Functionalized long-chain hydrocarbon monocarboxylic acids and dicarboxylic acids useful for the prevention or treatment of diseases

Abstract

The present invention provides compounds for treating diseases such as liver disease or colorectal cancer. [Solution] Compounds represented by the following chemical names, or pharmaceutically acceptable salts or solvates thereof, are provided: 4,4'-(1,2-phenylene)bis(1-butylcyclopropanecarboxylic acid), 6-[3-(5-carboxy-5-methylhexyl)-2-hydroxyphenyl]-2,2-dimethylhexanoic acid, 6-[3-(5-carboxy-5-methylhexyl)-4-hydroxyphenyl]-2,2-dimethylhexanoic acid, 4,4'-(3-methyl-1,2-phenylene)bis(1-butylcyclopropanecarboxylic acid), or 5-[3-(4-carboxy-4-methylpentyl)-2-hydroxyphenyl]-2,2-dimethylpentanoic acid.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Application No. 62 / 878,852, filed Jul. 26, 2019, and U.S. Provisional Application No. 62 / 901,739, filed Sep. 17, 2019, the disclosures of each of which are hereby incorporated by reference in their entireties.

[0002] The present invention provides compounds of formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (II), (III), (IIIA), and (IIIB), as well as their pharmaceutically acceptable salts and solvates, and compositions thereof. The present invention further provides methods for preventing or treating diseases including, but not limited to, liver diseases or abnormal liver symptoms, cancer (e.g., hepatocellular carcinoma or cholangiocarcinoma), malignant or benign tumors of the lung, liver, gallbladder, bile duct or digestive tract, intrahepatic or extrahepatic bile duct diseases, lipoprotein disorders, lipid and metabolic disorders, cirrhosis, fibrosis, glucose metabolism disorders, cardiovascular or related vascular disorders, steatosis, diseases resulting from fibrosis or cirrhosis, diseases associated with advanced inflammation (e.g., liver inflammation or lung inflammation), hepatocyte ballooning, peroxisome proliferator - activated receptor - related disorders, ATP - citrate lyase disorders, acetyl - coenzyme A carboxylase disorders, obesity, pancreatitis, or kidney diseases.

Background Art

[0003] Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies. Patients with chronic liver diseases such as cirrhosis and fibrosis have a higher risk of developing HCC. Therefore, patients with chronic liver diseases need to closely monitor the onset of HCC. Risk factors for HCC include cirrhosis, non - alcoholic fatty liver disease (NAFLD), non - alcoholic steatohepatitis (NASH), chronic alcohol intake, hepatitis B and C, type IIb hyperlipidemia, mixed lipid disorders, obesity, and type 2 diabetes.

[0004] Patients with type IIb hyperlipidemia have a high risk of developing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which may be caused by excessive production and accumulation of liver triglycerides. An increase in the levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides, in addition to the increase in LDL-C and triglyceride levels, is accompanied by mixed dyslipidemia, including type IIb hyperlipidemia characterized by an increase in apolipoprotein B, very low-density lipoprotein cholesterol (VLDL-C), intermediate-density lipoprotein cholesterol (IDL), and small dense low-density lipoprotein (LDL) levels.

[0005] Current treatment options for type IIb hyperlipidemia are limited. Statins can be effective in reducing LDL-C and decreasing inflammation, but they are generally not very effective in reducing triglyceride concentrations. Furthermore, high-dose statin therapy often has poor tolerance because it can cause muscle pain (myalgia) and increase the risk of serious muscle toxicity such as rhabdomyolysis in patients. Also, commonly used triglyceride-lowering agents administered in combination with statins often have poor tolerance. When administered with statins, fibrates are known to have drug-drug interactions, resulting in an increase in blood drug levels of statins, myalgia, an increased risk of muscle toxicity, and an increased safety risk. In fact, the interaction between the statin Baychol (cerivastatin) and the fibrate gemfibrozil resulted in severe muscle toxicity and death, raising safety concerns, and Baychol disappeared from the US market. Fish oil, which is used to lower triglyceride levels, needs to be taken multiple times a day and can cause fishy aftertaste, flatulence, or reflux. Niacin can cause flushing, especially when administered in combination with statins.

[0006] ​Hepatocellular adenomas are benign liver tumors whose genetic and pathophysiological mechanisms are not fully understood. These lesions present diagnostic and therapeutic challenges, and post-resection treatment remains difficult. Bile duct adenomas present similar therapeutic challenges. Adenomas of the digestive system are sporadic tumors arising from the glandular epithelium of the stomach, small intestine, bile ducts, colon, and rectum.

[0007] Gastrointestinal (digestive tract) cancers are cancers that affect the gastrointestinal tract and other organs contained within the digestive system. Gastrointestinal stromal tumors (GISTs) are a rare type of sarcoma that forms along the gastrointestinal tract, but most originate in the stomach or small intestine. The origin of gastrointestinal cancers has been strongly associated with chronic inflammation of the organ, which develops through a series of histopathological stages depending on the affected organ. In the case of gastrointestinal or GIST cancers, surgery is likely to be recommended to remove the tumor and / or help maintain normal function. Other treatment options include radiation therapy, chemotherapy, hormone therapy, or targeted therapy.

[0008] Therefore, there is a need for safe and effective therapies for the treatment or prevention of cancer (e.g., gastrointestinal cancer, hepatocellular carcinoma, or cholangiocarcinoma), malignant or benign tumors of the lungs, liver, gallbladder, bile ducts, or digestive tract, liver disease or abnormal liver symptoms, intrahepatic or extrahepatic bile duct disease, lipoprotein disorders, lipid and metabolic disorders, cirrhosis, fibrosis, glucose metabolism disorders, cardiovascular or related vascular disorders, fatty degeneration, diseases resulting from fibrosis or cirrhosis, diseases associated with advanced inflammation (e.g., inflammation of the liver or lungs), hepatocyte ballooning, peroxisome proliferator-activated receptor-associated disorders, ATP citrate lyase disorders, acetyl coenzyme A carboxylase disorders, obesity, pancreatitis, or kidney disease. [Overview of the project]

[0009] The present invention provides compounds of formulas (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (II), (III), (IIIA), and (IIIB), as well as pharmaceutically acceptable salts and solvates thereof (each compound, pharmaceutically acceptable salt, and solvate is referred to as "the compound of the present invention").

[0010] The present invention also provides compositions comprising i) an effective amount of the compound of the present invention and ii) a pharmaceutically acceptable carrier or vehicle (each composition shall be referred to as "the Composition of the Present Invention").

[0011] The present invention further provides a method for treating or preventing a disease, comprising administering an effective amount of the compound of the present invention to a subject in need thereof, wherein the disease is a liver disease or abnormal hepatic condition, cancer (e.g., hepatocellular carcinoma or cholangiocarcinoma), malignant or benign tumors of the lungs, liver, gallbladder, bile ducts or gastrointestinal tract, intrahepatic or extrahepatic bile duct disease, lipoprotein disorders, lipid and metabolic disorders, cirrhosis, fibrosis, glucose metabolism disorders, cardiovascular or related vascular disorders, steatosis, diseases resulting from fibrosis or cirrhosis, diseases associated with advanced inflammation (e.g., inflammation of the liver or lungs), hepatocyte ballooning, peroxisome proliferator-activated receptor-associated disorders, ATP citrate lyase disorders, acetyl coenzyme A carboxylase disorders, obesity, pancreatitis, or kidney disease.

[0012] The present invention further provides methods for treating or preventing diseases, wherein the diseases include cancer, lipid and metabolic disorders, liver disorders, cirrhosis, fibrosis, glucose metabolism disorders, peroxisome proliferator-activated receptor-related disorders, malignant or benign tumors of the lungs, liver, biliary tract and gastrointestinal tract, ATP citrate lyase disorders, acetyl coenzyme A carboxylase disorders, obesity, pancreatitis, and kidney diseases. This could be hepatocyte ballooning, inflammation of the liver, or inflammation of the lungs.

[0013] The present invention further relates to the concentrations in the plasma or serum of the subject, namely, the concentration of C-reactive protein (CRP), serum amyloid A (SAA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT), serum creatinine, 7α-hydroxy-4-cholesten-3-one (C4), protein:creatinine ratio, creatine kinase concentration, and angiopoietin-like protein 3 concentration. The present invention provides a method for reducing angiopoietin-like protein 4 concentration, angiopoietin-like protein 8 concentration, fibrinogen concentration, total cholesterol concentration, low-density lipoprotein cholesterol concentration, low-density lipoprotein concentration, very low-density lipoprotein cholesterol concentration, very low-density lipoprotein concentration, non-HDL cholesterol concentration, non-HDL concentration, apolipoprotein B concentration, lipoprotein (a) concentration, or serum triglyceride concentration, comprising administering an effective amount of the compound of the present invention to a subject in need thereof.

[0014] The present invention further provides a method for reducing triglyceride concentrations in the liver of a subject, comprising administering an effective amount of the compound of the present invention to a subject in need of such reduction.

[0015] The present invention further provides a method for increasing the concentration of high-density lipoprotein cholesterol or high-density lipoprotein in the plasma or serum of a subject, comprising administering an effective amount of the compound of the present invention to a subject in need thereof.

[0016] The present invention further provides a method for treating a disease, comprising administering an effective amount of the compound of the present invention to a subject in need thereof, wherein the disease is a gastrointestinal disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), or an autoimmune disease.

[0017] The present invention further provides a method for regressing, reducing the progression rate, or inhibiting the progression of fibrosis, hepatocyte ballooning, or liver inflammation, which comprises administering to a subject in need thereof an effective amount of a compound of the present invention.

[0018] The present invention further provides a method for inhibiting, reducing, or delaying the development of lipid synthesis, hepatic steatosis, hepatocyte ballooning or inflammation, liver fibrosis, pulmonary fibrosis, or cirrhosis in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of the present invention.

[0019] The present invention further provides a method for reducing the risk of developing or having atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, or restenosis in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of the present invention.

[0020] The present invention further provides a method for increasing the HDL concentration in the serum or plasma of a subject, which comprises administering to a subject in need thereof an effective amount of a compound of the present invention.

[0021] The present invention further provides a method for inhibiting NF-kB or stellate cell activation, which comprises administering to a subject in need thereof an effective amount of a compound of the present invention.

[0022] The present invention further provides a method for activating peroxisome proliferator-activated receptor (PPAR), which comprises administering to a subject in need thereof an effective amount of a compound of the present invention.

[0023] The present invention further provides a method for reducing the fat or cholesterol content of livestock meat or poultry eggs, which comprises administering to livestock or poultry an effective amount of a compound of the present invention.

[0024] The present invention further provides a method for modulating, directly inhibiting, or allosterically inhibiting ATP citrate lyase in a subject, comprising administering an effective amount of the compound of the present invention to a subject requiring such inhibition.

[0025] The present invention further provides a method for modulating, directly inhibiting, or allosterically inhibiting acetyl-CoA carboxylase 1 or acetyl-CoA carboxylase 2 in a subject, comprising administering an effective amount of the compound of the present invention to a subject requiring such inhibition.

[0026] The present invention further provides a method for treating or preventing a disease, comprising administering an effective amount of the composition of the present invention to a subject in need thereof, wherein the disease is cancer, lipid and metabolic disorders, liver disorders, cirrhosis, fibrosis, glucose metabolism disorders, peroxisome proliferator-activated receptor-associated disorders, malignant or benign tumors of the lungs, liver, biliary tract and gastrointestinal tract, ATP citrate lyase disorders, acetyl coenzyme A carboxylase disorders, obesity, pancreatitis, kidney disease, hepatocyte ballooning, inflammation of the liver, or inflammation of the lungs. [Brief explanation of the drawing]

[0027] [Figure 1A] The inhibitory effects of compounds I-32, I-61, I-1, and III-1 on lipid production in mouse primary hepatocytes, respectively, as a percentage compared to the control, are shown. [Figure 1B] The inhibitory effects of compounds I-32, I-61, I-1, and III-1 on lipid production in mouse primary hepatocytes, respectively, as a percentage compared to the control, are shown. [Figure 1C] The inhibitory effects of compounds I-32, I-61, I-1, and III-1 on lipid production in mouse primary hepatocytes, respectively, as a percentage compared to the control, are shown. [Figure 1D] The inhibitory effects of compounds I-32, I-61, I-1, and III-1 on lipid production in mouse primary hepatocytes, respectively, as a percentage compared to the control, are shown. [Figure 2A] The antiproliferative effects of compounds I-32, I-61, I-1, and III-1 on Hepa1-6 cells, respectively, as a percentage compared to the vehicle control, are shown. [Figure 2B] The antiproliferative effects of compounds I-32, I-61, I-1, and III-1 on Hepa1-6 cells, respectively, as a percentage compared to the vehicle control, are shown. [Figure 2C] The antiproliferative effects of compounds I-32, I-61, I-1, and III-1 on Hepa1-6 cells, respectively, as a percentage compared to the vehicle control, are shown. [Figure 2D] The antiproliferative effects of compounds I-32, I-61, I-1, and III-1 on Hepa1-6 cells, respectively, as a percentage compared to the vehicle control, are shown. [Figure 3A] The antiproliferative effects of compounds I-32, I-61, I-1, and III-1 on Hep3B cell proliferation, as a percentage compared to the vehicle control, are shown. [Figure 3B] The antiproliferative effects of compounds I-32, I-61, I-1, and III-1 on Hep3B cell proliferation, as a percentage compared to the vehicle control, are shown. [Figure 3C] The antiproliferative effects of compounds I-32, I-61, I-1, and III-1 on Hep3B cell proliferation, as a percentage compared to the vehicle control, are shown. [Figure 3D] The antiproliferative effects of compounds I-32, I-61, I-1, and III-1 on Hep3B cell proliferation, as a percentage compared to the vehicle control, are shown. [Figure 4A] The anticlonal effects of compounds I-32, I-61, I-1, and III-1, respectively, in Hepa1-6 cells as a percentage compared to the vehicle control are shown. [Figure 4B] The anticlonal effects of compounds I-32, I-61, I-1, and III-1, respectively, in Hepa1-6 cells as a percentage compared to the vehicle control are shown. [Figure 4C] The anticlonal effects of compounds I-32, I-61, I-1, and III-1, respectively, in Hepa1-6 cells as a percentage compared to the vehicle control are shown. [Figure 4D] The anticlonal effects of compounds I-32, I-61, I-1, and III-1, respectively, in Hepa1-6 cells as a percentage compared to the vehicle control are shown. [Figure 5A] The anticlonal effects of compounds I-32, I-61, I-1, and III-1, respectively, in Hep3B cells as a percentage compared to the vehicle control are shown. [Figure 5B] The anticlonal effects of compounds I-32, I-61, I-1, and III-1, respectively, in Hep3B cells as a percentage compared to the vehicle control are shown. [Figure 5C] The anticlonal effects of compounds I-32, I-61, I-1, and III-1, respectively, in Hep3B cells as a percentage compared to the vehicle control are shown. [Figure 5D] The anticlonal effects of compounds I-32, I-61, I-1, and III-1, respectively, in Hep3B cells as a percentage compared to the vehicle control are shown. [Figure 6A] This study demonstrates the antiproliferative effects of compound I-32 and sorafenib in Hep3B cells, in the presence or absence of the other compound. [Figure 6B] This study demonstrates the antiproliferative effects of compound I-32 and lenvatinib in Hep3B cells, in the presence or absence of the other compound. [Figure 6C] This study demonstrates the antiproliferative effects of compound I-61 and sorafenib in Hep3B cells, in the presence or absence of the other compound. [Figure 6D] This study demonstrates the antiproliferative effects of compound I-61 and lenvatinib in Hep3B cells, in the presence or absence of the other compound. [Figure 7A] This study demonstrates the antiproliferative effects of compound I-32 and sorafenib in Hepa1-6 cells, in the presence or absence of the other compound. [Figure 7B] This study demonstrates the antiproliferative effects of compound I-32 and lenvatinib in Hepa1-6 cells, in the presence or absence of the other compound. [Figure 7C] This study demonstrates the antiproliferative effects of compound I-61 and sorafenib in Hepa1-6 cells, in the presence or absence of the other compound. [Figure 7D] This study demonstrates the antiproliferative effects of compound I-61 and lenvatinib in Hepa1-6 cells, in the presence or absence of the other compound. [Figure 8A] This study demonstrates the synergistic antiproliferative effect of compound I-32 and sorafenib in Hep3B cells. [Figure 8B] This study demonstrates the synergistic antiproliferative effect of compound I-32 and lenvatinib in Hep3B cells. [Figure 8C] This study demonstrates the synergistic antiproliferative effects of compound I-61 and sorafenib in Hep3B cells. [Figure 8D] This study demonstrates the synergistic antiproliferative effects of compound I-61 and lenvatinib in Hep3B cells. [Modes for carrying out the invention]

[0028] definition The term "approximately" preceding a number means up to ±20% of that number. For example, "approximately" number means up to ±20% of that number, and in some embodiments, it means up to ±19%, up to ±18%, up to ±17%, up to ±16%, up to ±15%, up to ±14%, up to ±13%, up to ±12%, up to ±11%, up to ±10%, up to ±9%, up to ±8%, up to ±7%, up to ±6%, up to ±5%, up to ±4%, up to ±3%, up to ±2%, up to ±1%, up to ±1%, or any other number or range of numbers.

[0029] Throughout this specification, numerical ranges are provided for specific quantities. These ranges include all subranges within them. Thus, the range "50-80" includes all possible ranges within it (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range may be upper and lower limits of the range in which they are contained (e.g., the range 50-80 includes ranges with upper and lower limits such as 55-80, 50-75, etc.).

[0030] The term “pharmaceutically acceptable salt” includes both addition salts of acids and bases. A pharmaceutically acceptable salt can be obtained by reacting a compound of the present invention, acting as a base, with an inorganic or organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, or carbonate. A pharmaceutically acceptable salt can also be obtained by reacting a compound of the present invention, acting as an acid, with an inorganic or organic base to form a salt, such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ammonia, isopropylamine, or trimethylamine. Those skilled in the art will further recognize that pharmaceutically acceptable salts can be prepared by reacting a compound of the present invention with a suitable inorganic or organic acid or base using one of several known methods.

[0031] The term "solvate" refers to a solvated complex. Solvates can be formed by solvation (combination of a solvent molecule with a molecule or ion of the compound of the present invention), or they can be aggregates containing 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, hemihydrates, monohydrates, dihydrates, trihydrates, and hexahydrates. Solvates can be formed via hydration, including the absorption of water. A pharmaceutically acceptable salt may also be a solvate. If the solvate is obtained by crystallization from a solvent, the solvent may be an alcohol such as methanol or ethanol, an aldehyde, a ketone such as acetone, or an ester such as ethyl acetate.

[0032] The compounds of the present invention may have one or more chiral centers and therefore may be enantiomers, racemates, diastereomers, other stereoisomers, and mixtures thereof. The compounds of the present invention include all such possible isomers (including geometric isomers), whether or not they are specifically shown herein, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and resolution crystallization. Conventional techniques for the preparation or isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates using, for example, chiral high-pressure liquid chromatography (HPLC). Unless otherwise specified, the compounds of the present invention include both E and Z geometric isomers, where the compounds of the present invention contain an olefinic double bond or another geometric chiral center. Similarly, the compounds of the present invention include all tautomer forms.

[0033] When used in connection with the compounds of the present invention, “effective amount” means the amount of the compound of the present invention that is effective in treating or preventing a disease when administered to a subject, either alone or in combination with another pharmaceutically active agent.

[0034] When used in relation to other pharmaceutically active agents, "effective amount" means an amount of the other pharmaceutically active agent that is effective, either alone or in combination with the compound of the present invention, in treating or preventing a disease.

[0035] The "subject" is a human or a non-human mammal, such as a cattle, horse, cat, dog, rodent, or non-human primate. A human can be male or female, a child, adolescent, or adult. A female can be pre-menstrual or post-menstrual.

[0036] "Mammals" include humans, domesticated animals such as laboratory animals (e.g., mice, rats, rabbits, monkeys, dogs, etc.) and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domesticated wild animals.

[0037] All weight percentages referenced herein (i.e., "weight %", "wt%", and "weight / weight") are, unless otherwise indicated, relative to the total weight of the mixture or composition.

[0038] As used herein, the following terms have the meanings set forth below unless otherwise indicated.

[0039] "Halo," "Hal," or "halogen" refers to Br, Cl, F, or I.

[0040] "Alkyl" refers to a linear or branched hydrocarbon chain having 1 to 12 carbon atoms, with atoms bonded by single bonds and completely saturated. This includes alkyls with 1 to 12 carbon atoms. Alkyls with 1 to 12 carbon atoms are C1-C 12is alkyl, and an alkyl group having 1 to 10 carbon atoms is C1-C 10 is alkyl, and an alkyl group having 1 to 6 carbon atoms is C1-C6 alkyl, and an alkyl group having 1 to 5 carbon atoms is C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all the moieties described above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10 alkyl includes all the moieties described above for C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9 and C 10 alkyl. Similarly, C1-C 12 alkyl includes all the moieties described above, but also includes C 11 and C 12 alkyl. Non-limiting examples of C1-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 specified, an alkyl group can be unsubstituted or substituted with substituents disclosed herein.

[0041] "Alkylene" refers to a fully saturated, straight-chain or branched-chain divalent hydrocarbon having 1 to 12 carbon atoms. Non-limiting examples of C1-C 12 alkylene include methylene, ethylene, propylene, n-butylene, etc. The ends of each alkylene are bonded to atoms by single bonds. The bonding points of the alkylene chain can be one or two atoms. Unless otherwise specified, the alkylene chain can be unsubstituted or substituted with substituents disclosed herein.

[0042] An "alkenyl" refers to a linear or branched hydrocarbon chain having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is bonded to an atom by a single bond. Alkenyl groups with 2 to 12 carbon atoms are C2-C 12 Alkenyls are alkenyl groups that have 2 to 10 carbon atoms, C2-C 10 Alkenyl groups having 2 to 6 carbon atoms are C2-C6 alkenyls, and alkenyl groups having 2 to 5 carbon atoms are C2-C5 alkenyls. C2-C5 alkenyls include C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. C2-C6 alkenyls include all the parts described above for C2-C5 alkenyls, but also include C6 alkenyls. 10 Alkenyls include all the parts described above for C2-C5 alkenyls and C2-C6 alkenyls, but also C7, C8, C9 and C 10 This also includes alkenyls. Similarly, C2-C 12 Alkenil includes all the parts mentioned above, but C 11 and C 12 Includes alkenyls. C2-C 12Non-limiting examples of alkenyls include ethenyl(vinyl), 1-propenyl, 2-propenyl(allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl Examples include 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless otherwise specified, alkyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0043] "Alkenylene" refers to a linear or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. C2-C 12 Non-limiting examples of alkenylenes include etenylene, propenylene, and butenylene. Each end of an alkenylene chain is bonded to an atom by a single bond. The bonding sites of an alkenylene chain can be mediated by one or two atoms. Unless otherwise specified, alkenylene chains may be unsubstituted or substituted with substituents disclosed herein.

[0044] "Alkynyl" refers to a linear or branched hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is bonded to an atom by a single bond. Alkynyl groups with 2 to 12 carbon atoms are C2-C 12 Alkynnyl groups, which have 2 to 10 carbon atoms, are C2-C 10 Alkynyl groups with 2 to 6 carbon atoms are C2-C6 alkynyls, and alkynyl groups with 2 to 5 carbon atoms are C2-C5 alkynyls. C2-C5 alkynyls include C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. C2-C6 alkynyls include all the parts described above for C2-C5 alkynyls, but also include C6 alkynyls. 10 Alkynnyl includes all the parts described above for C2-C5 alkynyls and C2-C6 alkynyls, but also C7, C8, C9 and C 10 This also includes alkynyl. Similarly, C2-C 12 Alkinyl includes all of the above parts, but C 11 and C 12 Includes alkynyl. C2-C 12 Non-limiting examples of alkenyls include ethynyl, propynyl, butynyl, and pentynyl. Unless otherwise specified, alkyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0045] "Alkynylene" refers to a linear or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. C2-C 12 Non-limiting examples of alkylylenes include ethynylene, propynylene, and butynylene. Each end of an alkylylene chain is bonded to an atom via a single bond. The bonding sites of an alkylylene chain may be mediated by one or two atoms. Unless otherwise specified, alkylylene chains may be unsubstituted or substituted with substituents disclosed herein.

[0046] "alkoxy" is the formula -OR a This refers to the radical of the expression, where R is located in the formula. a This refers to an alkyl, alkenyl, or alkynyl radical as defined herein. Unless otherwise specified, the alkoxy group may be unsubstituted or substituted with substituents disclosed herein.

[0047] "Aryl" refers to a hydrocarbon ring radical comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. Aryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include condensed or crosslinked ring systems. Examples of aryl radicals, but not limited to, include aceantrilenyl, acenaphtylenyl, acephenantrilenyl, anthracenyl, azlenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, naphthalenyl, phenalenyl, phenantrenyl, phenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless otherwise specified, aryls may be unsubstituted or substituted with substituents disclosed herein.

[0048] "Arylene" refers to a divalent aryl group, where aryl is as defined herein. Unless otherwise specified, arylene groups may be unsubstituted or substituted with substituents disclosed herein.

[0049] "Arylalkyl" is defined by formula -R b -R c This refers to the radical of the expression, where R is located in the formula. b R is an alkylene group as defined herein, c is an aryl radical as defined herein, such as benzyl, diphenylmethyl, etc. Unless otherwise specified, arylalkyl groups may be unsubstituted or substituted with substituents disclosed herein. "Arylalkenyl" is defined as formula -R b -R cThis refers to the radical of the expression, where R is located in the formula. b R is an alkenylene group as defined herein, c is an aryl radical as defined herein. Unless otherwise specified, the aryl alkenyl group may be unsubstituted or substituted with substituents disclosed herein.

[0050] "Arylalkynyl" is derived from formula -R b -R c This refers to the radical of the expression, where R is located in the formula. b R is an alkynylene group as defined herein, c is an aryl radical as defined herein. Unless otherwise specified, the arylalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0051] "Cycloalkyl" refers to a non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon radical consisting of carbon and hydrogen atoms, having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and may include condensed or bridging ring systems, bonded to atoms by single bonds. Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl radicals include adamantyl and norbornyl. Examples include 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specified, cycloalkyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0052] "Aryloxy" refers to a radical of the formula -O(aryl), where the aryl radical is as defined herein. Examples of aryloxy include, but are not limited to, phenoxy(-O(phenyl)). Unless otherwise specified, the aryloxy group may be unsubstituted or substituted with substituents disclosed herein.

[0053] A "cycloalkenyl" refers to a non-aromatic, monocyclic or polycyclic hydrocarbon radical consisting of carbon and hydrogen atoms and having one or more carbon-carbon double bonds. Cycloalkenyls may have 3 to 20 carbon atoms, and in some embodiments, 3 to 10 carbon atoms, including condensed or bridging ring systems. The cycloalkenyl group is bonded to atoms by single bonds. Examples of monocyclic cycloalkenyl radicals include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Examples of polycyclic cycloalkenyl radicals include bicyclo[2.2.1]hepta-2-enyl. Unless otherwise specified, the cycloalkenyl group may be unsubstituted or substituted with substituents disclosed herein.

[0054] "Cycloalkynyl" refers to a non-aromatic, monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, and may include a condensed or bridging ring system having 5 to 20 carbon atoms, and in some embodiments, 5 to 10 carbon atoms, which are bonded to the rest of the molecule by single bonds. Examples of monocyclic cycloalkynyl radicals include cycloheptynyl and cyclooctinyl. Unless otherwise specified, the cycloalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0055] "Cycloalkylalkyl" is defined by formula -R b -R d This refers to the radical of the expression, where R is located in the formula. b R is an alkylene group as defined herein, d is a cycloalkyl radical as defined herein. Unless otherwise specified, cycloalkylalkyls may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkylalkenyl" is a cycloalkyl alkenyl of formula -R b -R d This refers to the radical of the expression, where R is located in the formula. b R is an alkenylene group as defined herein, dis a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkylalkenyl group may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkylalkynyl" is defined as formula -R b -R d This refers to the radical of the expression, where R is located in the formula. b R is an alkynylene group as defined herein, d is a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkylalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0056] "Cycloalkenylalkyl" is a compound of the formula -R b -R d This refers to the radical of the expression, where R is located in the formula. b R is an alkylene group as defined herein, d is a cycloalkenyl radical as defined herein. Unless otherwise specified, cycloalkenylalkyl groups may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkenylalkenyl" is defined as formula -R b -R d This refers to the radical of the expression, where R is located in the formula. b R is an alkenylene group as defined herein, d is a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkenylalkenyl group may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkenylalkynyl" is defined as formula -R b -R d This refers to the radical of the expression, where R is located in the formula. b R is an alkynylene group as defined herein, d This is a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkenylalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0057] "Cycloalkylalkyl" is derived from formula -Rb -R d This refers to the radical of the expression, where R is located in the formula. b R is an alkylene group as defined herein, d is a cycloalkynyl radical as defined herein. Unless otherwise specified, cycloalkynyl alkyl groups may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkynyl alkenyl" is defined as formula -R b -R d This refers to the radical of the expression, where R is located in the formula. b R is an alkenylene group as defined herein, d is a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkynylalkenyl group may be unsubstituted or substituted with substituents disclosed herein. "Cycloalkynylalkenyl" is defined as formula -R b -R d This refers to the radical of the expression, where R is located in the formula. b R is an alkynylene group as defined herein, d is a cycloalkyl radical as defined herein. Unless otherwise specified, the cycloalkynylalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0058] "Carbocyclyl," "carbocyclyl ring," or "carbocyclic ring" refers to a cyclic structure in which each atom forming the ring is carbon. Carbocyclyls, carbocyclyl rings, or carbocyclic rings may contain 3 to 20 carbon atoms within the ring. Examples of carbocyclyls, carbocyclyl rings, or carbocyclic rings as defined herein include aryl, cycloalkyl, cycloalkenyl, and cycloalkynyl rings. Carbocyclyls, carbocyclyl rings, or carbocyclic rings may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and may include condensed, bridged, and helical ring systems. Unless otherwise specified, carbocyclyl groups, carbocyclyl rings, or carbocyclic rings may be unsubstituted or substituted with substituents disclosed herein.

