US20230007838A1 - Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and their use for the prevention or treatment of disease - Google Patents

Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and their use for the prevention or treatment of disease Download PDF

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US20230007838A1
US20230007838A1 US17/571,107 US202217571107A US2023007838A1 US 20230007838 A1 US20230007838 A1 US 20230007838A1 US 202217571107 A US202217571107 A US 202217571107A US 2023007838 A1 US2023007838 A1 US 2023007838A1
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alkyl
alkenyl
alkynyl
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Daniela Carmen Oniciu
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Espervita Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C57/34—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings containing more than one carboxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C61/16—Unsaturated compounds
    • C07C61/39—Unsaturated compounds containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • This 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.
  • This invention further provides methods for preventing or treating a disease, including but not limited to, liver disease or an abnormal liver condition; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract; an intra- or extra-hepatic bile duct disease; a disorder of lipoprotein; a lipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular or related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease associated with increased inflammation (such as hepatic inflammation or pulmonary inflammation); hepatocyte ballooning; a peroxisome proliferator activated receptor-associated disorder; an ATP citrate lyase disorder; an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; or renal disease.
  • cancer such as hepatocellular
  • Hepatocellular carcinoma is one of the most common primary liver malignancies
  • Patients with chronic liver disease, such as liver cirrhosis and fibrosis, are at increased risk for development of HCC.
  • patients with chronic liver diseases should be closely monitored for development of HCC.
  • Risk factors for HCC include cirrhosis, non-alcoholic fatty liver disease (NAFLD), nonalcoholic stetohepatitis (NASH), chronic alcohol consumption, hepatitis B, and hepatitis C, type IIb hyperlipidemia, mixed dyslipidemia, obesity, and type 2 diabetes.
  • Type IIb hyperlipidemia patients have a high risk of developing NAFLD and non-alcoholic steatosis hepatitis (NASH), which can develop due to hepatic triglyceride overproduction and accumulation.
  • Elevated levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides are associated with mixed dyslipidemia, including type IIb hyperlipidemia which is characterized by elevation of apolipoprotein B, very low-density lipoprotein cholesterol (VLDL-C), intermediate density lipoprotein cholesterol (IDL), and small dense low-density lipoprotein (LDL) levels, in addition to elevation in LDL-C and triglyceride levels.
  • VLDL-C very low-density lipoprotein cholesterol
  • IDL intermediate density lipoprotein cholesterol
  • LDL small dense low-density lipoprotein
  • statins can be effective for lowering LDL-C and reducing inflammation, they are generally not very effective for lowering triglyceride concentrations. Further, high dose statin therapy is often not well tolerated because it can cause muscle pain (myalgia) and increase a patient's risk of serious muscle toxicity, such as rhabdomyolysis. Also, commonly used triglyceride-lowering agents that are administered in combination with statins are often not well-tolerated. When administered with statins, fibrates are known to have drug-drug interactions, resulting in increased statin blood drug levels, myalgia, an increased risk of muscle toxicity and an increased safety risk.
  • statin Baychol cerivastatin
  • fibrate gemfibrozil resulted in severe muscle toxicity and deaths and raised safety concerns that resulted in the removal of Baychol from the U.S. market.
  • Fish oil which has been used to lower triglyceride levels, needs to be taken multiple times daily and can cause a fish oil aftertaste, burping or regurgitation.
  • Niacin causes flushing, particularly when administered in combination with statins.
  • Hepatocellular adenomas are benign liver neoplasms whose genetics and pathophysiology are not entirely known. These lesions pose diagnostic and therapeutic challenges and treatments post-exeresis are still challenging. Bile duct adenomas raise the same therapeutic challenges. Digestive system adenomas are sporadic neoplasms, arising from the glandular epithelium of the stomach, small intestine, biliary tract, colon, and rectum.
  • Gastrointestinal (digestive) cancers are cancers that affect the gastrointestinal tract and other organs that are contained within the digestive system.
  • Gastrointestinal stromal tumor (GIST) is a rare type of sarcoma that forms along the gastrointestinal tract, but mostly starts in the stomach or small intestine. The origins of the digestive cancers were linked strongly to chronic inflammation of the organs that develop through a series of histopathologic stages dependent of the organ affected. For cancers of the gastrointestinal tract or GIST, surgery will likely be recommended to remove the tumor and/or to help maintain normal function. Other treatment options are radiotherapy, chemotherapy, hormone therapy, or targeted therapies.
  • cancer such as gastrointestinal cancer, hepatocellular carcinoma or cholangiocarcinoma
  • a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract liver disease or an abnormal liver condition, an intra- or extra-hepatic bile duct disease
  • a disorder of lipoprotein such as a lipid-and-metabolic disorder
  • cirrhosis such as fibrosis
  • a disorder of glucose metabolism such as hepatic inflammation or pulmonary inflammation
  • hepatocyte ballooning a peroxisome proliferator activated receptor-associated disorder; an ATP citrate lyase disorder; an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; or renal disease.
  • 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 (each compound, pharmaceutically acceptable salt and solvate being a “compound of the invention”).
  • compositions comprising i) an effective amount of a compound of the invention and ii) a pharmaceutically acceptable carrier or vehicle (each composition being a “composition of the invention”).
  • 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 liver disease or an abnormal liver condition; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract; an intra- or extra-hepatic bile duct disease; a disorder of lipoprotein; a lipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular or related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease associated with increased inflammation (such as hepatic inflammation or pulmonary inflammation); hepatocyte ballooning; a peroxisome proliferator activated receptor-associated disorder; an ATP citrate lyase disorder; an acetyl-coenzyme A carboxylase disorder;
  • the present invention further provides methods for treating or preventing a disease, wherein the disease is cancer, a lipid-and-metabolic disorder, a liver disorder, cirrhosis, fibrosis, a disorder of glucose metabolism, a peroxisome proliferator activated receptor-associated disorder, a malignant or benign tumor of the lung, liver, bile and digestive tract, an ATP citrate lyase disorder, an acetyl-coenzyme A carboxylase disorder, obesity, pancreatitis, renal disease, hepatocyte ballooning, hepatic inflammation, or pulmonary inflammation.
  • a disease is cancer, a lipid-and-metabolic disorder, a liver disorder, cirrhosis, fibrosis, a disorder of glucose metabolism, a peroxisome proliferator activated receptor-associated disorder, a malignant or benign tumor of the lung, liver, bile and digestive tract, an ATP citrate lyase disorder, an acetyl-coenzyme A carboxy
  • the present invention further provides methods for reducing in a subject's blood plasma or blood serum, the subject's C-reactive protein (CRP) concentration, 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, 7 ⁇ -hydroxy-4-cholesten-3-one (C4) concentration, protein:creatinine ratio, creatine kinase concentration, angiopoietin-like protein 3 concentration, angiopoietin-like protein 4 concentration, angiopoietin-like protein 8 concentration, fibrinogen concentration, total cholesterol concentration, low-density lipoprotein cholesterol concentration, low-density lipoprotein concentration, very low-density lipoprotein cholesterol concentration, very low-density lipoprotein concentration, non-HDL cholesterol concentration, non-HD
  • the present invention further provides methods for reducing triglyceride concentration in a subject's liver, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • the present invention further provides methods for elevating in a subject's blood plasma or blood serum a concentration of high-density lipoprotein cholesterol or high-density lipoprotein, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • 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 gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), or autoimmune disease.
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • the present invention further provides methods for regressing, reducing the rate of progression, or inhibiting progression, of fibrosis, hepatocyte ballooning or hepatic inflammation, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • the present invention further provides methods for inhibiting, reducing, or delaying advancement of a subject's lipid synthesis, liver steatosis, hepatocyte ballooning or inflammation, liver fibrosis, lung fibrosis, or cirrhosis, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • the present invention further provides methods for reducing a subject's risk of developing or having atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, or restenosis, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • the present invention further provides methods for elevating HDL concentration in a subject's blood serum or plasma, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • 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.
  • 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.
  • PPAR peroxisome proliferator-activated receptor
  • the present invention further provides methods for reducing the fat or cholesterol content of livestock meat or poultry eggs, comprising administering to the livestock or poultry an effective amount of a compound of the invention.
  • 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.
  • 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.
  • the present invention further provides method for 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, a lipid-and-metabolic disorder, a liver disorder, cirrhosis, fibrosis, a disorder of glucose metabolism, a peroxisome proliferator activated receptor-associated disorder, a malignant or benign tumor of the lung, liver, bile and digestive tract, an ATP citrate lyase disorder, an acetyl-coenzyme A carboxylase disorder, obesity, pancreatitis, renal disease, hepatocyte ballooning, hepatic inflammation, or pulmonary inflammation.
  • the disease is cancer, a lipid-and-metabolic disorder, a liver disorder, cirrhosis, fibrosis, a disorder of glucose metabolism, a peroxisome proliferator activated receptor-associated disorder, a malignant or benign tumor of the lung, liver, bile and digestive tract, an ATP citrate
  • FIGS. 1 A- 1 D show inhibitory effects of Compounds I-32, I-61, I-1, and III-1, respectively, on mouse primary hepatocyte lipogenesis as percent control.
  • FIGS. 2 A- 2 D show anti-proliferative effects of Compounds I-32, I-61, I-1, and III-1, respectively, on Hepa1-6 cells as a percent of vehicle control.
  • FIGS. 3 A- 3 D show anti-proliferative effects of Compounds I-32, I-61, I-1, and III-1, respectively, on Hep3B cell proliferation as a percent of vehicle control.
  • FIGS. 4 A- 4 D show anti-clonogenic effects of Compounds I-32, I-61, I-1, and III-1, respectively, in Hepa1-6 cells as a percent of vehicle control.
  • FIGS. 5 A- 5 D show anti-clonogenic effects of Compounds I-32, I-61, I-1, and III-1, respectively, in Hep3B cells as a percent of vehicle control.
  • FIG. 6 A shows anti-proliferation effects of Compound I-32 and sorafenib, in the absence or presence of the other, in Hep3B cells.
  • FIG. 6 B shows anti-proliferation effects of Compound I-32 and lenvatinib, in the absence or presence of the other, in Hep3B cells.
  • FIG. 6 C shows anti-proliferation effects of Compound I-61 and sorafenib, in the absence or presence of the other, in Hep3B cells.
  • FIG. 6 D shows anti-proliferation effects of Compound I-61 and lenvatinib, in the absence or presence of the other, in Hep3B cells.
  • FIG. 7 A shows anti-proliferation effects of Compound I-32 and sorafenib, in the absence or presence of the other, in Hepa1-6 cells.
  • FIG. 7 B shows anti-proliferation effects of Compound I-32 and lenvatinib, in the absence or presence of the other, in Hepa1-6 cells.
  • FIG. 7 C shows anti-proliferation effects of Compound I-61 and sorafenib, in the absence or presence of the other, in Hepa1-6 cells.
  • FIG. 7 D shows anti-proliferation effects of Compound I-61 and lenvatinib, in the absence or presence of the other, in Hepa1-6 cells.
  • FIG. 8 A shows synergistic anti-proliferation effect of Compound I-32 and sorafenib in Hep3B cells.
  • FIG. 8 B shows synergistic anti-proliferation effect of Compound I-32 and lenvatinib in Hep3B cells.
  • FIG. 8 C shows synergistic anti-proliferation effect of Compound I-61 and sorafenib in Hep3B cells.
  • FIG. 8 D shows synergistic anti-proliferation effect of Compound I-61 and lenvatinib in Hep3B cells.
  • a numerical value means ⁇ up to 20% of the numerical value.
  • “about” a numerical value means ⁇ up to 20% of the numerical value, in some embodiments, ⁇ up to 19%, ⁇ up to 18%, ⁇ up to 17%, ⁇ up to 16%, ⁇ up to 15%, ⁇ up to 14%, ⁇ 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 therein.
  • ranges are provided for certain quantities. These ranges comprise 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.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
  • pharmaceutically acceptable salt includes both an acid and a base addition salt.
  • Pharmaceutically acceptable salts can be obtained by reacting the compound of the invention functioning 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 obtained by reacting a compound of the invention functioning 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.
  • a salt for example, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ammonia, isopropylamine, trimethylamine, etc.
  • pharmaceutically acceptable salts can be prepared by reaction of the compounds of the invention with an appropriate inorganic or organic acid or base via any of a number of known methods.
  • solvate refers to a solvation complex.
  • Solvates can be formed by solvation (the combination of solvent molecules with molecules or ions of the compounds of the invention), or a solvate can be an aggregate that comprises a solute ion or molecule or a solvent molecules.
  • the solvent can 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.
  • the solvate can be formed via hydration, including via absorption of moisture.
  • a pharmaceutically acceptable salt can also be a solvate.
  • the solvent can be an alcohol, such as methanol or ethanol; an aldehyde; a ketone, such as acetone; or an ester, such as ethyl acetate.
  • the compounds of the invention can have one or more asymmetric centers and can thus 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 they are specifically depicted herein.
  • Optically active (+) and ( ⁇ ), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • an “effective amount” when used in connection with a compound of the invention means an amount of the compound of the invention that, when administered to a subject is effective to treat or prevent the disease, alone or with another pharmaceutically active agent.
  • an “effective amount” when used in connection with another pharmaceutically active agent means an amount of the other pharmaceutically active agent that is effective to treat or prevent the disease, alone or in combination with a compound of the invention.
  • a “subject” is a human or non-human mammal, e.g., a bovine, horse, feline, canine, rodent, or non-human primate.
  • the human can be a male or female, child, adolescent or adult.
  • the female can be premenarcheal or postmenarcheal.
  • “Mammal” includes a human, domestic animal such as a laboratory animal (e.g., mouse, rat, rabbit, monkey, dog, etc.) and household pet (e.g., cat, dog, swine, cattle, sheep, goat, horse, rabbit), and a non-domestic, wild animal.
  • a laboratory animal e.g., mouse, rat, rabbit, monkey, dog, etc.
  • household pet e.g., cat, dog, swine, cattle, sheep, goat, horse, rabbit
  • Halo refers to Br, Cl, F, or I.
  • Alkyl refers to a fully saturated, straight or branched hydrocarbon chain having from one to twelve carbon atoms, and which is attached to an atom by a single bond. Alkyls with a number of carbon atoms ranging from 1 to 12 are included. An alkyl group with 1 to 12 carbon atoms is a C 1 -C 12 alkyl, an alkyl group with 1 to 10 carbon atoms is a C 1 -C 10 alkyl, an alkyl group with 1 to 6 carbon atoms is a C 1 -C 6 alkyl and an alkyl group with 1 to 5 carbon atoms is a C 1 -C 5 alkyl.
  • a 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).
  • a C 1 -C 6 alkyl includes all moieties described above for C 1 -C 5 alkyls but also includes C 6 alkyls.
  • a C 1 -C 10 alkyl includes all 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.
  • a C 1 -C 12 alkyl includes all the foregoing moieties, but also includes C 11 and C 12 alkyls.
  • Non-limiting examples of C 1 -C 12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.
  • an alkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Alkylene refers to a fully saturated, straight or branched divalent hydrocarbon, and having from one to twelve carbon atoms.
  • C 1 -C 12 alkylene include methylene, ethylene, propylene, n-butylene, and the like.
  • Each alkylene terminus is attached to an atom by a single bond.
  • the points of attachment of the alkylene chain can be one or two atoms.
  • an alkylene chain can be unsubstituted or substituted with a substituent disclosed herein.
  • 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. Alkenyl groups with a number of carbon atoms ranging from 2 to 12 are included.
  • 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
  • an alkenyl group with 2 to 5 carbon atoms is a C 2 -C 5 alkenyl.
  • a C 2 -C 5 alkenyl includes C 5 alkenyls, C 4 alkenyls, C 3 alkenyls, and C 2 alkenyls.
  • a C 2 -C 6 alkenyl includes all moieties described above for C 2 -C 5 alkenyls but also includes C 6 alkenyls.
  • a C 2 -C 10 alkenyl includes all moieties described above for C 2 -C 5 alkenyls and C 2 -C 6 alkenyls, but also includes C 7 , C 8 , C 9 and C 10 alkenyls.
  • a C 2 -C 12 alkenyl includes all the foregoing moieties, but also includes C 11 and C 12 alkenyls.
  • Non-limiting examples of C 2 -C 12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-noneny
  • 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.
  • C 2 -C 12 alkenylene include ethenylene, propenylene, butenylene, and the like.
  • Each terminus of the alkenylene chain is attached to an atom by a single bond. The points of attachment of the alkenylene chain can be through one two atoms.
  • an alkenylene chain can be unsubstituted or substituted with a substituent disclosed herein.
  • 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. Alkynyl groups with a number of carbon atoms ranging from 2 to 12 are included.
  • An alkynyl group having 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
  • an alkynyl group with 2 to 5 carbon atoms is a C 2 -C 5 alkynyl.
  • a C 2 -C 5 alkynyl includes C 5 alkynyls, C 4 alkynyls, C 3 alkynyls, and C 2 alkynyls.
  • a C 2 -C 6 alkynyl includes all moieties described above for C 2 -C 5 alkynyls but also includes C 6 alkynyls.
  • a C 2 -C 10 alkynyl includes all moieties described above for C 2 -C 5 alkynyls and C 2 -C 6 alkynyls, but also includes C 7 , C 8 , C 9 and C 10 alkynyls.
  • a C 2 -C 12 alkynyl includes all the foregoing moieties, but also includes C 11 and C 12 alkynyls.
  • Non-limiting examples of C 2 -C 12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise, an alkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • 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.
  • C 2 -C 12 alkynylene include ethynylene, propynylene, butynylene, and the like.
  • Each terminus of the alkynylene chain is attached to an atom through a single bond. The points of attachment of the alkynylene chain can be through one or two atoms.
  • an alkynylene chain can be unsubstituted or substituted with a substituent disclosed herein.
  • Alkoxy refers to a radical of the formula —OR a where R a is an alkyl, alkenyl or alknyl radical as defined herein. Unless stated otherwise, an alkoxy group can be unsubstituted or substituted with a substituent disclosed herein.
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aceanthrylenyl, acenaphthylenyl, acephenanthrylenyl, anthracenyl, azulenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, naphthalenyl, phenalenyl, phenanthrenyl, phenyl, pleiadenyl, pyrenyl, and triphenylenyl.
  • the aryl can be unsubstituted or substituted with a substituent disclosed herein.
  • Arylene refers to a divalent aryl group, wherein the aryl is as defined herein. Unless stated otherwise, an arylene group can be unsubstituted or substituted with a substituent disclosed herein.
  • Arylalkyl refers to a radical of the formula —R b —R c where R b is an alkylene group as defined herein and R c is an aryl radical as defined herein, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise, an arylalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Arylalkenyl refers to a radical of the formula —R b —R c where R b is an alkenylene group as defined herein and R c is an aryl radical as defined herein. Unless stated otherwise, an arylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Arylalkynyl refers to a radical of the formula —R b —R c where R b is an alkynylene group as defined herein and R c is an aryl radical as defined herein. Unless stated otherwise, an arylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Cycloalkyl refers to a non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to an 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 stated otherwise, a cycloalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Aryloxy refers to a radical of the formula —O(aryl), wherein the aryl radical is as defined herein.
  • Aryloxy includes, but are is not limited to, phenoxy (—O(phenyl)). Unless stated otherwise, an aryloxy group can be unsubstituted or substituted with a substituent disclosed herein.
  • 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 can include fused or bridged ring systems, having from three to twenty carbon atoms, in some embodiments having from three to ten carbon atoms. A cycloalkenyl group is attached to an atom by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like.
  • Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless stated otherwise, a cycloalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Cycloalkynyl refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include 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 stated otherwise, a cycloalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Cycloalkylalkyl refers to a radical of the formula —R b —R d where R b is an alkylene group as defined herein and R d is a cycloalkyl radical as defined herein. Unless stated otherwise, a cycloalkylalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Cycloalkylalkenyl refers to a radical of the formula —R b —R d where R b is an alkenylene group as defined herein and R d is a cycloalkyl radical as defined herein.
  • a cycloalkylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Cycloalkylalkynyl” refers to a radical of the formula —R b —R d where R b is an alkynylene group as defined herein and R d is a cycloalkyl radical as defined herein. Unless stated otherwise, a cycloalkylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Cycloalkenylalkyl refers to a radical of the formula —R b —R d where R b is an alkylene group as defined herein and R d is a cycloalkenyl radical as defined herein. Unless stated otherwise, a cycloalkenylalkyl group can be unsubstituted or substituted with a substituent disclosed herein. “Cycloalkenylalkenyl” refers to a radical of the formula —R b —R d where R b is an alkenylene group as defined herein and R d is a cycloalkyl radical as defined herein.
  • a cycloalkenylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Cycloalkenylalkynyl” refers to a radical of the formula —R b —R d where R b is an alkynylene group as defined herein and R d is a cycloalkyl radical as defined herein.
  • a cycloalkenylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Cycloalkynylalkyl refers to a radical of the formula —R b —R d where R b is an alkylene group as defined herein and R d is a cycloalkynyl radical as defined herein. Unless stated otherwise, a cycloalkynylalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Cycloalkynylalkenyl refers to a radical of the formula —R b —R d where R b is an alkenylene group as defined herein and R d is a cycloalkyl radical as defined herein.
  • a cycloalkynylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Cycloalkynylalkynyl” refers to a radical of the formula —R b —R d where R b is an alkynylene group as defined herein and R d is a cycloalkyl radical as defined herein.
  • a cycloalkynylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Carbocyclyl refers to a ring structure, wherein the atoms which form the ring are each carbon.
  • the carbocyclyl, carbocyclic ring or carbocycle can comprise from 3 to 20 carbon atoms in the ring.
  • the carbocyclyl, carbocyclic ring or carbocycle includes aryl, cycloalkyl, cycloalkenyl and cycloalkynyl as defined herein.
  • the carbocyclyl, carbocyclic ring or carbocycle can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, and spiral ring systems. Unless stated otherwise, a carbocyclyl group, carbocyclic ring or carbocycle can be unsubstituted or substituted with a substituent disclosed herein.
  • Haloalkyl refers to an alkyl radical, as defined herein, that is substituted by one or more halo radicals, as defined herein, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise, a haloalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Haloalkenyl refers to an alkenyl radical, as defined herein, that is substituted by one or more halo radicals, as defined herein, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise, a haloalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Haloalkynyl refers to an alkynyl radical, as defined herein, that is substituted by one or more halo radicals, as defined herein, e.g., 1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwise, a haloalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Heterocyclyl refers to a 3- to 20-membered non-aromatic, partially unsaturated, or aromatic ring radical which includes two to twelve carbon atoms and from one to six nitrogen, oxygen or sulfur heteroatoms. Heterocycly include heteroaryls as defined herein. Unless stated otherwise, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, and spiral ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated.
  • 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-thiomorph
  • Heterocyclylalkyl refers to a radical of the formula —R b —R e where R b is an alkylene group as defined herein and R e is a heterocyclyl radical as defined herein. Unless stated otherwise, a heterocyclylalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Heterocyclylalkenyl refers to a radical of the formula —R b —R e where R b is an alkenylene group as defined herein and Re is a heterocyclyl radical as defined herein. Unless stated otherwise, a heterocyclylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Heterocyclylalkynyl refers to a radical of the formula —R b —R e where R b is an alkynylene group as defined herein and R e is a heterocyclyl radical as defined herein. Unless stated otherwise, a heterocyclylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • N-heterocyclyl refers to a heterocyclyl radical as defined herein including at least one nitrogen and where the point of attachment of the heterocyclyl radical of an atom of a compound of the invention is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise, an N-heterocyclyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Heteroaryl refers to a 5- to 20-membered ring system radical including hydrogen atoms, one to thirteen carbon atoms, one to six nitrogen, oxygen or sulfur heteroatoms, and at least one aromatic ring.
  • the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • heteroaryl examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, fur
  • N-heteroaryl refers to a heteroaryl radical as defined herein having at least one nitrogen atom and where the point of attachment of the heteroaryl radical to an atom of the compound of the invention is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise, an N-heteroaryl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Heteroarylalkyl refers to a radical of the formula —R b —R f where R b is an alkylene chain as defined herein and R f is a heteroaryl radical as defined herein. Unless stated otherwise, a heteroarylalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Heteroarylalkenyl refers to a radical of the formula —R b —R f where R b is an alkenylene chain as defined herein and R f is a heteroaryl radical as defined herein. Unless stated otherwise, a heteroarylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Heteroarylalkynyl refers to a radical of the formula —R b —R f where R b is an alkynylene chain as defined herein and R f is a heteroaryl radical as defined herein. Unless stated otherwise, a heteroarylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • Ring refers to a cyclic group which can be saturated or include one or more double or triple bonds.
  • a ring can be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless stated otherwise, a ring can be unsubstituted or substituted with a substituent disclosed herein.
  • Thioalkyl refers to a radical of the formula —SR a where R a is an alkyl, alkenyl, or alkynyl radical as defined herein. Unless stated otherwise, a thioalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • a group or radical disclosed herein can be substituted with one or more of the following substitutents: a halogen atom such as F, Cl, Br, and I; a 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 including one or more heteroatoms.
  • a halogen atom such as F, Cl, Br, and I
  • a hydroxyl, alkoxy, or ester thiol, thioalkyl, sulfone, sulfonyl, or sulfoxide
  • a group or radical disclosed herein can be alternatively or additionally substituted with one or more of the following substituents: oxo, carbonyl, carboxyl, or an ester group; or an imine, oxime, hydrazone, and nitrile.
  • a “point of attachment bond” denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
  • “XY ” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond.
  • the compound of the invention is a compound of Formula (IA):
  • Z 1 and Z 2 are independently —C(R 1A )(R 2A )—(CH 2 ) d —X A .
  • 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.
  • each p is 2, 3, 4, or 5.
  • each d is 0, 1, 2, or 3. In some embodiments, d is 0 or 1.
  • the compound of the invention is a compound of Formula (IA):
  • the compound of Formula (IA) has any one of the structures shown in Table A-1, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of the invention is a compound of Formula (IB):
  • the compound of Formula (IB) has any one of the structures shown in Table A-2, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of the invention is a compound of Formula (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 is —W—(CH 2 ) c —C(R 3 )(R 4 )—Y.
  • X is —COOH or —COOR 5 .
  • 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.
  • 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.
  • c is 0 or 1.
  • 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.
  • each carbon atom together with the R 1 and R 2 attached to the carbon atom independently form a —C 3 -C 7 cycloalkyl group. In some embodiments, each carbon atom together with the R 1 and R 2 attached to the carbon atom independently form a cyclopropyl ring.
  • 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.
  • 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.
  • R 3 and R 4 is independently H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl.
  • Y is —COOH or —COOR 5 .
  • 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.
  • p is 3, 4, 5, 6, or 7. In some embodiments, p is 4, 5, 6, or 7.
  • one or both of Z 1 and Z 2 is —W—(CH 2 ) c —C(R 3 )(R 4 )—Y, and R 3 and R 4 is independently H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl.
  • one or both of Z 1 and Z 2 is —W—(CH 2 ) c —C(R 3 )(R 4 )—Y, and Y is —COOH or —COOR 5 .
  • Z 1 and Z 2 is —W—(CH 2 ) c —C(R 3 )(R 4 )—Y
  • Y is —COOH or —COOR 5
  • R 5 is —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl.
  • Z 1 and Z 2 is —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.
  • the compound of Formula (IC) has of any one of the structures shown in Table A-3, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of the invention is a compound of Formula (TD):
  • Z 1 and Z 2 are independently —C(R 1A )(R 2A )—(CH 2 ) d —X A .
  • 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.
  • each p is 2, 3, 4, or 5.
  • each d is 0, 1, 2, or 3. In some embodiments, d is 0 or 1.
  • the compound of the invention is a compound of Formula (ID).
  • the compound of Formula (ID) has the structure shown in Table A-1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (ID) has the structure shown in Table A-5 which are mono- or di-substituted with —OH or methyl groups on the phenyl, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of the invention is a compound of Formula (IG):
  • the compound of Formula (IG), Q 1 and Q 2 are each H.
  • the compound of Formula (IG), p is 2, 3, 4, 5, 6, or 7. In some embodiments, the compound of Formula (IG), p is 2.
  • the compound of Formula (IG) has the structure shown in Table A-4, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of the invention is a compound of Formula (IE):
  • the compound of Formula (IE) has the structure shown in Table A-2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (IE) has the structure shown in Table A-6 which are mono- or di-substituted with —OH or methyl groups on the phenyl, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of the invention is a compound of Formula (IF):
  • the compound of Formula (IF) has the structure shown in Table A-3, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (IE) has the structure shown in Table A-7 which are mono- or di-substituted with —OH or methyl groups on the phenyl, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of the invention is a compound of Formula (IH).
  • the compound has the structure of formula (IJ), (IK), or (IL), or a pharmaceutically acceptable salt thereof:
  • Z 1 and Z 2 are each independently —C(R 1 )(R 2 )—(CH 2 ) c —X.
  • Z 1 and Z 2 is —W—(CH 2 ) c —C(R 3 )(R 4 )—Y.
  • X is —COOH or —COOR 5 .
  • each R 1 and R 2 is independently —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl.
  • each R 1 and R 2 is independently —C 1 -C 3 alkyl, —C 2 -C 3 alkenyl, or —C 2 -C 3 alkynyl.
  • R 1 and R 2 are methyl.
  • 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.
  • c is 0 or 1.
  • 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.
  • each carbon atom together with the R 1 and R 2 attached to the carbon atom independently form a —C 3 -C 7 cycloalkyl group.
  • each carbon atom together with the R 1 and R 2 attached to the carbon atom independently form a cyclopropyl ring.
  • 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.
  • 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.
  • R 3 and R 4 is independently H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl.
  • Y is —COOH or —COOR 5 .
  • 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.
  • p is 3, 4, 5, 6, or 7. In some embodiments, p is 4, 5, 6, or 7.
  • Z 1 and Z 2 is —W—(CH 2 ) c —C(R 3 )(R 4 )—Y, and R 3 and R 4 is independently H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl.
  • Z 1 and Z 2 is —W—(CH 2 ) c —C(R 3 )(R 4 )—Y, and Y is —COOH or —COOR 5 .
  • Z 1 and Z 2 is —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.
  • Z 1 and Z 2 is —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.
  • Q is independently methyl or —OH.
  • t is 1. In some embodiments, t is 2. In some embodiments, t is 3.
  • the compound of Formula (IH), (IJ), (IK), or (IL) has any one of the structures shown in Table A-5, Table A-6, or Table A-7, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of the invention is a compound 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.
  • R 3 is H, —OH, —O(C 1 -C 3 alkyl), or —C 1 -C 3 alkyl.
  • each Y is independently —O— or —S—.
  • 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.
  • each Z is independently —COOH or —COOR 5 . In some embodiments, each Z is —COOH.
  • each R 5 is independently —C 1 -C 3 alkyl, —C 2 -C 3 alkenyl, or —C 2 -C 3 alkynyl.
  • each n is independently 0, 1, or 2. In some embodiments, n is 1.
  • each m is independently 3, 4, 5, or 6. In some embodiments, each m is independently 4 or 5.
  • the compound of Formula (II) has any one of the structures shown in Table B1, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of the invention is a compound of Formula (III):
  • the compound of the invention is a compound of Formula (IIIA):
  • the compound of the invention is a compound of Formula
  • 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.
  • Z 1 and Z 2 are the same group: —OH, —COOH, or —COOR 5 .
  • both Z 1 and Z 2 is —C 1 -C 6 alkyl.
  • X is —S—, —S( ⁇ O)—, —S(O) 2 —, —NH—, —N(OH)—, —N( ⁇ O)—, N(alkyl)-, or —N(aryl)-.
  • X is O. In some embodiments of compounds of Formula (III), when X is O, m is 2, 3, 5, 6, or 7.
  • each n is independently 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.
  • each m is independently 4, 5, or 6. In some embodiments, m is 5 or 6. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 2 or 3.
  • R 1 and R 2 together with the attached carbon atom form a —C 3 -C 7 cycloalkyl group.
  • the compound of Formula (III) or (IIIA) has any one of the structures shown in Table B2, or a pharmaceutically acceptable salt or solvate thereof.
  • the composition of the invention comprises (i) an effective amount of a compound of the invention and (ii) a pharmaceutically acceptable carrier or vehicle.
  • composition of the invention comprises (i) an effective amount of 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.
  • composition comprising a compound of Formula (IA)
  • c is 0 or 1.
  • 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.
  • 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
  • the composition of the invention comprises an effective amount of a compound having a structure depicted in Tables A-1, A-2, A-3, or A-4, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the invention comprises an effective amount of a compound having a structure depicted in Table B1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the invention comprises an effective amount of a compound having a structure depicted in Table B2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the invention comprises an effective amount of a compound having a structure depicted in Table C, or a pharmaceutically acceptable salt or solvate thereof.
  • composition of the invention further comprises another pharmaceutically active agent.
  • the other pharmaceutically active agent is a statin, a thiazolidinedione or fibrate, a bile-acid-binding-resin, a niacin, an anti-obesity drug, a hormone, a tyrophostine, a sulfonylurea-based drug, a biguanide, an ⁇ -glucosidase inhibitor, an apolipoprotein A-I agonist, apolipoprotein E agonist, a phosphodiesterase type-5 inhibitor, a cardiovascular drug, an HDL-raising drug, an HDL enhancer, an agonist of the apolipoprotein A-I gene or protein, an agonist of the apolipoprotein A-IV gene or protein, an agonist of an apolipoprotein gene, an ATP citrate lyase modulator, an ATP citrate lyase allosteric inhibitor, an acetyl-CoA carboxylase modulator
  • the other pharmaceutically active agent is an antagonist or an 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 a proinflammatory function or increases an anti-inflammatory function of IL-6, CRP, TNF- ⁇ , MCP-1, MIP-1 ⁇ , CCR5, CCR2, NF- ⁇ B or TGF- ⁇ 1.
  • 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.
  • the other pharmaceutically active agent is a regulator of lipid metabolism- or -trafficking-related genes, a regulator of PPAR- ⁇ 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.
  • the other pharmaceutically active agent is a statin.
  • the statin is atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, dalvastatin, dihydrocompactin, or cerivastatin, or a pharmaceutically acceptable salt thereof.
  • statin is lovastatin.
  • the other pharmaceutically active agent is a fibrate.
  • the fibrate is fenofibrate, gemfibrozil, or fenofibric acid.
  • the other pharmaceutically active agent is sorafenib. In yet some other embodiments, the other pharmaceutically active agent is taxol. In yet some other embodiments, the other pharmaceutically active agent is carotuximab. In yet some other embodiments, the other pharmaceutically active agent is pembrolizumab. In yet some other embodiments, the other pharmaceutically active agent is lenvatinib. In yet some other embodiments, the other pharmaceutically active agent is avelumab. In some embodiments, the other pharmaceutically active agent is durvalumab. In yet some other embodiments, the other pharmaceutically active agent is tremelimumab. In yet some other embodiments the other pharmaceutically active agent is nivolumab.
  • the other pharmaceutically active agent is tazemetostat, cemiplimab, ABX196, T-cell receptor (TCR) immune cell therapy agent, such as LioCyxTM, IBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus or gene-modified oncolytic virus such as, but not limited to, telomelysin and imlygic; or an immunomodulating gene-therapy agent such as MDA-7/IL-24, GLIPR1/RTVP-1, and REIC/Dkk-3.
  • TCR T-cell receptor
  • 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, R05093151, pradigastat, Sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexo, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, ND-L02-s0201/BMS-986263, volixibat,
  • the other pharmaceutically active agent is pentamidine, Berberine, L-Carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, firsocostat, cilofexor, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, Tropifexor, S-adenosylmethionine, pentoxifylline, Olesoxime, AKR-001, Seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatini
  • the other pharmaceutically active agent is an anti-cancer agent, immunotherapeutic agent, oncologic virus, or vaccine.
  • the other pharmaceutically active agent is an anti-cancer agent.
  • the anti-cancer agent is sorafenib, taxol, lenvatinib, tazemetostat, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, R05093151 pradigastat, Sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturon
  • composition of the invention further comprises an anti-cancer agent.
  • the other pharmaceutically active agent is an immunotherapeutic agent.
  • the immunotherapeutic agent is pembrolizumab, avelumab, durvalumab, nivolumab, cemiplimab, ABX196, sintilimab, camrelizumab, spartalizumab, toripalimab, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305, ascrinvacumab, TCR T-cell therapy agent, sitravatinib, cytokine-based biologic agent IRX-2, bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SRF388, ET1402L1-CART, Glypican 3-specific Chimeric
  • composition of the invention further comprises an immunotherapeutic agent.
  • the other pharmaceutically active agent is an oncologic virus.
  • the oncologic virus is Pexastimogene Devacirepvec or Talimogene Laherparepvec.
  • the composition of the invention further comprises an oncologic virus.
  • the other pharmaceutically active agent is a vaccine.
  • the vaccine is GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase peptide vaccine, or IMA970A.
  • the composition of the invention further comprises a vaccine.
  • 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.
  • the composition of the invention further comprises two or more other pharmaceutically active agents.
  • the two or more other pharmaceutically active agents are oncolytic agents, such as, but not limited to, nanatinostat and valganciclovir.
  • the composition of the invention further comprises a pharmaceutically active agent: sorafenib, taxol, lenvatinib, tazemetostat, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, R05093151 pradigastat, Sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, sor
  • composition comprises (a) Compound I-1, Compound I-32, Compound I-61, or Compound III-1, or a pharmaceutically acceptable salt or solvate thereof and (b) a pharmaceutically active agent: sorafenib, taxol, lenvatinib, tazemetostat, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, R05093151 pradigastat, Sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilof
  • composition comprises a compound of the invention and a pharmaceutically active agent: sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, T-cell receptor (TCR) immune cell therapy agent, IBI-302, namodenoson, MM-310, tumor-injected oncolytic viruses or gene-modified oncolytic viruses, or immunomodulating gene-therapy agents.
  • a pharmaceutically active agent sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, T-cell receptor (TCR) immune
  • composition comprises (a) Compound I-1, Compound I-32, Compound I-61, or Compound III-1, or a pharmaceutically acceptable salt or solvate thereof and (b) a pharmaceutically active agent is sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, T-cell receptor (TCR) immune cell therapy agent, IBI-302, namodenoson, MM-310, tumor-injected oncolytic viruses or gene-modified oncolytic viruses, or immunomodulating gene-therapy agents.
  • TCR T-cell receptor
  • composition comprises a compound of the invention and sorafenib or lenvatinib.
  • 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.
  • composition comprises (a) Compound I-1 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib or lenvatinib.
  • composition comprises (a) Compound I-32 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib or lenvatinib.
  • composition comprises (a) Compound I-32 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib. In some embodiments, composition comprises (a) Compound I-32 or a pharmaceutically acceptable salt or solvate thereof and (b) lenvatinib. In some embodiments, composition comprises (a) Compound I-61 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib or lenvatinib. In some embodiments, composition comprises (a) Compound I-61 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib.
  • composition comprises (a) Compound I-61 or a pharmaceutically acceptable salt or solvate thereof and (b) lenvatinib. In some embodiments, composition comprises (a) Compound III-1 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib or lenvatinib.
  • Table D sets forth 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 of Table D refers to a particular compound of invention and another pharmaceutically active agent.
  • embodiment A1 refers to Compound I-1 (or a pharmaceutically acceptable salt or solvate thereof) and sorafenib
  • embodiment A2 refers to Compound I-32 (or a pharmaceutically acceptable salt or solvate thereof) and sorafenib
  • the compositions of the invention comprise an effective amount of a compound of the invention and another pharmaceutically active agent set forth in an embodiment of Table D.
  • the pharmaceutically acceptable carrier or vehicle includes, but is not limited to, a binder, filler, diluent, disintegrant, wetting agent, lubricant, glidant, coloring agent, dye-migration inhibitor, sweetening agent or flavoring agent.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized 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, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyeth
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder is hydroxypropylcellulose.
  • the binder or filler can be present from about 2% to about 49% by weight of the compositions of the invention provided herein or any range within these values. In some embodiments, the binder or filler is present in the composition of the invention from about 5% to about 15% by weight. In some embodiments, the binder or filler is present in the composition of the invention at about 5%, 6%, 7%, 8%, 9%, 8%, 10%, 11%, 12%, 13%, 14%, or 15% by weight or any range within any of these values.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • the diluent is lactose monohydrate.
  • the diluent is lactose monohydrate Fast-Flo 316 NF.
  • compositions of the invention can comprise a diluent, e.g., from about 5% to about 49% of a diluent by weight of composition or any range between any of these values.
  • the diluent is present in the compositions of the invention from about 15% to about 30% by weight.
  • the diluent is present in the composition of the invention at about 15%, 16%, 17%, 18%, 19%, 18%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight or any range within any of these values.
  • 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; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.
  • the amount of disintegrant in the compositions of the invention can vary.
  • the disintegrant is croscarmellose sodium.
  • the disintegrant is croscarmellose sodium NF (Ac-Di-Sol).
  • compositions of the invention can comprise a disintegrant, e.g., from about 0.5% to about 15% or from about 1% to about 10% by weight of a disintegrant.
  • 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 in any range within any of these values.
  • 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. of Boston, Mass.); and mixtures thereof.
  • the lubricant is magnesium stearate.
  • compositions of the invention can comprise a lubricant, e.g., about 0.1 to about 5% by weight of a lubricant.
  • 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 in any range within any of these values.
  • Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and talc, including asbestos-free talc.
  • Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
  • Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that provide a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, sucralose, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents 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 carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrolidone.
  • Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Solvents include glycerin, sorbitol, ethyl alcohol, and syrup.
  • non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil.
  • Organic acids include citric and tartaric acid.
  • Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
  • the compounds of the invention and the compositions of the invention can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.
  • compositions of the invention can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compositions of the invention can take such forms 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.
