WO2022189856A1 - Composés utiles pour le traitement des maladies du foie - Google Patents

Composés utiles pour le traitement des maladies du foie Download PDF

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WO2022189856A1
WO2022189856A1 PCT/IB2022/000106 IB2022000106W WO2022189856A1 WO 2022189856 A1 WO2022189856 A1 WO 2022189856A1 IB 2022000106 W IB2022000106 W IB 2022000106W WO 2022189856 A1 WO2022189856 A1 WO 2022189856A1
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alkyl
independently
group
haloalkyl
aryl
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PCT/IB2022/000106
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WO2022189856A9 (fr
Inventor
Jean-Louis Henri Dasseux
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Abionyx Pharma Sa
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Priority claimed from US17/195,334 external-priority patent/US20210300890A1/en
Priority claimed from US17/219,058 external-priority patent/US11634387B2/en
Application filed by Abionyx Pharma Sa filed Critical Abionyx Pharma Sa
Priority to IL305761A priority Critical patent/IL305761A/en
Priority to CN202280033302.1A priority patent/CN117500791A/zh
Priority to JP2023554886A priority patent/JP2024512376A/ja
Priority to EP22714000.1A priority patent/EP4305024A1/fr
Priority to AU2022233873A priority patent/AU2022233873A1/en
Priority to CA3212825A priority patent/CA3212825A1/fr
Priority to KR1020237034281A priority patent/KR20240019753A/ko
Publication of WO2022189856A1 publication Critical patent/WO2022189856A1/fr
Publication of WO2022189856A9 publication Critical patent/WO2022189856A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms
    • C07D333/10—Thiophene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention provides novel compounds, for example compounds of Formulae (A)-(H) and (J)-(AA), and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof, such as 2-(4-(3-hydroxy-3-(4-(methylthio)phenyl)prop-1-en-1-yl)-2,6-dimethylphenoxy)- 2-methylpropanoic acid (“Compound I”), 3-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3,5- dimethylphenyl)-1-(4-(methylthio)phenyl)prop-2-en-1-one (“Compound II”), and 3-(4-((1- hydroxy-2-methylpropan-2-yl)oxy)-3,5-dimethylphenyl)-1-(4-(methylthio)phenyl)prop-2-en-1-ol (“Compound III”), and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof, such as
  • the invention further provides pharmaceutical compositions comprising a novel compound described herein, for example a compound of Formulae (A)-(H) and (J)-(AA) or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, such as Compound I, Compound II or Compound III, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, and a pharmaceutically acceptable carrier or vehicle.
  • the compounds and compositions disclosed herein are useful for treating or preventing conditions, for example, liver disease such as liver fibrosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).
  • LDL-C low-density lipoprotein cholesterol
  • triglycerides are associated with mixed dyslipidemia.
  • Type lib hyperlipidemia a type of mixed dyslipidemia, 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.
  • Liver diseases such as a non-alcoholic fatty liver disease (NAFLD) comprise a spectrum of conditions ranging from relatively benign steatosis to more severe non-alcoholic steatohepatitis (NASH), the latter of which, if untreated, can lead to fibrosis, cirrhosis, liver failure, or hepatocellular carcinoma.
  • NAFLD and NASH can develop due to hepatic triglyceride overproduction and accumulation.
  • NAFLD is strongly associated with features of obesity, diabetes, dyslipidemia, hyperlipidemia and metabolic syndrome, including obesity, insulin resistance, type-2 diabetes mellitus, and dyslipidemia.
  • NASH can cause the liver to swell, become inflamed, become fibrotic, become damaged and become ultimately less functional.
  • NASH tends to develop in people who are overweight or obese, or have diabetes, mixed dyslipidemia, high cholesterol or high triglycerides or an inflammatory condition. NASH is marked by hepatocyte ballooning and liver inflammation, which can lead to liver damage and progress to scarring and irreversible changes, similar to the damage caused by heavy alcohol use.
  • Liver steatosis and fibrosis can also be induced by drugs, such as amiodarone, valproate, tamoxifen, methotrexate, and some chemotherapeutic and antiretroviral agents (Amacher, D.E., et a!. Semin. Liver Dis., 2014, 34, 205).
  • Drug-induced hepatic steatosis can be reversible and may involve drug accumulation in the liver.
  • NAFLD NAFLD
  • NASH fatty liver
  • drug-induced liver steatosis can lead to metabolic complications including elevation of liver enzymes, fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. Liver failure is life-threatening and therefore there is a need to develop therapies to delay development, prevent formation or reverse the condition of a fatty liver.
  • PPARs Peroxisome proliferator-activated receptors
  • cardiometabolic diseases including diabetes, insulin resistance, dyslipidemia, and liver diseases such as NAFLD and NASH.
  • PPARa Peroxisome proliferator-activated receptors
  • PPAR ⁇ and PPAR ⁇ Several PPAR agonists have been marketed, including fenofibrate (a PPARa agonist), bezafibrate (a PPAR pan agonist), pioglitazone (a PPARy agonist), and rosiglitazone (a PPARy agonist). Recently, PPAR agonists such as seladelpar (a PPAR5 agonist), lanifibranor (a pan agonist), and elafibranor (a dual PPARa/d agonist) have been studied for the treatment of NASH and primary biliary cholangitis (PBC).
  • PBC primary biliary cholangitis
  • PPAR ⁇ agonists have also been proposed as a treatment for acute kidney injury (AKI). See, e.g., WO 2018/067857.
  • AKI is a common occurrence in ICU patients, with an estimated incidence of >50% (Hoste et al., 2015, Intensive Care Med; 41 :1411-1423). Furthermore, increasing AKI severity is associated with increased mortality. Sepsis is the major cause of AKI, accounting for 45% to 70% of cases, and approximately 25% of sepsis is of intra-abdominal origin (Seymour et al., 2016, JAMA, 315:762-774; Bagshaw et al., 2007, Clin J Am Soc Nephrol, 2:431- 439).
  • Ischemia/reperfusion injury can cause AKI and is a common complication in subjects receiving an organ transplant, with an incidence of 50-75% after lung and heart transplantation (Gueler et al., 2014, Transplantation 98:337-338).
  • the PPAR ⁇ agonist ASP1128 also known as MA-0217
  • Astellas is being studied as a possible treatment for AKI following coronary artery bypass graft surgery and/or valve surgery.
  • no PPAR ⁇ agonist has been approved and marketed as a treatment for AKI.
  • the present invention provides novel compounds and their use to treat various disorders, for example, liver disorders such as NASH, kidney disorders such as AKI, and other conditions associated with PPARs.
  • liver disorders such as NASH
  • kidney disorders such as AKI
  • PPARs other conditions associated with PPARs.
  • the inventor believes that the clinical usefulness of PPAR agonists such as elafibranor are limited by their toxicity such that doses often cannot be increased sufficiently to reach an effective dose.
  • the subject invention provides novel compounds, including derivatives of elafibranor and related compounds, and derivatives of PPAR modulators described in WO 2011/020001 , WO 2017/06246, WO 2017/180818, and WO 2018/067857.
  • the therapeutic index (Tl) is a ratio that compares the dose at which a compound becomes toxic against the dose at which it is effective.
  • Tl is a ratio that compares the dose at which a compound becomes toxic against the dose at which it is effective.
  • One common measure of Tl is TD50/ED50, wherein TD 50 and ED 50 are the toxic and effective doses, respectively, for 50% of the population. The larger the Tl, the safer a compound is.
  • the one or more advantageous properties of the compounds of the disclosure can include, for example, better solubility, better kinetics, better absorption, better PPAR receptor selectivity at pharmaceutically effective doses, reduced drug metabolism by cytochrome P450 or other enzymes such as reductases, reduced glucuronidation, reduced toxicity, or a combination thereof.
  • the invention provides compounds of Formula (A)-(H) and (J)-(AA) and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof.
  • the present invention provides compounds of Formula (A):
  • each R 1 and R 2 is independently -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, phenyl, or benzyl; or alternatively, R 1 and R 2 together with the carbon atom to which R 1 and R 2 are attached form a C 3 -C 7 cycloalkyl group;
  • X is -CH 2 OH, -COOH, -COH, -COOR 3 , -COOCH 2 CONR 4 R 5 , -SO 3 H,
  • R 3 is -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, phenyl, or benzyl; each R 4 and R 5 is independently alkyl, aryl, or heteroaryl; or alternatively, R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached form a heterocycle; each R 6 and R 7 is independently H, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, or -C 2 -C 6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • the present invention also provides compounds of Formula (B): (B), and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof, wherein: each R 1 and R 2 is independently -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, phenyl, or benzyl; or alternatively, R 1 and R 2 together with the carbon atom to which R 1 and R 2 are attached form a C 3 -C 7 cycloalkyl group;
  • X is -CH 2 OH, -COH, -COOCH 2 CONR 4 R 5 , -SO 3 H,
  • R 3 is -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, phenyl, or benzyl; each R 4 and R 5 is independently alkyl, aryl, or heteroaryl; or alternatively, R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached form a heterocycle; each R 6 and R 7 is independently H, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, or -C 2 -C 6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • the present invention provides 2-(4-(3-hydroxy-3-(4-(methylthio)phenyl)prop-1-en-1-yl)- 2,6-dimethylphenoxy)-2-methylpropanoic acid (“Compound I”) and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs, thereof, wherein Compound I has the structure:
  • the present invention also provides 3-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3,5- dimethylphenyl)-1-(4-(methylthio)phenyl)prop-2-en-1-one (“Compound II”) and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof, wherein Compound II has the structure:
  • the present invention further provides 3-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)-3,5- dimethylphenyl)-1-(4-(methylthio)phenyl)prop-2-en-1-ol (“Compound III”) and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof, wherein Compound III has the
  • the present invention provides compounds of Formula (C) and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof wherein:
  • R 1 is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl, any of which is unsubstituted or substituted with C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, halogen, C 2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyi or pyridyl;
  • R 2 is C 2-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, 3-7 membered cycloalkyl, C 1-8 alkyl substituted with a 3-7 membered cycloalkyl, or C 1-6 alkyl substituted with phenyl, naphthyl or pyridyl, any of which is unsubstit
  • A is oxygen, sulfur or NR 9 in which R 9 is hydrogen or C 1-8 alkyl
  • X is a C 1-8 alkylene chain which is unsubstituted or substituted with C 1-8 alkyl, C 1-8 alkoxy or hydroxyl, and which has 0 or 1 double bonds;
  • B is CH or nitrogen
  • Z is oxygen or sulfur; each of R 6 and R 7 is independently hydrogen, C 1-8 alkyl, or C 1-8 haloalkyl; R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • the invention provides compounds of Formula (D)-(H) and (J)-(AA) and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof.
  • the present invention further provides a compound having the structure
  • the present invention further provides a compound having the structure acceptable salts, solvates, esters, amides, and prodrugs thereof.
  • the present invention further provides a compound having the structure pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof. [0022] The present invention further provides a compound having the structure pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof.
  • the invention provides compounds of Formula (D)-(H) and (J)-(AA), e.g., as described in Section 5.2 (including subparts) and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof.
  • the present invention further provides a compound having the structure salts, solvates, esters, amides, and prodrugs thereof.
  • the present invention further provides a compound having the structure (“Compoundn VII”) and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof.
  • the present invention further provides a compound having the structure
  • Compound VIII and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof.
  • 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”).
  • 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 liver disorder, dyslipidemia, dyslipoproteinemia, a renal disease, a disorder of glucose metabolism, a disorder of lipid metabolism, a disorder of glucid metabolism, a cardiovascular disease, a vascular disease, a metabolic syndrome, a complication associated with metabolic syndrome, a PPAR-associated disorder, septicemia, a thrombotic disorder, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, a cerebrovascular disease, a disorder related to neovascularization, hypertension, cancer, inflammation, an inflammatory disease, a neurodegenerative disease, an autoimmune disease, a neoplastic disease, muscle atrophy, cholestasis, mitochondrial dysfunction, an ocular disease, a lysosomal storage disease, a kidney disease (e.g., acute kidney injury), or impotence, comprising administering to a subject in need thereof an effective amount of a kidney disease (
  • the present invention further provides methods for treating or preventing hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, or dyslipidemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the present invention further provides methods for treating a subject having or preventing a subject from having an abnormally high concentration in a subject’s blood plasma or blood serum of high low-density lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein(a) (Lp(a)), apolipoprotein (a), or very low-density lipoprotein (VLDL), comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • LDL low-density lipoprotein
  • apo B apolipoprotein B
  • Lp(a) lipoprotein(a)
  • apolipoprotein (a) apolipoprotein
  • VLDL very low-density lipoprotein
  • the present invention further provides methods for treating a subject having or preventing a subject from having an abnormally low concentration in a subject’s blood plasma or blood serum of high-density lipoprotein (HDL), comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • a subject having or preventing a subject from having an abnormally low concentration in a subject s blood plasma or blood serum of high-density lipoprotein (HDL)
  • HDL high-density lipoprotein
  • the present invention further provides methods for treating a subject having or preventing a subject from having an abnormally reduced or deficient lipoprotein lipase concentration or activity 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 a composition of the invention.
  • the present invention provides methods for treating or preventing hypoalphalipoproteinemia, a lipoprotein abnormality associated with diabetes, a lipoprotein abnormality associated with obesity, a lipoprotein abnormality associated with Alzheimer's Disease, or familial combined hyperlipidemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the present invention further provides methods for reducing in a subject’s blood plasma or blood serum an abnormally high concentration of triglycerides, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein cholesterol, (non-HDL-C), lipoprotein(a) (Lp(a)), apolipoprotein B, HDL/(VLDL+LDL) ratio, apolipoprotein C-ll or apolipoprotein C-lll, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • LDL-C low-density lipoprotein cholesterol
  • VLDL-C very low-density lipoprotein cholesterol
  • non-HDL-C non-high-density lipoprotein cholesterol
  • Lp(a) lipoprotein(a)
  • apolipoprotein B HDL/(VLDL+LDL
  • the present invention further provides methods for elevating in a subject’s blood plasma or blood serum an abnormally low concentration of a high-density lipoprotein (HDL) associated protein, HDL-cholesterol, apolipoprotein A-l, or apolipoprotein E, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • HDL high-density lipoprotein
  • the present invention further provides methods for promoting clearance of triglycerides from 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 a composition of the invention.
  • the present invention further provides methods for increasing abnormally low glucose metabolism or increasing abnormally low lipid metabolism in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the present invention further provides methods for treating or preventing one or more symptoms of inflammation, systemic lupus erythematosus, lupus nephritis, or arthritis, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the present invention further provides methods for reducing the fat content of meat in livestock, comprising administering to livestock an effective amount of a compound of the invention or a composition of the invention.
  • the present invention further provides methods for reducing cholesterol content of a fowl egg, comprising administering to a fowl species an effective amount of a compound of the invention or a composition of the invention.
  • exemplary uses of the compounds and compositions of the disclosure are described in specific embodiments 55 to 163 in Section 7.1 and specific embodiments 214 to 322 in Section 7.2, infra.
  • a numerical value when immediately preceding 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.).
  • salts include 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.
  • 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, choline, betaine, etc.
  • inorganic base can include, but are not limited to, calcium hydroxide, postassium hydroxide, sodium hydroxide, and sodium carbonate.
  • Organic base can include, but are not limited to, primary amines, secondary amines, tertiary amines, substituted amines including naturally- occurring substituted amines, and cyclic amines, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, glucoasamine, N- alkylgucamines, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and the like.
  • primary amines such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine,
  • 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.
  • the language “substantially free of its corresponding opposite enantiomer” means having no more than about 10 mol %, in another embodiment no more than about 5 mol %, in another embodiment no more than about 2 mol %, in another embodiment no more than about 1 mol %, in another embodiment no more than about 0.5 mol % and in another embodiment no more than about 0.1 mol %, of its corresponding opposite enantiomer.
  • the language “substantially free of its corresponding opposite stereoisomer” means having no more than about 10 mol %, in another embodiment no more than about 5 mol %, in another embodiment no more than about 2 mol %, in another embodiment no more than about 1 mol %, in another embodiment no more than about 0.5 mol % and in another embodiment no more than about 0.1 mol %, of its corresponding opposite stereoisomer.
  • the language "substantially free of its corresponding other olefin configuration” means having no more than about 10 mol %, in another embodiment no more than about 5 mol %, in another embodiment no more than about 2 mol %, in another embodiment no more than about 1 mol %, in another embodiment no more than about 0.5 mol % and in another embodiment no more than about 0.1 mol %, of its corresponding other olefin configuration.
  • 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 a disorder or condition disclosed herein, 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 a disorder or condition disclosed herein, 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
  • 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 (alternatively represented as C 1-12 alkyl), an alkyl group with 1 to 10 carbon atoms is a C 1 -C 10 alkyl (alternatively represented as C 1 -10 alkyl), an alkyl group with 1 to 6 carbon atoms is a C 1 -C 6 alkyl (alternatively represented as C 1-6 alkyl), an alkyl group with 1 to 5 carbon atoms is a C 1 -C 5 alkyl (alternatively represented as C 1 -5 alkyl), and so on.
  • 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. In some embodiments, an alkyl group is unsubstituted.
  • Alkoxy refers to RO in which R is alkyl.
  • 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 (alternatively represented as C 2-12 alkenyl), an alkenyl group with 2 to 10 carbon atoms is a C 2 - C 10 alkenyl (alternatively represented as C 2-10 alkenyl), an alkenyl group with 2 to 6 carbon atoms is a C 2 -C 6 alkenyl (alternatively represented as C 2-6 alkenyl) and an alkenyl group with 2 to 5 carbon atoms is a C 2 -C 5 alkenyl (alternatively represented as C 2-5 alkenyl) and so on.
  • 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-non
  • 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 (alternatively represented as C 2-12 alkynyl), an alkynyl group with 2 to 10 carbon atoms is a C 2 -C 10 alkynyl (alternatively represented as C 2-10 alkynyl), an alkynyl group with 2 to 6 carbon atoms is a C 2 -C 6 alkynyl (alternatively represented as C 2-6 alkynyl) and an alkynyl group with 2 to 5 carbon atoms is a C 2 -C 5 alkynyl (alternatively represented as C 2 -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.
  • an alkyl group can be unsubstituted or substituted with a substituent disclosed herein. In some embodiments, an alkynyl group is unsubstituted.
  • 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. In some embodiments, an aryl group is unsubstituted.
  • 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. In some embodiments, a cycloalkyl group is unsubstituted.
  • Halo or “halogen” represents chloro, fluoro, bromo or iodo.
  • Haloalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen.
  • haloalkyl groups include trifluoromethyl (CF 3 ), difluoromethyl (CF 2 H), monofluoromethyl (CH 2 F), pentafluoroethyl (CF 2 CF 3 ), tetrafluoroethyl (CHFCF 3 ), monofluoroethyl (CH 2 CH 2 F), trifluoroethyl (CH 2 CF 3 ), tetrafluorotrifluoromethylethyl (CF(CF 3 ) 2 ).
  • Haloalkoxy refers to RO in which R is a haloalkyl group.
  • 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 quatemized.
  • 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
  • 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
  • the symbo (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” is bonded to another chemical entity via the point of attachment bond.
  • the compound of the invention is a compound of Formula (A): (A), or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein: each R 1 and R 2 is independently -C 1 -C 6 alkyl, - C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, phenyl, or benzyl: or alternatively, R 1 and R 2 together with the carbon atom to which R 1 and R 2 are attached form a C 3 -C 7 cycloalkyl group;
  • X is -CH 2 OH, -COOH, -COH, -COOR 3 , -COOCH 2 CONR 4 R 5 , -SO 3 H,
  • R 3 is -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, phenyl, or benzyl; each R 4 and R 5 is independently alkyl, aryl, or heteroaryl; or alternatively, R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached form a heterocycle; each R 6 and R 7 is independently H, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, or -C 2 -C 6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • the compound of Formula (A) is a racemate or a mixture of enantiomers or diastereomers.
  • the compound of Formula (A) has an olefin isomer configuration of (Z) or (E).
  • the hydroxyl-bearing allylic carbon atom of the compound of Formula (A) has an ( R )- or an (S)-stereochemistry.
  • the compound of Formula (A) is a (Z)-isomer (or cis) and has the compound of Formula ⁇ (Z)- A) is substantially free of its corresponding other olefin configuration (i.e., (E)-isomer).
  • the compound of formula (A) is an (E)- isomer (or trans) and has the structure: ((E)-A).
  • the compound of Formula ((E)- A) is substantially free of its corresponding other olefin configuration (i.e., (Z)-isomer).
  • the compound of Formula (A) has an hydroxyl-bearing allylic carbon atom having (R)-stereochemistry and has the structure: ((R)-A).
  • Formula ((R)- A) is substantially free of its corresponding opposite stereoisomer, i.e., a compound of Formula (A) whose hydroxyl-bearing allylic carbon atom has an (S)- stereochemistry.
  • the hydroxyl-bearing allylic carbon atom of the compound of Formula (A) has an (S)-stereochemistry and has the structure: X ((S)- A).
  • Formula ((S)- A) is substantially free of its corresponding opposite stereoisomer, i.e., a compound of Formula (A) whose hydroxyl-bearing allylic carbon atom has an (R)- stereochemistry.
  • the compound of Formula (A) is a (Z)-isomer (or cis), has an hydroxyl-bearing allylic carbon atom having an (R)-stereochemistry and has the structure: ((Z)-(R)-A).
  • the compound of Formula ((Z)-(R)-A) is substantially free of compounds of Formulae ⁇ (Z)-(S)-A), ((E)-(R)-A), or [(E)-(S)-A).
  • the compound of Formula (A) is a (Z)-isomer (or c/s), has an hydroxyl-bearing allylic carbon atom having an (S)-stereochemistry and has the structure: ((Z)-(S)-A).
  • the compound of Formula ((Z)-(S)-A) is substantially free of compounds of Formulae ((Z)-(R)-A), ((Z)-(R)-A), or ((Z)-(S)-A).
  • the compound of Formula (A) is an (E) -isomer (or cis), has an hydroxyl-bearing allylic carbon atom having an (R)-stereochemistry and has the structure: ((E)-(R)-A).
  • Formula ((E)-(R)-A) is substantially free of compounds of Formulae ((E)-(S)-A), ((Z)-(R)-A), or ((Z)-(S)-A).
  • the compound of Formula (A) is an (E)- isomer (or cis), has an hydroxyl-bearing allylic carbon atom having an (S)-stereochemistry and has the structure: ((E)-(S)- A).
  • Formula ((E)-(S)-A) is substantially free of compounds of Formulae ((E)-(R)-A), ((Z)-(R)-A), or (fZJ-(S)-A).
  • each R 1 and R 2 is independently -C 1 -C 6 alkyl. In some embodiments, each R 1 and R 2 is independently -C 1 -C 3 alkyl. In some embodiments, each R 1 and R 2 is independently methyl.
  • X is -CH 2 OH, -COOH, -COH, or -COOR 3 , or - COOCH 2 CONR 4 R 5
  • X is -CH 2 OH, -COOH, -COOR 3 , - COOCH 2 CONR 4 R 5 .
  • X is -CH 2 OH or -COOH.
  • R 3 is -C 1 -C 6 alkyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, or f-butyl.