[0059] "Haloalkyl" means an alkyl radical as defined herein that is substituted with one or more halo radicals as defined herein, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl. Unless otherwise specified, haloalkyls may be unsubstituted or substituted with substituents disclosed herein.

[0060] "Haloalkenyl" refers to an alkenyl radical as defined herein that is substituted with one or more halo radicals as defined herein, such as 1-fluoropropenyl and 1,1-difluorobutenyl. Unless otherwise specified, the haloalkenyl group may be unsubstituted or substituted with substituents disclosed herein.

[0061] "Haloalkynyl" refers to an alkynyl radical as defined herein that is substituted with one or more halo radicals as defined herein, such as 1-fluoropropynyl and 1-fluorobutynyl. Unless otherwise specified, the haloalkenyl group may be unsubstituted or substituted with substituents disclosed herein.

[0062] "Heterocyclyl" refers to a 3-20 membered non-aromatic, partially unsaturated, or aromatic cyclic radical containing 2-12 carbon atoms and 1-6 nitrogen, oxygen, or sulfur heteroatoms. Heterocyclyls include heteroaryls as defined herein. Unless otherwise stated, heterocyclyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include condensed, bridging, and helical ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized, and the nitrogen atom Heterocyclyl radicals can be optionally quaternized and partially or completely saturated. Examples of heterocyclyl radicals include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonil, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxothiomorpholinil, and 1,1-dioxothiomorpholinil. Unless otherwise specified, heterocyclyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0063] "Heterocyclylalkyl" is a compound of formulas -R b -R e This refers to the radical of the expression, where R is located in the formula. b R is an alkylene group as defined herein, e is a heterocyclyl radical as defined herein. Unless otherwise specified, heterocyclylalkyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0064] "Heterocyclylalkenyl" is represented by formula -R b -R e This refers to the radical of the expression, where R is located in the formula. b R is an alkenylene group as defined herein, e is a heterocyclyl radical as defined herein. Unless otherwise specified, the heterocyclyl alkenyl group may be unsubstituted or substituted with substituents disclosed herein.

[0065] "Heterocyclylalkynyl" is derived from formula -R b -R e This refers to the radical of the expression, where R is located in the formula.b R is an alkynylene group as defined herein, e is a heterocyclyl radical as defined herein. Unless otherwise specified, the heterocyclylalkynyl group may be unsubstituted or substituted with substituents disclosed herein.

[0066] "N-heterocyclyl" refers to a heterocyclyl radical as defined herein, comprising at least one nitrogen atom, wherein the bonding site of the atoms of the compounds of the present invention to the heterocyclyl radical is via the nitrogen atom in the heterocyclyl radical. Unless otherwise stated, the N-heterocyclyl group may be unsubstituted or substituted with substituents disclosed herein.

[0067] A "heteroaryl" refers to a 5-20 membered cyclic radical containing a hydrogen atom, 1-13 carbon atoms, 1-6 nitrogen, oxygen, or sulfur heteroatoms, and at least one aromatic ring. Heteroaryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic systems, which may include condensed or bridging cyclic systems. The nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophene), Benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranil, dibenzothiophene, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranil, 1-oxidepyridinyl, 1-oxidepyridinyl, 1-oxidepyridinyl Examples include dinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl. Unless otherwise specified, heteroaryl groups are either unsubstituted or substituted.

[0068] "N-Heteroaryl" refers to a heteroaryl radical as defined herein having at least one nitrogen atom, and the point of attachment of the heteroaryl radical to an atom of a compound of the invention is via a nitrogen atom in the heteroaryl radical. Unless otherwise specified, an N-heteroaryl group can be unsubstituted or substituted with substituents disclosed herein.

[0069] "Heteroarylalkyl" refers to a radical of the formula -R b -R f wherein R b is an alkylene chain as defined herein and R f is a heteroaryl radical as defined herein. Unless otherwise specified, a heteroarylalkyl group can be unsubstituted or substituted with substituents disclosed herein.

[0070] "Heteroarylalkenyl" refers to a radical of the formula -R b -R f wherein R b is an alkenylene chain as defined herein and R f is a heteroaryl radical as defined herein. Unless otherwise specified, a heteroarylalkenyl group can be unsubstituted or substituted with substituents disclosed herein.

[0071] "Heteroarylalkynyl" refers to a radical of the formula -R b -R f wherein R b is an alkynylene chain as defined herein and R f is a heteroaryl radical as defined herein. Unless otherwise specified, a heteroarylalkynyl group can be unsubstituted or substituted with substituents disclosed herein.

[0072] A “ring” refers to a cyclic group that can be saturated or that can contain one or more double or triple bonds. A ring can be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, a ring can be unsubstituted or substituted with substituents disclosed herein.

[0073] "Thioalkyl" is represented by formula -SR a This refers to the radical of the expression, where R is located in the formula. a is an alkyl, alkenyl, or alkynyl radical as defined herein. Unless otherwise specified, thioalkyl groups may be unsubstituted or substituted with substituents disclosed herein.

[0074] The groups or radicals disclosed herein may be substituted with one or more substituents from the following: halogen atoms such as F, Cl, Br, and I; hydroxyl, alkoxy or ester; thiol, thioalkyl, sulfone, sulfonyl or sulfoxide; amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide and enamine; trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl and triarylsilyl; and other groups, optionally comprising one or more heteroatoms.

[0075] The groups or radicals disclosed herein may be substituted, or additionally, with one or more of the following substituents: oxo, carbonyl, carboxyl, or ester groups, or imines, oximes, hydrazones, and nitriles.

[0076] Other examples of substituents include, but are not limited to, the following: Amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroarylalkyl, -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h -OC(=O)NR g R h , -OR g , -SR g -SOR g , -SO2R g , -OSO2R g , -SO2OR g ,=NSO2R g -SO2NR g R h -C(=O)R g , -C(=O)OR g -C(=O)NR g R h ,-CH2SO2R g , and -CH2SO2NR g R h And R g and R hHowever, these substituents are identical or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, or heteroarylalkyl, where each of the above substituents is either unsubstituted or substituted by one or more substituents disclosed herein.

[0077] Where used herein, the symbol [ka] A "bond point" indicates a bond between two chemical substances, where one substance is depicted as bonding to the bond point, and the other is not. For example, [ka] This indicates that the chemical substance "XY" binds to another chemical substance via a bonding point.

[0078] The compound of the present invention Compound of formula (IA) In some embodiments, the compounds of the present invention are compounds of formula (IA), [ka] or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. Z 1 and Z 2 Independently, -C(R 1A )(R 2A )-(CH2) d -X A or -W-(CH2) d -C(R 3 )(R 4 )-Y, Each d is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. Each R 1A and R 2A Each of these is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom R 1A and R 2A Together, they form a -C3-C7 cycloalkyl group, Each R 3 and R 4 Each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4 Together, they form a -C3-C7 cycloalkyl group, each X A These are independently H, -OH, -SO3H, [ka] And, Each R 6 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-. Each Y is independently -OH, -COOH, -COOR 5 , -SO3H, [ka] And, Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0079] In some embodiments of the compound of formula (IA), Z 1 and Z 2 Independently, -C(R 1A )(R 2A )-(CH2) d -X A That is the case.

[0080] In some embodiments of the compound of formula (IA), each R 1A and R 2A R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, each R 1A and R 2A R is independently a -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl. In some embodiments, each R 1A and R 2A is independently H or C1-C6 alkyl. In some embodiments, R 1A and R 2A It is methyl.

[0081] In some embodiments of the compound of formula (IA), each p is 2, 3, 4, or 5.

[0082] In some embodiments of the compound of formula (IA), each d is 0, 1, 2, or 3. In some embodiments, d is 0 or 1.

[0083] In some embodiments, the compounds of the present invention are compounds of formula (IA), [ka] or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 4, 5, 6, or 7. Z 1 and Z 2 Independently, -C(R 1 )(R 2 )-(CH2) c -X or -W-(CH2) c -C(R 3 )(R 4 )-Y, Each c is independently 0, 1, 2, or 3. Each R 1 and R 2 The R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom. 1 and R 2 Together, they form a -C3-C7 cycloalkyl group, Each R 3 and R 4 Each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4 Together, they form a -C3-C7 cycloalkyl group, Each X and Y is independently -OH, -COOH, -COOR 5 , -SO3H, [ka] And, Each R 6 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-. Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0084] In some embodiments, the compound of formula (IA) has one of the structures shown in Table A-1, or a pharmaceutically acceptable salt or solvate thereof. [Table 1-1] [Table 1-2]

[0085] Compound of formula (IB) In some embodiments, the compound of the present invention is a compound of formula (IB), [ka] or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. each Z 1 and Z 2 Independently, -C(R 1 )(R 2 )-(CH2) c -X or -W-(CH2) c -C(R 3 )(R 4 )-Y, Each c is independently 0, 1, 2, or 3. Each R1 and R 2 The R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom. 1 and R 2 Together, they form a -C3-C7 cycloalkyl group, Each R 3 and R 4 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, B r, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom. 3 and R 4 Together, they form a -C3-C7 cycloalkyl group, Each X and Y is independently -OH, -COOH, -COOR 5 , -SO3H, [ka] And, Each R 6 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-. Each R 5These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0086] In some embodiments, the compound of formula (IB) has one of the structures shown in Table A-2, or a pharmaceutically acceptable salt or solvate thereof. [Table 2-1] [Table 2-2]

[0087] Compounds of formula (IC) In some embodiments, the compounds of the present invention are compounds of formula (IC), [ka] or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. each Z 1 and Z 2 Independently, -C(R 1 )(R 2 )-(CH2) c -X or -W-(CH2) c -C(R 3 )(R 4 )-Y, Each c is independently 0, 1, 2, or 3. Each R 1 and R 2 The R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom. 1 and R 2 Together, they form a -C3-C7 cycloalkyl group, Each R3 and R 4 Each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4 Together, they form a -C3-C7 cycloalkyl group, Each X and Y is independently -OH, -COOH, -COOR 5 , -SO3H, [ka] And, Each R 6 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-. Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0088] In some embodiments of compounds of formula (IA), (IB), or (IC), Z 1 and Z 2 These are, independently, -C(R 1 )(R 2 )-(CH2) c -X. Several In this embodiment, Z 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Y.

[0089] In some embodiments of compounds of formula (IA), (IB), or (IC), X is -COOH or -COOR. 5 That is the case.

[0090] In some embodiments of compounds of formula (IA), (IB), or (IC), each R 1 and R 2 R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, each R 1 and R 2 R is independently a -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl. In some embodiments, R 1 and R 2 It is methyl.

[0091] In some embodiments of compounds of formula (IA), (IB), or (IC), Z 1 and Z 2 These are, independently, -C(R 1 )(R 2 )-(CH2) c -X, where X is either -COOH or -COOR 5 And R 1 and R 2 It is methyl.

[0092] In some embodiments of the compounds of formula (IA), (IB), or (IC), c is 0 or 1.

[0093] In some embodiments of compounds of formula (IA), (IB), or (IC), Z 1 and Z 2 These are -C(R 1 )(R 2 )-(CH2)c -X. In some embodiments, Z 1 and Z 2 These are -C(R 1 )(R 2 )-(CH2) c It is -X, and X is -COOH.

[0094] In some embodiments of compounds of formula (IA), (IB), or (IC), each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a -C3-C7 cycloalkyl group. In some embodiments, each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a cyclopropyl ring.

[0095] In some embodiments of compounds of formula (IA), (IB), or (IC), Z 1 and Z 2 These are -C(R 1 )(R 2 )-(CH2) c -X and at least one R 1 and one R 2 These, together with the carbon atoms to which they are bonded, form a -C3-C7 cycloalkyl group. In some embodiments, Z 1 and Z 2 These are -C(R 1 )(R 2 )-(CH2) c -X and at least one R 1 and one R 2 These, together with the carbon atoms to which they are bonded, form a cyclopropyl ring.

[0096] In some embodiments of compounds of formula (IA), (IB), or (IC), R 3 and R 4 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0097] In some embodiments of compounds of formula (IA), (IB), or (IC), Y is -COOH or -COOR. 5 That is the case.

[0098] In some embodiments of compounds of formula (IA), (IB), or (IC), R 5 is a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, R 5 These are -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0099] In some embodiments of the compounds of formula (IA), (IB), or (IC), p is 3, 4, 5, 6, or 7. That is the case. In some embodiments of compounds of formula (IA), (IB), or (IC), Z 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Y, R 3 and R 4 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, Z 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Y, and Y is -COOH or -COOR 5 In some embodiments, Z 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Y, where Y is -COOH or -COOR 5 And R 5 is a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, Z1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Y, where Y is -COOH or -COOR 5 And R 5 These are -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0100] In some embodiments, the compound of formula (IC) has one of the structures shown in Table A-3, or a pharmaceutically acceptable salt or solvate thereof. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0101] Compound of formula (ID) In some embodiments, the compound of the present invention is a compound of formula (ID), [ka] or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. Z 1 and Z 2 Independently, -C(R 1A )(R 2A )-(CH2) d -X A or -W-(CH2) d -C(R 3 )(R4 )-Y, Each d is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. Each R 1A and R 2A Each of these is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom R 1A and R 2A Together, they form a -C3-C7 cycloalkyl group, Each R 3 and R 4 Each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4 Together, they form a -C3-C7 cycloalkyl group, Q 1 and Q 2 These are independently H, OH, -C1-C6 alkyl, -O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR 1A , -NR 1A R 2A , F, Cl, Br, I, -CF3, -COR 1A Q is either a heteroaryl, heterocyclyl, or -V-OH group, or each carbon atom is independently bonded to a carbon atom. 1 and Q 2 Together, they form heterocyclyl or carbocykyl groups. V is (CH2) t or allerene, t is 0, 1, 2, 3, or 4. each X A These are independently H, -OH, -SO3H, [ka] And, Each R 6These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-. Each Y is independently -OH, -COOH, -COOR 5 , -SO3H, [ka] And, Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0102] In some embodiments of the compound of formula (ID), Z 1 and Z 2 Independently, -C(R 1A )(R 2A )-(CH2) d -X A That is the case.

[0103] In some embodiments of the compound of formula (ID), each R 1A and R 2A R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, each R 1A and R 2A R is independently a -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl. In some embodiments, each R1A and R 2A is independently H or C1-C6 alkyl. In some embodiments, R 1A and R 2A It is methyl.

[0104] In some embodiments of the compound of formula (ID), each p is 2, 3, 4, or 5.

[0105] In some embodiments of the compound of formula (ID), each d is 0, 1, 2, or 3. In some embodiments, d is 0 or 1.

[0106] In some embodiments, the compound of the present invention is a compound of formula (ID), [ka] or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 4, 5, 6, or 7. Z 1 and Z 2 Independently, -C(R 1 )(R 2 )-(CH2) c -X or -W-(CH2) c -C(R 3 )(R 4 )-Y, Each c is independently 0, 1, 2, or 3. Each R 1 and R 2 The R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom. 1 and R 2 Together, they form a -C3-C7 cycloalkyl group, Each R 3 and R 4Each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4 Together, they form a -C3-C7 cycloalkyl group, Q 1 and Q 2 These are independently H, OH, -C1-C6 alkyl, -O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR 1A , -NR 1A R 2A , F, Cl, Br, I, -CF3, -COR 1A Q is either a heteroaryl, heterocyclyl, or -V-OH group, or each carbon atom is independently bonded to a carbon atom. 1 and Q 2 Together, they form heterocyclyl or carbocykyl groups. Each R 1A and R 2A These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl. V is (CH2) t or allerene, t is 0, 1, 2, 3, or 4. Each X and Y is independently -OH, -COOH, -COOR 5 , -SO3H, [ka] And, Each R 6 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-. Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogens, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0107] In some embodiments, the compound of formula (ID) has the structure shown in Table A-1, or a pharmaceutically acceptable salt or solvate thereof. The compounds have the structures shown in Table A-5, or pharmaceutically acceptable salts or solvates thereof, in which the phenyl group is monosubstituted or disubstituted with an -OH or methyl group.

[0108] Compound of formula (IG) In some embodiments, the compound of the present invention is a compound of formula (IG), [ka] or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. Z 1 and Z 2 Independently, -C(R 1 )(R 2 )-(CH2) c -X or -W-(CH2) c -C(R 3 )(R 4 )-Y, Each c is independently 0, 1, 2, or 3. Each R 1 and R 2The R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom. 1 and R 2 Together, they form a -C3-C7 cycloalkyl group, Each R 3 and R 4 Each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4 Together, they form a -C3-C7 cycloalkyl group, Q 1 and Q 2 These are independently H, OH, -C1-C6 alkyl, -O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR 1A , -NR 1A R 2A , F, Cl, Br, I, -CF3, -COR 1A Q is either a heteroaryl, heterocyclyl, or -V-OH group, or each carbon atom is independently bonded to a carbon atom. 1 and Q 2 Together, they form heterocyclyl or carbocykyl groups. Each R 1A and R 2A These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl. V is (CH2) t or allerene, t is 0, 1, 2, 3, or 4. Each X and Y is independently -OH, -COOH, -COOR 5 , -SO3H, [ka] And, Each R 6These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-. Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0109] In some embodiments, in a compound of formula (IG), Q 1 and Q 2 These are H.

[0110] In some embodiments, in the compound of formula (IG), p is 2, 3, 4, 5, 6, or 7. In some embodiments, in the compound of formula (IG), p is 2.

[0111] In some embodiments, the compound of formula (IG) has the structure shown in Table A-4, or a pharmaceutically acceptable salt or solvate thereof. [Table 4]

[0112] Compounds of formula (IE) In some embodiments, the compounds of the present invention are compounds of formula (IE), [ka] or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. each Z 1 and Z 2 Independently, -C(R 1 )(R 2 )-(CH2) c -X or -W-(CH2) c -C(R 3 )(R 4 )-Y, Each c is independently 0, 1, 2, or 3. Each R 1 and R 2 The R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom. 1 and R 2 Together, they form a -C3-C7 cycloalkyl group, Each R 3 and R 4 Each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4 Together, they form a -C3-C7 cycloalkyl group, Q 1 and Q 2 These are independently H, OH, -C1-C6 alkyl, -O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR 1A , -NR 1A R 2A , F, Cl, Br, I, -CF3, -COR 1A Q is either a heteroaryl, heterocyclyl, or -V-OH group, or each carbon atom is independently bonded to a carbon atom. 1 and Q 2 Together, they form heterocyclyl or carbocykyl groups. Each R1A and R 2A These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl. V is (CH2) t or allerene, t is 0, 1, 2, 3, or 4. Each X and Y is independently -OH, -COOH, -COOR 5 , -SO3H, [ka] And, Each R 6 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-. Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0113] In some embodiments, the compound of formula (IE) has the structure shown in Table A-2, or a pharmaceutically acceptable salt or solvate thereof. The compounds have the structures shown in Table A-6, or pharmaceutically acceptable salts or solvates thereof, in which the phenyl group is monosubstituted or disubstituted with an -OH or methyl group.

[0114] Compounds of formula (IF) In some embodiments, the compounds of the present invention are compounds of formula (IF), [ka] or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. each Z 1 and Z 2 Independently, -C(R 1 )(R 2 )-(CH2) c -X or -W-(CH2) c -C(R 3 )(R 4 )-Y, Each c is independently 0, 1, 2, or 3. Each R 1 and R 2 The R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom. 1 and R 2 Together, they form a -C3-C7 cycloalkyl group, Each R 3 and R 4 Each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4 Together, they form a -C3-C7 cycloalkyl group, Q 1 and Q 2 These are independently H, OH, -C1-C6 alkyl, -O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR 1A , -NR 1A R 2A , F, Cl, Br, I, -CF3, -COR1A Q is either a heteroaryl, heterocyclyl, or -V-OH group, or each carbon atom is independently bonded to a carbon atom. 1 and Q 2 Together, they form heterocyclyl or carbocykyl groups. Each R 1A and R 2A These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl. V is (CH2) t or allerene, t is 0, 1, 2, 3, or 4. Each X and Y is independently -OH, -COOH, -COOR 5 , -SO3H, [ka] And, Each R 6 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-. Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0115] In some embodiments, the compound of formula (IF) has the structure shown in Table A-3, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula (IE) The compounds have the structures shown in Table A-7, or pharmaceutically acceptable salts or solvates thereof, in which the phenyl molecule is monosubstituted or disubstituted with an -OH or methyl group.

[0116] Compounds of formulas (IH) and (IJ)~(IL) In some embodiments, the compound of the present invention is a compound of formula (IH), [ka] or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. each Z 1 and Z 2 Independently, -C(R 1 )(R 2 )-(CH2) c -X or -W-(CH2) c -C(R 3 )(R 4 )-Y, Each c is independently 0, 1, 2, or 3. Each R 1 and R 2 The R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom. 1 and R 2 Together, they form a -C3-C7 cycloalkyl group, Each R 3 and R 4 Each carbon atom is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom is independently bonded to a carbon atom R 3 and R 4Together, they form a -C3-C7 cycloalkyl group, Q is independently -OH, methyl, or methoxy. t is 1, 2, 3, or 4. Each X and Y is independently -OH, -COOH, -COOR 5 , -SO3H, [ka] And, Each R 6 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where the -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, Each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-. Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups.

[0117] In some embodiments of formula (IH), the compound has the structure of formula (IJ), (IK), or (IL), or a pharmaceutically acceptable salt thereof. [ka]

[0118] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z 1 and Z2 These are, independently, -C(R 1 )(R 2 )-(CH2) c -X. In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Y.

[0119] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), X is -COOH or -COOR. 5 That is the case.

[0120] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each R 1 and R 2 R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each R 1 and R 2 R is independently a -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl. In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R 1 and R 2 It is methyl.

[0121] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z 1 and Z 2 These are, independently, -C(R 1 )(R 2 )-(CH2) c-X, where X is either -COOH or -COOR 5 And R 1 and R 2 It is methyl.

[0122] In some embodiments of the compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), c is 0 or 1.

[0123] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z 1 and Z 2 These are -C(R 1 )(R 2 )-(CH2) c -X. In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z 1 and Z 2 These are -C(R 1 )(R 2 )-(CH2) c It is -X, and each X is -COOH.

[0124] In some embodiments of the compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a C3-C7 cycloalkyl group. In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a cyclopropyl ring.

[0125] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z 1 and Z 2 These are -C(R1 )(R 2 )-(CH2) c -X and at least one R 1 and one R 2 These, together with the carbon atoms to which they are bonded, form a -C3-C7 cycloalkyl group. In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z 1 and Z 2 These are -C(R 1 )(R 2 )-(CH2) c -X and at least one R 1 and one R 2 These, together with the carbon atoms to which they are bonded, form a cyclopropyl ring.

[0126] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R 3 and R 4 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0127] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Y is -COOH or -COOR. 5 That is the case.

[0128] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R 5 is a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R 5 These are -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0129] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), p is 3, 4, 5, 6, or 7. In some embodiments, p is 4, 5, 6, or 7.

[0130] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z 1 And either or both of Z2 are -W-(CH2) c -C(R 3 )(R 4 )-Y, R 3 and R 4 In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Y, and Y is -COOH or -COOR 5 In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Y, and Y is -COOH or -COOR 5 And R 5 is a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z 1 and Z 2 One or both of them are -W-(CH2) c -C(R 3 )(R 4 )-Y, and Y is -COOH or -COOR5 And R 5 These are -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0131] In some embodiments of the compounds of formula (IH), (IJ), (IK), or (IL), Q is independently methyl or -OH.

[0132] In some embodiments of compounds of formula (IH), (IJ), (IK), or (IL), t is 1. In some embodiments, t is 2. In some embodiments, t The answer is 3.

[0133] In some embodiments, the compounds of formula (IH), (IJ), (IK), or (IL) have one of the structures shown in Table A-5, Table A-6, or Table A-7, or a pharmaceutically acceptable salt or solvate thereof. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 6-1] [Table 6-2] [Table 6-3] Table 6-4 Table 6-5 Table 6-6 Table 6-7 Table 6-8 Table 6-9 Table 6-10 Table 6-11 Table 6-12 Table 6-13 Table 6-14 Table 7-1 Table 7-2 Table 7-3 Table 7-4 Table 7-5 Table 7-6 Table 7-7 Table 7-8 Table 7-9 Table 7-10 Table 7-11 Table 7-12 Table 7-13 Table 7-14 Table 7-15 Table 7-16 Table 7-17 Table 7-18 Table 7-19 Table 7-20 Table 7-21 Table 7-22 Table 7-23 Table 7-24 Table 7-25 Table 7-26 Table 7-27 Table 7-28 Table 7-29 Table 7-30 Table 7-31 Table 7-32 Table 7-33 Table 7-34 Table 7-35 Table 7-36 Table 7-37 Table 7-38 Table 7-39

[0134] Compounds of formula (II) In some embodiments, the compound of the present invention is a compound of formula (II), [ka] or a pharmaceutically acceptable salt or solvate thereof, Each R 1 and R 2 Each of these is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom R 1 and R 2 Together, they form a -C3-C7 cycloalkyl group, Each n is independently 0, 1, 2, or 3. Each m is independently 1, 2, 3, 4, 5, 6, 7, 8, or 9. X is -C(=O)-, -CHR 3 -, -CH-CH2(OR 3 )-, -O-, -S-, -S(=O)-, -S(O)2-, -NR 3 -, -N(OH)-, -N(→O)-, or -Se- R 3 These are H, -OH, -O(C1-C6 alkyl), -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C7 cycloalkyl, C4-C7 cycloalkenyl, C5-C8 cycloalkynyl, phenyl, or benzyl, where each of the -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C7 cycloalkyl, C4-C7 cycloalkenyl, C5-C8 cycloalkynyl, phenyl, and benzyl is either unsubstituted or substituted with one or more halogens, -CN, -NO2, or -CF3 groups. Each Y is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O)2-, or -Se-. Each Z is independently -OH, -COOH, -COOR 5 -SO3H, -SO3R 5 , [ka] And, Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 6 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or - C2-C6 alkynyls, where -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0135] In some embodiments of the compound of formula (II), X is -C(=O)-, -CHR 3 X is -, -O-, -S-, -S(=O)-, or Se. In some embodiments, X is -C(=O)-, -CH(OH)-, -O-, -S-, -S(=O)-, or Se.

[0136] In some embodiments of the compound of formula (II), R 3 The group is H, -OH, -O(C1-C3 alkyl), or -C1-C3 alkyl.

[0137] In some embodiments of the compound of formula (II), each Y is independently -O- or -S-.

[0138] In some embodiments of the compound of formula (II), each R 1 and R 2 R is independently H, -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl. In some embodiments, each R 1 and R 2It is independently either H or methyl.

[0139] In some embodiments of the compound of formula (II), each Z is independently -COOH or -COOR 5 In some embodiments, each Z is -COOH.

[0140] In some embodiments of the compound of formula (II), each R 5 These are independently -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0141] In some embodiments of the compound of formula (II), each n is independently 0, 1, or 2. In some embodiments, n is 1.

[0142] In some embodiments of the compound of formula (II), each m is independently 3, 4, 5, or 6. In some embodiments, each m is independently 4 or 5.