  • 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 in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • suitable formulations for each of these methods 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.
  • compositions of the invention are suitable for oral administration. These compositions can comprise solid, semisolid, gelmatrix or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, without limitation, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups or any combination thereof. In some embodiments, compositions of the invention suitable for oral administration are in the form of a tablet or a capsule. In some embodiments, the composition of the invention is in a form of a tablet. In some embodiments, the composition of the invention is in a form of a capsule. In some embodiments, the compound of the invention is contained in a capsule.
  • capsules are immediate release capsules.
  • a capsule is a coni-Snap® hard gelatin capsule.
  • compositions of the invention can be in the form of compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, 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, thus protecting the active ingredients from the acidic environment of the stomach.
  • Enteric-coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate.
  • a film coating can impart the same general characteristics as a sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the coating is a film coating.
  • the film coating comprises Opadry White and simethicone emulsion 30% USP.
  • the compound of the invention is contained in a tablet. In some embodiments, the compound of the invention is contained in a compressed tablet. In some embodiments, the compound of the invention is contained in a film-coated compressed tablet. In some embodiments, the compositions of the invention are in the form of film-coated compressed tablets.
  • the compositions of the invention is prepared by fluid bed granulation of the compound of the invention with one or more pharmaceutically acceptable carrier, vehicle, or excipients.
  • the compositions of the invention prepared by fluid bed granulation process can provide tablet formulation with good flowability, good compressibility, fast dissolution, good stability, and/or minimal to no cracking.
  • the fluid bed granulation process allows preparation of formulations having high drug loading, such as over 70% or over 75% of a compound of the invention.
  • compositions of the invention can be in the form of soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • the soft elastic capsule is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells can contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid.
  • liquid, semisolid, and solid dosage forms can be encapsulated in a capsule.
  • suitable liquid and semisolid 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. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules can also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • compositions of the invention can be in liquid or semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion can be a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil.
  • Emulsions can include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative.
  • Suspensions can include a pharmaceutically acceptable suspending agent and 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 an alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs can be clear, sweetened, and hydroalcoholic solutions.
  • Syrups can be concentrated aqueous solutions of a sugar, for example, sucrose, and can comprise a preservative.
  • a solution in a polyethylene glycol can be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • compositions of the invention for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems.
  • Miccellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
  • compositions of the invention can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders can include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders can include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the above dosage forms. And, flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • compositions of the invention can be formulated as immediate or modified release dosage forms, including delayed-, extended, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions of the invention comprise a film-coating.
  • compositions of the invention can comprise another active ingredient that does not impair the composition's therapeutic or prophylactic efficacy or can comprise a substance that augments or supplements the composition's efficacy.
  • the tablet dosage forms can comprise the compound of the invention in powdered, crystalline, or granular form, and can further comprise a carrier or vehicle described herein, including binder, disintegrant, controlled-release polymer, lubricant, diluent, or colorant.
  • compositions of the invention can further comprise an excipient such as a diluent, a disintegrant, a wetting agent, a binder, a glidant, a lubricant, or any combination thereof.
  • a tablet comprises a binder.
  • the binder comprises microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, polyvinylpyrridone, hydroxypropyl cellulose, hydroxymethyl cellulose, or any combination thereof.
  • the tablet comprises a disintegrant.
  • the disintegrant comprises sodium croscarmellose, sodium starch glycolate, or any combination thereof.
  • the tablet comprises a lubricant.
  • the lubricant comprises magnesium stearate stearic acid, hydrogenated oil, sodium stearyl fumarate, or any combination thereof.
  • compositions of the invention are in the form of a tablet that comprises a binder such as any of the binders described herein.
  • compositions of the invention are in the form of a tablet that comprises a disintegrant such as any of the disintegrants described herein.
  • compositions of the invention are in the form of a tablet that comprises a lubricant such as any of the lubricants described herein.
  • the compositions of the invention can be in a modified release or a controlled release dosage form.
  • the compositions of the invention can comprise particles exhibiting a particular release profile.
  • the composition of the invention can comprise a compound of the invention in an immediate release form while also comprising a statin or a pharmaceutically acceptable salt thereof in a modified release form, both compressed into a single tablet.
  • Other combination and modification of release profile can be achieved as understood by one skilled in the art. Examples of modified release dosage forms suited for pharmaceutical compositions of the instant invention are described, without limitation, in U.S. Pat. Nos.
  • the compositions of the invention are a matrix-controlled release dosage form.
  • the compositions of the invention can comprise about 300 mg to about 600 mg of a compound of the invention provided as a matrix-controlled release form.
  • a matrix-controlled release form can further comprise another pharmaceutically active agent.
  • the release profile of the compound of the invention and of 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.
  • 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 the anti-cancer agent and from about 300 mg to about 600 mg of a compound of the invention. In some embodiment, the composition is in a matrix-controlled modified release dosage form.
  • 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 in a matrix-controlled modified release dosage form.
  • the matrix-controlled release form comprises an erodible matrix comprising water-swellable, erodible, or soluble polymers, including synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • the erodible matrix of the matrix-controlled release form comprises chitin, chitosan, dextran, or pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, 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; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), carrrboxymethyl ethyl cellulose (CMEC,) hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP),
  • EC
  • compositions of the invention are in a matrix-controlled modified release form comprising a non-erodible matrix.
  • the statin, the compound of the invention is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
  • the non-erodible matrix of the matrix-controlled release form comprises an insoluble polymer, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, a methyl acrylate-methyl methacrylate copolymer, an ethylene-vinylacetate copolymer, an ethylene/propylene copolymer, an ethylene/ethyl acrylate copolymer, a vinylchloride copolymer with vinyl acetate, a vinylidene chloride, an ethylene or a propylene, an ionomer polyethylene terephthalate, a butyl rubber epichlorohydrin rubber, an ethylene/vinyl alcohol copolymer, an ethylene/vinyl acetate/vinyl alcohol terpolymer, an ethylene/vinyloxyethanol copolymer
  • compositions of the invention that are 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.
  • the compositions of the invention comprise a tablets-in-capsule system, which can be a multifunctional and multiple unit system comprising versatile mini-tablets in a hard gelatin capsule.
  • the mini-tablets can be rapid-release, extended-release, pulsatile, delayed-onset extended-release minitablets, or any combination thereof.
  • combinations of mini-tablets or combinations of mini-tablets and minibeads comprising multiple active pharmaceutical agents can each have specific lag times, of release multiplied pulsatile drug delivery system (DDS), site-specific DDS, slow-quick DDS, quick/slow DDS and zero-order DDS.
  • DDS release multiplied pulsatile drug delivery system
  • compositions of the invention are in an osmotic-controlled release dosage form.
  • the osmotic-controlled release device comprises a one-chamber system, a two-chamber system, asymmetric membrane technology (AMT), an extruding core system (ECS), or any combination thereof.
  • such devices comprise at least two components: (a) the core which contains the active pharmaceutical agent(s); and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core.
  • the semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • the core of the osmotic device optionally comprises an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
  • osmogens which are capable of imbibing water to affect an 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,
  • Osmotic agents of different dissolution rates can be employed to influence how rapidly the compound of the invention dissolves following administration.
  • an amorphous sugar such as Mannogeme EZ (SPI Pharma, Lewes, Del.) can be included to provide faster delivery during the first couple of hours (e.g., about 1 to about 5 hrs) to promptly produce prophylactic or therapeutic efficacy, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time.
  • the compound of the invention is released from the compositions of the invention at such a rate to replace the amount of the compound of the invention metabolized or excreted by the subject.
  • the core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful for forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable polymers useful in 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-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copo
  • the semipermeable membranes can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119.
  • Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • the delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220.
  • the total amount of the compound of the invention released and the release rate can substantially be modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • the pharmaceutical composition in an osmotic controlled-release dosage form can further comprise additional conventional excipients as described herein to promote performance or processing of the formulation.
  • the osmotic 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).
  • the pharmaceutical composition provided herein is formulated as asymmetric membrane technology (AMT) controlled-release dosage form that comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients.
  • AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • the pharmaceutical composition provided herein is formulated as ESC controlled-release dosage form that comprises an osmotic membrane that coats a core comprising the compound of the invention, hydroxylethyl cellulose, and other pharmaceutically acceptable excipients.
  • compositions of the invention are a modified release dosage form that is fabricated as a multiparticulate-controlled release dosage form that comprises a plurality of particles, granules, or pellets, microparticulates, beads, microcapsules and microtablets, ranging from about 10 ⁇ m to about 3 mm, about 50 ⁇ m to about 2.5 mm, or from about 100 ⁇ m to 1 mm in diameter.
  • the multiparticulate-controlled release dosage forms can provide a prolonged release dosage form with an improved bioavailability.
  • Suitable carriers to sustain the release rate of the compound of the invention include, without limitation, ethyl cellulose, HPMC, HPMC-phtalate, colloidal silicondioxide and Eudragit-RSPM.
  • compositions of the invention in pellet form can comprise 50-80% (w/w) of a drug and 20-50% (w/w) of microcrystalline cellulose or other polymers.
  • Suitable polymers include, but are not limited to, microcrystalline wax, pregelatinized starch and maltose dextrin.
  • Beads can be prepared in capsule and tablet dosage forms. Beads in tablet dosage form can demonstrate a slower dissolution profile than microparticles in capsule form.
  • Microparticle fillers suitable for compositions and therapeutic or prophylactic methods of the invention include, without limitation, sorbitan monooleate (Span 80), HPMC, or any combination thereof.
  • Suitable dispersions for controlled release latex include, for example, ethyl-acrylate and methyl-acrylate.
  • compositions of the invention are in the form or microcapsules and/or microtablets.
  • microcapsules comprise extended release polymer microcapsules containing a statin and a compound of the invention with various solubility characteristics. Extended release polymer microcapsules can be prepared with colloidal polymer dispersion in an aqueous environment.
  • microcapsules suitable for the compositions and methods provided herein can be prepared using conventional microencapsulating techniques (Bodmeier & Wang, 1993).
  • Such multiparticulates can be made by the processes known to those skilled in the art, including wet- and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery ; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology ; Marcel Dekker: 1989. Excipients for such technologies are commercially available and described in US Pharmacopeia.
  • compositions of the invention can be blended with the compositions of the invention to aid in processing and forming the multiparticulates.
  • the resulting particles can themselves constitute the multiparticulate dosage form or can be coated by various film-forming materials, such as enteric polymers, water-swellable, or water-soluble polymers.
  • the multiparticulates can be further processed as a capsule or a tablet.
  • compositions of the invention are in a dosage form that has an instant releasing component and at least one delayed releasing component, and is capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from about 0.1 hour to about 24 hours.
  • compositions of the invention comprise from about 1 mg to about 1000 mg of a compound of the invention or any amount ranging from 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 ranging from 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 ranging from and to these values.
  • compositions of the invention comprise a compound of the invention in an amount that is a molar equivalent to about 1 mg to about 1000 mg of a compound of the invention or any amount ranging from 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 to about 1 mg to about 500 mg of a compound of the invention or any amount ranging from 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 to about 1 mg to about 400 mg of a compound of the invention or any amount ranging from and to these values.
  • compositions of the invention comprise a compound of the invention in an amount of about 10 wt % to about 99 wt % of the total weight of the composition of the invention.
  • the present invention provides methods for treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention, wherein the disease is liver disease or an abnormal liver condition; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract; an intra- or extra-hepatic bile duct disease; a disorder of lipoprotein; a lipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular or related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease resulting from steatosis, fibrosis, and cirrhosis; a disease associated with increased inflammation (such as hepatic inflammation or pulmonary inflammation); hepatocyte ballooning; a peroxisome proliferator activated receptor-associated disorder;
  • the present invention provides methods for treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention, wherein the disease is cancer, a lipid-and-metabolic disorder, a liver disorder, cirrhosis, fibrosis, a disorder of glucose metabolism, a peroxisome proliferator activated receptor-associated disorder, a malignant or benign tumor of the lung, liver, bile and digestive tract, an ATP citrate lyase disorder, an acetyl-coenzyme A carboxylase disorder, obesity, pancreatitis, renal disease, hepatocyte ballooning, hepatic inflammation, or pulmonary inflammation.
  • the disease is cancer, a lipid-and-metabolic disorder, a liver disorder, cirrhosis, fibrosis, a disorder of glucose metabolism, a peroxisome proliferator activated receptor-associated disorder, a malignant or benign tumor of the lung, liver, bile and digestive tract, an
  • the disease is cancer.
  • the cancer is hepatocellular carcinoma (HCC), HCC with cirrhosis, HCC without cirrhosis, cholangiocarcinoma, colorectal cancer, biliary cancer, or pulmonary cancer.
  • HCC hepatocellular carcinoma
  • HCC with cirrhosis HCC with cirrhosis
  • HCC without cirrhosis HCC without cirrhosis
  • cholangiocarcinoma cholangiocarcinoma
  • colorectal cancer colorectal cancer
  • biliary cancer or pulmonary cancer.
  • the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophogeal cancer, stomach 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,
  • gastrointestinal (digestive) cancer is gastrointestinal stromal tumor (GIST), esophagueal cancer, gallbladder cancer, gastrointestinal carcinoid tumor, cholangiocarcinoma, duodenal cancer, gastroesophageal (ge) junction cancer, islet cell cancer, lpancreatic cancer, stomach cancer, colon cancer, rectal cancer, colorectal cancer, anal cancer, liver cancer, biliary cancer, bile duct cancer, cancer of the small intestine, seudomyxoma peritonei, small bowel cancer, or cancer of unknown primary.
  • GIST gastrointestinal stromal tumor
  • esophagueal cancer gallbladder cancer
  • gastrointestinal carcinoid tumor cholangiocarcinoma
  • duodenal cancer duodenal cancer
  • gastroesophageal (ge) junction cancer islet cell cancer, lpancreatic cancer, stomach cancer, colon cancer, rectal cancer, colorectal cancer, anal cancer, liver cancer, bili
  • the hematopoietic cancer is non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), multiple myeloma (MM), B chronic lymphocytic leukemia (B-CLL), B and T 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).
  • NHL non-Hodgkin's lymphoma
  • BL Burkitt's lymphoma
  • MM multiple myeloma
  • B-CLL B chronic lymphocytic leukemia
  • ALL T acute lymphocytic leukemia
  • TCL T cell lymphoma
  • AML acute myeloid leukemia
  • HCL hairy cell leukemia
  • HL Hodgkin's Lymphoma
  • CML chronic my
  • the cancer is in any stage. In some embodiments, the cancer can be in stage 0, stage I, stage II, stage III, or stage IV. In some embodiments of the methods as disclosed herein, the disease is tumor and the tumor can be in any stage. In some embodiments, the tumor is grade 1, grade 2, grade 3, or grade 4.
  • the disease is a lipid-and-metabolic disorder.
  • 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 transferase (GGT), high low-density lipoprotein (LDL), high very-low-density lipoprotein (VLDL), high apolipoprotein B (ApoB) and ApoB/Lp(a) (lipoprotein(a)) ratio, high total cholesterol, low high-density lipoprotein (HDL), or high non-HDL-cholesterol in the subject's plasma or blood serum; or by high glucose and insulin resistance in a subject with diabetes.
  • the lipid-and-metabolic disorder is non-alcoholic
  • the disease is a disorder of glucose metabolism.
  • the disorder of glucose metabolism is type I diabetes or type II diabetes.
  • the disease is a disease resulting from steatosis, fibrosis, and cirrhosis.
  • the disease resulting from steatosis is inflammation.
  • the disease resulting from steatosis is NAFLD, NASH, or ASH.
  • the disease resulting from fibrosis is liver cirrhosis or liver failure.
  • the disease resulting from cirrhosis is, hepatocellular carcinoma, liver damage, or hepatic encephalopathy.
  • the present invention provides methods for reducing a concentration in a subject's blood plasma or blood serum the subject's C-reactive protein (CRP) concentration, 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, 7 ⁇ -hydroxy-4-cholesten-3-one (C4) concentration, protein:creatinine ratio, creatine kinase concentration, angiopoietin-like protein 3 concentration, angiopoietin-like protein 4 concentration, angiopoietin-like protein 8 concentration, fibrinogen concentration, total cholesterol concentration, low-density lipoprotein cholesterol concentration, low-density lipoprotein concentration, very low-density lipoprotein cholesterol concentration, very low-density lipoprotein concentration, non-HDL cholesterol concentration, non-
  • the present invention provides methods for reducing triglyceride concentration in a subject's liver, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • the present invention provides methods for elevating in a subject's blood plasma or blood serum a concentration of high-density lipoprotein cholesterol or high-density lipoprotein, comprising administering to a subject in need thereof an effective amount of a compound of the invention or the composition of the invention.
  • the present invention provides methods for increasing functionalization of the high-density lipoprotein cholesterol, without increasing its concentration in a subject's blood plasma or blood serum, comprising administering to a subject in need thereof an effective amount of a compound of the invention or the composition of the invention, wherein an amount or rate of excretion of cholesterol and triglycerides increases.
  • the present invention provides methods for treating a disease, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention, wherein the disease is gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), or autoimmune disease.
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • the disease is inflammatory bowel disease.
  • the inflammatory bowel disease is Crohn's Disease or ulcerative colitis.
  • the disease is autoimmune disease.
  • the autoimmune disease is systemic lupus erythematosus.
  • the present invention provides methods for regressing, reducing the rate of progression or inhibiting progression of fibrosis, hepatocyte ballooning or hepatic inflammation, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • the present invention provides methods for inhibiting, reducing, or delaying advancement of a subject's lipid synthesis, liver steatosis, hepatocyte ballooning or inflammation, liver fibrosis, lung fibrosis, or cirrhosis, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • the present invention provides methods for reducing a subject's risk of developing or having atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, or restenosis, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • the present invention provides methods for elevating HDL concentration in the subject's blood serum or plasma, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • 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 the compound of the invention or the composition of the invention.
  • 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 the compound of the invention or the composition of the invention.
  • PPAR peroxisome proliferator-activated receptor
  • the present invention provides methods for CCR2/CCR5 gene downregulation, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • 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 the compound of the invention or the composition of the invention.
  • the present invention provides methods for inhibiting an interleukin's activation or concentration, comprising administering to a subject in need thereof an effective amount of a compound of the invention or the composition of the invention.
  • the interleukin (IL) is IL-2, IL-6, IL-17 or IL-18.
  • the present invention provides methods for inhibiting fibrin/fibrinogen, gastrin, lactate dehydrogenase, prostatic acid phosphatase (PAP), thyroglobulin, urine catecholamine, urine vanillylmandelic acid (VMA) or urine homovanillic acid (HVA), comprising administering to a subject in need thereof an effective amount of a compound of the invention or the composition of the invention.
  • PAP prostatic acid phosphatase
  • VMA urine vanillylmandelic acid
  • HVA urine homovanillic acid
  • 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 the composition of the invention.
  • beta-hCG beta-human chorionic gonadotropin
  • B2M beta-2-microglobulin
  • B-cell immunoglobulin comprising administering to a subject in need thereof an effective amount of a compound of the invention or the composition of the invention.
  • 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 the composition of the invention.
  • AFP alpha-fetoprotein
  • the present invention also provides methods for inhibiting hepatic fatty acid or sterol synthesis, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • the present invention also provides methods for treating or preventing a disease or disorder that is capable of being treated or prevented by increasing HDL levels, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • the present invention also provides methods for treating or preventing a disease or disorder that is capable of being treated or prevented by lowering LDL levels, which comprises administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • the compounds of the invention favorably alter lipid metabolism at least in part by enhancing oxidation of fatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis. Accordingly, the invention also provides methods for treating or preventing a metabolic syndrome disorder, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention.
  • the present invention further provides methods for 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 composition of the invention.
  • the present invention further provides methods for modulating, directly inhibiting or allosterically inhibiting acetyl-CoA carboxylase 1 (ACC1) or acetyl-CoA carboxylase 2 (ACC2) in a subject, comprising administering to the subject an effective amount of a compound of the invention or composition of the invention.
  • ACC1 acetyl-CoA carboxylase 1
  • ACC2 acetyl-CoA carboxylase 2
  • the present invention further provides methods for reducing the fat or cholesterol content of livestock meat or poultry eggs, comprising administering to the livestock or poultry an effective amount of the compound of the invention or the composition of the invention.
  • the compound of the invention is administered to the subject in need thereof in the range from about 1 mg to about 1000 mg or any amount ranging from and to these values. In some embodiment, the compound of the invention is administered to the subject in need thereof in the rage from 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.
  • the compound of the invention is administered to the subject in need thereof in a daily dose ranging from about 1 mg to about 1000 mg or any amount ranging from and to these values. In some embodiments, the compound of the invention is administered to the 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.
  • the compound of the invention is administered to the subject in need thereof once a day at a dose of about 1 mg to about 1000 mg or any amount ranging from and to these values.
  • the compound of the invention is administered to the subject in need thereof twice a day, each dose comprising the compound of the invention in about 1 mg to about 500 mg or any amount ranging from and to these values. In some embodiment, the compound of the invention is administered to the subject in need thereof twice a day, each dose comprising the compound of the invention in 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.
  • the compound of the invention is administered to the subject in need thereof three times a day, each dose comprising the compound of the invention in about 1 mg to about 400 mg or any amount ranging from and to these values. In some embodiment, the compound of the invention is administered to the subject in need thereof three times a day, each dose comprising the compound of the invention in 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.
  • the methods further comprise administering an effective amount of another pharmaceutically active agent.
  • the other pharmaceutically active agent is administered concurrently or sequentially with (prior or subsequent to) the administration of the compound of the invention or the composition of the invention.
  • the other pharmaceutically active agent is a statin, a thiazolidinedione or fibrate, a bile-acid-binding-resin, a niacin, an anti-obesity drug, a hormone, a tyrophostine, a sulfonylurea-based drug, a biguanide, an ⁇ -glucosidase inhibitor, an apolipoprotein A-I agonist, apolipoprotein E agonist; a phosphodiesterase type-5 inhibitor, a cardiovascular drug, an HDL-raising drug, an HDL enhancer, a regulator of the apolipoprotein A-I gene, a regulator of the apolipoprotein A-IV gene, a regulator of the apolipoprotein gene, an ATP citrate lyase modulator, an ATP citrate lyase allosteric inhibitor, an acetyl-CoA carboxylase modulator, or an acetyl
  • the other pharmaceutically active agent is lovastatin.
  • the other pharmaceutically active agent is sorafenib; taxol; carotuximab; pembrolizumab; lenvatinib; avelumab; durvalumab; tremelimumab; nivolumab; tazemetostat; cemiplimab; ABX196; T-cell receptor (TCR) immune cell therapy agent; IBI-302; namodenoson; MM-310; a tumor-injected oncolytic virus or gene-modified oncolytic virus such as, but not limited to, telomelysin and imlygic; or an immunomodulating gene-therapy agent such as MDA-7/IL-24, GLIPR1/RTVP-1, and REIC/Dkk-3.
  • the methods further comprises administering two or more other pharmaceutically active agents.
  • the methods of the invention comprise administering two or more other pharmaceutically active agents, optionally in combination.
  • the two or more other pharmaceutically active agents are oncolytic agents, such as, but not limited to, nanatinostat and valganciclovir.
  • the methods of the invention comprise orally administering a compound of the invention and further comprise administering a tumor-injected oncolytic treatment. In some embodiments, the combination is administered orally.
  • the other pharmaceutically active agent is cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, nivolumub, firsocostat, apararenone, metformin, leucine-metformin-sildenafil combination (NS-0200), IMM-124E, RG-125, vitamin E, cysteamine, selonsertib, losartan, R05093151, 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, volix
  • 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.
  • 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, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, R05093151 pradigastat, Sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305,
  • the method 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, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, R05093151 pradigastat, Sitagliptin, vildagliptin, NGM282, pegbelfermin, PF
  • 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, T-cell receptor (TCR) immune cell therapy agent, IBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus, a gene-modified oncolytic virus, or an immunomodulating gene-therapy agent.
  • TCR T-cell receptor
  • 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, T-cell receptor (TCR) immune cell therapy agent, IBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus, a gene-modified oncolytic virus, or an immunomodulating gene-therapy agent.
  • TCR T-cell receptor
  • 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 set forth of an embodiment of Table D.
  • the other pharmaceutically active agent is administered concurrently with, prior to or subsequent to the administration of the compound of the invention or the composition of the invention.
  • the methods further comprise administering radiation therapy to the subject.
  • the radiation therapy is gamma ray radiation therapy or x-ray radiation therapy.
  • the radiation therapy is administered via a gamma ray or x-ray radiation apparatus.
  • the radiation therapy is administered concurrently with, prior to or subsequent to the administration of the compound of the invention or the composition of the invention. In some embodiments, the radiation therapy is administered prior to or subsequent to the administration of the compound of the invention or the composition of the invention.
  • the compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), and (IL), can be prepared via the synthetic methodologies illustrated in Schemes 1-7.
  • the starting materials useful for preparing the compounds of the invention and intermediates thereof are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.
  • A can be halogen, such as Cl, Br, or I. In some embodiments, A is Br.
  • B can be carbanions of esters of carboxylic or malonic esters.
  • Q 1 and Q2 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 the Q 1 and Q 2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group.
  • R 1A and R 2A are as defined herein for formula (I).
  • 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 the Q 1 and Q 2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group.
  • R 1A and R 2A are as defined herein for formula (I)
  • 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 the Q 1 and Q 2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group.
  • R 1A and R 2A are as defined herein for formula (I).
  • Scheme 3 illustrates the transformation of ortho, meta, or para co-haloalkyl substituted arenes of the formula 5, wherein p is an integer in the range of 2-5 and Hal is Cl, Br, or I, to dicarboxylic acids of the formula 7, wherein R 1 and R 2 are alkyl and/or aryl moieties or are connected in a three- to seven-membered cycle.
  • This transformation can be accomplished by two different, however related pathways.
  • esters of the formula R 1 R 2 CHCO 2 R 5 wherein R 1 and R 2 are alkyl and/or aryl moieties or are connected in a three- to seven-membered cycle and R 5 is typically ethyl or methyl, are deprotonated by strong bases, preferably, but not limited to, butyl lithium or lithium diisopropylamide, and then reacted with dihalides of the formula 5 to furnish the corresponding diesters of the formula 6.
  • strong bases preferably, but not limited to, butyl lithium or lithium diisopropylamide
  • dihalides of the formula 5 to furnish the corresponding diesters of the formula 6.
  • the reaction is performed at temperatures from about ⁇ 78° C. to about 25° C. and the reaction solvent is preferably THF or diethyl ether (see Larock, R. C. Comprehensive Organic Transformations.
  • this transformation of a dihalide of the formula 5 to a diacid of the formula 7 can also be achieved in one step, when a carboxylic acid of the formula R 1 R 2 CHCO 2 H, wherein R 1 and R 2 are alkyl and/or aryl, is deprotonated twice under conditions similar to the alkylation of R 1 R 2 CHCO 2 R 5 described above and subsequently reacted with dibromide 5 (for a discussion, see Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, pp 1717-1718).
  • isobutyric acid is deprotonated twice with n-butyl lithium and diisopropylamine in THE solution first at about ⁇ 20° C. and then at about 50° C.
  • Halide derivatives of type 5 can be obtained by several methods, described for instance in Gleiter et al., J. Org. Chem. 1992, 57, 252-258.
  • Q and Q 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 the Q 1 and Q 2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group.
  • R 1A and R 2A are as defined herein for formula (I).
  • Scheme 4 illustrates the synthesis of para, meta, and ortho di-bromoalkyl substituted arene compounds 5-Br from the parent dicarboxylic acids 10 wherein (p-1) is an integer in the range from 1-2.
  • Scheme 4 first outlines the esterification of compounds of the formula 10 to diesters of the formula 20, wherein R is an alkyl moiety such as, but not limited to, methyl, ethyl, or isopropyl using general procedures referenced in Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, pp 1932-1941 and Smith, M. B.; March, J. March's Advanced Organic Chemistry.
  • Diols 30 can be prepared from diesters 20 by well-known synthetic methods (for a discussion of suitable reduction methods, see for example Hudlicky, M. Reductions in Organic Chemistry, 2 nd ed.; ACS Monograph 188, Washington, D C, 1996, pp 212-216).
  • transformation of the alcohol functionalities in 30 to the bromo moieties in Compound 5-Br can be accomplished by a variety of standard methods as referenced in Larock, R. C. Comprehensive Organic Transformations.
  • a useful solvent for this conversion is water, as is described in Schimelpfenig, C. W. J. Org. Chem. 1975, 40, 1493-1494.
  • 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 the Q 1 and Q 2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group.
  • R 1A and R 2A are as defined herein for formula (I).
  • Scheme 5 illustrates the preparation of ortho, meta, and para substituted arene compounds with two 3-bromopropyl substituents of the formula 5A-Br.
  • Specific examples for the synthesis of compounds 5A-Br with meta and para substitution are given in Schimelpfenig, C. W. J. Org. Chem. 1975, 40, 1493-1494 and Gleiter et al., J. Org. Chem. 1992, 57, 252-258, respectively.
  • a compound of the formula 50 is treated with malonic acid and piperidine in pyridine solution at about 90-110° C. to give an ⁇ , ⁇ -unsaturated carboxylic acid of the formula 60. The end point of this conversion is typically indicated by cessation of the CO 2 effervescence.
  • 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 the Q 1 and Q 2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group.
  • R 1A and R 2A are as defined herein for formula (I).
  • Scheme 6 illustrates a general method for the chain elongation of bromides of the formula 90 with an alkyl chain consisting of (p-2) methylene groups to bromides of the formula 5-Br with an alkyl chain consisting of p methylene groups.
  • the conversion sequence from alkyl halides (such as 90) to carboxylic acid (such as 120) can be accomplished using a malonic ester synthesis referenced in Smith, M. B.; 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, R. C. Comprehensive Organic Transformations.
  • This tetraester is subsequently saponified using, for example, aqueous ethanol and potassium hydroxide, yielding the corresponding tetraacid of the formula 110.
  • the tetraacid is then decarboxylated at a temperature of ca. 200° C. to the diacid of the formula 120. After esterification with methanol and concentrated sulfuric acid (see Scheme 4) to diester 20.
  • 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 the Q 1 and Q 2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group.
  • R 1A and R 2A are as defined herein for formula (I).
  • Scheme 7 illustrates the synthesis of ortho, meta, and para substituted arene compounds of the formula 7 with ⁇ -carboxyalkyl substitution, wherein (p-1) is an integer in the range from 2-12 and R 1 and R 2 are either alkyl and/or aryl moieties or two alkyl moieties connected in a 3- to 7-membered cycle.
  • the synthesis starts with the twofold 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 reaction of the formed dianion of 3 with suitable electrophiles A-(CH 2 ) p-1 —CR 1 R 2 —CH 2 O-PG, wherein (p-1), R 1 , and R 2 are defined as 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, P. G.
  • Methyl arenes can be alkylated via deprotonation using lithium bases followed by alkylation with suitable electrophiles according to Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, p 88. See, Bates et al., J. Am. Chem. Soc. 1981, 103, 5052-5058, for an example for the preparation of xylene dianions.
  • the protective groups of 190 are removed to liberate the terminal hydroxylmethyl moieties in 200, which are the oxidized using a suitable oxidizing agent (Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, pp 1646-1648 and Smith, M. B.; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5 th ed.; John Wiley and Sons, New York, 2001, p 1537) to give a dicarboxylic acid of the formula 7.
  • a suitable oxidizing agent Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2 nd ed.; Wiley-VCH, New York, 1999, pp 1646-1648 and Smith, M. B.; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5 th ed.; John Wiley and Sons, New York,
  • m-xylene metal-3
  • n-butyl lithium and potassium tert-butoxide in hexanes, first at room temperature and then at reflux temperature.
  • Scheme 8 shows illustrative alternate syntheses of compounds I-1 and I-32.
  • Commercially available benzene-dicarboxaldehydes (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 U.S. Pat. No. 8,349,833 B2) in the presence of base (including but not limited to sodium or potassium hydroxide, potassium or sodium tert-butoxide, potassium or sodium carbonate, and sodium hydride), in the manner described in Le Bigot Y.
  • base including but not limited to sodium or potassium hydroxide, potassium or sodium tert-butoxide, potassium or sodium carbonate, and sodium hydride
  • the esters thus obtained are subjected to hydrolysis after the hydrogenation reaction is deemed substantially complete by using an appropriate analytical methods.
  • the reaction mixtures containing compounds of formula (250) or (260), respectively, are hydrolyzed in the presence of an alkaline earth metal salt or base, or oxide, or alkali metal salt or base. in refluxing alcohols for 2 to 96 hours.
  • Typical examples include, but are not limited to, hydrolysis with K 2 CO 3 in a refluxing mixture of DMSO and water.
  • Other suitable procedures are referenced 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.
  • the compound of Formula (III) or (IIIA) where X ⁇ O can be prepared by a Williamson synthesis, by reacting an alcohol with a derivative comprising a leaving group such as halide, tolylsulphonate or mesylate. See Scheme 9.
  • Mercaptoacetic acid dissolved in mixtures of ethanol and water is treated with a solution of sodium hydroxide in water to make sodium mercaptoacetate and is 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 provide crude compound II-3.
  • the crude compound II-3 can be purified by recrystallization from solvents or mixtures of solvents such as MIBE and heptane.
  • ketodiacid compound II-3 from Example 1 is achieved with sodium borohydride after salt formation with NaOH to yield compound II-1 (see U.S. Pat. No. 7,119,221 for suitable reaction conditions).
  • Compound II-3 (Example 1) is dissolved in NaOH solution (2 to 7 equiv) to form an intermediate disodium salt in water. Isopropanol is then added followed by addition of sodium borohydride (1.05 equiv) in portions. The reaction mixture is heated at about 45° C. for a few hours to yield compound II-1.
  • Such product can be purified by recrystallization from MIBE, heptane or mixtures.
  • Compound II-12 is prepared via a Williamson ether synthesis starting from 3-1 and 3-2 (prepared as described in Dasseux et al. U.S. Pat. No. 6,459,003).
  • the resulting 3-3 is deprotected in methanol in the presence of a catalytic amount of p-toluenesulphonic acid monohydrate to give diol 3-4.
  • This diol is then coupled with tert-butyl bromoacetate in a two-phase system of aqueous NaOH and toluene in the presence of tetrabutylammonium bromide as PTC catalyst, as described in U.S. Pat. No. 10,227,285.
  • this tert-butyl ester is cleaved under acidic conditions to afford compound II-12.
  • Compound 3-1 (prepared as described in U.S. Pat. No. 6,790,953) is treated with sodium sulfide similarly to the method by Edwards, D.; Stenlake, J. B. J. Pharmacy Pharmacol. 1955, 7, 852-860, to form thio ether 4-1, which is deprotected in methanol in the presence of a catalytic amount of pyridinium p-toluenesulphonate (PPTS) as described in Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977, 42(23), 3772-73.
  • PPTS pyridinium p-toluenesulphonate
  • the diol 4-2 thus obtained is reacted with tert-butyl bromoacetate under phase-transfer catalysis conditions using (Bu 4 N)(HSO 4 ) as catalyst, following the method of Nagatsugi, F.; Sasaki, S.; Maeda, M. J. Fluorine Chem. 1992, 56, 373-383, to obtain its tert-butyl ester 4-3.
  • Subsequent cleavage of tert-butyl ester by trifluoroacetic acid (TFA) affords free acid compound II-20 in 90% yield similar to the procedure in Nagatsugi, F.; Sasaki, S.; Maeda, M. J. Fluorine Chem. 1992, 56, 373-383.
  • Compound II-24 is prepared starting from compound II-12 (Example 4) using hydrogen peroxide as an oxidizer similarly to the procedure described in U.S. Pat. No. 6,673,780.
  • Example 7 Synthesis of (11-Carboxymethylsulfanyl-6-oxo-undecylsulfanyl)-acetic acid (Compound II-4) and (11-Carboxymethylsulfanyl-6-hydroxy-undecylsulfanyl)-acetic acid (Compound II-2)
  • Diol 7-3 may be purified by column chromatography on silica gel and mixtures of solvents, such as ethyl acetate and methylene chloride.
  • Compound 7-3 thus obtained is subjected to a Mitsunobu reaction to afford bromide 7-4, which is subsequently treated with the sodium salt of mercaptoacetic acid in an alcohol or a mixture of alcohols (ethanol, isopropanol) to provide diacid compound II-4.
  • Compound II-4 is reduced with sodium borohydride to provide compound II-2 (see Example 2).
  • bis(4-chlorobutyl ether) is converted via diacetate 8-1 [Kliem, A., Schniepp, L. E. J. Am. Chem. Soc, 1948, 70, 1839] to diol 8-2, which is further reacted with ethyl bromoacetate to provide 8-3.
  • Compound 8-3 is hydrolyzed to provide II-11.
  • bis(4-chlorobutyl ether) is treated with the dianion of hydroxyacetic acid to provide compound II-11 via autoclave or high temperatures.
  • diacetate 8-1 is treated with potassium carbonate in methanol similarly to the method described in Kliem, A., Schniepp, L. E. J. Am. Chem. Soc, 1948, 70, 1839, and the crude compound 8-2 is optionally purified by column chromatography.
  • Diol 8-2 is reacted deprotonated with sodium hydride (95% or 60% in mineral oil) in THE for about 2 h to about 4 h and then it is reacted with ethyl bromoacetate to give diester 8-3.
  • the last step, hydrolysis of 8-3 is carried out with KOH in ethyl alcohol for about 2 to about 8 h.
  • Crude compound II-11 is optionally purified by gradient column chromatography on silica gel using solvents such as EtOAc and hexanes and their mixtures.
  • 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 THE (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 THE (50 mL) was added slowly 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.
  • This intermediate (24.0 g, 66.2 mmol) was dissolved in EtOH (300 mL) and water (50 mL), KOH (85%, 15.0 g, 227 mmol) was added, and the reaction mixture was refluxed for 3 h. The solvent was evaporated, the residue was dissolved in water (150 mL) and extracted with MIBE (2 ⁇ 30 mL). The aqueous solution was acidified with aqueous HCl to pH 1-2.
  • the compound was prepared by a modified method than reported in Cram, D. J.; Allinger, N. L.; Steinberg, H. J. Amer. Chem. Soc. 1954, 76, 6132.
  • the compound is prepared according to Cram, D. J.; Allinger, N. L.; Steinberg, H. J. Am. Chem. Soc. 1954, 76, 6132-6141).
  • a solution of 4-[4-(3-methoxycarbonylpropyl)-phenyl]-butyric acid methyl ester (17.7 g, 63.6 mmol) in THE (50 mL) was added to a suspension of LiAlH 4 (7.2 g, 0.19 mol) in THE (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.
  • This known compound was prepared by a method different from the one described in Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata, Y.; Misumi, S. Bull. Chem. Soc. Japan 1972, 45, 1825-1833.
  • This known compound was prepared by a method different from the one described in 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.
  • the mixture was extracted with dichloromethane (3 ⁇ 100 mL) and the combined organic layers were successively washed 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 MgSO 4 , concentrated in vacuo, and dried in high vacuo to give the crude product (11.2 g) as a brown oil.
  • the mixture was stirred at ⁇ 78° C. for an additional hour, then allowed to slowly warm to room temperature over the next 2 h and stirred overnight.
  • the reaction mixture was cooled with an ice-bath and hydrolyzed by addition of saturated NH 4 Cl solution (100 mL) and deionized water (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 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).
  • Hep3B and murine liver cancer cells Hepa1-6 were seeded at a cell density of 3000 cells/well in 96-well plates using either 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% Antibiotic-Antimycotic solution (Thermo-Fisher Scientific).
  • DMEM Dulbecco's Modified Eagle's Medium
  • the cells were treated with 0 (vehicle control), 0.1, 0.5, 1, 5, 10, 30, 50 or 100 ⁇ M Compound I-32, I-61, I-1, or III-1 (final concentration of DMSO 0.1%) and were allowed to grow for 72 hours at 37° C.
  • 10 ⁇ l of PrestoBlueTM Cell Viability Reagent (Invitrogen) was added to each well and the plate was incubated at 37° C. for an additional 1-2 hours. After incubation, fluorescence signal was measured with an excitation/emission wavelength of 560/590 nm using a SpectraMax M5 Microplate Reader (Molecular Devices).
  • Liver cancer cell lines Hep3B (human) and Hepa1-6 (murine) were maintained in either 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% Antibiotic-Antimycotic (Thermo-Fisher Scientific). Each cell line was seeded at 1000 cells/well in 12-well plates. The next day, the media were replaced, and cells were treated with 0 (vehicle control, 0.1% DMSO), 1, 5, 10, 30, 50, or 100 ⁇ M Compound I-32, I-61, I-1, or III-1 (final concentration of DMSO 0.1%) for 7 days.
  • 0 vehicle control, 0.1% DMSO
  • Compound I-32, I-61, I-1, or III-1 final concentration of DMSO 0.1%) for 7 days.
  • Hep3B (supplied by ATCC) or Hepa1-6 (supplied by ATCC) cells were seeded in 96-well plates at a density of 500 cells/well with complete media.
  • media in each well was aspirated and replaced with 100 ⁇ l of fresh complete media and cells were treated with sorafenib or lenvatinib in the presence of or without the compounds of the invention, in a concentration dependent manner (Compound I-32 (100 ⁇ M) or Compound I-61 (100 ⁇ M) either alone or in combination with sorafenib (3 ⁇ M) or lenvatinib (0.5 ⁇ M)).
  • Compound I-32 (100 ⁇ M) or Compound I-61 (100 ⁇ M) either alone or in combination with sorafenib (3 ⁇ M) or lenvatinib (0.5 ⁇ M)
  • Sorafenib and lenvatinib have the following structure:
  • FIGS. 8 A- 8 D demonstrate that both Compounds I-32 and I-61 showed synergistic inhibition in the presence of sorafenib or lenvatinib.

