TW201016667A - Acetylsalicylic acid derivatives useful to treat metabolic syndromes - Google Patents

Abstract

The present invention provides compounds 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; 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

201016667 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to an acetohydrosalicylic acid derivative for the treatment of the following diseases: acid metabolism syndrome, dyslipidemia, cardiovascular disease, surrounding Nervous system and sacral nervous system disorders, blood diseases, cancer, inflammation, respiratory diseases, gastrointestinal diseases, diabetes and non-alcoholic fatty liver disease, pharmaceutical compositions including such compounds; including nicotinic acid receptor agonists A pharmaceutical composition of a compound in combination with other therapeutic agents; and a method for treating a condition such as metabolic syndrome, dyslipidemia, cardiovascular disease, peripheral nervous system and central nervous system disorder, blood using a compound or composition such as Shai Disease, cancer, inflammation, respiratory disease, gastrointestinal disease, diabetes, liver steatosis and nonalcoholic fatty liver disease. The present application claims the benefit of the provisional application of USSN 61/081,566, which is incorporated herein by reference. [Prior Art] Nicotinic acid (also known as niacin) and other nicotinic acid receptor (NAR) agonists are useful for the treatment of hyperlipidemia or hypercholesterolemia. Administration of NAR to patients with hyperlipidemia or sputum cholesterol reduces total cholesterol, VLDL-cholesterol and VLDL-cholesterol residues, LDL-cholesterol, triglycerides, and apolipoprotein a, while increasing the desired HDL_ cholesterol. A disadvantage of acid testing and (possibly) other NAR treatments is that the treatment is usually accompanied by a redness effect on the skin. The redness effect of the skin appears to be strongly reddening or filling 'usually accompanied by itchy skin, tingling, or fever, and sometimes accompanied by head 141541.doc 201016667 The painful redness of the skin itself is harmless. However, it is very unpleasant that niacin treatment shows a high rate of patient non-compliance. Some reports point to a non-compliance rate of 30-40% for patients with a smoke test. The skin redness effect is caused by the release of prostaglandins. Prostaglandins are known to cause vasodilation and subjective feelings of discomfort. The recognized role of prostaglandins in mediating skin redness effects suggests that inhibitors of prostaglandin synthesis can be used to prevent skin redness. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis by nucleating prostaglandin synthetase (also known as cyclooxygenase). Therefore, nsaid (especially aspirin (acetamidine)) is administered in combination with nicotinic acid to reduce the redness of the skin. This combination therapy has been successful. The administration of aspirin as part of this combination has the additional benefit of administering aspirin to prevent platelet aggregation (thrombosis) due to its long-acting inhibitor of platelet cyclooxygenase and irreversible

Chemical. Platelet cyclooxygenase cannot be restored by protein biosynthesis due to the lack of nuclei in platelets. The problem with combination therapy is that the patient must take two drugs (four) one drug. In addition, if a patient forgets to take an NSAID, it may experience a redness effect on the skin to lose confidence in taking any of the drugs. In view of the above, there is an urgent need in the industry for a novel compound that can be used to treat metabolic syndrome. SUMMARY OF THE INVENTION In many embodiments, the present invention provides a novel species of acetaminophen derivative nicotinic acid receptor agonist compound for the treatment of the following diseases: metabolism 141541.doc 201016667 Syndrome, abnormality of lipoprotein, Cardiovascular disease, peripheral nervous system and mesenteric nervous system reduction, blood diseases, cancer, inflammation, respiratory diseases, gastrointestinal diseases, diabetes and non-alcoholic fatty liver disease; pharmaceutical compositions including such compounds; package (4) (four) receptors Pharmaceutical compositions of agonist compounds in combination with other therapeutic agents; and methods of using such compounds and compositions to treat symptoms such as metabolic syndrome, dyslipidemia, cardiovascular disease, peripheral nervous system and central nervous system disorders, money Disease, cancer, inflammation, respiratory disease, gastrointestinal disease, diabetes, liver steatosis and nonalcoholic fatty liver disease. In one aspect, the application discloses a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound. The compound has the general structure shown in Formula I:

Wherein t G represents a hydrolyzable or metabolizable linking 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 "hydrolyzable or metabolizable linking group" as used herein means that the linking group is structured such that the compound of formula I or a salt, solvate, ester or prodrug thereof can be hydrolyzed or metabolized in vivo. Decompose to produce an active NSAID component: 141541.doc •6· 201016667 Ο

Η or an active NS AID derivative thereof, and an active nicotinic acid receptor agonist component R_OH or an active nicotinic acid receptor agonist derivative thereof.

As used herein, the phrase "recoverable residue of a final acid acceptor agonist" means that the R group is structured such that the compound of formula I or a salt, solvate, vinegar or prodrug thereof is hydrolyzed in vivo. Alternatively, the compound, salt, solvate, ester or prodrug is decomposed during metabolism to produce an active nicotinic acid receptor agonist component R-OH or an active nicotinic acid receptor agonist derivative thereof. The phrase "nicotinic acid receptor agonist" as used herein means any compound having an affinity (or binding to a nicotinic acid receptor (also referred to as "HM74A" or "GPR1〇9A"), And when administered to a patient in a therapeutically effective amount, it will result in a beneficial change in the patient's lipid profile, including elevated levels of high density lipoprotein (HDL). The compounds of formula I and their salts, solvates, esters and prodrugs are used in the treatment of the following receptors for the following receptors: metabolic syndrome, lipid abnormalities, cardiac tube disease, peripheral nervous system and t Nervous system disorders, blood disorders, cancer, inflammation, respiratory diseases, intestinal nonalcoholic lipids _. In the case of urinary disease and in another embodiment, the present invention relates to a pharmaceutical composition having 1 scoop of 'a therapeutically effective amount of at least one formula' of a compound, or a pharmaceutically acceptable salt, solvate, ester or ester thereof A drug, and at least one pharmaceutically acceptable carrier.上上接141541.doc 201016667, in another embodiment, the present invention relates to a treatment of a patient such as the following diseases or conditions, such as the following diseases or disorders, metabolic syndrome, dyslipidemia, cardiovascular Diseases, surrounding gods (4) and middle (4) systemic diseases, blood diseases, cancer fires, respiratory diseases, gastrointestinal diseases, diabetes and non-alcoholic fatty liver diseases. The method comprises administering to the patient an effective amount of at least one compound of the formula, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. In another embodiment, the invention relates to a method of treating a disease or condition such as a metabolic syndrome, dyslipidemia, cardiovascular disease, peripheral nervous system and central nervous system disorder, blood disease, cancer, inflammation. , respiratory diseases, gastrointestinal diseases, diabetes, liver steatosis and non-alcoholic fatty liver disease. The method comprises administering to a patient an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, vinegar or prodrug thereof, in combination with at least one other active ingredient selected from the group consisting of: Hydroxyl substituted azetidinone compound, substituted β-lacquer amine compound, HMG CoA reductase inhibitor compound, Hmg

CoA synthetase inhibitor, squalene synthesis inhibitor, squalene epoxidase inhibitor, sterol biosynthesis inhibitor, acid test derivative, bile acid integrator, inorganic cholesterol chelating agent, sulfhydryl-based CoA: cholesterol 〇_醯-transferase inhibitor, cholesteryl ester transfer protein inhibitor, fish oil containing omega 3 fatty acid, natural water-soluble fiber, phyto-alcohol and/or fatty acid ester of phyto-alcohol (for example, from Pronova Biocare, 〇 Sl〇, Norway

Omacor®), low-density serotonin receptor activator, antioxidant, ppar alpha agonist, PPAR gamma-agonist, FXR receptor modulator, LXR receptor agonist, lipoprotein synthesis inhibitor, renin vascular tone Inhibitor, microparticles 141541.doc 201016667

Triglyceride transporter inhibitor, bile acid reuptake inhibitor, PPAR δ agonist, triacetin synthesis inhibitor, squalene epoxidase inhibitor, low density lipoprotein receptor inducer, platelet aggregation Inhibitor, 5-L ◦ or FLAP inhibitor, PPAR δ partial agonist, acid or terminal acid receptor agonist, 5 ΗΤ transporter inhibitor, ΝΕ transporter inhibitor, CB! antagonist / inverse agonist , ghrelin antagonist, Η3 antagonist/inverse agonist, MCH1R antagonist, MCH2R agonist/antagonist, ΝΡΥ1 antagonist, ΝΡΥ5 antagonist, ΝΡΥ2 agonist, ΝΡΥ4 agonist, mGluR5 antagonist, Leptin, leptin agonist/modulator, lipoprotein derivative, tyrosin antagonist, orexin receptor antagonist, BRS3 agonist, CCK-A agonist, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 agonists, phentermine, 托 ratio S Topiramate, plant Compound 57, ghrelin antibody, Mc3r agonist, ACC2 inhibitor, β3 agonist, DGAT1 inhibitor, DGAT2 inhibitor, FAS inhibitor, PDE inhibitor, thyroid hormone beta agonist, UCP-1 activator, UCP- 2 Activator, UCP-3 activator, thiol estrogen, glucocorticoid agonist/antagonist, 11β HSD-1 inhibitor, SCD-1 inhibitor, lipase inhibitor, fatty acid transporter inhibitor, dicarboxyl Acid transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, antihypertensive agents, anti-lipidemia agents, DP receptor antagonists, apolipoprotein-Β secretion/microsomal glycerol Triacetate transfer protein (apo-B/MTP) inhibitor, sympathomimetic agonist, dopamine 141541.doc 201016667 kinesin, melanocyte stimulating hormone receptor analogue, melanin aggregation hormone antagonist, thin Similar to lepton, gaianin receptor antagonist, bombesin agonist, neuropeptide gamma antagonist, thyroxine agent, dehydroepiandrosterone, dehydroepiandrosterone Object Urocortin-binding protein antagonist, glucagon-like peptide-丨 receptor agonist, human guinea pig-associated protein (AGRP), neuromedin-u receptor agonist, norepinephrine-induced adenosine, Appetite suppressants, hormone-sensitive lipase antagonists, MSH-receptor analogues, alpha-glucosidase inhibitors, 邛〇A1 milan〇 reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporters Inhibitor (FATP). [Embodiment] The nicotinic acid receptor agonist compound of the present invention can be used for the treatment of conditions such as metabolic syndrome, dyslipidemia, cardiovascular disease, peripheral nervous system and central nervous system disorders, blood diseases, cancer, inflammation, Respiratory diseases, gastrointestinal diseases, diabetes, liver steatosis and nonalcoholic fatty liver disease and other diseases listed herein. One or more compounds of the invention may be administered alone or in combination with one or more other therapeutic agents described herein to provide a compound of formula I:

And its salts, solvates, esters and prodrugs, wherein ^ and feet are as defined above 141541.doc -10· 201016667

In one embodiment, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linking group selected from the group consisting of hydrazine, S, NR1, -0-alkyl-indole-, -〇-alkyl-S-, -S-alkylene-S-, -Ο-exylaryl-0-,-0-strandyl -S-, -S-Exylaryl_S_,·〇_arylalkylalkylarylalkyl-S-,-S-arylalkylene_s_,-〇_extended heteroaryl-aryl-S -, -S-heteroaryl-s_, polyalkylene glycol, _c(〇)〇_alkylene _ 〇-, -C(〇)〇_alkylene_s_, _〇_c ( 〇) _ alkyl alkyl 〇 _, _ 〇 _ 〇 〇 伸 伸 伸 伸 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -〇_ C(〇)-伸芳基_〇·,_〇_c(〇)_伸芳基_s_,_c(〇)〇·(), 杂-, -C(〇)〇_ Heteroaryl _s_, _〇_c(〇)_ hexaaryl C(O)-heteroaryl -8-, and ^(1) polyalkylene glycol; and wherein the 丨 represents the wind, Burning or aryl. In another embodiment, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linking group selected from the group consisting of hydrazine, S, NR1, -0(CH2)n〇_, _0(C(R2)2)〇-, -〇(CH2)nS-, -〇(C(R2)2)S-, -S(CH2)nS -, -S(C(R2)2)S-, _〇_ aryl 〇_ aryl_s_, _s aryl_s, _〇_heteroaryl-O-, _〇_heteroaryl_s_ , _s_heteroaryl, PEG (polyethylene glycol), and PPG (polypropylene glycol); and Ri represents hydrogen, alkyl or aryl; R2 represents an alkyl group, and η represents 〇-1 〇. In another embodiment, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a composition selected from the group consisting of 141541.doc •11 · 201016667 Group of linking groups: 〇, -C(0)0(CH2)n0-, -0C(0)(C(R2)2)0-, -C(0)0(CH2)nS-, -oc( o) (c(r2)2)s-, -C(0)S(CH2)nS-, -c(o)s(c(r2)2)s-, -c(o)o-aryl _ 0-, -c(o)o-aryl-s-, -c(o)s-aryl-s-, -c(o)o-heteroaryl-0-, -C(0)0- Heteroaryl-s-, -C(0)S-heteroaryl-s-, -C(0)PEG-(polyethylene glycol), and -C(0)PPG-(polypropylene glycol); and R1 Represents hydrogen, alkyl or aryl; R2 represents alkyl; and η represents 0-10. In another embodiment, the invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linking group selected from the group consisting of hydrazine, 3,:^11,;^((^3),-0-CH2-0-,-0-CH2CH2-0-,-0-(CH2)3-0-,-0-CH2-CH(CH3) -0-' -0-CH2-C(CH3)2-0- ' -0-CH2-S- ' -O-CH2CH2-S- ' -0- (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-phenyl-S-, -S-phenylene-S-, -O - in the other embodiment, the present invention relates to a compound of formula I, or a pharmaceutically acceptable compound thereof. In another embodiment, the present invention relates to a compound of formula I, or a pharmaceutically acceptable compound thereof. Accepted salts, solvates, esters or prodrugs wherein R represents a recoverable residue of a nicotinic acid receptor agonist having the structure:

The asterisk indicates the connection point with G. In another embodiment, the 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 The acid-receptor agonist is described in U.S. Patent Application Publication No. US 2008/001997, the entire disclosure of which is incorporated herein by reference. Among the compounds described in the above publications, a particularly preferred one is a recoverable residue of a nicotinic acid receptor agonist having the following structure:

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

R3 represents an alkyl group, especially an unsubstituted alkyl or haloalkyl group, or represents a cycloalkyl or heteroalkyl group; and R4 represents an anthracene, an alkyl group or a cycloalkyl group; and an asterisk indicates a point of attachment to G. Also preferred are recoverable residues of the nicotinic acid receptor agonist having the following structure:

141541.doc -13- 201016667 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; wherein R5 and R6 each independently represent a haloalkyl group, especially a fluoroalkyl group; and the asterisk indicates a point of attachment to G . In still another embodiment, the 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, The nicotinic acid receptor agonist is described in the following: International Patent Application Publication No. 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 No. 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; and US Patent Application Publication No. US 2006/0281810, US 2007/0072873, and US 2007 /0161650, the entire contents of all of which are incorporated herein by reference. In another embodiment, the invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R represents a nicotinic acid receptor agonist having the following structure Recovering residues: 141541.doc -14- 201016667 p

·〆0 where the asterisk indicates the point of connection with G. In still another embodiment, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein the serotonin receptor agonist has a structure which is recoverable Residues:

The asterisk indicates the connection point with G. In a particularly preferred embodiment, the present invention relates to compounds having the following structure:

Or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein the crucible has one of the above meanings. In a further preferred embodiment, the invention relates to compounds having the structure:

141541.doc -15· 201016667 or its pharmaceutically acceptable salt and solvate 'ester or prodrug, where G has one of the above meanings. In another preferred embodiment, the present invention relates to a compound having the following structure:

There is one of the above meanings in another compound: In a preferred embodiment, the present invention relates to the following structure

There is one of the above meanings in another compound: In a preferred embodiment, the present invention relates to the following structure

Or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G has one of the above meanings. , a chemical substance of the formula 1, and a pharmaceutically acceptable salt, solvate, ester thereof, 141541.doc 201016667, a nicotinic nicotinic steroid agonist, and thus may be a group, a lipid imbalance Symptoms of the disease, ^, , the nervous system and the middle (four) meridian diseases, cancer, inflammation, respiratory diseases, diabetes and non-cargo two gastroenterology, with Di Yu. Fatty liver disease, with the use of only bioequivalent amount; s party agonist phase 匕, the probability of redness or strict reduction "low odor" This is in one embodiment, the present invention relates to at least - Type! Change

A composition of a substance, or a pharmaceutically acceptable salt, solvate, vinegar or prodrug thereof, and a pharmaceutically acceptable carrier. In another embodiment, the composition of the present invention further comprises at least one additional therapeutic agent selected from the group consisting of: a substituted aziridine compound #, a substituted beta-lactam Compound, hmg Μ reductase inhibitor compound, HMG CoA synthetase inhibitor, horn synthase inhibitor, squalene epoxidase inhibitor, sterol biosynthesis inhibitor, nicotinic acid derivative, bile acid chelating agent , aspirin, (10) willow agent, vyt〇rin9, ezetimibe, inorganic cholesterol chelating agent, thiol c〇r cholesterol 0-thiol transferase inhibitor, cholesterol ester transfer protein inhibitor, fish oil containing omega 3 fatty acid, natural Water-soluble fiber, plant acid alkanol and/or fatty acid ester of plant alkanol, antioxidant, ppAR (1 agonist, PPAR γ-agonist, FXR receptor modulator, LXR receptor agonist, lipoprotein synthesis Inhibitors, renin-aspirin inhibitors, microsomal triglyceride transport inhibitors, bile acid reuptake inhibitors, ppAR § agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors ,low Apolipoprotein receptor inducer or activator, platelet aggregation inhibitor, 5_L〇 or 141541.doc -17- 201016667 FLAP inhibitor, PPAR δ partial agonist, nicotinic acid or nicotinic acid receptor agonist, 5ΗΤ transport Protein inhibitors, sputum transporter inhibitors, CB! antagonists/inverse agonists, ghrelin antagonists, Η3 antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, ΝΡΥ1 antagonists, ΝΡΥ5 antagonists Agent, ΝΡΥ2 agonist, ΝΡΥ4 agonist, mGluR5 antagonist, lipoprotein, lipoprotein agonist/modulator, lipoprotein derivative, opioid antagonist, orexin receptor antagonist, BRS3 agonist, CCK -A agonist, CNTF, CNTF derivative, CNTF agonist/modulator, 5HT2c agonist, Mc4r agonist, monoamine reuptake inhibitor, serotonin reuptake inhibitor, GLP-1 mimetic, phentermine, Topiramate, botanical drug compound 57, ghrelin antibody, Mc3r agonist, ACC2 inhibitor, β3 agonist, DGAT1 inhibitor, DGAT2 inhibitor, FAS inhibitor, PDE inhibitor, thyroid hormone beta agonist, UCP-1 live Agent, UCP-2 activator, UCP-3 activator, thiol estrogen, glucocorticoid agonist/antagonist, 11β HSD-1 inhibitor, SCD-1 inhibitor, lipase inhibitor, fatty acid transporter inhibition Agent, dicarboxylic acid transporter inhibitor, glucose transporter inhibitor, phosphate transporter inhibitor, antidiabetic agent, antihypertensive agent, anti-lipidemia agent, DPP-IV inhibitor, apolipoprotein-Β secretion /microsomal triglyceride transfer protein (apo-B/MTP) inhibitor, sympathomimetic agonist, dopamine agonist, melanocyte stimulating hormone receptor analogue, melanin aggregation hormone antagonist, leptin, glyphosate Peptide receptor antagonists, boll-peptide agonists, neuropeptide-Y antagonists, thyroxine agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin-binding protein antagonists, pancreatic hyperglycemia Prime peptide-1 receptor 141541.doc -18- 201016667 agonist, human guinea pig-associated protein (agrp), neurotransmitter u receptor agonist, norepinephrine-induced aorectal agent, appetite suppressant, Hormone sensitive fat Antagonists, MSH-receptor analogs, Chou # alpha # _ glucoside 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 invention relates to a composition wherein at least one other therapeutic agent is selected from the group consisting of HMG CoA reductase inhibitors consisting of: lovastatin, simvastatin, Pravastatin, atorvastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin; (rosuvastatin calcium), and pitavastatin; dip (pitavastatin). In a particularly preferred embodiment, the invention is directed to a composition wherein at least one other therapeutic agent is simvastatin. In another preferred embodiment, the invention is directed to a composition wherein at least one other therapeutic agent is a cholesterol ester transfer protein inhibitor. In another preferred embodiment, the invention relates to a composition wherein the cholesteryl ester transfer protein inhibitor is torcetrapib. In another preferred embodiment, the invention relates to a composition wherein at least one other therapeutic agent is Vy tor in®, ezetimibe, aspirin, ibuprofen or ethenamide or a combination thereof . In another preferred embodiment, the invention relates to a composition wherein at least one other therapeutic agent is a DPP-IV inhibitor or a GLP-1 mimetic. Non-limiting examples of compounds of formula I are shown in Table 1 below: 141541.doc • 19- 201016667 Table 1

141541.doc -20- 201016667

141541.doc -21 - 201016667 15 16 17 Αεού 18 Ac0\^x Λ—λ Ρ'Ν ° 〇V*"^T》 0ΑΝ Ν / 19 AcO X °V〇〇^Xta / 20 Η μ-ΝΗ I ι π Ν X JL 21 Η Ν 二Ν, ^ν^ΝΗ Η Ν^Ν>γ^ ?Ac 〇Λό 22 Η Ν8, 0AC ί β 〇Λ〇AcO^^ 141541.doc -22- 201016667

141541.doc -23- 201016667 30 31 32 Λ〇 〇 33 people. 34 people. Γ, 35 to "° 36 people. γνί 〇^^〇Τ° 141541.doc •24- 201016667

141541.doc -25- 201016667 47 Π | ----- Λ〇 〇 48 Λ U —------------ Table 1 shows the structure of representative compounds of the present invention. The tables and the compounds therein are not intended or should be construed as limiting the invention in any way. In Table 1 and throughout the disclosure, the abbreviation "Ac" means acetyl group, that is, -c(o)-ch3. It should be understood that the following terms used throughout the above and throughout this disclosure have the following meanings unless otherwise indicated: "Patient" encompasses both humans and animals. "Mammal" means humans and other mammals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and includes from about one to about 20 carbon atoms in the chain. Preferably, the alkyl chain contains from about (a) to about 12 carbon atoms. More preferably, the alkyl chain contains from about one to about six carbon atoms. Branched means that a straight-chain alkyl group is bonded to - or a plurality of lower alkyl groups, such as methyl, ethyl or propyl. "Lower alkyl" means a group having from about 1 to about 6 carbon atoms in a straight or branched chain. "Alkyl" may be unsubstituted or optionally substituted with one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl. , cyano, hydroxy, alkoxy, alkylthio, amine, hydrazine (eg, =N-OH), -NH(alkyl), -NH (cycloalkane 141541.doc -26- 201016667 base), - N(alkyl)2, -〇_C(0)-alkyl, _〇_c(〇)_aryl, 〇c(〇)_ %•院基,基基和-C(〇)〇- Burning base. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and tri-butyl. "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight-chain or branched and comprising from about 2 to about 15 carbon atoms in the chain. Preferably, the alkenyl chain has from about 2 to about 12 carbon atoms; and more preferably from about 2 to about 6 carbon atoms in the chain. Branched means that the straight chain is attached to one or more lower alkyl groups such as decyl, ethyl or propyl. "Lower carbon number alkenyl" means a group having from about 2 to about 6 carbon atoms in a straight or branched chain. "Alkenyl" may be unsubstituted or substituted, if desired, by one or more substituents which may be the same or different. Each substituent is independently selected from the group consisting of: i, alkyl, aryl, naphthenic Base, 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. 「 "Stretching base" means a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. Non-limiting examples of alkylene groups include methylene, ethyl and propyl. "Alkynyl" means an aliphatic hydrocarbon radical containing at least one carbon-carbon triple bond and which may be straight or branched and comprising from about 2 to about 15 carbon atoms in the chain. Preferably, the alkynyl chain has from about 2 to about 12 carbon atoms; and more preferably from about 2 to about 4 carbon atoms in the chain. Branched means that the straight alkynyl group is bonded to one or more lower alkyl groups such as decyl, ethyl or propyl. "Lower carbon alkynyl" means a group having from about 2 to about 6 141541.doc -27. 201016667 carbon atoms in a linear or branched chain. Non-limiting examples of suitable alkynyl groups include ethynyl, propionyl, 2-butynyl and 3-methylbutynyl. The "alkynyl group" may be unsubstituted or optionally substituted with one or more substituents which may be the same or different, and each substituent is independently selected from the group consisting of an alkyl group, an aryl group and a cycloalkyl group. "Aryl" means an aromatic monocyclic or multiple ring system comprising from about 6 to about 14 carbon atoms, preferably from about 6 to about 1 carbon. The aryl group may be substituted with one or more "t 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 naphthalene

Base 0

"Heteroaryl" means an aromatic monocyclic or polycyclic ring system comprising from about 5 to about 14 ring atoms, preferably from about 5 to about 10 ring atoms, wherein one or more ring atoms are removed An element other than carbon, such as only nitrogen, oxygen or sulfur or a group a thereof. Preferred heteroaryl groups contain from about 5 to about one ring atom. "Heteroaryl" may be substituted, as desired, with one or more 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. The nitrogen atom of the heteroaryl group can be oxidized to the corresponding cerium oxide as needed. "Heteroaryl" may also contain a heteroaryl group as defined above fused to an aryl group as defined above. Non-limiting examples of suitable heteroaryl groups include pyridinyl, pyridyl, furyl, thienyl, pyrimidinyl, pyridone (including pyridyl substituted pyridyl), isoxazolyl, isothiazolyl, oxazolyl , thiazolyl, pyrazolyl, furazolyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, pyridazinyl, hydroxydecyl, Imidazo[l,2-a]pyridyl, imidazo[2,! ^]thiazolyl, benzofurazinyl, 141541.doc -28 - 201016667 fluorenyl, aza, fluorenyl, benzimidazolyl, benzothienyl, quinolinyl thiazolyl thienopyridinyl, quin Oxazolinyl, thienopyrimidinyl, °Bilo and "bite base" rice saliva and bite base, isoindolyl, benzoxanthene, 1,2'4-tridecyl, Benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrazoisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl group wherein both an aryl group and an alkyl group are as defined above. Preferred aryl bases include low carbon number bases. Non-limiting examples of suitable aryl groups include a benzyl group, a 2-phenylethyl group and a benzyl group. The bond to the parent moiety is achieved via an alkyl group. "Alkylaryl" means an alkyl-aryl- group in which both an alkyl group and an aryl group are as defined above. Preferred alkylaryl groups include lower alkyl groups. A non-limiting example of a suitable alkyl aryl group is fluorenylphenyl. The bond to the parent moiety is achieved via an aryl group. "Cycloalkyl" means a non-aromatic monocyclic or polycyclic ring system comprising from about 3 to about one carbon atom, preferably from about 5 to about 1 carbon atom. Preferred cycloalkyl rings contain from about 5 to about 7 ring atoms. The cycloalkyl group may be optionally substituted by one or more "ring system substituents" which may be the same or different and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyl groups include cyclopropyl, oxime, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable polycyclic cycloalkyl groups include 1-naphthylalkyl, norbornyl, gold alkyl and the like. ""Alkylalkylalkyl" means a cycloalkyl moiety as defined above attached to the parent core via an alkyl moiety (as defined above). Non-limiting examples of suitable cycloalkylalkyl groups 141541.doc • 29· 201016667 include cyclohexylmethyl, gold steel methyl, and the like. "Cycloalkenyl" means a non-aromatic monocyclic or polycyclic ring comprising from about 3 to about 1 carbon atoms, preferably from about 5 to about 10 carbon atoms, containing at least one carbon-carbon double bond. Ring system, system. Preferably, the ring-dense ring contains from about 5 to about 7 ring atoms. The ring base may be substituted by - or a plurality of "ring system substituents" which may be the same or different and are as defined above. Non-limiting examples of suitable monocyclic ring dilute groups include cyclopentenyl, cyclohexenyl, cycloheptadienyl and the like. A non-limiting example of a suitable polycyclic ring dilute group is a group. Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above attached to the parent nucleus via an alkyl moiety (as defined above). Non-limiting examples of suitable cycloalkenylalkyl groups include cyclopentenyl indenyl, cyclohexenyl indenyl and: and the like. a heteroalkyl group having a hetero group selected from the group consisting of NH and N-alkyl groups selected from the group consisting of ruthenium and 8 and having the above-mentioned "heteroalkyl" hetero atom or a moiety selected from the group . Non-limiting examples of suitable miscellaneous groups include ch3-o-ch2-. ch3ch2-0-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, gas, bromine or iodine. Preferred are fluorine, gas and bromine. "Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system and, for example, substituted for hydrogen on the ring system. The ring system substituents may be the same or different, each independently selected from the group consisting of I41541.doc -30- 201016667: alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkane Alkyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, carbyl, peralkyl, alkoxy, aryloxy, aralkyloxy, fluorenyl , aryl, dentate, nitro, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl , alkylthio, arylthio, heteroarylthio, aralkylthio, heteroarylthio, cycloalkyl, heterocyclyl, _〇_C(〇)_alkyl, _〇_C(〇 Bufang φ, -OC(O)-cycloalkyl, pendant oxy, -C(=N_CN)_NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), hydrazine (eg, =N-OH), ΥιΥ2ν_, γ, γπ-alkyl-, Yjwqo)·, YiY2NS〇2_ and -SC^NY^2 'where 丫丨 and 丫2 may be the same or different and independently selected from the following Group of constituents: hydrogen, alkyl, aryl, cycloalkyl and aralkyl. "Cyclic system substituent" may also mean the simultaneous replacement of a single portion of two available hydrogens (one H on each carbon) on two adjacent carbon atoms in the ring system. Examples of this moiety form, for example, the following portions of a methylenedioxy group, a hexyldioxy group, a -C(CH3)2-, and the like:

