HK1089093A - (3-{3-'(2,4-bis-trifluormethyl-benzyl)-(5-ethyl-pyrimidin-2-yl)-amino!-propoxy}-phenyl)-acetic acid and related compounds as modulators of ppars and methods of treating metabolic disorders - Google Patents

Description

(3- { 3' - [ (2, 4-bis-trifluoromethyl-benzyl) - (5-ethyl-pyrimidin-2-yl) -amino ] -propoxy } -phenyl) -acetic acid and related compounds as PPAR modulators and methods of treating metabolic disorders

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. provisional application No.60/464,581 filed on 17/4/2003.

Technical Field

The present invention relates to the field of pharmaceutical chemistry. More particularly, the present invention relates to aryl compounds and methods of treating various diseases by using these compounds to modulate nuclear receptor mediated processes, particularly peroxisome proliferator-activated receptor (PPAR) mediated processes.

Background

Peroxisome proliferators are structurally diverse groups of compounds that, when administered to mammals, cause dramatic increases in the size and number of liver and kidney peroxisomes, while enhancing the ability of peroxisomes to metabolize fatty acids by increasing the expression of enzymes required for the oxidative cycle (Lazarow and Fujiki, Ann. Rev. cell biol.1: 489-19 (1985); Vamecq and Draye, Essays biochem.24: 1115-225 (1989); and Nelali et al, Cancer Res.48: 5316-5324 (1988)). Compounds that activate or interact with one or more PPARs are closely related to the modulation of triglyceride and cholesterol levels in animal models. The compounds included in this group are hypolipidemic (hypolipidimic) drugs of the class of the fenoxyarones, herbicides, and phthalate plasticizers (Reddy and Lalwani, Crit. Rev. Toxicol.12: 1-58 (1983)). Peroxisome proliferators can also be caused by diet or physiological factors such as high fat meals and cold adaptation.

Biological processes modulated by PPARs are those modulated by receptors or combinations of receptors that respond to PPAR receptor ligands. These processes include, for example, plasma lipid transport and regulation of fatty acid catabolism, insulin sensitivity and blood glucose levels, which are involved in hypoglycemia/hyperinsulinemia (e.g., dysfunction of pancreatic beta cells caused by insulin autoantibodies, insulin receptors, or autoantibodies that stimulate pancreatic beta cells, insulin secreting tumors (insulin secreting tumors) and/or by autoimmune hypoglycemia), macrophage differentiation leading to the formation of atherosclerotic plaques, inflammatory responses, carcinogenesis, hyperplasia, and adipocyte differentiation.

The PPAR subtypes include the two isoforms PPAR- α, PPAR- δ (also known as NUC1, PPAR- β, and FAAR), and PPAR- γ. These PPARs are capable of regulating the expression of a target gene by binding to a DNA sequence element called the PPAR response element (PPRE). To date, PPARs have been identified among enhancers of many genes encoding proteins that regulate lipid metabolism, suggesting that PPARs play a key role in the signaling cascade for adipogenesis and lipid homeostasis (h.keller and w.wahli, Trends endoodn.met.291-296, 4 (1993)).

The mechanism by which peroxisome proliferators exert their pleiotropic effects is known by identifying a member of the nuclear hormone receptor superfamily activated by these chemicals (Isseman and Green, Nature 347-. It was subsequently discovered that these receptors, termed PPAR- α (or PPAR α), are activated by a variety of medium and long chain fatty acids and stimulate the expression of genes encoding the following proteins: rat acetyl-CoA oxidase and hydratase-dehydrogenase (enzymes required for peroxisome beta oxidation), and rabbit cytochrome P4504A6, fatty acid ω -hydroxylase (Gottllich et al, Proc. Natl. Acad. Sci. USA 89: 4653-4657 (1992); Tugwood et al, EMBO J11: 433-439 (1992); Bardot et al, biochem. Biophys. Res. 192: 37-45 (1993); Muerhoff et al, J biol. chem.267: 19051-19053 (1992); and Marcus et al, Proc. Natl. Acad. Sci. USA 90 (12): 5723-5727 (1993)).

Activators of the nuclear receptor PPAR-gamma (or PPAR gamma) such as troglitazone have been shown clinically to have a lesser but important effect in increasing insulin action, reducing serum glucose and lowering serum triglyceride levels in type 2 diabetic patients. See, e.g., d.e.kelly et al, curr.opin.endocrinol.diabetes, 90-96, 5(2), (1998); M.D. Johnson et al, Ann.Pharmacother, 337-348, 32(3), (1997); and M.Leutenegger et al, curr.Ther.Res., 403. sub.416, 58(7), (1997).

PPAR- δ (or PPAR δ) is widely expressed in vivo and has been shown to be a valuable molecular target for the treatment of dyslipidemias (dyslipedimia) and other diseases. For example, in a recent study of insulin-resistant obese rhesus monkeys, a potent and selective PPAR-delta compound was found to lower VLDL and increase HDL in a dose-responsive manner (Oliver et al, Proc. Natl. Acad. Sci. U.S. A.98: 5305, 2001).

Since the PPARs have three isoforms and all have been found to play important roles in energy homeostasis and other important biological processes in the human body, and have also been found to be important molecular targets for the treatment of metabolic and other diseases (see Willson et al, J.Med.chem.43: 527-550(2000)), there is a desire in the art to identify compounds that are capable of selectively interacting with only one PPAR isoform, or with multiple PPAR isoforms. The compounds are useful in a wide variety of applications such as the treatment or prevention of obesity, the treatment or prevention of diabetes, dyslipidemia, metabolic syndrome X, and others.

Disclosure of Invention

Described herein are compounds capable of modulating peroxisome proliferator-activated receptor (PPAR) -mediated nuclear receptor processes, and methods of using the modulation in the treatment of metabolic diseases, disorders, and conditions. Carbocyclic aryl-derived compounds that mediate and/or inhibit peroxisome proliferator-activated receptor (PPAR) activity, and pharmaceutical compositions comprising these compounds are also described. The invention also describes the therapeutic or prophylactic use of these compounds and compositions, as well as methods of treating metabolic diseases, disorders, and conditions by administering effective amounts of these compounds.

In one aspect is a compound having the structure of formula I or a pharmaceutically acceptable N-oxide, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, pharmaceutically acceptable amide, or pharmaceutically acceptable solvate thereof:

wherein:

Ar₁selected from monocyclic heteroaromatic ring structures and bicyclic heteroaromatic ring structures;

Ar₂selected from monocyclic, bicyclic, and tricyclic carbocyclic aryl structures;

R₁selected from the group consisting of:

alkyl optionally substituted by a substituent selected from the group consisting of hydrogen, lower alkyl, optionally substituted carbocyclic or heterocyclic ring, halogen, perhaloalkyl, hydroxy, alkoxy, nitro, and amino;

optionally selected by one or more ofA five-or six-membered heteroaryl ring or a six-membered aryl ring substituted with the substituent in (1), said group consisting of optionally substituted C₁-C₈A linear, branched, or cyclic saturated or unsaturated alkyl group; an alkoxy group; a cyano group; a nitro group; an amino group; an amido group; perhaloalkyl and halogen;

R₂selected from the group consisting of:

hydrogen;

alkyl optionally substituted by a substituent selected from the group consisting of hydrogen, lower alkyl, optionally substituted carbocyclic or heterocyclic ring, halogen, perhaloalkyl, hydroxy, alkoxy, nitro, and amino;

a five-or six-membered heteroaryl ring or a six-membered aryl ring, optionally substituted by one or more substituents selected from the group consisting of optionally substituted C₁-C₈A linear, branched, or cyclic saturated or unsaturated alkyl group; an alkoxy group; halogen and perhaloalkyl;

cyano, nitro, amino, amido, perhaloalkyl, and halogen;

R₃selected from hydrogen, alkyl optionally substituted with a substituent selected from hydrogen, lower alkyl, optionally substituted carbocyclic or heterocyclic ring, hydroxy, halogen, amino, nitro, and cyano;

b is a five-or six-membered heteroaryl ring, or- (CH)₂)_j-C(O)OR₄Wherein when Ar is₂J is 0 or 1 when it is a bicyclic or tricyclic carbocyclic structure, and when Ar is₂J is 1 in the case of a monocyclic carbocyclic ring structure; and R is₄Selected from the group consisting of:

hydrogen;

alkyl optionally substituted with a substituent selected from hydrogen, lower alkyl, optionally substituted carbocyclic or heterocyclic;

five-or six-membered optionally substituted by one or more substituents selected from the following groupA heteroaryl ring or a six membered aryl ring, said group consisting of optionally substituted C₁-C₈Linear, branched, or cyclic saturated or unsaturated alkyl groups.

In a specific embodiment of this aspect, Ar₂Selected from the group consisting of: phenyl, naphthyl, anthracene, and phenanthrene. In another specific embodiment of this aspect, Ar₂Is phenyl. In another specific embodiment of this aspect, the compounds of the invention have the structure of formula (II):

in an alternative embodiment of this aspect, Ar₂Is naphthyl. In another specific embodiment of this aspect, Ar₂Optionally naphthyl or the compound has the structure of formula (II); for convenience, Ar is included₂Will be referred to as embodiment 2. In another specific embodiment of specific embodiment 2, R₁Is alkyl optionally substituted by one or more optionally substituted carbocyclic or heterocyclic rings. In another specific embodiment of specific embodiment 2, the alkyl is lower alkyl. In another specific embodiment of specific embodiment 2, the lower alkyl is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and sec-butyl.

In an alternative embodiment of embodiment 2, R₁Is alkyl substituted with optionally substituted phenyl (i.e., the carbocycle is phenyl). In another specific embodiment, the phenyl is optionally substituted with one or more substituents selected from the group consisting of: lower alkyl, halogen, perhaloalkyl, hydroxy, alkoxy, nitro, and amino. In another embodiment, the substituent is perhaloalkyl. And in another embodiment, the perhaloalkyl is trifluoromethyl.

In another embodiment of the compounds having the structure of formula (I), R₁Is 4-bis (trifluoromethyl) phenylmethyl.

In another embodiment of the compounds having the structure of formula (I), Ar₁Selected from the group consisting of: furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, imidazole, pyrazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine,Andin another specific embodiment, Ar₁Is pyridine, pyrimidine,OrIn another specific embodiment, Ar₁Is a pyrimidine.

In another specific embodiment of specific embodiment 2 (see above), R₂Is an optionally substituted alkyl group. In another embodiment, the alkyl is lower alkyl. In another embodiment, the lower alkyl is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and sec-butyl. And in another specific embodiment, R₂Is ethyl.

In another embodiment of the compounds having the structure of formula (I), R₃Is hydrogen, halogen or optionally substituted alkyl. In one embodiment R₃Is halogen. In an alternative embodiment, R₃Is an optionally substituted alkyl group, and is an optionally substituted lower alkyl group. In another embodiment, the optionally substituted amino acid isLower alkyl of the generation is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and sec-butyl. And in another specific embodiment, R₃Is methyl.

In an alternative group of embodiments of the compounds having the structure of formula (I), (a) Ar₂The substituent B and the substituent propoxy are mutually ortho-positioned; (b) ar (Ar)₂The substituent B and the substituent propoxy are meta-position; and (c) Ar₂The substituent B and the substituent propoxy are para to each other.

