WO2010009210A2

WO2010009210A2 - Acetylsalicyclic acid derivatives useful to treat metabolic syndromes

Info

Publication number: WO2010009210A2
Application number: PCT/US2009/050660
Authority: WO
Inventors: Amol Tendolkar; Anandan Palani; Xianhai Huang; Robert G. Aslanian
Original assignee: Schering Corporation
Priority date: 2008-07-17
Filing date: 2009-07-15
Publication date: 2010-01-21
Also published as: TW201016667A; WO2010009210A3; AR072813A1

Abstract

The present invention provides compounds of the Formula I: (I) wherein G represents a hydrolysable or metabolizable linker group; and R represents a recoverable residue of a nicotinic acid receptor agonist; and salts, solvates, esters and prodrugs thereof, as well as pharmaceutical compositions containing them, and methods of using them to treat metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, and non-alcoholic fatty liver diseases.

Description

ACETYLSALICYLIC ACID DERIVATIVES USEFUL TO TREAT METABOLIC SYNDROMES

Related Applications

This application claims benefit of provisional application USSN 61/081 ,566, filed on July 17, 2008, herein incorporated by reference.

Field of the Invention

The present invention relates to acetylsalicylic acid derivative nicotinic acid receptor agonist compounds useful for treating metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, and non-alcoholic fatty liver diseases; pharmaceutical compositions comprising such compounds; pharmaceutical compositions comprising nicotinic acid receptor agonist compounds in combination with other therapeutic agents; and methods of using the compounds and compositions to treat conditions such as metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, hepatic steatosis and non-alcoholic fatty liver disease.

Background of the Invention

Nicotinic acid, also known as niacin, and other nicotinic acid receptor (NAR) agonists are indicated for the treatment of hyperlipidemia or hypercholesteremia. Administration of NARs to hyperiipidemics or hypercholesteremias reduces total cholesterol, VLDL-cholesterol and VLDL- choiesterol remnants, LDL-cholesteroi, triglycerides and apolipoprotein a, while simultaneously increasing desirable HDL-choiesteroi. A disadvantage of nicotinic acid therapy, and, possibly, other NAR therapies, is a cutaneous flushing effect that often accompanies the treatment.

The cutaneous flushing effect is marked by intense flushing or redness, often accompanied by cutaneous itching, tingling, or warmth, and occasionally by headache. The cutaneous flushing effect is in itself harmless. Nevertheless, it is sufficiently unpleasant that nicotinic acid therapy is characterized by high rates of patient noncompliance. Some reports put patient noncompliance with nicotinic acid therapeutic regimens as high as 30-40%.

The cutaneous flushing effect is initiated by the release of prostaglandins.

Prostaglandins are known to cause vasodilation, as well as a subjective experience of discomfort. The putative role of prostaglandins in mediating the cutaneous flushing effect suggests that inhibitors of prostaglandin synthesis should be useful in preventing the cutaneous flushing effect.

Nonsteroidal anti-inflammatory drugs (NSAiDs) inhibit prostaglandin synthesis by blocking the enzyme prostaglandin synthetase, which is also known as cyclooxygenase. Accordingly, NSAIDs, especially aspirin (acetylsalicylic acid), have been administered in combination with nicotinic acid to reduce the cutaneous flushing effect. Such combination therapy has met with success. The administration of aspirin as a part of such combination therapy has the added benefit that aspirin administration prevents platelet aggregation (thrombosis) because it is a long-lasting inhibitor of platelet cyclooxygenase, and it irreversibly acetylates the enzyme. Platelet cyclooxygenase cannot be restored by protein biosynthesis because platelets lack a nucleus.

A problem with combination therapy is that patients must take two medicaments as opposed to one. Moreover, if the patient does not remember to take the NSAID, they may suffer the cutaneous flushing effect to such an extent as to discourage taking either medicament at all.

In view of the foregoing, there is a clear and continuing need for new compounds useful to treat metabolic syndromes.

Summary of the Invention

In its many embodiments, the present invention provides a novel class of acetylsalicylic acid derivative nicotinic acid receptor agonist compounds useful to treat metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, and non-alcoholic fatty liver disease; pharmaceutical compositions comprising such compounds; pharmaceutical compositions comprising nicotinic acid receptor agonist compounds in combination with other therapeutic agents; and methods of using the compounds and compositions to treat conditions such as metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, hepatic steatosis and non-alcoholic fatty liver disease. In one aspect, the present application discloses a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound, said compound having the general structure shown in Formula I:

wherein

G represents a hydrolysable or metabolizable linker group; and

R represents a recoverable residue of a nicotinic acid receptor agonist;

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. The phrase "hydrolysable or metabolizable linker group" as used herein means that the structure of linker group is such that the compound of the Formula I or the salt, solvate, ester or prodrug thereof can be broken down in vivo by hydrolysis or metabolism to yield the active NSAID component:

or an active NSAID derivative thereof; and an active nicotinic acid receptor agonist component R-OH or an active nicotinic acid receptor agonist derivative thereof. The phrase "a recoverable residue of a nicotinic acid receptor agonist" as used herein means that the structure of the R group is such that when the compound of the Formula I or the salt, solvate, ester or prodrug thereof is hydrolyzed or metabolized in vivo, the compound, salt, solvate, ester or prodrug is broken down to yield an active nicotinic acid receptor agonist component R-OH or an active nicotinic acid receptor agonist derivative thereof. As used herein, the phrase "nicotinic acid receptor agonist" means any compound that has affinity for (or binds to) the nicotinic acid receptor (also known as "HM74A" or "GPR109A") and when administered to a patient in an effective therapeutic amount results in a favorable modification of that patient's plasma lipid profile, including an elevation in serum levels of high density lipoprotein (HDL).

The compounds of Formula I and the salts, solvates, esters and prodrugs thereof are nicotinic acid receptor agonist compounds useful for treating metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, and non-alcoholic fatty liver disease. In another embodiment, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and at least one pharmaceutically acceptable carrier. In another embodiment, the present invention is directed to a method of treating a disease or disorder in a patient, such as metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, and non-alcoholic fatty liver disease. The method comprises administering to the patient an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

In another embodiment, the present invention is directed to a method of treating a disease or disorder in a patient, such as metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, hepatic steatosis, and nonalcoholic fatty liver disease. The method comprises administering to the patient an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one additional active ingredient selected from the group consisting of hydroxy- substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, inorganic cholesterol sequestrants, AcylCoA:Cholesterol O-acyltransferase inhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols (e.g., Omacor® from Pronova Biocare, Oslo, Norway), low-density lipoprotein receptor activators, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CBi antagonists/inverse agonists, ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1 R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 agonists, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC2 inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators. UCP-2 activators, UCP- 3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11 β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti- dyslipidemic agents, DP receptor antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

Detailed Description of the Invention

The nicotinic acid receptor agonist compounds of the present invention are useful for treating conditions such as metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, hepatic steatosis, and non-alcoholic fatty liver disease and other diseases listed herein. One or more compounds of the present invention can be administered alone or in combination with one or more other therapeutic agents as described herein.

The present invention provides compounds of Formula I:

and salts, solvates, esters and prodrugs thereof, wherein G and R are defined above.