"Heteroarylalkyl" means a heteroaryl moiety as defined above attached to the parent core via an alkyl moiety (as defined above). Non-limiting examples of suitable heteroaryl groups include 2·pyridylfluorenyl, quinolinylfluorenyl, and the like. "Heterocyclyl" means a non-aromatic saturated monocyclic or polycyclic ring system comprising from about 3 to about 1 ring atom, preferably about 5 14l 541.doc -31 - 201016667 = 10 ring atoms. An element other than carbon in one or more atomic systems of the ring system, such as argon θ' oxygen or sulfur or a group thereof. In the ring system A, there is no adjacent oxygen and/or a preferred heterocyclic group contains from about 5 to about one ring atom. Heterocyclyl: the prefix of the name aza, oxa or thia means at least nitrogen, oxygen or sulfonium; the substituents are present as ring atoms, respectively. Any of the heterocyclyl rings may be present in a form of pain, such as, for example, in the form of Ν 〇, _N(CBz), N(T〇S) 圏, and the like; The isoprotection can also be considered as part of the present invention. The heterocyclic group can be substituted by one or more "ring system substituents" which may be the same or different, as defined herein. The nitrogen or sulfur dimer of the heterocyclic group may be optionally used. Oxidation to the corresponding N-oxide, S-oxide or ss-oxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include a hexamethylene group, a hexahydrocarbyl group,淋 基 基, 硫 琳 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基It may mean simultaneously replacing a single moiety (eg, a few groups) of two available hydrogens on the same carbon atom of the ring system. An example of this moiety is pyrrolidone:

〇 「 "Heterocyclylalkyl" means a heterocyclyl moiety as defined above attached to the parent nucleus via an alkyl moiety (as defined above). Non-limiting examples of suitable heterocyclylalkyl groups include hexahydro. Bis-methyl, hexa-bi-β-pyridylmethyl 14154l.doc • 32- 201016667 and the like. "Heterocyclenyl" is intended to include from about 3 to about $ to about 1 ring atom (which causes the halogen to be removed from the carbon of the atomic system, for example, A. a nitrogen-free, oxygen- or sulfur-only atom or a combination thereof and a non-aromatic monocyclic or polycyclic ring having at least ❹, a carbon-carbon double bond or a carbon-nitrogen double bond. There is no basis in the ring system. Oxygen and/or sulfur atom. Preferably, the base ring contains from about 5 to about 6 ring atoms. The heterocyclenyl group name is preceded by a hetero, oxa or thia meaning at least a nitrogen, oxygen or sulfur atom. They are each present as a ring atom. The heterogeneous group may be substituted by - or a plurality of ring system substituents, and the "ring system substituent" in # is as defined above. The nitrogen or sulfur atom of the heterocyclic saccharide may be oxidized to the corresponding cerium oxide, S oxidant or S, S-dioxide as needed. Non-limiting examples of suitable heterocyclic fluorenyl groups include 1,2,3, tetrahydroindenyl, diterpene, M-dichloropurine, 1,2,3,6-tetrahydro Pyridyl, tetrahydropyrimidinyl, 2-pyrrolidinyl, pyrrolidinone 3-pyrroline, 2. imidazolinyl, 2-pyrazolyl, dihydroimidazolyl, dihydrooxazolyl, dihydrogen Oxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2 2 heptenyl, dihydrogen Phenyl, dihydrothiopyranyl and the like. "Heterocyclenyl" may also mean the simultaneous replacement of a single moiety (e.g., carbonyl) of two available hydrogens on the same carbon atom of the ring system. An example of this part is dehydropyrrolidine 141541.doc -33- 201016667

"Heterocyclenylalkyl" means a heterocycloalkenyl moiety as defined above attached to the parent nucleus via an alkyl moiety (as defined above). It should be noted that in the hetero atom-containing ring system of the present invention, no hydroxyl group is present on a carbon atom adjacent to ruthenium, osmium or S, and no N or S group is present on the carbon adjacent to the other hetero atom. So, for example, in the ring:

There is no _〇h on the carbon directly attached to the labels 2 and 5. It should also be noted that the tautomeric forms are considered in certain embodiments of the invention, such as, for example, the following:

"Quick-base" means an alkynyl-alkyl group- group in which the alkynyl group and the alkyl group are as defined above. Preferably, the fast alkyl group contains a lower alkynyl group and a lower alkyl group. The bond to the parent moiety is achieved via an alkyl group. Non-limiting examples of suitable alkynylalkyl groups include a propylmethyl group. "Miscellaneous" means a heteroaryl-alkyl- group in which both a heteroaryl group and an alkyl group are as defined above. Preferred heteroaralkyl groups contain a lower alkyl group. Suitable hetero- 141541.doc 201016667 Non-limiting examples of aralkyl groups include anthrapyridyl fluorenyl and quinolin-3-yl fluorenyl. The bond to the parent moiety is achieved via an alkyl group. "Hydroxyalkyl" means an HO-alkyl- group in which the alkyl group is as defined above. Preferred hydroxyalkyl groups contain a lower alkyl group. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Alkyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-c(〇)- group in which each group is as previously described. The bond to the parent moiety is achieved via several bases. Preferred sulfhydryl groups contain a low carbon number alkyl group. Non-limiting examples of suitable thiol groups include formazan, ethyl hydrazide and propyl fluorenyl. "Aryl" means an aryl-C(〇)- group in which the aryl group is as defined above. The bond to the parent moiety is achieved via a carbonyl group. Non-limiting examples of suitable groups include benzamidine and 1-naphthoquinone. "Hospital oxy" means an alkyl-oxy- group in which the alkyl group is as described above. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is achieved via ether oxygen. "Aryloxy" means an aryl-〇- group in which the aryl group is as defined above. Non-limiting examples of suitable and oxy groups include phenoxy and naphthyloxy. The bond to the parent moiety is achieved via ether oxygen. "Aralkyloxy" means an arylalkyl group wherein the aralkyl group is as defined above. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and hydrazine or 2 -thenyloxy. The bond to the parent moiety is achieved via ether oxygen. "Sulfur-based" means a group in which the base of the system is as described above. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond with the parent 141541.doc •35- 201016667 is achieved via sulfur. "Arylthio" means an aryl-s- group in which the aryl group is as defined above. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is achieved via sulfur. "Aralkylthio" means an aralkyl-S- group in which an aralkyl group is as defined above. A non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is achieved via 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 achieved via a carbonyl group. "Aryloxycarbonyl" means an aryl-o-c(o)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthyloxycarbonyl. The bond to the parent moiety is achieved via a carbonyl group. "Aralkoxycarbonyl" means an aralkyl-o-c(o)- group. A non-limiting example of a suitable aralkyloxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is achieved via a carbonyl group. "Alkylsulfonyl" means an alkyl-s(o2)- group. Preferred groups are those in which the alkyl group is a lower alkyl group. The bond to the parent moiety is achieved via a sulfonyl group. "Arylsulfonyl" means an aryl-s(o2)- group. The bond to the parent moiety is achieved via a sulfonyl group. The term "substituted" means that one or more hydrogen atoms on a given atom are substituted with a group selected from the specified group, with the proviso that the normal valence of the specified atom in the prior art is not exceeded and the substitution forms a stable compound. Substituting 141541.doc •36-201016667 and/or combinations of variables to allow stable compounds only when such combinations produce stable compounds or “stable structures” means robust enough to withstand the self-reactive mixture to a level of useful purity A compound that is isolated and formulated into an effective therapeutic agent. • The term “replaced as needed” means an optional substitution using a specified group, functional group or moiety. The term "purified", "in purified form" or "in Φ knife-extracted and purified form" with respect to a compound means the physical state of the compound after separation from a synthetic process (e.g., from a reaction mixture), or a natural source, or a combination thereof. Thus, the terms "purified," "in purified form," or "in isolated and purified form" refer to a process from a purification process or as described herein or well known to those skilled in the art (eg, chromatography, re The physical state of the compound after crystallization and the like is obtained in a purity sufficient to be characterized by standard analytical techniques as described herein or well known to those skilled in the art. The compound of formula I can be purified to a degree suitable for use as a pharmaceutically active substance. That is, the compound of formula I may have a purity of 95 wt% or higher (excluding adjuvants such as pharmaceutically acceptable carriers, solvents, etc., which are used to formulate compounds of formula I to be suitable for administration And the customary form to the patient, such as 'pill, capsule, IV solution, etc.). The purity may be 97 wt% or higher, or 99 wt ° / 〇 or higher. The purified compound of formula I comprises a single isomer of 95 wt% or greater, 97 wt% or greater, or 99 wt% or greater (as described above) having a purity (as described above). Further, the 'purified compound of formula I may comprise a mixture of isomers' each isomer having the structure of formula I, wherein the impurities (ie, 141541.doc • 37- 201016667 or other contaminants) , does not contain the adjuvant as described above) in an amount of 5 wt% or less, 3 wt% or less, or! Wt% or less. For example, the purified compound of formula I can be an isomeric mixture of compounds of structure (I) wherein the ratio of the amounts of the two isomers is about 1:1 and the two are equally divided The combined amount of the isomers is 95 wt% or more, 97 wt% or more, or 99 Wt% or more. It should also be noted that any carbon atom having an unsaturation valence and a hetero atom in the text, reaction schemes, examples, and tables herein are assumed to have a sufficient number of hydrogen atoms to saturate the valence. When a functional group in a compound is referred to as "protected," it is meant that the group is in a modified form to avoid undesired side reactions at the protected site when the compound is involved in the reaction. Suitable protecting groups are those who are familiar with the technology and can refer to standard textbooks (eg T. W. Greene et al.

Protective Groups in organic Synthesis (1991), Wiley, New York). When any variable (e.g., aryl, heterocycle, R2, etc.) occurs in either component or in Formula I more than once, the definition of each occurrence is independent of its definition at every other occurrence. The term "composition" as used herein is intended to cover a product comprising a specified quantity of the specified ingredients, and any product which may be produced directly or indirectly from a combination of specified quantities of the specified ingredients. Prodrugs and solvates of the compounds of the invention are also contemplated herein. Discussions on prodrugs are provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14, A.C.S. Symposium Series, and 141541.doc -38- 201016667

