl group substituted with heterocyclic group of R ² have 1-8 carbon atoms. It may be an alkoxy group having. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy and hexyloxy.

In some embodiments, the aryl moiety of the aryl substituted aryl of R ¹ and R ² can be an aryl group. Examples of aryl groups include phenyl and naphthyl. The substituent of the alkyl group of R ¹ and R ² may be a heterocyclic group having a 5 to 8 membered ring. Examples of heterocyclic groups include pyridyl, thienyl, furyl, thiazolyl, and quinolyl.

In some embodiments, R ¹ can be a heterocyclic group having a 5-8 membered ring comprising 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur and the other atom consisting of carbon. Benzene rings can be condensed with heterocyclic rings. Examples of condensed rings include quinoline rings and benzothiophene rings.

In some embodiments, Y can be an alkylene chain having 1 to 8 carbon atoms. Examples of alkylene chains include methylene and ethylene.

In some embodiments, R ³ can be 1 to 3 groups. In some embodiments, 2 or 3 groups of R ³ can be different from each other.

In some embodiments, R ⁶ can be an alkyl group having 1-8 carbon atoms substituted with amino. Examples of aminoalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl substituted with amino groups such as piperidino, pyrrolidino, dimethylamino and diethylamino. do.

In some embodiments, the compounds of formula (F) may be in the form of pharmaceutically acceptable salts, such as alkali metal salts, such as sodium salts and potassium salts.

In some embodiments, the compound of Formula (F) is a compound shown in Table 4, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.

5.2.7. Compounds of formula (G), (H) and (J)

In some embodiments, the compound of the invention is a compound of Formula (G): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

Each of R ¹ and R ⁴ is the same or different and is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;

R ² is hydrogen;

R ³ is C _1-8 alkyl, or R ³ is combined with R ² to form =O or =C(R ⁷ )(R ⁸ ), wherein each of R ⁷ and R ⁸ is the same or different; hydrogen or C _1-8 alkyl;

Each of R ⁵ and R ⁶ is the same or different and is a hydrogen atom, C _1-8 alkyl, C _1-8 haloalkyl;

X and Y are the same or different and each represents CH or N;

Z is oxygen or sulfur;

A is a 5-membered heterocyclic group that is pyrazole, thiophene, furan or pyrrole, wherein the heterocyclic group is unsubstituted or C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _2-8 alkyl Kenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _1-8 alkyl group substituted by 3- to 7-membered cycloalkyl group, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _{6- 10} aryl, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered heterocyclic group. substituted with C _1-8 alkyl;

B is a C _1-8 alkylene chain, which is unsubstituted or C _1-8 alkyl, a 3- to 7-membered cycloalkyl group, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 substituted by alkoxy, halogen, C _1-8 haloalkyl or C _1-8 haloalkoxy, and when the alkylene group has 2 to 6 carbon atoms the alkylene group optionally has a double bond;

q is 0, 1, 2, 3, 4 or 5;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In some embodiments, the compound of the invention is a compound of Formula (H): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

Each of R ¹¹ and R ¹³ is the same or different and is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;

R ¹² is hydrogen, C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to 7-membered cycloalkyl group substituent C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered heterocyclic group, C _6-10 aryl moiety and C _1- an aralkyl group with _{an 8} alkylene moiety, or a C _1-8 alkyl group with a 5- or 6-membered heterocyclic substituent;

R ¹⁴ and R ¹⁵ are the same or different and each is a hydrogen atom, C _1-8 alkyl or C _1-8 haloalkyl;

X ¹ is CH or N;

Z ¹ is oxygen or sulfur;

W ¹ is oxygen or CH ₂ when a bond a is present and OH when a bond a is absent;

q is 2, 3 or 4;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In some embodiments, the compound of the invention is a compound of Formula (J): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

Each of R ²¹ and R ²³ is the same or different and is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;

R ²² is hydrogen, C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to 7-membered cycloalkyl group substituent C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered heterocyclic group, C _6-10 aryl moiety and C _1- an aralkyl group with _{an 8} alkylene moiety, or a C _1-8 alkyl group with a 5- or 6-membered heterocyclic substituent;

R ²⁴ and R ²⁵ are the same or different and each is a hydrogen atom, C _1-8 alkyl or C _1-8 haloalkyl;

X ² is CH or N;

Z ² is oxygen or sulfur;

W ² is oxygen or CH ₂ when a bond a is present and OH when a bond a is absent;

r is 2, 3 or 4;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

With respect to formula (G), R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , a substituent of a 5-membered heterocyclic group for A or alkyl having 2 to 6 carbon atoms for B Examples of alkyl groups with 1 to 8 carbon atoms that can be substituents of the lene chain include methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl, and hexyl.

of an alkenyl group having 2 to 8 carbon atoms, which may be a substituent of a 5-membered heterocyclic group for R ¹ , R ⁴ , A or a substituent of an alkylene chain with 2 to 6 carbon atoms for B Examples include vinyl and allyl.

of an alkynyl group having 2 to 8 carbon atoms, which may be a substituent of a 5-membered heterocyclic group for R ¹ , R ⁴ , A or a substituent of an alkylene chain with 2 to 6 carbon atoms for B Examples include propargyl.

Examples of 3- to 7-membered cycloalkyl groups, which may be substituents of a 5-membered heterocyclic group for A or substituents of an alkylene chain having 2 to 6 carbon atoms for B, are cyclopropyl, cyclopentyl and Contains cyclohexyl.

Examples of alkoxy groups having 1 to 8 carbon atoms, which may be substituents of a 5-membered heterocyclic group for R ¹ , R ⁴ , A or substituents of an alkylene chain with 2 to 6 carbon atoms for B includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, i-butoxy, t-butoxy, pentyloxy and hexyloxy.

Examples of halogen atoms that may be substituents of an alkylene chain having 2 to 6 carbon atoms for R ¹ , R ⁴ or B include fluorine, chlorine and bromine.

R ¹ , R ⁴ , R ⁵ , R ⁶ , 1 to 8 carbon atoms, which may be substituents of a 5-membered heterocyclic group for A or substituents of an alkylene chain having 2 to 6 carbon atoms for B and examples of alkyl groups with halogen atom substituents include methyl, ethyl, propyl, isopropyl, butyl and t-butyl with substituents such as 1 to 3 fluorine, chlorine or bromine atoms. In some embodiments, the alkyl group having 1 to 8 carbon atoms and a halogen atom substituent is trifluoromethyl, chloromethyl, chloroethyl, 2-bromoethyl, or 2-fluoroethyl.

R ¹ , R ⁴ , having 1 to 8 carbon atoms and a halogen atom substituent, which can be a substituent of a 5-membered heterocyclic group for A or a substituent of an alkylene chain with 2 to 6 carbon atoms for B Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropyloxy, butyloxy and t-butyloxy with substituents such as 1 to 3 fluorine, chlorine or bromine atoms. In some embodiments, the alkoxy group having 1 to 8 carbon atoms and a halogen atom substituent is trifluoromethyloxy, chloromethyloxy, 2-chloroethyloxy, 2-bromoethyloxy, or 2-fluoroethyloxy.

Examples of acyl groups having 2 to 8 carbon atoms, which may be R ¹ or R ⁴ , include acetyl and propionyl.

Examples of aryl groups with 6 to 10 carbon atoms that can be substituents of a 5-membered heterocyclic group for R ¹ , R ⁴ or A include phenyl.

Examples of 5- or 6-membered heterocyclic groups that may be substituents of the 5-membered heterocyclic group for R ¹ , R ⁴ or A include pyridyl.

Examples of alkyl groups with 1 to 8 carbon atoms and 3- to 7-cycloalkyl group substituents, which may be substituents of the 5-membered heterocyclic group for A, include methyl with cyclopropyl, cyclopentyl or cyclohexyl substituents. , ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl and hexyl.

Examples of aralkyl groups (which have an aryl moiety of 6 to 10 carbon atoms and an alkylene moiety of 1 to 8 carbon atoms) that may be substituents of a 5-membered heterocyclic group for A are benzyl and Contains phenethyl.

Examples of alkyl groups having 1 to 8 carbon atoms and 5- or 6-membered heterocyclic groups that may be substituents of the 5-membered heterocyclic group for A include methyl, ethyl, propyl, iso, and pyridyl substituents. Includes propyl, butyl, i-butyl, t-butyl, pentyl and hexyl.

an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, which may be R ¹¹ or R ^{13 of formula (H) or R 21 or} R ²³ of formula (J) an alkynyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. Examples of alkoxy groups, acyl groups having 2 to 8 carbon atoms, aryl groups having 6 to 10 carbon atoms and 5- or 6-membered heterocyclic groups are for R ¹ and R ⁴ of formula (G) As described above.

an alkyl group having 1 to 8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkenyl group having 2 to 8 carbon atoms, which may be R ¹² of formula (H) or R ²² of formula (J) , alkynyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms and 3- to 7-membered cycloalkyl group substituents, 1 to 8 Alkyl groups with carbon atoms and halogen atom substituents, alkoxy groups with 1 to 8 carbon atoms and halogen atom substituents, aryl groups with 6 to 10 carbon atoms, 5- or 6-membered heterocyclic groups, 6 to 6-membered heterocyclic groups. Examples of aralkyl groups with an aryl moiety of 10 carbon atoms and an alkylene moiety of 1 to 8 carbon atoms and alkyl groups with 1 to 8 carbon atoms and a 5- or 6-membered heterocyclic substituent include: Substituents of the 5-membered heterocyclic group for A of formula (G) include those described above.

of an alkyl group having 1 to 8 carbon atoms and an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent, which may be R ¹⁴ or R ^{15 of formula (H) or R 24 or} R ²⁵ of formula (J) Examples include those described above for R ⁵ and R ⁶ of formula (G).

R ¹ in the formula (G), R ¹¹ in the formula (H), and R ²¹ in the formula (J) may be attached singly or in plural numbers (1 to 3) to a benzene ring or the like. When each of R ¹ , R ¹¹ and R ²¹ exists in plural numbers, the plurality groups may be the same or different.

R ⁴ in Formula (G), R ¹³ in Formula (H), and R ²³ in Formula (J) may be attached singly or in plural numbers (1 to 3) to a benzene ring or the like. When each of R ⁴ , R ¹³ and R ²³ exists in plural numbers, the plurality groups may be the same or different.

The substituents of the 5-membered heterocyclic group for A in Formula (G), R ¹² in Formula (H) and R ²² in Formula (J) may be present in single or plural numbers (1 or 2) on the heterocyclic ring. can be attached). When each of the substituents of the 5-membered heterocyclic group for A, R ¹² and R ²² is present in plural numbers, the plurality groups may be the same or different.

The compounds of formulas (G), (H) and (J) may be pharmacologically acceptable salts, such as alkali metal salts, for example sodium salts, potassium salts or lithium salts.

Compounds of formulas (G), (H) and (J) may exist in optically active forms and in the form of optical isomers, such as racemic forms of the compounds or geometric isomers, such as compounds in the cis- or trans form.

In some embodiments, the compound of Formula (G), (H), or (J) is a compound shown in Table 5, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.

5.2.8. Compounds of formula (K)

In some embodiments, the compound of the invention is a compound of Formula (K): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

A is CH or nitrogen;

B, when a bond a is present, is oxygen or C(R ⁸ )(R ⁹ ), where each R ⁸ and R ⁹ are independently hydrogen or C _1-8 alkyl; B, in the absence of bond a, is OH;

W ¹ is a bond, C(=O) or (C(R ¹⁰ )(R ¹¹ )) _m , where each R ¹⁰ and R ¹¹ is independently hydrogen or a C _1-8 alkyl group, and m is 1, 2 or 3;

X and Y are different from each other and each is an oxygen atom, a sulfur atom, a nitrogen atom or CR ¹² , where R ¹² is hydrogen or C _1-8 alkyl;

Z ¹ is a bond, oxygen, sulfur, or C(R ¹³ )(R ¹⁴ ), where each R ¹³ and R ¹⁴ are independently hydrogen or C _1-8 alkyl;

Each of R ¹ , R ² and R ³ is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;

Each R ⁴ and R ⁵ is independently hydrogen, C _1-8 alkyl, C _1-8 haloalkyl;

Each R ⁶ and R ⁷ is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl or C _1-8 haloalkyl;

r is 1, 2, 3, 4 or 5;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In formula (K), 1 for R ¹ , R ² , R 3 ^, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ Examples of alkyl groups having from 8 to 8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl, and hexyl.

Examples of alkenyl groups having 2 to 8 carbon atoms for R ¹ , R ² , R ³ , R ⁶ and R ⁷ include vinyl and allyl.

Examples of alkynyl groups having 2 to 8 carbon atoms for R ¹ , R ² , R ³ , R ⁶ and R ⁷ include propargyl.

Examples of alkoxy groups having 1 to 8 carbon atoms for R ¹ , R ² and R ³ are methoxy, ethoxy, propoxy, isopropoxy, butoxy, i-butoxy, t-butoxy, pentyl. Includes oxy and hexyloxy.

Examples of halogen atoms for R ¹ , R ² and R ³ include fluorine, chlorine and bromine.

Examples of alkyl groups having 1 to 8 carbon atoms substituted with halogen atoms for R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ include 1 to 3 halogen atoms, such as fluorine; Includes methyl, ethyl, propyl, isopropyl, butyl and t-butyl substituted by chlorine and bromine. In one embodiment, the substituent is trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl, or 2-fluoroethyl.

Examples of alkoxy groups having 1 to 8 carbon atoms substituted with halogen atoms for R ¹ , R ² and R ³ include methoxy, ethoxy substituted with 1 to 3 halogen atoms such as fluorine, chlorine or bromine. , propoxy, isopropoxy, butoxy and t-butoxy. In one embodiment, the substituent is trifluoromethyloxy, chloromethyloxy, 2-chloroethyloxy, 2-bromoethyloxy, or 2-fluoroethyloxy.

Examples of acyl groups having 2 to 8 carbon atoms for R ¹ , R ² and R ³ include acetyl and propionyl.

Examples of aryl groups having 6 to 10 carbon atoms for R ¹ , R ² and R ³ include phenyl.

Examples of 5- or 6-membered heterocyclic groups for R ¹ , R ² and R ³ include pyridyl.

R ¹ , R ² and R ³ in the formula (K) may be attached to a benzene ring or the like in the number of 1 to 3, where the same or different groups may be attached to the same ring.

The compounds provided herein represented by formula (K) may be in the form of pharmacologically acceptable salts, such as alkali metal salts, such as salts of sodium, potassium and lithium.

The compounds provided herein may be in the form of optically active forms and optical isomers, such as racemic forms, or geometric isomers, such as cis- or trans forms.

In some embodiments, the compound of Formula (K) is a compound shown in Table 6, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.

5.2.9. Compounds of formula (L)

In some embodiments, the compound of the invention is a compound of Formula (L): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

B, if bond a is present, is oxygen; B, in the absence of bond a, is OH;

W ² is a bond, C(=O) or CH ₂ ;

Z ² is oxygen or sulfur;

Each of R ²¹ , R ²² and R ²³ is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;

Each R ²⁴ and R ²⁵ is independently hydrogen, C _1-8 alkyl, C _1-8 haloalkyl;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In formula (L), for R ²¹ , R ²² and R ²³ an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms. , an alkoxy group with 1 to 8 carbon atoms, a halogen atom, an alkyl group with 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group with 1 to 8 carbon atoms substituted with a halogen atom, hydroxyl, nitro, Acyl groups having 2 to 8 carbon atoms, aryl groups having 6 to 10 carbon atoms and 5- or 6-membered heterocyclic groups are in some embodiments represented by R ¹ , R ² and R ³ in Formula (K) It may be written about.

In Formula (L), an alkyl group having 1 to 8 carbon atoms for R ²⁴ and R ²⁵ and an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, in some embodiments, are substituted for R ⁴ in Formula (K). and R ⁵ may be described.

R ²¹ , R ²² and R ²³ in the formula (L) may be attached to a benzene ring or the like in the number of 1 to 3, where the same or different groups may be attached to the same ring.

The compounds provided herein represented by formula (L) may be in the form of pharmacologically acceptable salts, such as alkali metal salts, such as salts of sodium, potassium and lithium.

The compounds provided herein may be in the form of optically active forms and optical isomers, such as racemic forms, or geometric isomers, such as cis- or trans forms.

5.2.10. Compounds of formula (M) and (N)

In some embodiments, the compound of the invention is a compound of Formula (M): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

Each W ¹ and W ² is independently nitrogen or CH;

X is nitrogen or CH;

Y is oxygen or sulfur;

Z is a bond, oxygen, sulfur or NR ⁵ where R ⁵ is hydrogen or C _1-8 alkyl;

Each R ¹ and R ² are independently hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl, 3- to 7-membered cycloalkyl group, C _2-8 alkenyl, C _2-8 alkynyl , C _1-8 alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered a heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene, or a C _1-8 alkyl with a 5- or 6-membered heterocyclic substituent;

Each R ³ and R ⁴ is independently hydrogen, C _1-8 alkyl, or C _1-8 haloalkyl;

A is a 5-membered heterocycle that is pyrazole, thiophene, furan, isoxazole, isothiazole or pyrrole, wherein the 5-membered heterocycle is unsubstituted or halogen, hydroxyl, nitro, amino, C _1-8 Alkyl, 3- to 7-membered cycloalkyl group, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _1-8 alkyl with 3- to 7-membered cycloalkyl substituents, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered heterocyclic group, aralkyl with C _6-10 aryl moiety and C _1-8 alkylene moiety group, or a C _1-8 alkyl group having a 5- or 6-membered heterocyclic substituent;

B is a bond or C _1-8 alkylene, which is unsubstituted or substituted by C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _1-8 alkoxy or halogen substituent, optionally wherein C _{1- 8} Alkylene has double or triple bonds;

r is 0, 1, 2 or 3;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In some embodiments, the compound of the invention is a compound of Formula (N): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

W ³ is nitrogen or CH;

Z ¹ is oxygen or sulfur;

Each R ¹¹ and R ¹² is independently hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl or C _1-8 haloalkoxy;

Each R ¹³ and R ¹⁴ is independently hydrogen or C _1-8 alkyl;

A ¹ is a 5-membered heterocycle that is pyrazole or thiophene, wherein the 5-membered heterocycle is unsubstituted or halogen, hydroxyl, nitro, amino, C _1-8 alkyl, C _1-8 alkoxy, C _{1 -8} haloalkyl or C _1-8 haloalkoxy;

m is 2, 3 or 4;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In some embodiments of compounds of formula (M), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , a substituent (if present) attached to the 5-membered heteroring of A and 1 to 8 carbon atoms The alkyl group having 1 to 8 carbon atoms for the substituent attached to the alkylene chain may be methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl or hexyl.

In one embodiment, the alkenyl group having 2 to 8 carbon atoms for the substituent attached to the 5-membered heteroring of R ¹ , R ² and A is vinyl or allyl.

In one embodiment, the alkynyl group having 2 to 8 carbon atoms for the substituent attached to the 5-membered heteroring of R ¹ , R ² and A is propargyl.

In one embodiment, a 3- to 7-membered cycloalkyl group for the substituent attached to the 5-membered heteroring of R ¹ , R ² and A. In another embodiment, the substituent is attached to an alkylene chain having 1 to 8 carbon atoms and is cyclopentyl or cyclohexyl.

In one embodiment, an alkoxy group having 1 to 8 carbon atoms for the substituent attached to the 5-membered heteroring of R ¹ , R ² and A. In another embodiment, the substituent is attached to an alkylene chain having 1 to 8 carbon atoms and is methoxy, ethoxy, propoxy, isopropoxy, butoxy, i-butoxy, t-butoxy, pentyl. It is oxy or hexyloxy.

In one embodiment, R ¹ and R ² are halogen and the substituent is attached to the 5-membered heteroring of A. In another embodiment, the substituent is attached to an alkylene chain having 1 to 8 carbon atoms and is fluorine, chlorine, or bromine.

In one embodiment, an alkyl group having 1 to 8 carbon atoms and a halogen substituent for the substituent attached to the 5-membered heteroring of R ¹ , R ² , R ⁵ and A has 1 to 3 halogen substituents, such as fluorine. , methyl, ethyl, propyl, isopropyl, butyl or t-butyl with chlorine or bromine. In another embodiment, the substituent is selected from trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl, and 2-fluoroethyl.

In one embodiment, an alkoxy group having 1 to 8 carbon atoms and a halogen substituent for the substituent attached to the 5-membered heteroring of R ¹ , R ² and A has 1 to 3 halogen substituents such as fluorine, chlorine or methoxy, ethoxy, propoxy, isopropoxy, butyloxy or t-butyloxy with bromine. In one embodiment, the substituent is selected from trifluoromethyloxy, chloromethyloxy, 2-chloroethyloxy, 2-bromoethyloxy, and 2-fluoroethyloxy.

In one embodiment, the aryl group having 6 to 10 carbon atoms for the substituent attached to the 5-membered heteroring of R ¹ , R ² and A is phenyl.

In one embodiment, the 5- or 6-membered heterocyclic group for the substituent attached to the 5-membered heteroring of R ¹ , R ² and A is pyridyl.

In one embodiment, the alkyl group having 1 to 8 carbon atoms and a 3- to 7-membered cycloalkyl group for the substituent attached to the 5-membered heteroring of R ¹ , R ² and A is a cyclopropyl substituent, a cyclopentyl substituent. or methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl or hexyl with a cyclohexyl substituent.

In one embodiment, an aralkyl group having an aryl moiety of 6 to 10 carbon atoms and an alkylene moiety of 1 to 8 carbon atoms for the substituent attached to the 5-membered heteroring of R ¹ , R ² and A is benzyl or phenethyl.

In one embodiment, the alkyl group having 1 to 8 carbon atoms and a 5- or 6-membered heterocyclic group for the substituent attached to the 5-membered heteroring of R ¹ , R ² and A is methyl with a pyridyl substituent. , ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl or hexyl.

In one embodiment, the 5-membered heterocycle that may have a substituent for A is a pyrazole or thiophene having a substituent. In another embodiment, the pyrazole has a substituent.

In one embodiment, the alkylene chain having 1 to 8 carbon atoms carrying a substituent for B is an alkylene chain having 1 to 4 carbon atoms. In another embodiment, the alkylene chain is an ethylene chain or a propylene chain.

In one embodiment, n is 0.

In some embodiments of compounds of formula (N), a halogen atom for R ¹¹ and R ¹² , an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, 1 to 8 carbon atoms. and the alkyl group having a halogen substituent and the alkoxy group having 1 to 8 carbon atoms and a halogen substituent may be those described above for R ¹ and R ² of formula (M).

In one embodiment, the alkyl groups having 1 to 8 carbon atoms for R ¹³ and R ¹⁴ may be those described above for R ³ and R ⁴ of Formula (M).

In one embodiment, a halogen atom attached to the pyrazole or thiophene for A ¹ in Formula (N), an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, 1 to 8 carbon atoms, Alkyl groups with 8 carbon atoms and halogen substituents and alkoxy groups with 1 to 8 carbon atoms and halogen substituents are those described above for the substituents attached to the 5-membered heteroring of A of formula (M).

In one embodiment, R ¹ of Formula (M) and R ¹¹ of Formula (N), benzene rings, etc. may have a number of R ¹ or R ¹¹ that are the same or different from one another. In another embodiment, the benzene ring, etc. may have 1 to 3 substituents other than hydrogen atoms.

In one embodiment, R ² of Formula (M) and R ¹² of Formula (N), the benzene ring of a benzisoxazole ring, etc. may have 1 to 3 numbers of R ² or R ¹² that are the same or different from each other. In another embodiment, the benzene ring, etc. of the benzisoxazole ring may have 1 to 3 substituents other than hydrogen atoms.

In one embodiment, the substituents attached to the 5-membered heteroring for A of Formula (M) and the substituents attached to the pyrazole or thiophene for A ¹ of Formula (N) may be the same or different from each other. Alternatively, it may exist as two numbers.

The compounds provided herein represented by formulas (M) and (N) may be in the form of pharmacologically acceptable salts, such as alkali metal salts, for example salts of sodium, potassium and lithium.

The compounds provided herein may be in the form of optically active forms and optical isomers, such as racemic forms, or geometric isomers, such as cis- or trans forms.

In some embodiments, the compound of Formula (M) or (N) is a compound shown in Table 7, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.

5.2.11. Compounds of formula (O), (P) and (Q)

In some embodiments, the compound of the invention is a compound of Formula (O): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

Each W ¹ and W ² is independently CH or nitrogen;

X is NR ⁵ or CR ⁶ R ⁷ ; Here, R ⁵ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkyl substituted with C _1-8 alkoxy, C _3-7 cycloalkyl, C substituted with C _3-7 cycloalkyl _1-8 alkyl, C _1-8 alkyl substituted with phenyl, C _2-8 acyl or C _2-8 alkenyl, and each of R ⁶ and R ⁷ is independently hydrogen or C _1-8 alkyl;

Y is (CR ⁸ R ⁹ ) _r , where each R ⁸ and R ⁹ are independently hydrogen or C _1-8 alkyl and r is 1, 2, 3 or 4; or

X and Y are combined to form CR ¹⁰ =CR ¹¹ or ethynylene, wherein each R ¹⁰ and R ¹¹ is independently hydrogen or C _1-8 alkyl;

G, when the bond a is present, is O, S or CR ¹² R ¹³ , where each of R ¹² and R ¹³ is independently hydrogen or C _1-8 alkyl; G, in the absence of bond a, is OH;

A is a 5-membered heterocyclic ring that is thiazole, oxazole, imidazole, pyrazole, thiophene, furan or pyrrole, wherein the heterocyclic ring is unsubstituted or C _1-8 alkyl, C _2-8 Alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro, C _2-8 acyl, C _6-10 aryl, or substituted with a 5- or 6-membered heterocyclic group;

B is C _1-8 alkylene, C _2-8 alkenylene or C _2-8 alkynylene chain, wherein the chain is unsubstituted or C _1-8 alkyl, C _3-7 cycloalkyl, C _1-8 alkoxy or substituted with halogen;

Each of R ¹ and R ² is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _{1- 8} haloalkoxy, hydroxyl, nitro, C _2-8 acyl, C _6-10 aryl, or a 5- or 6-membered heterocyclic group;

Each R ³ and R ⁴ is independently hydrogen or C _1-8 alkyl;

m is 0, 1, 2 or 3;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In some embodiments, the compound of the invention is a compound of Formula (P): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

G ^a , when a bond a is present, is O, S or CH ₂ ; G ^a is OH in the absence of bond a;

A ^a is a 5-membered heterocyclic ring that is thiazole, oxazole or thiophene, wherein the 5-membered heterocyclic ring is unsubstituted or C _1-8 alkyl, C _1-8 alkoxy, halogen, C _{1 -8} haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl;

B ^a is C _1-8 alkylene or C _2-8 alkenylene chain;

Each R ^1a and R ^2a is independently hydrogen, C _1-8 alkyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl ego;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In some embodiments, the compound of the invention is a compound of Formula (Q): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

G ^b , when a bond a is present, is O, S or CH ₂ ; G ^b is OH in the absence of bond a;

A ^b is a 5-membered heterocyclic ring that is thiazole, oxazole or thiophene, wherein the 5-membered heterocyclic ring is unsubstituted or C _1-8 alkyl, C _1-8 alkoxy, halogen, C _{1 -8} haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl;

B ^b is C _1-8 alkylene or C _2-8 alkenylene chain;

Each R ^1b and R ^2b is independently hydrogen, C _1-8 alkyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl ego;

R ^3b is hydrogen or C _1-8 alkyl;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In some embodiments, in Formula (O), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , The substituents of the 5-membered heterocyclic ring represented by A and the C _1-8 alkylene, C _2-8 alkenylene or C _2-8 alkynylene chain represented by B are C _1-8 alkylyl. You can. Examples of C _1-8 alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

In one embodiment, the substituent on the 5-membered heterocyclic ring represented by R ¹ , R ² , R ⁵ and A can be C _2-8 alkenyl. Examples of C _2-8 alkenyl include vinyl and allyl.

In one embodiment, the substituent on the 5-membered heterocyclic ring represented by R ¹ , R ² and A can be C _2-8 alkynyl. Examples of C _2-8 alkynyl include propargyl.

In one embodiment, the substituents of the 5-membered heterocyclic ring represented by R ¹ , R ² , A and C _1-8 alkylene, C _2-8 alkenylene or C _2-8 alkyl represented by B The substituent of the nylene chain may be C _1-8 alkoxy. Examples of C _1-8 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy and hexyloxy.

In one embodiment, the substituents of the 5-membered heterocyclic ring represented by R ¹ , R ² , A and C _1-8 alkylene, C _2-8 alkenylene or C _2-8 alkyl represented by B The substituent on the nylene chain may be halogen. Examples of halogens include fluorine, chlorine, and bromine.

In one embodiment, the substituent on the 5-membered heterocyclic ring represented by R ¹ , R ² , R ⁵ and A can be C _1-8 alkyl substituted with halogen. Examples of C _1-8 alkyl substituted with halogen include methyl, ethyl, propyl, isopropyl, butyl and t-butyl substituted with 1-3 halogens such as fluorine, chlorine and bromine. Trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fluoroethyl are preferred.

In one embodiment, the substituent on the 5-membered heterocyclic ring represented by R ¹ , R ² and A can be C _1-8 alkoxy substituted with halogen.

Examples of C _1-8 alkoxy substituted with halogen include methoxy, ethoxy, propoxy, isopropoxy, butoxy and t- substituted with 1-3 halogen atoms, such as fluorine atom, chlorine atom or bromine atom. Contains butoxy. In one embodiment, the substituents on R ¹ , R ² and the 5-membered heterocyclic ring are trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy, and 2-fluoroethoxy.

In one embodiment, the substituent on the 5-membered heterocyclic ring represented by R ¹ , R ² , R ⁵ and A can be C _2-8 acyl. Examples of C _2-8 acyl include acetyl and propionyl.

In one embodiment, the substituent on the 5-membered heterocyclic ring represented by R ¹ , R ² and A can be C _6-10 aryl. Examples of C _6-10 aryl include phenyl.

In one embodiment, the substituent on the 5-membered heterocyclic ring represented by R ¹ , R ² and A can be a 5-membered or 6-membered heterocyclic group. Examples of 5- or 6-membered heterocyclic groups include pyridyl.

In one embodiment, R ⁵ can be C _1-8 alkyl substituted with C _1-8 alkoxy.

Examples of C _1-8 alkyl substituted with C _1-8 alkoxy include methyl substituted with methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy or hexyloxy; Includes ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

In one embodiment, R ⁵ can be cycloalkyl of a 3- to 7-membered ring. Examples of cycloalkyls with 3- to 7-membered rings include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In one embodiment, R ⁵ can be C _1-8 alkyl substituted with cycloalkyl of a 3- to 7-membered ring. Examples of C _1-8 alkyl substituted with cycloalkyl of a 3- to 7-membered ring include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Includes t-butyl, pentyl and hexyl.

In one embodiment, R ⁵ can be C _1-8 alkyl substituted with phenyl.

Examples of C _1-8 alkyl substituted with phenyl include benzyl and phenethyl.

In one embodiment, the substituent on the C _1-8 alkylene, C _2-8 alkenylene or C _2-8 alkynylene chain represented by B can be cycloalkyl of a 3- to 7-membered ring. Examples of cycloalkyls with 3- to 7-membered rings include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In some embodiments, in Formula (P), the substituents of the 5-membered heterocyclic ring represented by R ^1a , R ^2a and A ^a are C _1-8 alkyl, C _1-8 alkoxy, halogen, halogen substituted. It may be C _1-8 alkyl, C _1-8 alkoxy substituted with halogen, and C _2-8 acyl. These examples are the same as those of the substituents of the 5-membered heterocyclic ring represented by R ¹ , R ² and A in the formula (O).

In some embodiments, in Formula (Q), the substituents of the 5-membered heterocyclic ring represented by R ^1b , R ^2b and A ^b are C _1-8 alkyl, C _1-8 alkoxy, halogen, halogen substituted. It may be C _1-8 alkyl, C _1-8 alkoxy substituted with halogen, and C _2-8 acyl. These examples are the same as those of the substituents of the 5-membered heterocyclic ring represented by R ¹ , R ² and A in the formula (O).

In one embodiment, in Formula (Q), R ^3b can be C _1-8 alkyl. Examples are the same as those for R ⁵ in formula (O).

In one embodiment, R ¹ , R ^{2 in Formula (O), R 1a} , R ^2a in Formula (P), R ^1b and ^{R 2b in} Formula (Q) are each attached to a ring, such as a benzene ring. It may be 1 to 3 groups. The 2 or 3 groups may be different from each other.

Compounds having formulas (O), (P) and (Q) may exist in the form of pharmaceutically acceptable salts. Examples of salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts.

Compounds having formulas (O), (P) and (Q) may also exist in the form of optical isomers, such as enantiomers or racemates, or geometric isomers, such as cis or trans. Additionally, isomers of these compounds are provided.

In some embodiments, the compound of formula (O), (P), or (Q) is a compound shown in Table 8, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.

5.2.12. Compounds of formula (R) and (S)

In some embodiments, the compound of the invention is a compound of Formula (R): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

Each W ¹ and W ² is independently CH or N;

^{and _ _ _} _{_ _ _ _} C _1-8 alkyl, C _1-8 alkyl substituted with a phenyl group, C _2-8 acyl, or C _2-8 alkenyl;

Each R ⁴ and R ⁵ is independently hydrogen or C _1-8 alkyl;

Y is (CR ⁶ R ⁷ ) _r , where each R ⁶ and R ⁷ are independently hydrogen or C _1-8 alkyl and r is 1, 2, 3 or 4;

A is a 5 or 6-membered heterocyclic group that is thiazole, oxazole, imidazole, pyrazole, thiophene, furan, pyrrole, pyridine or pyrimidine, or is a phenyl group, wherein A is a 5 or 6-membered heterocyclic group The group or phenyl group is unsubstituted or substituted with C _1-8 alkyl, 3-7 membered cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxyl, 3-7 membered cycloalkyl group C _1-8 alkyl group, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5 or 6-membered heterocyclic group, C _6-10 aryl group and C _1-8 alkyl substituted with an aralkyl group containing a C 1-8 alkyl group, or a C _1-8 alkyl group substituted with a 5 or 6-membered heterocyclic group;

B is a bond or C _1-8 alkylene, which is unsubstituted or substituted with C _1-8 alkyl, a 3-7 membered cycloalkyl group, C _1-8 alkoxy or halogen, and the number of carbon atoms in the alkylene chain is 2 In the above cases, it may have a double bond or triple bond;

D is N or CH;

E is O or S;

Each of R ¹ and R ² is independently H, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _{1- 8} haloalkoxy, nitro, C _2-8 acyl, C _6-10 aryl, or a 5 or 6-membered heterocyclic group;

m is 0, 1, 2 or 3;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In some embodiments, the compound of the invention is a compound of Formula (S): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

A ¹ is a 5 or 6-membered heterocyclic group that is thiazole, oxazole, pyridine or pyrimidine or is a phenyl group, wherein the 5 or 6-membered heterocyclic group or phenyl group is unsubstituted or C _1-8 substituted with alkyl or C _1-8 haloalkyl;

B ¹ is C _2-4 alkylene;

Each R ¹¹ and R ¹² is independently H, C _1-8 alkyl, halogen or C _1-8 haloalkyl;

R ¹³ is C _1-8 alkyl or C _1-8 haloalkyl, optionally where N to which R ¹³ is attached is attached to the 6th position of the benzisoxazole;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In some embodiments of compounds having formula (R), W ¹ and W ² are both CH.

In some embodiments of compounds having formula (R), X is CR ⁴ R ⁵ , CH ₂ or NR ³ and R ³ is an alkyl group having 1 to 8 carbon atoms. In another embodiment, R ³ is a methyl group.

In some embodiments of compounds having Formula (R), Y is CH ₂ .

In some embodiments of compounds having Formula (R), Z is a carboxyl group.

In some embodiments of the compound having formula (R), A is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, thiazole or oxazole, which may have a substituent selected from the group consisting of an alkyl group with 1 to 8 carbon atoms and a halogen atom substituent, an aryl group with 6 to 10 carbon atoms or a 5 or 6-membered heterocyclic group; an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent, It is a pyrazole which may have a substituent selected from the group consisting of an aryl group having 6 to 10 carbon atoms or a 5 or 6-membered heterocyclic group.

In some embodiments of compounds having Formula (R), B is an ethylene chain.

In some embodiments of compounds having formula (R), D is N.

In some embodiments of compounds having formula (R), E is O.

In some embodiments of the compound having formula (R), each R ¹ and R ² are independently selected from H, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, 1 to 8 carbon atoms, An alkoxy group with 8 carbon atoms, a halogen atom, an alkyl group with 1 to 8 carbon atoms and a halogen atom substituent, or an alkoxy group with 1 to 8 carbon atoms and a halogen atom substituent.

In some embodiments of compounds having formula (R), m is 0.

In some embodiments of compounds having Formula (S), R ¹³ is an alkyl group having 1 to 8 carbon atoms. In another embodiment, R ¹³ is a methyl group.

In some embodiments of compounds having Formula (S), p is 1.

In some embodiments of compounds having formula (S), A ¹ may have a substituent selected from the group consisting of an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. thiazole, oxazole or phenyl. In another embodiment, A ¹ is thiazole, which may have as a substituent an alkyl group with 1 to 8 carbon atoms.

In some embodiments of compounds having Formula (S), B ¹ is an ethylene chain.

In some embodiments of compounds having Formula (S), R ¹¹ is an alkyl group having 1 to 8 carbon atoms, a halogen atom, or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.

In some embodiments of compounds having formula (S), R ¹² is H, an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.

Compounds having formulas (R) and (S) may also exist in the form of optical isomers, such as enantiomers or racemates, or geometric isomers, such as cis or trans. Additionally, isomers of these compounds are provided.

Compounds having formulas (R) and (S) may exist in the form of pharmaceutically acceptable salts. Examples of salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts.

In some embodiments, the compound of Formula (R) or (S) is a compound shown in Table 9, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.

5.2.13. Compounds of formula (T)

In some embodiments, the compound of the invention is a compound of Formula (T): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

B ² is C _2-4 alkylene;

R ²⁰ is C _1-8 alkyl;

Each R ²¹ and R ²² is independently H, C _1-8 alkyl, halogen or C _1-8 haloalkyl;

R ²³ is C _1-8 alkyl or C _1-8 haloalkyl, optionally where N to which R ²³ is attached is attached to the 6th position of the benzisoxazole;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

In some embodiments, R ²³ is an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. In another embodiment, R ²³ is a methyl group.

In some embodiments, n is an integer from 1 to 4. In some embodiments, n is 1.