Abstract

This invention provides compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (II), (III), (IIIA), and (IIIB); pharmaceutically acceptable salts and solvates thereof, and compositions thereof. This invention further provides methods for treating a disease, including but not limited to, liver disease or an abnormal liver condition; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract; an intra- or extra-hepatic bile duct disease; a disorder of lipoprotein; a lipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular or related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease associated with increased inflammation (such as hepatic inflammation or pulmonary inflammation); hepatocyte ballooning; a peroxisome proliferator activated receptor-associated disorder; an ATP citrate lyase disorder; an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; or renal disease.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of U.S. application Ser. No. 17/240,513, filed Apr. 26, 2021, which is a continuation of U.S. application Ser. No. 16/937,154, filed Jul. 23, 2020, now U.S. Pat. No. 11,098,002, issued Aug. 24, 2021, which claims the benefit of U.S. Provisional Application No. 62/878,852, filed Jul. 26, 2019, and U.S. Provisional Application No. 62/901,739, filed Sep. 17, 2019, the disclosure of each of which is incorporated by reference herein in its entirety.
    • FIELD OF THE INVENTION
  • This 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. This invention further provides methods for preventing or treating a disease, including but not limited to, liver disease or an abnormal liver condition; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract; an intra- or extra-hepatic bile duct disease; a disorder of lipoprotein; a lipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular or related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease associated with increased inflammation (such as hepatic inflammation or pulmonary inflammation); hepatocyte ballooning; a peroxisome proliferator activated receptor-associated disorder; an ATP citrate lyase disorder; an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; or renal disease.
    • BACKGROUND OF THE INVENTION
  • Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies Patients with chronic liver disease, such as liver cirrhosis and fibrosis, are at increased risk for development of HCC. Thus, patients with chronic liver diseases should be closely monitored for development of HCC. Risk factors for HCC include cirrhosis, non-alcoholic fatty liver disease (NAFLD), nonalcoholic stetohepatitis (NASH), chronic alcohol consumption, hepatitis B, and hepatitis C, type IIb hyperlipidemia, mixed dyslipidemia, obesity, and type 2 diabetes.
  • Type IIb hyperlipidemia patients have a high risk of developing NAFLD and non-alcoholic steatosis hepatitis (NASH), which can develop due to hepatic triglyceride overproduction and accumulation. Elevated levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides are associated with mixed dyslipidemia, including type IIb hyperlipidemia which is characterized by elevation of apolipoprotein B, very low-density lipoprotein cholesterol (VLDL-C), intermediate density lipoprotein cholesterol (IDL), and small dense low-density lipoprotein (LDL) levels, in addition to elevation in LDL-C and triglyceride levels.
  • Current treatment options for treatment of type IIb hyperlipidemia are limited. While statins can be effective for lowering LDL-C and reducing inflammation, they are generally not very effective for lowering triglyceride concentrations. Further, high dose statin therapy is often not well tolerated because it can cause muscle pain (myalgia) and increase a patient's risk of serious muscle toxicity, such as rhabdomyolysis. Also, commonly used triglyceride-lowering agents that are administered in combination with statins are often not well-tolerated. When administered with statins, fibrates are known to have drug-drug interactions, resulting in increased statin blood drug levels, myalgia, an increased risk of muscle toxicity and an increased safety risk. Indeed, the interaction of the statin Baychol (cerivastatin) with the fibrate gemfibrozil resulted in severe muscle toxicity and deaths and raised safety concerns that resulted in the removal of Baychol from the U.S. market. Fish oil, which has been used to lower triglyceride levels, needs to be taken multiple times daily and can cause a fish oil aftertaste, burping or regurgitation. Niacin causes flushing, particularly when administered in combination with statins.
  • Hepatocellular adenomas are benign liver neoplasms whose genetics and pathophysiology are not entirely known. These lesions pose diagnostic and therapeutic challenges and treatments post-exeresis are still challenging. Bile duct adenomas raise the same therapeutic challenges. Digestive system adenomas are sporadic neoplasms, arising from the glandular epithelium of the stomach, small intestine, biliary tract, colon, and rectum.
  • Gastrointestinal (digestive) cancers are cancers that affect the gastrointestinal tract and other organs that are contained within the digestive system. Gastrointestinal stromal tumor (GIST), is a rare type of sarcoma that forms along the gastrointestinal tract, but mostly starts in the stomach or small intestine. The origins of the digestive cancers were linked strongly to chronic inflammation of the organs that develop through a series of histopathologic stages dependent of the organ affected. For cancers of the gastrointestinal tract or GIST, surgery will likely be recommended to remove the tumor and/or to help maintain normal function. Other treatment options are radiotherapy, chemotherapy, hormone therapy, or targeted therapies.
  • Thus, there is a need for a safe and effective therapy for treatment or prevention of cancer (such as gastrointestinal cancer, hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract; liver disease or an abnormal liver condition, an intra- or extra-hepatic bile duct disease; a disorder of lipoprotein; a lipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular or related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease associated with increased inflammation (such as hepatic inflammation or pulmonary inflammation); hepatocyte ballooning; a peroxisome proliferator activated receptor-associated disorder; an ATP citrate lyase disorder; an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; or renal disease.
    • SUMMARY OF THE INVENTION
  • 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 (each compound, pharmaceutically acceptable salt and solvate being a “compound of the invention”).
  • The present invention also provides compositions comprising i) an effective amount of a compound of the invention and ii) a pharmaceutically acceptable carrier or vehicle (each composition being a “composition of the invention”).
  • 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 liver disease or an abnormal liver condition; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract; an intra- or extra-hepatic bile duct disease; a disorder of lipoprotein; a lipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular or related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease associated with increased inflammation (such as hepatic inflammation or pulmonary inflammation); hepatocyte ballooning; a peroxisome proliferator activated receptor-associated disorder; an ATP citrate lyase disorder; an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; or renal disease.
  • The present invention further provides methods for treating or preventing a disease, wherein the disease is cancer, a lipid-and-metabolic disorder, a liver disorder, cirrhosis, fibrosis, a disorder of glucose metabolism, a peroxisome proliferator activated receptor-associated disorder, a malignant or benign tumor of the lung, liver, bile and digestive tract, an ATP citrate lyase disorder, an acetyl-coenzyme A carboxylase disorder, obesity, pancreatitis, renal disease, hepatocyte ballooning, hepatic inflammation, or pulmonary inflammation.
  • The present invention further provides methods for reducing in a subject's blood plasma or blood serum, the subject's C-reactive protein (CRP) concentration, 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: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 cholesterol concentration, non-HDL concentration, apolipoprotein B concentration, lipoprotein(a) concentration, or serum triglyceride concentration, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • The present invention further provides methods for reducing triglyceride concentration in a subject's liver, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • The present invention further provides methods for elevating in a subject's blood plasma or blood serum a concentration of high-density lipoprotein cholesterol or high-density lipoprotein, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • 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 gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), or autoimmune disease.
  • The present invention further provides methods for regressing, reducing the rate of progression, or inhibiting progression, of fibrosis, hepatocyte ballooning or hepatic inflammation, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • The present invention further provides methods for inhibiting, reducing, or delaying advancement of a subject's lipid synthesis, liver steatosis, hepatocyte ballooning or inflammation, liver fibrosis, lung fibrosis, or cirrhosis, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • The present invention further provides methods for reducing a subject's risk of developing or having atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, or restenosis, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • The present invention further provides methods for elevating HDL concentration in a subject's blood serum or plasma, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • 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.
  • 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.
  • The present invention further provides methods for reducing the fat or cholesterol content of livestock meat or poultry eggs, comprising administering to the livestock or poultry an effective amount of a compound of the invention.
  • 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.
  • 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.
  • The present invention further provides method for 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, a lipid-and-metabolic disorder, a liver disorder, cirrhosis, fibrosis, a disorder of glucose metabolism, a peroxisome proliferator activated receptor-associated disorder, a malignant or benign tumor of the lung, liver, bile and digestive tract, an ATP citrate lyase disorder, an acetyl-coenzyme A carboxylase disorder, obesity, pancreatitis, renal disease, hepatocyte ballooning, hepatic inflammation, or pulmonary inflammation.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIGS. 1A-1D show inhibitory effects of Compounds I-32, I-61, I-1, and III-1, respectively, on mouse primary hepatocyte lipogenesis as percent control.
  • FIGS. 2A-2D show anti-proliferative effects of Compounds I-32, I-61, I-1, and III-1, respectively, on Hepa1-6 cells as a percent of vehicle control.
  • FIGS. 3A-3D show anti-proliferative effects of Compounds I-32, I-61, I-1, and III-1, respectively, on Hep3B cell proliferation as a percent of vehicle control.
  • FIGS. 4A-4D show anti-clonogenic effects of Compounds I-32, I-61, I-1, and III-1, respectively, in Hepa1-6 cells as a percent of vehicle control.
  • FIGS. 5A-5D show anti-clonogenic effects of Compounds I-32, I-61, I-1, and III-1, respectively, in Hep3B cells as a percent of vehicle control.
  • FIG. 6A shows anti-proliferation effects of Compound I-32 and sorafenib, in the absence or presence of the other, in Hep3B cells. FIG. 6B shows anti-proliferation effects of Compound I-32 and lenvatinib, in the absence or presence of the other, in Hep3B cells. FIG. 6C shows anti-proliferation effects of Compound I-61 and sorafenib, in the absence or presence of the other, in Hep3B cells. FIG. 6D shows anti-proliferation effects of Compound I-61 and lenvatinib, in the absence or presence of the other, in Hep3B cells.
  • FIG. 7A shows anti-proliferation effects of Compound I-32 and sorafenib, in the absence or presence of the other, in Hepa1-6 cells. FIG. 7B shows anti-proliferation effects of Compound I-32 and lenvatinib, in the absence or presence of the other, in Hepa1-6 cells. FIG. 7C shows anti-proliferation effects of Compound I-61 and sorafenib, in the absence or presence of the other, in Hepa1-6 cells. FIG. 7D shows anti-proliferation effects of Compound I-61 and lenvatinib, in the absence or presence of the other, in Hepa1-6 cells.
  • FIG. 8A shows synergistic anti-proliferation effect of Compound I-32 and sorafenib in Hep3B cells. FIG. 8B shows synergistic anti-proliferation effect of Compound I-32 and lenvatinib in Hep3B cells. FIG. 8C shows synergistic anti-proliferation effect of Compound I-61 and sorafenib in Hep3B cells. FIG. 8D shows synergistic anti-proliferation effect of Compound I-61 and lenvatinib in Hep3B cells.
    •  DETAILED DESCRIPTION OF THE INVENTION Definitions
  • The term “about” when immediately preceding a numerical value means ±up to 20% of the numerical value. For example, “about” a numerical value means ±up to 20% of the numerical value, in some embodiments, ±up to 19%, ±up to 18%, ±up to 17%, ±up to 16%, ±up to 15%, ±up to 14%, ±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 therein.
  • Throughout the present specification, numerical ranges are provided for certain quantities. These ranges comprise 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.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
  • The term “pharmaceutically acceptable salt” includes both an acid and a base addition salt. Pharmaceutically acceptable salts can be obtained by reacting the compound of the invention functioning 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 obtained by reacting a compound of the invention functioning 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. Those skilled in the art will further recognize that pharmaceutically acceptable salts can be prepared by reaction of the compounds of the invention with an appropriate inorganic or organic acid or base via any of a number of known methods.
  • The term “solvate” refers to a solvation complex. Solvates can be formed by solvation (the combination of solvent molecules with molecules or ions of the compounds of the invention), or a solvate can be an aggregate that comprises a solute ion or molecule or a solvent molecules. The solvent can 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. The solvate can be formed via hydration, including via absorption of moisture. A pharmaceutically acceptable salt can also be a solvate. Where a solvate is obtained via crystallization from a solvent, the solvent can be an alcohol, such as methanol or ethanol; an aldehyde; a ketone, such as acetone; or an ester, such as ethyl acetate.
  • The compounds of the invention can have one or more asymmetric centers and can thus 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 they are specifically depicted herein. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation or isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds of the invention comprise an olefinic double bond or another center of geometric asymmetry, and unless specified otherwise, the compounds of the invention include both E and Z geometric isomers. Likewise, the compounds of the invention include all tautomeric forms.
  • An “effective amount” when used in connection with a compound of the invention means an amount of the compound of the invention that, when administered to a subject is effective to treat or prevent the disease, alone or with another pharmaceutically active agent.
  • An “effective amount” when used in connection with another pharmaceutically active agent means an amount of the other pharmaceutically active agent that is effective to treat or prevent the disease, alone or in combination with a compound of the invention.
  • A “subject” is a human or non-human mammal, e.g., a bovine, horse, feline, canine, rodent, or non-human primate. The human can be a male or female, child, adolescent or adult. The female can be premenarcheal or postmenarcheal.
  • “Mammal” includes a human, domestic animal such as a laboratory animal (e.g., mouse, rat, rabbit, monkey, dog, etc.) and household pet (e.g., cat, dog, swine, cattle, sheep, goat, horse, rabbit), and a non-domestic, wild animal.
  • All weight percentages (i.e., “% by weight” and “wt. %” and w/w) referenced herein, unless otherwise indicated, are relative to the total weight of the mixture or composition, as the case can be.
  • The terms below, as used herein, have the following meanings, unless indicated otherwise:
  • “Halo”, “Hal”, or “halogen” refers to Br, Cl, F, or I.
  • “Alkyl” refers to a fully saturated, straight or branched hydrocarbon chain having from one to twelve carbon atoms, and which is attached to an atom by a single bond. Alkyls with a number of carbon atoms ranging from 1 to 12 are included. An alkyl group with 1 to 12 carbon atoms is a C1-C12 alkyl, an alkyl group with 1 to 10 carbon atoms is a C1-C10 alkyl, an alkyl group with 1 to 6 carbon atoms is a C1-C6 alkyl and an alkyl group with 1 to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and C1 alkyl (i.e., methyl). A C1-C6 alkyl includes all moieties described above for C1-C5 alkyls but also includes C6 alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and C1-C6 alkyls, but also includes C7, C8, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise, an alkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Alkylene” refers to a fully saturated, straight or branched divalent hydrocarbon, and 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 terminus is attached to an atom by a single bond. The points of attachment of the alkylene chain can be one or two atoms. Unless stated otherwise, an alkylene chain can be unsubstituted or substituted with a substituent disclosed herein.
  • “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. Alkenyl groups with a number of carbon atoms ranging from 2 to 12 are included. An alkenyl group with 2 to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl group with 2 to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group with 2 to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl group with 2 to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C6 alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, C8, C9 and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes C11 and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-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 stated otherwise, an alkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “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 terminus of the alkenylene chain is attached to an atom by a single bond. The points of attachment of the alkenylene chain can be through one two atoms. Unless stated otherwise, an alkenylene chain can be unsubstituted or substituted with a substituent disclosed herein.
  • “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. Alkynyl groups with a number of carbon atoms ranging from 2 to 12 are included. An alkynyl group having 2 to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl group with 2 to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl group with 2 to 6 carbon atoms is a C2-C6 alkynyl and an alkynyl group with 2 to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes C6 alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, C8, C9 and C10 alkynyls. Similarly, a C2-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls. Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise, an alkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “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 terminus of the alkynylene chain is attached to an atom through a single bond. The points of attachment of the alkynylene chain can be through one or two atoms. Unless stated otherwise, an alkynylene chain can be unsubstituted or substituted with a substituent disclosed herein.
  • “Alkoxy” refers to a radical of the formula —ORa where Ra is an alkyl, alkenyl or alknyl radical as defined herein. Unless stated otherwise, an alkoxy group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. The aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aceanthrylenyl, acenaphthylenyl, acephenanthrylenyl, anthracenyl, azulenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, naphthalenyl, phenalenyl, phenanthrenyl, phenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise, the aryl can be unsubstituted or substituted with a substituent disclosed herein.
  • “Arylene” refers to a divalent aryl group, wherein the aryl is as defined herein. Unless stated otherwise, an arylene group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Arylalkyl” refers to a radical of the formula —Rb—Rc where Rb is an alkylene group as defined herein and Rc is an aryl radical as defined herein, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise, an arylalkyl group can be unsubstituted or substituted with a substituent disclosed herein. “Arylalkenyl” refers to a radical of the formula —Rb—Rc where Rb is an alkenylene group as defined herein and Rc is an aryl radical as defined herein. Unless stated otherwise, an arylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Arylalkynyl” refers to a radical of the formula —Rb—Rc where Rb is an alkynylene group as defined herein and Rc is an aryl radical as defined herein. Unless stated otherwise, an arylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Cycloalkyl” refers to a non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to an 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 stated otherwise, a cycloalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Aryloxy” refers to a radical of the formula —O(aryl), wherein the aryl radical is as defined herein. Aryloxy includes, but are is not limited to, phenoxy (—O(phenyl)). Unless stated otherwise, an aryloxy group can be unsubstituted or substituted with a substituent disclosed herein.
  • “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 can include fused or bridged ring systems, having from three to twenty carbon atoms, in some embodiments having from three to ten carbon atoms. A cycloalkenyl group is attached to an atom by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless stated otherwise, a cycloalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Cycloalkynyl” refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include 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 stated otherwise, a cycloalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Cycloalkylalkyl” refers to a radical of the formula —Rb—Rd where Rb is an alkylene group as defined herein and Rd is a cycloalkyl radical as defined herein. Unless stated otherwise, a cycloalkylalkyl group can be unsubstituted or substituted with a substituent disclosed herein. “Cycloalkylalkenyl” refers to a radical of the formula —Rb—Rd where Rb is an alkenylene group as defined herein and Rd is a cycloalkyl radical as defined herein. Unless stated otherwise, a cycloalkylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein. “Cycloalkylalkynyl” refers to a radical of the formula —Rb—Rd where Rb is an alkynylene group as defined herein and Rd is a cycloalkyl radical as defined herein. Unless stated otherwise, a cycloalkylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Cycloalkenylalkyl” refers to a radical of the formula —Rb—Rd where Rb is an alkylene group as defined herein and Rd is a cycloalkenyl radical as defined herein. Unless stated otherwise, a cycloalkenylalkyl group can be unsubstituted or substituted with a substituent disclosed herein. “Cycloalkenylalkenyl” refers to a radical of the formula —Rb—Rd where Rb is an alkenylene group as defined herein and Rd is a cycloalkyl radical as defined herein. Unless stated otherwise, a cycloalkenylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein. “Cycloalkenylalkynyl” refers to a radical of the formula —Rb—Rd where Rb is an alkynylene group as defined herein and Rd is a cycloalkyl radical as defined herein. Unless stated otherwise, a cycloalkenylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Cycloalkynylalkyl” refers to a radical of the formula —Rb—Rd where Rb is an alkylene group as defined herein and Rd is a cycloalkynyl radical as defined herein. Unless stated otherwise, a cycloalkynylalkyl group can be unsubstituted or substituted with a substituent disclosed herein. “Cycloalkynylalkenyl” refers to a radical of the formula —Rb—Rd where Rb is an alkenylene group as defined herein and Rd is a cycloalkyl radical as defined herein. Unless stated otherwise, a cycloalkynylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein. “Cycloalkynylalkynyl” refers to a radical of the formula —Rb—Rd where Rb is an alkynylene group as defined herein and Rd is a cycloalkyl radical as defined herein. Unless stated otherwise, a cycloalkynylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a ring structure, wherein the atoms which form the ring are each carbon. The carbocyclyl, carbocyclic ring or carbocycle can comprise from 3 to 20 carbon atoms in the ring. The carbocyclyl, carbocyclic ring or carbocycle includes aryl, cycloalkyl, cycloalkenyl and cycloalkynyl as defined herein. The carbocyclyl, carbocyclic ring or carbocycle can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, and spiral ring systems. Unless stated otherwise, a carbocyclyl group, carbocyclic ring or carbocycle can be unsubstituted or substituted with a substituent disclosed herein.
  • “Haloalkyl” refers to an alkyl radical, as defined herein, that is substituted by one or more halo radicals, as defined herein, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise, a haloalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Haloalkenyl” refers to an alkenyl radical, as defined herein, that is substituted by one or more halo radicals, as defined herein, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise, a haloalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Haloalkynyl” refers to an alkynyl radical, as defined herein, that is substituted by one or more halo radicals, as defined herein, e.g., 1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwise, a haloalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Heterocyclyl” refers to a 3- to 20-membered non-aromatic, partially unsaturated, or aromatic ring radical which includes two to twelve carbon atoms and from one to six nitrogen, oxygen or sulfur heteroatoms. Heterocycly include heteroaryls as defined herein. Unless stated otherwise, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, and spiral ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can 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 stated otherwise, a heterocyclyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Heterocyclylalkyl” refers to a radical of the formula —Rb—Re where Rb is an alkylene group as defined herein and Re is a heterocyclyl radical as defined herein. Unless stated otherwise, a heterocyclylalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Heterocyclylalkenyl” refers to a radical of the formula —Rb—Re where Rb is an alkenylene group as defined herein and Re is a heterocyclyl radical as defined herein. Unless stated otherwise, a heterocyclylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Heterocyclylalkynyl” refers to a radical of the formula —Rb—Re where Rb is an alkynylene group as defined herein and Re is a heterocyclyl radical as defined herein. Unless stated otherwise, a heterocyclylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “N-heterocyclyl” refers to a heterocyclyl radical as defined herein including at least one nitrogen and where the point of attachment of the heterocyclyl radical of an atom of a compound of the invention is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise, an N-heterocyclyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Heteroaryl” refers to a 5- to 20-membered ring system radical including hydrogen atoms, one to thirteen carbon atoms, one to six nitrogen, oxygen or sulfur heteroatoms, and at least one aromatic ring. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, 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 stated otherwise, a heteroaryl group can be unsubstituted or substituted.
  • “N-heteroaryl” refers to a heteroaryl radical as defined herein having at least one nitrogen atom and where the point of attachment of the heteroaryl radical to an atom of the compound of the invention is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise, an N-heteroaryl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Heteroarylalkyl” refers to a radical of the formula —Rb—Rf where Rb is an alkylene chain as defined herein and Rf is a heteroaryl radical as defined herein. Unless stated otherwise, a heteroarylalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Heteroarylalkenyl” refers to a radical of the formula —Rb—Rf where Rb is an alkenylene chain as defined herein and Rf is a heteroaryl radical as defined herein. Unless stated otherwise, a heteroarylalkenyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Heteroarylalkynyl” refers to a radical of the formula —Rb—Rf where Rb is an alkynylene chain as defined herein and Rf is a heteroaryl radical as defined herein. Unless stated otherwise, a heteroarylalkynyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • “Ring” refers to a cyclic group which can be saturated or include one or more double or triple bonds. A ring can be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless stated otherwise, a ring can be unsubstituted or substituted with a substituent disclosed herein.
  • “Thioalkyl” refers to a radical of the formula —SRa where Ra is an alkyl, alkenyl, or alkynyl radical as defined herein. Unless stated otherwise, a thioalkyl group can be unsubstituted or substituted with a substituent disclosed herein.
  • A group or radical disclosed herein can be substituted with one or more of the following substitutents: a halogen atom such as F, Cl, Br, and I; a 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 including one or more heteroatoms.
  • A group or radical disclosed herein can be alternatively or additionally substituted with one or more of the following substituents: oxo, carbonyl, carboxyl, or an ester group; or an imine, oxime, hydrazone, and nitrile.
  • Examples of other substituents include, but are not limited to:
  • an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroarylalkyl group, —NRgRh, —NRgC(═O)Rh, —NRgC(═O)NRgRh, —NRgC(═O)ORh, —NRgSO2Rh, —OC(═O)NRgRh, —ORg, —SRg, —SORg, —SO2Rg, —OSO2Rg, —SO2ORg, ═NSO2Rg, —SO2NRgRh, —C(═O)Rg, —C(═O)ORg, —C(═O)NRgRh, —CH2SO2Rg and —CH2SO2NRgRh, wherein Rg and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl or heteroarylalkyl, wherein each of the foregoing substituents is unsubstituted or substituted with one or more substituents disclosed herein.
  • As used herein, the symbol “
    Figure US20230007838A1-20230112-P00001
    ” (a “point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example, “XY
    Figure US20230007838A1-20230112-P00001
    ” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond.
  • The Compounds of the Invention
  • Compounds of Formula (IA)
  • In some embodiments, the compound of the invention is a compound of Formula (IA):
  • Figure US20230007838A1-20230112-C00001
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each p is independently 1, 2, 3, 4, 5, 6, or 7;
      • Z1 and Z2 are independently —C(R1A)(R2A)—(CH2)d—XA or —W—(CH2)d—C(R3)(R4)—Y;
      • each d is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
      • each R1A and R2A is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1A and R2A attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom together with the R3 and R4 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each XA is independently H, —OH, —SO3H,
  • Figure US20230007838A1-20230112-C00002
    Figure US20230007838A1-20230112-C00003
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
      • each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O)2—, or —Se—;
      • each Y is independently —OH, —COOH, —COOR5, —SO3H,
  • Figure US20230007838A1-20230112-C00004
    Figure US20230007838A1-20230112-C00005
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups.
  • In some embodiments of the compounds of Formula (IA), Z1 and Z2 are independently —C(R1A)(R2A)—(CH2)d—XA.
  • In some embodiments of the compounds of Formula (IA), each R1A and R2A is independently —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments, each R1A and R2A is independently —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl. In some embodiments, each R1A and R2A is independently H or —C1-C6 alkyl. In some embodiments, R1A and R2A are methyl.
  • In some embodiments of the compounds of Formula (IA), each p is 2, 3, 4, or 5.
  • In some embodiments of the compounds of Formula (IA), each d is 0, 1, 2, or 3. In some embodiments, d is 0 or 1.
  • In some embodiments, the compound of the invention is a compound of Formula (IA):
  • Figure US20230007838A1-20230112-C00006
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each p is independently 4, 5, 6, or 7;
      • Z1 and Z2 are independently —C(R1)(R2)—(CH2)c—X or —W—(CH2)c—C(R3)(R4)—Y;
      • each c is independently 0, 1, 2, or 3;
      • each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom together with the R3 and R4 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each X and Y is independently —OH, —COOH, —COOR5, —SO3H,
  • Figure US20230007838A1-20230112-C00007
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
      • each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O)2—, or —Se—; and
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups.
  • In some embodiments, the compound of Formula (IA) has any one of the structures shown in Table A-1, or a pharmaceutically acceptable salt or solvate thereof.
  • TABLE A-1
    Compound No. Structure and Name
    I-1
    Figure US20230007838A1-20230112-C00008
     