Bioreversible Carriers in Drug Design, (1987) Edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a prodrug) which can be converted in vivo to produce a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound. Transformation can be achieved by various mechanisms (e.g., by metabolic or chemical processes), for example, by hydrolysis in blood. A discussion of the use of prodrugs is provided in T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery System," ❹ (volume 14 of the ACS Symposium Series) and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press (1987) Order. 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, the prodrug may comprise substituting the acid group with a group such as: An ester formed by a hydrogen atom: (CrCO alkyl group, (C2-C12) alkanoyl-oxyindenyl group, 1-(alkylindolyloxy)ethyl group having 4 to 9 φ carbon atoms, having 5 to 1-mercapto-1-(alkylhydrazineoxy)-ethyl group having 10 carbon atoms, alkoxycarbonyloxyfluorenyl group having 3 to 6 carbon atoms, and having 4 to 7 carbon atoms. (alkoxycarbonyloxy)ethyl, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxy) having 3 to 9 carbon atoms Alkylcarbonyl)aminoindenyl group, 1-(N-(alkoxycarbonyl)amino)ethyl group having 4 to 10 carbon atoms, 3-mercapto group, 4-crotonolactone group, γ-butane Ester-4-yl, di-N,N-(C-alkylamino(C2-C3)alkyl (eg β-didecylaminoethyl), amidino-(CrC2)alkyl, N , N-di(CrCJ alkylamine mercaptoalkyl and hexahydropyridyl 141541.doc -39- 201016667 bite and (CVC3) alkyl, hydrazine a pyridyl (CVC3) alkyl or morpholine (c2-c3) or the like. Likewise, if the compound of formula I contains an alcohol function, the prodrug can be substituted for the alcohol group by using a group such as the following: Hydrogen atom formation: (Ci_c6) alkanoyloxymethyl, 1-UG-C6) alkenyloxy)ethyl, methyl((Cr C6)alkylnonyloxy)ethyl, (Ci- Ce) alkoxycarbonyloxymethyl, N_(C!-C6) alkoxycarbonylaminocarbonyl, amber fluorenyl, (Ci_c6)alkyl fluorenyl, α-amino group (C丨-CO alkyl, An aryl sulfhydryl group and an α-amino fluorenyl group, or an α-amino fluorenyl-α-amino fluorenyl group, wherein each α-amino fluorenyl group is independently selected from a naturally occurring L-amino acid, P (〇) (〇H)2, -P(〇)(〇(Ci-C6)alkyl)2 or a glycosyl group (this group is obtained by removing a hydroxyl group from a hemiacetal form of a carbohydrate) and the like. Where a compound of formula I is incorporated into an amine functional group, the prodrug can be formed by substituting a hydrogen atom in the amine group with a group such as: R-carbonyl, RO-carbonyl, NRR.-carbonyl (wherein R and R. Each independently (Ci_c丨〇)alkyl, (Cs-C7)cycloalkyl, benzyl , or R. carbonyl is a natural α-amino sulfhydryl group or a natural α-amino fluorenyl group, _(:(0Η)(:(0)0Υ1 (wherein γΐ system, (Cl_c6) alkyl or benzyl) , -C(〇Y2)Y3 (wherein γ2 is a (Cl_c4) alkyl group and Y3 is a (Cl_C6) alkyl group, a carboxyl group (C^C: 6) alkyl group, an amine group (CVC4) alkyl group or a mono-N- group. Or bis-N^CCi-Ce)alkylaminoalkyl), _c(Y4)Y5 (wherein γ4 is η or fluorenyl and Υ5 is mono-indenyl or di-N,N_(Cl_C6)alkyl Amino, morpholinyl, hexahydro"bipyridin-1-yl or pyrrolidinyl) and the like. One or more compounds of the present invention may be in the form of a solvate and a solvate with a pharmaceutically acceptable solvent (e.g., water, ethanol, and the like) 141541.doc • 40· 201016667 I in 'and the present invention is intended to cover a solvent combination Both physical and unsolvated forms. "Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic bonding and covalent bonding. 3 hydrogen bonding). In some cases, the solvate can be isolated, for example, when - or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both the solution phase and the solvable solvate. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

This class. "Hydrate" is a solvate in which the solvent molecule is h2?. The - or more compounds of the invention may be converted to solvates as desired. The preparation of solvates is generally known. Thus, for example, Μ Caira et al, j. Pharmaceutical Sci, 93(3), 6〇ι·6ιι ((10)4) describe the preparation of the antifungal agent fluconazole in ethyl acetate and from water. Solvate. Similar preparations of solvates, hemisolvates, hydrates and the like are described in Ec. van T〇nder et al, AAPS PharmSciTech., 5(1), article 12 (2〇〇4); and human L Bingham Et al., Chem. Commun. 603-604 (2001). A typical non-limiting process involves dissolving a compound of the invention in a desired amount of a desired solvent (organic solvent or water or a mixture of the two) above ambient temperature. The solution is cooled at a rate sufficient to form crystals, and the crystals are separated by standard methods. Analytical techniques such as IR spectroscopy show the presence of a solvent (or water) as a crystal of a solvate (or hydrate). j or "therapeutically effective amount" is intended to describe an amount of a compound or composition of the invention that is effective to inhibit the above conditions and thereby produce a desired therapeutic, ameliorating, inhibiting or preventing effect. 141541.doc • 41 · 201016667 A compound of formula i can form a salt which is also within the scope of the invention. It is to be understood that the compounds of formula I referred to herein include the salts thereof, unless otherwise stated. The term "salt" as used herein means an acidic salt formed using an inorganic acid and/or an organic acid, and an alkaline salt formed using an inorganic base and/or an organic base. Furthermore, when a compound of formula I contains a basic moiety such as, but not limited to, pyridine or imidazole, and an acidic moiety such as, but not limited to, a carboxylic acid, a zwitterion ("internal salt") can be formed and is encompassed by the term as used herein. Within the "salt". Preferred are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts, although other salts may also be employed. For example, a compound of formula I can be formed by lyophilizing a compound of formula I with a quantity (eg, equivalent) of an acid or base in a medium such as a medium in which the salt can be precipitated or in an aqueous medium, followed by lyophilization. Salt. Exemplary acid addition salts include acetate, ascorbate, benzoate, besylate, hydrogen sulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumaric acid Salt, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, water Salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate) and the like. Furthermore, acids which are generally considered to be suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, in 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 141541.doc -42- 201016667

Pharmaceutics (1986) 33 201-217 ; Anderson et al, The

Practice of Medicinal Chemistry (1996), Academic Press,

New York, and The Orange Book (Food & Drug Administration,

Washington, D.C. is on its website). The disclosures are hereby incorporated by reference. Exemplary basic salts include salt, metal salts (e.g., sodium, clock, and potassium), alkaline earth metal salts (e.g., calcium and magnesium salts), and organic bases (e.g., organic guanamines such as dicyclohexylamine, A salt formed by a third-butylamine and a salt formed with an amino acid (for example, arginine, lysine, and the like). The basic nitrogen-containing groups can be quaternized using reagents such as the following: lower alkyl alkyl dentates (for example, chlorides, bromides and iodides of methyl, ethyl and butyl), dialkyl sulfates Esters (eg, dimethyl sulfate, diethyl sulfate, and dibutyl sulfate), long-chain sulfides (eg, sulfhydryl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl Tooth compounds (eg, bases and phenethyl deserts) and others. For the purposes of the present invention, all such acidic and basic salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acidic salts and salts are considered equivalent to the free forms of the corresponding compounds. The pharmaceutically acceptable ester of the compound of the present invention comprises the following group: a carboxylic acid vinegar obtained by hydrating a hydroxyl group, wherein the non-thiol moiety of the carboxy group moiety of the vine group is selected from a linear chain or a branch An alkyl group (for example, an ethylene group, a n-propyl group, a tri-butyl group or a n-butyl group), an alkoxyalkyl group (for example, a methoxyindenyl group), an aromatic group (for example, a benzyl group) An aryloxyalkyl (eg, phenoxy) aryl group (eg, as desired, for example, halogen, Cw alkyl or 141541.doc -43- 201016667