In one embodiment, the present invention relates to a compound of the Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linker group selected from the group consisting of O, S, NR¹, -O-alkylene-O-, -O-alkylene-S-, -S-alkylene-S-, -O-arylene-O-, -O-arylene-S-, -S-arylene-S-, -O-arylalkylene-O-, -O-arylalkylene-S-, -S-arylalkylene-S-, -O-heteroarylene-O-, -O-heteroarylene-S-, -S-heteroarylene-S-, polyalkyleneglycol, -C(O)O-alkylene-O-, -C(O)O-alkylene-S-, -O-C(O)-alkylene-O-, -O-C(O)-alkylene-S-, -C(O)O-arylene-O-, -C(O)O-arylene-S-, -O-C(O)-arylene-O-, -O-C(O)-arylene-S-, -C(O)O-heteroarylene-O-, -C(O)O-heteroarylene-S-, -O-C(O)-heteroarylene-O-, -O-C(O)-heteroarylene-S-, and -C(O)-polyalkyleneglycol; and wherein R¹ represents hydrogen, alkyl or aryl.

In another embodiment, the present invention relates to a compound of the Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linker group selected from the group consisting

Of O, S₁ NR¹, -0(CH₂)_nO-, -O(C(R²)₂)O-, -O(CH₂)_nS-, -O(C(R²)₂)S-, -S(CH₂)_nS-, -S(C(R²)₂)S-, -O-aryl-O-; -O-aryl-S-; -S-aryl-S-; -O-heteroaryl-O-; -O-heteroaryl-S-; -S-heteroaryl-S-; PEG (polyethyleneglycol); and PPG (polypropyleneglycol); and R¹ represents hydrogen, alkyl or aryl; R² represents alkyl; and n represents 0-10.

In yet another embodiment, the present invention relates to a compound of the Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linker group selected from the group consisting of O; -C(O)O(CH₂)_nO-; -OC(O)(C(R²)₂)O-; -C(O)O(CH₂)_nS-; -OC(O)(C(R²)₂)S-; -C(O)S(CH₂)_nS-; -C(O)S(C(R²)₂)S-; -C(O)O-aryl-O-; -C(O)O-aryl-S-; -C(O)S-aryl-S-; -C(O)O-heteroaryl-O-; -C(O)O-heteroaryl-S-; -C(O)S-heteroaryl-S-; -C(O)PEG- (polyethyleneglycol); and -C(O)PPG- (polypropyleneglycol); and R¹ represents hydrogen, alkyl or aryl; R² represents alkyl; and n represents 0-10.

In another embodiment, the present invention relates to a compound of the Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linker group selected from the group consisting of O, S, NH, N(CH₃), -O-CH₂-O-, -O-CH₂CH₂-O-, -O-(CH₂)₃-O-, -O-CH₂-CH(CH₃)- O-, -O-CH₂-C(CH₃)₂-O-, -O-CH₂-S-, -O-CH₂CH₂-S-, -O-(CH₂)₃-S-, -O-CH₂-CH(CH₃)-S-, -O-CH₂-C(CH₃)₂-S-, -S-CH₂-S-, -S-CH₂CH₂-S-, -S-(CH₂)₃-S-, -S-CH₂-CH(CH₃)-S-, -S-CH₂-C(CH₃)₂-S-, -O-phenylene-O-, -O-phenylene-S-, -S-phenylene-S-, -O-pyridylene-O-, -O-pyridylene-S- and -S-pyridylene-S-. In another embodiment, the present invention relates to a compound of the Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist having the structure:

wherein the asterisk indicates the point of attachment to G,

In yet another embodiment, the present invention relates to a compound of the Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist, wherein the nicotinic acid receptor agonist is one described in United

States Patent Application Publication No. US 2008/0019978, the entire contents of which are hereby incorporated herein by reference. Among the compounds described in the abovementioned publication, particular preference is given to recoverable residues of a nicotinic acid receptor agonist having the structure:

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof;

wherein

R³ represents alkyl, especially unsubstituted alkyl or haloalkyl, or represents cycloalkyl or heteroalkyl; and R⁴ represents H, alkyl or cycloalkyl; and

the asterisk indicates the point of attachment to G.

Preference is likewise given to a recoverable residue of a nicotinic acid receptor agonist having the structure:

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; wherein

R⁵ and R⁶ each independently represent haloalkyl, especially fluoroalkyl; and

the asterisk indicates the point of attachment to G.

In yet another embodiment, the present invention relates to a compound of the Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist, wherein the nicotinic acid receptor agonist is one described in International Patent Application Publication Nos. WO 2004/033431 ; WO 2005/044816; WO 2005/051937; WO 2006/026273; WO 2006/069242; WO 2006/052555; WO 2007/035478; WO 2007/027532; WO 2005/077950; WO 2005/016867; WO 2005/016870; WO 2006/085108; WO 2006/045564; WO 2006/045565; WO 2006/085113; WO 2007/017261 ; WO 2007/017262; WO 2007/134986; WO 2007/015744; WO 2007/150025; WO 2007/150026; and WO 2007/134986; as well as United States Patent Application Publication Nos. US 2006/0281810; US 2007/0072873; and US 2007/0161650, the entire contents of all of which are hereby incorporated herein by reference.

In another embodiment, the present invention relates to a compound of the Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist having the structure:

wherein the asterisk indicates the point of attachment to G.

In yet another embodiment, the present invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist having the structure:

wherein the asterisk indicates the point of attachment to G.

In one particularly preferred embodiment, the present invention relates to compounds having the structure:

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G has one of the meanings given above.

In another particularly preferred embodiment, the present invention relates to compounds having the structure:

The compounds of the Formula I, and the pharmaceutically acceptable salts, solvates, esters and prodrugs thereof are nicotinic acid receptor agonists and, thus, are useful for treating metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, and non-alcoholic fatty liver diseases, possibly with a reduced incidence or severity of flushing compared to use of a bioequivalent amount of conventional nicotinic acid receptor agonist alone.

In one embodiment, the present invention relates to a composition comprising at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and a pharmaceutically acceptable carrier.

In another embodiment, the composition according to the present invention further comprises at least one additional therapeutic agent selected from the group consisting of hydroxy-substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, aspirin, NSAID agents, Vytorin®, ezetimibe, inorganic cholesterol sequestrants, AcylCoA:Cholesterol O-acyltransferaseinhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CBi antagonists/inverse agonists, ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1 R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 mimetics, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11 β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti-dyslipidemic agents, DPP-IV inhibitors, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, u-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

In a preferred embodiment, the present invention relates to a composition wherein the at least one additional therapeutic agent is an HMG CoA reductase inhibitor selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin.

In a particularly preferred embodiment, the present invention relates to a composition wherein the at least one additional therapeutic agent is simvastatin. In another preferred embodiment, the present invention relates to a composition wherein the at least one additional therapeutic agent is a cholesteryl ester transfer protein inhibitor.

In another particularly preferred embodiment, the present invention relates to a composition wherein the cholesteryl ester transfer protein inhibitor is torcetrapib.

In another particularly preferred embodiment, the present invention relates to a composition wherein the at least one additional therapeutic agent is Vytorin®, ezetimibe, aspirin, ibuprofen or acetaminophen or a combination thereof. In another particularly preferred embodiment, the present invention relates to a composition wherein the at least one additional therapeutic agent is DPP-IV inhibitor or a GLP-1 mimetic.