[0143] In some embodiments, the compound of formula (II) has one of the structures shown in Table B1, or a pharmaceutically acceptable salt or solvate thereof. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0144] Compounds of formulas (III), (IIIA), and (IIIB) In some embodiments, the compound of the present invention is a compound of formula (III), [ka] or a pharmaceutically acceptable salt or solvate thereof, R 1 and R 2 is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or R 1 and R 2 Together with the bonded carbon atom, it forms a -C3-C7 cycloalkyl group. Each m is independently 3, 4, 5, 6, or 7. Each n is independently 0, 1, 2, 3, 4, or 5. Each q is 0, 1, 2, 3, or 4. X is -O-, -S-, -S(=O)-, -S(O)2-, -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-. Z1 and Z2 are independently -C1-C6 alkyl, -OH, -COOH, -COOR 5 -SO3H, -SO3R 5 , [ka] And, Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 6 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0145] In some embodiments, the compound of the present invention is a compound of formula (IIIA), [ka] or a pharmaceutically acceptable salt or solvate thereof, R 1 and R 2 is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or R 1 and R 2 Together with the bonded carbon atom, it forms a -C3-C7 cycloalkyl group. Each m is independently 2, 3, 4, 5, 6, or 7. Each n is independently 0, 1, 2, 3, 4, or 5. Each q is 0, 1, 2, 3, or 4. X is -O-, -S-, -S(=O)-, -S(O)2-, -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-. Z1 and Z2 are -C1-C6 alkyl, -COOH, -COOR 5 , -SO3R 5 , [ka] Therefore, Z1 and Z2 are the same. Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups. And so, Each R 6These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0146] In some embodiments, the compound of the present invention is a compound of formula (IIIB), [ka] or a pharmaceutically acceptable salt or solvate thereof, R 1 and R 2 is independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or R 1 and R 2 Together with the bonded carbon atom, it forms a -C3-C7 cycloalkyl group. Each m is independently 2, 3, 4, 5, 6, or 7. Each n is independently 0, 1, 2, 3, 4, or 5. Each q is 0, 1, 2, 3, or 4. X is -S-, -S(=O)-, -S(O)2-, -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-. Z1 and Z2 are independently -C1-C6 alkyl, -OH, -COOH, -COOR 5 -SO3H, -SO3R 5 , [ka] And, Each R 5These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is either unsubstituted or substituted with one or more halogen, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 6 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl, where -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl is unsubstituted or substituted with one or two halogens, -OH, -O(C1-C6 alkyl), or phenyl groups. Each R 7 These are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl.

[0147] In some embodiments of the compounds of formulas (III) and (IIIB), each Z 1 and Z 2 These are independently -OH, -COOH, or -COOR 5 In some embodiments, each Z 1 and Z 2 These are independently C1-C6 alkyl groups.

[0148] In some embodiments of the compounds of formula (III), (IIIA), and (IIIB), Z 1 and Z 2 These are the same group, -OH, -COOH, or -COOR 5 In some embodiments, Z 1 and Z 2 Both are C1-C6 alkyl groups.

[0149] In some embodiments of the compound of formula (III), X is -S-, -S(=O)-, -S(O)2-, -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-.

[0150] In some embodiments of the compounds of formula (III) and (IIIA), X is O. In some embodiments of the compounds of formula (III), when X is O, m is 2, 3, 5, 6, or 7.

[0151] In some embodiments of the compounds of formulas (III), (IIIA), and (IIIB), each n is independently 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0152] In some embodiments of the compounds of formulas (III), (IIIA), and (IIIB), each m is independently 4, 5, or 6. In some embodiments, m is 5 or 6. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 2 or 3.

[0153] In some embodiments of the compounds of formula (III), (IIIA), and (IIIB), R 1 and R 2 It forms a -C3-C7 cycloalkyl group with the bonded carbon atom.

[0154] In some embodiments, the compound of formula (III) or (IIIA) has one of the structures shown in Table B2, or a pharmaceutically acceptable salt or solvate thereof. [Table 9]

[0155] Composition of the present invention In some embodiments, the composition of the present invention comprises (i) an effective amount of the compound of the present invention and (ii) a pharmaceutically acceptable carrier or vehicle.

[0156] In some embodiments, the composition of the present invention includes (i) an effective amount of the compound of formula (IA): [ka] or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. Z 1 and Z 2 Independently, -C(R 1 )(R 2 )-(CH2) c -COOH or -C(R 1 )(R 2 )-(CH2) c -COOR 5 And, Each c is independently 0, 1, 2, or 3. Each R 1 and R 2 The R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to a carbon atom. 1 and R 2 Together, they form a -C3-C7 cycloalkyl group, Each R 5 These are independently -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, phenyl, or benzyl, each of which is unsubstituted or contains one or more halogens, -OH, -O(C 1- A compound or a pharmaceutically acceptable salt or solvate thereof, which is substituted with a C6 alkyl group or a phenyl group, (ii) comprising a pharmaceutically acceptable carrier or vehicle.

[0157] In some embodiments of compositions containing the compound of formula (IA), each R 1 and R 2 R is independently a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, each R 1 and R 2 R is independently a -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl. In some embodiments, R 1 and R 2It is methyl.

[0158] In some embodiments of compositions containing the compound of formula (IA), c is 0 or 1.

[0159] In some embodiments of compositions containing the compound of formula (IA), R 5 is a -C1-C6 alkyl, -C2-C6 alkenyl, or -C2-C6 alkynyl. In some embodiments, R 5 These are -C1-C3 alkyl, -C2-C3 alkenyl, or -C2-C3 alkynyl.

[0160] In some embodiments of compositions containing a compound of formula (IA), the compound is compound I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, or I-10, or a pharmaceutically acceptable salt or solvate thereof, or [ka] It is a compound having the structure of the given compound, or a pharmaceutically acceptable salt or solvate thereof.

[0161] In some embodiments, the composition of the present invention comprises an effective amount of a compound having the structure shown in Table A-1, A-2, A-3, or A-4, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the present invention comprises an effective amount of a compound having the structure shown in Table B1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the present invention comprises an effective amount of a compound having the structure shown in Table B2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the present invention contains an effective amount of a compound having the structure shown in Table C, or a pharmaceutically acceptable salt or solvate thereof. [Table 10]

[0162] In some embodiments, the composition of the present invention further comprises another pharmaceutically active agent.

[0163] In some embodiments, other pharmaceutically active agents include statins, thiazolidinedions or fibrates, bile acid binding resins, niacin, anti-obesity drugs, hormones, thyrophostine, sulfonylurea-based drugs, biguanides, α-glucosidase inhibitors, apolipoprotein AI agonists, apolipoprotein E agonists, phosphodiesterase type-5 inhibitors, cardiovascular drugs, HDL-enhancing agents, HDL enhancers, apolipoprotein AI gene or protein agonists, apolipoprotein A-IV gene or protein agonists, apolipoprotein gene agonists, ATP citrate lyase modulators, ATP citrate lyase allosteric inhibitors, acetyl-CoA carboxylase modulators, or acetyl-CoA carboxylase allosteric inhibitors.

[0164] In some embodiments, the other pharmaceutically active agent is an antagonist or inhibitor of a pro-inflammatory gene or protein, or an agonist of an anti-inflammatory gene or protein. In some embodiments, the other pharmaceutically active agent inhibits or reduces the pro-inflammatory function of IL-6, CRP, TNF-α, MCP-1, MIP-1β, CCR5, CCR2, NF-κB, or TGF-β1, or increases its anti-inflammatory function.

[0165] In some embodiments, other pharmaceutically active agents affect the expression or function of fibrosis genes or proteins, or mitotic genes or proteins. In some embodiments, other pharmaceutically active agents modulate the expression or function of FGF-21, MMP-2, TIMP-1, ASK1, or type 3 collagen.

[0166] In some embodiments, other pharmaceutically active agents are regulators of lipid metabolism-related or transport-related genes, regulators of PPAR-α target genes such as HD(ECHS1), PDK4, and Cyp7A1, and regulators of SGLT1, SGL2, ApoC-III, Sulf-2, ANGPTL3, ANGPTL4, and LPL genes.

[0167] In some embodiments, the other pharmaceutically active agent is a statin. In some embodiments, the statin is atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, dalvastatin, dihydrocompactin, or cerivastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, the statin is lovastatin.

[0168] In some embodiments, the other pharmaceutically active agent is a fibrate. In some embodiments, the fibrate is fenofibrate, gemfibrozil, or fenofibrate. It is dibric acid.

[0169] In some embodiments, the other pharmaceutically active agent is sorafenib. In some other embodiments, the other pharmaceutically active agent is taxol. In some other embodiments, the other pharmaceutically active agent is carotuximab. In some other embodiments, the other pharmaceutically active agent is pembrolizumab. In some other embodiments, the other pharmaceutically active agent is lenvatinib. In some other embodiments, the other pharmaceutically active agent is avelumab. In some embodiments, the other pharmaceutically active agent is durvalumab. In some other embodiments, the other pharmaceutically active agent is tremelimumab. In some other embodiments, the other pharmaceutically active agent is nivolumab. In some other embodiments, other pharmaceutically active agents include T-cell receptor (TCR) immunotherapy agents such as tazemetostat, semiprimab, ABX196, and LioCyx™; TBI-302, namodenoson, MM-310; tumor injection oncolytic viruses or recombinant oncolytic viruses, for example, but not limited to telomericin and imlizic; or immunomodulatory genetherapy agents such as MDA-7 / IL-24, GLIPR1 / RTVP-1, and REIC / Dkk-3.

[0170] In some other embodiments, other pharmaceutically active agents include cenicliviroc, elafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, nivolumab, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, IMM-124E, RG-125, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegberfermin, PF-05231023, obeticholic acid, silofexol. Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, ND-L02-s0201 / BMS-986263, Borixivat, Amlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Roflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogritazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, or narumafen.In some embodiments, other pharmaceutically active agents include pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, sarogritazal magnesium, borixibat, filsocostat, silofexol, elafibrano, nalmefene, solithromycin, and 99m techne. Thium-mebrophenine, tropifexol, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, seradeluper, physogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, tramethicinib Nib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, zotilib citrate, cintilimab, camrelizumab, spartalis Mab, tripalimab, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305, askrinbakumab, citravatinib, cytokine-based biological agents IRX-2, bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SR. F388, ET1402L1-CART, Glypican 3-specific chimeric antigen receptor expressing T cells (CAR-T cells), CD147-targeting CAR-T cells, NKG2D-type CAR These include T cells, novel antigen-reactive T cells, Pexastimogene Devacirepvec, Talimogene Laherparepvec, GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase peptide vaccine, or IMA970A, Novantrone, Prednisone, Pixantrone, Loxoxantrone, Cytidine-phosphate-guanosine (CpG) DNA, Paclitaxel, Oraxol, MTL-CEBPA, Ribavirin, Elbasvir, Grazoprevir, Lipotecan, ZSP1241, U3-1784, Abadomide, INCAGN01949, or CMP-001.

[0171] In some embodiments, other pharmaceutically active agents are anticancer agents. In some embodiments, anticancer agents include sorafenib, taxol, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicliviroc, ellafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegberfermin, PF-05231023, and O Beticholic acid, silofexol, tropifexol, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, borixivat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipercast, oltipraz, MSDC-0602K, ASP9831, roflumilast, ellafibranol, pioglitazone, rosiglitazone, fenofibrate, saroglitazal, ranifibranol, aramcol, ipragliflozin, dapagliflozin, empagliflozin, BI1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Narmafen, Pentamidine, Berberine, L-Carnitine, EYP001a, Silymarin, Myricolinant, Ursodeoxycholic Acid, Metadoxine, Ezetimibe, Cystadan, L-Alanine, Sarogritazal Magnesium, Borixivat, Elafibranol, Narmefen, Solithromycin, 99m Technetium-Mebrophenine, S-Adenosylmethionine, Pentoxifylline, Oresoxime, AKR-001, Seradelpar, Physogatinib, Doxo Rubicin, cabozantinib, deferoxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, or zofilcrib citrate.

[0172] In some embodiments, the composition of the present invention further comprises an anticancer agent.

[0173] In some embodiments, other pharmaceutically active agents are immunotherapeutic agents. In some embodiments, immunotherapeutic agents include pembrolizumab, avelumab, durvalumab, nivolumab, semiprimab, ABX196, cintilimab, camrelizumab, spartalizumab, tripalimab, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305, askrinbakumab, TCR T-cell therapy agent, citravatinib, cytokine-based biological agent IRX-2, bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SRF388, and ET1402L1-CAR. These include T cells, glypican-3 specific chimeric antigen receptor-expressing T cells (CAR-T cells), CD147-targeted CAR-T cells, NKG2D-based CAR-T cells, or novel antigen-reactive T cells.

[0174] In some embodiments, the composition of the present invention further comprises an immunotherapy agent.

[0175] In some embodiments, the other pharmaceutically active agent is an oncovirus. In some embodiments, the oncovirus is Pexastimogene Devacirepvec or Talimogene Laherparepvec. In some embodiments, the composition of the present invention further comprises an oncovirus.

[0176] In some embodiments, the other pharmaceutically active agent is a vaccine. In some embodiments, the vaccine is GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase peptide vaccine, or IMA970A. In some embodiments, the composition of the present invention further comprises a vaccine.

[0177] In some embodiments, other pharmaceutically active agents include novantrone, prednisone, pixantrone, losoxantrone, cytidine-phosphate-guanosine (CpG)DNA, paclitaxel, olaxol, MTL-CEBPA, ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241, U3-1784, avadomide, INCAGN01949, or CMP-001.

[0178] In some embodiments, the composition of the present invention further comprises two or more other pharmaceutically active agents. In some embodiments, the two or more other pharmaceutically active agents are, but are not limited to, oncolytic agents such as nanatinostat and valganciclovir.

[0179] In some embodiments, the compositions of the present invention further include, as pharmaceutically active agents, sorafenib, taxol, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, senicliviroc, ellafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegberfermin, PF-05 231023, Oveticolate, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, Borixivat, Amlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Loflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogritazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI 1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Narmafen, Pentamidine, Berberine, L-Carnitine, EYP001a, Silymarin, Myricolinant, Ursodeoxycholic Acid, Metadoxine, Ezetimibe, Cystadan, L-Alanine, Sarogritazal Magnesium, Borixibat, Elafibranol, Narmefen, Solithromycin 99m Technetium-Mebrophenine, S-Adenosylmethionine, Pentoxifylline, Oresoxime, AKR-001, Seradelpar, Physogatinib, Doxorubicin, Cabozantinib, Deferoxamine, Itacitinib, Thiauranib, SF1126, Anlotinib, P1101, Vallitinib, SHR-1210, SHR6390, Capmatinib, Dabrafenib, Trametinib, Sapanicerthi Contains b, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, or zofilcrib citrate. In some embodiments of the compositions of the present invention, the composition comprises (a) Compound I-1, Compound I-32, Compound I-61, or Compound III-1, or a pharmaceutically acceptable salt or solvate thereof, and (b) as a pharmaceutically active agent, sorafenib, Taxol, Lenvatinib, Tazemetostat, TBI-302, Namodenoson, MM-310, Cenicliviroc, Elafibranol, Eicosapentaenoic acid, Garnicertive, LY2109761, LDE225, Filsocostat, Aparalenone, Metformin, Leucine-Metformin-Sildenafil combination, Vitamin E, Cysteamine, Seroncertib, Losartan, RO5093151, Prazigastat, Sitaglip Tin, Vildagliptin, NGM282, Pegberfermin, PF-05231023, Obeticholic acid, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, Borixivat, Amlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Loflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogritazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Narmafen, Pentamidine, Berberine, L-Carnitine, EYP001a, Silymarin, Myricolinant, Ursodeoxycholic Acid, Metadoxine, Ezetimibe, Cystadan, L-Alanine, Sarogritazal Magnesium, Borixivat, Elafibranol, Narmefen, Solithromycin, 99m Technetium-Mebrophenine, S-Adenosylmethionine, Pentoxifylline, Oresoxime, AKR-001, Seradelpar, Physogatinib, Doxol Includes Bicin, cabozantinib, deferoxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, or zofilcrib citrate.

[0180] In some embodiments of the compositions of the present invention, the composition comprises the compound of the present invention and, as a pharmaceutically active agent, sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, semiprimab, ABX196, a T-cell receptor (TCR) immunotherapy agent, TBI-302, namodenoson, MM-310, an oncolytic virus for tumor injection or a recombinant oncolytic virus, or an immunomodulatory gene therapy agent. In some embodiments, the composition comprises (a) compound I-1, compound I-32, compound I-61, or compound III-1, or a pharmaceutically acceptable salt or solvate thereof, and (b) a pharmaceutically active agent such as sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, semiprimab, ABX196, a T-cell receptor (TCR) immunotherapy agent, TBI-302, namodenoson, MM-310, an oncolytic virus or recombinant oncolytic virus for tumor injection, or an immunomodulatory gene therapy agent.

[0181] In some embodiments of the compositions of the present invention, the composition comprises the compound of the present invention and sorafenib or lenvatinib. In some embodiments, the composition comprises (a) compound I The composition comprises (a) compound I-1, compound I-32, compound I-61, or compound III-1, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib or lenvatinib. In some embodiments, the composition comprises (a) compound I-1, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib or lenvatinib. In some embodiments, the composition comprises (a) compound I-32, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib or lenvatinib. In some embodiments, the composition comprises (a) compound I-32, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib. In some embodiments, the composition comprises (a) compound I-32, or a pharmaceutically acceptable salt or solvate thereof, and (b) lenvatinib. In some embodiments, the composition comprises (a) compound I-61, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib or lenvatinib. In some embodiments, the composition comprises (a) compound I-61, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib. In some embodiments, the composition comprises (a) compound I-61, or a pharmaceutically acceptable salt or solvate thereof, and (b) lenvatinib. In some embodiments, the composition comprises (a) compound III-1, or a pharmaceutically acceptable salt or solvate thereof, and (b) sorafenib or lenvatinib.

[0182] Table D shows embodiments A1-A4, B1-B4, C1-C4, D1-D4, E1-E4, F1-F4, G1-G4, H1-H4, I1-I4, J1-J4, K1-K4, L1-L4, M1-M4, N1-N4, O1-O4, P1-P4, Q1-Q4, R1-R4, and S1-S4. Each embodiment in Table D refers to a specific compound of the present invention and another pharmaceutically active agent. For example, Embodiment A1 refers to compound I-1 (or a pharmaceutically acceptable salt or solvate thereof) and sorafenib, Embodiment A2 refers to compound I-32 (or a pharmaceutically acceptable salt or solvate thereof) and sorafenib, and so on. In some embodiments, the composition of the present invention contains an effective amount of the compound of the present invention and another pharmaceutically active agent described in the embodiments of Table D. [Table 11]

[0183] In some embodiments, the pharmaceutically acceptable carrier or vehicle is limited to: Examples of additives include binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow promoters, colorants, pigment transfer inhibitors, sweeteners, or flavoring agents.

[0184] The binder or granulator imparts cohesiveness to the tablets so that they remain intact after compression. Suitable binders or granulators include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500), sugars such as gelatin, sucrose, glucose, dextrose, molasses, and lactose, acacia, alginic acid, alginates, Irish moss extract, Panwar gum, Guttia gum, Isabugol husk mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), bee gum, and larch alabogalactan (larch). Examples include natural and synthetic gums such as arabogalactan, powdered tragacanth, and guar gum; celluloses such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC); microcrystalline celluloses such as AVCEL-PH-101, AVCEL-PH-103, AVCEL RC-581, and AVCEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof.

[0185] Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. In some embodiments, the binder is hydroxypropyl cellulose.

[0186] A binder or filler may be present in about 2% to about 49% by weight of the composition of the present invention provided herein, or in any range within these values. In some embodiments, the binder or filler is present in about 5% to about 15% by weight of the composition of the present invention. In some embodiments, the binder or filler is present in about 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 8% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, or 15% by weight of the composition of the present invention, or in any range within any of these values.

[0187] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantities, can impart certain properties to some compressible tablets, allowing them to disintegrate in the mouth by chewing. Such compressible tablets can be used as chewable tablets. In some embodiments, the diluent is lactose monohydrate. In some embodiments, the diluent is Fast-Flo 316 NF lactose monohydrate.

[0188] The compositions of the present invention may contain a diluent, for example, a diluent in an amount of about 5% to about 49% by weight of the composition, or any range between any of these values. In some embodiments, the diluent is present in the composition of the present invention in an amount of about 15% to about 30% by weight. In some embodiments, the diluent is present in the composition of the present invention in an amount of about 15% by weight, 16% by weight, 17% by weight, 18% by weight, 19% by weight, 18% by weight, 20% by weight, 21% by weight, 22% by weight, 23% by weight, 24% by weight, 25% by weight, 26% by weight, 27% by weight, 28% by weight, 29% by weight, or 30% by weight, or any range between any of these values.

[0189] Suitable disintegrants include, but are not limited to, agar, bentonite, methylcellulose, and Examples include cellulose such as carboxymethylcellulose, wood products, natural sponges, cation exchange resins, gums such as alginic acid, guar gum and bee gum HV, citrus fruit pulp, cross-linked cellulose such as croscarmellose, cross-linked polymers such as crospovidone, cross-linked starch, microcrystalline cellulose such as calcium carbonate and sodium starch glycolate, potassium polaritrin, starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch, clay, algin (align), and mixtures thereof. The amount of disintegrant in the composition 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).

[0190] The compositions of the present invention may contain a disintegrant, for example, about 0.5% to about 15% by weight or about 1% to about 10% by weight. In some embodiments, the compositions of the present invention contain a disintegrant in an amount of about 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 8% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, or 15% by weight of the composition, or in any range within any of these values.

[0191] Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycerol behenate and glycols such as 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 laureate, agar, starch, lycopodium, silica or silica gel, such as AEROSIL® 200 (WRGrace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co., Boston, MA), and mixtures thereof. In some embodiments, the lubricant is magnesium stearate.

[0192] The compositions of the present invention may contain a lubricant, for example, in about 0.1 to about 5% by weight. In some embodiments, the compositions of the present invention contain a lubricant in an amount of about 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, 0.9% by weight, 0.8% by weight, 1.0% by weight, 1.1% by weight, 1.2% by weight, 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, 2.6% by weight, 2.7% by weight, 2.8% by weight, 2.9% by weight, or 3.0% by weight of the composition, or any range within any of these values.

[0193] Suitable flow promoters include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), and talc (such as asbestos-free talc).

[0194] Colorants may include approved, certified, water-soluble FD&C dyes, water-insoluble FD&C dyes and lake pigments suspended on alumina hydrate, or mixtures thereof.

[0195] Flavoring agents include natural fragrances extracted from plants such as fruits, as well as synthetic blends of compounds that provide pleasant tastes, such as peppermint and methyl salicylate.

[0196] Examples of sweeteners include sucrose, lactose, mannitol, syrup, glycerin, sucralose, and artificial sweeteners such as saccharin and aspartame.

[0197] Suitable emulsifiers include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, bee gum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include glycerin, methyl and propylparabens, benzoic acid additives, sodium benzoate, and alcohol. Suitable humectants include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0198] Examples of solvents include glycerin, sorbitol, ethyl alcohol, and syrup.

[0199] Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of organic acids include citric acid and tartaric acid. Examples of carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0200] The compounds and compositions of the present invention can be formulated in formulations containing pharmaceutically acceptable carriers, adjuvants, and vehicles by various means for local or rectal administration, for example, by oral, parenteral, inhalation spray, topical, or rectal administration. As used herein, the term “parenteral” includes injection into the subcutaneous, intravenous, intramuscular, and intra-arterial regions by various infusion techniques. As used herein, intra-arterial and intravenous infusions include administration via a catheter.

[0201] The compounds and compositions of the present invention can be formulated according to a standard procedure that is suitable for the desired administration route. Therefore, the compositions of the present invention can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and may contain formulations such as suspending agents, stabilizers, and / or dispersants. The compounds and compositions of the present invention can be formulated as preparations suitable for implantation or infusion. Therefore, for example, the compositions of the present invention can be formulated with a suitable polymer material or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or a slightly soluble derivative (e.g., as a slightly soluble salt). The compounds and compositions of the present invention may also be in powder form for preparation with a suitable vehicle, such as sterile pyrogen-free water, before use. Suitable formulations 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.

[0202] In some embodiments, the compositions of the present 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, tongue, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, 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, the compositions of the present invention suitable for oral administration are in the form of tablets or capsules. In some embodiments, the compositions of the present 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 present invention It is contained in a capsule.

[0203] In some embodiments, the capsule is an immediate-release capsule. A non-limiting example of the capsule is the coni-snap® rigid gelatin capsule.

[0204] The compositions of the present invention may be in the form of compressed tablets, powder tablets, chewable lozenges, rapidly dissolving tablets, multi-compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that is resistant to the action of stomach acid while dissolving or disintegrating in the intestines, thus protecting the active ingredient from the acidic environment of the stomach. Examples of enteric coatings, but not limited to, include fatty acids, fats, phenyl salicylates, waxes, shellac, ammonium shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in masking undesirable 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 material. Examples of film coatings, but not limited to, include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings can impart the same general properties as sugar coatings. Multiple compression tablets are compression tablets manufactured through multiple compression cycles, including layered tablets and tablets that are press-coated or dry-coated.

[0205] In some embodiments, the coating is a film coating. In some embodiments, the film coating comprises Opadry White and 30% Simethicone Emulsion USP.

[0206] In some embodiments, the compound of the present invention is contained in a tablet. In some embodiments, the compound of the present invention is contained in a compressed tablet. In some embodiments, the compound of the present invention is contained in a film-coated compressed tablet. In some embodiments, the composition of the present invention is in the form of a film-coated compressed tablet.

[0207] In some embodiments, the compositions of the present invention are prepared by fluid-bed granulation of the compound of the present invention using one or more pharmaceutically acceptable carriers, vehicles, or excipients. In some embodiments, the compositions of the present invention prepared by the fluid-bed granulation process can provide tablet formulations with good flowability, good compressibility, rapid solubility, good stability, and / or minimal or no cracking. In some embodiments, the fluid-bed granulation process enables the preparation of formulations when the drug loading of the compound of the present invention is high, such as more than 70% or more than 75%.

[0208] The compositions of the present invention may be in the form of soft or hard capsules made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), may contain two sections, one of which slips into the other, thereby completely encapsulating the active ingredient. Flexible elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, that are plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are as described herein and include methyl and propylparabens, as well as sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein may be encapsulated. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oil, or triglycerides. The capsules may be prepared as described in U.S. Patents No. 4,328,245, No. 4,409,239, and No. 4,410,545. The capsules may also be coated with a coating known to those skilled in the art to adjust or maintain the solubility of the active ingredient.

[0209] The compositions of the present invention may be in liquid or semi-solid dosage forms, such as emulsions, solutions, suspensions, elixirs, and syrups. An emulsion may be a two-phase system in which one liquid is dispersed in the form of spheres throughout another liquid, and it may be oil-in-water or water-in-oil. An emulsion may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. A suspension may contain a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcohol solutions may contain pharmaceutically acceptable acetals, such as di-(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal (the term "lower" means alkyl having 1 to 6 carbon atoms), as well as water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs may be clear, sweet, and hydro-alcoholic solutions. A syrup may be a concentrated aqueous solution of sugar, such as sucrose, and may also contain a preservative. In the case of liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, thereby facilitating measurement during administration.

[0210] The compositions of the present invention for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle formulations may be prepared as described in U.S. Patent No. 6,350,458.

[0211] The compositions of the present invention can be provided as non-foaming or foaming granules and powders that can be reconstituted into liquid dosage forms. pharmaceutically acceptable carriers and excipients used in non-foaming granules or powders may include diluents, sweeteners, and wetting agents. pharmaceutically acceptable carriers and excipients used in foaming granules or powders may include organic acids and carbon dioxide sources.

[0212] Colorants and flavorings can be used in all of the above dosage forms. Flavorings and sweeteners are particularly useful in forming chewable tablets and lozenges.

[0213] The compositions of the present invention can be formulated as immediate-release or modified-release types, such as delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release types.

[0214] In some embodiments, the composition of the present invention includes a film coating.

[0215] The compositions of the present invention may contain other active ingredients that do not impair the therapeutic or preventive effects of the composition, or may contain substances that enhance or complement the effectiveness of the composition.

[0216] The tablet dosage form may be in powder, crystalline, or granular form and may contain the compound of the present invention, and may further contain a carrier or vehicle as described herein, such as a binder, disintegrant, controlled-release polymer, lubricant, diluent, or colorant.

[0217] In some embodiments, the compositions of the present invention may further include excipients such as diluents, disintegrants, wetting agents, binders, flow enhancers, lubricants, or any combination thereof. In some embodiments, the tablets include a binder. In some embodiments, the binder may be microcrystalline cellulose, dibasic calcium phosphate, sucrose, or corn starch. The tablets contain phenyl, polyvinylpyridone, hydroxypropylcellulose, hydroxymethylcellulose, or any combination thereof. In other embodiments, the tablets contain a disintegrant. In other embodiments, the disintegrant contains croscarmellose sodium, starch glycolate sodium, or any combination thereof. In other embodiments, the tablets contain a lubricant. In some embodiments, the lubricant contains magnesium stearate (stearic acid), hydrogenated oil, stearyl fumarate sodium, or any combination thereof.