    6-[4-(5-Carboxy-5-methyl-hexyl)-phenyl]-2,2,-dimethylhexanoic acid
    I-2
    Figure US20230007838A1-20230112-C00009
     
    7-(4-(5-Carboxy-5-methylhexyl)phenyl)-2,2-dimethylheptanoic acid
    I-3
    Figure US20230007838A1-20230112-C00010
     
    7,7′-(1,4-Phenylene)bis(2,2-dimethylheptanoic acid)
    I-4
    Figure US20230007838A1-20230112-C00011
     
    8-(4-(5-Carboxy-5-methylhexyl)phenyl)-2,2-dimethyloctanoic acid
    I-5
    Figure US20230007838A1-20230112-C00012
     
    1-(5-(4-(4-(1-carboxycyclopropyl)butyl)phenyl)pentyl)cyclopropane-1-carboxylic acid
    I-6
    Figure US20230007838A1-20230112-C00013
     
    1-(6-(4-(4-(1-carboxycyclopropyl)butyl)phenyl)hexyl)cyclopropane-1-carboxylic acid
    I-7
    Figure US20230007838A1-20230112-C00014
     
    1,1′-(1,4-phenylenebis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylic acid)
    I-8
    Figure US20230007838A1-20230112-C00015
     
    1-(4-(4-(6-carboxy-6-methylheptyl)phenyl)butyl)cyclopropane-1-carboxylic acid
    I-9
    Figure US20230007838A1-20230112-C00016
     
    1-(4-(4-(7-carboxy-7-methyloctyl)phenyl)butyl)cyclopropane-1-carboxylic acid
    I-10
    Figure US20230007838A1-20230112-C00017
     
    1-(5-(4-(6-carboxy-6-methylheptyl)phenyl)pentyl)cyclopropane-1-carboxylic acid
  • Compounds of Formula (IB′)
  • In some embodiments, the compound of the invention is a compound of Formula (IB):
  • Figure US20230007838A1-20230112-C00018
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each p is independently 1, 2, 3, 4, 5, 6, or 7;
      • each Z1 and Z2 is independently —C(R1)(R2)—(CH2)c—X or —C2, C(R3)(R4)—Y;
      • each c is independently 0, 1, 2, or 3;
      • each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom together with the R3 and R4 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each X and Y is independently —OH, —COOH, —COOR5, —SO3H,
  • Figure US20230007838A1-20230112-C00019
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
      • each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O)2—, or —Se—; and
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups.
  • In some embodiments, the compound of Formula (IB) has any one of the structures shown in Table A-2, or a pharmaceutically acceptable salt or solvate thereof.
  • TABLE A-2
    Compound No. Structure and Name
    I-31
    Figure US20230007838A1-20230112-C00020
     
    5-[3-(4-Carboxy-4-methylpentyl)phenyl]-2,2-dimethylpentanoic acid
    I-32
    Figure US20230007838A1-20230112-C00021
     
    6-[3-(5-Carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid
    I-33
    Figure US20230007838A1-20230112-C00022
     
    7-(3-(5-Carboxy-5-methylhexyl)phenyl)-2,2-dimethylheptanoic acid
    I-34
    Figure US20230007838A1-20230112-C00023
     
    7,7′-(1,3-Phenylene)bis(2,2-dimethylheptanoic acid)
    I-35
    Figure US20230007838A1-20230112-C00024
     
    8-(3-(5-Carboxy-5-methylhexyl)phenyl)-2,2-dimethyloctanoic acid
    I-36
    Figure US20230007838A1-20230112-C00025
     
    8,8′-(1,3-Phenylene)bis(2,2-dimethyloctanoic acid)
    I-37
    Figure US20230007838A1-20230112-C00026
     
    1-(6-(3-(7-carboxy-7-methyloctyl)phenyl)hexyl)cyclopropane-1-carboxylic acid
    I-38
    Figure US20230007838A1-20230112-C00027
     
    1,1′-(1,3-phenylenebis(hexane-6,1-diyl))bis(cyclopropane-1-carboxylic acid)
    I-39
    Figure US20230007838A1-20230112-C00028
     
    1-(4-(3-(6-carboxy-6-methylheptyl)phenyl)butyl)cyclopropane-1-carboxylic acid
    I-40
    Figure US20230007838A1-20230112-C00029
     
    1-(5-(3-(6-carboxy-6-methylheptyl)phenyl)pentyl)cyclopropane-1-carboxylic acid
    I-41
    Figure US20230007838A1-20230112-C00030
     
    1-(4-(3-(7-carboxy-7-methyloctyl)phenyl)butyl)cyclopropane-1-carboxylic acid
    I-42
    Figure US20230007838A1-20230112-C00031
     
    1-(5-(3-(4-(1-carboxy cyclopropyl)butyl)phenyl)pentyl)cyclopropane-1-carboxylic acid
    I-43
    Figure US20230007838A1-20230112-C00032
     
    1,1′-(1,3-phenylenebis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylic acid)
    I-44
    Figure US20230007838A1-20230112-C00033
     
    1-(6-(3-(4-(1-carboxycyclopropyl)butyl)phenyl)hexyl)cyclopropane-1-carboxylic acid
  • Compounds of Formula (IC)
  • In some embodiments, the compound of the invention is a compound of Formula (IC):
  • Figure US20230007838A1-20230112-C00034
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each p is independently 1, 2, 3, 4, 5, 6, or 7;
      • each Z1 and Z2 is independently —C(R1)(R2)—(CH2)c—X or —W—(CH2)c—C(R3)(R4)—Y;
      • each c is independently 0, 1, 2, or 3;
      • each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom together with the R3 and R4 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each X and Y is independently —OH, —COOH, —COOR5, —SO3H,
  • Figure US20230007838A1-20230112-C00035
    Figure US20230007838A1-20230112-C00036
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
      • each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O)2—, or —Se—; and
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups.
  • In some embodiments of the compounds of Formula (IA), (IB), or (IC), Z1 and Z2 are each independently —C(R1)(R2)—(CH2)c—X. In some embodiments, one or both of Z1 and Z2 is —W—(CH2)c—C(R3)(R4)—Y.
  • In some embodiments of the compounds of Formula (IA), (IB), or (IC), X is —COOH or —COOR5.
  • In some embodiments of the compounds of Formula (IA), (IB), or (IC), each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments, each R1 and R2 is independently —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl. In some embodiments, R1 and R2 are methyl.
  • In some embodiments of the compounds of Formula (IA), (IB), or (IC), Z1 and Z2 are each independently —C(R1)(R2)—(CH2)c—X, X is —COOH or —COOR5, and R1 and R2 are methyl.
  • In some embodiments of the compounds of Formula (IA), (IB), or (IC), c is 0 or 1.
  • In some embodiments of the compounds of Formula (IA), (IB), or (IC), Z1 and Z2 are each —C(R1)(R2)—(CH2)c—X. In some embodiments, Z1 and Z2 are each —C(R1)(R2)—(CH2)c—X and X is each —COOH.
  • In some embodiments of the compounds of Formula (IA), (IB), or (IC), each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group. In some embodiments, each carbon atom together with the R1 and R2 attached to the carbon atom independently form a cyclopropyl ring.
  • In some embodiments of the compounds of Formula (IA), (IB), or (IC), Z1 and Z2 are each —C(R1)(R2)—(CH2)c—X and at least one R1 and one R2 together with the carbon atom to which they are attached form a —C3-C7 cycloalkyl group. In some embodiments, Z1 and Z2 are each —C(R1)(R2)—(CH2)c—X and at least one R1 and one R2 together with the carbon atom to which they are attached form a cyclopropyl ring.
  • In some embodiments of the compounds of Formula (IA), (IB), or (IC), R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl.
  • In some embodiments of the compounds of Formula (IA), (IB), or (IC), Y is —COOH or —COOR5.
  • In some embodiments of the compounds of Formula (IA), (IB), or (IC), R5 is —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments, R5 is —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl.
  • In some embodiments of the 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 Z1 and Z2 is —W—(CH2)c—C(R3)(R4)—Y, and R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments, one or both of Z1 and Z2 is —W—(CH2)c—C(R3)(R4)—Y, and Y is —COOH or —COOR5. In some embodiments, one or both of Z1 and Z2 is —W—(CH2)c—C(R3)(R4)—Y, Y is —COOH or —COOR5, and R5 is —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments, one or both of Z1 and Z2 is —W—(CH2)c—C(R3)(R4)—Y, Y is —COOH or —COOR5, and R5 is —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl.
  • In some embodiments, the compound of Formula (IC) has of any one of the structures shown in Table A-3, or a pharmaceutically acceptable salt or solvate thereof.
  • TABLE A-3
    Compound No. Structure and Name
    I-61
    Figure US20230007838A1-20230112-C00037
     
    5-[2-(4-Carboxy-4-methylpentyl)-phenyl]-2,2-dimethylpentanoic acid
    I-62
    Figure US20230007838A1-20230112-C00038
     
    6,6′-(1,2-Phenylene)bis(2,2-dimethylhexanoic acid)
    I-63
    Figure US20230007838A1-20230112-C00039
     
    8-(2-(6-Carboxy-6-methylheptyl)phenyl)-2,2-dimethyloctanoic acid
    I-64
    Figure US20230007838A1-20230112-C00040
     
    7-(2-(5-Carboxy-5-methylhexyl)phenyl)-2,2-dimethylheptanoic acid
    I-65
    Figure US20230007838A1-20230112-C00041
     
    8,8′-(1,2-Phenylene)bis(2,2-dimethyloctanoic acid)
    I-66
    Figure US20230007838A1-20230112-C00042
     
    1-(4-(2-(5-carboxy-5-methylhexyl)phenyl)butyl)cyclopropane-1-
    carboxylic acid
    I-67
    Figure US20230007838A1-20230112-C00043
     
    1-(5-(2-(7-carboxy-7-methyloctyl)phenyl)pentyl)cyclopropane-1-
    carboxylic acid
    I-68
    Figure US20230007838A1-20230112-C00044
     
    1-(5-(2-(6-carboxy-6-methylheptyl)phenyl)pentyl)cyclopropane-1-
    carboxylic acid
    I-69
    Figure US20230007838A1-20230112-C00045
     
    1-(3-(2-(4-carboxy-4-methylpentyl)phenyl)propyl)cyclopropane-1-
    carboxylic acid
    I-70
    Figure US20230007838A1-20230112-C00046
     
    1-(5-(2-(5-carboxy-5-methylhexyl)phenyl)pentyl)cyclopropane-1-
    carboxylic acid
    I-71
    Figure US20230007838A1-20230112-C00047
     
    1-(6-(2-(7-carboxy-7-methyloctyl)phenyl)hexyl)cyclopropane-1-carboxylic
    acid
    I-72
    Figure US20230007838A1-20230112-C00048
     
    1,1′-(1,2-phenylenebis(butane-4,1-diyl))bis(cyclopropane-1-carboxylic
    acid)
    I-73
    Figure US20230007838A1-20230112-C00049
     
    1-(5-(2-(6-(1-carboxycyclopropyl)hexyl)phenyl)pentyl)cyclopropane-1-
    carboxylic acid
    I-74
    Figure US20230007838A1-20230112-C00050
     
    1,1′-(1,2-phenylenebis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylic
    acid)
    I-75
    Figure US20230007838A1-20230112-C00051
     
    1,1′-(1,2-phenylenebis(propane-3,1-diyl))bis(cyclopropane-1-
    carboxylic acid)
    I-76
    Figure US20230007838A1-20230112-C00052
     
    1-(5-(2-(4-(1-carboxycyclopropyl)butyl)phenyl)pentyl)cyclopropane-1-
    carboxylic acid
    I-77
    Figure US20230007838A1-20230112-C00053
     
