RU2839725C2 - Functionalised mono- and dicarboxylic acids with long hydrocarbon chain and use thereof for preventing or treating diseases - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: group of inventions relates to organic chemistry and includes 6,6'-(1,4-phenylene)bis(2,2-dimethylhexanoic acid), its pharmaceutically acceptable salts, compositions based thereon, use, methods of treatment and a method of inhibiting.

EFFECT: disclosed is 6,6'-(1,4-phenylene)bis(2,2-dimethylhexanoic acid), used for the treatment of hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis and inhibition, reduction or delay of hepatic fibrosis.

22 cl, 32 dwg, 1 tbl, 17 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[01] This application claims priority to U.S. Provisional Application No. 62/878,852, filed July 26, 2019, and U.S. Provisional Application No. 62/901,739, filed September 17, 2019, the disclosures of each of which are incorporated herein by reference in their entireties.

AREA OF TECHNOLOGY

[02] The present invention provides compounds of formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (II), (III), (IIIA), and (IIIB), and pharmaceutically acceptable salts and solvates thereof, and compositions thereof. The present invention further provides methods for preventing or treating a disease, including, but not limited to, a liver disease or pathological condition of the liver; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gallbladder, bile duct, or gastrointestinal tract; a disease of the intra- and extrahepatic bile ducts; a disorder of lipoprotein metabolism; lipid and metabolic disorders; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular disease or a vascular disorder related thereto; a disease resulting from steatosis, fibrosis, or cirrhosis; disease associated with increased inflammation (such as liver inflammation or pneumonia); hepatocyte ballooning; peroxisome proliferator-activated receptor-associated disease; ATP-citrate lyase disorder; acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis or kidney disease.

LEVEL OF TECHNOLOGY

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

[04] Patients with type IIb hyperlipidemia are at high risk of developing NAFLD and nonalcoholic steatohepatitis (NASH), which may result from excess production and accumulation of triglycerides in the liver. Elevated levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides are associated with mixed dyslipidemia, including type IIb hyperlipidemia, which is characterized by elevated levels of apolipoprotein B, very low-density lipoprotein cholesterol (VLDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and small dense low-density lipoprotein (LDL-C) in addition to elevated levels of LDL-C and triglycerides.

[05] Current treatment options for type IIb hyperlipidemia are limited. While statins can be effective in lowering LDL-C and reducing inflammation, they are generally not very effective in lowering triglyceride concentrations. In addition, high-dose statin therapy is often poorly tolerated because it can cause muscle pain (myalgia) and increase the patient’s risk of serious muscle toxicity such as rhabdomyolysis. Additionally, commonly used triglyceride-lowering agents given in combination with statins are often poorly tolerated. Fibrates are known to have drug-drug interactions when given with statins, resulting in elevated statin blood levels, myalgia, increased risk of muscle toxicity, and increased safety concerns. Indeed, interactions between the statin Baycol (cerivastatin) and the fibrate gemfibrozil have resulted in severe muscle toxicity and death, raising safety concerns that led to Baycol being withdrawn from the market in the United States. Fish oil, which is used to lower triglyceride levels, must be taken several times a day and can leave a fish oil taste, cause burping, or regurgitation. Niacin causes hot flashes, particularly when given in combination with statins.

[06] Hepatocellular adenomas are benign neoplasms of the liver whose genetics and pathophysiology are not fully understood. These lesions pose a diagnostic and therapeutic challenge, and treatment options after resection are difficult. Bile duct adenomas pose a similar therapeutic challenge. Adenomas of the digestive system are sporadic neoplasms arising from the glandular epithelium of the stomach, small intestine, bile ducts, colon, and rectum.

[07] Gastrointestinal (digestive) cancers are cancers that affect the gastrointestinal tract and other organs of the digestive system. Gastrointestinal stromal tumor (GIST) is a rare type of sarcoma that forms throughout the gastrointestinal tract, but most often begins in the stomach or small intestine. The etiology of digestive cancers is closely related to chronic organ inflammation, and through several histopathological stages they become dependent on the affected organ. In the case of gastrointestinal cancers or GISTs, surgery will likely be recommended to remove the tumor and/or help maintain normal function. Other treatment options include radiation therapy, chemotherapy, hormonal therapy, or targeted therapy.

[08] There is therefore a need for a safe and effective therapy for the treatment or prevention of cancer (such as gastrointestinal cancer, hepatocellular carcinoma, or cholangiocarcinoma); malignant or benign tumor of the lung, liver, gallbladder, bile duct, or gastrointestinal tract; liver disease or liver abnormality, intra- or extrahepatic bile duct disease; lipoprotein metabolism disorders; lipid and metabolic disorders; cirrhosis; fibrosis; glucose metabolism disorders; cardiovascular disease or a related vascular disorder; disease resulting from steatosis, fibrosis, or cirrhosis; disease associated with increased inflammation (such as hepatitis B or pneumonia); hepatocyte ballooning; peroxisome proliferator-activated receptor-related disease; ATP-citrate lyase activity disorder; disorders of acetyl-coenzyme A carboxylase activity; obesity; pancreatitis or kidney disease.

[09] ESSENCE OF THE INVENTION

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

[011] The present invention also provides compositions comprising i) an effective amount of a compound of the invention and ii) a pharmaceutically acceptable carrier or excipient (each composition being a “composition of the invention”).

[012] The present invention further provides methods for treating or preventing a disease comprising administering to a subject in need thereof an effective amount of a compound of the invention, wherein the disease is a liver disease or pathological condition of the liver; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gallbladder, bile duct, or gastrointestinal tract; an intra- or extrahepatic bile duct disease; a lipoprotein metabolism disorder; lipid and metabolic disorders; cirrhosis; fibrosis; a glucose metabolism disorder; a cardiovascular disease or a related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease associated with increased inflammation (such as liver inflammation or lung inflammation); hepatocyte ballooning; a peroxisome proliferator-activated receptor-associated disease; ATP citrate lyase deficiency; acetyl coenzyme A carboxylase deficiency; obesity; pancreatitis or kidney disease.

[013] The present invention further provides methods for treating or preventing a disease, wherein the disease is cancer, lipid and metabolic disorders, liver disease, cirrhosis, fibrosis, glucose metabolism disorder, peroxisome proliferator-activated receptor-associated disease, malignant or benign tumor of the lung, liver, bile duct and gastrointestinal tract, ATP citrate lyase activity disorder, acetyl-coenzyme A carboxylase activity disorder, obesity, pancreatitis, kidney disease, hepatocyte ballooning, liver inflammation or lung inflammation.

[014] The present invention further provides methods for reducing in the blood plasma or serum of a subject a C-reactive protein (CRP) concentration, a serum amyloid A (SAA) concentration, alanine aminotransferase (ALT) concentration, aspartate aminotransferase (AST) concentration, alkaline phosphatase (ALP) concentration, gamma-glutamyl transferase (GGT) concentration, serum creatinine concentration, 7α-hydroxy-4-cholesten-3-one (C4) concentration, protein to creatinine ratio, creatine kinase concentration, angiopoietin-like protein 3 concentration, 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 concentration cholesterol, non-HDL concentration, apolipoprotein B concentration, lipoprotein(a) concentration, or serum triglyceride concentration, wherein the methods comprise administering to a subject in need thereof an effective amount of a compound of the invention.

[015] The present invention further provides methods for reducing the concentration of triglycerides in the liver of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention.

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

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

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

[019] The present invention further provides methods for inhibiting, reducing, or slowing the progression of lipid synthesis, liver steatosis, hepatocyte ballooning or inflammation, liver fibrosis, pulmonary fibrosis, or cirrhosis in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention.

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

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

[022] The present invention further provides methods for inhibiting NF-kB or stellate cell activation comprising administering to a subject in need thereof an effective amount of a compound of the invention.

[023] The present invention further provides methods for activating PPAR (peroxisome proliferator-activated receptor) comprising administering to a subject in need thereof an effective amount of a compound of the invention.

[024] The present invention further provides methods for reducing the fat or cholesterol content of animal meat or bird eggs, comprising administering to the animal or bird an effective amount of a compound of the invention.

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

[026] The present invention further provides methods for modulating, directly inhibiting, or allosterically inhibiting acetyl CoA carboxylase 1 or acetyl CoA carboxylase 2 in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention.

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

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[028] Figs. 1A-1D show the inhibitory effects of compounds I-32 , I-61 , I-1 , and III-1 , respectively, on lipogenesis in primary mouse hepatocytes as a percentage control.

[029] Figs. 2A-2D show the antiproliferative effects of compounds I-32 , I-61 , I-1 , and III-1 , respectively, on Hepa1-6 cells as a percentage of vehicle control.

[030] Figs. 3A-3D show the antiproliferative effects of compounds I-32 , I-61 , I-1 , and III-1 , respectively, on Hep3B cell proliferation as a percentage of vehicle control.

[031] Figs. 4A-4D show the anticlonogenic effects of compounds I-32 , I-61 , I-1 , and III-1 , respectively, on Hepa1-6 cells as a percentage of vehicle control.

[032] Figs. 5A-5D show the anticlonogenic effects of compounds I-32 , I-61 , I-1 , and III-1 , respectively, on Hep3B cells as a percentage of vehicle control.

[033] Fig. 6A shows the antiproliferative effects of compound I-32 and sorafenib, in the presence or absence of the other, on Hep3B cells. Fig. 6B shows the antiproliferative effects of compound I-32 and lenvatinib, in the presence or absence of the other, on Hep3B cells. Fig. 6C shows the antiproliferative effects of compound I-61 and sorafenib, in the presence or absence of the other, on Hep3B cells. Fig. 6D shows the antiproliferative effects of compound I-61 and lenvatinib, in the presence or absence of the other, on Hep3B cells.

[034] Fig. 7A shows the antiproliferative effects of compound I-32 and sorafenib, in the presence or absence of the other, on Hepa1-6 cells. Fig. 7B shows the antiproliferative effects of compound I-32 and lenvatinib, in the presence or absence of the other, on Hepa1-6 cells. Fig. 7C shows the antiproliferative effects of compound I-61 and sorafenib, in the presence or absence of the other, on Hepa1-6 cells. Fig. 7D shows the antiproliferative effects of compound I-61 and lenvatinib, in the presence or absence of the other, on Hepa1-6 cells.

[035] Fig. 8A shows the synergistic antiproliferative effect of compound I-32 and sorafenib on Hep3B cells. Fig. 8B shows the synergistic antiproliferative effect of compound I-32 and lenvatinib on Hep3B cells. Fig. 8C shows the synergistic antiproliferative effect of compound I-61 and sorafenib on Hep3B cells. Fig. 8D shows the synergistic antiproliferative effect of compound I-61 and lenvatinib on Hep3B cells.

DETAILED DESCRIPTION OF THE ESSENCE OF THE INVENTION

[036] Definitions

[037] The term "about" immediately preceding a numerical value means up to ±20% of that numerical value. For example, "about" a numerical value means up to ±20% of that numerical value, in some embodiments, 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 ±less than 1%, or any other value or range of values within that range.

[038] In the present description, numerical ranges are presented for specific quantities. These ranges include all subranges therein. Thus, the range "from 50 to 80" includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Moreover, all values within a given range may be an extreme point for the range encompassed by it (e.g., the range 50-80 includes ranges with endpoints such as 55-80, 50-75, etc.).

[039] The term "pharmaceutically acceptable salt" includes both an acid addition salt and a base addition salt. Pharmaceutically acceptable salts can be prepared by reacting a compound of the invention acting as a base with an inorganic or organic acid to form a salt, for example, 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, carbonic acid, etc. Pharmaceutically acceptable salts can also be prepared by reacting a compound of the invention acting as an acid with an inorganic or organic base to form a salt, for example, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ammonia, isopropylamine, trimethylamine, etc. It will also be appreciated by those skilled in the art that pharmaceutically acceptable salts can be prepared by reacting the compounds of the invention with a suitable inorganic or organic acid or base by any of a number of known methods.

[040] The term "solvate" refers to a solvation complex. Solvates may be formed by solvation (combination of solvent molecules with molecules or ions of the compounds of the invention), or the solvate may be an aggregate that contains an ion or molecule of the solute or molecules of the solvent. The solvent may be water, in which case the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, etc. A solvate may be formed by hydration, including by absorption of moisture. 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.

[041] The compounds of the invention may have one or more asymmetric centers and thus may be enantiomers, racemates, diastereomers, other stereoisomers, and mixtures thereof. The compounds of the invention include all such possible isomers (including geometric isomers), as well as their racemic and optically pure forms, whether or not specifically described herein. Optically active (+) and (-), ( R )- and ( S )-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or separated using conventional techniques, such as chromatography and fractional crystallization. Conventional methods for preparing or isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemate using, for example, chiral high performance liquid chromatography (HPLC). Where the compounds of the invention contain an olefinic double bond or other center of geometric asymmetry, and unless otherwise indicated, the compounds of the invention include both the E- and Z-geometric isomers. Likewise, the compounds of the invention include all tautomeric forms.

[042] An "effective amount" when used in connection with a compound of the invention means an amount of a compound of the invention that, when administered to a subject, will be effective in treating or preventing a disease, alone or with another pharmaceutically active agent.

[043] An “effective amount” when used in conjunction with another pharmaceutically active agent means an amount of the other pharmaceutically active agent that will be effective in treating or preventing a disease, alone or in combination with a compound of the invention.

[044] A "subject" is a human or non-human mammal, such as a bovine, equine, cat, dog, rodent, or non-human primate. A human may be male or female, a child, an adolescent, or an adult. A female may be premenarcheal or postmenarcheal.

[045] "Mammal" includes a human, a domesticated animal such as a laboratory animal (e.g., mouse, rat, rabbit, monkey, dog, etc.), a pet (e.g., cat, dog, pig, cattle, sheep, goat, horse, rabbit), and a non-domesticated, wild animal.

[046] All weight percentages (i.e., "% by weight," "wt. %," and "w/wt") referred to herein, unless otherwise indicated, are based on the total weight of the mixture or composition, as the case may be.

[047] The following terms used in this document have the following meanings unless otherwise specified:

[048] The terms "halo", "Hal" or "halogen" refer to Br, Cl, F or I.

[049] “Alkyl” refers to a fully saturated straight or branched hydrocarbon chain having from one to twelve carbon atoms and which is attached to the atom by a single bond. Included are alkyls having from 1 to 12 carbon atoms. An alkyl group having 1 to 12 carbon atoms is C ₁ -C ₁₂ alkyl, an alkyl group having 1 to 10 carbon atoms is C ₁ -C ₁₀ alkyl, an alkyl group having 1 to 6 carbon atoms is C ₁ -C ₆ alkyl, and an alkyl group having 1 to 5 carbon atoms is C ₁ -C ₅ alkyl. C ₁ -C ₅ alkyl includes C ₅ alkyls, C ₄ alkyls, C ₃ alkyls, C ₂ alkyls, and C ₁ alkyl (i.e., methyl). C ₁ -C ₆ alkyl includes all of the moieties described above for C ₁ -C ₅ alkyls, but also includes C ₆ alkyls. C ₁ -C ₁₀ alkyl includes all of the moieties described above for C ₁ -C ₅ alkyls and C ₁ -C ₆ alkyls, but also includes C ₇ , C ₈ , C ₉ , and C ₁₀ alkyls. Similarly, C ₁ -C ₁₂ alkyl includes all of the above groups, but also includes C ₁₁ and C ₁₂ alkyls. Non-limiting examples of _C1 - _C12 alkyl include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specified, an alkyl group may be unsubstituted or substituted with a substituent described herein.

[050] "Alkylene" refers to a fully saturated, straight or branched chain, divalent hydrocarbon having from one to twelve carbon atoms. Non-limiting examples of _C1 - _C12 alkylene include methylene, ethylene, propylene, n-butylene, and the like. Each alkylene end is attached to an atom by a single bond. The attachment points of the alkylene chain may be on one or two atoms. Unless otherwise specified, the alkylene chain may be unsubstituted or substituted with a substituent described herein.

[051] "Alkenyl" refers to a straight or branched hydrocarbon chain having from two to twelve carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to an atom by a single bond. Included are alkenyl groups having from 2 to 12 carbon atoms. An alkenyl group with 2 to 12 carbon atoms is a C ₂ -C ₁₂ alkenyl, an alkenyl group with 2 to 10 carbon atoms is a C ₂ -C ₁₀ alkenyl, an alkenyl group with 2 to 6 carbon atoms is a C ₂ -C ₆ alkenyl, and an alkenyl group with 2 to 5 carbon atoms is a C ₂ -C ₅ alkenyl. _C2 - _C5 alkenyl includes _C5 alkenyls, _C4 alkenyls, _C3 alkenyls, and _C2 alkenyls. _C2 - _C6 alkenyl includes all of the moieties described above for _C2 - _C5 alkenyls, but also includes _C6 alkenyls. _C2 - _C10 alkenyl includes all of the moieties described above for _C2 - _C5 alkenyls and _C2 - _C6 alkenyls, but also includes _C7 , _C8 , _C9 , and _C10 alkenyls. Similarly, _C2 - _C12 alkenyl includes all of the above groups, but also includes _C11 and _C12 alkenyls. Non-limiting examples of _C2 - _C12 alkenyl 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, 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, the alkyl group may be unsubstituted or substituted with a substituent described herein.

[052] "Alkenylene" refers to a straight or branched divalent hydrocarbon chain radical having from two to twelve carbon atoms and having one or more carbon-carbon double bonds. Non-limiting examples of _C2 - _C12 alkenylene include ethenylene, propenylene, butenylene, and the like. Each end of the alkenylene chain is attached to an atom by a single bond. The attachment points of the alkenylene chain may be on one to two atoms. Unless otherwise specified, the alkenylene chain may be unsubstituted or substituted with a substituent described herein.

[053] "Alkynyl" refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to an atom by a single bond. Included are alkynyl groups having from 2 to 12 carbon atoms. An alkynyl group having from 2 to 12 carbon atoms is a C ₂ -C ₁₂ alkynyl, an alkynyl group with 2 to 10 carbon atoms is a C ₂ -C ₁₀ alkynyl, an alkynyl group with 2 to 6 carbon atoms is a C ₂ -C ₆ alkynyl, and an alkynyl group with 2 to 5 carbon atoms is a C ₂ -C ₅ alkynyl. _C2 - _C5 alkynyl includes _C5 alkynyls, _C4 alkynyls, _C3 alkynyls, and _C2 alkynyls. _C2 - _C6 alkynyl includes all of the moieties described above for _C2 - _C5 alkynyls, but also includes _C6 alkynyls. _C2 - _C10 alkynyl includes all of the moieties described above for _C2 - _C5 alkynyls and _C2 - _C6 alkynyls, but also includes _C7 , _C8 , _C9 , and _C10 alkynyls. Similarly, _C2 - _C12 alkynyl includes all of the above groups, but also includes _C11 and _C12 alkynyls. Non-limiting examples of _C2 - _C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl, and the like. Unless otherwise specified, the alkyl group may be unsubstituted or substituted with a substituent described herein.

[054] "Alkynylene" refers to a straight or branched divalent hydrocarbon chain radical having from two to twelve carbon atoms and having one or more carbon-carbon triple bonds. Non-limiting examples of _C2 - _C12 alkynylene include ethynylene, propynylene, butynylene, and the like. Each end of the alkynylene chain is attached to an atom via a single bond. The attachment points of the alkynylene chain may be on one or two atoms. Unless otherwise specified, the alkynylene chain may be unsubstituted or substituted with a substituent described herein.

[055] "Alkoxy" refers to a radical of the formula -OR _a , wherein R _a is an alkyl, alkenyl, or alkynyl radical as defined herein. Unless otherwise specified, an alkoxy group may be unsubstituted or substituted with a substituent described herein.

[056] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. An aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may contain fused or bridged ring systems. Aryl radicals include, but are not limited to, aceanthrylyl, acenaphthylenyl, acephenanthrylenyl, anthracenyl, azulenyl, chrysenyl, fluoranthenyl, fluorenyl, ac-indacenyl, s-indacenyl, indanyl, indenyl, naphthalenyl, phenalenyl, phenanthrenyl, phenyl, pleiadenyl, pyrenyl, and thiphenylenyl. Unless otherwise specified, aryl may be unsubstituted or substituted with a substituent described herein.

[057] "Arylene" refers to a divalent aryl group, where aryl is defined herein. Unless otherwise specified, an arylene group may be unsubstituted or substituted with a substituent described herein.

[058] "Arylalkyl" refers to a radical of the formula -R _b -R _c , wherein R _b is an alkylene group as defined herein and R _c is an aryl radical as defined herein, such as benzyl, diphenylmethyl, and the like. Unless otherwise specified, an arylalkyl group may be unsubstituted or substituted with a substituent as described herein. "Arylalkenyl" refers to a radical of the formula -R _b -R _c , wherein R _b is an alkenylene group as defined herein and R _c is an aryl radical as defined herein. Unless otherwise specified, an arylalkenyl group may be unsubstituted or substituted with a substituent as described herein.

[059] "Arylalkynyl" refers to a radical of the formula -R _b -R _c , wherein R _b is an alkynylene group as defined herein and R _c is an aryl radical as defined herein. Unless otherwise specified, an arylalkynyl group may be unsubstituted or substituted with a substituent as described herein.

[060] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting of carbon and hydrogen atoms, which may contain fused or bridged ring systems, containing from three to twenty carbon atoms, preferably containing from three to ten carbon atoms, and which is attached to the atom by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specified, a cycloalkyl group may be unsubstituted or substituted with a substituent described herein.

[061] "Aryloxy" refers to a radical of the formula -O(aryl), wherein the aryl radical is defined herein. Aryloxy includes, but is not limited to, phenoxy (-O(phenyl)). Unless otherwise specified, an aryloxy group may be unsubstituted or substituted with a substituent described herein.

[062] "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. Cycloalkenyl may contain fused or bridged ring systems having from three to twenty carbon atoms, in some embodiments having from three to ten carbon atoms. The cycloalkenyl group is attached to the atom by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl, and the like. Unless otherwise specified, a cycloalkenyl group may be unsubstituted or substituted with a substituent described herein.

[063] "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, which may contain fused or bridged ring systems, having from five to twenty carbon atoms, in some embodiments having from five to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise specified, a cycloalkynyl group may be unsubstituted or substituted with a substituent described herein.

[064] "Cycloalkylalkyl" refers to a radical of the formula -R _b -R _d , wherein R _b is an alkylene group as defined herein and R _d is a cycloalkyl radical as defined herein. Unless otherwise specified, a cycloalkylalkyl group may be unsubstituted or substituted with a substituent as described herein. "Cycloalkylalkenyl" refers to a radical of the formula -R _b -R _d , wherein R _b is an alkenylene group as defined herein and R _d is a cycloalkyl radical as defined herein. Unless otherwise specified, a cycloalkylalkenyl group may be unsubstituted or substituted with a substituent as described herein. "Cycloalkylalkynyl" refers to a radical of the formula -R _b -R _d , wherein R _b is an alkynylene group as defined herein and R _d is a cycloalkyl radical as defined herein. Unless otherwise specified, a cycloalkylalkynyl group may be unsubstituted or substituted with a substituent as described herein.