In some embodiments, R ²⁰ is an alkyl group having 1 to 8 carbon atoms. In another embodiment, R ²⁰ is methyl.

In some embodiments, B ² is an alkylene chain having 2 to 4 carbon atoms. In another embodiment, B ² is an ethylene chain.

In some embodiments, each R ²¹ and R ²² is independently H, an alkyl group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. In another embodiment, R ²¹ is an alkyl group having 1 to 8 carbon atoms, a halogen atom, or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. In another embodiment, R ²² is H, an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.

In some embodiments, N(R ²³ )((CH ₂ ) _n -R ^x ) is attached to the 6th position of the benzisoxazole.

Compounds having formula (T) may also exist in the form of optical isomers, such as enantiomers or racemates, or geometric isomers, such as cis or trans. Additionally, isomers of these compounds are provided.

Compounds having formula (T) may exist in the form of pharmaceutically acceptable salts. Examples of salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts.

5.2.14. Compounds of formula (U)

In some embodiments, the compound of the invention is a compound of Formula (U): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

R ¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-8 alkyl, C _3-7 cycloalkyl, C2-C8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} acyl, a C _6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered a C _1-8 alkyl group with a heterocyclic substituent;

R ² is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkoxy substituent. a C _1-8 alkyl group, C _2-8 acyl, C _6-10 aryl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety;

Each of R ³ , R ⁴ , R ⁵ and R ⁶ is independently hydrogen, C _1-8 alkyl or C _1-8 haloalkyl;

X is oxygen, sulfur or NR ⁷ ; where R ⁷ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, C _2-8 acyl or C _{2- 8} alkenyl;

Y is oxygen, sulfur, NR ⁸ or a bond, where R ⁸ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 acyl or C _2-8 alkenyl;

p is 0 or 1;

A, when a bond a is present, is oxygen, CH ₂ , N-NH ₂ or N-OR ⁹ , where R ⁹ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 an acyl, C _2-8 alkenyl, or aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety; A, in the absence of bond a, is OH;

B, when p=1, is halogen, hydroxyl, nitro, amino, C _1-8 alkyl, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} a benzene ring with or without a substituent which is an acyl group, a C _6-10 aryl group, or an aralkyl group with a C _6-10 aryl moiety and a C 1 -C 8 alkylene moiety of 1-8 carbon atoms, and p When =0, it is a condensed ring that is indole, benzofuran, benzisoxazole or 1,2-benzisothiazole, wherein the condensed ring is halogen, hydroxyl, nitro, amino, C _1-8 alkyl group, C _{3 -7} cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _1-8 alkyl with 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C1 -C _1-8 alkyl with a C 8 alkoxy substituent, C _1-8 haloalkoxy group, C _2-8 acyl, C _6-10 aryl, or C _6-10 aryl moiety and C _1-8 alkylene moiety with or without an aralkyl group having a substituent;

Y is bonded to the benzene ring of B;

(C(R ³ )(R ⁴ )) _m is bonded at its 3-position to the condensed ring of B;

m is an integer from 1 to 4;

n is 0, 1, 2, 3, 4 or 5;

Y is a union when n=0;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

In some embodiments, R ¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, a 2-8 Alkenyl group having carbon atoms, alkynyl group having 2-8 carbon atoms, alkoxy group having 1-8 carbon atoms, having 1-8 carbon atoms and having 3- to 7-membered cycloalkyl substituent. alkyl group, having 1 to 8 carbon atoms and having a halogen substituent, alkyl group having 1 to 8 carbon atoms and having an alkoxy substituent having 1 to 8 carbon atoms, alkyl group having 1 to 8 carbon atoms and having a halogen substituent Alkoxy groups with substituents, acyl groups with 2-8 carbon atoms, aryl groups with 6-10 carbon atoms, 5- or 6-membered heterocyclic groups, aryl moieties with 6-10 carbon atoms, and It refers to an aralkyl group having an alkylene moiety of 1-8 carbon atoms, or an alkyl group having 1-8 carbon atoms and a 5- or 6-membered heterocyclic substituent.

In some embodiments, R ² is hydrogen, an alkyl group having 1-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, a 3- to 7-membered cycloalkyl substituent having 1-8 carbon atoms. an alkyl group having 1-8 carbon atoms and having a halogen substituent, an alkyl group having 1-8 carbon atoms and having an alkoxy substituent having 1-8 carbon atoms, an alkyl group having 2-8 carbon atoms an acyl group having, an aryl group having 6-10 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms.

In some embodiments, each R ³ , R ⁴ , R ⁵ and R ⁶ independently represents hydrogen, an alkyl group having 1-8 carbon atoms, or an alkyl group having 1-8 carbon atoms and a halogen substituent.

^In some embodiments ^, It refers to an aralkyl group having an aryl moiety of carbon atoms and an alkylene moiety of 1 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms or an alkenyl group having 2 to 8 carbon atoms.

In some embodiments, Y is oxygen, sulfur, NR ⁸ or a bond, and R ⁸ is hydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and a halogen substituent, 2- It refers to an acyl group with 8 carbon atoms or an alkenyl group with 2-8 carbon atoms.

In some embodiments, p is 0 or 1.

In some embodiments, A is oxygen, CH ₂ , N-NH ₂ or N-OR ⁹ and R ⁹ is hydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and a halogen substituent. an alkyl group having, an acyl group having 2-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, or an aryl moiety having 6-10 carbon atoms and an alkylene moiety having 1-8 carbon atoms. It represents an aralkyl group having .

In some embodiments, B, when p=1, is halogen, hydroxyl, nitro, amino, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, 2-8 carbons. alkenyl group having 2 to 8 carbon atoms, alkynyl group having 2 to 8 carbon atoms, alkoxy group having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms and having 3- to 7-membered cycloalkyl substituent. group, an alkyl group having 1 to 8 carbon atoms and having a halogen substituent, an alkyl group having 1 to 8 carbon atoms and having an alkoxy substituent having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and having a halogen substituent an alkoxy group having, an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, or an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms. represents a benzene ring with or without a substituent selected from the group consisting of aralkyl groups with has a ring, wherein the condensed ring is halogen, hydroxyl, nitro, amino, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkenyl group having 2-8 carbon atoms. , an alkynyl group having 2-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3- to 7-membered cycloalkyl substituent, 1-8 an alkyl group having 1 to 8 carbon atoms and a halogen substituent, an alkyl group having 1 to 8 carbon atoms and an alkoxy substituent having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms and a halogen substituent, 2 -consisting of an acyl group having 8 carbon atoms, an aryl group having 6-10 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms. It may or may not have a substituent selected from the group.

In some embodiments, Y is linked to the benzene ring of B.

In some embodiments, -(C(R ³ )(R ⁴ )) _m - is attached to the condensed ring of B at its 3-position.

In some embodiments, m is an integer from 1 to 4.

In some embodiments, n is an integer from 0 to 5.

In some embodiments, Y is a bond when n=0.

Compounds having formula (U) may also exist in the form of optical isomers, such as enantiomers or racemates, or geometric isomers, such as cis or trans. Additionally, isomers of these compounds are provided.

Compounds having formula (U) may exist in the form of pharmaceutically acceptable salts. Examples of salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts.

5.2.15. Compounds of formula (V)

In some embodiments, the compound of the invention is a compound of Formula (V): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

R ¹¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-8 alkyl, C _3-7 cycloalkyl, C2-C8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} acyl, a C _6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered a C _1-8 alkyl group with a heterocyclic substituent;

R ¹² is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkoxy substituent. a C _1-8 alkyl group, C _2-8 acyl, C _6-10 aryl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety;

Each of R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ is independently hydrogen, C _1-8 alkyl or C _1-8 haloalkyl;

Y ¹ is oxygen, sulfur, NR ¹⁸ or a bond, where R ¹⁸ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 acyl or C _2-8 alkenyl;

A ¹ , when a bond a is present, is oxygen, CH ₂ , N-NH ₂ or N-OR ¹⁹ , where R ¹⁹ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _{2- 8} acyl, C _2-8 alkenyl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety; A ¹ , in the absence of bond a, is OH;

Q ¹ is hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl group, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to C _1-8 alkyl with a 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _2-8 acyl, C _6-10 aryl, or an aralkyl group having a C _6-10 aryl moiety and a C _1-8 alkylene moiety;

r is 1, 2, 3 or 4;

s is 1, 2, 3, 4 or 5;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

In some embodiments, R ¹¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, a 2-8 Alkenyl group having carbon atoms, alkynyl group having 2-8 carbon atoms, alkoxy group having 1-8 carbon atoms, having 1-8 carbon atoms and having 3- to 7-membered cycloalkyl substituent. alkyl group, having 1 to 8 carbon atoms and having a halogen substituent, alkyl group having 1 to 8 carbon atoms and having an alkoxy substituent having 1 to 8 carbon atoms, alkyl group having 1 to 8 carbon atoms and having a halogen substituent Alkoxy groups with substituents, acyl groups with 2-8 carbon atoms, aryl groups with 6-10 carbon atoms, 5- or 6-membered heterocyclic groups, aryl moieties with 6-10 carbon atoms, and It refers to an aralkyl group having an alkylene moiety of 1-8 carbon atoms, or an alkyl group having 1-8 carbon atoms and a 5- or 6-membered heterocyclic substituent.

In some embodiments, R ¹² is hydrogen, an alkyl group having 1-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, a 3- to 7-membered cycloalkyl substituent having 1-8 carbon atoms. an alkyl group having 1-8 carbon atoms and having a halogen substituent, an alkyl group having 1-8 carbon atoms and having an alkoxy substituent having 1-8 carbon atoms, an alkyl group having 2-8 carbon atoms an acyl group having, an aryl group having 6-10 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms.

In some embodiments, each R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ independently represents hydrogen, an alkyl group having 1-8 carbon atoms, or an alkyl group having 1-8 carbon atoms and a halogen substituent.

In some embodiments, Y ¹ is oxygen, sulfur, NR ¹⁸ or a bond, and R ¹⁸ is hydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and a halogen substituent, 2 -Represents an acyl group with 8 carbon atoms or an alkenyl group with 2-8 carbon atoms.

In some embodiments, A ¹ is oxygen, CH ₂ , N-NH ₂ or N-OR ¹⁹ and R ¹⁹ is hydrogen, an alkyl group having 1-8 carbon atoms, a halogen substituent having 1-8 carbon atoms. an alkyl group having, an acyl group having 2-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, or an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms. It represents an aralkyl group having a T.

In some embodiments, Q ¹ is hydrogen, halogen, hydroxyl, nitro, amino, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, alkenyl having 2-8 carbon atoms. group, alkynyl group having 2-8 carbon atoms, alkoxy group having 1-8 carbon atoms, alkyl group having 1-8 carbon atoms and having 3- to 7-membered cycloalkyl substituent, 1-8 an alkyl group having 1 to 8 carbon atoms and having a halogen substituent, an alkyl group having 1 to 8 carbon atoms and having an alkoxy substituent having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms. indicates.

In some embodiments, r is an integer from 1 to 4.

In some embodiments, s is an integer from 1 to 5.

Compounds having formula (V) may also exist in the form of optical isomers, such as enantiomers or racemates, or geometric isomers, such as cis or trans. Additionally, isomers of these compounds are provided.

Compounds having formula (V) may exist in the form of pharmaceutically acceptable salts. Examples of salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts.

In some embodiments, the compound of Formula (V) is a compound shown in Table 10, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.

5.2.16. Compounds of formula (W)

In some embodiments, the compound of the invention is a compound of Formula (W): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

R ²¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-8 alkyl, C _3-7 cycloalkyl, C2-C8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} acyl, a C _6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered a C _1-8 alkyl group with a heterocyclic substituent;

R ²² is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkoxy substituent. a C _1-8 alkyl group, C _2-8 acyl, C _6-10 aryl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety;

Each R ²³ , R ²⁴ , R ²⁵ and R ²⁶ is independently hydrogen, C _1-8 alkyl or C _1-8 haloalkyl;

Y ² is oxygen, sulfur, NR ²⁸ or a bond, where R ²⁸ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 acyl or C _2-8 alkenyl;

Q ² is hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl group, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to C _1-8 alkyl with a 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _2-8 acyl, C _6-10 aryl, or an aralkyl group having a C _6-10 aryl moiety and a C _1-8 alkylene moiety;

t is 1, 2, 3 or 4;

u is 1, 2, 3, 4 or 5;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

In some embodiments, R ²¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, 2-8 Alkenyl group having carbon atoms, alkynyl group having 2-8 carbon atoms, alkoxy group having 1-8 carbon atoms, having 1-8 carbon atoms and having 3- to 7-membered cycloalkyl substituent. alkyl group, having 1 to 8 carbon atoms and having a halogen substituent, alkyl group having 1 to 8 carbon atoms and having an alkoxy substituent having 1 to 8 carbon atoms, alkyl group having 1 to 8 carbon atoms and having a halogen substituent Alkoxy groups with substituents, acyl groups with 2-8 carbon atoms, aryl groups with 6-10 carbon atoms, 5- or 6-membered heterocyclic groups, aryl moieties with 6-10 carbon atoms, and It refers to an aralkyl group having an alkylene moiety of 1-8 carbon atoms, or an alkyl group having 1-8 carbon atoms and a 5- or 6-membered heterocyclic substituent.

In some embodiments, R ²² is hydrogen, an alkyl group having 1-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, a 3- to 7-membered cycloalkyl substituent having 1-8 carbon atoms. an alkyl group having 1-8 carbon atoms and having a halogen substituent, an alkyl group having 1-8 carbon atoms and having an alkoxy substituent having 1-8 carbon atoms, an alkyl group having 2-8 carbon atoms an acyl group having, an aryl group having 6-10 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms.

In some embodiments, each R ²³ , R ²⁴ , R ²⁵ and R ²⁶ independently represents hydrogen, an alkyl group having 1-8 carbon atoms, or an alkyl group having 1-8 carbon atoms and a halogen substituent.

In some embodiments, Y ² is oxygen, sulfur, NR ²⁸ or a bond, and R ²⁸ is hydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and a halogen substituent, 2 -Represents an acyl group with 8 carbon atoms or an alkenyl group with 2-8 carbon atoms.

In some embodiments, Q ² is hydrogen, halogen, hydroxyl, nitro, amino, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, alkenyl having 2-8 carbon atoms. group, alkynyl group having 2-8 carbon atoms, alkoxy group having 1-8 carbon atoms, alkyl group having 1-8 carbon atoms and having 3- to 7-membered cycloalkyl substituent, 1-8 an alkyl group having 1 to 8 carbon atoms and having a halogen substituent, an alkyl group having 1 to 8 carbon atoms and having an alkoxy substituent having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms. indicates.

In some embodiments, t is an integer from 1 to 4.

In some embodiments, u is an integer from 1 to 5.

Compounds having formula (W) may also exist in the form of optical isomers, such as enantiomers or racemates, or geometric isomers, such as cis or trans. Additionally, isomers of these compounds are provided.

Compounds having formula (W) may exist in the form of pharmaceutically acceptable salts. Examples of salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts.

In some embodiments, the compound of Formula (W) is a compound shown in Table 11, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.

5.2.17. Compounds of formula (X)

In some embodiments, the compound of the invention is a compound of Formula (X): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;

Q ¹ is CH or N;

R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;

x is 1 or 2;

R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;

Each R ²⁰ is independently hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;

R ³ is CH ₃ or CD ₃ ;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

("화합물 VI") 또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물이다.In some embodiments, the compound

(“Compound VI”) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

5.2.18. Compounds of formula (Y)

In some embodiments, the compound of the invention is a compound of Formula (Y): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;

Q ¹ is CH or N;

R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;

x is 1 or 2;

R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;

Each R ²⁰ is independently hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;

R ³ is CH ₃ or CD ₃ ;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

5.2.19. Compounds of formula (Z)

In some embodiments, the compound of the invention is a compound of Formula (Z): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;

Q ¹ is CH or N;

R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;

x is 1 or 2;

R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;

Each R ²⁰ is independently hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;

R ³ is CH ₃ or CD ₃ ;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

5.2.20. Compounds of formula (AA)

In some embodiments, the compound of the invention is a compound of formula (AA): or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof:

here

L is (CH ₂ ) ₅ , which is unsubstituted or substituted by one methyl group;

R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;

R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;

x is 0 or 1;

R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;

R ³ is C _1-4 haloalkyl, NO ₂ , CN, halogen or C(O)O(C _1-4 alkyl);

R ²⁰ is hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

5.2.21. Additional compounds

In some embodiments, the compounds of the invention

(“Compound VII”) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

In some embodiments, the compounds of the invention

(“Compound VIII”) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

5.3. Composition of the present invention

In some embodiments, the compositions of the invention comprise (i) an effective amount of a compound of the invention and (ii) a pharmaceutically acceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of the racemate of Compound I, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. Includes. In some embodiments, the compositions of the invention comprise (i) an effective amount of a mixture of enantiomers of Compound I, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. Includes. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is a hydroxyl-having (R)-enantiomer. having an allyl carbon atom) and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is a hydroxyl-having (R)-enantiomer. having an allyl carbon atom) and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (S)-enantiomer of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is a hydroxyl-having (S)-enantiomer. having an allyl carbon atom) and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is a hydroxyl-having (S)-enantiomer. having an allyl carbon atom) and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition comprises the (R)-enantiomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or precursor thereof. Virtually no drugs. In some embodiments, the compositions of the invention comprise (i) an effective amount of a non-racemic mixture of the (R)-enantiomer and (S)-enantiomer of Compound I, or a pharmaceutically acceptable salt, solvate, or ester thereof, amide or prodrug and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the non-racemic mixture has an excess of the (R)-enantiomer relative to the (S)-enantiomer. In some embodiments, the non-racemic mixture has an excess of the (S)-enantiomer relative to the (R)-enantiomer.

In some embodiments, the compositions of the invention comprise (i) an effective amount of the (Z)-isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or Includes vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of the (Z)-isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or and a vehicle, wherein the composition is substantially free of the (E)-isomer of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of the (E)-isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or Includes vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of the (E)-isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or and a vehicle, wherein the composition is substantially free of the (Z)-isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of a non-equivalent mixture of the (Z)-isomer and (E)-isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or precursor thereof; (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the non-equivalent mixture has an excess of the (Z)-isomer relative to the (E)-isomer. In some embodiments, the non-equivalent mixture has an excess of (E)-isomer compared to the (Z)-isomer.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is the (Z)-isomer and (R)- and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is the (Z)-isomer and (R)- (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition comprises compounds ((Z)-(S)-I), ((E)- (R)-I) or ((E)-(S)-I) or pharmaceutically acceptable salts thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is the (Z)-isomer and (S)- and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is the (Z)-isomer and (S)- (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition comprises compounds ((Z)-(R)-I), ((E)- (R)-I) or ((E)-(S)-I) or pharmaceutically acceptable salts thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is the (E)-isomer and (R)- and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is the (E)-isomer and (R)- (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition comprises compounds ((E)-(S)-I), ((Z)- (R)-I) or ((Z)-(S)-I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is the (E)-isomer and (S)- and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound I is the (E)-isomer and (S)- (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition comprises compounds ((E)-(R)-I), ((Z)- (R)-I) or ((Z)-(S)-I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of the (Z)-isomer of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or Includes vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of the (Z)-isomer of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or and a vehicle, wherein the composition is substantially free of the (E)-isomer of Compound II or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of the (E)-isomer of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or Includes vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of the (E)-isomer of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or and a vehicle, wherein the composition is substantially free of the (Z)-isomer of Compound II or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of a non-equivalent mixture of the (Z)-isomer and (E)-isomer of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide or precursor thereof; (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the non-equivalent mixture has an excess of the (Z)-isomer relative to the (E)-isomer. In some embodiments, the non-equivalent mixture has an excess of (E)-isomer compared to the (Z)-isomer.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of a racemate of Compound III, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. Includes. In some embodiments, the compositions of the invention comprise (i) an effective amount of a mixture of enantiomers of Compound III, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. Includes. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is a hydroxyl-bearing (R)-enantiomer; having an allyl carbon atom) and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is a hydroxyl-bearing (R)-enantiomer; having an allyl carbon atom) and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (S)-enantiomer of Compound III or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is a hydroxyl-having (S)-enantiomer; having an allyl carbon atom) and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is a hydroxyl-having (S)-enantiomer; having an allyl carbon atom) and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition comprises the (R)-enantiomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or precursor thereof. Virtually no drugs. In some embodiments, the compositions of the invention comprise (i) an effective amount of a non-racemic mixture of the (R)-enantiomer and (S)-enantiomer of Compound III, or a pharmaceutically acceptable salt, solvate, or ester thereof, amide or prodrug and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the non-racemic mixture has an excess of the (R)-enantiomer relative to the (S)-enantiomer. In some embodiments, the non-racemic mixture has an excess of the (S)-enantiomer relative to the (R)-enantiomer.

In some embodiments, the compositions of the invention comprise (i) an effective amount of the (Z)-isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or Includes vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of the (Z)-isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or and a vehicle, wherein the composition is substantially free of the (E)-isomer of Compound III or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of the (E)-isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or Includes vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of the (E)-isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or and a vehicle, wherein the composition is substantially free of the (Z)-isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of a non-equivalent mixture of the (Z)-isomer and (E)-isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or precursor thereof; (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the non-equivalent mixture has an excess of the (Z)-isomer relative to the (E)-isomer. In some embodiments, the non-equivalent mixture has an excess of (E)-isomer compared to the (Z)-isomer.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is the (Z)-isomer and (R)- and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is the (Z)-isomer and (R)- (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition comprises compounds ((Z)-(S)-III), ((E)- (R)-III) or ((E)-(S)-III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is the (Z)-isomer and (S)- and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is the (Z)-isomer and (S)- (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition comprises compounds ((Z)-(R)-III), ((E)- (R)-III) or ((E)-(S)-III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is the (E)-isomer and (R)- and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is the (E)-isomer and (R)- (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition comprises compounds ((E)-(S)-III), ((Z)- (R)-III) or ((Z)-(S)-III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is the (E)-isomer and (S)- and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein Compound III is the (E)-isomer and (S)- (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition comprises compounds ((E)-(R)-III), ((Z)- (R)-III) or ((Z)-(S)-III) or a pharmaceutically acceptable salt thereof.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound IV or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound V or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound VI or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound VIa or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound VIb or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound VII or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.

In some embodiments, the compositions of the invention comprise (i) an effective amount of Compound VIII or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.

In some embodiments, the compositions of the invention further comprise another therapeutically active agent.

Compositions of the invention further comprising another therapeutically active agent are “combinations of the invention”. The present invention provides combinations of the present invention. Combinations of the invention may include one or more therapeutically active agents.

In some embodiments, other therapeutically active agents include lipid-lowering drugs, statins, cholesterol absorption inhibitors, antibodies to PCSK9, siRNA PCSK9, antifibrotic agents, thyroid hormones, selective thyroid receptor-β agonists, apoptosis signal-regulating kinase 1 (ASK1). ) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, integrin antagonists, or non-steroidal farnesoid X receptor (FXR) agonists.

In some embodiments, the lipid-lowering drug is gemfibrozil, fenofibrate, bezafibrate, clofibrate, cipropibrate, clinofibrate, etophylline, pyrifibrate, symfibrate, tocofibrate, or pemafibrate. . In some embodiments, the lipid-lowering drug is gemfibrozil, fenofibrate, bezafibrate, or pemafibrate.

In some embodiments, the statin is atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, dalvastatin, dihydrocompactin, or cerivastatin, or a pharmaceutically acceptable salt or solvent thereof. It's cargo. In some embodiments, the statin is atorvastatin, simvastatin, pravastatin, or rosuvastatin, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the cholesterol absorption inhibitor is ezetimibe.

In some embodiments, the antibody against PCSK9 is evolocumab, alirocumab, bococizumab, 1D05-IgG2 (Merck), RG7652 (Genentech), LY3015014 (Eli Lilly) or LGT-209 (Novartis/Cyon Therapeutics). In some embodiments, the antibody against PCSK9 is evolocumab or alirocumab.

In some embodiments, siRNA PCSK9 is an siRNA, such as inclisiran, that interferes with the production of PCSK9.

In some embodiments, the antifibrotic agent is nitazoxanide, tizoxanide or tizoxanide glucuronide, nintedanib, imatinib, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the selective thyroid receptor-β agonist is VK2809 (Viking Therapeutics), MGL-3196 (Madrigal Pharmaceuticals), MGL-3745 (Madrigal Pharmaceuticals), SKL -14763, sobetirome, BCT304 (ITL Pharma), ZYT1 (Zydus Cadila), MB-0781 (Metabasis) or eprothyrom.

In some embodiments, the ASK1 inhibitor is seronsertip.

In some embodiments, the ACC inhibitor is pyrsocostat.

In some embodiments, the integrin antagonist is an α5β1 inhibitor or a pan integrin inhibitor. In some embodiments, the integrin antagonist is IDL-2965 (Indalo Therapeutics). In some embodiments, the integrin antagonist is CLT-28643 (ClanoTech AB).

In some embodiments, the integrin antagonist is 3-(6-methoxypyridin-3-yl)-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2 -yl)propyl)-1H-indazol-1-yl)propanoic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-1H- indazol-1-yl)propanoic acid; 3-(6-methoxypyridin-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; (S)-2-(((benzyloxy)carbonyl)amino)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-2H-indazol-2-yl)propanoic acid; 3-phenyl-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propoxy)-1H-indazol-1-yl)propanoic acid ; (S)-3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-2H-indazol-2-yl)propanoic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl )-2H-indazol-2-yl)propanoic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(6-((2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl )methyl)-2H-indazol-2-yl)propanoic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(6-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl )-2H-indazol-2-yl)propanoic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(6-(2-(2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridine-3 -yl)ethyl)-2H-indazol-2-yl)propanoic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrazolo [4,3-b]pyridin-1-yl)propanoic acid; 3-(5-(2-((4,5-dihydroimidazol-2-yl)amino)ethoxy)-1H-indazol-1-yl)-3-(6-methoxypyridin-3- 1) propanoic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)-2-((2 ,4,6-trimethylphenyl)sulfonamido)propanoic acid; 2-(((benzyloxy)carbonyl)amino)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; 3-(quinoxalin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole -1-day) propanoic acid; (R)-3-(quinoxalin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; (S)-3-(quinoxalin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; 3-(3,5-dichlorophenyl)-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-propyl)-1H-indazole -1-day) propanoic acid; 3-(quinoxalin-2-yl)-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-1H-indazole- 1-day) propanoic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-1H- indazol-1-yl)propanoic acid; 3-(3,5-dichlorophenyl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-propyl)-1H-indazole -1-day) propanoic acid; 3-(quinoxalin-2-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-1H-indazole- 1-day) propanoic acid; 3-(3-(dimethylcarbamoyl)phenyl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-1H- indazol-1-yl)propanoic acid; 3-(3-(dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-1H- indazol-1-yl)propanoic acid; 3-(dibenzo[b,d]furan-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl) -1H-indazol-1-yl)propanoic acid; 3-(3-((dimethylamino)methyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-1H -indazol-1-yl)propanoic acid; 3-(quinoxalin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-1H-indazole- 1-day) propanoic acid; 3-(3,5-dichlorophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-ethyl)-1H-indazole -1-day) propanoic acid; 3-(3-(dimethylcarbamoyl)phenyl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; 3-(dibenzo[b,d]furan-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy )-1H-indazol-1-yl)propanoic acid; 6,6,6-trifluoro-3-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-1H-indazole-1 -yl)hexanoic acid; 3-(3,5-dichlorophenyl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-ethoxy)-1H-inda sol-1-yl)propanoic acid; 3-(quinoxalin-2-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole -1-day) propanoic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; 3-(3-(dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; (S)-2-(((benzyloxy)carbonyl)amino)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl )-1H-indazol-1-yl)propanoic acid; (R)-3-(3-(dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-1H-indazol-1-yl)propanoic acid; (S)-3-(3-(dimethylcarbamoyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-1H-indazol-1-yl)propanoic acid; 2-(((benzyloxy)carbonyl)amino)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; (R)-3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-1H-indazol-1-yl)propanoic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-1H-indazol-1-yl)propanoic acid; 3-(5-chloropyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H- indazol-1-yl)propanoic acid; 3-(3,5-dichlorophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-ethoxy)-1H-inda sol-1-yl)propanoic acid; 3-(3-fluoro-4-methoxyphenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; 3-cyclopropyl-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1-H-indazol-1-yl ) propanoic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)octanoic acid; 3-(2,3-dihydrobenzofuran-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy )-1H-indazol-1-yl)propanoic acid; 3-(quinolin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole- 1-day) propanoic acid (48); 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(thiophene -2-day) propanoic acid; 3-(pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole- 1-day) propanoic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(3-cyanophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole- 1-day) propanoic acid; 3-(5-fluoropyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; 3-(dibenzo[b,d]furan-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy )-1H-indazol-1-yl)propanoic acid; 3-(4,6-dimethylpyrimidin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy) -1H-indazol-1-yl)propanoic acid; 3-(2-methylbenzo[d]thiazol-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-1H-indazol-1-yl)propanoic acid; 3-(4-phenoxyphenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole- 1-day) propanoic acid; 3-(3-morpholinophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-ethoxy)-1H-inda sol-1-yl)propanoic acid; 3-(3-(1H-pyrrol-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy )-1H-indazol-1-yl)propanoic acid; 3-(3-((dimethylamino)methyl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; 3-(pyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole- 1-day) propanoic acid; 3-(3-(2-oxopyrrolidin-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl )Ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(1-propylpyrazol-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl )-2H-indazol-2-yl)propanoic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-2H-indazol-2-yl)propanoic acid; 3-(2-methylpyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; (S)-3-(6-methoxypyridin-3-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl )-2H-indazol-2-yl)propanoic acid; 3-(3-(3,5-dimethylpyrazol-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2- 1) ethoxy)-1H-indazol-1-yl) propanoic acid; 4-(4-(benzyloxy)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-inda sol-1-yl)butanoic acid; 3-(6-methoxypyridin-3-yl)-3-(3-methyl-5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-1H-indazol-1-yl)propanoic acid; 3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (3S)-3-(6-methoxypyridin-3-yl)-3-(6-(2-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)ethyl )-2H-indazol-2-yl)propanoic acid; 4-phenyl-2-((5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)methyl ) butanoic acid; 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2 -yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(pyridin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole- 1-day) propanoic acid; 2-(1-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)cyclopropyl) acetic acid; 3-(2-ethoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; 4-(4-fluorophenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole- 1-day) butanoic acid; 3-(5-methoxypyrazin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; 3-(quinoxalin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole -1-day) propanoic acid; (S)-3-(quinolin-3-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-2H- indazol-2-yl)propanoic acid; (S)-3-(6-((2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-2H-indazol-2-yl)- 3-(quinolin-3-yl)propanoic acid; (3S)-3-(quinolin-3-yl)-3-(6-(2-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)-ethyl)-2H -indazol-2-yl)propanoic acid; (S)-3-(3-(2-oxopyrrolidin-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (R)-3-(3-(2-oxopyrrolidin-1-yl)phenyl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-fluoro-6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Ethoxy)-1H-indazol-1-yl)propanoic acid; (S)-3-(quinolin-3-yl)-3-(6-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-2H- indazol-2-yl)propanoic acid; (3S)-3-(quinolin-3-yl)-3-(6-(3-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)-propyl)-2H -indazol-2-yl)propanoic acid; 3-(5-(hydroxymethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy )-1H-indazol-1-yl)propanoic acid; 3-(6-(2-hydroxy-2-methylpropoxy)-5-methylpyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1, 8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-yl)-3-(5-(2-(5,6,7,8 -tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(2-methoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; 3-(2-(2-oxopyrrolidin-1-yl)pyridin-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(isoquinolin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole -1-day) propanoic acid; 3-(pyrido[2,3-b]pyrazin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(1,8-naphthyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; 3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-yl)-3-(5-(2-(5,6,7,8 -tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (S)-2-(((benzyloxy)carbonyl)amino)-3-(5-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methoxy) -2H-indazol-2-yl)propanoic acid; (R)-3-(5-(hydroxymethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- 1) ethoxy)-1H-indazol-1-yl) propanoic acid; (S)-3-(5-(hydroxymethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2- 1) ethoxy)-1H-indazol-1-yl) propanoic acid; 3-(1,8-naphthyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; 3-(5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(1- (tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridin-5-yl)propanoic acid; 3-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-((dimethylamino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2- 1) ethoxy)-1H-indazol-1-yl) propanoic acid; (S)-3-(2-ethoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Ethoxy)-1H-indazol-1-yl)propanoic acid; (R)-3-(2-ethoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(2,3-dihydro-[1,4]deoxyno[2,3-b]pyridin-7-yl)-3-(5-(2-(5,6,7,8-tetra hydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(benzo[d]thiazol-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; 3-(2-morpholinopyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy) -1H-indazol-1-yl)propanoic acid; 3-(2-(methylamino)pyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy )-1H-indazol-1-yl)propanoic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-1H- pyrazolo[4,3-b]pyridin-1-yl)propanoic acid; 3-(6-methoxypyridazin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; 3-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthy ridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (S)-3-(2-methoxypyrimidin-5-yl)-3-(6-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl)-2H-indazol-2-yl)propanoic acid; 3-(2-(azetidin-1-yl)pyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2- 1) ethoxy)-1H-indazol-1-yl) propanoic acid; 3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthy ridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(oxazol-5-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl )Ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(7-ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)-3-(5-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(((tert-butoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-morpholinopyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; 3-(5-(methylsulfonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy )-1H-indazol-1-yl)propanoic acid; 3-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthy ridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(pyrrolidin-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2- 1) ethoxy)-1H-indazol-1-yl) propanoic acid; (R)-3-(pyrido[2,3-b]pyrazin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine- 2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (S)-3-(pyrido[2,3-b]pyrazin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine- 2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-([1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(aminomethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy) -1H-indazol-1-yl)propanoic acid; 3-([1,3]dioxolo[4,5-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(6-(1H-pyrazol-1-yl)pyridin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2 -yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine- 2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(2-methyl-2H-pyrazolo[4,3-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthy ridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthy ridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (R)-3-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1, 8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (S)-3-(5-(1,3-dioxolan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1, 8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthy ridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(1H-pyrazol-5-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2 -yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(6-morpholinopyrazin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)- 1H-indazol-1-yl)propanoic acid; 3-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine- 2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (R)-3-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8 -naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (S)-3-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8 -naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (R)-3-(2-methoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Ethoxy)-1H-indazol-1-yl)propanoic acid; (S)-3-(2-methoxypyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(6-methoxypyrazin-2-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; (R)-3-(5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1, 8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (S)-3-(5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1, 8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(morpholine-4-carbonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2- 1) ethoxy)-1H-indazol-1-yl) propanoic acid; 3-(5-(dimethylcarbamoyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-cyclopropylpyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H -indazol-1-yl)propanoic acid; 3-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine- 2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(azetidine-1-carbonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2- 1) ethoxy)-1H-indazol-1-yl) propanoic acid; 3-(5-((2-(dimethylamino)ethyl)carbamoyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (S)-3-(2-methylpyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-1H-indazol-1-yl)propanoic acid; (R)-3-(2-methylpyrimidin-5-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(1H-pyrazol-1-yl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2 -yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)hexanoic acid; 3-(5-(dimethylamino)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy) -1H-indazol-1-yl)propanoic acid; 3-cyclohexyl-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propane mountain; (R)-3-(5-(methylsulfonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- 1) ethoxy)-1H-indazol-1-yl) propanoic acid; (S)-3-(5-(methylsulfonyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- 1)-ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(((methoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (R)-3-(5-(((methoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1, 8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (S)-3-(5-(((methoxycarbonyl)amino)methyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1, 8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(methylsulfonamidomethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Ethoxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(acetamidomethyl)pyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Toxy)-1H-indazol-1-yl)propanoic acid; 3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazol-1-yl)-3-(5, 6,7,8-tetrahydro-1,8-naphthyridin-3-yl)propanoic acid; 4-((6-(2-carboxy-1-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-indazole -1-yl)ethyl)pyrazin-2-yl)amino)butanoic acid; 3-(6-methoxypyridin-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-1H- indazol-1-yl)propanoic acid; (R)-3-(5-(2-((R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-inda zol-1-yl)-3-(2-methylpyrimidin-5-yl)propanoic acid; (S)-3-(5-(2-((R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-inda zol-1-yl)-3-(2-methylpyrimidin-5-yl)propanoic acid; (R)-3-(5-(2-((S)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-inda zol-1-yl)-3-(2-methylpyrimidin-5-yl)propanoic acid; (S)-3-(5-(2-((S)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)-1H-inda zol-1-yl)-3-(2-methylpyrimidin-5-yl)propanoic acid; 3-(6-methoxypyridin-3-yl)-3-(5-(2-(1-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6- 1) ethoxy)-1H-indazol-1-yl) propanoic acid; (S)-3-(5-(2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)ethoxy)-1H-inda zol-1-yl)-3-(6-methoxypyridin-3-yl)propanoic acid; and (R)-3-(5-(2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)ethoxy)-1H- indazol-1-yl)-3-(6-methoxypyridin-3-yl)propanoic acid; or a pharmaceutically acceptable salt thereof. See US 2019/0256496, which is incorporated herein by reference in its entirety.

In some embodiments, the integrin antagonist is (S)-3-(3-(2-methoxyethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetra hydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; (S)-3-(3-((R)-2-methoxypropoxylphenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8 -naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; (S)-3-(3-((S)-2-methoxypropoxylphenyl)-4-4R)-3 -(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; (S)-3-(3-(2-methoxy-2-methylpropoxy)phenyl)-44(R)-3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; 3-(3-(((S)-1-methoxypropan-2-yl)oxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; (S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)- 3-(3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)butanoic acid; (S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)- 3-(3-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)butanoic acid; (S)-3-(3,5-bis(2-methoxyethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8 -naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; (3S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)- 3-(3-(tetrahydrofuran-3-yl)phenyl)butanoic acid; (3S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)- 3-(3-(tetrahydrofuran-3-yl)phenyl)butanoic acid; (S)-3-(3-((1-methoxy-2-methylpropan-2-yl)oxy)phenyl)-4-4R)-3-(2-(5,6,7,8-tetra hydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; (S)-3-(3-(((R)-1-methoxypropan-2-yl)oxy)phenyl)-4-((R)-3-(2-(5,6,7,8 -tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; (S)-3-(3-(2-isopropoxyethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthy Lidin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; (S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)- 3-(3-(((R)-tetrahydrofuran-2-yl)methoxy)phenyl)butanoic acid; (S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)- 3-(3-(((S)-tetrahydrofuran-2-yl)methoxy)phenyl)butanoic acid; (S)-3-(2-fluoro-5-(2-methoxyethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1 ,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; 3-(3-((1,3-dimethoxypropan-2-yl)oxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1, 8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; 3-(3-(2-fluoroethoxy)-5-(2-methoxyethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro -1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; 3-(3-(3-methoxypropoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl ) ethyl) pyrrolidin-1-yl) butanoic acid; or 3-(3-(oxetan-3-ylmethoxy)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2 -yl)ethyl)pyrrolidin-1-yl)butanoic acid; or a pharmaceutically acceptable salt thereof. See US 2019/0112306, which is incorporated herein by reference in its entirety.