In another specific embodiment of the compounds having the structure of formula (I), B is an aromatic heterocycle selected from the group consisting of: furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, imidazole, pyrazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine,Andin another embodiment, B is tetrazole.

In another embodiment of the compounds having the structure of formula (I), B is- (CH)₂)_j-C(O)OR₄. In another embodiment, R₄Is hydrogen or optionally substituted alkyl. In a specific embodiment of this option, R₄Is hydrogen. In an alternative embodiment, R₄Is an alkyl group. In another embodiment of the latter embodiment, the alkyl is lower alkyl. In another embodiment, the lower alkyl is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and sec-butyl.

In another specific embodiment of specific embodiment 2 (see above), Ar₁Selected from the group consisting of: furan, furan,Thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiadoline, pyridazine, pyrimidine, pyrazine, piperazine, triazine, imidazole, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiadoline, pyridazine, pyrimidine, pyrazine, piperazine,Andin another specific embodiment, Ar₁Is pyridine, pyrimidine,OrIn another specific embodiment, Ar₁Is a pyrimidine.

In another specific embodiment of specific embodiment 2 (see above), B is a heteroaromatic ring selected from the group consisting of: furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thianaphthene, pyridazine, pyrimidine, pyrazine, piperazine, triazine, morpholine, pyrazine,andin another embodiment, B is tetrazole.

In another specific embodiment of specific embodiment 2, B is- (CH)₂)_i-C(O)OR₄. In another embodiment, R₄Is hydrogen or optionally substituted alkyl. In an alternative embodiment, R₄Is hydrogen. In an alternative embodiment to this embodiment, R₄Is an optionally substituted alkyl group. In another embodiment of the latter alternative, the alkyl group is a lower alkaneAnd (4) a base. In another embodiment, the lower alkyl is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and sec-butyl.

In another specific embodiment of the compounds having the structure of formula (I), the compound is selected from the group consisting of:

and

or a pharmaceutically acceptable N-oxide, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, pharmaceutically acceptable amide, or pharmaceutically acceptable solvate thereof.

In another specific embodiment of the compounds having the structure of formula (I), the compound is selected from the group consisting of:

andor a pharmaceutically acceptable N-oxide, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, pharmaceutically acceptable amide, or pharmaceutically acceptable salt thereofA solvate.

A compound having the structure of formula (III):

another aspect presented herein is a method of modulating the function of a Peroxisome Proliferator Activated Receptor (PPAR) comprising contacting the PPAR with a compound having the structure of formula (I) and monitoring a change in cell phenotype, cell proliferation, PPAR activity, or PPAR binding to a natural binding partner. In another specific embodiment of this aspect, the PPAR is selected from the group consisting of: PPAR α, PPAR δ and PPAR γ.

Another aspect described herein is a method of inhibiting adipogenesis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound having the structure of formula (I).

In a specific embodiment of this aspect, a therapeutically effective amount of an effective amount of Ar wherein₂A compound having the structure of formula (I) which is phenyl. In another embodiment of this aspect, a therapeutically effective amount of an effective amount of Ar wherein₂A compound having the structure of formula (I) which is naphthyl. In another embodiment of this aspect, a therapeutically effective amount of a compound having the structure of formula (II) is administered to the mammal.

Another aspect described herein is a method of inhibiting adipogenesis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound having the structure of formula (III).

Another aspect presented herein is a method of treating a disease comprising identifying a patient in need of treatment and administering to the patient a therapeutically effective amount of a compound having the structure of formula (I). In another embodiment, the disease is a PPAR-modulated disease. In another or alternative embodiment, the disease is a metabolic diseaseA disease or disorder. In another or alternative embodiment, the disease is selected from the group consisting of: obesity, diabetes, hyperinsulinemia, metabolic syndrome X, polycystic ovary syndrome, menopause, diseases associated with oxidative stress, inflammatory responses to tissue injury, emphysema pathogenesis, organ damage associated with ischemia, cardiac damage caused by doxorubicin, drug-induced hepatotoxicity, atherosclerosis, and highly toxic lung injury (hyperoxic lung injury). In one such case, a therapeutically effective amount of Ar therein is administered to the mammal₂A compound having the structure of formula (I) which is phenyl. In another case, a therapeutically effective amount of Ar therein is administered to the mammal₂A compound having the structure of formula (I) which is naphthyl. In another case, a therapeutically effective amount of a compound having the structure of formula (II) is administered to the mammal.

Another aspect described herein is a method of treating a PPAR-modulated disease, comprising identifying a patient in need of treatment and administering to the patient a therapeutically effective amount of a compound having the structure of formula (III).

Another aspect presented herein is a pharmaceutical composition comprising a compound having the structure of formula (I) and a pharmaceutically acceptable diluent, excipient, or carrier. In a specific embodiment of this aspect, Ar₂Is an aryl group. In another specific embodiment of this aspect, Ar₂Is naphthyl. In another specific embodiment of this aspect, the compound has the structure of formula (II). Another aspect presented herein is a pharmaceutical composition comprising a compound having the structure of formula (III) and a pharmaceutically acceptable diluent, excipient, or carrier.

Detailed Description

The invention discloses a process for preparing a compound represented by the formula (I) through-O- (CH)₂）₃-NR₁A substituted carbocyclic aryl fragment with the radical linked to an optionally substituted heterocyclic fragment, which canModulate at least one Peroxisome Proliferator Activated Receptor (PPAR) function and may additionally confer selective activation of hPPAR-gamma. In one embodiment the carbocyclic aryl moiety is naphthyl, and in another embodiment is phenyl. In a particular embodiment, when the carbocyclic aryl group is phenyl, -CH₂C(O)OR₄Substituent and-O- (CH)₂)₃-NR₁-the linking groups are meta to each other on the phenyl ring.

The compounds described herein are capable of activating both PPAR-delta and PPAR-gamma or both PPAR-alpha and PPAR-delta, or all three PPAR subtypes, or alternatively predominantly hPPAR-gamma, hPPAR-alpha or hPPAR-delta.

The present invention relates to a method of modulating the function of at least one peroxide-enhanced activated receptor (PPAR) comprising the step of contacting the PPAR with a compound of formula I as described herein. Changes in cell phenotype, cell proliferation, PPAR activity, PPAR expression, or PPAR binding to a natural binding partner can be monitored. Such methods may be in the form of disease treatment, biological assays, cellular assays, biochemical assays, and the like.

The present invention describes a method of treating a disease comprising identifying a patient in need of treatment and administering to the patient a therapeutically effective amount of a compound of formula I as described herein. Thus, in certain embodiments, the disease to be treated by the methods of the invention is selected from the group consisting of: obesity, diabetes, hyperinsulinemia, metabolic syndrome X, polycystic ovary syndrome, menopause, diseases associated with oxidative stress, inflammatory response to tissue injury, emphysema pathogenesis, organ damage associated with ischemia, doxorubicin-induced cardiac injury, drug-induced hepatotoxicity, atherosclerosis, and virulent lung injury.

I. Chemical terminology

"acetyl" means-C (═ O) CH₃A group.

The term "acyl" includes alkyl, aryl, or heteroaryl substituents attached to a compound through a carbonyl functionality (e.g., -c (o) -alkyl, -c (o) -aryl, and the like).

"alkoxy" refers to a RO-group, wherein R is as defined herein.

"Alkoxyalkyloxy" refers to a ROR' O-group, where R is defined herein.

"alkoxyalkyl" refers to the group R 'OR-, wherein R and R' are defined herein.

As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group. The alkyl fragment may be a "saturated alkyl", meaning that it does not include any alkene or alkyne fragments. The alkyl fragment may also be an "unsaturated alkyl", which means that it comprises at least one alkene or alkyne fragment. An "alkene" segment refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, while an "alkyne" segment refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight-chain, or cyclic.

An "alkyl" moiety may have from 1 to 40 carbon atoms (whenever appearing herein, a numerical range such as "1 to 40" refers to each integer in the range; for example, "1 to 40 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 40 carbon atoms, although the present definition also encompasses the term "alkyl" as it appears without a specified numerical range). The alkyl group may be a "medium alkyl group" containing 1 to 20 carbon atoms. The alkyl group may also be a "lower alkyl" group containing 1 to 5 carbon atoms. The alkyl group of the compounds of the present invention may be designated as "C₁-C₄Alkyl "or similar designations. By way of example only, "C₁-C₄Alkyl "means one to four carbon atoms in the alkyl chain, i.e. the alkyl chain is selected from the group consisting of: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, substituted or unsubstituted,Isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Alkyl groups may be optionally substituted.

The term "alkylamino" refers to the group-NRR ', where R and R' are defined herein. R and R' together may optionally form a ring system.

The term "alkylene" refers to alkyl groups substituted at both ends (i.e., diradicals). Thus methylene (-CH)₂-) ethylene (-CH₂CH₂-) and propylene (-CH)₂CH₂CH₂-) is an example of an alkylene group. Similarly, "alkenylene" and "alkynylene" refer to bi-basic alkene and alkyne fragments, respectively. The alkylene group may be optionally substituted.

"amide" is a chemical fragment having the general formula-C (O) NHR or-NHC (O) R, wherein R is optionally substituted and is selected from the group consisting of: alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon). An amide may be an amino acid or peptide molecule attached to a molecule of the invention, thereby forming a prodrug. Any amine, hydroxyl, or carboxyl side chain on the compounds of the present invention may be amidated. Methods and specific Groups for preparing the amides are well known to those skilled in the art and can be readily found in the references, such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed.，John Wiley &Sons, new york, NY, 1999, which is incorporated herein by reference in its entirety.

"C-acylamino" means-C (═ O) -NR₂Wherein R is as defined herein.

"N-acylamino" refers to an RC (═ O) NH-group, where R is defined herein.

The term "aromatic" or "aryl" refers to an aromatic group having at least one conjugated pi-electron containing system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aromatic (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share an adjacent pair of carbon atoms) groups. The term "carbocycle" refers to a compound that contains one or more covalently closed ring structures and the atoms that form the ring backbone are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom other than carbon. The aromatic group or aryl group may be optionally substituted.

"O-carbamoyl" refers to the group-OC (═ O) -NR, where R is as defined herein.

"N-carbamoyl" refers to a ROC (═ O) NH-group, where R is defined herein.

"O-carboxy" refers to an RC (═ O) O-group, where R is defined herein.

"C-carboxy" refers to the group — C (═ O) OR, where R is defined herein.

"cyano" refers to the group-CN.

The term "cycloalkyl" refers to a monocyclic or polycyclic group that contains only carbon and hydrogen, and may be saturated, partially unsaturated, or fully unsaturated. Cycloalkyl groups may be optionally substituted. Preferred cycloalkyl groups include groups having three to twelve ring atoms, more preferably 5 to 10 ring atoms. Illustrative examples of cycloalkyl groups include the following fragments:

and the like.

The term "ester" refers to a chemical moiety having the general formula-COOR, wherein R may be optionally substituted and is selected from the group consisting of: alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon). Any amine, hydroxyl, or carboxyl side chain on the compounds of the present invention may be esterified. For preparing the esterMethods and specific groups of (A) are well known to those skilled in the art and can be readily found in the references, e.g., Greene and Wuts, Protective group in Organic Synthesis, 3^rd Ed.，John Wiley &Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine. Preferred halo groups are fluoro, chloro and bromo.