  • n is 0, 1 , 2, or 3. In some embodiments, n is 0, 1 , or 2. In some embodiments, n is 0 or 1.
  • the compound of the invention is Compound I having the solvate, ester, amide, or prodrug thereof.
  • Compound I is a racemate or a mixture of enantiomers. In some embodiments, Compound I has an olefin isomer configuration of (Z) or (E). In some embodiments, Compound I has an hydroxyl-bearing allylic carbon atom having an (R)- or an (S)-stereochemistry.
  • Compound I is a (Z)-isomer (or cis) and has the structure: and is substantially free of its corresponding other olefin configuration (i.e., (E)-isomer).
  • Compound I is an (E)-isomer (or trans) and has the structure: isomer and is substantially free of its corresponding other olefin configuration (i.e., (Z)-isomer).
  • Compound I has an hydroxyl-bearing allylic carbon atom having an (R)-enantiomer and has the structure: [0088] ((R)-l). In some embodiments, Compound I has an hydroxyl-bearing allylic carbon atom having an (R)-enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., (S)-enantiomer).
  • Compound I has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer and has the structure:
  • Compound I has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., (R)-enantiomer).
  • Compound I is a non-racemic mixture of its (R)-enantiomer and (S)-enantiomer.
  • the non-racemic mixture has an excess of (R)-enantiomer relative to (S)-enantiomer.
  • the non-racemic mixture has an excess of (S)-enantiomer relative to ( R)- enantiomer.
  • Compound I is a (Z)-isomer (or cis), has an hydroxyl-bearing allylic carbon atom having an (R)-enantiomer and has the structure:
  • Compound ((Z)-(R)-I) is substantially free of Compounds ((Z)-(S)-I), ((E)-(R)-I), or ((E)-(S)-I).
  • Compound I is a (Z)-isomer, has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer and has the structure:
  • Compound ((Z)-(S)-I) is substantially free of Compounds ((Z)-(R)-I), ((E)-(R)-I), or ((E)-(S)-I).
  • Compound I is an (E)-isomer (or trans), has an hydroxyl-bearing allylic carbon atom having an (R)-enantiomer and has the structure: ((E)-(R)-I).
  • Compound ((E)-(R)-I) is substantially free of Compounds (E)-(S)-I), ((Z)-(R)-I), or ((Z)-(S)-I).
  • Compound I is an (E)-isomer, has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer and has the structure: ((E)-(S)-I).
  • Compound ((E)-(S)- 1) is substantially free of Compounds ((E)-(R)-I), ((Z)-(R)-I), or ((Z)-(S)-I).
  • the compound of the invention is Compound III having the structure: (III), or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • Compound III is a racemate or a mixture of enantiomers. In some embodiments, Compound III has an olefin isomer configuration of (Z) or (E). In some embodiments, Compound III has an hydroxyl-bearing allylic carbon atom having an (R)- or an (S)-stereochemistry.
  • Compound III is a (Z)-isomer (or cis) and has the structure:
  • Compound III is a (Z)- isomer and is substantially free of its corresponding other olefin configuration (i.e., (E)-isomer).
  • Compound III is an (E)- isomer (or trans) and has the structure: isomer and is substantially free of its corresponding other olefin configuration (i.e., (Z)-isomer).
  • Compound III has an hydroxyl-bearing allylic carbon atom having an (R)-enantiomer and has the structure: ( (R)-lll).
  • Compound III has an hydroxyl-bearing allylic carbon atom having an (R)-enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., (S)-enantiomer).
  • Compound III has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer and has the structure:
  • Compound III has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., (R)- enantiomer).
  • Compound III is a non-racemic mixture of its ( R )- enantiomer and (S)-enantiomer.
  • the non-racemic mixture has an excess of (R)-enantiomer relative to (S)-enantiomer.
  • the non-racemic mixture has an excess of (S)-enantiomer relative to (R)-enantiomer.
  • Compound III is an (Z)- isomer (or cis), has an hydroxyl-bearing allylic carbon atom having an (R)-enantiomer and has the structure: ((Z)-(R)-lll).
  • Compound ((Z)-(R)- III) is substantially free of Compounds ((Z)-(S)-III), ((E)-(R)- III), or ((E)-(S)-ill).
  • Compound III is an (Z)- isomer, has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer and has the structure:
  • Compound ((Z)-(S)-III) is substantially free of Compounds ((Z)-(R)-III), ((E)-(R)- III), or ((E)- ⁇ S)- III).
  • Compound I is an (E)-isomer (or trans), has an hydroxyl-bearing allylic carbon atom having an (R)-enantiomer and has the structure: ((E)- (R)- III). In some embodiments, Compound ((E)-(R)-
  • III is substantially free of Compounds ((E)-(S)- III), ((Z)-(R)-III), or ((Z)-(S)-III).
  • Compound III is an (E)-isomer, has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer and has the structure: ((E)-(S)-III). In some embodiments, Compound ((E)-(S)-
  • III is substantially free of Compounds ((E)-(R)-III), ((Z)-(R)- III), or ((Z)-(S)-III).
  • the compounds of the invention are compounds of Formula (B): (B), or a pharmaceutically acceptable salt, solvate ester, amide, or prodrug thereof, wherein: each R 1 and R 2 is independently -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, phenyl, or benzyl; or alternatively, R 1 and R 2 together with the carbon atom to which R 1 and R 2 are attached form a C 3 -C 7 cycloalkyl group;
  • X is -CH 2 OH, -COH, -COOCH 2 CONR 4 R 5 , -SO 3 H,
  • R 3 is -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, phenyl, or benzyl; each R 4 and R 5 is independently alkyl, aryl, or heteroaryl; or alternatively, R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached form a heterocycle; each R 6 and R 7 is independently H, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, or -C 2 -C 6 alkynyl; and n is 0, 1 , 2, 3, or 4.
  • the compound of Formula (B) is a racemate or a mixture of enantiomers. In some embodiments, the compounds of Formula (B) has an olefin isomer configuration of (Z) or (E).
  • the compounds of Formula (B) is a (Z)-isomer (or cis) and has ((Z)-B). In some embodiments, the compounds of Formula (B) is a (Z)-isomer and is substantially free of its corresponding other olefin configuration (i.e., (E)-isomer).
  • the compounds of Formula (B) is an (E)-isomer (or trans) and has the structure: ((E)- B).
  • the compounds of Formula (B) is an (E)- isomer and is substantially free of its corresponding other olefin configuration (i.e., (Z)-isomer).
  • each R 1 and R 2 is independently - C 1 -C 6 alkyl. In some embodiments, each R 1 and R 2 is independently -C 1 -C 3 alkyl. In some embodiments, each R 1 and R 2 is independently methyl. [0110] In some embodiments of compounds of Formula (B), X is -CH 2 OH, -COH, or - COOCH 2 CONR 4 R 5 . In some embodiments, X is -CH 2 OH.
  • R 3 is -C 1 -C 6 alkyl. In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, or f-butyl.
  • n is 0, 1, 2, or 3. In some embodiments, n is 0, 1 , or 2. In some embodiments, n is 0 or 1.
  • the compound of the invention is Compound II having the structure (II), or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • Compound II has an olefin isomer configuration of (Z) or (E).
  • Compound II is a (Z)-isomer (or cis) and has the structure:
  • Compound II is a (Z)-isomer and is substantially free of its corresponding other olefin configuration (i.e. , (E)-isomer).
  • Compound II is an (E)-isomer (or trans) and has the structure: ((E)-ll). In some embodiments, Compound II is an (E)- isomer and is substantially free of its corresponding other olefin configuration (i.e., (Z)-isomer).
  • the compounds of the invention are compounds of Formula (C): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein: R 1 is phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl or benzothienyl, any of which is unsubstituted or substituted with C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, halogen, C 2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;
  • R 2 is C 2-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, 3-7 membered cycloalkyl, C 1-8 alkyl substituted with a 3-7 membered cycloalkyl, or C 1-6 alkyl substituted with phenyl, naphthyl or pyridyl, any of which is unsubstituted or substituted with C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, halogen, C 2-7 acyl, benzoyl, hydroxyl, nitro, amino, phenyl or pyridyl;
  • A is oxygen, sulfur or NR 9 in which R 9 is hydrogen or C 1-8 alkyl
  • X is a C 1-8 alkylene chain which is unsubstituted or substituted with C 1-8 alkyl, C 1-8 alkoxy or hydroxyl, and which has 0 or 1 double bonds;
  • B is CH or nitrogen
  • Z is oxygen or sulfur; each of R 6 and R 7 is independently hydrogen, C 1-8 alkyl, or C 1-8 haloalkyl; R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1 , 2, 3, or 4.
  • examples of the alkyl groups having 1 -8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl.
  • alkyl groups having 1-8 carbon atoms and a halogen substituent examples include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl which are substituted with 1-3 halogens such as fluorine, chlorine, and bromine.
  • halogens such as fluorine, chlorine, and bromine.
  • Examples include trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fluoroethyl.
  • alkoxy groups having 1-8 carbon atoms examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and pentyloxy.
  • alkoxy groups having 1-8 carbon atoms and a halogen substituent examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy groups substituted with 1-3 halogen atoms such as fluorine atom, chlorine atom or bromine atom. Trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy and 2-fluoroethoxy are included.
  • alkenyl groups having 2-8 carbon atoms examples include vinyl and ally).
  • alkynyl groups having 2-8 carbon atoms examples include propargyl.
  • Examples of 3-7 membered cycloalkyl groups include cyclohexyl and cyclopentyl.
  • alkyl groups having 1-8 carbon atoms and a 3-7 membered cycloalkyl substituent include cyclohexylmethyl and cyclopentylmethyl.
  • the compound of the Formula (C) can be present in the form of geometrical isomers such as cis and trans and optical isomers. These isomers are included in the compounds provided. Further, the compounds provided can be in the form of pharmaceutically acceptable salts, such as alkali metal salts, e.g., sodium or potassium salt.
  • R X is CH 2 OH, COH, or COOCH 2 CONR 4 R 5 . In other embodiments, R X is CH 2 OH.
  • the compound of Formula (C) is or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compound of Formula (C) is a compound shown in Table 1 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compounds of the invention are compounds of Formula (D): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein: each of R 1 and R 2 independently is a hydrogen, a halogen, nitro, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl having 1 to 3 halogens, C 1-8 haloalkoxy having 1 to 3 halogens, C 2-8 alkenyl, C 2-8 alkynyl, 3-7 membered cycloalkyl, C 1-8 alkyl substituted with 3-7 membered cycloalkyl, C 6-10 aryl which is optionally substituted, arylalkyl group which has a C 6-10 aryl moiety and C 1-8 alkyl moiety, a heterocyclic group or a heterocyclic-alkyl group having a C 1-8 alkyl group; each occurrence of R 3 , R 4 , and R
  • Y is C 1-8 alkylene;
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • halogen atoms for R 1 and R 2 include fluorine, chlorine, and bromine.
  • Examples of alkyl groups having 1-8 carbon atoms for R 1 , R 2 , R 3 , R 4 and R 5 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and pentyl.
  • alkoxy groups having 1-8 carbon atoms for R 1 and R 2 include methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, t-butyloxy, and pentyloxy.
  • alkyl groups having 1-8 carbon atoms which has 1-3 halogen substituents for R 1 and R 2 include chloromethyl, fluoromethyl, bromomethyl, chloroethyl, 2-fluoroethyl, and trifluoromethyl.
  • alkoxy groups having 1-8 carbon atoms which has 1-3 halogen substituents for R 1 and R 2 include chloromethoxy, fluoromethoxy, bromomethoxy, 2- chloroethoxy, 2-fluoroethoxy, and trifluoroethoxy.
  • alkenyl groups having 2-8 carbon atoms for R 1 and R 2 include vinyl or allyl.
  • the alkynyl group having 2-8 carbon atoms can be, for example, propargyl.
  • the cycloalkyl group having 3-7 carbon atoms can be, for example, cyclohexyl or cyclopentyl.
  • the alkyl group having a 3-7 membered cycloalkyl substituent can be, for example, cyclohexylmethyl or cyclopentylmethyl.
  • the aryl group for the aryl group optionally having a substituent for R 1 and R 2 can be, for example, phenyl or naphthyl.
  • arylalkyl groups optionally having a substituent include benzyl and phenethyl.
  • heterocyclic groups for the heterocyclic group optionally having a substituent include a 5-7 membered cyclic group having ring-forming 1-4 hetero atoms such as nitrogen, oxygen and sulfur.
  • a 5-7 membered cyclic group having ring-forming 1-4 hetero atoms such as nitrogen, oxygen and sulfur.
  • pyridyl, thienyl and furyl can be included.
  • a benzene ring condensed with the heterocyclic group such as quinolyl or benzothienyl can be included.
  • heterocyclic groups for the heterocyclic ring-alkyl group (the alkyl moiety has 1-8 carbon atoms) optionally having a substituent can be the same as that described hereinbefore for the heterocyclic group optionally having a substituent.
  • the alkyl group preferably has 1-3 carbon atoms.
  • the substituent for the substituents of the aryl group optionally having a substituent, the arylalkyl group (the aryl moiety has 6-10 carbon atoms, and the alkyl moiety has 1-8 carbon atoms) optionally having a substituent, the heterocyclic group optionally having a substituent, and a heterocyclic ring-alkyl group (the alkyl moiety has 1-8 carbon atoms) optionally having a substituent can be a halogen atom such as chlorine, bromine, or fluorine, nitro, hydroxyl, amino, an alkyl amino group having 1-8 carbon atoms such as methylamino, or ethylamino, a dialkylamino group having 2-10 carbon atoms such as dimethylamino, an alkyl group having 1- 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, or butyl, an alkoxy group having 1-8 carbon atoms such as
  • the compound of Formula (D) is a compound shown in Table 2 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compounds of the invention are compounds of Formula (E): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein: each of R 11 and R 12 independently is hydrogen, halogen, nitro, hydroxyl, amino, C 1-8 alkyl, an C 1-8 alkoxy, C 1-8 haloalkyl group having 1 to 3 halogens, C 1-8 haloalkoxy group having 1 to 3 halogens, C 2-8 alkenyl, C 2-8 alkynyl, a 3-7 membered cycloalkyl, C 1-8 alkyl having a 3-7 membered cycloalkyl substituent, or phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolyl, or benzothienyl group which optionally has a substituent which is a halogen atom, nitro,
  • Y 1 is C 1-8 alkylene
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H, each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle
  • each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl
  • n is 0, 1, 2, 3, or 4.
  • the halogen atom, alkoxy groups having 1-8 carbon atoms, alkyl group having 1-8 carbon atoms which has 1-3 halogen substituents, alkoxy group having 1-8 carbon atoms which has 1-3 halogen substituents, alkenyl group having 2-8 carbon atoms, alkynyl group having 2-8 carbon atoms, cycloalkyl group having 3-7 carbon atoms, alkyl group having 1-8 carbon atoms which has a cycloalkyl group of 3-7 carbon atoms for R 11 and R 12 can be those described for the halogen atom, alkoxy group, alkyl group having 1-8 carbon atoms which has a halogen substituent, alkoxy group having 1-8 carbon atoms which has a halogen substituent, alkenyl, alkynyl, cycloalkyl group, and alkyl group having 1-8 carbon atoms which has a cycloalkyl group of 3-7 carbon atoms for R 11 and R 12
  • the alkyl group having 1-8 carbon atoms for R 11 , R 12 , R 14 , and R 15 can be an alkyl group described for R 1 , R 2 , R 3 , R 4 and R 5 of Formula (D).
  • R 11 or R 12 is phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolyl, or benzothienyl
  • these rings can in some embodiments have such substituents a halogen atom such as chlorine, bromine, or fluorine, nitro, hydroxyl, amino, an alkyl amino group having 1-8 carbon atoms such as methylamino, or ethylamino, a dialkylamino group having 2-10 carbon atoms such as dimethylamino, an alkyl group having 1-8 carbon atoms such as methyl, ethyl, propyl, isopropyl, or butyl, an alkoxy group having 1-8 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, or butoxy, an alkyl group having 1-8 carbon atoms which has 1-3 halogen substituents such as chlorine, bromine,
  • the compound provided can be a stereoisomer such as cis or trans, or an optical isomer. These isomers are included in the invention.
  • the compound provided includes a pharmaceutically acceptable salt such as an alkali metal salt, e.g., sodium salt or potassium salt. Further, the compounds provided can be in the form of pharmaceutically acceptable salts such as alkali metal salts, e.g., sodium salt and potassium salt.
  • the compound of Formula (E) is a compound shown in Table 3 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compounds of the invention are compounds of Formula (F): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • A is O, S or NR 7 in which R7 is hydrogen or C 1-8 alkyl
  • B 1 is CW or N in which W is hydrogen or a bond
  • B 2 is O, S or NR 8 in which R 8 is hydrogen or C 1-8 alkyl
  • Y is C 1-8 alkylene, which is unsubstituted or substituted with C 1-8 alkyl or C 1-8 haloalkyl having
  • Z is NH, O or S
  • R 1 is aryl, which is unsubstituted or substituted with C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl having 1-3 halogens, hydroxyl, nitro, amino, phenyl, pyridyl or halogen, or a heterocyclic group having a five to eight membered ring comprising one to three hetero atoms each of which is independently nitrogen, oxygen or sulfur and the other atoms are carbon, optionally wherein a benzene ring is condensed with the heterocyclic ring;
  • R 2 is C 2-8 alkyl, C 1-8 haloalkyl having with 1-3 halogens, C 3-7 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-4 alkyl substituted with aryl, which is unsubstituted or substituted with C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl having 1-3
  • R 3 is halogen, trifluoromethyl, C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl; each of R 4 and R 5 is hydrogen, C 1-8 alkyl or C 1-8 haloalkyl having 1-3 halogens; each of Z and R 3 is attached to the benzene ring, and X 2 is not attached to the benzene ring;
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H, each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , the substituent of the alkylene chain of Y, the substituent of the aryl and the heterocyclic group of R 3 , the substituent of the alkyl group substituted with aryl of R 2 , and the substituent of the alkyl group substituted with a heterocyclic group of R 2 can in some embodiments be an alkyl group having 1-8 carbon atoms.
  • the alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • R 2 can be an alkyl group having 2-8 carbon atoms.
  • alkyl groups include ethyl, propyl, iso-propyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • R 2 , R 4 , R 5 , the substituent of the alkylene chain of Y, the substituent of the aryl or heterocyclic group of R 1 , the substituent of the alkyl group substituted with aryl of R 2 , and the substituent of the alkyl group substituted with a heterocyclic group of R 2 can be an alkyl groups having 1-8 carbon atoms substituted with 1-3 halogens.
  • the haloalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl which are substituted with 1-3 halogens such as fluorine, chlorine, and bromine.
  • the group is trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl or 2-fluoroethyl.
  • R 2 and R 3 can be an alkenyl group having 2-8 carbon atoms.
  • alkenyl groups include vinyl and allyl.
  • R 2 and R 3 can be an alkynyl group having 2-8 carbon atoms.
  • alkynyl groups include propargyl.
  • R 3 can be a halogen atom.
  • the halogen atoms include fluorine, chlorine and bromine.
  • R 2 can be a cycloalkyl group having 3-7 carbon atoms.
  • cycloalkyl groups examples include cyclopropyl, cyclopentyl and cyclohexyl.
  • the substituent of the aryl or heterocyclic group of R 1 , the substituent of the alkyl group substituted with aryl of R 2 , and the substituent of the alkyl group substituted with a heterocyclic group of R 2 can be an alkoxy groups having 1-8 carbon atoms.
  • the alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy and hexyloxy.
  • R 1 and the aryl moiety of the aryl substituted with alkyl of R 2 can be an aryl group.
  • the aryl groups include phenyl and naphthyl.
  • R 1 and the substituent of the alkyl group of R 2 can be a heterocyclic group having five to eight membered ring. Examples of the heterocyclic groups include pyridyl, thienyl, furyl, thiazolyl and quinolyl.
  • R 1 can be a heterocyclic group having five to eight membered ring comprising one to three hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur and the other atoms consisting of carbon.
  • a benzene ring can be condensed with the heterocyclic ring. Examples of the condensed rings include quinoline ring and benzothiophene ring
  • Y can be an alkylene chain having 1 to 8 carbon atoms. Examples of the alkylene chains include methylene and ethylene.
  • R 3 can be one to three groups. In some embodiments, two or three groups of R 3 can be different from each other.
  • R6 can be an alkyl group having 1-8 carbon atoms substituted with amino.
  • the aminoalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl which are substituted with an amino group such as piperidino, pyrrolidino, dimethylamino, and diethylamino.
  • the compounds of the Formula (F) can be in the form of pharmaceutically acceptable salts such as alkali metal salts, e.g., sodium salt and potassium salt.
  • the compound of Formula (F) is a compound shown in Table 4 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compounds of the invention are compounds of Formula (G): (G) or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein: each of R 1 and R 4 , which are the same or different, is a hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl; C 1-8 haloalkoxy; hydroxyl, nitro, C 2.8 acyl group, C 6-10 aryl, or a 5- or 6-membered heterocyclic group;
  • R 2 is hydrogen
  • X and Y are the same or different and each represents CH or N;
  • Z is oxygen or sulfur
  • A is a 5-membered heterocyclic group which is pyrazole, thiophene, furan or pyrrole, wherein the heterocyclic group is unsubstituted or substituted with C 1-8 alkyl having a substituent which is C 1-8 alkyl, 3- to 7-membered cycloalkyl, C 2-8 alkenyl, C 2.8 alkynyl, C 1-8 alkoxy, C 1-8 alkyl group substituted with a 3- to 7-membered cycloalkyl group, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 6-10 aryl, 5- or 6-membered heterocyclic group, an aralkyl group having a C 6-10 aryl moiety and a C 1-8 alkylene moiety, or 5- or 6-membered heterocyclic group;
  • B is a C 1-8 alkylene chain which is unsubstituted or substituted with C 1-8 alkyl, 3- to 7-membered cycloalkyl group, C 2-8 alkenyl, C 2.8 alkynyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl or C 1-8 haloalkoxy, the alkylene group optionally having a double bond in the case that the alkylene group has 2 to 6 carbon atoms; q is 0, 1, 2, 3, 4, or 5; R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • the compounds of the invention are compounds of Formula (H): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein: each of R 11 and R 13 , which are the same or different, is a hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl; C 1-8 haloalkoxy; hydroxyl, nitro, C 2-8 acyl group, C 6-10 aryl, or a 5- or 6-membered heterocyclic group;
  • R 12 is hydrogen, C 1-8 alkyl, a 3- to 7-membered cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 1-8 alkyl having a 3- to 7-membered cycloalkyl group substituent, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 6-10 aryl, a 5- or 6-membered heterocyclic group, an aralkyl group having a C 6- 10 aryl moiety and a C 1-8 alkylene moiety, or a C 1-8 alkyl group having a 5- or 6-membered heterocyclic substituent;
  • R 14 and R 15 are the same or different and each is a hydrogen atom, C 1-8 alkyl, or C 1-8 haloalkyl;
  • X 1 is CH or N
  • Z 1 is oxygen or sulfur
  • W 1 is oxygen or CH 2 when bond a is present and OH when bond a is absent; q is 2, 3, or 4.