[0218] In some embodiments, the composition of the present invention is in the form of a tablet comprising a binder, for example, any of the binders described herein.

[0219] In some embodiments, the composition of the present invention is in the form of a tablet comprising a disintegrant, for example, any of the disintegrants described herein.

[0220] In some embodiments, the composition of the present invention is in the form of a tablet containing a lubricant, for example, any of the lubricants described herein.

[0221] In some embodiments, the compositions of the present invention may be in modified-release or controlled-release dosage forms. In some embodiments, the compositions of the present invention may include particles exhibiting a specific release profile. For example, the compositions of the present invention may comprise an immediate-release form of the compound of the present invention and a modified-release form of a statin or a pharmaceutically acceptable salt thereof, both compressed into a single tablet. Other combinations and modifications of release profiles can be carried out as understood by those skilled in the art. Examples of modified release formulations suitable for the pharmaceutical compositions of the present invention are not limited to, but include 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, and 5,739,108. These are listed in documents No. 5,891,474, No. 5,922,356, No. 5,972,891, No. 5,980,945, No. 5,993,855, No. 6,045,830, No. 6,087,324, No. 6,113,943, No. 6,197,350, No. 6,248,363, No. 6,264,970, No. 6,267,981, No. 6,376,461, No. 6,419,961, No. 6,589,548, No. 6,613,358, and No. 6,699,500.

[0222] In some embodiments, the compositions of the present invention are matrix-controlled release formulations. For example, a composition of the present invention may contain about 300 mg to about 600 mg of the compound of the present invention, provided in a matrix-controlled release form. In some embodiments, the matrix-controlled release form may further contain another pharmaceutically active agent. In some embodiments, the release profiles of the compound of the present invention and the other pharmaceutically active agent may be the same or different. Preferred matrix-controlled release formulations are described, for example, in Takada et al., “Encyclopedia of Controlled Drug Delivery,” Vol. 2, Mathiowitz ed., Wiley, 1999.

[0223] In some embodiments, the composition of the present invention comprises about 10 mg to about 400 mg of another pharmaceutically active agent and about 300 mg to about 600 mg of the compound of the present invention. In some embodiments, the composition of the present invention comprises about 10 mg to about 400 mg of an anticancer agent and about 300 mg to about 600 mg of the compound of the present invention. In some embodiments, the composition is a matrix-controlled modified release formulation.

[0224] In some embodiments, the composition of the present invention comprises about 10 mg to about 40 mg of a statin and about 300 mg to about 600 mg of the compound of the present invention, and the composition is a matrix-controlled modified release formulation.

[0225] In some embodiments, the matrix-controlled release form includes an erosive matrix containing water-swellable, erosive, or soluble polymers, including synthetic polymers, as well as naturally occurring polymers and derivatives such as polysaccharides and proteins.

[0226] In some embodiments, the erosive matrix in a matrix-controlled release form is chitin, chitosan, dextran or pullulan, gum agar, gum arabic, gum karaya, locust bean gum, tragacanth gum, carrageenan, gatti gum, guar gum, xanthan gum or scleroglucan, starch (e.g., dextrin or maltodextrin), hydrophilic colloid (e.g., pectin), phosphatide (e.g., lecithin), alginate, propylene glycol alginate, gelatin, collagen, cellulose compounds (e.g., ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), carboxymethylethylcellulose (CMEC), hydroxyethylcellulose (H Roxypropylcellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT) or ethyl hydroxyethylcellulose (EHEC)), polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerin fatty acid ester, polyacrylamide, polyacrylic acid, ethacrylic acid or methacrylic acid copolymer (EUDRAGIT® (Rohm) This includes poly(2-hydroxyethyl methacrylate), polylactic acid, L-glutamic acid and ethyl-L-glutamate copolymers, biodegradable lactic acid-glycolic acid copolymers, poly-D-(-)-3-hydroxybutyrate, or other acrylic acid derivatives (e.g., homopolymers and butyl methacrylate copolymers, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate or chloride (trimethylaminoethyl) methacrylate), or any combination thereof.

[0227] In other embodiments, the compositions of the present invention are matrix-controlled modified release forms containing a non-erosive matrix. In some embodiments, the statin compounds of the present invention are dissolved or dispersed in an inert matrix and, after administration, are released primarily by diffusion through the inert matrix. In some embodiments, the non-erosive matrix in a matrix-controlled release form may be an insoluble polymer, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl chloride-vinyl acetate copolymer, vinylidene chloride, ethylene or propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinyl oxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, or a hydrophilic polymer, such as ethyl cellulose, cellulose acetate, crospovidone or crosslinked partially hydrolyzed polyvinyl acetate, or an aliphatic compound (e.g., carnauba wax). This includes microcrystalline wax or triglycerides, or any combination thereof.

[0228] The compositions of the present invention, which are modified release formulations, can be prepared by methods known to those skilled in the art, such as direct compression, drying or wet granulation, subsequent compression, melt granulation, and subsequent compression.

[0229] In some embodiments, the compositions of the present invention include an in-capsule tablet system, which may be a multifunctional and multi-unit system comprising a versatile minitablet in a rigid gelatin capsule. The minitablet may be an immediate-release, sustained-release, pulsed-release, delayed-sustained-release minitablet, or any combination thereof. In some embodiments, a combination of minitablets, or a combination of minitablets and minibeads containing multiple active agents, may each have a specific lag time for a multiple pulsed-release drug delivery system (DDS), site-directed DDS, delayed-rapid DDS, rapid / delayed DDS, and zero-order DDS.

[0230] In some embodiments, the composition of the present invention is in an osmotically controlled release form.

[0231] In some embodiments, the osmotic pressure-controlled release device includes a one-chamber system, a two-chamber system, asymmetric membrane technology (AMT), an extrusion core system (ECS), or any combination thereof. In some embodiments, such a device comprises at least two components, namely (a) a core containing an active drug(s), and (b) a semipermeable membrane enclosing the core and having at least one delivery port. The semipermeable membrane controls the inflow of water from the aqueous environment to the core during use, so as to cause drug release by extrusion through the delivery port(s).

[0232] In some embodiments, the core of the osmotic device optionally contains an osmotic agent that generates a driving force for the transport of water from the device's operating environment to the core. One class of penetrating agents useful in the compositions of the present invention includes, but is not limited to, water-swellable hydrophilic polymers also called "osmopolymers" or "hydrogels," hydrophilic vinyl and acrylic polymers, polysaccharides (e.g., calcium alginate), polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic acid) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers having hydrophobic monomers (e.g., methyl methacrylate and vinyl acetate), hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate.

[0233] Another class of penetrants useful in the compositions of the present invention includes osmogens that can absorb water to influence the osmotic pressure gradient across the entire barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts (e.g., magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium), sugars (e.g., dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol), and organic acids (e.g., ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid). Examples include succinic acid and tartaric acid, urea, and mixtures thereof.

[0234] The degree of rapid dissolution of the compound of the present invention after administration can be influenced by using penetrating agents with different dissolution rates. For example, by including an amorphous sugar such as Mannogeme EZ (SPI Pharma, Lewes, DE), faster delivery can be provided during the first few hours (e.g., about 1 to about 5 hours) to rapidly produce prophylactic or therapeutic efficacy, and then the remaining amount can be released gradually and continuously to maintain the desired level of therapeutic or prophylactic effect over a long period of time. In some embodiments, the compound of the present invention is released from the composition of the present invention at a rate that replaces the amount of the compound of the present invention that is metabolized or excreted by the subject.

[0235] The core can also contain a wide variety of other excipients and carriers described herein to improve the performance of the dosage form or to improve its stability or processability.

[0236] Materials useful for forming semipermeable films include various grades of acrylic, vinyl, ether, polyamide, polyester, and cellulose derivatives, which are either permeable and water-insoluble at physiologically appropriate pH, or readily become water-insoluble through chemical changes such as crosslinking. Examples of suitable polymers useful for forming coatings include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, nitrocellulose, 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 Examples include p-toluenesulfonate, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, 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 halide, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0237] Semipermeable membranes can be hydrophobic microporous membranes, as disclosed in U.S. Patent No. 5,798,119, in which the pores are substantially filled with gas and not wetted by an aqueous medium, but are permeable to water vapor. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyhalogenated vinyl, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0238] Delivery ports(s) on a semipermeable film can be formed by post-coating by mechanical or laser drilling. Delivery ports(s) can also be formed in situ by erosion of a water-soluble material plug or by rupture of a thinner portion of the film over a recess in the core. In addition, delivery ports can be formed during the coating process, as in the case of asymmetric film coatings of the type disclosed in U.S. Patents 5,612,059 and 5,698,220.

[0239] The total amount and release rate of the compound of the present invention released depend on the thickness and porosity of the semipermeable membrane, and the core The composition, as well as the number, size, and location of the delivery ports, can be substantially adjusted.

[0240] In some embodiments, the osmotically controlled release formulation of the pharmaceutical composition may further include additional conventional excipients described herein to enhance the performance or processing of the formulation.

[0241] Osmotically controlled release formulations can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy (above), 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).

[0242] In some embodiments, the pharmaceutical compositions provided in the present invention are formulated as asymmetric membrane technology (AMT) controlled-release formulations comprising an asymmetric permeable membrane coating a core containing an active ingredient(s) and other pharmaceutically acceptable excipients. See U.S. Patent No. 5,612,059 and WO2002 / 17918. AMT controlled-release formulations can be prepared according to conventional methods and techniques known to those skilled in the art, such as direct compression, dry granulation, wet granulation, and dip coating.

[0243] In some embodiments, the pharmaceutical compositions provided herein are formulated as ESC-controlled release formulations comprising a permeable membrane coating a core containing the compound of the present invention, hydroxyethylcellulose, and other pharmaceutically acceptable excipients.

[0244] In some embodiments, the compositions of the present invention are modified release formulations manufactured as multi-particle controlled release formulations, comprising a plurality of particles, granules, or pellets, fine particles, beads, microcapsules, and microtablets ranging in diameter from approximately 10 μm to approximately 3 mm, approximately 50 μm to approximately 2.5 mm, or approximately 100 μm to approximately 1 mm.

[0245] Multi-particle controlled-release formulations can provide long-release formulations with improved bioavailability. Suitable carriers for maintaining the release rate of the compounds of the present invention include, but are not limited to, ethylcellulose, HPMC, HPMC-phthalate, colloidal silicon dioxide, and Eudragit-RSPM.

[0246] The pelletized composition of the present invention may contain 50-80% (w / w) of a drug and 20-50% (w / w) of microcrystalline cellulose or other polymers. Suitable polymers include, but are not limited to, microcrystalline waxes, pregelatinized starch, and maltose dextrin.

[0247] The beads can be prepared in capsule and tablet dosage forms. Beads in tablet dosage forms may exhibit a slower dissolution profile than microparticles in capsule form. Suitable microparticle fillers for the compositions and therapeutic or preventive 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 latex include, for example, ethyl acrylate and methyl acrylate.

[0248] In some embodiments, the compositions of the present invention are in the form of microcapsules and / or microtablets. In some embodiments, the microcapsules contain statins and The present invention includes sustained-release polymer microcapsules containing compounds having various solubility properties. These sustained-release polymer microcapsules can be prepared in an aqueous environment using a colloidal polymer dispersion. In other embodiments, microcapsules suitable for the compositions and methods provided herein can be prepared using conventional microencapsulation techniques (Bodmeier & Wang, 1993).

[0249] Such multiparticulates can be produced by processes known to those skilled in the art, such as wet and dry granulation, extrusion / spheroidization, roller compression, melt-solidification, 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 such technologies are commercially available and listed in the United States Pharmacopeia.

[0250] Other excipients described herein can be blended with the compositions of the present invention to assist in the processing and formation of multiplicative materials. The resulting particles can constitute multiplicative dosage forms themselves or can be coated with various film-forming materials such as enteric polymers, water-swellable polymers, or water-soluble polymers. The multiplicative materials can further be processed into capsules or tablets.

[0251] In other embodiments, the composition of the present invention is a dosage form comprising an immediate-release component and at least one delayed-release component, which can discontinuously release the compound in the form of at least two consecutive pulses with a time difference of about 0.1 hours to about 24 hours.

[0252] In some embodiments, the composition of the present invention contains about 1 mg to about 1000 mg or any amount of the compound of the present invention within this range. In some embodiments, the composition of the present invention contains about 1 mg to about 500 mg or any amount of the compound of the present invention within this range. In some embodiments, the composition of the present invention contains about 1 mg to about 400 mg or any amount of the compound of the present invention within this range.

[0253] In other embodiments, the composition of the present invention contains an amount of the compound of the present invention that is about 1 mg to about 1000 mg, or any amount of molar equivalent within this range. In other embodiments, the composition of the present invention contains an amount of the compound of the present invention that is about 1 mg to about 500 mg, or any amount of molar equivalent within this range. In other embodiments, the composition of the present invention contains an amount of the compound of the present invention that is about 1 mg to about 400 mg, or any amount of molar equivalent within this range.

[0254] In some embodiments, the composition of the present invention contains the compound of the present invention in an amount of about 10% to about 99% by weight, based on the total weight of the composition of the present invention.

[0255] Method of the present invention The present invention provides a method for treating or preventing a disease, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof, wherein the disease is a liver disease or abnormal liver condition, cancer (e.g., hepatocellular carcinoma or cholangiocarcinoma), malignant or benign tumors of the lungs, liver, gallbladder, bile duct or gastrointestinal tract, intrahepatic or extrahepatic bile duct disease, lipoprotein disorders, lipid and metabolic disorders, cirrhosis, fibrosis, glucose metabolism disorders, cardiovascular or related vascular disorders, diseases resulting from fatty degeneration, fibrosis or cirrhosis, diseases resulting from fatty degeneration, fibrosis and cirrhosis, diseases associated with advanced inflammation (e.g., inflammation of the liver or lungs), hepatocyte ballooning, peroxisome proliferator-activated receptor-associated disorders, ATP citrate lyase disorders, acetyl coenzyme A carboxylase disorders, obesity, pancreatic It is inflammation or kidney disease.

[0256] The present invention provides a method for treating or preventing a disease, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof, wherein the disease is cancer, lipid and metabolic disorders, liver disorders, cirrhosis, fibrosis, glucose metabolism disorders, peroxisome proliferator-activated receptor-associated disorders, malignant or benign tumors of the lungs, liver, biliary tract and gastrointestinal tract, ATP citrate lyase disorders, acetyl coenzyme A carboxylase disorders, obesity, pancreatitis, kidney disease, hepatocyte ballooning, liver inflammation, or lung inflammation.

[0257] In some embodiments of the methods disclosed herein, the disease is cancer. In some embodiments, the cancer is hepatocellular carcinoma (HCC), HCC with cirrhosis, HCC without cirrhosis, cholangiocarcinoma, colorectal cancer, biliary tract cancer, or lung cancer. In some embodiments, the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, intralymphatic sarcoma, synoviomas, mesothelioma, primary myelosarcoma, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, gastric cancer, oral cancer, nasal cancer, laryngeal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma Seminomas, embryonic carcinomas, nephroblastomas, cervical cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, epithelial carcinomas, gliomas, glioblastomas, pleomorphic astrocytomas, medulloblastomas, craniopharyngiomas, ependymocytes, pineal gland tumors, hemangioblastomas, acoustic neuromas, oligodendrogliomas, meningiomas, skin cancers, melanomas, neuroblastomas, retinoblastomas, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute granulocytic leukemia (AML), acute promyelocytic leukemia (APL), acute monocytic leukemia, acute erythroblastic leukemia (acute This includes erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphoblastic leukemia, acute undifferentiated leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, multiple myeloma, lymphoblastic leukemia, myelogenous leukemia, lymphocytic leukemia, myelocytic leukemia, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, Waldenstrom macroglobulinemia, H chain disease, gastrointestinal cancer, head and neck cancer, hematopoietic carcinoma, or polycythemia vera.

[0258] In some embodiments, gastrointestinal (digestive) cancers include gastrointestinal stromal tumors (GIST), esophageal cancer, gallbladder cancer, gastrointestinal carcinoid tumors, bile duct cancer, duodenal cancer, gastroesophageal (GE) junction cancer, islet cell carcinoma, pancreatic cancer, gastric cancer, colon cancer, rectal cancer, colorectal cancer, anal cancer, liver cancer, biliary tract cancer, bile duct cancer, small intestine cancer, seudomyxoma peritonei, small bowel cancer, or cancer of unknown primary origin.

[0259] In some embodiments, hematopoietic carcinomas include non-Hodgkin lymphoma (NHL), Burkitt lymphoma (BL), multiple myeloma (MM), chronic lymphocytic leukemia B (B-CLL), acute lymphoblastic leukemia B and T (ALL), T-cell lymphoma (TCL), acute myeloid leukemia (AML), hairy cell leukemia (HCL), Hodgkin lymphoma (HL), or chronic myeloid leukemia (CML).

[0260] In some embodiments of the methods disclosed herein, the cancer is at any stage. In some embodiments, the cancer may be stage 0, stage I, stage II, stage III, or stage IV. In some embodiments of the methods disclosed herein, the disease is a tumor, and the tumor may be at any stage. In some embodiments, the tumor may be grade 1, grade 2, grade 3, or grade 4.

[0261] In some embodiments of the methods disclosed herein, the disease is a lipid and metabolic disorder. In some embodiments, lipid and metabolic disorders are characterized by high C-reactive protein (CRP), high serum amyloid A (SAA), high alanine aminotransferase (ALT), high aspartate aminotransferase (AST), high alkaline phosphatase (ALP), high gamma glutamyltransferase (GGT), high low-density lipoprotein (LDL), high very low-density lipoprotein (VLDL), high apolipoprotein B (ApoB) and ApoB / Lp(a) (lipoprotein(a)) ratio, high total cholesterol, low high-density lipoprotein (HDL), or high non-HDL cholesterol in subjects with diabetes, or by high glucose and insulin resistance. In some embodiments, lipid and metabolic disorders are non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or alcoholic steatohepatitis (ASH).

[0262] In some embodiments of the methods disclosed herein, the disease is a glucose metabolism disorder. In some embodiments, the glucose metabolism disorder is type 1 diabetes or type 2 diabetes.

[0263] In some embodiments of the methods disclosed herein, the disease is a disease resulting from fatty degeneration, fibrosis, and cirrhosis. In some embodiments, the disease resulting from fatty degeneration is inflammation. In some embodiments, the disease resulting from fatty degeneration is NAFLD, NASH, or ASH. In some embodiments, the disease resulting from fibrosis is cirrhosis or liver failure. In some embodiments, the disease resulting from cirrhosis is hepatocellular carcinoma, liver injury, or hepatic encephalopathy.

[0264] The present invention relates to the concentrations in the plasma or serum of the subject, namely, the concentration of C-reactive protein (CRP), serum amyloid A (SAA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT), serum creatinine, 7α-hydroxy-4-cholesten-3-one (C4), protein:creatinine ratio, creatine kinase concentration, angiopoietin-like protein 3 concentration, and angiopoietin-like protein 3. The present invention provides a method for reducing tin-like protein 4 concentration, angiopoietin-like protein 8 concentration, fibrinogen concentration, total cholesterol concentration, low-density lipoprotein cholesterol concentration, low-density lipoprotein concentration, very low-density lipoprotein cholesterol concentration, very low-density lipoprotein concentration, non-HDL cholesterol concentration, non-HDL concentration, apolipoprotein B concentration, lipoprotein (a) concentration, or serum triglyceride concentration, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0265] The present invention provides a method for reducing triglyceride concentrations in the liver of a subject, comprising administering an effective amount of the compound or composition of the present invention to a subject requiring such reduction.

[0266] The present invention provides a method for increasing the concentration of high-density lipoprotein cholesterol or high-density lipoprotein in the plasma or serum of a subject, comprising administering an effective amount of the compound or composition of the present invention to a subject requiring such an increase.

[0267] The present invention provides a method for increasing the functionalization of high-density lipoprotein cholesterol without increasing the concentration of high-density lipoprotein cholesterol in the plasma or serum of a subject, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof, thereby increasing the amount or rate of cholesterol and triglyceride excretion.

[0268] The present invention provides a method for treating a disease, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof, wherein the disease is a gastrointestinal disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), or autoimmune disease.

[0269] In some embodiments of the methods disclosed herein, the disease is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

[0270] In some embodiments of the methods disclosed herein, the disease is an autoimmune disease. In some embodiments, the autoimmune disease is systemic lupus erythematosus.

[0271] The present invention provides a method for regressing, reducing the rate of progression of, or inhibiting the progression of fibrosis, hepatocyte ballooning, or hepatic inflammation, comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0272] The present invention provides a method for inhibiting, reducing, or delaying the development of target lipid synthesis, hepatic steatosis, hepatocyte ballooning or inflammation, hepatic fibrosis, pulmonary fibrosis, or cirrhosis, comprising administering an effective amount of the compound or composition of the present invention to a target requiring such action.

[0273] The present invention provides a method for reducing the risk of a subject developing or having atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, or restenosis, comprising administering an effective amount of the compound of the present invention to a subject in need.

[0274] The present invention provides a method for increasing the HDL concentration in the serum or plasma of a subject, comprising administering an effective amount of the compound or composition of the present invention to a subject in need of such an increase.

[0275] The present invention provides a method for inhibiting NF-κB or astrocyte activation, comprising administering an effective amount of the compound or composition of the present invention to a subject requiring such inhibition.

[0276] The present invention provides a method for activating PPARs (peroxisome proliferator-activated receptors) in a subject, comprising administering an effective amount of the compound or composition of the present invention to a subject requiring such activation.

[0277] The present invention provides a method for downregulating the CCR2 / CCR5 genes, comprising administering an effective amount of the compound of the present invention to a subject requiring such downregulation.

[0278] The present invention provides a method for inhibiting one or more of NF-κB activation, CCR2 activation, CCR5 activation, and astrocytocyte activation, comprising administering an effective amount of the compound or composition of the present invention to a subject requiring such inhibition.

[0279] The present invention provides a method for inhibiting the activation or concentration of interleukins, comprising administering an effective amount of the compound or composition of the present invention to a subject requiring such inhibition. In some embodiments, the interleukin (IL) is IL-2, IL-6, IL-17, or IL-18.

[0280] This invention relates to fibrin / fibrinogen, gastrin, lactate dehydrogenase, and prostatic acid. The present invention provides a method for inhibiting phosphatase (PAP), thyroglobulin, urinary catecholamines, urinary vanillylmandelic acid (VMA), or urinary homovanillic acid (HVA), comprising administering an effective amount of the compound or composition of the present invention to a subject requiring such inhibition.

[0281] The present invention provides a method for inhibiting beta-human chorionic gonadotropin (beta-hCG), beta-2-microglobulin (B2M), and B-cell immunoglobulin, comprising administering an effective amount of the compound or composition of the present invention to a subject requiring such inhibition.

[0282] The present invention provides a method for inhibiting alpha-fetoprotein (AFP), comprising administering an effective amount of the compound or composition of the present invention to a subject requiring such inhibition.

[0283] The present invention also provides a method for inhibiting fatty acid or sterol synthesis in the liver, comprising administering an effective amount of the compound or composition of the present invention to a subject requiring such inhibition.

[0284] The present invention also provides a method for treating or preventing a disease or disorder that can be treated or prevented by increasing HDL levels, the method comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0285] The present invention also provides a method for treating or preventing a disease or disorder that can be treated or prevented by lowering LDL levels, the method comprising administering an effective amount of the compound or composition of the present invention to a subject in need thereof.

[0286] While not bound by theory, the compounds of the present invention are thought to favorably alter lipid metabolism, at least in part, by enhancing fatty acid oxidation via the ACC / malonyl-CoA / CPT-I regulatory axis. Accordingly, the present invention also provides a method for treating or preventing metabolic syndrome disorders, comprising administering an effective amount of the compounds or compositions of the present invention to a subject in need thereof.

[0287] The present invention further provides a method for modulating, directly inhibiting, or allosterically inhibiting ATP citrate lyase in a subject, comprising administering to the subject an effective amount of the compound or composition of the present invention.

[0288] The present invention further provides a method for modulating, directly inhibiting, or allosterically inhibiting acetyl-CoA carboxylase 1 (ACC1) or acetyl-CoA carboxylase 2 (ACC2) in a subject, comprising administering to the subject an effective amount of the compound or composition of the present invention.

[0289] The present invention further provides a method for reducing the fat or cholesterol content of livestock meat or poultry eggs, comprising administering an effective amount of the compound or composition of the present invention to the livestock or poultry.

[0290] In some embodiments of the methods disclosed herein, the compounds of the present invention are administered to subjects requiring them in amounts ranging from about 1 mg to about 1000 mg, or any amount within this range. In some embodiments, the compounds of the present invention are administered to subjects requiring them in about It is administered in the range of 1 mg to approximately 900 mg, approximately 1 mg to approximately 800 mg, approximately 1 mg to approximately 700 mg, approximately 1 mg to approximately 600 mg, approximately 1 mg to approximately 500 mg, approximately 1 mg to approximately 400 mg, or approximately 1 mg to approximately 300 mg.

[0291] In some embodiments of the methods disclosed herein, the compounds of the present invention are administered to subjects requiring them in a daily dose ranging from about 1 mg to about 1000 mg, or any amount within this range. In some embodiments, the compounds of the present invention are administered to subjects requiring them in a daily dose of about 1000 mg, about 950 mg, about 900 mg, about 850 mg, about 800 mg, about 750 mg, about 700 mg, about 650 mg, about 600 mg, about 550 mg, about 500 mg, about 450 mg, about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.

[0292] In some embodiments of the methods disclosed herein, the compounds of the present invention are administered once daily to subjects requiring them in doses of about 1 mg to about 1000 mg, or any amount within this range.

[0293] In some embodiments of the methods disclosed herein, the compound of the present invention is administered twice daily to a subject requiring it, with each dose comprising the compound of the present invention in an amount of about 1 mg to about 500 mg, or any amount within this range. In some embodiments, the compound of the present invention is administered twice daily to a subject requiring it, with each dose comprising the compound of the present invention in an amount of about 500 mg, about 450 mg, about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.

[0294] In some embodiments of the methods disclosed herein, the compound of the present invention is administered three times daily to a subject requiring it, with each dose comprising the compound of the present invention in an amount of about 1 mg to about 400 mg, or any amount within this range. In some embodiments, the compound of the present invention is administered three times daily to a subject requiring it, with each dose comprising the compound of the present invention in an amount of about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.

[0295] In some embodiments of the methods disclosed herein, the method further comprises administering an effective amount of another pharmaceutically active agent. In some embodiments, the other pharmaceutically active agent is administered simultaneously with or sequentially (before or after) the administration of the compound or composition of the present invention. In some embodiments, the other pharmaceutically active agent is a statin, thiazolidinedione or fibrate, bile acid binding resin, niacin, anti-obesity drugs, hormones, thyrophostine, sulfonylurea-based drugs, biguanides, α-glucosidase inhibitors, apolipoprotein AI agonists, apolipoprotein E agonists, phosphodiesterase type-5 inhibitors, cardiovascular drugs, HDL-enhancing agents, HDL enhancers, apolipoprotein AI gene modulators, apolipoprotein A-IV gene modulators, apolipoprotein gene modulators, ATP citrate lyase modulators, ATP citrate lyase allosteric inhibitors, acetyl-CoA carboxylase modulators, or acetyl-CoA carboxylase allosteric inhibitors. In some embodiments, other pharmaceutically active agents include lovastatin. In some embodiments, other pharmaceutically active agents include sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, semiprimab, ABX196, T-cell receptor (TCR) immunotherapy agents, TBI-302, namodenoson, MM-310, tumor injection oncolytic viruses or recombinant oncolytic viruses (telomere). These include, but are not limited to, lysine and imiligic, or immunomodulatory gene therapy agents (such as MDA-7 / IL-24, GLIPR1 / RTVP-1, and REIC / Dkk-3).

[0296] In some embodiments of the methods disclosed herein, the method further comprises administering two or more other pharmaceutically active agents. In some embodiments, the method of the present invention comprises administering two or more other pharmaceutically active agents in any combination. In some embodiments, the two or more other pharmaceutically active agents are, but are not limited to, oncolytic agents such as nanatinostat and valganciclovir. In other embodiments, the method of the present invention comprises orally administering the compound of the present invention and further comprises administering tumor injection oncolytic therapy. In some embodiments, this combination is administered orally.

[0297] In some embodiments, other pharmaceutically active agents include cenicliviroc, elafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, nivolumab, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination (NS-0200), IMM-124E, RG-125, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegberfermin, PF-05231023, obeticholic acid, silofexol, and tropif Xexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, ND-L02-s0201 / BMS-986263, Borixivat, Amlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Loflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogritazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, narumafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, sarogritazal magnesium, borixivat, solithromycin, 99m technetium-mebrophenine, tropifexol, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, or ceradelpar.