Ci·4 alkoxy or amine substituted phenyl); (2) sulfonate, such as a ketone- or aralkyl sulfonyl group (eg, methanesulfonyl); (3) an amino acid ester ( For example, L-guanidinium or L-isoleumidyl); (4) phosphonates and (5) mono-, di- or tri-disc vinegar. The phosphate ester can be further esterified with, for example, (: 12 () alcohol or a reactive derivative thereof, or with 2,3-di(C6_24) mercaptoglycerol. Compounds of formula I, and salts, solvates thereof, Esters and prodrugs may exist in their tautomeric form (for example, as a guanamine or an imino ether). All such tautomeric forms are contemplated herein as part of the present invention. For the palm center, and thus in the form of a non-reference stereoisomer. All stereoisomeric forms of the compounds of formula I and mixtures thereof (including racemic mixtures) are intended to form part of the invention. The invention encompasses all geometric and positional isomers. For example, if a compound of formula I is incorporated into a double bond or a fused ring, then the reverse form and mixtures of the two are included within the scope of the invention. The physicochemical differences of the isomers can be separated into their respective non-pairs by methods well known to those skilled in the art (for example, by chromatography and/or fractional crystallization). Opposite The construct can be isolated by converting the enantiomeric mixture to diastereomeric by reaction with a suitable optically active compound (for example, a palmitic aid such as palmitic alcohol or Mosher helium). The mixture of the constructs, the diastereomers are separated and the individual diastereomers are converted (eg, hydrolyzed) to the corresponding pure enantiomers. Similarly, some of the compounds of formula J can be divorced. a conformation (eg, a 'substituted diaryl group) and is considered to be one of the knives enantiomers of the present invention may also be obtained by using a palmitic HPLC column 141541.doc 201016667 formula & Different tautomeric forms exist, and all such forms are encompassed within the scope of the invention. Likewise, all keto-enol and imine-lean amine forms of the compound such as phase 1 are included in the invention. All stereoisomers (eg, geometric isomers, optical isomers of the compounds (including salts, solvates, vinegars and prodrugs of such compounds, and salts, solvates and vinegars of such prodrugs) Body and the like) (eg, due to each substituent An asymmetric carbon atom, including an enantiomeric form (which may exist even in the absence of an asymmetric carbon atom), a rotamer form, a ligation isomer form, and a diastereomer It is also within the scope of the invention to include 'positional isomers (e.g., ... groups and groups) within the scope of the invention. (For example, if a compound of formula) is incorporated into a double bond or a fused ring, Both the cis and the reverse forms and mixtures of the two are included within the scope of the invention. Also, by way of example, all of the 9 keto-enol and imine-enamine forms of the compounds are included in the present invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may, for example, be a mixture of racemates or be mixed with all other or other selected stereoisomers. . The palm center of the present invention may have an S or 11 configuration as defined by the IUPAC 1974 Recommendations. The use of "salt", "solvent", "ester", "prodrug" and the like is equivalent to the enantiomers, stereoisomers, rotamers, tautomers of the compounds of the invention. Salts, solvates, esters and prodrugs of a conformation, positional isomer, racemate or other drug. 141541.doc •45· 201016667 The present invention also encompasses isotopically labeled compounds of the invention, which are described herein, except that one or more atoms are replaced by atoms having a different atomic mass or mass than the natural atomic or mass number. The compounds described are identical. Examples of isotopes which may be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and gas isotopes such as 2H, 3H, I3C, 14C, 15N, 18〇, 17〇, 31p, 32p, 35S, respectively. , 18p and 36〇. Certain isotopically-labeled compounds of Formula I (e.g., those used as well as Mc-labeled) can be used for compound and/or matrix tissue distribution analysis. Gas (ie, 3 and carbon-14 (ie, 14c) isotopes are preferred for their ease of preparation and detection. In addition, substitution with heavier isotopes such as hydrazine (ie 2H) provides some of the greater metabolic stability. Therapeutic advantages (e.g., increased in vivo half-life or reduced required dose) and thus may be preferred in some circumstances. The isotopically labeled compounds may generally be similar to those disclosed in the various schemes and/or examples below. The procedure is carried out by substituting a reagent which is suitably isotopically labeled with a reagent which is not isotopically labeled. The present invention is intended to comprise a polymorphic form of a compound of the formula 及, and a salt, solvate of the compound of formula j, Polymorphic forms of the esters and prodrugs. The compounds of the invention have pharmacological properties; in particular, the compounds of the formula may be agonists of the acid accepting receptors. The compounds of the formula I according to the invention, or their pharmaceutically acceptable Accepted salt solvates, or vinegar, may be used to treat diseases or conditions that include dyslipidemia and metabolic syndrome. It may be in any suitable form according to standard medical practice (eg, alone or A compound of formula i, or a pharmaceutically acceptable salt or solvate thereof, for administration of a pharmaceutically acceptable carrier, excipient or diluent phase in a pharmaceutical composition 141541.doc • 46 - 201016667) Or an ester. A compound of formula I, or a pharmaceutically acceptable salt, solvate or vinegar thereof, can be administered orally or parenterally (including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal or topical routes of administration). Or, if so selected, by a combination of one or more of the above methods. A pharmaceutical combination comprising at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof The composition may be in the form of Φ suitable for oral administration, for example, lozenges, troches, capsules, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups or elixirs. Prepared by any conventional pharmaceutical method, and may also contain a sweetener, a flavoring agent, a coloring agent and a preservative. A compound of formula I, or a pharmaceutically acceptable salt, solvate or ester thereof, administered to a patient Or the amount of prodrug can be Depending on the age, weight and response of the patient and the severity of the condition being treated, for example, a compound of formula I, or a pharmaceutically acceptable salt, lysate, ester, or pharmaceutically acceptable salt thereof, administered to a patient, Or the amount of prodrug may range from about 0.1 mg/kg body weight/day to about 60 mg/kg/d. In one embodiment, the amount is from about 5 mg/kg/d to about 40 mg/kg. /d. In another embodiment, the amount is from about 5 mg/kg/d • to about 10 mg/kg/d. In another embodiment, the amount is about 11118/]^/(1 to About 5 mg/kg/d. In yet another embodiment, the amount is about j 1 ^ / 1 <; § / (1 to about 3 mg / kg / d. In a particular 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 yet another particular embodiment, this amount is about 1 mg/kg/d. 141541.doc -47- 201016667 A compound of formula i, or a pharmaceutically acceptable salt, solvate or pharmaceutically acceptable salt thereof, may also be administered in combination with other therapeutic agents. For example, one or more compounds of Formula I, or a pharmaceutically acceptable salt, solvate, or ester thereof, can be administered with one or more other active ingredients selected from the group consisting of: Hydroxyl substituted nitrogen Heterocyclic butanone compound, substituted β-indoleamine compound, HMG CoA reductase inhibitor compound, HMG CoA synthetase inhibitor, squalene synthesis inhibitor, squalene epoxidase inhibitor, sterol biosynthesis Synthetic inhibitor, acid test derivative, bile acid sequestrant, inorganic cholesterol chelating agent, sulfhydryl-based CoA: cholesterol Ο-hydrazinotransferase inhibitor, cholesteryl ester transfer protein inhibitor, fish oil containing c〇3 fatty acid, natural Water-soluble fiber, fatty acid ester of plant alkanol and/or plant alkanol, antioxidant, PPAR α agonist, PPAR γ-agonist, FXR receptor modulator, LXR receptor agonist, lipoprotein synthesis inhibition Agent, renin angiotensin inhibitor, microsomal triglyceride transporter inhibitor, bile acid reuptake inhibitor, PPAR δ agonist, triglyceride synthesis inhibitor, squalene epoxidase Agent, low-density lipoprotein receptor inducer or activator, platelet aggregation inhibitor, 5-LO or FLAP inhibitor, PPAR δ partial agonist, nicotinic acid or nicotinic acid receptor agonist, 5ΗΤ transporter inhibitor , ΝΕ transporter inhibitors, CB! antagonists/inverse agonists, ghrelin antagonists, Η3 antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, ΝΡΥ1 antagonists, ΝΡΥ5 antagonists, ΝΡΥ2 agonists Agent, ΝΡΥ4 agonist, mGluR5 antagonist, lipoprotein, lipoprotein agonist/modulator, lipoprotein derivative, opioid antagonist, orexin receptor antagonist, BRS3 agonist, CCK-A agonist , CNTF, CNTF derivative 141541.doc -48- 201016667 Biological, CNTF agonist/modulator, 5ht2c agonist, Mc4r agonist, monoamine reuptake inhibitor, serotonin reuptake inhibitor, GLP-1, GLP-1 Agonist, GLP-1 mimetic, phentermine, topiramate, botanical drug compound 57, ghrelin antibody, Mc3r agonist, ACC inhibitor, β3 agonist, DGAT1 inhibitor, DGAT2 inhibitor, FAS inhibitor, PDE inhibition Agent Adenosine beta agonist, ucp-1 activator, UCP-2 activator, UCP-3 activator, thiol estrogen, glucocorticoid agonist / sputum antagonist, HSD-1 inhibitor, SCD-1 inhibitor , lipase inhibitors, fatty acid transporter inhibitors, dicarboxylic acid transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, antihypertensive agents, anti-lipidemia agents, DP Body antagonists, apolipoprotein-sputum secretion/microsomal triglyceride transfer protein (ap〇_B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte stimulating hormone receptor analogues, Melanin-concentrating hormone antagonist, leptin, galanin receptor antagonist, bombesin agonist, neuropeptide γ agonist sputum agent, pseudo-sex gland hormone agent, dechlorinated epirubicin, denitrification Analogs, urocortin-binding protein antagonists, glucagon-like peptide_1 receptor agonists, human guinea pig-associated protein (AGRP), neurotransmitter U receptor agonists, norepinephrine-induced degeneration Appetite, appetite suppressant, stimulating Sensitive lipase antagonists, MSH-receptor analogs, alpha] -glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, inhibitors of fatty acid binding protein (FABP), and fatty acid transporter protein inhibitors (FATP). Non-limiting examples of hydroxy-substituted azetidinone compounds and substituted β-indoleamine compounds used in combination with the nicotinic acid receptor agonists of the invention are disclosed in 141541.doc -49· 201016667 U.S. Patent Nos. 5,767,1,5,5,624,920, 5,668,990, 5,656,624, 5,688,787, 5,756,470, U.S. Patent Application Serial No. 2002/0137,690, and No. 2002/0137689 And PCT Patent Application No. WO 2002/066464 (the entire contents of each of which is incorporated herein by reference). A preferred azetidinone compound is ezetimibe (e.g., ZETIA® available from Schering-Plough Corporation). A non-limiting example of a HMG CoA reductase inhibitor compound for use in combination with a nicotinic acid receptor agonist of the invention is lovastatin (e.g., MEVACOR® available from Merck & Co.), simvastatin (e.g., , purchased from Merck & Co., ZOCOR®, pravastatin (for example, PRAVACHOL® from Bristol Meyers Squibb), atorvastat, butyl (for example, LIPITOR® from Pfizer), fluorine Rutastatin, cerivastatin, CI-981, rivastatin (7-(4-fluorophenyl)-2,6-diisopropyl-5-methoxyindolyl)-pyridin-3-yl -3,5-dihydroxy-6-heptanoate), rosuvastatin calcium (CRESTOR® from AstraZeneca Pharmaceuticals), pitavastatin (eg, NK-104, Negma Kowa, Japan). A non-limiting example of an HMG CoA synthetase inhibitor for use in combination with a nicotinic acid receptor agonist of the invention is, for example, L-659, 699 ((E, E)-11-[3'R-(hydroxy-A) Base)-4'-Sideoxy-2'R-oxabutanyl]-3,5,7R-trimethyl- 2,4-H-dicarboxylic acid). A non-limiting example of an angular f-ene synthesis inhibitor for use in combination with a nicotinic acid receptor agonist of the invention is, for example, squalene 1. A squalene epoxidase for use in combination with a nicotinic acid receptor agonist of the invention 141541.doc -50- 201016667 A non-limiting example of an inhibitor is, for example, NB-598 hydrochloride ((E)-N-B Base-N-(6,6-dimethyl-2-hept-4-ynyl)-3-[(3,3--thiophen-5-yl)methyl-rolling] phenyl-methylamine). A non-limiting example of a sterol biosynthesis inhibitor for use in combination with a nicotinic acid receptor agonist of the invention is, for example, DMP-565. Used in combination with an acid-accepting agonist of the present invention for an acid-testing derivative (for example, a compound comprising a pyridine-3-carboxylate structure or a pyrazine-2-furoate structure, comprising an acid form, a salt, Non-limiting examples of esters, zwitterions and tautomeric oximes are niceritrol, nicofuranose and acipimox (5-methyl 0 to 0 桊- 2-carboxylic acid 4-oxide). A non-limiting example of a bile acid sequestrant for use in combination with a nicotinic acid receptor agonist of the invention is cholestyramine (a styrene-diethylene containing a quaternary ammonium cationic group capable of binding bile acids) a benzene copolymer, such as QUESTRAN® or QUESTRAN LIGHT® from Bristol-Myers Squibb, colestipol (diethyltriamine and 1-gas-2,3-epoxy) Copolymers of propane, such as COLESTID® tablets from Pharmacia), colesevelam hydrochioride (eg, WelChol® tablets (San ( polyallylamine hydrochloride)) from Sankyo, used Epoxy propylene cross-linking and alkylation with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide), water-soluble derivatives (eg 3,3-ionene, N-(ring) Alkyl)alkylamines and polyglucamides, insoluble quaternized polystyrenes, saponins, and mixtures thereof. A non-limiting example of a mixture of inorganic cholesterol chelate 141541.doc-51-201016667 in combination with a nicotinic acid receptor agonist of the present invention is strontium salicylic acid plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacid . A non-limiting example of a thiol-CoA:cholesterol-hydrazinotransferase ("AC AT") inhibitor used in combination with a nicotinic acid receptor agonist of the invention is avasimibe ([[2 , 4,6-anthracene (1-methylethyl)phenyl]ethinyl]aminosulfonic 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 gland), and P. Chang et al., "Current, New and Future Treatments in Dyslipidaemia and Atherosclerosis", Drugs, July 2000; 60(1); 55-93 Compounds (which are incorporated herein by reference). Non-limiting examples of cholesterol ester transfer protein ("CETP") inhibitors for use in combination with a nicotinic acid receptor agonist of the invention are disclosed in the following: PCT Patent Application No. WO 00/38721, U.S. Patent 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, Nos. 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 No. 6,677,379, No. 6,677,375, No. 6,677,353, No. 6,677,341, No. 6,605,624, No. 6,586,433, No. 6,451,830 141541.doc -52-201016667, No. 6,451,823, No. 6,462,092, 6,458,849, 6,458,803, 6,455,519, 6,583,183, 6,562,9 76, 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 incorporated by reference) In this article); compounds described below: Yan Xia et al, "Substituted 1,3,5-Triazines As Cholesteral Ester Transfer Protein Inhibitors", Bioorganic & Medicinal Chemistry Letters, Vol. 6, No. 7, 1996, Pages 919-922 (which is incorporated herein by reference); the natural products set forth below: 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 (which is incorporated herein by reference); the compounds set forth below: Barrett et al. J. φ Am. Chem Soc., 188, 7863-63 (1996), which is incorporated herein by reference in its entirety in its entirety in the the the the the the the the , 10629-34 (1995), which is incorporated herein by reference in its entirety herein in its entirety in its entirety in the the the the the the the Incorporated herein; a compound set forth below: Lee et al. J. Antibiotics, 49, 693-96 (1996) (which is incorporated herein by reference); the compounds set forth below: Busch et al. Lipids , 25, 216-220, (1990) (which is incorporated herein by reference); the compounds set forth below: Morton and 141541.doc • 53- 201016667

Zilversmit J. Lipid Res., 35, 836-47 (1982), which is incorporated herein by reference in its entirety in its entirety in its entirety in the the the the the the the the the the the the the (1996) (incorporated herein by reference); the compounds set forth below: Bisgaier et al. Lipids, 29, 81 1-8 (1994), which is incorporated herein by reference in its entirety herein A compound of the formula 818, 448, which is incorporated herein by reference, which is incorporated herein by reference in its entirety in its entirety in its entirety in /3 5937, WO 9914174, WO 9839299, and WO 9914215 (each incorporated herein by reference); European application EP 796846, EP 801 060, 818 448, and 81 8 197 (each of which is incorporated by reference a compound of the present invention; a probucol or a derivative thereof (e.g., AGI-1067 and other derivatives disclosed in U.S. Patent Nos. 6,121,319 and 6,147,250, incorporated herein by reference) );Low-density lipoprotein( LDL) receptor activators (e.g., HOE-402, which is an imidazolidinyl-pyrimidine derivative that directly stimulates LDL receptor activity, as described by M. Huettinger et al., "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb. 1993; 13:1 005-12, which is cited by

The formula is incorporated herein; 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline (for example, Toperp, described in WO 00/017164, WO 00/017166, WO 00 /140190, WO 00/213797, and WO 2005/033082 (each incorporated herein by reference). Tochap can be combined with an HMG-CoA reductase inhibitor (eg, atorvastatin) (WO 00/213797, WO 141541.doc-54-201016667 2004/056358, WO 2004/056359, and WO2005/011634) A non-limiting example of a fish oil containing an omega 3 fatty acid for use in combination with an acid-receptor agonist of the present invention is 3-PUFA. Non-limiting examples of GLP-1 mimetics for use in combination with a nicotinic acid receptor agonist of the invention comprise insulin secretagogue-3, insulin secretagogue-4, Byetta-exenatide, benefit Liraglutinide, CJC-1131 (ConjuChem), 依泽那太-1^11 (人11171111), 81]^-51077 (Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and revealed in international disclosure The compound of WO 00/07617. Non-limiting examples of natural water soluble fibers for use in combination with the nicotinic acid receptor agonists of the invention are valerian, coca, oat and pectin. A non-limiting example of a plant residual alkanol and/or a fatty acid ester of a plant alkanol used in combination with a nicotinic acid receptor agonist of the invention is a dihydrositosterol ester in BENECOL® Margarine. A non-limiting example of an antioxidant for use in combination with a nicotinic acid receptor agonist of the invention comprises probucol. Non-limiting examples of PPAR alpha agonists for use in combination with a nicotinic acid receptor agonist of the invention include becloHbrate, benzabibrate, ciproHbrate, sulphate Clofibrate, etoHbrate, fenofibrate and gemHbrozil. A non-limiting example of a lipoprotein synthesis inhibitor for use in combination with a nicotinic acid receptor agonist of the invention comprises a final acid (niacin or nicotinic acid). 5HT (serotonin) used in combination with a nicotinic acid receptor agonist of the invention I41541.doc • 55- 201016667 Non-limiting examples of transport inhibitors include paroxetine, fluoxetine, Huoxetine, fen Fenfluramine, fluvoxamine, sertraline, and imipramine. Non-limiting examples of NE (de-adrenergic) transport inhibitors for use in combination with a nicotinic acid receptor agonist of the invention include GW 320659, desipramine, talsupram, and novo Nofenfensine °