[065] "Cycloalkenylalkyl" refers to a radical of the formula -R _b -R _d , wherein R _b is an alkylene group as defined herein and R _d is a cycloalkenyl radical as defined herein. Unless otherwise specified, a cycloalkenylalkyl group may be unsubstituted or substituted with a substituent as described herein. "Cycloalkenylalkenyl" refers to a radical of the formula -R _b -R _d , wherein R _b is an alkenylene group as defined herein and R _d is a cycloalkyl radical as defined herein. Unless otherwise specified, a cycloalkenylalkenyl group may be unsubstituted or substituted with a substituent as described herein. "Cycloalkenylalkynyl" refers to a radical of the formula -R _b -R _d , wherein R _b is an alkynylene group as defined herein and R _d is a cycloalkyl radical as defined herein. Unless otherwise specified, a cycloalkenylalkynyl group may be unsubstituted or substituted with a substituent as described herein.

[066] "Cycloalkynylalkyl" refers to a radical of the formula -R _b -R _d , wherein R _b is an alkylene group as defined herein and R _d is a cycloalkynyl radical as defined herein. Unless otherwise specified, a cycloalkynylalkyl group may be unsubstituted or substituted with a substituent as described herein. "Cycloalkynylalkenyl" refers to a radical of the formula -R _b -R _d , wherein R _b is an alkenylene group as defined herein and R _d is a cycloalkyl radical as defined herein. Unless otherwise specified, a cycloalkynylalkenyl group may be unsubstituted or substituted with a substituent as described herein. "Cycloalkynylalkynyl" refers to a radical of the formula -R _b -R _d , wherein R _b is an alkynylene group as defined herein and R _d is a cycloalkyl radical as defined herein. Unless otherwise specified, a cycloalkynylalkynyl group may be unsubstituted or substituted with a substituent as described herein.

[067] The terms "carbocyclyl," "carbocyclic ring," or "carbocycle" refer to a ring structure in which each atom forming the ring is carbon. A carbocyclyl, carbocyclic ring, or carbocycle may contain from 3 to 20 carbon atoms in the ring. Carbocyclyl, carbocyclic ring, or carbocycle includes aryl, cycloalkyl, cycloalkenyl, and cycloalkynyl, as defined herein. A carbocyclyl, carbocyclic ring, or carbocycle may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may contain fused, bridged, and helical ring systems. Unless otherwise specified, a carbocyclyl group, carbocyclic ring, or carbocycle may be unsubstituted or substituted with a substituent described herein.

[068] "Haloalkyl" refers to an alkyl radical, as defined herein, that is substituted with one or more halogen radicals, as defined herein, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless otherwise specified, a haloalkyl group may be unsubstituted or substituted with a substituent described herein.

[069] "Haloalkenyl" refers to an alkenyl radical, as defined herein, that is substituted with one or more halogen radicals, as defined herein, such as 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless otherwise specified, a haloalkenyl group may be unsubstituted or substituted with a substituent described herein.

[070] "Haloalkynyl" refers to an alkynyl radical, as defined herein, that is substituted with one or more halogen radicals, as defined herein, such as 1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless otherwise specified, a haloalkenyl group may be unsubstituted or substituted with a substituent described herein.

[071] "Heterocyclyl" refers to a 3-20 membered non-aromatic partially unsaturated or aromatic ring radical that contains 2-12 carbon atoms and 1 to 6 nitrogen, oxygen, or sulfur heteroatoms. Heterocyclyl includes heteroaryls as defined herein. Unless otherwise specified, a heterocyclyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may contain fused, bridged, and helical ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified, a heterocyclyl group may be unsubstituted or substituted with a substituent described herein.

[072] “Heterocyclylalkyl” refers to a radical of the formula -R _b -R _e , wherein R _b is an alkylene group as defined herein and R _e is a heterocyclyl radical as defined herein. Unless otherwise specified, a heterocyclylalkyl group may be unsubstituted or substituted with a substituent as described herein.

[073] "Heterocyclylalkenyl" refers to a radical of the formula -R _b -R _e , wherein R _b is an alkenylene group as defined herein and R _e is a heterocyclyl radical as defined herein. Unless otherwise specified, a heterocyclylalkenyl group may be unsubstituted or substituted with a substituent as described herein.

[074] "Heterocyclylalkynyl" refers to a radical of the formula -R _b -R _e , wherein R _b is an alkynylene group as defined herein and R _e is a heterocyclyl radical as defined herein. Unless otherwise specified, a heterocyclylalkynyl group may be unsubstituted or substituted with a substituent as described herein.

[075] "N-heterocyclyl" refers to a heterocyclyl radical as described herein containing at least one nitrogen atom, wherein the point of attachment of the heterocyclyl radical atom of a compound of the invention is at the nitrogen atom in the heterocyclyl radical. Unless otherwise specified, an N-heterocyclyl group may be unsubstituted or substituted with a substituent described herein.

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

[077] "N-heteroaryl" refers to a heteroaryl radical as described herein containing at least one nitrogen atom, wherein the point of attachment of the heteroaryl radical to an atom of a compound of the invention is at the nitrogen atom in the heteroaryl radical. Unless otherwise specified, an N-heteroaryl group may be unsubstituted or substituted with a substituent described herein.

[078] "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 may be unsubstituted or substituted with a substituent as described herein.

[079] "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 may be unsubstituted or substituted with a substituent as described herein.

[080] "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 may be unsubstituted or substituted with a substituent as described herein.

[081] "Ring" refers to a cyclic group that may be saturated or contain one or more double or triple bonds. The ring may be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, the ring may be unsubstituted or substituted with a substituent described herein.

[082] “Thioalkyl” refers to a radical of the formula -SR _a , wherein R _a is an alkyl, alkenyl, or alkynyl radical as defined herein. Unless otherwise specified, a thioalkyl group may be unsubstituted or substituted with a substituent described herein.

[083] A group or radical described herein may be substituted with one or more of the following substituents: a halogen atom 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 containing one or more heteroatoms.

[084] A group or radical described herein may be alternatively or additionally substituted with one or more of the following substituents: oxo, carbonyl, carboxyl or ester group; or imine, oxime, hydrazone and nitrile.

[085] Examples of other substituents include, but are not limited to:

[086] amino, cyano, hydroxyl, imino, nitro, oxo, thiooxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroarylalkyl group, -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 SO ₂ R _h , -OC(=O)NR _g R _h , -OR _g , -SR _g , -SOR _g , -SO ₂ R _g , -OSO ₂ R _g , -SO ₂ OR _g , =NSO ₂ R _g , -SO ₂ NR _g R _h , -C(=O)R _g , -C(=O)OR _g , -C(=O)NR _g R _h , -CH ₂ SO ₂ R _g and -CH ₂ SO ₂ NR _g R _h , where R _g and R _h are the same or different and independently represent 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, each of the foregoing substituents being unsubstituted or substituted with one or more substituents described herein.

[087] As used in this document, the symbol " "("attachment site bond") refers to a bond that represents the attachment site of two chemical compounds, one of which is depicted as being attached to an attachment site bond and the other of which is not depicted as being attached to an attachment site bond. For example, " " indicates that the chemical compound "XY" is bonded to another chemical compound through a point of attachment bond.

[088] Compounds of the present invention

[089] Compounds of formula (IA)

[090] In some embodiments, a compound of the invention is a compound of formula (IA):

(IA)

[091] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[092] p in each case is independently equal to 1, 2, 3, 4, 5, 6, or 7;

[093] Z ¹ and Z ² independently represent -C(R ^1A )(R ^2A )-(CH ₂ ) _d -X ^A or -W-(CH ₂ ) _d -C(R ³ )(R ⁴ )-Y;

[094] d is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 in each case;

[095] each R ^1A and R ^2A independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, or each carbon atom together with R ^1A and R ^2A attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[096] each R ³ and R ⁴ independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -O(C _1- C ₆ alkyl), phenyl, benzyl, Cl, Br, CN, NO ₂ or CF ₃ , or each carbon atom together with R ³ and R ⁴ attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[097] each X ^A independently represents H, -OH, -SO ₃ H,

,

,

,

;

[098] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups;

[099] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl;

[0100] each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) _2- , or -Se-;

[0101] each Y independently represents -OH, -COOH, -COOR ⁵ , -SO ₃ H,

,

,

,

; And

[0102] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups.

[0103] In some embodiments of compounds of Formula (IA), Z ¹ and Z ² are independently -C(R ^1A )(R ^2A )-(CH ₂ ) _d -X ^A .

[0104] In some embodiments of compounds of Formula (IA), each R ^1A and R ^2A is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl. In some embodiments, each R ^1A and R ^2A is independently -C _1- C ₃ alkyl, -C _2- C ₃ alkenyl, or -C _2- C ₃ alkynyl. In some embodiments, each R ^1A and R ^2A is independently H or -C _1- C ₆ alkyl. In some embodiments, R ^1A and R ^2A are methyl.

[0105] In some embodiments of compounds of formula (IA), p in each occurrence is 2, 3, 4, or 5.

[0106] In some embodiments of compounds of formula (IA), d is 0, 1, 2, or 3 in each occurrence. In some embodiments, d is 0 or 1.

[0107] In some embodiments, a compound of the invention is a compound of formula (IA):

(IA)

[0108] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0109] p in each case is independently equal to 4, 5, 6, or 7;

[0110] Z ¹ and Z ² independently represent -C(R ¹ )(R ² )-(CH ₂ ) _c -X or -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y;

[0111] c in each case is independently equal to 0, 1, 2 or 3;

[0112] each R¹and R²independently represents -C_1-C₆alkyl, -C_2-C₆alkenyl, -C_2-C₆alkynyl, phenyl or benzyl, or each carbon atom together with R¹and R², attached to a carbon atom, independently forms -C₃-C₇cycloalkyl group;

[0113] each R ³ and R ⁴ independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -O(C _1- C ₆ alkyl), phenyl, benzyl, Cl, Br, CN, NO ₂ or CF ₃ , or each carbon atom together with R ³ and R ⁴ attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0114] each X and Y independently represents -OH, -COOH, -COOR ⁵ , -SO ₃ H,

,

,

,

[0115] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups;

[0116] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl;

[0117] each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) _2- , or -Se-; and

[0118] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups.

[0119] In some embodiments, the compound of formula (IA) has any of the structures shown in Table A-1, or a pharmaceutically acceptable salt or solvate thereof.

[0120] Table A-1

Connection No. Structure and name I-1
6-[4-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid I-2
7-(4-(5-carboxy-5-methylhexyl)phenyl)-2,2-dimethylheptanoic acid I-3
7,7'-(1,4-phenylene)bis(2,2-dimethylheptanoic acid) I-4
8-(4-(5-carboxy-5-methylhexyl)phenyl)-2,2-dimethyloctanoic acid I-5
1-(5-(4-(4-(1-carboxycyclopropyl)butyl)phenyl)pentyl)cyclopropane-1-carboxylic acid I-6
1-(6-(4-(4-(1-carboxycyclopropyl)butyl)phenyl)hexyl)cyclopropane-1-carboxylic acid I-7
1,1'-(1,4-phenylenebis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylic acid) I-8
1-(4-(4-(6-carboxy-6-methylheptyl)phenyl)butyl)cyclopropane-1-carboxylic acid I-9
1-(4-(4-(7-carboxy-7-methyloctyl)phenyl)butyl)cyclopropane-1-carboxylic acid I-10
1-(5-(4-(6-carboxy-6-methylheptyl)phenyl)pentyl)cyclopropane-1-carboxylic acid

[0121] Compounds of formula (IB)

[0122] In some embodiments, a compound of the invention is a compound of formula (IB):

[0123] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0124] p in each case is independently 1, 2, 3, 4, 5, 6, or 7;

[0125] each Z ¹ and Z ² independently represents -C(R ¹ )(R ² )-(CH ₂ ) _c -X or -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y;

[0126] c in each case is independently equal to 0, 1, 2 or 3;

[0127] each R ¹ and R ² independently represents -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, or each carbon atom together with R ¹ and R ² attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0128] each R ³ and R ⁴ independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -O(C _1- C ₆ alkyl), phenyl, benzyl, Cl, Br, CN, NO ₂ or CF ₃ , or each carbon atom together with R ³ and R ⁴ attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0129] each X and Y independently represents -OH, -COOH, -COOR ⁵ , -SO ₃ H,

,

,

,

[0130] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups;

[0131] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl;

[0132] each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) _2- , or -Se-; and

[0133] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups.

[0134] In some embodiments, the compound of formula (IB) has any of the structures shown in Table A-2, or a pharmaceutically acceptable salt or solvate thereof.

[0135] Table A-2

Connection No. Structure and name I-31
5-[3-(4-carboxy-4-methylpentyl)phenyl]-2,2-dimethylpentanoic acid I-32
6-[3-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid I-33
7-(3-(5-carboxy-5-methylhexyl)phenyl)-2,2-dimethylheptanoic acid I-34
7,7'-(1,3-phenylene)bis(2,2-dimethylheptanoic acid) I-35
8-(3-(5-carboxy-5-methylhexyl)phenyl)-2,2-dimethyloctanoic acid I-36
8,8'-(1,3-phenylene)bis(2,2-dimethyloctanoic acid) I-37
1-(6-(3-(7-carboxy-7-methyloctyl)phenyl)hexyl)cyclopropane-1-carboxylic acid I-38
1,1'-(1,3-phenylenebis(hexane-6,1-diyl))bis(cyclopropane-1-carboxylic acid) I-39
1-(4-(3-(6-carboxy-6-methylheptyl)phenyl)butyl)cyclopropane-1-carboxylic acid I-40
1-(5-(3-(6-carboxy-6-methylheptyl)phenyl)pentyl)cyclopropane-1-carboxylic acid I-41
1-(4-(3-(7-carboxy-7-methyloctyl)phenyl)butyl)cyclopropane-1-carboxylic acid I-42
1-(5-(3-(4-(1-carboxycyclopropyl)butyl)phenyl)pentyl)cyclopropane-1-carboxylic acid I-43
1,1'-(1,3-phenylenebis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylic acid) I-44
1-(6-(3-(4-(1-carboxycyclopropyl)butyl)phenyl)hexyl)cyclopropane-1-carboxylic acid

[0136] Compounds of formula (IC)

[0137] In some embodiments, a compound of the invention is a compound of formula (IC):

[0138] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0139] p in each case is independently 1, 2, 3, 4, 5, 6, or 7;

[0140] each Z ¹ and Z ² independently represents -C(R ¹ )(R ² )-(CH ₂ ) _c -X or -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y;

[0141] c in each case is independently equal to 0, 1, 2 or 3;

[0142] each R ¹ and R ² independently represents -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, or each carbon atom together with R ¹ and R ² attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0143] each R ³ and R ⁴ independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -O(C _1- C ₆ alkyl), phenyl, benzyl, Cl, Br, CN, NO ₂ or CF ₃ , or each carbon atom together with R ³ and R ⁴ attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0144] each X and Y independently represents -OH, -COOH, -COOR ⁵ , -SO ₃ H,

,

,

,

[0145] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl), or phenyl groups;

[0146] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl;

[0147] each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) _2- , or -Se-; and

[0148] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups.

[0149] In some embodiments of compounds of formula (IA), (IB), or (IC), Z ¹ and Z ² are each independently -C(R ¹ )(R ² )-(CH ₂ ) _c -X. In some embodiments, one or both of Z ¹ and Z ² are -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y.

[0150] In some embodiments of compounds of formula (IA), (IB), or (IC), X is -COOH or -COOR ⁵ .

[0151] In some embodiments of compounds of Formula (IA), (IB), or (IC), each R ¹ and R ² is independently -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, or -C ₂ -C ₆ alkynyl. In some embodiments, each R ¹ and R ² is independently -C ₁ -C ₃ alkyl, -C ₂ -C ₃ alkenyl, or -C ₂ -C ₃ alkynyl. In some embodiments, R ¹ and R ² are methyl.

[0152] In some embodiments of compounds of formula (IA), (IB), or (IC), Z ¹ and Z ² are each independently -C(R ¹ )(R ² )-(CH ₂ ) _c -X, X is -COOH or -COOR ⁵ , and R ¹ and R ² are methyl.

[0153] In some embodiments of compounds of formula (IA), (IB), or (IC), c is 0 or 1.

[0154] In some embodiments of compounds of formula (IA), (IB), or (IC), Z ¹ and Z ² are each -C(R ¹ )(R ² )-(CH ₂ ) _c -X. In some embodiments, Z ¹ and Z ² are each -C(R ¹ )(R ² )-(CH ₂ ) _c -X, and X is each -COOH.

[0155] In some embodiments of compounds of formula (IA), (IB), or (IC), each carbon atom, together with R¹and R², attached to a carbon atom, independently forms -C₃-C₇cycloalkyl group. In some embodiments, each carbon atom together with R¹and R², attached to a carbon atom, independently form a cyclopropyl ring.

[0156] In some embodiments of compounds of Formula (IA), (IB), or (IC), Z ¹ and Z ² are each -C(R ¹ )(R ² )-(CH ₂ ) _c -X and at least one R ¹ and one R ^2, together with the carbon atom to which they are attached, form a -C ₃ -C ₇ cycloalkyl group. In some embodiments, Z ¹ and Z ² are each -C(R ¹ )(R ² )-(CH ₂ ) _c -X and at least one R ¹ and one R ^2, together with the carbon atom to which they are attached, form a cyclopropyl ring.

[0157] In some embodiments of compounds of formula (IA), (IB), or (IC), R ³ and R ⁴ are independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl.

[0158] In some embodiments of compounds of formula (IA), (IB), or (IC), Y is -COOH or -COOR ⁵ .

[0159] In some embodiments of compounds of formula (IA), (IB), or (IC), R ⁵ is -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl. In some embodiments, R ⁵ is -C _1- C ₃ alkyl, -C _2- C ₃ alkenyl, or -C _2- C ₃ alkynyl.

[0160] In some embodiments of compounds of formula (IA), (IB), or (IC), p is 3, 4, 5, 6, or 7. In some embodiments, p is 4, 5, 6, or 7.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), one or both of Z ¹ and Z ² are -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y, and R ³ and R ⁴ are independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl. In some embodiments, one or both of Z ¹ and Z ² are -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y, and Y is -COOH or -COOR ⁵ . In some embodiments, one or both of Z ¹ and Z ² are -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y, Y is -COOH or -COOR ⁵ , and R ⁵ is -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl. In some embodiments, one or both of Z ¹ and Z ² are -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y, Y is -COOH or -COOR ⁵ , and R ⁵ is -C _1- C ₃ alkyl, -C _2- C ₃ alkenyl, or -C _2- C ₃ alkynyl.

[0161] In some embodiments, the compound of formula (IC) has any of the structures shown in Table A-3, or a pharmaceutically acceptable salt or solvate thereof.

[0162] Table A-3

Connection No. Structure and name I-61
5-[2-(4-carboxy-4-methylpentyl)-phenyl]-2,2-dimethylpentanoic acid I-62
6,6'-(1,2-phenylene)bis(2,2-dimethylhexanoic acid) I-63
8-(2-(6-carboxy-6-methylheptyl)phenyl)-2,2-dimethyloctanoic acid I-64
7-(2-(5-carboxy-5-methylhexyl)phenyl)-2,2-dimethylheptanoic acid I-65
8,8'-(1,2-phenylene)bis(2,2-dimethyloctanoic acid) I-66
1-(4-(2-(5-carboxy-5-methylhexyl)phenyl)butyl)cyclopropane-1-carboxylic acid I-67
1-(5-(2-(7-carboxy-7-methyloctyl)phenyl)pentyl)cyclopropane-1-carboxylic acid I-68
1-(5-(2-(6-carboxy-6-methylheptyl)phenyl)pentyl)cyclopropane-1-carboxylic acid I-69
1-(3-(2-(4-carboxy-4-methylpentyl)phenyl)propyl)cyclopropane-1-carboxylic acid I-70
1-(5-(2-(5-carboxy-5-methylhexyl)phenyl)pentyl)cyclopropane-1-carboxylic acid I-71
1-(6-(2-(7-carboxy-7-methyloctyl)phenyl)hexyl)cyclopropane-1-carboxylic acid I-72
1,1'-(1,2-phenylenebis(butane-4,1-diyl))bis(cyclopropane-1-carboxylic acid) I-73
1-(5-(2-(6-(1-carboxycyclopropyl)hexyl)phenyl)pentyl)cyclopropane-1-carboxylic acid I-74
1,1'-(1,2-phenylenebis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylic acid) I-75
1,1'-(1,2-phenylenebis(propane-3,1-diyl))bis(cyclopropane-1-carboxylic acid) I-76
1-(5-(2-(4-(1-carboxycyclopropyl)butyl)phenyl)pentyl)cyclopropane-1-carboxylic acid I-77
1,1'-(1,2-phenylenebis(hexane-6,1-diyl))bis(cyclopropane-1-carboxylic acid)

[0163] Compounds of formula (ID)

[0164] In some embodiments, a compound of the invention is a compound of formula (ID):

[0165] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0166] p in each case is independently 1, 2, 3, 4, 5, 6, or 7;

[0167] Z ¹ and Z ² are independently -C(R ^1A )(R ^2A )-(CH ₂ ) _d -X ^A or -W-(CH ₂ ) _d -C(R ³ )(R ⁴ )-Y;

[0168] d is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 in each case;

[0169] each R ^1A and R ^2A independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, or each carbon atom together with R ^1A and R ^2A attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0170] each R ³ and R ⁴ independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -O(C _1- C ₆ alkyl), phenyl, benzyl, Cl, Br, CN, NO ₂ or CF ₃ , or each carbon atom together with R ³ and R ⁴ attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0171] Q ¹ and Q ² are independently H, OH, -C _1- C ₆ alkyl, -O(C _1- C ₆ alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR ^1A , -NR ^{1AR 2A} , F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl, heterocyclyl or -V-OH, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group;

[0172] V is ( _CH2 ) _t or arylene;

[0173] t is 0, 1, 2, 3, or 4;

[0174] each X ^A independently represents H, -OH, -SO ₃ H,

,

,

,

[0175] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl), or phenyl groups;

[0176] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl;

[0177] each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) _2- , or -Se-;

[0178] each Y independently represents -OH, -COOH, -COOR ⁵ , -SO ₃ H,

,

,

,

And

[0179] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups.

[0180] In some embodiments of compounds of Formula (ID), Z ¹ and Z ² are independently -C(R ^1A )(R ^2A )-(CH ₂ ) _d -X ^A .

[0181] In some embodiments of compounds of Formula (ID), each R ^1A and R ^2A is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl. In some embodiments, each R ^1A and R ^2A is independently -C _1- C ₃ alkyl, -C _2- C ₃ alkenyl, or -C _2- C ₃ alkynyl. In some embodiments, each R ^1A and R ^2A is independently H or -C _1- C ₆ alkyl. In some embodiments, R ^1A and R ^2A are methyl.

[0182] In some embodiments of compounds of formula (ID), p in each occurrence is 2, 3, 4, or 5.