In some embodiments, the integrin antagonist has the structure:

or a pharmaceutically acceptable salt thereof. See U.S. Patent No. 10,214,522, which is incorporated herein by reference in its entirety.

In some embodiments, the integrin antagonist has the structure:

or a pharmaceutically acceptable salt thereof. See US 2018/0072684, which is incorporated herein by reference in its entirety.

In some embodiments, the non-steroidal farnesoid

In some embodiments, the combination of the invention includes seronsertib, pyrsocostat, or cilofexor. In some embodiments, the combination of the invention includes seronsertib and pyrsocostat. In some embodiments, the combination of the invention includes seronsertib and cilofexor. In some embodiments, the combination of the invention includes pyrsocostat and cilofexor. In some embodiments, the combination of the invention includes seronsertib, pyrsocostat, and cilofexor.

In some embodiments, pharmaceutically acceptable carriers or vehicles include, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye-transfer inhibitors, sweeteners, or flavoring agents.

Binders or granulating agents impart cohesiveness to the tablets and ensure that the tablets remain intact after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch and pre-gelatinized starches (e.g. STARCH 1500); gelatin; Sugars such as sucrose, glucose, dextrose, molasses, and lactose; Natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwer gum, gatti gum, psyllium mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), bigum, rachis arabogalactan. , powdered tragacanth and guar gum; Cellulose, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); Microcrystalline cellulose, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixtures thereof.

Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. In some embodiments, the binder is hydroxypropylcellulose.

The binder or filler may be present from about 2% to about 49% by weight or any range within these values of the compositions of the invention provided herein. In some embodiments, the binder or filler is present in the compositions of the present invention at about 5% to about 15% by weight. In some embodiments, the binder or filler comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 8%, about 10%, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight or about 15% by weight or any range within any of these values.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dried starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart properties to some compressed tablets that enable them to disintegrate in the mouth upon chewing. These compressed tablets can be used as chewable tablets. In some embodiments, the diluent is lactose monohydrate. In some embodiments, the diluent is lactose monohydrate Fast-Flo 316 NF.

The compositions of the present invention may include a diluent, for example, any range of diluent from about 5% to about 49% by weight of the composition or any of these values. In some embodiments, the diluent is present in the compositions of the present invention at about 15% to about 30% by weight. In some embodiments, the diluent comprises about 15%, about 16%, about 17%, about 18%, about 19%, about 18%, about 20%, about 21% by weight in the compositions of the invention. %, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight or about 30% by weight or any of these. It exists in an arbitrary range of values.

Suitable disintegrants include agar; bentonite; Cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; Cation-exchange resin; alginic acid; Gums such as guar gum and bigum HV; citrus pulp; crosslinked cellulose, such as croscarmellose; crosslinked polymers such as crospovidone; cross-linked starch; calcium carbonate; Microcrystalline cellulose, such as sodium starch glycolate; Polacrylin Potassium; Starches such as corn starch, potato starch, tapioca starch and pre-gelatinized starch; clay; I know; and mixtures thereof. The amount of disintegrant in the compositions of the present invention may vary. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is Croscarmellose Sodium NF (Ac-Di-Sol).

Compositions of the present invention may include a disintegrant, for example, from about 0.5% to about 15% by weight or from about 1% to about 10% by weight of a disintegrant. In some embodiments, the compositions of the invention comprise a disintegrant in about 5%, about 6%, about 7%, about 8%, about 9%, about 8%, about 10%, by weight of the composition. About 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight or about 15% by weight, or any range within any of these values.

Suitable lubricants include calcium stearate; Magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; Hydrogenated vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; Silica or silica gel, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Camper) Nee (Cabot Co., Boston, Mass.); and mixtures thereof. In some embodiments, the lubricant is magnesium stearate.

Compositions of the present invention may include a lubricant, for example, from about 0.1 to about 5 weight percent of a lubricant. In some embodiments, the compositions of the invention comprise a lubricant in about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.8%, 1.0%, 1.1%, 1.2% by weight of the composition. , 1.3% by weight, 1.4% by weight, 1.5% by weight, 1.6% by weight, 1.7% by weight, 1.8% by weight, 1.9% by weight, 2.0% by weight, 2.1% by weight, 2.2% by weight, 2.3% by weight, 2.4% by weight, 2.5% by weight. weight percent, 2.6 weight percent, 2.7 weight percent, 2.8 weight percent, 2.9 weight percent or 3.0 weight percent or in any range within any of these values.

Suitable glidants include colloidal silicon dioxide, Cap-O-Sil® (Cabot Company, Boston, Mass.), and talc, such as asbestos-free talc.

Colorants include any approved and certified water-soluble FD&C dyes and water-insoluble FD&C dyes and color lakes suspended in alumina hydrate and mixtures thereof.

Flavoring agents include natural flavoring agents extracted from plants such as fruit, and synthetic blends of compounds that provide a pleasant taste sensation such as peppermint and methyl salicylate.

Sweeteners include sucrose, lactose, mannitol, syrup, glycerin, sucralose and artificial sweeteners such as saccharin, stevioside (stevia) and aspartame.

Suitable emulsifiers include gelatin, acacia, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80) and triethanol. Contains amine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, bigum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparabens, benzoic acid, sodium benzoate, and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

Solvents include glycerin, sorbitol, ethyl alcohol, and syrup.

Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

The compounds of the invention and compositions of the invention may be formulated for administration by a variety of means, such as orally, parenterally, by inhalation spray, topically or rectally, in preparations containing pharmaceutically acceptable carriers, adjuvants and vehicles. It can be. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, and intraarterial injection using various injection techniques. As used herein, intra-arterial and intravenous injections include administration through a catheter.

Compounds of the present invention and compositions of the present invention can be formulated according to routine procedures adapted to the desired route of administration. Accordingly, the compositions of the present invention may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending agents, stabilizing agents and/or dispersing agents. The compounds of the present invention and compositions of the present invention may be formulated as preparations suitable for implantation or injection. Thus, for example, the compositions of the invention may be formulated with suitable polymers or hydrophobic materials (e.g. as emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives (e.g. as sparingly soluble salts). You can. The compounds of the invention and compositions of the invention may be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, prior to use. Preparations suitable for each of these administration methods can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

In some embodiments, the compositions of the invention are suitable for oral administration. These compositions may include solid, semi-solid, gel matrix, or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicinal chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions. , suspensions, solutions, wafers, sprinkles, elixirs, syrups, or any combination thereof. In some embodiments, compositions of the invention suitable for oral administration are in the form of tablets or capsules. In some embodiments, the compositions of the invention are in the form of tablets. In some embodiments, the compositions of the present invention are in the form of capsules. In some embodiments, the compounds of the invention are contained in capsules.

In some embodiments, the capsule is an immediate release capsule. A non-limiting example of a capsule is coni-snap® hard gelatin capsule.

The compositions of the present invention may be in the form of compressed tablets, wet tablets, chewable lozenges, fast dissolving tablets, multiple compressed tablets or enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, protecting the active ingredient from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating that can be beneficial in covering unpleasant tastes or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings can impart the same general characteristics as sugar coatings. Multi-compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets and press-coated or dry-coated tablets.

In some embodiments, the coating is a film coating. In some embodiments, the film coating comprises Opadry White and Simethicone Emulsion 30% USP.

In some embodiments, the compounds of the invention are contained in tablets. In some embodiments, the compounds of the invention are contained in compressed tablets. In some embodiments, the compounds of the invention are contained in film-coated compressed tablets. In some embodiments, the compositions of the invention are in the form of film-coated compressed tablets.

In some embodiments, compositions of the invention are prepared by fluid bed granulation of a compound of the invention and one or more pharmaceutically acceptable carriers, vehicles, or excipients. In some embodiments, compositions of the invention prepared by a fluidized bed granulation process can provide tablet formulations with good flowability, good compressibility, rapid dissolution, good stability, and/or minimal to no cracking. In some embodiments, the fluidized bed granulation process allows for the preparation of formulations with high drug loading, such as greater than 70% or greater than 75% of the compounds of the invention.

Compositions of the present invention may be in the form of soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules, also known as dry-fill capsules (DFC), may comprise two sections, one sliding over the other to completely enclose the active ingredient. Soft elastomeric capsules (SEC) are soft spherical shells, such as gelatin shells, that have been plasticized by the addition of glycerin, sorbitol or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methyl- and propyl-parabens and sorbic acid. Liquid, semi-solid and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions are described in U.S. Pat. No. 4,328,245; 4,409,239; and 4,410,545. Capsules may also be coated, as known to those skilled in the art, to modify or sustain the dissolution of the active ingredients.

Compositions of the invention may be in liquid or semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system in which one liquid may be dispersed in the form of globules throughout another liquid, which may be oil-in-water or water-in-oil. Emulsions may contain pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers and preservatives. Suspensions may contain pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions include pharmaceutically acceptable acetals, such as di-(lower alkyl)acetals of lower alkyl aldehydes (the term "lower" refers to alkyls having 1 to 6 carbon atoms), such as acetaldehyde diethyl Acetal; and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. The elixir may be a clear, sweetened hydroalcoholic solution. The syrup may be a concentrated aqueous solution of a sugar, such as sucrose, and may contain a preservative. For liquid dosage forms, solutions, for example in polyethylene glycol, may be diluted with a pharmaceutically acceptable liquid carrier, for example water, in an amount sufficient to conveniently measure for administration.

Compositions of the invention for oral administration may also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.

Compositions of the present invention may be provided as non-effervescent or effervescent granules and powders to be reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide.

Colorants and flavoring agents may be used in all of the above dosage forms. And, flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

Compositions of the invention can be formulated as immediate or modified release dosage forms, including delayed-, extended-, pulse-, controlled, targeted- and programmed-release forms.

In some embodiments, the compositions of the present invention include a film-coating.

The compositions of the present invention may contain another active ingredient that does not impair the therapeutic or prophylactic efficacy of the composition, or may contain substances that augment or supplement the effectiveness of the composition.

Tablet dosage forms may contain a compound of the invention in powdered, crystalline or granular form and may further include a carrier or vehicle described herein, such as a binder, disintegrant, controlled-release polymer, lubricant, diluent, or colorant. You can.

In some embodiments, the compositions of the present invention may further include excipients such as diluents, disintegrants, wetting agents, binders, glidants, lubricants, or any combination thereof. In some embodiments, the tablet includes a binder. And, in some embodiments, the binder includes microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, polyvinylpyridone, hydroxypropyl cellulose, hydroxymethyl cellulose, or any combination thereof. In another embodiment, the tablet includes a disintegrant. In other embodiments, the disintegrant includes sodium croscarmellose, sodium starch glycolate, or any combination thereof. In another embodiment, the tablet includes a lubricant. And, in some embodiments, the lubricant includes magnesium stearate, stearic acid, hydrogenated oil, sodium stearyl fumarate, or any combination thereof.

In some embodiments, the compositions of the invention are in the form of a tablet comprising a binder, such as any of the binders described herein.

In some embodiments, the compositions of the invention are in the form of a tablet comprising a disintegrant, such as any of the disintegrants described herein.

In some embodiments, the compositions of the invention are in the form of a tablet comprising a lubricant, such as any of the lubricants described herein.

In some embodiments, the compositions of the invention may be in modified or controlled release dosage forms. In some embodiments, compositions of the present invention may include particles that exhibit a particular release profile. For example, a composition of the present invention may include a compound of the present invention in immediate release form, both compressed into a single tablet, and also a statin or a pharmaceutically acceptable salt, solvate, ester, amide thereof in modified release form. Or it may contain a prodrug. Other combinations and variations of release profiles can be achieved as understood by those skilled in the art. Examples of modified release dosage forms suitable for the pharmaceutical compositions of the present invention include, but are not limited to, U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.

In some embodiments, the compositions of the invention are matrix-controlled release dosage forms. In some embodiments, the release profiles of the compounds of the invention and other pharmaceutically active agents are the same or different. Suitable matrix-controlled release dosage forms are described, for example, in Takada et al. in "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz ed., Wiley, 1999].

In some embodiments, the matrix-controlled release form comprises an erodible matrix comprising water-swellable, erodible, or soluble polymers, such as synthetic polymers and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

In some embodiments, the erodible matrix in a matrix-controlled release form is chitin, chitosan, dextran, or pullulan; Agar gum, gum Arabic, gum Karaya, locust bean gum, gum tragacanth, carrageenan, gum gati, guar gum, xanthan gum or scleroglucan; starch, such as dextrin or maltodextrin; Hydrophilic colloids such as pectin; Phosphatides such as lecithin; alginate; propylene glycol alginate; gelatin; Collagen; Cellulose, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethyl cellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate ( CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methyl cellulose (HPMC), HPMCP , HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT) or ethylhydroxy ethylcellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid ester; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactide; A copolymer of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymer; poly-D-(-)-3-hydroxybutyric acid; or other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate or (trimethylaminoethyl) methacrylate chloride. coalescence; or any combination thereof.

In another embodiment, the compositions of the present invention are in a matrix-controlled modified release form comprising a non-erodible matrix. In some embodiments, the statin, a compound of the invention, is dissolved or dispersed in an inert matrix and, upon administration, is released primarily by diffusion through the inert matrix. In some embodiments, the non-erodible matrix of the matrix-controlled release form is an insoluble polymer, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene. , polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinylacetate copolymer, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, vinyl acetate, vinylidene chloride, vinyl with ethylene or propylene. Chloride copolymer, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon. , plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers or hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone or cross-linked partially hydrolyzed polyvinyl acetate; Fatty compounds such as carnauba wax, microcrystalline wax or triglycerides; or any combination thereof.

The compositions of the present invention, which are modified release dosage forms, can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.

In some embodiments, the compositions of the present invention comprise a tablet-in-capsule system, which may be a multi-functional and multi-unit system comprising multi-purpose mini-tablets within hard gelatin capsules. Mini-tablets may be rapid-release, extended-release, pulsed, delayed-onset extended-release minitablets, or any combination thereof. In some embodiments, combinations of mini-tablets containing multiple active pharmaceutical agents or combinations of mini-tablets and minibeads, each with a specific lag time of release, multiple pulsed drug delivery systems (DDS), site-specific You can have DDS, slow-fast DDS, fast/slow DDS, and zero-order DDS.

In some embodiments, the compositions of the invention are in an osmotically-controlled release dosage form.

In some embodiments, the osmotic-controlled release device comprises a 1-chamber system, a 2-chamber system, asymmetric membrane technology (AMT), extruded core system (ECS), or any combination thereof. In some embodiments, such devices include at least two components: (a) a core containing the active pharmaceutical agent(s); and (b) a semipermeable membrane having at least one delivery port, encapsulating the core. The semipermeable membrane controls the influx of water from the aqueous use environment into the core to cause drug release through the delivery port(s) by extrusion.

In some embodiments, the core of the osmotic device optionally includes an osmotic agent that creates a driving force for the transport of water from the use environment into the core of the device. One class of osmotic agents useful in the compositions of the present invention includes water-swellable hydrophilic polymers, also referred to as “osmopolymers” or “hydrogels,” which include hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide, etc. Seed (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP) ), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium cross Carmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil , gelatin, xanthan gum, and sodium starch glycolate.

Another class of osmotic agents useful in the compositions of the invention include osmogens, which can absorb water and affect the osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulfate; Sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; Organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea; and mixtures thereof.

Osmotic agents of different dissolution rates may be used, which affect how rapidly the compounds of the invention dissolve after administration. For example, amorphous sugars such as Mannogeme EZ (SPI Pharma, Lewes, DE) are included to provide faster delivery over the first few hours (e.g., about 1 to about 5 hours). Prophylactic or therapeutic efficacy can be produced quickly by providing, and the desired level of therapeutic or prophylactic effect can be maintained over an extended period of time by slowly and continuously releasing the remaining amount. In some embodiments, the compounds of the invention are released from the compositions of the invention at a rate that replaces the amount of compounds of the invention that are metabolized or excreted by the subject.

The core may also include a wide variety of other excipients and carriers, as described herein, to enhance the performance of the dosage form or to facilitate stability or processing.

Materials useful for forming semipermeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water-permeable and water-insoluble at physiologically appropriate pH or are susceptible to being rendered water-insoluble by chemical modification, such as cross-linking. Includes. Examples of suitable polymers useful for forming coatings include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl. Carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and their copolymers, starch. , dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.

The semipermeable membrane may also be a hydrophobic microporous membrane as disclosed in U.S. Pat. No. 5,798,119, where the pores are substantially filled with gas and are not wetted by an aqueous medium but are permeable to water vapor. These hydrophobic but water vapor permeable membranes are typically made of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinylidene. It consists of fluoride, polyvinyl esters and ethers, natural waxes and synthetic waxes.

Delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) may also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane on an indentation in the core. Additionally, delivery ports may be formed during the coating process, such as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.

The total amount and rate of release of the compounds of the invention released can be substantially adjusted through the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size and location of delivery ports.

In some embodiments, the pharmaceutical composition in the osmotic controlled-release dosage form may further comprise additional conventional excipients as described herein to facilitate performance or processing of the formulation.

Osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27].

In some embodiments, the pharmaceutical compositions provided herein are formulated as an asymmetric membrane technology (AMT) controlled-release dosage form comprising an asymmetric osmotic membrane coating a core containing the active ingredient(s) and other pharmaceutically acceptable excipients. See US Patent No. 5,612,059 and WO 2002/17918. AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip-coating methods.

In some embodiments, the pharmaceutical compositions provided herein are formulated as an ESC controlled-release dosage form comprising an osmotic membrane coating a core containing a compound of the invention, hydroxylethyl cellulose, and other pharmaceutically acceptable excipients.

In some embodiments, the compositions of the invention comprise a plurality of particles, granules or pellets, microparticulates, beads, microcapsules ranging in diameter from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to 1 mm. and modified release dosage forms manufactured as multiparticulate-controlled release dosage forms including microtablets.

Multiparticulate-controlled release dosage forms can provide sustained release dosage forms with improved bioavailability. Carriers suitable for sustaining the release rate of the compounds of the invention include, but are not limited to, ethyl cellulose, HPMC, HPMC-phthalate, colloidal silicon dioxide, and Eudragit-RSPM.

Compositions of the invention in pellet form may comprise 50-80% (w/w) drug and 20-50% (w/w) microcrystalline cellulose or other polymer. Suitable polymers include, but are not limited to, microcrystalline wax, pregelatinized starch, and maltose dextrin.

Beads can be manufactured in capsule and tablet dosage forms. Beads in tablet dosage form may exhibit a slower dissolution profile than microparticles in capsule form. Microparticle fillers suitable for the compositions and therapeutic or prophylactic methods of the present invention include, but are not limited to, sorbitan monooleate (Span 80), HPMC, or any combination thereof. Suitable dispersions for controlled release latexes include, for example, ethyl-acrylate and methyl-acrylate.

In some embodiments, the compositions of the invention are in the form of microcapsules and/or microtablets. In some embodiments, the microcapsules comprise extended release polymeric microcapsules containing a statin and a compound of the invention with varying solubility characteristics. Extended release polymer microcapsules can be prepared using colloidal polymer dispersions in an aqueous environment. In other embodiments, microcapsules suitable for the compositions and methods provided herein can be prepared using conventional microencapsulation techniques (Bodmeier & Wang, 1993).

Such multiparticulates can be produced by methods known to those skilled in the art, such as wet- and dry-granulation, extrusion/spheronization, roller-compression, melt-coagulation and spray-coating of seed cores. . See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989]. Excipients for this technique are commercially available and described in the United States Pharmacopoeia.

Other excipients as described herein may be blended with the compositions of the present invention to assist in processing and forming multiparticulates. The resulting particles can themselves constitute multiparticulate dosage forms or can be coated with various film-forming materials such as enteric polymers, water-swellable or water-soluble polymers. Multiparticulates can be further processed into capsules or tablets.

In another embodiment, the composition of the present invention has an instantaneous release component and at least one delayed release component and is capable of providing discontinuous release of the compound in the form of at least two continuous pulses with a time interval of 0.1 hour to 24 hours. It exists in dosage form.

In some embodiments, the compositions of the invention comprise any amount of a compound of the invention ranging from about 1 mg to about 1000 mg or between these values. In some embodiments, the compositions of the invention comprise an amount of a compound of the invention ranging from about 1 mg to about 500 mg or any amount in between these values. In some embodiments, the compositions of the invention comprise an amount of a compound of the invention ranging from about 1 mg to about 400 mg or any amount in between these values.

In other embodiments, the compositions of the invention comprise a compound of the invention in an amount molar equivalent to about 1 mg to about 1000 mg of the compound of the invention or any amount ranging between these values. In other embodiments, the compositions of the invention comprise a compound of the invention in an amount molar equivalent to about 1 mg to about 500 mg of the compound of the invention or any amount ranging between these values. In other embodiments, the compositions of the invention comprise a compound of the invention in an amount molar equivalent to about 1 mg to about 400 mg of a compound of the invention or any amount ranging between these values.

In some embodiments, the compositions of the invention include compounds of the invention in an amount from about 10% to about 99% by weight of the total weight of the composition of the invention.

5.4. Method of the invention

The present invention relates to liver disorders, dyslipidemia, dyslipoproteinemia, renal diseases, glucose metabolism disorders, lipid metabolism disorders, glucose metabolism disorders, cardiovascular diseases, vascular diseases, metabolic syndrome, complications associated with metabolic syndrome, PPAR-related disorders, bacteremia, Thrombotic disorders, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, cerebrovascular disease, disorders related to neovascularization, hypertension, cancer, inflammation, inflammatory diseases, neurodegenerative diseases, autoimmune diseases, A method for treating or preventing neoplastic disease, muscle atrophy, cholestasis, mitochondrial dysfunction, eye disease, lysosomal storage disease or erectile dysfunction, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention. A method comprising administering is provided. The present invention provides a method of treating or preventing kidney disease (e.g., acute kidney injury), comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention.

In some embodiments, the invention provides a method of treating or preventing a liver disorder, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the liver disorder involves pathological destruction, inflammation, degeneration, apoptosis, or proliferation of liver cells. In some embodiments, the liver disorder is liver fibrosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH).

In some embodiments, the invention provides alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), bilirubin, gamma-glutamyltransferase (GGT), A method of reducing abnormally high concentrations of L-lactate dehydrogenase (LD), prothrombin time (PT), creatinine or total protein, comprising administering to a subject in need thereof an effective amount of a compound or composition of the invention. Provides a method comprising administering. In some embodiments, the invention provides a method of raising abnormally low concentrations of albumin or total protein in plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. Provides a method of inclusion.

An “abnormally high concentration” of ALT in a subject's plasma or serum is greater than 56 units/liter. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of ALT in a subject's plasma or serum ranges from about 7 units/liter to about 56 units/liter.

An “abnormally high concentration” of AST in a subject's plasma or serum is greater than 48 units/liter. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of AST in a subject's plasma or serum ranges from about 8 units/liter to about 48 units/liter.

An “abnormally high concentration” of ALP in a subject's plasma or serum is greater than 129 units/liter. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of ALP in a subject's plasma or serum ranges from about 40 units/liter to about 129 units/liter.

An “abnormally low concentration” of albumin in a subject's plasma or serum is less than 3.5 g/dL. In some embodiments, the elevation is to normal concentration. In some embodiments, the normal concentration of albumin in a subject's plasma or serum ranges from about 3.5 g/dL to about 5.0 g/dL.

An “abnormally high concentration” of bilirubin in a subject's plasma or serum is greater than 1.2 mg/dL. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of bilirubin in a subject's plasma or serum ranges from about 0.1 mg/dL to about 1.2 mg/dL.

An “abnormally high concentration” of GGT in a subject's plasma or serum is greater than 61 units/liter. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of GGT in a subject's plasma or serum ranges from about 8 units/liter to about 61 units/liter.

An “abnormally high concentration” of LD in a subject's plasma or serum is greater than 222 units/liter. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of LD in the subject's plasma or serum ranges from about 122 units/liter to about 222 units/liter.

An “abnormally high concentration” of PT in a subject's plasma or serum is greater than 12.5 seconds. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of PT in the subject's plasma or serum ranges from about 9.4 seconds to about 12.5 seconds.

An “abnormally high concentration” of creatinine in a subject's plasma or serum is greater than 1.5 mg/dL, which corresponds to a glomerular filtration rate (GFR) of approximately 30 mL/min and is indicative of renal failure. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of creatinine in a subject's plasma or serum ranges from about 0.84 mg/dL to about 1.21 mg/dL (about 74.3 μmol/L to about 107 μmol/L).

An “abnormally high concentration” of total protein in a subject's plasma or serum is greater than 7.9 g/dL. An “abnormally low concentration” of total protein in a subject's plasma or serum is less than 6.3 g/dL. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the elevation is to normal concentration. In some embodiments, the normal concentration of total protein in a subject's plasma or serum ranges from about 6.3 g/dL to about 7.9 g/dL.

In some embodiments, the invention provides a method of treating or preventing NAFLD or NASH, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention.

In some embodiments, the invention provides a method of treating or preventing dyslipidemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, dyslipidemia is hyperlipidemia or abnormally low concentrations of high-density lipoprotein cholesterol (HDL-C) in the subject's plasma or serum. The term “dyslipidemia” refers to a disorder that causes or is caused by abnormal levels of circulating lipids.

In some embodiments, the invention provides methods for restoring plasma or serum concentrations of total-cholesterol, low-density lipoprotein cholesterol (LDL-C), HDL-C, non-HDL-C, or free triglycerides to normal or recommended concentrations or ratios. do. Accordingly, in cases where the level of lipids in plasma or serum is abnormally high, a compound of the present invention or a composition of the present invention can be administered to the patient to restore the level to normal. Normal levels of lipids are well known to those skilled in the art. For example, normal blood levels of total-cholesterol, low-density lipoprotein cholesterol (LDL-C), HDL-C, non-HDL-C, free triglycerides, and other parameters related to lipid metabolism are determined by the American Heart Association, the Web of National Lipids Association site and on the website of the National Heart, Lung, and Blood Institute's National Cholesterol Education Program. In some embodiments, the recommended concentration of HDL-C in plasma or serum is greater than 35 mg/dl. In some embodiments, the recommended concentration of LDL-C in plasma or serum is less than 100 mg/dl. In some embodiments, the recommended LDL-C:HDL-C ratio in plasma or serum is less than 5:1, and in some embodiments, 3.5:1. In some embodiments, the recommended concentration of free triglycerides in plasma or serum is less than 200 mg/dl.

In some embodiments, the invention provides a method of treating or preventing hyperlipidemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the hyperlipidemia is hypercholesterolemia, familial hypercholesterolemia, hypertriglyceridemia, or familial combined hyperlipidemia. In some embodiments, hyperlipidemia is caused by abnormally reduced or deficient lipoprotein lipase levels or activity in the subject's plasma or serum, or abnormally high concentrations of ketone bodies, lipoprotein(a) cholesterol (Lp(a)- C), characterized by low-density lipoprotein (LDL), very low-density lipoprotein cholesterol (VLDL-C) or non-esterified fatty acids (NEFA). In some embodiments, reduced or deficient lipoprotein lipase levels or activity are the result of a lipoprotein lipase mutation. In some embodiments, reduced or deficient lipoprotein lipase levels or activity are the result of a mutation within the gene encoding lipoprotein lipase.

Non-limiting examples of ketone bodies include acetoacetate, beta-hydroxybutyrate, and acetone. An “abnormally high concentration” of ketone bodies in a subject's plasma or serum is greater than 1 mg/dL (<0.1 mmol/L). In some embodiments, the invention provides a method of reducing abnormally high concentrations of ketone bodies in the plasma or serum of a subject, wherein the concentration is at least 1 mg/dL. In some embodiments, the decrease is a decrease to a normal level. In some embodiments, a normal level is less than 1 mg/dL (<0.1 mmol/L). Devkota, B. P. et al. Medscape emedicine, updated Oct. 30, 2015].

An “abnormally high concentration” of VLDL-C in a subject's plasma or serum is greater than 30 mg/dL (1.7 mmol/L). In some embodiments, the invention provides a method of reducing VLDL-C concentration in plasma or serum of a subject, wherein the VLDL-C concentration is greater than 30 mg/dL. In some embodiments, the decrease is a decrease to a normal level. In some embodiments, normal levels range from 2 mg/dL to 30 mg/dL (0.1 to 1.7 mmol/L).

An “abnormally high concentration” of NEFA is greater than 0.9 mM in the plasma or serum of a non-fasting subject. The “abnormally high concentration” of NEFA in the plasma or serum of a fasting subject is greater than 1.8 mM in the fasting state. The “abnormally high concentration” of NEFA in a subject's plasma or serum during a 15-hour fast is greater than 1.1 nM. The “abnormally high concentration” of NEFA in a subject's plasma or serum during a 20-hour fast is greater than 1.3 mM. The “abnormally high concentration” of NEFA in a subject's plasma or serum during a 15-hour fast is greater than 1.1 nM. The “abnormally high concentration” of NEFA in a subject's plasma or serum during a 24-hour fast is greater than 1.8 mM. In some embodiments, the invention provides a method of reducing the concentration of NEFA in plasma or serum of a subject, wherein the concentration of NEFA is greater than 0.9mM, in some embodiments greater than 1.1mM, in some embodiments greater than 1.5mM, and in some embodiments Embodiments provide methods of greater than 1.8 mM. In some embodiments, the decrease is a decrease to a normal level. In some embodiments, normal levels are 1.8 mM or less, in some embodiments are 1.5 mM or less, in some embodiments are 1.1 mM or less, and in some embodiments are 0.9 mM or less. Horowitz, G. L. et al. See Medscape emedicine, updated July 25, 2019.

In some embodiments, the invention provides a method of treating or preventing dyslipoproteinemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, dyslipoproteinemia is an abnormally high concentration of LDL, apolipoprotein (a), or VLDL in the subject's plasma or serum, or an abnormally low concentration of high-density lipoprotein (HDL) or lipoprotein lipase in the subject's plasma or serum. Features: In some embodiments, abnormally low concentrations of lipoprotein lipase are associated with lipoprotein lipase mutations, hypoalphalipoproteinemia, lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, lipoprotein abnormalities associated with Alzheimer's disease, or familial combined hyperlipidemia. The term “dyslipoproteinemia” refers to a disorder that causes or is caused by abnormal concentrations of circulating lipoproteins in the plasma or serum of a subject. In cases where the concentration of lipoproteins in plasma or serum is too high, a compound of the present invention or a composition of the present invention can be administered to the subject to restore the normal concentration of lipoproteins. Conversely, if the concentration of lipoproteins in plasma or serum is too low, the compound of the present invention or the composition of the present invention can be administered to the subject to restore the concentration to normal. Normal concentrations of lipoproteins are reported in medical journals known to those skilled in the art.

In some embodiments, the invention provides a method of treating or preventing renal disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the renal disease is a glomerular disease, tubular disease, tubulointerstitial disease, acute or rapidly progressive renal failure, chronic renal failure, nephrolithiasis, or tumor. In some embodiments, the renal disease is hypertension, nephrosclerosis, microangiopathic hemolytic anemia, atherosclerotic renal disease, diffuse cortical necrosis, or neuroembolism.

In some embodiments, the glomerular disease is acute glomerulonephritis, chronic glomerulonephritis, rapidly progressive glomerulonephritis, nephrotic syndrome, focal proliferative glomerulonephritis, glomerular lesion associated with a systemic disease, Goodpasture syndrome, multiple myeloma, diabetes, neoplasm, Sickle cell disease, or chronic inflammatory disease. In some embodiments, the glomerular lesion associated with a systemic disease is systemic lupus erythematosus.

In some embodiments, the tubular disease is acute tubular necrosis, acute renal failure, polycystic kidney disease, medullary cavernous kidney, medullary cystic disease, nephrogenic diabetes, or renal tubular acidosis.

In some embodiments, the tubulointerstitial disease is pyelonephritis, drug- or toxin-induced tubulointerstitial nephritis, hypercalcemic nephropathy, or hypokalemic nephropathy.

In some embodiments, the tumor is renal cell carcinoma or nephroblastoma.

In some embodiments, the renal disease is hypertension. In some embodiments, the hypertension is essential hypertension, hyperpiesa, hyperpiersis, malignant hypertension, secondary hypertension, or white coat hypertension.

In some embodiments, the renal disease is kidney disease.

In some embodiments, the invention provides a method of treating or preventing a disorder of glucose metabolism, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. The term “disorder of glucose metabolism” refers to a disorder that causes or is caused by abnormal glucose storage and/or utilization. If indicators of glucose metabolism (i.e., insulin, glucose, or glycated hemoglobin in the subject's plasma or serum) are too high, a compound of the invention or a composition of the invention may be administered to the subject to restore normal levels. Normal indicators of glucose metabolism are reported in medical journals known to those skilled in the art. See US 7,709,682 B2.

In some embodiments, the invention provides a method for reducing abnormally high concentrations of glucose in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. provides. The “abnormally high concentration” of glucose in the plasma or serum of a subject in the fasting state (10-16 hours without eating) is greater than 5.6 mmol/L (100 mg/dL). In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of glucose is less than 5.6 mmol/L in the fasting state. In some embodiments, a fasting glucose plasma or serum concentration ranging from 5.6 mmol/L to 6 mmol/L (100-109 mg/dL) may be indicative of pre-diabetes. In some embodiments, a fasting glucose plasma or serum concentration ranging from 6.1 mmol/L to 6.9 mmol/L (110-125 mg/dL) may be indicative of diabetes. In some embodiments, a fasting glucose plasma or serum concentration of 7 mmol/L (126 mg/dL) or greater is indicative of diabetes.

In some embodiments, the abnormally high concentration of glucose in the subject's plasma or serum is measured with a glucose tolerance test (GTT).

An “abnormally high concentration” of glucose in a subject's plasma or serum in a 1-hour GTT is greater than 10 mmol/L (180 mg/dL). In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration at a 1-hour GTT is less than 10 mmol/L (180 mg/dL).

The “abnormally high concentration” of glucose in the subject's plasma or serum at a 2-hour GTT using a 75 g intake is greater than 7.8 mmol/L (140 mg/dL), which is indicative of hyperglycemia. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration in a 2-hour GTT using a 75 g intake is less than 7.8 mmol/L (140 mg/dL). In some embodiments, a glucose concentration of 7.8 mmol/L (140 mg/dL) to 11.1 mmol/L (200 mg/dL) in the subject's plasma or serum at the 2-hour GTT using a 75 g intake is indicated for impaired glucose tolerance. represents. In some embodiments, a glucose concentration greater than 11.1 mmol/L in a 2-hour GTT using a 75 g intake is indicative of diabetes.

In some embodiments, the invention provides a method of increasing abnormally low glucose metabolism in a subject, wherein the subject's glucose concentration in the subject's plasma or serum is greater than 7.8 mmol/L (140 mg/dL) in a 2-hour GTT. Provides a method. In some embodiments, the invention provides a method of treating or preventing a disorder of glucose metabolism in a subject, wherein the subject's glucose concentration in the subject's plasma or serum is between 7.8 mmol/L (140 mg/dL) and 11.1 mmol/L (140 mg/dL) in a 2-hour GTT. Methods in the range of mmol/L (200 mg/dL) are provided. In some embodiments, the invention provides a method of treating or preventing a disorder of glucose metabolism in a subject, wherein the subject's glucose concentration in the subject's plasma or serum is greater than 11.1 mmol/L (200 mg/dL) in a 2-hour GTT. Provides a method.

In some embodiments, the invention provides a method of reducing abnormally high levels of HbA _1c in plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. Provides a method. An “abnormally high level” of hemoglobin A1c (HbA _1c ) in a subject's plasma or serum is greater than or equal to 6.5% (expressed as % NGSP units). In some embodiments, the decrease is a decrease to a normal level. In some embodiments, normal levels of HbA _1c range from about 4% to about 5.9%. In some embodiments, the invention provides a method of reducing HbA _1c levels in plasma or serum of a subject, wherein the HbA _1c level is greater than 7%, greater than 8%, or greater than 9%. Horowitz, GL et al. See Medscape emedicine, updated July 25, 2019.

In some embodiments, the invention provides a method of increasing abnormally low glucose metabolism in a subject, wherein the subject's HbA _1c level in the subject's plasma or serum is at least 6.5% and the subject's fasting glucose concentration is at least 126 mg/dL ( ≥ 7.0 mmol/L). Selvin, E. et al. Ann Intern Med. Published online June 18, 2018].

In some embodiments, the invention provides a method of treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has an HbA _1c of at least 6.5%. In some embodiments, the invention provides a method of treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has an HbA _1c of at least 6.5% and a fasting glucose concentration of at least 126 mg/dL (7.0 mmol/L) in the subject's plasma or serum. Provides a method of having .

In some embodiments, the invention provides a method of reducing abnormally high concentrations of glucose in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound or composition of the invention, Provided herein is a method wherein the subject is pregnant. An “abnormally high concentration” of glucose in the plasma or serum of a fasting pregnant subject is greater than 5.3 mmol/L (95 mg/dL).

In some embodiments, the present invention provides a method of reducing abnormally high concentrations of glucose in the plasma or serum of a subject, comprising administering to a subject in need thereof (i) a glucose solution as part of a two-stage gestational diabetes trial, and (ii) Methods are provided comprising administering an effective amount of a compound or composition of the invention. In the Phase 2 Gestational Diabetes Trial, the "abnormally high concentration" of glucose in a subject's plasma or serum one hour after drinking a glucose solution is greater than 10 mmol/L (180 mg/dL). In a two-step procedure, the first step is a 50 g glucose dose. If blood glucose levels above 7.8 mmol/L (140 mg/dL) are induced, a 100 g glucose dose follows. The "abnormally high concentration" of glucose in a subject's plasma or serum two hours after drinking a glucose solution in the Phase 2 Gestational Diabetes Trial is greater than 8.6 mmol/L (155 mg/dL). The "abnormally high concentration" of glucose in a subject's plasma or serum three hours after drinking a glucose solution in the Phase 2 Gestational Diabetes Trial is greater than 7.8 mmol/L (140 mg/dL).