A non-limiting example of a CBj# I agent/inverse agonist for use in combination with a nicotinic acid receptor agonist of the invention comprises rimonabant, SR-147778 (Sanofi Aventis) And the compounds described in the following: U.S. Patent No. 5,532,237, U.S. Patent No. 4,973,587, U.S. Patent No. 5,013,837, U.S. Patent No. 5,081,122, U.S. Patent No. 5,1,12,820, U.S. Patent No. 5,292,736 No. 5,624,941, U.S. Patent No. 6,028,084, WO 96/33 159, WO 98/33765, WO 98/43636, W098/43635, 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-65 8546 (each of which is incorporated by reference) \This article). Non-limiting examples of ghrelin antagonists for use in combination with a nicotinic acid receptor agonist of the invention include those described in WO 01/87335 and WO 02/08250 (each of which is incorporated by reference) Incorporated herein. The ghrelin antagonist is also known as GHS (growth hormone promoting bifid receptor) 141541.doc • 56- 201016667 Antagonist. The pharmaceutical combinations and methods of the invention thus comprise the use of a GHS antagonist in place of a ghrelin antagonist (in combination with an acid-receptor agonist of the invention). Non-limiting examples of H3 antagonists/inverse agonists for use in combination with an acid-receptor agonist of the invention include ° thioperamide, N-(4-pentenyl)aminocarbamate 3- (1Η-imidazol-4-yl)propyl ester, clobenpropit, iodophenpropit, imoproxifan, and GT2394 (Gliatech), which are described in WO 02/15905 (in The reference is incorporated herein by reference in Kiec-Kononowicz, Κ· et al, Pharmazie, 55: 349-55 (2000) (in the context of the bow | incorporated herein) 0-[3-( 1Η-imidazol-4-yl)propanol]carbamate, as described in Lazewska, D. et al, Pharmazie, 56: 927-32 (200 1) (incorporated herein by reference) Hydrogen pyridine histamine H3-receptor antagonist, described in S., A. et al., Arch. Pharm. (Weinheim) 334: 45-52 (2001) (incorporated herein by reference) Anthrone derivatives and related compounds, substituted N-phenylamino phthalates described in Reidemeister, S. et al, Pharmazie, 55: 83-6 (2000), incorporated herein by reference. And elaborated on Sasse, A. et al. J. Med Chem 43:.. 3335-43 (2000) where in the Phouesay (proxifan) derivative thereof (each of the above references by key incorporated herein by reference). Non-limiting examples of MCH1R (melanin-concentrating hormone 1 receptor) antagonists and MCH2R (melanin-aggregating hormone 2 receptor) agonists/antagonists used in combination with a nicotinic acid receptor agonist of the invention include those described therein WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, 141541.doc-57-201016667 WO 02/5 1809 and 曰 Patent No. 13226269 (each of the above references) Incorporated herein by reference) and T-226296 (Takeda). Non-limiting examples of NPY1 antagonists for use in combination with a nicotinic acid receptor agonist of the invention include those described in U.S. Patent No. 6,001,836, WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85 173 and WO 01/89528 (each of which is incorporated herein by reference) and BIBP 3226 'J-115814 > BIBO 3304 ' LY-357897 > CP-671906 and GI-264879A. Non-limiting examples of NPY5 antagonists for use in combination with a nicotinic acid receptor agonist of the invention include those described in U.S. Patent No. 6,140,354, U.S. Patent No. 6,191,160, U.S. Patent No. 6,258,837, U.S. Patent No. 6,313,298, U.S. Patent No. 6,337,332, U.S. Patent No. 6,329,395, U.S. Patent No. 6,340,683, U.S. Patent No. 6,326,375, U.S. Patent 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 04/141541.doc -58 - 201016667 1 10375, WO 05/000217 and Norman et al., J. Med. Chem· 43: 4288-4312 (2000) (each of which is incorporated herein by reference); and 152, 804, GW-569180A, GW-5 94884A, GW-587081X, GW-548118X; FR226928, FR240662, FR 252384; 1229U91 > GI-264879A 'CGP71683A' LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104. Non-limiting examples of NPY2 agonists for use in combination with a nicotinic acid receptor agonist of the invention include PYY3-36, NPY3- as described in Batterham, et al, Nature. 41 8:650-654 (2003) 36, and other Y2 agonists (eg, 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-[Lys28-Glu32]-(25-36)-pNPY (Cabrele & Beck-Sickinger J-Pept- Sci. 6:97-122 (2000))) (Each of the above references is hereby incorporated by reference). Non-limiting examples of NPY4 agonists for use in combination with a nicotinic acid receptor agonist of the invention include pancreatic peptides as described in Batterham et al, J. Clin. Endocrinol. Metab. 88: 3989-3992 (2003) (PP), and other Y4 agonists (e.g., 1229 U91 (Raposinho et al, Neuroendocrinology. 71: 2-7 (2000))) (both of which are incorporated herein by reference). A non-limiting example of an mGluR5 (metabolic glutamate 5 subtype receptor) antagonist for use in combination with a nicotinic acid receptor agonist of the invention comprises 2-f-group-6-141541.doc-59-201016667 (benzene Ethylene group)-"bipyridine (MPEP) and (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) (MTEP) and their compounds as described below : Anderson J. et al., J, Eur J Pharmacol. Jul. 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 which is incorporated herein by reference).

Non-limiting examples of lipoproteins, lipoprotein derivatives, and lipoprotein agonists/modulators used in combination with a nicotinic acid receptor agonist of the invention comprise recombinant human lipoprotein (PEG-OB, Hoffman) La Roche) and recombinant metformin human lipoprotein (Amgen). Lipid leptin derivatives (e.g., truncated forms of lipoproteins) for use in the present invention include those described in U.S. Patent No. 5,552,524, U.S. Patent No. 5,552,523, U.S. Patent No. 5,552,522, U.S. Patent 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 96/23 520 (described above) Each of the references is incorporated herein by reference. Non-limiting examples of opioid antagonists for use in combination with a nicotinic acid receptor agonist of the invention include nalmefene (Revex_TM), 3-methoxynaltrexone, Naro A ketone (naloxone), and naltrexone, and an opioid antagonist as described in WO 00/21 509, incorporated herein by reference. Orexin receptor antagonists used in combination with a nicotinic acid receptor agonist of the invention 141541.doc-60-201016667 Non-limiting examples of anti-reagents include SB-334867-A, and they are described in WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838 (each of which is incorporated herein by reference). Non-limiting examples of CNTF (specific ciliary neurotrophic factor) used in combination with the nicotinic acid receptor agonist 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 used in combination with the nicotinic acid receptor agonists of the invention comprise Aso Axokine (Regeneron) and theirs are described in WO 94/09134, WO 98/22128, and WO 99/43 813, each of which is incorporated herein by reference. Non-limiting examples of 5HT2c agonists for use in combination with a nicotinic acid receptor agonist of the invention include BVT933, DPCA37215, WAY WAY161503, and R-1065, and are described in U.S. Patent 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 02/4 457 (each incorporated herein by reference) The middle. Non-limiting examples of Mc4r agonists for use in combination with a nicotinic acid receptor agonist of the invention include CHIR8603 6 (Chiron), ME-10142 and ME-10145 (Melacure) and those described in WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715, and WO 02/141541.doc • 61 · 201016667 12178 (each incorporated herein by reference). Non-limiting examples of monoamine reuptake inhibitors for use in combination with an acid-receptor agonist of the present invention include sibutramine (MeridiaTM/ReductilTM), and they are described in WO 01/27068, WO 01/62341, U.S. Patent No. 4,746,680, U.S. Patent No. 4,806,570, U.S. Patent No. 5,436,272, and U.S. Patent No. 2002/0006, the entire disclosure of each of which is incorporated herein by reference. Non-limiting examples of serotonin reuptake inhibitors for use in combination with a nicotinic acid receptor agonist of the invention include dexfenfluramine, fluoxetine, and those described in U.S. Patent No. 6,365,633. WO 01/27060, and WO 01/162341, each of which is incorporated herein by reference. A non-limiting example of a thiol estrogen for use in combination with a nicotinic acid receptor agonist of the invention comprises oleoyl estrone. Non-limiting examples of HSD-1 inhibitors for use in combination with a nicotinic acid receptor agonist of the invention are described in WO 03/065983 and WO 03/104207, both of which are incorporated herein by reference. ) Chinese. A non-limiting example of a lipase inhibitor for use in combination with a final acid receptor agonist of the invention comprises orlistat. The anti-diabetic agent used in combination with the alkali acid receptor agonist of the present invention comprises % guanidine, meglitinide, α-phospholipidase inhibitor, α_glucoside hydrolase inhibitor, ppAR-γ activation Agent, ppARa/γ agonist, biguanide, ΡΤΡ-1Β inhibitor, 〇卩_1乂 inhibitor, DPP-IV inhibitor, insulin secretagogue, fatty acid oxidation inhibitor, Α2 antagonist, c-junamine 141541. Doc 62 - 201016667 basal end kinase inhibitor, insulin, insulin mimetic, glycogen phosphorylase inhibitor, VPAC2 receptor agonist, glucokinase activator, and non-thiazolidinedione PPAR ligand. Non-limiting examples of sulfonylureas for use in combination with a nicotinic acid receptor agonist of the invention include hexyl urea acetate, sulphonylurea, diabinese, glibenclamide, glibenclamide Glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glicious gland (glisolamide), tolazamide and tolbutamide. Non-limiting examples of meltelatin used in combination with a nicotinic acid receptor agonist of the invention include repaglinide, mitiglinide and nateglinide. Non-limiting examples of alpha-amylase inhibitors for use in combination with a nicotinic acid receptor agonist of the invention comprise amylase aprotin, trestatin and AI-3688 ° φ and the nicotinic acid of the invention Non-limiting examples of alpha-glucoside hydrolase inhibitors used in combination with a body agonist include sugar lysine, liposome, camiglibose, emiglitate, miglitol ), voglibose, pradimicin-Q, saporin (8 Wang 11) 〇 31 has 1^11), (1; 1^0-711, %01 ^-25,637, MDL-73,945 and MOR 14 ° Non-limiting examples of PPAR-gamma agonists for use in combination with a nicotinic acid receptor agonist of the invention include bagliglitazone, ciglitazone ), daglitazone (darglitazone), englitazone 141541.doc -63- 201016667 (6 called 320116), isaglitazone (丨3&amp;§山&amp;201^) (1^€:〇 555), &quot;pioglitazone, rosiglitazone, troglitazone, tesaglitazar, nigret _ (netoglit Azone), 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 PP ARa/gamma agonists used in combination with an alkali acid receptor agonist 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 for use in combination with a nicotinic acid receptor agonist of the invention include succinimide, metformin and phenformin. In combination with a nicotinic acid receptor agonist of the invention Non-limiting examples of PTP-1B inhibitors (protein tyrosine phosphatase-1B inhibitors) include Α-401, 674, KR61639, OC-060062, OC-83839, OC-297962, MC52445, and MC52453 ° with the present invention Non-limiting examples of DPP-IV inhibitors (dipeptidyl peptidase I Vi inhibitors) used in combination with nicotinic acid receptor agonists include sitagliptin, saxagliptin, dina Deagliptin, vildagliptin, alogliptin, agliren's benzoate, Galvu s (Novartis), ΑΒΤ-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph), BI-A and BI-B (Boehringer Ingelheim), SYR-322 (Takeda) , MP-513 (Mitsubishi), DP-893 (Pfizer) and R0-141541.doc -64-201016667 0730699 (Roche), thiazolidine isoleucinate, NVP-DPP728, P32/98, LAF 237, TSL 225, Non-limiting examples of insulin secretagogues for use in combination with pyridoxine pyridoxine, guanidine 2A/2B/2C, CD-26 inhibitors and SDZ 274-444 ° in combination with a nicotinic acid receptor agonist of the invention include Lino Linogliride and A-4166. Non-limiting examples of fatty acid oxidation inhibitors for use in combination with a nicotinic acid receptor agonist of the invention include clomoxir and etomoxir.非 Non-limiting examples of A2 antagonists for use in combination with a nicotinic acid receptor agonist of the invention include 11 megaglyzed, iglidole, ediglidole ), °m idazoxan, earoxan and fluparoxan. Non-limiting examples of insulin mimetics for use in combination with a nicotinic acid receptor agonist of the invention include biota, LP-100, novarapid, insulin detemir, insulin ❹ insulin (insulin ❹ Lispro), insulin glargine, sinensis suspension (slow and ultra-slow), Lys-Pro insulin, GLP-1 (73-7) (insulintropin), and GLP-1 (7-36)-NH2. Non-limiting examples of glycogen phosphorylase inhibitors for use in combination with a nicotinic acid receptor agonist of the invention comprise CP-368, 296, CP-316, 819 and BAYR3401 in combination with a nicotinic acid receptor agonist of the invention Non-limiting examples of non-thiazolidinedione PPAR ligands include JT-501 and farglitazar (GW-2570/GI-262579). 141541.doc -65- 201016667 The anti-hyperglycemic agent used in combination with the acid-receptor agonist of the present invention comprises a diuretic, a β-adrenergic blocker, an α-adrenergic blocker, an aldosterone inhibitor , αΐ blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin π receptor antagonists, endothelin antagonists, vasodilators, a2a agonists, And α/β adrenergic blockers A non-limiting example of a diuretic used in combination with the niacin acid receptor agonist of the present invention comprises an air ketone, a gas plug. Qin, dichlorphenamide, hydrofluorothiazide, indapamide, hydroquinone, bumetanide, ethacrynic acid, furosemide ), tosemide, amiloride, guanbenzine, spironolactone, and epirenone ° beta-adrenal gland in combination with a nicotinic acid receptor agonist of the invention Non-limiting examples of priming blockers include acebutolol, atenolol, betaxolol, bevantolol, bisoprolol, Bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, meto Metaprolol, nadolol, nebivolol, penbutolol, pindolol, propanolol, sotalol ( Sotalol), tertatolol, tililol (radiation 113〇1〇1) and ° sylogol (timolo) l). 141541.doc -66-201016667 A non-limiting example of an alpha guanidine blocker for use in combination with a nicotinic acid receptor agonist of the invention comprises terazin sin, urapidil, 0 bottom 0 sit 0 Qin (prazosin), Buona 0 (bunazosin), Qu Mawei sitting "«秦(trimazosin), 多沙0坐0秦 (doxazosin), 蔡派地尔 (naftopidil), 吲哚拉明 ( Indoramin), WHIP164 and XEN01O. Non-limiting examples of calcium channel blockers for use in combination with a nicotinic acid receptor agonist of the invention include aml〇dipine, aranidipine, azelnidipine, bani Barnidipine, benidipine, bepridil, cinaldipine, clevidipine, diltiazem, efenidipine, felodipine ( Felodipine), gallopamil, isradipine, lacidipine, lemildipine, lercanidipine, nicardipine, benzophenidine Nifedipine), nilvadipine, nimodipine, nisoldipine, nitrendipine, manidipine, pranidipine, and verapamil Verapamil). Non-limiting examples of angiotensin converting enzyme inhibitors for use in combination with a nicotinic acid receptor agonist of the invention include alapril, benazepril, ceralopril, Captopril, cilazapril, deLapril, enalapril, fosinopril, midazolam 141541.doc -67- 201016667 (imidapril), lisinopril, moteltopril, moexipril, quinapril, quinaprilat, ramipril ), perindopril, peridropril, quanipril, spirapril, temocapril, trandolapril, and zofen Zofenopril. Non-limiting examples of the use of a neutral endopeptidase inhibitor in combination with a nicotinic acid receptor agonist of the invention include omapatrilat, candoxatril, ecadotril, Fosidotril, sampatrilat, AVE7688 and ER4030. Non-limiting examples of angiotensin II receptor antagonists for use in combination with a nicotinic acid receptor agonist of the invention include candesartan, eprosartan, irbesartan ), losartan, pratosartan, tasosartan, telmisartan, valsartan, EXP-3137, F16828K, RNH6270, aerated sand Tandan potassium and valsartan potassium-hydrogen thiazide. Non-limiting examples of endothelin antagonists for use in combination with a nicotinic acid receptor agonist of the invention include tezosentan, A308165 and YM62899. Non-limiting examples of vasodilators for use in combination with a nicotinic acid receptor agonist of the invention include hydralazine or apresoline, clonidine or catapres, minoxidil or loniten, and For alcohol (nicotinyl alcohol or roniacol). -68 - 141541.doc 201016667 Non-limiting examples of a2a agonists used in combination with a nicotinic acid receptor agonist of the invention include lofidine (l〇fexidine), tiamenidine, mosoni Moxonidine, rilmenidine and gUan〇benz. Non-limiting examples of alpha/beta adrenergic blockers for use in combination with a nicotinic acid receptor agonist of the invention include nipradil(R), arotinolol, and amines (anl〇sulalol). In a particularly preferred embodiment, the invention relates to a composition comprising a first component and a second component, the first component being at least one compound of formula I, or a salt, solvate, ester or prodrug thereof, The second component is at least one compound selected from the group consisting of LIPITOR®, ZETIA®, VYTORIN®, ZOCOR®, and CRESTOR®. In another preferred embodiment, the invention relates to a composition comprising a first component and a first component, the first component being at least one compound of formula I, or a salt, solvate, ester or prodrug thereof The second component is a small plate aggregation inhibitor. In a particularly preferred embodiment, the invention relates to a composition comprising a first component and a second component, the first component of which is at least one compound of formula I, or a salt, solvate, ester or prodrug thereof, The second component is a platelet aggregation inhibitor, wherein the platelet aggregation inhibitor is a thrombin receptor antagonist, in particular, for example, U.S. Patent Nos. 6,063,847, 6,326,380, 7,037,920, 6,645,987, Thrombin receptor antagonists as set forth in Nos. 7,235,567, 6,894, 065, and 7, 3,04, 078, the entire contents of each of which are incorporated herein by reference. Those skilled in the art will appreciate that the compounds of the invention described herein 141541.doc • 69· 201016667 exhibit excellent nicotinic acid receptor agonist activity. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Any § on the inactive shape 胄. The total xiao composition and each individual dosage unit may contain a fixed amount of "one or more pharmaceutically active agents". The overall composition is a material that has not yet formed a separate dosage unit. Exemplary dosage units are oral dosage units such as lozenges, pills, and the like. Similarly, the method of treating a patient by administering a pharmaceutical composition of the present invention as described herein is also intended to encompass administration of the above-described overall composition and separate doses of 〇τ&gt; -* 兀0 for the preparation of a medicament from the compound of the present invention. For pharmaceutical compositions, the pharmaceutically acceptable inert carrier can be either solid or liquid. The solid form preparations contain powders, troches, dispersed granules, capsules, pills and suppositories. Powders and lozenges ^ include about 5. /. Up to about 95% active ingredient. Suitable solid carriers are well known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, pills and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of preparing various compositions can be found in A. Germaro (ed.), Remingt〇n, s pharmaceuticai