[0183] In some embodiments of compounds of formula (ID), d is 0, 1, 2, or 3 in each occurrence. In some embodiments, d is 0 or 1.

[0184] In some embodiments, a compound of the invention is a compound of formula (ID):

(ID)

[0185] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0186] p in each case is independently equal to 4, 5, 6, or 7;

[0187] Z ¹ and Z ² are independently -C(R ¹ )(R ² )-(CH ₂ ) _c -X or -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y;

[0188] c in each case is independently equal to 0, 1, 2 or 3;

[0189] each R¹and R²independently represents -C_1-C₆alkyl, -C_2-C₆alkenyl, -C_2-C₆alkynyl, phenyl or benzyl, or each carbon atom together with R¹and R², attached to a carbon atom, independently forms -C₃-C₇cycloalkyl group;

[0190] each R ³ and R ⁴ independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -O(C _1- C ₆ alkyl), phenyl, benzyl, Cl, Br, CN, NO ₂ or CF ₃ , or each carbon atom together with R ³ and R ⁴ attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0191] Q ¹ and Q ² are independently H, OH, -C _1- C ₆ alkyl, -O(C _1- C ₆ alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR ^1A , -NR ^{1AR 2A} , F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl, heterocyclyl or -V-OH, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group;

[0192] each R ^1A and R ^2A is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl;

[0193] V is ( _CH2 ) _t or arylene;

[0194] t is 0, 1, 2, 3, or 4;

[0195] each X and Y independently represents -OH, -COOH, -COOR ⁵ , -SO ₃ H,

,

,

,

[0196] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups;

[0197] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl;

[0198] each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) _2- , or -Se-; and

[0199] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups.

[0200] In some embodiments, the compound of formula (ID) has a structure shown in Table A-1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula (ID) has a structure shown in Table A-5, which is mono- or di-substituted with -OH or methyl groups on phenyl, or a pharmaceutically acceptable salt or solvate thereof.

[0201] Compounds of formula (IG)

[0202] In some embodiments, a compound of the invention is a compound of formula (IG):

(IG)

[0203] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0204] p in each case is independently 1, 2, 3, 4, 5, 6, or 7;

[0205] Z ¹ and Z ² are independently -C(R ¹ )(R ² )-(CH ₂ ) _c -X or -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y;

[0206] c in each case is independently equal to 0, 1, 2 or 3;

[0207] each R¹and R²independently represents -C_1-C₆alkyl, -C_2-C₆alkenyl, -C_2-C₆alkynyl, phenyl or benzyl, or each carbon atom together with R¹and R², attached to a carbon atom, independently forms -C₃-C₇cycloalkyl group;

[0208] each R ³ and R ⁴ independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -O(C _1- C ₆ alkyl), phenyl, benzyl, Cl, Br, CN, NO ₂ or CF ₃ , or each carbon atom together with R ³ and R ⁴ attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0209] Q ¹ and Q ² are independently H, OH, -C _1- C ₆ alkyl, -O(C _1- C ₆ alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR ^1A , -NR ^{1AR 2A} , F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl, heterocyclyl or -V-OH, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group;

[0210] each R ^1A and R ^2A is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl;

[0211] V is ( _CH2 ) _t or arylene;

[0212] t is 0, 1, 2, 3, or 4;

[0213] each X and Y independently represents -OH, -COOH, -COOR ⁵ , -SO ₃ H,

,

,

,

[0214] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups;

[0215] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl;

[0216] each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) _2- , or -Se-; and

[0217] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups.

[0218] In some embodiments of a compound of formula (IG), Q ¹ and Q ² are each H.

[0219] In some embodiments of the compound of formula (IG), p is 2, 3, 4, 5, 6, or 7. In some embodiments of the compound of formula (IG), p is 2.

[0220] In some embodiments, the compound of formula (IG) has the structure shown in Table A-4, or a pharmaceutically acceptable salt or solvate thereof.

[0221] Table A-4

Connection No. Structure and name I-78
4,4'-(1,4-phenylene)bis(2,2-dimethylbutanoic acid)

[0222] Compounds of formula (IE)

[0223] In some embodiments, a compound of the invention is a compound of formula (IE):

[0224] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0225] p in each case is independently 1, 2, 3, 4, 5, 6, or 7;

[0226] each Z ¹ and Z ² independently represents -C(R ¹ )(R ² )-(CH ₂ ) _c -X or -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y;

[0227] c in each case is independently equal to 0, 1, 2 or 3;

[0228] each R ¹ and R ² independently represents -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, or each carbon atom together with R ¹ and R ² attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0229] each R ³ and R ⁴ independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -O(C _1- C ₆ alkyl), phenyl, benzyl, Cl, Br, CN, NO ₂ or CF ₃ , or each carbon atom together with R ³ and R ⁴ attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0230] Q ¹ and Q ² are independently H, OH, -C _1- C ₆ alkyl, -O(C _1- C ₆ alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR ^1A , -NR ^{1AR 2A} , F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl, heterocyclyl or -V-OH, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group;

[0231] each R ^1A and R ^2A is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl;

[0232] V is ( _CH2 ) _t or arylene;

[0233] t is 0, 1, 2, 3, or 4;

[0234] each X and Y independently represents -OH, -COOH, -COOR ⁵ , -SO ₃ H,

,

,

,

[0235] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl), or phenyl groups;

[0236] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl;

[0237] each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) _2- , or -Se-; and

[0238] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups.

[0239] In some embodiments, the compound of formula (IE) has a structure shown in Table A-2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula (IE) has a structure shown in Table A-6, which is mono- or di-substituted with -OH or methyl groups on phenyl, or a pharmaceutically acceptable salt or solvate thereof.

[0240] Compounds of formula (IF)

[0241] In some embodiments, a compound of the invention is a compound of formula (IF):

[0242] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0243] p in each case is independently 1, 2, 3, 4, 5, 6, or 7;

[0244] each Z ¹ and Z ² independently represents -C(R ¹ )(R ² )-(CH ₂ ) _c -X or -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y;

[0245] c in each case is independently equal to 0, 1, 2 or 3;

[0246] each R ¹ and R ² independently represents -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, or each carbon atom together with R ¹ and R ² attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0247] each R ³ and R ⁴ independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -O(C _1- C ₆ alkyl), phenyl, benzyl, Cl, Br, CN, NO ₂ or CF ₃ , or each carbon atom together with R ³ and R ⁴ attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0248] Q ¹ and Q ² are independently H, OH, -C _1- C ₆ alkyl, -O(C _1- C ₆ alkyl), phenoxy, aryloxy, benzyl, -S-aryl, -SR ^1A , -NR ^{1AR 2A} , F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl, heterocyclyl or -V-OH, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group;

[0249] each R ^1A and R ^2A is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl;

[0250] V is ( _CH2 ) _t or arylene;

[0251] t is 0, 1, 2, 3, or 4;

[0252] each X and Y independently represents -OH, -COOH, -COOR ⁵ , -SO ₃ H,

,

,

,

[0253] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl), or phenyl groups;

[0254] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl;

[0255] each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) _2- , or -Se-; and

[0256] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups.

[0257] In some embodiments, the compound of formula (IF) has a structure shown in Table A-3, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula (IE) has a structure shown in Table A-7, which is mono- or di-substituted with -OH or methyl groups on phenyl, or a pharmaceutically acceptable salt or solvate thereof.

[0258] Compounds of formulas (IH) and (IJ)-(IL)

[0259] In some embodiments, a compound of the invention is a compound of formula (IH):

[0260] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0261] p in each instance is independently 1, 2, 3, 4, 5, 6, or 7;

[0262] each Z ¹ and Z ² independently represents -C(R ¹ )(R ² )-(CH ₂ ) _c -X or -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y;

[0263] c in each case is independently equal to 0, 1, 2 or 3;

[0264] each R ¹ and R ² independently represents -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, or each carbon atom together with R ¹ and R ² attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0265] each R ³ and R ⁴ independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -O(C _1- C ₆ alkyl), phenyl, benzyl, Cl, Br, CN, NO ₂ or CF ₃ , or each carbon atom together with R ³ and R ⁴ attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0266] Q is independently -OH, methyl, or methoxy;

[0267] t is 1, 2, 3, or 4;

[0268] each X and Y independently represents -OH, -COOH, -COOR ⁵ , -SO ₃ H,

,

,

,

[0269] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl), or phenyl groups;

[0270] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl;

[0271] each W is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) _2- , or -Se-; and

[0272] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups.

[0273] In some embodiments of formula (IH), the compound has a structure of formula (IJ), (IK), or (IL), or a pharmaceutically acceptable salt thereof:

[0274] In some embodiments of the compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z ¹ and Z ² are each independently -C(R ¹ )(R ² )-(CH ₂ ) _c -X. In some embodiments of the compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), one or both of Z ¹ and Z ² are -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y.

[0275] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), X is -COOH or -COOR ⁵ .

[0276] In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each R ¹ and R ² is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each R ¹ and R ² is independently -C _1- C ₃ alkyl, -C _2- C ₃ alkenyl, or -C _2- C ₃ alkynyl. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R ¹ and R ² are methyl.

[0277] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z ¹ and Z ² are each independently -C(R ¹ )(R ² )-(CH ₂ ) _c -X, X is -COOH or -COOR ⁵ , and R ¹ and R ² are methyl.

[0278] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), c is 0 or 1.

[0279] In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z ¹ and Z ² are each -C(R ¹ )(R ² )-(CH ₂ ) _c -X. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z ¹ and Z ² are each -C(R ¹ )(R ² )-(CH ₂ ) _c -X, and X is each -COOH.

[0280] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each carbon atom together with R¹and R², attached to a carbon atom, independently forms -C₃-C₇cycloalkyl group. In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each carbon atom together with R¹and R², attached to a carbon atom, independently form a cyclopropyl ring.

[0281] In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z ¹ and Z ² are each -C(R ¹ )(R ² )-(CH ₂ ) _c -X and at least one R ¹ and one R ² , together with the carbon atom to which they are attached, form a -C ₃ -C ₇ cycloalkyl group. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z ¹ and Z ² are each -C(R ¹ )(R ² )-(CH ₂ ) _c -X and at least one R ¹ and one R ^2, together with the carbon atom to which they are attached, form a cyclopropyl ring.

[0282] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R ³ and R ⁴ are independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl.

[0283] In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Y is -COOH or -COOR ⁵ .

[0284] In some embodiments of the compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R ⁵ is -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl. In some embodiments of the compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R ⁵ is -C _1- C ₃ alkyl, -C _2- C ₃ alkenyl, or -C _2- C ₃ alkynyl.

[0285] 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.

[0286] In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), one or both of Z ¹ and Z ² are -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y, and R ³ and R ⁴ are independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), one or both of Z ¹ and Z ² are -W-(CH ₂ ) _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), one or both of Z ¹ and Z ² are -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y, Y is -COOH or -COOR ⁵ , and R ⁵ is -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl. In some embodiments of compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), one or both of Z ¹ and Z ² are -W-(CH ₂ ) _c -C(R ³ )(R ⁴ )-Y, Y is -COOH or -COOR ⁵ , and R ⁵ is -C _1- C ₃ alkyl, -C _2- C ₃ alkenyl, or -C _2- C ₃ alkynyl.

[0287] In some embodiments of a compound of formula (IH), (IJ), (IK), or (IL), Q is independently methyl or -OH.

[0288] In some embodiments of a compound of formula (IH), (IJ), (IK), or (IL), t is 1. In some embodiments, t is 2. In some embodiments, t is 3.

[0289] In some embodiments, a compound of formula (IH), (IJ), (IK), or (IL) has any of the structures shown in Table A-5, Table A-6, or Table A-7, or a pharmaceutically acceptable salt or solvate thereof.

[0290] Table A-5 .

Structure Structure

[0291] Table A-6

Structure Structure

[0292] Table A-7

Structure Structure

[0293] Compounds of formula (II)

[0294] In some embodiments, a compound of the invention is a compound of formula (II):

(II),

[0295] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0296] each R ¹ and R ² independently represents H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, or each carbon atom together with R ¹ and R ² attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0297] n in each case is independently equal to 0, 1, 2, or 3;

[0298] m in each case is independently 1, 2, 3, 4, 5, 6, 7, 8, or 9;

[0299] X is -C(=O)-, ^-CHR3- , -CH- _CH2 ( ^OR3 )-, -O-, -S-, -S(=O)-, -S(O) _2- , ^-NR3- , -N(OH)-, -N(→O)-, or -Se-;

[0300] R ³ is H, -OH, -O(C _1- C ₆ alkyl), -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -C ₃ -C ₇ cycloalkyl, C ₄ -C ₇ cycloalkenyl, C ₅ -C ₈ cycloalkynyl, phenyl or benzyl, wherein each -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, -C ₃ -C ₇ cycloalkyl, C ₄ -C ₇ cycloalkenyl, C ₅ -C ₈ cycloalkynyl, phenyl and benzyl is unsubstituted or substituted by one or more halogen, -CN, -NO ₂ or -CF ₃ groups;

[0301] each Y is independently -O-, -NH-, -N(OH)-, -N(→O)-, -S-, -S(=O)-, -S(O) _2- , or -Se-;

[0302] each Z is independently -OH, -COOH, -COOR ⁵ , -SO ₃ H, -SO ₃ R ⁵ ,

,

,

,

[0303] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups;

[0304] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl), or phenyl groups; and

[0305] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl.

[0306] In some embodiments of compounds of formula (II), X is -C(=O)-, -CHR ³ -, -O-, -S-, -S(=O)-, or Se. In some embodiments, X is -C(=O)-, -CH(OH)-, -O-, -S-, -S(=O)-, or Se.

[0307] In some embodiments of compounds of formula (II), R ³ is H, -OH, -O(C _1- C ₃ alkyl), or -C _1- C ₃ alkyl.

[0308] In some embodiments of compounds of formula (II), each Y is independently -O- or -S-.

[0309] In some embodiments of compounds of formula (II), each R ¹ and R ² is independently H, -C _1- C ₃ alkyl, -C _2- C ₃ alkenyl, or -C _2- C ₃ alkynyl. In some embodiments, each R ¹ and R ² is independently H or methyl.

[0310] In some embodiments of compounds of formula (II), each Z is independently -COOH or -COOR ⁵ . In some embodiments, each Z is -COOH.

[0311] In some embodiments of compounds of formula (II), each R ⁵ is independently -C ₁ -C ₃ alkyl, -C ₂ -C ₃ alkenyl, or -C ₂ -C ₃ alkynyl.

[0312] In some embodiments of compounds of formula (II), n at each occurrence is independently 0, 1, or 2. In some embodiments, n is 1.

[0313] In some embodiments of compounds of formula (II), m is independently 3, 4, 5, or 6 at each occurrence. In some embodiments, m is independently 4 or 5 at each occurrence.

[0314] In some embodiments, the compound of formula (II) has any of the structures shown in Table B1, or a pharmaceutically acceptable salt or solvate thereof.

[0315] Table B1

Connection No. Structure and name II-1
(9-carboxymethylsulfanyl-5-hydroxynonylsulfanyl)-acetic acid II-2
(11-carboxymethylsulfanyl-6-hydroxyundecylsulfanyl)-acetic acid II-3
(9-carboxymethylsulfanyl-5-oxononylsulfanyl)-acetic acid II-4
(11-carboxymethylsulfanyl-6-oxoundecylsulfanyl)-acetic acid II-5
[4-(4-carboxymethylsulfanylbutoxy)-butylsulfanyl]-acetic acid II-6
[5-(5-carboxymethylsulfanylpentyloxy)-pentylsulfanyl]-acetic acid II-7
(9-carboxymethoxy-5-hydroxynonyloxy)-acetic acid II-8
(11-carboxymethoxy-6-hydroxyundecyloxy)-acetic acid II-9
(9-carboxymethoxy-5-oxononyloxy)-acetic acid II-10
(11-carboxymethoxy-6-oxoundecyloxy)-acetic acid II-11
[4-(4-carboxymethoxybutoxy)-butoxy]-acetic acid II-12
[5-(5-carboxymethoxypentyloxy)-pentyloxy]-acetic acid II-13
[4-(4-carboxymethylsulfanylbutylselanyl)-butylsulfanyl]-acetic acid II-14
[5-(5-carboxymethylsulfanylpentylselanyl)-pentylsulfanyl]-acetic acid II-15
[4-(4-carboxymethoxybutylselanyl)-butoxy]-acetic acid II-16
[5-(5-carboxymethoxypentylselanyl)-pentyloxy]-acetic acid II-17
[4-(4-carboxymethylsulfanylbutylsulfanyl)-butylsulfanyl]-acetic acid II-18
[5-(5-carboxymethylsulfanylpentylsulfanyl)-pentylsulfanyl]-acetic acid II-19
[4-(4-carboxymethoxybutylsulfanyl)-butoxy]-acetic acid II-20
[5-(5-carboxymethoxypentylsulfanyl)-pentyloxy]-acetic acid II-21
[4-(4-carboxymethylsulfanylbutane-1-sulfinyl)-butylsulfanyl]-acetic acid II-22
[5-(5-carboxymethylsulfanylpentane-1-sulfinyl)-pentylsulfanyl]-acetic acid II-23
[4-(4-carboxymethoxybutane-1-sulfinyl)-butoxy]-acetic acid II-24
[5-(5-carboxymethoxy-pentane-1-sulfinyl)-pentyloxy]-acetic acid

[0316] Compounds of formula (III), (IIIA) and (IIIB)

[0317] In some embodiments, a compound of the invention is a compound of formula (III):

(III)

[0318] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0319] R ¹ and R ² are 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 together with the attached carbon atom form a -C ₃ -C ₇ cycloalkyl group;

[0320] m in each case is independently equal to 3, 4, 5, 6, or 7;

[0321] n in each case is independently 0, 1, 2, 3, 4, or 5;

[0322] q in each case is 0, 1, 2, 3, or 4;

[0323] X is -O-, -S-, -S(=O)-, -S(O) _2- , -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-;

[0324] Z ₁ and Z ₂ independently represent -C _1- C ₆ alkyl, -OH, -COOH, -COOR ⁵ , -SO ₃ H, -SO ₃ R ⁵ ,

,

,

,

[0325] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups;

[0326] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl), or phenyl groups; and

[0327] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl.

[0328] In some embodiments, a compound of the invention is a compound of formula (IIIA):

(IIIA)

[0329] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0330] R ¹ and R ² are 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 together with the attached carbon atom form a -C ₃ -C ₇ cycloalkyl group;

[0331] m in each case is independently equal to 2, 3, 4, 5, 6, or 7;

[0332] n in each case is independently 0, 1, 2, 3, 4, or 5;

[0333] q in each case is 0, 1, 2, 3, or 4;

[0334] X is -O-, -S-, -S(=O)-, -S(O) _2- , -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-;

[0335] Z ₁ and Z ₂ are -C _1- C ₆ alkyl, -COOH, -COOR ⁵ , -SO ₃ R ⁵ ,

, ,

,

where Z ₁ and Z ₂ are the same;

[0336] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups;

[0337] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl), or phenyl groups; and

[0338] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl.

[0339] In some embodiments, a compound of the invention is a compound of formula (IIIB):

(IIIB)

[0340] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0341] R ¹ and R ² are 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 together with the attached carbon atom form a -C ₃ -C ₇ cycloalkyl group;

[0342] m in each case is independently equal to 2, 3, 4, 5, 6, or 7;

[0343] n in each case is independently 0, 1, 2, 3, 4, or 5;

[0344] q in each case is 0, 1, 2, 3, or 4;

[0345] X is -S-, -S(=O)-, -S(O) _2- , -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl)-;

[0346] Z ₁ and Z ₂ independently represent -C _1- C ₆ alkyl, -OH, -COOH, -COOR ⁵ , -SO ₃ H, -SO ₃ R ⁵ ,

,

,

,

[0347] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups;

[0348] each R ⁶ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl, wherein the -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl is unsubstituted or substituted with one or two halogen, -OH, -O(C _1- C ₆ alkyl), or phenyl groups; and

[0349] each R ⁷ is independently H, -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, or -C _2- C ₆ alkynyl.

[0350] In some embodiments of compounds of formula (III) and (IIIB), each Z ¹ and Z ² is independently -OH, -COOH, or -COOR ⁵ . In some embodiments, each Z ¹ and Z ² is independently -C _1- C ₆ alkyl.

[0351] In some embodiments of compounds of formula (III), (IIIA), and (IIIB), Z ¹ and Z ² are the same group: -OH, -COOH, or -COOR ⁵ . In some embodiments, Z ¹ and Z ² are -C _1- C ₆ alkyl.

[0352] In some embodiments of compounds of formula (III), X is -S-, -S(=O)-, -S(O) ₂ -, -NH-, -N(OH)-, -N(→O)-, N(alkyl)-, or -N(aryl).

[0353] In some embodiments of compounds of formula (III) and (IIIA), X is O. In some embodiments of compounds of formula (III), when X is O, m is 2, 3, 5, 6, or 7.

[0354] In some embodiments of compounds of Formula (III), (IIIA), and (IIIB), n is each independently 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0355] In some embodiments of compounds of formula (III), (IIIA), and (IIIB), m is in each case independently equal to 4, 5, or 6. In some embodiments, m is 5 or 6. In some embodiments, m is early 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 2 or 3.

[0356] In some embodiments of compounds of formula (III), (IIIA), or (IIIB), R ¹ and R ^2, together with the attached carbon atom, form a -C ₃ -C ₇ cycloalkyl group.

[0357] In some embodiments, the compound of formula (III) or (IIIA) has any of the structures shown in Table B2, or a pharmaceutically acceptable salt or solvate thereof.

[0358] Table B2

Connection No. Structure and name III-10
1,1'-(oxybis(propane-3,1-diyl))bis(cyclopropane-1-carboxylic acid) III-11
1-(3-(4-(1-carboxycyclopropyl)butoxy)propyl)cyclopropane-1-carboxylic acid III-12
1-(2-(4-(1-carboxycyclopropyl)butoxy)ethyl)cyclopropane-1-carboxylic acid III-13
1,1'-(oxybis(butane-4,1-diyl))bis(cyclopropane-1-carboxylic acid) III-14
1-(5-(2-(1-carboxycyclopropyl)ethoxy)pentyl)cyclopropane-1-carboxylic acid III-15
1-(3-((5-(1-carboxycyclopropyl)pentyl)oxy)propyl)cyclopropane-1-carboxylic acid III-16
1-(5-(4-(1-carboxycyclopropyl)butoxy)pentyl)cyclopropane-1-carboxylic acid III-17
1,1'-(oxybis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylic acid) III-18
1-(5-((6-(1-carboxycyclopropyl)hexyl)oxy)pentyl)cyclopropane-1-carboxylic acid III-19
1,1'-(oxybis(hexane-6,1-diyl))bis(cyclopropane-1-carboxylic acid) III-20
1-(6-((7-(1-carboxycyclopropyl)heptyl)oxy)hexyl)cyclopropane-1-carboxylic acid III-21
1,1'-(oxybis(heptane-7,1-diyl))bis(cyclopropane-1-carboxylic acid)

[0359] Compositions of the present invention

[0360] In some embodiments, a composition of the invention comprises (i) an effective amount of a compound of the invention and (ii) a pharmaceutically acceptable carrier or excipient.