[0298] In some embodiments of the methods disclosed herein, a method for treating or preventing a disease comprises administering compound I-1, compound I-32, compound I-61, or compound III-1, or a pharmaceutically acceptable salt or solvate thereof.

[0299] In some embodiments of the methods disclosed herein, a method for treating or preventing a disease comprises an effective amount of (a) a compound of the present invention and (b) another pharmaceutically active agent, such as sorafenib, taxol, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, senicliviroc, ellafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, ceroncertib, losartan, R O5093151, Prazigastat, Sitagliptin, Vildagliptin, NGM282, Pegberfermin, PF-05231023, Oveticolic acid, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, Borixivat, Amlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Roflumilast, Elafibranol, Pioglitazone, Rosig Ritazone, fenofibrate, saroglitazal, ranifibranol, aramcol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazal magnesium, borixivat, ellafibranol, nalmefen, solithromycin, 99m technetium-mebrophenine, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, ceradelpar, physogatinib, doxorubicin, This includes administering cabozantinib, deferoxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, or zofilcrib citrate. In some embodiments of the methods disclosed herein, a method for treating or preventing a disease comprises an effective amount of (a) compound I-1, compound I-32, compound I-61, or compound III-1, or a pharmaceutically acceptable salt or solvate thereof, and (b) another pharmaceutically active agent such as sorafenib, taxol, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicliviroc, or elafibranol. Eicosapentaenoic acid, garnicertive, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegberfermin, PF-05231023, obeticholic acid, silofexol,Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, Borixivat, Amlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Loflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogritazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI 1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Narmafen, Pentamidine, Berberine, L-Carnitine, EYP001a, Silymarin, Myricolinant, Ursodeoxycholic Acid, Metadoxine, Ezetimibe, Cystadan, L-Alanine, Sarogritazal Magnesium, Borixivat, Elafibranol, Nalmefene, Solithromycin, 99m Technetium-Mebrophenine, S-Adenosylmethionine, Pentoxifylline, Oresoxime, AKR-001, Seradelpar, Physogatinib, Doxorubicin, This includes administering cabozantinib, deferoxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, or zoctiliclib citrate.

[0300] In some embodiments of the methods disclosed herein, a method for treating or preventing a disease comprises an effective amount of (a) a compound of the present invention and (b) another pharmaceutically active agent, such as sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, semiprimab, A The treatment involves administering BX196, a T-cell receptor (TCR) immunotherapy agent, TBI-302, namodenoson, MM-310, an oncolytic virus for tumor injection, a genetically modified oncolytic virus, or an immunomodulatory gene therapy agent. In some embodiments of the methods disclosed herein, a method for treating or preventing a disease comprises administering an effective amount of (a) compound I-1, compound I-32, compound I-61, or compound III-1, or a pharmaceutically acceptable salt or solvate thereof, and (b) another pharmaceutically active agent, such as sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, semiprimab, ABX196, a T-cell receptor (TCR) immunotherapy agent, TBI-302, namodenoson, MM-310, tumor injection oncolytic virus, recombinant oncolytic virus, or immunomodulatory gene therapy agent.

[0301] In some embodiments, the method of the present invention involves administering an effective amount of the compound of the present invention and another pharmaceutically active agent described in the embodiments of Table D to a subject requiring it. In some embodiments, the other pharmaceutically active agent is administered simultaneously with, before, or after the administration of the compound of the present invention or the composition of the present invention.

[0302] In some embodiments of the methods disclosed herein, the methods further include being applied to radiotherapy. In some embodiments, the radiotherapy is gamma-ray radiotherapy or X-ray radiotherapy. In some embodiments, the radiotherapy is applied via a gamma-ray or X-ray radiation device.

[0303] In some embodiments, radiotherapy is administered simultaneously with, before, or after the administration of the compound or composition of the present invention. In some embodiments, radiotherapy is administered before or after the administration of the compound or composition of the present invention.

[0304] Method for producing the compound of the present invention Synthesis and General Protocols Compounds of formulas (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), and (IL) (collectively referred to as "Formula (I)") can be prepared by the synthetic methodologies shown in Schemes 1 to 7. Starting materials useful for preparing the compounds of the present invention and their intermediates are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.

[0305] Scheme 1: General composition of equation (I) [ka]

[0306] In Scheme 1, A can be a halogen such as Cl, Br, or I. In some embodiments, A is Br. In Scheme 1, B can be a carbanion of a carboxylic acid or malonic acid ester. In Scheme 1, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0307] Scheme 2: General composition of equation (I) [ka]

[0308] In Scheme 2, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0309] Scheme 3: General composition of equation (I) (wherein Z is -C(R 1 )(R 2 )-(CH2) c -X is COOR 5 , or COOH, where c is 0). [ka]

[0310] In Scheme 3, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0311] Scheme 3 is a dicarboxylic acid of formula 7 (wherein R is an integer in the range of 2 to 5) of the ortho, meta, or para ω-haloalkyl-substituted arenes of formula 5 (wherein p is an integer in the range of 2 to 5, and Hal is Cl, Br, or I) 1 Furthermore, R 2 This represents a conversion to an alkyl and / or aryl moiety (or linked to a 3- to 7-membered ring). This conversion can be carried out by two different, but related, pathways. According to the first method, formula R 1 R 2 CHCO2R 5 Ester of (wherein R 1 Furthermore, R 2 The alkyl and / or aryl moiety, or linked to a 3- to 7-membered ring, 5 The compound (which is typically ethyl or methyl) is deprotonated with a strong base, preferably with butyllithium or lithium diisopropylamide, and then reacted with the dihalide of formula 5 to provide the corresponding diester of formula 6. Generally, the reaction takes place at temperatures of about -78°C to about 25°C. The reaction is carried out at a temperature, and the reaction solvent is preferably THF or diethyl ether (for further discussion regarding the scope of this method, see Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd See ed.;Wiley-VCH, New York, 1999, pp 1725-1726. For specific examples of this method, see Dasseux et al., US6, 646, 170 and US6, 410, 802, Oniciu et al. US10, 227, 285, and Ackerley et al., J.Med.Chem. 1995, 38, 1608-1628). In the second step, the diester of formula 6 is saponified (for an overview, see Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, pp 1959-1968, and Smith, MB; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5 th See John Wiley and Sons, New York, 2001, pp. 469-474, to obtain the diacid of formula 7. Alternatively, this conversion of the dihalide of formula 5 to the diacid of formula 7 is also obtained from formula R 1 R 2 CHCO2H (in the formula, R 1 and R 2 The carboxylic acid is alkyl and / or aryl, as described above. 1 R 2 CHCO2R 5 This can also be carried out in one step by deprotonating twice under conditions similar to the alkylation process, followed by reaction with dibromide 5 (for discussion, see Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd See ed.;Wiley-VCH, New York, 1999, pp 1717-1718). For example, the compound of formula 5 (ortho, p=3, Hal=Br) is reacted with lithioethyl isobutyrate (prepared from ethyl isobutyrate with lithium diisopropylamide) in a solvent mixture of THF and DMPU at a temperature in the range of approximately -78°C to room temperature to obtain the corresponding diester of formula 7 (ortho, p=3). This diester is then hydrolyzed under standard conditions (aqueous ethanol solution, potassium hydroxide, reflux temperature), re-acidified with dilute hydrochloric acid solution, and then the dicarboxylic acid of formula 7 (ortho substitution pattern, R 1 =R 2=methyl, and p=3) is obtained. Alternatively, as described in Gleiter et al., J. Org. Chem. 1992, 57, 252-258, isobutyric acid is deprotonated twice with n-butyllithium and diisopropylamine in THF solution, first at about -20°C and then at about 50°C. After recooling to about -20°C, the compound of formula 5 (ortho, R) in THF is obtained. 1 =R 2 A solution of (=methyl, p=3, Hal=Br) is added dropwise while maintaining the temperature below 10°C. The mixture is then stirred first at room temperature and then at about 40°C, and post-treatment is carried out in a typical manner to obtain the corresponding diacid 7. Type 5 halogenated derivatives can be obtained by several methods, such as those described, for example, Gleiter et al., J. Org. Chem. 1992, 57, 252-258.

[0312] Scheme 4: General synthesis of compound 5-Br (compound 5 where Hal=Br) [ka]

[0313] In Scheme 4, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0314] Scheme 4 shows the synthesis of para, meta, and orthodibromoalkyl-substituted arene compounds 5-Br (wherein (p-1) is an integer in the range of 1 to 2) from the parent dicarboxylic acid 10. Scheme 4 is first described in Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, pp 1932-1941, and Smith, MB; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5 th An overview of the esterification of the compound of formula 10 to the diester of formula 20 (wherein R is an alkyl moiety, such as methyl, ethyl, or isopropyl, but not limited to the formula) is outlined using the general procedure referenced in ed.; John Wiley and Sons, New York, 2001, pp 484–486. The diol 30 can be prepared from diester 20 by known synthetic methods (for consideration of preferred reduction methods, see, for example, Hudlicky, M., Reductions in Organic Chemistry, 2001). nd See ed.;ACS Monograph 188, Washington, DC, 1996, pp 212-216). In the next step, the conversion of the alcohol functional group in compound 5-Br in 30 to the bromo moiety is described in Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, pp. This can be carried out by various standard methods referenced in 693-695. For example, the compound of formula 10 having a para substitution pattern and (p-1)=1 (available from Aldrich Chemical Co., Milwaukee, Wisconsin) is treated with excess methanol and concentrated sulfuric acid at reflux temperature to obtain the corresponding dimethyl ester of formula 2. The procedure that can be used for this conversion is referenced, for example, in Schimelpfenig, CWJ Org. Chem. 1975, 40, 1493-1494, which is incorporated herein by reference. In addition, as referenced in Reynolds et al., US2,789,970, application No. 397,037 filed December 8, 1953, the compound of formula 20 (para, (p-1)=1) is treated with an aprotonated organic solvent (e.g., THF or diethyl sulfuric acid). In a ether, the metal hydride complex can be converted to the corresponding compound of formula 30 by reaction with, preferably, lithium aluminum hydride, but not limited to this. Furthermore, the diol (para, p=1) of formula 30 can be converted to the bromide of formula 5-Br(para, p=1) by treatment at high temperature with sodium bromide and concentrated sulfuric acid. A useful solvent for this conversion is water, as described in Schimelpfenig, CWJ Org. Chem. 1975, 40, 1493-1494.

[0315] Scheme 5: General synthesis of compound 5A-Br [ka]

[0316] In Scheme 5, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1AIt can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0317] Scheme 5 shows the preparation of ortho, meta, and para-substituted arene compounds having two 3-bromopropyl substituents of formula 5A-Br. Specific examples for the synthesis of compounds 5A-Br with meta and para substitutions are described in Schimelpfenig, CWJ Org. Chem. 1975, 40, 1493-1494 and Gleiter et al., J. Org. Chem. 1992, 57, 252-258, respectively. For example, the compound of formula 50 is treated with malonic acid and piperidine in a pyridine solution at about 90-110°C to obtain the α,β-unsaturated carboxylic acid of formula 60. The endpoint of this conversion is typically indicated by the cessation of CO2 effervescence. This procedure is known as the Knoevenagel-Doebner reaction, and a useful reaction protocol for this conversion is described in Organikum, Organisch-Chemisches Grundpraktikum, VEB Verlag Deutscher Wissenschaften, Berlin 1984, pp 572-574. The reduction of the compound of formula 60 to the compound of formula 70 is described in Hudlicky, M. Reductions in Organic Chemistry, 2 ndAs discussed in ed.;ACS Monograph 188, Washington, DC, 1996, pp 196-197, this can be carried out by catalytic hydrogenation on colloidal palladium, Raney nickel, or copper chromate. The conversion of the compound of formula 60 to the corresponding compound 70 by meta-substitution by treatment with hydrogen gas in an aqueous sodium hydroxide solution on a palladium / carbon catalyst at a pressure of about 20-60 psi is incorporated herein by reference in its entirety by Schimelpfenig, CWJ Org. Chem. 1975, 40, 1493- This is reported in 1494. Subsequently, the further conversion of the compound of formula 70 to the compound of formula 5A-Br can be carried out according to the methodology described in scheme 4.

[0318] Scheme 6: General synthesis of compound 5-Br by chain elongation [ka]

[0319] In Scheme 6, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R 2A This is as defined herein for formula (I).

[0320] Scheme 6 shows a general method for chain extension from a bromide of formula 90 having an alkyl chain of (p-2) methylene groups to a bromide of formula 5-Br having an alkyl chain of p methylene groups. The conversion sequence from alkyl halides (e.g., 90) to carboxylic acids (e.g., 120) is described in Smith, MB; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5. th ed.; John Wiley and Sons, New York, 2001, p 549, and Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd This can be carried out using the malonic acid ester synthesis referenced in ed.;Wiley-VCH, New York, 1999, p 1765. Generally, the monoalkylation of malonic acid esters (where R is typically ethyl or methyl) is performed using a combination of a sodium ethoxide base solvent in ethanol, which inhibits the formation of dialkylation byproducts (Organic Reactions, Volume IX, editor-in-chief: R. Adams; Robert E. Krieger Publishing Company, Malabar, Florida, 1957, p 132) to obtain the compound of formula 100. The compound of formula 100 is then saponified to obtain the compound of formula 110, which can be decarboxylated to the compound of formula 120 by heating it to a temperature above its melting point. Next, the conversion of dicarboxylic acid 120 to the chain-extended dibromide 5-Br via diester 20 is carried out according to the methodology described in Scheme 4. Alternatively, the direct decarbalkoxylation of geminal diester 100 to the compound of formula 20 can be carried out by treatment with water and DMSO, with or without the addition of salt. This can be done. However, the rate of decarbalkoxylation of these substrates can be improved by adding salts such as KCN, NaCl, or LiCl to the water / DMSO solvent (Fakhri, SA; Yousefi, BHTetrahedron). (2000, 56, 8301-8308). For example, ethyl malonate is reacted with sodium metal in ethanol and a solution of the compound of formula 90 ((p-2)=2), and ethyl malonate is added to obtain the corresponding compound of formula 100. This tetraester is then saponified, for example, using aqueous ethanol and potassium hydroxide to obtain the corresponding tetraacid of formula 110. The tetraacid is then decarboxylated at a temperature of about 200°C to obtain the diacid of formula 120. After esterification with methanol and concentrated sulfuric acid (see scheme 4), diester 20 is obtained. A useful method for converting the tetraester of formula 100 (ortho, (p-2)=1, R=ethyl) to the diester of formula 20 is described in Fakhri, SA; Yousefi, BHTetrahedron 2000, 56, 8301-8308, which is incorporated herein by reference in its entirety.

[0321] Scheme 7: General synthesis of the compound of formula 7 [ka]

[0322] In Scheme 7, Q 1 and Q 2 These are, independently, -O-alkyl, -S-alkyl, -S-aryl, and -NR. 1A R 2A NHR 1A Phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF3, -COR 1A It can be a heteroaryl or heterocycline, or each carbon atom may be independently bonded to a carbon atom Q 1 and Q 2 Together with it, it can form a heterocyclyl or carbocykyl group. 1A and R2A This is as defined herein for formula (I).

[0323] Scheme 7 shows the synthesis of ortho, meta, and para-substituted arene compounds of formula 7 by ω-carboxyalkyl substitution, where (p-1) is an integer in the range of 2 to 12, and R 1 and R 2 This is either an alkyl moiety and / or an aryl moiety, or two alkyl moieties linked by a 3- to 7-membered ring. The synthesis begins with two deprotonations of ortho-, meta-, or para-xylene 3 with a strong base, not limited to a combination of n-butyllithium and tert-potassium butoxide, in an aprotic solvent such as hexane, and then the dianion of the formed 3 and a suitable electrophile A-(CH2) p-1 -CR 1 R 2 -CH2O-PG(wherein, (p-1), R 1 and R 2 It is defined as above, and reacts with (where A is Cl, Br, or I). "PG" is a hydroxyl protecting group. Examples of hydroxyl protecting groups are incorporated herein by reference to Greene, TW; Wuts, PGMP (Protective groups in organic synthesis, 3) rd ed., John Wiley and Sons, New York, 1999, pp 17-24 It is described in 5. Methylarene is described in Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2. ndAccording to ed.;Wiley-VCH, New York, 1999, p 88, alkylation can be performed via deprotonation with a lithium base followed by alkylation with a suitable electrophile. For example, see Bates et al., J.Am.Chem.Soc.1981, 103, 5052-5058 for an example of xylenedianion preparation. In the next step, the protecting group of 190 is removed to liberate the terminal hydroxylmethyl moiety in 200, which is then oxidized using a suitable oxidizing agent (Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, pp 1646-1648, and Smith, MB; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5 th (ed.; John Wiley and Sons, New York, 2001, p 1537), a dicarboxylic acid of formula 7 is obtained. For example, m-xylene (meta-3) is reacted with n-butyllithium and potassium tert-butoxide in hexane, first at room temperature and then at reflux temperature. After cooling to 0°C, the compound of formula 180 (A=Br, (p-1)=3, R 1 =R 2 =methyl, PG=tetrahydropyranil (prepared according to Dasseux et al., US6,646,170 and US6,410,802) are added, and the reaction is continued at reflux temperature. After normal workup and purification by column chromatography, the corresponding compound of formula 190 is obtained. Then, 190~200 (R 1 , R 2 Deprotection of methyl (p=3) is carried out by heating in methanol and concentrated hydrochloric acid aqueous solution (Vogel, A.Vogel's textbook of practical organic chemistry, 5 th(ed., Longman Scientific and Technical, 1989, p. 552). Next, compound 200 was treated with pyridinium dichromate in N,N'-dimethylformamide according to Vedejs, E.; Dent, WH, III; Gapinski, DM; McClure, CKJAm. Chem. Soc. 1987, 109, 5437-5446 to obtain the dicarboxylic acid of formula 7 (meta, p=3, R 1 , R 2 (=methyl).

[0324] Scheme 8 shows exemplary alternative synthetic methods for compounds I-1 and I-32. A commercially available benzene-dicarboxyaldehyde (Sigma-Aldrich, AK Scientific, etc.) is reacted with (5-ethoxy-4,4-dimethyl-5-oxopentyl)triphenylphosphonium bromide (220) (prepared as described in Oniciu, D, C. et al., WO2012 / 054535 and US8, 349, 833B2) in the presence of a base (not limited to sodium or potassium hydroxide, tert-potassium or sodium butoxide, potassium or sodium carbonate, and sodium hydride) as a mixture of cis and trans isomers by the method described in Le Bigot Y. et al., 1988, Tetrahedron 44(4), pp.1057-1072. A mixture of cis and trans isomers of formula (230) or (240) can be catalytically reduced by methods for the hydrogenation of olefins known in the art, such as those described in H.-U. Blaser, F. Spindler, M. Thommen, The Handbook of Homogeneous Hydrogenation, JG De Vries, CJ Elsevier, Eds. (Wiley-VCH, 2008), chap. 37, Scharnagl, F. Ket al., Sci. Adv. 2018; 4:eaau1248, 21 September 2018, and the references cited herein. The ester thus obtained can be hydrolyzed after the hydrogenation reaction is deemed substantially complete using appropriate analytical methods. The reaction mixtures containing the compounds of formula (250) or (260), respectively, are hydrolyzed in refluxed alcohol for 2 to 96 hours in the presence of an alkaline earth metal salt or base, or an oxide, or an alkali metal salt or base. Typical examples, but not limited to, include hydrolysis with K2CO3 in a refluxed mixture of DMSO and water. Other preferred procedures are referred to in Houben-Weyl, Methoden der Organische Chemie, Georg Thieme Verlag Stuttgart 1964, vol.XII / 2, pp.143-210 and 872-879, or Anderson, NG, Practical Process Research & Development, Academic Press, London, 2000, pp.93-94 and 181-182.

[0325] Scheme 8. Exemplary synthesis of compounds I-1 and I-32. [ka]

[0326] Scheme 9. General synthesis of compounds of formula (III) or (IIIA) (wherein X=O, Z 1 , Z 2 =COOH, q=0, and R 1 and R 2 (They form a cyclopropyl ring together.) [ka]

[0327] Compounds of formula (III) or (IIIA) where X=O can be prepared by Williamson synthesis by reacting an alcohol with a derivative containing a leaving group, such as a halide, tolylsulfonate, or mesylate. See Scheme 9.

[0328] Example of synthesis Example 1: Synthesis of (9-carboxymethylsulfanyl-5-oxo-nonylsulfanyl)acetic acid (compound II-3) [ka]

[0329] In THF, the reaction of 5-bromovallate ethyl with lithium diisopropylamide at room temperature produces ketone ester 1-1 (see, for example, Cooke, MPJ Org. Chem. 1993, 58, 2910-2912; Stetter, H.; Rauhut, H. Chem. Ber. 1958, 91). Decarboxylation of 1-1 by reflux of HCl / EtOH (Cooke, MPJ Org. Chem. 1993, 58, 2910-2912) produces crude 1-2, which can be purified by column chromatography using a system such as silica gel and a mixture of ethyl acetate / hexane in a ratio of 1 / 20 to 1 / 8. Mercaptoacetic acid dissolved in a mixture of ethanol and water is treated with an aqueous sodium hydroxide solution to prepare sodium mercaptoacetate, which is then used in steps 1-2 in a solvent such as ethanol, as described in Agnus, A., Louis, Gissebrecht, JP, Weiss, R., J. Am. Chem. Soc., 1984, 106, 93 or Riesen, PC; Kaden, TA Helv. Chim. Acta. 1995, 78, 1325-1333, to obtain crude compound II-3. Crude compound II-3 can be purified by recrystallization from a solvent or solvent mixture such as MTBE and heptane.

[0330] Example 2: (9-carboxymethylsulfanyl-5-hydroxy-nonylsulfanyl Synthesis of )-acetic acid (compound II-1) [ka]

[0331] The keto acid compound II-3 from Example 1 is reduced with sodium borohydride after salt formation with NaOH to obtain compound II-1 (see U.S. Patent No. 7,119,221 for preferred reaction conditions). Compound II-3 (Example 1) is dissolved in NaOH solution (2-7 equivalents) to form a disodium intermediate salt in water. Isopropanol is then added, followed by the addition of sodium borohydride (1.05 equivalents) in fractional amounts. The reaction mixture is heated at approximately 45°C for several hours to obtain compound II-1. This product can be purified by recrystallization from MTBE, heptane, or a mixture.

[0332] Example 3: Synthesis of [5-(5-carboxymethoxy-pentyloxy)-pentyloxy]acetic acid (compound II-12) [ka]

[0333] Compound II-12 is prepared via Williamson ether synthesis starting from 3-1 and 3-2 (as described in Dasseux et al., US6,459,003). The resulting 3-3 is meta-analyzed in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate. Deprotection in ethanol yields diol 3-4. This diol is then bonded with tert-butylbromoacetic acid in a two-phase system of aqueous NaOH and toluene in the presence of tetrabutylammonium bromide as a PTC catalyst, as described in U.S. Patent No. 10,227,285. Finally, this tert-butyl ester is cleaved under acidic conditions to obtain compound II-12.

[0334] Example 4: Synthesis of [5-(5-carboxymethoxy-pentylsulfanyl)-pentyloxy]acetic acid (compound II-20) [ka]

[0335] Compound 3-1 (prepared as described in U.S. Patent No. 6,790,953) is treated with sodium sulfide to form thioether 4-1, similar to the method described by Edwards, D.; Stenlake, JBJ Pharmacy Pharmacol. 1955, 7, 852-860. This is then deprotected in methanol in the presence of a catalytic amount of pyridinium p-toluenesulfonate (PPTS), as described by Miyashita, N.; Yoshikoshi, A.; Grieco, PAJ Org. Chem. 1977, 42(23), 3772-73. The resulting diol 4-2 is then reacted with tert-butylbromoacetic acid under phase transition catalytic conditions using (Bu4N)(HSO4) as a catalyst, according to the method described by Nagatsugi, F.; Sasaki, S.; Maeda, MJ Fluorine Chem. 1992, 56, 373-383, to obtain its tert-butyl ester 4-3. Subsequently, the tert-butyl ester was cleaved with trifluoroacetic acid (TFA) to obtain free acid compound II-20 in 90% yield, similar to the procedure described in Nagatsugi, F.; Sasaki, S.; Maeda, MJ Fluorine Chem. 1992, 56, 373-383.

[0336] Example 5: Synthesis of [5-(5-carboxymethoxy-pentane-1-sulfinyl)-pentyloxy]acetic acid (compound II-24) [ka]

[0337] Using hydrogen peroxide as an oxidizing agent, compound II-24 was prepared, starting with compound II-12 (Example 4), in the same manner as described in U.S. Patent No. 6,673,780.

[0338] Example 6: Synthesis of [5-(5-carboxymethylsulfanyl-pentyloxy)-pentylsulfanyl]acetic acid (compound II-6) [ka]

[0339] Compounds 6-1 and 6-2 were analyzed using the following sources: Harrison, GC; Diehl, H. Organic Synthesis 1955 Coll. Vol 3,370, and Francis, GW; Berg, JFActa Chem. Scand. B, respectively. It is obtained according to the method described in 1977, 31, 721-722. 5-Chloropentan-1-ol is commercially available, and 3-4 is prepared as described in Example 3: i.e., mercaptoacetic acid (8.1 g, 87.9 mmol) was dissolved in deionized water / ethanol solution (50 mL / 40 mL). An aqueous solution of sodium hydroxide (7.0 g, 175.5 mmol) (50 mL) was added under stirring. To this mixture, bis(4-chlorobutyl ether) (7.0 g, 35.1 mmol) in ethanol (20 mL) was added dropwise over 30 minutes. The mixture was heated under reflux for 20 hours, after which the ethanol was evaporated. The residue was diluted with water (20 mL). The aqueous layer was extracted with MTBE (4 × 20 mL), and the organic layer was discarded. The aqueous layer was acidified to pH 2 with concentrated HCl (approximately 12 mL) and extracted with MTBE (4 × 30 mL). The mixed organic layers were checked for the presence of starting mercaptoacetic acid by TLC (silica, CH2Cl2:MeOH=9:1) (R f =0.7 (bright blue spot due to phosphomolybdic acid / EtOH). The organic layer was washed with water until the starting acid was completely gone (divided into approximately 700 mL). The solvent was removed under reduced pressure to obtain a colorless oily substance (7.7 g), which was allowed to solidify at room temperature. This solid was recrystallized from heptane / MTBE (50 / 60 mL) to obtain good white crystals (6.2 g, yield 57%, purity 99%-RI, 91%-UV, mp 43-44°C). A further amount of product was obtained from the mother liquor (0.87 g, mp 38-40°C).

[0340] Example 7: Synthesis of (11-carboxymethylsulfanyl-6-oxo-undecylsulfanyl)-acetic acid (compound II-4) and (11-carboxymethylsulfanyl-6-hydroxy-undecylsulfanyl)-acetic acid (compound II-2) [ka]

[0341] The synthesis of compounds II-4 and II-2 begins with 1,11-dibromoundecane-6-one (7-4) prepared as described above, starting from commercially available 6-bromohexanol. Protection of the hydroxyl group of 6-bromohexanol with dihydropyran yields intermediate 7-1, as described in U.S. Patents 6,646,170 and 6,410,802. 7-1 is reacted with ToSMIC in dimethylacetamide (DMAc) in the presence of sodium amylate (NaOAm-t) to form intermediate 7-2, which is converted to diol 7-3. Removal of the THP protecting group and conversion of the isocyanotosyl fragment to a ketone group proceeds simultaneously over approximately 12–24 hours in a mixture of solvents such as methylene chloride and methanol, in the presence of an aqueous solution of HCl. Diol 7-3 can be purified by column chromatography on silica gel and a mixture of solvents such as ethyl acetate and methylene chloride. Compound 7-3 obtained in this way is subjected to the Mitsunobu reaction to obtain bromide 7-4, which is then treated with the sodium salt of mercaptoacetic acid in an alcohol or a mixture of alcohols (ethanol, isopropanol) to obtain diacid compound II-4. Compound II-4 is reduced with sodium borohydride to obtain compound II-2 (see Example 2).

[0342] Example 8: Synthesis of [4-(4-carboxymethoxy-butoxy)-butoxy]acetic acid (compound II-11) [ka]

[0343] Commercially available bis(4-chlorobutyl ether) is converted to diol 8-2 via diacetate 8-1 [Kliem, A., Schniepp, LEJAm.Chem.Soc, 1948, 70, 1839], and this is further reacted with ethyl bromoethyl to obtain 8-3. Compound 8-3 is hydrolyzed to obtain II-11. Alternatively, bis(4-chlorobutyl ether) is treated with the dianion of hydroxyacetic acid, and compound II-11 is obtained by autoclaving or heating.