Sciences, 18th edition, (1990), Mack PubUshing c〇, ―Plus, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. Examples may be the water or water-propylene glycol solution (parenteral injection) or the addition of sweeteners and opacifiers to oral solutions, suspensions and emulsions. Liquid form preparations can also be administered intranasally 141541.doc •70· 201016667. The sterilizable preparation suitable for inhalation may comprise a solution and a powdery solid which may be combined with a carrier (for example, an inert compressed gas (for example, nitrogen)) which can be attached to the medicinal drug. A solid form preparation intended to be converted into a liquid form preparation for oral or parenteral administration prior to use. The liquid forms include solutions, suspensions and emulsions. Φ The inventive compound may also be delivered transdermally. The compositions may be in the form of a cream, lotion, aerosol, and/or lotion, and may be included in a matrix or storage transdermal patch which is conventional in the art for this purpose. The compounds of the invention may also be administered subcutaneously. Preferably, the compound is administered orally. Preferably, the pharmaceutical preparation is in unit dosage form. In this form, the preparation can be subdivided into units of the appropriate size containing the appropriate amount (for example, an effective amount to achieve the desired purpose) of the active ingredient. The amount of active compound in a unit dosage formulation may vary from about 1 mg to about 1 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, depending on the particular application. Or adjust The actual dosage used may vary depending on the patient's needs and the severity of the condition being treated. Those skilled in the art will be able to determine the appropriate dosage regimen for the particular situation. For convenience, the total daily dose may be divided into several And administered as needed within one day. The clinical attending physician may adjust the 141541.doc-71 - 201016667 compound and/or after considering factors such as the age, condition, and size of the patient and the severity of the symptoms being treated. Or the amount and frequency of administration of a pharmaceutically acceptable salt thereof. The typical recommended dosage regimen for oral administration may range from about 1 mg/day to about 500 mg/day, preferably from 1 mg/day to 200 mg/day. Between two to four doses. If the compound of formula I releases acetamidine salicylic acid when it is hydrolyzed or metabolized in vivo, the amount of acetyl salicylic acid released should be bioequivalent to no more than 80 mg / day. Another aspect of the invention comprises a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and a pharmaceutically acceptable carrier Agent, vehicle or dilution A kit of the present invention comprising a kit of at least one compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound and a quantity of at least one of the above therapeutic agents. The present invention is disclosed by the following preparations and examples, but is not to be construed as limiting the scope of the invention. The skilled person will clarify the alternative mechanism pathways and similar structures. In displaying NMR data, the 1 Η spectrum is attached to the Variant VXR-200 (200 MHz, *H) 'Varian Gemini-300 (300 MHz) 'Varian Mercury VX-400 (400 Obtained in MHz), or on Bruker-Biospin AV-500 (500 MHz), reported in ppm, proton number and multiplicity are stated in parentheses. This analysis was performed using an Applied Biosystems API-100 mass spectrometer and a C18 column (10-95% CH3CN-H20 (containing 0.05% TFA) gradient) when the LC/MS data was presented. The observed parent ion is given. The following solvents and reagents may refer to the abbreviations in parentheses: 141541.doc -72- 201016667

Me = mercapto Et = ethyl Pr = propyl ' Bu = butyl

Ph=phenyl Ac=acetamidine μ1 = microliter

AcOEt or EtOAc=acetic acid ethyl acetate AcOH or HOAc=acetic acid ACN=acetonitrile atm=atmospheric pressure

Boc or BOC=T-butoxycarbonyl DCE=Diethylacetone DCM or CH2C12=Dichloromethane DIPEA=Diisopropylethylamine φ DMAP=4-Dimethylaminopyridine DMF = Dimercaptopurine Amine DMS = dimethyl sulfide DMSO = disulfoxide EDCI = (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Fmoc or FMOC = 9-fluorenyl decyloxycarbonyl g=克h=hour hal=halogen 141541.doc -73- 201016667 HOBt=l-hydroxybenzotriazole LAH=lithium hydride aluminum LCMS=liquid chromatography mass spectrometry min=minute mg=mgmL=mlmmol=mimo Ear MCPBA = 3-chloroperoxybenzoic acid MeOH = methanol MS = mass spectrometry NMR = nuclear magnetic resonance spectrum RT or rt = room temperature (ambient temperature, about 25 ° C) TEA or Et3N = triethylamine TFA = trifluoroacetic acid THF = tetrahydrooxan TLC = thin layer chromatography TMS = trimethyl fluorite Tr = triphenylmethyl exemplification The compounds of the invention can generally be prepared as described in the preparation of the reaction schemes and the following examples. Use commercially available solvents, reagents and intermediates according to the accepted state. Prepare non-marketed reagents and intermediates as follows. Obtain 4 NMR spectra on Gemini AS- 141541.doc -74- 201016667 400 (400 MHz) The proton number, multiplicity, and coupling constant (Hertz) are reported in parentheses at a low magnetic field distance of Me4Si. When the LC/MS data is presented, the analysis is performed using the following conditions: Applied Biosystems API-100 Mass Spectrometer and Shimadzu SCL-10A LC column (Altech Platinum C18, 3 μm, 33 mm x 7 mm ID; gradient flow: 0 min-10% CH3CN, 5 min-95% CH3CN, 7 min-95% CH3CN, 7.5 min-10% CH3CN, 9 min-stop. Give retention time and observed precursor ions.

General synthetic reaction ring: Reaction Figure 1

* A-B

Reaction diagram 2

·► A-L + B .......A-L~B

Reaction ring 3 triphosgene 〇 -A-L + B .......* A-L-^;

0-B 141541.doc -75· 201016667

Compound la (1 g) in CH2C12 (2.0 mL) was added dropwise to a solution of Compound 2 (0.53 mL) and NEt3 (0.74 mL). The reaction mixture was stirred for 3 h then diluted with EtOAc / EtOAc (1 N). The aqueous phase was extracted with EtOAc (3x) and EtOAc (EtOAc) The solvent was removed under reduced pressure and the residue was purified using EtOAc EtOAc EtOAc EtOAc Step 2:

NEt3 (0.8 mL) was added dropwise to a mixture of compound lc (1.1 g) and ld (0.90 g, hydrochloride). The reaction mixture was stirred for 8 hours and then diluted with EtOAc / NaHC. The water was extracted with EtOAc (3x) 141541.doc -76 - 201016667 phase and the organic phase was washed with water (lx), brine and dried (MgS〇4). The solvent was removed under reduced pressure and the residue was purified using flash chromatography using EtOAc EtOAc EtOAc Electrospray MS [M+l] + 346.2. Other compounds of formula I (comprising the compounds of Table 1), and salts, solvates, esters and prodrugs thereof, can be prepared by preparation analogous to those described in the preparation examples above. Although the invention has been described in connection with the specific embodiments described above, many alternatives, modifications, and other variations are apparent to those skilled in the art. All such alternatives, modifications, and variations are intended to be within the spirit and scope of the invention. 141541.doc -77-

Claims (1)