[0361] In some embodiments, the composition of the invention comprises (i) an effective amount of a compound of formula (IA):

(IA)

[0362] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0363] p in each case is independently 1, 2, 3, 4, 5, 6, or 7;

[0364] Z ¹ and Z ² are independently -C(R ¹ )(R ² )-(CH ₂ ) _c -COOH or -C(R ¹ )(R ² )-(CH ₂ ) _c -COOR ⁵ ;

[0365] c in each case is independently equal to 0, 1, 2 or 3;

[0366] each R ¹ and R ² independently represents -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, or each carbon atom together with R ¹ and R ² attached to the carbon atom independently forms a -C ₃ -C ₇ cycloalkyl group;

[0367] each R ⁵ is independently -C _1- C ₆ alkyl, -C _2- C ₆ alkenyl, -C _2- C ₆ alkynyl, phenyl or benzyl, each being unsubstituted or substituted with one or more halogen, -OH, -O(C _1- C ₆ alkyl) or phenyl groups; and

[0368] (ii) a pharmaceutically acceptable carrier or excipient.

[0369] In some embodiments of a composition comprising a compound of Formula (IA), each R ¹ and R ² is independently -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, or -C ₂ -C ₆ alkynyl. In some embodiments, each R ¹ and R ² is independently -C ₁ -C ₃ alkyl, -C ₂ -C ₃ alkenyl, or -C ₂ -C ₃ alkynyl. In some embodiments, R ¹ and R ² are methyl.

[0370] In some embodiments of a composition comprising a compound of formula (IA), c is 0 or 1.

[0371] In some embodiments of a composition comprising a compound of formula (IA), R ⁵ is -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, or -C ₂ -C ₆ alkynyl. In some embodiments, R ⁵ is -C ₁ -C ₃ alkyl, -C ₂ -C ₃ alkenyl, or -C ₂ -C ₃ alkynyl.

[0372] In some embodiments of a composition comprising 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 a compound having the structure or , or a pharmaceutically acceptable salt or solvate thereof.

[0373] In some embodiments, a composition of the invention comprises an effective amount of a compound having a structure shown in Tables A-1, A-2, A-3, or A-4, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a composition of the invention comprises an effective amount of a compound having a structure shown in Table B1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a composition of the invention comprises an effective amount of a compound having a structure shown in Table B2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a composition of the invention comprises an effective amount of a compound having a structure shown in Table C, or a pharmaceutically acceptable salt or solvate thereof.

[0374] Table C

Connection No. Structure and name III-1
5-[4-(4-carboxy-4-methylpentyl)phenyl]-2,2-dimethylpentanoic acid

[0375] In some embodiments, the composition of the invention further comprises another pharmaceutically active agent.

[0376] In some embodiments, the other pharmaceutically active agent is a statin, a thiazolidinedione or fibrate, a bile acid binding resin, niacin, an antiobesity drug, a hormone, tyrofostin, a sulfonylurea drug, a biguanide, an alpha-glucosidase inhibitor, an apolipoprotein A-I agonist, an apolipoprotein E agonist, a phosphodiesterase type 5 inhibitor, a cardiovascular drug, an HDL-elevating drug, an HDL enhancer, an apolipoprotein A-I gene or protein agonist, an apolipoprotein A-IV gene or protein agonist, an apolipoprotein gene agonist, an ATP citrate lyase modulator, an allosteric ATP citrate lyase inhibitor, an acetyl CoA carboxylase modulator, or allosteric inhibitor of acetyl-CoA carboxylase.

[0377] In some embodiments, the other pharmaceutically active agent is an antagonist or inhibitor of a proinflammatory 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 proinflammatory function or increases the anti-inflammatory function of IL-6, CRP, TNF-α, MCP-1, MIP-1β, CCR5, CCR2, NF-κB, or TGF-β1.

[0378] In some embodiments, the other pharmaceutically active agent affects the expression or function of a fibrosis gene or protein or a mitogenesis gene or protein. In some embodiments, the other pharmaceutically active agent regulates the expression or function of FGF-21, MMP-2, TIMP-1, ASK1, or collagen type 3.

[0379] In some embodiments, the other pharmaceutically active agent is a regulator of genes associated with lipid metabolism or migration, a regulator of PPAR-α target genes such as, but not limited to, HD (ECHS1), PDK4 and Cyp7A1, a regulator of SGLT1, SGL2, ApoC-III, Sulf-2, ANGPTL3, ANGPTL4 and LPL genes.

[0380] 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.

[0381] In some embodiments, the other pharmaceutically active agent is a fibrate. In some embodiments, the fibrate is fenofibrate, gemfibrozil, or fenofibric acid.

[0382] In some embodiments, the other pharmaceutically active agent is sorafenib. In yet other embodiments, the other pharmaceutically active agent is taxol. In yet other embodiments, the other pharmaceutically active agent is carotuximab. In yet other embodiments, the other pharmaceutically active agent is pembrolizumab. In yet other embodiments, the other pharmaceutically active agent is lenvatinib. In yet other embodiments, the other pharmaceutically active agent is avelumab. In some embodiments, the other pharmaceutically active agent is durvalumab. In yet other embodiments, the other pharmaceutically active agent is tremelimumab. In yet other embodiments, the other pharmaceutically active agent is nivolumab. In yet other embodiments, the other pharmaceutically active agent is tazemetostat, cemiplimab, ABX196, a T cell receptor (TCR) immunocellular therapy such as LioCyx ^™ , TBI-302, namodenoson, MM-310, an intratumorally injectable oncolytic virus or a genetically modified oncolytic virus such as, but not limited to, telomelysin and imligic; or an immunomodulatory gene therapy such as MDA-7/IL-24, GLIPR1/RTVP-1, and REIC/Dkk-3.

[0383] In yet some other embodiments, the other pharmaceutically active agent is cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, nivolumub, firsocostat, apararenone, metformin, leucine-metformin-sildenafil combination, IMM-124E, RG-125, vitamin E, cysteamine, selonsertib, losartan, RO5093151, pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, ND-L02-s0201/BMS-986263, volixibate, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196 or nalmafen. In some embodiments, the other pharmaceutically active agent is pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricorylant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, volixibat, firsocostat, cilofexor, elafibranor, nalmefene, solithromycin, 99m technetium mebrofenin, tropifexor, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib, sunitinib, zotiraciclib citrate, sintilimab, camrelizumab, spartalizumab, toripalimab, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305, ascreenvacumab, sitravatinib, IRX-2 cytokine-based biologic, bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SRF388, ET1402L1-CART, glypican 3-specific chimeric antigen receptor T cells (CAR T cells), CD147-targeted CAR T cells, NKG2D-based CAR T cells, neoantigen-reactive T cells, pexastimogene devacirepvec, talimogene laherparepvec, GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase-targeted peptide vaccine, or IMA970A, novantrone, prednisone, pixantrone, losoxantrone, cytidine-phosphate-guanosine (CpG) DNA, paclitaxel, oraxol, MTL-CEBPA, ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241, U3-1784, avadomide, INCAGN01949, or CMP-001.

[0384] In some embodiments, the other pharmaceutically active agent is an anticancer agent. In some embodiments, the anti-cancer agent is sorafenib, taxol, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, selonsertib, losartan, RO5093151, pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibate, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, volixibate, elafibranor, nalmefene, solithromycin, 99m technetium-mebrophenine, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib, sunitinib or zotiraciclib citrate.

[0385] In some embodiments, the composition of the invention further comprises an anticancer agent.

[0386] In some embodiments, the other pharmaceutically active agent is an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is pembrolizumab, avelumab, durvalumab, nivolumab, cemiplimab, ABX196, sintilimab, camrelizumab, spartalizumab, toripalimab, XmAb20717 bispecific antibody, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305, ascrinacumab, TCR T cell therapeutic, sitravatinib, IRX-2 cytokine biologic, bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SRF388, ET1402L1-CART, glypican 3-specific chimeric antigen receptor T cells (CAR T cells), CD147-targeted CAR T cells, NKG2D-based CAR T cells, or neoantigen-reactive T cells.

[0387] In some embodiments, the composition of the invention further comprises an immunotherapeutic agent.

[0388] In some embodiments, the other pharmaceutically active agent is an oncology virus. In some embodiments, the oncology virus is pexastimogene devacirepvec or talimogene laherparepvec. In some embodiments, the composition of the invention further comprises an oncology virus.

[0389] 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, a DNAJB1-PRKACA fusion kinase-targeting peptide vaccine, or IMA970A. In some embodiments, the composition of the invention further comprises a vaccine.

[0390] In some embodiments, the other pharmaceutically active agent is novantrone, prednisone, pixantrone, losoxantrone, cytidine-phosphate-guanosine (CpG) DNA, paclitaxel, oraxol, MTL-CEBPA, ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241, U3-1784, avadomide, INCAGN01949, or CMP-001.

[0391] In some embodiments, the composition of the invention further comprises two or more other pharmaceutically active agents. In some embodiments, the two or more other pharmaceutically active agents are oncolytic agents, such as, but not limited to, nanatinostat and valganciclovir.

[0392] In some embodiments, the composition of the invention further comprises a pharmaceutically active agent: sorafenib, taxol, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, selonsertib, losartan, RO5093151, pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibate, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, volixibate, elafibranor, nalmefene, solithromycin, 99m technetium-mebrofenine, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib, sunitinib or zotiraciclib citrate. In some embodiments, a composition of the invention 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: sorafenib, taxol, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, selonsertib, losartan, RO5093151, pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibate, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricorylant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99m technetium mebrofenin, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, physogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib, sunitinib or zotiraciclib citrate.

[0393] In some embodiments of the composition of the invention, the composition comprises a compound of the invention and a pharmaceutically active agent: sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, a T-cell receptor (TCR) immunocellular therapy agent, TBI-302, namodenoson, MM-310, intratumorally injectable oncolytic viruses or genetically modified oncolytic viruses, or immunomodulatory gene therapy agents. 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) the pharmaceutically active agent is sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, a T-cell receptor (TCR) immunocellular therapy agent, TBI-302, namodenoson, MM-310, intratumorally injectable oncolytic viruses or genetically modified oncolytic viruses, or immunomodulatory gene therapy drugs.

[0394] In some embodiments of a composition of the invention, the composition comprises a compound of the invention and sorafenib or lenvatinib. 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) 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.

[0395] Table D provides 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 relates to a particular compound of the invention and another pharmaceutically active agent. For example, Embodiment A1 relates to compound I-1 (or a pharmaceutically acceptable salt or solvate thereof) and sorafenib; Embodiment A2 relates to compound I-32 (or a pharmaceutically acceptable salt or solvate thereof) and sorafenib, etc. In some embodiments, the compositions of the invention comprise an effective amount of a compound of the invention and another pharmaceutically active agent as set forth in the embodiment of Table D.

[0396] Table D . Embodiments

1 2 3 4 Compound I-1 or a pharmaceutically acceptable salt or solvate thereof Compound I-32 or a pharmaceutically acceptable salt or solvate thereof Compound I-61 or a pharmaceutically acceptable salt or solvate thereof Compound III-1 or a pharmaceutically acceptable salt or solvate thereof A sorafenib A1 A2 A3 A4 B lenvatinib B1 B2 B3 B4 C Taxol C1 C2 C3 C4 D carotuximab D1 D2 D3 D4 E pembrolizumab E1 E2 E3 E4 F avelumab F1 F2 F3 F4 G durvalumab G1 G2 G3 G4 H tremelimumab H1 H2 H3 H4 I nivolumab I1 I2 I3 I4 J tazemetostat J1 J2 J3 J4 K cemiplimab K1 K2 K3 K4 L ABX196 L1 L2 L3 L4 M T-cell receptor (TCR) immunotherapy agent M1 M2 M3 M4 N TBI-302 N1 N2 N3 N4 O sedated sleep O1 O2 O3 O4 P MM-310 P1 P2 P3 P4 Q tumor-injectable oncolytic virus Q1 Q2 Q3 Q4 R genetically modified oncolytic virus R1 R2 R3 R4 S drug for immunomodulatory gene therapy S1 S2 S3 S4

[0397] In some embodiments, the pharmaceutically acceptable carrier or excipient includes, but is not limited to, a binder, filler, diluent, disintegrant, wetting agent, lubricant, glidant, colorant, dye slip agent, sweetener, or flavoring agent.

[0398] Binders or granulators impart cohesive properties to the tablet, ensuring that the tablet remains 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); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, Irish moss extract, panwar gum, ghatti gum, isapol husk mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), veegum, larch arabogalactan, powdered tragacanth gum, and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hooke, Pa.); and mixtures thereof.

[0399] Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. In some embodiments, the binder is hydroxypropyl cellulose.

[0400] The binder or filler may be present in an amount of from about 2% to about 49% by weight of the compositions of the invention provided herein, or any range therebetween. In some embodiments, the binder or filler is present in the composition of the invention in an amount of from about 5% to about 15% by weight. In some embodiments, the binder or filler is present in the composition of the invention in an amount of about 5%, 6%, 7%, 8%, 9%, 8%, 10%, 11%, 12%, 13%, 14%, or 15% by weight, or any range therebetween.

[0401] 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 amounts, can impart properties to certain compressed tablets that allow them to dissolve in the mouth upon chewing. Such compressed 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.

[0402] The compositions of the invention may comprise a diluent in an amount of, for example, about 5% to about 49% of the diluent by weight of the composition, or any range between any of these values. In some embodiments, the diluent is present in the compositions of the invention in an amount of about 15% to about 30% by weight. In some embodiments, the diluent is present in the compositions of the invention in an amount of about 15%, 16%, 17%, 18%, 19%, 18%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight, or any range between any of these values.

[0403] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose such as sodium starch glycolate; potassium polacrilin; starches such as corn starch, potato starch, tapioca starch and pregelatinized starch; clays; algins and mixtures thereof. The amount of disintegrant in the compositions of the invention can vary. In some embodiments, the disintegrant is sodium croscarmellose. In some embodiments, the disintegrant is sodium croscarmellose NF (Ac-Di-Sol).

[0404] The compositions of the invention may comprise a disintegrant in an amount of, for example, from about 0.5% to about 15% or from about 1% to about 10% by weight of the disintegrant. In some embodiments, the compositions of the invention comprise a disintegrant in an amount of about 5%, 6%, 7%, 8%, 9%, 8%, 10%, 11%, 12%, 13%, 14%, or 15% by weight of the composition, or any range between any of these values.

[0405] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil including 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 gels such as AEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co. Boston, Mass.), and mixtures thereof. In some embodiments, the lubricant is magnesium stearate.

[0406] The compositions of the invention can comprise a lubricant in an amount of, for example, about 0.1 to about 5% by weight of the lubricant. In some embodiments, the compositions of the invention comprise a lubricant in an amount of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.8%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3.0% by weight of the composition, or any range between any of these values.

[0407] Suitable glide enhancers include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. Boston, MA), and talc, including asbestos-free talc.

[0408] Dyes include any approved certified water-soluble FD and C dyes and water-insoluble FD and C dyes suspended on aluminum oxide hydrate and lakes and mixtures thereof.

[0409] Flavors include natural flavors extracted from plants, such as fruits, and synthetic mixtures of compounds that provide a pleasant taste sensation, such as mint and methyl salicylate.

[0410] Sweeteners include sucrose, lactose, mannitol, syrups, glycerin, sucralose, and artificial sweeteners such as saccharin and aspartame.

[0411] 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. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, veegum, acacia, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0412] Solvents include glycerin, sorbitol, ethyl alcohol and syrup.

[0413] Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0414] The compounds of the invention and the compositions of the invention can be formulated for administration by a variety of routes, including orally, parenterally, via inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants, and excipients. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, and intra-arterial injections using a variety of infusion techniques. As used herein, intra-arterial and intravenous injection includes administration via catheters.

[0415] The compounds of the invention and the compositions of the invention can be formulated according to conventional procedures adapted to the desired route of administration. Accordingly, the compositions of the invention can take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compounds of the invention and the compositions of the invention can be formulated as a preparation suitable for implantation or injection. Thus, for example, the compositions of the invention can be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g. as a sparingly soluble salt). The compounds of the invention and the compositions of the invention can be presented in powder form for mixing with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. Suitable formulations for each of these routes of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0416] In some embodiments, the compositions of the invention are suitable for oral administration. These compositions may comprise solid, semi-solid, gelatinous, or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, troches, wafers, pellets, medicated chewing gums, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, capsule implants, breakable capsules, elixirs, syrups, or any combination thereof. In some embodiments, the compositions of the invention suitable for oral administration are in the form of a tablet or capsule. In some embodiments, the composition of the invention is in the form of a tablet. In some embodiments, the composition of the invention is in the form of a capsule. In some embodiments, the compound of the invention is contained in a capsule.

[0417] In some embodiments, the capsules are immediate release capsules. A non-limiting example of a capsule is a coni-snap® hard gelatin shell capsule.

[0418] The compositions of the invention may be presented in the form of compressed tablets, disintegrating tablets, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thereby protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammonium shellacs, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be useful to mask an unpleasant taste or odor and to protect the tablets from oxidation. Film-coated tablets are compressed tablets coated with a thin layer or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating may impart the same general characteristics as a sugar coating. Multiple-compressed tablets are compressed tablets produced by more than one compression cycle, including multilayer tablets and press-coated or dry-coated tablets.

[0419] In some embodiments, the coating is a film coating. In some embodiments, the film coating comprises a white Opadry coating and a simethicone emulsion 30% USP.

[0420] In some embodiments, a compound of the invention is contained in a tablet. In some embodiments, a compound of the invention is contained in a compressed tablet. In some embodiments, a compound of the invention is contained in a compressed film-coated tablet. In some embodiments, the compositions of the invention are in the form of compressed film-coated tablets.

[0421] In some embodiments, the compositions of the invention are prepared by fluid bed granulation of a compound of the invention with one or more pharmaceutically acceptable carriers, excipients, or excipients. In some embodiments, the compositions of the invention prepared by fluid bed granulation can provide a tablet formulation with good flowability, good compressibility, rapid dissolution, good stability, and/or minimal or no fracturing. In some embodiments, the fluid bed granulation process allows for the preparation of formulations having a high drug content, such as greater than 70% or greater than 75% of the compound of the invention.

[0422] The compositions of the invention can be presented in the form of soft or hard capsules, which can be made from gelatin, methylcellulose, starch or calcium alginate. A hard gelatin capsule, also known as a dry fill capsule (DFC), can comprise two sections, one of which fits over the other, thereby completely enclosing the active ingredient. A soft elastic capsule (SEC) is a soft globular shell, such as a gelatin shell, which is plasticized by the addition of glycerol, sorbitol or a similar polyol. Soft gelatin shells can contain a preservative to prevent the growth of microorganisms. Suitable preservatives are described herein, including methyl and propyl parabens and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules can also be coated in a manner known to those skilled in the art to modify or maintain dissolution of the active ingredient.

[0423] The compositions of the invention can be in liquid or semi-solid dosage form, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion can be a two-phase system in which one liquid is dispersed as small beads in another liquid, which can be an oil-in-water or a water-in-oil. Emulsions can include pharmaceutically acceptable non-aqueous liquids or solvent, an emulsifying agent and a preservative. Suspensions can include a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions can include a pharmaceutically acceptable acetal, such as a di-(lower alkyl)acetal of a lower alkyl aldehyde (the term "lower" means alkyl having from 1 to 6 carbon atoms), for example, acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs may be clear, sweetened, and aqueous-alcoholic solutions. Syrups may be concentrated aqueous solutions of a sugar, such as sucrose, and may contain a preservative. For a liquid dosage form, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, to provide convenient measurement for administration.

[0424] The compositions of the invention for oral administration may also be presented in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms may be prepared as described in U.S. Patent No. 6,350,458.

[0425] The compositions of the invention may be presented as non-effervescent or effervescent granules and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and a source of carbon dioxide.

[0426] Colorants and flavorings may be used in all of the above dosage forms. In addition, flavorings and sweeteners are particularly useful in the production of chewable tablets and lozenges.

[0427] The compositions of the invention may be formulated as immediate or modified release dosage forms, including delayed, sustained, pulsed, controlled, targeted, and programmed release dosage forms.

[0428] In some embodiments, the compositions of the invention comprise a film coating.

[0429] The compositions of the invention may contain another active ingredient that does not reduce the therapeutic or prophylactic effectiveness of the composition, or may contain a substance that enhances or increases the effectiveness of the composition.

[0430] Tablet dosage forms may contain a compound of the invention in powder, crystalline, or granular form and may further contain a carrier or excipient described herein, including a binder, disintegrant, controlled release polymer, lubricant, diluent, or colorant.

[0431] In some embodiments, the compositions of the invention may further comprise an excipient such as a diluent, a disintegrant, a wetting agent, a binder, a glidant, a lubricant, or any combination thereof. In some embodiments, the tablet comprises a binder. Furthermore, in some embodiments, the binder comprises microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, polyvinylpyrridone, hydroxypropyl cellulose, hydroxymethylcellulose, or any combination thereof. In other embodiments, the tablet comprises a disintegrant. In other embodiments, the disintegrant comprises sodium croscarmellose, sodium starch glycolate, or any combination thereof. In other embodiments, the tablet comprises a lubricant. Furthermore, in some embodiments, the lubricant comprises magnesium stearate, stearic acid, hydrogenated oil, sodium stearyl fumarate, or any combination thereof.

[0432] In some embodiments, the compositions of the invention are in the form of a tablet that contains a binder, such as any of the binders described herein.

[0433] In some embodiments, the compositions of the invention are in the form of a tablet that contains a disintegrant, such as any of the disintegrants described herein.

[0434] In some embodiments, the compositions of the invention are provided in the form of a tablet that contains a lubricant, such as any of the lubricants described herein.

[0435] In some embodiments, the compositions of the invention may be presented in a modified release or controlled release dosage form. In some embodiments, the compositions of the invention may comprise particles that exhibit a particular release profile. For example, a composition of the invention may comprise a compound of the invention in an immediate release form, which may also comprise a statin or a pharmaceutically acceptable salt thereof in a modified release form, wherein both forms are compressed into a single tablet. Other combinations and modifications of the release profile may be achieved as will be appreciated by one of skill in the art. Examples of modified release dosage forms suitable for the pharmaceutical compositions of the present invention are described, without limitation, in 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; 5591767; 5120548; 5073543; 5639476; 5354556; 5639480; 5733566; 5739108; 5891474; 5922356; 5972891; 5980945; 5993855; 6045830; 6087324; 6113943; 6197350; 6248363; 6264970; 6267981; 6376461; 6419961; 6589548; 6613358 and 6699500.

[0436] In some embodiments, the compositions of the invention are provided in a matrix-controlled release dosage form. For example, the compositions of the invention can comprise from about 300 mg to about 600 mg of a compound of the invention provided in a matrix-controlled release dosage form. In some embodiments, the matrix-controlled release dosage form can further comprise another pharmaceutically active agent. In some embodiments, the release profile of the compound of the invention and the other pharmaceutically active agent is the same or different. Suitable matrix-controlled release dosage forms are described, for example, in Takada et al in “Encyclopedia of Controlled Drug Delivery,” Vol. 2, Mathiowitz ed., Wiley, 1999.