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H, each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X6 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • the compounds of the invention are compounds of Formula (J): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein: each of R 21 and R 23 , which are the same or different, is a hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl; C 1-8 haloalkoxy; hydroxyl, nitro, C 2-8 acyl group, C 6-10 aryl, ora 5- or 6-membered heterocyclic group;
  • R 22 is hydrogen, C 1-8 alkyl, a 3- to 7-membered cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 1-8 alkyl having a 3- to 7-membered cycloalkyl group substituent, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 6-10 aryl, a 5- or 6-membered heterocyclic group, an aralkyl group having a C 6- 10 aryl moiety and a C 1-8 alkylene moiety, or a C 1-8 alkyl group having a 5- or 6-membered heterocyclic substituent;
  • R 24 and R 25 are the same or different and each is a hydrogen atom, C 1-8 alkyl, or C 1-8 haloalkyl;
  • X 2 is CH or N
  • Z 2 is oxygen or sulfur
  • W 2 is oxygen or CH 2 when bond a is present and OH when bond a is absent; r is 2, 3, or 4.
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • examples of the alkyl groups having 1 to 8 carbon atoms which can be R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , the substituent of the 5-membered heterocyclicgroup for A, or the substituent of the alkylene chain having 2 to 6 carbon atoms for B include methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl and hexyl.
  • alkenyl groups having 2 to 8 carbon atoms which can be R 1 , R 4 , the substituent of the 5-membered heterocyclic group for A, or the substituent of the alkylene chain having 2 to 6 carbon atoms for B include vinyl and allyl.
  • alkynyl groups having 2 to 8 carbon atoms which can be R 1 , R 4 , the substituent of the 5-membered heterocyclic group for A, or the substituent of the alkylene chain having 2 to 6 carbon atoms for B include propargyl.
  • Examples of the 3- to 7-membered cycloalkyl groups which can be the substituent of the 5-membered heterocyclic group for A, or the substituent of the alkylene chain having 2 to 6 carbon atoms for B include cyclopropyl, cyclopentyl and cyclohexyl.
  • alkoxy groups having 1 to 8 carbon atoms which can be R 1 , R 4 , the substituent of the 5-membered heterocyclic group for A, or the substituent of the alkylene chain having 2 to 6 carbon atoms for B include methoxy, ethoxy, propoxy, isopropoxy, butoxy, i- butoxy, t-butoxy, pentyloxy and hexyloxy.
  • Examples of the halogen atoms which can be R 1 , R 4 , or the substituent of the alkylene chain having 2 to 6 carbon atoms for B include fluorine, chlorine, and bromine.
  • Examples of the alkyl groups having 1 to 8 carbon atoms and a halogen atom substituent which can be R 1 , R 4 , R 5 , R 6 , the substituent of the 5-membered heterocyclic group for A, or the substituent of the alkylene chain having 2 to 6 carbon atoms for B include methyl, ethyl, propyl, isopropyl, butyl and t-butyl which have substituents such as 1 to 3 fluorine, chlorine or bromine atoms.
  • the alkyl group having 1 to 8 carbon atoms and a halogen atom substituent is trifluoromethyl, chloromethyl, chloroethyl, 2-bromoethyl, or 2- fluoroethyl.
  • alkoxy groups having 1 to 8 carbon atoms and a halogen atom substituent which can be R 1 , R 4 , the substituent of the 5-membered heterocyclic group for A, or the substituent of the alkylene chain having 2 to 6 carbon atoms for B include methoxy, ethoxy, propoxy, isopropyloxy, butyloxy and t-butyloxy which have substituents such as 1 to 3 fluorine, chlorine or bromine atoms.
  • the alkoxy group having 1 to 8 carbon atoms and a halogen atom substituent is trifluoromethyloxy, chloromethyloxy, 2-chloroethyloxy, 2- bromoethyloxy, or 2-fluoroethyloxy.
  • acyl groups having 2 to 8 carbon atoms which can be R 1 or R 4 , include acetyl and propionyl.
  • Examples of the aryl groups having 6 to 10 carbon atoms which can be R 1 , R 4 , or the substituent of the 5-membered heterocyclic group for A, include phenyl.
  • Examples of the 5- or 6-membered heterocyclic groups which can be R 1 , R 4 , or the substituent of the 5-membered heterocyclic group for A, include pyridyl.
  • alkyl groups having 1 to 8 carbon atoms and a 3- to 7-cycloalkyl group substituent which can be the substituent of the 5-membered heterocyclic group for A include methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl and hexyl which have cyclopropyl, cyclopentyl, or cyclophexyl substituent.
  • Examples of the aralkyl groups (which have an aryl moiety of 6 to 10 carbon atoms and an alkylene moiety of 1 to 8 carbon atoms) which can be the substituent of the 5-membered heterocyclic group for A, include benzyl and phenethyl.
  • alkyl groups having 1 to 8 carbon atoms and a 5- or 6-membered heterocyclic group which can be the substituent of the 5-membered heterocyclic group for A include methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl and hexyl which have a pyridyl substituent.
  • alkyl groups having 1 to 8 carbon atoms examples include alkenyl groups having 2 to 8 carbon atoms, alkynyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, halogen atoms, alkyl groups having 1 to 8 carbon atoms and a halogen atom substituent, alkoxy groups having 1 to 8 carbon atoms and a halogen atom substituent, acyl groups having 2 to 8 carbon atoms, aryl groups having 6 to 10 carbon atoms, and 5- or 6- membered heterocyclic groups which can be R 11 or R 13 of the Formula (H) or R 21 or R 23 of the Formula (J) are those described hereinabove for R 1 and R 4 of the Formula (G).
  • alkyl groups having 1 to 8 carbon atoms and alkyl groups having 1 to 8 carbon atoms and a halogen atom substituent which can be R 14 or R 15 of the Formula (H) or R 24 or R 25 of the Formula (J) include those described hereinabove for R 5 and R 6 of the Formula (G).
  • R 1 in the Formula (G), R 11 in the formula (H), and R 21 in the formula (J) can be attached to the benzene ring or the like in a single or plural number (1 to 3). If each of R 1 , R 11 and R 21 is present in a plural number, the plural groups can be the same or different.
  • R 4 in the Formula (G), R 13 in the Formula (H), and R 23 in the Formula (J) can be attached to the benzene ring or the like in a single or plural number (1 to 3). If each of R 4 , R 13 and R 23 is present in a plural number, the plural groups can be the same or different.
  • the substituent group of the 5-membered heterocyclic group for A in the Formula (G), R 12 in the formula (H), and R 22 in the Formula (J) can be attached to the heterocyclic ring in a single or plural number (1 or 2). If each of the substituent group of the 5-membered heterocyclic group for A, R 12 and R 22 is present in plural number, the plural groups can be the same or different.
  • the compounds of the Formulas (G), (H) and (J) can be pharmacologically acceptable salts such as alkali metal salts, for example, sodium salts, potassium salts, or lithium salts.
  • the compounds of the Formulas (G), (H) and (J) can be present in the optically active forms, and in the form of optical isomers such as compounds of a racemic form or geometric isomers such as compounds of a cis- or trans form.
  • the compound of Formula (G), (H), or (J) is a compound shown in Table 5 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compounds of the invention are compounds of Formula (K):
  • A is CH or nitrogen
  • B when bond a is present, is oxygen or C(R 8 )(R 9 ) in which each of R 8 and R 9 is independently hydrogen or C 1-8 alkyl; B, when bond a is absent, is OH;
  • X and Y differ from each other, and each is an oxygen atom, a sulfur atom, a nitrogen atom, or CR 12 in which R 12 is a hydrogen or CI-B alkyl;
  • Z 1 is a bond, oxygen, sulfur, or C(R 13 )(R 14 ) in which each of R 13 and R 14 is independently a hydrogen or C 1-8 alkyl; each of R 1 , R 2 , and R 3 , is independently a hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl; C 1-8 haloalkoxy; hydroxyl, nitro, C 2-8 acyl group, C 6-10 aryl, or a 5- or 6-membered heterocyclic group; each of R 4 and R 5 is independently hydrogen, C 1-8 alkyl, C 1-8 haloalkyl; each of R 6 and R 7 is independently hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, or C 1-8 haloalkyl r is 1, 2, 3, 4, or 5; R X is CH 2 OH, COH, COOC
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • examples of the alkyl groups having 1 to 8 carbon atoms for R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 include methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl and hexyl.
  • Examples of the alkenyl groups having 2 to 8 carbon atoms for R 1 , R 2 , R 3 , R 6 and R 7 include vinyl and allyl.
  • Examples of the alkynyl groups having 2 to 8 carbon atoms for R 1 , R 2 , R 3 , R 6 and R 7 include propargyl.
  • Examples of the alkoxy groups having 1 to 8 carbon atoms for R 1 , R 2 , and R 3 include methoxy, ethoxy, propoxy, isopropoxy, butoxy, i-butoxy, t-butoxy, pentyloxy and hexyloxy.
  • Examples of the halogen atoms for R 1 , R 2 , and R 3 include fluorine, chlorine, and bromine.
  • Examples of the alkyl groups having 1 to 8 carbon atoms which are substituted with a halogen atom for R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl which are substituted with 1 to 3 halogen atoms such as fluorine, chlorine, and bromine.
  • substituents are trifluoromethyl, chloromethyl, 2-chloroethyl, 2- bromoethyl, or 2-flouroethyl.
  • alkoxy groups having 1 to 8 carbon atoms which are substituted with a halogen atom for R 1 , R 2 , and R 3 include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and t- butoxy which are substituted with 1 to 3 halogen atoms such as fluorine, chlorine, or bromine.
  • substituents are tritluoromethyloxy, chloromethyloxy, 2-chloroethyloxy, 2- bromoethyloxy, or 2-flouroethyloxy.
  • Examples of the acyl groups having 2 to 8 carbon atoms for R 1 , R 2 and R 3 include acetyl and propionyl.
  • Examples of the aryl groups having 6 to 10 carbon atoms for R 1 , R 2 and R 3 include phenyl.
  • Examples of the 5- or 6-membered heterocyclic groups for R 1 , R 2 and R 3 include pyridyl.
  • R 1 , R 2 and R 3 in the Formula (K) can be attached to the benzene ring or the like in numbers of 1 to 3 in which the same or different groups can be attached to the same ring.
  • the compounds provided herein which are represented by the Formula (K) can be in the form of a pharmacologically acceptable salts such as alkali metal salts, e.g., salts of sodium, potassium and lithium.
  • the compounds provided herein can be in the optically active forms, and in the form of optical isomers such as compounds of a racemic form or geometric isomers such as compounds of a cis- or trans form.
  • the compound of Formula (K) is a compound shown in Table 6 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • Z 2 is oxygen or sulfur; each of R 21 , R 22 , and R 23 is independently a hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl; C 1-8 haloalkoxy; hydroxyl, nitro, C 2-8 acyl group, C 6-10 aryl, or a 5- or 6-membered heterocyclic group; each of R 24 and R 25 is independently hydrogen, C 1-8 alkyl, C 1-8 haloalkyl; R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H, each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C
  • the alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkynyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, halogen atoms, alkyl groups having 1 to 8 carbon atoms which are substituted with a halogen atom, alkoxy groups having 1 to 8 carbon atoms which are substituted with a halogen atom, hydroxyls, nitros, acyl groups having 2 to 8 carbon atoms, aryl groups having 6 to 10 carbon atoms, and 5- or 6-membered heterocyclic groups for R 21 , R 22 and R 23 can in some embodiments be those described for R 1 , R 2 and R 3 in the Formula (K).
  • the alkyl groups having 1 to 8 carbon atoms and alkyl groups having 1 to 8 carbon atoms which are substituted with a halogen atom for R 24 and R 25 can in some embodiments be those described for R 4 and R 5 in the Formula (K).
  • R 21 , R 22 and R 23 in the Formula (L) can be attached to the benzene ring or the like in numbers of 1 to 3 in which the same or different groups can be attached to the same ring.
  • the compounds provided herein which are represented by the Formula (L) can be in the form of a pharmacologically acceptable salts such as alkali metal salts, e.g., salts of sodium, potassium and lithium.
  • the compounds provided herein can be in the optically active forms, and in the form of optical isomers such as compounds of a racemic form or geometric isomers such as compounds of a cis- or trans form.
  • the compounds of the invention are compounds of Formula (M): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof , wherein: each of W and W 2 is independently nitrogen or CH;
  • X is nitrogen or CH
  • Y is oxygen or sulfur
  • Z is a bond, oxygen, sulfur or NR 5 , in which R 5 is hydrogen or C 1-8 alkyl; each of R 1 and R 2 is independently hydrogen, halogen, hydroxyl, nitro, amino, C 1-8 alkyl, 3- to 7- membered cycloalkyl group, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 1-8 alkyl having a 3- to 7- membered cycloalkyl substituent, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 6-10 aryl, 5- or 6- membered heterocyclic group, an aralkyl group having C 6-10 aryl moiety and a C 1-6 alkylene, or C 1-8 alkyl having a 5- or 6-membered heterocyclic substituent; each of R 3 and R 4 is independently hydrogen, C 1-8 alkyl, or C 1-8 haloalkyl; A is a 5-membered heterocycle which is pyrazo
  • B is a bond or C 1-8 alkylene which is unsubstituted or substituted with C 1-8 alkyl, 3- to 7- membered cycloalkyl, C 1-8 alkoxy or a halogen substituent, optionally wherein the C 1-8 alkylene has a double or triple bond;
  • r is 0, 1, 2, or 3;
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H, each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1 , 2, 3, or 4.
  • the compounds of the invention are compounds of Formula (N); a or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • W 3 is nitrogen or CH
  • Z 1 is oxygen or sulfur; each of R 11 and R 12 is independently hydrogen, halogen, hydroxyl, nitro, amino, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, or C 1-8 haloalkoxy’ each of R 13 and R 14 is independently hydrogen or C 1-8 alkyl;
  • a 1 is a 5-membered heterocycle which is pyrazole or thiophene, in which the 5-membered heterocycle is unsubstituted or substituted with halogen, hydroxyl, nitro, amino, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, or C 1-8 haloalkoxy;
  • m is 2, 3, or 4;
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • the alkyl group having 1 to 8 carbon atoms for R 1 , R 2 , R 3 , R 4 , R 5 , a substituent attached to the 5-membered hetero ring of A (when present), and a substituent attached to an alkylene chain having 1 to 8 carbon atoms can be methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl, or hexyl.
  • the alkenyl group having 2 to 8 carbon atoms for R 1 , R 2 and a substituent is attached to the 5-membered hetero ring of A and is vinyl or allyl.
  • a substituent is attached to the alkylene chain having 1 to 8 carbon atoms and is cyclopentyl or cyclohexyl.
  • a substituent is attached to the alkylene chain having 1 to 8 carbon atoms and is methoxy, ethoxy, propoxy, isopropoxy, butoxy, i-butoxy, t-butoxy, pentyloxy, or hexyloxy.
  • R 1 and R 2 is halogen
  • a substituent is attached to the 5-membered hetero ring of A.
  • a substituent is attached to the alkylene chain having 1 to 8 carbon atoms and is fluorine, chlorine, or bromine.
  • the alkyl group having 1 to 8 carbon atoms and a halogen substituent for R 1 , R 2 , R 5 wherein a substituent is attached to the 5-membered hetero ring of A and is methyl, ethyl, propyl, isopropyl, butyl or t-butyl which has 1 to 3 halogen substituents such as fluorine, chlorine or bromine.
  • the substituents are selected from trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl, and 2-fluoroethyl.
  • the substituents are selected from trifluoromethyloxy, chloromethyloxy, 2-chloroethyloxy, 2-bromoethyloxy, and 2- fluoroethyloxy.
  • the aryl group having 6 to 10 carbon atoms for R 1 , R 2 , and a substituent is attached to the 5-membered hetero ring of A and is phenyl.
  • the 5- or 6-membered heterocyclic group for R 1 , R 2 , and a substituent is attached to the 5-membered hetero ring of A and is pyridyl.
  • the alkyl group having 1 to 8 carbon atoms and 3- to 7-membered cycloalkyl group for R 1 , R 2 , and a substituent is attached to the 5-membered hetero ring of A and is methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl, or hexyl which has a cyclopropyl substituent, a cyclopentyl substituent, or a cyclohexyl substituent.
  • the aralkyl having an aryl moiety of 6 to 10 carbon atoms and an alkylene moiety of 1 to 8 carbon atoms for R 1 , R 2 , and a substituent is attached to the 5- membered hetero ring of A and is benzyl or phenethyl.
  • the alkyl group having 1 to 8 carbon atoms and 5- or 6-membered heterocyclic group for R 1 , R 2 , and a substituent is attached to the 5-memberedhetero ring of A and is methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, pentyl, or hexyl which has a pyridyl substituent.
  • the 5-membered hetero ring which may have a substituent for A, is pyrazole or thiophene having a substituent.
  • pyrazole is having a substituent.
  • the alkylene chain having 1 to 8 carbon atoms which has substituent for B is an alkylene chain having I to 4 carbon atoms.
  • the alkylene chain is an ethylene chain or a propylene chain.
  • n 0.
  • the halogen atom, alkyl group having 1 to 8 carbon atoms, alkoxy group having 1 to 8 carbon atoms, alkyl group having 1 to 8 carbon atoms and a halogen substituent, and alkoxy group having 1 to 8 carbon atoms and a halogen substituent for R 11 and R 12 can be those described hereinbefore for R 1 and R 2 of the Formula (M).
  • the alkyl group having 1 to 8 carbon atoms for R 13 and R 14 can be those described hereinbefore for R 3 and R 4 of the Formula (M).
  • the halogen atom, alkyl group having 1 to 8 carbon atoms, alkoxy group having 1 to 8 carbon atoms, alkyl group having 1 to 8 carbon atoms and a halogen substituent, and alkoxy group having 1 to 8 carbon atoms and a halogen substituent which is attached to pyrazole or thiophene for A 1 in the Formula (N) are those described hereinbefore for the substituents attached to the 5-membered hetero ring of A of the Formula (M).
  • R 1 of the Formula (M) and R 11 of the Formula (N), the benzene ring or the like can have 1 to 3 number of R 1 or R 11 which are the same or different from each other.
  • the benzene ring or the like can have 1 to 3 substituents other than a hydrogen atom.
  • R 2 of the Formula (M) and R 12 of the Formula (N), the benzene ring of the benzisoxazole ring or the like can have 1 to 3 number of R 2 or R 12 which are the same or different from each other.
  • the benzene ring of the benzisoxazole ring or the like can have 1 to 3 substituents other than a hydrogen atom.
  • the substituent attached to the 5-membered hetero ring for A of the Formula (M) and the substituent attached to pyrazole or thiophene for A 1 of the Formula (N) can be present in 1 or 2 number which can be the same or different from each other.
  • the compounds provided herein which are represented by the Formula (M) and (N) can be in the form of a pharmacologically acceptable salts such as alkali metal salts, e.g., salts of sodium, potassium and lithium.
  • the compounds provided herein can be in the optically active forms, and in the form of optical isomers such as compounds of a racemic form or geometric isomers such as compounds of a cis- or trans form.
  • the compound of Formula (M) or (N) is a compound shown in Table 7 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compounds of the invention are compounds of Formula (O): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein: each of W 1 and W 2 independently is CH or nitrogen;
  • X is NR 5 or CR 6 R 7 ; wherein R 5 is hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkyl substituted with C 1-8 alkoxy, C 3-7 cycloalkyl, C 1-8 alkyl substituted with C 3-7 cycloalkyl, C 1-8 alkyl substituted with phenyl, C 2-8 acyl, or C 2-8 alkenyl, and each of R 6 and R 7 independently is hydrogen or C 1-8 alkyl; Y is (CR 8 R 9 ) r , wherein each of R 8 and R 9 independently is hydrogen or C 1-8 alkyl, and r is 1, 2, 3, or 4; or
  • G when bond a is present, is O, S or CR 12 R 13 , wherein each of R 12 and R 13 independently is hydrogen or C 1-8 alkyl; G, when bond a is absent, is OH;
  • A is a five-membered heterocyclic ring which is thiazole, oxazole, imidazole, pyrazole, thiophene, furan, or pyrrole, wherein the heterocyclic ring is unsubstituted or substituted with C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl, haloalkoxy, hydroxyl, nitro, C 2-8 acyl, C 6-10 aryl, or a five-membered or six-membered heterocyclic group;
  • B is a C 1-8 alkylene, C 2-8 alkenylene or C 2-8 alkynylene chain, wherein the chain is unsubstituted or substituted with C 1-8 alkyl, C 3-7 cycloalkyl, C 1-8 alkoxy, or halogen; each of R 1 and R 2 independently is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl, C 1-8 haloalkoxy, hydroxyl, nitro, C 2-8 acyl, C 6-10 aryl, or a five- membered or six-membered heterocyclic group; each of R 3 and R 4 independently is hydrogen or C 1-8 alkyl; m is 0, 1, 2, or 3; R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • the compounds of the invention are compounds of Formula (P): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • G a when bond a is present, is O, S or CH 2 ;
  • G a when bond a is absent, is OH.
  • a a is five-membered heterocyclic ring which is thiazole, oxazole, or thiophene, wherein the five- membered heterocyclic ring is unsubstituted or is substituted with C 1-8 alkyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl, C 1-8 haloalkoxy, hydroxyl, nitro, or C 2-8 acyl;
  • B a is a C 1-8 alkylene or C 2-8 alkenylene chain; each of R 1a and R 2a independently is hydrogen, C 1-8 alkyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl, C 1-8 haloalkoxy, hydroxyl, nitro, or C 2.8 acyl; R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is O, 1 , 2, 3, or 4.
  • the compounds of the invention are compounds of Formula (Q): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • G b when bond a is present, is O, S or CH 2 ; G b , when bond a is absent, is OH;
  • a b is five-membered heterocyclic ring which is thiazole, oxazole, or thiophene, wherein the five- membered heterocyclic ring is unsubstituted or is substituted with C 1-8 alkyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl, C 1-8 haloalkoxy, hydroxyl, nitro, or C 2-8 acyl;
  • B b is a C 1-8 alkylene or C 2-8 alkenylene chain; each of R 1b and R 2b independently is hydrogen, C 1-8 alkyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl, C 1-8 haloalkoxy, hydroxyl, nitro, or C 2-8 acyl;
  • R 3b is hydrogen or C 1-8 alkyl
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H, each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 a substituent of the five-membered heterocyclic ring represented by A, and a substituent of the C 1-8 alkylene, C 2-8 alkenylene or C 2-8 alkynylene chain represented by B can be C 1-8 alkyl.
  • Examples of the C 1-8 alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • R 1 , R 2 , R 5 , and a substituent of the five-membered heterocyclic ring represented by A can be C 2-8 alkenyl.
  • Eamples of the C 2-8 alkenyl include vinyl and allyl.
  • R 1 , R 2 , and a substituent of the five-membered heterocyclic ring represented by A can be C 2-8 alkynyl.
  • Examples of the C 2-8 alkynyl include propargyl.
  • R 1 , R 2 , a substituent of the five-membered heterocyclic ring represented by A, and a substituent of the C 1-8 alkylene, C 2-8 alkenylene or C 2-8 alkynylene chain represented by B can be C 1-8 alkoxy.
  • Examples of the C 1-8 alkoxy in-clude methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, and hexyloxy.