The terms "haloalkyl", "haloalkenyl", "haloalkynyl", "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures substituted with one or more halo groups or combinations thereof. The terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy, respectively, where the halogen is fluorine.

The terms "heteroalkyl," "heteroalkenyl," "heteroalkynyl" include alkyl, alkenyl, and alkynyl groups that are optionally substituted and that have one or more backbone chain atoms selected from non-carbon atoms, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof.

The term "heteroaryl" or "heteroaryl" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl groups may be optionally substituted. An "heteroaryl" or "heteroaryl" moiety containing N refers to an aromatic group in which at least one ring backbone atom is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. Illustrative examples of aryl groups include the following fragments:

and the like.

The term "heterocycle" refers to heteroaromatic and heteroalicyclic groups containing 1 to 4 heteroatoms each selected from O, S and N, wherein the ring system of each heterocyclic group possesses 4 to 10 atoms, provided that the ring of the group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups whose ring system contains only 4 atoms, whereas an aromatic heterocyclic group must have at least 5 atoms in the ring system. The heterocyclic group includes benzo-fused ring systems. An example of a 4-membered heterocyclyl group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl. One example of a 6-membered heterocyclic group is pyridyl, and one example of a 10-membered heterocyclic group is quinolyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thienylalkyl, piperazinyl, azetidinyl, oxetanyl, thienylidene, homopiperidinyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, triazepinyl, 1, 2, 3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, thioxanyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolidinyl, thiomorpholinyl, piperidino, piperazinyl, oxazinyl, piperazinyl, oxapinyl, piperazinyl, and the like, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indolyl, and quinolizinyl. Examples of the aromatic heterocyclic group are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl (furazanyl), benzofurazanyl (benzofurazanyl), benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furylpyridinyl. The aforementioned groups derived as above listed groups may be C-linked or N-linked at possible positions. For example, the group derived from pyrrole may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, the groups derived from imidazole may be imidazol-1-yl or imidazol-3-yl (all N-linkages) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-linkages). Such heterocyclic groups include benzo-fused ring systems as well as ring systems substituted with one or two oxy (═ O) moieties such as pyrrolidin-2-one. The heterocyclic group may be optionally substituted.

"heteroalicyclic" group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. The group may be fused to an aryl or heteroaryl group. Examples of heteroalicyclic groups include:

and the like.

The term "membered ring" may include any cyclic structure. The term "member" is intended to mean the number of backbone atoms making up the ring. Thus, for example: cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings, and cyclopentyl, pyrrole, furan and thiophene are 5-membered rings.

The "isocyanato" group refers to the-NCO group.

An "isothiocyanate" group refers to an-NCS group.

"mercaptoalkyl" refers to the R 'SR-group, where R and R' are defined herein.

"Mercaptometrcaptyl" refers to the RSR' S-group, where R is defined herein.

"mercapto" refers to an RS-group, wherein R is defined herein.

The terms "nucleophile" and "electrophile" are used herein in their ordinary sense as is well known in synthetic and/or physico-organic chemistry. Carbon electrophiles typically contain one or more carbon atoms that are substituted with any moiety having a greater Bolin charge than the carbon atom itselfAlkyl, alkenyl, alkynyl or aromatic (sp) substituted by a negative atom or group³、sp²Or sp hybridized) carbon atoms. Examples of carbon electrophiles include, but are not limited to, carbonyl (aldehydes, ketones, esters, amides), oximes, hydrazones, epoxides, aziridines, alkyl, alkenyl, and aromatic halides, acyl, sulfonate esters (aryl, alkyl, etc.). Other examples of carbon electrophiles include unsaturated carbon atoms electron-conjugated to electron-withdrawing groups, examples being carbon atoms of 6-carbon or fluorine substituted aryl groups of alpha-unsaturated ketones. General methods for producing carbon electrophiles, in particular for producing precisely controlled products, are well known to the person skilled in the art of organic synthesis

The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced with halogen atoms.

The substituents R or R' which are themselves present alone and do not contain a numerical designation, refer to optionally substituted substituents selected from the group consisting of: alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon).

"sulfinyl" group refers to the group-S (═ O) -R, where R is defined herein.

"N-sulfonamido" radical means RS (═ O)₂NH-group, wherein R is as defined herein.

An "S-sulfonamido" group is-S (═ O)₂NR groups, wherein R is as defined herein.

The "N-thiocarbamoyl" group refers to the ROC (═ S) NH-group, where R is defined herein.

An "O-thiocarbamoyl" group refers to the group-OC (═ S) -NR, where R is defined herein.

"thiocyanate" group means a-CNS group.

"Trihalomethylsulfinamido" radical means X₃CS(＝O)₂NR-group, wherein X and R are as defined herein.

Trihalomethylsulfonyl "Radical is X₃CS(＝O)₂-radicals, in which X is halogen.

Unless otherwise indicated, when a substituent is considered to be "optionally substituted", this means that the substituent is a group that may be substituted with one or more groups each and independently selected from the following group: alkyl, perfluoroalkyl, perfluoroalkoxy, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino including mono-and disubstituted amino groups, and protected derivatives thereof. Protecting groups capable of forming protected derivatives of the above substituents are well known to those skilled in the art and may be found in references such as Greene and Wuts, supra.

Particular embodiments of the molecules of the present invention may have one or more chiral centers and each chiral center may exist in either the R or S configuration. The present invention includes all diastereomers, enantiomers, epimers, and suitable mixtures thereof. If desired, the stereoisomers may be obtained by methods well known in the art, for example by separation of the stereoisomers by chiral chromatography columns. Furthermore, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, iso, trans, entgegen (e) and zusammen (z) isomers and suitable mixtures thereof.

In certain instances, tautomers may be present for compounds of the invention. All tautomers are encompassed by formula I and provided by the present invention.

In addition, the compounds of the present invention may exist in unsolvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention.

Methods of modulating protein function

In another aspect, the invention relates to a method of modulating at least one peroxide-enhanced biologically activated receptor (PPAR) function comprising the step of contacting a PPAR with a compound of formula I as described herein. Changes in cell phenotype, cell proliferation, PPAR activity, or PPAR binding to a natural binding partner can be monitored. This method can be used as a model for disease treatment, biological tests, cell tests, biochemical tests, and the like. In certain embodiments, the PPAR may be selected from the group consisting of: PPAR α, PPAR δ, and PPAR γ.

The term "activation" refers to increasing the cellular function of a PPAR. The term "inhibit" refers to a decrease in cellular function of a PPAR. PPAR function may interact with natural binding partners or catalytic activities.

The term "cellular phenotype" refers to the appearance of a cell or tissue or the function of a cell or tissue. Examples of cell or tissue phenotypes are cell size (shrinking or enlarging), cell proliferation (increasing or decreasing cell number), cell differentiation (changing or not changing cell shape), cell survival, apoptosis (cell death), or utilization of metabolic nutrients (e.g. glucose uptake). Alterations or invariance of the cell phenotype are readily determined by techniques well known in the art.

The term "cell proliferation" refers to the rate at which a group of cells divide. The number of cells grown in the vessel can be quantified by one skilled in the art by visually counting the number of cells in a defined area using a common light microscope. Or quantifying the rate of cell proliferation by optically measuring the density of cells in an appropriate medium using a laboratory instrument.

The term "contacting" as used herein means that a compound of the invention is contacted with a PPAR of interest in a manner such that the compound is capable of interacting directly, i.e., by interacting with the PPAR itself, or indirectly, i.e., by interacting with another PPARThe ways in which PPAR activity is dependent on molecular interactions to influence PPAR activity are put together. Such "contacting" can be accomplished in a test tube, a petri dish, a test organism (e.g., a murine, hamster, or primate), and the like. In vitro, the contact involves only the compound and the PPAR of interest or all cells. The cells can also be maintained or grown in a cell culture dish and contacted with the compound in the environment. In the context of the present invention, the ability of a particular compound to affect a PPAR related disease, i.e., the IC of the compound₅₀This can be determined in vivo and prior to attempting to use the compound in more complex living organisms. For cells in vitro, various methods exist and are well known to those skilled in the art for achieving contact of the PPAR with the compound, including but not limited to direct cell microinjection and many transmembrane carrier techniques.

The term "modulate" refers to the ability of a compound of the invention to alter PPAR function. Modulators may activate the activity of a PPAR, may activate or inhibit the activity of a PPAR depending on the concentration of the compound exposed to the PPAR, or may inhibit the activity of a PPAR. The term "modulate" also refers to altering the function of a PPAR by increasing or decreasing the likelihood of complex formation between the PPAR and a natural binding partner. Modulators may increase the likelihood of complex formation between the PPAR and the natural binding partner, or may increase or decrease the likelihood of complex formation between the PPAR and the natural binding partner, or may decrease the likelihood of complex formation between the PPAR and the natural binding partner, depending on the concentration of the compound exposed to the PPAR.

The term "monitoring" relates to observing the effect of the method on the addition of a compound of the invention to a cell. The effect may be manifested as a change in cell phenotype, cell proliferation, PPAR activity, or the interaction between a PPAR and a natural binding partner. Of course, the term "monitoring" includes detecting whether a change actually occurs or does not occur.

A. Exemplary test

The following test methods are provided by way of example only. Compounds can be tested for their ability to bind hPPAR-gamma, hPPAR-alpha, or PPAR-delta by Scintillation Proximity Assay technology (SPA). The PPAR ligand binding domain (LBO) can be expressed and purified in e.coli (e.coli) as a poly histidine peptide (polyHis) tagged fusion protein. LBO was then labeled with biotin and immobilized on streptavidin-modified scintillation proximity beads (beads). The beads were then incubated with constant amounts of the appropriate radioligand eH-BRL 49653 for PPAR, 2- (4(2- (2, 3-ditrito-1-heptyl-3- (2, 4-difluorophenyl) ureido) ethyl) phenoxy) -2 methylbutyric acid for hPPAR- α (described in WO 1008002), and GW 2433 for PPAR- δ (see Brown, P.J et al, chem. biol.1997, 4, 909-918 for synthesis for the structure and synthesis of the ligand) and various concentrations of the test compound, and radioactivity bound to the beads was determined by scintillation counting after equilibration. The amount of non-specific binding determined by the control well containing 50M of the corresponding unlabeled ligand was subtracted from each data point. CPM plots of ligand concentration versus radioligand binding were established for each test compound and apparent K values were estimated from a non-linear least squares fit of the data assuming simple competitive binding. Details of this Assay have been reported elsewhere (see Blancard, S.G et al, "Development of science research for Peroxisome promoter-activated receptor gamma Ligand Binding Domain" anal. biochem.1998, 257, 112-119).