[0437] In some embodiments, the compositions of the invention comprise from about 10 mg to about 400 mg of another pharmaceutically active agent and from about 300 mg to about 600 mg of a compound of the invention. In some embodiments, the compositions of the invention comprise from about 10 mg to about 400 mg of an anticancer agent and from about 300 mg to about 600 mg of a compound of the invention. In some embodiments, the composition is in a matrix-controlled modified release dosage form.

[0438] In some embodiments, the compositions of the invention comprise from about 10 mg to about 40 mg of a statin and from about 300 mg to about 600 mg of a compound of the invention, wherein the composition is presented in a matrix-controlled modified release dosage form.

[0439] In some embodiments, the matrix-controlled release formulation comprises an erodible matrix comprising water-swellable, erodible, or soluble polymers, including synthetic polymers, as well as naturally occurring polymers and derivatives such as polysaccharides and proteins.

[0440] In some embodiments, the erodible matrix of the matrix-controlled release formulation comprises chitin, chitosan, dextran, or pullulan; agar-agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenan, gum ghatti, guar gum, xanthan gum, or scleroglucan; starches such as dextrin or maltodextrin; hydrophilic colloids such as pectin; phosphatides such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; celluloses such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethyl cellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT) or ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol esters of fatty acids; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid ( ^EUDRAGIT® , Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable copolymers of lactic acid and glycolic acid; poly-D-(-)-3-hydroxybutyric acid or other acrylic acid derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate or (trimethylaminoethyl) methacrylate chloride; or any combination thereof.

[0441] In other embodiments, the compositions of the invention are in a matrix-controlled modified release form comprising a non-erodible matrix. In some embodiments, the statin compound of the invention is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix after administration. In some embodiments, the non-erodible matrix of the controlled release matrix mold comprises 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, polyethylene terephthalate ionomer, butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, or a hydrophilic polymer such as ethyl cellulose, cellulose acetate, crospovidone, or cross-linked partially hydrolyzed polyvinyl acetate; a fatty compound such as carnauba wax, microcrystalline wax, or triglyceride; or any combination thereof.

[0442] Compositions of the invention that are presented in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt granulation followed by compression.

[0443] In some embodiments, the compositions of the invention comprise a tablet-in-capsule system, which may be a multifunctional and multicomponent system comprising universal mini-tablets in a hard gelatin capsule. The mini-tablets may be quick-release, extended-release, pulsatile-release, delayed-release mini-tablets, or any combination thereof. In some embodiments, all combinations of mini-tablets or all combinations of mini-tablets and mini-granules containing multiple active pharmaceutical agents may have a specific release delay time of a pulsatile drug delivery system (DDS), a site-specific DDS, a slow-fast phase DDS, a fast/slow phase DDS, and a zero-order DDS.

[0444] In some embodiments, the compositions of the invention are presented in an osmotically controlled release dosage form.

[0445] In some embodiments, an osmotically controlled release device comprises a single chamber system, a dual chamber system, an asymmetric membrane technology (AMT), an extrudable core system (ECS), or any combination thereof. In some embodiments, such devices comprise at least two components: (a) a core that contains the active pharmaceutical agent(s); and (b) a semipermeable membrane with at least one delivery port that encapsulates the core. The semipermeable membrane controls the influx of water into the core from the aqueous medium used to cause the release of the drug by extrusion through the delivery port(s).

[0446] In some embodiments, the core of the osmotic device optionally comprises an osmotic agent that provides a driving force for transporting water from the use medium into the core of the device. One class of osmotic agents useful in the compositions of the invention comprises water-swellable hydrophilic polymers, which are also referred to as "osmopolymers" or "hydrogels", including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large blocks of PEO, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate.

[0447] Another class of osmotic agents useful in the compositions of the invention comprises osmogens that are capable of absorbing water and affecting the osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea and mixtures thereof.

[0448] Osmotic agents with different dissolution rates can be used to influence how quickly a compound of the invention will dissolve after administration. For example, an amorphous sugar such as Mannogeme EZ (SPI Pharma, Lewes, Delaware) can be included to provide faster delivery during the first few hours (e.g., from about 1 hour to about 5 hours) to quickly provide a prophylactic or therapeutic effect and gradually and continuously release the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In some embodiments, a compound of the invention is released from the compositions of the invention at a rate such that it replaces the amount of the compound of the invention metabolized or excreted by the subject.

[0449] The core may also include a wide variety of other excipients and carriers, as described herein, to enhance the efficacy of the dosage form or to provide stability or processing.

[0450] Materials useful for forming the semipermeable membrane include various grades of acrylics, vinyls, esters, polyamides, polyesters, and cellulose derivatives that are water permeable and insoluble in water at physiologically significant pH levels or that can be rendered insoluble in water by chemical modification such as cross-linking. Examples of suitable polymers useful for forming the coating include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, acetate agar, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxylated ethylene vinyl acetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyesters, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0451] Semipermeable membranes may also be a hydrophobic microporous membrane, the pores being substantially filled with gas and not wetted by an aqueous medium, but permeable to water vapor, as described in U.S. Patent No. 5,798,119. Such a hydrophobic but water vapor permeable membrane is typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyesters, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0452] The delivery port(s) on the semipermeable membrane may be formed after coating by mechanical or laser drilling. The delivery port(s) may also be formed in situ by eroding a plug of water-soluble material or by rupturing a thinner portion of the membrane over a depression in the core. In addition, the delivery ports may be formed during the coating process, as is the case with asymmetric membrane coatings of the type described in U.S. Patent Nos. 5,612,059 and 5,698,220.

[0453] The total amount of the compound of the invention released and the rate of release can be substantially modulated by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size and position of the delivery ports.

[0454] In some embodiments, the pharmaceutical composition in an osmotically controlled release dosage form may further comprise additional conventional excipients as described herein to provide efficacy or processing of the composition.

[0455] Osmotically controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art ( see Remington: The Science and Practice of Pharmacy , supra; Santus and Baker, J. Controlled Release 1995 , 35 , 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000 , 26 , 695-708; Verma et al., J. Controlled Release 2002 , 79 , 7-27).

[0456] In some embodiments, the pharmaceutical composition provided herein is formulated as a controlled release dosage form based on asymmetric membrane technology (AMT), which comprises an asymmetric osmotic membrane that coats a core containing the active ingredient(s) and other pharmaceutically acceptable excipients. See U.S. Patent No. 5,612,059 and WO 2002/17918. AMT-based controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip coating.

[0457] In some embodiments, the pharmaceutical composition provided herein is formulated as an ESC controlled release dosage form that comprises an osmotic membrane that coats a core comprising a compound of the invention, hydroxyethylcellulose, and other pharmaceutically acceptable excipients.

[0458] In some embodiments, the compositions of the invention are a modified release dosage form that is formulated as a multiparticulate controlled release dosage form that comprises a plurality of particles, granules or pellets, microparticles, microspheres, microcapsules, and microtablets that range in diameter from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to 1 mm.

[0459] Controlled release multiparticulate dosage forms can provide a sustained release dosage form with improved bioavailability. Suitable carriers for maintaining the release rate of a compound of the invention include, but are not limited to, ethylcellulose, HPMC, HPMC-phthalate, colloidal silicon dioxide, and Eudragit-RSPM.

[0460] Compositions of the invention in granular form may contain 50-80% (w/w) of the drug substance and 20-50% (w/w) of microcrystalline cellulose or other polymers. Suitable polymers include, but are not limited to, microcrystalline wax, pregelatinized starch, and maltodextrin.

[0461] Microspheres can be prepared in capsule and tablet dosage forms. Microspheres in a tablet dosage form can exhibit a slower dissolution profile than microparticles in capsule form. Microparticle excipients useful in the compositions and therapeutic or prophylactic methods of the 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.

[0462] In some embodiments, the compositions of the invention are in the form of microcapsules and/or microtablets. In some embodiments, the microcapsules comprise extended-release polymeric microcapsules comprising a statin and a compound of the invention with different solubility characteristics. Extended-release polymeric microcapsules can be prepared with a colloidal polymer dispersion in an aqueous medium. In other embodiments, microcapsules suitable for the compositions and methods provided herein can be prepared using conventional microencapsulation techniques (Bodmeier & Wang, 1993).

[0463] Such multiparticulates can be prepared by processes known to those skilled in the art, including wet and dry granulation, extrusion followed by spheronization, roller compaction, melt solidification, and spray coating of granulated 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 are described in the United States Pharmacopeia.

[0464] Other excipients, as described herein, can be mixed with the compositions of the invention to facilitate processing and formation of the multiparticulates. The resulting particles can themselves constitute a dosage form as a multiparticulate or can be coated with various film-forming materials, such as enteric polymers, water-swellable or water-soluble polymers. The multiparticulates can be further processed as a capsule or tablet.

[0465] In other embodiments, the compositions of the invention are presented in a dosage form that has an immediate release component and at least one delayed release component and is capable of providing continuous release of the compound in at least two successive pulses separated in time by intervals of from about 0.1 hour to about 24 hours.

[0466] In other embodiments, the compositions of the invention comprise from about 1 mg to about 1000 mg of a compound of the invention, or any amount between and to these values. In some embodiment, the compositions of the invention comprise from about 1 mg to about 500 mg of a compound of the invention, or any amount between and to these values. In some embodiment, the compositions of the invention comprise from about 1 mg to about 400 mg of a compound of the invention, or any amount between and to these values.

[0467] In other embodiments, the compositions of the invention comprise a compound of the invention in an amount that is a molar equivalent of from about 1 mg to about 1000 mg of the compound of the invention, or any amount between and to these values. In other embodiments, the compositions of the invention comprise a compound of the invention in an amount that is a molar equivalent of from about 1 mg to about 500 mg of the compound of the invention, or any amount between and to these values. In other embodiments, the compositions of the invention comprise a compound of the invention in an amount that is a molar equivalent of from about 1 mg to about 400 mg of the compound of the invention, or any amount between and to these values.

[0468] In some embodiments, the compositions of the invention comprise a compound of the invention in an amount of from about 10% by weight to about 99% by weight of the total weight of the composition of the invention.

[0469] Methods of the Present Invention

[0470] The present invention provides methods for treating or preventing a disease comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention, wherein the disease is a liver disease or pathological condition of the liver; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gallbladder, bile duct, or gastrointestinal tract; an intra- or extrahepatic bile duct disease; a lipoprotein metabolism disorder; lipid and metabolic disorders; cirrhosis; fibrosis; a glucose metabolism disorder; a cardiovascular disease or a related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease associated with increased inflammation (such as liver inflammation or lung inflammation); hepatocyte ballooning; a peroxisome proliferator-activated receptor-associated disease; ATP citrate lyase deficiency; acetyl coenzyme A carboxylase deficiency; obesity; pancreatitis or kidney disease.

[0471] The present invention provides methods for treating or preventing a disease comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention, wherein the disease is cancer, lipid and metabolic disorders, liver disease, cirrhosis, fibrosis, glucose metabolism disorder, peroxisome proliferator-activated receptor-associated disease, malignant or benign tumor of the lung, liver, bile duct and gastrointestinal tract, ATP citrate lyase activity disorder, acetyl-coenzyme A carboxylase activity disorder, obesity, pancreatitis, kidney disease, hepatocyte ballooning, liver inflammation or lung inflammation.

[0472] In some embodiments of the methods as described herein, the disease is cancer. In some embodiments, the cancer is hepatocellular carcinoma (HCC), HCC with cirrhosis, HCC without cirrhosis, cholangiocarcinoma, colorectal cancer, bile duct cancer, or lung cancer. In some embodiments, the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, 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, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, multiple myeloma, lymphoblastic leukemia, myelogenous leukemia, lymphocytic leukemia, myelocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, gastrointestinal cancer, head and neck cancer, hematopoietic cancer, or polycythemia vera.

[0473] In some embodiments, the gastrointestinal tract (digestive system) cancer is a gastrointestinal stromal tumor (GIST), esophageal cancer, gallbladder cancer, gastrointestinal carcinoid tumor, cholangiocarcinoma, duodenal cancer, gastroesophageal junction cancer, islet cell cancer, pancreatic cancer, gastric cancer, colon cancer, rectal cancer, colorectal cancer, anus cancer, liver cancer, biliary cancer, bile duct cancer, small intestinal cancer, pseudomyxoma peritonei, small intestinal cancer, or cancer of no known primary.

[0474] In some embodiments, the hematopoietic cancer is non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), multiple myeloma (MM), chronic B-cell lymphocytic leukemia (B-CLL), B- and T-cell acute lymphocytic leukemia (ALL), T-cell lymphoma (TCL), acute myeloid leukemia (AML), hairy cell leukemia (HCL), Hodgkin's lymphoma (HL), or chronic myeloid leukemia (CML).

[0475] In some embodiments of the methods as described herein, the cancer is a cancer at any stage. In some embodiments, the cancer may be at stage 0, stage I, stage II, stage III, or stage IV. In some embodiments of the methods as described herein, the disease is a tumor, and the tumor may be at any stage. In some embodiments, the tumor may be a grade 1, grade 2, grade 3, or grade 4 tumor.

[0476] In some embodiments of the methods as described herein, the disease is a lipid and metabolic disorder. In some embodiments, 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-glutamyl transpeptidase (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, high high-density lipoprotein (HDL), or high non-HDL cholesterol in the plasma or serum of the subject; or high glucose or insulin resistance in a subject with diabetes. In some embodiments, the lipid and metabolic disorders are nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or alcoholic steatohepatitis (ASH).

[0477] In some embodiments of the methods as described herein, the disease is a disorder of glucose metabolism. In some embodiments, the disorder of glucose metabolism is type I diabetes or type II diabetes.

[0478] In some embodiments of the methods as described herein, the disease is a disease resulting from steatosis, fibrosis, and cirrhosis. In some embodiments, the disease resulting from steatosis is inflammation. In some embodiments, the disease resulting from steatosis is NAFLD, NASH, or ASH. In some embodiments, the disease resulting from fibrosis is liver cirrhosis or liver failure. In some embodiments, the disease resulting from cirrhosis is hepatocellular carcinoma, liver injury, or hepatic encephalopathy.

[0479] The present invention provides methods for reducing in the blood plasma or serum of a subject a C-reactive protein (CRP) concentration, a serum amyloid A (SAA) concentration, alanine aminotransferase (ALT) concentration, aspartate aminotransferase (AST) concentration, alkaline phosphatase (ALP) concentration, gamma-glutamyl transferase (GGT) concentration, serum creatinine concentration, 7α-hydroxy-4-cholesten-3-one (C4) concentration, protein to creatinine ratio, creatine kinase concentration, angiopoietin-like protein 3 concentration, 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 concentration cholesterol, non-HDL concentration, apolipoprotein B concentration, lipoprotein(a) concentration, or serum triglyceride concentration, wherein the methods comprise administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0480] The present invention provides methods for reducing the concentration of triglycerides in the liver of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0481] The present invention provides methods for increasing the concentration of high-density lipoprotein cholesterol or HDL in the blood plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0482] The present invention provides methods for increasing the functionalization of high-density lipoprotein cholesterol without increasing its concentration in the blood plasma or serum of a subject, the methods comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention, wherein the amount or rate of elimination of cholesterol and triglycerides is increased.

[0483] The present invention provides methods for treating a disease comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention, wherein the disease is a gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), or an autoimmune disease.

[0484] In some embodiments of the methods as described herein, the disease is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

[0485] In some embodiments of the methods as described herein, the disease is an autoimmune disease. In some embodiments, the autoimmune disease is systemic lupus erythematosus.

[0486] The present invention provides methods for regressing, reducing the rate of progression, or inhibiting the progression of fibrosis, hepatocyte ballooning, or liver inflammation, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0487] The present invention provides methods for inhibiting, reducing, or slowing the progression of lipid synthesis, hepatic steatosis, hepatocyte ballooning or inflammation, liver fibrosis, pulmonary fibrosis, or cirrhosis in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0488] The present invention provides methods for reducing the risk of developing atherosclerosis, coronary artery disease, peripheral vascular disease, stroke, or restenosis in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention.

[0489] The present invention provides methods for increasing the concentration of HDL in the serum or plasma of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0490] The present invention provides methods for inhibiting NF-kB or stellate cell activation comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0491] The present invention provides methods for activating PPAR (peroxisome proliferator-activated receptor) in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0492] The present invention provides methods for downregulating CCR2/CCR5 genes comprising administering to a subject in need thereof an effective amount of a compound of the invention.

[0493] The present invention provides methods for inhibiting one or more of NF-kB activation, CCR2 activation, CCR5 activation, and stellate cell activation, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0494] The present invention provides methods for inhibiting the activation or concentration of an interleukin, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the interleukin (IL) is IL-2, IL-6, IL-17, or IL-18.

[0495] The present invention provides methods for inhibiting fibrin/fibrinogen, gastrin, lactate dehydrogenase, prostatic acid phosphatase (PAP), thyroglobulin, urinary catecholamines, urinary vanillylmandelic acid (VMA), or urinary homovanillic acid (HVA), comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0496] The present invention provides methods for inhibiting beta-human chorionic gonadotropin (beta-hCG), beta-2-microglobulin (B2M), B-cell immunoglobulin, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0497] The present invention provides methods for inhibiting alpha-fetoprotein (AFP), comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0498] The present invention also provides methods for inhibiting fatty acid or sterol synthesis in the liver, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0499] The present invention also provides methods for treating or preventing a disease or disorder that can be treated or prevented by increasing HDL levels, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0500] The present invention also provides methods for treating or preventing a disease or disorder that can be treated or prevented by lowering LDL levels, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0501] Without being limited by theory, it is believed that the compounds of the invention 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 methods for treating or preventing metabolic syndrome, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.

[0502] The present invention further provides methods of modulating, directly inhibiting, or allosterically inhibiting ATP citrate lyase in a subject, comprising administering to the subject an effective amount of a compound of the invention or a composition of the invention.

[0503] The present invention further provides methods of 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 a compound of the invention or a composition of the invention.

[0504] The present invention further provides methods for reducing the fat or cholesterol content of animal meat or bird eggs comprising administering to the animal or bird an effective amount of a compound of the invention or a composition of the invention.

[0505] In some embodiments of the methods as described herein, a compound of the invention is administered to a subject in need thereof in an amount in the range of about 1 mg to about 1000 mg, or any amount between and including these values. In some embodiments, a compound of the invention is administered to a subject in need thereof in an amount in the range of about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, or about 1 mg to about 300 mg.

[0506] In some embodiments of the methods as described herein, a compound of the invention is administered to a subject in need thereof in a daily dose in the range of about 1 mg to about 1000 mg, or in any amount between and including these values. In some embodiments, a compound of the invention is administered to a subject in need thereof at 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.

[0507] In some embodiments of the methods as described herein, a compound of the invention is administered to a subject in need thereof once daily at a dose of from about 1 mg to about 1000 mg, or any amount between and including these values.

[0508] In some embodiments of the methods as described herein, a compound of the invention is administered to a subject in need thereof twice daily, wherein each dose comprises a compound of the invention in an amount of from about 1 mg to about 500 mg, or any amount between and including. In some embodiments, a compound of the invention is administered to a subject in need thereof twice daily, wherein each dose comprises a compound of the 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.

[0509] In some embodiments of the methods as described herein, a compound of the invention is administered to a subject in need thereof three times per day, wherein each dose comprises a compound of the invention in an amount of from about 1 mg to about 400 mg, or any amount between and including. In some embodiments, a compound of the invention is administered to a subject in need thereof three times per day, wherein each dose comprises a compound of the 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.

[0510] In some embodiments of the methods as described herein, the methods further comprise administering an effective amount of another pharmaceutically active agent. In some embodiments, the other pharmaceutically active agent is administered simultaneously or sequentially (before or after) with administration of a compound of the invention or a composition of the invention. In some embodiments, the other pharmaceutically active agent is a statin, a thiazolidinedione or fibrate, a bile acid binding resin, niacin, an anti-obesity drug, a hormone, tyrofostin, a sulfonylurea drug, a biguanide, an alpha-glucosidase inhibitor, an apolipoprotein A-I agonist, an apolipoprotein E agonist, a phosphodiesterase type 5 inhibitor, a cardiovascular drug, an HDL-elevating drug, an HDL enhancer, an apolipoprotein A-I gene regulator, an apolipoprotein A-IV gene regulator, an apolipoprotein gene regulator, an ATP-citrate lyase modulator, an allosteric ATP-citrate lyase inhibitor, an acetyl-CoA carboxylase modulator, or an allosteric acetyl-CoA carboxylase inhibitor. In some embodiments, the other pharmaceutically active agent is lovastatin. In some embodiments, the other pharmaceutically active agent is sorafenib; taxol; carotuximab; pembrolizumab; lenvatinib; avelumab; durvalumab; tremelimumab; nivolumab; tazemetostat; cemiplimab; ABX196; a T cell receptor (TCR) immunocellular therapy; TBI-302; namodenoson; MM-310; an intratumorally injectable oncolytic virus or a genetically modified oncolytic virus such as, but not limited to, telomelysin and imligic; or an immunomodulatory gene therapy agent such as MDA-7/IL-24, GLIPR1/RTVP-1, and REIC/Dkk-3.

[0511] In some embodiments of the methods as described herein, the methods further comprise administering two or more other pharmaceutically active agents. In some embodiments, the methods of the invention comprise administering two or more other pharmaceutically active agents, optionally in combination. In some embodiments, the two or more other pharmaceutically active agents are oncolytic agents, such as, but not limited to, nanatinostat and valganciclovir. In other embodiments, the methods of the invention comprise orally administering a compound of the invention and further comprise administering an intratumorally injectable oncolytic agent. In some embodiments, the combination is administered orally.

[0512] In some embodiments, the other pharmaceutically active agent is cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, nivolumub, firsocostat, apararenone, metformin, the combination of leucine-metformin-sildenafil (NS-0200), IMM-124E, RG-125, vitamin E, cysteamine, selonsertib, losartan, RO5093151, pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, ND-L02-s0201/BMS-986263, volixibate, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricorylant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, volixibat, solithromycin, 99m technetium-mebrofenin, tropifexor, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, or seladelpar.

[0513] In some embodiments of the methods as described herein, the methods for treating or preventing a disease comprise administering Compound I-1 , Compound I-32 , Compound I-61 , or Compound III-1 , or a pharmaceutically acceptable salt or solvate thereof.

[0514] In some embodiments of the methods as described herein, the methods for treating or preventing a disease comprise administering an effective amount of (a) a compound of the invention and (b) another pharmaceutically active agent that is sorafenib, taxol, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, the combination of leucine-metformin-sildenafil, vitamin E, cysteamine, selonsertib, losartan, RO5093151, pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricorylant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, volixibate, elafibranor, nalmefene, solithromycin, 99m technetium-mebrofenine, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, fizogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib, sunitinib, or zotiraciclib citrate. In some embodiments of the methods as described herein, the methods for treating or preventing a disease comprise 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 that is sorafenib, taxol, lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, leucine-metformin-sildenafil combination, vitamin E, cysteamine, selonsertib, losartan, RO5093151, pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, volixibate, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafen, pentamidine, berberine, L-carnitine, EYP001a, silymarin, myricorylant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadan, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99m technetium mebrofenin, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib, sunitinib or zotiraciclib citrate.