  • R 1 , R 2 , a substituent of the five-membered heterocyclic ring represented by A, and a substituent of the C 1-8 alkylene, C 2-8 alkenylene or C 2-8 alkynylene chain represented by B can be halogen.
  • the halogen include fluorine, chlorine, and bromine.
  • R 1 , R 2 , R 5 , and a substituent of the five-membered heterocyclic ring represented by A can be C 1-8 alkyl substituted with halogen.
  • the C 1-8 alkyl substituted with halogen include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl which are substituted with 1-3 halogens such as fluorine, chlorine, and bromine. Preferred are trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl, and 2-fluoroethyl.
  • R 1 , R 2 , and a substituent of the five-membered heterocyclic ring represented by A can be C 1-8 alkoxy substituted with halogen.
  • Examples of the C 1-8 alkoxy substituted with halogen include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and t-butoxy which are substituted with 1-3 halogen atoms such as fluorine atom, chlorine atom, or bromine atom.
  • R 1 , R 2 , and a substituent of the five- membered heterocyclic ring are trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2- bromoethoxy, and 2-fluoroethoxy.
  • R 1 , R 2 , R 5 , and a substituent of the five-membered heterocyclic ring represented by A can be C 2-8 acyl.
  • Examples of the C 2-8 acyl include acetyl and propionyl.
  • R 1 , R 2 , and a substituent of the five-membered heterocyclic ring represented by A can be aryl. Examples of the C 6-10 aryl include phenyl. [0252] In one embodiment, R 1 , R 2 , and a substituent of the five-membered heterocyclic ring represented by A can be a five-membered or six-membered heterocyclic group. Examples of the five-membered or six-membered heterocyclic group include pyridyi.
  • R 5 can be C 1-8 alkyl substituted with C 1-8 alkoxy.
  • Examples of the C 1-8 alkyl substituted with C 1-8 alkoxy include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl which are substituted with methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, or hexyloxy.
  • R 5 can be cycloalkyl of three-membered to seven-membered ring.
  • examples of the cycloalkyl of three-membered to seven-membered ring include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 5 can be C 1-8 alkyl substituted with cycloalkyl of three-membered to seven-membered ring.
  • Examples of the C 1-8 alkyl substituted with cycloalkyl of three- membered to seven-membered ring include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl and hexyl which are substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 5 can be C 1-8 alkyl substituted with phenyl.
  • Examples of the C 1-8 alkyl substituted with phenyl include benzyl and phenethyl.
  • a substituent of the C 1-8 alkylene, C 2-8 alkenylene or C 2-8 alkynylene chain represented by B can be cycloalkyl of three-membered to seven-membered ring.
  • Examples of the cycloalkyl of three-membered to seven-membered ring include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 1a , R 2a , and a substituent of five-membered heterocyclic ring represented by A a can be C 1-8 alkyl, C 1-8 alkoxy, halogen, C 1-8 alkyl substituted with halogen, C 1-8 alkoxy substituted with halogen, and C 2-8 acyl. Examples of them are the same as the examples of R 1 , R 2 , and the substituent of the five-membered heterocyclic ring represented by A in the Formula (O).
  • R 1b , R 2b , and a substituent of five-membered heterocyclic ring represented by A b can be C 1-8 alkyl, C 1-8 alkoxy, halogen, C 1-8 alkyl substituted with halogen, C 1-8 alkoxy substituted with halogen, and C 2-8 acyl. Examples of them are the same as the examples of R 1 , R 2 , and the substituent of the five-membered heterocyclic ring represented by A in the Formula (O).
  • R 3b can be C 1-8 alkyl. Examples are the same as the examples of R 5 in the Formula (O).
  • R 1b and R 2b in the Formula (Q) can be one to three groups attached to the rings, such as benzene ring.
  • the two or three groups can be different from each other.
  • the compounds having the Formulae (O), (P), and (Q) can be present in the form of a pharmaceutically acceptable salt.
  • the salt include an alkali metal salt, such as sodium salt, potassium salt and lithium salt.
  • the compounds having the Formulae (O), (P), and (Q) can also be present in the form of an optical isomer such as enantiomer or racemic body, or a geometrical isomer such as cis or trans. Also provided are isomers of these compounds.
  • the compound of Formula (O), (P), or (Q) is a compound shown in Table 8 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compounds of the invention are compounds of Formula (R): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein: each of W 1 and W 2 is independently CH or N; X is NR 3 or CR 4 R 5 , in which R 3 is C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkyl substituted with C 1-8 alkoxy, C 1-8 alkyl substituted with a 3-7 membered cycloalkyl, C 1-8 alkyl substituted with a phenyl group, C 2-8 acyl, or C 2-8 alkenyl; each of R 4 and R 5 is independently hydrogen or C 1-8 alkyl;
  • Y is (CR 6 R 7 )r, in which each of R 6 and R 7 is independently hydrogen or C 1-8 alkyl and r is 1, 2, 3, or 4;
  • A is a 5 or 6-membered heterocyclic group which is thiazole, oxazole, imidazole, pyrazole, thiophene, furan, pyrrole, pyridine or pyrimidine, or a phenyl group, wherein the 5 or 6- membered heterocyclic group or phenyl group is unsubstituted or substituted with C 1-8 alkyl, 3-7 membered cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxyl, C 1-8 alkyl group substituted with a 3-7 membered cycloalkyl group, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 6-10 aryl, a 5 or 6- membered heterocyclic group, aralkyl group comprising a C 6-10 aryl group and a C 1-8 alkyl group, or C 1-8 alkyl group substituted with a 5 or 6-membere
  • B is a bond or C 1-8 alkylene which is unsubstituted or substituted with C 1-8 alkyl, a 3-7 membered cycloalkyl group, C 1-8 alkoxy or a halogen, and which may have a double bond or triple bond when the carbon number of the alkylene chain is 2 or more;
  • D is N or CH
  • R 1 and R 2 are independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halogen, C 1-8 haloalkyl, C 1-8 haloalkoxy, nitro, C 2-8 acyl, C 6-10 aryl, or a 5 or 6-membered heterocyclic group; m 0, 1, 2, or 3; R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • the compounds of the invention are compounds of Formula (S): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • a 1 is a 5 or 6-membered heterocyclic group which is thiazole, oxazole, pyridine or pyrimidine, or a phenyl group, wherein the 5 or 6-membered heterocyclic group or phenyl group is unsubstituted or substituted with C 1-8 alkyl or C 1-8 haloalkyl;
  • B 1 is C 2 -4 alkylene; each of R 11 and R 12 is independently H, C 1-8 alkyl, halogen, or C 1-8 haloalkyl;
  • R 13 is C 1-8 alkyl or C 1-8 haloalkyl, optionally wherein the N to which R 13 is attached is attached to the 6th position of benzisoxazole;
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • both W 1 and W 2 are CH.
  • X is CR 4 R 5 , CH 2 , or NR 3
  • R 3 is an alkyl group having 1 to 8 carbon atoms. In another embodiment, R 3 is a methyl group.
  • Y is CH 2 .
  • Z is a carboxylic group.
  • A is thiazole or oxazole which may have a substituent selected from the group consisting of an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent, an aryl group having 6 to 10 carbon atoms or a 5 or 6-membered heterocyclic group; pyrazole which may have a substituent selected from the group consisting of an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent, an
  • B is an ethylene chain.
  • D is N.
  • E is O.
  • each of R 1 and R 2 is independently H, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent or an alkoxy group having 1 to 8 carbon atoms and a halogen atom substituent.
  • R 13 is an alkyl group having 1 to 8 carbon atoms. In another embodiment, R 13 is a methyl group.
  • p is 1.
  • a 1 is thiazole, oxazole or phenyl which may have a substituent selected from the group consisting of an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.
  • a 1 is thiazole which may have an alkyl group having 1 to 8 carbon atoms as a substituent.
  • B 1 is an ethylene chain.
  • R 11 is an alkyl group having 1 to 8 carbon atoms, a halogen atom or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.
  • R 12 is H, an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.
  • the compounds having the Formulae (R) and (S) can also be present in the form of an optical isomer such as enantiomer or racemic body, or a geometrical isomer such as cis or trans. Also provided are isomers of these compounds.
  • the compounds having the Formulae (R) and (S) can be present in the form of a pharmaceutically acceptable salt.
  • the salt include an alkali metal salt, such as sodium salt, potassium salt and lithium salt.
  • the compound of Formula (R) or (S) is a compound shown in Table 9 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compounds of the invention are compounds of Formula (T): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • B 2 is C 2 -4 alkylene
  • R 20 is C alkyl; each of R 21 and R 22 is independently H, C 1-8 alkyl, halogen, or C 1-8 haloalkyl;
  • R 23 is C alkyl or C 1-8 haloalkyl, optionally wherein the N to which R 23 is attached is attached to the 6th position of benzisoxazole;
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • R 23 is an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. In another embodiment, R 23 is a methyl group.
  • n is an integer of 1 to 4. In some embodiments, n is 1.
  • R 20 is an alkyl group having 1 to 8 carbon atoms. In another embodiment, R 20 is methyl.
  • B 2 is an alkylene chain having 2 to 4 carbon atoms. In another embodiment, B 2 is an ethylene chain.
  • each of R 21 and R 22 is independently H, an alkyl group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.
  • R 21 is an alkyl group having 1 to 8 carbon atoms, a halogen atom or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.
  • R 22 is H, an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.
  • N(R 23 )((CH 2 ) n -R x ) is attached to the 6th position of benzisoxazole.
  • the compounds having the Formula (T) can also be present in the form of an optical isomer such as enantiomer or racemic body, or a geometrical isomer such as cis or trans. Also provided are isomers of these compounds.
  • the compounds having the Formula (T) can be present in the form of a pharmaceutically acceptable salt.
  • the salt include an alkali metal salt, such as sodium salt, potassium salt and lithium salt.
  • the compounds of the invention are compounds of Formula (U): ora pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • R 1 is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-8 alkyl, C 3-7 cycloalkyl, C 2 - C8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 1-8 alkyl having a 3- to 7-membered cycloalkyl substituent, C 1-8 haloalkyl, C 1-8 alkyl having a C 1-8 alkoxy substituent, C 1-8 haloalkoxy, C 2-8 acyl, C 6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group having a C 6- 10 aryl moiety and a C 1-8 alkylene moiety, or a C 1-8 alkyl group having a 5- or 6-membered heterocyclic substituent;
  • R 2 is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 alkyl having a 3- to 7-membered cycloalkyl substituent, C 1-8 haloalkyl, C 1-8 alkyl group having a C 1-8 alkoxy substituent, C 2-8 acyl, C 6-10 aryl, or an aralkyl group having a C 6-10 aryl moiety and a C 1-8 alkylene moiety; each of R 3 , R 4 , R 5 and R 6 independently is hydrogen, C 1-8 alkyl, or C 1-8 haloalkyl;
  • X is oxygen, sulfur or NR 7 ; where R 7 is hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, an aralkyl group having a C 6-10 aryl moiety and a C 1-8 alkylene moiety, C 2-8 acyl, or C 2-8 alkenyl;
  • Y is oxygen, sulfur, NR 8 or a bond, where R 8 is hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 acyl, or C 2-8 alkenyl; p is 0 or 1;
  • A, when bond a is absent, is OH;
  • Y is bonded to the benzene ring of B
  • (C(R 3 )(R 4 )) m is bonded to the condensed ring of B at its 3-position; m is an integer of 1 to 4; n is 0, 1 , 2, 3, 4, or 5;
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl.
  • R 1 represents hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3- to 7- membered cycloalkyl substituent, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an alkyl group having 1-8 carbon atoms and an alkoxy substituent having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, a 5- or 6- membered heterocyclic group, an aralkyl
  • R 2 represents hydrogen, an alkyl group having 1-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3- to 7-membered cycloalkyl substituent, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an alkyl group having 1-8 carbon atoms and having an alkoxy substituent having 1-8 carbon atoms, an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms.
  • each of R 3 , R 4 , R 5 and R 6 independently represents hydrogen, an alkyl group having 1-8 carbon atoms, or an alkyl group having 1-8 carbon atoms and having a halogen substituent.
  • X is oxygen, sulfur or NR 7 , R 7 representing hydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms, an acyl group having 2-8 carbon atoms, or an alkenyl group having 2-8 carbon atoms.
  • Y is oxygen, sulfur, NR or a bond
  • R 8 representing hydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, or an alkenyl group having 2-8 carbon atoms.
  • p is 0 or 1.
  • A is oxygen, CH 2 , N-NH 2 or N-OR 9 , R 9 representing hydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1 -8 carbon atoms.
  • Y is bonded to the benzene ring of B.
  • -(C(R 3 )(R 4 )) m - is bonded to the condensed ring of B at its 3- position.
  • m is an integer of 1 to 4.
  • n is an integer of 0 to 5.
  • the compounds having the Formula (U) can also be present in the form of an optical isomer such as enantiomer or racemic body, or a geometrical isomer such as cis or trans. Also provided are isomers of these compounds.
  • the compounds having the Formula (U) can be present in the form of a pharmaceutically acceptable salt.
  • the salt include an alkali metal salt, such as sodium salt, potassium salt and lithium salt.
  • the compounds of the invention are compounds of Formula (V): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • R 11 is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-8 alkyl, C 3-7 cycloalkyl, C 2 - C8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 1-8 alkyl having a 3- to 7-membered cycloalkyl substituent, C 1-8 haloalkyl, C 1-8 alkyl having a C 1-8 alkoxy substituent, C 1-8 haloalkoxy, C 2-8 acyl, C 6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group having a C 6 - 1 0 aryl moiety and a C 1-8 alkylene moiety, or a C 1-8 alkyl group having a 5- or 6-membered heterocyclic substituent;
  • R 12 is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 alkyl having a 3- to 7-membered cycloalkyl substituent, C 1-8 haloalkyl, C 1-8 alkyl group having a C 1-8 alkoxy substituent, C 2-8 acyl, C 6-10 aryl, or an aralkyl group having a C 6-10 aryl moiety and a C 1-8 alkylene moiety; each of R 13 , R 14 , R 15 and R 16 independently is hydrogen, C 1-8 alkyl, or C 1-8 haloalkyl;
  • Y 1 is oxygen, sulfur, NR 18 or a bond, where R 18 is hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 acyl, or C 2-8 alkenyl;
  • a 1 when bond a is present, is oxygen CH 2 , N-NH 2 or N-OR 19 , where R 19 is hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 acyl, C 2-8 alkenyl, or an aralkyl group having a C 6-10 aryl moiety and a C 1- 8 alkylene moiety;
  • a 1 when bond a is absent, is OH;
  • Q 1 is hydrogen, halogen, hydroxyl, nitro, amino, C 1-8 alkyl group, C 3-7 cycloalkyl, C 2-8 alkenyl, C 2 - 8 alkynyl, alkoxy, C alkyl having a 3- to 7-membered cycloalkyl substituent, C haloalkyl, C 1-8 alkyl having a C 1-8 alkoxy substituent, C 1-8 haloalkoxy, C 2-8 acyl, C 6-10 aryl, or an aralkyl group having
  • R 11 represents hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3- to 7- membered cycloalkyl substituent, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an alkyl group having 1-8 carbon atoms and an alkoxy substituent having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, a 5- or 6- membered heterocyclic group, an aralkyl
  • R 12 represents hydrogen, an alkyl group having 1-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3- to 7-membered cycloalkyl substituent, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an alkyl group having 1-8 carbon atoms and having an alkoxy substituent having 1-8 carbon atoms, an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms.
  • each of R 13 , R 14 , R 15 and R 16 independently represents hydrogen, an alkyl group having 1-8 carbon atoms, or an alkyl group having 1-8 carbon atoms and having a halogen substituent.
  • Y 1 is oxygen, sulfur, NR 18 or a bond
  • R 18 representing hydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, or an alkenyl group having 2-8 carbon atoms.
  • a 1 is oxygen CH 2 , N-NH 2 or N-OR 19 , R 19 representing hydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms.
  • Q 1 represents hydrogen, halogen, hydroxyl, nitro, amino, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, an alkoxy group having 1- 8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3- to 7-membered cycloalkyl substituent, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an alkyl group having 1-8 carbon atoms and an alkoxy substituent having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene
  • s is an integer of 1 to 5.
  • the compounds having the Formula (V) can also be present in the form of an optical isomer such as enantiomer or racemic body, or a geometrical isomer such as cis or trans. Also provided are isomers of these compounds.
  • the compounds having the Formula (V) can be present in the form of a pharmaceutically acceptable salt.
  • the salt include an alkali metal salt, such as sodium salt, potassium salt and lithium salt.
  • the compound of Formula (V) is a compound shown in Table 10 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compounds of the invention are compounds of Formula (W): (W) or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • R 21 is hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-8 alkyl, C 3-7 cycloalkyl, C 2 - C8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 1-8 alkyl having a 3- to 7-membered cycloalkyl substituent, C 1-8 haloalkyl, C 1-8 alkyl having a C 1-8 alkoxy substituent, C 1-8 haloalkoxy, C 2-8 acyl, C 6-10 aryl group, a 5- or 6-membered heterocyclic group, an aralkyl group having a C 6- 10 aryl moiety and a C 1-8 alkylene moiety, or a C 1-8 alkyl group having a 5- or 6-membered heterocyclic substituent;
  • R 22 is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 alkyl having a 3- to 7-membered cycloalkyl substituent, C 1-8 haloalkyl, C 1-8 alkyl group having a C 1-8 alkoxy substituent, C 2-8 acyl, C 6-10 aryl, or an aralkyl group having a C 6-10 aryl moiety and a C 1-8 alkylene moiety; each of R 23 , R 24 , R 25 and R 26 independently is hydrogen, C 1-8 alkyl, or C 1-8 haloalkyl;
  • Y 2 is oxygen, sulfur, NR 28 or a bond, where R 28 is hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 acyl, or C 2-8 alkenyl;
  • Q 2 is hydrogen, halogen, hydroxyl, nitro, amino, C 1-8 alkyl group, C 3-7 cycloalkyl, C 2-8 alkenyl, C 2. 8 alkynyl, C 1-8 alkoxy, C 1-8 alkyl having a 3- to 7-membered cycloalkyl substituent, C 1-8 haloalkyl, C 1-8 alkyl having a C 1-8 alkoxy substituent, C 1-8 haloalkoxy, C 2-8 acyl, C 6-10 aryl, or an aralkyl group having a C 6-10 aryl moiety and a C 1-8 alkylene moiety; t is 1 , 2, 3, or 4; u is 1 , 2, 3, 4, or 5; R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl.
  • R 21 represents hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3- to 7- membered cycloalkyl substituent, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an alkyl group having 1-8 carbon atoms and an alkoxy substituent having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, a 5- or 6- membered heterocyclic group, an aralkyl
  • R 22 represents hydrogen, an alkyl group having 1-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a 3- to 7-membered cycloalkyl substituent, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an alkyl group having 1-8 carbon atoms and having an alkoxy substituent having 1-8 carbon atoms, an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, or an aralkyl group having an aryl moiety of 6-10 carbon atoms and an alkylene moiety of 1-8 carbon atoms.
  • each of R 23 , R 24 , R 25 and R 26 independently represents hydrogen, an alkyl group having 1-8 carbon atoms, or an alkyl group having 1-8 carbon atoms and having a halogen substituent.
  • Y 2 is oxygen, sulfur, NR 28 or a bond, R 28 representing hydrogen, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, or an alkenyl group having 2-8 carbon atoms.
  • Q 2 represents hydrogen, halogen, hydroxyl, nitro, amino, an alkyl group having 1-8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, an alkoxy group having 1- 8 carbon atoms, an alkyl group having 1 -8 carbon atoms and having a 3- to 7-membered cycloalkyl substituent, an alkyl group having 1-8 carbon atoms and having a halogen substituent, an alkyl group having 1-8 carbon atoms and an alkoxy substituent having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms and having a halogen substituent, an acyl group having 2-8 carbon atoms, an aryl group having 6-10 carbon atoms, or an aralkyl group having an aryl moiety of 6- 10 carbon atoms and an alky
  • t is an integer of 1 to 4.
  • u is an integer of 1 to 5.
  • the compounds having the Formula (W) can also be present in the form of an optical isomer such as enantiomer or racemic body, or a geometrical isomer such as cis or trans. Also provided are isomers of these compounds.
  • the compounds having the Formula (W) can be present in the form of a pharmaceutically acceptable salt.
  • the salt include an alkali metal salt, such as sodium salt, potassium salt and lithium salt.
  • the compound of Formula (W) is a compound shown in Table 11 or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compounds of the invention are compounds of Formula (X): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • R 1 is hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, CN, C 1-4 alkoxy, C 1-4 haloalkoxy, or C 3-6 cycloalkyl;
  • Q 1 is CH or N;
  • R 2 is hydrogen, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, S( C 1-4 alkyl), SO 2 ( C 1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C ⁇ C-R 2A , O(CH 2 ) m R 2B , NH( C 1-4 alkyl), N(C 1-4 alkyl) 2 , or C(O)( C 1-4 alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 alkyl, formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or 3; x is 1 or 2;
  • R 2A and R 2B are each independently C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl; each R 20 is independently hydrogen, halogen, C 1-4 alkyl, CN, or C 1-4 alkoxy;
  • R 3 is CH 3 or CD3;
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H, each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; and each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl.
  • the compounds of the invention are compounds of Formula (Y): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • R 1 is hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, CN, C 1-4 alkoxy, C 1-4 haloalkoxy, or C 3-6 cycloalkyl;
  • Q 1 is CH or N
  • R 2 is hydrogen, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, S(C 1-4 alkyl), SO 2 (C 1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C ⁇ C-R 2A , O(CH 2 )mR 2B , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , or C(O)(C 1-4 alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 alkyl, formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or 3; x is 1 or 2;
  • R 2A and R 2B are each independently C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl; each R 20 is independently hydrogen, halogen, C 1-4 alkyl, CN, or C 1-4 alkoxy;
  • R 3 is CH 3 or CD 3 ;
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; and each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl.
  • the compounds of the invention are compounds of Formula (Z): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein: R 1 is hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, CN, C 1-4 alkoxy, C 1-4 haloalkoxy, or C 3-6 cycloalkyl;
  • Q 1 is CH or N
  • R 2 is hydrogen, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, S( C 1-4 alkyl), SO 2 (C 1-4 -alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C ⁇ C-R 2A , O(CH 2 ) m R 2B , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , or C(O)(C 1-4 alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 alkyl, formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or 3; x is 1 or 2;
  • R 2A and R 2B are each independently C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl; each R 20 is independently hydrogen, halogen, C 1-4 alkyl, CN, or C 1-4 alkoxy;
  • R 3 is CH 3 or CD 3 ;
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H, each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; and each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl.