B. Transfection assay

The transfection assay methods described below are provided for example only. The functional potency of the compounds can be screened in CV-1 cells for their ability to activate PPAR subtypes in a transient transfection assay (a trans-activation assay). The previously identified chimeric receptor systems were used to compare the relative transcriptional activity of each receptor subtype on the same target gene and to prevent endogenous receptor activation from complicating interpretation of the results. See, e.g., Lehmann, j.m.; moore, l.b.; Smith-Oliver, T.A; wilkinson, w.o.; willson, t.m.; kliewer, S.A., Antiadiabatically ligand is a high affinity ligand for peroxisome-activated receptor (PPAR), J.biol.chem., 1995, 270, 12953-6. The ligand binding domains of murine and human PPAR- α, PPAR- γ, and PPAR- δ were each fused to the yeast transcription factor GAL4DNA binding domain. CV-1 cells were transiently transfected with the expression vector of each PPAR chimera and a receptor construct (construct) containing five copies of GAL4DNA binding site driven expression of secreted placental alkaline phosphatase (spa) and p-galactosidase. After 16 hours, the medium was changed to DME medium supplemented with 10% defatted fetal bovine serum and the appropriate concentration of test compound. After a further 24 hours, cell extracts were prepared and assayed for activity on alkaline phosphatase and p-galactosidase. Transfection efficiency with p-galactosidase activity as an internal standard to correct for alkaline phosphatase activity (see, e.g., Kliewer, S.A., et al. Cell 1995, 83, 813-819.) rosiglitazone was used as a positive control in the hPPAR assay. The positive control in the hPPAR-alpha and hPPAR-delta assays is 2- [4- (2- (3- (4-fluorophenyl) -1-heptylureido) ethyl) -phenoxy ] -2-methylpropionic acid, which can be prepared according to the method described in Brown, PeterJ, et al, Synthesis (7), 778-782(1997), or patent publication WO 9736579.

Target disease to be treated

In another aspect, the invention relates to a method of treating a disease comprising identifying a patient in need of treatment and administering to the patient a therapeutically effective amount of a compound of formula I as described herein.

The biological processes modulated by PPARs are processes modulated by receptors, or combinations of receptors, that respond to the PPAR receptor ligands described herein. These processes include, for example, plasma lipid transport and regulation of fatty acid catabolism, insulin sensitivity and blood glucose levels, which are involved in hypoglycemia/hyperinsulinemia (e.g., caused by pancreatic beta cell dysfunction due to insulin autoantibodies, insulin receptors or autoantibodies that stimulate pancreatic beta cells, insulin secreting tumors and/or autoimmune hypoglycemia), macrophage differentiation leading to the formation of atherosclerotic plaques, inflammatory responses, carcinogenesis, hyperplasia, and adipocyte differentiation.

Non-insulin dependent diabetes mellitus (NIDDM), or type 2 diabetes, is the more common form of diabetes, with 90-95% of patients with hyperglycemia suffering from this form of disease. Resistance to insulin metabolism is one of the key features of non-insulin dependent diabetes mellitus (NIDDM). Insulin resistance is characterized by decreased glucose uptake and utilization by insulin-sensitive target organs, such as adipocytes and skeletal muscle, and impaired inhibition of hepatic glucose output. Functional insulin deficiency and the inability of insulin to inhibit hepatic glucose output lead to fasting hyperglycemia. Pancreatic beta cells compensate for this insulin resistance by secreting higher levels of insulin. However, beta cells are unable to maintain high levels of insulin output and, ultimately, glucose-induced insulin secretion is reduced, leading to deterioration of glucose homeostasis and subsequent development of overt diabetes.

Strong evidence has shown that PPAR γ is a valuable molecular target for the development of drugs for the treatment of insulin resistance (see Willson et al, j.med.chem.43: 527-550 (2000)). In fact, the PPAR γ agonists rosiglitazone (Avandia) and pioglitazone (Actos) are insulin sensitizers and are currently marketed drugs for the treatment of type 2 diabetes.

Obesity is an excessive accumulation of adipose tissue. Recent studies in this field have shown that PPAR γ plays a crucial role in adipocyte gene expression and differentiation. Adipose tissue excess is associated with the development of serious diseases such as non-insulin dependent diabetes mellitus (NIDDM), hypertension, coronary artery disease, hyperlipidemia obesity, and certain malignancies. Adipocytes can also affect the glucose homeostasis by producing tumor necrosis factor alpha (TNF α) and other molecules. PPAR γ activators, particularly troglitazone, have been found to convert cancerous tissue in one of the liposarcomas of adipose tumors to normal cells (PNAS 96: 3951-. Therefore, PPAR γ activators can be effectively used for the treatment of obesity as well as breast cancer and colon cancer.

In addition, PPAR γ activators, such as troglitazone, have been used to treat polycystic ovary syndrome (PCO). This is a syndrome characterized by chronic anovulation and hyperandrogenism in women. Women with this syndrome often have insulin resistance and an increased risk of non-insulin dependent diabetes mellitus. (Dunaif, Scott, Finegood, Quintana, Whitcomb, J.Clin.Endocrinol.Metab., 81: 3299, 1996)

Furthermore, it has recently been found that PPAR γ activators increase progesterone production and inhibit steroid production in granulosa cell cultures, and are therefore useful in the treatment of menopause. (USP 5,814,647 Urban et al, September 29, 1998; B.Lohrke et al, Journal of Edocrinology, 159, 429-39, 1998). Menopause is defined as a syndrome of endocrine, physical and psychological changes that occur at the end of the female reproductive phase.

PPAR α is activated by a variety of medium and long chain fatty acids and is involved in stimulating fatty acid β -oxidation in tissues such as liver, heart, skeletal muscle, and brown adipose tissue (Isseman and Green, supra; Beck et al, Proc. R. Soc. Lond.247: 83-87, 1992; Gotticher et al, Proc. Natl. Acad. Sci.USA 89: 4653-. Pharmacological PPAR α activators, such as fenofibrate, clofibrate, gemfibrozil (gemfibrozil), and bezafibrate, are also involved in a significant drop in plasma triglycerides and a modest reduction in LDL cholesterol, and they are particularly useful in the treatment of hypertriglyceridemia, hyperlipidemia, and obesity. PPAR α is also known to be associated with inflammatory diseases (Schoonjans, k., Current Opinion in lipiodology, 8, 159-66, 1997).

PPAR α agonists are also useful for raising HDL levels and thus for treating atherosclerotic diseases (Leibowitz et al; WO/9728149). Atherosclerotic diseases include vascular disease, coronary heart disease, cerebrovascular disease and peripheral vascular disease. Coronary heart disease includes CHD death, myocardial infarction, and coronary artery remodeling. Cerebrovascular disorders include ischemic and hemorrhagic stroke and transient ischemic attacks.

The third subtype of PPAR, PPAR δ (PPAR β, NUC1), is widely expressed in vivo and has been demonstrated to be a valuable molecular target for the treatment of dyslipidemia and other diseases. For example, it has recently been found in studies on insulin resistant obese rhesus monkeys that a potent and selective PPAR δ compound can lower VLDL and increase HDL in a dose-responsive manner (Oliver et al, Proc. Natl. Acad. Sci. U.S.A.98: 5305, 2001).

The compounds described herein activate both PPAR α and PPAR γ, or both PPAR δ and PPAR γ, or all three PPAR subtypes, and are therefore useful in the treatment of dyslipidaemia associated with atherosclerosis, non-insulin dependent diabetes mellitus, metabolic syndrome X (stals, b. et al, curr. pharm. des., 3(1), 1-14(1997)), and Familial Complex Hyperlipidaemia (FCH). Metabolic syndrome X is a syndrome characterized by an initial insulin resistant state, which produces hyperinsulinemia, dyslipidemia, and decreased glucose tolerance, which can progress to non-insulin dependent diabetes mellitus (type 2 diabetes) characterized by hyperglycemia. FCH is characterized by hypercholesterolemia and hypertriglyceridemia in the same patient and family.

Thus, in certain embodiments, the disease treated by the methods of the invention is selected from the group consisting of: obesity, diabetes, hyperinsulinemia, metabolic syndrome X, polycystic ovary syndrome, menopause, diseases related to oxidative stress, inflammatory response to tissue injury, emphysema pathogenesis, organ injury related to ischemia, heart disease caused by doxorubicin, hepatotoxicity caused by drugs, atherosclerosis, and virulent lung injury.

Pharmaceutical compositions

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula I as described herein, in combination with a pharmaceutically acceptable diluent, excipient, or carrier.

The term "pharmaceutical composition" refers to a mixture of a compound of the present invention with other chemical ingredients, such as carriers, diluents, or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. There are a variety of techniques for administering compounds in the art, including but not limited to: intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration. Pharmaceutical compositions can also be obtained by reacting the compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

The term "carrier" refers to a compound or chemical agent that is relatively non-toxic. The carrier may facilitate the binding of the compound into a cell or tissue. For example, Human Serum Albumin (HSA) is a commonly used carrier because it facilitates the uptake of many organic compounds into cells or tissues of an organism.

The term "diluent" refers to a compound used to dilute a desired compound prior to administration. Diluents can be used to stabilize the compound by providing a more stable environment. Salts dissolved in buffer solutions (providing pH control) are used in the art as diluents. One commonly used buffer solution is phosphate buffer salt. This is a naturally occurring buffer salt in the blood system. Since buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely alter the biological activity of a compound.

The term "physiologically acceptable" refers to a carrier or diluent that does not abrogate the biological activity or properties of the compound and is non-toxic.

The term "pharmaceutically acceptable salt" refers to a compound that does not significantly stimulate the organism to which it is administered and does not abrogate the biological activity or properties of the compound. Pharmaceutically acceptable salts can be obtained by reacting a compound of the present invention with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutically acceptable salts may also be obtained by reacting a compound of the invention with a base to form a salt, such as an ammonium salt, an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, a salt with an organic base, such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods well known in the art.

"prodrug" refers to a substance that is converted in vivo to the parent drug. Prodrugs are often more useful because they are easier to administer than the parent drug in some cases. They can be bioavailable, for example, by oral administration, whereas their parents cannot. The prodrug has superior solubility in pharmaceutical compositions than its parent drug. A non-limiting example of a prodrug is a compound of the invention administered as an ester ("prodrug") which facilitates transport across the cell membrane where water solubility is detrimental to its mobility, but then, once inside the cell where water solubility is favorable, the ester is hydrolyzed metabolically to the active entity, the carboxylic acid. Another example of a prodrug is a short peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to reveal the active fragment.

The compounds described herein may be administered to human patients by themselves or in pharmaceutical compositions in admixture with other active ingredients or with suitable carriers or excipients, such as in combination therapy. Techniques for formulating and administering the compounds of the present application can be found in "Remington's Pharmaceutical Sciences," 20th ed, written by Alfonso Gennaro in 2000.

A. Route of administration

Suitable routes of administration may include, for example, oral, rectal, transmucosal, pulmonary, ocular or enteral administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intraspinal injection, and intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection.

Alternatively, the compound may be administered locally rather than systemically, e.g., the compound is injected directly into the organ, usually in the form of a depot or sustained release formulation. Furthermore, the drug may be administered in a targeted drug delivery system, for example in the form of liposomes coated with organ-specific antibodies. The liposomes will be targeted to the organ and selectively absorbed.

B. Component/formulation

The pharmaceutical compositions of the invention may be prepared in a manner known per se, e.g. by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping (enterwrapping) or compressing processes.

The pharmaceutical compositions used according to the invention may thus be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The appropriate prescription will depend on the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be suitably employed and are understood in the art, as described in Remington's Pharmaceutical Sciences, supra.

For intravenous injection, the medicaments of the invention may be formulated as aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the prescription. Such penetrants are well known in the art. For other parenteral injections, the medicaments of the invention may be formulated as aqueous or non-aqueous solutions with buffers or excipients which are preferably physiologically compatible. Such excipients are well known in the art.