Non-limiting examples of compounds of the Formula I are depicted in Table 1 below: Table 1

Table 1 shows structures of representative compounds of this invention. The table and the compounds therein are not intended, nor should they be construed, to limit this invention in any manner whatsoever.

In Table 1 and throughout the disclosure, the abbreviation "Ac" means acetyl, i.e., -C(O)-CH₃. As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

"Patient" includes both human and animals.

"Mammal" means humans and other mammalian animals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, oxime (e.g., =N-OH), -NH(alkyl), -NH(cycloalkyl), -N(alkyl)₂, -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

"Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene.

"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

"Heteroary!" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non- limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1 -b]thiazo!yl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.

"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non- limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1 -decalinyl, norbomyl, adamantyl and the like.

"Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.

"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.

"Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.

"Heteroalkyl" means an alkyl moiety as defined above interrupted in the carbon chain by a heteroatom selected from the group consisting of O and S or by a heterogroup selected from the group consisting of NH and N-alkyl. Non- limiting examples of suitable heteroalkyls include CH₃-O-CH₂-, CH₃CH₂-O-CH₂-, CH₃-CH₂-S-CH₂-, CH₃-CH₂-NH-CH₂-CH₂-, CH₃-CH₂-N(Et)-CH₂-CH₂- (where Et means CH₃-CH₂-) and the like.

"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.

"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -O-C(O)- alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, oxo, -C(=N-CN)-NH₂, -C(=NH)-NH₂₎ -C(=NH)-NH(alkyl), oxime (e.g., =N-OH), Y₁Y₂N-, Y^aN-alkyl-, Y₁Y₂NC(O)-, Y₁Y₂NSO₂- and -SO₂NY₁Y₂, wherein Y₁ and Y₂ can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH₃)₂- and the like which form moieties such as, for example:

"Heteroarylalkyl" means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.

"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), - N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:

"Heterocyclylalkyl" means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like. "Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl, 1 ,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4- dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone:

"Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.

It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:

there is no -OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, the moieties:

are considered equivalent in certain embodiments of this invention.

"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.

"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1 - naphthoyl.

"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1 - or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.

"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.

"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

"Alkylsulfonyl" means an alkyl-S(O₂)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

"Arylsulfonyl" means an aryl-S(O₂)- group. The bond to the parent moiety is through the sulfonyl. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

The compounds of Formula I can be purified to a degree suitable for use as a pharmaceutically active substance. That is, the compounds of Formula I can have a purity of 95 wt % or more (excluding adjuvants such as pharmaceutically acceptable carriers, solvents, etc., which are used in formulating the compound of Formula I into a conventional form, such as a pill, capsule, IV solution, etc. suitable for administration into a patient). The purity can be 97 wt % or more, or, 99 wt % or more. A purified compound of Formula I includes a single isomer having a purity, as discussed above, of 95 wt % or more, 97 wt % or more, or 99 wt % or more, as discussed above.

Alternatively, the purified compound of Formula I can include a mixture of isomers, each having a structure according to Formula I, where the amount of impurity (i.e., compounds or other contaminants, exclusive of adjuvants as discussed above) is 5 wt % or less, 3 wt % or less, or 1 wt % or less. For example, the purified compound of Formula I can be an isomeric mixture of compounds of Structure (I), where the ratio of the amounts of the two isomers is approximately 1 :1 , and the combined amount of the two isomers is 95 wt % or more, 97 wt % or more, or 99 wt % or more.

It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991 ), Wiley, New York. When any variable (e.g., aryl, heterocycle, R², etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) |4 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

For example, if a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C₁-C₈)alkyl,

(C₂-Ci₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl-1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 - (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl-1 - (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C₁-C₂)alkyl, N,N-di (Cr

C₂)alkylcarbamoyl-(C₁-C₂)alkyl and piperidino-, pyrrolidino- or morpholino(C₂- C₃)alkyl, and the like.

Similarly, if a compound of Formula I contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C₁-C₆)alkanoyloxymethyl, 1 -((Cr C₆)alkanoyloxy)ethyl, 1 -methyl-1 -((CrC₆)alkanoyloxy)ethyl, (Cr C₆)alkoxycarbonyloxymethyl, N-(C₁-C6)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, or α- aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)₂, -P(O)(O(Cr C₆)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

If a compound of Formula I incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (C_1-Cio)alkyl, (C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, -C(OH)C(O)OY¹ wherein Y¹ is H, (C_rC₆)alkyl or benzyl, -C(OY²) Y³ wherein Y² is (CrC₄) alkyl and Y³ is (C_rC₆)alkyl, carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— or di-N,N-(C_1-C₆)alkylaminoalkyl, — C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵ is mono-N — or di-N,N-(C_1-C₆)alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1 -yl, and the like.

One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical ScL, 93(3), 601 -611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate). "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1 ) 1 -19; P. Gould, International J. of Pharmaceutics (1986) 33 201 -217; Anderson et al, The

Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C_1-4alkyl, or C_1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C_1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C₆-24)acyl glycerol.

Compounds of Formula I₁ and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. The compounds of Formula I may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula I as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula I may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula I may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention. All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P₁ ³⁵S, ¹⁸F, and ³⁶CI, respectively. Certain isotopically-labelled compounds of Formula I (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half- life or reduced dosage requirements) and hence may be preferred in some circumstances, lsotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention.

The compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be agonists of the nicotinic acid receptors.

The compounds of Formula I of the present invention, or pharmaceutically acceptable salts, solvates, or esters thereof are useful in treating diseases or conditions including dyslipidemia and metabolic syndrome. The compounds of Formula I, or pharmaceutically acceptable salts, solvates, or esters thereof, can be administered in any suitable form, e.g., alone, or in combination with a pharmaceutically acceptable carrier, excipient or diluent in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds of Formula I, or pharmaceutically acceptable salts, solvates, or esters thereof, can be administered orally or parenterally, including intravenous, intramuscular, interperitoneal, subcutaneous, rectal, or topical routes of administration, or if so selected, by a combination of one or more of the above- shown methods. Pharmaceutical compositions comprising at least one compound of

Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof can be in a form suitable for oral administration, e.g., as tablets, troches, capsules, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups, or elixirs. Oral compositions may be prepared by any conventional pharmaceutical method, and may also contain sweetening agents, flavoring agents, coloring agents, and preserving agents.

The amount of compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, administered to a patient can be determined by a physician based on the age, weight, and response of the patient, as well as by the severity of the condition treated. For example, the amount of compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, administered to the patient can range from about 0.1 mg/kg body weight per day to about 60 mg/kg/d. In one embodiment, the amount is from about 0.5 mg/kg/d to about 40 mg/kg/d. In another embodiment, the amount is from about 0.5 mg/kg/d to about 10 mg/kg/d. In another embodiment, the amount is from about 1 mg/kg/d to about 5 mg/kg/d. In still another embodiment, the amount is from about 1 mg/kg/d to about 3 mg/kg/d. In a specific embodiment, the amount is about 1 mg/kg/d. In another specific embodiment, the amount is about 3 mg/kg/d. In another specific embodiment, the amount is about 5 mg/kg/d. In another specific embodiment, the amount is about 7 mg/kg/d. In still another specific embodiment, the amount is about 10 mg/kg/d.