[0515] In some embodiments of the methods as described herein, the methods for treating or preventing a disease comprise administering an effective amount of (a) a compound of the invention and (b) another pharmaceutically active agent that is sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, a T cell receptor (TCR) immunocellular therapy agent, TBI-302, namodenoson, MM-310, an intratumorally injectable oncolytic virus, a genetically modified oncolytic virus, or an immunomodulatory gene therapy agent. In some embodiments of the methods as described herein, the methods for treating or preventing a disease comprise 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 that is sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, a T cell receptor (TCR) immunocellular therapy agent, TBI-302, namodenoson, MM-310, an intratumorally injectable oncolytic virus, a genetically modified oncolytic virus, or an immunomodulatory gene therapy agent.

[0516] In some embodiments, the methods of the invention comprise administering to a subject in need thereof an effective amount of a compound of the invention and another pharmaceutically active agent as set forth in the embodiment in Table D. In some embodiments, the other pharmaceutically active agent is administered simultaneously, prior to, or sequentially with the administration of a compound of the invention or a composition of the invention.

[0517] In some embodiments of the methods as described herein, the methods further comprise administering radiation therapy to the subject. In some embodiments, the radiation therapy is gamma radiation therapy or x-ray radiation therapy. In some embodiments, the radiation therapy is performed using a gamma radiation or x-ray machine.

[0518] In some embodiments, radiation therapy is administered concurrently with, prior to, or sequentially with administration of a compound of the invention or a composition of the invention. In some embodiments, radiation therapy is administered prior to or sequentially with administration of a compound of the invention or a composition of the invention.

[0519] Methods for preparing compounds of the invention

[0520] Synthesis and General Protocols

[0521] Compounds of formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), and (IL) (collectively, "formula (I)") can be prepared using the synthetic methodologies demonstrated in Schemes 1-7. Starting materials useful for preparing the compounds of the invention and their intermediates are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.

[0522] Scheme 1 : General synthesis of formula (I)

[0523] 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 carboxylic acid or malonic acid ester carbanions. In Scheme 1, Q ¹ and Q ² can each independently be -O-alkyl, -S-alkyl, -S-aryl, -NR ^1A R ^2A , NHR ^1A , phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl, or heterocyclyl, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group. R ^1A and R ^2A are defined herein for Formula (I).

[0524] Scheme 2 : General synthesis of formula (I)

[0525] In Scheme 2, Q ¹ and Q ² can each independently be -O-alkyl, -S-alkyl, -S-aryl, -NR ^1A R ^2A , NHR ^1A , phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl or heterocyclyl, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group. R ^1A and R ^2A are defined herein for formula (I)

[0526] Scheme 3 : General synthesis of formula (I), where Z is -C(R ¹ )(R ² )-(CH ₂ ) _c -X, X is COOR ⁵ or COOH, and c is 0.

[0527] In Scheme 3, Q ¹ and Q ² can each independently be -O-alkyl, -S-alkyl, -S-aryl, -NR ^1A R ^2A , NHR ^1A , phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl, or heterocyclyl, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group. R ^1A and R ^2A are defined herein for formula (I).

[0528] Scheme 3 shows the conversion of ortho- , meta- , or para -ω-haloalkyl-substituted arenes of formula 5 , where p is an integer in the range 2-5 and Hal is Cl, Br, or I, to dicarboxylic acids of formula 7 , where R ¹ and R ² are alkyl and/or aryl moieties or are linked into a 3-7-membered ring. This transformation can be accomplished in two different, albeit related, pathways. According to the first method, esters of formula R ¹ R ² CHCO ₂ R ⁵ , where R ¹ and R ² are alkyl and/or aryl moieties or are linked in a 3-7 membered ring, and R ⁵ is typically ethyl or methyl, are deprotonated with strong bases, preferably, but not limited to, butyl lithium or lithium diisopropylamide, and then reacted with dihalides of formula 5 to form the corresponding diesters of formula 6 . In general, the reaction is carried out at temperatures from about -78°C to about 25°C, and the reaction solvent is preferably THF or diethyl ether (for a discussion of the scope of this method, see Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations , ^2nd ed.; Wiley-VCH, New York, 1999, pp 1725-1726. For specific examples of this method, see Dasseux et al ., US 6,646,170 and US 6,410,802, Oniciu et al. US 10,227,285 and Ackerley et al. , J. Med. Chem. 1995 , 38 , 1608-1628). In the second step, the diester of formula 6 is saponified (for a review, see Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations , ^2nd ed.; Wiley-VCH, New York, 1999, pp 1959-1968 and Smith, MB; March, J. March 's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure , ^5th ed.; John Wiley and Sons, New York, 2001, pp 469-474) to a dibasic acid of formula 7 . Alternatively, this conversion of the dihalide of formula 5 to ^the dibasic _acid of formula 7 can also be achieved in a single step when a carboxylic acid of formula ^R1R2CHCO2H , where ^R1 and ^R2 are alkyl and/or aryl, is deprotonated twice under conditions analogous to _the alkylation ^{of R1R2CHCO2R5} described above and subsequently reacted with dibromide 5 (for a discussion, see Larock, ^RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations , ^2nd ed.; Wiley-VCH, New York, 1999, pp 1717-1718). For example, a compound of formula 5 ( ortho , p=3, Hal=Br) is reacted with lithium ethyl isobutyrate (prepared from ethyl isobutyrate with lithium diisopropylamide) in a solvent mixture of THF and DMPU at a temperature in the range of about -78°C to room temperature to give the corresponding diester of formula 7 ( ortho , p=3). This diester is then hydrolyzed under standard conditions (aqueous ethanol, potassium hydroxide, reflux temperature) to give, after re-acidification with dilute aqueous hydrochloric acid, the dicarboxylic acid of formula 7 with the ortho substitution pattern, R ¹ =R ² =methyl and p=3. In another method, which is described by Gleiter et al. , J. Org. Chem. 1992 , 57 , 252-258, isobutyric acid is deprotonated twice with n -butyl lithium and diisopropylamine in THF solution, first at about -20°C and then at about 50°C. After recooling to about -20°C, a solution of compound of formula 5 ( ortho , R ¹ =R ² =methyl, p =3, Hal =Br) in THF is then added dropwise, maintaining the temperature below 10°C. The mixture is then stirred first at room temperature and then at about 40°C and worked up in the usual manner to give the corresponding diacid 7 . Halide derivatives of type 5 can be prepared by several methods, described, for example, by Gleiter et al. , J. Org. Chem. 1992 , 57 , 252-258.

[0529] Scheme 4 : Total synthesis of compound 5-Br (compound 5 , where Hal=Br)

[0530] In Scheme 4, Q ¹ and Q ² can each independently be -O-alkyl, -S-alkyl, -S-aryl, -NR ^1A R ^2A , NHR ^1A , phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl, or heterocyclyl, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group. R ^1A and R ^2A are defined herein for formula (I).

[0531] Scheme 4 shows the synthesis of para- , meta- , and ortho- dibromoalkyl-substituted aryl compounds 5-Br from starting dicarboxylic acids 10 , where (p-1) is an integer ranging from 1 to 2. Scheme 4 first describes the esterification of compounds of Formula 10 to diesters of Formula 20 , where R is an alkyl moiety such as, but not limited to, methyl, ethyl, or isopropyl, using the general procedures referenced in Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations , ^2nd ed.; Wiley-VCH, New York, 1999, pp 1932–1941 and Smith, M. B.; March, J. March 's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure , ^5th ed.; John Wiley and Sons, New York, 2001, pp 484-486. Diols 30 can be prepared from diesters 20 by well-known synthetic methods (for a discussion of suitable reduction methods, see, e.g., Hudlicky, M. Reductions in Organic Chemistry , ^2nd ed.; ACS Monograph 188, Washington, DC, 1996, pp 212-216). In the next step, the conversion of the alcohol functional groups in 30 to the bromine moieties in the compound 5-Br can be achieved by various standard methods, as mentioned in Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations , ^2nd ed.; Wiley-VCH, New York, 1999, pp 693-695. For example, a compound of formula 10 with a para substitution pattern and (p-1)=1 (available from Aldrich Chemical Co., Milwaukee, WI) is treated with excess methanol and concentrated sulfuric acid at reflux temperature to give the corresponding dimethyl ester of formula 2. A procedure that can be used for this transformation is mentioned, for example, in Schimelpfenig, CW J. Org. Chem. 1975 , 40 , 1493-1494, incorporated herein by reference. Additionally, a compound of formula 20 ( para , (p-1)=1) can be converted to the corresponding compound of formula 30 by reaction with a metal hydride complex, preferably, but not limited to, lithium aluminum hydride, in an aprotic organic solvent such as THF or diethyl ether, as mentioned in Reynolds et al . US 2,789,970, application No. 397,037, filed December 8, 1953. Furthermore, the diol of formula 30 ( para , p=1) can be converted to the bromide of formula 5-Br ( para , p=1) by treatment with sodium bromide and concentrated sulfuric acid at elevated temperature. A useful solvent for this conversion is water, as described in Schimelpfenig, CW J. Org. Chem. 1975 , 40 , 1493-1494.

[0532] Scheme 5 : Total synthesis of compound 5A-Br

[0533] In Scheme 5, Q ¹ and Q ² can each independently be -O-alkyl, -S-alkyl, -S-aryl, -NR ^1A R ^2A , NHR ^1A , phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl, or heterocyclyl, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group. R ^1A and R ^2A are defined herein for formula (I).

[0534] Scheme 5 shows the preparation of ortho- , meta-, and para- substituted aryl compounds with two 3-bromopropyl substituents of formula 5A-Br . Specific examples of the synthesis of meta- and para- substituted compounds of 5A-Br are provided by Schimelpfenig, CW J. Org. Chem. 1975 , 40 , 1493-1494 and Gleiter et al. , J. Org. Chem. 1992 , 57 , 252-258, respectively. For example, a compound of formula 50 is treated with malonic acid and piperidine in pyridine solution at about 90-110°C to give the α,β-unsaturated carboxylic acid of formula 60 . The end point of this transformation is generally indicated by the cessation of CO ₂ evolution. This procedure is known as the Knoevenagel-Doebner reaction and a suitable reaction protocol for this transformation is given in Organikum, Organisch-Chemisches Grundpraktikum , VEB Verlag Deutscher Wissenschaften, Berlin 1984 , pp 572-574. Reduction of compounds of formula 60 to compounds of formula 70 can be achieved by catalytic hydrogenation over colloidal palladium, Raney nickel, or copper chromite as discussed in Hudlicky, M. Reductions in Organic Chemistry , ^2nd ed.; ACS Monograph 188, Washington, DC, 1996, pp 196-197. Conversion of a compound of formula 60 by meta- substitution to the corresponding compound 70 by treatment with hydrogen gas at a pressure of from about 20 to 60 psi can be achieved. inch and a palladium on carbon catalyst in aqueous sodium hydroxide solution is described in Schimelpfenig, CW J. Org. Chem. 1975 , 40 , 1493-1494, which is incorporated herein by reference in its entirety. Further conversion of compounds of formula 70 to compounds of formula 5A-Br can then be accomplished according to the methodology described in Scheme 4.

[0535] Scheme 6 : Total synthesis of 5-Br via chain extension

[0536] In Scheme 6, Q ¹ and Q ² can each independently be -O-alkyl, -S-alkyl, -S-aryl, -NR ^1A R ^2A , NHR ^1A , phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl, or heterocyclyl, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group. R ^1A and R ^2A are defined herein for formula (I).

[0537] Scheme 6 shows a general method for chain extension of bromides of formula 90 with an alkyl chain consisting of (p-2) methylene groups to bromides of formula 5-Br with an alkyl chain consisting of p methylene groups. The sequence of transformation from alkyl halides (such as 90) to a carboxylic acid (such as 120 ) can be accomplished via the malonic ester synthesis mentioned 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 ed.; Wiley-VCH, New York, 1999, p 1765. In general, monoalkylation of malonic acid esters (R is typically ethyl or methyl) uses a base-solvent combination of sodium ethoxide in ethanol, which inhibits the formation of dialkylated by-products ( Organic Reactions, Volume IX , editor-in-chief: R. Adams; Robert E. Krieger Publishing Company, Malabar, Florida, 1957, p 132) to give compounds of formula 100. Compounds of formula 100 are then saponified to give compounds of formula 110 , which can be heated above their melting point to decarboxylate to compounds of formula 120 . Conversion of dicarboxylic acids 120 via diesters 20 to the chain-extended 5-Br dibromides is then accomplished according to the methodologies described in Scheme 4. Alternatively, direct decarbalkoxylation of geminal diesters 100 to compounds of formula 20 can be achieved by treatment with water and DMSO in the presence or absence of added salts. However, addition of salts such as KCN, NaCl, or LiCl to the water/DMSO solvent can enhance the rate of decarbalkoxylation of these substrates (Fakhri, SA; Yousefi, BH Tetrahedron 2000 , 56 , 8301-8308). For example, ethyl malonate is reacted with sodium metal in ethanol, and a solution of a compound of formula 90 with (p-2)=2 and ethyl malonate is added to afford the corresponding compound of formula 100 . This tetraester is then saponified using, for example, aqueous ethanol and potassium hydroxide to give the corresponding tetrabasic acid of formula 110. The tetrabasic acid is then decarboxylated at about 200°C to the dibasic acid of formula 120. After esterification with methanol and concentrated sulfuric acid (see Scheme 4) to the diester 20. Useful methods for converting the tetraester of formula 100 ( ortho , (p-2)=1, R=ethyl) to the diester of formula 20 are described in Fakhri, S. A.; Yousefi, B. H. Tetrahedron 2000 , 56 , 8301-8308, which is incorporated herein by reference in its entirety.

[0538] Scheme 7 : General synthesis of compounds of formula 7

[0539] In Scheme 7, Q ¹ and Q ² can each independently be -O-alkyl, -S-alkyl, -S-aryl, -NR ^1A R ^2A , NHR ^1A , phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, -CF ₃ , -COR ^1A , heteroaryl, or heterocyclyl, or each carbon atom together with Q ¹ and Q ² attached to the carbon atom independently form a heterocyclyl or carbocyclyl group. R ^1A and R ^2A are defined herein for formula (I).

[0540] Scheme 7 shows the synthesis of ortho- , meta- , and para- substituted aryl compounds of formula 7 by ω-carboxyalkyl substitution, where (p-1) is an integer in the range 2-12, and R ¹ and R ² are alkyl and/or aryl moieties or two alkyl moieties joined in a 3-7 membered ring. The synthesis begins with the double deprotonation of ortho- , meta- , or para -xylene 3 with a strong base such as, but not limited to, a combination of n -butyl lithium and potassium tert -butoxide in an aprotic solvent such as, but not limited to, hexane and reacting the resulting dianion 3 with suitable electrophiles A-( _CH2 ) _p-1 - ^CR1R2 _- ^CH2O -PG, where (p-1), ^R1 , and ^R2 are defined above and A is Cl, Br, or I. "PG" is a hydroxyl protecting group. Examples of hydroxyl protecting groups are described in Greene, T. W.; Wuts, PGM Protective groups in organic synthesis , ^3rd ed., John Wiley and Sons, New York, 1999, pp 17-245, which is incorporated herein by reference. Methylarenes can be alkylated by deprotonation using lithium bases followed by alkylation with suitable electrophiles according to Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations , ^2nd ed.; Wiley-VCH, New York, 1999, p 88. For examples of the preparation of xylene dianions, see Bates et al. , J. Am. Chem. Soc. 1981 , 103 , 5052–5058. In the next step, the protecting groups 190 are removed to release the terminal hydroxylmethyl moieties at 200 , which are then oxidized using a suitable oxidizing agent (Larock, RC Comprehensive Organic Transformations. A Guide to Functional Group Preparations , ^2nd ed.; Wiley-VCH, New York, 1999, pp 1646–1648 and Smith, MB; March, J. March 's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure , ^5th ed.; John Wiley and Sons, New York, 2001, p 1537) to give the dicarboxylic acid of formula 7. For example, m -xylene ( meta - 3 ) is reacted with n -butyl lithium and potassium tert -butoxide in hexanes, first at room temperature and then at reflux temperature. After cooling to 0°C, a compound of formula 180 (A=Br, (p-1)=3, ^R1 = ^R2 =methyl, PG=tetrahydropyranyl, prepared according to Dasseux et al ., US 6,646,170 and US 6,410,802) is added and the reaction is continued at reflux temperature to yield, after the usual work-up and purification by column chromatography, the corresponding compound of formula 190 . Deprotection of 190-200 ( ^R1 , R2 ⁼ methyl, p=3) is then accomplished by heating in methanol and concentrated aqueous hydrochloric acid (Vogel, A. I. Vogel 's textbook of practical organic chemistry , ^5th ed., Longman Scientific and Technical, 1989, p. 552). This compound 200 is then treated with pyridinium dichromate in N,N' -dimethylformamide according to Vedejs, E.; Dent, WH, III; Gapinski, DM; McClure, CK J. Am. Chem. Soc. 1987 , 109 , 5437-5446 to give the dicarboxylic acid of formula 7 ( meta , p=3; R ¹ , R ² =methyl).

[0541] Scheme 8 shows illustrative alternative routes to the synthesis of compounds I-1 and I-32 . Commercially available benzenedicarboxaldehydes (Sigma-Aldrich, AK Scientific, etc.) are reacted with (5-ethoxy-4,4-dimethyl-5-oxopentyl)triphenylphosphonium bromide ( 220) (prepared as described in Oniciu, D, C. et al., WO2012/054535 and US 8349833 B2) in the presence of a base (including, but not limited to, sodium or potassium hydroxide, potassium or sodium tert-butoxide, potassium or sodium carbonate, and sodium hydride) in a manner described in Le Bigot Y. et al., 1988, Tetrahedron 44(4), pp. 1057-1072, as a mixture of cis and trans isomers. A mixture of cis and trans isomers of formula ( 230 ) or ( 240 ) can be catalytically reduced by olefin hydrogenation methods known in the art, such as those described by H.-U. Blaser, F. Spindler, M. Thommen, The Handbook of Homogeneous Hydrogenation, J. G. De Vries, C. J. Elsevier, Eds. (Wiley-VCH, 2008), chap. 37; Scharnagl, F. K. et al., Sci. Adv. 2018; 4: eaau1248, 21 September 2018; and in the references cited herein. The esters thus obtained are hydrolyzed after the hydrogenation reaction is deemed to be substantially complete, using appropriate analytical methods. Reaction mixtures containing compounds of formula ( 250 ) or ( 260 ), respectively, are hydrolyzed in the presence of an alkaline earth metal salt or base, or _an alkali metal oxide or salt or base in refluxed alcohols for 2-96 hours. Typical examples include, but are not limited to, hydrolysis with _K2CO3 in a refluxed mixture of DMSO and water. Other suitable procedures are indicated in Houben-Weyl, Methoden der Organische Chemie, Georg Thieme Verlag Stuttgart 1964, vol. XII/2, pp. 143-210 and 872-879, or Anderson, N.G., Practical Process Research & Development, Academic Press, London, 2000, pp.93-94 and 181-182.

[0542] Scheme 8. Illustrative synthesis of compounds I-1 and I-32.

[0543] Scheme 9 . General synthesis of compounds of formula (III) or (IIIA), where X=O, Z ¹ , Z ² =COOH, q=0, and R ¹ and R ² together form a cyclopropyl ring

[0544] A compound of formula (III) or (IIIA), where X=O, can be prepared by the Williamson synthesis by reacting an alcohol with a derivative containing a leaving group such as a halide, tolyl sulfonate, or mesylate. See Scheme 9.

[0545] Synthesis of compounds according to examples

[0546] Example 1. Synthesis of (9-carboxymethylsulfanyl-5-oxononylsulfanyl)-acetic acid (compound II-3 )

[0547] Reaction of ethyl 5-bromovalerate with lithium diisopropylamide in THF at room temperature gives the keto acid ester 1-1 (see, e.g., Cooke, M. P. J. Org. Chem. 1993 , 58 , 2910-2912; Stetter, H.; Rauhut, H. Chem. Ber. 1958 , 91). Decarboxylation of 1-1 by refluxing in HCl/EtOH (Cooke, M. P. J. Org. Chem. 1993 , 58 , 2910-2912) gives crude 1-2 , which can be purified by column chromatography using systems such as silica gel and ethyl acetate/hexanes mixtures in ratios from 1/20 to 1/8. Mercaptoacetic acid dissolved in mixtures of ethanol and water is treated with a solution of sodium hydroxide in water to give sodium mercaptoacetate and used to treat 1-2 in solvents such as ethanol as described in Agnus, A., Louis, Gissebrecht, J. P., Weiss, R., J. Am. Chem. Soc. , 1984 , 106 , 93 or Riesen, P. C.; Kaden, T. A. Helv. Chim. Acta., 1995 , 78 , 1325-1333, to give crude compound II-3 . Crude compound II-3 can be purified by recrystallization from solvents or solvent mixtures such as MTBE and heptane.

[0548] Example 2. Synthesis of (9-carboxymethylsulfanyl-5-hydroxynonylsulfanyl)-acetic acid (compound II-1 )

[0549] Reduction of the dibasic keto acid compound II-3 from Example 1 is achieved with sodium borohydride after salt formation with NaOH to yield compound II-1 (for suitable reaction conditions , see U.S. Patent No. 7,119,221). Compound II-3 (Example 1) is dissolved in a solution of NaOH (2-7 equiv.) to form an intermediate disodium salt in water. Isopropanol is then added followed by the addition of sodium borohydride (1.05 equiv.) in portions. The reaction mixture is heated at about 45°C for several hours to yield compound II-1 . This product can be purified by recrystallization from MTBE, heptane, or mixtures.

[0550] Example 3. Synthesis of [5-(5-carboxymethoxypentyloxy)-pentyloxy]-acetic acid (compound II-12 )

[0551] Compound II-12 is prepared by Williamson ether synthesis starting from 3-1 and 3-2 (prepared as described in Dasseux et al. US 6,459,003). The resulting 3-3 is deprotected in methanol in the presence of a catalytic amount of p -toluenesulfonic acid monohydrate to give the diol 3-4 . This diol is then coupled with tert -butyl bromoacetate in a biphasic system of aqueous NaOH and toluene in the presence of tetrabutylammonium bromide as a PTC catalyst as described in US Patent No. 10,227,285. Finally, this tert -butyl ether is cleaved under acidic conditions to give compound II-12 .