[0344] Specifically, diacetate 8-1 is treated with potassium carbonate in methanol, similar to the method described in Kliem, A., Schniepp, LEJAm. Chem. Soc, 1948, 70, 1839, and crude compound 8-2 is optionally purified by column chromatography. Diol 8-2 is deprotonated with sodium hydride (95% or 60% in mineral oil) in THF for about 2 to 4 hours, and then reacted with ethyl bromoethyl acetate to obtain diester 8-3. The final step, hydrolysis of 8-3, is carried out with KOH in ethyl alcohol for about 2 to 8 hours. The product is then subjected to workup including acidification with aqueous HCl followed by extraction with methylene chloride to obtain crude compound II-11. Crude compound II-11 is optionally purified by gradient column chromatography on silica gel using solvents such as siRNA and hexane, or mixtures thereof.

[0345] Example 9: Synthesis of 5,5'-(1,4-phenylene)bis(2,2-dimethylpentanoic acid) (compound I-78) [ka]

[0346] (4-methoxycarbonylmethylphenyl)-methyl acetate (A2) Concentrated sulfuric acid (40 mL) was added to phenylene diacetic acid (A1) (25.0 g, 0.129 mol) in MeOH (300 mL). The reaction mixture was heated under reflux overnight. Most of the MeOH was evaporated under vacuum. The residue was diluted with ethyl acetate (300 mL) and water (300 mL). The aqueous solution was separated and extracted with ethyl acetate (2 × 100 mL). The mixed organic solution was washed with water (100 mL), saturated NaHCO3 solution (2 × 100 mL), and brine (100 mL), and dried on MgSO4. The solvent was evaporated to obtain (4-methoxycarbonylmethylphenyl)-methyl acetate as a white solid (27.1 g, 95%, 92.3%) by HPLC. Mp59~60℃ (51~54℃, Dynamit Nobel, UK Patent No. 1495472, Application No. 9008 / 75, filed March 4, 1975). 1 H NMR (CDCl3): δ= 7.25 (s, 4H), 3.70 (s, 6H), 3.60 (s, 4H). 13 C NMR (CDCl3): δ= 174.0, 132.5, 129.0, 52.0, 40.5.

[0347] 2-[4-(2-hydroxyethyl)-phenyl]-ethanol(A3) (4-methoxycarbonylmethylphenyl)-methyl acetate (A2) (26.5 g, 0.12 mol) in THF (100 mL) was added to a solution of LiAlH4 (11.0 g, 0.29 mol) in THF (300 mL) with stirring at room temperature. The reaction mixture was heated under reflux for 2 hours. Water (100 mL) was carefully added, followed by a diluted aqueous HCl solution (75 mL of concentrated HCl in 100 mL of water). The aqueous phase was extracted with ELISA (2 × 100 mL). The mixed organic solution was washed with water (100 mL), saturated NaHCO3 solution (150 mL), and brine (100 mL), and dried on MgSO4. The solvent was evaporated to obtain 2-[4-(2-hydroxyethyl)-phenyl]ethanol (18.68 g, 94%, 93.5% purity by HPLC) as a white solid. Mp89~90℃ (87~88℃, Reynolds et al., US2,789,970, Application No. 397,037, filed December 8, 1953). 1 ¹H NMR (CDCl3): δ=7.17 (s, 4 H), 3.78 (t, J = 6.6 Hz, 4H), 2.81 (t, J = 6.6 Hz, 4H), 2.30 (br s, 2H). 13 C NMR (CDCl3): δ = 136.9, 129.4, 63.8, 39.0.

[0348] 1,4-Bis-(2-bromoethyl)-benzene(A4) Concentrated sulfuric acid (30.0g) is mixed with 2-[4-(2-hydroxyethyl)-phenyl]-ethanol (A3) (18.29g, 0.11mol) and NaBr (40.0g, 0.39mol). The mixture was added dropwise over 1 hour to a boiling mixture of (1) and water (50 mL). The reaction mixture was refluxed for 1 hour. The additional portion of sulfuric acid (10 mL) and NaBr (16.0 g, 0.16 mol) was added, and refluxing was continued for 1.5 hours. Water (100 mL) was added to the cooled mixture, and the product was extracted with methylene chloride (3 × 100 mL). The mixed organic solution was washed with water (100 mL) and brine (100 mL) and dried on MgSO4. The solvent was evaporated, and the residue was purified by column chromatography (silica gel, SiO:hexane = 1:1). The solid product was recrystallized from hexane to obtain 1,4-bis-(2-bromoethyl)-benzene (22.27 g, 69%, purity 99.8% by HPLC) as a white solid. Mp71~72℃ (70~71℃, Longone, DT; Kusefoglu, SH; Gladysz, JAJOrg. Chem. 1977, 42, 2787-2788). 1 H NMR (CDCl3): δ= 7.18 (s, 4H), 3.57 (t, J = 2.2 Hz, 4H), 3.16 (t, J = 7.8 Hz, 4H). 13 C NMR (CDCl3): δ= 138.6, 130.0, 4 0.1, 34.0.

[0349] 4-[4-(3-carboxy-3-methylbutyl)-phenyl]-2,2-dimethylbutyrate A solution of lithium diisopropylamide (89 mL, 0.16 mol, 1.8 M in heptane / THF / EtPh) was added dropwise to a solution of ethyl isobutyrate (18.0 g, 155 mmol) in THF (100 mL) at -78°C. The reaction mixture was stirred for 1 hour, and a solution of 1,4-bis-(2-bromoethyl)-benzene (A4) (20.0 g, 68.5 mmol) in THF (50 mL) was slowly added, followed by the addition of DMPU (10 mL). The reaction mixture was warmed to room temperature over 2 hours and stirred at 40-50°C for 1 hour. Water (200 mL) was added, the aqueous solution was separated, and extracted with ELISA (3 × 80 mL). The mixed organic solution was washed with water (100 mL) and brine (100 mL). After concentration under reduced pressure, the residue was purified by column chromatography (silica gel, HCl:heptane, 1:10) to obtain 4-[4-(3-ethoxycarbonyl-3-methylbutyl)-phenyl]-2,2-dimethylbutyrate ethyl ester (24.0 g). This intermediate (24.0 g, 66.2 mmol) was dissolved in EtOH (300 mL) and water (50 mL), KOH (85%, 15.0 g, 227 mmol) was added, and the reaction mixture was refluxed for 3 hours. The solvent was evaporated, and the residue was dissolved in water (150 mL) and extracted with MTBE (2 × 30 mL). The aqueous solution was acidified to pH 1-2 with HCl aqueous solution. The precipitate was filtered, recrystallized from CHCl3 / EtOH (1:1), and dried in vacuum to obtain 4-[4-(3-carboxy-3-methylbutyl)-phenyl]-2,2-dimethylbutyric acid (13.6 g, 64%, 94.8% purity by HPLC) as white crystals (compound I-78). Mp 214~215°C. Elemental analysis (C 18 H 26 O4): Calculated value of C: C, 70.56; H, 8.55 Measured values: C 70.78, H 8.64. 1 1H NMR (CD3OD): δ = 7.06 (s, 4H), 4.90 (s, 2H), 2.54-2.48 (m, 4H), 1 .80-1.74 (m, 4H), 1.22 (m, 12H). 13 ¹ 3OD): δ= 181.5, 140.9, 129.2, 44.3, 43.2, 3 2.3, 25.8. C 18 H 26 O4(M + HRMS calculated value for ) is 306.1831, and measured value is 306.1831.

[0350] Example 10: Synthesis of 6,6'-(1,4-phenylene)bis(2,2-dimethylhexanoic acid) (Compound I-1) [ka]

[0351] 4-[4-(3-methoxycarbonylpropyl)-phenyl]-methyl butyrate (B1) The compound was prepared by a modified method described in Cram, DJ; Allinger, NL; Steinberg, H.A.A. Mer. Chem. Soc. 1954, 76, 6132.

[0352] Under an N2 atmosphere, sodium (3.5 g, 0.152 mol) was dissolved in EtOH (200 mL), and ethyl malonate (50.0 g, 0.31 mol) was added to the warmed solution. The reaction mixture was refluxed for 5 minutes, and a solution of 1,4-bis-(2-bromoethyl)-benzene (A4) (22.02 g, 75.4 mmol) in ethyl malonate (50 mL) was added dropwise at room temperature over 5 minutes. The reaction mixture was refluxed for 0.5 hours. After adding water (150 mL) and ethyl ammonium (200 mL), the solvent was evaporated, and the residue was dissolved in ethyl ammonium (200 mL). The solution was washed with water (100 mL) and brine (100 mL), dried on MgSO4, and concentrated under vacuum. The residue was dried at 80-100°C (oil bath) under high vacuum. The obtained crude 2-{2-[4-(3,3-bis-ethoxycarbonylpropyl)-phenyl]-ethyl}malonate diethyl ester was dissolved in an aqueous EtOH solution (80%, 200 mL), and KOH (85%, 35.0 g, 0.53 mol) was added. The reaction mixture was heated under reflux for 2 hours. The solvent was partially evaporated, and HCl (150 mL) was added. The aqueous layer was separated and extracted with HCl (2 × 100 mL). The mixed organic solution was washed with brine (100 mL), dried on MgSO4, and concentrated. Crude 2-{2-[4-(3,3-bis-carboxypropyl)-phenyl]-ethyl}malonic acid (28.0 g) was heated in an oil bath at 200-210°C for 1.5 hours. The obtained crude 4-[4-(3-carboxypropyl)-phenyl]-butyric acid (16.3 g) was dissolved in MeOH (100 mL), and concentrated sulfuric acid (40 mL) was added. The reaction mixture was refluxed for 5 hours, then stirred overnight at room temperature. The MeOH was partially evaporated, the residue was dissolved in ELISA (150 mL), washed with water (150 mL) and brine (150 mL), and dried on MgSO4. The solvent was evaporated to obtain crude 4-[4-(3-methoxycarbonylpropyl)-phenyl]-butyrate methyl ester (B1) (17.9 g, 85%) as a yellow oil, which was used in the next step without purification. 1 1H NMR (CDCl3): δ = 7. 10 (s, 4H), 3.67 (s, 6H), 2.59 (t, J = 7.4 Hz , 4H), 2.33 (t, J = 7.4 Hz, 4H), 1.95-1.90 (m, 4H). 13 C NMR (CDCl3): δ = 174.0, 138.9, 128 0.4, 51.5, 34.6, 33.3, 26.5.

[0353] 4-[4-(4-hydroxybutyl)-phenyl]-butan-1-ol(B2) The compound was prepared according to Cram, DJ; Allinger, NL; Steinberg, H.A.A.m. Chem. Soc. 1954, 76, 6132-6141. A solution of 4-[4-(3-methoxycarbonylpropyl)-phenyl]-methyl butyrate (17.7 g, 63.6 mmol) in THF (50 mL) was added to a suspension of LiAlH4 (7.2 g, 0.19 mol) in THF (300 mL) with stirring at 0°C. The reaction mixture was heated under reflux for 1 hour. Water (100 mL) and aqueous HCl (10%, 200 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (2 × 50 mL). The mixed organic solution was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (silica gel, ETOAc:hexane, 1:1) to obtain 4-[4-(4-hydroxybutyl)-phenyl]-butan-1-ol (7.5g, 53%, 96.2% purity by HPLC) as white crystals. Mp 60~62℃ (60.5~62.4℃, Cram, DJ; Allinger, NL; Steinberg, HJAm.Chem.Soc.1954, 76, 6132-6141). 1 H NMR (CDCl3): δ = 7.10 (s, 4H), 3.63 (t, J = 6.4H z, 4H), 2.61 (t, J = 7.1 Hz, 4H), 2.12 (br s, 2H), 1.71-1.57 (m, 8H). 13 C NMR (CDCl3): δ = 140.7, 129.4, 63.8, 36.3, 33.4, 28.67.

[0354] 1,4-Bis-(4-bromobutyl)-benzene(B3) Concentrated sulfuric acid (30 mL) was added dropwise over 1 hour to a boiling mixture of 4-[4-(4-hydroxybutyl)-phenyl]-butan-1-ol (9.4 g, 42.3 mmol), NaBr (17.4 g, 0.169 mol), and water (50 mL). The reaction mixture was refluxed for 1 hour. An additional 10 mL of concentrated sulfuric acid was added over 20 minutes, and reflux was continued for 1.5 hours. After adding water (300 mL) and methylene chloride (500 mL), the aqueous solution was separated and extracted with methylene chloride (2 × 50 mL). The mixed organic solution was washed with water (200 mL) and brine (150 mL) and dried over MgSO4. The solvent was evaporated, and the residue was purified by column chromatography (silica gel, SiO:hexane, 1:20) to obtain 1,4-bis-(4-bromobutyl)benzene (11.8 g, 80%, 96.1% purity by HPLC) as an oily substance. 1 H NMR (CDCl3): δ = 7.14 (s, 4H), 3.46 (t, J = 6.6 Hz, 4H), 2.65 (t, J = 7.5 Hz, 4H), 1.96-1.89 (m, 4H), 1.83-1.75 (m, 4H). 13 ¹³C NMR (CDCl3): δ = 139.5, 128.6, 34.7, 34.0, 32.5, 30.1. This procedure was performed by Cram, DJ; All This will be done by modifying the description by Inger, NL; Steinberg, HJAm.Chem.Soc.1954, 76, 6132-6141.

[0355] 6-[4-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid A solution of lithium diisopropylamide (90 mmol, 1.8 M in heptane / THF / EtPh, 50 mL) was added dropwise to a solution of ethyl isobutyrate (8.97 g, 77.2 mmol) in THF (200 mL) at -78°C. After stirring the reaction mixture for 1 hour, a solution of 1,4-bis-(4-bromobutyl)-benzene (11.2 g, 32.2 mmol) in THF (50 mL) was slowly added, followed by the addition of DMPU (10 mL). The reaction mixture was warmed to room temperature over 2 hours and stirred at 40-50°C for 1 hour. Water (200 mL) was added, the aqueous solution was separated, and extracted with SiO (3 × 80 mL). The mixed organic solution was washed with water (100 mL) and brine (100 mL). The solvent was evaporated, and the residue was dissolved in EtOH (100 mL). Water (50 mL) and KOH (85%, 15.0%) (g, 227 mmol) was added, and the reaction mixture was refluxed for 3 hours. Water (200 mL) was added, and after cooling to room temperature, the reaction mixture was acidified to pH 1 with concentrated HCl and stirred for 1 hour. The precipitate was filtered, washed with water, and dissolved in methylene chloride (400 mL). The solution was dried over MgSO4 and evaporated under vacuum. The residue was dissolved in Depositphotos:hexane (1:30, 200 mL) under heating and cooled in a freezer. The solution was decanted from the oily material and evaporated to a volume of 60 mL. The mixture was stirred overnight, the precipitate was filtered, washed with hexane, and dried under vacuum to obtain 6-[4-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid (8.02 g, 69%, purity 96.4% by HPLC) as a white solid (compound I-1). Mp 129~131°C. Elemental analysis (C 22 H 34 O4): Calculated values: C, 72.89; H, 9.45. Measured values: C, 72.90; H, 9.49. 1 H NMR (CDCl3): δ = 7.05 (s, 4H), 2.66-2.62 (m, 4H), 1.68-1.56 (m, 4H), 1.53-1.47 (m, 4H), 1.17 (s, 12H), 1.08-0.98 (m, 4H). 1 3C NMR (CDCl3): δ = 185.3, 138.6, 128.5, 42.3, 41.5, 34.5, 30.6, 25.0, 23.2. C 22 H 34 O4(M + HRMS calculated value for ) is 362.2457, and the measured value is 362.2453.

[0356] Example 11: Synthesis of 1,4-bis(4-carboxy-4-methylpentyl)benzene (Compound III-1) [ka]

[0357] 1,4-Bis(2-methoxycarbonylethyl)benzene(C2) Under an Ar atmosphere, a solution of 1,4-bis(2-carboxyethyl)benzene (C1) (10.0 g, 45.0 mmol) in anhydrous methanol (75 mL) and concentrated sulfuric acid (5.0 g) was refluxed for 5 hours. The reaction mixture was cooled to room temperature, the crystals were filtered, washed with MeOH (30 mL), and dried in vacuum to obtain 1,4-bis(2-methoxycarbonylethyl)benzene (11.0 g, 99%) as white crystals. Mp 116~117°C (116~118°C, Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata, Y.; Misumi, S. Bull. Chem. Soc. Japan 1972, 45, 1825-1833). 1 H NMR (CDCl3): δ = 7.11 (s, 4 H), 3.69 (s, 6 H), 2.94 (t, J = 8.1 Hz, 4 H), 2.62 (t, J = 8.2 Hz, 4 H). 13 ¹¹¹ NMR (CDCl3): δ = 173.3, 138.4, 128.4, 51.6, 35.6, 30.5. This known compound is attributed to Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata, Y.; Misumi, S. Bull. It was prepared by a method different from the one described in Chem.Soc.Japan 1972, 45, 1825-1833.

[0358] 1,4-Bis(3-hydroxypropyl)benzene(C3) C3 was prepared according to Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata, Y.; Misumi, S. Bull. Chem. Soc. Japan 1972, 45, 1825-1833. Under an Ar atmosphere, lithium aluminum hydride (5.2 g, 13.7 mmol) was added in divided portions to anhydrous THF (300 mL). A solution of 1,4-bis(2-methoxycarbonylethyl)benzene (11.5 g, 45.9 mmol) in THF (50 mL) was added dropwise over 1 hour to induce an exothermic reaction. The reaction mixture was refluxed for 5 minutes and stirred at room temperature for 3 hours. Hydrolysis was then performed using water (100 mL) and a 10% aqueous solution of NH4Cl (50 mL). The organic layer was separated, and the aqueous solution was extracted with RINKAN (100 mL). The organic phase was mixed, washed with brine (50 mL), dried over MgSO4, and concentrated to obtain 1,4-bis(3-hydroxypropyl)benzene (9.0 g, quantitative) as an oily substance, which was used in the next step without further purification. 1 H NMR (DMSO-d6): δ = 7.10 (s, 4 H), 4.43 (br s, 2 H), 3.41 (t, J = 8.1 Hz, 4 H), 2.59 (t, J = 8.2 Hz, 4 H), 1.71 (m, 2 H). 13 C NMR (DMSO-d6): δ = 139.0, 127.0, 60.0, 34.5, 31.2.

[0359] 1,4-Bis(3-bromopropyl)benzene(C4) An emulsion of 1,4-bis(3-hydroxypropyl)benzene (9.0 g, 46.3 mmol) and sodium bromide (24.0 g, 0.23 mol) in deionized water (25 mL) was heated under reflux, and concentrated sulfuric acid (17 mL) was added dropwise over 1 hour. After the addition, heating under reflux was continued for a further 3.5 hours. The solution was cooled to room temperature, diluted with water (40 mL), and extracted with CH2Cl2 (2 × 150 mL). The mixed organic layer was washed with saturated NaHCO3 solution (100 mL) and saturated NaCl solution (100 mL), and dried on MgSO4. The solvent was evaporated, and the residue was purified by column chromatography (silica gel, SiO:hexane = 1:40) to obtain 1,4-bis(3-bromopropyl)benzene (11.6 g, 78%) as a colorless oil. 1 H NMR (CDCl3): δ = 7.15 (s, 4 H), 3.41 (t, J = 6.6 Hz, 4 H), 2.77 (t, J = 7.1 Hz, 4 H), 2.18 (m, 4 H). 13 ¹¹¹ NMR (CDCl) 3): δ = 138.3, 128.7, 34.2, 33.4, 33.3. This publicly known value. The compound was prepared by a method different from those described in Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata, Y.; Misumi, S. Bull. Chem. Soc. Japan 1972, 45, 1825-1833 and Ruzicka, L.; Buijs, JB; Stoll, M. Helv. Chim. Acta 1932, 15, 1220.

[0360] 1,4-Bis(4-ethoxycarboxy-4-methylpentyl)benzene (C5) Under an N2 atmosphere, lithium diisopropylamide (1.8 M solution in heptane / THF / EtPh, 46.7 mL, 84.0 mmol) was added dropwise to a solution of ethyl isobutyrate (9.0 g, 77.5 mmol) in anhydrous THF (300 mL) at -78°C. After 1 hour, a solution of 1,4-bis(3-bromopropyl)benzene (11.6 g, 36.3 mmol) in anhydrous THF (70 mL) was added dropwise, followed by the addition of DMPU (20 mL). The reaction mixture was heated to room temperature overnight, then cooled in an ice bath, and hydrolyzed with saturated NH4Cl solution (100 mL). Water (100 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 50 mL). The mixed organic layer was washed with saturated NaCl solution (100 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (HCl:hexane, 1:10) and 1,4-bis(4-ethoxycarb) Xy-4-methylpentyl)benzene (13.3 g, 94%) was obtained as a colorless oil. 1 H NMR (CDCl3): δ = 7.09 (s, 4 H), 4.11 (q, J = 7.1 Hz, 4 H), 2.57 (m, 4 H), 1.57 (m, 8 H) , 1.24 (t, J = 7.1 Hz, 6 H), 1.47 (s, 12 H). 13 C NMR (CDCl3): δ = 177.9, 139.6, 128.2, 60.1, 42.0, 40.2, 35.8, 26.8, 25.1, 14.2. C 24 H 39 O4(Mon + HRMS calculated value for ): 391.2838, measured value: 391.28 36.

[0361] 1,4-Bis(4-carboxy-4-methylpentyl)benzene A solution of 1,4-bis(4-ethoxycarboxy-4-methylpentyl)benzene (13.0 g, 33.3 mmol) and potassium hydroxide (85%, 7.0 g, 106 mmol) in ethanol (25 mL) and water (15 mL) was heated under reflux for 3.5 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and acidified to pH 1 with HCl (2 M aqueous solution). A precipitate formed immediately. The mixture was stirred for 1 hour, the precipitate was filtered, and washed with water (2 × 50 mL). The crude precipitate was dissolved in methylene chloride (700 mL), and the solution was dried overnight on MgSO4. The solvent was evaporated, and the residue was recrystallized (methylene chloride:hexane = 1:1) to obtain 1,4-bis(4-carboxy-4-methylpentyl)benzene (9.5 g, 85%, 100% purity by HPLC) as white crystals (compound III-1). Mp131℃ (125~126℃, Gleiter, R.; Kramer, R.; Irngartinger, H.; Bissinger, C. Synthesis and Properties of 4,4,9,9-Tetramethyl

[12] paracyclophane-5,6,7,8-tetrone. J.Org.Chem.1992,57,252-258). Elemental analysis (C 20 H 30 O4): Calculated values: C, 71.82; H, 9.04; Measured values: C, 71.10; H, 9.00. 1 H NMR (CDCl3): δ = 7.07 (br s, 4 H), 2.55 (m, 4 H), 1.59 (m, 8 H), 1.18 (s, 12 H). 13 ¹³C NMR (CDCl3): δ = 184.9, 139.6, 128.1, 42.1, 40.3, 35.8, 26. 8, 24.9. This known compound is Gleiter, R.; Kramer, R.; I rngartinger, H.; Bissinger, C. Synthesis and It was prepared by a modified method of the method described in Properties of 4,4,9,9-Tetramethyl

[12] paracyclophane-5,6,7,8-tetrone. J.Org.Chem. 1992, 57, 252-258.

[0362] Example 12: Synthesis of 5,5'-(1,3-phenylene)bis(2,2-dimethylpentanoic acid) (compound I-31) [ka]

[0363] Dimethyl m-benzene-bis(2,2-dimethyl)pentanoate (D2) Under an Ar atmosphere, lithium diisopropylamide (H) was added to a solution of ethyl isobutyrate (21.2 g, 24.4 mL, 183 mmol) in anhydrous THF (200 mL) at -78°C. 2.0 M (91.5 mL, 183 mmol) of butane / THF / ethylbenzene was added dropwise. After 1 hour, a solution of m-bis(3-bromopropyl)benzene (D1) in anhydrous THF (50 mL) (prepared according to Schimelpfenig, CWJ Org. Chem. 1975, 40, 1493-1494 and Effenberger, F.; Kurtz, W. Chem. Ber. 1973, 106, 511-524, 26.6 g, 83.1 mmol) was added dropwise, followed by the addition of DMPU (25 mL). The reaction mixture was heated to room temperature overnight, then cooled in an ice bath, and hydrolyzed with saturated NH4Cl solution (100 mL). Deionized water (100 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 100 mL). The mixed organic phase was washed with saturated NaCl solution (100 mL), 1N hydrochloric acid (2 × 100 mL), saturated NaHCO3 solution (100 mL), and saturated NaCl solution (100 mL). The mixed organic phase was dried on MgSO4, concentrated in vacuum, and dried in high vacuum. The residue was purified by flash chromatography on silica (hexane / ethyl acetate = 95 / 5) to obtain diethyl 5,5'-(1,3-phenylene)bis(2,2-dimethylpentanoic acid) (15.7 g, 48%) as a yellow oil. 1 H NMR (CDCl3): δ = 7.17 (t, 1 H, J = 7.0 Hz), 6.97 (m, 3 H), 4.09 (q, 4 H, J = 7.3 Hz), 2.55 (m, 4 H), 1 .56 (m, 8 H), 1.22 (t, 6 H, J = 7.3 Hz), 1.15 (s, 12 H). 13 C NMR (CDCl3): δ = 178.02, 142.37, 128.58, 128.32, 125.86, 60.31, 42.25, 40.52, 36.48, 27.03, 25.30, 14.39.

[0364] 5,5'-(1,3-phenylene)bis(2,2-dimethylpentanoic acid) A solution of diethyl 5,5'-(1,3-phenylene)bis(2,2-dimethylpentanoic acid)(D2) (10.6 g, 27.14 mmol) and potassium hydroxide (85%, 6.3 g, 95.00 mmol) in ethanol (20 mL) and water (10 mL) was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and the ethanol was removed under reduced pressure. The remaining aqueous solution was extracted with dichloromethane (2 × 50 mL). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid (10 mL) and extracted with dichloromethane (3 × 50 mL). The mixed organic layer was washed with saturated NaCl solution (50 mL), dried on MgSO4, concentrated under vacuum, and dried under high vacuum to obtain a viscous oily substance (9.3 g). This oily substance was crystallized from pentane / dichloromethane (75 mL / 5 mL) at -5°C to obtain 5,5'-(1,3-phenylene)bis(2,2-dimethylpentanoic acid) (4.78 g, 49%, 93.2% purity by HPLC) as a white powder (compound I-31). Mp 79°C. Elemental analysis (C 20 H 30 O4): Calculated values: C, 71.82; H, 9.04; Measured values: C, 71.71; H, 9.22. 1 H NMR (DMSO-d6): δ = 12.2 - 11.7 (mb r, 2 H), 7.17 (m, 1 H), 6.98 (m, 3 H), 2.52 (m, 4 H), 1.49 (m, 8 H), 1.07 (s, 12 H). 13 C NMR (DMSO-d6): δ = 178.86, 141.96, 128.26, 125.69, 41.21, 39.91, 35.68, 26.62, 25.06. C 30 H 31 O3(MH + HRMS calculated value for ) is 335.2222, and the measured value is 335. 2232.

[0365] Example 13: Synthesis of 6-[3-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid (compound I-32) [ka]

[0366] [1,3-bis(5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-phenylene(E2)] A solution of N-butyllithium (38.8 mL, 2.5 M in hexane / THF / EtPh, 96.9 mmol) was added at room temperature to a mixture of m-xylene (E1) (5.0 g, 47.1 mmol) and potassium tert-butoxide (5.4 g, 48.1 mmol) in hexane (100 mL). The reaction mixture was heated under reflux for 1 hour. A yellow precipitate formed. The reaction mixture was cooled to 0°C, and 2-(5-bromo-2,2-dimethylpentyloxy)-tetrahydropyran (prepared according to Dasseux et al., US6646170 and US6410802, 30.0 g, 107.5 mmol) was added dropwise. The reaction mixture was heated under reflux for 20 hours. Water (150 mL) was added to separate the organic phase. The aqueous solution was extracted with ELISA (2 × 100 mL). The organic phases were mixed, washed with brine (50 mL), and dried on MgSO4. The solvent was evaporated, and the residue was purified by column chromatography (silica gel, Depositphotos:hexane, 1:30) to obtain [1,3-bis(5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]phenylene (14.8 g, 62%, 96.1% purity by HPLC) as an oil. 1 H NMR (CDCl3): δ = 7.17-7.14 (m, 1H), 7.00-6.98 (m, 3H), 4.54 (t, J = 3.0 Hz, 2H), 3.78-3.86 (m, 2H), 3.50-3.45 (m, 2H), 3.47 (d, J = 9.1Hz, 2H) 2.98 (d, J = 9.1 Hz, 2H), 2.59 (t, J = 7.6 Hz , 4H), 1.90-1.28 (m, 24H), 0.89 (s, 12H). 13 C NMR (CDCl3): δ = 142.8, 128.5, 128.1, 125.6, 99.1, 77.5, 61.8, 39.2, 36.0, 34.2, 32.5 , 30.7, 25.6, 24.6, 23.7, 19.4. C 32 H 54 O4(M + HRMS calculated value for ) is 501.3943, and the measured value is 501.3943.