For oral administration, the compounds can be readily formulated by mixing the active compounds with pharmaceutically acceptable carriers or excipients well known in the art. The carrier enables the compounds of the present invention to be formulated as tablets, powders, pills, lozenges (dragee), capsules, liquids, gels, syrups, elixirs, slurries (syrup), suspensions, and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by: mixing one or more solid excipients with one or more compounds of the invention, optionally grinding the resulting mixture, and granulating the mixture, if desired after addition of suitable auxiliaries, to give tablets or dragee cores. Suitable excipients are, in particular, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, microcrystalline cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; or other excipients such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

The cores may be suitably coated. For this purpose, condensed sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions (lacquer solutions), and suitable organic solvents or solvent mixtures. Dyes or pigments may also be added to the tablets or dragee coatings for identifying or characterizing different combinations of active compound doses.

Pharmaceutical preparations for oral use include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The plug-in capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All dosages for oral administration should be in dosages suitable for such administration.

For buccal or sublingual administration, the composition may take the form of a tablet, lozenge, or gel formulated in conventional manner.

For administration by inhalation, the compounds for use according to the present invention may conveniently be administered in the form of an aerosol spray from a pressurised canister or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for releasing a metered value. Gelatin capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, such as bolus injection or continuous infusion. Injectable formulations can be in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical dosage forms for parenteral administration comprise an aqueous solution of the active compound in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injectable suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, artificial fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension may also optionally contain suitable stabilizers or agents that increase the solubility of the compounds to produce a highly concentrated solution.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas (retentienema) containing conventional suppository bases such as cocoa butter and other glycerides.

In addition to the dosage forms previously described, the compounds may be formulated as a depot preparation. Such long acting dosage forms may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil), or with ion exchange resins, or as sparingly soluble derivatives such as a sparingly soluble salt.

The pharmaceutical carrier for the hydrophobic compounds of the present invention is a cosolvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a solution of 10% ethanol, 10% polyethylene glycol 300, 10% polyethylene glycol 40 castor oil (PEG-40 castor oil), and 70% water. The cosolvent system can well dissolve hydrophobic compounds, and has low toxicity when administered systemically. Naturally, the proportion of the co-solvent system can be varied widely without destroying its solubility and toxicity characteristics. Moreover, the composition of the co-solvent may vary: as other low toxicity non-polar surfactants may be used in place of PEG-40 castor oil, the number of polyethylene glycol 300 moieties may vary; other biocompatible polymers may be substituted for polyethylene glycol, such as polyvinylpyrrolidone; and other sugars or polysaccharides may be included in the aqueous solution.

Alternatively, other hydrophobic pharmaceutical compound delivery systems may be employed. Liposomes and emulsions are well known examples of carriers for the administration of hydrophobic drugs. Although usually at the expense of high toxicity, certain organic solvents such as N-methylpyrrolidone may also be employed. In addition, the compounds may be delivered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. A variety of sustained release materials have been identified and are well known to those skilled in the art. Depending on the chemical nature, the extended release capsules can release the compound over several weeks up to more than 100 days. Depending on the chemical nature and biological stability of the therapeutic drug, additional protein stabilization strategies may be applied.

Many of the compounds of the present invention may take the form of salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed from a variety of acids including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in water or other protic solvents than the corresponding free acid or base forms.

Methods of treatment, dosages and combinationsTreatment of

The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits.

As used herein, the term "therapeutically effective amount" refers to an amount of a compound administered that is capable of alleviating one or more symptoms of a disease, disorder, or condition being treated to a certain degree. With reference to the treatment of diabetes or dyslipidemia, a therapeutically effective amount refers to an amount having the following effect: (1) lowering blood glucose levels; (2) normalizing lipids such as triglycerides, low density lipoproteins; and/or (3) alleviating to some extent (or, preferably, eliminating) one or more symptoms associated with the disease, disorder, or condition being treated.

Compositions comprising the compounds described herein may be administered for both prophylactic and therapeutic treatment. In therapeutic applications, the compositions are administered to a subject already suffering from a PPAR-mediated, modulated or associated disease, disorder, or condition, including but not limited to the metabolic diseases, disorders, or conditions described above, in an amount sufficient to cure or at least partially arrest the symptoms of the disease, disorder, or condition. The amount effective for this use will depend on the severity and course of the disease, disorder or condition, previous treatment, the patient's health and response to the drug, and the diagnosis of the treating physician. It is believed that determination of such a therapeutically effective amount by routine experimentation (e.g., dose escalation clinical trials) is well within the ability of those skilled in the art.

In prophylactic applications, compositions containing the compounds of the present invention are administered to a susceptible patient or patient at risk of a particular disease, condition, or condition, including but not limited to the above-mentioned metabolic diseases, conditions, or conditions, mediated by, modulated by, or associated with a PPAR. This amount is defined as a "prophylactically effective amount or dose". In this use, the exact dosage will also depend on the patient's health, weight, etc. It is believed that determination of such a prophylactically effective amount by routine experimentation (e.g., a dose escalation clinical trial) is well within the ability of those skilled in the art.

The term "increase" refers to an enhancement or prolongation of the efficacy or duration of a desired effect. Thus, for increasing the effect of a therapeutic agent, the term "increase" refers to the ability to enhance or prolong the efficacy or duration of the effect of other therapeutic agents on a system. "increasing an effective amount" as used herein refers to an amount sufficient to increase the effect of another therapeutic agent in a desired system. When used in a patient, an effective amount for this use will depend on the severity and course of the disease, disorder or condition (including but not limited to metabolic disease), previous treatments, the patient's health and response to the drug, and the diagnosis of the treating physician. It is believed that determination of such an enhancing effective amount by routine experimentation will be well within the ability of those skilled in the art.

Once the patient's condition has improved, it is administered at a maintenance dose if necessary. Thereafter, as a function of the condition, the dosage or frequency of administration, or both, may be reduced to a level that maintains the improved disease, condition, or disorder. When the symptoms have been alleviated to the desired level, treatment may be discontinued. However, upon any recurrence of symptoms, the patient may need to be treated intermittently on a long-term basis.

The amount of a given drug corresponding to that dose will depend on such factors as the particular compound, the state of the disease and its severity, the characteristics of the patient or subject in need of treatment (e.g., body weight), but can nevertheless be routinely determined in a manner well known in the art based on the particular circumstances surrounding the case, including, for example, the particular drug administered, the route of administration, the disease being treated, and the patient or subject being treated. However, the dose normally applied for adult treatment is typically in the range of 0.02-5000mg per day, preferably 1-1500mg per day. The required dosage can conveniently be presented in the form of a single dose or in divided doses administered at appropriate intervals, for example two, three, four or more times per day.

In some cases, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient receiving one of the compounds of the present invention is hypertension, then it may be appropriate to administer an antihypertensive drug in combination with the initial therapeutic drug. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein can be potentiated by the administration of an adjuvant (i.e., an adjuvant which itself has only a minimal therapeutic effect, but in combination with another therapeutic agent, the beneficial overall effect on the patient is enhanced). Alternatively, by way of example only, the beneficial effect on a patient may be potentiated by administering one of the compounds described herein, together with another therapeutic agent (which also includes a treatment regimen) that is also therapeutically effective. By way of example only, in the treatment of diabetes comprising administration of one of the compounds described herein, an enhanced therapeutic effect may be obtained by also providing the patient with another diabetes treatment drug. In any event, regardless of the disease, condition, or disorder being treated, the overall beneficial effect experienced by the patient may be a simple addition of the two therapeutic agents or a synergistic effect that the patient may experience.

Specific, non-limiting examples of possible combination therapies include compounds of formula (I) and the use of the following drugs: (a) stating and/or other lipid lowering drugs such as MTP inhibitors and LDLR up-regulators; (b) antidiabetic agents, such as metformin, sulfonylureas, or PPAR-gamma, PPAR-alpha, and PPAR-gamma/PPAR-alpha modulators (e.g., thiazolidinediones such as pioglitazone and rosiglitazone); and (c) antihypertensive agents such as angiotensin antagonists such as telmisartan, calcium channel antagonists such as lacidipine, and ACE inhibitors such as enalapril.

In any case, the combination therapeutic agents (one of which is one of the compounds described herein) may be administered in any order or simultaneously. If administered simultaneously, the combination therapy may be provided in a single unified form, or in multiple forms (which may be, for example only, a single pill or two separate pills). One of the therapeutic agents may be administered in a multi-dose form or both may be administered in a multi-dose form. If not administered simultaneously, the timing between doses may vary from above zero weeks to below four weeks.

VI. Synthesis of Compounds of the invention

The compounds of the invention can be synthesized using standard synthetic techniques well known to those skilled in the art or using methods well known in the art in conjunction with the methods described herein. The following synthetic methods are available as guidelines.

A. Formation of covalent bonds by reaction of electrophiles with nucleophiles

Examples of selected covalent bonds and precursor functional groups capable of forming them are listed in the table entitled "examples of covalent bonds and precursors thereof". The precursor functional groups are shown as electrophilic and nucleophilic groups. The functional groups on the organic species can be attached directly, or through any useful spacer or linker as defined below.

TABLE 1

Examples of covalent bonds and precursors thereof

Product of covalent bonds	Electrophiles	Nucleophiles
			Carboxamides	Active esters	Amine/aniline
Carboxamides	Acyl azides	Amine/aniline
			Carboxamides	Acyl halide	Amine/aniline
Esters	Acyl halide	Alcohol/phenol
			Esters	Acyl nitriles	Alcohol/phenol
Carboxamides	Acyl nitriles	Amine/aniline
			Imine(s)	Aldehydes	Amine/aniline
Hydrazone(s)	Aldehydes or ketones	Hydrazine
			Oxime compounds	Aldehydes or ketones	Hydroxylamine compounds
Alkylamine	Alkyl halides	Amine/aniline
			Esters as pesticides	Alkyl halides	Carboxylic acids
Thioethers	Alkyl halides	Thiols
			Ether compounds	Alkyl halides	Alcohol/phenol
Thioethers	Alkyl sulfonic acid ester	Thiols
			Esters	Alkyl sulfonic acid ester	Carboxylic acids
Ether compounds	Alkyl sulfonic acid ester	Alcohol/phenol
			Esters	Anhydrides of	Alcohol/phenol

Carboxamides	Anhydrides of	Amine/aniline
			Thiophenol	Halogenated aryl radicals	Thiols
Aryl amines	Halogenated aryl radicals	Amines as pesticides
			Thioethers	Azindines	Thiols
Borate esters	Borate esters	Diols
			Carboxamides	Carboxylic acids	Amine/aniline
Esters as pesticides	Carboxylic acids	Alcohol(s)
			Hydrazine	Hydrazides	Carboxylic acids
N-acyl ureas or anhydrides	Carbodiimides	Carboxylic acids
			Esters as pesticides	Diazoalkanes	Carboxylic acids
Thioethers	Epoxide compound	Thiols
			Thioethers	Haloacetamide	Thiols
Ammotriazines	Halotriazines	Amine/aniline
			Triazinyl ethers	Halotriazines	Alcohol/phenol
Amidines	Imide esters	Amine/aniline
			Urea	Isocyanates	Amine/aniline
Carbamates, their preparation and their use	Isocyanates	Alcohol/phenol
			Thiourea	Isothiocyanates	Amine/aniline
Thioethers	Maleimide	Thiols
			Phosphite esters	Phosphoramidates	Alcohol(s)
Silyl ethers	Halogenated monosilane	Alcohol(s)
			Alkylamine	Sulfonic acid ester	Amine/aniline
Thioethers	Sulfonic acid ester	Thiols
			Esters as pesticides	Sulfonic acid ester	Carboxylic acids
Ether compounds	Sulfonic acid ester	Alcohol(s)
			Sulfonamides	Sulfonyl halides	Amine/aniline
Sulfonic acid ester	Sulfonyl halides	Phenol/alcohol

Generally, carbon electrophiles are susceptible to attack by a complementary nucleophile, including the carbon nucleophile, wherein the attacking nucleophile provides an electron pair to the carbon electrophile to form a new chemical bond between the nucleophile and the carbon electrophile.