In some embodiments, the invention provides a method of treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has a disorder of glucose tolerance. In some embodiments, the invention provides a method of treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has diabetes. In some embodiments, the invention provides a method of treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has been identified as having undiagnosed diabetes. In some embodiments, the invention provides a method of treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has gestational diabetes.

In some embodiments, the invention provides a method for reducing abnormally high concentrations of insulin in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound or composition of the invention. provides. An “abnormally high concentration” of insulin in the plasma or serum of a fasting subject is greater than 25 mIU/L (>174 pmol/L). In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of insulin in the plasma or serum of a subject in a fasting state is less than 25 mIU/L (<174 pmol/L). Buppajarntham, S. et al. Medscape emedicine, updated Jan. 2, 2019].

In some embodiments, the invention provides a method for reducing abnormally high concentrations of insulin in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound or composition of the invention. provides.

In some embodiments, the method further comprises administering glucose to the subject. In some embodiments, the method does not include administering glucose to the subject. In some embodiments, the subject is fasting.

In some embodiments, the subject has an abnormal concentration of insulin in the subject's plasma or blood glucose 30 minutes after glucose administration. The “abnormally high concentration” of insulin in a subject's plasma or serum 30 minutes after glucose administration is greater than 230 mIU/L (>1597 pmol/L). In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of insulin in a subject's plasma or serum 30 minutes after glucose administration ranges from about 30 mIU/L to about 230 mIU/L (208-1597 pmol/L). See [Buppajarntham, 2019].

In some embodiments, the subject has an abnormal concentration of insulin in the subject's plasma or serum 1 hour after glucose administration. The “abnormally high concentration” of insulin in a subject's plasma or serum one hour after glucose administration is greater than 276 mIU/L (>1917 pmol/L). In some embodiments, the invention provides a method for reducing abnormally high concentrations of insulin in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound or composition of the invention. provides. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of insulin in a subject's plasma or serum one hour after glucose administration ranges from about 18 mIU/L to about 276 mIU/L (125-1917 pmol/L). See [Buppajarntham, 2019].

In some embodiments, the subject has an abnormal concentration of insulin in the subject's plasma or blood glucose 2 hours after glucose administration. The “abnormally high concentration” of insulin in a subject's plasma or serum 2 hours after glucose administration is greater than 166 mIU/L (>1153 pmol/L). In some embodiments, the invention provides a method for reducing abnormally high concentrations of insulin in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound or composition of the invention. provides. In some embodiments, the normal concentration of insulin in a subject's plasma or serum two hours after glucose administration ranges from about 16 mIU/L to about 166 mIU/L (111-1153 pmol/L). See [Buppajarntham, 2019].

In some embodiments, the subject has an abnormal concentration of insulin in the subject's plasma or blood glucose 3 hours after glucose administration. An “abnormally high concentration” of insulin in a subject's plasma or serum 3 hours after glucose administration is greater than 25 mIU/L (>174 pmol/L). In some embodiments, the invention provides a method for reducing abnormally high concentrations of insulin in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound or composition of the invention. provides. In some embodiments, the normal concentration of insulin in the subject's plasma or serum at least 3 hours after glucose administration is less than 25 mIU/L (<174 pmol/L). See [Buppajarntham, 2019].

In some embodiments, the invention provides a method of treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has an insulin concentration in the subject's plasma or serum greater than 25 mIU/L in the fasting state or 3 hours after glucose administration. method is provided. See [Buppajarntham, 2019].

In some embodiments, the disorder of glucose metabolism is a disorder of glucose tolerance; insulin resistance; Insulin resistance-related breast, colon, or prostate cancer; diabetes; pancreatitis; High blood pressure; polycystic ovarian disease; or abnormally high concentrations of blood insulin or glucose in the subject's plasma or serum. In some embodiments, the diabetes is non-insulin dependent diabetes mellitus (NIDDM), insulin dependent diabetes mellitus (IDDM), gestational diabetes mellitus (GDM), or maturity-onset diabetes of the young (MODY).

In some embodiments, the invention provides a method of treating or preventing metabolic syndrome (Syndrome X), comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the invention provides a method of treating or preventing symptoms of metabolic syndrome (Syndrome X), comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. do. In some embodiments, the condition is impaired glucose tolerance, hypertension, dyslipidemia, or dyslipoproteinemia.

In some embodiments, the invention provides a method of treating or preventing a vascular disease or cardiovascular disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. The term “cardiovascular disease” refers to diseases of the heart or circulatory system. In some embodiments, the vascular disease or cardiovascular disease is peripheral vascular disease, coronary heart disease, stroke, restenosis, arteriosclerosis, ischemia, endothelial dysfunction, ischemia-reperfusion injury, myocardial infarction, or cerebral infarction.

In some embodiments, the invention provides a method of treating or preventing a PPAR-related disorder, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the PPAR-associated disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, breast cancer, colon cancer, or prostate cancer. In some embodiments, the PPAR-related disorder is a vascular disease, a muscle disease, a demyelinating disease, a muscle structural disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a mitochondrial dysfunction, a beta oxidation disease, or a metabolic disease. In some embodiments, the PPAR-related disorder is characterized by an abnormally low concentration of HDL, an abnormally low concentration of apolipoprotein A-I (apo A-I), an abnormally high concentration of VLDL-C, an abnormally high concentration of HDL in the subject's plasma or serum. low-density lipoprotein cholesterol (LDL-C), abnormally high levels of triglycerides, abnormally high levels of apolipoprotein B (apo B), abnormally high levels of apolipoprotein C-III (apo C-III), or abnormally reduced Ratio of post-heparin hepatic lipase versus lipoprotein lipase activity. In some embodiments, the PPAR-associated disorder is an abnormally high concentration of HDL or an abnormally low concentration of apo A-I in the subject's lymphatic or cerebral fluid.

In some embodiments, the PPAR-related disorder is an abnormally low concentration of lipoprotein lipase activity in post-heparin plasma (plasma of a subject following an intravenous injection of heparin) in a subject. In some embodiments, the invention provides a method of raising abnormally low concentrations of lipoprotein lipase activity in post-heparin plasma comprising administering to a subject in need thereof an effective amount of a compound or composition of the invention. Provides a method. The “abnormally low concentration” of lipoprotein lipase activity in post-heparinized plasma is less than 30 U/L. In some embodiments, the elevation is to normal concentration. In some embodiments, normal concentrations range from about 30 U/L to about 153 U/L (Nakajima et al. Clin Chim Acta. 2018 Dec;487:54-59).

In some embodiments, the invention provides a method of treating or preventing a PPAR-related disorder in a subject, wherein the subject has lipoprotein lipase activity in post-heparin plasma of less than 30 U/L.

In some embodiments, the subject is a male subject. An “abnormally high concentration” of HDL for a male subject is greater than 75 mg/dL.

In some embodiments, the subject is a female subject. An “abnormally high concentration” of HDL for a female subject is greater than 90 mg/dL.

In some embodiments, the invention provides a method for reducing abnormally high concentrations of HDL in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. provides. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration for a male subject is less than 75 mg/dL. In some embodiments, the normal concentration for a female subject is less than 90 mg/dL. In some embodiments, the invention provides a method of treating or preventing a PPAR-related disorder in a male subject, wherein the subject has an HDL concentration in the subject's plasma or serum greater than 75 mg/dL. In some embodiments, the invention provides a method of treating or preventing a PPAR-related disorder in a female subject, wherein the subject has an HDL concentration in the subject's plasma or serum greater than 90 mg/dL. Hassan, M. et al. Glob Cardiol Sci Pract. 2016 Dec 30; 2016(4): e201634].

In some embodiments, the muscle disease is a muscular dystrophy disease. In some embodiments, the muscular dystrophy disease is Duchenne muscular dystrophy, Becker muscular dystrophy, girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, opharyngeal muscular dystrophy, distal muscular dystrophy, or Emery-Dreyfus. It is muscular dystrophy.

In some embodiments, the demyelinating disease is multiple sclerosis, Charcot-Marie-Tooth disease, Pelisseus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, or Guillain-Barré syndrome.

In some embodiments, the muscle structure disorder is Besrem myopathy, centronuclear disease, congenital fibrous imbalance, distal muscular dystrophy (MD), Duchenne & Becker MD, Emery-Dreyfus MD, facioscapulohumeral MD, hyaline body myopathy, Zone MD, muscle sodium channel disorder, myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline body disease, opharyngeal MD, or stress urinary incontinence.

In some embodiments, the neuronal activation disorder is amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve lesion, peripheral neuropathy, spinal muscular atrophy, maturity. Ulnar nerve paralysis or toxic neuromuscular disorder.

In some embodiments, the muscle fatigue disorder is chronic fatigue syndrome, diabetes (type I or type II), glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS (mitochondrial encephalopathy, lactic acidosis) and apoplexy-like episode) syndrome, mucopolysaccharidosis, Pompe disease, or thyrotoxic myopathy.

In some embodiments, the muscle mass disorder is cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, critical illness myopathy, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, or systemic lupus erythematosus.

In some embodiments, the mitochondrial disease is Alper's disease, chronic progressive extraocular ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), Leber hereditary optic neuropathy (LHON), MELAS, myoclonic epilepsy, and heterogeneous-red myofiber disease (MERRF). ), neurogenic muscle weakness (NARP), ataxia, retinitis pigmentosa, Pearson syndrome, mitochondrial dysfunction or loss of mitochondrial function (e.g., due to drugs that affect mitochondrial function).

In some embodiments, the mitochondrial dysfunction is drug-induced mitochondrial dysfunction.

In some embodiments, the beta oxidation disease is systemic carnitine transporter, carnitine palmitoyltransferase (CPT) II deficiency, very long chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, medium chain acyl-CoA dehydrogenase deficiency, CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, or riboflavin-responsive disorder of β-oxidation (RR-MADD).

In some embodiments, the metabolic disease is hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia, HLD non-cholesterolemia, VLDL hyperproteinemia, dyslipoproteinemia, apolipoprotein A-I hypoproteinemia. Hyperglycemia, atherosclerosis, arteriosclerosis disease, cardiovascular disease, cerebrovascular disease, peripheral circulation disease, metabolic syndrome, syndrome X, obesity, diabetes, type I diabetes, type II diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance. , hyperinsulinism, diabetic complications, cardiac dysfunction, myocardial infarction, cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), thrombosis, Alzheimer's disease, neurodegenerative disease, dehydration Primary disease, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, trichiasis, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease or pancreatitis.

In some embodiments, the invention provides a method of treating or preventing bacteremia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the bacteremia is septic shock.

In some embodiments, the invention provides a method of treating or preventing a thrombotic disorder, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the thrombotic disorder is a high concentration of fibrinogen in the subject's plasma or serum or promotion of fibrinolysis.

In some embodiments, the invention provides a method of treating or preventing obesity, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the obesity is abdominal obesity. In some embodiments, the method of treating or preventing obesity further comprises promoting weight loss in the subject.

In some embodiments, the invention provides a method of treating or preventing diabetic nephropathy, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the method of treating or preventing diabetic nephropathy further comprises treating or preventing kidney disease that occurs as a result of diabetes. In some embodiments, the invention provides a method of treating or preventing diabetes, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention.

In some embodiments, the invention provides a method of treating or preventing diabetic retinopathy, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, methods of treating or preventing diabetic retinopathy are directed to treating or preventing complications of diabetes that can lead to or cause blindness.

In some embodiments, the invention provides a method of treating or preventing cerebrovascular disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the cerebrovascular disease is cerebral ischemia.

In some embodiments, the invention provides a method of treating or preventing a disorder associated with angiogenesis, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the disorder associated with neovascularization is retinopathy or diabetes.

In some embodiments, the invention provides a method of treating or preventing hypertension, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, methods of treating or preventing high blood pressure involve treating or preventing blood flow that occurs through the subject's blood vessels at greater than normal forces.

In some embodiments, the invention provides a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the cancer is human sarcoma or human carcinoma. In some embodiments, the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, hemangiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelioma, synovium, mesothelioma, Ewing tumor, leiomyosarcoma, Rhabdomyosarcoma, colon carcinoma, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, oral cancer, nasal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary adenocarcinoma, cyst. Adenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder Carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma, leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute promyelocytic leukemia, acute monocytic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, Acute undifferentiated leukemia, chronic myelocytic leukemia, hairy cell leukemia, lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, myelocytic leukemia, polycythemia vera, multiple myeloma, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, Waldenstrom Macroglobulinemia or heavy chain disease.

In some embodiments, the leukemia is acute or chronic lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, lymphocytic leukemia, or myeloid leukemia. In some embodiments, the myelocytic leukemia is acute and myeloblastic, promyelocytic, myelomonocytic, monocytic, or erythroleukemia.

In some embodiments, the lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.

In some embodiments, the invention provides a method of treating or preventing an inflammatory disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the inflammatory disease is multiple sclerosis, chronic inflammatory disorder of the joints, arthritis, respiratory distress syndrome, inflammatory bowel disease, inflammatory lung disorder, inflammatory disorder, inflammatory disorder of the gums, tuberculosis, leprosy, inflammatory disease of the kidney, skin. Inflammatory disorders, inflammatory diseases of the central nervous system, systemic lupus erythematosus (SLE), or inflammatory diseases of the heart.

In some embodiments, the arthritis is rheumatoid arthritis or osteoarthritis.

In some embodiments, the inflammatory bowel disease is ileitis, ulcerative colitis, or Crohn's disease.

In some embodiments, the inflammatory lung disorder is asthma or chronic obstructive airway disease.

In some embodiments, the inflammatory disorder of the eye is corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis, or endophthalmitis.

In some embodiments, the inflammatory disorder of the gums is periodontitis or gingivitis.

In some embodiments, the inflammatory disease of the kidney is glomerulonephritis or nephropathy.

In some embodiments, the inflammatory disorder of the skin is acne, sclerodermatitis, psoriasis, eczema, photoaging, or wrinkles.

In some embodiments, the inflammatory disease of the central nervous system is AIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer's disease, encephalomyelitis, or viral or autoimmune encephalitis.

In some embodiments, the inflammatory disease of the heart is cardiomyopathy.

In some embodiments, the invention provides a method of treating or preventing a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the neurodegenerative disease is Alzheimer's disease or Huntington's disease.

In some embodiments, the invention provides a method of treating or preventing an autoimmune disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the autoimmune disease is immune-complex vasculitis, systemic lupus, or erythema.

In some embodiments, the invention provides a method of treating or preventing a neoplastic disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the neoplastic disease is carcinogenesis.

In some embodiments, the invention provides a method of treating or preventing cholestasis, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention.

In some embodiments, the cholestasis is an intrahepatic cholestatic disease or an extrahepatic cholestatic disease. In some embodiments, the intrahepatic cholestatic disease is primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), progressive familial intrahepatic cholestasis (PFIC), or Alagille syndrome (AS). In some embodiments, the method of treating or preventing intrahepatic cholestatic disease includes preventing or reducing the risk of developing intrahepatic cholestatic disease, e.g., in a patient who has not yet experienced or shown symptoms of intrahepatic cholestatic disease. Prevent clinical symptoms of intrahepatic cholestatic disease from developing in subjects who may be susceptible to the disease (i.e., prevent). In some embodiments, the method of treating or preventing intrahepatic cholestatic disease includes inhibiting intrahepatic cholestatic disease, e.g., arresting or reducing the occurrence of intrahepatic cholestatic disease or one or more of its clinical symptoms; Including reducing the frequency, duration or severity.

In some embodiments, the invention provides a method of treating or preventing an eye disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the ocular condition is dry eye, meibomian gland dysfunction, keratoconjunctival epithelial disorder, corneal epithelial disorder, or corneal ulcer. In some embodiments, the ocular disease is dry eye syndrome, corneal ulcer, superficial punctate keratitis, corneal epithelial erosion, ocular allergic disease associated with a corneal lesion, such as vernal conjunctivitis or atopic keratoconjunctivitis. In some embodiments, the eye condition is hyperevaporative dry eye. In some embodiments, the ocular condition is damage to corneal epithelial cells. In some embodiments, damage to corneal epithelial cells is associated with an endogenous disease, such as Sjögren's syndrome, Stevens-Johnson syndrome, keratoconjunctivitis sicca (dry eye), etc. In some embodiments, damage to the corneal epithelial cells is associated with an extrinsic disease, such as post-surgery, drug use, trauma, corneal ulcers, meibomianitis, extrinsic disease during contact lens wear, etc. In some embodiments, damage to corneal epithelial cells is associated with ocular allergic diseases involving corneal lesions, such as vernal conjunctivitis, atopic keratoconjunctivitis, etc. In some embodiments, the ocular disease is superficial punctate keratitis and corneal epithelial erosion.

In some embodiments, the method of treating or preventing an ocular disease promotes proliferation of meibomian gland epithelial cells and corneal epithelial cells.

In some embodiments, the invention provides a method of treating or preventing a lysosomal storage disorder, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the lysosomal storage disorder is neuronal ceroid lipofuscinosis, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal Degeneration (CBD), Dementia with Lewy bodies (DLB), disorders of the autophagy pathway, Tay-Sachs disease, Fabry disease, Niemann-Pick disease, Gaucher disease, Hunter syndrome, alpha-mannoside accumulation, aspartylglucosaminuria, cholesterol These include lyl ester storage disease, chronic hexosaminidase A deficiency, cystine accumulation disease, Danon disease, Faber disease, fucoside accumulation disease, galactosialic acidosis, or Batten disease.

In some embodiments, the invention provides a method of treating or preventing kidney disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, the kidney disease is renal ischemia reperfusion injury. In some embodiments, the kidney disease is acute kidney injury. In some embodiments, methods of treating or preventing kidney disease lower a subject's risk for acute kidney injury following coronary artery bypass grafting, transplantation, and/or valve surgery.

In some embodiments, the subject has AKI. In other embodiments, the subject is at risk for AKI.

AKI can be characterized by a rapid decline in kidney function that can be caused by a number of factors, such as reduced renal blood flow, glomerulonephritis, use of nephrotoxic antibiotics, use of anticancer drugs, and sepsis.

Acute kidney injury can be diagnosed, for example, when a subject exhibits changes in one or more of serum creatinine levels, glomerular filtration rate, or urine output. For example, AKI can be characterized by a serum creatinine level that is at least 1.5 times baseline, where baseline refers to the subject's serum creatinine level up to the previous 7 days. For example, a patient with AKI may have a serum creatinine level between 1.5 and 1.9 times baseline, between 2.0 and 2.9 times baseline, or at least 3.0 times baseline. Alternatively, AKI may be characterized by an increase in serum creatinine of at least 0.3 mg/dL or at least 0.4 mg/dL, e.g., an increase in serum creatinine of at least 0.3 mg/dL within a 48 hour period.

Alternatively, AKI may be characterized by a glomerular filtration rate of less than 90 mL/min/1.73 m ² . For example, a subject with AKI may have 60-89 mL/min/1.73 m ² , 30-59 mL/min/1.73 m ² , 15-29 mL/min/1.73 m ² or 15 mL/min/1.73 m ² May have a glomerular filtration rate of less than 10%.

Alternatively, AKI is characterized by the subject having a urine output of less than 0.5 mL/Kg over 6 hours, less than 0.5 mL/Kg over 12 hours, less than 0.3 mL/Kg over 12 hours, or anuria for more than 12 hours. You can do this.

AKI can be classified using the KDIGO criteria shown in Table 12 (Kidney Disease Improving Global Outcomes. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney International Supplements 2012; 2: 1-138]).

AKI includes specific kidney diseases (e.g., acute interstitial nephritis, acute glomerular and vasculitic nephropathy); non-specific conditions (eg, ischemia, toxic injury); In addition, it may occur with extrarenal pathologies (e.g., prerenal azotemia and acute postrenal obstructive nephropathy). More than one of these conditions can coexist in the same subject and, more importantly, epidemiological evidence supports the concept that even mild reversible AKI has important clinical consequences, including increased risk of death. Additionally, because the signs and clinical outcomes of AKI can be very similar (even indistinguishable) regardless of whether the etiology is primarily within the kidney or primarily from external stress on the kidney, AKI may be associated with a direct effect on the kidney. It encompasses both impairment and acute impairment of function.

In some embodiments, the subject with or at risk for AKI has diabetes, underlying renal insufficiency, nephritic syndrome, atherosclerotic disease, sepsis, hypotension, hypoxia, myoglobinuria-hematuria, or liver disease. In some embodiments, the subject is elderly, pregnant, a surgical patient, or has been exposed to a nephrotoxic agent. In a specific embodiment, the subject having AKI or at risk of AKI is a surgical patient. Accordingly, in certain embodiments, compounds of the disclosure are administered to surgical patients following surgery, eg, following cardiovascular surgery, such as coronary artery bypass graft (CABG) surgery and/or heart valve surgery.

In some embodiments, the subject has sepsis (e.g., associated with a gram-negative bacterial infection). Sepsis may, in some embodiments, be caused by an intra-abdominal infection or may be urosepsis. Sepsis is a risk factor for AKI. Accordingly, in some embodiments, the subject may be at risk for AKI, for example due to sepsis.

In some embodiments, the subject has a Short Sequential Organ Failure Assessment (SOFA) score of 1 to 4, e.g., a score of 1, 2, 3, or 4 prior to treatment with a compound of the disclosure (Vincent et al. 1996, Intensive Care Med, 22:707-710].

In some embodiments, the subject has AKI secondary to an infection or is at risk of AKI due to an infection, e.g., a viral infection, e.g., COVID-19.

In some embodiments, the subject with AKI or at risk of AKI has been exposed to a nephrotoxic agent. Nephrotoxic agents are drugs or chemicals that can cause AKI. Drugs or chemicals that can cause AKI include cisplatin; gentamicin; Cephaloridine; cyclosporine; amphotericin; carbon tetrachloride; trichlorethylene; and dichloroacetylene.

In some embodiments, the invention provides a method of treating or preventing erectile dysfunction, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. In some embodiments, erectile dysfunction may be caused by damage to nerves, arteries, smooth muscles, or fibrous tissue; diabetes; kidney disease; alcoholism; multiple sclerosis; atherosclerosis; vascular disease; Or it is caused by a neurological disease. In some embodiments, methods of treating or preventing erectile dysfunction are directed to treating or preventing erectile dysfunction.

The present invention provides a method for treating or preventing hyperlipidemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, or dyslipidemia, by administering an effective amount of a compound of the present invention or a composition of the present invention to a subject in need thereof. Provides a method including: In some embodiments, the hypercholesterolemia is homozygous familial hypercholesterolemia.

The present invention relates to abnormally high concentrations of high low density lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein (a) (Lp(a)), apolipoprotein (a) or very low density lipoprotein ( Provided is a method of treating or preventing a subject having VLDL), comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

“Abnormally high concentrations” of lipoprotein-cholesterol may depend on the number of risk factors and whether treatment is for primary or secondary prevention. As used herein, “primary prevention” refers to treatment aimed at avoiding developing or developing a disease or condition in a subject. As used herein, “secondary prevention” refers to treatment aimed at detecting a disease or condition early and preventing the disease or condition from worsening or progressing. Recommended lipoprotein-cholesterol concentrations are based on published guidelines by the National Lipid Institute or the National Heart, Lung, and Blood Institute of the National Institutes of Health, such as the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP). III Final Report), 2002]. The ATP III Final Report is incorporated herein by reference in its entirety for all purposes.

In some embodiments, the invention provides a method of reducing abnormally high concentrations of apo B in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. Provides a method. In some embodiments, the “abnormally high concentration” of Apo B in the subject's plasma or serum is greater than 130 mg/dL. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of apo B in the subject's plasma or serum is less than 130 mg/dL. In some embodiments, the subject is a male subject. In some embodiments, the subject is a female subject. In some embodiments, the invention provides methods of treating a subject with an Apo B plasma or serum concentration greater than 130 mg/dL. In some embodiments, the invention provides treatment for a subject with an Apo B plasma or serum concentration greater than 130 mg/dL when the subject has 0-1 coronary heart disease (CHD) risk factors and has a low risk of CHD. Provides a way to do this.

In some embodiments, the invention provides methods of treating a subject with an Apo B plasma or serum concentration greater than 110 mg/dL when the subject is at intermediate risk of CHD with two or more CHD risk factors. In some embodiments, the “abnormally high concentration” of Apo B in the subject's plasma or serum is greater than 110 mg/dL. In some embodiments, the subject has two or more CHD risk factors. In some embodiments, the subject has CHD or CHD risk equivalent. In some embodiments, the invention provides methods of treating a subject with an Apo B plasma or serum concentration greater than 90 mg/dL, when the subject has CHD or CHD risk equivalent.

In some embodiments, the invention provides a method of reducing abnormally high concentrations of Lp(a) in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. Provides a method of inclusion. An “abnormally high concentration” of Lp(a) in a subject's plasma or serum is greater than 10 mg/dL. In some embodiments, abnormally high concentrations of Lp(a) are associated with increased cardiovascular risk. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the subject's normal concentration of Lp(a) in plasma or serum is less than 10 mg/dL. In some embodiments, the normal concentration of Lp(a) in the subject's plasma or serum is less than 50 mg/dL (see Banach, M. J Am Heart Assoc. 2016 Apr; 5(4): e003597). In some embodiments, the invention provides a method of treating a subject with an Lp(a) plasma concentration greater than 50 mg/dL, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. Provides a way to do this.

The present invention provides a method for treating or preventing a subject having an abnormally high Apo B/Apo A-I ratio in the subject's plasma or serum, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention. Provides a method comprising administering. In some embodiments, the invention provides a method of reducing an abnormally high apo B/apo A-I ratio in plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. Provides a method of inclusion. The subject's plasma or serum has an “abnormally high” apo B/apo A-I ratio greater than 0.9. In some embodiments, the decrease is a decrease to a normal level. In some embodiments, the normal apo B/apo A-I ratio in the subject's plasma or serum is less than 0.9. In some embodiments, the normal apo B/apo A-I ratio in the subject's plasma or serum is less than 0.7. In some embodiments, the subject has an apo B/apo A-I ratio greater than 0.9 in the subject's plasma or serum. In some embodiments, the subject has an apo B/apo A-I ratio greater than 0.7 in the subject's plasma or serum. See Walldius, G. et al. J Intern Med. 2006 May;259(5):493-519].

In some embodiments, a male subject whose plasma or serum has an Apo B/Apo A-I ratio greater than 0.9 is considered for primary prevention treatment. In some embodiments, a female subject whose plasma or serum has an Apo B/Apo A-I ratio greater than 0.8 is considered for primary prevention treatment. In some embodiments, the subject is a male subject and the Apo B/Apo A-I ratio in the subject's plasma or serum is greater than 0.9. In some embodiments, the subject is a female subject and the subject's plasma or serum has an apo B/apo A-I ratio greater than 0.8. See [Walldius, 2006].

In some embodiments, a male subject whose plasma or serum has an Apo B/Apo A-I ratio greater than 0.7 is considered for secondary prevention treatment. In some embodiments, a female subject whose plasma or serum has an Apo B/Apo A-I ratio greater than 0.6 is considered for secondary prevention treatment. In some embodiments, the subject is a male subject and the Apo B/Apo A-I ratio in the subject's plasma or serum is greater than 0.7. In some embodiments, the subject is a female subject and the subject's plasma or serum has an apo B/apo A-I ratio greater than 0.6. See [Walldius, 2006].

The present invention provides a method for treating or preventing a subject having an abnormally low concentration of high-density lipoprotein (HDL) in the subject's plasma or serum, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or of the present invention. A method comprising administering a composition is provided.

The present invention provides a method for treating or preventing a subject having abnormally reduced or deficient lipoprotein lipase concentration or activity in the subject's plasma or serum, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or the present invention. A method comprising administering a composition is provided. In some embodiments, reduced or deficient lipoprotein lipase levels or activity are the result of a lipoprotein lipase mutation. In some embodiments, reduced or deficient lipoprotein lipase levels or activity are the result of a mutation within the gene encoding lipoprotein lipase.

In some embodiments, the invention provides a method of raising abnormally low concentrations of lipoprotein lipase in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound or composition of the invention. Provides a method. The “abnormally reduced concentration” of lipoprotein lipase in the subject's serum is less than 46 ng/mL. In some embodiments, the subject has an increased risk of future coronary artery disease. In some embodiments, the elevation is to normal concentration. In some embodiments, the normal concentration of lipoprotein lipase in the subject's serum is greater than 46 ng/mL. In some embodiments, the invention provides a method of treating a subject with a lipoprotein lipase plasma or serum concentration of less than 46 ng/mL, comprising administering to the subject in need thereof an effective amount of a compound or composition of the invention. Provides a method. Rip, J. et al. Arterioscler Thromb Vasc Biol. 2006 Mar;26(3):637-42. Epub 2005 Dec 22].

The present invention provides a method for treating or preventing a subject having abnormally high levels of lipoprotein-associated phospholipase A ₂ (Lp-PLA ₂ ) in the subject's plasma or serum, comprising administering to a subject in need thereof an effective amount. A method comprising administering a compound of the present invention or a composition of the present invention is provided. An “abnormally high concentration” of Lp-PLA ₂ in a subject's plasma or serum is greater than 200 ng/mL. In some embodiments, the subject is at risk of developing cardiovascular disease. In some embodiments, the risk is high.

In some embodiments, the invention provides a method of reducing abnormally high concentrations of Lp-PLA ₂ in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. Provides a method of inclusion. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of Lp-PLA ₂ in the subject's plasma or serum concentration is less than 200 ng/mL. In some embodiments, the invention provides methods of treating a subject with Lp-PLA ₂ plasma or serum concentration greater than 200 ng/mL. See Davidson, MH et al., The American Journal of Cardiology, 2008, 101, S51.

The present invention provides a method for treating or preventing hypoalphalipoproteinemia, lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, lipoprotein abnormalities associated with Alzheimer's disease, or familial combined hyperlipidemia, wherein an effective amount of the compound of the present invention is administered to a subject in need thereof. Or a method comprising administering the composition of the present invention is provided.

The present invention provides triglycerides, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) (Lp( a)), as a method of reducing abnormally high concentrations of apolipoprotein B, HDL/(VLDL+LDL) ratio, apolipoprotein C-II (apo C-II) or apolipoprotein C-III (apo C-III) , a method comprising administering an effective amount of a compound of the present invention or a composition of the present invention to a subject in need thereof.

An “abnormally high concentration” of triglycerides in a subject's serum is greater than 150 mg/dL. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the subject's normal concentration of triglycerides in serum is less than 150 mg/dL. In some embodiments, the invention provides a method of reducing serum triglyceride concentration in a subject, wherein the subject has a serum triglyceride concentration of at least 200 mg/dL. In some embodiments, the invention provides a method of reducing serum triglyceride concentration in a subject, wherein the subject has a serum triglyceride concentration of at least 500 mg/dL.

An “abnormally high concentration” of LDL-C in a subject's plasma or serum for primary prevention is greater than 100 mg/dL. The “abnormally high concentration” of LDL-C in a subject's plasma or serum for secondary prevention in subjects with risk factors is greater than 70 mg/dL. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the subject's normal concentration of LDL-C in plasma or serum is less than 100 mg/dL, where the subject is being considered for primary prevention. In some embodiments, the subject's normal concentration of LDL-C in plasma or serum is less than 70 mg/dL. In some embodiments, the subject has risk factors and is being considered for secondary prevention. See [Walldius, 2006].

In some embodiments, the “abnormally high concentration” of LDL-C in the subject's plasma or serum is greater than 160 mg/dL. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the subject's normal concentration of LDL-C in plasma or serum is less than 160 mg/dL. In some embodiments, the subject has 0-1 CHD risk factors. In some embodiments, the invention provides methods of treating a subject with an LDL-C plasma or serum concentration greater than 160 mg/dL. In some embodiments, the invention provides methods of treating a subject with an LDL-C plasma or serum concentration greater than 160 mg/dL. In some embodiments, the subject has 0-1 CHD risk factors. See [Walldius, 2006].

In some embodiments, the “abnormally high concentration” of LDL-C in the subject's plasma or serum is greater than 130 mg/dL. In some embodiments, the subject has two or more CHD risk factors. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the subject's normal concentration of LDL-C in plasma or serum is less than 130 mg/dL. In some embodiments, the subject has two or more CHD risk factors. In some embodiments, the invention provides methods of treating a subject with an LDL-C plasma or serum concentration greater than 130 mg/dL. In some embodiments, the subject has two or more CHD risk factors. See [Walldius, 2006].

In some embodiments, the “abnormally high concentration” of LDL-C in the subject's plasma or serum is greater than 100 mg/dL. In some embodiments, the subject has CHD or CHD risk equivalent. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the subject's normal concentration of LDL-C in plasma or serum is less than 100 mg/dL. In some embodiments, the subject has CHD or CHD risk equivalent. In some embodiments, the invention provides methods of treating a subject with an LDL-C plasma or serum concentration greater than 100 mg/dL. In some embodiments, the subject has CHD or CHD risk equivalent. See [Walldius, 2006].

An “abnormally high concentration” of Apo C-III concentration in a subject's plasma or serum is greater than 7.87 mg/dL. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of apo C-III concentration in the subject's plasma or serum is less than 7.87 mg/dL. In some embodiments, the invention provides a method of treating a subject, wherein the subject has an Apo C-III plasma or serum concentration greater than 8 mg/dL. In some embodiments, the invention provides a method of treating a subject, wherein the subject has an Apo C-III plasma or serum concentration greater than 7.9 mg/dL. In some embodiments, the invention provides a method of treating a subject, wherein the subject has an Apo C-III plasma or serum concentration greater than 7.87 mg/dL. In some embodiments, abnormally high concentrations of apo C-III are associated with a higher risk of coronary artery disease. See Capelleveen et al. Arterioscler Thromb Vasc Biol. 2017 Jun; 37(6): 1206-1212].

The present invention provides a method for reducing abnormally high LDL-C/HDL-C ratio in plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention. provides.

In some embodiments, the “abnormally high ratio” of LDL-C/HDL-C in plasma or serum of a male subject for primary prevention is greater than 3.0. In some embodiments, the reduction is a reduction to normal ratio. In some embodiments, the normal ratio of LDL-C/HDL-C in plasma or serum of a male subject is less than 3.0, wherein the subject is being considered for primary prevention. In some embodiments, the invention provides a method of treating a male subject who has an LDL-C/HDL-C ratio greater than 3.0 in the subject's plasma or serum. In some embodiments, the method is for primary prevention.

In some embodiments, the “abnormally high ratio” of LDL-C/HDL-C in plasma or serum of a female subject for primary prevention is greater than 2.5. In some embodiments, the reduction is a reduction to normal ratio. In some embodiments, the normal ratio of LDL-C/HDL-C in plasma or serum of a female subject is less than 2.5, wherein the subject is being considered for primary prevention. In some embodiments, the invention provides a method of treating a female subject who has an LDL-C/HDL-C ratio greater than 2.5 in the subject's plasma or serum. In some embodiments, the method is for primary prevention. See [Walldius, 2006].

In some embodiments, the “abnormally high ratio” of LDL-C/HDL-C in the plasma or serum of a male subject for secondary prevention is greater than 2.5. In some embodiments, the reduction is a reduction to normal ratio. In some embodiments, the normal ratio of LDL-C/HDL-C in plasma or serum of a male subject is less than 2.5, wherein the subject is being considered for secondary prevention. In some embodiments, the invention provides a method of treating a male subject who has an LDL-C/HDL-C ratio greater than 2.5 in the subject's plasma or serum. In some embodiments, the method is for secondary prevention. See [Walldius, 2006].

In some embodiments, the “abnormally high ratio” of LDL-C/HDL-C in the plasma or serum of a female subject for secondary prevention is greater than 2.0. In some embodiments, the reduction is a reduction to normal ratio. In some embodiments, the normal ratio of LDL-C/HDL-C in plasma or serum of a female subject is less than 2.0, wherein the subject is being considered for secondary prevention. In some embodiments, the invention provides methods of treating a female subject who has an LDL-C/HDL-C ratio greater than 2.0 in the subject's plasma or serum. In some embodiments, the method is for secondary prevention. See [Walldius, 2006].

The present invention provides a method for reducing abnormally high concentrations of non-HDL-C in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound or composition of the present invention. to provide.

In some embodiments, the “abnormally high concentration” of non-HDL-C in the subject's plasma or serum is greater than 190 mg/dL. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the subject's normal concentration of non-HDL-C in plasma or serum is less than 190 mg/dL. In some embodiments, the subject has 0-1 CHD risk factors. In some embodiments, the invention provides a method of reducing a subject's non-HDL-C concentration in the subject's plasma or serum, wherein the non-HDL-C concentration is greater than 190 mg/dL. In some embodiments, the subject has 0-1 CHD risk factors. See [Walldius, 2006].

In some embodiments, the “abnormally high concentration” of non-HDL-C in the subject's plasma or serum is greater than 160 mg/dL. In some embodiments, the subject has two or more CHD risk factors. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the subject's normal concentration of non-HDL-C in plasma or serum is less than 160 mg/dL. In some embodiments, the subject has two or more CHD risk factors. In some embodiments, the invention provides a method of reducing a subject's non-HDL-C concentration in the subject's plasma or serum, wherein the subject's non-HDL-C concentration is greater than 160 mg/dL. In some embodiments, the subject has two or more CHD risk factors. See [Walldius, 2006].

In some embodiments, the “abnormally high concentration” of non-HDL-C in the subject's plasma or serum is greater than 130 mg/dL. In some embodiments, the subject has CHD or CHD risk equivalent. In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the subject's normal concentration of non-HDL-C in plasma or serum is less than 130 mg/dL. In some embodiments, the subject has CHD or CHD risk equivalent. In some embodiments, the invention provides a method of reducing a subject's non-HDL-C concentration in the subject's plasma or serum, wherein the subject's non-HDL-C concentration is greater than 130 mg/dL. In some embodiments, the subject has CHD or CHD risk equivalent. See [Walldius, 2006].

The present invention provides a method for increasing abnormally low concentrations of high-density lipoprotein (HDL)-related protein, HDL-cholesterol (HDL-C), apolipoprotein A-I, or apolipoprotein E in the plasma or serum of a subject, comprising: A method is provided comprising administering an effective amount of a compound of the present invention or a composition of the present invention to a person. In some embodiments, the HDL-associated protein is apolipoprotein A-I (apo A-I), apolipoprotein A-II (apo A-II), apolipoprotein A-IV (apo A-IV), or apolipoprotein E (apo E). .

In some embodiments, the “abnormally low concentration” of HDL-C in the subject's plasma or serum is less than 40 mg/dL. In some embodiments, the elevation is to normal concentration. In some embodiments, the normal concentration of HDL-C in the subject's plasma or serum is greater than 40 mg/dL. In some embodiments, the invention provides a method of increasing HDL-C concentration in plasma or serum of a subject, wherein the subject's HDL-C concentration is less than 40 mg/dL. In some embodiments, the subject is a male subject. In some embodiments, the subject is a female subject.