201016667 VII. Application for Patent Park: 1. A compound of formula I: Wherein G represents a hydrolyzable or metabolizable linking group; and R represents a recoverable residue of an acid receptor agonist; or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein G represents a linking group selected from the group consisting of hydrazine, S, NR, 〇 _alkylene_〇·, _〇_alkylene_s_, _s_alkylene_S_,_0-exylaryl-0_,-0-exylaryl-S-, ·S-strandyl _S_ , -〇-arylalkylene, 〇_,·〇_arylalkylene_s_, _sarylalkyl-S-,-〇-heteroaryl-0-,-0-heteroaryl S_, _s_heteroaryl_S_, polyalkylene glycol, _C(0)0-alkylene·〇·,·〇(〇)〇_alkyl-S-, -〇-C( 0)-Extended alkyl _ 〇 _, · 〇 &lt; (〇) alkyl, _c (o) 0 · extended aryl 〇, _c (0) 0 · extended aryl _s, 〇 c ((7)芳aryl-〇_,-0_C(0)-Exoaryl-S-, -c(〇)〇_ Heteroaryl _〇_, &lt;(〇)〇·(heteroaryl-s-, -oc(o)-heteroaryl-〇...0_c(0)_heteroaryl-S- and -C(0)-polyalkylene glycol; and ruler 1 represents hydrogen, alkyl or aryl The compound of claim 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, 141541.doc 201016667, S or prodrug, wherein G represents a selected from the following Linking groups of the group: Ο, S, NR1, -0(CH2)n0-, -〇(c(R2)2)〇_, -0(CH2)nS- . -〇(C(R2)2 S-^-S(CH2)nS-^-S(C(R2)2)S-. -O-arylaryl, -s-aryl-s-, -〇_heteroaryl_〇_ , -o-heteroaryl_s_, _s_heteroaryl_s_, PEG (polyethylene glycol) and PPG (polypropylene glycol); and R1 represents hydrogen, alkyl or aryl; R2 represents alkyl; Representative 0-1 〇. 4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, vinegar or prodrug thereof, wherein R represents a nicotinic acid receptor agonist having the following structure Residue: 0 The asterisk indicates the connection point with G. 5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R represents a recoverable residue of an acid accepting receptor agonist having the following structure: wherein 141541.doc 201016667 r3 represents an alkyl group, a cycloalkyl group or a heteroalkyl group; and R4 represents an anthracene, an alkyl group or a cycloalkyl group; and an asterisk indicates a point of attachment to G. 6. The compound of 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 following structure: Wherein R5 and R6 each independently represent a halogenated alkyl group; and the asterisk indicates a point of attachment to G. 7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, vinegar or prodrug thereof wherein R represents a recoverable residue of a nicotinic acid receptor agonist having the following structure: The asterisk indicates the connection point with G. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt, or a remedy, wherein R represents a recoverable residue of a final acid acceptor agonist having the structure: 141,541. Doc 201016667 Ο where the asterisk indicates the point of connection with G. 9. A compound selected from the group consisting of compounds having the formula: 141541.doc -4- 201016667 141541.doc 201016667 141541.doc -6- 201016667 Οο. ❹ w σ, ester and prodrug. And a pharmaceutically acceptable salt thereof. A composition comprising a compound of 黾 一 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 11. A composition comprising at least one of the compounds of claim 9 and a pharmaceutically acceptable carrier. 12. The composition of claim 1 (), further comprising at least one other therapeutic agent selected from the group consisting of: a hydroxy substituted azetidinium compound, a substituted indolamine compound, HMG c〇A reductase inhibitor compound, HMG CoA synthetase inhibitor, squalene synthesis inhibitor, hornene epoxidase inhibitor, sterol biosynthesis inhibitor, final acid derivative, bile acid sequestrant Aspirin, aspirin, NSAid, Vytorin®, ezetimibe, inorganic cholesterol chelating agent, sulfhydryl-based CoA: cholesterol Ο-hydrazinotransferase inhibitor, cholesterol ester transfer protein inhibitor, ω3 fatty acid Fish oil, natural water soluble 141541.doc 201016667 Fiber, plant alkaloid and/or fatty alcohol ester of plant alkanol, antioxidant, PPAR alpha agonist, PPAR gamma-agonist, FXR receptor modulator, LXR receptor Agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport inhibitors, bile acid reuptake inhibitors, PPAR δ agonists, triglyceride synthesis Agent, squalene epoxidase inhibitor, low-density lipoprotein receptor inducer or activator, platelet aggregation inhibitor, 5-LO or FLAP inhibitor, PPAR δ partial agonist, nicotinic acid or nicotinic acid Somatostatin, 5ΗΤ transporter inhibitor, ΝΕ transporter inhibitor, CB, antagonist/inverse agonist, ghrelin antagonist, Η3 antagonist/inverse agonist, MCH1R antagonist, MCH2R agonist/ Antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptin, lipoprotein agonists/modulators, lipid raft protein derivatives, tyrosin antagonists , orexin receptor antagonist, BRS3 agonist, CCK-A agonist, CNTF, CNTF derivative, CNTF agonist/modulator, 5HT2c agonist, Mc4r agonist, monoamine reuptake inhibitor, serum Reuptake inhibitor, GLP-1 mimetic, phentermine, topiramate, phytopharm compound 57, ghrelin antibody, Mc3r agonist, ACC inhibitor, β3 agonism Agent, DGAT1 inhibitor, DGAT 2 inhibitors, FAS inhibitors, PDE inhibitors, scorpion hormone beta agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, thiol estrogens, glucocorticoid agonists / antagonist Agent, 11β HSD-1 inhibitor, SCD-1 inhibitor, lipase inhibitor, fatty acid transporter inhibits 201016667, dicarboxylic acid transporter inhibitor, glucose transporter inhibitor, phosphate transporter inhibitor, anti-diabetes Agents, antihypertensive agents, anti-lipidemia agents, DPP-IV inhibitors, apolipoprotein-B secreting/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, Dopamine agonist, melanocyte stimulating hormone receptor analogue, melanin aggregation hormone antagonist, lepton, galanin receptor antagonist, bombesin agonist, nerve Peptide-gamma antagonist, pseudo-salvoid agent, dehydroepiandrosterone, analog of dehydroepiandrosterone, urocortin-binding protein antagonist, glucagon-like peptide-1 receptor agonist, human Guinea pig-associated protein (AGRP), Interleukin U receptor agonist, norepinephrine-induced anorectic agent, appetite suppressant, hormone-sensitive lipase antagonist, MSH-receptor analog, alpha-glucosidase inhibitor, apo A1 Milano reverse cholesterol transport inhibitor, fatty acid binding protein inhibitor (FABP) and fatty acid transporter inhibitor (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, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, pitavastat ; pitavastatin, torcetrapib, Vytorin®, ezetimibe, ass CL, ibuprofen, acetaminophen, DPP-IV inhibitor, GLP-1 mimetic And their combinations. The composition of claim 11, further comprising at least one other therapeutic agent selected from the group consisting of a hydroxy substituted azetidinone compound, a substituted β-indoleamine compound , HMG CoA reductase inhibitor compound, HMG CoA synthetase inhibitor, squalene synthesis inhibitor, squalene epoxidase inhibitor, sterol biosynthesis inhibitor, nicotinic acid derivative, bile acid sequestrant, Aspirin, NS AID, Vytorin®, ezetimibe, inorganic cholesterol chelating agent, sulfhydryl-based CoA: cholesterol Ο-hydrazinotransferase inhibitor, cholesteryl ester transfer protein inhibitor, fish oil containing ω3 fatty acid, natural water-soluble fiber , plant stanol and/or phyto-alcoholic fatty acid S, antioxidant, PPAR alpha agonist, PPAR gamma-agonist, FXR receptor modulator, LXR receptor agonist, lipoprotein synthesis inhibitor, kidney Angiotensin inhibitor, microsomal triglyceride transport inhibitor, bile acid reuptake inhibitor, PPAR δ agonist, triglyceride S synthetic inhibitor, squalene epoxidase Formulation, low-density lipoprotein receptor inducer or activator, platelet aggregation inhibitor, 5-LO or FLAP inhibitor, PPAR δ partial agonist, nicotinic acid or nicotinic acid receptor agonist, 5ΗΤ transporter inhibitor , ΝΕ transporter inhibitors, CB i antagonists/inverse agonists, ghrelin antagonists, Η3 antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, ΝΡΥ1 antagonists, ΝΡΥ5 antagonists, ΝΡΥ2 Agonists, ΝΡΥ4 agonists, mGluR5 antagonists, lipoproteins, lipoprotein agonists/modulators, lipoprotein derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A Agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonism 141541.doc •10-201016667 agents, monoamine reuptake inhibitors, serotonin reuptake inhibitors, mimics, Futmin, tropimyl ester, botanical drug compound 57, ghrelin antibody, Mc3r agonist, (10) preparation, agonist, dgati inhibitor, DGAT2 inhibitor, FAS inhibitor, pDE inhibitor, thyroid hormone P Agent, UCP-1 activator, UCP-2 activator, UCP-3 activator, tyrosine estrogen, glucocorticoid agonist/antagonist, 11β HSD-1 inhibitor, SCD-1 inhibitor, lipase Inhibitor, fatty acid φ transporter inhibitor, acid transporter inhibitor, glucose transporter egg inhibitor, citrate transporter inhibitor, antidiabetic agent, anti-hypotension agent, anti-lipid metabolism agent, inhibitor , apolipoprotein_B secretion / microsomal triglyceride transfer protein (叩. _ B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte stimulating hormone receptor analogues, melanin-concentrating hormone antagonists, leptin, galanin receptor antagonists, bombesin agonist Agent, neuropeptide-Y antagonist, thyroxine agent, dehydroepiandrosterone, similar to dehydroepiandrosterone, urocortin-binding protein antagonist, glucagon-like peptide-丨 receptor agonist Human pulse-associated protein (AGRp), neurotransmitter u receptor agonist, norepinephrine-induced anorectic agent, appetite suppressant, hormone-sensitive lipase antagonist, Cong-receptor analogue, ^Glucosinase inhibitor, apo A1 milan 〇 reverse cholesterol transport inhibitor, fatty acid binding protein inhibitor (FABp) and fatty acid transporter (FATP) gentleman-monthly composition 14, wherein the at least one other The therapeutic agent is selected from the group consisting of: lovastatin&gt;, butyl, simva (iv), pravastatin, 14154I.doc*11 201016667 atorvastatin, fluvastatin, cerivastatin, rivastatin Rosuvva (four), skin Cerivastatin, torcetrapib, ν_η⑧, wheat cloth ezetimibe, aspirin, ibuprofen, numerous acetylglucosamine, 〇1 &gt; 1 &gt; _ ^ inhibitor, GLP-1 mimetics, and combinations thereof. The use of a compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof for the preparation of a medicament for use in the treatment of a disease of a patient Symptoms, blood lipids ~ vascular disease, peripheral nervous system and central nervous system disorders, blood diseases, cancer, inflammation, respiratory diseases, gastrointestinal diseases, diabetes or non-alcoholic fatty liver disease. 17. The use of claim 16, wherein the medicament is used in combination with at least one other therapeutic agent selected from the group consisting of a hydroxy substituted azetidinone compound, a substituted indolamine compound, HMG c 〇a reductase inhibitor compound, HMG CoA synthetase inhibitor, squalene synthesis inhibitor, squalene epoxidase inhibitor, sterol biosynthesis inhibitor, nicotinic acid derivative, bile acid sequestrant, inorganic Cholesterol chelating agent, aspirin, NSAID agent, ezetimibe, vytorin®, thiol CoA: cholesterol 〇-hydrazinotransferase inhibitor, cholesteryl ester transfer protein inhibitor, fish oil containing omega 3 fatty acid, natural water-soluble fiber, plant Fatty alcohols and/or fatty alcohol esters of plant alkanols, Omacor®, antioxidants, PPAR alpha agonists, PP AR gamma agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibition Agent, renin angiotensin inhibitor, microsomal triglyceride transporter inhibitor, bile acid reuptake inhibitor, PPAR δ agonist, triglyceride synthesis inhibition 141541.doc • 12· 201016667 Agent, horn agrochemical 5 oxy-enzyme y p in 丨丨 丨, p preparation, low-density lipoprotein receptor inducer or activated d platelet aggregation inhibitor, 5_LO or FLAP inhibitor, 15 knife agonist, Nicotinic acid or nicotinic acid receptor agonist, 5HT transporter inhibitor, NE transporter inhibitor, Cl bucker/reverse activator, ghrelin antagonist, % antagonist/reverse agonist, MCH1R Antagonists, MCH2R agonists/antagonists, Νργι antagonists, 5 antagonists ΝΡΥ2 agonists, NpY4a agonists, mGiuR5 antagonists, lipoproteins, lipoprotein agonists/modulators, lipoproteins Derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK_A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Me4r agonists, monoamine reuptake inhibitors , serotonin reuptake inhibitor, GLP-1 mimetic, phentermine, topiramate, botanical drug compound 57, ghrelin antibody, ll1 (; 311 agonist, Acc inhibitor, β3 agonist, DGAT1 inhibitor, DGAT2 inhibitor, FAS inhibitor, PDE inhibitor, Thyroid hormone p agonist, ucp-丨 activation sputum, UCP-2 activator, UCP-3 activator, thiol estrogen, glucocorticoid agonist/antiboosting agent, 11 β HSD-1 inhibitor, SCD- 1 inhibitor, lipase inhibitor, fatty acid transporter inhibitor, dicarboxylic acid transporter inhibitor, glucose transporter inhibitor, phosphate transporter inhibitor, antidiabetic agent, antihypertensive agent, anti-lipid metabolism agent , DPP-IV inhibitors, apolipoprotein-Β secretion/microsomal triglyceride transfer protein (apo_B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte stimulating hormone receptor analogues, Melanin-concentrating hormone antagonist, leptin, galanin receptor antagonist, bell I4154I.doc -13· 201016667 peptide agonist, neuropeptide-γ antagonist, thyroxine agent, dehydroepiandrosterone, dehydrogenation Analogs of epiandrosterone, urocortin-binding protein antagonist, glucagon-like peptide-1 receptor agonist, human guinea pig-associated protein (AGRP), neurotransmitter receptor agonist, norepinephrine Inspiring Anorectic agents, appetite suppressants, hormone-sensitive lipase antagonists, MSH-receptor analogues, alpha-glucosidase inhibitors, ap〇A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP) and Fatty acid transporter inhibitor (FATP). 18. Use of at least one compound of claim 9, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, for the manufacture of a medicament for the treatment of a disease in a patient: metabolic syndrome ' Dyslipidemia, cardiovascular disease, peripheral nervous system and sacral nervous system disorders, blood diseases, cancer, inflammation, respiratory diseases, gastroenterology, diabetes or nonalcoholic fatty liver disease. 19. The use of claim 18, wherein the medicament is used in combination with at least one other therapeutic agent selected from the group consisting of a hydroxy substituted azetidinone compound, a substituted beta-endoamine compound, HMG C〇a reductase inhibitor compound, HMG C〇A synthetase inhibitor, horn f dilute synthesis inhibitor, horn epoxide epoxidase inhibitor, sterol biosynthesis inhibitor, niacin acid, bile acid chelate Mixture, inorganic cholesterol chelating agent, aspirin, NS genus, ezetimibe, Μ-8, thioglycol 〇 酿 酿 转移 transductase inhibitor, cholesterol vinegar transfer egg: inhibitor, fish oil containing c〇3 fatty acid, Natural water-soluble fiber, plant Cuihao alcohol and / or plant (four) material. Coffee (10) 8, anti-oxidation 141541.doc _ 14- 201016667 agent, PPAR α agonist, PPAR γ-agonist, FXR receptor modulator, LXR receptor agonist, lipoprotein synthesis inhibitor, renin angiotensin inhibitor , microsomal triglyceride transporter inhibitor, bile acid reuptake inhibitor, PPAR δ agonist, triacetin synthesis inhibitor, squalene epoxidase inhibitor, low density lipoprotein receptor inducer Or activator, platelet aggregation inhibitor, 5-LO or FLAP inhibitor, PPAR δ partial agonist, acid or acid agonist, 5HT transporter inhibitor, sputum transporter inhibitor, CBt antagonist /Inverse agonist, ghrelin antagonist, H3 antagonist/inverse agonist, MCH1R antagonist, MCH2R agonist/antagonist, NPY1 antagonist, NPY5 antagonist, NPY2 agonist, NPY4 agonist, mGluR5 antagonist, lipid Leptin, lipoprotein agonist/modulator, lipoprotein derivative, tyrosin antagonist, orexin receptor antagonist, BRS3 agonist, CCK-A agonist, CNTF, CNTF derivative, CNTF agonist / Conditioner, 5HT 2c agonist, Mc4r agonist, monoamine reuptake inhibitor, serotonin reuptake inhibitor, GLP-1 mimetic, phentermine, tropine ester, botanical drug compound 57, ghrelin antibody, Mc3r agonist, ACC inhibitor, β3 agonist, DGAT1 inhibitor, DGAT2 inhibitor, FAS inhibitor, PDE inhibitor, thyroid hormone beta agonist, UCP-1 activator, UCP-2 activator, UCP-3 activator, sulfhydryl Estrogen, glucocorticoid agonist/antagonist, 11β HSD-1 inhibitor, SCD-1 inhibitor, lipase inhibitor, fatty acid transporter inhibitor, dicarboxylic acid transporter inhibitor, glucose transporter inhibitor, Phosphate transporter inhibitors, antidiabetic agents, antihypertensive agents, anti-lipid metabolism 141541.doc -15- 201016667 Obstacle agents, DPP-IV inhibitors, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitor, sympathomimetic agonist, dopamine agonist, melanocyte stimulating hormone receptor analogue, melanin aggregation hormone antagonist, leptin, galanin receptor antagonist, bombesin Agonist , neuropeptide-Y antagonist, thyroxine agent, dehydroepiandrosterone, analog of dehydroepiandrosterone, urocortin-binding protein antagonist, glucagon-like peptide-1 receptor agonist, human Guinea pig-associated protein (AGRP), neurotransmitter U receptor agonist, norepinephrine-induced anorectic agent, appetite suppressant, hormone-sensitive lipase antagonist, MSH-receptor analogue, alpha-gluco Glycosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP) and fatty acid transporter inhibitors (FATP). 141541.doc 16- 201016667 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 〇5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 141541.doc