  • the compounds of the invention are compounds of Formula (AA): or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
  • L is (CH 2 ) 5 , which is unsubstituted or substituted by one methyl group
  • R 1 is hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, CN, C 1-4 alkoxy, C 1-4 haloalk oxy, or C 3-6 cycloalkyl;
  • R 2 is hydrogen, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, S(C 1-4 alkyl), S02(C-4-alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, C ⁇ C-R 2A , O(CH 2 ) m R 2B , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , or C(O)(C 1-4 alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 alkyl, formyl, acetyl, acetoxy, or carboxy, and wherein m is 1, 2, or 3; x is 0 or 1 ;
  • R 2A and R 2B are each independently C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl;
  • R 3 is C 1-4 haloalkyl, NO 2 , CN, halogen, or C(O)O(C 1-4 alkyl);
  • R 20 is hydrogen, halogen, C 1-4 alkyl, CN, or C 1-4 alkoxy;
  • R X is CH 2 OH, COH, COOCH 2 CONR X4 R X5 , SO 3 H,
  • each R X4 and R X5 is independently alkyl, aryl, or heteroaryl; or alternatively, R X4 and R X5 together with the carbon atom to which R X4 and R X5 are attached form a heterocycle; and each R X6 and R X7 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl.
  • the compound of the invention is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • Compound VII or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • the compound of the invention is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe-N-[0341]
  • Compound VIII or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • compositions of the invention comprise (i) an effective amount of a compound of the invention and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of a racemate of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of a mixture of enantiomers of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I has an hydroxyl-bearing allylic carbon atom having an (R)-enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I has an hydroxyl-bearing allylic carbon atom having an (R)- enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of the (S)-enantiomer of Compound I or a pharmaceutically acceptable salt or thereof.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of the (R)-enantiomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • compositions of the invention comprise (i) an effective amount of a non-racemic mixture of an (R)-enantiomer and an (S)-enantiomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • the non- racemic mixture has an excess of (R)-enantiomer relative to (S)-enantiomer.
  • the non-racemic mixture has an excess of (S)-enantiomer relative to ( R )- enantiomer.
  • compositions of the invention comprise (i) an effective amount of a (Z)-isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of a (Z)- isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of the (E)-isomer of Compound I or a pharmaceutically acceptable salt or thereof.
  • compositions of the invention comprise (i) an effective amount of an (E)-isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of an (E)- isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of the (Z)-isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • compositions of the invention comprise (i) an effective amount of a non-equal mixture of a (Z)-isomer and an (E)- isomer of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • the non-equal mixture has an excess of (Z)-isomer relative to (E)- isomer. In some embodiments, the non-equal mixture has an excess of (E)- isomer relative to (Z)-isomer.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I is an (Z)-isomer and has an hydroxyl-bearing allylic carbon atom having an (R)-stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle,.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I is an (Z)-isomer and has an hydroxyl-bearing allylic carbon atom having an (R)-stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of Compounds ((Z)-(S)-I), ((E)-(R)-I), or ((E)-(S)-I), or a pharmaceutically acceptable salt or thereof.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I is an (Z)-isomer and has an hydroxyl-bearing allylic carbon atom having an (S)-stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I is an (Z)-isomer and has an hydroxylbearing allylic carbon atom having an (S)-stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of Compounds ((Z)-(R)-I), ((E)-(R)-I), or ((E)-(S)-I), or a pharmaceutically acceptable salt or thereof.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I is an (E)-isomer and has an hydroxyl-bearing allylic carbon atom having an (R)- stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I is an (E)- isomer and has an hydroxyl-bearing allylic carbon atom having an (R)- stereochemistry, (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of Compounds (E)-(S)- 1), ((Z)-(R)-I), or ((Z)-(S)-I), or a pharmaceutically acceptable salt or thereof.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I is an (E)-isomer and has an hydroxyl-bearing allylic carbon atom having an (S)-stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound I is an (E)-isomer and has an hydroxyl-bearing allylic carbon atom having an (S)-stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of Compounds ((E)-(R)-I), ((Z)-(R)-I), or ((Z)-(S)-I), or a pharmaceutically acceptable salt or thereof.
  • the composition of the invention comprises (i) an effective amount of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • the composition of the invention comprises (i) an effective amount of a (Z)-isomer of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • the composition of the invention comprises (i) an effective amount of a (Z)-isomer of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of the (E)-isomer of Compound II or a pharmaceutically acceptable salt or thereof.
  • the composition of the invention comprises (i) an effective amount of an (E)- isomer of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • the composition of the invention comprises (i) an effective amount of an fE>isomer of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of the (Z)-isomer of Compound II or a pharmaceutically acceptable salt or thereof.
  • the compositions of the invention comprise (i) an effective amount of a non-equal mixture of a (Z)-isomer and an (E)-isomer of Compound II or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • the non-equal mixture has an excess of (Z)-isomer relative to (E)- isomer. In some embodiments, the non-equal mixture has an excess of (E)- isomer relative to (Z)-isomer.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of a racemate of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of a mixture of enantiomers of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III has an hydroxyl-bearing allylic carbon atom having an (R)-enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III has an hydroxyl-bearing allylic carbon atom having an (R)-enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of the (S)-enantiomer of Compound III or a pharmaceutically acceptable salt or thereof.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III has an hydroxyl-bearing allylic carbon atom having an (S)-enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of the (R)-enantiomer of Compound 111 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • compositions of the invention comprise (i) an effective amount of a non-racemic mixture of an (R)-enantiomer and an (S)-enantiomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • the non- racemic mixture has an excess of (/ ⁇ -enantiomer relative to (S)-enantiomer.
  • the non-racemic mixture has an excess of (S)-enantiomer relative to (R)- enantiomer.
  • compositions of the invention comprise (i) an effective amount of a (ZJ-isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of a (Z)- isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of the (E)- isomer of Compound III or a pharmaceutically acceptable salt or thereof.
  • compositions of the invention comprise (i) an effective amount of an (E)-isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of an (E)- isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of the (Z)-isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
  • compositions of the invention comprise (i) an effective amount of a non-equal mixture of a (Z)-isomer and an (E)- isomer of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • the non-equal mixture has an excess of (Z)-isomer relative to (E)-isomer. In some embodiments, the non-equal mixture has an excess of (E)-isomer relative to (Z)-isomer.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III is an (Z)-isomer and has an hydroxyl-bearing allylic carbon atom having an (R)-stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle,.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III is an (Z)-isomer and has an hydroxyl-bearing allylic carbon atom having an (R)-stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of Compounds ((Z)-(S)-lll), ((E)-(R)-lll), or ((E)-(S)-III), or a pharmaceutically acceptable salt or thereof.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III is an (Z)-isomer and has an hydroxyl-bearing allylic carbon atom having an (S)- stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III is an (Z)-isomer and has an hydroxyl-bearing allylic carbon atom having an (S)- stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of Compounds ((Z)-(R)-III), ((E)-(R)-lll), or ((E)-(S)-III), or a pharmaceutically acceptable salt or thereof.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III is an (E)-isomer and has an hydroxyl-bearing allylic carbon atom having an (R)-stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III is an (E)-isomer and has an hydroxyl-bearing allylic carbon atom having an (R)-stereochemistry, (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of Compounds (E)-(S)- III), ((Z)-(R)-III), or ((Z)--S)-III), or a pharmaceutically acceptable salt or thereof.
  • compositions of the invention comprise (i) an effective amount of Compound Ilf or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III is an (E)-isomer and has an hydroxyl-bearing allylic carbon atom having an (S)- stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound III or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein Compound III is an (E)-isomer and has an hydroxyl-bearing allylic carbon atom having an (S)- stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the compositions are substantially free of Compounds ((E)-(R)-III), ((Z)-(R)- III), or ((Z)-(S)-lll), or a pharmaceutically acceptable salt or thereof.
  • compositions of the invention comprise (i) an effective amount of Compound IV or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound V or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound VI or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound Via or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound Vlb or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound VII or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention comprise (i) an effective amount of Compound VIII or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
  • compositions of the invention further comprise another therapeutically active agent.
  • a composition of the invention further comprising another therapeutically active agent is a “combination of the invention.”
  • the present invention provides combinations of the invention.
  • the combination of the invention can comprise one or more therapeutically active agents.
  • the other therapeutically active agent is a lipid lowering drug, a statin, a cholesterol absorption inhibitor, an antibody against PCSK9, an siRNA PCSK9, an anti-fibrotic agent, a thyroid hormone, a selective thyroid receptor-b agonist, apoptosis signalregulating kinase 1 (ASK1) inhibitor, acetyl-CoA carboxylase (ACC) inhibitor, an integrin antagonist, or a non-steroidal Farnesoid X receptor (FXR) agonist.
  • ASK1 apoptosis signalregulating kinase 1
  • ACC acetyl-CoA carboxylase
  • FXR non-steroidal Farnesoid X receptor
  • the lipid lowering drug is gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate, clinofibrate, etofylline, pirifibrate, simfibrate, tocofibrate, or pemafibrate.
  • the lipid lowering drug is gemfibrozil, fenofibrate, bezafibrate, or pemafibrate.
  • statin is atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, dalvastatin, dihydrocompactin, or cerivastatin, or a pharmaceutically acceptable salt or solvate thereof.
  • statin is atorvastatin, simvastatin, pravastatin or rosuvastatin, or a pharmaceutically acceptable salt or solvate thereof.
  • the cholesterol absorption inhibitor is ezetimibe.
  • the antibody against PCSK9 is evolocumab alirocumab, bococizumab, 1D05-lgG2 (Merck), RG7652 (Genentech), LY3015014 (Eli Lilly), or LGT-209 (Novartis/Cyon Therapeutics).
  • the antibody against PCSK9 is evolocumab or alirocumab.
  • the siRNA PCSK9 is an siRNA interfering with production of PCSK9 such as inclisiran.
  • the anti-fibrotic agent is nitazoxamide, tizoxanide, or tizoxanide glucuronide, nintedanib, imatinib, or a pharmaceutically acceptable salt or solvate thereof.
  • the selective thyroid receptor-b agonist is VK2809 (Viking Therapeutics), MGL-3196 (Madrigal Pharmaceuticals), MGL-3745 (Madrigal Pharmaceuticals), SKL-14763, sobetirome, BCT304 (ITL Pharma), ZYT1 (Zydus Cadila), MB-0781 (Metabasis), or eprotirome.
  • the ASK1 inhibitor is selonsertib.
  • the ACC inhibitor is firsocostat.
  • the integrin antagonist is an a5b1 inhibitor or a pan integrin inhibitor.
  • the integrin antagonist is IDL-2965 (Indalo Therapeutics).
  • the integrin antagonist is CLT-28643 (ClanoTech AB).
  • the integrin antagonist is 3-(6-Methoxypyridin-3-yl)-3-(4-(3- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-- yl)propyl)-1H-indazol-1-yl)propanoic acid; 3-(6- Methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)-1H-indazol-1- yl)propanoic acid; 3-(6-Methoxypyridin-3-yl)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-- yl)ethoxy)-1H-indazol-1-yl)propanoic acid; (S)-2-(((Benzyloxy)
  • the integrin antagonist is (S)-3-(3-(2-methoxyethoxy)phenyl)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-nap- hthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid; (S)-3-(3- ((R)-2-methoxypropoxylphenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,- 8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid; (S)-3-(3-((S)-2-methoxypropoxylphenyl)-4-4R)-3-(2- (5,6,7,8-tetrahydro-1,8- -naphthyridin-2-yl)ethyl)pyrrolidin-1
  • the integrin antagonist has the structure
  • the integrin antagonist has the structure
  • the non-steroidal Farnesoid X receptor (FXR) agonist is cilofexor.
  • the combinations of the invention comprise selonsertib, firsocostat or cilofexor. In some embodiments, the combinations of the invention comprise selonsertib and firsocostat. In some embodiments, the combinations of the invention comprises selonsertib and cilofexor. In some embodiments, the combinations of the invention comprises fircosostat and cilofexor. In some embodiments, the combinations of the invention comprise selonsertib, firsocostat and cilofexor.
  • 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, hydroxye
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.
  • 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%, about 6%, about 7%, about 8%, about 9%, about 8%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% by weight or any range within any of these values.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, 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.
  • 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.
  • the diluent is present in the composition of the invention at about 15%, about 16%, about 17%, about 18%, about 19%, about 18%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 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 pregelatinized 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%, about 6%, about 7%, about 8%, about 9%, about 8%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 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, com 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, MA); 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, MA), 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, stevioside (Stevia) 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.
  • 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.
  • compositions of the invention suitable for oral administration are in the form of a tablet or a capsule.
  • the composition of the invention is in a form of a tablet.
  • the composition of the invention is in a form of a capsule.
  • 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.
  • 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.
  • 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.
  • a pharmaceutically acceptable liquid carrier e.g., water
  • 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.
  • 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.
  • 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.
  • 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, solvate, ester, amide, or prodrug thereof in a modified release form, both compressed into a single tablet.
  • a statin or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof in a modified release form, both compressed into a single tablet.
  • compositions of the invention are a matrix-controlled release dosage form.
  • 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.
  • 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), carrrboxym ethyl ethyl cellulose (CMEC,) hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA),
  • EC ethy
  • 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 minitablets 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
  • the 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, adip
  • 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 (SP1 Pharma, Lewes, DE) 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 copoly
  • 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.
  • 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-re!ease 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 asymmetric membrane technology
  • 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.
  • 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.
  • the 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 0.1 hr to 24 hrs.
  • 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 embodiments, 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 embodiments, 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 liver disorder, dyslipidemia, dyslipoproteinemia, a renal disease, a disorder of glucose metabolism, a disorder of lipid metabolism, a disorder of glucid metabolism, a cardiovascular disease, a vascular disease, a metabolic syndrome, a complication associated with metabolic syndrome, a PPAR- associated disorder, septicemia, a thrombotic disorder, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, a cerebrovascular disease, a disorder related to neovascularization, hypertension, cancer, inflammation, an inflammatory disease, a neurodegenerative disease, an autoimmune disease, a neoplastic disease, muscle atrophy, cholestasis, mitochondrial dysfunction, an ocular disease, a lysosomal storage disease, or impotence, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the present invention compris
  • the present invention provides methods for treating or preventing a liver disorder, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the liver disorder involves pathological disruption, inflammation, degeneration, apoptosis, or proliferation of liver cells.
  • the liver disorder is liver fibrosis, fatty liver disease, nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).
  • the present invention provides methods for reducing an abnormally high concentration of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), bilirubin, gamma-glutamyltransferase (GGT), L-lactate dehydrogenase (LD), prothrombin time (PT), creatinine, or total protein 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 a composition of the invention.
  • ALT alanine transaminase
  • AST aspartate transaminase
  • ALP alkaline phosphatase
  • GGT gamma-glutamyltransferase
  • LD L-lactate dehydrogenase
  • PT prothrombin time
  • the present invention provides methods for elevating an abnormally low concentration of albumin or total protein, 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 a composition of the invention.
  • An “abnormally high concentration” of ALT in a subject’s blood plasma or blood serum is greater than 56 units/liter.
  • the reducing is to a normal concentration.
  • the normal concentration of ALT in a subject’s blood plasma or blood serum ranges from about 7 units/liter to about 56 units/liter.
  • An “abnormally high concentration” of AST in a subject’s blood plasma or blood serum is greater than 48 units/liter.
  • the reducing is to a normal concentration.
  • the normal concentration of AST in a subject’s blood plasma or blood serum ranges from about 8 units/liter to about 48 units/liter.
  • An “abnormally high concentration” of ALP in a subject’s blood plasma or blood serum is greater than 129 units/liter.
  • the reducing is to a normal concentration.
  • the normal concentration of ALP in a subject’s blood plasma or blood serum ranges from about 40 units/liter to about129 units/liter.
  • An “abnormally low concentration” of albumin in a subject’s blood plasma or blood serum is less than 3.5 g/dL.
  • the elevating is to a normal concentration.
  • the normal concentration of albumin in a subject’s blood plasma or blood serum ranges from about 3.5 g/dL to about 5.0 g/dL.
  • An “abnormally high concentration” of bilirubin in a subject’s blood plasma or blood serum is greater than 1.2 mg/dL.
  • the reducing is to a normal concentration.
  • the normal concentration of bilirubin in a subject’s blood plasma or blood serum ranges from about 0.1 mg/dL to about 1.2 mg/dL.
  • An “abnormally high concentration” of GGT in a subject’s blood plasma or blood serum is greater than 61 units/liter. In some embodiments, the reducing is to a normal concentration.
  • the normal concentration of GGT in a subject’s blood plasma or blood serum ranges from about 8 units/liter to about 61 units/liters.
  • An “abnormally high concentration” of LD in a subject’s blood plasma or blood serum is greater than 222 units/liter.
  • the reducing is to a normal concentration.
  • the normal concentration of LD in a subject’s blood plasma or blood serum ranges from about 122 units/liter to about 222 units/liters.
  • An “abnormally high concentration” of PT in a subject’s blood plasma or blood serum is greater than 12.5 seconds.
  • the reducing is to a normal concentration.
  • the normal concentration of PT in a subject’s blood plasma or blood serum ranges from about 9.4 seconds to about 12.5 seconds.
  • An “abnormally high concentration” of creatinine in a subject’s blood plasma or blood serum is greater than 1.5 mg/dL, which corresponds to a glomerular filtration rate (GFR) of approximately 30 mL/min and indicative of renal failure.
  • the reducing is to a normal concentration.
  • the normal concentration of creatinine in a subject’s blood plasma or blood serum ranges from about 0.84 mg/dL to about 1.21 mg/dL. (about 74.3 ⁇ mol/L to about 107 ⁇ mol/L).
  • An “abnormally high concentration” of total protein in a subject’s blood plasma or blood serum is greater than 7.9 g/dL.
  • An “abnormally low concentration” of total protein in a subject’s blood plasma or blood serum is less than 6.3 g/dL.
  • the reducing is to a normal concentration.
  • the elevating is to a normal concentration.
  • the normal concentration of total protein in a subject’s blood plasma or blood serum ranges from about 6.3 g/dL to about 7.9 g/dL.
  • the present invention provides methods for treating or preventing NAFLD or NASH, 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 treating or preventing dyslipidemia, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • the dyslipidemia is hyperlipidemia or an abnormally low concentration of high density lipoprotein cholesterol (HDL-C) in the subject’s blood plasma or blood serum.
  • HDL-C high density lipoprotein cholesterol
  • the term “dyslipidemia” refers to a disorder that leads to or is manifested by an aberrant level of circulating lipids.
  • the present invention provides methods for restoring blood plasma or blood serum concentration of total-cholesterol, low density lipoprotein cholesterol (LDL-C), HDL-C, non-HDL-C or free triglycerides to a normal or recommended concentration or ratio. Accordingly, to the extent that levels of lipids in the blood plasma or blood serum are abnormally high, the compounds of the invention or the compositions of the invention can be administered to a patient to restore normal levels. Normal levels of lipids are well known to those skilled in the art.
  • lipid metabolism normal blood levels of total-cholesterol, low density lipoprotein cholesterol (LDL-C), HDL-C, non-HDL-C, free triglycerides and others parameters relating to lipid metabolism can be found at the web site of the American Heart Association, The National Lipid Association and that of the National Cholesterol Education Program of the National Heart, Lung and Blood Institute.
  • a recommended concentration of HDL-C in the blood plasma or the blood serum is above 35 mg/dl.
  • a recommended concentration of LDL-C in the blood plasma or the blood serum is below 100 mg/dl.
  • a recommended LDL-C:HDL-C ratio in the blood plasma or in the blood serum is below 5:1 , in some embodiments, 3.5:1. In some embodiments, a recommended concentration of free triglycerides in the blood plasma or the blood serum is less than 200 mg/dl.
  • the present invention provides methods for treating or preventing hyperlipidemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • hyperlipidemia is hypercholesterolemia, familial hypercholesterolemia, hypertriglyceridemia, or familial combined hyperlipidemia.
  • hyperlipidemia is characterized by an abnormally reduced or deficient lipoprotein lipase level or activity in the subject’s blood plasma or blood serum, or an abnormally high concentration of ketone bodies, lipoprotein(a) cholesterol (Lp(a)-C), low density lipoprotein (LDL), very low density lipoproteins cholesterol (VLDL-C) or non-esterified fatty acids (NEFA) in the subject’s blood plasma or blood serum.
  • the reduced or deficient lipoprotein lipase level or activity is a result of a lipoprotein lipase mutation.
  • the reduced or deficient lipoprotein lipase level or activity is a result of a mutation in a gene encoding a lipoprotein lipase.
  • Non-limiting examples of ketone bodies include acetoacetate, beta-hydroxybutyrate, and acetone.
  • An “abnormally high concentration” of ketone bodies in a subject’s blood plasma or blood serum is 1 mg/dL or greater ( ⁇ 0.1 mmol/L).
  • the present invention provides methods for reducing an abnormally high concentration of ketone bodies in a subject’s blood plasma or blood serum, wherein the concentration is 1 mg/dL or greater.
  • the reducing is to a normal level.
  • the normal level is less than 1 mg/dL ( ⁇ 0.1 mmol/L). See Devkota, B. P. et al. Medscape emedicine, updated Oct. 30, 2015.
  • an “abnormally high concentration” of VLDL-C in a subject’s blood plasma or blood serum is greater than 30 mg/dL (1.7 mmol/L)
  • the present invention provides methods for reducing VLDL-C concentration in a subject’s blood plasma or blood serum, wherein the VLDL-C concentration is greater than 30 mg/dL.
  • the reducing is to a normal level. In some embodiments, the normal level ranges from 2 mg/dL to 30 mg/dL (0.1 to 1.7 mmol/L).
  • An “abnormally high concentration” of NEFA is in a subject’s blood plasma or blood serum in a non-fasting state is 0.9 mM or greater.
  • An “abnormally high concentration” of NEFA in a subject’s blood plasma or blood serum in a fasting state is greater than 1.8 mM at a fasting state.
  • An “abnormally high concentration” of NEFA in a subject’s blood plasma or blood serum at 15-hour fasting is greater than 1.1 nM.
  • An “abnormally high concentration” of NEFA in a subject’s blood plasma or blood serum at 20-hour fasting is greater than 1.3 mM.
  • an “abnormally high concentration” of NEFA in a subject’s blood plasma or blood serum at 15-hour fasting is greater than 1.1 nM.
  • An “abnormally high concentration” of NEFA in a subject's blood plasma or blood serum at 24-hour fasting is greater than 1.8 mM.
  • the present invention provides methods for reducing NEFA concentration in a subject’s blood plasma or blood serum, wherein the NEFA concentration is greater than 0.9 mM, in some embodiments greater than 1.1 mM, in some embodiments greater than 1.5 mM and in some embodiments greater than 1.8 mM.
  • the reducing is to a normal level.
  • the normal level is 1.8 mM or less, in some embodiments 1.5 mM or less, in some embodiments 1.1 mM or less and in some embodiments 0.9 mM or less. See Horowitz, G. L. et al. Medscape emedicine, updated July 25, 2019.
  • the present invention provides methods for treating or preventing dyslipoproteinemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the dyslipoproteinemia is characterized by an abnormally high concentration of LDL, apolipoprotein (a) or VLDL in a subject’s blood plasma or blood serum, or an abnormally low concentration of high density lipoprotein (HDL) or lipoprotein lipase in a subject’s blood plasma or blood serum.
  • the abnormally low concentration of the lipoprotein lipase is associated with: a lipoprotein lipase mutation, hypoalphalipoproteinemia, a lipoprotein abnormality associated with diabetes, a lipoprotein abnormality associated with obesity, a lipoprotein abnormality associated with Alzheimer’s disease, or familial combined hyperlipidemia.