[0367] 6-[3-(6-hydroxy-5,5-dimethylhexyl)-phenyl]-2,2-dimethylhexane-1-ol(E3) A concentrated aqueous solution of HCl (20 mL) was added to 1,3-bis(5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]phenylene (18.0 g, 35.7 mmol) in MeOH (200 mL). The reaction mixture was heated under reflux for 2 hours and stirred overnight at room temperature. The MeOH was evaporated under vacuum, and the residue was dissolved in methylene chloride (200 mL). The solution was washed with water (100 mL), saturated NaHCO3 solution (100 mL), and brine (100 mL), and dried on MgSO4. The solvent was evaporated, and the residue was purified by column chromatography (silica gel, Depositphotos:hexane = 1:1) to obtain 6-[3-(6-hydroxy-5,5-dimethylhexyl)-phenyl]-2,2-dimethylhexane-1-ol (10.41 g, 87%, 86.4% by HPLC) as an oily substance. Ta. 1 H NMR (CDCl3): δ = 7.21-7.19 (m, 1H), 7.02-6.99 (3H), 3.32 (s, 4H), 2.62 (t, J = 7.8 Hz, 4H), 1.64-1.26 (m, 12H), 0.89 (s, 12H). 13 C NMR (CDCl3): δ = 142.6, 128.5, 128.1, 125.6, 71.9, 38.4, 35.8, 35.0, 32.4, 23.7, 23. 5. C 22 H 38 O4(M +HRMS calculated value for ): 335.2950, ​​measured value :335.2950.

[0368] 6-[3-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid At room temperature, pyridinium dichromate (74.85 g, 199 mmol) was added to a solution of 6-[3-(6-hydroxy-5,5-dimethylhexyl)-phenyl]-2,2-dimethylhexane-1-ol (8.5 g, 25.4 mmol) in DMF (200 mL). The reaction mixture was stirred for 30 hours, then heated to 40°C for 10 hours. Ethyl acetate (100 mL) was added, followed by water (200 mL) and concentrated H2SO4 (20 mL) under stirring. The organic layer was separated, and the aqueous layer was extracted with siRNA (3 × 100 mL). The mixed organic solution was washed with water (100 mL), saturated NaHCO3 solution (100 mL), and brine (2 × 100 mL), and dried on MgSO4. The solvent was evaporated, and the residue was purified by column chromatography (silica gel, siRNA:hexane = 1:1). The resulting oily substance was stirred in Et2O:hexane (1:10, 50 mL) for 3 hours, and the precipitated solid product was filtered (7.2 g, 78%, 96.1% by HPLC) (compound I-32). Mp 99~101°C. Elemental analysis (C 22 H 34 O4): Calculated values: C, 72.89; H, 9.45; Measured values: C, 73.02; H, 9.57. 1 1H NMR (CDCl3): δ = 7.19-7.16 (m, 1H), 6.99-6.94 (m, 3H), 2.58 (t, J = 7.1 Hz, 4H), 1.63-1.56 (m, 8H), 1.32 -1.22 (m, 4H), 1.18 (s, 12H). 13 13C NMR (CDCl3) ): δ = 185.5, 142.2, 128.6, 128.3, 126.0, 42.0, 40.8, 35.7, 31.0, 25.1, 24.4. C 22 H 35 O4(Mon +HRMS calculated value for ) is 363.2535, and the measured value is 363.2530.

[0369] Example 14: Synthesis of 5,5'-(1,2-phenylene)bis(2,2-dimethylpentanoic acid) (compound I-61) [ka]

[0370] 3-[2-(3-hydroxypropyl)-phenyl]-propanol(F2) Under an Ar atmosphere, 3-[2-(2-ethoxycarbonylethyl)-phenyl]-propionate ethyl ester (Fak) was added to a suspension of lithium aluminum hydride (3.0 g, 78.2 mmol) in anhydrous THF (100 mL) at room temperature for 50 minutes with stirring. Prepared according to hri, SA; Behrooz, YHTetrahedron 2000, 56, 8301-8308, 14.5 g (52.1 mmol) of THF (100 mL) solution was added dropwise. The mixture was stirred for 2 hours, then cooled in an ice bath and carefully hydrolyzed by dropwise addition of deionized water (100 mL). Hydrolysis was completed by dropwise addition of 10% sulfuric acid at room temperature and stirring overnight. The mixture was extracted with dichloromethane (200 mL, 2 × 100 mL). The mixed organic layer was washed with saturated sodium chloride solution (100 mL), dried over MgSO4, concentrated under vacuum, and dried under high vacuum to obtain 3-[2-(3-hydroxypropyl)-phenyl]-propanol (8.6 g, 85%, 87.9% purity by GC) as a turbid oil, which was used without further purification for the next step. 1 H NMR (CDCl3): δ = 7.20 - 7.05 (m, 4 H), 3.67 (t, 4 H, J = 6.1 Hz), 3.50 - 3.20 (m br., 2 H), 2.72 (m, 4 H), 1.82 (m, 4 H). 13 C NMR (CDCl3): δ = 139.98, 129.43, 126.24, 62.35, 34.36, 29.01. C 12 H 19 O2(MH + HRM regarding ) S calculated value: 195.1385, measured value: 195.1388. This known compound was prepared by a method different from the one described in Uenaka, M.; Kubota, B. Bull. Chem. Soc. Jpn. 1936, 11, 19-26.

[0371] 1,2-Bis-(3-bromopropyl)-benzene(F3) A mixture of 3-[2-(3-hydroxypropyl)-phenyl]-propanol (8.6 g, 44.27 mmol), sodium bromide (18.6 g, 180.62 mmol), and water (16 mL) was refluxed, and concentrated sulfuric acid (13.3 mL) was added dropwise over 20 minutes. The solution was further refluxed for 75 minutes, then cooled to room temperature and diluted with deionized water (200 mL). The mixture was extracted with dichloromethane (3 × 100 mL), and the mixed organic layer was successively washed with water (100 mL), saturated sodium bicarbonate solution (100 mL), 10% sodium thiosulfate aqueous solution (200 mL), and saturated sodium chloride solution (100 mL). The organic layer was dried over MgSO4, concentrated under vacuum, and dried under high vacuum to obtain the crude product (11.2 g) as a brown oily substance. The crude substance was purified by flash chromatography (silica, hexane, then hexane / ethyl acetate = 90 / 10) to obtain 1,2-bis-(3-bromopropyl)benzene (8.25 g, 58%, 95.9% purity by GC) as a viscous yellow oil. 1 H NMR (CDCl3): δ = 7.16 (s, 4 H), 3.33 (t, 4 H, J = 6.3 Hz), 2.79 (m, 4 H), 2.12 (m, 4 H). 13 ¹¹C NMR (CDCl3): δ = 138.69 , 129.69, 126.66, 34.14, 33.62, 30.99. C 12 H 16 Br2(M + HRMS calculated value: 317.9619, measured value: 317.9624 This known compound was prepared by a method different from the one described in Uenaka, M.; Kubota, B. Bull. Chem. Soc. Jpn. 1936, 11, 19-26.

[0372] 5-[2-(4-ethoxycarbonyl-4-methylpentyl)-phenyl]-2,2-dimethylpentanoate ethyl ester (F4) Under an Ar atmosphere, a solution of ethyl isobutyrate (8.7 g, 10.0 mL, 74.98 mmol) in anhydrous THF (100 mL) was added dropwise over 15 minutes at -78°C to a solution of lithium diisopropylamide (2.0 M, 41.2 mL, 82.48 mmol in heptane / THF / ethylbenzene). After 85 minutes, a solution of 1,2-bis-(3-bromopropyl)-benzene (8.0 g, 74.98 mmol) in anhydrous THF (25 mL) was added dropwise over 10 minutes, followed by the dropwise addition of DMPU (15 mL). The mixture was stirred at -78°C for a further 1 hour, then slowly warmed to room temperature over the next 2 hours and stirred overnight. The reaction mixture was cooled in an ice bath and hydrolyzed by adding saturated NH4Cl solution (100 mL) and deionized water (100 mL). The layers were separated, and the aqueous layer was converted to ethyl acetate (3 × 1 Extraction was performed with (00 mL). The mixed organic layer was washed with water (100 mL), 1N hydrochloric acid (100 mL), water (100 mL), and saturated sodium chloride solution (100 mL). The organic phase was then dried over MgSO4 and concentrated under vacuum to obtain the crude product (14.0 g) as a red oil. Purification by flash chromatography (silica, hexane / ethyl acetate = 95 / 5) yielded 5-[2-(4-ethoxycarbonyl-4-methylpentyl)-phenyl]-2,2-dimethylpentanoate ethyl ester (8.2 g, 84%, 79% purity by GC) as a pale yellow oil. 1 1H NMR (CDCl3): δ = 7.11 (s, 4 H), 4.10 (q, 4 H, J = 7.0 Hz), 2.5 6 (t, 4 H, J = 7.6 Hz), 1.68 - 1.42 (m, 8 H), 1.23 (t, 6 H, J = 7.0 Hz), 1.16 (s, 16 H). 13 C NMR (CDCl3): δ = 177.95, 140.01, 129.12, 126 .04, 60.34, 42.26, 40.79, 33.11, 26.75, 25.29, 14.41. C 24 H 39 O4(Mon + HRMS calculated value for ) is 391.2848, and the measured value is 391.2846.

[0373] 5,5'-(1,2-phenylene)bis(2,2-dimethylpentanoic acid) (or 5-[2-(4-carboxy-4-methylpentyl)-phenyl]-2,2-dimethylpentanoic acid) A solution of 5-[2-(4-ethoxycarbonyl-4-methylpentyl)-phenyl]-2,2-dimethylpentanoate ethyl ester (8.3 g, 21.25 mmol) and potassium hydroxide (>85%, 4.91 g, 74.38 mmol) in ethanol (20 mL) and water (10 mL) was heated under reflux for 4 hours. After cooling to room temperature, the mixture was diluted with water (50 mL) and concentrated to approximately 60 mL in vacuum. This aqueous solution was extracted with dichloromethane (2 × 30 mL) and then acidified to pH 1 with 1N hydrochloric acid (8 mL). The aqueous layer was extracted with dichloromethane (3 × 30 mL). The mixed organic extract was washed with saturated NaCl solution (30 mL), dried on MgSO4, concentrated in vacuum, and the crude product (5.50 g) was obtained as a white solid / viscous oil. Crude material was crystallized from heptane / dichloromethane at -5°C to obtain a small amount of white crystals, which were washed with cooled heptane (10 mL) and dried under high vacuum (5.05 g, 71%, 98.3% purity by HPLC) (Compound I-61). Mp 108~109°C. Elemental analysis (C 20 H 30 O4): Calculated values: C, 71.82; H, 9.04; Measured values: C, 71.14; H, 9.06. 1H NMR (DMSO-d6): δ = 12.7 - 11.5 (m br, 2 H), 7.11 (s, 4 H), 2.55 (t, 4 H, J = 7.3 Hz), 1.62 - 1.38 (m, 8 H) , 1.09 (s, 12 H). 13 ¹³C NMR (DMSO-d6): δ = 178. 83, 139.69, 128.98, 125.89, 41.25, 40.20, 32.49, 26.57, 25.04. C 20 H 31 O4(Mon + HRM regarding ) S-calculated value: 335.2222, measured value: 335.2232.

[0374] Biological assays Example 15: Antiproliferative effects of compounds I-32, I-61, I-1, and III-1 in Hep3B and Hepa1-6 liver cancer cells. Human liver cancer cells (Hep3B) and mouse liver cancer cells (Hepa1-6) were seeded in 96-well plates at a cell density of 3000 cells / well. For Hep3B cells, Eagle's Minimum Essential Medium (Corning) was used, and for Hepa1-6 cells, Dulbecco's Modified Eagle Medium (DMEM) High Glucose (Gibco) was used. 10% fetal bovine serum (FBS, Gibco) and 1% antibiotic-antimycotic solution (Thermo-Fisher Scientific) were added. The following day, the cells were treated with compounds I-32, I-61, I-1, or III-1 (0.1% of the final concentration of DMSO) at concentrations of 0 (vehicle control), 0.1, 0.5, 1, 5, 10, 30, 50, or 100 μM, and grown at 37°C for 72 hours. On day 5, 10 μL of PrestoBlue® cell viability reagent (Invitrogen) was added to each well, and the plates were incubated at 37°C for a further 1-2 hours. After incubation, the fluorescence signal was measured at excitation / emission wavelengths of 560 / 590 nm using a SpectraMax M5 microplate reader (Molecular Devices).

[0375] The effects of compounds I-32, I-61, I-1, and III-1 on cell proliferation in Hepa1-6 cells are shown in Figures 2A-2D as percentages relative to the vehicle control (DMSO, 0.1% final concentration) (n=4 replicates, single experiment, error bars represent standard deviation). The effects of compounds I-32, I-61, I-1, and III-1 on Hep3B cell proliferation are shown in Figures 3A-3D as percentages relative to the vehicle control (DMSO, 0.1% final concentration) (n=5, single experiment, error bars represent standard deviation).

[0376] Example 16: Anticlonal effects of compounds I-32, I-61, I-1, and III-1 in Hep3B and Hep1-6 liver cancer cells. For Hep3B cells, Eagle's Minimum Essential Medium (Corning) was used, or for Hepa1-6 cells, High Glucose DMEM (Gibco) was used. Liver cancer cell lines Hep3B (human) and Hepa1-6 (mouse) were maintained by supplementing with 10% FBS (Gibco) and 1% Antibiotic-Antimycotic (Thermo-Fisher Scientific). Each cell line was seeded at 1000 cells / well in 12-well plates. The following day, the medium was changed, and the cells were treated for 7 days with compounds I-32, I-61, I-1, or III-1 (final concentration 0.1% DMSO) at concentrations of 0 (vehicle control, 0.1% DMSO), 1, 5, 10, 30, 50, or 100 μM. On day 9, the medium was removed, and the cells were fixed in 10% formalin (500 μl) at room temperature for 10 minutes, washed with 1× PBS, and stained with crystal violet. After 10 minutes, the plates were rinsed three times with tap water to remove excess dye. The plates were dried overnight, and then the number of colonies (>50 cells) in each well was counted using a light microscope, as previously described by Villani LA, et al.

[0377] The effects of compounds I-32, I-61, I-1, and III-1 on clonality in Hepa1-6 cells are shown in Figures 4A-4D as percentages relative to the vehicle control (DMSO, 0.1% final concentration) (n=2, error bars represent standard deviation). The effects of compounds I-32, I-61, I-1, and III-1 on clonality in Hep3B cells are shown in Figures 5A-5D as percentages relative to the vehicle control (DMSO, 0.1% final concentration) (n=2, error bars represent standard deviation).

[0378] Table 1 summarizes the biological results from Examples 15-17. ND = Not measured. [Table 12]

[0379] Example 17: Synergistic effect of an exemplary compound of the present invention with sorafenib or lenvatinib. Combination studies with the compounds of the present invention were conducted to measure the potential synergistic effects of sorafenib or lenvatinib in the presence of compound I-32 or compound I-61. In a separate experiment, ICs for growth inhibition by sorafenib in the absence of the compounds of the present invention and by lenvatinib in the absence of the compounds of the present invention were performed. 50 These levels were measured at 3 μM and 0.5 μM, respectively, in Hep3B cells, and at 5 μM and 30 μM, respectively, in Hepa1-6 cells (data not shown).

[0380] Hep3B (provided by ATCC) or Hepa1-6 (provided by ATCC) cells were seeded in complete medium at a density of 500 cells / well in 96-well plates. On day 2, the culture medium in each well was aspirated and replaced with 100 μl of fresh complete medium. Cells were treated with sorafenib or lenvatinib in a concentration-dependent manner (compound I-32 (100 μM) or compound I-61 (100 μM)) in or out of the presence of the compounds of the present invention, either alone or in combination with sorafenib (3 μM) or lenvatinib (0.5 μM). The cells were then incubated in an incubator for 72 hours. On day 5, 10 μl of Presto Blue (Invitrogen, catalog no. A13261) cell viability reagent was added to each 96-well plate and incubated at 37°C for 1–2 hours. After incubation, fluorescence was measured at excitation / emission wavelengths of 560 / 590 nm. Results are shown as mean ± standard deviation (SD). All bar and line graphs were created using GraphPad Prism 8 software. IC of proliferation 50 The values ​​were calculated using a nonlinear regression model in Graph Pad Prism 8. For each cell type, the combination treatment showed reduced cell proliferation compared to sorafenib or lenvatinib alone. Results for Hep3B cells are shown in Figures 6A-6B, and results for Hepa1-6 cells are shown in Figures 7A-7B.

[0381] Sorafenib and lenvatinib have the following structures. [ka]

[0382] Because further inhibition of cell proliferation was observed in the combination study, the results were analyzed using CompuSyn software (provided by ComboSyn Inc.) to investigate whether there were any synergistic or additive effects on antiproliferative activity. Figures 8A–8D show that both compounds I-32 and I-61 showed synergistic inhibition in the presence of sorafenib or lenvatinib.

Claims

1. Compound of formula (ID): 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. Z １ and Z ２ are each independently, -C(R １Ａ )(R ２Ａ )-(CH ２ ) ｄ -X Ａ or -W-(CH ２ ) ｄ -C(R ３ )(R ４ )-Y, and Each d is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. Each R １Ａ and R ２Ａ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ The R is alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to the carbon atom. １Ａ and R ２Ａ Together with, -C ３ -C ７ Forms a cycloalkyl group, Each R ３ and R ４ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkinyl, -O(C) １ -C ６ Alkyl, phenyl, benzyl, Cl, Br, CN, NO ２ , or CF ３ Either each carbon atom is independently bonded to the carbon atom R ３ and R ４ Together with, -C ３ -C ７ Forms a cycloalkyl group, Q １ and Q ２ However, independently, H, OH, -C １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR １Ａ , -NR １Ａ R ２Ａ , F, Cl, Br, I, -CF ３ , -COR １Ａ , heteroaryl, heterocyclyl, or -V-OH, or each carbon atom independently bonded to the carbon atom Q １ and Q ２ Together, they form heterocyclyl or carbocykyl groups. V is (CH ２ ) ｔ or allerene, t is 0, 1, 2, 3, or 4, Each X Ａ However, independently, H, -OH, -SO ３ H, 【Chemistry 2】 And, Each R ６ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is an alkynyl, and the above-C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The alkynyl is either unsubstituted or has one or two halogens, -OH, -O(C) １ -C ６ Substituted with alkyl or phenyl groups, Each R ７ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is alkinyl, Each W independently has -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) ２ -, or -Se-, Each Y independently becomes -OH, -COOH, -COOR ５ , -SO ３ H, 【Transformation 3】 And, Each R ５ is independently, -C １ -C ６ alkyl, -C ２ -C ６ alkenyl, -C ２ -C ６ alkynyl, phenyl, or benzyl, each of which is unsubstituted or substituted with one or more halogens, -OH, -O(C １ -C ６ alkyl), or a phenyl group, said compound or a pharmaceutically acceptable salt or solvate thereof.

2. Z １ and Z ２ are each independently -C(R １Ａ )(R ２Ａ )-(CH ２ ) ｄ -X Ａ is the compound or pharmaceutically acceptable salt or solvate according to claim 1.

3. Each R １Ａ and R ２Ａ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ A compound or pharmaceutically acceptable salt or solvate according to claim 1 or 2, which is an alkynyl.

4. Each R １Ａ and R ２Ａ However, independently, -C １ -C ３ Alkyl, -C ２ -C ３ Alkenyl, or -C ２ -C ３ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 3, which is an alkynyl.

5. R １Ａ and R ２Ａ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 4, wherein is methyl.

6. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 5, wherein d is 0, 1, 2, or 3.

7. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 6, wherein d is 0 or 1.

8. Compounds of formula (IG): 【Chemistry 4】 or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. Z １ and Z ２ However, independently, -C(R １ ) (Caution ２ )-(CH ２ ) ｃ -X or -W- (CH ２ ) ｃ -C(R ３ ) (Caution ４ ) - Y, Each c is independently 0, 1, 2, or 3. Each R １ and R ２ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ The R is alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to the carbon atom. １ and R ２ Together with, -C ３ -C ７ Forms a cycloalkyl group, Each R ３ and R ４ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkinyl, -O(C) １ -C ６ Alkyl, phenyl, benzyl, Cl, Br, CN, NO ２ , or CF ３ Either each carbon atom is independently bonded to the carbon atom R ３ and R ４ Together with, -C ３ -C ７ Forms a cycloalkyl group, Q １ and Q ２ However, independently, H, OH, -C １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR １Ａ , -NR １Ａ R ２Ａ , F, Cl, Br, I, -CF ３ , -COR １Ａ Q is either a heteroaryl, heterocyclyl, or -V-OH group, or each carbon atom is independently bonded to the carbon atom. １ and Q ２ Together, they form heterocyclyl or carbocykyl groups. Each R １Ａ and R ２Ａ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, phenyl, or benzyl, V is (CH ２ ) ｔ or allerene, t is 0, 1, 2, 3, or 4, Each X and Y independently becomes -OH, -COOH, -COOR ５ , -SO ３ H, 【Transformation 5】 And, Each R ６ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is an alkynyl, and the above-C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The alkynyl is either unsubstituted or has one or two halogens, -OH, -O(C) １ -C ６ Substituted with alkyl or phenyl groups, Each R ７ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is alkinyl, Each W independently has -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) ２ -, or -Se-, Each R ５ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, phenyl, or benzyl, each unsubstituted or containing one or more halogens, -OH, -O(C) １ -C ６ The compound or a pharmaceutically acceptable salt or solvate thereof, which is substituted with an alkyl group or a phenyl group.

9. The compound according to claim 8, wherein p is 2.

10. Compound of formula (ID): 【Transformation 6】 or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 4, 5, 6, or 7. Z １ and Z ２ However, independently, -C(R １ ) (Caution ２ )-(CH ２ ) ｃ -X or -W- (CH ２ ) ｃ -C(R ３ ) (Caution ４ ) - Y, Each c is independently 0, 1, 2, or 3. Each R １ and R ２ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ The R is alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to the carbon atom. １ and R ２ Together with, -C ３ -C ７ Forms a cycloalkyl group, Each R ３ and R ４ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkinyl, -O(C) １ -C ６ Alkyl, phenyl, benzyl, Cl, Br, CN, NO ２ , or CF ３ Either each carbon atom is independently bonded to the carbon atom R ３ and R ４ Together with, -C ３ -C ７ Forms a cycloalkyl group, Q １ and Q ２ However, independently, H, OH, -C １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR １Ａ , -NR １Ａ R ２Ａ , F, Cl, Br, I, -CF ３ , -COR １Ａ , heteroaryl, heterocyclyl, or -V-OH, or each carbon atom independently bonded to the carbon atom Q １ and Q ２ Together, they form heterocyclyl or carbocykyl groups. V is (CH ２ ) ｔ or allerene, t is 0, 1, 2, 3, or 4, Each X and Y independently becomes -OH, -COOH, -COOR ５ , -SO ３ H, 【Transformation 7】 And, Each R ６ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is an alkynyl, and the above-C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The alkynyl is either unsubstituted or has one or two halogens, -OH, -O(C) １ -C ６ Substituted with alkyl or phenyl groups, Each R ７ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is alkinyl, Each W independently has -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) ２ -, or -Se-, Each R ５ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, phenyl, or benzyl, each unsubstituted or containing one or more halogens, -OH, -O(C) １ -C ６ The compound or a pharmaceutically acceptable salt or solvate thereof, which is substituted with an alkyl group or a phenyl group.

11. Compounds of formula (IE) or formula (IF): 【Transformation 8】 or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. Each Z １ and Z ２ However, independently, -C(R １ ) (Caution ２ )-(CH ２ ) ｃ -X or -W- (CH ２ ) ｃ -C(R ３ ) (Caution ４ ) - Y, Each c is independently 0, 1, 2, or 3. Each R １ and R ２ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ The R is alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to the carbon atom. １ and R ２ Together with, -C ３ -C ７ Forms a cycloalkyl group, Each R ３ and R ４ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkinyl, -O(C) １ -C ６ Alkyl, phenyl, benzyl, Cl, Br, CN, NO ２ , or CF ３ Either each carbon atom is independently bonded to the carbon atom R ３ and R ４ Together with, -C ３ -C ７ Forms a cycloalkyl group, Q １ and Q ２ However, independently, H, OH, -C １ -C ６ Alkyl, -O(C) １ -C ６ Alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR １Ａ , -NR １Ａ R ２Ａ , F, Cl, Br, I, -CF ３ , -COR １Ａ Q is either a heteroaryl, heterocyclyl, or -V-OH group, or each carbon atom is independently bonded to the carbon atom. １ and Q ２ Together, they form heterocyclyl or carbocykyl groups. V is (CH ２ ) ｔ or allerene, t is 0, 1, 2, 3, or 4, Each X and Y independently becomes -OH, -COOH, -COOR ５ , -SO ３ H, 【Chemistry 9】 And, Each R ６ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is an alkynyl, and the above-C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The alkynyl is either unsubstituted or has one or two halogens, -OH, -O(C) １ -C ６ Substituted with alkyl or phenyl groups, Each R ７ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is alkinyl, Each W independently has -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) ２ -, or -Se-, Each R ５ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, phenyl, or benzyl, each unsubstituted or containing one or more halogens, -OH, -O(C) １ -C ６ The compound or a pharmaceutically acceptable salt or solvate thereof, which is substituted with an alkyl group or a phenyl group.

12. Z １ and Z ２ However, each independently, -C(R １ ) (Caution ２ )-(CH ２ ) ｃ -X, the compound or pharmaceutically acceptable salt or solvate according to claim 10 or 11 。

13. X is -COOH or -COOR ５ The compound or pharmaceutically acceptable salt or solvate according to any one of claims 10 to 12.

14. Each R １ and R ２ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 10 to 13, which is an alkynyl.

15. Each R １ and R ２ However, independently, -C １ -C ３ Alkyl, -C ２ -C ３ Alkenyl, or -C ２ -C ３ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 10 to 14, which is an alkynyl.

16. R １ and R ２ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 10 to 15, wherein is methyl.

17. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 10 to 16, wherein c is 0 or 1.

18. Z １ and Z ２ One or both of are -W-(CH ２ ) ｃ -C(R ３ ) (Caution ４ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 11, wherein the compound is -Y.

19. R ３ and R ４ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The compound or pharmaceutically acceptable salt or solvate according to claim 18, which is an alkynyl.

20. Y is -COOH or -COOR ５ The compound or pharmaceutically acceptable salt or solvate according to claim 18.

21. R ５ However, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The compound or pharmaceutically acceptable salt or solvate according to claim 20, which is an alkynyl.

22. R ５ However, -C １ -C ３ Alkyl, -C ２ -C ３ Alkenyl, or -C ２ -C ３ The compound or pharmaceutically acceptable salt or solvate according to claim 20, which is an alkynyl.

23. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 8 and 10 to 22, wherein p is 4, 5, 6, or 7.

24. The above compound has the following structure 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 A compound according to claim 11, or a pharmaceutically acceptable salt or solvate thereof, having the above.

25. The above compound has the following structure 【Chemistry 11】 The compound according to claim 10, or a pharmaceutically acceptable salt or solvate thereof, having the above.

26. The above compound has the following structure 【Chemistry 12】 The compound according to claim 8, or a pharmaceutically acceptable salt or solvate thereof, having the above.

27. Compounds of formula (IH): 【Chemistry 13】 or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. Each Z １ and Z ２ However, independently, -C(R １ ) (Caution ２ )-(CH ２ ) ｃ -X, or -W-(CH ２ ) ｃ -C(R ３ ) (Caution ４ ) - Y, Each c is independently 0, 1, 2, or 3. Each R １ and R ２ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ The R is alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to the carbon atom. １ and R ２ Together with, -C ３ -C ７ Forms a cycloalkyl group, Each R ３ and R ４ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkinyl, -O(C) １ -C ６ Alkyl, phenyl, benzyl, Cl, Br, CN, NO ２ , or CF ３ Either each carbon atom is independently bonded to the carbon atom R ３ and R ４ Together with, -C ３ -C ７ Forms a cycloalkyl group, Q is independently -OH, methyl, or methoxy. t is 1, 2, 3, or 4, Each X and Y independently becomes -OH, -COOH, -COOR ５ , -SO ３ H, 【Chemistry 14】 And, Each R ６ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is an alkynyl, and the above-C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The alkynyl is either unsubstituted or has one or two halogens, -OH, -O(C) １ -C ６ Substituted with alkyl or phenyl groups, Each R ７ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is alkinyl, Each W independently has -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) ２ -, or -Se-, Each R ５ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, phenyl, or benzyl, each unsubstituted or containing one or more halogens, -OH, -O(C) １ -C ６ The compound or a pharmaceutically acceptable salt or solvate thereof, which is substituted with an alkyl group or a phenyl group.