In some embodiments, the “abnormally low concentration” of HDL-C in the plasma or serum of a male subject is less than 45 mg/dL. In some embodiments, the normal concentration of HDL-C in plasma or serum of a male subject is greater than 45 mg/dL. In some embodiments, the invention provides a method of increasing HDL-C concentration in plasma or serum of a male subject, wherein the subject's HDL-C concentration is less than 45 mg/dL.

In some embodiments, the “abnormally low concentration” of HDL-C in the plasma or serum of a female subject is less than 50 mg/dL. In some embodiments, the normal concentration of HDL-C in plasma or serum of a female subject is greater than 50 mg/dL. In some embodiments, the normal concentration of HDL-C in plasma or serum of a female subject is greater than 55 mg/dL. In some embodiments, the invention provides a method of increasing HDL-C concentration in plasma or serum of a female subject, wherein the subject's HDL-C concentration is less than 50 mg/dL. In some embodiments, the invention provides a method of increasing HDL-C concentration in plasma or serum of a female subject, wherein the subject's HDL-C concentration is less than 55 mg/dL.

In some embodiments, the invention provides a method of increasing the HDL-C concentration in the subject's plasma or serum to greater than or equal to 45 mg/dL, wherein the subject's HDL-C concentration in the subject's plasma or serum is less than 40 mg/dL. provides. In some embodiments, the invention provides a method of increasing the HDL-C concentration in the subject's plasma or serum to 50 mg/dL or greater, wherein the subject's HDL-C concentration in the subject's plasma or serum is less than 40 mg/dL. provides. In some embodiments, the invention provides a method of increasing the HDL-C concentration in the subject's plasma or serum to greater than or equal to 55 mg/dL, wherein the subject's HDL-C concentration in the subject's plasma or serum is less than 40 mg/dL. provides.

In some embodiments, the invention provides a method of increasing the HDL-C concentration in plasma or serum of a male subject to at least 50 mg/dL, wherein the subject's HDL-C concentration in plasma or serum is less than 45 mg/dL. Provides a method. In some embodiments, the invention provides a method of increasing the HDL-C concentration in plasma or serum of a female subject to 50 mg/dL or greater, wherein the subject's HDL-C concentration in plasma or serum is less than 50 mg/dL. Provides a method. In some embodiments, the invention provides a method of increasing the HDL-C concentration in plasma or serum of a female subject to 55 mg/dL or greater, wherein the subject's HDL-C concentration in plasma or serum is less than 50 mg/dL. Provides a method.

The present invention provides a method of promoting the clearance of triglycerides from the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound or composition of the present invention.

The present invention provides a method for increasing abnormally low glucose metabolism or abnormally low lipid metabolism in a subject, comprising administering to a subject in need thereof an effective amount of a compound or composition of the present invention. provides. In some embodiments, the method of increasing abnormally low glucose metabolism increases insulin sensitivity or oxygen consumption in the subject. In some embodiments, the method of increasing abnormally low glucose metabolism reduces blood insulin, blood glucose, or glycated hemoglobin in the subject's plasma or serum. In some embodiments, the method of increasing abnormally low lipid metabolism reduces the concentration of LDL or free triglycerides in the subject's plasma or serum or inhibits saponified or non-saponifiable fatty acid synthesis.

In some embodiments, a subject with abnormally low glucose metabolism has abnormally high concentrations of glucose or hemoglobin (Hb) in the subject's plasma or serum. In some embodiments, the invention provides methods of reducing abnormally high concentrations of glucose or hemoglobin in plasma or serum of a subject. In some embodiments, the method increases abnormally low glucose metabolism. An “abnormally high concentration” of glucose in a subject's plasma or serum at a 2-hour GTT is greater than 7.8 mmol/L (140 mg/dL). In some embodiments, the decrease is a decrease to normal concentration. In some embodiments, the normal concentration of glucose in the subject's plasma or serum at a 2-hour GTT is less than 7.8 mmol/L (140 mg/dL). In some embodiments, the invention provides a method of increasing abnormally low glucose metabolism in the subject's plasma or serum, wherein the subject's glucose concentration in the subject's plasma or serum at the 2-hour GTT is 7.8 mmol/L (140 mg /dL) provides a method of exceeding. In some embodiments, the invention provides a method of increasing abnormally low glucose metabolism in a subject, wherein the subject's glucose concentration in the subject's plasma or serum at the 2-hour GTT is between 7.8 mmol/L (140 mg/dL) and A method in the range of 11.1 mmol/L (200 mg/dL) is provided. In some embodiments, the invention provides a method of increasing abnormally low glucose metabolism in a subject, wherein the subject's glucose concentration in the subject's plasma or serum at the 2-hour GTT is greater than 11.1 mmol/L (200 mg/dL) method is provided.

In some embodiments, the invention provides a method of increasing abnormally low glucose metabolism in a subject, wherein the subject has impaired glucose tolerance. In some embodiments, the invention provides a method of increasing abnormally low glucose metabolism in a subject, wherein the subject has diabetes. In some embodiments, the invention provides a method of increasing abnormally low glucose metabolism in a subject, wherein the subject has gestational diabetes.

Low lipid metabolism can be characterized by dyslipidemia (using LDL-C, TG, non-HDL-chol, Apo B, Apo C-III or Apo C-II values) as well as elevated concentrations of transaminases. . In some embodiments, the subject with low lipid metabolism also has dyslipidemia.

The present invention provides a method for treating or preventing symptoms of a disease selected from inflammation, systemic lupus erythematosus, lupus nephritis or arthritis, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. Provides a method. In some embodiments, the arthritis is adjuvant arthritis or type II collagen-induced arthritis. In some embodiments, the condition is nephritis, renal failure, or decreased renal function. In some embodiments, decreased kidney function requires kidney dialysis.

The present invention provides a method for reducing the fat content of meat in livestock, comprising administering to the livestock an effective amount of a compound of the invention or a composition of the invention.

The present invention provides a method for reducing the cholesterol content of poultry eggs, comprising administering to a poultry species an effective amount of a compound or composition of the present invention.

In some embodiments, the methods of the invention provide for administering a dosage form of a compound of the invention or a composition of the invention hourly, daily, weekly, or monthly. The dosage forms and formulations of the present invention may be administered three times a day, twice a day, or once a day. The dosage form of the present invention may be administered with or without food. The appropriate treatment duration, dosage, and route of administration may be determined and/or adjusted by the physician.

In some embodiments of the methods of the invention, the subject is a human subject.

5.5. Synthesis of Compounds of the Invention

The compounds of the present invention can be synthesized by conventional means. Exemplary methods for synthesizing exemplary compounds of Formula (A) and Formula (B) are described in Examples 1-3 below. WO 2011/020001, the contents of which are incorporated herein by reference in their entirety, describes PPAR modulator compounds (described therein as compounds of formula (I)-(XX)) and methods for their synthesis. Compounds of formula (I)-(XX) described in WO 2011/020001 can be used as starting materials for the synthesis of compounds of formula (C)-(H) and (J)-(W) of the present invention, respectively. For example, compounds of WO 2011/020001 with ketones can be reduced with a reducing agent such as NaBH ₄ , optionally in the presence of a Lewis acid such as CeCl ₃ or in an alcohol solvent such as methanol to convert the ketone group into a hydroxyl group. Similarly, the carboxylic acid groups of the compounds of WO 2011/020001 can be reduced to hydroxymethyl groups using a reducing reagent such as LiAlH ₄ followed by aqueous acid work-up to obtain the compounds of the invention.

WO 2017/062468, the contents of which are incorporated herein by reference in their entirety, describes PPAR modulator compounds (described therein as compounds of formula (I)-(III)) and methods for their synthesis. Compounds of formula (I)-(III) described in WO 2017/06246 can be used as starting materials for the synthesis of compounds of formula (X)-(Z) of the present invention, respectively. The carboxylic acid groups of the compounds of WO 2017/06246 can be reduced to hydroxymethyl groups using a reducing reagent such as LiAlH ₄ followed by aqueous acid work-up to obtain the compounds of the invention.

WO 2017/180818, the contents of which are incorporated herein by reference in their entirety, describes PPAR modulator compounds (described therein as compounds of formula (I)) and methods for their synthesis. Compounds of formula (I) described in WO 2017/180818 can be used as starting materials for the synthesis of compounds of formula (AA) of the present invention. The carboxylic acid groups of the compounds of WO 2017/180818 can be reduced to hydroxymethyl groups using a reducing reagent such as LiAlH ₄ followed by aqueous acid work-up to obtain the compounds of the invention.

WO 2018/067857, the contents of which are incorporated herein by reference in their entirety, describes PPAR modulator compounds (described therein as Compounds A, B and C) and methods for their synthesis. Compounds B and C described in WO 2018/067857 can be used as starting materials for the synthesis of compounds VII and VIII. The carboxylic acid groups of the compounds of WO 2017/180818 can be reduced to hydroxymethyl groups using a reducing reagent such as LiAlH ₄ followed by aqueous acid work-up to obtain the compounds of the invention.

For the selective reduction of carboxylic acids in compounds having both ketone and carboxylic acid groups, for example some compounds described in WO 2011/020001, the compounds are reacted with ethylene, for example in the presence of a catalytic acid such as 0.1 M HCl. An acetal compound can be formed by protecting the ketone by reacting with glycol. Acetals can be removed after reduction of the carboxylic acid groups, for example by aqueous acid work-up. For the selective reduction of ketones in compounds having both ketone and carboxylic acid groups, for example some compounds described in WO 2011/020001, the ketones can be selectively reduced using less reactive reducing agents, such as NaBH ₄ .

6. Examples

6.1. Example 1. Synthesis of Compound I

(Z)-2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropane The acid (“Compound A”) is synthesized according to US2006/0142611. Compound A is then reduced using a reducing agent such as NaBH ₄ , optionally in the presence of a Lewis acid such as CeCl ₃ or in an alcohol solvent such as methanol to obtain the Compound I racemate. The Compound I racemate is then resolved using chiral high-performance liquid chromatography to obtain its (S)- and (R)-enantiomers, each of which is substantially free of its corresponding opposite enantiomer.

6.2. Example 2. Synthesis of Compound II

Acetal compound B is synthesized from compound A and ethylene glycol in the presence of a catalytic acid such as 0.1 M HCl. Specifically, for acetal formation on α,β-unsaturated ketones, see, for example, Dong, JL., et al. ACS Omega, 2018, 3, 4974]. Compound II is subsequently obtained by reducing the carboxyl group of compound B to a hydroxymethyl group using a reducing reagent such as LiAlH ₄ followed by aqueous acid work-up to remove the acetal.

6.3. Example 3. Synthesis of Compound III

Compound II is optionally reduced using a reducing agent such as NaBH ₄ in the presence of a Lewis acid such as CeCl ₃ or in an alcohol solvent such as methanol to obtain the Compound III racemate. The Compound III racemate is then resolved using chiral high-performance liquid chromatography to obtain its (S)- and (R)-enantiomers, each of which is substantially free of its corresponding opposite enantiomer.

6.4. Example 4. Effects on hepatic and peripheral insulin sensitivity in rats fed a high-fat/moderate fructose diet (Western diet)

After 8 weeks of high-fat diet, rats were treated with pioglitazone (10 mg/kg), metformin (50 mg/kg), exemplary compounds of the invention (3 and 10 mg/kg), alone or with metformin (50 mg/kg). together) and GW501516 (2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenok [C]acetic acid) (10 mg/kg; Ligand/GSK) for 5 weeks. Body weight can be reduced by metformin, and this effect can be accentuated when associated with a dose of 10 mg/kg of an exemplary compound of the invention. After 17 days of treatment, rats are allowed to fast for 4 hours and blood is sampled.

Glucose tolerance is assessed by an oral glucose load performed after a 6-hour fast after 21 days of treatment.

After 5 weeks of treatment, a euglycemic-hyperinsulinemic clamp procedure is performed on awake rats. Two doses of insulin are injected using 3H-glucose: 0.2 U/kg/h to evaluate the effect on hepatic glucose production (HGP) and to suppress HGP and then to evaluate the effect on systemic glucose utilization. 0.8 U/kg/h.

6.4.1. animal model

Male Sprague Dawley (SD) rats (250-275 g) are first fed a Western diet for 8 weeks to induce insulin resistance. A first set of rats underwent an oral glucose tolerance test (OGTT) after 3 weeks of treatment (half of the rats/clamp arm group), and a second set also underwent an OGTT after 3 weeks of treatment (half of the rats/clamp arm group). Group) Histological studies are performed (3 rats/group).

Each set of rats is screened and randomized into several groups according to their fasting (4 hours) plasma glucose, insulin levels (for Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) calculations) and body weight. Rats that do not respond to Western diet are excluded from the study.

Congenital mildly obese and insulin-resistant rats are assigned to different treatment groups and continued on a Western diet until the end of the experiment. Considering this, two series were started with an interval of one week.

6.4.2. process

Dosing regimen: Rats are treated once daily via oral route in the morning. The duration of treatment is 5 to 5.5 weeks.

6.4.3. test group

Group 1: Vehicle (n=12)

Group 2: pioglitazone, 10 mg/kg (n=12)

Group 3: Metformin, 50 mg/Kg (n=12)

Group 4: Exemplary compounds of the invention, 3 mg/Kg (n=12)

Group 5: Exemplary compounds of the invention, 10 mg/Kg (n=12)

Group 6: Exemplary compounds of the invention, 3 mg/Kg + metformin 50 mg/kg (n=12)

Group 7: Exemplary compounds of the invention, 10 mg/Kg + metformin 50 mg/kg (n=12)

Group 8: GW501216, 10 mg/Kg (n=12)

6.4.4. fasting conditions

Fasting conditions for OGTT and clamp procedures: Food is removed from the cage, and bedding is changed just before lights out (7:30 to 8:00 am). Then, each experiment begins after about 6 hours of fasting (1:30 to 2:00 pm).

Fasting conditions for plasma parameters: Food is removed from cages and bedding is changed 4 hours after lights out (11:30 am to noon). Then, after 4 hours of fasting (4:00 pm), blood collection begins.

6.4.5. Oral glucose tolerance test

After 3 weeks of treatment, rats are fasted for 6 hours and subjected to oral glucose loading (2.5 g/kg body weight). Blood glucose is measured 30 minutes before the glucose load and at 0, 15, 30, 60, 90, and 120 minutes.

6.4.6. Euglycemic-hyperinsulinemic two-stage clamp with 3H-glucose

After 4 weeks of treatment, the catheter is implanted in the femoral vein under isoflurane anesthesia and a period of 5-6 days is observed for recovery. Rats that do not regain weight are excluded from the study. The estimate of acceptable weight loss on the day of perfusion is 5% in groups where treatment should not affect body weight (as observed during weight follow-up) (vehicle, pioglitazone and exemplary compounds of the invention, mg/kg group). It is fixed at 10% in the group where the treatment reduces body weight (5 different groups). On the morning of the clamp procedure, rats are handled and allowed to fast for 6 hours before injection of tracer, glucose, and insulin. Initiation of the clamp procedure is performed in the middle of the dark cycle.

A euglycemic-hyperinsulinemic two-stage insulin clamp is performed using 0.2 U/kg/h and 0.8 U/kg/h insulin infusions associated with 3H-glucose infusions. Afterwards, the following parameters are evaluated:

Whole body glucose utilization

liver glucose production

Glucose infusion rate

Whole body glycogen and glycolysis rate

6.4.7. In vivo glucose utilization

During the clamp procedure, detectable plasma D[3-3H]glucose enrichment was achieved by first injecting a D-[3-3H]glucose bolus (30 μCi) followed by injection at a 4 μCi/min/kg infusion rate for all experiments. guaranteed. First an insulin bolus (100 mU) is injected, followed by insulin at a rate of 0.2 U/kg/h for the first 2 hours and 0.8 U/kg/h for 120 to 210 minutes.

Throughout the infusion, glycemia is assessed using a blood glucose meter from the tip of the tail vein when necessary. Euglycemia is maintained by periodically adjusting the variable infusion of 30% glucose (every 10 minutes). Plasma glucose concentration and D-[3-3H]glucose specific activity during the steady phase in 10 μl of blood sampled from the tip of the tail vein every 20 min from 60 to 120 min during the first phase and from 150 to 210 min during the second phase. decide

To measure glucose turnover, D-[3-3H]glucose enrichment is determined from whole blood after deproteinization by Zn(OH) ₂ precipitate. Briefly, an aliquot of the supernatant is evaporated to dryness and the radioactivity corresponding to D-3-3H is determined. In a second aliquot of the same supernatant, the glucose concentration is assessed by the glucose oxidase method (Biomerieux, France).

6.4.8. calculate

Calculations for glucose turnover measurements are made from parameters obtained during infusion at steady-state conditions (60-120 and 160-210 minutes). Briefly, D-[3-3H]glucose specific activity is calculated by dividing D-[3-3H]glucose enrichment by plasma glucose concentration. Calculate whole body glucose turnover by dividing the rate of D[3-3H]glucose by the D-[3-3H]glucose plasma specific activity. For each rat, the mean value is calculated and averaged with the values from the same group of rats. The systemic glycolysis rate is measured by assessing the amount of tritium accumulated in the blood during 3H-glucose infusion, and the systemic glycogen synthesis rate is calculated by the difference between the systemic glucose conversion rate and the systemic glycolytic rate.

6.4.9. Blood, tissue collection and biochemistry

At the end of the clamp procedure (9.5 hours fasting), perirenal, retroperitoneal, epididymal and inguinal fat pad and liver weights are recorded. Blood is collected from cardiac puncture, and plasma is stored at -80°C for further assays if necessary (depending on the radioactivity status of the sample). Liver triglyceride content is assessed (enzyme-colorimetric method) as well as liver and adipose tissue TNF-α content (enzyme-linked immunosorbent assay (ELISA) method). See US 2011/0092517, which is incorporated herein by reference in its entirety.

6.5. Example 5. Mouse and rat PPAR transcriptional activation in cell-based transactivation assays

6.5.1. Assay using GAL4-PPAR chimeric receptor

6.5.1.1. Receptor expression plasmid

An established chimeric receptor system (Lehmann JM et al. J Biol Chem. 1997; 272(6):3406-10) is used to allow comparison of the relative transcriptional activity of receptor subtypes. Homo sapiens (hs) (NM_006238, NM_015869, NM_001001928), macaca mulatta (mm) ( NM_001033029 , NM_011144, U10375, NM_011146) and the mammalian expression vectors pSG5-GAL4-PPARα, pSG5-GAL4-PPARγ and pSG5-GAL4-PPARδ from rattus norvegicus (r) (NM_013141, NM_013196, NM_013124) (which are respectively yeast Human PPARα (amino acids 167–468 for hs and m, amino acids 167–467 for mm), PPARγ1 (amino acids 167–467 for mm) fused to the transcription factor GAL4 DNA binding domain (amino acids 1–147) and the human glucocorticoid receptor (amino acids 1–76) amino acids 176–477 for hs, amino acids 204–505 for m and mm from PPARγ) and the ligand binding domain (LBD) of PPARδ (amino acids 139–441 for hs and mm, amino acids 139–440 for m). expression) is cloned.

Reporter plasmid: MH100x4-tk-luc (Forman B M et al. Cell. 1995 81(4):541-50) is used as the reporter plasmid.

6.5.1.2. Transient transfection assay

The African green monkey kidney cell line CV-1 is used for transfection assays. CV-1 cells were seeded in 24-well plates at 0.5x10 ⁵ cells per well and cultured for 24 hours. The transfection mixture for the chimeric receptor consisted of 30 ng of receptor expression plasmid, 120 ng of reporter plasmid, 350 ng of pCMX-β-galactosidase (βGAL) expression plasmid as a control for transfection efficiency, 250 ng of pGEM4 carrier plasmid, and lipofection. Contains 2 μL of reagent (Lipofectamine 2000, Invitrogen). These mixtures are added to the cells and incubated for 5 hours according to the manufacturer's instructions. After transfection, the cells are incubated for an additional 40 hours in the presence of exemplary compounds of the invention or different concentrations of the respective reference compounds. Cell lysates are prepared with lysis buffer (passive lysis buffer, Promega) and used for luciferase and βGAL assays. Luciferase and βGAL activities are measured by the Luciferase Assay System (E4030, Promega) and the βGAL Enzyme Assay System (E2000, Promega). Assays are performed in triplicate for GAL4-chimeras. Repeat the experiment at least three times.

6.5.1.3. Calculation of relative PPAR transactivation activity

Each point of PPAR transcriptional activity relative to maximal activity is calculated based on the following values:

Luciferase activity of cells treated with positive controls (10 ^-5 M GW-590735 for hPPARα, 3x10 ^-5 M rosiglitazone maleate for hPPARγ assay and 10 ^-5 M GW-501516 for hPPARδ) as maximal activity and Luciferase activity of cells treated with 0.1% DMSO as minimum activity.

6.5.1.4. EC ₅₀ calculation of value

EC ₅₀ values, defined as the concentration of exemplary compounds of the invention and GW-501516 to produce 50% of maximum reporter activity, are recalculated with Prism software (Graphpad Software).

6.5.1.5. Experiments using 10% serum vs. 0.1% serum.

Experiments at two serum concentrations: 10% and 0.1%. EC50 is calculated as previously described.

First, the assay is set up and the GAL4-chimera/reporter plasmid is verified using the Homo-sapiens sequences of different PPARs. Experiments are performed at 10% and 0.1% serum using GW501516 (PPARδ agonist).

Plasmid reference is as shown in US 2011/0092517, which is incorporated herein by reference in its entirety.

6.6. Example 6. Synthesis of Compound IV

Acetal compound B is synthesized from compound A (see WO 2011/020001; US 7,265,137) and ethylene glycol in the presence of a catalytic acid such as 0.1 M HCl. Subsequently, the carboxyl group of compound B is reduced to an alcohol using a reducing reagent such as LiAlH ₄ followed by an aqueous acid work-up to remove the acetal to give compound IV.

6.7. Example 7. Synthesis of compounds V, Va and Vb

Compound V is synthesized from compound A (see WO 2011/020001; US 7,265,137) by reducing the carboxylic acid and ketone groups to the corresponding alcohols using a reducing reagent such as LiAlH ₄ to obtain compound V. Compound V is then resolved using chiral high-performance liquid chromatography to obtain its (S)- and (R)-enantiomers, each of which is substantially free of its corresponding opposite enantiomer.

6.8. Example 8. Metabolic profiling of compounds of the invention in cryopreserved hepatocytes

6.8.1. purpose

The purpose of this study is to develop specific compounds of formula (A)-(H) and (J)-(AA), Compound IV, Compound V, Compound VI, Compound Va, Compound Vb, To investigate the formation of metabolites of compounds of the invention, including Compound VI, Compound VII and Compound VIII, incubated in human and cynomolgus monkey cryopreserved hepatocytes.

6.8.2. black description

Compounds of the invention (each a “test article” for purposes of the assay) were incubated in cryopreserved hepatocytes from humans and cynomolgus monkeys to provide comparative data on phase I and phase II liver metabolites.

6.8.2.1. matter

Use the following substances:

CNC-00X

Human liver hepatocyte, male

Cynomolgus monkey liver hepatocytes, male

Dulbecco's modified Eagle's medium (DMEM)

ITS+1 solution, dexamethasone (Sigma)

Hepatocyte Incubation Medium (Xenotech)

7-ethoxycoumarin and 7-hydroxycoumarin (Sigma)

Mass spectrometer equipped with LC sample introduction system

6.8.2.2. procedure

Each sample consists of a compound of the invention at a final concentration of 10 μM (diluted from 10 mM DMSO stock solution, 0.2% DMSO in final incubation) and cryopreserved hepatocytes at 100,000 viable cells per well in a final volume of 100 μL. The incubation buffer for human hepatocytes is supplemented DMEM (supplements are dexamethasone, 3.3 mM; insulin and transferrin, 5 μg/mL each; and selenium, 5 ng/mL). The incubation buffer for monkey hepatocytes is hepatocyte incubation medium without additional supplements. Samples are incubated at 37°C in 96-well plates in a humidified incubator, 95% air/5% CO ₂ with gentle shaking. At T=0, 60 or 120 min, the reaction is stopped by adding 100 μL of acetonitrile containing the internal standard (metoprolol). Positive controls 7-ethoxycoumarin and 7-hydroxycoumarin are incubated in the same manner as each evaluated compound.

Samples are centrifuged and then analyzed by LC-MS using electrospray ionization and SIM monitoring. The positive control is assayed for 7-hydroxycoumarin using a fluorescence plate reader.

Metabolite identification is performed using LC/MS methods for up to 5 days.

Metabolite profiling is based on mass chromatograms of the relevant components of the test article.

LC/MS sensitivity for test article metabolites is assumed to be the same as for the test article.

6.8.3. result

Compounds of the present invention are confirmed to be metabolized to compounds with PPAR agonist activity and/or their metabolites.

7. Specific Embodiments

7.1. Specific Embodiments, Group 1

Various aspects of the disclosure are described in numbered embodiments presented in the numbered paragraphs below, where references to previously numbered embodiments refer to previously numbered embodiments in this Section 7.1.

1. A compound of formula (A) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here

Each R ¹ and R ² is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl; or alternatively, R ¹ and R ² together with the carbon atoms to which R ¹ and R ² are attached form a C _3- C ₇ cycloalkyl group;

X is -CH ₂ OH, -COOH, -COH, -COOR ³ , -COOCH ₂ CONR ⁴ R ⁵ , -SO ₃ H,

이고;

ego;

R ³ is -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl;

Each R ⁴ and R ⁵ is independently alkyl, aryl or heteroaryl; or alternatively, R ⁴ and R ⁵ together with the carbon atoms to which R ⁴ and R ⁵ are attached form a heterocycle;

Each R ⁶ and R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl;

n is 0, 1, 2, 3 or 4.

2. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 1, wherein the compound is a racemate or a mixture of enantiomers or diastereomers.

3. The compound or pharmaceutically acceptable salt, solvate, ester, amide of the compound according to embodiment 1, wherein the compound has a hydroxyl-bearing allyl carbon atom with (R)-stereochemistry and has the structure: or prodrug:

4. The compound or pharmaceutically acceptable salt, solvate, ester, amide of the compound according to embodiment 1, wherein the compound has a hydroxyl-bearing allyl carbon atom with (S)-stereochemistry and has the structure: or prodrug:

5. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 3 or 4, wherein the compound is substantially free of its corresponding opposite stereoisomer.

6. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 3 to 5, wherein the compound has the olefinic isomeric configuration of (Z) or (E).

7. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 1, wherein the compound is a (Z)-isomer and has the structure:

8. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 1, wherein the compound is the (E)-isomer and has the structure:

9. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 7 or 8, wherein the compound is substantially free of its corresponding other olefin configuration.

10. The compound or pharmaceutically acceptable salt of the compound, solvent according to any one of embodiments 7 to 9, wherein the compound has a hydroxyl-bearing allylic carbon atom with (R)- or (S)-stereochemistry. Cargo, ester, amide or prodrug.

11. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 to 10, wherein each R ¹ and R ² is independently —C _1- C ₃ alkyl. .

12. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 to 10, wherein each R ¹ and R ² is independently methyl.

_13. The compound or pharmaceutically acceptable salt ^, solvate ^of the compound according to any one of embodiments 1 to ₁₂ ^, wherein , ester, amide or prodrug.

14. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 to 12, wherein X is -CH ₂ OH or -COOH.

15. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 to 14, wherein n is 0 or 1.

16. Compounds of formula (B) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

Each R ¹ and R ² is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl; or alternatively, R ¹ and R ² together with the carbon atoms to which R ¹ and R ² are attached form a C _3- C ₇ cycloalkyl group;

X is -CH ₂ OH, -COH, -COOCH ₂ CONR ⁴ R ⁵ , -SO ₃ H,

이고;

ego;

R ³ is -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl;

Each R ⁴ and R ⁵ is independently alkyl, aryl or heteroaryl; or alternatively, R ⁴ and R ⁵ together with the carbon atoms to which R ⁴ and R ⁵ are attached form a heterocycle;

Each R ⁶ and R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl;

n is 0, 1, 2, 3 or 4.

17. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 1, wherein the compound is a mixture of (Z)- and (E)-isomers.

18. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 16, wherein the compound is a (Z)-isomer and has the structure:

19. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 16, wherein the compound is the (E)-isomer and has the structure:

20. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 18 or 19, wherein the compound is substantially free of its corresponding other olefin configuration.

21. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 16 to 20, wherein each R ¹ and R ² is independently —C _1- C ₃ alkyl. .

22. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 16 to 20, wherein each R ¹ and R ² is independently methyl.

23. The compound or ^{pharmaceutically} acceptable salt, solvate _, ester _, ^amide or prodrug of the compound according to any one of embodiments 16 to 22, wherein .

24. The compound according to any one of embodiments 16 to 22, wherein X is -CH ₂ OH, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

25. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 16 to 24, wherein n is 0 or 1.

26. Structure:

를 갖는 화합물 또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물.

A compound having or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

27. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 26, wherein the compound is a racemate or a mixture of enantiomers.

28. The compound or pharmaceutically acceptable salt, solvate, ester, amide of the compound according to embodiment 26, wherein the compound has a hydroxyl-bearing allyl carbon atom with (R)-stereochemistry and has the structure: or prodrug:

29. The compound or pharmaceutically acceptable salt, solvate, ester, amide of the compound according to embodiment 26, wherein the compound has a hydroxyl-bearing allyl carbon atom with (S)-stereochemistry and has the structure: or prodrug:

30. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 28 or 29, wherein the compound is substantially free of its corresponding opposite enantiomer.

31. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 28 to 30, wherein the compound has the olefin isomeric configuration of (Z) or (E).

32. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of embodiment 26, wherein the compound is a (Z)-isomer and has the structure:

33. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of embodiment 26, wherein the compound is the (E)-isomer and has the structure:

34. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 32 or 33, wherein the compound is substantially free of its corresponding other olefin configuration.

35. The compound or pharmaceutically acceptable salt of the compound, solvent according to any one of embodiments 32 to 34, wherein the compound has a hydroxyl-bearing allylic carbon atom with (R)- or (S)-stereochemistry. Cargo, ester, amide or prodrug.

36. Structure:

를 갖는 화합물 또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물.

A compound having or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

37. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 36, wherein the compound is a mixture of (Z)- and (E)-isomers.

38. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 36, wherein the compound is a (Z)-isomer and has the structure:

39. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 36, wherein the compound is the (E)-isomer and has the structure:

40. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 38 or 39, wherein the compound is substantially free of its corresponding other olefin configuration.

41. Structure:

를 갖는 화합물 또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물.

A compound having or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

42. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 41, wherein the compound is a racemate or a mixture of enantiomers.

43. The compound or pharmaceutically acceptable salt, solvate, ester, amide of the compound according to embodiment 41, wherein the compound has a hydroxyl-bearing allyl carbon atom with (R)-stereochemistry and has the structure: or prodrug:

44. The compound or pharmaceutically acceptable salt, solvate, ester, amide of the compound according to embodiment 41, wherein the compound has a hydroxyl-bearing allyl carbon atom with (S)-stereochemistry and has the structure: or prodrug:

45. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 43 or 44, wherein the compound is substantially free of its corresponding opposite enantiomer.

46. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 43 to 45, wherein the compound has the olefin isomeric configuration of (Z) or (E).

47. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 41, wherein the compound is a (Z)-isomer and has the structure:

48. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of embodiment 41, wherein the compound is an (E)-isomer and has the structure:

49. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 47 or 48, wherein the compound is substantially free of its corresponding other olefin configuration.

50. The compound or pharmaceutically acceptable salt of the compound, solvent according to any one of embodiments 47 to 49, wherein the compound has a hydroxyl-bearing allylic carbon atom with (R)- or (S)-stereochemistry. Cargo, ester, amide or prodrug.

51. A composition comprising an effective amount of a compound of any one of embodiments 1 to 50 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound and a pharmaceutically acceptable carrier or vehicle.

52. The composition of embodiment 51, further comprising another therapeutically active agent.

53. The method of embodiment 52, wherein the other therapeutically active agent is a lipid-lowering drug, a statin, a cholesterol absorption inhibitor, an antibody against PCSK9, siRNA PCSK9, an antifibrotic agent, a thyroid hormone, a selective thyroid receptor-β agonist, an apoptosis signal-regulating kinase. 1 (ASK1) inhibitor, acetyl-CoA carboxylase (ACC) inhibitor, integrin antagonist, or non-steroidal farnesoid X receptor (FXR) agonist.

54. The method of embodiment 53,

The lipid-lowering drug is gemfibrozil, fenofibrate, bezafibrate, clofibrate, cipropibrate, clinofibrate, etophylline, pyrifibrate, symfibrate, tocofibrate, or pemafibrate;

The statin is atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, dalvastatin, dihydrocompactin, or cerivastatin, or a pharmaceutically acceptable salt, solvate, ester, or amide thereof. or is a prodrug;

The cholesterol absorption inhibitor is ezetimibe;

Antibodies to PCSK9 are evolocumab, alirocumab, bococizumab, 1D05-IgG2, RG7652, LY3015014, or LGT-209;

siRNA PCSK9 is inclisiran;

The antifibrotic agent is nitazoxanide, tizoxanide or tizoxanide glucuronide or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof;

the selective thyroid receptor-β agonist is VK2809, MGL-3196, MGL-3745, SKL-14763, sobetirome, BCT304, ZYT1, MB-0781, or eprothyrom;

The ASK1 inhibitor is seronsertib;

The ACC inhibitor is pyrsocostat;

the integrin antagonist is an α5β1 inhibitor or a pan integrin inhibitor; or

A composition wherein the FXR agonist is cilofexor.

55. Liver disorders, dyslipidemia, dyslipoproteinemia, renal disease, glucose metabolism disorder, lipid metabolism disorder, glucose metabolism disorder, cardiovascular disease, vascular disease, metabolic syndrome, complications associated with metabolic syndrome, PPAR-related disorder, bacteremia, thrombosis. Sexual disorders, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, cerebrovascular disease, disorders related to angiogenesis, hypertension, cancer, inflammation, inflammatory diseases, neurodegenerative diseases, autoimmune diseases, neovascularization A method for treating or preventing physical disease, muscular atrophy, cholestasis, mitochondrial dysfunction, eye disease, lysosomal storage disease, kidney disease, or erectile dysfunction, comprising administering to a subject in need thereof an effective amount of any one of embodiments 1 to 50. A method comprising administering a compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

56. The method of embodiment 55, wherein the liver disorder involves pathological destruction, inflammation, degeneration, apoptosis or proliferation of liver cells.

57. The method of embodiment 55, wherein the liver disorder is liver fibrosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH).

58. The method of embodiment 55, wherein the dyslipidemia is hyperlipidemia or an abnormally low concentration of high-density lipoprotein cholesterol (HDL-C) in the subject's plasma or serum.

59. The method of embodiment 58, wherein the hyperlipidemia is hypercholesterolemia, familial hypercholesterolemia, hypertriglyceridemia, or familial combined hyperlipidemia.

60. The method of embodiment 58, wherein the hyperlipidemia is caused by abnormally reduced or deficient lipoprotein lipase levels or activity in the subject's plasma or serum, or abnormally high concentrations of ketone bodies, lipoprotein(a) cholesterol (Lp( a)-C), low density lipoprotein (LDL), very low density lipoprotein cholesterol (VLDL-C) or non-esterified fatty acids.

61. The method of embodiment 60, wherein the reduced or deficient lipoprotein lipase level or activity is the result of a mutation in the gene encoding the lipoprotein lipase.

62. The method of embodiment 55, wherein the dyslipoproteinemia is an abnormally high concentration of LDL, apolipoprotein (a), or VLDL in the subject's plasma or serum, or an abnormally low concentration of high-density lipoprotein (HDL) in the subject's plasma or serum. or a method characterized by lipoprotein lipase.

63. The method of embodiment 62, wherein the abnormally low concentration of lipoprotein lipase is associated with a lipoprotein lipase mutation, hypoalphalipoproteinemia, lipoprotein abnormality associated with diabetes, lipoprotein abnormality associated with obesity, lipoprotein abnormality associated with Alzheimer's disease, or familial combined hyperlipidemia. How to do it.

64. The method of embodiment 55, wherein the renal disease is a glomerular disease, tubular disease, tubulointerstitial disease, acute or rapidly progressive renal failure, chronic renal failure, nephrolithiasis, or tumor.

65. The method of embodiment 64,

The glomerular disease is acute glomerulonephritis, chronic glomerulonephritis, rapidly progressive glomerulonephritis, nephrotic syndrome, focal proliferative glomerulonephritis, glomerular lesion associated with a systemic disease, Goodpasture syndrome, multiple myeloma, diabetes mellitus, neoplasm, sickle cell disease, or chronic Is an inflammatory disease;

the tubular disease is acute tubular necrosis, acute renal failure, polycystic kidney disease, medullary cavernous kidney, medullary cystic disease, nephrogenic diabetes, or renal tubular acidosis;

The tubulointerstitial disease is pyelonephritis, drug- or toxin-induced tubulointerstitial nephritis, hypercalcemic nephropathy, or hypokalemic nephropathy; or

Wherein the tumor is renal cell carcinoma or nephroblastoma.

66. The method of embodiment 65, wherein the glomerular lesion associated with a systemic disease is systemic lupus erythematosus.

67. The method of embodiment 55, wherein the renal disease is hypertension, nephrosclerosis, microangiopathic hemolytic anemia, atherosclerotic renal disease, diffuse cortical necrosis, or neuronal index.

68. The method of embodiment 67, wherein the hypertension is essential hypertension, hyperpiesa, hyperpiersis, malignant hypertension, secondary hypertension, or white coat hypertension.

69. The method of embodiment 55, wherein the impaired glucose metabolism is an impaired glucose tolerance; insulin resistance; Insulin resistance-related breast, colon, or prostate cancer; diabetes; pancreatitis; High blood pressure; polycystic ovarian disease; or an abnormally high concentration of blood insulin or glucose in the subject's plasma or serum.

70. The method of embodiment 69, wherein the diabetes is non-insulin dependent diabetes mellitus (NIDDM), insulin dependent diabetes mellitus (IDDM), gestational diabetes mellitus (GDM), or maturity-onset diabetes of the young (MODY).

71. The method of embodiment 55, wherein the vascular disease or cardiovascular disease is peripheral vascular disease, coronary heart disease, stroke, restenosis, arteriosclerosis, ischemia, endothelial dysfunction, ischemia-reperfusion injury, myocardial infarction, or cerebral infarction.

72. The method of embodiment 55, wherein the PPAR-associated disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, breast cancer, colon cancer, or prostate cancer.