  • the term "dyslipoproteinemia” refers to a disorder that leads to or is manifested by an aberrant concentration of circulating lipoproteins in a subject’s blood plasma or blood serum. To the extent that the concentrations of lipoproteins in the blood plasma or blood serum are too high, the compounds of the invention or the compositions of the invention can be administered to the subject to restore to normal concentrations of lipoproteins.
  • the compounds of the invention or the compositions of the invention can be administered to the subject to restore to normal concentrations.
  • Normal concentrations of lipoproteins are reported in medical treatises known to those of skill in the art.
  • the present invention provides methods for treating or preventing a renal disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the renal disease is a glomerular disease, a tubular disease, a tubulointerstitial disease, acute or rapidly progressive renal failure, chronic renal failure, nephrolithiasis, or a tumor.
  • the renal disease is hypertension, nephrosclerosis, microangiopathic hemolytic anemia, atheroembolic renal disease, diffuse cortical necrosis, or a renal infarct.
  • the glomerular disease is an acute glomerulonephritis, a chronic glomerulonephritis, a rapidly progressive glomerulonephritis, a nephrotic syndrome, a focal proliferative glomerulonephritis, a glomerular lesion associated with systemic disease, Goodpasture syndrome, multiple myeloma, diabetes, neoplasia, sickle cell disease or a chronic inflammatory disease.
  • the glomerular lesion associated with systemic disease is systemic lupus erythematosus.
  • the tubular disease is an acute tubular necrosis, an acute renal failure, a polycystic renal disease, medullary sponge kidney, a medullary cystic disease, nephrogenic diabetes, or a renal tubular acidosis.
  • the tubulointerstitial disease is pyelonephritis, a drug- or toxin- induced tubulointerstitial nephritis, a hypercalcemic nephropathy, or a hypokalemic nephropathy.
  • the tumor is renal cell carcinoma or nephroblastoma.
  • the renal disease is hypertension.
  • the hypertension is an essential hypertension, hyperpiesa, hyperpiersis, a malignant hypertension, a secondary hypertension, or a white-coat hypertension.
  • the renal disease is a kidney disease.
  • the present invention provides methods for treating or preventing a disorder of glucose metabolism, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • disorder of glucose metabolism refers to a disorder that leads to or is manifested by aberrant glucose storage and/or utilization.
  • indicia of glucose metabolism i.e . insulin, glucose, or glycated hemoglobin in a subject’s blood plasma or blood serum
  • the compounds of the invention or the compositions of the invention can be administered to a subject to restore to normal levels. Normal indicia of glucose metabolism are reported in medical treatises known to those of skill in the art. See US 7,709,682 B2.
  • the present invention provides methods for reducing an abnormally high concentration of glucose 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 a composition of the invention.
  • An “abnormally high concentration" of glucose in a subject’s blood plasma or blood serum at a fasted state (10-16 hours without eating) is greater than 5.6 mmol/L (100 mg/dL).
  • the reducing is to a normal concentration.
  • the normal concentration of glucose is less than 5.6 mmol/L at fasted state.
  • a fasted glucose blood plasma or blood serum concentration in the range of 5.6 mmol/L to 6 mmol/L (100-109 mg/dL) may indicate prediabetes.
  • a fasted glucose blood plasma or blood serum concentration in the range of 6.1 mmol/L to 6.9 mmol/L (110-125 mg/dL) can indicate diabetes.
  • a fasted glucose blood plasma or blood serum concentration of 7 mmol/L (126 mg/dL) and above indicates diabetes.
  • the abnormally high concentration of glucose in a subject’s blood plasma or blood serum is measured in a glucose tolerance test (GTT).
  • GTT glucose tolerance test
  • An “abnormally high concentration” of glucose in a subject’s blood plasma or blood serum in a one-hour GTT is greater than 10 mmol/L (180 mg/dL). In some embodiments, the reducing is to a normal concentration. In some embodiments, the normal concentration in a one-hour GTT is less than 10 mmol/L (180 mg/dL).
  • An “abnormally high concentration” of glucose in a subject’s blood plasma or blood serum in a two-hour GTT with 75 g intake is greater than 7.8 mmol/L (140 mg/dL), which indicates hyperglycemia. In some embodiments, the reducing is to a normal concentration.
  • the normal concentration in two-hour GTT with 75 g intake is less than 7.8 mmol/L (140 mg/dL).
  • a glucose concentration in a subject s blood plasma or blood serum between 7.8 mmol/L (140 mg/dL) and 11.1 mmol/L (200 mg/dL) in two- hour GTT with 75 g intake indicates impaired glucose tolerance.
  • a glucose concentration above 11.1 mmol/L in two-hour GTT with 75 g intake indicates diabetes.
  • the present invention provides methods for increasing abnormally low glucose metabolism in a subject, wherein the subject’s glucose concentration in the subject’s blood plasma or blood serum is greater than 7.8 mmol/L (140 mg/dL) in a two- hour GTT. In some embodiments, the present invention provides methods treating or preventing a disorder of glucose metabolism in a subject, wherein the subject’s glucose concentration in the subject’s blood plasma or blood serum is in the range of 7.8 mmol/L (140 mg/dL) to 11.1 mmol/L (200 mg/dL) in a two-hour GTT.
  • the present invention provides methods for treating or preventing a disorder of glucose metabolism in a subject, wherein the subject’s glucose concentration in the subject’s blood plasma or blood serum is greater than 11.1 mmol/L (200 mg/dL) in a two-hour GTT.
  • the present invention provides methods for reducing an abnormally high level of HbA 1c 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 a composition of the invention.
  • An “abnormally high level” of hemoglobin A1c (HbA 1c ) in a subject’s blood plasma or blood serum is 6.5% or greater (expressed in % NGSP units).
  • the reducing is to a normal level.
  • the normal levels of HbA 1c is in the range of about 4% to about 5.9%.
  • the present invention provides methods for reducing HbA 1c level in a subject’s blood plasma or blood serum, wherein the HbA 1c level is greater than 7%, greater than 8%, or greater than 9%. See Horowitz, G. L. et al. Medscape emedicine, updated July 25, 2019.
  • the present invention provides methods for increasing abnormally low glucose metabolism in a subject, wherein the subject’s HbA 1c level is 6.5% or greater and the subject's fasting glucose concentration is 126 mg/dL or greater (3 7.0 mmol/L), in the subject’s blood plasma or blood serum. See Selvin, E. et al. Ann Intern Med. Published online June 18, 2018.
  • the present invention provides methods for treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has HbA 1c greater than or equal to 6.5%. In some embodiments, the present invention provides methods for treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has HbA 1c greater than or equal to 6.5% and fasting glucose concentration greater than or equal to 126 mg/dL (7.0 mmol/L) in the subject’s blood plasma or blood serum.
  • the present invention provides methods for reducing an abnormally high concentration of glucose 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 a composition of the invention, wherein the subject is pregnant.
  • An “abnormally high concentration” of glucose in a pregnant subject’s blood plasma or blood serum at fasted state is greater than 5.3 mmol/L (95 mg/dL).
  • the present invention provides methods for reducing an abnormally high concentration of glucose in a subject’s blood plasma or blood serum, comprising administering to a subject in need thereof (i) a glucose solution as part of a two-step gestational diabetes test and (ii) an effective amount of a compound of the invention or a composition of the invention.
  • An "abnormally high concentration” of glucose in a subject’s blood plasma or blood serum at 1 hour after drinking the glucose solution in a two-step gestational diabetes test is greater than 10 mmol/L (180 mg/dL).
  • the first step is a 50 g glucose dose.
  • the present invention provides methods for treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has impaired glucose tolerance. In some embodiments, the present invention provides methods for treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has diabetes.
  • the present invention provides methods for treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has confirmed undiagnosed diabetes. In some embodiments, the present invention provides methods for treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has gestational diabetes.
  • the present invention provides methods for reducing abnormally high concentration of insulin 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 a composition of the invention.
  • An “abnormally high concentration” of insulin in a subject’s blood plasma or blood serum at a fasted state is greater than 25 mlU/L (>174 ⁇ moi/L).
  • the reducing is to a normal concentration.
  • the normal concentration of insulin in a subject’s blood plasma or blood serum at a fasted state is less than 25 mlU/L ( ⁇ 174 pmol/L). See Buppajarntham, S. et al. Medscape emedicine, updated Jan. 2, 2019.
  • the present invention provides methods for reducing abnormally high concentration of insulin 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 a composition of the invention.
  • the methods further comprise administering glucose to the subject. In some embodiments, the methods do not comprise administering glucose to the subject. In some embodiments, the subject is in a fasted state.
  • the subject has an abnormally concentration of insulin in the subject’s blood plasma or blood glucose at 30 minutes after glucose administration.
  • An "abnormally high concentration"’ of insulin in a subject’s blood plasma or blood serum at 30 minutes after glucose administration is greater than 230 mlU/L (>1597 pmol/L).
  • the reducing is to a normal concentration.
  • the normal concentration of insulin in a subject’s blood plasma or blood serum at 30 minutes after glucose administration is in the range of about 30 mlU/L to about 230 mlU/L (208-1597 pmol/L). See Buppajarntham, 2019.
  • the subject has an abnormally concentration of insulin in the subject’s blood plasma or blood serum at 1 hour after glucose administration.
  • An “abnormally high concentration” of insulin in a subject’s blood plasma or blood serum at 1 hour after glucose administration is greater than 276 mlU/L (>1917 pmol/L).
  • the present invention provides methods for reducing abnormally high concentration of insulin 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 a composition of the invention.
  • the reducing is to a normal concentration.
  • the normal concentration of insulin in a subject’s blood plasma or blood serum at 1 hour after glucose administration is in the range of about 18 mlU/L to about 276 mlU/L (125-1917 pmol/L). See Buppajarntham, 2019.
  • the subject has an abnormally concentration of insulin in the subject’s blood plasma or blood glucose at 2 hours after glucose administration.
  • An “abnormally high concentration” of insulin in a subject’s blood plasma or blood serum at 2 hour after glucose administration is greater than 166 mlU/L (>1153 pmol/L).
  • the present invention provides methods for reducing an abnormally high concentration of insulin 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 a composition of the invention.
  • the normal concentration of insulin in a subject’s blood plasma or blood serum at 2 hours after glucose administration is in the range of about 16 mlU/L to about 166 mlU/L (HI- 1153 pmol/L). See Buppajarntham, 2019.
  • the subject has an abnormally concentration of insulin in the subject’s blood plasma or blood glucose at 3 hours after glucose administration.
  • An “abnormally high concentration” of insulin in a subject’s blood plasma or blood serum at 3 hours after glucose administration is greater than 25 mlU/L (> 174 pmol/L).
  • the present invention provides methods for reducing an abnormally high concentration of insulin 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 a composition of the invention.
  • the normal concentration of insulin in a subject s blood plasma or blood serum at
  • the present invention provides methods for treating or preventing a disorder of glucose metabolism in a subject, wherein the subject has insulin concentration in the subject’s blood plasma or blood serum above 25 mlU/L at a fasted state or after 3 hours after glucose administration. See Buppajarntham, 2019.
  • the disorder of glucose metabolism is an impaired glucose tolerance; an insulin resistance; an insulin resistance-related breast, colon or prostate cancer; diabetes; pancreatitis; hypertension; polycystic ovarian disease; or an abnormally high concentration of blood insulin or glucose in the subject’s blood plasma or blood serum.
  • the diabetes is non-insulin dependent diabetes mellitus (NIDDM), insulin dependent diabetes mellitus (IDDM), gestational diabetes mellitus (GDM), or maturity onset diabetes of the young (MODY).
  • the present invention provides methods for treating or preventing a metabolic syndrome (syndrome X), comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the present invention provides methods for treating or preventing a symptom of a metabolic syndrome (syndrome X), comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the symptom is impaired glucose tolerance, hyper tension, dyslipidemia, or dyslipoproteinemia.
  • the present invention provides methods for treating or preventing a vascular disease or cardiovascular disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • cardiovascular disease refers to a disease of the heart or circulatory system.
  • the vascular disease or the cardiovascular disease is a peripheral vascular disease, a coronary heart disease, stroke, restenosis, arteriosclerosis, ischemia, an endothelium dysfunction, an ischemia-reperfusion injury, a myocardial infarction, or a cerebral infarction.
  • the present invention provides methods for treating or preventing a PPAR-associated disorder, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the PPAR-associated disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, an inflammatory bowel disease, breast cancer, colon cancer, or prostate cancer.
  • the PPAR-associated disorder is a vascular disease, a muscular disease, a demyelinating disease, a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a mitochondrial dysfunction, a beta oxidation disease, or a metabolic disease.
  • the PPAR-associated disorder is an abnormally low concentration of HDL, an abnormally low concentration of apolipoprotein A-l (apo A-l), an abnormally high concentration of VLDL-C, an abnormally high concentration of low density lipoprotein cholesterol (LDL-C), an abnormally high concentration of triglyceride, an abnormally high concentration of apolipoprotein B (apo B), an abnormally high concentration of apolipoprotein C-lll (apo C-lll) or an abnormally reduced ratio of postheparin hepatic lipase to lipoprotein lipase activity in the subject’s blood plasma or blood serum.
  • the PPAR-associated disorder is an abnormally high concentration of HDL or an abnormally low concentration of apo A-l in the subject's lymph or cerebral fluid.
  • the PPAR-associated disorder is abnormally low concentration of lipoprotein lipase activity in the post-heparin plasma in a subject (subject’s blood plasma after intravenous injection of heparin).
  • the present invention provides methods for elevating an abnormally low concentration of lipoprotein lipase activity in the postheparin plasma, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • An “abnormally low concentration” of lipoprotein lipase activity in the post-heparin plasma is less than 30 U/L.
  • the elevating is to a normal concentration.
  • the normal concentration is in the range from about 30 U/L to about 153 U/L (See Nakajima et al. Clin Chim Acta. 2018 Dec;487:54-59).
  • the present invention provides methods for treating or preventing a PPAR-associated disorder in a subject, wherein the subject has lipoprotein lipase activity in the post-heparin plasma of less than 30 U/L.
  • the subject is a male subject.
  • An “abnormally high concentration” of HDL in a male subject is greater than 75 mg/dL.
  • the subject is a female subject.
  • An "abnormally high concentration” of HDL for a female subject is greater than 90 mg/dL.
  • the present invention provides methods for reducing an abnormally high concentration of HDL 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 a composition of the invention.
  • the reducing is to a normal concentration.
  • the normal concentration for a male subject is less than 75 mg/dL.
  • the normal concentration for a female subject is less than 90 mg/dl_.
  • the present invention provides methods for treating or preventing a PPAR-associated disorder in a male subject, wherein the subject has HDL concentration in the subject’s blood plasma or blood serum greater than 75 mg/dL. In some embodiments, the present invention provides methods for treating or preventing a PPAR-associated disorder in a female subject, wherein the subject has HDL concentration in the subject’s blood plasma or blood serum greater than 90 mg/dL. See Hassan, M. et. at. Glob Cardiol Sci Pract. 2016 Dec 30; 2016(4): e201634.
  • the muscular disease is a muscular dystrophy disease.
  • the muscular dystrophy disease is Duchenne muscular dystrophy, Becker muscular dystrophy, a limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, or Emery-Dreifuss muscular dystrophy.
  • the demyelinating disease is multiple sclerosis, Charcot-Marie- Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, or Guillian-Barre syndrome.
  • the muscle structure disorder is Bethlem myopathy, central core disease, congenital fiber type disproportion, distal muscular dystrophy (MD), Duchenne & Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, a muscle sodium channel disorder, myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline body disease, oculopharyngeal MD, or stress urinary incontinence.
  • MD distal muscular dystrophy
  • Duchenne & Becker MD Emery-Dreifuss MD
  • facioscapulohumeral MD hyaline body myopathy
  • limb-girdle MD a muscle sodium channel disorder
  • myotonic chondrodystrophy myotonic dystrophy
  • myotubular myopathy nemaline body disease
  • oculopharyngeal MD or stress urinary
  • the neuronal activation disorder is amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, a nerve lesion, peripheral neuropathy, spinal muscular atrophy, tardy ulnar nerve palsy, or toxic myoneural disorder.
  • the muscle fatigue disorder is chronic fatigue syndrome, diabetes (type I or II), a glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome, mucopolysaccharidosis, Pompe disease, or thyrotoxic myopathy.
  • the muscle mass disorder is cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, critical illness myopathy, inclusion body myositis, muscular atrophy (disuse), sarcopenia, steroid myopathy, or systemic lupus erythematosus.
  • the mitochondrial disease is Alpers's disease, chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayra syndrome (KSS), Leber hereditary optic neuropathy (LHON), MELAS, myoclonic epilepsy and ragged-red fiber disease (MERRF), neurogenic muscle weakness (NARP), ataxia, retinitis pigmentosa, Pearson syndrome, a mitochondrial malfunction, or a mitochondrial loss of functionality (for example, due to a drug affecting mitochondrial functions).
  • CPEO chronic progressive external ophthalmoplegia
  • KSS Kearns-Sayra syndrome
  • LHON Leber hereditary optic neuropathy
  • MELAS myoclonic epilepsy and ragged-red fiber disease
  • NARP neurogenic muscle weakness
  • ataxia retinitis pigmentosa
  • Pearson syndrome a mitochondrial malfunction
  • a mitochondrial loss of functionality for example, due to a drug affecting mitochondrial functions.
  • the mitochondrial dysfunction is a drug induced mitochondrial dysfunction.
  • the beta oxidation disease is systemic carnitine transporter, carnitine palmitoyltransferase (CPT) II deficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, or riboflavin-responsive disorders of b-oxidation (RR-MADD).
  • CPT carnitine palmitoyltransferase
  • LCHAD or VLCAD very long-chain acyl-CoA dehydrogenase
  • MCAD medium-chain acyl-CoA dehydrogenase
  • SCAD short-chain acyl-CoA dehydrogenase
  • RR-MADD riboflavin-responsive disorders of b-oxidation
  • the metabolic disease is hyperlipidemia, dyslipidemia, hyperchlolesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia, HLD non-cholesterolemia, VLDL hyperproteinemia, dyslipoproteinemia, apolipoprotein A-l hypoproteinemia, atherosclerosis, a disease of arterial sclerosis, a disease of cardiovascular system, cerebrovascular disease, peripheral circulatory disease, metabolic syndrome, syndrome X, obesity, diabetes, type I diabetes, type II diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism, a diabetic complication, cardiac insufficiency, cardiac infarction, cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a thrombus, Alzheimer disease, a neurodegenerative disease, a demyelinating disease, multiple sclerosis, adrenal leukodystrophy, dermatitis,
  • the present invention provides methods for treating or preventing septicemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • septicemia is septic shock.
  • the present invention provides methods for treating or preventing a thrombotic disorder, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the thrombotic disorder is high concentration of fibrinogen in the subject’s blood plasma or blood serum, or promotion of fibrinolysis.
  • the present invention provides methods for treating or preventing obesity, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the obesity is abdominal obesity.
  • the methods for treating or preventing obesity further comprise promoting weight reduction in the subject.
  • the present invention provides methods for treating or preventing diabetic nephropathy, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the methods for treating or preventing diabetic nephropathy further comprise treating or preventing a kidney disease that develops as a result of diabetes mellitus.
  • the present invention provides methods for treating or preventing diabetes mellitus, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the present invention provides methods for treating or preventing diabetic retinopathy, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the methods for treating or preventing diabetic retinopathy result in treating or preventing a complication of diabetes that can lead to or cause blindness.
  • the present invention provides methods for treating or preventing a cerebrovascular disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the cerebrovascular disease is cerebral ischemia.
  • the present invention provides methods for treating or preventing a disorder related to neovascularization, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the disorder related to neovascularization is retinopathy or diabetes.
  • the present invention provides methods for treating or preventing hypertension, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the methods for treating or preventing hypertension result in treating or preventing blood flow that occurs through the subject’s vessels at a greater than normal force.
  • the present invention provides methods for treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the cancer is a human sarcoma or human carcinoma.
  • the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, oral cancer, nasal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, chor
  • the leukemia is acute or chronic lymphoblastic leukemia, myelogenous leukemia, lymphocyticleukemia, lymphocytic leukemia, or myelocytic leukemia.
  • the myelocytic leukemia is acute and is myeloblastic, promyelocytic, myelomonocytic, monocytic or erythroleukemia
  • the lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.
  • the present invention provides methods for treating or preventing an inflammatory disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the inflammatory disease is multiple sclerosis, a chronic inflammatory disorder of a joint, arthritis, a respiratory distress syndrome, an inflammatory bowel disease, an inflammatory lung disorder, an inflammatory disorder, an inflammatory disorder of the gum, tuberculosis, leprosy, an inflammatory disease of the kidney, an inflammatory disorder of the skin, an inflammatory disease of the central nervous system, a systemic lupus erythematosus (SLE) or an inflammatory disease of the heart.
  • SLE systemic lupus erythematosus
  • the arthritis is rheumatoid arthritis or osteoarthritis.
  • the inflammatory bowel disease is ileitis, ulcerative colitis or Crohn’s disease.
  • the inflammatory lung disorder is asthma or chronic obstructive airway disease.
  • the inflammatory disorder of the eye is corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathic ophthalmitis or endophthalmitis.
  • the inflammatory disorder of the gum is periodontitis or gingivitis.
  • the inflammatory disease of the kidney is glomerulonephritis or nephrosis.
  • the inflammatory disorder of the skin is acne, sclerodermatitis, psoriasis, eczema, photoaging or wrinkles.
  • the inflammatory disease of the central nervous system is AIDS- related neurodegeneration, stroke, neurotrauma, Alzheimer’s disease, encephalomyelitis, or viral or autoimmune encephalitis.
  • the inflammatory disease of the heart is cardiomyopathy.
  • the present invention provides methods for treating or preventing a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the neurodegenerative disease is Alzheimer’s disease or Huntington’s disease.
  • the present invention provides methods for treating or preventing an autoimmune disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the autoimmune disease is immune-complex vasculitis, systemic lupus or erythematodes.
  • the present invention provides methods for treating or preventing a neoplastic disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the neoplastic disease is carcinogenesis.
  • the present invention provides methods for treating or preventing cholestasis, comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • the cholestasis is intrahepatic cholestatic disease or extrahepatic cholestatic disease.
  • the intrahepatic cholestatic disease is primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), progressive familial intrahepatic cholestasis (PFIC), or Alagille syndrome (AS).
  • PBC primary biliary cholangitis
  • PSC primary sclerosing cholangitis
  • PFIC progressive familial intrahepatic cholestasis
  • AS Alagille syndrome
  • the methods for treating or preventing intrahepatic cholestatic disease result in preventing or reducing the risk of developing an intrahepatic cholestatic disease, e.g., causing the clinical symptoms of an intra hepatic cholestatic disease to not develop in a subject who may be predisposed to an intrahepatic cholestatic disease by who does not yet experience or display symptoms of the intrahepatic cholestatic disease (i.e., prophylaxis).
  • the methods for treating or preventing intrahepatic cholestatic disease comprise inhibiting an intrahepatic cholestatic disease, e.g., arresting or reducing the development of the intrahepatic cholestatic disease or reducing the number, frequency, duration or severity of one or more of its clinical symptoms.