    1,1′-(1,2-phenylenebis(hexane-6,1-diyl))bis(cyclopropane-1-carboxylic
    acid)
  • Compounds of Formula (ID)
  • In some embodiments, the compound of the invention is a compound of Formula (TD):
  • Figure US20230007838A1-20230112-C00054
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each p is independently 1, 2, 3, 4, 5, 6, or 7;
      • Z1 and Z2 are independently —C(R1A)(R2A)—(CH2)d—XA or —W—(CH2)d—C(R3)(R4)—Y;
      • each d is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
      • each R1A and R2A is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1A and R2A attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom together with the R3 and R4 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • Q1 and Q2 are independently H, OH, —C1-C6 alkyl, —O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, —S-aryl, —SR1A, —NR1AR2A, F, Cl, Br, I, —CF3, —COR1A, heteroaryl, heterocyclyl, or —V—OH, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group;
      • V is (CH2)t or arylene;
      • t is 0, 1, 2, 3, or 4;
      • each XA is independently H, —OH, —SO3H,
  • Figure US20230007838A1-20230112-C00055
    Figure US20230007838A1-20230112-C00056
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
      • each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O)2—, or —Se—;
      • each Y is independently —OH, —COOH, —COOR5, —SO3H,
  • Figure US20230007838A1-20230112-C00057
    Figure US20230007838A1-20230112-C00058
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups.
  • In some embodiments of the compounds of Formula (ID), Z1 and Z2 are independently —C(R1A)(R2A)—(CH2)d—XA.
  • In some embodiments of the compounds of Formula (ID), each R1A and R2A is independently —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments, each R1A and R2A is independently —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl. In some embodiments, each R1A and R2A is independently H or —C1-C6 alkyl. In some embodiments, R1A and R2A are methyl.
  • In some embodiments of the compounds of Formula (ID), each p is 2, 3, 4, or 5.
  • In some embodiments of the compounds of Formula (ID), each d is 0, 1, 2, or 3. In some embodiments, d is 0 or 1.
  • In some embodiments, the compound of the invention is a compound of Formula (ID).
  • Figure US20230007838A1-20230112-C00059
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each p is independently 4, 5, 6, or 7;
      • Z1 and Z2 are independently —C(R1)(R2)—(CH2)c—X or —W—(CH2)c—C(R3)(R4)—Y;
      • each c is independently 0, 1, 2, or 3;
      • each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom together with the R3 and R4 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • Q1 and Q2 are independently H, OH, —C1-C6 alkyl, —O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, —S-aryl, —SR1A, —NR1AR2A, F, Cl, Br, I, —CF3, —COR1A, heteroaryl, heterocyclyl, or —V—OH, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group;
      • each R1A and R2A is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl;
      • V is (CH2)t or arylene;
      • t is 0, 1, 2, 3, or 4;
      • each X and Y is independently —OH, —COOH, —COOR5, —SO3H,
  • Figure US20230007838A1-20230112-C00060
    Figure US20230007838A1-20230112-C00061
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
      • each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O)2—, or —Se—; and
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups.
  • In some embodiments, the compound of Formula (ID) has the structure shown in Table A-1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (ID) has the structure shown in Table A-5 which are mono- or di-substituted with —OH or methyl groups on the phenyl, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of Formula (IG)
  • In some embodiments, the compound of the invention is a compound of Formula (IG):
  • Figure US20230007838A1-20230112-C00062
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each p is independently 1, 2, 3, 4, 5, 6, or 7;
      • Z1 and Z2 are independently —C(R1)(R2)—(CH2)c—X or —W—(CH2)c—C(R3)(R4)—Y;
      • each c is independently 0, 1, 2, or 3;
      • each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom together with the R3 and R4 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • Q1 and Q2 are independently H, OH, —C1-C6 alkyl, —O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, —S-aryl, —SR1A, —NR1AR2A, F, Cl, Br, I, —CF3, —COR1A, heteroaryl, heterocyclyl, or —V—OH, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group;
      • each R1A and R2A is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl;
      • V is (CH2)t or arylene;
      • t is 0, 1, 2, 3, or 4;
      • each X and Y is independently —OH, —COOH, —COOR5, —SO3H,
  • Figure US20230007838A1-20230112-C00063
    Figure US20230007838A1-20230112-C00064
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
      • each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O)2—, or —Se—; and
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups.
  • In some embodiments, the compound of Formula (IG), Q1 and Q2 are each H.
  • In some embodiments, the compound of Formula (IG), p is 2, 3, 4, 5, 6, or 7. In some embodiments, the compound of Formula (IG), p is 2.
  • In some embodiments, the compound of Formula (IG) has the structure shown in Table A-4, or a pharmaceutically acceptable salt or solvate thereof.
  • TABLE A-4
    Compound
    No. Structure and Name
    I-78
    Figure US20230007838A1-20230112-C00065
  • Compounds of Formula (IE)
  • In some embodiments, the compound of the invention is a compound of Formula (IE):
  • Figure US20230007838A1-20230112-C00066
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each p is independently 1, 2, 3, 4, 5, 6, or 7;
      • each Z1 and Z2 is independently —C(R1)(R2)—(CH2)c—X or —W—(CH2)c—C(R3)(R4)—Y;
      • each c is independently 0, 1, 2, or 3;
      • each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom together with the R3 and R4 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • Q1 and Q2 are independently H, OH, —C1-C6 alkyl, —O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, —S-aryl, —SR1A, —NR1AR2A, F, Cl, Br, I, —CF3, —COR1A, heteroaryl, heterocyclyl, or —V—OH, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group;
      • each R1A and R2A is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl;
      • V is (CH2)t or arylene;
      • t is 0, 1, 2, 3, or 4;
      • each X and Y is independently —OH, —COOH, —COOR5, —SO3H,
  • Figure US20230007838A1-20230112-C00067
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
      • each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O)2—, or —Se—; and
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups.
  • In some embodiments, the compound of Formula (IE) has the structure shown in Table A-2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (IE) has the structure shown in Table A-6 which are mono- or di-substituted with —OH or methyl groups on the phenyl, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of Formula (IF)
  • In some embodiments, the compound of the invention is a compound of Formula (IF):
  • Figure US20230007838A1-20230112-C00068
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each p is independently 1, 2, 3, 4, 5, 6, or 7;
      • each Z1 and Z2 is independently —C(R1)(R2)—(CH2)c—X or —W—(CH2)c—C(R3)(R4)—Y;
      • each c is independently 0, 1, 2, or 3;
      • each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom together with the R3 and R4 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • Q1 and Q2 are independently H, OH, —C1-C6 alkyl, —O(C1-C6 alkyl), phenoxy, aryloxy, benzyl, —S-aryl, —SR1A, —NR1AR2A, F, Cl, Br, I, —CF3, —COR1A, heteroaryl, heterocyclyl, or —V—OH, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group;
      • each R1A and R2A is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl;
      • V is (CH2)t or arylene;
      • t is 0, 1, 2, 3, or 4;
      • each X and Y is independently —OH, —COOH, —COOR5, —SO3H,
  • Figure US20230007838A1-20230112-C00069
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
      • each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O)2—, or —Se—; and
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups.
  • In some embodiments, the compound of Formula (IF) has the structure shown in Table A-3, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (IE) has the structure shown in Table A-7 which are mono- or di-substituted with —OH or methyl groups on the phenyl, or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of Formulas (IH) and (IJ)-(IL)
  • In some embodiments, the compound of the invention is a compound of Formula (IH).
  • Figure US20230007838A1-20230112-C00070
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each p is independently 1, 2, 3, 4, 5, 6, or 7;
      • each Z1 and Z2 is independently —C(R1)(R2)—(CH2)c—X or —W—(CH2)c—C(R3)(R4)—Y;
      • each c is independently 0, 1, 2, or 3;
      • each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —O(C1-C6 alkyl), phenyl, benzyl, Cl, Br, CN, NO2, or CF3, or each carbon atom together with the R3 and R4 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • Q is independently —OH, methyl, or methoxy;
      • t is 1,2,3, or 4;
      • each X and Y is independently —OH, —COOH, —COOR5, —SO3H,
  • Figure US20230007838A1-20230112-C00071
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
      • each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O)2—, or —Se—; and
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups.
  • In some embodiments of formula (IH), the compound has the structure of formula (IJ), (IK), or (IL), or a pharmaceutically acceptable salt thereof:
  • Figure US20230007838A1-20230112-C00072
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) Z1 and Z2 are each independently —C(R1)(R2)—(CH2)c—X. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), one or both of Z1 and Z2 is —W—(CH2)c—C(R3)(R4)—Y.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), X is —COOH or —COOR5.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each R1 and R2 is independently —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R1 and R2 are methyl.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z1 and Z2 are each independently —C(R1)(R2)—(CH2)c—X, X is —COOH or —COOR5, and R1 and R2 are methyl.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), c is 0 or 1.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z1 and Z2 are each —C(R1)(R2)—(CH2)c—X. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z1 and Z2 are each —C(R1)(R2)—(CH2)c—X and X is each —COOH.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL) each carbon atom together with the R1 and R2 attached to the carbon atom independently form a cyclopropyl ring.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z1 and Z2 are each —C(R1)(R2)—(CH2)c—X and at least one R1 and one R2 together with the carbon atom to which they are attached form a —C3-C7 cycloalkyl group. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Z1 and Z2 are each —C(R1)(R2)—(CH2)c—X and at least one R1 and one R2 together with the carbon atom to which they are attached form a cyclopropyl ring.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), Y is —COOH or —COOR5.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R5 is —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), R5 is —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl.
  • In some embodiments of the 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.
  • In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), one or both of Z1 and Z2 is —W—(CH2)c—C(R3)(R4)—Y, and R3 and R4 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), one or both of Z1 and Z2 is —W—(CH2)c—C(R3)(R4)—Y, and Y is —COOH or —COOR5. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), one or both of Z1 and Z2 is —W—(CH2)c—C(R3)(R4)—Y, Y is —COOH or —COOR5, and R5 is —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), one or both of Z1 and Z2 is —W—(CH2)c—C(R3)(R4)—Y, Y is —COOH or —COOR5, and R5 is —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl.
  • In some embodiments of the compound of Formula (IH), (IJ), (IK), or (IL), Q is independently methyl or —OH.
  • In some embodiments of the compound of Formula (IH), (IJ), (IK), or (IL), t is 1. In some embodiments, t is 2. In some embodiments, t is 3.
  • In some embodiments, the compound of Formula (IH), (IJ), (IK), or (IL) has any one of the structures shown in Table A-5, Table A-6, or Table A-7, or a pharmaceutically acceptable salt or solvate thereof.
  • TABLE A-5
    Structure
    Figure US20230007838A1-20230112-C00073
    Figure US20230007838A1-20230112-C00074
    Figure US20230007838A1-20230112-C00075
    Figure US20230007838A1-20230112-C00076
    Figure US20230007838A1-20230112-C00077
    Figure US20230007838A1-20230112-C00078
    Figure US20230007838A1-20230112-C00079
    Figure US20230007838A1-20230112-C00080
    Figure US20230007838A1-20230112-C00081
    Figure US20230007838A1-20230112-C00082
    Figure US20230007838A1-20230112-C00083
    Figure US20230007838A1-20230112-C00084
    Figure US20230007838A1-20230112-C00085
    Figure US20230007838A1-20230112-C00086
    Figure US20230007838A1-20230112-C00087
    Figure US20230007838A1-20230112-C00088
    Figure US20230007838A1-20230112-C00089
    Figure US20230007838A1-20230112-C00090
    Figure US20230007838A1-20230112-C00091
    Figure US20230007838A1-20230112-C00092
    Figure US20230007838A1-20230112-C00093
    Figure US20230007838A1-20230112-C00094
    Figure US20230007838A1-20230112-C00095
    Figure US20230007838A1-20230112-C00096
    Figure US20230007838A1-20230112-C00097
    Figure US20230007838A1-20230112-C00098
    Figure US20230007838A1-20230112-C00099
    Figure US20230007838A1-20230112-C00100
    Figure US20230007838A1-20230112-C00101
    Figure US20230007838A1-20230112-C00102
    Figure US20230007838A1-20230112-C00103
    Figure US20230007838A1-20230112-C00104
    Figure US20230007838A1-20230112-C00105
    Figure US20230007838A1-20230112-C00106
    Figure US20230007838A1-20230112-C00107
    Figure US20230007838A1-20230112-C00108
    Figure US20230007838A1-20230112-C00109
    Figure US20230007838A1-20230112-C00110
    Figure US20230007838A1-20230112-C00111
    Figure US20230007838A1-20230112-C00112
    Figure US20230007838A1-20230112-C00113
    Figure US20230007838A1-20230112-C00114
    Figure US20230007838A1-20230112-C00115
    Figure US20230007838A1-20230112-C00116
    Figure US20230007838A1-20230112-C00117
    Figure US20230007838A1-20230112-C00118
    Figure US20230007838A1-20230112-C00119
    Figure US20230007838A1-20230112-C00120
    Figure US20230007838A1-20230112-C00121
    Figure US20230007838A1-20230112-C00122
    Figure US20230007838A1-20230112-C00123
    Figure US20230007838A1-20230112-C00124
    Figure US20230007838A1-20230112-C00125
    Figure US20230007838A1-20230112-C00126
    Figure US20230007838A1-20230112-C00127
    Figure US20230007838A1-20230112-C00128
    Figure US20230007838A1-20230112-C00129
    Figure US20230007838A1-20230112-C00130
    Figure US20230007838A1-20230112-C00131
    Figure US20230007838A1-20230112-C00132
    Figure US20230007838A1-20230112-C00133
    Figure US20230007838A1-20230112-C00134
    Figure US20230007838A1-20230112-C00135
    Figure US20230007838A1-20230112-C00136
    Figure US20230007838A1-20230112-C00137
    Figure US20230007838A1-20230112-C00138
    Figure US20230007838A1-20230112-C00139
    Figure US20230007838A1-20230112-C00140
    Figure US20230007838A1-20230112-C00141
    Figure US20230007838A1-20230112-C00142
    Figure US20230007838A1-20230112-C00143
    Figure US20230007838A1-20230112-C00144
    Figure US20230007838A1-20230112-C00145
    Figure US20230007838A1-20230112-C00146
    Figure US20230007838A1-20230112-C00147
    Figure US20230007838A1-20230112-C00148
    Figure US20230007838A1-20230112-C00149
    Figure US20230007838A1-20230112-C00150
    Figure US20230007838A1-20230112-C00151
    Figure US20230007838A1-20230112-C00152
    Figure US20230007838A1-20230112-C00153
    Figure US20230007838A1-20230112-C00154
    Figure US20230007838A1-20230112-C00155
    Figure US20230007838A1-20230112-C00156
    Figure US20230007838A1-20230112-C00157
    Figure US20230007838A1-20230112-C00158
    Figure US20230007838A1-20230112-C00159
    Figure US20230007838A1-20230112-C00160
    Figure US20230007838A1-20230112-C00161
    Figure US20230007838A1-20230112-C00162
    Figure US20230007838A1-20230112-C00163
    Figure US20230007838A1-20230112-C00164
    Figure US20230007838A1-20230112-C00165
    Figure US20230007838A1-20230112-C00166
    Figure US20230007838A1-20230112-C00167
    Figure US20230007838A1-20230112-C00168
    Figure US20230007838A1-20230112-C00169
    Figure US20230007838A1-20230112-C00170
    Figure US20230007838A1-20230112-C00171
    Figure US20230007838A1-20230112-C00172
    Figure US20230007838A1-20230112-C00173
    Figure US20230007838A1-20230112-C00174
    Figure US20230007838A1-20230112-C00175
    Figure US20230007838A1-20230112-C00176
    Figure US20230007838A1-20230112-C00177
    Figure US20230007838A1-20230112-C00178
    Figure US20230007838A1-20230112-C00179
    Figure US20230007838A1-20230112-C00180
    Figure US20230007838A1-20230112-C00181
    Figure US20230007838A1-20230112-C00182
    Figure US20230007838A1-20230112-C00183
    Figure US20230007838A1-20230112-C00184
    Figure US20230007838A1-20230112-C00185
    Figure US20230007838A1-20230112-C00186
    Figure US20230007838A1-20230112-C00187
    Figure US20230007838A1-20230112-C00188
    Figure US20230007838A1-20230112-C00189
    Figure US20230007838A1-20230112-C00190
    Figure US20230007838A1-20230112-C00191
    Figure US20230007838A1-20230112-C00192
    Figure US20230007838A1-20230112-C00193
    Figure US20230007838A1-20230112-C00194
  • TABLE A-6
    Structure
    Figure US20230007838A1-20230112-C00195
    Figure US20230007838A1-20230112-C00196
    Figure US20230007838A1-20230112-C00197
    Figure US20230007838A1-20230112-C00198
    Figure US20230007838A1-20230112-C00199
    Figure US20230007838A1-20230112-C00200
    Figure US20230007838A1-20230112-C00201
    Figure US20230007838A1-20230112-C00202
    Figure US20230007838A1-20230112-C00203
    Figure US20230007838A1-20230112-C00204
    Figure US20230007838A1-20230112-C00205
    Figure US20230007838A1-20230112-C00206
    Figure US20230007838A1-20230112-C00207
    Figure US20230007838A1-20230112-C00208
    Figure US20230007838A1-20230112-C00209
    Figure US20230007838A1-20230112-C00210
    Figure US20230007838A1-20230112-C00211
    Figure US20230007838A1-20230112-C00212
    Figure US20230007838A1-20230112-C00213
    Figure US20230007838A1-20230112-C00214
    Figure US20230007838A1-20230112-C00215
    Figure US20230007838A1-20230112-C00216
    Figure US20230007838A1-20230112-C00217
    Figure US20230007838A1-20230112-C00218
    Figure US20230007838A1-20230112-C00219
    Figure US20230007838A1-20230112-C00220
    Figure US20230007838A1-20230112-C00221
    Figure US20230007838A1-20230112-C00222
    Figure US20230007838A1-20230112-C00223
    Figure US20230007838A1-20230112-C00224
    Figure US20230007838A1-20230112-C00225
    Figure US20230007838A1-20230112-C00226
    Figure US20230007838A1-20230112-C00227
    Figure US20230007838A1-20230112-C00228
    Figure US20230007838A1-20230112-C00229
    Figure US20230007838A1-20230112-C00230
    Figure US20230007838A1-20230112-C00231
    Figure US20230007838A1-20230112-C00232
    Figure US20230007838A1-20230112-C00233
    Figure US20230007838A1-20230112-C00234
    Figure US20230007838A1-20230112-C00235
    Figure US20230007838A1-20230112-C00236
    Figure US20230007838A1-20230112-C00237
    Figure US20230007838A1-20230112-C00238
    Figure US20230007838A1-20230112-C00239
    Figure US20230007838A1-20230112-C00240
    Figure US20230007838A1-20230112-C00241
    Figure US20230007838A1-20230112-C00242
    Figure US20230007838A1-20230112-C00243
    Figure US20230007838A1-20230112-C00244
    Figure US20230007838A1-20230112-C00245
    Figure US20230007838A1-20230112-C00246
    Figure US20230007838A1-20230112-C00247
    Figure US20230007838A1-20230112-C00248
    Figure US20230007838A1-20230112-C00249
    Figure US20230007838A1-20230112-C00250
    Figure US20230007838A1-20230112-C00251
    Figure US20230007838A1-20230112-C00252
    Figure US20230007838A1-20230112-C00253
    Figure US20230007838A1-20230112-C00254
    Figure US20230007838A1-20230112-C00255
    Figure US20230007838A1-20230112-C00256
    Figure US20230007838A1-20230112-C00257
    Figure US20230007838A1-20230112-C00258
    Figure US20230007838A1-20230112-C00259
    Figure US20230007838A1-20230112-C00260
    Figure US20230007838A1-20230112-C00261
    Figure US20230007838A1-20230112-C00262
    Figure US20230007838A1-20230112-C00263
    Figure US20230007838A1-20230112-C00264
    Figure US20230007838A1-20230112-C00265
    Figure US20230007838A1-20230112-C00266
    Figure US20230007838A1-20230112-C00267
    Figure US20230007838A1-20230112-C00268
    Figure US20230007838A1-20230112-C00269
    Figure US20230007838A1-20230112-C00270
    Figure US20230007838A1-20230112-C00271
    Figure US20230007838A1-20230112-C00272
    Figure US20230007838A1-20230112-C00273
    Figure US20230007838A1-20230112-C00274
    Figure US20230007838A1-20230112-C00275
    Figure US20230007838A1-20230112-C00276
    Figure US20230007838A1-20230112-C00277
    Figure US20230007838A1-20230112-C00278
    Figure US20230007838A1-20230112-C00279
    Figure US20230007838A1-20230112-C00280
    Figure US20230007838A1-20230112-C00281
    Figure US20230007838A1-20230112-C00282
    Figure US20230007838A1-20230112-C00283
    Figure US20230007838A1-20230112-C00284
    Figure US20230007838A1-20230112-C00285
    Figure US20230007838A1-20230112-C00286
    Figure US20230007838A1-20230112-C00287
    Figure US20230007838A1-20230112-C00288
    Figure US20230007838A1-20230112-C00289
    Figure US20230007838A1-20230112-C00290
    Figure US20230007838A1-20230112-C00291
    Figure US20230007838A1-20230112-C00292
    Figure US20230007838A1-20230112-C00293
    Figure US20230007838A1-20230112-C00294
    Figure US20230007838A1-20230112-C00295
    Figure US20230007838A1-20230112-C00296
    Figure US20230007838A1-20230112-C00297
    Figure US20230007838A1-20230112-C00298
    Figure US20230007838A1-20230112-C00299
    Figure US20230007838A1-20230112-C00300
    Figure US20230007838A1-20230112-C00301
    Figure US20230007838A1-20230112-C00302
    Figure US20230007838A1-20230112-C00303
    Figure US20230007838A1-20230112-C00304
    Figure US20230007838A1-20230112-C00305
    Figure US20230007838A1-20230112-C00306
    Figure US20230007838A1-20230112-C00307
    Figure US20230007838A1-20230112-C00308
    Figure US20230007838A1-20230112-C00309
    Figure US20230007838A1-20230112-C00310
    Figure US20230007838A1-20230112-C00311
    Figure US20230007838A1-20230112-C00312
    Figure US20230007838A1-20230112-C00313
    Figure US20230007838A1-20230112-C00314
    Figure US20230007838A1-20230112-C00315
    Figure US20230007838A1-20230112-C00316
    Figure US20230007838A1-20230112-C00317
    Figure US20230007838A1-20230112-C00318
    Figure US20230007838A1-20230112-C00319
    Figure US20230007838A1-20230112-C00320
    Figure US20230007838A1-20230112-C00321
    Figure US20230007838A1-20230112-C00322
    Figure US20230007838A1-20230112-C00323
    Figure US20230007838A1-20230112-C00324
    Figure US20230007838A1-20230112-C00325
    Figure US20230007838A1-20230112-C00326
    Figure US20230007838A1-20230112-C00327
    Figure US20230007838A1-20230112-C00328
    Figure US20230007838A1-20230112-C00329
    Figure US20230007838A1-20230112-C00330
    Figure US20230007838A1-20230112-C00331
    Figure US20230007838A1-20230112-C00332
    Figure US20230007838A1-20230112-C00333
    Figure US20230007838A1-20230112-C00334
    Figure US20230007838A1-20230112-C00335
    Figure US20230007838A1-20230112-C00336
    Figure US20230007838A1-20230112-C00337
    Figure US20230007838A1-20230112-C00338
    Figure US20230007838A1-20230112-C00339
    Figure US20230007838A1-20230112-C00340
    Figure US20230007838A1-20230112-C00341
    Figure US20230007838A1-20230112-C00342
    Figure US20230007838A1-20230112-C00343
    Figure US20230007838A1-20230112-C00344
    Figure US20230007838A1-20230112-C00345
    Figure US20230007838A1-20230112-C00346
    Figure US20230007838A1-20230112-C00347
    Figure US20230007838A1-20230112-C00348
    Figure US20230007838A1-20230112-C00349
    Figure US20230007838A1-20230112-C00350
    Figure US20230007838A1-20230112-C00351
    Figure US20230007838A1-20230112-C00352
    Figure US20230007838A1-20230112-C00353
    Figure US20230007838A1-20230112-C00354
    Figure US20230007838A1-20230112-C00355
    Figure US20230007838A1-20230112-C00356
    Figure US20230007838A1-20230112-C00357
    Figure US20230007838A1-20230112-C00358
    Figure US20230007838A1-20230112-C00359
    Figure US20230007838A1-20230112-C00360
    Figure US20230007838A1-20230112-C00361
    Figure US20230007838A1-20230112-C00362
    Figure US20230007838A1-20230112-C00363
    Figure US20230007838A1-20230112-C00364
    Figure US20230007838A1-20230112-C00365
    Figure US20230007838A1-20230112-C00366
    Figure US20230007838A1-20230112-C00367
    Figure US20230007838A1-20230112-C00368
    Figure US20230007838A1-20230112-C00369
    Figure US20230007838A1-20230112-C00370
    Figure US20230007838A1-20230112-C00371
    Figure US20230007838A1-20230112-C00372
    Figure US20230007838A1-20230112-C00373
    Figure US20230007838A1-20230112-C00374
    Figure US20230007838A1-20230112-C00375
    Figure US20230007838A1-20230112-C00376
    Figure US20230007838A1-20230112-C00377
    Figure US20230007838A1-20230112-C00378
    Figure US20230007838A1-20230112-C00379
    Figure US20230007838A1-20230112-C00380
    Figure US20230007838A1-20230112-C00381
    Figure US20230007838A1-20230112-C00382
    Figure US20230007838A1-20230112-C00383
    Figure US20230007838A1-20230112-C00384
    Figure US20230007838A1-20230112-C00385
    Figure US20230007838A1-20230112-C00386
    Figure US20230007838A1-20230112-C00387
    Figure US20230007838A1-20230112-C00388
    Figure US20230007838A1-20230112-C00389
    Figure US20230007838A1-20230112-C00390
    Figure US20230007838A1-20230112-C00391
    Figure US20230007838A1-20230112-C00392
    Figure US20230007838A1-20230112-C00393
    Figure US20230007838A1-20230112-C00394
    Figure US20230007838A1-20230112-C00395
    Figure US20230007838A1-20230112-C00396
    Figure US20230007838A1-20230112-C00397
    Figure US20230007838A1-20230112-C00398
    Figure US20230007838A1-20230112-C00399
    Figure US20230007838A1-20230112-C00400
    Figure US20230007838A1-20230112-C00401
    Figure US20230007838A1-20230112-C00402
    Figure US20230007838A1-20230112-C00403
    Figure US20230007838A1-20230112-C00404
    Figure US20230007838A1-20230112-C00405
    Figure US20230007838A1-20230112-C00406
    Figure US20230007838A1-20230112-C00407
    Figure US20230007838A1-20230112-C00408
    Figure US20230007838A1-20230112-C00409
    Figure US20230007838A1-20230112-C00410
    Figure US20230007838A1-20230112-C00411
    Figure US20230007838A1-20230112-C00412
    Figure US20230007838A1-20230112-C00413
    Figure US20230007838A1-20230112-C00414
    Figure US20230007838A1-20230112-C00415
    Figure US20230007838A1-20230112-C00416
    Figure US20230007838A1-20230112-C00417
    Figure US20230007838A1-20230112-C00418
    Figure US20230007838A1-20230112-C00419
    Figure US20230007838A1-20230112-C00420
    Figure US20230007838A1-20230112-C00421
    Figure US20230007838A1-20230112-C00422
    Figure US20230007838A1-20230112-C00423
    Figure US20230007838A1-20230112-C00424
    Figure US20230007838A1-20230112-C00425
    Figure US20230007838A1-20230112-C00426
    Figure US20230007838A1-20230112-C00427
    Figure US20230007838A1-20230112-C00428
    Figure US20230007838A1-20230112-C00429
    Figure US20230007838A1-20230112-C00430
    Figure US20230007838A1-20230112-C00431
    Figure US20230007838A1-20230112-C00432
    Figure US20230007838A1-20230112-C00433
    Figure US20230007838A1-20230112-C00434
    Figure US20230007838A1-20230112-C00435
    Figure US20230007838A1-20230112-C00436
    Figure US20230007838A1-20230112-C00437
    Figure US20230007838A1-20230112-C00438
    Figure US20230007838A1-20230112-C00439
    Figure US20230007838A1-20230112-C00440
    Figure US20230007838A1-20230112-C00441
    Figure US20230007838A1-20230112-C00442
    Figure US20230007838A1-20230112-C00443
    Figure US20230007838A1-20230112-C00444
    Figure US20230007838A1-20230112-C00445
    Figure US20230007838A1-20230112-C00446
    Figure US20230007838A1-20230112-C00447
    Figure US20230007838A1-20230112-C00448
    Figure US20230007838A1-20230112-C00449
    Figure US20230007838A1-20230112-C00450
    Figure US20230007838A1-20230112-C00451
    Figure US20230007838A1-20230112-C00452
    Figure US20230007838A1-20230112-C00453
    Figure US20230007838A1-20230112-C00454
    Figure US20230007838A1-20230112-C00455
    Figure US20230007838A1-20230112-C00456
    Figure US20230007838A1-20230112-C00457
    Figure US20230007838A1-20230112-C00458
    Figure US20230007838A1-20230112-C00459
    Figure US20230007838A1-20230112-C00460
    Figure US20230007838A1-20230112-C00461
    Figure US20230007838A1-20230112-C00462
    Figure US20230007838A1-20230112-C00463
    Figure US20230007838A1-20230112-C00464
    Figure US20230007838A1-20230112-C00465
    Figure US20230007838A1-20230112-C00466
    Figure US20230007838A1-20230112-C00467
    Figure US20230007838A1-20230112-C00468
    Figure US20230007838A1-20230112-C00469
    Figure US20230007838A1-20230112-C00470
    Figure US20230007838A1-20230112-C00471
    Figure US20230007838A1-20230112-C00472
    Figure US20230007838A1-20230112-C00473
    Figure US20230007838A1-20230112-C00474
    Figure US20230007838A1-20230112-C00475
    Figure US20230007838A1-20230112-C00476
    Figure US20230007838A1-20230112-C00477
    Figure US20230007838A1-20230112-C00478
    Figure US20230007838A1-20230112-C00479
    Figure US20230007838A1-20230112-C00480
    Figure US20230007838A1-20230112-C00481
    Figure US20230007838A1-20230112-C00482
    Figure US20230007838A1-20230112-C00483
    Figure US20230007838A1-20230112-C00484
    Figure US20230007838A1-20230112-C00485
    Figure US20230007838A1-20230112-C00486
    Figure US20230007838A1-20230112-C00487
    Figure US20230007838A1-20230112-C00488
    Figure US20230007838A1-20230112-C00489
    Figure US20230007838A1-20230112-C00490
    Figure US20230007838A1-20230112-C00491
    Figure US20230007838A1-20230112-C00492
    Figure US20230007838A1-20230112-C00493
    Figure US20230007838A1-20230112-C00494
    Figure US20230007838A1-20230112-C00495
    Figure US20230007838A1-20230112-C00496
    Figure US20230007838A1-20230112-C00497
    Figure US20230007838A1-20230112-C00498
    Figure US20230007838A1-20230112-C00499
    Figure US20230007838A1-20230112-C00500
    Figure US20230007838A1-20230112-C00501
    Figure US20230007838A1-20230112-C00502
    Figure US20230007838A1-20230112-C00503
    Figure US20230007838A1-20230112-C00504
    Figure US20230007838A1-20230112-C00505
    Figure US20230007838A1-20230112-C00506
    Figure US20230007838A1-20230112-C00507
    Figure US20230007838A1-20230112-C00508
    Figure US20230007838A1-20230112-C00509
    Figure US20230007838A1-20230112-C00510
  • TABLE A-7
    Structure
    Figure US20230007838A1-20230112-C00511
    Figure US20230007838A1-20230112-C00512
    Figure US20230007838A1-20230112-C00513
    Figure US20230007838A1-20230112-C00514
    Figure US20230007838A1-20230112-C00515
    Figure US20230007838A1-20230112-C00516
    Figure US20230007838A1-20230112-C00517
    Figure US20230007838A1-20230112-C00518
    Figure US20230007838A1-20230112-C00519
    Figure US20230007838A1-20230112-C00520
    Figure US20230007838A1-20230112-C00521
    Figure US20230007838A1-20230112-C00522
    Figure US20230007838A1-20230112-C00523
    Figure US20230007838A1-20230112-C00524
    Figure US20230007838A1-20230112-C00525
    Figure US20230007838A1-20230112-C00526
    Figure US20230007838A1-20230112-C00527
    Figure US20230007838A1-20230112-C00528
    Figure US20230007838A1-20230112-C00529
    Figure US20230007838A1-20230112-C00530
    Figure US20230007838A1-20230112-C00531
    Figure US20230007838A1-20230112-C00532
    Figure US20230007838A1-20230112-C00533
    Figure US20230007838A1-20230112-C00534
    Figure US20230007838A1-20230112-C00535
    Figure US20230007838A1-20230112-C00536
    Figure US20230007838A1-20230112-C00537
    Figure US20230007838A1-20230112-C00538
    Figure US20230007838A1-20230112-C00539
    Figure US20230007838A1-20230112-C00540
    Figure US20230007838A1-20230112-C00541
    Figure US20230007838A1-20230112-C00542
    Figure US20230007838A1-20230112-C00543
    Figure US20230007838A1-20230112-C00544
    Figure US20230007838A1-20230112-C00545
    Figure US20230007838A1-20230112-C00546
    Figure US20230007838A1-20230112-C00547
    Figure US20230007838A1-20230112-C00548
    Figure US20230007838A1-20230112-C00549
    Figure US20230007838A1-20230112-C00550
    Figure US20230007838A1-20230112-C00551
    Figure US20230007838A1-20230112-C00552
    Figure US20230007838A1-20230112-C00553
    Figure US20230007838A1-20230112-C00554
    Figure US20230007838A1-20230112-C00555
    Figure US20230007838A1-20230112-C00556
    Figure US20230007838A1-20230112-C00557
    Figure US20230007838A1-20230112-C00558
    Figure US20230007838A1-20230112-C00559
    Figure US20230007838A1-20230112-C00560
    Figure US20230007838A1-20230112-C00561
    Figure US20230007838A1-20230112-C00562
    Figure US20230007838A1-20230112-C00563
    Figure US20230007838A1-20230112-C00564
    Figure US20230007838A1-20230112-C00565
    Figure US20230007838A1-20230112-C00566
    Figure US20230007838A1-20230112-C00567
    Figure US20230007838A1-20230112-C00568
    Figure US20230007838A1-20230112-C00569
    Figure US20230007838A1-20230112-C00570
    Figure US20230007838A1-20230112-C00571
    Figure US20230007838A1-20230112-C00572
    Figure US20230007838A1-20230112-C00573
    Figure US20230007838A1-20230112-C00574
    Figure US20230007838A1-20230112-C00575
    Figure US20230007838A1-20230112-C00576
    Figure US20230007838A1-20230112-C00577
    Figure US20230007838A1-20230112-C00578
    Figure US20230007838A1-20230112-C00579
    Figure US20230007838A1-20230112-C00580
    Figure US20230007838A1-20230112-C00581
    Figure US20230007838A1-20230112-C00582
    Figure US20230007838A1-20230112-C00583
    Figure US20230007838A1-20230112-C00584
    Figure US20230007838A1-20230112-C00585
    Figure US20230007838A1-20230112-C00586
    Figure US20230007838A1-20230112-C00587
    Figure US20230007838A1-20230112-C00588
    Figure US20230007838A1-20230112-C00589
    Figure US20230007838A1-20230112-C00590
    Figure US20230007838A1-20230112-C00591
    Figure US20230007838A1-20230112-C00592
    Figure US20230007838A1-20230112-C00593
    Figure US20230007838A1-20230112-C00594
    Figure US20230007838A1-20230112-C00595
    Figure US20230007838A1-20230112-C00596
    Figure US20230007838A1-20230112-C00597
    Figure US20230007838A1-20230112-C00598
    Figure US20230007838A1-20230112-C00599
    Figure US20230007838A1-20230112-C00600
    Figure US20230007838A1-20230112-C00601
    Figure US20230007838A1-20230112-C00602
    Figure US20230007838A1-20230112-C00603
    Figure US20230007838A1-20230112-C00604
    Figure US20230007838A1-20230112-C00605
    Figure US20230007838A1-20230112-C00606
    Figure US20230007838A1-20230112-C00607
    Figure US20230007838A1-20230112-C00608
    Figure US20230007838A1-20230112-C00609
    Figure US20230007838A1-20230112-C00610
    Figure US20230007838A1-20230112-C00611
    Figure US20230007838A1-20230112-C00612
    Figure US20230007838A1-20230112-C00613
    Figure US20230007838A1-20230112-C00614
    Figure US20230007838A1-20230112-C00615
    Figure US20230007838A1-20230112-C00616
    Figure US20230007838A1-20230112-C00617
    Figure US20230007838A1-20230112-C00618
    Figure US20230007838A1-20230112-C00619
    Figure US20230007838A1-20230112-C00620
    Figure US20230007838A1-20230112-C00621
    Figure US20230007838A1-20230112-C00622
    Figure US20230007838A1-20230112-C00623
    Figure US20230007838A1-20230112-C00624
    Figure US20230007838A1-20230112-C00625
    Figure US20230007838A1-20230112-C00626
    Figure US20230007838A1-20230112-C00627
    Figure US20230007838A1-20230112-C00628
    Figure US20230007838A1-20230112-C00629
    Figure US20230007838A1-20230112-C00630
    Figure US20230007838A1-20230112-C00631
    Figure US20230007838A1-20230112-C00632
    Figure US20230007838A1-20230112-C00633
    Figure US20230007838A1-20230112-C00634
    Figure US20230007838A1-20230112-C00635
    Figure US20230007838A1-20230112-C00636
    Figure US20230007838A1-20230112-C00637
    Figure US20230007838A1-20230112-C00638
    Figure US20230007838A1-20230112-C00639
    Figure US20230007838A1-20230112-C00640
    Figure US20230007838A1-20230112-C00641
    Figure US20230007838A1-20230112-C00642
    Figure US20230007838A1-20230112-C00643
    Figure US20230007838A1-20230112-C00644
    Figure US20230007838A1-20230112-C00645
    Figure US20230007838A1-20230112-C00646
    Figure US20230007838A1-20230112-C00647
    Figure US20230007838A1-20230112-C00648
    Figure US20230007838A1-20230112-C00649
    Figure US20230007838A1-20230112-C00650
    Figure US20230007838A1-20230112-C00651
    Figure US20230007838A1-20230112-C00652
    Figure US20230007838A1-20230112-C00653
    Figure US20230007838A1-20230112-C00654
    Figure US20230007838A1-20230112-C00655
    Figure US20230007838A1-20230112-C00656
    Figure US20230007838A1-20230112-C00657
    Figure US20230007838A1-20230112-C00658
    Figure US20230007838A1-20230112-C00659
    Figure US20230007838A1-20230112-C00660
    Figure US20230007838A1-20230112-C00661
    Figure US20230007838A1-20230112-C00662
    Figure US20230007838A1-20230112-C00663
    Figure US20230007838A1-20230112-C00664
    Figure US20230007838A1-20230112-C00665
    Figure US20230007838A1-20230112-C00666
    Figure US20230007838A1-20230112-C00667
    Figure US20230007838A1-20230112-C00668
    Figure US20230007838A1-20230112-C00669
    Figure US20230007838A1-20230112-C00670
    Figure US20230007838A1-20230112-C00671
    Figure US20230007838A1-20230112-C00672
    Figure US20230007838A1-20230112-C00673
    Figure US20230007838A1-20230112-C00674
    Figure US20230007838A1-20230112-C00675
    Figure US20230007838A1-20230112-C00676
    Figure US20230007838A1-20230112-C00677
    Figure US20230007838A1-20230112-C00678
    Figure US20230007838A1-20230112-C00679
    Figure US20230007838A1-20230112-C00680
    Figure US20230007838A1-20230112-C00681
    Figure US20230007838A1-20230112-C00682
    Figure US20230007838A1-20230112-C00683
    Figure US20230007838A1-20230112-C00684
    Figure US20230007838A1-20230112-C00685
    Figure US20230007838A1-20230112-C00686
    Figure US20230007838A1-20230112-C00687
    Figure US20230007838A1-20230112-C00688
    Figure US20230007838A1-20230112-C00689
    Figure US20230007838A1-20230112-C00690
    Figure US20230007838A1-20230112-C00691
    Figure US20230007838A1-20230112-C00692
    Figure US20230007838A1-20230112-C00693
    Figure US20230007838A1-20230112-C00694
    Figure US20230007838A1-20230112-C00695
    Figure US20230007838A1-20230112-C00696
    Figure US20230007838A1-20230112-C00697
    Figure US20230007838A1-20230112-C00698
    Figure US20230007838A1-20230112-C00699
    Figure US20230007838A1-20230112-C00700
    Figure US20230007838A1-20230112-C00701
    Figure US20230007838A1-20230112-C00702
    Figure US20230007838A1-20230112-C00703
    Figure US20230007838A1-20230112-C00704
    Figure US20230007838A1-20230112-C00705
    Figure US20230007838A1-20230112-C00706
    Figure US20230007838A1-20230112-C00707
    Figure US20230007838A1-20230112-C00708
    Figure US20230007838A1-20230112-C00709
    Figure US20230007838A1-20230112-C00710
    Figure US20230007838A1-20230112-C00711
    Figure US20230007838A1-20230112-C00712
    Figure US20230007838A1-20230112-C00713
    Figure US20230007838A1-20230112-C00714
    Figure US20230007838A1-20230112-C00715
    Figure US20230007838A1-20230112-C00716
    Figure US20230007838A1-20230112-C00717
    Figure US20230007838A1-20230112-C00718
    Figure US20230007838A1-20230112-C00719
    Figure US20230007838A1-20230112-C00720
    Figure US20230007838A1-20230112-C00721
    Figure US20230007838A1-20230112-C00722
    Figure US20230007838A1-20230112-C00723
    Figure US20230007838A1-20230112-C00724
    Figure US20230007838A1-20230112-C00725
    Figure US20230007838A1-20230112-C00726
    Figure US20230007838A1-20230112-C00727
    Figure US20230007838A1-20230112-C00728
    Figure US20230007838A1-20230112-C00729
    Figure US20230007838A1-20230112-C00730
    Figure US20230007838A1-20230112-C00731
    Figure US20230007838A1-20230112-C00732
    Figure US20230007838A1-20230112-C00733
    Figure US20230007838A1-20230112-C00734
    Figure US20230007838A1-20230112-C00735
    Figure US20230007838A1-20230112-C00736
    Figure US20230007838A1-20230112-C00737
    Figure US20230007838A1-20230112-C00738
    Figure US20230007838A1-20230112-C00739
    Figure US20230007838A1-20230112-C00740
    Figure US20230007838A1-20230112-C00741
    Figure US20230007838A1-20230112-C00742
    Figure US20230007838A1-20230112-C00743
    Figure US20230007838A1-20230112-C00744
    Figure US20230007838A1-20230112-C00745
    Figure US20230007838A1-20230112-C00746
    Figure US20230007838A1-20230112-C00747
    Figure US20230007838A1-20230112-C00748
    Figure US20230007838A1-20230112-C00749
    Figure US20230007838A1-20230112-C00750
    Figure US20230007838A1-20230112-C00751
    Figure US20230007838A1-20230112-C00752
    Figure US20230007838A1-20230112-C00753
    Figure US20230007838A1-20230112-C00754
    Figure US20230007838A1-20230112-C00755
    Figure US20230007838A1-20230112-C00756
    Figure US20230007838A1-20230112-C00757
    Figure US20230007838A1-20230112-C00758
    Figure US20230007838A1-20230112-C00759
    Figure US20230007838A1-20230112-C00760
    Figure US20230007838A1-20230112-C00761
    Figure US20230007838A1-20230112-C00762
    Figure US20230007838A1-20230112-C00763
    Figure US20230007838A1-20230112-C00764
    Figure US20230007838A1-20230112-C00765
    Figure US20230007838A1-20230112-C00766
    Figure US20230007838A1-20230112-C00767
    Figure US20230007838A1-20230112-C00768
    Figure US20230007838A1-20230112-C00769
    Figure US20230007838A1-20230112-C00770
    Figure US20230007838A1-20230112-C00771
    Figure US20230007838A1-20230112-C00772
    Figure US20230007838A1-20230112-C00773
    Figure US20230007838A1-20230112-C00774
    Figure US20230007838A1-20230112-C00775
    Figure US20230007838A1-20230112-C00776
    Figure US20230007838A1-20230112-C00777
    Figure US20230007838A1-20230112-C00778
    Figure US20230007838A1-20230112-C00779
    Figure US20230007838A1-20230112-C00780
    Figure US20230007838A1-20230112-C00781
    Figure US20230007838A1-20230112-C00782
    Figure US20230007838A1-20230112-C00783
    Figure US20230007838A1-20230112-C00784
    Figure US20230007838A1-20230112-C00785
    Figure US20230007838A1-20230112-C00786
    Figure US20230007838A1-20230112-C00787
    Figure US20230007838A1-20230112-C00788
    Figure US20230007838A1-20230112-C00789
    Figure US20230007838A1-20230112-C00790
    Figure US20230007838A1-20230112-C00791
    Figure US20230007838A1-20230112-C00792
    Figure US20230007838A1-20230112-C00793
    Figure US20230007838A1-20230112-C00794
    Figure US20230007838A1-20230112-C00795
    Figure US20230007838A1-20230112-C00796
    Figure US20230007838A1-20230112-C00797
    Figure US20230007838A1-20230112-C00798
    Figure US20230007838A1-20230112-C00799
    Figure US20230007838A1-20230112-C00800
    Figure US20230007838A1-20230112-C00801
    Figure US20230007838A1-20230112-C00802
    Figure US20230007838A1-20230112-C00803
    Figure US20230007838A1-20230112-C00804
    Figure US20230007838A1-20230112-C00805
    Figure US20230007838A1-20230112-C00806
    Figure US20230007838A1-20230112-C00807
    Figure US20230007838A1-20230112-C00808
    Figure US20230007838A1-20230112-C00809
    Figure US20230007838A1-20230112-C00810
    Figure US20230007838A1-20230112-C00811
    Figure US20230007838A1-20230112-C00812
    Figure US20230007838A1-20230112-C00813
    Figure US20230007838A1-20230112-C00814
    Figure US20230007838A1-20230112-C00815
    Figure US20230007838A1-20230112-C00816
    Figure US20230007838A1-20230112-C00817
    Figure US20230007838A1-20230112-C00818
    Figure US20230007838A1-20230112-C00819
    Figure US20230007838A1-20230112-C00820
    Figure US20230007838A1-20230112-C00821
    Figure US20230007838A1-20230112-C00822
    Figure US20230007838A1-20230112-C00823
    Figure US20230007838A1-20230112-C00824
    Figure US20230007838A1-20230112-C00825
    Figure US20230007838A1-20230112-C00826
    Figure US20230007838A1-20230112-C00827
    Figure US20230007838A1-20230112-C00828
    Figure US20230007838A1-20230112-C00829
    Figure US20230007838A1-20230112-C00830
    Figure US20230007838A1-20230112-C00831
    Figure US20230007838A1-20230112-C00832
    Figure US20230007838A1-20230112-C00833
    Figure US20230007838A1-20230112-C00834
    Figure US20230007838A1-20230112-C00835
    Figure US20230007838A1-20230112-C00836
    Figure US20230007838A1-20230112-C00837
    Figure US20230007838A1-20230112-C00838
    Figure US20230007838A1-20230112-C00839
    Figure US20230007838A1-20230112-C00840
    Figure US20230007838A1-20230112-C00841
    Figure US20230007838A1-20230112-C00842
    Figure US20230007838A1-20230112-C00843
    Figure US20230007838A1-20230112-C00844
    Figure US20230007838A1-20230112-C00845
    Figure US20230007838A1-20230112-C00846
    Figure US20230007838A1-20230112-C00847
    Figure US20230007838A1-20230112-C00848
    Figure US20230007838A1-20230112-C00849
    Figure US20230007838A1-20230112-C00850
    Figure US20230007838A1-20230112-C00851
    Figure US20230007838A1-20230112-C00852
    Figure US20230007838A1-20230112-C00853
    Figure US20230007838A1-20230112-C00854
    Figure US20230007838A1-20230112-C00855
    Figure US20230007838A1-20230112-C00856
    Figure US20230007838A1-20230112-C00857
    Figure US20230007838A1-20230112-C00858
    Figure US20230007838A1-20230112-C00859
    Figure US20230007838A1-20230112-C00860
    Figure US20230007838A1-20230112-C00861
    Figure US20230007838A1-20230112-C00862
    Figure US20230007838A1-20230112-C00863
    Figure US20230007838A1-20230112-C00864
    Figure US20230007838A1-20230112-C00865
    Figure US20230007838A1-20230112-C00866
    Figure US20230007838A1-20230112-C00867
    Figure US20230007838A1-20230112-C00868
    Figure US20230007838A1-20230112-C00869
    Figure US20230007838A1-20230112-C00870
    Figure US20230007838A1-20230112-C00871
    Figure US20230007838A1-20230112-C00872
    Figure US20230007838A1-20230112-C00873
    Figure US20230007838A1-20230112-C00874
    Figure US20230007838A1-20230112-C00875
    Figure US20230007838A1-20230112-C00876
    Figure US20230007838A1-20230112-C00877
    Figure US20230007838A1-20230112-C00878
    Figure US20230007838A1-20230112-C00879
    Figure US20230007838A1-20230112-C00880
    Figure US20230007838A1-20230112-C00881
    Figure US20230007838A1-20230112-C00882
    Figure US20230007838A1-20230112-C00883
    Figure US20230007838A1-20230112-C00884
    Figure US20230007838A1-20230112-C00885
    Figure US20230007838A1-20230112-C00886
    Figure US20230007838A1-20230112-C00887
    Figure US20230007838A1-20230112-C00888
    Figure US20230007838A1-20230112-C00889
    Figure US20230007838A1-20230112-C00890
    Figure US20230007838A1-20230112-C00891
    Figure US20230007838A1-20230112-C00892
    Figure US20230007838A1-20230112-C00893
    Figure US20230007838A1-20230112-C00894
    Figure US20230007838A1-20230112-C00895
    Figure US20230007838A1-20230112-C00896
    Figure US20230007838A1-20230112-C00897
    Figure US20230007838A1-20230112-C00898
    Figure US20230007838A1-20230112-C00899
    Figure US20230007838A1-20230112-C00900
    Figure US20230007838A1-20230112-C00901
    Figure US20230007838A1-20230112-C00902
  • Compounds of Formula (II)
  • In some embodiments, the compound of the invention is a compound of Formula (II):
  • Figure US20230007838A1-20230112-C00903
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each R1 and R2 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each n is independently 0, 1, 2, or 3;
      • each m is independently 1, 2, 3, 4, 5, 6, 7, 8 or 9;
      • X is —C(═O)—, —CHR3—, —CH—CH2(OR3)—, —O—, —S—, —S(═O)—, —S(O)2—, —NR3—, —N(OH)—, —N(→O)—, or —Se—;
      • R3 is H, —OH, —O(C1-C6 alkyl), —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C3-C7 cycloalkyl, C4-C7 cycloalkenyl, C5-C8 cycloalkynyl, phenyl, or benzyl, each —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C3-C7 cycloalkyl, C4-C7 cycloalkenyl, C5-C8 cycloalkynyl, phenyl and benzyl being unsubstituted or substituted with one or more halogen, —CN, —NO2, or —CF3 groups;
      • each Y is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—, —S(═O)—, —S(O)2—, or —Se—;
      • each Z is independently —OH, —COOH, —COOR5, —SO3H, —SO3R5,
  • Figure US20230007838A1-20230112-C00904
    Figure US20230007838A1-20230112-C00905
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups; and
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl.
  • In some embodiments of compounds of Formula (II), X is —C(═O)—, —CHR3—, —O—, —S—, —S(═O)—, or Se. In some embodiments, X is —C(═O)—, —CH(OH)—, —O—, —S—, —S(═O)—, or Se.
  • In some embodiments of compounds of Formula (II), R3 is H, —OH, —O(C1-C3 alkyl), or —C1-C3 alkyl.
  • In some embodiments of compounds of Formula (II), each Y is independently —O— or —S—.
  • In some embodiments of compounds of Formula (II), each R1 and R2 is independently H, —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl. In some embodiments, each R1 and R2 is independently H or methyl.
  • In some embodiments of compounds of Formula (II), each Z is independently —COOH or —COOR5. In some embodiments, each Z is —COOH.
  • In some embodiments of compounds of Formula (II), each R5 is independently —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl.
  • In some embodiments of compounds of Formula (II), each n is independently 0, 1, or 2. In some embodiments, n is 1.
  • In some embodiments of compounds of Formula (II), each m is independently 3, 4, 5, or 6. In some embodiments, each m is independently 4 or 5.
  • In some embodiments, the compound of Formula (II) has any one of the structures shown in Table B1, or a pharmaceutically acceptable salt or solvate thereof.
  • TABLE B1
    Compound No. Structure and Name
    II-1
    Figure US20230007838A1-20230112-C00906
    II-2
    Figure US20230007838A1-20230112-C00907
    II-3
    Figure US20230007838A1-20230112-C00908
    II-4
    Figure US20230007838A1-20230112-C00909
    II-5
    Figure US20230007838A1-20230112-C00910
    II-6
    Figure US20230007838A1-20230112-C00911
    II-7
    Figure US20230007838A1-20230112-C00912
    II-8
    Figure US20230007838A1-20230112-C00913
    II-9
    Figure US20230007838A1-20230112-C00914
    II-10
    Figure US20230007838A1-20230112-C00915
    II-11
    Figure US20230007838A1-20230112-C00916
    II-12
    Figure US20230007838A1-20230112-C00917
    II-13
    Figure US20230007838A1-20230112-C00918
    II-14
    Figure US20230007838A1-20230112-C00919
    II-15
    Figure US20230007838A1-20230112-C00920
    II-16
    Figure US20230007838A1-20230112-C00921
    II-17
    Figure US20230007838A1-20230112-C00922
    II-18
    Figure US20230007838A1-20230112-C00923
    II-19
    Figure US20230007838A1-20230112-C00924
    II-20
    Figure US20230007838A1-20230112-C00925
    II-21
    Figure US20230007838A1-20230112-C00926
    II-22
    Figure US20230007838A1-20230112-C00927
    II-23
    Figure US20230007838A1-20230112-C00928
    II-24
    Figure US20230007838A1-20230112-C00929
  • Compounds of Formula (III), (IIIA), and (IIIB)
  • In some embodiments, the compound of the invention is a compound of Formula (III):
  • Figure US20230007838A1-20230112-C00930
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • R1 and R2 are independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or R1 and R2 together with the attached carbon atom form a —C3-C7 cycloalkyl group;
      • each m is independently 3, 4, 5, 6, or 7;
      • each n is independently 0, 1, 2, 3, 4, or 5;
      • each q is 0, 1, 2, 3, or 4;
      • X is —O—, —S—, —S(═O)—, —S(O)2—, —NH—, —N(OH)—, —N(→O)—, N(alkyl)-, or —N(aryl)-;
      • Z1 and Z2 are independently —C1-C6 alkyl, —OH, —COOH, —COOR5, —SO3H, —SO3R5,
  • Figure US20230007838A1-20230112-C00931
    Figure US20230007838A1-20230112-C00932
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups; and
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl.
  • In some embodiments, the compound of the invention is a compound of Formula (IIIA):
  • Figure US20230007838A1-20230112-C00933
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • R1 and R2 are independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or R1 and R2 together with the attached carbon atom form a —C3-C7 cycloalkyl group;
      • each m is independently 2, 3, 4, 5, 6, or 7;
      • each n is independently 0, 1, 2, 3, 4, or 5;
      • each q is 0, 1, 2, 3, or 4;
      • X is —O—, —S—, —S(═O)—, —S(O)2—, —NH—, —N(OH)—, —N(→O)—, N(alkyl)-, or —N(aryl)-;
      • Z1 and Z2 are —C1-C6 alkyl, —COOH, —COOR5, —SO3R5,
  • Figure US20230007838A1-20230112-C00934
  • wherein Z1 and Z2 are the same,
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups; and
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl.
  • In some embodiments, the compound of the invention is a compound of Formula
  • Figure US20230007838A1-20230112-C00935
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • R1 and R2 are independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or R1 and R2 together with the attached carbon atom form a —C3-C7 cycloalkyl group;