73. The method of embodiment 55, wherein the PPAR-related disorder is a vascular disease, a muscle disease, a demyelinating disease, a muscle structural disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a mitochondrial dysfunction, a beta oxidation disease, or a metabolic disease. How to do it.

74. The method of embodiment 73,

The muscle disease is a muscular dystrophy disease;

the demyelinating disease is multiple sclerosis, Charcot-Marie-Tooth disease, Pelisseus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, or Guillain-Barre syndrome;

Disorders of muscle structure include Beslem myopathy, central nuclear disease, congenital fibrous imbalance, distal muscular dystrophy (MD), Duchenne & Becker MD, Emery-Dreyfus MD, facioscapulohumeral MD, hyaline body myopathy, zone MD, and muscle sodium channels. is a disorder, myotonic chondrodystrophy, myotonic dystrophy, tubular myopathy, nemaline body disease, opharyngeal MD, or stress urinary incontinence;

Disorders of neuronal activation include amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve lesions, peripheral neuropathy, spinal muscular atrophy, chronic ulnar nerve palsy, or toxicity. have a neuromuscular disorder;

Muscle fatigue disorders include chronic fatigue syndrome, diabetes (type I or type II), glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome, mucopolysaccharidosis, Pompe disease, or thyrotoxic myopathy;

The muscle mass disorder is cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, critical illness myopathy, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, or systemic lupus erythematosus;

Mitochondrial diseases include Alper's disease, chronic progressive extraocular ophthalmoplegia (CPEO), Kearns-Sayer syndrome (KSS), Leber hereditary optic neuropathy (LHON), MELAS, myoclonic epilepsy and heterogeneous-red myofiber disease (MERRF), and neurogenic muscle attenuation (NARP), ataxia, retinitis pigmentosa, Pearson syndrome, mitochondrial dysfunction or loss of mitochondrial function;

Beta oxidation disorders include systemic carnitine transporter, carnitine palmitoyltransferase (CPT) II deficiency, very long chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, and medium chain acyl-CoA dehydrogenase deficiency. (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, or riboflavin-responsive disorder of β-oxidation (RR-MADD); or

Metabolic diseases include hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia, HLD non-cholesterolemia, VLDL hyperproteinemia, dyslipoproteinemia, apolipoprotein A-I hypoproteinemia, and atherosclerosis. , arteriosclerosis disease, cardiovascular disease, cerebrovascular disease, peripheral circulation disease, metabolic syndrome, syndrome X, obesity, diabetes, type I diabetes, type II diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism, Diabetic complications, cardiac dysfunction, myocardial infarction, cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), thrombosis, Alzheimer's disease, neurodegenerative disease, demyelinating disease, multiple sclerosis. , adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, trichiasis, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease or pancreatitis.

75. The method of embodiment 74, wherein the muscular dystrophy disease is Duchenne muscular dystrophy, Becker muscular dystrophy, girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, opharyngeal muscular dystrophy, distal muscular dystrophy, or Emery's. -Dreyfus muscular dystrophy method.

76. The method of embodiment 55, wherein the PPAR-associated disorder comprises an abnormally low concentration of HDL, an abnormally low concentration of apolipoprotein A-I (apo A-I), an abnormally high concentration of VLDL-C, an abnormally high concentration of HDL in the plasma or serum of the subject. Concentrations of low-density lipoprotein cholesterol (LDL-C), abnormally high concentrations of triglycerides, abnormally high concentrations of apolipoprotein B (apo B), abnormally high concentrations of apolipoprotein C-III (apo C-III), or abnormally high concentrations of apolipoprotein C-III (apo C-III) Method for reducing the ratio of post-heparin hepatic lipase to lipoprotein lipase activity.

77. The method of embodiment 55, wherein the PPAR-associated disorder is an abnormally high concentration of HDL or an abnormally low concentration of apo A-I in the lymphatic or cerebral fluid of the subject.

78. The method of embodiment 55, wherein the obesity is abdominal obesity.

79. The method of embodiment 55, wherein the cerebrovascular disease is cerebral ischemia.

80. The method of embodiment 55, wherein the disorder associated with neovascularization is retinopathy or diabetes.

81. The method of embodiment 55, wherein the cancer is human sarcoma or human carcinoma.

82. The method of embodiment 55, wherein the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, hemangiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelioma, synovium, mesothelioma, Ewing tumor, Leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, oral cancer, nasal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary carcinoma. Adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular tumor, lung carcinoma, small cell lung. Carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma, leukemia, acute Lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute promyelocytic leukemia, acute monocytic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute non-lymphatic Cystogenic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, hairy cell leukemia, lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, myelocytic leukemia, polycythemia vera, multiple myeloma, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma , Waldenstrom's macroglobulinemia or heavy chain disease.

83. The method of embodiment 82, wherein the leukemia is acute or chronic lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, lymphocytic leukemia, or myeloid leukemia.

84. The method of embodiment 83, wherein the myelocytic leukemia is acute and myeloblastic, promyelocytic, myelomonocytic, monocytic, or erythroleukemia.

85. The method of embodiment 83, wherein the lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.

86. The method of embodiment 55, wherein the inflammatory disease is multiple sclerosis, chronic inflammatory disorder of the joints, arthritis, respiratory distress syndrome, inflammatory bowel disease, inflammatory lung disorder, inflammatory disorder, inflammatory disorder of the gums, tuberculosis, leprosy, inflammatory disease of the kidney. , an inflammatory disorder of the skin, an inflammatory disease of the central nervous system, systemic lupus erythematosus (SLE), or an inflammatory disease of the heart.

87. The method of embodiment 86,

The arthritis is rheumatoid arthritis or osteoarthritis;

Inflammatory bowel disease is ileitis, ulcerative colitis, or Crohn's disease;

Inflammatory lung disorder is asthma or chronic obstructive airway disease;

The inflammatory disorder of the eye is corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis, or endophthalmitis;

An inflammatory disorder of the gums is periodontitis or gingivitis;

Inflammatory disease of the kidney is glomerulonephritis or nephropathy;

Inflammatory disorders of the skin are acne, sclerodermatitis, psoriasis, eczema, photoaging, or wrinkles;

The inflammatory disease of the central nervous system is AIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer's disease, encephalomyelitis, or viral or autoimmune encephalitis; or

How an inflammatory disease of the heart is cardiomyopathy.

88. The method of embodiment 55, wherein the neurodegenerative disease is Alzheimer's disease or Huntington's disease.

89. The method of embodiment 55, wherein the autoimmune disease is immune-complex vasculitis, systemic lupus, or erythema.

90. The method of embodiment 55, wherein the neoplastic disease is carcinogenesis.

91. The method of embodiment 55, wherein the cholestasis is an intrahepatic cholestatic disease or an extrahepatic cholestatic disease.

92. The method of embodiment 91, wherein the intrahepatic cholestatic disease is primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), progressive familial intrahepatic cholestasis (PFIC), or Alagille syndrome (AS).

93. The method of embodiment 55, wherein the eye disease is dry eye, meibomian gland dysfunction, corneal conjunctival epithelial disorder, corneal epithelial disorder, or corneal ulcer.

94. The method of embodiment 55, wherein the lysosomal storage disorder is neuronal ceroid lipofuscinosis, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Lewy body dementia (DLB), disorders of the autophagy pathway, Tay-Sachs disease, Fabry disease, Niemann-Pick disease, Gaucher disease, Hunter syndrome, alpha-mannoside accumulation, aspartylglucosaminuria, Cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystine accumulation disease, Danon disease, Faber disease, fucoside accumulation disease, galactosialic acidosis, or Batten disease.

95. The method of embodiment 55, wherein the renal disease is renal ischemia reperfusion injury.

96. The method of embodiment 55, wherein the erectile dysfunction is caused by damage to nerves, arteries, smooth muscles, or fibrous tissue; diabetes; kidney disease; alcoholism; multiple sclerosis; atherosclerosis; vascular disease; or resulting from a neurological disease.

97. A method of treating or preventing hyperlipidemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia or dyslipidemia, comprising administering to a subject in need thereof an effective amount of a compound or compound of any one of embodiments 1 to 50. A method comprising administering a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of

98. The method of embodiment 97, wherein the hypercholesterolemia is homozygous familial hypercholesterolemia.

99. Abnormally high concentrations of high low density lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein(a) (Lp(a)), apolipoprotein(a), or very low density lipoprotein (VLDL) in the subject's plasma or serum ), comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt, solvate, ester, amide or compound of any one of embodiments 1 to 50. A method comprising administering a prodrug.

100. A method of treating or preventing a subject having abnormally low concentrations of high-density lipoprotein (HDL) in the subject's plasma or serum, comprising administering to a subject in need thereof an effective amount of any one of embodiments 1-50. A method comprising administering a compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

101. A method of treating or preventing a subject having abnormally reduced or deficient lipoprotein lipase concentration or activity in the subject's plasma or serum, comprising administering to a subject in need thereof an effective amount of any one of embodiments 1 to 50. A method comprising administering a compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

102. The method of embodiment 101, wherein the reduced or deficient lipoprotein lipase level or activity is the result of a mutation in the gene encoding the lipoprotein lipase.

103. A method of treating or preventing hypoalphalipoproteinemia, lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, lipoprotein abnormalities associated with Alzheimer's disease, or familial combined hyperlipidemia, comprising administering to a subject in need thereof an effective amount of embodiments 1 to 50. A method comprising administering either a compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

104. Triglycerides, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein(a) (Lp(a) in the subject's plasma or serum )), A method of reducing abnormally high concentrations of apolipoprotein B, HDL/(VLDL+LDL) ratio, apolipoprotein C-II or apolipoprotein C-III, comprising administering to a subject in need thereof an effective amount of embodiments 1 to A method comprising administering a compound of any one of 50 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

105. A method of increasing abnormally low concentrations of high-density lipoprotein (HDL)-related protein, HDL-cholesterol, apolipoprotein A-I or apolipoprotein E in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of embodiment 1 A method comprising administering a compound of any one of to 50 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

106. The method of embodiment 105, wherein the HDL-associated protein is apolipoprotein A-I (apo A-I), apolipoprotein A-II (apo A-II), apolipoprotein A-IV (apo A-IV), or apolipoprotein E (apo E) Method.

107. A method of promoting the clearance of triglycerides from the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 50 or a pharmaceutically acceptable salt, solvate, ester of the compound, A method comprising administering an amide or prodrug.

108. A method of increasing abnormally low glucose metabolism or lipid metabolism in a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 50 or a pharmaceutically acceptable salt, solvate, ester of the compound, A method comprising administering an amide or prodrug.

109. The method of embodiment 108, wherein the method of increasing abnormally low glucose metabolism increases the subject's insulin sensitivity or oxygen consumption or reduces blood insulin, blood glucose, or glycated hemoglobin in the subject's plasma or serum. .

110. The method of embodiment 108, wherein the method of increasing abnormally low lipid metabolism reduces the concentration of LDL or free triglycerides in the plasma or serum of the subject or inhibits saponified or non-saponifiable fatty acid synthesis.

111. A method of treating or preventing symptoms of a disease selected from inflammation, systemic lupus erythematosus, lupus nephritis or arthritis, comprising providing to a subject in need thereof an effective amount of a compound or compounds of any one of embodiments 1 to 50 or a pharmaceutically acceptable compound. A method comprising administering a salt, solvate, ester, amide or prodrug.

112. The method of embodiment 111, wherein the arthritis is adjuvant arthritis or type II collagen-induced arthritis.

113. The method of embodiment 111, wherein the condition is nephritis, renal failure, or decreased renal function.

114. A method of reducing the fat content of meat in livestock, comprising administering to the livestock an effective amount of a compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of any one of embodiments 1 to 50. How to include it.

115. A method of reducing the cholesterol content of poultry eggs, comprising administering to the poultry species an effective amount of a compound of any one of embodiments 1 to 50 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound. How to include it.

116. A method of treating a subject having or at risk for acute kidney injury (AKI), comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, solvate of any one of embodiments 1 to 50, A method comprising administering an ester, amide or prodrug.

117. The method of embodiment 116, wherein the compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound is administered intravenously, optionally wherein the method comprises intravenous administration once daily, optionally for 3 days. How to do it.

118. The method of embodiment 116, wherein the compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound is administered orally.

119. The method of any one of embodiments 116 to 118, wherein the AKI is sepsis-related AKI.

120. The method of any one of embodiments 116 to 118, wherein the AKI is ischemia/reperfusion AKI.

121. The method of any one of embodiments 116 to 118, wherein the AKI is from acute interstitial nephritis.

122. The method of any one of embodiments 116 to 118, wherein the AKI is from glomerular nephropathy.

123. The method of any one of embodiments 116 to 118, wherein the AKI is from acute vasculitic kidney disease.

124. The method of any one of embodiments 116 to 118, wherein the AKI is from ischemia.

125. The method of any one of embodiments 116 to 118, wherein the AKI is from toxic injury.

126. The method of any one of embodiments 116 to 118, wherein the AKI is from prerenal azotemia.

127. The method of any one of embodiments 116 to 118, wherein the AKI is from acute postrenal destructive nephropathy.

128. The method of any one of embodiments 116 to 118, wherein the AKI is from diabetes.

129. The method of any one of embodiments 116 to 118, wherein the AKI is from underlying renal insufficiency.

130. The method of any one of embodiments 116 to 118, wherein the AKI is from nephritic syndrome.

131. The method of any one of embodiments 116 to 118, wherein the AKI is from atherosclerotic disease.

132. The method of any one of embodiments 116 to 118, wherein the AKI is from hypotension.

133. The method of any one of embodiments 116 to 118, wherein the AKI is from hypoxia.

134. The method of any one of embodiments 116 to 118, wherein the AKI is from myoglobinuria-hematuria.

135. The method of any one of embodiments 116 to 118, wherein the AKI is from a liver disease.

136. The method of any one of embodiments 116 to 118, wherein the AKI is secondary to a viral infection, optionally wherein the viral infection is COVID-19.

137. The method of embodiment 136, wherein the subject has a viral infection, optionally wherein the viral infection is COVID-19.

138. The method of any one of embodiments 116 to 119, wherein the subject has sepsis.

139. The method of embodiment 137, wherein the sepsis is associated with a Gram-negative bacterial infection.

140. The method of embodiment 138 or embodiment 139, wherein the subject has an intra-abdominal infection.

141. The method of embodiment 138 or embodiment 139, wherein the subject has urosepsis.

142. The method of any one of embodiments 116 to 141, wherein the subject is elderly.

143. The method of any one of embodiments 116 to 142, wherein the subject is a surgical patient.

144. The method of embodiment 143, wherein the surgical patient has optionally undergone cardiovascular surgery, which is coronary artery bypass graft (CABG) surgery and/or heart valve surgery.

145. The method of any one of embodiments 116 to 141, wherein the subject is pregnant.

146. The method of any one of embodiments 116 to 145, wherein the subject is exposed to a nephrotoxic agent.

147. The method of embodiment 146, wherein the nephrotoxic agent comprises cisplatin, gentamicin, cephaloridine, cyclosporin, amphotericin, carbon tetrachloride, trichloroethylene, dichloroacetylene, or combinations thereof.

148. The method of any one of embodiments 116 to 147, wherein the subject has AKI.

149. The method of embodiment 148, wherein the effective amount is effective for reducing the severity of AKI.

150. The method of any one of embodiments 116 to 147, wherein the subject is at risk for AKI.

151. The method of any one of embodiments 116 to 147, wherein the subject is optionally at risk of AKI following cardiovascular surgery, which is coronary artery bypass graft (CABG) surgery and/or heart valve surgery.

152. The method of embodiment 150 or embodiment 151, wherein the effective amount is effective in reducing the likelihood of developing AKI in the subject.

153. The method of any one of embodiments 150 to 152, wherein the effective amount is effective for delaying the onset of AKI.

154. The method of any one of embodiments 150 to 152, wherein the effective amount is effective for preventing AKI.

155. The method of any one of embodiments 150 to 152, wherein when the subject develops AKI, the effective amount is effective to reduce the severity of AKI.

156. The method of any one of embodiments 116 to 155, wherein the subject has a SOFA score of 1 to 4 prior to administration of the compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound or pharmaceutical composition. method.

157. The method of embodiment 156, wherein the subject has a SOFA score of 2 to 4 prior to administration.

158. The method of embodiment 156, wherein the subject has a SOFA score of 1 prior to administration.

159. The method of embodiment 156, wherein the subject has a SOFA score of 2 prior to administration.

160. The method of embodiment 156, wherein the subject has a SOFA score of 3 prior to administration.

161. The method of embodiment 156, wherein the subject has a SOFA score of 4 prior to administration.

162. The method of any one of embodiments 116 to 161, wherein the subject has an endotoxin activity level of > 0.6 prior to administration.

163. The method of any one of embodiments 116 to 162, wherein the effective amount is effective to reduce the level of endotoxin activity in the subject.

7.2. Specific Embodiments, Group 2

Various aspects of the disclosure are described in numbered embodiments presented in the numbered paragraphs below, where references to previously numbered embodiments refer to previously numbered embodiments in this Section 7.2.

1. A compound of formula (C) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here

R ¹ is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl, any of which is unsubstituted or C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy , C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;

R ² is C 1-8 substituted with C _2-8 alkyl, _{C 1-8} haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkyl alkyl, or C _1-6 alkyl substituted with phenyl, naphthyl or pyridyl, any of which is unsubstituted or C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy, C _{1- 8} substituted with haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;

A is oxygen, sulfur or NR ⁹ , where R ⁹ is hydrogen or C _1-8 alkyl;

X is a C _1-8 alkylene chain, which is unsubstituted or substituted with C _1-8 alkyl, C _1-8 alkoxy or hydroxyl and has 0 or 1 double bond;

Y is C(=O), C(=N-OR ¹⁰ ), CH(OR ¹¹ ), CH=CH, C≡C or C(=CH ₂ ), where each of R ¹⁰ and R ¹¹ is hydrogen or C _1-8 alkyl;

Each of R ³ , R ⁴ and R ⁵ is independently hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _{2 -8} alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl; optionally wherein at least one of R ³ , R ⁴ and R ⁵ is not hydrogen;

B is CH or nitrogen;

Z is oxygen or sulfur;

Each R ⁶ and R ⁷ is independently hydrogen, C _1-8 alkyl, or C _1-8 haloalkyl;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

2. The method of embodiment 1, wherein R ¹ is phenyl, which is C _1-8 alkyl, C _1-8 alkyl with 1-3 halogen atoms, C _1-8 alkoxy, C with 1-3 halogen atoms _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl. A compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound.

3. The compound of Embodiment 1 or Embodiment 2, wherein R ² is C _2-8 alkyl, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

4. The method of any one of embodiments 1 to 3, wherein R ¹ is attached at the second position, and (i) R ⁴ is attached at the 4th position and --X--Y- is attached at the 5th position; or (ii) R ⁴ is attached at the 5th position and --X--Y-- is attached at the 4th position; or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound. .

5. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 to 4, wherein A is oxygen or sulfur.

6. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 to 5, wherein X is a C _1-8 alkylene chain.

7. The compound according to any one of embodiments 1 to 6, wherein Y is C(=O), or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

8. The compound or pharmaceutically acceptable salt of the compound according to any one of embodiments 1 to 7, wherein each of R ³ , R ⁴ and R ⁵ is hydrogen, C _1-8 alkyl or C _1-8 alkyl with halogen. , solvate, ester, amide or prodrug.

9. The compound according to any one of embodiments 1 to 8, wherein B is CH, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

10. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 to 9, wherein Z is oxygen.

11. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 to 10, wherein each of R ⁶ and R ⁷ is hydrogen or C1-4 alkyl.

12. According to embodiment 1,

R ¹ is phenyl or naphthyl, each of which is C _1-8 alkyl, C _1-8 alkyl with halogen, C _1-8 alkoxy, C _1-8 alkoxy with halogen, C _2-8 alkenyl, C may have one or more substituents selected from the group consisting of _2-8 alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl and pyridyl;

R ² is C _2-8 alkyl;

A is oxygen or sulfur;

X is a C _1-8 alkylene chain, which may have a C _1-8 alkyl substituent and may contain a double bond;

Y is C(=O), CH=CH or C(=CH ₂ );

Each of R ³ , R ⁴ and R ⁵ is hydrogen, C _1-8 alkyl, C _1-8 alkyl with halogen, C _1-8 alkoxy, C _1-8 alkoxy with halogen, C _2-8 alkenyl, C _2-8 alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;

B is CH;

Z is oxygen or sulfur;

each of R ⁶ and R ⁷ is hydrogen or C _1-8 alkyl

A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound.

13. The compound of embodiment 12, wherein X is a C _1-8 alkylene chain, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

14. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 12, wherein R ¹ is attached at the second position.

15. The compound or a pharmaceutically acceptable salt, solvate, ester of the compound according to any one of embodiments 12 to 14, wherein R ³ , R ⁴ and R ⁵ other than hydrogen are located ortho-position with respect to Z. , amide or prodrug.

16. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 1, wherein R ¹ is phenyl substituted with CF ₃ .

17. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 1 or embodiment 16, wherein R ² is isopropyl.

18. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1, 16 and 17, wherein A is sulfur.

19. The compound according to any one of embodiments 1 and 16 to 18, wherein X is CH ₂ CH ₂ or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

20. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 and 16 to 19, wherein Y is C(=O).

21. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 and 16 to 19, wherein Y is CH(OH).

22. The compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 and 16 to 21, wherein R ³ is CH ₃ and R ⁴ and R ⁵ are each hydrogen. .

23. The compound according to any one of embodiments 1 and 16 to 22, wherein B is CH, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

24. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 and 16 to 23, wherein Z is oxygen.

25. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 1 and 16 to 24, wherein R ⁶ and R ⁷ are each hydrogen.

26. Compounds of formula (D) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

Each of R ¹ and R ² is independently hydrogen, halogen, nitro, C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl having 1 to 3 halogens, C having 1 to 3 halogens _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl, C _1-8 alkyl substituted with 3-7 membered cycloalkyl, optionally substituted C _6-10 aryl , an arylalkyl group with a C _6-10 aryl moiety and a C _1-8 alkyl moiety, a heterocyclic group or a heterocyclic-alkyl group with a C _1-8 alkyl group;

Each occurrence of R ³ , R ⁴ and R ⁵ is independently hydrogen or C _1-8 alkyl;

A is an oxygen atom, a sulfur atom, or NR ³ ;

^{Each of X 1} _, SO ₂ NH, CH=CH, C≡C or a combination;

Y is C _1-8 alkylene;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

27. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 26, wherein X ¹ is C(=O), CH(OH) or a bond.

28. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 26 or embodiment 27, wherein X ² is C(=O), CH(OH) or a bond.

29. Compounds of formula (E) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

Each R ¹¹ and R ¹² is independently hydrogen, halogen, nitro, hydroxyl, amino, C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl group having 1 to 3 halogens, 1 to C _1-8 haloalkoxy group with 3 halogens, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl, C _1-8 alkyl with 3-7 membered cycloalkyl substituent, or a phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl group, which optionally has a halogen atom, nitro, hydroxyl, amino, C _1-8 alkyl, C _1-8 Alkoxy, C _1-8 haloalkyl with 1 to 3 halogens, C _1-8 haloalkoxy with 1 to 3 halogens, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl group, a C _1-8 alkyl group with a 3-7 membered cycloalkyl substituent, a phenyl or pyridyl substituent;

^{Each of _ _} _{_ _} NH, CH=CH, C≡C or a bond, where each R ¹⁴ and R ¹⁵ is hydrogen or C _1-8 alkyl;

Y ¹ is C _1-8 alkylene;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

30. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 29, wherein X ¹ is C(=O), CH(OH) or a bond.

31. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 29 or embodiment 30, wherein Z ¹ is C(=O), CH(OH) or a bond.

32. The compound or pharmaceutically acceptable salt, solvate, ester, amide of the compound according to any one of embodiments 29 to 31, wherein X ¹ -Y ¹ -Z ¹ is bonded to the 3 or 4 position of the phenyl ring. or prodrug.

33. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 29 to 32, wherein X ¹ is a bond and Z ¹ is (C=O).

34. The compound or pharmaceutically acceptable salt, ^solvate , ^ester , amide or compound according to any one of embodiments ²⁹ to 33, wherein Prodrug.

35. The method of any one of embodiments 29 to 34, wherein R ¹¹ is a phenyl or naphthyl group, which is optionally chlorine, fluorine, hydroxyl, an alkyl group having 1-5 carbon atoms and 2- of a 5-membered ring. The compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound having a substituent selected from the group consisting of an alkyl group having 1-5 carbon atoms attached to the position.

36. The compound or a pharmaceutically acceptable salt, solvate of the compound according to any one of embodiments 29 to 35, wherein R ¹² is an alkyl group having 3-6 carbon atoms, bonded to the 5-position of the 5-membered ring, Ester, amide or prodrug.

37. Compounds of formula (F) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

A is O, S or NR ⁷ , where R ⁷ is hydrogen or C _1-8 alkyl;

B ¹ is CW or N, where W is hydrogen or a bond; B ² is O, S or NR ⁸ , where R ⁸ is hydrogen or C _1-8 alkyl;

^Each of ^{X 1 and} , wherein each R ⁹ and R ¹⁰ is hydrogen or C _1-8 alkyl;

Y is C _1-8 alkylene, which is unsubstituted or substituted with C _1-8 alkyl or C _1-8 haloalkyl with 1-3 halogens;

Z is NH, O or S;

R ¹ is unsubstituted or aryl substituted with C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl with 1-3 halogens, hydroxyl, nitro, amino, phenyl, pyridyl or halogen. , or a heterocyclic group having a 5- to 8-membered ring, each of which is independently nitrogen, oxygen or sulfur, and the other atom is carbon, optionally wherein the benzene ring is condensed with the heterocyclic ring and ;

R ² is C _2-8 alkyl, C _1-8 haloalkyl with 1-3 halogens, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, unsubstituted or C _{1 -8} alkyl, C _1-8 alkoxy, C _1-8 haloalkyl with 1-3 halogens, C _1-4 alkyl substituted with hydroxyl, nitro, amino, phenyl, pyridyl or aryl substituted with halogen, or C _1-4 alkyl substituted with a heterocyclic group having a 5 to 8 membered ring having 1 to 3 heteroatoms each independently being nitrogen, oxygen or sulfur;

R ³ is halogen, trifluoromethyl, C _1-8 alkyl, C _2-8 alkenyl or C _2-8 alkynyl;

each of R ⁴ and R ⁵ is hydrogen, C _1-8 alkyl or C _1-8 haloalkyl with 1-3 halogens;

Each of Z and R ³ is attached to a benzene ring and X ² is not attached to a benzene ring;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

38. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 37, wherein X ¹ is C(=O), CH(OH) or a bond.

39. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 37 or embodiment 38, wherein X ² is C(=O), CH(OH) or a bond.

40. Compounds of formula (G) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

Each of R ¹ and R ⁴ is the same or different and is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;

R ² is hydrogen;

R ³ is C _1-8 alkyl, or R ³ is combined with R ² to form =O or =C(R ⁷ )(R ⁸ ), wherein each of R ⁷ and R ⁸ is the same or different; hydrogen or C _1-8 alkyl;

Each of R ⁵ and R ⁶ is the same or different and is a hydrogen atom, C _1-8 alkyl, C _1-8 haloalkyl;

X and Y are the same or different and each represents CH or N;

Z is oxygen or sulfur;

A is a 5-membered heterocyclic group that is pyrazole, thiophene, furan or pyrrole, wherein the heterocyclic group is unsubstituted or C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _2-8 alkyl Kenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _1-8 alkyl group substituted by 3- to 7-membered cycloalkyl group, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _{6- 10} aryl, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered heterocyclic group. substituted with C _1-8 alkyl;

B is a C _1-8 alkylene chain, which is unsubstituted or C _1-8 alkyl, a 3- to 7-membered cycloalkyl group, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 substituted by alkoxy, halogen, C _1-8 haloalkyl or C _1-8 haloalkoxy, and when the alkylene group has 2 to 6 carbon atoms the alkylene group optionally has a double bond;

q is 0, 1, 2, 3, 4 or 5;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

41. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 40, wherein A is pyrazole.

42. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 41, wherein -(CH ₂ ) _q - is attached to the pyrazole at its 1-position.

43. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 41, wherein -(CH ₂ ) _q - is attached to the pyrazole at its 3-position.

44. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 42 or 43, wherein -B- is attached to the pyrazole at its 4- or 5-position.

45. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 40, wherein A is thiophene, furan or pyrrole.

46. The compound or pharmaceutically acceptable salt, solvate, ester, amide or precursor of the compound according to embodiment 45, wherein -(CH ₂ ) _q - is attached at its 2-position to a 5-membered heterocyclic group. drug.

47. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 40, wherein A is thiophene.

48. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 47, wherein -(CH ₂ ) _q - is attached to the thiophene at its 2-position.

49. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 40 to 48, wherein q is 0.

50. The compound according to any one of embodiments 40 to 49, wherein each of X and Y is CH, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

51. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 40 to 50, wherein R ² in combination with R ³ represents =O.

52. The method of any one of embodiments 40 to 51, wherein B represents an alkylene chain having 2 to 4 carbon atoms, optionally an alkyl group having 1 to 8 carbon atoms and 1 to 8 carbon atoms and a halogen A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound having a substituent selected from the group consisting of an alkyl group having an atomic substituent.

53. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 40 to 52, wherein B is an ethylene chain.

54. The method of any one of embodiments 40 to 53, wherein R ¹ and R ⁴ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms. , a halogen atom, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent, or an alkoxy group having 1 to 8 carbon atoms and a halogen atom substituent, or a pharmaceutically acceptable salt, solvate, ester of the compound. , amide or prodrug.

55. The compound or pharmaceutically acceptable compound according to any one of embodiments 40 to 54, wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. Salt, solvate, ester, amide or prodrug.

56. The method of any one of embodiments 40 to 55, wherein the substituent optionally attached to the heterocyclic group for A is an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound.

57. Compounds of formula (H) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

Each of R ¹¹ and R ¹³ is the same or different and is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;

R ¹² is hydrogen, C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to 7-membered cycloalkyl group substituent C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered heterocyclic group, C _6-10 aryl moiety and C _1- an aralkyl group with _{an 8} alkylene moiety, or a C _1-8 alkyl group with a 5- or 6-membered heterocyclic substituent;

R ¹⁴ and R ¹⁵ are the same or different and each is a hydrogen atom, C _1-8 alkyl or C _1-8 haloalkyl;

X ¹ is CH or N;

Z ¹ is oxygen or sulfur;

W ¹ is oxygen or CH ₂ when a bond a is present and OH when a bond a is absent;

q is 2, 3 or 4;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

58. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 57, wherein X ¹ is CH.

59. The compound or a pharmaceutically acceptable salt, solvate, ester, amide or precursor of the compound according to embodiment 57 or 58, wherein R ¹¹ -phenyl or R ¹¹ -pyridyl is attached to the pyrazole at the 1-position. drug.

60. The compound or pharmaceutically acceptable salt, solvate, ester, amide or precursor of the compound according to embodiment 57 or 58, wherein R ¹¹ -phenyl or R ¹¹ -pyridyl is attached to the pyrazole at the 3-position. drug.

61. The compound according to any one of embodiments 57 to 60, wherein -(CH ₂ ) _q - is attached to the pyrazole at the 4- or 5-position, or a pharmaceutically acceptable salt, solvate, ester of the compound, Amide or prodrug.

62. The method of any one of embodiments 57 to 61, wherein R ¹¹ and R ¹³ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms. , a halogen atom, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent, or an alkoxy group having 1 to 8 carbon atoms and a halogen atom substituent, or a pharmaceutically acceptable salt, solvate, ester of the compound. , amide or prodrug.

63. The method of any one of embodiments 57 to 61, wherein R ¹¹ and R ¹³ are the same or different and each is an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound representing a group.

64. The compound or pharmaceutically acceptable compound according to any one of embodiments 57 to 63, wherein R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. Salt, solvate, ester, amide or prodrug.

65. The method of any one of embodiments 57 to 64, wherein R ¹² is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, 1 to 8 carbon atoms and a halogen atom. A compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound, which represents an alkyl group with a substituent or an alkoxy group with 1 to 8 carbon atoms and a halogen atom substituent.

66. The compound according to any one of embodiments 57 to 64, or the pharmaceutical form of the compound, wherein R ¹² represents an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. Acceptable salts, solvates, esters, amides or prodrugs.

67. The compound according to any one of embodiments 57 to 66, wherein q is 2, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

68. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 57 to 67, wherein bond a is absent and W ¹ is OH.

69. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 57 to 67, wherein bond a is present and W ¹ is oxygen.

70. Compounds of formula (J) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

Each of R ²¹ and R ²³ is the same or different and is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;

R ²² is hydrogen, C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to 7-membered cycloalkyl group substituent C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered heterocyclic group, C _6-10 aryl moiety and C _1- an aralkyl group with _{an 8} alkylene moiety, or a C _1-8 alkyl group with a 5- or 6-membered heterocyclic substituent;

R ²⁴ and R ²⁵ are the same or different and each is a hydrogen atom, C _1-8 alkyl or C _1-8 haloalkyl;

X ² is CH or N;

Z ² is oxygen or sulfur;

W ² is oxygen or CH ₂ when a bond a is present and OH when a bond a is absent;

r is 2, 3 or 4;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

71. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 70, wherein X ² is CH.

72. The compound or pharmaceutically acceptable salt, solvate, ester, amide or precursor of the compound according to embodiment 70 or 71, wherein R ²¹ -phenyl or R ²¹ -pyridyl is attached at the 2-position to the thiophene. drug.

73. The method of any one of embodiments 70 to 72, wherein R ²¹ and R ²³ are the same or different and each is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms. , a halogen atom, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent, or an alkoxy group having 1 to 8 carbon atoms and a halogen atom substituent, or a pharmaceutically acceptable salt, solvate, or ester of the compound. , amide or prodrug.

74. The method of any one of embodiments 70 to 72, wherein R ²¹ and R ²³ are the same or different and each is an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound representing a group.

75. The compound or pharmaceutically acceptable compound according to any one of embodiments 70 to 74, wherein R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. Salt, solvate, ester, amide or prodrug.

76. The method of any one of embodiments 70 to 75, wherein R ²² is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, 1 to 8 carbon atoms and a halogen atom. A compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound, which represents an alkyl group with a substituent or an alkoxy group with 1 to 8 carbon atoms and a halogen atom substituent.

77. The compound according to any one of embodiments 70 to 75, or the pharmaceutical form of the compound, wherein R ²² represents an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. Acceptable salts, solvates, esters, amides or prodrugs.

78. The compound according to any one of embodiments 70 to 77, wherein r is 2, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

79. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 70 to 78, wherein bond a is absent and W ² is OH.

80. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 70 to 78, wherein bond a is present and W ² is oxygen.

81. Compounds of formula (K) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

A is CH or nitrogen;

B, when a bond a is present, is oxygen or C(R ⁸ )(R ⁹ ), where each R ⁸ and R ⁹ are independently hydrogen or C _1-8 alkyl; B, in the absence of bond a, is OH;

W ¹ is a bond, C(=O) or (C(R ¹⁰ )(R ¹¹ )) _m , where each R ¹⁰ and R ¹¹ is independently hydrogen or a C _1-8 alkyl group, and m is 1, 2 or 3;

X and Y are different from each other and each is an oxygen atom, a sulfur atom, a nitrogen atom or CR ¹² , where R ¹² is hydrogen or C _1-8 alkyl;

Z ¹ is a bond, oxygen, sulfur, or C(R ¹³ )(R ¹⁴ ), where each R ¹³ and R ¹⁴ are independently hydrogen or C _1-8 alkyl;

Each of R ¹ , R ² and R ³ is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;

Each R ⁴ and R ⁵ is independently hydrogen, C _1-8 alkyl, C _1-8 haloalkyl;

Each R ⁶ and R ⁷ is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl or C _1-8 haloalkyl;

r is 1, 2, 3, 4 or 5;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

82. The compound according to embodiment 81, wherein A is CH, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

83. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 81 or 82, wherein W ¹ is a bond.

84. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 81 or 82, wherein W ¹ is methylene or C(=O).

85. The compound or pharmaceutically acceptable salt, solvate, ester, amide or precursor of the compound according to any one of embodiments 81 to 84, wherein X and Y are different from each other and each is an oxygen atom, a sulfur atom or a nitrogen atom. drug.

86. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 85, wherein X is a sulfur atom and Y is a nitrogen atom.

87. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 81 to 86, wherein Z ¹ is an oxygen atom or a sulfur atom.

88. The method of any one of embodiments 81 to 87, wherein R ¹ , R ² and R ³ are independently a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, Pharmaceutically acceptable compounds or compounds containing an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted by a halogen atom or an alkoxy group having 1 to 8 carbon atoms substituted by a halogen atom. A salt, solvate, ester, amide, or prodrug.

89. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 81 to 88, wherein each R ⁴ and R ⁵ is independently a hydrogen atom or methyl.

90. The compound according to any one of embodiments 81 to 89, wherein each R ⁶ and R ⁷ is independently a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, or a pharmaceutically acceptable salt, solvate, ester of the compound. , amide or prodrug.

91. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 81 to 90, wherein n is an integer from 2 to 4.

92. The compound of embodiment 91, wherein n is 2, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

93. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 81 to 92, wherein bond a is absent and B is OH.

94. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 81 to 92, wherein bond a is present and B is oxygen.

95. Compounds of formula (L) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

B, if bond a is present, is oxygen; B, in the absence of bond a, is OH;

W ² is a bond, C(=O) or CH ₂ ;

Z ² is oxygen or sulfur;

Each of R ²¹ , R ²² and R ²³ is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;

Each R ²⁴ and R ²⁵ is independently hydrogen, C _1-8 alkyl, C _1-8 haloalkyl;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

96. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 95, wherein W ² is a bond.

97. Embodiment 95 or 96, wherein R ²¹ , R ²² and R ²³ are independently a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, 1 to 8 an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted by a halogen atom, or an alkoxy group having 1 to 8 carbon atoms substituted by a halogen atom, or a pharmaceutically acceptable salt of the compound, Solvate, ester, amide or prodrug.

98. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 95 to 97, wherein each R ²⁴ and R ²⁵ is independently a hydrogen atom or methyl.

99. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 95 to 98, wherein bond a is absent and B is OH.

100. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 95 to 98, wherein bond a is present and B is oxygen.