  • the present invention provides methods for treating or preventing an ocular disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the ocular disease is dry eye, meibomian gland dysfunction, a keratoconjunctiva epithelial disorder, a corneal epithelial disorder, or a corneal ulcer.
  • the ocular disease is dry eye syndrome, corneal ulcer, superficial punctuate keratitis, corneal epithelial erosion, an ocular allergic disease associated with corneal lesion such as vernal conjunctivitis, or atopic keratoconjunctivitis.
  • the ocular disease is hyperevaporative dry eye.
  • the ocular disease is injury of corneal epithelial cells.
  • the injury of corneal epithelial cells is associated with endogenous diseases such as Sjogren's syndrome, Stevens-Johnson syndrome, keratoconjunctivitis sicca (dry eye) or the like.
  • the injury of corneal epithelial cells is associated with exogenous diseases such as post-operation, drug use, trauma, corneal ulcer, meibomianitis, exogenous diseases during wearing contact lenses or the like.
  • the injury of corneal epithelial cells is associated with ocular allergic diseases accompanying corneal lesion such as vernal conjunctivitis, atopic keratoconjunctivitis or the like.
  • the ocular disease is superficial punctuate keratitis and corneal epithelial erosion.
  • the methods for treating or preventing an ocular disease result in promoting proliferation of meibomian gland epithelial cells and corneal epithelial cells.
  • the present invention provides methods for treating or preventing a lysosomal storage disorder, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the lysosomal storage disorder is neuronal ceroid lipofuscinosis, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), dementia with Lewy bodies (DLB), a disorder of the autophagy pathway, Tay-Sach's disease, Fabry disease, Niemann-Pick disease, Gaucher disease, Hunter syndrome, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Farber disease, fucos
  • the present invention provides methods for treating or preventing a kidney disease, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the kidney disease is renal ischemia reperfusion injury.
  • the kidney disease is acute kidney injury.
  • the methods for treating or preventing a kidney disease result in lowering the subject's risk for acute kidney injury following coronary artery bypass graft, transplantation, and/or valve surgery.
  • the subject has AKI. In other embodiments, the subject is at risk for AKI.
  • AKI can be characterized by rapid decline in renal functions, which can be caused by a number of factors, such as a reduction in renal blood flow, glomerulonephritis, use of nephrotoxic antibiotics, use of anticancer agents, and sepsis.
  • Acute kidney injury can be diagnosed, for example, when a subject exhibits changes in one or more of serum creatinine level, glomerular filtration rate, or urine output.
  • AKI can be characterized by a serum creatinine level of at least 1.5 times baseline, wherein baseline refers to the subject’s serum creatinine level no more than 7 days prior.
  • a patient having AKI can have a serum creatinine level is 1.5 to 1.9 times baseline, 2.0 to 2.9 times baseline, or 3.0 or more times baseline.
  • AKI can be characterized by an increase in serum creatinine of at least 0.3 mg/dL or at least 0.4 mg/dL, for example by an increase of serum creatinine of at least 0.3 mg/dL within a 48 hour period.
  • AKI can be characterized by a glomerular filtration rate of less than 90 mL/min/1.73 m 2 .
  • a subject having AKI can have glomerular filtration rate of 60-89 mL/min/1.73 m 2 , 30-59 ml_/min/1.73 m 2 , 15-29 mL/min/1.73 m 2 , or less than 15 mL/min/1.73 m 2 .
  • AKI can be characterized by a subject having a urine output of less than 0.5 mL/Kg over 6 hours, less than 0.5 mL/Kg over 12 hours, less than 0.3 nnL/Kg over 12 hours, or anuria for 12 or more hours.
  • AKI can be classified using the KDIGO criteria (Kidney Disease Improving Global Outcomes. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney International Supplements 2012; 2: 1-138) shown in Table 12.
  • AKI can occur with specific kidney diseases (e.g., acute interstitial nephritis, acute glomerular and vasculitic renal diseases); non-specific conditions (e.g., ischemia, toxic injury); as well as extrarenal pathology (e.g.,prerenal azotemia, and acute postrenal obstructive nephropathy). More than one of these conditions may coexist in the same subject and, more importantly, epidemiological evidence supports the notion that even mild, reversible AKI has important clinical consequences, including increased risk of death.
  • kidney diseases e.g., acute interstitial nephritis, acute glomerular and vasculitic renal diseases
  • non-specific conditions e.g., ischemia, toxic injury
  • extrarenal pathology e.g.,prerenal azotemia, and acute postrenal obstructive nephropathy
  • AKI encompasses both direct injury to the kidney as well as acute impairment of function.
  • the subject having AKI or at risk of AKI has diabetes, underlying renal insufficiency, nephritic syndrome, atherosclerotic disease, sepsis, hypotension, hypoxia, myoglobinuria-hematuria, or liver disease.
  • the subject is elderly, pregnant, a surgical patient, or has been exposed to a nephrotoxic agent.
  • the subject having AKI or at risk of AKI is a surgical patient.
  • a compound of the disclosure is administered to a surgical patient after surgery, e.g., after a cardiovascular procedure such as coronary artery bypass graft (CABG) surgery and/or heart valve surgery.
  • CABG coronary artery bypass graft
  • the subject has sepsis (e.g., associated with a gram-negative bacterial infection).
  • the sepsis can in some embodiments be caused by an intra-abdominal cavity infection or be urosepsis.
  • Sepsis is a risk factor for AKI.
  • the subject can be at risk for AKI, for example due to sepsis.
  • the subject has a shortened sequential organ failure assessment score (SOFA) score of 1 to 4 before treatment with a compound of the disclosure, e.g., a score of 1, 2, 3, or 4 (see, Vincent ei al. 1996, Intensive Care Med, 22:707-710).
  • SOFA sequential organ failure assessment score
  • the subject has AKI secondary to an infection or is at risk of AKI due to an infection, for example a viral infection, e.g., COVID-19.
  • an infection for example a viral infection, e.g., COVID-19.
  • the subject having AKI or at risk of AKI has been exposed to a nephrotoxic agent.
  • a nephrotoxic agent is a drug or chemical capable of causing AKI.
  • Drugs or chemicals capable of causing AKI include, but are not limited to, cisplatin; gentamicin; cephaloridine; cyclosporine; amphotericin; carbon tetrachloride; trichloroethylene; and dichloroacetylene.
  • the present invention provides methods for treating or preventing impotence, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the impotence results from damages to a nerve, artery, smooth muscles, or fibrous tissue; diabetes; kidney disease; alcoholism; multiple sclerosis; atherosclerosis; vascular disease; or neurologic disease.
  • the methods for treating or preventing impotence results in treating or preventing erectile dysfunction.
  • the present invention provides methods for treating or preventing hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, or dyslipidemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the hypercholesterolemia is homozygous familial hypercholesterolemia.
  • the present invention provides methods for treating a subject having or preventing a subject from having an abnormally high concentration in a subject’s blood plasma or blood serum of high low-density lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein(a) (Lp(a)), a polipoprotein (a), or very low-density lipoprotein (VLDL), comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • LDL low-density lipoprotein
  • apo B apolipoprotein B
  • Lp(a) lipoprotein(a)
  • a polipoprotein a
  • VLDL very low-density lipoprotein
  • An “abnormally high concentration” of lipoprotein-cholesterol can depend on the number of risk factors and whether the treatment is for a primary or a secondary prevention.
  • a “primary prevention” refers to a treatment aimed to avoid a subject developing or getting a disease or a condition.
  • a “secondary prevention” refers to a treatment aimed to detect a disease or a condition early and prevent the disease or condition from getting worse or advancing.
  • the present invention provides methods for reducing an abnormally high concentration of apo B 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 a composition of the invention.
  • an “abnormally high concentration” of apo B in a subject's blood plasma or blood serum is greater than 130 mg/dL.
  • the reducing is to a normal concentration.
  • the normal concentration of apo B in a subject’s blood plasma or blood serum is less than 130 mg/dL.
  • the subject is a male subject. In some embodiments, the subject is a female subject.
  • the present invention provides methods for treating a subject with apo B blood plasma or blood serum concentration of greater than 130 mg/dL. In some embodiments, the present invention provides methods for treating a subject with apo B blood plasma or blood serum concentration of greater than 130 mg/dL, when the subject is at low risk of coronary heart disease (CHD) having 0-1 CHD risk factors.
  • CHD coronary heart disease
  • the present invention provides methods for treating a subject with apo B blood plasma or blood serum concentration of greater than 110 mg/dL, when the subject is at moderate risk of CHD having 2 or more CHD risk factors.
  • an “abnormally high concentration” of apo B in a subject’s blood plasma or blood serum is greater than 110 mg/dL.
  • the subject has 2 or more CHD risk factors.
  • the subject has a CHD or a CHD risk equivalent.
  • the present invention provides methods for treating a subject with apo B blood plasma or blood serum concentration of greater than 90 mg/dL, when the subject has a CHD or a CHD risk equivalent.
  • the present invention provides methods for reducing an abnormally high concentration of Lp(a) 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 a composition of the invention.
  • An “abnormally high concentration” of Lp(a) in a subject’s blood plasma or blood serum is greater than 10 mg/dL.
  • the abnormally high concentration of Lp(a) is associated with an increase in cardiovascular risk.
  • the reducing is to a normal concentration.
  • the normal concentration of Lp(a) in a subject’s blood plasma or blood serum is less than 10 mg/dL.
  • the normal concentration of Lp(a) in a subject's blood plasma or blood serum is less than 50 mg/dL (See, Banach, M. J Am Heart Assoc. 2016 Apr; 5(4): e003597).
  • the present invention provides methods for treating a subject with Lp(a) blood plasma concentration of greater than 50 mg/dL, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the present invention provides methods for treating a subject having or preventing a subject from having an abnormally high apo B/apo A-l ratio 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 a composition of the invention.
  • the present invention provides methods for reducing an abnormally high apo B/apo A-l ratio 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 a composition of the invention.
  • An "abnormally high" apo B/apo A-l ratio in a subject’s blood plasma or blood serum is greater than 0.9.
  • the reducing is to a normal level.
  • a normal apo B/apo A-l ratio in a subject’s blood plasma or blood serum is less than 0.9.
  • the normal apo B/apo A-l ratio in a subject’s blood plasma or blood serum is less than 0.7.
  • the subject has an apo B/apo A-l ratio in a subject’s blood plasma or blood serum of greater than 0.9.
  • the subject has an apo B/apo A-l ratio in a subject’s blood plasma or blood serum of greater than 0.7. See Wa!ldius, G. et al. J Intern Med. 2006 May;259(5):493-519.
  • a male subject having an apo B/apo A-l ratio in the male subject’s blood plasma or blood serum of greater than 0.9 is considered for a primary prevention treatment.
  • a female subject having an apo B/apo A-l ratio in the female subject’s blood plasma or blood serum of greater than 0.8 is considered for a primary prevention treatment.
  • the subject is a male subject and has an apo B/apo A-l ratio in the subject’s blood plasma or blood serum of greater than 0.9.
  • the subject is a female subject and has an apo B/apo A-l ratio in the subject’s blood plasma or blood serum of greater than 0.8. See Walldius, 2006.
  • a male subject having an apo B/apo A-l ratio in the male subject’s blood plasma or blood serum of greater than 0.7 is considered for a secondary prevention treatment.
  • a female subject having an apo B/apo A-l ratio in the female subject’s blood plasma or blood serum of greater than 0.6 is considered for a secondary prevention treatment.
  • the subject is a male subject and has an apo B/apo A-l ratio in the subject’s blood plasma or blood serum of greater than 0.7.
  • the subject is a female subject and has an apo B/apo A-l ratio in the subject’s blood plasma or blood serum of greater than 0.6. See Walldius, 2006.
  • the present invention provides methods for treating a subject having or preventing a subject from having an abnormally low concentration in a subject’s blood plasma or blood serum of high-density lipoprotein (HDL), comprising administering to a subject in need thereof an effective amount of the compound of the invention or the composition of the invention.
  • HDL high-density lipoprotein
  • the present invention provides methods for treating a subject having or preventing a subject from having an abnormally reduced or deficient lipoprotein lipase concentration or activity 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 a composition of the invention.
  • the reduced or deficient lipoprotein lipase level or activity is a result of a lipoprotein lipase mutation.
  • the reduced or deficient lipoprotein lipase level or activity is a result of a mutation in a gene encoding a lipoprotein lipase.
  • the present invention provides methods for elevating an abnormally low concentration of lipoprotein lipase 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 a composition of the invention.
  • An “abnormally reduced concentration” of lipoprotein lipase in a subject’s blood serum is less than 46 ng/mL.
  • the subject has an increased risk for future coronary artery disease.
  • the elevating is to a normal concentration.
  • the normal concentration of lipoprotein lipase in a subject’s blood serum is greater than 46 ng/mL.
  • the present invention provides methods for treating a subject with lipoprotein lipase blood plasma or blood serum concentration of less than 46 ng/mL, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. See Rip, J. et al. Arterioscler Thromb Vase Biol. 2006 Mar;26(3):637-42. Epub 2005 Dec 22.
  • the present invention provides methods for treating a subject having or preventing a subject from having an abnormally high concentration of lipoprotein-associated phospholipase A2 (LP-PLA 2 ) 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 a composition of the invention.
  • An “abnormally high concentration” of LP-PLA 2 in a subject’s blood plasma or blood serum is greater than 200 ng/mL.
  • the subject has a risk for developing cardiovascular disease. In some embodiments, the risk is high.
  • the present invention provides methods for reducing an abnormally high concentration of Lp-PLA 2 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 a composition of the invention.
  • the reducing is to a normal concentration.
  • the normal concentration of Lp-PLA 2 in a subject’s blood plasma or blood serum concentration is less than 200 ng/mL.
  • the present invention provides methods for treating a subject with Lp-PLA 2 blood plasma or blood serum concentration of greater than 200 ng/mL See Davidson, M. H. et al, The American Journal of Cardiology, 2008, 101, S51.
  • the present invention provides methods for treating or preventing hypoalphalipoproteinemia, a lipoprotein abnormality associated with diabetes, a lipoprotein abnormality associated with obesity, a lipoprotein abnormality associated with Alzheimer's Disease, or familial combined hyperlipidemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the present invention provides methods for reducing in a subject’s blood plasma or blood serum an abnormally high concentration of triglyceride, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), non-high-density lipoprotein cholesterol, (non-HDL-C), lipoprotein(a) (Lp(a)), apolipoprotein B, HDL/(VLDL+LDL) ratio, apolipoprotein C-ll (apo C-ll) or apolipoprotein C-lll (apo C-lll), comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • LDL-C low-density lipoprotein cholesterol
  • VLDL-C very low-density lipoprotein cholesterol
  • non-HDL-C lipoprotein(a)
  • Lp(a) lipoprotein(a)
  • apolipoprotein B HDL/(V
  • An “abnormally high concentration” of triglyceride in a subject’s blood serum is greater than 150 mg/dL .
  • the reducing is to a normal concentration.
  • the normal concentration of triglyceride in a subject’s blood serum is less than 150 mg/dL.
  • the present invention provides methods for reducing a subject’s blood serum triglyceride concentration, where the subject has a blood serum triglyceride concentration greater than or equal to 200 mg/dL.
  • the present invention provides methods for reducing a subject’s blood serum triglyceride concentration, where the subject has a blood serum triglyceride concentration greater than or equal to 500 mg/dL.
  • An “abnormally high concentration” of LDL-C in a subject’s blood plasma or blood serum for primary prevention is greater than 100 mg/dL.
  • An “abnormally high concentration” of LDL-C in a subject’s blood plasma or blood serum for secondary prevention in a subject with risk factors is greater than 70 mg/dL.
  • the reducing is to a normal concentration.
  • the normal concentration of LDL-C in a subject’s blood plasma or blood serum is less than 100 mg/dL, wherein the subject is being considered for primary prevention.
  • the normal concentration of LDL-C in a subject’s blood plasma or blood serum is less than 70 mg/dL.
  • the subject has risk factors and is being considered for secondary prevention. See Walldius, 2006.
  • an “abnormally high concentration” of LDL-C in a subject’s blood plasma or blood serum is greater than 160 mg/dL.
  • the reducing is to a normal concentration.
  • the normal concentration of LDL-C in a subject’s blood plasma or blood serum is less than 160 mg/dL.
  • the subject has 0- 1 CHD risk factors.
  • the present invention provides methods for treating a subject with LDL-C blood plasma or blood serum concentration of greater than 160 mg/dL
  • the present invention provides methods for treating a subject with LDL-C blood plasma or blood serum concentration of greater than 160 mg/dL.
  • the subject has 0-1 CHD risk factors. See Walldius, 2006.
  • an “abnormally high concentration” of LDL-C in a subject’s blood plasma or blood serum is greater than 130 mg/dL.
  • the subject has 2 or more CHD risk factors.
  • the reducing is to a normal concentration.
  • the normal concentration of LDL-C in a subject’s blood plasma or blood serum is less than 130 mg/dL.
  • the subject has 2 or more CHD risk factors.
  • the present invention provides methods for treating a subject with LDL-C blood plasma or blood serum concentration of greater than 130 mg/dL.
  • the subject has 2 or more CHD risk factors. See Walldius, 2006.
  • an “abnormally high concentration” of LDL-C in a subject’s blood plasma or blood serum is greater than 100 mg/dL.
  • the subject has a CHD or a CHD risk equivalent.
  • the reducing is to a normal concentration.
  • the normal concentration of LDL-C in a subject’s blood plasma or blood serum is less than 100 mg/dL.
  • the subject has a CHD or a CHD risk equivalent.
  • the present invention provides methods for treating a subject with LDL-C blood plasma or blood serum concentration of greater than 100 mg/dL.
  • the subject has a CHD or a CHD risk equivalent. See Walldius, 2006.
  • An “abnormally high concentration” of apo C-lll concentration in a subject’s blood plasma or blood serum is greater than 7.87 mg/dL.
  • the reducing is to a normal concentration, In some embodiments, the normal concentration of apo C-lll concentration in a subject’s blood plasma or blood serum is less than 7.87 mg/dL.
  • the present invention provides methods for treating a subject, where the subject has an apo C-lll blood plasma or blood serum concentration greater than 8 mg/dL. In some embodiments, the present invention provides methods for treating a subject, where the subject has an apo C-lll blood plasma or blood serum concentration greater than 7.9 mg/dL.
  • the present invention provides methods for treating a subject, where the subject has an apo C-lll blood plasma or blood serum concentration greater than 7.87 mg/dL.
  • the abnormally high concentration of apo C-lll is associated with high risk of coronary artery disease. See Capelleveen et at. Arterioscler Thromb Vase Biol. 2017 Jun; 37(6): 1206-1212.
  • the present invention provides methods for reducing in a subject’s blood plasma or blood serum an abnormally high LDL-C/HDL-C ratio, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • an “abnormally high ratio” of LDL-C/HDL-C in a male subject’s blood plasma or blood serum for primary prevention is greater than 3.0.
  • the reducing is to a normal ratio.
  • the normal ratio of LDL-C/HDL-C in a male subject’s blood plasma or blood serum is less than 3.0, wherein the subject is being considered for primary prevention.
  • the present invention provides methods for treating a male subject with an LDL-C/HDL-C ratio in a subject’s blood plasma or blood serum of greater than 3.0.
  • the me method is for primary prevention.
  • an “abnormally high ratio” of LDL-C/HDL-C in a female subject’s blood plasma or blood serum for primary prevention is greater than 2.5.
  • the reducing is to a normal ratio.
  • the normal ratio of LDL-C/HDL-C in a female subject’s blood plasma or blood serum is less than 2.5, wherein the subject is being considered for primary prevention.
  • the present invention provides methods for treating a female subject with an LDL-C/HDL-C ratio in a subject’s blood plasma or blood serum of greater than 2.5.
  • the me method is for primary prevention. See Walldius, 2006.
  • an “abnormally high ratio” of LDL-C/HDL-C in a male subject’s blood plasma or blood serum for secondary prevention is greater than 2.5.
  • the reducing is to a normal ratio.
  • the normal ratio of LDL- C/HDL-C in a male subject’s blood plasma or blood serum is less than 2.5, wherein the subject is being considered for secondary prevention.
  • the present invention provides methods for treating a male subject with an LDL-C/HDL-C ratio in a subject’s blood plasma or blood serum of greater than 2.5.
  • the me method is for secondary prevention. See Walldius, 2006.
  • an “abnormally high ratio” of LDL-C/HDL-C in a female subject’s blood plasma or blood serum for secondary prevention is greater than 2.0.
  • the reducing is to a normal ratio.
  • the normal ratio of LDL- C/HDL-C in a female subject’s blood plasma or blood serum is less than 2.0, wherein the subject is being considered for secondary prevention.
  • the present invention provides methods for treating a female subject with an LDL-C/HDL-C ratio in a subject’s blood plasma or blood serum of greater than 2.0.
  • the me method is for secondary prevention. See Walldius, 2006.
  • the present invention provides methods for reducing in a subject’s blood plasma or blood serum an abnormally high concentration of non-HDL-C, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • an “abnormally high concentration” of non-HDL-C in a subject's blood plasma or blood serum is greater than 190 mg/dL.
  • the reducing is to a normal concentration.
  • the normal concentration of non-HDL-C in a subject’s blood plasma or blood serum is less than 190 mg/dL.
  • the subject has 0-1 CHD risk factors.
  • the present invention provides methods for reducing a subject’s non-HDL-C concentration in the subject's blood plasma or blood serum, wherein the non-HDL-C concentration is greater than 190 mg/dL.
  • the subject has 0-1 CHD risk factors. See Walldius, 2006.
  • an “abnormally high concentration" of non-HDL-C in a subject's blood plasma or blood serum is greater than 160 mg/dL.
  • the subject has 2 or more CHD risk factors.
  • the reducing is to a normal concentration.
  • the normal concentration of non-HDL-C in a subject’s blood plasma or blood serum is less than 160 mg/dL.
  • the subject has 2 or more CHD risk factors.
  • the present invention provides methods for reducing a subject's non-HDL-C concentration in the subject’s blood plasma or blood serum, wherein the subject’s non-HDL-C concentration is greater than 160 mg/dL.
  • the subject has 2 or more CHD risk factors. See Walldius, 2006.
  • an “abnormally high concentration” of non-HDL-C in a subject’s blood plasma or blood serum is greater than 130 mg/dL.
  • the subject has a CHD or a CHD risk equivalent.
  • the reducing is to a normal concentration.
  • the normal concentration of non-HDL-C in a subject’s blood plasma or blood serum is less than 130 mg/dL.
  • the subject has a CHD or a CHD risk equivalent.
  • the present invention provides methods for reducing a subject's non-HDL-C concentration in the subject’s blood plasma or blood serum, wherein the subject’s non-HDL-C concentration is greater than 130 mg/dL.
  • the subject has a CHD or a CHD risk equivalent. See Walldius, 2006.
  • the present invention provides methods for elevating in a subject’s blood plasma or blood serum an abnormally low concentration of a high-density lipoprotein (HDL)-associated protein, HDL-cholesterol (HDL-C), apolipoprotein A-l, or apolipoprotein E, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the HDL-associated protein is apolipoprotein A-l (apo A-l), apolipoprotein A-ll (apo A-ll), apolipoprotein A-IV (apo A-IV) or apolipoprotein E (apo E).