      • each m is independently 2, 3, 4, 5, 6, or 7;
      • each n is independently 0, 1, 2, 3, 4, or 5;
      • each q is 0, 1, 2, 3, or 4;
      • X is —S—, —S(═O)—, —S(O)2—, —NH—, —N(OH)—, —N(→O)—, N(alkyl)-, or —N(aryl)-;
      • Z1 and Z2 are independently —C1-C6 alkyl, —OH, —COOH, —COOR5, —SO3H, —SO3R5,
  • Figure US20230007838A1-20230112-C00936
    Figure US20230007838A1-20230112-C00937
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups;
      • each R6 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl, wherein the —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl is unsubstituted or substituted with one or two halogen, —OH, —O(C1-C6 alkyl), or phenyl groups; and
      • each R7 is independently H, —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl.
  • In some embodiments of compounds of Formula (III) and (IIIB), each Z1 and Z2 is independently —OH, —COOH, or —COOR5. In some embodiments, each Z1 and Z2 is independently —C1-C6 alkyl.
  • In some embodiments of compounds of Formula (III), (IIIA), and (IIIB), Z1 and Z2 are the same group: —OH, —COOH, or —COOR5. In some embodiments, both Z1 and Z2 is —C1-C6 alkyl.
  • 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)-.
  • 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.
  • In some embodiments of compounds of Formula (III), (IIA), and (IB), each n is independently 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.
  • In some embodiments of compounds of Formula (III), (IIIA), and (IIB), each m is independently 4, 5, or 6. In some embodiments, m is 5 or 6. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 2 or 3.
  • In some embodiments of compounds of Formula (III), (IIIA), and (IIIB), R1 and R2 together with the attached carbon atom form a —C3-C7 cycloalkyl group.
  • In some embodiments, the compound of Formula (III) or (IIIA) has any one of the structures shown in Table B2, or a pharmaceutically acceptable salt or solvate thereof.
  • TABLE B2
    Compound No. Structure and Name
    III-10
    Figure US20230007838A1-20230112-C00938
    III-11
    Figure US20230007838A1-20230112-C00939
    III-12
    Figure US20230007838A1-20230112-C00940
    III-13
    Figure US20230007838A1-20230112-C00941
    III-14
    Figure US20230007838A1-20230112-C00942
    III-15
    Figure US20230007838A1-20230112-C00943
    III-16
    Figure US20230007838A1-20230112-C00944
    III-17
    Figure US20230007838A1-20230112-C00945
    III-18
    Figure US20230007838A1-20230112-C00946
    III-19
    Figure US20230007838A1-20230112-C00947
    III-20
    Figure US20230007838A1-20230112-C00948
    III-21
    Figure US20230007838A1-20230112-C00949
  • Compositions of the Invention
  • In some embodiments, the composition of the invention comprises (i) an effective amount of a compound of the invention and (ii) a pharmaceutically acceptable carrier or vehicle.
  • In some embodiments, the composition of the invention comprises (i) an effective amount of a compound of Formula (IA):
  • Figure US20230007838A1-20230112-C00950
  • or a pharmaceutically acceptable salt or solvate thereof, wherein:
      • each p is independently 1, 2, 3, 4, 5, 6, or 7;
      • Z1 and Z2 is independently —C(R1)(R2)—(CH2)c—COOH or —C(R1)(R2)—(CH2)c—COOR5;
      • each c is independently 0, 1, 2, or 3;
      • each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl or benzyl, or each carbon atom together with the R1 and R2 attached to the carbon atom independently form a —C3-C7 cycloalkyl group;
      • each R5 is independently —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, phenyl, or benzyl, each being unsubstituted or substituted with one or more halogen, —OH, —O(C1-C6 alkyl), or phenyl groups; and
  • (ii) a pharmaceutically acceptable carrier or vehicle.
  • In some embodiments of the composition comprising a compound of Formula (IA), each R1 and R2 is independently —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments, each R1 and R2 is independently —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl. In some embodiments, R1 and R2 are methyl.
  • In some embodiments of the composition comprising a compound of Formula (IA), c is 0 or 1.
  • In some embodiments of the composition comprising a compound of Formula (IA), R5 is —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl. In some embodiments, R5 is —C1-C3 alkyl, —C2-C3 alkenyl, or —C2-C3 alkynyl.
  • In some embodiments of the 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
  • Figure US20230007838A1-20230112-C00951
  • or a pharmaceutically acceptable salt or solvate thereof.
  • In some embodiments, the composition of the invention comprises an effective amount of a compound having a structure depicted in Tables A-1, A-2, A-3, or A-4, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the invention comprises an effective amount of a compound having a structure depicted in Table B1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the invention comprises an effective amount of a compound having a structure depicted in Table B2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition of the invention comprises an effective amount of a compound having a structure depicted in Table C, or a pharmaceutically acceptable salt or solvate thereof.
  • TABLE C
    Compound No. Structure and Name
    III-1
    Figure US20230007838A1-20230112-C00952
  • In some embodiments, the composition of the invention further comprises another pharmaceutically active agent.
  • In some embodiments, the other pharmaceutically active agent is a statin, a thiazolidinedione or fibrate, a bile-acid-binding-resin, a niacin, an anti-obesity drug, a hormone, a tyrophostine, a sulfonylurea-based drug, a biguanide, an α-glucosidase inhibitor, an apolipoprotein A-I agonist, apolipoprotein E agonist, a phosphodiesterase type-5 inhibitor, a cardiovascular drug, an HDL-raising drug, an HDL enhancer, an agonist of the apolipoprotein A-I gene or protein, an agonist of the apolipoprotein A-IV gene or protein, an agonist of an apolipoprotein gene, an ATP citrate lyase modulator, an ATP citrate lyase allosteric inhibitor, an acetyl-CoA carboxylase modulator, or an acetyl-CoA carboxylase allosteric inhibitor.
  • In some embodiments, the other pharmaceutically active agent is an antagonist or an 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 a proinflammatory function or increases an anti-inflammatory function of IL-6, CRP, TNF-α, MCP-1, MIP-1β, CCR5, CCR2, NF-κB or TGF-β1.
  • 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.
  • In some embodiments, the other pharmaceutically active agent is a regulator of lipid metabolism- or -trafficking-related genes, 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.
  • 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, statin is lovastatin.
  • In some embodiments, the other pharmaceutically active agent is a fibrate. In some embodiment, the fibrate is fenofibrate, gemfibrozil, or fenofibric acid.
  • In some embodiments, the other pharmaceutically active agent is sorafenib. In yet some other embodiments, the other pharmaceutically active agent is taxol. In yet some other embodiments, the other pharmaceutically active agent is carotuximab. In yet some other embodiments, the other pharmaceutically active agent is pembrolizumab. In yet some other embodiments, the other pharmaceutically active agent is lenvatinib. In yet some other embodiments, the other pharmaceutically active agent is avelumab. In some embodiments, the other pharmaceutically active agent is durvalumab. In yet some other embodiments, the other pharmaceutically active agent is tremelimumab. In yet some other embodiments the other pharmaceutically active agent is nivolumab. In yet some other embodiments the other pharmaceutically active agent is tazemetostat, cemiplimab, ABX196, T-cell receptor (TCR) immune cell therapy agent, such as LioCyx™, IBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus or gene-modified oncolytic virus such as, but not limited to, telomelysin and imlygic; or an immunomodulating gene-therapy agent such as MDA-7/IL-24, GLIPR1/RTVP-1, and REIC/Dkk-3.
  • 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, R05093151, pradigastat, Sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexo, tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide, ND-L02-s0201/BMS-986263, 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, or nalmafene. In some embodiments, the other pharmaceutically active agent is pentamidine, Berberine, L-Carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, firsocostat, cilofexor, elafibranor, nalmefene, solithromycin, 99mTechnetium-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, R07119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, R07070179, axitinib, sunitinib, zotiraciclib citrate, sintilimab, camrelizumab, spartalizumab, toripalimab, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IB1I305, ascrinvacumab, sitravatinib, cytokine-based biologic agent IRX-2, bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SRF388, ET1402L1-CART, Glypican 3-specific Chimeric Antigen Receptor Expressing T Cells (CAR-T cells), CD147-targeted CAR-T cells, NKG2D-based CAR T-cells, neoantigen reactive T cells, Pexastimogene Devacirepvec, Talimogene Laherparepvec, GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase peptide vaccine, or IMA970A, novantrone, prednisone, pixantrone, losoxantrone, Cytidine-phosphate-guanosine (CpG) DNA, paclitaxel, oraxol, MTL-CEBPA, ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241, U3-1784, avadomide, INCAGN01949, or CMP-001.
  • In some embodiments, the other pharmaceutically active agent is an anti-cancer agent, immunotherapeutic agent, oncologic virus, or vaccine.
  • In some embodiments, the other pharmaceutically active agent is an anti-cancer agent. In some embodiments, the anti-cancer agent is sorafenib, taxol, lenvatinib, tazemetostat, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, R05093151 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, nalmafene, pentamidine, Berberine, L-Carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, Olesoxime, AKR-001, Seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, R07119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, R07070179, axitinib, sunitinib, or zotiraciclib citrate.
  • In some embodiments, the composition of the invention further comprises an anti-cancer agent.
  • 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, bispecific antibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305, ascrinvacumab, TCR T-cell therapy agent, sitravatinib, cytokine-based biologic agent IRX-2, bempegaldesleukin, DKN-01, PTX-9908, AK104, PT-112, SRF388, ET1402L1-CART, Glypican 3-specific Chimeric Antigen Receptor Expressing T Cells (CAR-T cells), CD147-targeted CAR-T cells, NKG2D-based CAR T-cells, or neoantigen reactive T cells.
  • In some embodiments, the composition of the invention further comprises an immunotherapeutic agent.
  • In some embodiments, the other pharmaceutically active agent is an oncologic virus. In some embodiments, the oncologic virus is Pexastimogene Devacirepvec or Talimogene Laherparepvec. In some embodiments, the composition of the invention further comprises an oncologic virus.
  • In some embodiments, the other pharmaceutically active agent is a vaccine. In some embodiments, the vaccine is GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase peptide vaccine, or IMA970A. In some embodiments, the composition of the invention further comprises a vaccine.
  • 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.
  • 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.
  • In some embodiments, the composition of the invention further comprises a pharmaceutically active agent: sorafenib, taxol, lenvatinib, tazemetostat, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, R05093151 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, nalmafene, pentamidine, Berberine, L-Carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, Olesoxime, AKR-001, Seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, R07119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, R07070179, axitinib, sunitinib, or zotiraciclib citrate. In some embodiments of the composition of the invention, composition comprises (a) Compound I-1, Compound I-32, Compound I-61, or Compound III-1, or a pharmaceutically acceptable salt or solvate thereof and (b) a pharmaceutically active agent: sorafenib, taxol, lenvatinib, tazemetostat, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, R05093151 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, nalmafene, pentamidine, Berberine, L-Carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, Olesoxime, AKR-001, Seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, R07119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, R07070179, axitinib, sunitinib, or zotiraciclib citrate.
  • In some embodiments of the composition of the invention, composition comprises a compound of the invention and a pharmaceutically active agent: sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, T-cell receptor (TCR) immune cell therapy agent, IBI-302, namodenoson, MM-310, tumor-injected oncolytic viruses or gene-modified oncolytic viruses, or immunomodulating gene-therapy agents. In some embodiments, composition comprises (a) Compound I-1, Compound I-32, Compound I-61, or Compound III-1, or a pharmaceutically acceptable salt or solvate thereof and (b) a pharmaceutically active agent is sorafenib, taxol, carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, T-cell receptor (TCR) immune cell therapy agent, IBI-302, namodenoson, MM-310, tumor-injected oncolytic viruses or gene-modified oncolytic viruses, or immunomodulating gene-therapy agents.
  • In some embodiments of the composition of the invention, composition comprises a compound of the invention and sorafenib or lenvatinib. In some embodiments, 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, composition comprises (a) Compound I-1 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib or lenvatinib. In some embodiments, composition comprises (a) Compound I-32 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib or lenvatinib. In some embodiments, composition comprises (a) Compound I-32 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib. In some embodiments, composition comprises (a) Compound I-32 or a pharmaceutically acceptable salt or solvate thereof and (b) lenvatinib. In some embodiments, composition comprises (a) Compound I-61 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib or lenvatinib. In some embodiments, composition comprises (a) Compound I-61 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib. In some embodiments, composition comprises (a) Compound I-61 or a pharmaceutically acceptable salt or solvate thereof and (b) lenvatinib. In some embodiments, composition comprises (a) Compound III-1 or a pharmaceutically acceptable salt or solvate thereof and (b) sorafenib or lenvatinib.
  • Table D sets forth 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 of Table D refers to a particular compound of invention and another pharmaceutically active agent. For example, embodiment A1 refers to Compound I-1 (or a pharmaceutically acceptable salt or solvate thereof) and sorafenib; embodiment A2 refers to Compound I-32 (or a pharmaceutically acceptable salt or solvate thereof) and sorafenib; etc. In some embodiments, the compositions of the invention comprise an effective amount of a compound of the invention and another pharmaceutically active agent set forth in an embodiment of Table D.
  • TABLE D
    Embodiments
    1 2 3 4
    Compound 1-1 Compound I- Compound I- Compound
    or a 32 or a 61 or a III-1 or a
    pharmaceutically pharmaceutically pharmaceutically pharmaceutically
    acceptable acceptable acceptable acceptable
    salt or solvate salt or solvate salt or solvate salt or solvate
    thereof thereof thereof 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 M1 M2 M3 M4
    (TCR) immune
    cell therapy
    N TBI-302 N1 N2 N3 N4
    O namodenoson O1 O2 O3 O4
    P MM-310 P1 P2 P3 P4
    Q tumor-injected Q1 Q2 Q3 Q4
    oncolytic virus
    R gene-modified R1 R2 R3 R4
    oncolytic virus
    S immunomodulating S1 S2 S3 S4
    gene-
    therapy agent
  • In some embodiments, the pharmaceutically acceptable carrier or vehicle includes, but is not limited to, a binder, filler, diluent, disintegrant, wetting agent, lubricant, glidant, coloring agent, dye-migration inhibitor, sweetening agent or flavoring agent.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized 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, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixtures thereof.
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. In some embodiments, the binder is hydroxypropylcellulose.
  • The binder or filler can be present from about 2% to about 49% by weight of the compositions of the invention provided herein or any range within these values. In some embodiments, the binder or filler is present in the composition of the invention from about 5% to about 15% by weight. In some embodiments, the binder or filler is present in the composition of the invention at about 5%, 6%, 7%, 8%, 9%, 8%, 10%, 11%, 12%, 13%, 14%, or 15% by weight or any range within any of these values.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. In some embodiments, the diluent is lactose monohydrate. In some embodiments, the diluent is lactose monohydrate Fast-Flo 316 NF.
  • The compositions of the invention can comprise a diluent, e.g., from about 5% to about 49% of a diluent by weight of composition or any range between any of these values. In some embodiments, the diluent is present in the compositions of the invention from about 15% to about 30% by weight. In some embodiments, the diluent is present in the composition of the invention at about 15%, 16%, 17%, 18%, 19%, 18%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight or any range within any of these values.
  • 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; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of disintegrant in the compositions of the invention can vary. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is croscarmellose sodium NF (Ac-Di-Sol).
  • The compositions of the invention can comprise a disintegrant, e.g., from about 0.5% to about 15% or from about 1% to about 10% by weight of a 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 in any range within any of these values.
  • 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. of Boston, Mass.); and mixtures thereof. In some embodiments, the lubricant is magnesium stearate.
  • The compositions of the invention can comprise a lubricant, e.g., about 0.1 to about 5% by weight of a 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 in any range within any of these values.
  • Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and talc, including asbestos-free talc.
  • Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
  • Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that provide a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, sucralose, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents 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 carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Solvents include glycerin, sorbitol, ethyl alcohol, and syrup.
  • Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
  • The compounds of the invention and the compositions of the invention can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term “parenteral” as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.
  • The compounds of the invention and the compositions of the invention can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compositions of the invention can take such forms 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 in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Suitable formulations for each of these methods 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.
  • In some embodiments, the compositions of the invention are suitable for oral administration. These compositions can comprise solid, semisolid, gelmatrix or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, without limitation, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups or any combination thereof. In some embodiments, compositions of the invention suitable for oral administration are in the form of a tablet or a capsule. In some embodiments, the composition of the invention is in a form of a tablet. In some embodiments, the composition of the invention is in a form of a capsule. In some embodiments, the compound of the invention is contained in a capsule.
  • In some embodiments, capsules are immediate release capsules. Non-limiting example of a capsule is a coni-Snap® hard gelatin capsule.
  • The compositions of the invention can be in the form of compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, 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, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. A film coating can impart the same general characteristics as a sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • In some embodiments, the coating is a film coating. In some embodiments, the film coating comprises Opadry White and simethicone emulsion 30% USP.
  • In some embodiments, the compound of the invention is contained in a tablet. In some embodiments, the compound of the invention is contained in a compressed tablet. In some embodiments, the compound of the invention is contained in a film-coated compressed tablet. In some embodiments, the compositions of the invention are in the form of film-coated compressed tablets.
  • In some embodiments, the compositions of the invention is prepared by fluid bed granulation of the compound of the invention with one or more pharmaceutically acceptable carrier, vehicle, or excipients. In some embodiments, the compositions of the invention prepared by fluid bed granulation process can provide tablet formulation with good flowability, good compressibility, fast dissolution, good stability, and/or minimal to no cracking. In some embodiments, the fluid bed granulation process allows preparation of formulations having high drug loading, such as over 70% or over 75% of a compound of the invention.
  • The compositions of the invention can be in the form of soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), can comprise of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells can contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semisolid 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. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules can also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • The compositions of the invention can be in liquid or semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion can be a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions can include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative. Suspensions can include a pharmaceutically acceptable suspending agent and 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 an alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs can be clear, sweetened, and hydroalcoholic solutions. Syrups can be concentrated aqueous solutions of a sugar, for example, sucrose, and can comprise a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol can be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • The compositions of the invention for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Miccellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
  • The compositions of the invention can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders can include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders can include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the above dosage forms. And, flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • The compositions of the invention can be formulated as immediate or modified release dosage forms, including delayed-, extended, pulsed-, controlled, targeted-, and programmed-release forms.
  • In some embodiments, the compositions of the invention comprise a film-coating.
  • The compositions of the invention can comprise another active ingredient that does not impair the composition's therapeutic or prophylactic efficacy or can comprise a substance that augments or supplements the composition's efficacy.
  • The tablet dosage forms can comprise the compound of the invention in powdered, crystalline, or granular form, and can further comprise a carrier or vehicle described herein, including binder, disintegrant, controlled-release polymer, lubricant, diluent, or colorant.
  • In some embodiments, the compositions of the invention can 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, a tablet comprises a binder. And, in some embodiments, the binder comprises microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, polyvinylpyrridone, hydroxypropyl cellulose, hydroxymethyl cellulose, 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. And, in some embodiments, the lubricant comprises magnesium stearate stearic acid, hydrogenated oil, sodium stearyl fumarate, or any combination thereof.
  • In some embodiments, the compositions of the invention are in the form of a tablet that comprises a binder such as any of the binders described herein.
  • In some embodiments, the compositions of the invention are in the form of a tablet that comprises a disintegrant such as any of the disintegrants described herein.
  • In some embodiments, the compositions of the invention are in the form of a tablet that comprises a lubricant such as any of the lubricants described herein.
  • In some embodiments, the compositions of the invention can be in a modified release or a controlled release dosage form. In some embodiments, the compositions of the invention can comprise particles exhibiting a particular release profile. For example, the composition of the invention can comprise a compound of the invention in an immediate release form while also comprising a statin or a pharmaceutically acceptable salt thereof in a modified release form, both compressed into a single tablet. Other combination and modification of release profile can be achieved as understood by one skilled in the art. Examples of modified release dosage forms suited for pharmaceutical compositions of the instant invention are described, without limitation, in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.
  • In some embodiments, the compositions of the invention are a matrix-controlled release dosage form. For example, the compositions of the invention can comprise about 300 mg to about 600 mg of a compound of the invention provided as a matrix-controlled release form. In some embodiments, a matrix-controlled release form can further comprise another pharmaceutically active agent. In some embodiments, the release profile of the compound of the invention and of 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.
  • 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 the anti-cancer agent and from about 300 mg to about 600 mg of a compound of the invention. In some embodiment, the composition is in a matrix-controlled modified release dosage form.
  • 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 in a matrix-controlled modified release dosage form.
  • In some embodiments, the matrix-controlled release form comprises an erodible matrix comprising water-swellable, erodible, or soluble polymers, including synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • In some embodiments, the erodible matrix of the matrix-controlled release form comprises chitin, chitosan, dextran, or pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, 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; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), carrrboxymethyl ethyl cellulose (CMEC,) hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), or ethylhydroxy ethylcellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT©, Rohm America, Inc., Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; or other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, or (trimethylaminoethyl)methacrylate chloride; or any combination thereof.
  • 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, the compound of the invention is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. In some embodiments, the non-erodible matrix of the matrix-controlled release form comprises an insoluble polymer, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, a methyl acrylate-methyl methacrylate copolymer, an ethylene-vinylacetate copolymer, an ethylene/propylene copolymer, an ethylene/ethyl acrylate copolymer, a vinylchloride copolymer with vinyl acetate, a vinylidene chloride, an ethylene or a propylene, an ionomer polyethylene terephthalate, a butyl rubber epichlorohydrin rubber, an ethylene/vinyl alcohol copolymer, an ethylene/vinyl acetate/vinyl alcohol terpolymer, an ethylene/vinyloxyethanol copolymer, a polyvinyl chloride, a plasticized nylon, a plasticized polyethyleneterephthalate, a natural rubber, a silicone rubber, a polydimethylsiloxane, a silicone carbonate copolymer, or a hydrophilic polymer, such as an ethyl cellulose, a cellulose acetate, a crospovidone, or a cross-linked partially hydrolyzed polyvinyl acetate; a fatty compound, such as a carnauba wax, a microcrystalline wax, or a triglyceride; or any combination thereof.
  • The compositions of the invention that are 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.
  • In some embodiments, the compositions of the invention comprise a tablets-in-capsule system, which can be a multifunctional and multiple unit system comprising versatile mini-tablets in a hard gelatin capsule. The mini-tablets can be rapid-release, extended-release, pulsatile, delayed-onset extended-release minitablets, or any combination thereof. In some embodiments, combinations of mini-tablets or combinations of mini-tablets and minibeads comprising multiple active pharmaceutical agents can each have specific lag times, of release multiplied pulsatile drug delivery system (DDS), site-specific DDS, slow-quick DDS, quick/slow DDS and zero-order DDS.
  • In some embodiments, the compositions of the invention are in an osmotic-controlled release dosage form.
  • In some embodiments, the osmotic-controlled release device comprises a one-chamber system, a two-chamber system, asymmetric membrane technology (AMT), an extruding core system (ECS), or any combination thereof. In some embodiments, such devices comprise at least two components: (a) the core which contains the active pharmaceutical agent(s); and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • In some embodiments, the core of the osmotic device optionally comprises an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents useful in the compositions of 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 PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.
  • Another class of osmotic agents useful in the compositions of the invention comprises osmogens, which are capable of imbibing water to affect an 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.
  • Osmotic agents of different dissolution rates can be employed to influence how rapidly the compound of the invention dissolves following administration. For example, an amorphous sugar, such as Mannogeme EZ (SPI Pharma, Lewes, Del.) can be included to provide faster delivery during the first couple of hours (e.g., about 1 to about 5 hrs) to promptly produce prophylactic or therapeutic efficacy, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In some embodiments, the compound of the invention is released from the compositions of the invention at such a rate to replace the amount of the compound of the invention metabolized or excreted by the subject.
  • The core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful for forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in 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-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • The semipermeable membranes can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • The delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220.
  • The total amount of the compound of the invention released and the release rate can substantially be modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • In some embodiments, the pharmaceutical composition in an osmotic controlled-release dosage form can further comprise additional conventional excipients as described herein to promote performance or processing of the formulation.
  • The osmotic 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).
  • In some embodiments, the pharmaceutical composition provided herein is formulated as asymmetric membrane technology (AMT) controlled-release dosage form that comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • In some embodiments, the pharmaceutical composition provided herein is formulated as ESC controlled-release dosage form that comprises an osmotic membrane that coats a core comprising the compound of the invention, hydroxylethyl cellulose, and other pharmaceutically acceptable excipients.
  • In some embodiments, the compositions of the invention are a modified release dosage form that is fabricated as a multiparticulate-controlled release dosage form that comprises a plurality of particles, granules, or pellets, microparticulates, beads, microcapsules and microtablets, ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or from about 100 μm to 1 mm in diameter.
  • The multiparticulate-controlled release dosage forms can provide a prolonged release dosage form with an improved bioavailability. Suitable carriers to sustain the release rate of the compound of the invention include, without limitation, ethyl cellulose, HPMC, HPMC-phtalate, colloidal silicondioxide and Eudragit-RSPM.
  • Compositions of the invention in pellet form can comprise 50-80% (w/w) of a drug and 20-50% (w/w) of microcrystalline cellulose or other polymers. Suitable polymers include, but are not limited to, microcrystalline wax, pregelatinized starch and maltose dextrin.
  • Beads can be prepared in capsule and tablet dosage forms. Beads in tablet dosage form can demonstrate a slower dissolution profile than microparticles in capsule form. Microparticle fillers suitable for compositions and therapeutic or prophylactic methods of the invention include, without limitation, sorbitan monooleate (Span 80), HPMC, or any combination thereof. Suitable dispersions for controlled release latex include, for example, ethyl-acrylate and methyl-acrylate.
  • In some embodiments, the compositions of the invention are in the form or microcapsules and/or microtablets. In some embodiments, microcapsules comprise extended release polymer microcapsules containing a statin and a compound of the invention with various solubility characteristics. Extended release polymer microcapsules can be prepared with colloidal polymer dispersion in an aqueous environment. In other embodiments, microcapsules suitable for the compositions and methods provided herein can be prepared using conventional microencapsulating techniques (Bodmeier & Wang, 1993).
  • Such multiparticulates can be made by the processes known to those skilled in the art, including wet- and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989. Excipients for such technologies are commercially available and described in US Pharmacopeia.
  • Other excipients as described herein can be blended with the compositions of the invention to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate dosage form or can be coated by various film-forming materials, such as enteric polymers, water-swellable, or water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet.
  • In other embodiments, the compositions of the invention are in a dosage form that has an instant releasing component and at least one delayed releasing component, and is capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from about 0.1 hour to about 24 hours.
  • In some embodiments, the compositions of the invention comprise from about 1 mg to about 1000 mg of a compound of the invention or any amount ranging from 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 ranging from 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 ranging from 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 to about 1 mg to about 1000 mg of a compound of the invention or any amount ranging from 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 to about 1 mg to about 500 mg of a compound of the invention or any amount ranging from 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 to about 1 mg to about 400 mg of a compound of the invention or any amount ranging from and to these values.
  • In some embodiments, the compositions of the invention comprise a compound of the invention in an amount of about 10 wt % to about 99 wt % of the total weight of the composition of the invention.
  • Methods of the Invention
  • The present invention provides methods for treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention, wherein the disease is liver disease or an abnormal liver condition; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract; an intra- or extra-hepatic bile duct disease; a disorder of lipoprotein; a lipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular or related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease resulting from steatosis, fibrosis, and cirrhosis; a disease associated with increased inflammation (such as hepatic inflammation or pulmonary inflammation); hepatocyte ballooning; a peroxisome proliferator activated receptor-associated disorder; an ATP citrate lyase disorder; an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; or renal disease.
  • The present invention provides methods for treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention, wherein the disease is cancer, a lipid-and-metabolic disorder, a liver disorder, cirrhosis, fibrosis, a disorder of glucose metabolism, a peroxisome proliferator activated receptor-associated disorder, a malignant or benign tumor of the lung, liver, bile and digestive tract, an ATP citrate lyase disorder, an acetyl-coenzyme A carboxylase disorder, obesity, pancreatitis, renal disease, hepatocyte ballooning, hepatic inflammation, or pulmonary inflammation.
  • In some embodiments of the methods as disclosed herein, the disease is cancer. In some embodiments, the cancer is hepatocellular carcinoma (HCC), HCC with cirrhosis, HCC without cirrhosis, cholangiocarcinoma, colorectal cancer, biliary cancer, or pulmonary cancer. In some embodiments, the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophogeal cancer, stomach 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, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia (AML), acute promyelocytic leukemia (APL), acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, multiple myeloma, lymphoblastic leukemia, myelogenous leukemia, lymphocytic leukemia, myelocytic leukemias, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, Waldenström's macroglobulinemia, heavy chain disease, gastrointestinal cancer, head-and-neck cancer, hematopoietic cancer, or polycythemia vera.
  • In some embodiments, gastrointestinal (digestive) cancer is gastrointestinal stromal tumor (GIST), esophagueal cancer, gallbladder cancer, gastrointestinal carcinoid tumor, cholangiocarcinoma, duodenal cancer, gastroesophageal (ge) junction cancer, islet cell cancer, lpancreatic cancer, stomach cancer, colon cancer, rectal cancer, colorectal cancer, anal cancer, liver cancer, biliary cancer, bile duct cancer, cancer of the small intestine, seudomyxoma peritonei, small bowel cancer, or cancer of unknown primary.
  • In some embodiments, the hematopoietic cancer is non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), multiple myeloma (MM), B chronic lymphocytic leukemia (B-CLL), B and T 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).
  • In some embodiments of the methods as disclosed herein, the cancer is in any stage. In some embodiments, the cancer can be in stage 0, stage I, stage II, stage III, or stage IV. In some embodiments of the methods as disclosed herein, the disease is tumor and the tumor can be in any stage. In some embodiments, the tumor is grade 1, grade 2, grade 3, or grade 4.
  • In some embodiments of the methods as disclosed 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 transferase (GGT), high low-density lipoprotein (LDL), high very-low-density lipoprotein (VLDL), high apolipoprotein B (ApoB) and ApoB/Lp(a) (lipoprotein(a)) ratio, high total cholesterol, low high-density lipoprotein (HDL), or high non-HDL-cholesterol in the subject's plasma or blood serum; or by high glucose and insulin resistance in a subject with diabetes. In some embodiments, the lipid-and-metabolic disorder is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or alcoholic steatohepatitis (ASH).
  • In some embodiments of the methods as disclosed 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.
  • In some embodiments of the methods as disclosed herein, the disease is a disease resulting from steatosis, fibrosis, and cirrhosis. In some embodiment, the disease resulting from steatosis is inflammation. In some embodiment, the disease resulting from steatosis is NAFLD, NASH, or ASH. In some embodiment, the disease resulting from fibrosis is liver cirrhosis or liver failure. In some embodiment, the disease resulting from cirrhosis is, hepatocellular carcinoma, liver damage, or hepatic encephalopathy.
  • The present invention provides methods for reducing a concentration in a subject's blood plasma or blood serum the subject's C-reactive protein (CRP) concentration, 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: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 cholesterol concentration, non-HDL concentration, apolipoprotein B concentration, lipoprotein(a) concentration, or serum triglyceride concentration, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • The present invention provides methods for reducing triglyceride concentration in a subject's liver, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • The present invention provides methods for elevating in a subject's blood plasma or blood serum a concentration of high-density lipoprotein cholesterol or high-density lipoprotein, comprising administering to a subject in need thereof an effective amount of a compound of the invention or the composition of the invention.
  • The present invention provides methods for increasing functionalization of the high-density lipoprotein cholesterol, without increasing its concentration in a subject's blood plasma or blood serum, comprising administering to a subject in need thereof an effective amount of a compound of the invention or the composition of the invention, wherein an amount or rate of excretion of cholesterol and triglycerides increases.
  • The present invention provides methods for treating a disease, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention, wherein the disease is gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), or autoimmune disease.
  • In some embodiments of the methods as disclosed herein, the disease is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn's Disease or ulcerative colitis.
  • In some embodiments of the methods as disclosed herein, the disease is autoimmune disease. In some embodiments, the autoimmune disease is systemic lupus erythematosus.
  • The present invention provides methods for regressing, reducing the rate of progression or inhibiting progression of fibrosis, hepatocyte ballooning or hepatic inflammation, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • The present invention provides methods for inhibiting, reducing, or delaying advancement of a subject's lipid synthesis, liver steatosis, hepatocyte ballooning or inflammation, liver fibrosis, lung fibrosis, or cirrhosis, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • The present invention provides methods for reducing a subject's risk of developing or having atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, or restenosis, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • The present invention provides methods for elevating HDL concentration in the subject's blood serum or plasma, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • 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 the compound of the invention or the composition of the invention.
  • 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 the compound of the invention or the composition of the invention.
  • The present invention provides methods for CCR2/CCR5 gene downregulation, comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • 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 the compound of the invention or the composition of the invention.
  • The present invention provides methods for inhibiting an interleukin's activation or concentration, comprising administering to a subject in need thereof an effective amount of a compound of the invention or the composition of the invention. In some embodiments, the interleukin (IL) is IL-2, IL-6, IL-17 or IL-18.
  • The present invention provides methods for inhibiting fibrin/fibrinogen, gastrin, lactate dehydrogenase, prostatic acid phosphatase (PAP), thyroglobulin, urine catecholamine, urine vanillylmandelic acid (VMA) or urine homovanillic acid (HVA), comprising administering to a subject in need thereof an effective amount of a compound of the invention or the composition of the invention.
  • 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 the composition of the invention.
  • 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 the composition of the invention.
  • The present invention also provides methods for inhibiting hepatic fatty acid or sterol synthesis, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • The present invention also provides methods for treating or preventing a disease or disorder that is capable of being treated or prevented by increasing HDL levels, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • The present invention also provides methods for treating or preventing a disease or disorder that is capable of being treated or prevented by lowering LDL levels, which comprises administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • Without being limited by theory, it is believed that the compounds of the invention favorably alter lipid metabolism at least in part by enhancing oxidation of fatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis. Accordingly, the invention also provides methods for treating or preventing a metabolic syndrome disorder, comprising administering to a subject in need thereof an effective amount of a compound of the invention or composition of the invention.
  • The present invention further provides methods for 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 composition of the invention.
  • The present invention further provides methods for modulating, directly inhibiting or allosterically inhibiting acetyl-CoA carboxylase 1 (ACC1) or acetyl-CoA carboxylase 2 (ACC2) in a subject, comprising administering to the subject an effective amount of a compound of the invention or composition of the invention.
  • The present invention further provides methods for reducing the fat or cholesterol content of livestock meat or poultry eggs, comprising administering to the livestock or poultry an effective amount of the compound of the invention or the composition of the invention.
  • In some embodiments of the methods as disclosed herein, the compound of the invention is administered to the subject in need thereof in the range from about 1 mg to about 1000 mg or any amount ranging from and to these values. In some embodiment, the compound of the invention is administered to the subject in need thereof in the rage from 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.
  • In some embodiments of the methods as disclosed herein, the compound of the invention is administered to the subject in need thereof in a daily dose ranging from about 1 mg to about 1000 mg or any amount ranging from and to these values. In some embodiments, the compound of the invention is administered to the 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.
  • In some embodiments of the methods as disclosed herein, the compound of the invention is administered to the subject in need thereof once a day at a dose of about 1 mg to about 1000 mg or any amount ranging from and to these values.
  • In some embodiments of the methods as disclosed herein, the compound of the invention is administered to the subject in need thereof twice a day, each dose comprising the compound of the invention in about 1 mg to about 500 mg or any amount ranging from and to these values. In some embodiment, the compound of the invention is administered to the subject in need thereof twice a day, each dose comprising the compound of the invention in 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.
  • In some embodiments of the methods as disclosed herein, the compound of the invention is administered to the subject in need thereof three times a day, each dose comprising the compound of the invention in about 1 mg to about 400 mg or any amount ranging from and to these values. In some embodiment, the compound of the invention is administered to the subject in need thereof three times a day, each dose comprising the compound of the invention in 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.
  • In some embodiments of the methods as disclosed herein, the methods further comprise administering an effective amount of another pharmaceutically active agent. In some embodiments, the other pharmaceutically active agent is administered concurrently or sequentially with (prior or subsequent to) the administration of the compound of the invention or the composition of the invention. In some embodiments, the other pharmaceutically active agent is a statin, a thiazolidinedione or fibrate, a bile-acid-binding-resin, a niacin, an anti-obesity drug, a hormone, a tyrophostine, a sulfonylurea-based drug, a biguanide, an α-glucosidase inhibitor, an apolipoprotein A-I agonist, apolipoprotein E agonist; a phosphodiesterase type-5 inhibitor, a cardiovascular drug, an HDL-raising drug, an HDL enhancer, a regulator of the apolipoprotein A-I gene, a regulator of the apolipoprotein A-IV gene, a regulator of the apolipoprotein gene, an ATP citrate lyase modulator, an ATP citrate lyase allosteric inhibitor, an acetyl-CoA carboxylase modulator, or an acetyl-CoA carboxylase allosteric 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; T-cell receptor (TCR) immune cell therapy agent; IBI-302; namodenoson; MM-310; a tumor-injected oncolytic virus or gene-modified oncolytic virus such as, but not limited to, telomelysin and imlygic; or an immunomodulating gene-therapy agent such as MDA-7/IL-24, GLIPR1/RTVP-1, and REIC/Dkk-3.
  • In some embodiments of the methods as disclosed herein, the methods further comprises 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 a tumor-injected oncolytic treatment. In some embodiments, the combination is administered orally.
  • In some embodiments, the other pharmaceutically active agent is cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, nivolumub, firsocostat, apararenone, metformin, leucine-metformin-sildenafil combination (NS-0200), IMM-124E, RG-125, vitamin E, cysteamine, selonsertib, losartan, R05093151, 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, 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, nalmafene, pentamidine, berberine, L-carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, solithromycin, 99m technetium-mebrofenin, tropifexor, S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, or seladelpar.
  • In some embodiments of the methods as disclosed 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.
  • In some embodiments of the methods as disclosed 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, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, R05093151 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, nalmafene, pentamidine, Berberine, L-Carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, Olesoxime, AKR-001, Seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, R07119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, R07070179, axitinib, sunitinib, or zotiraciclib citrate. In some embodiments of the methods as disclosed herein, the method 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, IBI-302, namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin, Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine, selonsertib, losartan, R05093151 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, nalmafene, pentamidine, Berberine, L-Carnitine, EYP001a, silymarin, miricorilant, ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat, elafibranor, nalmefene, solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline, Olesoxime, AKR-001, Seladelpar, fisogatinib, doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, P1101, varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib, sapanisernib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, R07119929, guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, R07070179, axitinib, sunitinib, or zotiraciclib citrate.