The compounds of Formula I, or pharmaceutically acceptable salts, solvates, or esters thereof, can also be administered in combination with other therapeutic agents. For example one or more compounds of Formula I or pharmaceutically acceptable salts, solvates, or esters thereof, can be administered with one or more additional active ingredients selected from the group consisting of hydroxy-substituted azetidinone compounds, substituted β- lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, inorganic cholesterol sequestrants, AcylCoA:Cholesterol O- acyltransferase inhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, PPAR α agonists, PPAR y- agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CBi antagonists/inverse agonists, ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1 R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 , GLP-1 agonists, GLP-1 mimetics, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11 β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, anti-diabetic agents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptor antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apo A1 miiano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

Non-limiting examples of hydroxy-substituted azetidinone compounds and substituted β-lactam compounds useful in combination with the nicotinic acid receptor agonists of the present invention are those disclosed in U.S. Pat. Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688,787, 5,756,470, U.S. Patent Application Nos. 2002/0137690 and 2002/0137689 and PCT Patent Application No. WO 2002/066464, each of which is incorporated herein by reference in their entirety. A preferred azetidinone compound is ezetimibe (for example, ZETIA® which is available from Schering-Plough Corporation).

Non-limiting examples of HMG CoA reductase inhibitor compounds useful in combination with the nicotinic acid receptor agonists of the present invention are lovastatin (for example MEVACOR® which is available from Merck & Co.), simvastatin (for example ZOCOR® which is available from Merck & Co.), pravastatin (for example PRAVACHOL® which is available from Bristol Meyers Squibb), atorvastatin (for example LIPITOR® which is available from Pfizer), fluvastatin, cerivastatin, CI-981 , rivastatin (sodium 7-(4-fluorophenyl)-2,6- diisopropyl-5-methoxymethylpyridin-3-yl)-3,5-dihyd- roxy-6-heptanoate), rosuvastatin calcium (CRESTOR® from AstraZeneca Pharmaceuticals), pitavastatin (such as NK-104 of Negma Kowa of Japan).

A non-limiting example of a HMG CoA synthetase inhibitor useful in combination with the nicotinic acid receptor agonists of the present invention is, for example, L-659,699 ((E₁E)-1 1-[3'R-(hydroxy-methyl)-4'-oxo-2'R-oxetanyl]- 3,5,7R-trimethyl-2,4- -undecadienoic acid).

A non-limiting example of a squalene synthesis inhibitor useful in combination with the nicotinic acid receptor agonists of the present invention is, for example, squalestatin 1. A non-limiting example of a squalene epoxidase inhibitor useful in combination with the nicotinic acid receptor agonists of the present invention is, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3¹- bithiophen-5-yl)me- thoxy]benzene-methanamine hydrochloride).

A non-limiting example of a sterol biosynthesis inhibitor useful in combination with the nicotinic acid receptor agonists of the present invention is, for example, DMP-565.

Non-limiting examples of nicotinic acid derivatives (e.g., compounds comprising a pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers) useful in combination with the nicotinic acid receptor agonists of the present invention are niceritrol, nicofuranose and acipimox (5-methyl pyrazine-2-carboxylic acid 4- oxide).

Non-limiting examples of bile acid sequestrants useful in combination with the nicotinic acid receptor agonists of the present invention are cholestyramine (a styrene-divinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available from Bristol-Myers Squibb), colestipol (a copolymer of diethylenetriamine and 1 -chloro-2,3-epoxypropane, such as COLESTID® tablets which are available from Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets (poly(allylamine hydrochloride) cross- linked with epichlorohydrin and alkylated with 1 -bromodecane and (6- bromohexyl)-trimethylammonium bromide) which are available from Sankyo), water soluble derivatives such as 3,3-ioene, N-(cycloalkyl)alkylamines and poliglusam, insoluble quaternized polystyrenes, saponins and mixtures thereof.

Non-limiting examples of inorganic cholesterol sequestrants useful in combination with the nicotinic acid receptor agonists of the present invention are bismuth salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids. Non-limiting examples of AcylCoA:Cholesterol O-acyltransferase ("ACAT") inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention are avasimibe ([[2,4,6-tris(1 -methylethyl)phenyl]acetyl]sulfamic acid, 2,6-bis(1 -methylethyl)phenyl ester, formerly known as CI-1011 ), HL-004, lecimibide (DuP-128) and CL-277082 (N-(2,4-difluorophenyl)-N-[[4-(2,2- dimethylpropyl)phenyl]methyl]-N-heptyl- urea), and the compounds described in P. Chang et al., "Current, New and Future Treatments in Dyslipidaemia and Atherosclerosis", Drugs July 2000; 60(1 ); 55-93, which is incorporated by reference herein. Non-limiting examples of cholesteryl ester transfer protein ("CETP") inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention are those disclosed in PCT Patent Application No. WO 00/38721 , U.S. Pat. Nos. 6,147,090, 6,958,346, 6,924,313 6,906,082, 6,861 ,561 , 6,803,388, 6,794,396, 6,787,570, 6,753,346, 6,723,752, 6,723,753, 6,710,089, 6,699,898, 6,696,472, 6,696,435, 6,683,113, 5,519,001 , 5,512,548, 6,410,022, 6,426,365, 6,448,295, 6,387,929, 6,683,099, 6,677,382, 6,677,380, 6,677,379, 6,677,375, 6,677,353, 6,677,341 , 6,605,624, 6,586,433, 6,451 ,830, 6,451 ,823, 6,462,092, 6,458,849, 6,458,803, 6,455,519, 6,583,183, 6,562,976, 6,555,113, 6,544,974, 6,521 ,607, 6,489,366, 6,482,862, 6,479,552, 6,476,075, 6,476,057, and 6,897,317, each of which are incorporated herein by reference; compounds described in Yan Xia et a!., "Substituted 1 ,3,5-Triazines As Cholesteral Ester Transfer Protein Inhibitors", Bioorganic & Medicinal Chemistry Letters, vol. 6, No. 7, 1996, pp. 919-922, herein incorporated by reference; natural products described in S. Coval et al., "Wiedendiol-A and -B, Cholesteryl Ester Transfer Protein Inhibitors From The Marine Sponge Xestosponga Wiedenmayeri", Bioorganic & Medicinal Chemistry Letter, vol. 5, No. 6, pp. 605-610, 1995, herein incorporated by reference; the compounds described in Barrett et al. J. Am. Chem. Soc, 188, 7863-63 (1996), herein incorporated by reference; the compounds described in Kuo et al. J. Am. Chem. Soc, 117, 10629-34 (1995), herein incorporated by reference; the compounds described in Pietzonka et al. Bioorg, Med. Chem. Lett. 6, 1951 -54 (1996), herein incorporated by reference; the compounds described in Lee et al. J. Antibiotics, 49, 693-96 (1996), herein incorporated by reference; the compounds described by Busch et al. Lipids, 25, 216-220, (1990), herein incorporated by reference; the compounds described in

Morton and Zilversmit J. Lipid Res., 35, 836-47 (1982), herein incorporated by reference; the compounds described in Connolly et al. Biochem. Biophys. Res. Comm., 223, 42-47 (1996), herein incorporated by reference; the compounds described in Bisgaier et al. Lipids, 29, 811 -8 (1994), herein incorporated by reference; the compounds described in EP 818448, herein incorporated by reference; the compounds described in JP 10287662, herein incorporated by reference; the compounds described in PCT applications WO 98/35937, WO 9914174, WO 9839299, and WO 9914215, each of which is herein incorporated by reference; the compounds of EP applications EP 796846, EP 801060,