28. The compound according to claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of the following formulas: (IJ), (IK), or (IL): 【Chemistry 15】

29. The compound according to claim 28, wherein t is 1, 2, or 3.

30. Z １ and Z ２ However, each independently, -C(R １ ) (Caution ２ )-(CH ２ ) ｃ -X, which is the compound or pharmaceutically acceptable salt or solvate according to any one of claims 27 to 29.

31. X is -COOH or -COOR ５ The compound or pharmaceutically acceptable salt or solvate according to any one of claims 27 to 30.

32. Each R １ and R ２ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 27 to 31, which is an alkynyl.

33. Each R １ and R ２ However, independently, -C １ -C ３ Alkyl, -C ２ -C ３ Alkenyl, or -C ２ -C ３ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 27 to 32, which is an alkynyl.

34. R １ and R ２ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 27 to 33, wherein is methyl.

35. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 27 to 34, wherein c is 0 or 1.

36. The aforementioned compound is one of the following structures 【Chemistry 16-1】 【Chemistry 16-2】 【Chemistry 16-3】 【Chemistry 16-4】 【Chemistry 16-5】 【Chemistry 16-6】 【Chemistry 16-7】 【Chemistry 16-8】 【Chemistry 16-9】 【Chemistry 16-10】 【Chemistry 16-11】 【Chemistry 16-12】 [Chemistry 16-13] [Chemistry 16-14] 【Chemistry 16-15】 【Chemistry 16-16】 [Chemistry 16-17] [Chemistry 16-18] [Chemistry 16-19] [Chemistry 16-20] [Chemistry 16-21] [Chemistry 16-22] [Chemistry 16-23] [Chemistry 16-24] [Chemistry 16-25] [Chemistry 16-26] [Chemistry 16-27] [Chemistry 16-28] [Chemistry 16-29] 【Chemistry 16-30】 【Chemistry 16-31】 [Chemistry 16-32] [Chemistry 16-33] [Chemistry 16-34] 【Chemistry 16-35】 [Chemistry 16-36] [Chemistry 16-37] [Chemistry 16-38] [Chemistry 16-39] [Chemistry 16-40] 【Chemistry 16-41】 [Chemistry 16-42] [Chemistry 16-43] [Chemistry 16-44] [Chemistry 16-45] [Chemistry 16-46] [Chemistry 16-47] [Chemistry 16-48] [Chemistry 16-49] 【Chemistry 16-50】 【Chemistry 16-51】 [Chemistry 16-52] [Chemistry 16-53] [Chemistry 16-54] 【Chemistry 16-55】 [Chemistry 16-56] [Chemistry 16-57] [Chemistry 16-58] The compound according to claim 27, or a pharmaceutically acceptable salt or solvate thereof, having the above.

37. A composition comprising an effective amount of a compound, a pharmaceutically acceptable salt, or a solvate of a compound according to any one of claims 1 to 36, and a pharmaceutically acceptable carrier or vehicle.

38. (i) Compounds of formula (IA) in effective amounts: 【Chemistry 17】 or a pharmaceutically acceptable salt or solvate thereof, Each p is independently 1, 2, 3, 4, 5, 6, or 7. Z １ and Z ２ However, independently, -C(R １ ) (Caution ２ )-(CH ２ ) ｃ -COOH or -C(R) １ ) (Caution ２ )-(CH ２ ) ｃ - COOR ５ And, Each c is independently 0, 1, 2, or 3. Each R １ and R ２ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ The R is alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to the carbon atom. １ and R ２ Together with, -C ３ -C ７ Forms a cycloalkyl group, Each R ５ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, phenyl, or benzyl, each unsubstituted or containing one or more halogens, -OH, -O(C) １ -C ６ A compound or a pharmaceutically acceptable salt or solvate thereof, which is substituted with an alkyl group or a phenyl group, (ii) A composition comprising a pharmaceutically acceptable carrier or vehicle.

39. Each R １ and R ２ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenil, also Ha-C ２ -C ６ The composition according to claim 38, wherein the component is alkynyl.

40. Each R １ and R ２ However, independently, -C １ -C ３ Alkyl, -C ２ -C ３ Alkenyl, or -C ２ -C ３ The composition according to claim 38, wherein the component is alkynyl.

41. R １ and R ２ The composition according to any one of claims 38 to 40, wherein is methyl.

42. The composition according to any one of claims 38 to 41, wherein c is 0 or 1.

43. R ５ However, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The composition according to any one of claims 38 to 42, wherein the composition is alkynyl.

44. R ５ However, -C １ -C ３ Alkyl, -C ２ -C ３ Alkenyl, or -C ２ -C ３ The composition according to any one of claims 38 to 43, wherein the composition is alkynyl.

45. The above compound has the following structure [Chemistry 18] The composition according to claim 38, or having a pharmaceutically acceptable salt or solvate thereof.

46. Compound of formula (II): 【Chemistry 19】 or a pharmaceutically acceptable salt or solvate thereof, Each R １ and R ２ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ The R is alkynyl, phenyl, or benzyl, or each carbon atom is independently bonded to the carbon atom. １ and R ２ Together with, -C ３ -C ７ Forms a cycloalkyl group, Each n is independently 0, 1, 2, or 3. Each m is independently 1, 2, 3, 4, 5, 6, 7, 8, or 9. X is -C(=O)-, -CHR ３ -eno-CH-CH ２ (OR ３ )-, -O-, -S-, -S(=O)-, -S(O) ２ -, -NR ３ -, -N(OH)-, -N(→O)-, or -Se- R ３ However, H, -OH, -O(C) １ -C ６ Alkyl), -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkinyl, -C ３ -C ７ Cycloalkyl, C ４ -C ７ Cycloalkenyl, C ５ -C ８ Cycloalkynyl, phenyl, or benzyl, each -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkinyl, -C ３ -C ７ Cycloalkyl, C ４ -C ７ Cycloalkenyl, C ５ -C ８ Cycloalkynyl, phenyl, and benzyl are either unsubstituted or contain one or more halogens, -CN, or -NO ２ , or -CF ３ Substituted with the base, Each Y independently has -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) ２ -, or -Se-, Each Z independently corresponds to -OH, -COOH, -COOR ５ , -SO ３ H, -SO ３ R ５ , 【Chemistry 20】 And, Each R ５ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, phenyl, or benzyl, each unsubstituted or containing one or more halogens, -OH, -O(C) １ -C ６ Substituted with alkyl or phenyl groups, Each R ６ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is an alkynyl, and the above-C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The alkynyl is either unsubstituted or has one or two halogens, -OH, -O(C) １ -C ６ Substituted with alkyl or phenyl groups, Each R ７ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The compound or a pharmaceutically acceptable salt or solvate thereof, which is an alkynyl compound.

47. X is -C(=O)-, -CHR ３ The compound or pharmaceutically acceptable salt or solvate according to claim 46, wherein the compound is -, -O-, -S-, -S(=O)-, or Se.

48. R ３ However, H, -OH, -O(C) １ -C ３ Alkyl), or -C １ -C ３ A compound or pharmaceutically acceptable salt or solvate according to claim 46 or 47, which is alkyl.

49. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 46 to 48, wherein each Y is independently -O- or -S-.

50. Each R １ and R ２ However, independently, H, -C １ -C ３ Alkyl, -C ２ -C ３ Alkenyl, or -C ２ -C ３ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 46 to 49, which is an alkynyl.

51. Each R １ and R ２ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 46 to 50, wherein the compound is independently H or methyl.

52. Each Z independently becomes -COOH or -COOR ５ The compound or pharmaceutically acceptable salt or solvate according to any one of claims 46 to 51.

53. Each R ５ However, independently, -C １ -C ３ Alkyl, -C ２ -C ３ Alkenyl, or -C ２ -C ３ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 46 to 52, which is an alkynyl.

54. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 46 to 51, wherein Z is -COOH.

55. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 46 to 54, wherein each n is independently 0, 1, or 2.

56. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 46 to 55, wherein n is 1.

57. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 46 to 56, wherein each m is independently 3, 4, 5, or 6.

58. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 46 to 57, wherein each m is independently 4 or 5.

59. The following structure 【Chemistry 21-1】 【Chemistry 21-2】 The compound according to claim 46, or a pharmaceutically acceptable salt or solvate thereof, having the above.

60. A composition comprising an effective amount of a compound, a pharmaceutically acceptable salt, or a solvate of a compound according to any one of claims 46 to 59, and a pharmaceutically acceptable carrier or vehicle.

61. Compound of formula (IIIA): 【Chemistry 22】 or a pharmaceutically acceptable salt or solvate thereof, R １ and R ２ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, phenyl, or benzyl, or R １ and R ２ However, together with the bonded carbon atom, -C ３ -C ７ Forms a cycloalkyl group, Each m is independently 2, 3, 4, 5, 6, or 7. Each n is independently 0, 1, 2, 3, 4, or 5. Each q is 0, 1, 2, 3, or 4. X is -O-, -S-, -S(=O)-, -S(O) ２ -, -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-, Z １ and Z ２ However, -C １ -C ６ Alkyl, -COOH, -COOR ５ , -SO ３ R ５ , 【Chemistry 23】 And, During the ceremony, Z １ and Z ２ They are the same, Each R ５ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, phenyl, or benzyl, each unsubstituted or containing one or more halogens, -OH, -O(C) １ -C ６ Substituted with alkyl or phenyl groups, Each R ６ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is an alkynyl, and the above-C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The alkynyl is either unsubstituted or has one or two halogens, -OH, -O(C) １ -C ６ Substituted with alkyl or phenyl groups, Each R ７ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The compound or a pharmaceutically acceptable salt or solvate thereof, which is an alkynyl compound.

62. Compounds of formula (IIIB): 【Chemistry 24】 or a pharmaceutically acceptable salt or solvate thereof, R １ and R ２ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, phenyl, or benzyl, or R １ and R ２ However, together with the bonded carbon atom, -C ３ -C ７ Forms a cycloalkyl group, Each m is independently 2, 3, 4, 5, 6, or 7. Each n is independently 0, 1, 2, 3, 4, or 5. Each q is 0, 1, 2, 3, or 4. X is -S-, -S(=O)-, -S(O) ２ -, -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-, Z １ and Z ２ However, independently, -C １ -C ６ Alkyl, -OH, -COOH, -COOR ５ , -SO ３ H, -SO ３ R ５ , 【Chemistry 25】 And, Each R ５ However, independently, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, phenyl, or benzyl, each unsubstituted or containing one or more halogens, -OH, -O(C) １ -C ６ Substituted with alkyl or phenyl groups, Each R ６ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ It is an alkynyl, and the above-C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The alkynyl is either unsubstituted or has one or two halogens, -OH, -O(C) １ -C ６ Substituted with alkyl or phenyl groups, Each R ７ However, independently, H, -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, or -C ２ -C ６ The compound or a pharmaceutically acceptable salt or solvate thereof, which is an alkynyl compound.

63. Each Z １ and Z ２ However, independently, -OH, -COOH, or -COOR ５ The compound or pharmaceutically acceptable salt or solvate according to claim 61 or 62.

64. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 61 to 63, wherein each n is independently 0 or 1.

65. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 61 to 63, wherein n is 0.

66. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 61 to 63, wherein n is 1.

67. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 61 to 66, wherein each m is independently 4, 5, or 6.

68. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 61 to 66, wherein m is 4.

69. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 61 to 66, wherein m is 5.

70. A compound or pharmaceutically acceptable salt or solvate according to any one of claims 61 to 66, wherein m is 6.

71. Each Z １ and Z ２ However, independently, -C １ -C ６ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 61 to 70, which is alkyl.

72. R １ and R ２ However, together with the bonded carbon atom, -C ３ -C ７ A compound or pharmaceutically acceptable salt or solvate according to any one of claims 61 to 71 that forms a cycloalkyl group.

73. The following structure 【Chemistry 26】 The compound according to claim 61, or a pharmaceutically acceptable salt or solvate thereof, having the above.

74. A composition comprising an effective amount of a compound, a pharmaceutically acceptable salt, or a solvate of a compound according to any one of claims 61 to 73, and a pharmaceutically acceptable carrier or vehicle.

75. The composition according to any one of claims 37 to 45, 60, and 74, further comprising another pharmaceutically active agent.

76. The composition according to claim 75, wherein the other pharmaceutically active agent is a statin, thiazolidinedione or fibrate, bile acid binding resin, niacin, anti-obesity drug, hormone, thyrophostine, sulfonylurea-based drug, biguanide, α-glucosidase inhibitor, apolipoprotein A-I agonist, apolipoprotein E agonist, phosphodiesterase type-5 inhibitor, cardiovascular drug, HDL-upperminator, HDL enhancer, apolipoprotein A-I gene or protein agonist, apolipoprotein A-IV gene or protein agonist, apolipoprotein gene agonist, ATP citrate lyase regulator, ATP citrate lyase allosteric inhibitor, acetyl-CoA carboxylase regulator, or acetyl-CoA carboxylase allosteric inhibitor.

77. The composition according to claim 75, wherein the other pharmaceutically active agent is a statin, and the statin is lovastatin.

78. The other pharmaceutically active agents mentioned above include sorafenib, taxol, cenicliviroc, ellafibranolic acid, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, nivolumab, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, IMM-124E, RG-125, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegberfermin, PF-05231023, obeticholic acid, silofexol, and tropifexol. , EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, ND-L02-s0201 / BMS-986263, Borixivat, Amlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Loflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogritazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI The composition according to claim 75, wherein the composition is 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, narumafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, sarogritazal magnesium, borixivat, solithromycin, 99m technetium-mebrophenine, tropifexol, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, or ceradelpar.

79. The composition according to claim 75, wherein the other pharmaceutically active agent is an anticancer agent, an immunotherapy agent, an oncovirus, or a vaccine.

80. The aforementioned anticancer drugs are sorafenib, taxol, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, senicliviroc, ellafibranol, eicosapentaenoic acid, garnicertib, LY2109761, LDE225, and filsokos. Tat, Aparalenone, Metformin, Leucine-Metformin-Sildenafil combination, Vitamin E, Cysteamine, Seroncertib, Losartan, RO5093151, Prazigastat, Sitagliptin, Vildagliptin, NGM282, Pegberfermin, PF-05231023, Oveticolic acid, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Lila Glutide, Semaglutide, Exenatide, Borixivat, Amlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Roflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Saroglitazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI 1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Narmafen, Pentamidine, Berberine, L-Carnitine, EYP001a, Silymarin, Myricolinant, Ursodeoxycholic Acid, Metadoxine, Ezetimibe, Cystadan, L-Alanine, Sarogritazal Magnesium, Borixibat, Elafibranol, Narmefen, Solithromycin, 99m Technetium-Mebrophenine, S-Adenosylmethionine, Pentoxifylline, Oresoxime, AKR-001, Seradelpar, Physogatinib, Doxorubicin, Cabo The composition according to claim 79, wherein the composition is zantinib, deferoxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, or zofilcrib citrate.

81. The aforementioned immunotherapy agents include pembrolizumab, avelumab, durvalumab, nivolumab, semiprimab, ABX196, cintilimab, camrelizumab, spartalizumab, tripalimab, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305, and A The composition according to claim 79, wherein the composition is scrimbakumab, LioCyx, citravatinib, cytokine-based biological agent IRX-2, bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SRF388, ET1402L1-CART, glypican 3-specific chimeric antigen receptor expressing T cells (CAR-T cells), CD147-targeted CAR-T cells, NKG2D-based CAR-T cells, or novel antigen-reactive T cells.

82. The composition according to claim 79, wherein the tumor virus is Pexastimogene Devacirepvec or Talimogene Laherparepvec.

83. The composition according to claim 79, wherein the vaccine is GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase peptide vaccine, or IMA970A.

84. The composition according to claim 75, wherein the other pharmaceutically active agent is novantrone, prednisone, pixantrone, losoxantrone, cytidine-phosphate-guanosine (CpG)DNA, paclitaxel, olaxol, MTL-CEBPA, ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241, U3-1784, avadomide, INCAGN01949, or CMP-001.

85. A method for treating or preventing a disease, comprising administering an effective amount of a compound, pharmaceutically acceptable salt or solvate of a compound according to any one of claims 1 to 36, 46 to 59, and 61 to 73 to a subject in need thereof, wherein the disease is a liver disease or abnormal hepatic condition, cancer, malignant or benign tumor of the lung, liver, gallbladder, bile duct or gastrointestinal tract, intrahepatic or extrahepatic bile duct disease, lipoprotein disorder, lipid and metabolic disorder, cirrhosis, fibrosis, glucose metabolic disorder, cardiovascular or related vascular disorder, fatty degeneration, disease resulting from fibrosis or cirrhosis, disease associated with advanced inflammation, hepatocyte ballooning, peroxisome proliferator-activated receptor-associated disorder, ATP citrate lyase disorder, acetyl coenzyme A carboxylase disorder, obesity, pancreatitis, or kidney disease.

86. The method according to claim 85, wherein the disease is cancer, and the cancer is hepatocellular carcinoma (HCC), HCC with cirrhosis, HCC without cirrhosis, cholangiocarcinoma, colorectal cancer, biliary tract cancer, or lung cancer.

87. The disease is cancer, and the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, lymphangiosarcoma, synoviomas, mesothelioma, primary myelosarcoma, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, gastric cancer, oral cancer, nasal cancer, laryngeal cancer, squamous cell carcinoma, basal cell carcinoma Horticoid carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminomas, embryonic carcinoma, nephroblastoma, cervical cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, epithelial carcinoma, glioma, glioblastoma, pleomorphic carcinoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymocyteoma, pineal glandoma, hemangioblastoma, acoustic neuroma, oligodendroglioma Meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute granulocytic leukemia (AML), acute promyelocytic leukemia (APL), acute monocytic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute anaplastic leukemia, chronic myeloid leukemia The method according to claim 85, wherein the condition is (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, multiple myeloma, lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, myeloid leukemia, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, Waldenstrom macroglobulinemia, H chain disease, gastrointestinal cancer, head and neck cancer, hematopoietic carcinoma, or polycythemia vera.

88. The method according to claim 85, wherein the disease is a lipid and metabolic disorder, and the lipid and metabolic disorder is characterized by high C-reactive protein (CRP), high serum amyloid A (SAA), high alanine aminotransferase (ALT), high aspartate aminotransferase (AST), high alkaline phosphatase (ALP), high gamma glutamyltransferase (GGT), high low-density lipoprotein (LDL), high very low-density lipoprotein (VLDL), high apolipoprotein B (ApoB) and ApoB / Lp(a) (lipoprotein(a)) ratio, high total cholesterol, low high-density lipoprotein (HDL), or high non-HDL cholesterol in the plasma or serum of the subject, or by high glucose and insulin resistance in the subject having diabetes.

89. The method according to claim 85, wherein the disease is a lipid and metabolic disorder, and the lipid and metabolic disorder is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or alcoholic steatohepatitis (ASH).

90. The method according to claim 85, wherein the disease is a glucose metabolism disorder, and the glucose metabolism disorder is type 1 diabetes or type 2 diabetes.

91. The concentration in the target plasma or serum, i.e., the C-reactive protein (C) of the target. RP concentration, serum amyloid A (SAA) concentration, alanine aminotransferase (ALT) concentration, aspartate aminotransferase (AST) concentration, alkaline phosphatase (ALP) concentration, gamma glutamyltransferase (GGT) concentration, serum creatinine concentration, 7α-hydroxy-4-cholesten-3-one (C4) concentration, protein:creatinine ratio, creatine kinase concentration, angiopoietin-like protein 3 concentration, angiopoietin-like protein 4 concentration, angiopoietin-like protein 8 concentration, fibrinogen concentration A method for reducing total cholesterol concentration, low-density lipoprotein cholesterol concentration, low-density lipoprotein concentration, very low-density lipoprotein cholesterol concentration, very low-density lipoprotein concentration, non-HDL cholesterol concentration, non-HDL concentration, apolipoprotein B concentration, lipoprotein (a) concentration, or serum triglyceride concentration, the method comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, or solvate of a compound according to any one of claims 1 to 36, 46 to 59, and 61 to 73.

92. A method for reducing the triglyceride concentration in the liver of a subject, comprising administering to the subject in need of such reduction an effective amount of a compound, pharmaceutically acceptable salt or solvate of a compound according to any one of claims 1 to 36, 46 to 59, and 61 to 73.

93. A method for increasing the concentration of high-density lipoprotein cholesterol or high-density lipoprotein in the plasma or serum of a subject, comprising administering to the subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt or solvate of a compound according to any one of claims 1 to 36, 46 to 59, and 61 to 73.

94. A method for treating a disease, comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt or solvate of a compound according to any one of claims 1 to 36, 46 to 59, and 61 to 73, wherein the disease is a gastrointestinal disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), or an autoimmune disease.

95. The method according to claim 94, wherein the disease is an inflammatory bowel disease, and the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

96. The method according to claim 94, wherein the disease is an autoimmune disease, and the autoimmune disease is systemic lupus erythematosus.

97. A method for regressing, reducing the rate of progression of, or inhibiting the progression of fibrosis, hepatocyte ballooning, or inflammation of the liver, comprising administering to a subject in need thereof a compound, pharmaceutically acceptable salt, or solvate of any one of the compounds described in claims 1 to 36, 46 to 59, and 61 to 73.

98. A method for inhibiting, reducing, or delaying the development of lipid synthesis, hepatic steatosis, hepatocyte ballooning and inflammation, hepatic fibrosis, pulmonary fibrosis, or cirrhosis in a target, comprising administering to the target in need of such treatment an effective amount of a compound, pharmaceutically acceptable salt, or solvate of a compound according to any one of claims 1 to 36, 46 to 59, and 61 to 73.

99. A method for increasing the HDL concentration in the serum or plasma of a subject, comprising administering to the subject in need of such increase an effective amount of a compound, pharmaceutically acceptable salt or solvate of a compound according to any one of claims 1 to 36, 46 to 59, and 61 to 73.

100. A method for inhibiting NF-κB or astrocytocyte activation, comprising administering to a subject requiring such inhibition an effective amount of a compound, pharmaceutically acceptable salt or solvate of a compound according to any one of claims 1 to 36, 46 to 59, and 61 to 73.

101. A method for activating PPAR (peroxisome proliferator-activated receptor) in a subject, comprising administering to the subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt or solvate of a compound according to any one of claims 1 to 36, 46 to 59, and 61 to 73.

102. A method for modulating, directly inhibiting, or allosterically inhibiting ATP citrate lyase in a subject, comprising administering to the subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, or solvate of a compound according to any one of claims 1 to 36, 46 to 59, and 61 to 73.

103. A method for modulating, directly inhibiting, or allosterically inhibiting acetyl-CoA carboxylase 1 or acetyl-CoA carboxylase 2 in a subject, comprising administering to the subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, or solvate of a compound according to any one of claims 1 to 36, 46 to 59, and 61 to 73.

104. A method for reducing the fat or cholesterol content of livestock meat or poultry eggs, comprising administering to the livestock or poultry an effective amount of a compound, pharmaceutically acceptable salt or solvate of any one of the compounds described in claims 1 to 36, 46 to 59, and 61 to 73.

105. A method for treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of the composition according to any one of claims 37-45, 60, and 74, wherein the disease is cancer, lipid and metabolic disorders, liver disorders, cirrhosis, fibrosis, glucose metabolism disorders, peroxisome proliferator-activated receptor-associated disorders, malignant or benign tumors of the lungs, liver, biliary tract and gastrointestinal tract, ATP citrate lyase disorders, acetyl coenzyme A carboxylase disorders, obesity, pancreatitis, kidney disease, liver inflammation, or lung inflammation.

106. The method according to any one of claims 85 to 105, further comprising administering an effective amount of another pharmaceutically active agent.

107. The method according to claim 106, wherein the other pharmaceutically active agent is a statin, thiazolidinedione or fibrate, bile acid binding resin, niacin, anti-obesity drug, hormone, thyrophostine, sulfonylurea-based drug, biguanide, α-glucosidase inhibitor, apolipoprotein A-I agonist, apolipoprotein E agonist, phosphodiesterase type-5 inhibitor, cardiovascular drug, HDL-upperminator, HDL enhancer, apolipoprotein A-I gene regulator, apolipoprotein A-IV gene regulator, apolipoprotein gene regulator, ATP citrate lyase regulator, ATP citrate lyase allosteric inhibitor, acetyl-CoA carboxylase regulator, or acetyl-CoA carboxylase allosteric inhibitor.

108. The method according to claim 106, wherein the other pharmaceutically active agent is a statin, and the statin is lovastatin.

109. The other pharmaceutically active agents mentioned above include sorafenib, taxol, carotuximab, and pembrol. The method according to claim 106, wherein the agent is zumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, semiprimab, ABX196, a T-cell receptor (TCR) immunotherapy agent, TBI-302, namodenoson, MM-310, an oncolytic virus for tumor injection or a recombinant oncolytic virus, or an immunomodulatory gene therapy agent.

110. Other pharmaceutically active agents include cenicliviroc, elafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, nivolumab, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, IMM-124E, RG-125, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegberfermin, PF-05231023, obeticholic acid, silofexol, tropifexol, and EDP. -305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, ND-L02-s0201 / BMS-986263, Borixivat, Amlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Roflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogritazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI The method according to claim 106, wherein the active ingredient is 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, narumafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricolinant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, sarogritazal magnesium, borixivat, solithromycin, 99m technetium-mebrophenine, tropifexol, S-adenosylmethionine, pentoxifylline, oresoxime, AKR-001, or ceradelpar.

111. The method according to claim 106, wherein the other pharmaceutically active agent is an anticancer agent, an immunotherapy agent, an oncovirus, or a vaccine.

112. The aforementioned anticancer drugs include sorafenib, taxol, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, senicliviroc, ellafibranol, eicosapentaenoic acid, garnicertive, LY2109761, LDE225, filsocostat, aparalenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, ceroncertib, losartan, RO5093151, prazigastat, sitagliptin, vildagliptin, NGM282, pegberfermin, PF-05231023, and oveticol. Acid, Silofexol, Tropifexol, EDP-305, INT-767, Galactoarabino-Rhamnogalacturonate, Liraglutide, Semaglutide, Exenatide, Borixivat, Amlexanox, PF-06835919, Leptin, Metreleptin, Simtuzumab, Tipercast, Ortipraz, MSDC-0602K, ASP9831, Loflumilast, Elafibranol, Pioglitazone, Rosiglitazone, Fenofibrate, Sarogritazal, Ranifibranol, Aramcol, Ipragliflozin, Dapagliflozin, Empagliflozin, BI 1467335, Rosuvastatin, Atorvastatin, Pitavastatin, VK2809, MGL-3196, Narmafen, Pentamidine, Berberine, L-Carnitine, EYP001a, Silymarin, Myricolinant, Ursodeoxycholic Acid, Metadoxine, Ezetimibe, Cystadan, L-Alanine, Sarogritazal Magnesium, Borixivat, Elafibranol, Narmefen, Solithromycin, 99m Technetium-Mebrophenine, S-Adenosylmethionine, Pentoxifylline, Oresoxime, AKR-001, Seradelpar, Physogatinib, Doxorubicin, Cabozantinib, Def The method according to claim 106, wherein the present agent is eroxamine, itacitinib, thiauranib, SF1126, anlotinib, P1101, vallitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanicertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrhodostat, copanlisib, MIV-818, bororanib, RO7070179, axitinib, sunitinib, or zofilcrib citrate.

113. The aforementioned immunotherapy agents include pembrolizumab, avelumab, durvalumab, nivolumab, semiprimab, ABX196, cintilimab, camrelizumab, spartalizumab, tripalimab, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305, and A The method according to claim 106, wherein the T cells are scrimbakumab, LioCyx, citravatinib, cytokine-based biologic IRX-2, bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SRF388, ET1402L1-CART, glypican 3-specific chimeric antigen receptor expressing T cells (CAR-T cells), CD147-targeted CAR-T cells, NKG2D-based CAR-T cells, or novel antigen-reactive T cells.

114. The method according to claim 106, wherein the tumor virus is Pexastimogene Devacirepvec or Talimogene Laherparepvec.

115. The method according to claim 106, wherein the vaccine is GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase peptide vaccine, or IMA970A.

116. The method according to claim 106, wherein the other pharmaceutically active agent is novantrone, prednisone, pixantrone, losoxantrone, cytidine-phosphate-guanosine (CpG)DNA, paclitaxel, olaxol, MTL-CEBPA, ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241, U3-1784, avadomide, INCAGN01949, or CMP-001.

117. The method according to any one of claims 85 to 116, further comprising administering radiotherapy to the subject.

118. The method according to claim 117, wherein the radiotherapy is gamma-ray radiotherapy or X-ray radiotherapy.

119. The method according to claim 117 or 118, wherein the radiotherapy is administered via a radiotherapy device.

120. The method according to any one of claims 117 to 119, wherein the radiotherapy is administered simultaneously with, before, or after the administration of, the compound, a pharmaceutically acceptable salt, or a solvate.

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