Suitable carbon nucleophiles include, but are not limited to, alkyl, alkenyl, aryl, and alkynyl grignard reagents, organolithium, organozinc, alkyl, alkenyl, aryl, and alkynyl tin reagents (organostannanes), alkyl, alkenyl, aryl, and alkynyl borane reagents (organoboranes and organoborates); these carbon nucleophiles have the advantage of being kinetically stable in water or polar organic solvents. Other carbon nucleophiles include phosphonium ylides, enolic and enolic salt reagents; these carbon nucleophiles have the advantage of being relatively easy to generate from precursors well known to those skilled in the art of synthetic organic chemistry. When used in conjunction with a carbon electrophile, the carbon nucleophile may generate a new carbon-carbon bond between the carbon nucleophile and the carbon electrophile.

Non-carbon nucleophiles are suitable for coupling to carbon electrophiles including, but not limited to, primary and secondary amines, thiols, thiolates, and thioethers, alcohols, alkoxides, azides, semicarbazides. When used in conjunction with a carbon electrophile, these non-carbon nucleophiles typically form a heteroatom bond (C-X-C), where X is a heteroatom, e.g., oxygen or nitrogen.

B. Use of protecting groups

The term "protecting group" refers to a chemical moiety that blocks some or all of the reactive moiety and prevents the moiety from participating in a chemical reaction until the protecting group is removed. Preferably, each protecting group is removed by a different method. The protective groups removed under completely different reaction conditions achieve a differential removal (differential removal). The protecting group can be removed by acid, base and hydrolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and can be used to protect carboxyl and hydroxyl reactive moieties in the presence of a Cbz group which can be removed by hydrolysis and an amino group protected by a base labile Fmoc group. The carboxylic acid and hydroxyl reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl groups in the presence of carbamate blocked amine groups that are stable with acid labile groups such as t-butyl carbamate or both acid and base but removable by hydrolysis.

The carboxylic acid and hydroxyl reactive moieties may also be blocked using hydrolytically removable protecting groups such as benzyl, while the amine groups capable of hydrogen bonding to the acid may be blocked using base labile groups such as Fmoc. The carboxylic acid reaction fragment may be blocked with a protecting group capable of being removed by oxidation, such as 2, 4-dimethoxybenzyl, while the amino group present at the same time may be blocked with a fluoride-labile silyl carbamate.

The allyl blocking group is effective in the presence of acid and base protecting groups, since the former are stable and can subsequently be protected by metals or π -The acid catalyst is removed. For example, allyl-protected carboxylic acids can be protected with Pd in the presence of an acid-labile tert-butyl carbamate or a base-labile amine acetate protecting group_0-Catalytic reaction to remove the protection. Yet another form of protecting group is a resin to which a compound or intermediate can be bound. As long as the residue is bound to the resin, the functional group is blocked from participating in the reaction. Once released from the resin, the functional group can participate in the reaction.

Typical blocking/protecting groups are selected from:

allyl Bn Cbz alloc Me

t-butyl TBDMS Teoc Boc

(C₆H₅)₃C-

pMBn trityl acetyl Fmoc

Other protecting Groups are described in Greene and Wuts, Protective Groups in organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.

C. Synthetic route

The compounds of the present invention can be synthesized using the general synthetic methods and examples set forth below.

Route 1

Example 1A: synthesis of 3- (2, 4-bis-trifluoromethyl-benzylamino) -propan-1-ol (3) (scheme 1).

3-hydroxypropylamine (5.62mL, 73.5mmol, 1.2 equivalents) was dissolved in 250mL of TMOF/MeOH (1: 5) (TMOF ═ trimethyl orthoformate), and 2, 4-bis (trifluoromethyl) benzaldehyde (14.83g, 61.2mmol, 1.0 equivalents) was then added to the solution with stirring at room temperature. The resulting solution was stirred at room temperature for 6 hours and then cooled to 0 ℃. Under vigorous stirring, NaBH is added in portions₄Added to the cooled reaction solution. After TLC showed that the reduction was complete, the reaction mixture was concentrated under reduced pressure. The residue was diluted with 250mL ethyl acetate, washed with water, brine, and then Na₂SO₄And (5) drying. After removal of the solvent, 17.1g (yield 93%) of the expected 3- (2, 4-bis-trifluoromethyl-benzylamino) -propan-1-ol (3) were obtained as a colorless oil.¹H NMR(400MHz，CDCl₃)，(ppm)：7.9(s，1H)，7.75(m，2H)，4.0(s，2H)，3.8(t，2H)，2.85(t，2H)，1.76(m，2H)。

Example 1B: synthesis of 3-butylamino-propan-1-ol (4) (scheme 1).

Compound (4) was synthesized according to the method described for compound (3).¹H NMR(400MHz，CDCl₃)，(ppm)：3.82(t，2H)，2.90(br，2H)，2.88(t，2H)，2.61(t，2H)，1.68(m，2H)，1.45(m，2H)，1.35(m，2H)，0.90(t，3H)。

Route 2

Example 2A: synthesis of 3- [ (2, 4-bis-trifluoromethyl-benzyl) - (5-ethyl-pyrimidin-2-yl) -amino ] -propan-1-ol (5a) (scheme 2).

Intermediate (3) (12.23g, 40.6mmol, 1.0 equiv.), 2-chloro-5-ethylpyrimidine (4.9mL, 40.6mmol, 1.0 equiv.), triethylamine (11.3mL, 81.2mmol, 2.0 equiv.), and 50mL of toluene were charged into a pressure-resistant flask. After the flask was sealed, it was heated to 180 ℃ with stirring. After reacting at the same temperature for 48 hours, the reaction mixture was cooled to room temperature and then diluted with 100mL of ethyl acetate. The resulting solution was washed with water, brine and Na₂SO₄And (5) drying. After removal of the solvent, the residue was purified by chromatography to give 7.7g (yield 46%) of the product (5a) as a light brown solid.¹HNMR(400MHz，CDCl₃)，(ppm)：8.15(s，2H)，7.90(s，1H)，7.67(d，1H)，7.30(d，1H)，5.02(s，2H)，3.71(m，2H)，3.53(m，2H)，2.42(q，2H)，1.75(m，2H)，1.15(t，3H)。

Example 2B: compounds 5b-5i were synthesized according to the procedure described for compound 5 a. (scheme 2).

3- [ butyl- (5-ethyl-pyrimidin-2-yl) -amino]-propan-1-ol (5 b).¹H NMR(400MHz，CDCl₃)，(ppm)：8.10(s，2H)，5.15(s，1H)，3.71(t，3H)，3.45(m，4H)，2.42(q，2H)，1.76(m，2H)，1.55(m，2H)，1.35(m，2H)，1.16(t，3H)，0.97(t，3H)。

3- [ butyl-pyridin-2-yl-amino]-propan-1-ol (5 c).¹H NMR(400MHz，CDCl₃)，(ppm)：8.01(d，1H)，7.40(m，1H)，6.45(m，2H)，5.70(s，1H)，3.71(t，2H)，3.45(t，2H)，3.22(t，2H)，1.76(m，2H)，1.65(m，2H)，1.35(m，2H)，0.97(t，3H)。

3- [ benzothiazol-2-yl-butyl-amino]-propan-1-ol (5 d).¹H NMR(400MHz，CDCl₃)，(ppm)：7.55(d，1H)，7.47(d，1H)，7.26(m，1H)，6.98(t，1H)，5.29(br，1H)，3.82(t，2H)，3.55(m，2H)，3.32(t，2H)，1.80(m，2H)，1.71(m，2H)，1.39(m，2H)，0.97(t，3H)。

3- [ benzoxazol-2-yl-butyl-amino]-propan-1-ol (5 e).¹H NMR(400MHz，CDCl₃)，(ppm)：7.31(d，1H)，7.28(d，1H)，7.13(m，1H)，6.98(t，1H)，5.00(br，1H)，3.72(t，2H)，3.59(m，2H)，3.47(t，2H)，1.82(m，2H)，1.69(m，2H)，1.40(m，2H)，0.99(t，3H)。

3- [ benzothiazol-2-yl- (4-trifluoromethyl-benzyl) -amino]-propan-1-ol (5 f).¹H NMR(400MHz，CDCl₃)，δppm：7.61(d，2H)，7.55(d，2H)，7.42(d，2H)，7.32(t，1H)，7.10(t，1H)，4.69(s，2H)，3.82(t，2H)，3.60(t，2H)，1.79(m，2H)。

3- [ benzothiazol-2-yl- (2, 4-bis-trifluoromethyl-benzyl) -amino]-propan-1-ol (5 g).¹HNMR(400MHz，CDCl₃)，δppm：7.98(s，1H)，7.76(d，1H)，7.56(m，3H)，7.31(t，1H)，7.11(t，1H)，4.89(s，2H)，3.77(t，2H)，3.62(t，2H)，1.84(m，2H)。

3- [ (benzoxazol-2-yl) - (2, 4-bis-trifluoromethyl-benzyl) -amino]-propan-1-ol (5 h).¹HNMR(400MHz，CDCl₃)，(ppm)：7.97(s，1H)，7.78(d，1H)，7.54(d，1H)，7.38(d，1H)，7.24(m，2H)，7.07(m，1H)，5.00(s，2H)，4.37(br，1H)，3.77(m，2H)，3.66(m，2H)，1.85(m，2H)。

3- [ (2, 4-bis-trifluoromethyl-benzyl) - (pyridin-2-yl) -amino]-propan-1-ol (5 i).¹H NMR(400MHz，CDCl₃)，(ppm)：7.97(s，1H)，7.67(d，1H)，7.44(d，1H)，6.91(d，1H)，6.61(t，2H)，6.50(d，1H)，5.04(s，2H)，4.37(br， 1H)，3.73(m，2H)，3.66(m，2H)，1.85(m，2H)。

Route 3

Example 3A: synthesis of (3- {3- [ butyl- (5-ethyl-pyrimidin-2-yl) -amino ] -propoxy } -phenyl) -acetic acid (7b) (scheme 3).