818448, and 818197, each of which is herein incorporated by reference; probucol or derivatives thereof, such as AGI-1067 and other derivatives disclosed in U.S. Pat. Nos. 6,121 ,319 and 6,147,250, herein incorporated by reference; low- density lipoprotein (LDL) receptor activators such as HOE-402, an imidazolidinyl- pyrimidine derivative that directly stimulates LDL receptor activity, described in M. Huettinger et al., "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb. 1993; 13:1005- 12, herein incorporated by reference; 4-carboxyamino-2-substituted-1 ,2,3,4- tetrahydroquinolines, e.g., torcetrapib, described in WO 00/017164, WO 00/017166, WO 00/140190, WO 00/213797, and WO 2005/033082 (each of which is herein incorporated by reference). Torcetrapib can be combined with HMG-CoA reductase inhibitors such as atorvastatin (WO 00/213797, WO 2004/056358, WO 2004/056359, and WO2005/011634). A non-limiting example of a fish oil containing Omega 3 fatty acids useful in combination with the nicotinic acid receptor agonists of the present invention is 3-PUFA.

Non-limiting examples of GLP-1 mimetics useful in combination with the nicotinic acid receptor agonists of the present invention include exendin-3, exendin-4, Byetta-Exanatide, Liraglutinide, CJC-1 131 (ConjuChem), Exanatide- LAR (Amylin) BIM-51077 (Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and compounds disclosed in International Publication No. WO 00/07617.

Non-limiting examples of natural water soluble fibers useful in combination with the nicotinic acid receptor agonists of the present invention are psyllium, guar, oat and pectin.

A non-limiting example of a plant stanol and/or fatty acid ester of plant stanols useful in combination with the nicotinic acid receptor agonists of the present invention is the sitostanol ester used in BENECOL® margarine. A non-limiting example of an anti-oxidant useful in combination with the nicotinic acid receptor agonists of the present invention includes probucol.

Non-limiting examples of PPAR α agonists useful in combination with the nicotinic acid receptor agonists of the present invention include beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil. Non-limiting examples of lipoprotein synthesis inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include niacin or nicotinic acid.

Non-limiting examples of 5HT (serotonin) transport inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine.

Non-limiting examples of NE (norepinephrine) transport inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include GW 320659, despiramine, talsupram, and nomifensine.

Non-limiting examples of CBi antagonists/inverse agonists useful in combination with the nicotinic acid receptor agonists of the present invention include rimonabant, SR-147778 (Sanofi Aventis), and the compounds described in U.S. Pat. No. 5,532,237, U.S. Pat. No. 4,973,587, U.S. Pat. No. 5,013,837, U.S. Pat. No. 5,081 ,122, U.S. Pat. No. 5,112,820, U.S. Pat. No. 5,292,736, U.S. Pat. No. 5,624,941 , U.S. Pat. No. 6,028,084, WO 96/33159, WO 98/33765, WO 98/43636, WO 98/43635, WO 01/09120, WO 98/31227, WO 98/41519, WO 98/37061 , WO 00/10967, WO 00110968, WO 97/29079, WO 99/02499, WO 01/58869, WO 02/076949, and EP-658546 (each of the preceding references is herein incorporated by reference).

Non-limiting examples of ghrelin antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include those described in WO 01/87335 and WO 02/08250 (each of the preceding references is herein incorporated by reference). Ghrelin antagonists are also known as GHS (growth hormone secretagogue receptor) antagonists. The pharmaceutical combinations and methods of the present invention therefore comprehend the use GHS antagonists in place of ghrelin antagonists (in combination with the nicotinic acid receptor agonists of the present invention). Non-limiting examples of H₃ antagonists/inverse agonists useful in combination with the nicotinic acid receptor agonists of the present invention include thioperamide, 3-(1 H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, and GT2394 (Gliatech), those described in: WO 02/15905 (herein incorporated by reference); O-[3-(1 H- imidazol-4-yl)propanol]carbamates described in Kiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000) (herein incorporated by reference), piperidine- containing histamine H₃-receptor antagonists described in Lazewska, D. et al., Pharmazie, 56:927-32 (2001 ) (herein incorporated by reference), benzophenone derivatives and related compounds described in Sasse, A. et al., Arch. Pharm. (Weinheim) 334:45-52 (2001 ) (herein incorporated by reference), substituted N- phenylcarbamates described in Reidemeister, S. et al., Pharmazie, 55:83-6 (2000) (herein incorporated by reference), and proxifan derivatives described in Sasse, A. et al., J. Med. Chem. 43:3335-43 (2000) (each of the preceding references is herein incorporated by reference).

Non-limiting examples of MCH1 R (melanin-concentrating hormone 1 receptor) antagonists and MCH2R (melanin-concentrating hormone 2 receptor) agonists/antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include those described in WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, WO 02/51809, and JP 13226269 (each of the preceding references is herein incorporated by reference), and T-226296 (Takeda).

Non-limiting examples of NPY1 antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include those described in U.S. Pat. No. 6,001 ,836, WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528 (each of the preceding references is herein incorporated by reference); and BIBP3226, J- 115814, BIBO 3304, LY-357897, CP-671906, and GI-264879A. Non-limiting examples of NPY5 antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include those described in U.S. Pat. No. 6,140,354, U.S. Pat. No. 6,191 ,160, U.S. Pat. No. 6,258,837, U.S. Pat. No. 6,313,298, U.S. Pat. No. 6,337,332, U.S. Pat. No. 6,329,395, U.S. Pat. No. 6,340,683, U.S. Pat. No. 6,326,375, U.S. Pat. No. 6,335,345, EP- 01010691 , EP-01044970, WO 97/19682, WO 97/20820, WO 97/20821 , WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201 , WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, WO 02/49648, WO 01/14376, WO 04/110375, WO 05/000217 and Norman et al., J. Med. Chem. 43:4288-4312 (2000) (each of the preceding references is herein incorporated by reference); and 152,804, GW-569180A, GW-594884A, GW- 587081 X, GW-548118X; FR226928, FR 240662, FR252384; 1229U91 , Gl- 264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104.

Non-limiting examples of NPY2 agonists useful in combination with the nicotinic acid receptor agonists of the present invention include PYY3-36 as described in Batterham, et al., Nature. 418:650-654 (2003), NPY3-36, and other Y2 agonists such as N acetyl [Leu(28,31)] NPY 24-36 (White-Smith and Potter, Neuropeptides 33:526-33 (1999)), TASP-V (Malis et al., Br. J. Pharmacol. 126:989-96 (1999)), cyclo-(28/32)-Ac-[l_ys28-Glu32]-(25-36)-pNPY (Cabrele and Beck-Sickinger J-Pept-Sci. 6:97-122 (2000)) (each of the preceding references is herein incorporated by reference). Non-limiting examples of NPY4 agonists useful in combination with the nicotinic acid receptor agonists of the present invention include pancreatic peptide (PP) as described in Batterham et al., J. Clin. Endocrinol. Metab. 88:3989-3992 (2003), and other Y4 agonists such as 1229U91 (Raposinho et al., Neuroendocrinology. 71.2-7(2000) (both references are herein incorporated by reference).