101. Compounds of formula (M) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

Each W ¹ and W ² is independently nitrogen or CH;

X is nitrogen or CH;

Y is oxygen or sulfur;

Z is a bond, oxygen, sulfur or NR ⁵ where R ⁵ is hydrogen or C _1-8 alkyl;

Each R ¹ and R ² are independently hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl, 3- to 7-membered cycloalkyl group, C _2-8 alkenyl, C _2-8 alkynyl , C _1-8 alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered a heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene, or a C _1-8 alkyl with a 5- or 6-membered heterocyclic substituent;

Each R ³ and R ⁴ is independently hydrogen, C _1-8 alkyl, or C _1-8 haloalkyl;

A is a 5-membered heterocycle that is pyrazole, thiophene, furan, isoxazole, isothiazole or pyrrole, wherein the 5-membered heterocycle is unsubstituted or halogen, hydroxyl, nitro, amino, C _1-8 Alkyl, 3- to 7-membered cycloalkyl group, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _1-8 alkyl with 3- to 7-membered cycloalkyl substituents, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered heterocyclic group, aralkyl with C _6-10 aryl moiety and C _1-8 alkylene moiety group, or a C _1-8 alkyl group having a 5- or 6-membered heterocyclic substituent;

B is a bond or C _1-8 alkylene, which is unsubstituted or substituted by C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _1-8 alkoxy or halogen substituent, optionally wherein C _{1- 8} Alkylene has double or triple bonds;

r is 0, 1, 2 or 3;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

102. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 101, wherein each W ¹ and W ² represents CH.

103. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 101, wherein W ¹ represents CH and W ² represents a nitrogen atom.

104. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 101 to 103, wherein X represents a nitrogen atom.

105. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of any one of embodiments 101 to 103, wherein X represents a nitrogen atom and Y represents an oxygen atom.

106. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 101 to 103, wherein X represents CH and Y represents an oxygen atom.

107. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 101 to 106, wherein Z represents an oxygen atom or a sulfur atom.

108. The method of any one of embodiments 101 to 107, wherein each R ¹ and R ² are independently a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, an alkyl group having 1 to 8 carbon atoms, A compound or pharmaceutically acceptable salt of a compound, which represents an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and a halogen substituent, or an alkoxy group having 1 to 8 carbon atoms and a halogen substituent. , solvate, ester, amide or prodrug.

109. The compound or pharmaceutically acceptable salt of the compound, solvent according to any one of embodiments 101 to 108, wherein each R ³ and R ⁴ independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. Cargo, ester, amide or prodrug.

110. The method of any one of embodiments 101 to 109, wherein A represents pyrazole, thiophene or furan, and is selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, an amino group, an alkyl group having 1 to 8 carbon atoms, 3- to 7-membered cycloalkyl group, alkenyl group with 2 to 8 carbon atoms, alkynyl group with 2 to 8 carbon atoms, alkoxy group with 1 to 8 carbon atoms, 1 to 8 carbons alkyl groups with 1 to 8 carbon atoms and halogen substituents, alkyl groups with 1 to 8 carbon atoms and halogen substituents, alkoxy groups with 1 to 8 carbon atoms and halogen substituents, 6 to 10 carbon atoms an aryl group having, a 5- or 6-membered heterocyclic group, an aralkyl group having an aryl moiety of 6 to 10 carbon atoms and an alkylene moiety of 1 to 8 carbon atoms, and 1 to 8 carbon atoms A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound, which may have a substituent selected from the group consisting of an alkyl group with an atom and a 5- or 6-membered heterocyclic substituent.

111. The method of any one of embodiments 101 to 109, wherein A represents pyrazole, thiophene or furan, which is a halogen atom, a hydroxyl group, a nitro group, an amino group, an alkyl group having 1 to 8 carbon atoms, Compounds which may have a substituent selected from the group consisting of an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and a halogen substituent, or an alkoxy group having 1 to 8 carbon atoms and a halogen substituent. or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

112. The method of any one of embodiments 101 to 109, wherein A represents pyrazole, and is selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, an amino group, an alkyl group having 1 to 8 carbon atoms, and 1 to 8 carbon atoms. A compound or pharmaceutically acceptable use of the compound, which may have a substituent selected from the group consisting of an alkoxy group having 1 to 8 carbon atoms and a halogen substituent, and an alkoxy group having 1 to 8 carbon atoms and a halogen substituent. Acceptable salts, solvates, esters, amides or prodrugs.

113. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 101 to 112, wherein B represents an alkylene chain having 2 to 4 carbon atoms.

114. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 101 to 113, wherein n is 0.

115. Compounds of formula (N) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

W ³ is nitrogen or CH;

Z ¹ is oxygen or sulfur;

Each R ¹¹ and R ¹² is independently hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl or C _1-8 haloalkoxy;

Each R ¹³ and R ¹⁴ is independently hydrogen or C _1-8 alkyl;

A ¹ is a 5-membered heterocycle that is pyrazole or thiophene, wherein the 5-membered heterocycle is unsubstituted or halogen, hydroxyl, nitro, amino, C _1-8 alkyl, C _1-8 alkoxy, C _{1 -8} haloalkyl or C _1-8 haloalkoxy;

m is 2, 3 or 4;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

116. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 115, wherein W ³ represents CH.

117. The method of embodiment 115 or 116, wherein A ¹ represents pyrazole, which contains a halogen atom, a hydroxyl group, a nitro group, an amino group, an alkyl group having 1 to 8 carbon atoms, a 1 to 8 carbon atom A compound or pharmaceutically acceptable form of a compound which may have a substituent selected from the group consisting of an alkoxy group having 1 to 8 carbon atoms and a halogen substituent, or an alkoxy group having 1 to 8 carbon atoms and a halogen substituent. Salt, solvate, ester, amide or prodrug.

118. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 115 to 117, wherein m is 2 or 3.

119. Compounds of formula (O) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

Each W ¹ and W ² is independently CH or nitrogen;

X is NR ⁵ or CR ⁶ R ⁷ ; Here, R ⁵ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkyl substituted with C _1-8 alkoxy, C _3-7 cycloalkyl, C substituted with C _3-7 cycloalkyl _1-8 alkyl, C _1-8 alkyl substituted with phenyl, C _2-8 acyl or C _2-8 alkenyl, and each of R ⁶ and R ⁷ is independently hydrogen or C _1-8 alkyl;

Y is (CR ⁸ R ⁹ ) _r , where each R ⁸ and R ⁹ are independently hydrogen or C _1-8 alkyl and r is 1, 2, 3 or 4; or

X and Y are combined to form CR ¹⁰ =CR ¹¹ or ethynylene, wherein each R ¹⁰ and R ¹¹ is independently hydrogen or C _1-8 alkyl;

G, when the bond a is present, is O, S or CR ¹² R ¹³ , where each of R ¹² and R ¹³ is independently hydrogen or C _1-8 alkyl; G, in the absence of bond a, is OH;

A is a 5-membered heterocyclic ring that is thiazole, oxazole, imidazole, pyrazole, thiophene, furan or pyrrole, wherein the heterocyclic ring is unsubstituted or C _1-8 alkyl, C _2-8 Alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro, C _2-8 acyl, C _6-10 aryl, or substituted with a 5- or 6-membered heterocyclic group;

B is C _1-8 alkylene, C _2-8 alkenylene or C _2-8 alkynylene chain, wherein the chain is unsubstituted or C _1-8 alkyl, C _3-7 cycloalkyl, C _1-8 alkoxy or substituted with halogen;

Each of R ¹ and R ² is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _{1- 8} haloalkoxy, hydroxyl, nitro, C _2-8 acyl, C _6-10 aryl, or a 5- or 6-membered heterocyclic group;

Each R ³ and R ⁴ is independently hydrogen or C _1-8 alkyl;

m is 0, 1, 2 or 3;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

120. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 119, wherein each of W ¹ and W ² is CH.

121. The compound of embodiments 119 or 120, wherein X is CR ⁶ R ⁷ or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

122. The compound of embodiments 119 or 120, wherein X is CH ₂ or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

123. The compound of embodiments 119 or 120, wherein X is NR ⁵ or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

124. The compound of embodiment 119 or 120, wherein X is NH, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

125. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiments 119 or 120, wherein X is NR ³ and R ⁵ is C _1-8 alkyl.

126. The compound according to any one of embodiments 119 to 125, wherein Y is CH ₂ or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

127. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 119 to 126, wherein Z is carboxyl.

128. The method of any one of embodiments 119 to 127, wherein A is thiazole, which is C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, halogen substituted Substituent selected from the group consisting of C _1-8 alkyl, C _1-8 alkoxy substituted by halogen, hydroxyl, nitro, C _2-8 acyl, C _6-10 aryl and 5- or 6-membered heterocyclic group A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound that may be substituted with.

129. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 119 to 128, wherein B is an ethylene chain.

130. The method of any one of embodiments 119 to 129, wherein each R ¹ and R ² are independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkoxy, halogen, halogen. A compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound that is C _1-8 alkoxy substituted by C _1-8 alkyl or halogen.

131. The compound or pharmaceutically acceptable compound according to any one of embodiments 119 to 129, wherein each R ¹ and R ² are independently hydrogen, C _1-8 alkyl, halogen or C _1-8 alkyl substituted by halogen. A salt, solvate, ester, amide, or prodrug.

132. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 119 to 131, wherein each of R ³ and R ⁴ is hydrogen.

133. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 119 to 132, wherein m is 0.

134. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 119 to 133, wherein bond a is absent and G is OH.

135. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 119 to 133, wherein bond a is present and G is oxygen.

136. Compounds of formula (P) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

G ^a , when a bond a is present, is O, S or CH ₂ ; G ^a is OH in the absence of bond a;

A ^a is a 5-membered heterocyclic ring that is thiazole, oxazole or thiophene, wherein the 5-membered heterocyclic ring is unsubstituted or C _1-8 alkyl, C _1-8 alkoxy, halogen, C _{1 -8} haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl;

B ^a is C _1-8 alkylene or C _2-8 alkenylene chain;

Each R ^1a and R ^2a is independently hydrogen, C _1-8 alkyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl ego;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

137. The method of embodiment 136, wherein A ^a is thiazole, which is C _1-8 alkyl, C _1-8 alkoxy, halogen, C _1-8 alkyl substituted by halogen, C _1-8 alkoxy substituted by halogen, hyde A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound which may be substituted with a substituent selected from the group consisting of roxyl, nitro and C _2-8 acyl.

138. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 136 or 137, wherein B ^a is an ethylene chain.

139. The method of any one of embodiments 136 to 138, wherein each R ^1a and R ^2a is independently hydrogen, C _1-8 alkyl, C _1-8 alkoxy, halogen, C _1-8 alkyl substituted with halogen, or halogen. A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound that is C _1-8 alkoxy substituted.

140. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 136 to 139, wherein the bond a is absent and G ^a is OH.

141. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 136 to 139, wherein the bond a is present and G ^a is oxygen.

142. Compounds of formula (Q) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

G ^b , when a bond a is present, is O, S or CH ₂ ; G ^b is OH in the absence of bond a;

A ^b is a 5-membered heterocyclic ring that is thiazole, oxazole or thiophene, wherein the 5-membered heterocyclic ring is unsubstituted or C _1-8 alkyl, C _1-8 alkoxy, halogen, C _{1 -8} haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl;

B ^b is C _1-8 alkylene or C _2-8 alkenylene chain;

Each R ^1b and R ^2b is independently hydrogen, C _1-8 alkyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl ego;

R ^3b is hydrogen or C _1-8 alkyl;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

143. The method of embodiment 142, wherein A ^b is thiazole, which is C _1-8 alkyl, C _1-8 alkoxy, halogen, C _1-8 alkyl substituted by halogen, C _1-8 alkoxy substituted by halogen, hyde A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound, wherein the compound is substituted with a substituent selected from the group consisting of roxyl, nitro and C _2-8 acyl.

144. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 142 or 143, wherein B ^b is an ethylene chain.

145. The method of any one of embodiments 142 to 144, wherein each R ^1b and R ^2b is independently hydrogen, C _1-8 alkyl, C _1-8 alkoxy, halogen, C _1-8 alkyl substituted with halogen, or halogen. A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound that is C _1-8 alkoxy substituted.

146. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 142 to 145, wherein the bond a is absent and G ^b is OH.

147. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 142 to 145, wherein the bond a is present and G ^b is oxygen.

148. Compounds of formula (R) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

Each W ¹ and W ² is independently CH or N;

^{and _ _ _} _{_ _ _ _} C _1-8 alkyl, C _1-8 alkyl substituted with a phenyl group, C _2-8 acyl, or C _2-8 alkenyl;

Each R ⁴ and R ⁵ is independently hydrogen or C _1-8 alkyl;

Y is (CR ⁶ R ⁷ ) _r , where each R ⁶ and R ⁷ are independently hydrogen or C _1-8 alkyl and r is 1, 2, 3 or 4;

A is a 5 or 6-membered heterocyclic group that is thiazole, oxazole, imidazole, pyrazole, thiophene, furan, pyrrole, pyridine or pyrimidine, or is a phenyl group, wherein A is a 5 or 6-membered heterocyclic group The group or phenyl group is unsubstituted or substituted with a C _1-8 alkyl, 3-7 membered cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxyl, 3-7 membered cycloalkyl group. C _1-8 alkyl group, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5 or 6-membered heterocyclic group, C _6-10 aryl group and C _1-8 alkyl substituted with an aralkyl group containing a C 1-8 alkyl group, or a C _1-8 alkyl group substituted with a 5 or 6-membered heterocyclic group;

B is a bond or C _1-8 alkylene, which is unsubstituted or substituted with C _1-8 alkyl, a 3-7 membered cycloalkyl group, C _1-8 alkoxy or halogen, and the number of carbon atoms in the alkylene chain is 2 In the above cases, it may have a double bond or triple bond;

D is N or CH;

E is O or S;

Each of R ¹ and R ² is independently H, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _{1- 8} haloalkoxy, nitro, C _2-8 acyl, C _6-10 aryl, or a 5 or 6-membered heterocyclic group;

m is 0, 1, 2 or 3;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

149. Compounds of formula (S) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

A ¹ is a 5 or 6-membered heterocyclic group that is thiazole, oxazole, pyridine or pyrimidine or is a phenyl group, wherein the 5 or 6-membered heterocyclic group or phenyl group is unsubstituted or C _1-8 substituted with alkyl or C _1-8 haloalkyl;

B ¹ is C _2-4 alkylene;

Each R ¹¹ and R ¹² is independently H, C _1-8 alkyl, halogen or C _1-8 haloalkyl;

R ¹³ is C _1-8 alkyl or C _1-8 haloalkyl, optionally where N to which R ¹³ is attached is attached to the 6th position of the benzisoxazole;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

150. Compounds of formula (T) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

B ² is C _2-4 alkylene;

R ²⁰ is C _1-8 alkyl;

Each R ²¹ and R ²² is independently H, C _1-8 alkyl, halogen or C _1-8 haloalkyl;

R ²³ is C _1-8 alkyl or C _1-8 haloalkyl, optionally where N to which R ²³ is attached is attached to the 6th position of the benzisoxazole;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

n is 0, 1, 2, 3 or 4.

151. Compounds of formula (U) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

R ¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-8 alkyl, C _3-7 cycloalkyl, C2-C8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} acyl, a C _6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered a C _1-8 alkyl group with a heterocyclic substituent;

R ² is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkoxy substituent. a C _1-8 alkyl group, C _2-8 acyl, C _6-10 aryl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety;

Each of R ³ , R ⁴ , R ⁵ and R ⁶ is independently hydrogen, C _1-8 alkyl or C _1-8 haloalkyl;

X is oxygen, sulfur or NR ⁷ ; where R ⁷ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, C _2-8 acyl or C _{2- 8} alkenyl;

Y is oxygen, sulfur, NR ⁸ or a bond, where R ⁸ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 acyl or C _2-8 alkenyl;

p is 0 or 1;

A, when a bond a is present, is oxygen, CH ₂ , N-NH ₂ or N-OR ⁹ , where R ⁹ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 an acyl, C _2-8 alkenyl, or aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety; A, in the absence of bond a, is OH;

B, when p=1, is halogen, hydroxyl, nitro, amino, C _1-8 alkyl, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} a benzene ring with or without a substituent which is an acyl group, a C _6-10 aryl group, or an aralkyl group with a C _6-10 aryl moiety and a C 1 -C 8 alkylene moiety of 1-8 carbon atoms, and p When =0, it is a condensed ring that is indole, benzofuran, benzisoxazole or 1,2-benzisothiazole, wherein the condensed ring is halogen, hydroxyl, nitro, amino, C _1-8 alkyl group, C _{3 -7} cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _1-8 alkyl with 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C1 -C _1-8 alkyl with a C 8 alkoxy substituent, C _1-8 haloalkoxy group, C _2-8 acyl, C _6-10 aryl, or C _6-10 aryl moiety and C _1-8 alkylene moiety with or without an aralkyl group having a substituent;

Y is bonded to the benzene ring of B;

(C(R ³ )(R ⁴ )) _m is bonded at its 3-position to the condensed ring of B;

m is an integer from 1 to 4;

n is 0, 1, 2, 3, 4 or 5;

Y is a union when n=0;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

152. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 151, wherein the bond a is absent and A is OH.

153. Embodiment 151, wherein the bond a is present and A is oxygen, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

154. Compounds of formula (V) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

R ¹¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-8 alkyl, C _3-7 cycloalkyl, C2-C8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} acyl, a C _6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered a C _1-8 alkyl group with a heterocyclic substituent;

R ¹² is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkoxy substituent. a C _1-8 alkyl group, C _2-8 acyl, C _6-10 aryl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety;

Each of R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ is independently hydrogen, C _1-8 alkyl or C _1-8 haloalkyl;

Y ¹ is oxygen, sulfur, NR ¹⁸ or a bond, where R ¹⁸ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 acyl or C _2-8 alkenyl;

A ¹ , when a bond a is present, is oxygen, CH ₂ , N-NH ₂ or N-OR ¹⁹ , where R ¹⁹ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _{2- 8} acyl, C _2-8 alkenyl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety; A ¹ , in the absence of bond a, is OH;

Q ¹ is hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl group, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to C _1-8 alkyl with a 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _2-8 acyl, C _6-10 aryl, or an aralkyl group having a C _6-10 aryl moiety and a C _1-8 alkylene moiety;

r is 1, 2, 3 or 4;

s is 1, 2, 3, 4 or 5;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

155. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 154, wherein the bond a is absent and A ¹ is OH.

156. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment 154, wherein the bond a is present and A ¹ is oxygen.

157. Compounds of formula (W) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

R ²¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-8 alkyl, C _3-7 cycloalkyl, C2-C8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} acyl, a C _6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered a C _1-8 alkyl group with a heterocyclic substituent;

R ²² is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkoxy substituent. a C _1-8 alkyl group, C _2-8 acyl, C _6-10 aryl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety;

Each R ²³ , R ²⁴ , R ²⁵ and R ²⁶ is independently hydrogen, C _1-8 alkyl or C _1-8 haloalkyl;

Y ² is oxygen, sulfur, NR ²⁸ or a bond, where R ²⁸ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 acyl or C _2-8 alkenyl;

Q ² is hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl group, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to C _1-8 alkyl with a 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _2-8 acyl, C _6-10 aryl, or an aralkyl group having a C _6-10 aryl moiety and a C _1-8 alkylene moiety;

t is 1, 2, 3 or 4;

u is 1, 2, 3, 4 or 5;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

158. Compounds of formula (X) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;

Q ¹ is CH or N;

R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;

x is 1 or 2;

R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;

Each R ²⁰ is independently hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;

R ³ is CH ₃ or CD ₃ ;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

159. Compounds of formula (Y) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;

Q ¹ is CH or N;

R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;

x is 1 or 2;

R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;

Each R ²⁰ is independently hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;

R ³ is CH ₃ or CD ₃ ;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

160. Compounds of formula (Z) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;

Q ¹ is CH or N;

R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;

x is 1 or 2;

R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;

Each R ²⁰ is independently hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;

R ³ is CH ₃ or CD ₃ ;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

161. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 158 to 160, wherein R ³ is CH ₃ .

162. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 158 to 161, wherein Q ¹ is CH.

163. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 158 to 161, wherein Q ¹ is N.

164. The method of any one of embodiments 158 to 163, wherein R ² is halogen, -C ₁ -C ₄ -alkyl, -C ₁ -C ₄ -haloalkyl, -C ₁ -C ₄ -haloalkoxy, -S( C ₁ -C ₄ -alkyl) or furanyl, wherein furanyl may be optionally substituted with -C ₁ -C ₄ -alkyl, or a pharmaceutically acceptable salt, solvate, ester, amide or of the compound. Prodrug.

165. The method of any one of embodiments 158 to 163, wherein R ² is halogen, -CH ₃ , -C ₁ -haloalkyl, -C ₁ -haloalkoxy, -SCH ₃ or furanyl, and wherein furanyl is -CH A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound which may be optionally substituted with ₃ .

166. The compound or pharmaceutically acceptable salt of the compound according to any one of embodiments 158 to 163, wherein R ² is halogen, -CH ₃ , -C ₁ -haloalkyl, -C ₁ -haloalkoxy or -SCH ₃ , Solvate, ester, amide or prodrug.

167. The compound according to any one of embodiments 158 to 163, or the pharmaceutical form of the compound, wherein R ² is chloro, unsubstituted furanyl, -CH ₃ , -CF ₃ , -OCF ₃ , -OCHF ₂ or -SCH ₃ Acceptable salts, solvates, esters, amides or prodrugs.

168. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 158 to 163, wherein R ² is -CF ₃ or -OCF ₃ .

169. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 158 to 163, wherein R ² is -CF ₃ .

170. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 158 to 169, wherein R ¹ is hydrogen or halogen.

171. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 158 to 170, wherein R ¹ is hydrogen or fluoro.

172. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 158 to 171, wherein each R ²⁰ is independently hydrogen or halogen.

173. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 158 to 171, wherein R ²⁰ is hydrogen or fluoro.

174. The method of any one of embodiments 158 to 163, wherein R ¹ is hydrogen or fluoro, R ² is C ₁ -C ₄ -haloalkyl or C ₁ -C ₄ -haloalkoxy, and R ²⁰ is hydrogen, A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound where x is an integer having the value 1.

175. The compound or compounds according to any one of embodiments 158 to 163, wherein R ¹ is hydrogen, R ² is trifluoromethyl or trifluoromethoxy, R ²⁰ is hydrogen and x is an integer having the value of 1. A pharmaceutically acceptable salt, solvate, ester, amide or prodrug of

176. Compounds of formula (AA) or pharmaceutically acceptable salts, solvates, esters, amides or prodrugs thereof:

here

L is (CH ₂ ) ₅ , which is unsubstituted or substituted by one methyl group;

R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;

R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;

x is 0 or 1;

R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;

R ³ is C _1-4 haloalkyl, NO ₂ , CN, halogen or C(O)O(C _1-4 alkyl);

R ²⁰ is hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;

^R _{_ _} ^{_ _} _{_}

이고;

ego;

Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R}

^{Each R} _{_ _ _}

177. The method of embodiment 176, wherein the compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound has the formula:

178. The method of embodiment 176, wherein the compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound has the formula:

179. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 176 to 178, wherein R ³ is halomethyl, CN or halogen.

180. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 176 to 178, wherein R ³ is CF ₃ , Cl or CN.

181. The method of any one of embodiments 176 to 180, wherein R ² is hydrogen, halogen, CN, C ₁ -C ₄ -alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -haloalkyl, S(C ₁ -C ₄ -alkyl) or furanyl, where furanyl may be optionally substituted with C ₁ -C ₄ -alkyl; A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound where x is 0 or 1.

182. The method of any one of embodiments 176 to 180, wherein R ² is H, halogen, CN, CH ₃ , halomethyl, halomethoxy, methoxy or furanyl, wherein furanyl may be optionally substituted with CH ₃ There is; A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound wherein R ²⁰ is methyl or halogen.

183. The method of any one of embodiments 176 to 180, wherein R ² is H, F, Cl, CN, CF ₃ , OCF ₃ or furanyl; The compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound where x is 0.

184. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 176 to 183, wherein R ¹ is hydrogen.

185. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to any one of embodiments 176 to 184, wherein R ¹ is hydrogen or fluoro.

186. The compound or pharmaceutically acceptable salt, solvate, _ester ^{, amide} or prodrug of the compound according to any one of embodiments ₁ to 185, wherein ^R

187. The compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound according to embodiment ₁₈₆ , wherein ^R

188. The compound according to any one of embodiments 1 to 187, wherein n is 0, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

189. The compound according to any one of embodiments 1 to 187, wherein n is 1, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물인 화합물 또는 화합물의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물.190. According to embodiment 1,

or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound.

또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물인 화합물 또는 화합물의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물.191. According to embodiment 1,

or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound.

또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물인 화합물 또는 화합물의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물.192. According to embodiment 1,

or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound.

또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물인 화합물 또는 화합물의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물.193. According to embodiment 1,

or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound.

또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물인 화합물 또는 화합물의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물.194. According to embodiment 158,

or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of a compound.

인 화합물 또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물.195.

A phosphorus compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

인 화합물 또는 그의 제약상 허용되는 염, 용매화물, 에스테르, 아미드 또는 전구약물.196.

A phosphorus compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

197. A compound selected from the compounds shown in Table 1, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

198. A compound selected from the compounds shown in Table 2, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

199. A compound selected from the compounds shown in Table 3, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

200. A compound selected from the compounds shown in Table 4, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

201. A compound selected from the compounds shown in Table 5, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

202. A compound selected from the compounds shown in Table 6, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

203. A compound selected from the compounds shown in Table 7, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

204. A compound selected from the compounds shown in Table 8, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

205. A compound selected from the compounds shown in Table 9, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

206. A compound selected from the compounds shown in Table 10, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

207. A compound selected from the compounds shown in Table 11, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

208. The compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt of the compound.

209. A pharmaceutically acceptable salt of the compound according to any one of embodiments 1 to 207, which is an alkali metal salt, optionally a sodium or potassium salt.

210. A pharmaceutical composition comprising the compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound and a pharmaceutically acceptable carrier or vehicle.

211. The pharmaceutical composition of embodiment 210, further comprising a second therapeutically active agent.

212. The method of embodiment 211, wherein the second therapeutically active agent is a lipid lowering drug, a statin, a cholesterol absorption inhibitor, an antibody against PCSK9, siRNA PCSK9, an antifibrotic agent, a thyroid hormone, a selective thyroid receptor-β agonist, apoptotic signaling-modulation. A pharmaceutical composition that is a kinase 1 (ASK1) inhibitor, an acetyl-CoA carboxylase (ACC) inhibitor, an integrin antagonist, or a non-steroidal farnesoid X receptor (FXR) agonist.

213. The method of embodiment 212, wherein the lipid lowering drug is gemfibrozil, fenofibrate, bezafibrate, clofibrate, cipropibrate, clinofibrate, etophylline, pyrifibrate, symfibrate, tocofibrate or Mafibrate; The statin is atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, dalvastatin, dihydrocompactin, or cerivastatin, or a pharmaceutically acceptable salt, solvate, ester, or amide thereof. or is a prodrug; The cholesterol absorption inhibitor is ezetimibe; Antibodies to PCSK9 are evolocumab, alirocumab, bococizumab, 1D05-IgG2, RG7652, LY3015014, or LGT-209; siRNA PCSK9 is inclisiran; The antifibrotic agent is nitazoxanide, tizoxanide or tizoxanide glucuronide or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof; the selective thyroid receptor-β agonist is VK2809, MGL-3196, MGL-3745, SKL-14763, sobetirome, BCT304, ZYT1, MB-0781, or eprothyrom; The ASK1 inhibitor is seronsertib; The ACC inhibitor is pyrsocostat; the integrin antagonist is an α5β1 inhibitor or a pan integrin inhibitor; or a pharmaceutical composition wherein the FXR agonist is cilofexor.

214. Liver disorder, dyslipidemia, dyslipoproteinemia, renal disease, glucose metabolism disorder, lipid metabolism disorder, glucose metabolism disorder, cardiovascular disease, vascular disease, metabolic syndrome, complications associated with metabolic syndrome, PPAR-related disorder, bacteremia, thrombosis. Sexual disorders, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, cerebrovascular disease, disorders related to angiogenesis, hypertension, cancer, inflammation, inflammatory diseases, neurodegenerative diseases, autoimmune diseases, neovascularization A method of treating or preventing physical disease, muscular atrophy, cholestasis, mitochondrial dysfunction, eye disease, lysosomal storage disease, kidney disease, or erectile dysfunction, comprising administering to a subject in need thereof an effective amount of any of embodiments 1 to 207. A method comprising administering a compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

215. The method of embodiment 214, wherein the liver disorder involves pathological destruction, inflammation, degeneration, apoptosis or proliferation of liver cells.

216. The method of embodiment 214, wherein the liver disorder is liver fibrosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH).

217. The method of embodiment 214, wherein the dyslipidemia is hyperlipidemia or abnormally low concentrations of high-density lipoprotein cholesterol (HDL-C) in the subject's plasma or serum.

218. The method of embodiment 217, wherein the hyperlipidemia is hypercholesterolemia, familial hypercholesterolemia, hypertriglyceridemia, or familial combined hyperlipidemia.

219. The method of embodiment 217, wherein the hyperlipidemia is caused by abnormally reduced or deficient lipoprotein lipase levels or activity in the subject's plasma or serum, or abnormally high concentrations of ketone bodies, lipoprotein(a) cholesterol (Lp( a)-C), low density lipoprotein (LDL), very low density lipoprotein cholesterol (VLDL-C) or non-esterified fatty acids.

220. The method of embodiment 219, wherein the reduced or deficient lipoprotein lipase level or activity is the result of a mutation in the gene encoding the lipoprotein lipase.

221. The method of embodiment 214, wherein the dyslipoproteinemia is an abnormally high concentration of LDL, apolipoprotein (a), or VLDL in the subject's plasma or serum, or an abnormally low concentration of high-density lipoprotein (HDL) in the subject's plasma or serum. or a method characterized by lipoprotein lipase.

222. The method of embodiment 221, wherein the abnormally low concentration of lipoprotein lipase is associated with a lipoprotein lipase mutation, hypoalphalipoproteinemia, lipoprotein abnormality associated with diabetes, lipoprotein abnormality associated with obesity, lipoprotein abnormality associated with Alzheimer's disease, or familial combined hyperlipidemia. How to do it.

223. The method of embodiment 214, wherein the renal disease is a glomerular disease, tubular disease, tubulointerstitial disease, acute or rapidly progressive renal failure, chronic renal failure, nephrolithiasis, or tumor.

224. The method of embodiment 223, wherein the glomerular disease is acute glomerulonephritis, chronic glomerulonephritis, rapidly progressive glomerulonephritis, nephrotic syndrome, focal proliferative glomerulonephritis, glomerular lesion associated with a systemic disease, Goodpasture syndrome, multiple myeloma, diabetes mellitus, neoplasm, sickle cell disease, or chronic inflammatory disease; the tubular disease is acute tubular necrosis, acute renal failure, polycystic kidney disease, medullary cavernous kidney, medullary cystic disease, nephrogenic diabetes, or renal tubular acidosis; The tubulointerstitial disease is pyelonephritis, drug- or toxin-induced tubulointerstitial nephritis, hypercalcemic nephropathy, or hypokalemic nephropathy; or wherein the tumor is renal cell carcinoma or nephroblastoma.

225. The method of embodiment 224, wherein the glomerular lesion associated with a systemic disease is systemic lupus erythematosus.

226. The method of embodiment 214, wherein the renal disease is hypertension, nephrosclerosis, microangiopathic hemolytic anemia, atherosclerotic renal disease, diffuse cortical necrosis, or neuroindex.

227. The method of embodiment 226, wherein the hypertension is essential hypertension, hyperpiesa, hyperpeacea, malignant hypertension, secondary hypertension, or white coat hypertension.

228. The method of embodiment 214, wherein the impaired glucose metabolism is an impaired glucose tolerance; insulin resistance; Insulin resistance-related breast, colon, or prostate cancer; diabetes; pancreatitis; High blood pressure; polycystic ovarian disease; or an abnormally high concentration of blood insulin or glucose in the subject's plasma or serum.

229. The method of embodiment 228, wherein the diabetes is non-insulin dependent diabetes mellitus (NIDDM), insulin dependent diabetes mellitus (IDDM), gestational diabetes mellitus (GDM), or maturity-onset diabetes of the young (MODY).

230. The method of embodiment 214, wherein the vascular disease or cardiovascular disease is peripheral vascular disease, coronary heart disease, stroke, restenosis, arteriosclerosis, ischemia, endothelial dysfunction, ischemia-reperfusion injury, myocardial infarction, or cerebral infarction.

231. The method of embodiment 214, wherein the PPAR-associated disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, breast cancer, colon cancer, or prostate cancer.

232. The method of embodiment 214, wherein the PPAR-related disorder is a vascular disease, a muscle disease, a demyelinating disease, a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a mitochondrial dysfunction, a beta oxidation disease, or a metabolic disease. How to do it.

233. The method of embodiment 232, wherein the muscle disease is a muscular dystrophy disease; the demyelinating disease is multiple sclerosis, Charcot-Marie-Tooth disease, Pelisseus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, or Guillain-Barré syndrome; Disorders of muscle structure include Beslem myopathy, central nuclear disease, congenital fibrous imbalance, distal muscular dystrophy (MD), Duchenne & Becker MD, Emery-Dreyfus MD, facioscapulohumeral MD, hyaline body myopathy, zone MD, and muscle sodium channels. is a disorder, myotonic chondrodystrophy, myotonic dystrophy, tubular myopathy, nemaline body disease, opharyngeal MD, or stress urinary incontinence; Disorders of neuronal activation include amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve lesions, peripheral neuropathy, spinal muscular atrophy, chronic ulnar nerve palsy, or toxicity. Is a neuromuscular disorder; Muscle fatigue disorders include chronic fatigue syndrome, diabetes (type I or type II), glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome, mucopolysaccharidosis, Pompe disease, or thyrotoxic myopathy; The muscle mass disorder is cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, critical illness myopathy, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, or systemic lupus erythematosus; Mitochondrial diseases include Alper's disease, chronic progressive extraocular ophthalmoplegia (CPEO), Kearns-Sayer syndrome (KSS), Leber hereditary optic neuropathy (LHON), MELAS, myoclonic epilepsy and heterogeneous-red myofiber disease (MERRF), and neurogenic muscle attenuation (NARP), ataxia, retinitis pigmentosa, Pearson syndrome, mitochondrial dysfunction or loss of mitochondrial function; Beta oxidation disorders include systemic carnitine transporter, carnitine palmitoyltransferase (CPT) II deficiency, very long chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, and medium chain acyl-CoA dehydrogenase deficiency. (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, or riboflavin-responsive disorder of β-oxidation (RR-MADD); or metabolic disease is hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia, HLD non-cholesterolemia, VLDL hyperproteinemia, dyslipoproteinemia, apolipoprotein A-I hypoproteinemia, atherosclerosis Sclerosis, arteriosclerosis disease, cardiovascular disease, cerebrovascular disease, peripheral circulation disease, metabolic syndrome, syndrome X, obesity, diabetes, type I diabetes, type II diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism , diabetic complications, cardiac dysfunction, myocardial infarction, cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), thrombosis, Alzheimer's disease, neurodegenerative disease, demyelinating disease, multifocal disease Sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, trichiasis, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease or pancreatitis.

234. The method of embodiment 233, wherein the muscular dystrophy disease is Duchenne muscular dystrophy, Becker muscular dystrophy, girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, opharyngeal muscular dystrophy, distal muscular dystrophy, or Emery's. -Dreyfus muscular dystrophy method.

235. The method of embodiment 214, wherein the PPAR-associated disorder is characterized by an abnormally low concentration of HDL, an abnormally low concentration of apolipoprotein A-I (apo A-I), an abnormally high concentration of VLDL-C, an abnormally high concentration of HDL in the subject's plasma or serum. Concentrations of low-density lipoprotein cholesterol (LDL-C), abnormally high concentrations of triglycerides, abnormally high concentrations of apolipoprotein B (apo B), abnormally high concentrations of apolipoprotein C-III (apo C-III), or abnormally high concentrations of apolipoprotein C-III (apo C-III) Method for reducing the ratio of post-heparin hepatic lipase to lipoprotein lipase activity.

236. The method of embodiment 214, wherein the PPAR-associated disorder is an abnormally high concentration of HDL or an abnormally low concentration of apo A-I in lymph or brain fluid of the subject.

237. The method of embodiment 214, wherein the obesity is abdominal obesity.

238. The method of embodiment 214, wherein the cerebrovascular disease is cerebral ischemia.

239. The method of embodiment 214, wherein the disorder associated with neovascularization is retinopathy or diabetes.

240. The method of embodiment 214, wherein the cancer is human sarcoma or human carcinoma.

241. The method of embodiment 214, wherein the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, hemangiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelioma, synovium, mesothelioma, Ewing's tumor, Leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, oral cancer, nasal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary carcinoma. Adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular tumor, lung carcinoma, small cell lung. Carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma, leukemia, acute Lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute promyelocytic leukemia, acute monocytic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute non-lymphatic Cystogenic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, hairy cell leukemia, lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, myelocytic leukemia, polycythemia vera, multiple myeloma, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma , Waldenstrom's macroglobulinemia or heavy chain disease.

242. The method of embodiment 241, wherein the leukemia is acute or chronic lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, lymphocytic leukemia, or myelocytic leukemia.

243. The method of embodiment 242, wherein the myelocytic leukemia is acute and myeloblastic, promyelocytic, myelomonocytic, monocytic, or erythroleukemia.

244. The method of embodiment 242, wherein the lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.

245. The method of embodiment 214, wherein the inflammatory disease is multiple sclerosis, chronic inflammatory disorder of the joints, arthritis, respiratory distress syndrome, inflammatory bowel disease, inflammatory lung disorder, inflammatory disorder, inflammatory disorder of the gums, tuberculosis, leprosy, inflammatory disease of the kidney. , an inflammatory disorder of the skin, an inflammatory disease of the central nervous system, systemic lupus erythematosus (SLE), or an inflammatory disease of the heart.

246. The method of embodiment 245, wherein the arthritis is rheumatoid arthritis or osteoarthritis; Inflammatory bowel disease is ileitis, ulcerative colitis, or Crohn's disease; Inflammatory lung disorder is asthma or chronic obstructive airway disease; The inflammatory disorder of the eye is corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis, or endophthalmitis; An inflammatory disorder of the gums is periodontitis or gingivitis; Inflammatory disease of the kidney is glomerulonephritis or nephropathy; Inflammatory disorders of the skin are acne, sclerodermatitis, psoriasis, eczema, photoaging, or wrinkles; The inflammatory disease of the central nervous system is AIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer's disease, encephalomyelitis, or viral or autoimmune encephalitis; or how the inflammatory disease of the heart is cardiomyopathy.