Ethanol (5b) (162mg, 0.69mmol) and triphenylphosphine (218mg, 0.83mmol) were dissolved in 5mL of diethyl ether, followed by the addition of methyl 3-hydroxyphenylacetate (115mg, 0.69 mmol). The resulting solution was cooled to 0 ℃ and then diisopropyl azodicarboxylate (163L, 0.83mmol) was added in three portions with stirring. After stirring at the same temperature for 10min, the reaction mixture was warmed to room temperature and stirred overnight. The resulting precipitate was filtered through a pad of silica gel and the organic solution was concentrated. The residue was purified by chromatography to give 11mg (yield 4%) of the expected ester (6b) which was hydrolyzed with 1N LiOH (60L, 0.06mmol) in 2mL THF/MeOH (3: 1) to give 9.0mg of product (7 b).¹H NMR(400MHz，CDCl₃)，(ppm)：8.16(s，2H)，7.22(m，1H)，6.81(m，3H)，3.99(t，2H)，3.70(t，2H)，3.61(s，2H)，3.54(t，2H)，2.43(q，2H)，2.10(m，2H)，1.59(m，2H)，1.31(m，2H)，1.18(t，3H)，0.89(t，3H)。

Example 3b compounds 7a and 7c-7i were synthesized according to the same method described for compound 7 b. (see scheme 3).

(3- {3- [ (2, 4-bis-trifluoromethyl-benzyl) - (5-ethyl-pyrimidin-2-yl) -amino]-propoxy } -phenyl) - Acetic acid (7 a). ¹H NMR(400MHz，CDCl₃)，(ppm)：8.18(s，2H)，7.90(s，1H)，7.67(d，1H)，7.38(d，1H)，7.21(t，1H)，6.85(t，1H)，6.76(m，2H)，5.11(s，2H)，4.00(t，2H)，3.78(t，2H)，3.60(s，2H)，2.47(q，2H)，2.15(m，2H)，1.21(t，3H)。

{3- [3- (butyl-pyridin-2-yl-amino) -propoxy group]-phenyl } -acetic acid (7 c). ¹H NMR(400MHz，CDCl₃)(ppm)：8.11(m，1H)，7.39(m，1H)，7.22(m，1H)，6.85(m，3H)，6.49(m，2H)，3.98(t，2H)，3.71(t，2H)，3.67(s，2H)，3.42(t，2H)，2.10(m，2H)，1.55(m，2H)，1.31(m，2H)，0.89(t，3H)。

{3- [3- (benzothiazol-2-yl-butyl-amino) -propoxy]-phenyl } -ethylase (7 d). ¹H NMR(400MHz，CDCl₃)，(ppm)：7.51(d，1H)，7.46(d，1H)，7.23(m，2H)，7.00(t，1H)，6.78(m，2H)，4.00(t，2H)，3.73(t，2H)，3.57(s，2H)，3.45(t，2H)，2.16(m，2H)，1.66(m，2H)，1.37(m，2H)，0.89(t，3H)。

{3- [3- (benzoxazol-2-yl-butyl-amino) -propoxy]-phenyl } -acetic acid (7 e). ¹H NMR(400MHz，CDCl₃)，(ppm)：7.36(d，1H)，7.21(m，2H)，7.14(t，1H)，6.98(t，1H)，6.84(m，2H)，4.02(t，2H)，3.72(t，2H)，3.61(s，2H)，3.52(t，2H)，2.17(m，2H)，1.66(m，2H)，1.37(m，2H)，0.90(t，3H)。

(3- {3- [ benzothiazol-2-yl- (4-trifluoromethyl-benzyl) -amino]-propoxy } -phenyl) -acetic acid (7 f). ¹H NMR(400MHz，CDCl₃)，δppm：7.59(d，4H)，7.41(d，2H)，7.31(t，1H)，7.24(t，1H)，7.10(t，1H)，6.89(d，1H)，6.83(s，1H)，6.79(d，1H)，4.88(s，2H)，4.02(t，2H)，3.73(t，2H)，3.63(s，2H)，2.21(m，2H)。

(3- {3- [ benzothiazol-2-yl- (2, 4-bis-trifluoromethyl-benzyl) -amino]-propoxy } -phenyl) -acetic acid (7 g). ¹H NMR(400MHz，CDCl₃)，δppm：7.92(s，1H)，7.72(d，1H)，7.59(m，3H)，7.31(t，1H)，7.24(t，1H)，7.10(t，1H)，6.86(d，1H)，6.80(s，1H)，6.79(d，1H)，5.11(s，2H)，4.03(t，2H)，3.74(t，2H)，3.59(s，2H)，2.22(m，2H)。

(3- {3- [ benzoxazol-2-yl- (2, 4-bis-trifluoromethyl-benzyl) -amino]-propoxy } -phenyl) -acetic acid (7 h). ¹H NMR(400MHz，CDCl₃)，δppm：7.92(s，1H)，7.72(d，1H)，7.57(d，1H)，7.39(d，1H)，7.20(m，3H)，7.04(t，1H)，6.86(d，1H)，6.76(m，2H)，5.07(s，2H)，4.03(t，2H)，3.76(t，2H)，3.59(s，2H)，2.20(m，2H)。

(3- {3- [ (2, 4-bis-trifluoromethyl-benzyl) -pyridin-2-yl) -amino]-propoxy } -phenyl) -acetic acid (7 i). ¹HNMR(400MHz，CDCl₃)，δ(ppm)：8.18(m，1H)，7.91(s，1H)，7.67(d，1H)，7.40(m，2H)，7.23(t，1H)，6.87(d，1H)，6.79(m，2H)，6.60(m，1H)，6.49(d，2H)，5.02(s，2H)，4.01(t，2H)，3.72(t，2H)，3.41(s，2H)，2.15(m，2H)。

Example 4: the following naphthyl derivatives were synthesized according to a method analogous to that described in example 3A using the appropriate hydroxynaphthaleneacetic esters.

1- {3- [ (2, 4-bis-trifluoromethyl-benzyl) - (5-ethyl-pyrimidin-2-yl) -amino]-propoxy } -naphthalene-2-carboxylic acid ester Acid (8 a).

¹H NMR(400MHz，CDCl₃)，δ(ppm)：8.22(s，2H)，8.14(m，2H)，7.97(m，2H)，7.72(m，2H)，7.62(m，2H)，7.45(d，1H)，5.21(s，2H)，4.33(t，2H)，3.95(t，2H)，2.55(q，2H)，2.39(m，2H)，1.23(t，3H)。

6- {3- [ (2, 4-bis-trifluoromethyl-benzyl) - (5-ethyl-pyrimidin-2-yl) -amino]-propoxy } -naphthalene-2-carboxylic acid ester And (8b) an acid.

¹H NMR(400MHz，CDCl₃)，δ(ppm)：8.52(s，1H)，8.21(s，2H)，8.12(d，1H)，7.91(s，1H)，7.82(d，1H)，7.73(m，2H)，7.40(d，1H)，7.11(m，2H)，5.15(s，2H)，4.13(t，2H)，3.85(t，2H)，2.46(q，2H)，2.25(m，2H)，1.19(t，3H)。

3- {3- [ (2, 4-bis-trifluoromethyl-benzyl) - (5-ethyl-pyrimidin-2-yl) -amino]-propoxy } -naphthalene -2-carboxylic acid (8 c).

¹H NMR(400MHz，CDCl₃)，δ(ppm)：8.73(s，1H)，8.09(s，2H)，7.91(m，2H)，7.71(m，2H)，7.52(t，1H)，7.41(m，2H)，7.15(s，1H)，5.15(s，2H)，4.31(t，2H)，3.89(t，2H)，2.39(q，2H)，2.27(m，2H)，1.05(t，3H)。

1- {3- [ butyl- (5-ethyl-pyrimidin-2-yl) -amino]-propoxy } -naphthalene-2-carboxylic acid (8 d).

¹H NMR(400MHz，CDCl₃)，δ(ppm)：8.16(s，2H)，8.15(s，1H)，8.06(d，1H)，7.89(d，1H)，7.69(d，1H)，7.60(m，2H)，4.33(t，2H)，3.87(t，2H)，3.59(t，2H)，2.44(q，2H)，2.32(m，2H)，1.61(m，2H)，1.35(m，2H)，1.16(t，3H)，0.95(t，3H)。

1- [3- (butyl-pyridin-2-yl-oxy) -propoxy]-naphthalene-2-carboxylic acid (8 e).

¹H NMR(400MHz，CDCl₃)，δ(ppm)：8.14(s，1H)，8.13(d，1H)，8.00(d，1H)，7.85(d，1H)，7.63(d，1H)，7.54(m，2H)，7.45(m，1H)，6.52(m，2H)，4.31(t，2H)，3.88(t，2H)，3.43(t，2H)，2.27(m，2H)，1.61(m，2H)，1.36(m，2H)，0.95(t，3H)。

1- {3- (benzothiazol-2-yl-butyl-amino) -propoxy]-naphthalene-2-carboxylic acid (8 f).

¹H NMR(400MHz，CDCl₃)δppm.8.18(d，1H)，7.78(d，1H)，7.53(d，2H)，7.26(m，3H)，7.60(d，1H)，7.40(t，1H)，7.85(t，1H)，4.05(t，2H)，3.72(t，2H)，3.42(t，2H)，2.30(t，2H)，1.59(t，2H)，1.25(q，2H)，0.88(t，3H)。

1- {3- (benzothiazol-2-yl- (4-trifluoromethyl-benzyl) amino]-propoxy } -naphthalene-2-carboxylic acid (8g)。

¹H NMR(400MHz，CDCl₃)，δppm.8.14(d，1H)，8.00(d，1H)，7.86(d，1H)，7.57-7.67(m，6H)，7.50(t，1H)，7.46(d，2H)，7.31(t，1H)，7.10(t，1H)，4.91(s，2H)，4.30(t，2H)，3.96(t，2H)，2.39(t，2H)。

1- [3- (benzoxazol-2-yl-butyl-amino) -propoxy]Naphthalene-2-carboxylic acid (8 h).

¹H NMR(400MHz，CDCl₃)，δ(ppm)：8.16(d，1H)，7.99(d，1H)，7.86(d，1H)，7.65(d，1H)，7.59(t，1H)，7.52(t，1H)，7.41(d，1H)，7.26(d，1H)，7.16(t，1H)，7.01(t，1H)，4.32(t，2H)，3.92(t，2H)，3.58(t，2H)，2.36(m，2H)，1.70(m，2H)，1.40(m，2H)，0.97(t，3H)。

1- {3- [ benzoxazol-2-yl- (2, 4-bis-trifluoromethyl-benzyl) -amino]-propoxy } -naphthalene-2-carboxylic acid (8i)。

¹H NMR(400MHz，CDCl₃)，δ(ppm)：8.23(d，1H)，8.17(m，1H)，7.94(s，1H)，7.86(s，1H)，7.84(s，1H)，7.70(d，1H)，7.59(m，2H)，7.49(m，3H)，6.62(dt，1H)，6.56(d，1H)，5.10(s，2H)，4.23(t，2H)，3.93(t，2H)，2.32(m，2H)。

Example 5: biological activity

The compounds were evaluated in cell-based assays to determine their activity on human PPARs. The human PPAR-GAL4 chimera plasmid was prepared by fusing the amplified cDNA encoding PPAR LBD to the C-terminus of the yeast GAL4DNA binding domain. CV-1 cells were grown and transiently transfected with PerFectin (GTS, San Diego, Calif.) and fluorescein receptor according to the manufacturer's protocol. Eight hours after transfection, 50L of cells were replaced in 384-well plates (1X 10)⁵Individual cells/well). After sixteen hours, cells were treated with compound or 1% DMSO for 24 hours. The luciferase activity was then assayed by Britelite (Perkin Elmer) and by Perkin Elmer Viewlu according to the manufacturer's protocolx or Molecular DevicesAcquest.