Non-limiting examples of mGluR5 (Metabotropic glutamate subtype 5 receptor) antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and (3-[(2-methyl-1 ,3-thiazol-4-yl)ethynyl]pyridine) (MTEP) and those compounds described in Anderson J. et al., J, Eur J Pharmacol. JuI. 18, 2003;473(1):35-40; Cosford N. et al., Bioorg Med Chem Lett. Feb. 10, 2003;13(3):351 -4; and Anderson J. et al., J Pharmacol Exp Ther. December 2002:303(3): 1044-51 (each of the preceding references is herein incorporated by reference). Non-limiting examples of leptins, leptin derivatives, and leptin agonists/modulators useful in combination with the nicotinic acid receptor agonists of the present invention include recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen). Leptin derivatives (e.g., truncated forms of leptin) useful in the present invention include those described in U.S. Pat. No. 5,552,524, U.S. Pat. No. 5,552,523, U.S. Pat. No. 5,552,522, U.S. Pat. No. 5,521 ,283, WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, and WO 96/23520 (each of the preceding references is herein incorporated by reference). Non-limiting examples of opioid antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include nalmefene (Revex.™), 3-methoxynaltrexone, naloxone, and naltrexone, as well as opioid antagonists described in WO 00/21509 (herein incorporated by reference).

Non-limiting examples of orexin receptor antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include SB- 334867-A, as well as those described in WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838 (each of the preceding references is herein incorporated by reference).

Non-limiting examples of CNTF (specific ciliary neurotrophic factors) useful in combination with the nicotinic acid receptor agonists of the present invention include GI-181771 (Glaxo-SmithKline); SR146131 (Sanofi Aventis); butabindide; PD170,292, PD 149164 (Pfizer).

Non-limiting examples of CNTF derivatives and CNTF agonists/modulators useful in combination with the nicotinic acid receptor agonists of the present invention include axokine (Regeneron) and those described in WO 94/09134, WO 98/22128, and WO 99/43813 (each of which is herein incorporated by reference).

Non-limiting examples of 5HT2c agonists useful in combination with the nicotinic acid receptor agonists of the present invention include BVT933, DPCA37215, WAY161503, and R-1065, as well as those described in U.S. Pat. No. 3,914,250, WO 02/6596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457 (each of which is herein incorporated by reference). Non-limiting examples of Mc4r agonists useful in combination with the nicotinic acid receptor agonists of the present invention include CHIR86036 (Chiron); ME-10142, and ME-10145 (Melacure), as well as those described in WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715, and WO 02/12178 (each of which is herein incorporated by reference). Non-limiting examples of monoamine reuptake inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include sibutramine (Meridia™/Reductil™), as well as those described in WO 01/27068, WO 01/62341 , U.S. Pat. No. 4,746,680, U.S. Pat. No. 4,806,570, U.S. Pat. No. 5,436,272, and US 2002/0006964 (each of which is herein incorporated by reference).

Non-limiting examples of serotonin reuptake inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include dexfenfluramine, fluoxetine, and those described in U.S. Pat. No. 6,365,633, WO 01/27060, and WO 01/162341 (each of which is herein incorporated by reference).

A non-limiting example of an acyl-estrogen useful in combination with the nicotinic acid receptor agonists of the present invention includes oleoyl-estrone. Non-limiting examples of 11 β HSD-1 inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include those described in WO 03/065983 and WO 03/104207 (both of which are herein incorporated by reference).

A non-limiting example of a lipase inhibitor useful in combination with the nicotinic acid receptor agonists of the present invention include orlistat. Anti-diabetic agents useful in combination with the nicotinic acid receptor agonists of the present invention include sulfonylureas, meglitinides, α-amylase inhibitors, α-glucoside hydrolase inhibitors, PPAR-γ agonists, PPARα/γ agonists, biguanides, PTP-1 B inhibitors, DP-IV inhibitors, DPP-IV inhibitors, insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino- terminal kinase inhibitors, insulin, insulin mimetics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, glucokinase activators, and non- thiazolidinedione PPAR ligands. Non-limiting examples of sulfonylureas useful in combination with the nicotinic acid receptor agonists of the present invention include acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide.

Non-limiting examples of meglitinides useful in combination with the nicotinic acid receptor agonists of the present invention include repaglinide, mitiglinide and nateglinide. Non-limiting examples of α-amylase inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include tendamistat, trestatin, and AI-3688.

Non-limiting examples of α-glucoside hydrolase inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include acarbose, adipose, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, CDK-711 , MDL-25,637, MDL-73,945, and MOR 14.

Non-limiting examples of PPAR-γ agonists useful in combination with the nicotinic acid receptor agonists of the present invention include balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone (MCC-555), pioglitazone, rosiglitazone, troglitazone, tesaglitazar, netoglitazone, GW-409544, GW-501516, CLX-0921 , 5-BTZD, GW-0207, LG-100641 , LY-300512, LY-519818, R483 (Roche), and T131 (Tularik).

Non-limiting examples of PPARα/γ agonists useful in combination with the nicotinic acid receptor agonists of the present invention include CLX-0940, GW- 1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB 219994.

Non-limiting examples of biguanides useful in combination with the nicotinic acid receptor agonists of the present invention include buformin, metformin, and phenformin.

Non-limiting examples of PTP-1 B inhibitors (protein tyrosine phosphatase- 1 B inhibitors) useful in combination with the nicotinic acid receptor agonists of the present invention include A-401 ,674, KR 61639, OC-060062, OC-83839, OC- 297962, MC52445, and MC52453. Non-limiting examples of DPP-IV inhibitors (dipeptidyl peptidase IVi inhibitors) useful in combination with the nicotinic acid receptor agonists of the present invention include sitagliptin, saxagliptin, denagliptin, vildagliptin, alogliptin, alogliptin benzoate, Galvus (Novartis), ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph), Bl-A and Bl-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513 (Mitsubishi), DP-893 (Pfizer) and RO- 0730699 (Roche), isoleucine thiazolidide, NVP-DPP728, P32/98, LAF 237, TSL 225, valine pyrrolidide, TMC-2A/2B/2C, CD-26 inhibitors, and SDZ 274-444.

Non-limiting examples of insulin secretagogues useful in combination with the nicotinic acid receptor agonists of the present invention include linogliride and A-4166.

Non-limiting examples of fatty acid oxidation inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include clomoxir and etomoxir. Non-limiting examples of A2 antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include midaglizole, isaglidole, deriglidole, idazoxan, earoxan, and fluparoxan.

Non-limiting examples of insulin mimetics useful in combination with the nicotinic acid receptor agonists of the present invention include biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente), Lys-Pro insulin, GLP-1 (73-7) (insulintropin), and GLP-1 (7- 36)-NH₂).

Non-limiting examples of glycogen phosphorylase inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include CP-368,296, CP-316,819, and BAYR3401.

Non-limiting examples of non-thiazolidinedione PPAR ligands useful in combination with the nicotinic acid receptor agonists of the present invention include JT-501 and farglitazar (GW-2570/GI-262579). Anti-hypertensive agents useful in combination with the nicotinic acid receptor agonists of the present invention include diuretics, β-adrendergic blockers, α-adrenergic blockers, aldosterone inhibitors, alpha 1 blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin Il receptor antagonists, endothelin antagonists, vasodilators, alpha 2a agonists, and α/β adrenergic blockers.