247. The method of embodiment 214, wherein the neurodegenerative disease is Alzheimer's disease or Huntington's disease.

248. The method of embodiment 214, wherein the autoimmune disease is immune-complex vasculitis, systemic lupus, or erythema.

249. The method of embodiment 214, wherein the neoplastic disease is carcinogenesis.

250. The method of embodiment 214, wherein the cholestasis is an intrahepatic cholestatic disease or an extrahepatic cholestatic disease.

251. The method of embodiment 250, wherein the intrahepatic cholestatic disease is primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), progressive familial intrahepatic cholestasis (PFIC), or Alagille syndrome (AS).

252. The method of embodiment 214, wherein the eye disease is dry eye, meibomian gland dysfunction, corneal conjunctival epithelial disorder, corneal epithelial disorder, or corneal ulcer.

253. The method of embodiment 214, wherein the lysosomal storage disorder is neuronal ceroid lipofuscinosis, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Lewy body dementia (DLB), disorders of the autophagy pathway, Tay-Sachs disease, Fabry disease, Niemann-Pick disease, Gaucher disease, Hunter syndrome, alpha-mannoside accumulation, aspartylglucosaminuria, Cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystine accumulation disease, Danon disease, Faber disease, fucoside accumulation disease, galactosialic acidosis, or Batten disease.

254. The method of embodiment 214, wherein the renal disease is renal ischemia reperfusion injury.

255. The method of embodiment 214, wherein the erectile dysfunction is caused by damage to nerves, arteries, smooth muscles, or fibrous tissue; diabetes; kidney disease; alcoholism; multiple sclerosis; atherosclerosis; vascular disease; or resulting from a neurological disease.

256. A method of treating or preventing hyperlipidemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia or dyslipidemia, comprising administering to a subject in need thereof an effective amount of the compound or compound of any one of embodiments 1 to 207. A method comprising administering a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of

257. The method of embodiment 256, wherein the hypercholesterolemia is homozygous familial hypercholesterolemia.

258. Abnormally high concentrations of high low density lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein(a) (Lp(a)), apolipoprotein(a), or very low density lipoprotein (VLDL) in the subject's plasma or serum ), comprising administering to a subject in need thereof an effective amount of a compound of any one of Embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or compound of the compound. A method comprising administering a prodrug.

259. A method of treating or preventing a subject having an abnormally low concentration of high-density lipoprotein (HDL) in the subject's plasma or serum, comprising administering to a subject in need thereof an effective amount of any one of embodiments 1 to 207. A method comprising administering a compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

260. A method of treating or preventing a subject having abnormally reduced or deficient lipoprotein lipase concentration or activity in the subject's plasma or serum, comprising administering to a subject in need thereof an effective amount of any one of embodiments 1 to 207. A method comprising administering a compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

261. The method of embodiment 260, wherein the reduced or deficient lipoprotein lipase level or activity is the result of a mutation in the gene encoding the lipoprotein lipase.

262. A method of treating or preventing hypoalphalipoproteinemia, lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, lipoprotein abnormalities associated with Alzheimer's disease, or familial combined hyperlipidemia, comprising administering to a subject in need thereof an effective amount of embodiments 1 to 207. A method comprising administering either a compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

263. Triglycerides, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein(a) (Lp(a) in the subject's plasma or serum )), A method of reducing abnormally high concentrations of apolipoprotein B, HDL/(VLDL+LDL) ratio, apolipoprotein C-II or apolipoprotein C-III, comprising administering to a subject in need thereof an effective amount of embodiments 1 to 207 A method comprising administering a compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of any one of the compounds.

264. A method of increasing abnormally low concentrations of high-density lipoprotein (HDL)-related protein, HDL-cholesterol, apolipoprotein A-I or apolipoprotein E in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of embodiment 1 A method comprising administering a compound of any one of to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.

265. The method of embodiment 264, wherein the HDL-associated protein is apolipoprotein A-I (apo A-I), apolipoprotein A-II (apo A-II), apolipoprotein A-IV (apo A-IV), or apolipoprotein E (apo E) Method.

266. A method of promoting the clearance of triglycerides from the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester of the compound, A method comprising administering an amide or prodrug.

267. A method of increasing abnormally low glucose metabolism or lipid metabolism in a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester of the compound, A method comprising administering an amide or prodrug.

268. The method of embodiment 267, wherein the method of increasing abnormally low glucose metabolism increases the subject's insulin sensitivity or oxygen consumption or reduces blood insulin, blood glucose, or glycated hemoglobin in the subject's plasma or serum. .

269. The method of embodiment 267, wherein the method of increasing abnormally low lipid metabolism reduces the concentration of LDL or free triglycerides in the plasma or serum of the subject or inhibits saponified or non-saponifiable fatty acid synthesis.

270. A method of treating or preventing symptoms of a disease selected from inflammation, systemic lupus erythematosus, lupus nephritis or arthritis, comprising providing to a subject in need thereof an effective amount of a compound or compounds of any one of embodiments 1 to 207 or a pharmaceutically acceptable compound. A method comprising administering a salt, solvate, ester, amide, or prodrug.

271. The method of embodiment 270, wherein the arthritis is adjuvant arthritis or type II collagen-induced arthritis.

272. The method of embodiment 270, wherein the condition is nephritis, renal failure, or decreased renal function.

273. A method of reducing the fat content of meat in livestock, comprising administering to the livestock an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound. How to include it.

274. A method of reducing the cholesterol content of poultry eggs, comprising administering to the poultry species an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound. How to include it.

275. A method of treating a subject having or at risk of acute kidney injury (AKI), comprising administering to the subject (i) an effective amount of the compound of any one of Embodiments 1 to 207, or a pharmaceutically acceptable salt of the compound, A method comprising administering a solvate, ester, amide or prodrug or (ii) the pharmaceutical composition of embodiment 210 or embodiment 211.

276. The method of embodiment 275, wherein (i) the compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound or (ii) the pharmaceutical composition is administered intravenously, optionally for 3 days. A method comprising intravenous administration once daily.

277. The method of embodiment 275, wherein (i) the compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound or (ii) the pharmaceutical composition is administered orally.

278. The method of any one of embodiments 275 to 277, wherein the AKI is sepsis-related AKI.

279. The method of any one of embodiments 275 to 277, wherein the AKI is ischemia/reperfusion AKI.

280. The method of any one of embodiments 275 to 277, wherein the AKI is from acute interstitial nephritis.

281. The method of any one of embodiments 275 to 277, wherein the AKI is from glomerular nephropathy.

282. The method of any one of embodiments 275 to 277, wherein the AKI is from acute vasculitic kidney disease.

283. The method of any one of embodiments 275 to 277, wherein the AKI is from ischemia.

284. The method of any one of embodiments 275 to 277, wherein the AKI is from toxic injury.

285. The method of any one of embodiments 275 to 277, wherein the AKI is from prerenal azotemia.

286. The method of any one of embodiments 275 to 277, wherein the AKI is from acute postrenal destructive nephropathy.

287. The method of any one of embodiments 275 to 277, wherein the AKI is from diabetes.

288. The method of any one of embodiments 275 to 277, wherein the AKI is from underlying renal insufficiency.

289. The method of any one of embodiments 275 to 277, wherein the AKI is from nephritic syndrome.

290. The method of any one of embodiments 275 to 277, wherein the AKI is from atherosclerotic disease.

291. The method of any one of embodiments 275 to 277, wherein the AKI is from hypotension.

292. The method of any one of embodiments 275 to 277, wherein the AKI is from hypoxia.

293. The method of any one of embodiments 275 to 277, wherein the AKI is from myoglobinuria-hematuria.

294. The method of any one of embodiments 275 to 277, wherein the AKI is from a liver disease.

295. The method of any one of embodiments 275 to 277, wherein the AKI is secondary to a viral infection, optionally wherein the viral infection is COVID-19.

296. The method of embodiment 295, wherein the subject has a viral infection, optionally wherein the viral infection is COVID-19.

297. The method of any one of 275 to 278, wherein the subject has sepsis.

298. The method of embodiment 296, wherein the sepsis is associated with a Gram-negative bacterial infection.

299. The method of embodiment 297 or embodiment 298, wherein the subject has an intra-abdominal infection.

300. The method of embodiment 297 or embodiment 298, wherein the subject has urosepsis.

301. The method of any one of embodiments 275 to 300, wherein the subject is elderly.

302. The method of any one of embodiments 275 to 301, wherein the subject is a surgical patient.

303. The method of embodiment 302, wherein the surgical patient has optionally undergone cardiovascular surgery, which is coronary artery bypass graft (CABG) surgery and/or heart valve surgery.

304. The method of any one of embodiments 275 to 300, wherein the subject is pregnant.

305. The method of any one of embodiments 275 to 304, wherein the subject is exposed to a nephrotoxic agent.

306. The method of embodiment 305, wherein the nephrotoxic agent comprises cisplatin, gentamicin, cephaloridine, cyclosporin, amphotericin, carbon tetrachloride, trichloroethylene, dichloroacetylene, or combinations thereof.

307. The method of any one of embodiments 275 to 306, wherein the subject has AKI.

308. The method of embodiment 307, wherein the effective amount is effective for reducing the severity of AKI.

309. The method of any one of embodiments 275 to 306, wherein the subject is at risk for AKI.

310. The method of any one of embodiments 275 to 306, wherein the subject is optionally at risk of AKI following cardiovascular surgery, which is coronary artery bypass graft (CABG) surgery and/or heart valve surgery.

311. The method of embodiment 309 or embodiment 310, wherein the effective amount is effective in reducing the likelihood of developing AKI in the subject.

312. The method of any one of embodiments 309 to 311, wherein the effective amount is effective in delaying the onset of AKI.

313. The method of any one of embodiments 309 to 311, wherein the effective amount is effective for preventing AKI.

314. The method of any one of embodiments 309 to 311, wherein when the subject develops AKI, the effective amount is effective to reduce the severity of AKI.

315. The method of any one of embodiments 275 to 314, wherein the subject has a SOFA score of 1 to 4 prior to administration of the compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound or pharmaceutical composition. method.

316. The method of embodiment 315, wherein the subject has a SOFA score of 2 to 4 prior to administration.

317. The method of embodiment 315, wherein the subject has a SOFA score of 1 prior to administration.

318. The method of embodiment 315, wherein the subject has a SOFA score of 2 prior to administration.

319. The method of embodiment 315, wherein the subject has a SOFA score of 3 prior to administration.

320. The method of embodiment 315, wherein the subject has a SOFA score of 4 prior to administration.

321. The method of any one of embodiments 275 to 320, wherein the subject has an endotoxin activity level of > 0.6 prior to administration.

322. The method of any one of embodiments 275 to 321, wherein the effective amount is effective to reduce the level of endotoxin activity in the subject.

8. INCORPORATED BY REFERENCE

All publications, patents, patent applications, and other documents cited in this application are used for all purposes to the same extent as if each individual publication, patent, patent application, or other document was individually indicated to be incorporated by reference. For this purpose, its entirety is incorporated herein by reference. In case any inconsistency exists between the teachings of one or more of the references incorporated herein and this disclosure, the teachings of this specification are intended.

Claims (47)

A compound of formula (C) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
R ¹ is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl, any of which is unsubstituted or C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy , C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;
R ² is C 1-8 substituted with C _2-8 alkyl, _{C 1-8} haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkyl alkyl, or C _1-6 alkyl substituted with phenyl, naphthyl or pyridyl, any of which is unsubstituted or C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy, C _{1- 8} substituted with haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;
A is oxygen, sulfur or NR ⁹ , where R ⁹ is hydrogen or C _1-8 alkyl;
X is a C _1-8 alkylene chain, which is unsubstituted or substituted with C _1-8 alkyl, C _1-8 alkoxy or hydroxyl and has 0 or 1 double bond;
Y is C(=O), C(=N-OR ¹⁰ ), CH(OR ¹¹ ), CH=CH, C≡C or C(=CH ₂ ), where each of R ¹⁰ and R ¹¹ is hydrogen or C _1-8 alkyl;
Each of R ³ , R ⁴ and R ⁵ is independently hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _{2 -8} alkynyl, halogen, C _2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl; optionally wherein at least one of R ³ , R ⁴ and R ⁵ is not hydrogen;
B is CH or nitrogen;
Z is oxygen or sulfur;
Each R ⁶ and R ⁷ is independently hydrogen, C _1-8 alkyl, or C _1-8 haloalkyl;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (D) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
Each of R ¹ and R ² is independently hydrogen, halogen, nitro, C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl having 1 to 3 halogens, C having 1 to 3 halogens _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl, C _1-8 alkyl substituted with 3-7 membered cycloalkyl, optionally substituted C _6-10 aryl , an arylalkyl group with a C _6-10 aryl moiety and a C _1-8 alkyl moiety, a heterocyclic group or a heterocyclic-alkyl group with a C _1-8 alkyl group;
Each occurrence of R ³ , R ⁴ and R ⁵ is independently hydrogen or C _1-8 alkyl;
A is an oxygen atom, a sulfur atom, or NR ³ ;
^{Each of X 1} _, SO ₂ NH, CH=CH, C≡C or a combination;
Y is C _1-8 alkylene;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (E) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
Each R ¹¹ and R ¹² is independently hydrogen, halogen, nitro, hydroxyl, amino, C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl group having 1 to 3 halogens, 1 to C _1-8 haloalkoxy group with 3 halogens, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl, C _1-8 alkyl with 3-7 membered cycloalkyl substituent, or a phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl group, which optionally has a halogen atom, nitro, hydroxyl, amino, C _1-8 alkyl, C _1-8 Alkoxy, C _1-8 haloalkyl with 1 to 3 halogens, C _1-8 haloalkoxy with 1 to 3 halogens, C _2-8 alkenyl, C _2-8 alkynyl, 3-7 membered cycloalkyl group, a C _1-8 alkyl group with a 3-7 membered cycloalkyl substituent, a phenyl or pyridyl substituent;
^{Each of _ _} _{_ _} NH, CH=CH, C≡C or a bond, where each R ¹⁴ and R ¹⁵ is hydrogen or C _1-8 alkyl;
Y ¹ is C _1-8 alkylene;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. Compound of formula (F) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
A is O, S or NR ⁷ , where R ⁷ is hydrogen or C _1-8 alkyl;
B ¹ is CW or N, where W is hydrogen or a bond; B ² is O, S or NR ⁸ , where R ⁸ is hydrogen or C _1-8 alkyl;
^Each of ^{X 1 and} , wherein each R ⁹ and R ¹⁰ is hydrogen or C _1-8 alkyl;
Y is C _1-8 alkylene, which is unsubstituted or substituted with C _1-8 alkyl or C _1-8 haloalkyl with 1-3 halogens;
Z is NH, O or S;
R ¹ is unsubstituted or aryl substituted with C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl with 1-3 halogens, hydroxyl, nitro, amino, phenyl, pyridyl or halogen. , or a heterocyclic group having a 5- to 8-membered ring, each of which is independently nitrogen, oxygen or sulfur, and the other atom is carbon, optionally wherein the benzene ring is condensed with the heterocyclic ring and ;
R ² is C _2-8 alkyl, C _1-8 haloalkyl with 1-3 halogens, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, unsubstituted or C _{1 -8} alkyl, C _1-8 alkoxy, C _1-8 haloalkyl with 1-3 halogens, C _1-4 alkyl substituted with hydroxyl, nitro, amino, phenyl, pyridyl or aryl substituted with halogen, or C _1-4 alkyl substituted with a heterocyclic group having a 5 to 8 membered ring having 1 to 3 heteroatoms each independently being nitrogen, oxygen or sulfur;
R ³ is halogen, trifluoromethyl, C _1-8 alkyl, C _2-8 alkenyl or C _2-8 alkynyl;
each of R ⁴ and R ⁵ is hydrogen, C _1-8 alkyl or C _1-8 haloalkyl with 1-3 halogens;
Each of Z and R ³ is attached to a benzene ring and X ² is not attached to a benzene ring;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (G) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
Each of R ¹ and R ⁴ is the same or different and is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;
R ² is hydrogen;
R ³ is C _1-8 alkyl, or R ³ is combined with R ² to form =O or =C(R ⁷ )(R ⁸ ), wherein each of R ⁷ and R ⁸ is the same or different; hydrogen or C _1-8 alkyl;
Each of R ⁵ and R ⁶ is the same or different and is a hydrogen atom, C _1-8 alkyl, C _1-8 haloalkyl;
X and Y are the same or different and each represents CH or N;
Z is oxygen or sulfur;
A is a 5-membered heterocyclic group that is pyrazole, thiophene, furan or pyrrole, wherein the heterocyclic group is unsubstituted or C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _2-8 alkyl Kenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _1-8 alkyl group substituted by 3- to 7-membered cycloalkyl group, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _{6- 10} aryl, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered heterocyclic group. substituted with C _1-8 alkyl;
B is a C _1-8 alkylene chain, which is unsubstituted or C _1-8 alkyl, a 3- to 7-membered cycloalkyl group, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 substituted by alkoxy, halogen, C _1-8 haloalkyl or C _1-8 haloalkoxy, and when the alkylene group has 2 to 6 carbon atoms the alkylene group optionally has a double bond;
q is 0, 1, 2, 3, 4 or 5;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (H) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
Each of R ¹¹ and R ¹³ is the same or different and is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;
R ¹² is hydrogen, C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to 7-membered cycloalkyl group substituent C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered heterocyclic group, C _6-10 aryl moiety and C _1- an aralkyl group with _{an 8} alkylene moiety, or a C _1-8 alkyl group with a 5- or 6-membered heterocyclic substituent;
R ¹⁴ and R ¹⁵ are the same or different and each is a hydrogen atom, C _1-8 alkyl or C _1-8 haloalkyl;
X ¹ is CH or N;
Z ¹ is oxygen or sulfur;
W ¹ is oxygen or CH ₂ when a bond a is present and OH when a bond a is absent;
q is 2, 3 or 4;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. Compound of formula (J) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
Each of R ²¹ and R ²³ is the same or different and is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;
R ²² is hydrogen, C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to 7-membered cycloalkyl group substituent C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered heterocyclic group, C _6-10 aryl moiety and C _1- an aralkyl group with _{an 8} alkylene moiety, or a C _1-8 alkyl group with a 5- or 6-membered heterocyclic substituent;
R ²⁴ and R ²⁵ are the same or different and each is a hydrogen atom, C _1-8 alkyl or C _1-8 haloalkyl;
X ² is CH or N;
Z ² is oxygen or sulfur;
W ² is oxygen or CH ₂ when a bond a is present and OH when a bond a is absent;
r is 2, 3 or 4;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. Compound of formula (K) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
A is CH or nitrogen;
B, when a bond a is present, is oxygen or C(R ⁸ )(R ⁹ ), where each R ⁸ and R ⁹ are independently hydrogen or C _1-8 alkyl; B, in the absence of bond a, is OH;
W ¹ is a bond, C(=O) or (C(R ¹⁰ )(R ¹¹ )) _m , where each R ¹⁰ and R ¹¹ is independently hydrogen or a C _1-8 alkyl group, and m is 1, 2 or 3;
X and Y are different from each other and each is an oxygen atom, a sulfur atom, a nitrogen atom or CR ¹² , where R ¹² is hydrogen or C _1-8 alkyl;
Z ¹ is a bond, oxygen, sulfur, or C(R ¹³ )(R ¹⁴ ), where each R ¹³ and R ¹⁴ are independently hydrogen or C _1-8 alkyl;
Each of R ¹ , R ² and R ³ is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;
Each R ⁴ and R ⁵ is independently hydrogen, C _1-8 alkyl, C _1-8 haloalkyl;
Each R ⁶ and R ⁷ is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl or C _1-8 haloalkyl;
r is 1, 2, 3, 4 or 5;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (L) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
B, if bond a is present, is oxygen; B, in the absence of bond a, is OH;
W ² is a bond, C(=O) or CH ₂ ;
Z ² is oxygen or sulfur;
Each of R ²¹ , R ²² and R ²³ is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl; C _1-8 haloalkoxy; hydroxyl, nitro, C _2-8 acyl group, C _6-10 aryl, or 5- or 6-membered heterocyclic group;
Each R ²⁴ and R ²⁵ is independently hydrogen, C _1-8 alkyl, C _1-8 haloalkyl;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (M) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
Each W ¹ and W ² is independently nitrogen or CH;
X is nitrogen or CH;
Y is oxygen or sulfur;
Z is a bond, oxygen, sulfur or NR ⁵ where R ⁵ is hydrogen or C _1-8 alkyl;
Each R ¹ and R ² are independently hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl, 3- to 7-membered cycloalkyl group, C _2-8 alkenyl, C _2-8 alkynyl , C _1-8 alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered a heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene, or a C _1-8 alkyl with a 5- or 6-membered heterocyclic substituent;
Each R ³ and R ⁴ is independently hydrogen, C _1-8 alkyl, or C _1-8 haloalkyl;
A is a 5-membered heterocycle that is pyrazole, thiophene, furan, isoxazole, isothiazole or pyrrole, wherein the 5-membered heterocycle is unsubstituted or halogen, hydroxyl, nitro, amino, C _1-8 Alkyl, 3- to 7-membered cycloalkyl group, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _1-8 alkyl with 3- to 7-membered cycloalkyl substituents, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5- or 6-membered heterocyclic group, aralkyl with C _6-10 aryl moiety and C _1-8 alkylene moiety group, or a C _1-8 alkyl group having a 5- or 6-membered heterocyclic substituent;
B is a bond or C _1-8 alkylene, which is unsubstituted or substituted by C _1-8 alkyl, 3- to 7-membered cycloalkyl, C _1-8 alkoxy or halogen substituent, optionally wherein C _{1- 8} Alkylene has double or triple bonds;
r is 0, 1, 2 or 3;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (N) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
W ³ is nitrogen or CH;
Z ¹ is oxygen or sulfur;
Each R ¹¹ and R ¹² is independently hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl, C _1-8 alkoxy, C _1-8 haloalkyl or C _1-8 haloalkoxy;
Each R ¹³ and R ¹⁴ is independently hydrogen or C _1-8 alkyl;
A ¹ is a 5-membered heterocycle that is pyrazole or thiophene, wherein the 5-membered heterocycle is unsubstituted or halogen, hydroxyl, nitro, amino, C _1-8 alkyl, C _1-8 alkoxy, C _{1 -8} haloalkyl or C _1-8 haloalkoxy;
m is 2, 3 or 4;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (O) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
Each W ¹ and W ² is independently CH or nitrogen;
X is NR ⁵ or CR ⁶ R ⁷ ; Here, R ⁵ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkyl substituted with C _1-8 alkoxy, C _3-7 cycloalkyl, C substituted with C _3-7 cycloalkyl _1-8 alkyl, C _1-8 alkyl substituted with phenyl, C _2-8 acyl or C _2-8 alkenyl, and each of R ⁶ and R ⁷ is independently hydrogen or C _1-8 alkyl;
Y is (CR ⁸ R ⁹ ) _r , where each R ⁸ and R ⁹ are independently hydrogen or C _1-8 alkyl and r is 1, 2, 3 or 4; or
X and Y are combined to form CR ¹⁰ =CR ¹¹ or ethynylene, wherein each R ¹⁰ and R ¹¹ is independently hydrogen or C _1-8 alkyl;
G, when the bond a is present, is O, S or CR ¹² R ¹³ , where each of R ¹² and R ¹³ is independently hydrogen or C _1-8 alkyl; G, in the absence of bond a, is OH;
A is a 5-membered heterocyclic ring that is thiazole, oxazole, imidazole, pyrazole, thiophene, furan or pyrrole, wherein the heterocyclic ring is unsubstituted or C _1-8 alkyl, C _2-8 Alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro, C _2-8 acyl, C _6-10 aryl, or substituted with a 5- or 6-membered heterocyclic group;
B is C _1-8 alkylene, C _2-8 alkenylene or C _2-8 alkynylene chain, wherein the chain is unsubstituted or C _1-8 alkyl, C _3-7 cycloalkyl, C _1-8 alkoxy or substituted with halogen;
Each of R ¹ and R ² is independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _{1- 8} haloalkoxy, hydroxyl, nitro, C _2-8 acyl, C _6-10 aryl, or a 5- or 6-membered heterocyclic group;
Each R ³ and R ⁴ is independently hydrogen or C _1-8 alkyl;
m is 0, 1, 2 or 3;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (P) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
G ^a , when a bond a is present, is O, S or CH ₂ ; G ^a is OH in the absence of bond a;
A ^a is a 5-membered heterocyclic ring that is thiazole, oxazole or thiophene, wherein the 5-membered heterocyclic ring is unsubstituted or C _1-8 alkyl, C _1-8 alkoxy, halogen, C _{1 -8} haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl;
B ^a is C _1-8 alkylene or C _2-8 alkenylene chain;
Each R ^1a and R ^2a is independently hydrogen, C _1-8 alkyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl ego;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (Q) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
G ^b , when a bond a is present, is O, S or CH ₂ ; G ^b is OH in the absence of bond a;
A ^b is a 5-membered heterocyclic ring that is thiazole, oxazole or thiophene, wherein the 5-membered heterocyclic ring is unsubstituted or C _1-8 alkyl, C _1-8 alkoxy, halogen, C _{1 -8} haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl;
B ^b is C _1-8 alkylene or C _2-8 alkenylene chain;
Each R ^1b and R ^2b is independently hydrogen, C _1-8 alkyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _1-8 haloalkoxy, hydroxyl, nitro or C _2-8 acyl ego;
R ^3b is hydrogen or C _1-8 alkyl;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (R) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
Each W ¹ and W ² is independently CH or N;
^{and _ _ _} _{_ _ _ _} C _1-8 alkyl, C _1-8 alkyl substituted with a phenyl group, C _2-8 acyl, or C _2-8 alkenyl;
Each R ⁴ and R ⁵ is independently hydrogen or C _1-8 alkyl;
Y is (CR ⁶ R ⁷ ) _r , where each R ⁶ and R ⁷ are independently hydrogen or C _1-8 alkyl and r is 1, 2, 3 or 4;
A is a 5 or 6-membered heterocyclic group that is thiazole, oxazole, imidazole, pyrazole, thiophene, furan, pyrrole, pyridine or pyrimidine, or is a phenyl group, wherein A is a 5 or 6-membered heterocyclic group The group or phenyl group is unsubstituted or substituted with a C _1-8 alkyl, 3-7 membered cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxyl, 3-7 membered cycloalkyl group. C _1-8 alkyl group, C _1-8 haloalkyl, C _1-8 haloalkoxy, C _6-10 aryl, 5 or 6-membered heterocyclic group, C _6-10 aryl group and C _1-8 alkyl substituted with an aralkyl group containing a C 1-8 alkyl group, or a C _1-8 alkyl group substituted with a 5 or 6-membered heterocyclic group;
B is a bond or C _1-8 alkylene, which is unsubstituted or substituted with C _1-8 alkyl, a 3-7 membered cycloalkyl group, C _1-8 alkoxy or halogen, and the number of carbon atoms in the alkylene chain is 2 In the above cases, it may have a double bond or triple bond;
D is N or CH;
E is O or S;
Each of R ¹ and R ² is independently H, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, halogen, C _1-8 haloalkyl, C _{1- 8} haloalkoxy, nitro, C _2-8 acyl, C _6-10 aryl, or a 5 or 6-membered heterocyclic group;
m is 0, 1, 2 or 3;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (S) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
A ¹ is a 5 or 6-membered heterocyclic group that is thiazole, oxazole, pyridine or pyrimidine or is a phenyl group, wherein the 5 or 6-membered heterocyclic group or phenyl group is unsubstituted or C _1-8 substituted with alkyl or C _1-8 haloalkyl;
B ¹ is C _2-4 alkylene;
Each R ¹¹ and R ¹² is independently H, C _1-8 alkyl, halogen or C _1-8 haloalkyl;
R ¹³ is C _1-8 alkyl or C _1-8 haloalkyl, optionally where N to which R ¹³ is attached is attached to the 6th position of the benzisoxazole;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. A compound of formula (T) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
B ² is C _2-4 alkylene;
R ²⁰ is C _1-8 alkyl;
Each R ²¹ and R ²² is independently H, C _1-8 alkyl, halogen or C _1-8 haloalkyl;
R ²³ is C _1-8 alkyl or C _1-8 haloalkyl, optionally where N to which R ²³ is attached is attached to the 6th position of the benzisoxazole;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _}
n is 0, 1, 2, 3 or 4. Compound of formula (U) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
R ¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-8 alkyl, C _3-7 cycloalkyl, C2-C8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} acyl, a C _6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered a C _1-8 alkyl group with a heterocyclic substituent;
R ² is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkoxy substituent. a C _1-8 alkyl group, C _2-8 acyl, C _6-10 aryl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety;
Each of R ³ , R ⁴ , R ⁵ and R ⁶ is independently hydrogen, C _1-8 alkyl or C _1-8 haloalkyl;
X is oxygen, sulfur or NR ⁷ ; where R ⁷ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, C _2-8 acyl or C _{2- 8} alkenyl;
Y is oxygen, sulfur, NR ⁸ or a bond, where R ⁸ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 acyl or C _2-8 alkenyl;
p is 0 or 1;
A, when a bond a is present, is oxygen, CH ₂ , N-NH ₂ or N-OR ⁹ , where R ⁹ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 an acyl, C _2-8 alkenyl, or aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety; A, in the absence of bond a, is OH;
B, when p=1, is halogen, hydroxyl, nitro, amino, C _1-8 alkyl, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} a benzene ring with or without a substituent which is an acyl group, a C _6-10 aryl group, or an aralkyl group with a C _6-10 aryl moiety and a C 1 -C 8 alkylene moiety of 1-8 carbon atoms, and p When =0, it is a condensed ring that is indole, benzofuran, benzisoxazole or 1,2-benzisothiazole, wherein the condensed ring is halogen, hydroxyl, nitro, amino, C _1-8 alkyl group, C _{3 -7} cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _1-8 alkyl with 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C1 -C _1-8 alkyl with a C 8 alkoxy substituent, C _1-8 haloalkoxy group, C _2-8 acyl, C _6-10 aryl, or C _6-10 aryl moiety and C _1-8 alkylene moiety with or without an aralkyl group having a substituent;
Y is bonded to the benzene ring of B;
(C(R ³ )(R ⁴ )) _m is bonded at its 3-position to the condensed ring of B;
m is an integer from 1 to 4;
n is 0, 1, 2, 3, 4 or 5;
Y is a union when n=0;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _} Compound of formula (V) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
R ¹¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-8 alkyl, C _3-7 cycloalkyl, C2-C8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} acyl, a C _6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered a C _1-8 alkyl group with a heterocyclic substituent;
R ¹² is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkoxy substituent. a C _1-8 alkyl group, C _2-8 acyl, C _6-10 aryl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety;
Each of R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ is independently hydrogen, C _1-8 alkyl or C _1-8 haloalkyl;
Y ¹ is oxygen, sulfur, NR ¹⁸ or a bond, where R ¹⁸ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 acyl or C _2-8 alkenyl;
A ¹ , when a bond a is present, is oxygen, CH ₂ , N-NH ₂ or N-OR ¹⁹ , where R ¹⁹ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _{2- 8} acyl, C _2-8 alkenyl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety; A ¹ , in the absence of bond a, is OH;
Q ¹ is hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl group, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to C _1-8 alkyl with a 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _2-8 acyl, C _6-10 aryl, or an aralkyl group having a C _6-10 aryl moiety and a C _1-8 alkylene moiety;
r is 1, 2, 3 or 4;
s is 1, 2, 3, 4 or 5;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _} A compound of formula (W) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
R ²¹ is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-8 alkyl, C _3-7 cycloalkyl, C2-C8 alkenyl, C _2-8 alkynyl, C _1-8 Alkoxy, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _{2- 8} acyl, a C _6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety, or a 5- or 6-membered a C _1-8 alkyl group with a heterocyclic substituent;
R ²² is hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _1-8 alkyl with a 3- to 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkoxy substituent. a C _1-8 alkyl group, C _2-8 acyl, C _6-10 aryl, or an aralkyl group with a C _6-10 aryl moiety and a C _1-8 alkylene moiety;
Each R ²³ , R ²⁴ , R ²⁵ and R ²⁶ is independently hydrogen, C _1-8 alkyl or C _1-8 haloalkyl;
Y ² is oxygen, sulfur, NR ²⁸ or a bond, where R ²⁸ is hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _2-8 acyl or C _2-8 alkenyl;
Q ² is hydrogen, halogen, hydroxyl, nitro, amino, C _1-8 alkyl group, C _3-7 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, 3- to C _1-8 alkyl with a 7-membered cycloalkyl substituent, C _1-8 haloalkyl, C _1-8 alkyl with a C _1-8 alkoxy substituent, C _1-8 haloalkoxy, C _2-8 acyl, C _6-10 aryl, or an aralkyl group having a C _6-10 aryl moiety and a C _1-8 alkylene moiety;
t is 1, 2, 3 or 4;
u is 1, 2, 3, 4 or 5;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _} A compound of formula (X) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;
Q ¹ is CH or N;
R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;
x is 1 or 2;
R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;
Each R ²⁰ is independently hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;
R ³ is CH ₃ or CD ₃ ;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _} A compound of formula (Y) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;
Q ¹ is CH or N;
R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;
x is 1 or 2;
R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;
Each R ²⁰ is independently hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;
R ³ is CH ₃ or CD ₃ ;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _} A compound of formula (Z) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;
Q ¹ is CH or N;
R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;
x is 1 or 2;
R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;
Each R ²⁰ is independently hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;
R ³ is CH ₃ or CD ₃ ;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _} A compound of formula (AA) or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof:

here
L is (CH ₂ ) ₅ , which is unsubstituted or substituted by one methyl group;
R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, CN, C _1-4 alkoxy, C _1-4 haloalkoxy or C _3-6 cycloalkyl;
R ² is hydrogen, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, S(C _1-4 alkyl) , SO ₂ (C _1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C≡CR ^2A , O(CH ₂ ) _m R ^2B , NH(C _1-4 alkyl ), N(C _1-4 alkyl) ₂ or C(O)(C _1-4 alkyl), where aryl and heteroaryl are unsubstituted or halogen, OH, CN, C _1-4 alkyl, formyl, substituted with acetyl, acetoxy or carboxy, where m is 1, 2 or 3;
x is 0 or 1;
R ^2A and R ^2B are each independently C _1-4 alkyl, C _1-4 haloalkyl, or C _3-6 cycloalkyl;
R ³ is C _1-4 haloalkyl, NO ₂ , CN, halogen or C(O)O(C _1-4 alkyl);
R ²⁰ is hydrogen, halogen, C _1-4 alkyl, CN or C _1-4 alkoxy;
^R _{_ _} ^{_ _} _{_}

ego;
Each R ^X4 and R ^X5 is independently alkyl, aryl or heteroaryl; ^{or alternatively , R
Each R} _{_ _ _} The structure of claim 1:

A compound having or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. The structure of claim 1:

A compound having or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. The structure of claim 1:

A compound having or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. The structure of claim 1:

A compound having or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. structure

A compound having or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.

A phosphorus compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. structure

A compound having or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. The compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt of the compound. A pharmaceutical composition comprising the compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound and a pharmaceutically acceptable carrier or vehicle. The method according to any one of claims 1 to 31, wherein the liver disorder, dyslipidemia, dyslipoproteinemia, renal disease, glucose metabolism disorder, lipid metabolism disorder, glucose metabolism disorder, cardiovascular disease, vascular disease, metabolic syndrome, metabolic syndrome Complications associated with, PPAR-related disorders, bacteremia, thrombotic disorders, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, cerebrovascular disease, disorders related to neovascularization, hypertension, cancer, inflammation, A compound or a compound thereof for use in treating or preventing inflammatory diseases, neurodegenerative diseases, autoimmune diseases, neoplastic diseases, muscular dystrophy, cholestasis, mitochondrial dysfunction, ocular diseases, lysosomal storage diseases, renal diseases or erectile dysfunction. Pharmaceutically acceptable salt, solvate, ester, amide or prodrug. The compound according to any one of claims 1 to 31 for use in treating or preventing hyperlipidemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, or dyslipidemia, or a pharmaceutically acceptable compound thereof. Salt, solvate, ester, amide or prodrug. 32. The method of any one of claims 1 to 31, wherein abnormally high concentrations of high low density lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein(a) (Lp(a)) in the plasma or serum of the subject , a compound for use in treating or preventing apolipoprotein (a) or very low density lipoprotein (VLDL), or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate thereof, for use in treating or preventing abnormally low concentrations of high-density lipoprotein (HDL) in the plasma or serum of a subject. , ester, amide or prodrug. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvent thereof, for use in treating or preventing abnormally reduced or deficient lipoprotein lipase concentration or activity in the plasma or serum of the subject. Cargo, ester, amide or prodrug. The method according to any one of claims 1 to 31, for use in treating or preventing hypoalphalipoproteinemia, lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, lipoprotein abnormalities associated with Alzheimer's disease, or familial combined hyperlipidemia. The compound or its pharmaceutically acceptable salt, solvate, ester, amide or prodrug. 32. The method of any one of claims 1 to 31, wherein the subject's plasma or serum has abnormally high concentrations of triglycerides, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and non-high-density lipoproteins. For use to reduce cholesterol (non-HDL-C), lipoprotein(a) (Lp(a)), apolipoprotein B, HDL/(VLDL+LDL) ratio, apolipoprotein C-II or apolipoprotein C-III A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. 32. Use according to any one of claims 1 to 31 to increase abnormally low concentrations of high-density lipoprotein (HDL)-related protein, HDL-cholesterol, apolipoprotein A-I or apolipoprotein E in the plasma or serum of the subject. A compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. 32. A compound according to any one of claims 1 to 31 for use in promoting clearance of triglycerides from the plasma or serum of a subject, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. 32. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof for use in increasing abnormally low glucose metabolism or lipid metabolism in a subject. 32. The compound according to any one of claims 1 to 31 for use in treating or preventing symptoms of inflammation, systemic lupus erythematosus, lupus nephritis or arthritis, or a pharmaceutically acceptable salt, solvate or ester thereof, Amide or prodrug. 32. A compound according to any one of claims 1 to 31 for use in reducing the fat content of meat in livestock, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. 32. A compound according to any one of claims 1 to 31 for use in reducing the cholesterol content of poultry eggs, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. 32. The method of any one of claims 1 to 31, wherein the subject has or is at risk of acute kidney injury (AKI) is administered (i) an effective amount of the compound or a pharmaceutically acceptable salt, solvate, or ester of the compound. , a compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof for use in a method of treating said subject, comprising administering the amide or prodrug.