Table: active compound

Pharmaceutical dosage form examples

Merely as a guide, the compounds of formula (I) may be formulated into pharmaceutical compositions according to the following general examples.

Parenteral composition

To prepare a parenteral composition suitable for administration by injection, 100mg of a water-soluble salt of a compound of formula (I) is dissolved in DMSO and then mixed with 10mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

Oral composition

To prepare a pharmaceutical composition suitable for oral delivery, 100mg of a compound of formula (I) is mixed with 750mg of lactose. The mixture is incorporated into an oral dosage unit form suitable for oral administration, such as a hard gelatin capsule.

Those skilled in the art will appreciate that the compounds and uses disclosed herein may be useful as PPAR modulators that provide therapeutic effects.

Those skilled in the art will recognize that these methods and compounds are adaptable and can be used to adapt for carrying out the stated objectives or to achieve the stated end points as well as the stated and inherent benefits therein. The methods, processes, and compounds described herein are illustrative and are not intended to limit the scope of the invention. Variations and other uses will occur to those skilled in the art which are encompassed by the spirit of the invention and are defined by the scope of the claims.

It will be apparent to those skilled in the art that various changes and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention.

Those skilled in the art will recognize that the various aspects and embodiments of the invention set forth herein can be practiced separately from or in combination with one another. Accordingly, combinations of the individual embodiments are within the scope of the invention, as claimed herein.

All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in all cases herein, any of the terms "comprising," "essentially comprising," and "consisting of" may be substituted with two other terms. The terms or expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms or expressions of excluding equivalents of the features shown and described or portions thereof. It will be appreciated that various modifications are possible within the scope of the invention as claimed. It should therefore be appreciated that although the present invention has been specifically disclosed by certain embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Furthermore, while various features and aspects of the invention are described in terms of Markush groups (Markushgroups), those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as being selected from the group consisting of: bromine, chlorine, and iodine, claims reciting X as bromine and chlorine in full.

Other specific embodiments are within the following claims.

Claims (70)

1. A compound having the structure of formula (I) or a pharmaceutically acceptable N-oxide, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, pharmaceutically acceptable amide, or pharmaceutically acceptable solvate thereof:

wherein:

Ar₁selected from monocyclic heteroaromatic ring structuresA bicyclic heteroaromatic ring structure;

Ar₂selected from monocyclic, bicyclic, and tricyclic carbocyclic aryl structures;

R₁selected from the group consisting of:

alkyl optionally substituted with a substituent selected from hydrogen, lower alkyl, optionally substituted carbocyclic or heterocyclic ring, halogen, perhaloalkyl, hydroxy, alkoxy, nitro and amino;

a five-or six-membered heteroaromatic ring or a six-membered aromatic ring optionally substituted by one or more substituents selected from the group consisting of optionally substituted C₁-C₈A linear, branched, or cyclic saturated or unsaturated alkyl group; an alkoxy group; a cyano group; a nitro group; an amino group; an amido group; perhaloalkyl and halogen;

R₂selected from the group consisting of:

hydrogen;

alkyl optionally substituted by a substituent selected from the group consisting of hydrogen, lower alkyl, optionally substituted carbocyclic or heterocyclic ring, halogen, perhaloalkyl, hydroxy, alkoxy, nitro, and amino;

a five-or six-membered heteroaromatic ring or a six-membered aromatic ring optionally substituted by one or more substituents selected from the group consisting of optionally substituted C₁-C₈A linear, branched, or cyclic saturated or unsaturated alkyl group; an alkoxy group; halogen and perhaloalkyl;

cyano, nitro, amino, amido, perhaloalkyl, and halogen;

R₃selected from hydrogen, alkyl optionally substituted with a substituent selected from hydrogen, lower alkyl, optionally substituted carbocyclic or heterocyclic ring, hydroxy, halogen, amino, nitro, and cyano;

b is a five-or six-membered heteroaromatic ring, or- (CH)₂)_j-C(O)OR₄Wherein when Ar is₂J is 0 or 1 when it is a bicyclic or tricyclic carbocyclic structure and when Ar is₂J is 1 in the case of a monocyclic carbocyclic ring structure; and is

R₄Selected from the group consisting of:

hydrogen;

alkyl optionally substituted with a substituent selected from hydrogen, lower alkyl, optionally substituted carbocyclic or heterocyclic ring;

a five-or six-membered heteroaromatic ring or a six-membered aromatic ring optionally substituted by one or more substituents selected from the group consisting of optionally substituted C₁-C₈Linear, branched, or cyclic saturated or unsaturated alkyl groups.

2. The compound of claim 1, wherein Ar₂Selected from phenyl, naphthyl, anthracene, and phenanthrene.

3. The compound of claim 2, wherein Ar₂Is phenyl.

4. The compound of claim 3, having the structure:

5. the compound of claim 2, wherein Ar₂Is naphthyl.

6. A compound according to claim 4 or claim 5, wherein R is₁Is alkyl optionally substituted with one or more optionally substituted carbocyclic or heterocyclic rings.

7. The compound of claim 6, wherein said alkyl is lower alkyl.

8. The compound of claim 7, wherein the lower alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and sec-butyl.

9. The compound of claim 6, wherein said carbocycle is phenyl.

10. The compound of claim 9, wherein said phenyl is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halogen, perhaloalkyl, hydroxy, alkoxy, nitro, and amino.

11. The compound of claim 10, wherein the substituent is perhaloalkyl.

12. The compound of claim 11, wherein the perhaloalkyl is trifluoromethyl.

13. A compound of claim 1, wherein R₁Is an alkyl group substituted with a 4-bis (trifluoromethyl) phenylmethyl group.

14. The compound of claim 1, wherein Ar₁Is a nitrogen-containing or oxygen-containing heterocyclic ring.

15. The compound of claim 14, wherein Ar₁Selected from furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, imidazole, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine,And

16. the compound of claim 15, wherein Ar₁Is pyridine, pyrimidine, Or

17. The compound of claim 16, wherein Ar₁Is a pyrimidine.

18. A compound according to any one of claims 4 or claim 5, wherein R is₂Is an optionally substituted alkyl group.

19. The compound of claim 18, wherein said alkyl is lower alkyl.

20. The compound of claim 19, wherein the lower alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and sec-butyl.

21. The compound of claim 20, wherein R₂Is ethyl.

22. A compound of claim 1, wherein R₃Is hydrogen, halogen or optionally substituted alkyl.

23. The compound of claim 22, wherein said optionally substituted alkyl is optionally substituted lower alkyl.

24. The compound of claim 23, wherein the optionally substituted lower alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and sec-butyl.

25. A compound of claim 1, wherein R₃Is methyl.

26. A compound of claim 1, wherein R₃Is hydrogen.

27. The compound of claim 1, wherein Ar₂The B and the propoxy substituent groups are ortho to each other.

28. The compound of claim 1, wherein Ar₂The substituent B and the substituent propoxy are meta-position to each other.

29. The compound of claim 1, wherein Ar₂The substituent B and the substituent propoxy are para to each other.

30. The compound of claim 1, wherein B is a heteroaromatic ring selected from the group consisting of furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, pyridine, imidazole, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine,Andand (4) forming.

31. The compound of claim 30, wherein B is tetrazole.

32. The compound of claim 1, wherein B is- (CH)₂)_j-C(O)OR₄。

33. The compound of claim 32, wherein R₄Is hydrogen or optionally substituted alkyl.

34. The compound of claim 33, wherein said alkyl is lower alkyl.

35. The compound of claim 34, wherein the lower alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and sec-butyl.

36. The compound of claim 33, wherein R₄Is hydrogen.

37. A compound according to any one of claim 4 or claim 5, wherein Ar is₁Is a nitrogen-containing or oxygen-containing heterocyclic ring.

38. The compound of claim 37, wherein Ar₁Selected from: furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, imidazole, pyrazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine,And

39. the compound of claim 38, wherein Ar₁Is pyridine, pyrimidine,Or

40. The method of claim 39Compound of formula (I) wherein Ar₁Is a pyrimidine.

41. The compound according to any one of claims 4 or 5, wherein B is a heteroaromatic ring selected from the group consisting of furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, and mixtures thereof,Andand (4) forming.

42. The compound of claim 41, wherein B is tetrazole.

43. A compound according to any one of claim 4 or claim 5, wherein B is- (CH)₂)_j-C(O)OR₄。

44. The compound of claim 43, wherein R₄Is hydrogen or optionally substituted alkyl.

45. The compound of claim 44, wherein said alkyl is lower alkyl.

46. The compound of claim 45, wherein the lower alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and sec-butyl.

47. A compound according to any one of claims 4 or claim 5, wherein R is₄Is hydrogen.

48. The compound of claim 4, selected from:

and

or a pharmaceutically acceptable N-oxide, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, pharmaceutically acceptable amide, or pharmaceutically acceptable solvate thereof.

49. The compound of claim 5, selected from:

andor a pharmaceutically acceptable N-oxide, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, pharmaceutically acceptable amide, or pharmaceutically acceptable solvate thereof.

50. A compound having the structure of formula (III):

51. a method of modulating Peroxisome Proliferator Activated Receptor (PPAR) function comprising contacting the PPAR with a compound of claim 1 and monitoring a change in cell phenotype, cell proliferation, activity of the PPAR, or binding of the PPAR to a natural binding partner.

52. The method of claim 51 in which the PPAR is selected from PPAR α, PPAR δ, and PPAR γ.

53. A method of inhibiting adipogenesis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.

54. The method of claim 53, comprising administering to the mammal a therapeutically effective amount of a compound of claim 3.

55. The method of claim 54, comprising administering to the mammal a therapeutically effective amount of a compound of claim 4.

56. The method of claim 53, comprising administering to the mammal a therapeutically effective amount of a compound of claim 5.

57. A method of inhibiting adipogenesis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of claim 50.

58. A method of treating a disease comprising identifying a patient in need of such treatment and administering to the patient a therapeutically effective amount of a compound of claim 1.

59. The method of claim 58, wherein the disease is a PPAR-modulated disease or condition.

60. The method of claim 58, wherein the disease is a metabolic disease or disorder.

61. The method of claim 58, wherein the disease is selected from the group consisting of: obesity, diabetes, hyperinsulinemia, metabolic syndrome X, polycystic ovary syndrome, menopause, diseases associated with oxidative stress, inflammatory response to tissue injury, emphysema pathogenesis, organ damage associated with ischemia, doxorubicin-induced cardiac injury, drug-induced hepatotoxicity, atherosclerosis, and virulent lung injury.

62. The method of any one of claims 59-61, comprising administering to the mammal a therapeutically effective amount of a compound of claim 3.

63. The method of any one of claims 59-61, comprising administering to the mammal a therapeutically effective amount of a compound of claim 4.

64. The method of any one of claims 59-61, comprising administering to the mammal a therapeutically effective amount of a compound of claim 5.

65. A method of treating a PPAR-modulated disease or condition, comprising identifying a patient in need of treatment, and administering to the patient a therapeutically effective amount of a compound of claim 50.

66. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent, excipient, or carrier.

67. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable diluent, excipient, or carrier.

68. A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable diluent, excipient, or carrier.

69. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable diluent, excipient, or carrier.

70. A pharmaceutical composition comprising a compound of claim 50 and a pharmaceutically acceptable diluent, excipient, or carrier.