  • In some embodiments of the methods as disclosed 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, T-cell receptor (TCR) immune cell therapy agent, IBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus, a gene-modified oncolytic virus, or an immunomodulating gene-therapy agent. In some embodiments of the methods as disclosed 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, T-cell receptor (TCR) immune cell therapy agent, IBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus, a gene-modified oncolytic virus, or an immunomodulating gene-therapy agent.
  • 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 set forth of an embodiment of Table D. In some embodiments, the other pharmaceutically active agent is administered concurrently with, prior to or subsequent to the administration of the compound of the invention or the composition of the invention.
  • In some embodiments of the methods as disclosed herein, the methods further comprise administering radiation therapy to the subject. In some embodiments, the radiation therapy is gamma ray radiation therapy or x-ray radiation therapy. In some embodiments, the radiation therapy is administered via a gamma ray or x-ray radiation apparatus.
  • In some embodiments, the radiation therapy is administered concurrently with, prior to or subsequent to the administration of the compound of the invention or the composition of the invention. In some embodiments, the radiation therapy is administered prior to or subsequent to the administration of the compound of the invention or the composition of the invention.
  • Methods for Making the Compounds of the Invention
  • Synthesis and General Protocols
  • The compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), and (IL), (collectively “Formula (I)”) can be prepared via the synthetic methodologies illustrated in Schemes 1-7. The starting materials useful for preparing the compounds of the invention and intermediates thereof are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.
  • Figure US20230007838A1-20230112-C00953
  • In Scheme 1, A can be halogen, such as Cl, Br, or I. In some embodiments, A is Br. In Scheme 1, B can be carbanions of esters of carboxylic or malonic esters. In Scheme 1, Q1 and Q2 can each independently be —O-alkyl, —S-alkyl, —S-aryl, —NR1AR2A NHR1A phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, —CF3, —COR1A, heteroaryl, or heterocyclyl, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group. R1A and R2A are as defined herein for formula (I).
  • Figure US20230007838A1-20230112-C00954
  • In Scheme 2, Q1 and Q2 can each independently be —O-alkyl, —S-alkyl, —S-aryl, —NR1AR2A NHR1A, phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, —CF3, —COR1A heteroaryl, or heterocyclyl, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group. R1A and R2A are as defined herein for formula (I)
  • Figure US20230007838A1-20230112-C00955
  • In Scheme 3, Q1 and Q2 can each independently be —O-alkyl, —S-alkyl, —S-aryl, —NR1AR2A, NHR1A, phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, —CF3, —COR1A heteroaryl, or heterocyclyl, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group. R1A and R2A are as defined herein for formula (I).
  • Scheme 3 illustrates the transformation of ortho, meta, or para co-haloalkyl substituted arenes of the formula 5, wherein p is an integer in the range of 2-5 and Hal is Cl, Br, or I, to dicarboxylic acids of the formula 7, wherein R1 and R2 are alkyl and/or aryl moieties or are connected in a three- to seven-membered cycle. This transformation can be accomplished by two different, however related pathways. According to the first method, esters of the formula R1R2CHCO2R5, wherein R1 and R2 are alkyl and/or aryl moieties or are connected in a three- to seven-membered cycle and R5 is typically ethyl or methyl, are deprotonated by strong bases, preferably, but not limited to, butyl lithium or lithium diisopropylamide, and then reacted with dihalides of the formula 5 to furnish the corresponding diesters of the formula 6. Generally, the reaction is performed at temperatures from about −78° C. to about 25° C. and the reaction solvent is preferably THF or diethyl ether (see Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2nd ed.; Wiley-VCH, New York, 1999, pp 1725-1726 for a discussion of the scope of this method. See, Dasseux et al., U.S. Pat. Nos. 6,646,170 and 6,410,802, Oniciu et al. U.S. Pat. No. 10,227,285 and Ackerley et al., J. Med. Chem. 1995, 38, 1608-1628 for specific examples of this method). In the second step, a diester of the formula 6 is saponified (see Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2nd ed.; Wiley-VCH, New York, 1999, pp 1959-1968 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 469-474 for an overview) to a diacid of the formula 7. As an alternative, this transformation of a dihalide of the formula 5 to a diacid of the formula 7 can also be achieved in one step, when a carboxylic acid of the formula R1R2CHCO2H, wherein R1 and R2 are alkyl and/or aryl, is deprotonated twice under conditions similar to the alkylation of R1R2CHCO2R5 described above and subsequently reacted with dibromide 5 (for a discussion, see Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2nd ed.; Wiley-VCH, New York, 1999, pp 1717-1718). For example, a compound of the formula 5 (ortho, p=3, Hal=Br) is reacted with lithio ethyl isobutyrate (prepared from ethyl isobutyrate with lithium diisopropylamide) in a solvent mixture of THE and DMPU at a temperature ranging from about −78° C. to room temperature, affording the corresponding diester of formula 7 (ortho, p=3). This diester is subsequently hydrolyzed under standard conditions (aqueous ethanol, potassium hydroxide, reflux temperature) to provide, after re-acidification with dilute aqueous hydrochloric acid, the dicarboxylic acid of the formula 7 with ortho substitution pattern, R1=R2=methyl and p=3. In another method, which is described in Gleiter et al., J. Org. Chem. 1992, 57, 252-258, isobutyric acid is deprotonated twice with n-butyl lithium and diisopropylamine in THE solution first at about −20° C. and then at about 50° C. After re-cooling to about −20° C., a solution of a compound of the formula 5 (ortho, R1=R2=methyl, p=3, Hal=Br) in THE is then added dropwise, while the temperature is kept below 10° C. The mixture is subsequently stirred first at room temperature and then at about 40° C., and worked up in a typical manner to afford the corresponding diacid 7. Halide derivatives of type 5 can be obtained by several methods, described for instance in Gleiter et al., J. Org. Chem. 1992, 57, 252-258.
  • Figure US20230007838A1-20230112-C00956
  • In Scheme 4, Q and Q can each independently be —O-alkyl, —S-alkyl, —S-aryl, —NR1AR2A, NHR1A phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, —CF3, —COR1A heteroaryl, or heterocyclyl, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group. R1A and R2A are as defined herein for formula (I).
  • Scheme 4 illustrates the synthesis of para, meta, and ortho di-bromoalkyl substituted arene compounds 5-Br from the parent dicarboxylic acids 10 wherein (p-1) is an integer in the range from 1-2. Scheme 4 first outlines the esterification of compounds of the formula 10 to diesters of the formula 20, wherein R is an alkyl moiety such as, but not limited to, methyl, ethyl, or isopropyl using 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 for example Hudlicky, M. Reductions in Organic Chemistry, 2nd ed.; ACS Monograph 188, Washington, D C, 1996, pp 212-216). In the next step, transformation of the alcohol functionalities in 30 to the bromo moieties in Compound 5-Br can be accomplished by a variety of standard methods as referenced in Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2nd ed.; Wiley-VCH, New York, 1999, pp 693-695. For example, a compound of the formula 10 with para substitution pattern and (p-1)=1 (available from Aldrich Chemical Co., Milwaukee, Wis.) is treated with an excess of methanol and concentrated sulfuric acid at reflux temperature to give the corresponding dimethyl ester of the formula 2. A procedure that can be used for this transformation is, for example, referenced in Schimelpfenig, C. W. J. Org. Chem. 1975, 40, 1493-1494, incorporated by reference herein. In addition, a compound of the formula 20 (para, (p-1)=1) can be transformed to the corresponding compound of the formula 30 by reaction with a complex metal hydride, preferably, but not limited to, lithium aluminum hydride in an aprotic organic solvent, such as THE or diethyl ether, as referenced in Reynolds et al. U.S. Pat. No. 2,789,970, Appl. No. 397,037, filed Dec. 8, 1953. Further, a diol of the formula 30 (para, p=1) can be converted to a bromide of the 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 is described in Schimelpfenig, C. W. J. Org. Chem. 1975, 40, 1493-1494.
  • Figure US20230007838A1-20230112-C00957
  • In Scheme 5, Q1 and Q2 can each independently be —O-alkyl, —S-alkyl, —S-aryl, —NR1AR2A, NHR1A, phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, —CF3, —COR1A heteroaryl, or heterocyclyl, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group. R1A and R2A are as defined herein for formula (I).
  • Scheme 5 illustrates the preparation of ortho, meta, and para substituted arene compounds with two 3-bromopropyl substituents of the formula 5A-Br. Specific examples for the synthesis of compounds 5A-Br with meta and para substitution are given in Schimelpfenig, C. W. J. Org. Chem. 1975, 40, 1493-1494 and Gleiter et al., J. Org. Chem. 1992, 57, 252-258, respectively. For example, a compound of the formula 50 is treated with malonic acid and piperidine in pyridine solution at about 90-110° C. to give an α,β-unsaturated carboxylic acid of the formula 60. The end point of this conversion is typically indicated by cessation of the CO2 effervescence. This procedure is known as a Knoevenagel-Doebner reaction and a useful reaction protocol for this conversion is given in Organikum, Organisch-Chemisches Grundpraktikum, VEB Verlag Deutscher Wissenschaften, Berlin 1984, pp 572-574. Reduction of compounds of the formula 60 to compounds of the formula 70 can be accomplished 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, D C, 1996, pp 196-197. Conversion of a compound of the formula 60 with meta substitution to the corresponding compound 70 by treatment with hydrogen gas at pressures from ca. 20-60 psi and palladium on carbon catalyst in aqueous sodium hydroxide solution is reported in Schimelpfenig, C. W. J. Org. Chem. 1975, 40, 1493-1494, which is included herein as a reference in its entirety. The further transformation of compounds of the formula 70 to compounds of formula 5A-Br can then be accomplished according to the methodology described in Scheme 4.
  • Figure US20230007838A1-20230112-C00958
  • In Scheme 6, Q1 and Q2 can each independently be —O-alkyl, —S-alkyl, —S-aryl, —NR1AR2A, NHR1A phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, —CF3, —COR1Aheteroaryl, or heterocyclyl, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group. R1A and R2A are as defined herein for formula (I).
  • Scheme 6 illustrates a general method for the chain elongation of bromides of the formula 90 with an alkyl chain consisting of (p-2) methylene groups to bromides of the formula 5-Br with an alkyl chain consisting of p methylene groups. The conversion sequence from alkyl halides (such as 90) to carboxylic acid (such as 120) can be accomplished using a malonic ester synthesis referenced in Smith, M. B.; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5th ed.; John Wiley and Sons, New York, 2001, p 549 and Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2nd ed.; Wiley-VCH, New York, 1999, p 1765. Generally, the monoalkylation of malonic esters (R is typically ethyl or methyl) employs the base-solvent combination of sodium ethoxide in ethanol, which inhibits the formation of dialkylated side-products (Organic Reactions, Volume IX, editor-in-chief: R. Adams; Robert E. Krieger Publishing Company, Malabar, Fla., 1957, p 132) to give compounds of the formula 100. Compounds of the formula 100 are then saponified to give compounds of the formula 110, which can be heated above their melting point for decarboxylation to compounds of the formula 120. The transformation from dicarboxylic acids 120 via diesters 20 to the chain-elongated dibromides 5-Br is then conducted according to the methodologies described in Scheme 4. Alternatively, a direct decarbalkoxylation of geminal diesters 100 to compounds of the formula 20 can be achieved by treatment with water and DMSO with or without the presence of added salts. However, the addition of salts such as KCN, NaCl or LiCl to the water/DMSO solvent can enhance the decarbalkoxylation rates of theses substrates (Fakhri, S. A.; Yousefi, B. H. Tetrahedron 2000, 56, 8301-8308). For example, ethyl malonate is reacted with sodium metal in ethanol and a solution of a compound of the formula 90 with (p-2)=2, and ethyl malonate is added to give the corresponding compound of the formula 100. This tetraester is subsequently saponified using, for example, aqueous ethanol and potassium hydroxide, yielding the corresponding tetraacid of the formula 110. The tetraacid is then decarboxylated at a temperature of ca. 200° C. to the diacid of the formula 120. After esterification with methanol and concentrated sulfuric acid (see Scheme 4) to diester 20. Useful methods for the transformation of a tetraester of the formula 100 (ortho, (p-2)=1, R=ethyl) to a diester of the formula 20 are described in Fakhri, S. A.; Yousefi, B. H. Tetrahedron 2000, 56, 8301-8308, which is included herein in its entirety as a reference.
  • Figure US20230007838A1-20230112-C00959
  • In Scheme 7, Q1 and Q2 can each independently be —O-alkyl, —S-alkyl, —S-aryl, —NR1AR2A, NHR1A, phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, —CF3, —COR1A heteroaryl, or heterocyclyl, or each carbon atom together with the Q1 and Q2 attached to the carbon atom independently form a heterocyclyl or a carbocyclyl group. R1A and R2A are as defined herein for formula (I).
  • Scheme 7 illustrates the synthesis of ortho, meta, and para substituted arene compounds of the formula 7 with ω-carboxyalkyl substitution, wherein (p-1) is an integer in the range from 2-12 and R1 and R2 are either alkyl and/or aryl moieties or two alkyl moieties connected in a 3- to 7-membered cycle. The synthesis starts with the twofold 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 reaction of the formed dianion of 3 with suitable electrophiles A-(CH2)p-1—CR1R2—CH2O-PG, wherein (p-1), R1, and R2 are defined as 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, P. G. M. Protective groups in organic synthesis, 3rd ed., John Wiley and Sons, New York, 1999, pp 17-245, which is incorporated herein by reference. Methyl arenes can be alkylated via deprotonation using lithium bases followed by alkylation with suitable electrophiles according to Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2nd ed.; Wiley-VCH, New York, 1999, p 88. See, Bates et al., J. Am. Chem. Soc. 1981, 103, 5052-5058, for an example for the preparation of xylene dianions. In the following step, the protective groups of 190 are removed to liberate the terminal hydroxylmethyl moieties in 200, which are the oxidized using a suitable oxidizing agent (Larock, R. C. Comprehensive Organic Transformations. A Guide to Functional Group Preparations, 2nd ed.; Wiley-VCH, New York, 1999, pp 1646-1648 and Smith, M. B.; March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 5th ed.; John Wiley and Sons, New York, 2001, p 1537) to give a dicarboxylic acid of the 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 the formula 180 (A=Br, (p-1)=3, R1=R2=methyl, PG=tetrahydropyranyl, prepared according to Dasseux et al., U.S. Pat. Nos. 6,646,170 and 6,410,802) is added and reaction is continued at reflux temperature, affording, after the usual workup and purification by column chromatography, the corresponding compound of the formula 190. Deprotection of 190 to 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, W. H., III; Gapinski, D. M.; McClure, C. K. J. Am. Chem. Soc. 1987, 109, 5437-5446 to yield the dicarboxylic acid of the formula 7 (meta, p=3; R1,R2=methyl).
  • Scheme 8 shows illustrative alternate syntheses of compounds I-1 and I-32. Commercially available benzene-dicarboxaldehydes (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 U.S. Pat. No. 8,349,833 B2) in the presence of base (including but not limited to sodium or potassium hydroxide, potassium or sodium tert-butoxide, potassium or sodium carbonate, and sodium hydride), in the manner described in Le Bigot Y. et al., 1988, Tetrahedron 44(4), pp. 1057-1072, as a mixture of cis and trans isomers. The mixture of cis and trans isomers of formula (230) or (240) can be reduced catalytically by methods for the hydrogenation of olefins known in the art, such as the methods 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 Sep. 2018; and references cited herein. The esters thus obtained are subjected to hydrolysis after the hydrogenation reaction is deemed substantially complete by using an appropriate analytical methods. The reaction mixtures containing compounds of formula (250) or (260), respectively, are hydrolyzed in the presence of an alkaline earth metal salt or base, or oxide, or alkali metal salt or base. in refluxing alcohols for 2 to 96 hours. Typical examples include, but are not limited to, hydrolysis with K2CO3 in a refluxing mixture of DMSO and water. Other suitable procedures are referenced 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.
  • Figure US20230007838A1-20230112-C00960
  • Figure US20230007838A1-20230112-C00961
  • The compound of Formula (III) or (IIIA) where X═O can be prepared by a Williamson synthesis, by reacting an alcohol with a derivative comprising a leaving group such as halide, tolylsulphonate or mesylate. See Scheme 9.
    • SYNTHESIS EXAMPLES Example 1: Synthesis of (9-Carboxymethylsulfanyl-5-oxo-nonylsulfanyl)-acetic acid (Compound II-3)
  • Figure US20230007838A1-20230112-C00962
  • Reaction of ethyl 5-bromovalerate with lithium diisopropylamide in THE at room temperature produces ketone 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) produces crude 1-2, which can be purified by column chromatography using systems such as silica gel and mixtures of ethyl acetate/hexanes 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 make sodium mercaptoacetate and is 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 provide crude compound II-3. The crude compound II-3 can be purified by recrystallization from solvents or mixtures of solvents such as MIBE and heptane.
    • Example 2: Synthesis of (9-Carboxymethylsulfanyl-5-hydroxy-nonylsulfanyl)-acetic acid (Compound II-1)
  • Figure US20230007838A1-20230112-C00963
  • The reduction of ketodiacid compound II-3 from Example 1 is achieved with sodium borohydride after salt formation with NaOH to yield compound II-1 (see U.S. Pat. No. 7,119,221 for suitable reaction conditions). Compound II-3 (Example 1) is dissolved in NaOH solution (2 to 7 equiv) to form an intermediate disodium salt in water. Isopropanol is then added followed by addition of sodium borohydride (1.05 equiv) in portions. The reaction mixture is heated at about 45° C. for a few hours to yield compound II-1. Such product can be purified by recrystallization from MIBE, heptane or mixtures.
    • Example 3: Synthesis of [5-(5-Carboxymethoxy-pentyloxy)-pentyloxy]-acetic acid (Compound II-12)
  • Figure US20230007838A1-20230112-C00964
  • Compound II-12 is prepared via a Williamson ether synthesis starting from 3-1 and 3-2 (prepared as described in Dasseux et al. U.S. Pat. No. 6,459,003). The resulting 3-3 is deprotected in methanol in the presence of a catalytic amount of p-toluenesulphonic acid monohydrate to give diol 3-4. This diol is then coupled with tert-butyl bromoacetate in a two-phase system of aqueous NaOH and toluene in the presence of tetrabutylammonium bromide as PTC catalyst, as described in U.S. Pat. No. 10,227,285. Finally, this tert-butyl ester is cleaved under acidic conditions to afford compound II-12.
    • Example 4: Synthesis of [5-(5-Carboxymethoxy-pentylsulfanyl)-pentyloxy]-acetic acid (Compound II-20)
  • Figure US20230007838A1-20230112-C00965
  • Compound 3-1 (prepared as described in U.S. Pat. No. 6,790,953) is treated with sodium sulfide similarly to the method by Edwards, D.; Stenlake, J. B. J. Pharmacy Pharmacol. 1955, 7, 852-860, to form thio ether 4-1, which is deprotected in methanol in the presence of a catalytic amount of pyridinium p-toluenesulphonate (PPTS) as described in Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977, 42(23), 3772-73. The diol 4-2 thus obtained is reacted with tert-butyl bromoacetate under phase-transfer catalysis conditions using (Bu4N)(HSO4) as catalyst, following the method of Nagatsugi, F.; Sasaki, S.; Maeda, M. J. Fluorine Chem. 1992, 56, 373-383, to obtain its tert-butyl ester 4-3. Subsequent cleavage of tert-butyl ester by trifluoroacetic acid (TFA) affords free acid compound II-20 in 90% yield similar to the procedure in Nagatsugi, F.; Sasaki, S.; Maeda, M. J. Fluorine Chem. 1992, 56, 373-383.
    • Example 5: Synthesis of [5-(5-Carboxymethoxy-pentane-1-sulfinyl)-pentyloxy]-acetic acid (Compound II-24)
  • Figure US20230007838A1-20230112-C00966
  • Compound II-24 is prepared starting from compound II-12 (Example 4) using hydrogen peroxide as an oxidizer similarly to the procedure described in U.S. Pat. No. 6,673,780.
    • Example 6: Synthesis of [5-(5-Carboxymethylsulfanyl-pentyloxy)-pentylsulfanyl]-acetic acid (Compound II-6)
  • Figure US20230007838A1-20230112-C00967
  • Compounds 6-1 and 6-2 are obtained according 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-Chloro-pentan-1-ol is commercially available and 3-4 is prepared as described in Example 3, as follows: mercaptoacetic acid (8.1 g, 87.9 mmol) was dissolved in deionized water/ethanol solution (50 mL/40 mL). A solution of sodium hydroxide (7.0 g, 175.5 mmol) in water (50 mL) was added under stirring. To this mixture, bis(4-chlorobutyl ether) (7.0 g, 35.1 mmol) in ethanol (20 mL) was added dropwise over 30 min. This mixture was heated to reflux for 20 h, with subsequent evaporation of ethanol. The residue was diluted with water (20 mL). The aqueous layer was extracted with MIBE (4×20 mL) and the organic layers were discarded. The aqueous layer was acidified with concd HCl to pH 2 (ca. 12 mL) and extracted with MIBE (4×30 mL). The combined organic layers were checked by TLC (silica, CH2Cl2:MeOH=9:1) for presence of starting mercaptoacetic acid (Rf=0.7; bright blue spot with phosphomolybdic acid/EtOH). The organic layer was washed with water until the starting acid was completely gone (ca. 700 mL in portions). The solvent was removed under reduced pressure to give a colorless oil (7.7 g), which solidified at rt. This solid was recrystallized from heptane/MIBE (50/60 mL) to give nice white crystals (6.2 g, yield 57%; purity 99%-RI, 91%—UV, mp 43-44° C.). An additional amount of the product was obtained from the mother liquor (0.87 g, mp 38-40° C.).
    • Example 7: Synthesis of (11-Carboxymethylsulfanyl-6-oxo-undecylsulfanyl)-acetic acid (Compound II-4) and (11-Carboxymethylsulfanyl-6-hydroxy-undecylsulfanyl)-acetic acid (Compound II-2)
  • Figure US20230007838A1-20230112-C00968
  • The synthesis of compounds II-4 and II-2 begins with 1,11-dibromoundecan-6-one (7-4), prepared as shown in above, starting with commercially available 6-bromohexanol. Protection of 6-bromohexanol's hydroxyl group with dihydropyran affords intermediate 7-1 as described in U.S. Pat. Nos. 6,646,170 and 6,410,802. Reaction of 7-1 with TosMIC in dimethyl acetamide (DMAc) in the presence of sodium amylate (NaOAm-t) leads to formation of intermediate 7-2, which is transformed to diol 7-3. The removal of the THP-protective groups and the transformation of the isocyano-tosyl-fragment into the ketone group proceeds simultaneously in mixture of solvents, such as methylene chloride, methanol, in the presence of aqueous HCl in about 12 to 24 hours. Diol 7-3 may be purified by column chromatography on silica gel and mixtures of solvents, such as ethyl acetate and methylene chloride. Compound 7-3 thus obtained is subjected to a Mitsunobu reaction to afford bromide 7-4, which is subsequently treated with the sodium salt of mercaptoacetic acid in an alcohol or a mixture of alcohols (ethanol, isopropanol) to provide diacid compound II-4. Compound II-4 is reduced with sodium borohydride to provide compound II-2 (see Example 2).
    • Example 8: Synthesis of [4-(4-Carboxymethoxy-butoxy)-butoxy]-acetic acid (Compound II-11)
  • Figure US20230007838A1-20230112-C00969
  • Commercially available bis(4-chlorobutyl ether) is converted via diacetate 8-1 [Kliem, A., Schniepp, L. E. J. Am. Chem. Soc, 1948, 70, 1839] to diol 8-2, which is further reacted with ethyl bromoacetate to provide 8-3. Compound 8-3 is hydrolyzed to provide II-11. Alternatively, bis(4-chlorobutyl ether) is treated with the dianion of hydroxyacetic acid to provide compound II-11 via autoclave or high temperatures.
  • Specifically, diacetate 8-1 is treated with potassium carbonate in methanol similarly to the method described in Kliem, A., Schniepp, L. E. J. Am. Chem. Soc, 1948, 70, 1839, and the crude compound 8-2 is optionally purified by column chromatography. Diol 8-2 is reacted deprotonated with sodium hydride (95% or 60% in mineral oil) in THE for about 2 h to about 4 h and then it is reacted with ethyl bromoacetate to give diester 8-3. The last 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 workup, including acidification with aqueous HCl followed by extraction with methylene chloride, to provide 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 and their mixtures.
    • Example 9: Synthesis of 5,5′-(1,4-Phenylene)bis(2,2-dimethylpentanoic acid) (Compound I-78)
  • Figure US20230007838A1-20230112-C00970
    • (4-Methoxycarbonylmethylphenyl)-acetic acid methyl ester (A2)
  • 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 vacuum. The residue was diluted with EtOAc (300 mL) and water (300 mL). The aqueous solution was separated and extracted with EtOAc (2×100 mL). The combined organic solutions were washed with water (100 mL), saturated NaHCO3 solution (2×100 mL) and brine (100 mL), and dried over MgSO4. The solvent was evaporated to yield (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, British patent 1495472, Appl. No. 9008/75, filed Mar. 4, 1975). 1H NMR (CDCl3): δ=7.25 (s, 4H), 3.70 (s, 6H), 3.60 (s, 4H). 13C NMR (CDCl3): δ=174.0, 132.5, 129.0, 52.0, 40.5.
    • 2-[4-(2-Hydroxyethyl)-phenyl]-ethanol (A3)
  • (4-Methoxycarbonylmethylphenyl)-acetic acid methyl ester (A2) (26.5 g, 0.12 mol) in THE (100 mL) was added to a solution of LiAlH4 (11.0 g, 0.29 mol) in THE (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 addition of dilute, aqueous HCl (75 mL concd HCl in 100 mL of water). The aqueous phase was extracted with EtOAc (2×100 mL). The combined organic solutions were washed with water (100 mL), saturated NaHCO3 solution (150 mL) and brine (100 mL), and dried over MgSO4. The solvent was evaporated to yield 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. U.S. Pat. No. 2,789,970, Appl. No. 397,037, filed Dec. 8, 1953). 1H NMR (CDCl3): 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). 13C NMR (CDCl3): δ=136.9, 129.4, 63.8, 39.0.
    • 1,4-Bis-(2-bromoethyl)-benzene (A4)
  • Concentrated sulfuric acid (30.0 g) was added dropwise over 1 h into a boiling 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 heating at reflux 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 product was recrystallized from hexanes to yield 1,4-bis-(2-bromoethyl)-benzene (22.27 g, 69%, 99.8% pure by HPLC) as a white solid. Mp 71-72° C. (70-71° C., Longone, D. T.; Küsefoglu, S. H.; Gladysz, J. A. J. Org. Chem. 1977, 42, 2787-2788. 1H NMR (CDCl3): δ=7.18 (s, 4H), 3.57 (t, J=2.2 Hz, 4H), 3.16 (t, J=7.8 Hz, 4H). 13C NMR (CDCl3): δ=138.6, 130.0, 40.1, 34.0.
    • 4-[4-(3-Carboxy-3-methylbutyl)-phenyl]-2,2-dimethylbutyric acid
  • 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 THE (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 THE (50 mL) was added slowly 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, 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) and water (50 mL), KOH (85%, 15.0 g, 227 mmol) was 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 MIBE (2×30 mL). The aqueous solution was acidified with aqueous HCl to pH 1-2. The precipitate was filtered, recrystallized from CHCl3/EtOH (1:1), and dried in vacuum 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 (C18H26O4): Calcd for C, 70.56; H, 8.55, found: C, 70.78; H, 8.64. 1H NMR (CD3OD): δ=7.06 (s, 4H), 4.90 (s, 2H), 2.54-2.48 (m, 4H), 1.80-1.74 (m, 4H), 1.22 (m, 12H). 13C NMR (CD3OD): δ=181.5, 140.9, 129.2, 44.3, 43.2, 32.3, 25.8. HRMS calcd for C18H26O4(M+): 306.1831, found: 306.1831.
    • Example 10: Synthesis of 6,6′-(1,4-phenylene)bis(2,2-dimethylhexanoic acid) (Compound I-1)
  • Figure US20230007838A1-20230112-C00971
    • 4-[4-(3-Methoxycarbonylpropyl)-phenyl]-butyric acid methyl ester (B1)
  • The compound was prepared by a modified method than reported in Cram, D. J.; Allinger, N. L.; Steinberg, H. J. Amer. Chem. Soc. 1954, 76, 6132.
  • 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 the room temperature over 5 min. The reaction mixture was heated to reflux for 0.5 h. After the 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 MgSO4, and concentrated in vacuo. The residue was dried in high vacuum at 80-100° C. (oil bath). The obtained 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 MgSO4, and concentrated. The crude 2-{2-[4-(3,3-bis-carboxypropyl)-phenyl]-ethyl}malonic acid (28.0 g) was heated on an oil bath at 200-210° C. for 1.5 h. The obtained, crude 4-[4-(3-carboxypropyl)-phenyl]-butyric acid (16.3 g) was dissolved in MeOH (100 mL) and concentrated sulfuric acid (40 mL) was added. The reaction mixture was refluxed for 5 h, then stirred overnight at room temperature. The MeOH was partially evaporated, the residue was dissolved in EtOAc (150 mL), washed with water (150 mL) and brine (150 mL), and dried over MgSO4. The solvent was evaporated to yield crude 4-[4-(3-methoxycarbonylpropyl)-phenyl]-butyric acid methyl ester (B1) (17.9 g, 85%) as a yellow oil, which was used without purification for the next step. 1H NMR (CDCl3): δ=7.10 (s, 4H), 3.67 (s, 6H), 2.59 (t, J=7.4 Hz, 4H), 2.33 (t, J=7.4 Hz, 4H), 1.95-1.90 (m, 4H). 13C NMR (CDCl3): δ=174.0, 138.9, 128.4, 51.5, 34.6, 33.3, 26.5.
    • 4-[4-(4-Hydroxybutyl)-phenyl]-butan-1-ol (B2)
  • The compound is prepared according to Cram, D. J.; Allinger, N. L.; Steinberg, H. J. Am. Chem. Soc. 1954, 76, 6132-6141). A solution of 4-[4-(3-methoxycarbonylpropyl)-phenyl]-butyric acid methyl ester (17.7 g, 63.6 mmol) in THE (50 mL) was added to a suspension of LiAlH4 (7.2 g, 0.19 mol) in THE (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 (2×50 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 yield 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, D. J.; Allinger, N. L.; Steinberg, H. J. Am. Chem. Soc. 1954, 76, 6132-6141). 1H NMR (CDCl3): 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). 13C NMR (CDCl3): δ=140.7, 129.4, 63.8, 36.3, 33.4, 28.67.
    • 1,4-Bis-(4-bromobutyl)-benzene (B3)
  • Concentrated sulfuric acid (30 mL) was added dropwise to a boiling mixture of 4-[4-(4-hydroxybutyl)-phenyl]-butan-1-ol (9.4 g, 42.3 mmol), NaBr (17.4 g, 0.169 mol) and water (50 mL) over 1 h. The reaction mixture was refluxed for 1 h. Additional concentrated sulfuric acid (10 mL) was added over 20 min and refluxing was continued for 1.5 h. After the addition of 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 MgSO4. The solvent was evaporated and residue was purified by column chromatography (silica gel, EtOAc:hexanes, 1:20) to yield 1,4-bis-(4-bromobutyl)-benzene (11.8 g, 80%, 96.1% pure by HPLC) as an oil. 1H NMR (CDCl3): δ=7.14 (s, 4H), 3.46 (t, J=6.6 Hz, 4H), 2.65 (t, J=7.5 Hz, 4H), 1.96-1.89 (m, 4H), 1.83-1.75 (m, 4H). 13C NMR (CDCl3): δ=139.5, 128.6, 34.7, 34.0, 32.5, 30.1. This procedure is modified from the one described by Cram, D. J.; Allinger, N. L.; Steinberg, H. J. Am. Chem. Soc. 1954, 76, 6132-6141.
    • 6-[4-(5-Carboxy-5methylhexyl)-phenyl]-2,2-dimethylhexanoic acid
  • A solution of lithium diisopropylamide (90 mmol, 1.8 M in heptane/THF/EtPh, 50 mL) was added dropwise to a solution of ethyl isobutyrate (8.97 g, 77.2 mmol) in THE (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 THE (50 mL) was added slowly, followed by addition of 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, 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). 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 addition of 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 with MgSO4 and evaporated in vacuum. The residue was dissolved under heating in EtOAc:hexanes (1:30, 200 mL) and cooled in a freezer. The solution was decanted from the oil and evaporated to a volume of 60 mL. The mixture was stirred overnight, the precipitate was filtered, washed with hexanes, and dried in vacuum to yield 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): Calcd for C, 72.89; H, 9.45. Found: C, 72.90; H, 9.49. 1H NMR (CDCl3): δ=7.05 (s, 4H), 2.66-2.62 (m, 4H), 1.68-1.56 (m, 4H), 1.53-1.47 (m, 4H), 1.17 (s, 12H), 1.08-0.98 (m, 4H). 13C NMR (CDCl3): δ=185.3, 138.6, 128.5, 42.3, 41.5, 34.5, 30.6, 25.0, 23.2. HRMS calcd for C22H34O4(M+): 362.2457, found: 362.2453.
    • Example 11: Synthesis of 1,4-Bis(4-carboxy-4-methylpentyl)benzene (Compound III-1)
  • Figure US20230007838A1-20230112-C00972
    • 1,4-Bis(2-methoxycarbonylethyl)benzene (C2)
  • 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 vacuum to yield 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). 1H NMR (CDCl3): δ=7.11 (s, 4H), 3.69 (s, 6H), 2.94 (t, J=8.1 Hz, 4H), 2.62 (t, J=8.2 Hz, 4H). 13C NMR (CDCl3): δ=173.3, 138.4, 128.4, 51.6, 35.6, 30.5. This known compound was prepared by a method different from the one described in Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata, Y.; Misumi, S. Bull. Chem. Soc. Japan 1972, 45, 1825-1833.
    • 1,4-Bis(3-hydroxypropyl)benzene (C3)
  • C3 was prepared according to Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata, Y.; Misumi, S. Bull. Chem. Soc. Japan 1972, 45, 1825-1833. Under Ar-atmosphere, lithium aluminum hydride (5.2 g, 13.7 mmol) was added in portions to anhydrous THE (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 a 10% aqueous solution of NH4Cl (50 mL). The organic layer was separated and the water solution was extracted with EtOAc (100 mL). The organic phases were combined, washed with brine (50 mL), dried over MgSO4, and concentrated to afford 1,4-bis(3-hydroxypropyl)benzene (9.0 g, quantitative) as an oil, which was used without further purification for the next step. 1H NMR (DMSO-d6): δ=7.10 (s, 4H), 4.43 (br s, 2H), 3.41 (t, J=8.1 Hz, 4H), 2.59 (t, J=8.2 Hz, 4H), 1.71 (m, 2H). 13C NMR (DMSO-d6): δ=139.0, 127.0, 60.0, 34.5, 31.2.
    • 1,4-Bis(3-bromopropyl)benzene (C4)
  • An emulsion of 1,4-bis(3-hydroxypropyl)benzene (9.0 g, 46.3 mmol) and sodium bromide (24.0 g, 0.23 mol) in deionized water (25 mL) was heated to reflux, while concentrated sulfuric acid (17 mL) was added dropwise over 1 h. After the addition, heating under reflux was continued for additional 3.5 h. The solution was cooled to room temperature, diluted with water (40 mL), and extracted with CH2Cl2 (2×150 mL). The combined organic layers were washed with saturated solution of NaHCO3 (100 mL), saturated NaCl solution (100 mL) and dried over MgSO4. The solvent was evaporated and the residue was purified by column chromatography (silica gel, EtOAc:hexanes, 1:40) to yield 1,4-bis(3-bromopropyl)benzene (11.6 g, 78%) as a colorless oil. 1H NMR (CDCl3): 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). 13C NMR (CDCl3): δ=138.3, 128.7, 34.2, 33.4, 33.3. This known compound was prepared by a method different from the one described in 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.
    • 1,4-Bis(4-ethoxycarboxy-4-methylpentyl)benzene (C5)
  • Under N2-atmosphere, to a solution of ethyl isobutyrate (9.0 g, 77.5 mmol) in anhydrous THF (300 mL) was added dropwise lithium diisopropylamide (1.8 M solution in heptane/THF/EtPh, 46.7 mL, 84.0 mmol) at −78° C. After 1 h, a solution of 1,4-bis(3-bromopropyl)benzene (11.6 g, 36.3 mmol) in anhydrous THE (70 mL) was added dropwise, followed by the addition of DMPU (20 mL). The reaction mixture was allowed to warm to room temperature overnight, then cooled with an ice-bath, and hydrolyzed with saturated NH4Cl solution (100 mL). Water (100 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated NaCl solution (100 mL), dried with MgSO4, and concentrated in vacuum. 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. 1H NMR (CDCl3): δ=7.09 (s, 4H), 4.11 (q, J=7.1 Hz, 4H), 2.57 (m, 4H), 1.57 (m, 8H), 1.24 (t, J=7.1 Hz, 6H), 1.47 (s, 12H). 13C NMR (CDCl3): δ=177.9, 139.6, 128.2, 60.1, 42.0, 40.2, 35.8, 26.8, 25.1, 14.2. HRMS calcd for C24H39O4(MH+): 391.2838, found: 391.2836.
    • 1,4-Bis(4-carboxy-4-methylpentyl)benzene
  • A solution of 1,4-bis(4-ethoxycarboxy-4-methylpentyl)benzene (13.0 g, 33.3 mmol) and potassium hydroxide (85%, 7.0 g, 106 mmol) in ethanol (25 mL) and water (15 mL) was heated 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 precipitate was dissolved in methylene chloride (700 mL) and the solution was dried over MgSO4 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.; Kramer, R.; Irngartinger, H.; Bissinger, C. Synthesis and Properties of 4,4,9,9-Tetramethyl[12]paracyclophane-5,6,7,8-tetrone. J. Org. Chem. 1992, 57, 252-258). Elemental analysis (C20H30O4): Calcd for C, 71.82; H, 9.04; found: C, 71.10; H, 9.00. 1H NMR (CDCl3): δ=7.07 (br s, 4H), 2.55 (m, 4H), 1.59 (m, 8H), 1.18 (s, 12H). 13C NMR (CDCl3): 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 modified to the one described in Gleiter, R.; Kramer, R.; Irngartinger, H.; Bissinger, C. Synthesis and Properties of 4,4,9,9-Tetramethyl[12]paracyclophane-5,6,7,8-tetrone. J. Org. Chem. 1992, 57, 252-258.
    • Example 12: Synthesis of 5,5′-(1,3-Phenylene)bis(2,2-dimethylpentanoic acid) (Compound I-31)
  • Figure US20230007838A1-20230112-C00973
    • Dimethyl m-benzene-bis(2,2-dimethyl)pentanoate (D2)
  • Under Ar-atmosphere, to a solution of ethyl isobutyrate (21.2 g, 24.4 mL, 183 mmol) in anhydrous THE (200 mL) was added dropwise lithium diisopropylamide (2.0 M in heptane/THF/ethylbenzene, 91.5 mL, 183 mmol) at −78° C. After 1 h, a solution of m-bis(3-bromopropyl)benzene (D1) (prepared according to Schimelpfenig, C. W. 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 THE (50 mL) was added dropwise, followed by the addition of DMPU (25 mL). The reaction mixture was allowed to warm to room temperature overnight, then cooled with an ice-bath, and hydrolyzed with saturated NH4Cl solution (100 mL). Deionized water (100 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 mL). The 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 in high vacuo. The residue was purified by flash chromatography on silica (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. 1H NMR (CDCl3): δ=7.17 (t, 1H, J=7.0 Hz), 6.97 (m, 3H), 4.09 (q, 4H, J=7.3 Hz), 2.55 (m, 4H), 1.56 (m, 8H), 1.22 (t, 6H, J=7.3 Hz), 1.15 (s, 12H). 13C NMR (CDCl3): δ=178.02, 142.37, 128.58, 128.32, 125.86, 60.31, 42.25, 40.52, 36.48, 27.03, 25.30, 14.39.
    • 5,5′-(1,3-Phenylene)bis(2,2-dimethylpentanoic acid)
  • 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 mixture was cooled to room temperature, diluted with water (50 mL), and the ethanol was removed under reduced pressure. The remaining aqueous solution was extracted with dichloromethane (2×50 mL). The aqueous layer was acidified with concd hydrochloric acid (10 mL) to pH 1 and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated NaCl solution (50 mL), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to give a viscous oil (9.3 g). This oil was crystallized from pentane/dichloromethane (75 mL/5 mL) at −5° C. to afford 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 (C20H30O4): Calcd for C, 71.82; H, 9.04; found: C, 71.71; H, 9.22. 1H NMR (DMSO-d6): δ=12.2-11.7 (m br, 2H), 7.17 (m, 1H), 6.98 (m, 3H), 2.52 (m, 4H), 1.49 (m, 8H), 1.07 (s, 12H). 13C NMR (DMSO-d6): δ=178.86, 141.96, 128.26, 125.69, 41.21, 39.91, 35.68, 26.62, 25.06. HRMS calcd for C30H31O3(MH+): 335.2222, found: 335.2232.
    • Example 13: Synthesis of 6-[3-(5-Carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid (Compound I-32)
  • Figure US20230007838A1-20230112-C00974
    • [1,3-Bis(5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-phenylene (E2)
  • 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 was formed. The reaction mixture was cooled to 0° C. and 2-(5-bromo-2,2-dimethylpentyloxy)-tetrahydropyran (prepared according to Dasseux et al., U.S. Pat. Nos. 6,646,170 and 6,410,802, 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 MgSO4. 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. 1H NMR (CDCl3): δ=7.17-7.14 (m, 1H), 7.00-6.98 (m, 3H), 4.54 (t, J=3.0 Hz, 2H), 3.78-3.86 (m, 2H), 3.50-3.45 (m, 2H), 3.47 (d, J=9.1 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). 13C NMR (CDCl3): δ=142.8, 128.5, 128.1, 125.6, 99.1, 77.5, 61.8, 39.2, 36.0, 34.2, 32.5, 30.7, 25.6, 24.6, 23.7, 19.4. HRMS calcd for C32H54O4(M+): 501.3943, found: 501.3943.
    • 6-[3-(6-Hydroxy-5,5-dimethylhexyl)-phenyl]-2,2-dimethylhexan-1-ol (E3)
  • 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 vacuum and the residue was dissolved in methylene chloride (200 mL). The solution was washed with water (100 mL), saturated NaHCO3 solution (100 mL) and brine (100 mL), and dried over MgSO4. 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. 1H NMR (CDCl3): δ=7.21-7.19 (m, 1H), 7.02-6.99 (3H), 3.32 (s, 4H), 2.62 (t, J=7.8 Hz, 4H), 1.64-1.26 (m, 12H), 0.89 (s, 12H). 13C NMR (CDCl3): δ=142.6, 128.5, 128.1, 125.6, 71.9, 38.4, 35.8, 35.0, 32.4, 23.7, 23.5. HRMS calcd for C22H38O4(M+): 335.2950, found: 335.2950.
    • 6-[3-(5-Carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid
  • 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 the addition of water (200 mL) and concd H2SO4 (20 mL) under 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 NaHCO3 solution (100 mL) and brine (2×100 mL) and dried over MgSO4. The solvent was evaporated and the residue was purified by column chromatography (silica gel, EtOAc:hexanes, 1:1). The obtained oil was stirred in Et2O:hexanes (1:10, 50 mL) for 3 h and the precipitated solid product was filtered (7.2 g, 78%, 96.1% by HPLC) (Compound I-32). Mp 99-101° C. Elemental analysis (C22H34O4): Calcd for C, 72.89; H, 9.45; found: C, 73.02; H, 9.57. 1H NMR (CDCl3): δ=7.19-7.16 (m, 1H), 6.99-6.94 (m, 3H), 2.58 (t, J=7.1 Hz, 4H), 1.63-1.56 (m, 8H), 1.32-1.22 (m, 4H), 1.18 (s, 12H). 13C NMR (CDCl3): δ=185.5, 142.2, 128.6, 128.3, 126.0, 42.0, 40.8, 35.7, 31.0, 25.1, 24.4. HRMS calcd for C22H35O4(MH+): 363.2535, found: 363.2530.
    • Example 14: Synthesis of 5,5′-(1,2-Phenylene)bis(2,2-dimethylpentanoic acid) (Compound I-61)
  • Figure US20230007838A1-20230112-C00975
    • 3-[2-(3-Hydroxypropyl)-phenyl]-propanol (F2)
  • Under Ar-atmosphere, to a stirred suspension of lithium aluminum hydride (3.0 g, 78.2 mmol) in anhydrous THE (100 mL) was added dropwise a solution of 3-[2-(2-ethoxycarbonylethyl)-phenyl]-propionic acid ethyl ester (prepared according to Fakhri, S. A.; Behrooz, Y. H. Tetrahedron 2000, 56, 8301-8308; 14.5 g, 52.1 mmol) in THE (100 mL) over 50 min at room temperature. The mixture was stirred for 2 h, then cooled with 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 saturated sodium chloride solution (100 mL), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to give 3-[2-(3-hydroxypropyl)-phenyl]-propanol (8.6 g, 85%, 87.9% pure by GC) as a turbid oil, which was used without further purification for the next step. 1H NMR (CDCl3): δ=7.20-7.05 (m, 4H), 3.67 (t, 4H, J=6.1 Hz), 3.50-3.20 (m br., 2H), 2.72 (m, 4H), 1.82 (m, 4H). 13C NMR (CDCl3): δ=139.98, 129.43, 126.24, 62.35, 34.36, 29.01. HRMS calcd for C12H19O2 (MH+): 195.1385, found: 195.1388. This known compound was prepared by a method different than the one described in Uenaka, M.; Kubota, B. Bull. Chem. Soc. Jpn. 1936, 11, 19-26.
    • 1,2-Bis-(3-bromopropyl)-benzene (F3)
  • A mixture of 3-[2-(3-hydroxypropyl)-phenyl]-propanol (8.6 g, 44.27 mmol), sodium bromide (18.6 g, 180.62 mmol) and water (16 mL) was heated at reflux while concentrated sulfuric acid (13.3 mL) was added dropwise over 20 min. The solution was heated for 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 successively washed 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 in high vacuo to give the crude product (11.2 g) as a brown oil. The crude material was purified by flash chromatography (silica, hexanes, then hexanes/ethyl acetate=90/10), affording 1,2-bis-(3-bromopropyl)-benzene (8.25 g, 58%, 95.9% pure by GC) as a viscous, yellow oil. 1H NMR (CDCl3): δ=7.16 (s, 4H), 3.33 (t, 4H, J=6.3 Hz), 2.79 (m, 4H), 2.12 (m, 4H). 13C NMR (CDCl3): δ=138.69, 129.69, 126.66, 34.14, 33.62, 30.99. HRMS calcd for C12H16Br2 (M+): 317.9619, found: 317.9624. This known compound was prepared by a method different than the one described in Uenaka, M.; Kubota, B. Bull. Chem. Soc. Jpn. 1936, 11, 19-26.
    • 5-[2-(4-Ethoxycarbonyl-4-methylpentyl)-phenyl]-2,2-dimethylpentanoic acid ethyl ester (F4)
  • Under Ar-atmosphere, to a solution of ethyl isobutyrate (8.7 g, 10.0 mL, 74.98 mmol) in anhydrous THE (100 mL) was added dropwise over 15 min a solution of lithium diisopropylamide (2.0 M in heptane/THF/ethyl benzene, 41.2 mL, 82.48 mmol) 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 dropwise addition of DMPU (15 mL). The mixture was stirred at −78° C. for an additional hour, then allowed to slowly warm to room temperature over the next 2 h and stirred overnight. The reaction mixture was cooled with an ice-bath and hydrolyzed by addition of saturated NH4Cl solution (100 mL) and deionized water (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×100 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 yield the crude product (14.0 g) as a reddish oil. Purification by flash chromatography (silica, hexane/ethyl acetate=95/5) afforded 5-[2-(4-ethoxycarbonyl-4-methylpentyl)-phenyl]-2,2-dimethylpentanoic acid ethyl ester (8.2 g, 84%, 79% pure by GC) as a slightly yellowish oil. 1H NMR (CDCl3): δ=7.11 (s, 4H), 4.10 (q, 4H, J=7.0 Hz), 2.56 (t, 4H, J=7.6 Hz), 1.68-1.42 (m, 8H), 1.23 (t, 6H, J=7.0 Hz), 1.16 (s, 16H). 13C NMR (CDCl3): δ=177.95, 140.01, 129.12, 126.04, 60.34, 42.26, 40.79, 33.11, 26.75, 25.29, 14.41. HRMS calcd for C24H39O4(MH+): 391.2848, found: 391.2846.
    • 5,5′-(1,2-phenylene)bis(2,2-dimethylpentanoic acid) (or 5-[2-(4-carboxy-4-methylpentyl)-phenyl]-2,2-dimethylpentanoic acid)
  • A solution of 5-[2-(4-ethoxycarbonyl-4-methylpentyl)-phenyl]-2,2-dimethylpentanoic acid ethyl ester (8.3 g, 21.25 mmol) and potassium hydroxide (>85%, 4.91 g, 74.38 mmol) in ethanol (20 mL) and water (10 mL) was heated at reflux for 4 h. After cooling to room temperature, the mixture was diluted with water (50 mL) and concentrated in vacuo to ca. 60 mL volume. This aqueous solution was extracted with dichloromethane (2×30 mL) and then acidified with 1 N hydrochloric acid (8 mL) to pH 1. The aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic extracts were washed with saturated NaCl solution (30 mL), dried over MgSO4, and concentrated in vacuo to furnish the crude product (5.50 g) as a white solid/viscous oil. The crude material was crystallized from heptane/dichloromethane at −5° C. to afford tiny white crystals that were washed with cold heptane (10 mL) and dried in high vacuo (5.05 g, 71%, 98.3% pure by HPLC) (Compound I-61). Mp 108-109° C. Elemental analysis (C20H30O4): Calcd for C, 71.82; H, 9.04; found: C, 71.14; H, 9.06. 1H NMR (DMSO-d6): δ=12.7-11.5 (m br, 2H), 7.11 (s, 4H), 2.55 (t, 4H, J=7.3 Hz), 1.62-1.38 (m, 8H), 1.09 (s, 12H). 13C NMR (DMSO-d6): δ=178.83, 139.69, 128.98, 125.89, 41.25, 40.20, 32.49, 26.57, 25.04. HRMS calcd for C20H31O4(MH+): 335.2222, found: 335.2232.
  • Biological Assays
    • Example 15: Anti-Proliferative Effects of Compounds I-32, I-61, I-1, and III-1 in Hep3B and Hepa1-6 Liver Cancer Cells
  • Human liver cancer cells Hep3B and murine liver cancer cells Hepa1-6, respectively, were seeded at a cell density of 3000 cells/well in 96-well plates using either 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% Antibiotic-Antimycotic solution (Thermo-Fisher Scientific). The next day, the 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 concentration of DMSO 0.1%) and were allowed to grow for 72 hours 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 hours. After incubation, fluorescence signal was measured with an excitation/emission wavelength of 560/590 nm using a SpectraMax M5 Microplate Reader (Molecular Devices).
  • The effects of Compounds I-32, I-61, I-1, and III-1 on cell proliferation in Hepa1-6 cells as a percent of vehicle control (DMSO, 0.1% final concentration) are shown in FIGS. 2A-2D, respectively (n=4 replicates, single experiment, error bar represents the standard deviation). The effects of the Compounds I-32, I-61, I-1, and III-1 on Hep3B cell proliferation as a percent of vehicle control (DMSO, 0.1% final concentration) are shown in FIGS. 3A-3D, respectively (n=5, single experiment, error bar represents the standard deviation).
    • Example 16: Anti-Clonogenic Effects of Compounds I-32, I-61, I-1, and III-1 in Hep3B and Hep1-6 Liver Cancer Cells
  • Liver cancer cell lines Hep3B (human) and Hepa1-6 (murine) were maintained in either 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% Antibiotic-Antimycotic (Thermo-Fisher Scientific). Each cell line was seeded at 1000 cells/well in 12-well plates. The next day, the media were replaced, and cells were treated with 0 (vehicle control, 0.1% DMSO), 1, 5, 10, 30, 50, or 100 μM Compound I-32, I-61, I-1, or III-1 (final concentration of DMSO 0.1%) for 7 days. On day 9, the media were removed, and cells were fixed with 10% formalin (500 μl) for 10 minutes at room temperature, washed with 1×PBS and stained with crystal violet. After 10 minutes the excess stain was removed by rinsing three times with tap water. The plates were allowed to dry overnight, then the number of colonies (>50 cells) in each well were counted using light microscopy as described previously by Villiani L. A., et al.
  • The effects of Compounds I-32, I-61, I-1, and III-1 on clonogenicity in Hepa1-6 cells as a percent of vehicle control (DMSO, 0.1% final concentration) are shown in FIGS. 4A-4D, respectively (n=2, error bars represent the standard deviation). The effects of Compounds I-32, I-61, I-1, and III-1 on clonogenicity in Hep3B cells as a percent of vehicle control (DMSO, 0.1% final concentration) are shown in FIGS. 5A-5D, respectively (n=2, error bars represent the standard deviation).
  • Table 1 summarizes the biology results from Examples 15-17. ND=not determined.
  • TABLE 1
    Effects on de Novo Lipogenesis (DNL), Clonogenicity and Cancer
    Cell Proliferation of Illustrative Compounds of the Invention in Human (h) and Murine (m)
    cells (IC50 or % Proliferation Reduction, respectively).
    Assay Cell Line
    IC50 (μM)
    Compound Compound Compound Compound
    I-1 I-32 I-61 III-1
    DNL primary 12.1 8.3 ND ND
    hepatocytes (m)
    Clonogenicity Hepa1-6 (m) 55.6 52.3 73.4 61.0
    Clonogenicity Hep3B (h) 53.9 41.7 57.3 55.6
    % reduction vs control at 100 μM
    Mean (Standard Deviation)
    Compound Compound Compound Compound
    I-1 I-32 I-61 III-1
    Cancer Cell Hepa1-6 (m) 25.9 (5.7) 18.6 (3.1) 21.8 (8.9) 15.7 (6.7)
    Proliferation
    Cancer Cell Hep3B (h) 41.8 (8.4) 30.8 (2.6) 35.7(5.8) 29.7 (6.2)
    Proliferation
    • Example 17: Synergistic Effect of Illustrative Compounds of the Invention with Sorafenib or Lenvatinib
  • Combination studies were undertaken with the compounds of the invention to determine potential synergy of sorafenib or lenvatinib in the presence of compound I-32 or compound I-61. In a separate experiment, the IC50 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).
  • Hep3B (supplied by ATCC) or Hepa1-6 (supplied by ATCC) cells were seeded in 96-well plates at a density of 500 cells/well with complete media. On day 2, media in each well was aspirated and replaced with 100 μl of fresh complete media and cells were treated with sorafenib or lenvatinib in the presence of or without the 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)). Then, cells were incubated in an incubator for 72 h. On day 5, 10 μl of presto blue (Invitrogen, cat # A13261) cell viability reagent was added in each 96-well plate and incubated at 37° C. for 1-2 h. After incubation, fluorescence was measured with an excitation/emission wavelength of 560/590 nm. Results were indicated as mean±standard deviation (SD). All bar diagrams and line graphs were prepared using Graph Pad Prism 8 software. Proliferation IC50 values were calculated using a non-linear regression model in Graph pad Prism 8. For each cell type, combination treatment showed a decrease in cell proliferation when compared to sorafenib or lenvatinib alone. Results in Hep3B cells are presented in FIGS. 6A-6B and results in Hepa1-6 cells are presented in FIGS. 7A-7B.
  • Sorafenib and lenvatinib have the following structure:
  • Figure US20230007838A1-20230112-C00976
  • Since additional inhibition of cell proliferation was observed in the combination studies, the results were analyzed using CompuSyn software (provided by ComboSyn Inc.) to examine if there was a synergistic or additive effect on the antiproliferative activity. FIGS. 8A-8D demonstrate that both Compounds I-32 and I-61 showed synergistic inhibition in the presence of sorafenib or lenvatinib.