  • an “abnormally low concentration” of HDL-C in a subject’s blood plasma or blood serum is less than 40 mg/dL.
  • the elevating is to a normal concentration.
  • the normal concentration of HDL-C in a subject’s blood plasma or blood serum is greater than 40 mg/dL
  • the present invention provides methods for elevating HDL-C concentration in a subject’s blood plasma or blood serum, where the subject’s HDL-C concentration is less than 40 mg/dL.
  • the subject is a male subject. In some embodiments, the subject is a female subject.
  • an “abnormally low concentration” of HDL-C in a male subject’s blood plasma or blood serum is less than 45 mg/dL.
  • the normal concentration of HDL-C in a male subject’s blood plasma or blood serum is greater than 45 mg/dL.
  • the present invention provides methods for elevating HDL-C concentration in a male subject’s blood plasma or blood serum, where the subject’s HDL-C concentration is less than 45 mg/dL.
  • an “abnormally low concentration” of HDL-C in a female subject’s blood plasma or blood serum is less than 50 mg/dL. In some embodiments, the normal concentration of HDL-C in a female subject’s blood plasma or blood serum is greater than 50 mg/dL. In some embodiments, the normal concentration of HDL-C in a female subject’s blood plasma or blood serum is greater than 55 mg/dL. In some embodiments, the present invention provides methods for elevating HDL-C concentration in a female subject’s blood plasma or blood serum, where the subject’s HDL-C concentration is less than 50 mg/dL. In some embodiments, the present invention provides methods for elevating HDL-C concentration in a female subject’s blood plasma or blood serum where the subject’s HDL-C concentration is lower than 55 mg/dL.
  • the present invention provides methods for elevating HDL-C concentration in a subject’s blood plasma or blood serum to 45 mg/dL or greater, where the subject’s HDL-C concentration in a subject’s blood plasma or blood serum is less than 40 mg/dL. In some embodiments, the present invention provides methods for elevating HDL-C concentration in a subject’s blood plasma or blood serum to 50 mg/dL or greater, where the subject’s HDL-C concentration in a subject’s blood plasma or blood serum is less than 40 mg/dL.
  • the present invention provides methods for elevating HDL-C concentration in a subject’s blood plasma or blood serum to 55 mg/dL or greater, where the subject’s HDL-C concentration in a subject’s blood plasma or blood serum is less than 40 mg/dL.
  • the present invention provides methods for elevating HDL-C concentration in a male subject’s blood plasma or blood serum to 50 mg/dL or greater, where the subject’s HDL-C concentration in a subject’s blood plasma or blood serum is less than 45 mg/dL.
  • the present invention provides methods for elevating HDL-C concentration in a female subject’s blood plasma or blood serum to 50 mg/dL or greater, where the subject’s HDL-C concentration in a subject’s blood plasma or blood serum is less than 50 mg/dL In some embodiments, the present invention provides methods for elevating HDL-C concentration in a female subject’s blood plasma or blood serum to 55 mg/dL or greater, where the subject’s HDL-C concentration in a subject’s blood plasma or blood serum is less than 50 mg/dL.
  • the present invention provides methods for promoting clearance of triglyceride from a subject's blood plasma or blood serum, 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 increasing an abnormally low glucose metabolism or increasing an abnormally low lipid metabolism in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the method for increasing an abnormally low glucose metabolism increases insulin sensitivity or oxygen consumption in a subject.
  • the method for increasing an abnormally low glucose metabolism reduces blood insulin, blood glucose, or glycated hemoglobin in a subject’s blood plasma or blood serum.
  • the methods for increasing an abnormally low lipid metabolism reduces a concentration of LDL or free triglyceride in a subject’s blood plasma or blood serum, or inhibits saponified or non-saponified fatty acid synthesis.
  • a subject with abnormally low glucose metabolism has an abnormally high concentration of glucose or hemoglobin (Hb) in the subject’s blood plasma or blood serum.
  • the present invention provides methods for reducing an abnormally high concentration of glucose or hemoglobin in a subject’s blood plasma or blood serum.
  • the method increases abnormally low glucose metabolism.
  • An “abnormally high concentration” of glucose in a subject’s blood plasma or blood serum in a two- hour GTT is greater than 7.8 mmol/L (140 mg/dL).
  • reducing is to a normal concentration.
  • the normal concentration of glucose in a subject’s blood plasma or blood serum in a two-hour GTT is less than 7.8 mmol/L (140 mg/dL).
  • the present invention provides methods for increasing abnormally low glucose metabolism in a subject’s blood plasma or blood serum, where the subject’s glucose concentration in the subject’s blood plasma or blood serum in a two-hour GTT is greater than 7.8 mmol/L (140 mg/dL).
  • the present invention provides methods for increasing abnormally low glucose metabolism in a subject, where the subject’s glucose concentration in the subject’s blood plasma or blood serum in a two-hour GTT ranges from 7.8 mmol/L (140 mg/dL) to 11.1 mmol/L (200 mg/dL). In some embodiments, the present invention provides methods for increasing abnormally low glucose metabolism in a subject, where the subject’s glucose concentration in the subject’s blood plasma or blood serum in a two-hour GTT is above 11.1 mmol/L (200 mg/dL). [0596] In some embodiments, the present invention provides methods for increasing abnormally low glucose metabolism in a subject, where the subject has impaired glucose tolerance. In some embodiments, the present invention provides methods for increasing abnormally low glucose metabolism in a subject, where the subject has diabetes. In some embodiments, the present invention provides methods for increasing abnormally low glucose metabolism in a subject, where the subject has gestational diabetes.
  • a low lipid metabolism can be characterized by dyslipidemia (using the LDL-C, TGs, non-HDL-chol, apo B, apo C-lll or apo C-ll values) but also with elevated concentration of transaminases.
  • the subject having a low lipid metabolism also has dyslipidemia.
  • the present invention provides methods for treating or preventing a symptom of a disease selected from inflammation, systemic lupus erythematosus, lupus nephritis, or arthritis, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
  • the arthritis is adjuvant arthritis or type II collagen-induced arthritis.
  • the symptom is nephritis, kidney failure, or kidney function reduction.
  • the kidney function reduction requires renal dialysis.
  • the present invention provides methods for reducing fat content of meat in livestock, comprising administering to livestock an effective amount of a compound of the invention or a composition of the invention.
  • the present invention provides methods for reducing cholesterol content of a fowl egg, comprising administering to a fowl species an effective amount of a compound of the invention or a composition of the invention.
  • the methods of the invention provide administering a dosage form of the compounds of the invention or the compositions of the invention hourly, daily, weekly, or monthly.
  • the dosage forms and formulations of the present invention may be administered three times a day, twice a day or once a day.
  • the dosage forms of the present invention can be administered with food or without food. An appropriate length of the treatment, dosages, and route of administration can be determined and/or adjusted by a physician.
  • the subject is a human subject.
  • compounds of WO 2011/020001 having a ketone can be reduced with a reducing agent, such as NaBFL, optionally in the presence of a Lewis acid, such as CeCL, or in an alcohol solvent, such as methanol, to provide convert the ketone group to a hydroxyl group.
  • a reducing agent such as NaBFL
  • a Lewis acid such as CeCL
  • an alcohol solvent such as methanol
  • carboxylic acid groups of compounds of WO 2011/020001 can be reduced to a hydroxymethyl group using a reducing reagent, such as LiAIH 4 , followed by an aqueous acid workup to provide a compound of the invention.
  • WO 2017/062468 describe PPAR modulator compounds (described therein as compounds of Formulas (l)-(lll)) and processes for their synthesis.
  • Compounds of Formulas (l)-(lll) described in WO 2017/06246 can be used as starting materials for synthesis of compounds of Formulas (X)-(Z) of the present invention, respectively.
  • Carboxylic acid groups of compounds of WO 2017/06246 can be reduced to a hydroxymethyl group using a reducing reagent, such as LiAIH 4 , followed by an aqueous add workup to provide a compound of the invention.
  • WO 2017/180818 the contents of which are incorporated herein by reference in their entireties, describe PPAR modulator compounds (described therein as compounds of Formulas (I)) and processes for their synthesis.
  • Compounds of Formula (I) described in WO 2017/180818 can be used as starting materials for synthesis of compounds of Formula (AA) of the present invention.
  • Carboxylic acid groups of compounds of WO 2017/180818 can be reduced to a hydroxymethyl group using a reducing reagent, such as LiAIH 4 , followed by an aqueous acid workup to provide a compound of the invention.
  • a reducing reagent such as LiAIH 4
  • WO 2018/067857 the contents of which are incorporated herein by reference in their entireties, describe PPAR modulator compounds (described therein as compounds A, B, and C) and processes for their synthesis.
  • Compounds B and C described in WO 2018/067857 can be used as starting materials for synthesis of Compounds VII and VIII.
  • Carboxylic acid groups of compounds of WO 2017/180818 can be reduced to a hydroxymethyl group using a reducing reagent, such as LiAIH 4 , followed by an aqueous acid workup to provide a compound of the invention,
  • the ketone can be protected, for example by reacting the compound with ethylene glycol in the presence of catalytic acid, such as 0.1 M HCI, to form an acetal compound.
  • the acetal can be removed following reduction of the carboxylic acid group, for example by aqueous acid workup.
  • ketone for selective reduction of a ketone in a compound having both a ketone and a carboxylic acid group, e.g., some compounds described in WO 2011/020001, the ketone can be selectively reduced by employing a less reactive reducing agent such as NaBFL. 6.
  • Compound A (Z)-2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl)phenoxy)-2- methylpropanoic add (“Compound A”) is synthesized according to US2006/0142611. Compound A is then reduced using a reducing agent, such as NaBH 4 , optionally in the presence of a Lewis acid, such as CeCl 3 , or in an alcohol solvent, such as methanol, to provide Compound I racemate. Compound I racemate is then resolved to provide its (S)- and ( R )- enantiomers, each being substantially free of its corresponding opposite enantiomer, using a chiral high performance liquid chromatography.
  • a reducing agent such as NaBH 4
  • a Lewis acid such as CeCl 3
  • alcohol solvent such as methanol
  • Acetal Compound B is synthesized from Compound A and ethylene glycol in the presence of catalytic acid, such as 0.1 M HCI. See, e.g., Dong, J-L., et al. ACS Omega, 2018, 3, 4974 for acetal formation specifically on a,b-unsaturated ketones.
  • the carboxyl group of Compound B is subsequently reduced to a hydroxymethyl group using a reducing reagent, such as LiAIH 4 , followed by an aqueous acid workup, which removes the acetal to provide Compound II.
  • a reducing reagent such as LiAIH 4
  • Compound II is reduced using a reducing agent, such as NaBH 4 , optionally in the presence of a Lewis acid, such as CeCh, or in an alcohol solvent, such as methanol, to provide Compound III racemate.
  • a reducing agent such as NaBH 4
  • a Lewis acid such as CeCh
  • an alcohol solvent such as methanol
  • Example 4 Hepatic and Peripheral Insulin Sensitive Effects in Rats Fed a High Fat/Medium Fructose Diet (Western Diet) [0611] After 8 weeks of high fat diet, rats are treated for 5 weeks with pioglitazone (10 mg/kg), metformin (50 mg/kg), an illustrative compound of the invention (3 and 10 mg/kg), alone or in association with metformin (50 mg/kg), and GW501516 (2-[2-methyl-4-[[4-methyl-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid) (10 mg/kg; ligand/GSK). Body weight can be decreased by metformin and this effect can be emphasized when it is associated with the illustrative compound of the invention in a dose of 10 mg/kg. After 17 days of treatment, rats are fasted for 4 hours and blood is sampled.
  • the glucose tolerance is assessed after 21 days of treatment by an oral glucose load performed after 6 hours of fasting.
  • mice Male Sprague Dawley (SD) rats (250-275 g) are first fed with the western diet during 8 weeks for inducing insulin resistance. The first set of rats undergoes an oral glucose tolerance test (OGTT) after 3 weeks of treatment (half rats/group of the clamp arm) and the second set also undergoes an OGTT after 3 weeks of treatment (half rats/group of clamp arm) and the histology study (3 rats/group).
  • OGTT oral glucose tolerance test
  • Rats of each set are screened and randomized into the several groups according to their fasted (4 h) plasma glucose, insulin levels (for homeostatic model assessment of insulin resistance (HOMA-IR) calculation) and body weight. Rats that do not respond to the western diet are excluded from the study.
  • Dosage regimen Rats are treated once daily via the oral route, in the morning. The duration of the treatment is between 5 and 5.5 weeks.
  • rats are fasted for 6 hours and an oral glucose load (2.5 g/kg body weight) is performed. Blood glucose is measured 30 minutes before glucose load and at 0, 15, 30, 60, 90 and 120 minutes.
  • a bolus (30 ⁇ Ci) of D-[3-3H]glucose is first injected followed by 4 ⁇ Ci/min/kg infusion rate during all the experiment to ensure a detectable plasma D[3-3H]glucose enrichment.
  • a bolus of insulin (100 mU) is first injected, and insulin is then infused at a rate of 0.2 U/kg/h for the first 2 hours and 0.8 U/kg/h from 120 minutes to 210 minutes.
  • glycaemia is assessed with a blood glucose meter from the tip of the tail vein when needed. Euglycemia is maintained by periodically (every 10 minutes) adjusting a variable infusion of 30% glucose.
  • Plasma glucose concentrations and D-[3- 3H]glucose specific activity are determined during stable phase in 10 ⁇ I of blood sampled from the tip of the tail vein every 20 minutes from 60 to 120 minutes during the first step and from 150 to 210 minutes during the second step,
  • D-[3-3H]glucose enrichments are determined from total blood after deproteinization by a Zn(OH) 2 precipitate. Briefly, an aliquot of the supernatant is evaporated to dryness to determine the radioactivity corresponding to D-3-3H. In a second aliquot of the same supernatant, glucose concentration is assessed by the glucose oxidase method (Biomerieux, France).
  • [001] Calculations for glucose turnover measurements are made from parameters obtained during the infusions in steady-state condition (60-120 and 160-210 minutes). Briefly, the D-[3- 3H]glucose specific activity is calculated by dividing the D-[3-3H]glucose enrichment by the plasma glucose concentration. The whole body glucose turnover rate is calculated by dividing the rate of D[3-3H]glucose by the D-[3-3H]glucose plasma specific activity. For each rat, the mean values are calculated and averaged with values from rats of the same group. The whole body glycolysis rate are measured by assessing the amount of tritiated water accumulated in the blood during the 3H-glucose infusion and the whole body glycogen synthesis rate are calculated by the difference between the whole body glucose turnover and the whole body glycolysis rate.
  • Reporter plasmid MH100x4-tk-luc (Forman B M et al. Cell. 199581(4):541-50) is used as the reporter plasmid.
  • the African green monkey kidney cell line, CV-1 is used for the transfection assays.
  • CV- 1 cells are seeded in 24-well plates at 0.5x10 5 cells per well and are cultured for 24 hours.
  • Transfection mixtures for chimera receptors contain 30 ng of receptor expression plasmid, 120 ng of the reporter plasmid, 350 ng of pCMX- ⁇ -galactosidase ( ⁇ GAL) expression plasmid as a control for transfection efficiency, 250 ng of pGEM4 carrier plasmid and 2 ⁇ L of a lipofection reagent (Lipofectamine 2000, Invitrogen). These mixtures are added to cells and incubated for 5 hours according to the manufacturer's instructions.
  • cells are incubated for an additional 40 hours in the presence of the illustrative compounds of the invention or each reference compound at different concentrations.
  • Cell lysates are prepared with a lysis buffer (Passive Lysis Buffer, Promega) and used in the luciferase and ⁇ GAL assays.
  • the luciferase and ⁇ GAL activity are measured with the Luciferase assay system (E4030, Promega) and with the ⁇ GAL enzyme assay system (E2000, Promega).
  • Assays are performed in triplicate for GAL4-chimeras. Experiments are repeated at least three times.
  • EC50 values defined as the concentration of the illustrative compound of the invention and GW-501516 to produce 50% of maximal reporter activity re calculated with Prism software (Graphpad Software). 6.5.1.5. Experiments with 10% Serum vs 0.1% Serum.
  • the assay is set up and the GAL4-chimeras/reporter plasmids are validated using homo-sapiens sequences of the different PPAR.
  • the experiments are conducted at 10% and 0.1% serum with GW501516 (PPAR ⁇ agonist).
  • Plasmid Reference is as indicated in US 2011/0092517, which is hereby incorporated by reference in its entirety.
  • Acetal Compound B is synthesized from Compound A (see, WO 2011/020001; US 7,265,137) and ethylene giycol in the presence of catalytic acid, such as 0.1 M HCI.
  • the carboxyl group of Compound B is subsequently reduced to the alcohol using a reducing reagent, such as LiAIH 4 , followed by an aqueous acid workup, which removes the acetal to provide Compound IV.
  • a reducing reagent such as LiAIH 4
  • Compound V is synthesized from Compound A (see, WO 2011/020001; US 7,265,137) by reducing the carboxylic acid and ketone groups to the corresponding alcohols using a reducing reagent, such as LiAIH 4 , provide Compound V.
  • Compound V is then resolved to provide its (S)- and (R)-enantiomers, each being substantially free of its corresponding opposite enantiomer, using a chiral high performance liquid chromatography.
  • the objective of this study is to investigate the formation of metabolites of compounds of the invention incubated in human and cynomolgus monkey cryopreserved hepatocytes, including the specific compounds of Formulae (A)-(H) and (J)-(AA) described in Section 5.2 (including subparts thereof), Compound IV, Compound V, Compound VI, Compound Va, Compound Vb, Compound VI, Compound VII, and Compound VIII.
  • the compounds of the invention are incubated in cryopreserved hepatocytes from human and cynomolgus monkey to provide comparative data on Phase I and II hepatic metabolites.
  • Each sample consists of a compound of the invention at 10 mM (diluted from 10 mM DMSO stocks, 0.2% DMSO in the final incubation) and cryopreserved hepatocytes at 100,000 viable cells per well final concentration in a final volume of 100 ⁇ L.
  • the incubation buffer for human hepatocytes is supplemented DMEM (supplements are dexamethasone, 3.3 mM; insulin and transferrin, 5 ⁇ g/mL each; selenium, 5 ng/mL).
  • the incubation buffer for monkey hepatocytes is hepatocyte incubation medium without additional supplementation.
  • the positive controls 7-ethoxycoumarin and 7- hydroxycoumarin are incubated in the same way as each evaluated compound.
  • Metabolite profiling is based on mass chromatograms of test article related components.
  • Compounds of the invention are found to be metabolized to compounds having PPAR agonist activity and/or metabolites thereof.
  • a compound of Formula (A) (A), or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein: each R 1 and R 2 is independently -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, phenyl, or benzyl; or alternatively, R 1 and R 2 together with the carbon atom to which R 1 and R 2 are attached form a C 3 -C7 cycloalkyl group;
  • X is -CH 2 OH, -COOH, -COH, -COOR 3 , -COOCH 2 CONR 4 R 5 , -SO 3 H,
  • R 3 is -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, phenyl, or benzyl; each R 4 and R 5 is independently alkyl, aryl, or heteroaryl; or alternatively, R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached form a heterocycle; each R 6 and R 7 is independently H, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, or -C 2 -C 6 alkynyl; and n is 0, 1, 2, 3, or 4,
  • X is -CH 2 OH, -COH, -COOCH 2 CONR 4 R 5 , -SO 3 H,
  • R 3 is -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, phenyl, or benzyl; each R 4 and R 5 is independently alkyl, aryl, or heteroaryl; or alternatively, R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached form a heterocycle; each R 6 and R 7 is independently H, -CiXe alkyl, -C 2 -C 6 alkenyl, or -C 2 -C 6 alkynyl; and n is 0, 1, 2, 3, or 4.
  • composition comprising an effective amount of the compound or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound of any one of embodiments 1-50 and a pharmaceutically acceptable carrier of vehicle.
  • composition of embodiment 51 further comprising another therapeutically active agent.
  • composition of embodiment 52 wherein the other therapeutically active agent is a lipid lowering drug, statin, a cholesterol absorption inhibitor, an antibody against PCSK9, an siRNA PCSK9, an anti-fibrotic agent, a thyroid hormone, a selective thyroid receptor-b agonist, apoptosis signal-regulating kinase 1 (ASK1) inhibitor, acetyl-CoA carboxylase (ACC) inhibitor, an integrin antagonist, or a non-steroidal Farnesoid X receptor (FXR) agonist.
  • ASK1 apoptosis signal-regulating kinase 1
  • ACC acetyl-CoA carboxylase
  • FXR non-steroidal Farnesoid X receptor
  • the lipid lowering drug is gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate, clinofibrate, etofylline, pirifibrate, simfibrate, tocofibrate, or pemafibrate;
  • the statin is atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, dalvastatin, dihydrocompactin, or cerivastatin, ora pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof;
  • the cholesterol absorption inhibitor is ezetimibe;
  • the antibody against PCSK9 is evolocumab alirocumab, bococizumab, 1D05-
  • the siRNA PCSK9 is inclisiran;
  • the anti-fibrotic agent is nitazoxamide, tizoxanide, or tizoxanide glucuronide, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof;
  • the selective thyroid receptor-b agonist is VK2809, MGL-3196, MGL-3745, SKL-14763, sobetirome, BCT304, ZYT1, MB-0781, or eprotirome;
  • the ASK1 inhibitor is selonsertib;
  • the ACC inhibitor is firsocostat;
  • the integrin antagonist is an a5b1 inhibitor or a pan integrin inhibitor; or the FXR agonist is cilofexor.

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Abstract

La présente invention concerne des composés, par exemple, des formules (A)-(H) et (J)-(AA) et des sels, solvates, esters, amides et promédicaments pharmaceutiquement acceptables de ceux-ci. L'invention concerne en outre des compositions pharmaceutiques comprenant un composé de l'invention, et un vecteur ou un véhicule pharmaceutiquement acceptable. Les composés et les compositions divulgués ici sont utiles pour traiter ou prévenir diverses maladies et affections, par exemple une maladie du foie telle que la fibrose du foie, la stéatose hépatique, la stéatose hépatique non alcoolique (NAFLD)) ou la stéatohépatite non alcoolique (NASH), et des maladies rénales telles que l'insuffisance rénale aiguë (AKI).
PCT/IB2022/000106 2021-03-08 2022-03-08 Composés utiles pour le traitement des maladies du foie WO2022189856A1 (fr)

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IL305761A IL305761A (en) 2021-03-08 2022-03-08 Useful compounds for treating liver diseases
CN202280033302.1A CN117500791A (zh) 2021-03-08 2022-03-08 可用于治疗肝脏疾病的化合物
JP2023554886A JP2024512376A (ja) 2021-03-08 2022-03-08 肝疾患の処置に有用な化合物
EP22714000.1A EP4305024A1 (fr) 2021-03-08 2022-03-08 Composés utiles pour le traitement des maladies du foie
AU2022233873A AU2022233873A1 (en) 2021-03-08 2022-03-08 Compounds useful for treating liver diseases
CA3212825A CA3212825A1 (fr) 2021-03-08 2022-03-08 Composes utiles pour le traitement des maladies du foie
KR1020237034281A KR20240019753A (ko) 2021-03-08 2022-03-08 간 질환을 치료하는 데 유용한 화합물

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