[0552] Example 4. Synthesis of [5-(5-carboxymethoxypentylsulfanyl)-pentyloxy]-acetic acid (compound II-20 )

[0553] Compound 3-1 (prepared as described in U.S. Patent No. 6,790,953) is treated with sodium sulfide analogous to the method described by Edwards, D.; Stenlake, J. B. J. Pharmacy Pharmacol. 1955 , 7 , 852-860, to form the thioether 4-1 , which is deprotected in methanol in the presence of a catalytic amount of pyridinium p -toluenesulfonate (PPTS) as described by Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977 , 42(23) , 3772-73. The thus obtained diol 4-2 is reacted with tert -butyl bromoacetate under phase transfer catalysis conditions using (Bu ₄ N)(HSO ₄ ) as a catalyst following the method of Nagatsugi, F.; Sasaki, S.; Maeda, M. J. Fluorine Chem. 1992 , 56 , 373-383, to give its tert -butyl ester 4-3 . Subsequent cleavage of the tert -butyl ester with trifluoroacetic acid (TFA) gives the free acid compound II-20 in 90% yield similar to the procedure of Nagatsugi, F.; Sasaki, S.; Maeda, M. J. Fluorine Chem. 1992 , 56 , 373-383.

[0554] Example 5. Synthesis of [5-(5-carboxymethoxypentane-1-sulfinyl)-pentyloxy]-acetic acid (compound II-24 )

[0555] Compound II-24 is prepared starting from compound II-12 (Example 4) using hydrogen peroxide as an oxidizing agent similar to the procedure described in U.S. Patent No. 6,673,780.

[0556] Example 6. Synthesis of [5-(5-carboxymethylsulfanylpentyloxy)-pentylsulfanyl]-acetic acid (compound II-6 )

[0557] Compounds 6-1 and 6-2 were prepared according to the methods described in Harrison, G. C.; Diehl, H. Organic Synthesis 1955 Coll. Vol 3 , 370 and Francis, G. W.; Berg, J. F. Acta Chem. Scand. B 1977 , 31 , 721-722, respectively. 5-Chloropentan-1-ol is commercially available and 3-4 was prepared as described in Example 3, as follows: mercaptoacetic acid (8.1 g, 87.9 mmol) was dissolved in a solution of deionized water/ethanol (50 mL/40 mL). A solution of sodium hydroxide (7.0 g, 175.5 mmol) in water (50 mL) was added with stirring. To this mixture was added dropwise bis(4-chlorobutyl ether) (7.0 g, 35.1 mmol) in ethanol (20 mL) over 30 min. The mixture was heated to reflux for 20 h followed by evaporation of the ethanol. The residue was diluted with water (20 mL). The aqueous layer was extracted with MTBE (4 x 20 mL) and the organic layers were discarded. The aqueous layer was acidified with conc. HCl to pH 2 (ca. 12 mL) and extracted with MTBE (4 x 30 mL). The combined organic layers were checked by TLC (silica gel, CH ₂ Cl ₂ : MeOH = 9:1) for the presence of starting mercaptoacetic acid (R _f = 0.7; bright blue spot with phosphomolybdic acid/EtOH). The organic layer was washed with water until the starting acid completely disappeared (ca. 700 ml in portions). The solvent was removed under reduced pressure to give a colourless oil (7.7 g), which solidified at room temperature. This solid was recrystallized from heptane/MTBE (50/60 ml) to give nice white crystals (6.2 g, 57% yield; purity 99% -RI, 91% -UV, mp 43-44 °C). Additional product was obtained from the mother liquor (0.87 g, mp 38-40 °C).

[0558] Example 7. Synthesis of (11-carboxymethylsulfanyl-6-oxoundecylsulfanyl)-acetic acid (compound II-4 ) and (11-carboxymethylsulfanyl-6-hydroxyundecylsulfanyl)-acetic acid (compound II-2 )

[0559] The synthesis of compounds II-4 and II-2 begins with 1,11-dibromoundecan-6-one ( 7-4 ), prepared as shown above, starting from commercially available 6-bromohexanol. Protection of the hydroxyl group of 6-bromohexanol with dihydropyran gives intermediate 7-1 , as described in U.S. Patent Nos. 6,646,170 and 6,410,802. Reaction of 7-1 with TosMIC in dimethylacetamide (DMAc) in the presence of sodium amylate (NaOAm-t) gives intermediate 7-2 , which is converted to the diol 7-3 . The removal of the THP protecting groups and the conversion of the isocyanatotosyl moiety into a ketone group occur simultaneously in a mixture of solvents such as methylene chloride, methanol, in the presence of aqueous HCl for about 12-24 hours. Diol 7-3 can be purified by column chromatography on silica gel and mixtures of solvents such as ethyl acetate and methylene chloride. The compound 7-3 thus obtained undergoes a Mitsunobu reaction to give bromide 7-4 , which is then treated with sodium mercaptoacetate in alcohol or a mixture of alcohols (ethanol, isopropanol) to give diacid compound II-4 . Compound II-4 is reduced with sodium borohydride to give compound II-2 (see Example 2).

[0560] Example 8. Synthesis of [4-(4-carboxymethoxybutoxy)-butoxy]-acetic acid (compound II-11 )

[0561] Commercially available bis(4-chlorobutyl ether) is converted with the diacetate 8-1 [Kliem, A., Schniepp, LE J. Am. Chem. Soc., 1948 , 70 , 1839] to the diol 8-2 , which is further reacted with ethyl bromoacetate to give 8-3 . Compound 8-3 is hydrolyzed to give II-11 . Alternatively, bis(4-chlorobutyl ether) is treated with the dianion of hydroxyacetic acid to give compound II-11 using an autoclave or high temperatures.

[0562] In particular, the diacetate 8-1 is treated with potassium carbonate in methanol similar to the method described by Kliem, A., Schniepp, LE J. Am. Chem. Soc., 1948 , 70 , 1839, and the crude compound 8-2 is optionally purified by column chromatography. The diol 8-2 is deprotonated with sodium hydride (95% or 60% in mineral oil) in THF for about 2 h to about 4 h, and then reacted with ethyl bromoacetate to give the diester 8-3 . The final step, hydrolysis of 8-3 , is carried out with KOH in ethyl alcohol for about 2 to about 8 h. The product is then subjected to work-up including acidification with aqueous HCl followed by extraction with methylene chloride to afford crude compound II-11 . Crude compound II-11 is optionally purified by gradient column chromatography on silica gel using solvents such as EtOAc and hexanes, as well as mixtures thereof.

[0563] Example 9. Synthesis of 5,5'-(1,4-phenylene)bis(2,2-dimethylpentanoic acid) (compound I-78 )

[0564] (4-Methoxycarbonylmethylphenyl)-acetic acid methyl ester (A2)

[0565] Concentrated sulfuric acid (40 mL) was added to phenylenediacetic acid ( A1 ) (25.0 g, 0.129 mol) in MeOH (300 mL). The reaction mixture was heated to reflux overnight. Most of the MeOH was evaporated in vacuo. The residue was diluted with EtOAc (300 mL) and water (300 mL). The aqueous solution was separated and extracted with EtOAc (2 x 100 mL). The combined organic solutions were washed with water (100 mL), saturated NaHCO ₃ solution (2 x 100 mL), and brine (100 mL) and dried over MgSO ₄ . The solvent was evaporated to give (4-methoxycarbonylmethylphenyl)-acetic acid methyl ester (27.1 g, 95%, 92.3% by HPLC) as a white solid. mp 59-60°C (51-54°C, Dynamit Nobel, GB Patent 1495472, application no. 9008/75, filed 4 March 1975). ¹ H NMR (CDCl ₃ ): δ=7.25 (s, 4H), 3.70 (s, 6H), 3.60 (s, 4H). ¹³ C NMR (CDCl ₃ ): δ=174.0, 132.5, 129.0, 52.0, 40.5.

[0566] 2-[4-(2-hydroxyethyl)-phenyl]-ethanol (A3)

[0567] Methyl (4-methoxycarbonylmethyl-phenyl)-acetate ( A2 ) (26.5 g, 0.12 mol) in THF (100 mL) was added to a solution of LiAlH ₄ (11.0 g, 0.29 mol) in THF (300 mL) at room temperature with stirring. The reaction mixture was heated to reflux for 2 h. Water (100 mL) was carefully added followed by dilute aqueous HCl (75 mL conc. HCl in 100 mL water). The aqueous phase was extracted with EtOAc (2×100 mL). The combined organic solutions were washed with water (100 mL), saturated NaHCO ₃ solution (150 mL), and brine (100 mL) and dried over MgSO ₄ . The solvent was evaporated to give 2-[4-(2-hydroxyethyl)phenyl]ethanol (18.68 g, 94%, 93.5% pure by HPLC) as a white solid. mp 89-90°C (87-88°C, Reynolds et al . US 2,789,970, application #397,037, filed December 8, 1953). ¹ H NMR (CDCl ₃ ): δ=7.17 (s, 4H), 3.78 (t, J =6.6 Hz, 4H), 2.81 (t, J =6.6 Hz, 4H), 2.30 (br s, 2H). ¹³ C NMR (CDCl ₃ ): δ=136.9, 129.4, 63.8, 39.0.

[0568] 1,4-bis-(2-bromoethyl)-benzene (A4)

[0569] Concentrated sulfuric acid (30.0 g) was added dropwise over 1 h to a refluxing mixture of 2-[4-(2-hydroxyethyl)-phenyl]-ethanol ( A3 ) (18.29 g, 0.11 mol), NaBr (40.0 g, 0.39 mol), and water (50 mL). The reaction mixture was heated to reflux for 1 h. Additional portions of sulfuric acid (10 mL) and NaBr (16.0 g, 0.16 mol) were added and refluxing was continued for 1.5 h. Water (100 mL) was added to the cooled mixture and the product was extracted with methylene chloride (3×100 mL). The combined organic solutions were washed with water (100 mL) and brine (100 mL) and dried over _MgSO4 . The solvent was evaporated and the residue was purified by column chromatography (silica gel, EtOAc:hexanes, 1:1). The solid was recrystallized from hexanes to give 1,4-bis-(2-bromoethyl)benzene (22.27 g, 69%, 99.8% pure by HPLC) as a white solid. mp 188.5 71-72°C (70-71°C, Longone, DT; Küsefoglu, SH; Gladysz, JA J. Org. Chem. 1977 , 42 , 2787-2788. ¹ H NMR (CDCl ₃ ): δ=7.18 (s, 4H), 3.57 (t, J =2.2 Hz, 4H), 3.16 (t, J =7.8 Hz, 4H). ¹³ C NMR (CDCl ₃ ): δ=138.6, 130.0, 40.1, 34.0.

[0570] 4-[4-(3-carboxy-3-methylbutyl)phenyl]-2,2-dimethylbutyric acid

[0571] 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 h 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 DMPU (10 mL). The reaction mixture was warmed to room temperature over 2 h and stirred for 1 h at 40-50 °C. Water (200 mL) was added and the aqueous solution was separated and extracted with EtOAc (3×80 mL). The combined organic solutions were washed with water (100 mL) and brine (100 mL). After concentration under reduced pressure, the residue was purified by column chromatography (silica gel, EtOAc:heptane, 1:10) to give 4-[4-(3-ethoxycarbonyl-3-methylbutyl)phenyl]-2,2-dimethylbutyric acid ethyl ester (24.0 g). This intermediate (24.0 g, 66.2 mmol) was dissolved in EtOH (300 mL), water (50 mL), KOH (85%, 15.0 g, 227 mmol) were added, and the reaction mixture was refluxed for 3 h. The solvent was evaporated, the residue was dissolved in water (150 mL) and extracted with MTBE (2×30 mL). The aqueous solution was acidified with aqueous HCl to pH 1-2. The precipitate was filtered, recrystallized from CHCl ₃ /EtOH (1:1), and dried in vacuo to give 4-[4-(3-carboxy-3-methylbutyl)phenyl]-2,2-dimethylbutyric acid (13.6 g, 64%, 94.8% pure by HPLC) as white crystals (compound I-78 ). mp 214-215°C. Elemental analysis (C ₁₈ H ₂₆ O ₄ ): calculated for C, 70.56; H, 8.55, found: C, 70.78; H, 8.64. ¹ H NMR (CD ₃ OD): 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 C NMR (CD ₃ OD): δ=181.5, 140.9, 129.2, 44.3, 43.2, 32.3, 25.8. HRMS calculated for C ₁₈ H ₂₆ O ₄ (M ⁺ ): 306.1831, found: 306.1831.

[0572] Example 10. Synthesis of 6,6'-(1,4-phenylene)bis(2,2-dimethylhexanoic acid) (compound I-1 )

[0573] 4-[4-(3-methoxycarbonylpropyl)-phenyl]-butyric acid methyl ester (B1)

[0574] The compound was prepared by a method modified from that described by Cram, DJ; Allinger, NL; Steinberg, H. J. Amer. Chem. Soc. 1954 , 76 , 6132.

[0575] Under _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 warm solution. The reaction mixture was heated to reflux for 5 min 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 min. The reaction mixture was heated to reflux for 0.5 h. After addition of water (150 mL) and EtOAc (200 mL), the solvents were evaporated and the residue was dissolved in EtOAc (200 mL). The solution was washed with water (100 mL) and brine (100 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was dried under high vacuum at 80-100 °C (oil bath). The resulting crude 2-{2-[4-(3,3-bis-ethoxycarbonylpropyl)-phenyl]-ethyl}malonic acid diethyl ester was dissolved in aqueous EtOH (80%, 200 mL) and KOH (85%, 35.0 g, 0.53 mol) was added. The reaction mixture was heated to reflux for 2 h. The solvent was partially evaporated and EtOAc (150 mL) was added. The aqueous layer was separated and extracted with EtOAc (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over MgSO ₄ 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 h. The resulting 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 h, then stirred overnight at room temperature. MeOH was partially evaporated and the residue was dissolved in EtOAc (150 mL), washed with water (150 mL) and brine (150 mL) and dried over MgSO ₄ . The solvent was evaporated to give crude 4-[4-(3-methoxycarbonylpropyl)-phenyl]-butyric acid methyl ester ( B1 ) (17.9 g, 85%) as yellow oil, which was used in the next step without further purification. ¹ H NMR (CDCl ₃ ): 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 (CDCl ₃ ): δ=174.0, 138.9, 128.4, 51.5, 34.6, 33.3, 26.5.

[0576] 4-[4-(4-hydroxybutyl)-phenyl]-butan-1-ol (B2)

[0577] The compound was prepared according to Cram, D. J.; Allinger, N. L.; Steinberg, H. J. Am. Chem. Soc. 1954 , 76 , 6132-6141). A solution of methyl 4-[4-(3-methoxycarbonylpropyl)-phenyl]-butyrate (17.7 g, 63.6 mmol) in THF (50 mL) was added to a suspension of LiAlH ₄ (7.2 g, 0.19 mol) in THF (300 mL) with stirring at 0 °C. The reaction mixture was heated to reflux for 1 h. Water (100 mL) and aqueous HCl (10%, 200 mL) were added. The aqueous layer was separated and extracted with EtOAc (2 x 50 mL). The combined organic solutions were washed with brine, dried over _MgSO4 and concentrated. The residue was purified by column chromatography (silica gel, ETOAc:hexanes, 1:1) to give 4-[4-(4-hydroxybutyl)phenyl]butan-1-ol (7.5 g, 53%, 96.2% pure by HPLC) as white crystals. mp 60-62°C (60.5-62.4°C, Cram, DJ; Allinger, NL; Steinberg, H. J. Am. Chem. Soc. 1954 , 76 , 6132-6141). ¹ H NMR (CDCl ₃ ): δ=7.10 (s, 4H), 3.63 (t, J =6.4 Hz, 4H), 2.61 (t, J =7.1 Hz, 4H), 2.12 (br s, 2H), 1.71-1.57 (m, 8H). ¹³ C NMR (CDCl ₃ ): δ=140.7, 129.4, 63.8, 36.3, 33.4, 28.67.

[0578] 1,4-bis-(4-bromobutyl)benzene (B3)

[0579] Concentrated sulfuric acid (30 mL) was added dropwise to a refluxing 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) over 1 h. The reaction mixture was heated under reflux for 1 h. Additional concentrated sulfuric acid (10 mL) was added over 20 min and reflux was continued for 1.5 h. After adding water (300 mL) and methylene chloride (500 mL), the aqueous solution was separated and extracted with methylene chloride (2×50 mL). The combined organic solutions were washed with water (200 mL) and brine (150 mL) and dried over MgSO ₄ . The solvent was evaporated and the residue was purified by column chromatography (silica gel, EtOAc:hexanes, 1:20) to give 1,4-bis-(4-bromobutyl)benzene (11.8 g, 80%, 96.1% pure by HPLC) as an oil. ¹ H NMR (CDCl ₃ ): 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 C NMR (CDCl ₃ ): δ=139.5, 128.6, 34.7, 34.0, 32.5, 30.1. This procedure is modified from that described by Cram, DJ; Allinger, NL; Steinberg, H. J. Am. Chem. Soc. 1954 , 76 , 6132–6141.

[0580] 6-[4-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid

[0581] 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. The reaction mixture was stirred for 1 h before a solution of 1,4-bis-(4-bromobutyl)benzene (11.2 g, 32.2 mmol) in THF (50 mL) was slowly added followed by DMPU (10 mL). The reaction mixture was warmed to room temperature over 2 h and stirred for 1 h at 40-50 °C. Water (200 mL) was added and the aqueous solution was separated and extracted with EtOAc (3 x 80 mL). The combined organic solutions were 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) were added and the reaction mixture was heated to reflux for 3 h. After adding water (200 mL) and cooling to room temperature, the reaction mixture was acidified with concentrated HCl to pH 1 and stirred for 1 h. The precipitate was filtered, washed with water and dissolved in methylene chloride (400 mL). The solution was dried over MgSO ₄ and evaporated in vacuo. The residue was dissolved with heating in EtOAc:hexanes (1:30, 200 mL) and cooled in the freezer. The solution was decanted from the oil and evaporated to a volume of 60 mL. The mixture was stirred overnight and the precipitate was filtered, washed with hexanes and dried in vacuo to give 6-[4- ₍ 5-carboxy-5-methylhexyl)phenyl]-2,2-dimethylhexanoic acid (8.02 g, 69%, 96.4% pure by HPLC) as a white solid (Compound I-1 ). mp 129-131°C. Elemental analysis ( _C22H34O4 ): calculated for C, 72.89; H, _9.45 . Found: C, 72.90; H, 9.49. ¹ H NMR (CDCl ₃ ): 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). ¹³ C NMR (CDCl ₃ ): δ=185.3, 138.6, 128.5, 42.3, 41.5, 34.5, 30.6, 25.0, 23.2. HRMS calcd for C ₂₂ H ₃₄ O ₄ (M ⁺ ): 362.2457, found: 362.2453.

[0582] Example 11. Synthesis of 1,4-bis(4-carboxy-4-methylpentyl)benzene (compound III-1 )

[0583] 1,4-bis(2-methoxycarbonylethyl)benzene (C2)

[0584] Under 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 heated to reflux for 5 h. The reaction mixture was cooled to room temperature, the crystals were filtered, washed with MeOH (30 mL), and dried in vacuo to give 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 (CDCl ₃ ): δ=7.11 (s, 4H), 3.69 (s, 6 H), 2.94 (t, J =8.1 Hz, 4H), 2.62 (t, J =8.2 Hz, 4H). ¹³ C NMR (CDCl ₃ ): δ=173.3, 138.4, 128.4, 51.6, 35.6, 30.5. This known compound was prepared by a method different from that described by Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata, Y.; Misumi, S. Bull. Chem. Soc. Japan 1972 , 45 , 1825-1833.

[0585] 1,4-bis(3-hydroxypropyl)benzene (C3)

[0586] 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 portionwise 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 h, resulting in an exothermic reaction. The reaction mixture was refluxed for 5 min and stirred at room temperature for 3 h. It was then hydrolyzed with water (100 mL) and 10% aqueous _NH4Cl (50 mL). The organic layer was separated and the aqueous solution was extracted with EtOAc (100 mL). The organic phases were combined, washed with brine (50 mL), dried over _MgSO4 and concentrated to give 1,4-bis(3-hydroxypropyl)benzene (9.0 g, quant.) as an oil, which was used in the next step without further purification. ¹ H NMR (DMSO-d ₆ ): δ=7.10 (s, 4H), 4.43 (br s, 2 H), 3.41 (t, J =8.1 Hz, 4H), 2.59 (t, J =8.2 Hz, 4H), 1.71 (m, 2 H). ¹³ C NMR (DMSO-d ₆ ): δ=139.0, 127.0, 60.0, 34.5, 31.2.

[0587] 1,4-bis(3-bromopropyl)benzene (C4)

[0588] 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 to reflux while concentrated sulfuric acid (17 mL) was added dropwise over 1 h. After the addition, heating to reflux was continued for an additional 3.5 h. The solution was cooled to room temperature, diluted with water (40 mL), and extracted with CH ₂ Cl ₂ (2 x 150 mL). The combined organic layers were washed with saturated NaHCO ₃ solution (100 mL), saturated NaCl solution (100 mL), and dried over MgSO ₄ . The solvent was evaporated and the residue was purified by column chromatography (silica gel, EtOAc:hexanes, 1:40) to give 1,4-bis(3-bromopropyl)benzene (11.6 g, 78%) as a colorless oil. ¹ H NMR (CDCl ₃ ): δ = 7.15 (s, 4H), 3.41 (t, J = 6.6 Hz, 4H), 2.77 (t, J = 7.1 Hz, 4H), 2.18 (m, 4H). ¹³ C NMR (CDCl ₃ ): δ = 138.3, 128.7, 34.2, 33.4, 33.3. This known compound was prepared by a method different from that described by Matsuoka, T., Negi, T., Otsubo, T., Sakata, Y., Misumi, S. Bull. Chem. Soc., Japan, 1972 , 45 , 1825-1833 and Ruzicka, L.; Buijs, J. B.; Stoll, M. Helv. Chim. Acta 1932 , 15 , 1220.

[0589] 1,4-bis(4-ethoxycarboxy-4-methylpentyl)benzene (C5)

[0590] Under N ₂ 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 h, 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 DMPU (20 mL). The reaction mixture was allowed to warm to room temperature overnight, then cooled in an ice bath and hydrolyzed with saturated NH ₄ Cl 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 combined organic layers were washed with saturated NaCl solution (100 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc:hexanes, 1:10) to give 1,4-bis(4-ethoxycarboxy-4-methylpentyl)benzene (13.3 g, 94%) as a colorless oil. ¹ H NMR (CDCl ₃ ): δ = 7.09 (s, 4H), 4.11 (q, J = 7.1 Hz, 4H), 2.57 (m, 4H), 1.57 (m, 8 H), 1.24 (t, J = 7.1 Hz, 6 H), 1.47 (s, 12 H). ¹³ C NMR (CDCl ₃ ): δ=177.9, 139.6, 128.2, 60.1, 42.0, 40.2, 35.8, 26.8, 25.1, 14.2. HRMS calcd for C ₂₄ H ₃₉ O ₄ (MH ⁺ ): 391.2838, found: 391.2836.