Claims (12)

1.-120. (canceled)
121. A method for treating or preventing renal cell carcinoma, comprising administering to a subject in need thereof an effective amount of a compound having the structure:
Figure US20230007838A1-20230112-C00977
or a pharmaceutically acceptable salt or solvate thereof.
122. The method of claim 121, further comprising administering an effective amount of another pharmaceutically active agent.
123. The method of claim 121, further comprising administering to the subject sorafenib, lenvatinib, bevacizumab, avelumab, axitinib, cabozantinib, ipilimumab, pembrolizumab, nivolumab, sunitinib, temsirolimus, durvalumab, bempegaldesleukin, tremelimumab, vorolanib, toripalimab, atezolizumab, camrelizumab, cemiplimab, guadecitabine, sitravatinib, or pexastimogene devacirepvec.
124. The method of claim 121, further comprising administering to the subject sorafenib or lenvatinib.
125. A method for treating or preventing colorectal cancer, comprising administering to a subject in need thereof an effective amount of a compound having the structure:
Figure US20230007838A1-20230112-C00978
or a pharmaceutically acceptable salt or solvate thereof.
126. The method of claim 125, further comprising administering an effective amount of another pharmaceutically active agent.
127. The method of claim 125, further comprising administering to the subject sorafenib, lenvatinib, bevacizumab, ramucirumab, pembrolizumab, nivolumab, avelumab, durvalumab, eicosapentaenoic acid, anlotinib, camrelizumab, atezolizumab, cabozantinib, trametinib, or tremelimumab.
128. The method of claim 125, further comprising administering to the subject sorafenib or lenvatinib.
129. A composition comprising:
(i) an effective amount of a compound having the structure:
Figure US20230007838A1-20230112-C00979
or a pharmaceutically acceptable salt or solvate thereof;
(ii) bevacizumab, avelumab, axitinib, cabozantinib, ipilimumab, pembrolizumab, nivolumab, sunitinib, temsirolimus, durvalumab, bempegaldesleukin, tremelimumab, vorolanib, toripalimab, atezolizumab, camrelizumab, cemiplimab, guadecitabine, sitravatinib, pexastimogene devacirepvec, ramucirumab, eicosapentaenoic acid, anlotinib, or trametinib; and
(iii) a pharmaceutically acceptable carrier or vehicle.
130. The composition of claim 129 comprising an effective amount of a compound having the structure:
Figure US20230007838A1-20230112-C00980
or a pharmaceutically acceptable salt or solvate thereof.
131. The composition of claim 129 comprising an effective amount of a compound having the structure:
Figure US20230007838A1-20230112-C00981
or a pharmaceutically acceptable salt or solvate thereof.
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