Non-limiting examples of diuretics useful in combination with the nicotinic acid receptor agonists of the present invention include chlorthalidone, chlorthiazide, dichlorophenamide, hydroflumethiazide, indapamide, hydrochlorothiazide, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, triamterene, spironolactone, and epirenone.

Non-limiting examples of β-adrendergic blockers useful in combination with the nicotinic acid receptor agonists of the present invention include acebutolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol, penbutolol, pindolol, propanolol, sotalol, tertatolol, tilisolol, and timolol.

Non-limiting examples of alpha 1 blockers useful in combination with the nicotinic acid receptor agonists of the present invention include terazosin, urapidil, prazosin, bunazosin, trimazosin, doxazosin, naftopidil, indoramin, WHIP 164, and XEN010.

Non-limiting examples of calcium channel blockers useful in combination with the nicotinic acid receptor agonists of the present invention include amlodipine, aranidipine, azelnidipine, bamidipine, benidipine, bepridil, cinaldipine, clevidipine, diltiazem, efonidipine, felodipine, gallopamil, isradipine, lacidipine, lemildipine, lercanidipine, nicardipine, nifedipine, nilvadipine, nimodepine, nisoldipine, nitrendipine, manidipine, pranidipine, and verapamil.

Non-limiting examples of angiotensin converting enzyme inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include alacepril, benazepril, ceronapril, captopril, cilazapril, delapril, enalapril, fosinopril, imidapril, losinopril, moveltopril, moexipril, quinapril, quinaprilat, ramipril, perindopril, peridropril, quanipril, spirapril, temocapril, trandolapril, and zofenopril.

Non-limiting examples of neutral endopeptidase inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include omapatrilat, cadoxatril, ecadotril, fosidotril, sampatrilat, AVE7688, and ER4030.

Non-limiting examples of angiotensin Il receptor antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include candesartan, eprosartan, irbesartan, losartan, pratosartan, tasosartan, telisartan, valsartan, EXP-3137, F16828K, RNH6270, losartan monopotassium, and losartan potassium-hydrochlorothiazide.

Non-limiting examples of endothelin antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include tezosentan, A308165, and YM62899.

Non-limiting examples of vasodilators useful in combination with the nicotinic acid receptor agonists of the present invention include hydralazine (apresoline), clonidine (catapres), minoxidil (loniten), and nicotinyl alcohol (roniacol). Non-limiting examples of alpha 2a agonists useful in combination with the nicotinic acid receptor agonists of the present invention include lofexidine, tiamenidine, moxonidine, rilmenidine, and guanobenz.

Non-limiting examples of α/β adrenergic blockers useful in combination with the nicotinic acid receptor agonists of the present invention include nipradilol, arotinolol, and amosulalol.

In one particularly preferred embodiment, the present invention relates to a composition comprising a first ingredient, which first ingredient is at least one compound of Formula I, or a salt, solvate, ester or prodrug thereof, and a second ingredient, which second ingredient is at least one compound selected from the group consisting of LIPITOR®, ZETIA®, VYTORIN®, ZOCOR® and CRESTOR®.

In another particularly preferred embodiment, the present invention relates to a composition comprising a first ingredient, which first ingredient is at least one compound of Formula I, or a salt, solvate, ester or prodrug thereof, and a second ingredient, which second ingredient is a platelet aggregation inhibitor.

In an especially preferred embodiment, the present invention relates to a composition comprising a first ingredient, which first ingredient is at least one compound of Formula I, or a salt, solvate, ester or prodrug thereof, and a second ingredient, which second ingredient is a platelet aggregation inhibitor, wherein the platelet aggregation inhibitor is a thrombin receptor antagonist, most especially a thrombin receptor antagonist as described in U.S. Patents Nos. 6,063,847; 6,326,380; 7,037,920; 6,645,987; 7,235,567; 6,894,065; and 7,304,078, for example, the entire contents of which are hereby incorporated by reference.

It will be appreciated by those skilled in the art that the herein-described inventive compounds exhibit excellent nicotinic acid receptor agonist activity. The term "pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium state, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18^th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitable sized unit doses containing appropriate quantities of the active component, e.g. an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated.

Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses. As the compound of Formula I releases acetylsalicylic acid when hydrolyzed or metabolized in vivo, the amount of acetylsalicylic acid released should be bioequivalent to not more than 80 mg/day ingested. Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent. Yet another aspect of this invention is a kit comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and an amount of at least one therapeutic agent listed above, wherein the amounts of the two or more ingredients result in a desired therapeutic effect. The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.

Where NMR data are presented, ¹H spectra were obtained on either a Variant VXR-200 (200 MHz, ¹H), Varian Gemini-300 (300 MHZ), Varian Mercury VX-400 (400MHz), or Bruker-Biospin AV-500(500MHz), and are reported as ppm with number of protons and multiplicities indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Applied Biosystems API- 100 mass spectrometer and C18 column, 10-95% CH₃CN-H₂O (with 0.05% TFA) gradient. The observed parent ion is given.

The following solvents and reagents may be referred to by their abbreviations in parenthesis:

Me = methyl

Et = ethyl Pr = propyl

Bu = butyl

Ph = phenyl

Ac = acetyl μl = microliters

AcOEt or EtOAc = ethyl acetate

AcOH or HOAc = acetic acid

ACN = acetonitrile atm = atmosphere Boc or BOC = tert-butoxycarbonyl

DCE = dichloroethane

DCM or CH₂Cl₂ = dichloromethane

DIPEA = diisopropylethylamine

DMAP = 4-dimethylaminopyridine DMF = dimethylformamide

DMS = dimethylsulfide

DMSO = dimethyl sulfoxide

EDCI = 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimine

Fmoc or FMOC = 9-fluorenylmethoxycarbonyl g = grams h = hour hal = halogen

HOBt = 1 -hydroxybenzotriazole

LAH = lithium aluminum hydride LCMS = liquid chromatography mass spectrometry min = minute mg = milligrams ml_ = milliliters mmol = millimoles

MCPBA = 3-chloroperoxybenzoie acid

MeOH = methanol

MS = mass spectrometry

NMR = nuclear magnetic resonance spectroscopy RT or rt = room temperature (ambient, about 25°C)

TEA or Et₃N = triethylamine

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin layer chromatography TMS = trimethylsilyl

Tr = triphenylmethyl

Examples

The compounds of this invention can be prepared as generally described in the Preparation Schemes, and the following examples.

General Methods

Solvents, reagents, and intermediates that are commercially available were used as received. Reagents and intermediates that are not commercially available were prepared in the manner described below. ¹H NMR spectra were obtained on a Gemini AS-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in

Hertz indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron, 33 mm x 7mm ID; gradient flow: 0 min - 10% CH₃CN, 5 min - 95% CH₃CN, 7 min - 95% CH₃CN, 7.5 min - 10% CH₃CN, 9 min - stop. The retention time and observed parent ion are given.

General synthetic schemes:

Scheme 1.

Scheme 2.

Scheme 3.