[0591] 1,4-bis(4-carboxy-4-methylpentyl)benzene

[0592] 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 to reflux for 3.5 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and acidified with HCl (2 M solution in water) to pH 1. A precipitate formed immediately. The mixture was stirred for 1 h, the precipitate was filtered and washed with water (2×50 mL). The crude residue was dissolved in methylene chloride (700 mL), and the solution was dried over MgSO ₄ overnight. The solvent was evaporated and the residue was recrystallized (methylene chloride:hexanes, 1:1) to give 1,4-bis(4-carboxy-4-methylpentyl)benzene (9.5 g, 85%, 100% pure by HPLC) as white crystals (compound III-1 ). mp 131°C (125-126°C, Gleiter, R.; Krämer, 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 O ₄ ): calculated for C, 71.82; H, 9.04; found: C, 71.10; H, 9.00. ¹ H NMR (CDCl ₃ ): δ=7.07 (br s, 4H), 2.55 (m, 4H), 1.59 (m, 8 H), 1.18 (s, 12 H). ¹³ C NMR (CDCl ₃ ): δ=184.9, 139.6, 128.1, 42.1, 40.3, 35.8, 26.8, 24.9. This known compound was prepared by a method different from that described by Gleiter, R.; Krämer, 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.

[0593] Example 12. Synthesis of 5,5'-(1,3-phenylene)bis(2,2-dimethylpentanoic acid) (compound I-31 )

[0594] Dimethyl m -benzene- bis (2,2-dimethyl)pentanoate (D2)

[0595] Under Ar atmosphere, lithium diisopropylamide (2.0 M in heptane/THF/ethylbenzene, 91.5 mL, 183 mmol) was added dropwise to a solution of ethyl isobutyrate (21.2 g, 24.4 mL, 183 mmol) in anhydrous THF (200 mL) at -78°C. After 1 h, a solution of m - bis (3-bromopropyl)benzene ( D1 ) (prepared according to Schimelpfenig, CW J. Org. Chem. 1975 , 40 , 1493–1494 and Effenberger, F.; Kurtz, W. Chem. Ber. 1973 , 106 , 511–524; 26.6 g, 83.1 mmol) in anhydrous THF (50 mL) was added dropwise, followed by DMPU (25 mL). The reaction mixture was allowed to warm to room temperature overnight, then cooled in an ice bath and hydrolyzed with saturated NH ₄ Cl 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 combined organic layers were washed with saturated NaCl solution (100 mL), 1 N hydrochloric acid (2×100 mL), saturated _NaHCO3 solution (100 mL) and saturated NaCl solution (100 mL). The combined organic phases were dried over _MgSO4 , concentrated in vacuo and dried under high vacuum. The residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate = 95/5) to give diethyl 5,5'-(1,3-phenylene)bis(2,2-dimethylpentanoate) (15.7 g, 48%) as a yellowish oil. ¹ H NMR (CDCl ₃ ): δ=7.17 (t, 1 H, J =7.0 Hz), 6.97 (m, 3H), 4.09 (q, 4 H, J =7.3 Hz), 2.55 (m, 4H), 1.56 (m, 8 H), 1.22 (t, 6 H, J =7.3 Hz), 1.15 (s, 12 H). ¹³ C NMR (CDCl ₃ ): 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.

[0596] 5,5'-(1,3-phenylene)bis(2,2-dimethylpentanoic acid)

[0597] A solution of diethyl 5,5'-(1,3-phenylene)bis(2,2-dimethylpentanoate) ( 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 to reflux for 4 h. The reaction 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 x 50 mL). The aqueous layer was acidified with conc. hydrochloric acid (10 mL) to pH 1 and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated NaCl solution (50 mL), dried over MgSO ₄ , concentrated in vacuo and dried under high vacuum to give a viscous oil (9.3 g). This oil was crystallized from pentane/dichloromethane (75 mL/5 mL) at -5 °C to give 5,5'-(1,3-phenylene)bis(2,2-dimethylpentanoic acid) (4.78 g, 49%, 93.2% pure by HPLC) as a white powder (compound I-31 ). mp 79 °C. Elemental analysis (C ₂₀ H ₃₀ O ₄ ): calculated for C, 71.82; H, 9.04; Found: C, 71.71; H, 9.22. ¹ H NMR (DMSO-d ₆ ): δ=12.2-11.7 (m br, 2 H), 7.17 (m, 1H), 6.98 (m, 3H), 2.52 (m, 4H), 1.49 (m, 8 H), 1.07 (s, 12 H). ¹³ C NMR (DMSO-d ₆ ): δ=178.86, 141.96, 128.26, 125.69, 41.21, 39.91, 35.68, 26.62, 25.06. HRMS calcd for C ₃₀ H ₃₁ O ₃ (MH ⁺ ): 335.2222, found: 335.2232.

[0598] Example 13. Synthesis of 6-[3-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid (compound I-32 )

[0599] [1,3-bis(5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-phenylene (E2)

[0600] A solution of n -butyl lithium (38.8 mL, 2.5 M in hexanes/THF/EtPh, 96.9 mmol) was added to a mixture of m -xylene ( E1 ) (5.0 g, 47.1 mmol) and potassium tert -butoxide (5.4 g, 48.1 mmol) in hexanes (100 mL) at room temperature. The reaction mixture was heated to reflux for 1 h. 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 to reflux for 20 h. Water (150 mL) was added and the organic phase was separated. The aqueous solution was extracted with EtOAc (2×100 mL). The organic phases were combined, washed with brine (50 mL) and dried over MgSO ₄ . The solvent was evaporated and the residue was purified by column chromatography (silica gel, EtOAc:hexanes, 1:30) to give [1,3-bis(5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-phenylene (14.8 g, 62%, 96.1% pure by HPLC) as an oil. ¹ H NMR (CDCl ₃ ): 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 =9.1 Hz, 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 (CDCl ₃ ): 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. HRMS calculated for C ₃₂ H ₅₄ O ₄ (M ⁺ ): 501.3943, found: 501.3943.

[0601] 6-[3-(6-hydroxy-5,5-dimethylhexyl)-phenyl]-2,2-dimethylhexan-1-ol (E3)

[0602] Concentrated aqueous 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 to reflux for 2 h and stirred overnight at room temperature. MeOH was evaporated in vacuo and the residue was dissolved in methylene chloride (200 mL). The solution was washed with water (100 mL), saturated NaHCO ₃ solution (100 mL), and brine (100 mL) and dried over MgSO ₄ . The solvent was evaporated and the residue was purified by column chromatography (silica gel, EtOAc:hexanes, 1:1) to give 6-[3-(6-hydroxy-5,5-dimethylhexyl)phenyl]-2,2-dimethylhexan-1-ol (10.41 g, 87%, 86.4% by HPLC) as an oil. ¹ H NMR (CDCl ₃ ): 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, 12 H), 0.89 (s, 12H). ¹³ C NMR (CDCl ₃ ): δ=142.6, 128.5, 128.1, 125.6, 71.9, 38.4, 35.8, 35.0, 32.4, 23.7, 23.5. HRMS calculated for _C22H38O4 ( _M ⁺ ₎ : 335.2950, found: 335.2950.

[0603] 6-[3-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid

[0604] Pyridinium dichromate (74.85 g, 199 mmol) was added to a solution of 6-[3-(6-hydroxy-5,5-dimethylhexyl)phenyl]-2,2-dimethylhexan-1-ol (8.5 g, 25.4 mmol) in DMF (200 mL) at room temperature. The reaction mixture was stirred for 30 h, then heated to 40 °C for 10 h. Ethyl acetate (100 mL) was added followed by water (200 mL) and conc. H ₂ SO ₄ (20 mL) with stirring. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic solutions were washed with water (100 mL), saturated NaHCO ₃ solution (100 mL), and brine (2×100 mL) and dried over MgSO ₄ . The solvent was evaporated and the residue was purified by column chromatography (silica gel, EtOAc:hexanes, 1:1). The resulting oil was stirred in Et ₂ O:hexanes (1:10, 50 mL) for 3 h and the precipitated solid was filtered (7.2 g, 78%, 96.1% by HPLC) (compound I-32 ). mp 99-101 °C. Elemental analysis (C ₂₂ H ₃₄ O ₄ ): calculated for C, 72.89; H, 9.45; found: C, 73.02; H, 9.57. ¹ H NMR (CDCl ₃ ): 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 C NMR (CDCl ₃ ): δ=185.5, 142.2, 128.6, 128.3, 126.0, 42.0, 40.8, 35.7, 31.0, 25.1, 24.4. MSHR calculated for _C22H35O4 (MH ⁺ ₎ : 363.2535, found: _363.2530 .

[0605] Example 14. Synthesis of 5,5'-(1,2-phenylene)bis(2,2-dimethylpentanoic acid) (compound I-61 )

[0606] 3-[2-(3-hydroxypropyl)-phenyl]-propanol (F2)

[0607] Under Ar atmosphere, to a stirred suspension of lithium aluminum hydride (3.0 g, 78.2 mmol) in anhydrous THF (100 mL) was added dropwise a solution of ethyl 3-[2-(2-ethoxycarbonylethyl)-phenyl]-propionate (prepared according to Fakhri, SA; Behrooz, YH Tetrahedron 2000 , 56 , 8301–8308; 14.5 g, 52.1 mmol) in THF (100 mL) over 50 min at room temperature. The mixture was stirred for 2 h, then cooled in an ice bath and carefully hydrolyzed by dropwise addition of deionized water (100 mL). The 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 combined organic layers were washed with brine (100 mL), dried over _MgSO4 , concentrated in vacuo and dried under high vacuum to give 3-[2-(3-hydroxypropyl)phenyl]propanol (8.6 g, 85%, 87.9% pure by GC) as a cloudy oil, which was used in the next step without further purification. ¹ H NMR ( _CDCl3 ): δ=7.20-7.05 (m, 4H), 3.67 (t, 4 H, J =6.1 Hz), 3.50-3.20 (m br, 2 H), 2.72 (m, 4H), 1.82 (m, 4H). ¹³ C NMR (CDCl ₃ ): δ=139.98, 129.43, 126.24, 62.35, 34.36, 29.01. HRMS calculated for C ₁₂ H ₁₉ O ₂ (MH ⁺ ): 195.1385, found: 195.1388. This known compound was prepared by a method different from that described by Uenaka, M.; Kubota, B. Bull. Chem. Soc. Jpn. 1936 , 11 , 19-26.

[0608] 1,2- bis- (3-bromopropyl)-benzene (F3)

[0609] 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 heated to reflux while concentrated sulfuric acid (13.3 mL) was added dropwise over 20 min. The solution was heated for an additional 75 min at reflux, then cooled to room temperature and diluted with deionized water (200 mL). The mixture was extracted with dichloromethane (3×100 mL), and the combined organic layers were washed successively with water (100 mL), saturated sodium bicarbonate solution (100 mL), 10% aqueous sodium thiosulfate solution (200 mL), and saturated sodium chloride solution (100 mL). The organic layer was dried over _MgSO4 , concentrated in vacuo and dried under high vacuum to give the crude product (11.2 g) as a brown oil. The crude material was purified by flash chromatography (silica gel, hexanes then hexanes/ethyl acetate=90/10) to give 1,2- bis- (3-bromopropyl)-benzene (8.25 g, 58%, 95.9% pure by GC) as a yellow viscous oil. ¹ H NMR ( _CDCl3 ): δ=7.16 (s, 4H), 3.33 (t, 4 H, J =6.3 Hz), 2.79 (m, 4H), 2.12 (m, 4H). ¹³ C NMR (CDCl ₃ ): δ=138.69, 129.69, 126.66, 34.14, 33.62, 30.99. HRMS calculated for C ₁₂ H ₁₆ Br ₂ (M ⁺ ): 317.9619, found: 317.9624. This known compound was prepared by a method different from that described by Uenaka, M.; Kubota, B. Bull. Chem. Soc. Jpn. 1936 , 11 , 19-26.

[0610] Ethyl ester of 5-[2-(4-ethoxycarbonyl-4-methylpentyl)phenyl]-2,2-dimethylpentanoic acid (F4)

[0611] Under Ar, to a solution of ethyl isobutyrate (8.7 g, 10.0 mL, 74.98 mmol) in anhydrous THF (100 mL) was added dropwise over 15 min at -78 °C. After 85 min, 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 min, followed by the dropwise addition of DMPU (15 mL). The mixture was stirred at -78 °C for an additional hour, then allowed to warm slowly to room temperature over another 2 h 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 extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (100 mL), 1 N hydrochloric acid (100 mL), water (100 mL), and saturated sodium chloride solution (100 mL). The organic phase was then dried over _MgSO4 and concentrated in vacuo to give the crude product (14.0 g) as a reddish oil. Purification by flash chromatography (silica gel, hexane/ethyl acetate=95/5) gave ethyl 5-[2-(4-ethoxycarbonyl-4-methylpentyl)phenyl]-2,2-dimethylpentanoate (8.2 g, 84%, 79% pure by GC) as a slightly yellowish oil. ¹ H NMR (CDCl ₃ ): δ=7.11 (s, 4H), 4.10 (q, 4 H, J =7.0 Hz), 2.56 (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 (CDCl ₃ ): δ=177.95, 140.01, 129.12, 126.04, 60.34, 42.26, 40.79, 33.11, 26.75, 25.29, 14.41. HRMS calcd for C ₂₄ H ₃₉ O ₄ (MH ⁺ ): 391.2848, found: 391.2846.

[0612] 5,5'-(1,2-phenylene)bis(2,2-dimethylpentanoic acid) (or 5-[2-(4-carboxy-4-methylpentyl)phenyl]-2,2-dimethylpentanoic acid)

[0613] A solution of ethyl 5-[2-(4-ethoxycarbonyl-4-methylpentyl)phenyl]-2,2-dimethylpentanoate (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 to reflux for 4 h. After cooling to room temperature, the mixture was diluted with water (50 mL) and concentrated in vacuo to a volume of about 60 mL. This aqueous solution was extracted with dichloromethane (2 x 30 mL) and then acidified with 1 N hydrochloric acid (8 mL) to pH 1. The aqueous layer was extracted with dichloromethane (3 x 30 mL). The combined organic extracts were washed with saturated NaCl solution (30 mL), dried over MgSO ₄ and concentrated in vacuo to give the crude product (5.50 g) as a white solid/viscous oil. The crude material was crystallized from heptane/dichloromethane at -5 °C to give tiny white crystals which were washed with cold heptane (10 mL) and dried under high vacuum (5.05 g, 71%, 98.3% pure by HPLC) (compound I-61 ). mp 108-109 °C. Elemental analysis (C ₂₀ H ₃₀ O ₄ ): calculated for C, 71.82; H, 9.04; Found: C, 71.14; H, 9.06. ¹ H NMR (DMSO-d ₆ ): δ=12.7-11.5 (m br, 2 H), 7.11 (s, 4H), 2.55 (t, 4 H, J = 7.3 Hz), 1.62-1.38 (m, 8 H), 1.09 (s, 12 H). ¹³ C NMR (DMSO-d ₆ ): δ=178.83, 139.69, 128.98, 125.89, 41.25, 40.20, 32.49, 26.57, 25.04. HRMS calcd for C ₂₀ H ₃₁ O ₄ (MH ⁺ ): 335.2222, found: 335.2232.

[0614] Biological research

[0615] Example 15. Antiproliferative effects of compounds I-32, I-61, I-1 and III-1 in liver cancer cells Hep3B and Hepa1-6

[0616] Human Hep3B liver cancer cells and murine Hepa1-6 liver cancer cells, respectively, were seeded at a density of 3000 cells/well in 96-well plates using Eagle's minimum essential medium (Corning) for Hep3B or Dulbecco's modified Eagle's medium (DMEM) high glucose (Gibco) for Hepa1-6 cells supplemented with 10% fetal bovine serum (FBS, Gibco) and 1% antifungal antibiotic solution (Thermo-Fisher Scientific). The following day, cells were treated with 0 (vehicle control), 0.1, 0.5, 1, 5, 10, 30, 50, or 100 μM compound I-32 , I-61 , I-1 , or III-1 (final DMSO concentration 0.1%) and allowed to grow for 72 h at 37°C. On day 5, 10 μl of PrestoBlue™ Cell Viability Reagent (Invitrogen) was added to each well and the plate was incubated at 37°C for an additional 1–2 h. After incubation, the fluorescence signal was measured using excitation/emission wavelengths of 560/590 nm using a SpectraMax M5 microplate reader (Molecular Devices).

[0617] The effects of compounds I-32 , I-61 , I-1 , and III-1 on Hepa1-6 cell proliferation as a percentage of vehicle control (DMSO, 0.1% final concentration) are shown in Figs. 2A-2D , respectively (n=4 replicates, one experiment, error bars represent standard deviation). The effects of compounds I-32 , I-61 , I-1 , and III-1 on Hep3B cell proliferation as a percentage of vehicle control (DMSO, 0.1% final concentration) are shown in Figs. 3A-3D , respectively (n=5, one experiment, error bars represent standard deviation).

[0618] Example 16. Anticlonogenic effects of compounds I-32, I-61, I-1 and III-1 in liver cancer cells Hep3B and Hep1-6.

[0619] Hep3B (human) and Hepa1-6 (mouse) liver cancer cell lines were maintained in Eagle's Minimum Essential Medium (Corning) for Hep3B cells or high glucose DMEM (Gibco) for Hepa1-6 cells supplemented with 10% FBS (Gibco) and 1% antifungal antibiotic solution (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 with 0 (vehicle control, 0.1% DMSO), 1, 5, 10, 30, 50, or 100 μM I-32 , I-61 , I-1 , or III-1 (final DMSO concentration 0.1%) for 7 days. On day 9, the medium was removed and the cells were fixed with 10% formalin (500 μl) for 10 min at room temperature, washed with 1X PBS and stained with crystal violet. After 10 min, excess dye was removed by washing three times with tap water. The plates were allowed to dry overnight, then the number of colonies (>50 cells) in each well was counted by light microscopy as described previously by Villiani LA, et al .

[0620] The effects of compounds I-32 , I-61 , I-1 , and III-1 on Hepa1-6 cell clonogenicity as a percentage of vehicle control (DMSO, 0.1% final concentration) are shown in Figs. 4A-4D , respectively (n=2, error bars represent standard deviation). The effects of compounds I-32 , I-61 , I-1 , and III-1 on Hep3B cell clonogenicity as a percentage of vehicle control (DMSO, 0.1% final concentration) are shown in Figs. 5A-5D , respectively (n=2, error bars represent standard deviation).

[0621] Table 1 shows the biological results from Examples 15-17. “NO” means “not determined.”

[0622] Table 1. Effects of illustrative compounds of the invention on de novo lipogenesis (DNL), clonogenicity, and proliferation of human (h) and murine (m) cancer cells (IC ₅₀ or % reduction in proliferation, respectively).

Analysis Cell line IC ₅₀ (µM) Compound
I-1 Compound
I-32 Compound
I-61 Compound
III-1 DNL Primary hepatocytes (m) 12.1 8.3 BUT BUT Clonogenicity Hepa1-6 (m) 55.6 52.3 73.4 61.0 Clonogenicity Hep3B(h) 53.9 41.7 57.3 55.6 % reduction compared to control at 100 µM
Mean (standard deviation) Compound
I-1 Compound
I-32 Compound
I-61 Compound
III-1 Proliferation of cancer cells Hepa1-6 (m) 25.9 (5.7) 18.6 (3.1) 21.8 (8.9) 15.7 (6.7) Proliferation of cancer cells Hep3B(h) 41.8 (8.4) 30.8 (2.6) 35.7 (5.8) 29.7 (6.2)

[0623] Example 17. Synergistic effect of illustrative compounds of the invention with sorafenib or lenvatinib.

[0624] Combination studies with compounds of the invention were conducted to determine the potential synergy of sorafenib or lenvatinib in the presence of compound I-32 or compound I-61. In a separate experiment, the IC ₅₀ value for inhibition of proliferation by sorafenib in the absence of a compound of the invention and lenvatinib in the absence of a compound of the invention was determined to be 3 μM and 0.5 μM, respectively, in Hep3B cells and 5 μM and 30 μM, respectively, in Hepa1-6 cells (data not shown).

[0625] Hep3B cells (supplied by ATCC) or Hepa1-6 cells (supplied by ATCC) were seeded in 96-well plates at a density of 500 cells/well with complete medium. On day 2, the medium in each well was aspirated and replaced with 100 μl of fresh complete medium, and the cells were treated with sorafenib or lenvatinib in the presence or absence of compounds of the invention in a concentration-dependent manner (compound I-32 (100 μM) or compound I-61 (100 μM), either alone or in combination with sorafenib (3 μM) or lenvatinib (0.5 μM)). The cells were then incubated in the incubator for 72 h. On day 5, 10 μl of presto blue cell viability assay reagent (Invitrogen, cat #A13261) was added to each 96-well plate and incubated at 37°C for 1–2 h. After incubation, fluorescence was measured using excitation/emission wavelengths of 560/590 nm. Results were reported as mean ± standard deviation (SD). All histograms and line graphs were generated using Graph Pad Prism 8 software. Proliferation IC ₅₀ values were calculated using a nonlinear regression model in Graph pad Prism 8. For each cell type, the combination treatment demonstrated a decrease in cell proliferation compared with sorafenib or lenvatinib treatment alone. The results for Hep3B cells are shown in Fig. 6A-6B , and the results for Hepa1-6 cells are shown in Fig. 7A-7B .

[0626] Sorafenib and lenvatinib have the following structure:

[0627] Because additive inhibition of cell proliferation was observed in the combination studies, the results were analyzed using CompuSyn software (provided by ComboSyn Inc.) to determine whether there was a synergistic or additive effect on antiproliferative activity. Figures 8A-8D show that both I-32 and I-61 demonstrated synergistic inhibition in the presence of sorafenib or lenvatinib.

Claims (34)

1. A compound having the structure or a pharmaceutically acceptable salt thereof. 2. A composition for the treatment of hepatocellular carcinoma (HCC), comprising: (i) an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier or excipient. 3. A composition for the treatment of non-alcoholic fatty liver disease (NAFLD), comprising: (i) an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier or excipient. 4. A composition for the treatment of non-alcoholic steatohepatitis (NASH), comprising: (i) an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier or excipient. 5. A composition for inhibiting, reducing or delaying the development of liver fibrosis in a subject, comprising: (i) an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier or excipient. 6. A composition for the treatment of cirrhosis, comprising: (i) an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier or excipient. 7. The composition according to claim 2, further comprising an effective amount of sorafenib or lenvatinib. 8. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the treatment of hepatocellular carcinoma (HCC) in a subject. 9. The use according to claim 8, wherein the treatment comprises administering sorafenib or lenvatinib to the subject. 10. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the treatment of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) in a subject. 11. A method for treating hepatocellular carcinoma (HCC), comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 12. The method of claim 11, wherein the treatment comprises administering sorafenib or lenvatinib to the subject. 13. A method for treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 14. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of hepatocellular carcinoma (HCC) in a subject. 15. The use according to claim 14, wherein the treatment comprises administering sorafenib or lenvatinib to the subject. 16. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) in a subject. 17. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for inhibiting, reducing or delaying the development of liver fibrosis in a subject. 18. A method for inhibiting, reducing or delaying the development of liver fibrosis in a subject, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 19. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting, reducing or delaying the development of liver fibrosis in a subject. 20. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for treating cirrhosis in a subject. 21. A method for treating cirrhosis, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 22. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cirrhosis in a subject.

Images