Preparative example 1

Step 1 :

Compound 1a (1 g) in CH₂Cl₂ (2.0 ml.) was added dropwise to a solution of compound 2 (0.53 ml_) and NEt₃ (0.74 ml_) at room temperature. The reaction mixture was stirred for 3 hours before it was diluted with EtOAc/HCl (1 N). Aqueous phase was extracted with EtOAc (3x), and the combined organic phases was washed with water (1x), brine, and dried (MgSO₄). The solvent was removed under reduced presure and the residue was purified using flash chromatography with 20% EtOAc/hexane as the eluting solvent to give compound 1c. Step 2:

NEt₃ (0.8 mL) was added dropwise to a mixture of compounds 1c (1.1 g) and "Id (0.90 g, HCl salt). The reaction mixture was stirred for 8 hours before it was diluted with EtOAc/NaHCO₃ (saturated). Aqueous phase was extracted with EtOAc (3x), and the combined organic phases was washed with water (1 x), brine, and dried (MgSO₄). The solvent was removed under reduced presure and the residue was purified using flash chromatography with 20% EtOAc/hexane as the eluting solvent to give compound 1. Electrospray MS [M+1]⁺ 346.2.

Other compounds of Formula I, including those in Table 1 , and the salts, solvates, esters and prodrugs thereof, can be prepared analogously to the preparations described in the foregoing preparation example.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

CLAIMSWhat is claimed is:

1. A compound of the Formula I:

wherein

G represents a hydrolysable or metabolizable linker group; and

R represents a recoverable residue of a nicotinic acid receptor agonist;

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

2. The compound according to claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linker group selected from the group consisting of O, S, NR¹, -O-alkylene-O-, -O-alkylene-S-, -S-alkylene-S-, -O-arylene-O-, -O-arylene-S-, -S-arylene-S-, -O-arylalkylene-O-, -O-arylalkylene-S-, -S-arylalkylene-S-, -O-heteroarylene-O-, -O-heteroarylene-S-, -S-heteroarylene-S-, polyalkyleneglycol, -C(O)O-alkylene- O-, -C(O)O-alkylene-S-, -O-C(O)-alkylene-O-, -O-C(O)-alkylene-S-, -C(O)O-arylene-O-, -C(O)O-arylene-S-, -O-C(O)-arylene-O-, -O-C(O)-aryIene-S-,

-C(O)O-heteroarylene-O-, -C(O)O-heteroarylene-S-, -O-C(O)-heteroarylene-O-, -O-C(O)-heteroarylene-S-, and -C(O)-polyalkyleneglyeol; and R¹ represents hydrogen, alkyl or aryl.

3. The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linker group selected from the group consisting of O, S, NR¹, -O(CH₂)_nO-, -O(C(R²)₂)O-₍ -0(CH₂)_nS-, -0(C(R²)₂)S-, -S(CH₂)_nS-, -S(C(R²)₂)S-, -O-aryl-O-; -O-aryl-S-; -S-aryl-S-; -O-heteroaryl-O-; -O-heteroaryl-S-; -S-heteroaryl-S-; PEG (polyethyleneglycol); and PPG (polypropyleneglycol); and R¹ represents hydrogen, alkyl or aryl ; R² represents alkyl; and n represents 0-10.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist having the structure:

wherein the asterisk indicates the point of attachment to G.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist having the structure:

wherein R³ represents alkyl, cycloalkyl or heteroalkyl; and R⁴ represents H, alkyl or cycloalkyl; and

the asterisk indicates the point of attachment to G.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist having the structure:

wherein

R⁵ and R⁶ each independently represent haloalkyl; and the asterisk indicates the point of attachment to G.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist having the structure:

wherein the asterisk indicates the point of attachment to G.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a recoverable residue of a nicotinic acid receptor agonist having the structure:

wherein the asterisk indicates the point of attachment to G.

9. A compound selected from the group consisting of compounds of the structural formula:

and pharmaceutically acceptable salts, solvates, esters and prodrugs thereof.

10. A composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.

11. A composition comprising at least one compound of claim 9 and a pharmaceutically acceptable carrier.

12. The composition of claim 10, further comprising at least one additional therapeutic agent selected from the group consisting of hydroxy- substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, aspirin, NSAID agents, Vytorin®, ezetimibe, inorganic cholesterol sequestrants, AcylCoA:Cholesterol O- acyltransferaseinhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, PPAR α agonists, PPAR v- agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CBi antagonists/inverse agonists, ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1 R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 mimetics, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP- 3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11 β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti- dyslipidemic agents, DPP-IV inhibitors, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti- related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, u-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

13. The composition of claim 12, wherein the at least one additional therapeutic agent is selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, pravastatin, torcetrapib, Vytorin®, ezetimibe, aspirin, ibuprofen, acetaminophen, DPP-IV inhibitor, GLP-1 mimetics and combinations thereof.

14. The composition of claim 11 , further comprising at least one additional therapeutic agent selected from the group consisting of hydroxy- substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, aspirin, NSAID agents, Vytorin®, ezetimibe, inorganic cholesterol sequestrants, AcylCoA:Cholesterol O- acyltransferaseinhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, PPAR α agonists, PPAR y- agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CBi antagonists/inverse agonists, ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1 R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 mimetics, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone 1 agonists, UCP-1 activators, UCP-2 activators, UCP- 3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11 β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti- dyslipidemic agents, DPP-IV inhibitors, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti- related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

15. The composition of claim 14, wherein the at least one additional therapeutic agent is selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, pravastatin, torcetrapib, Vytorin®, ezetimibe, aspirin, ibuprofen, acetaminophen, DPP-IV inhibitors, GLP-1 mimetics and combinations thereof.

16. A method of treating metabolic syndrome, dyslipidemia, a cardiovascular disease, a disorder of the peripheral and central nervous system, a hematological disease, cancer, inflammation, a respiratory disease, a gastroenterological disease, diabetes or non-alcoholic fatty liver disease in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

17. The method of claim 16, further comprising administering at least one additional therapeutic agent selected from the group consisting of hydroxy- substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants) inorganic cholesterol sequestrants, aspirin, NSAID agent, ezetimibe, Vytorin®, AcylCoA:Cholesterol O- acyltransferase inhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stands and/or fatty acid esters of plant stanols, Omacor®, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CBi antagonists/inverse agonists, ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1 R antagonists,

MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 mimetics, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP- 3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti- dyslipidemic agents, DPP-IV inhibitors, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti- related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

18. A method of treating metabolic syndrome, dyslipidemia, a cardiovascular disease, a disorder of the peripheral and central nervous system, a hematological disease, cancer, inflammation, a respiratory disease, a gastroenterological disease, diabetes or non-alcoholic fatty liver disease in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of at least one compound of claim 9, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

19. The method of claim 18, further comprising administering at least one additional therapeutic agent selected from the group consisting of hydroxy- substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors nicotinic acid derivatives, bile acid sequestrants, inorganic cholesterol sequestrants, aspirin, NSAID agent, ezetimibe, Vytorin®, AcylCoA:Cholesterol O- acyltransferase inhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, Omacor®, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CBi antagonists/inverse agonists, ghrelin antagonists, H₃ antagonists/inverse agonists, MCH1 R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 mimetics, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP- 3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11 β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti- dyslipidemic agents, DPP-IV inhibitors, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti- related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists,

MSH-receptor analogs, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).