MXPA06000624A

MXPA06000624A - Ppar active compounds

Info

Publication number: MXPA06000624A
Application number: MXPA/A/2006/000624A
Authority: MX
Inventors: R Artis Dean; N Ibrahim Prabha; R Hurt Clarence; Arnold James; Krupka Heike; Lin Jack; V Milburn Michael; Wang Weiru; Zhang Chao
Original assignee: Arnold James; R Artis Dean; Hurt Clarence; N Ibrahim Prabha; Krupka Heike; Lin Jack; V Milburn Michael; Plexxikon Inc; Wang Weiru; Zhang Chao
Priority date: 2003-07-17
Filing date: 2006-01-16
Publication date: 2006-10-17

Abstract

Compounds are described that are active on PPARs, including pan-active compounds. Also described are methods for developing or identifying compounds having a desired selectivity profile.

Description

PPAR ACTIVE COMPOUNDS BACKGROUND OF THE INVENTION The present invention relates to the field of agonists for the family of nuclear receptors identified as peroxisome proliferator-activated receptors. The following description is provided solely to assist the reader's understanding. None of the cited references or the information provided is admitted to be the prior art to the present invention. Each of the references cited herein is incorporated by reference in its entirety, to the same extent, as if each reference were individually indicated to be incorporated herein in its entirety. The peroxisome proliferator-activated receptors (PPARs) form a subfamily in the nuclear receptor superfamily. Three isoforms, encoded by separate genes, have been identified so far: PPAR ?, PPARa and PPARd. Are there two PPAR isoforms? expressed in the level of proteins in mice and humans,? 1 and? 2. These differ only in that the latter has 30 additional amino acids at its N-terminus due to the use of the differential promoter within the same gene, and the subsequent alternative RNA processing. PPARγ2 is expressed mainly in adipose tissue, whereas PPARγ1 is expressed in a wide range of tissues. The murine PPARa was the first member of this subclass of the nuclear receptor to be cloned; Since then it has been cloned from human beings. PPARa is expressed in numerous metabolically active tissues, including the liver, kidney, heart, skeletal muscle, and brown fat. This also occurs in monoliths, vascular endothelium, and vascular smooth muscle cells. The activation of PPARa induces proliferation of hepatic peroxisome, hepatomegaly and hepatocarcinogenesis in rodents. These toxic effects are lost in humans, although the same compounds activate PPARa through species. Human PPARd was cloned in the early 90s and subsequently cloned from rodents. PPARd is expressed in a wide range of tissues and cells with the highest levels of expression found in the digestive tract, heart, kidney, liver, adipose tissue and brain. So far, no specific PPARd gene targets have been identified. PPARs are ligand-dependent transcription factors that regulate target gene expression by binding to peroxisome proliferator response elements (PPREs) at regulated gene enhancer sites. PPARs possess a modulatory structure composed of functional domains that include a DNA binding domain (DBD) and a ligand binding domain (LBD). The DBD binds specifically in the regulatory region of PPAR response genes. The DBD, located in the C-terminal half of the receptor contains the ligand-dependent activation domain, AF-2. Each receptor binds to its PPRE as a hodimeric with a retinoid X receptor (RXR). By joining an agonist, the conformation of a PPAR is altered and stabilized so that a split bond is formed in part of the AF-2 domain, it is created and the recruitment of transcriptional coactivators occurs. Coactivators increase the ability of nuclear receptors to initiate the process of transcription. The result of the interaction of the PPAR-coactivator induced by agonist in the PPRE is an increase in the genetic transcription. The deregulation of gene expression by PPARs seems to occur through indirect mechanisms. (Bergen &Wagner, 2002, Diab Tech. &Ther., 4: 163-174). The first cloning of a PPAR (PPARa) occurred in the course of research for the molecular target of the peroxisome proliferative agents of rodents. Since then, numerous fatty acids and their derivatives that include a variety of eicosanoids and prostaglandins have been shown to serve as ligands for PPARs. In this way, these receptors can play a central role in the perception of nutrient levels and in the modulation of their metabolism. In addition, PPARs are the main targets of the selected classes of synthetic compounds that have been used in the successful treatment of diabetes and dyslipidemia. As such, an understanding of the molecular and physiological characteristics of these receptors has become extremely important for the development and utilization of drugs used to treat metabolic disorders. In addition, due to their great interest within the research community, a wide range of additional roles for PPARs have been discovered; PPARa and PPAR? they can play a role in a wide range of episodes involving the vasculature, including atherosclerotic plaque formation and stability, thrombosis, vascular tone, angiogenesis and cancer. Among the synthetic ligands identified for PPARs are thiazolidinediones (TZD). These compounds were originally developed on the basis of their insulin sensitive effects in pharmacological studies with animals.

Subsequently, TDZ was found to induce adipocyte differentiation and increased expression of adipocyte genes, including adipocyte fatty acid binding protein aP2. Independently, was it discovered that PPAR? interacted with a regulatory element of the aP2 gene that controlled its specific expression of adipocytes. On the basis of these seminal observations, experiments were performed that determined that the TZDs were PPAR? and agonists and demonstrated a decisive correlation between their PPAR activities? in vitro and their insulin-sensitive actions in vivo (Bergen &Wagner, 2002, Diabetes Tech. & Ther., 4: 163-174). Several TZDs, including troglitazone, rosiglitazone and pioglitazone, have insulin and anti-diabetic sensitization activity in humans with type 2 diabetes and impaired glucose tolerance. The Farglitazar is a selective PPAR-? Agonist. without very potent TZD that was recently shown to have antidiabetic efficacy as well as to alter lipids in humans. In addition to these PPAR ligands? potent, a subset of non-spheroidal anti-inflammatory drugs (NSAIDs), including ndometacin. Fenoprofen and ibuprofen, have they deployed PPAR activities? and PPARa weak. (Bergen &Wagner, 2002, Diabetes Tech. &Ther., 4: 163-174). Fibrates, the amphipathic carboxylic acids that have been proven to be useful in the treatment of hypertriglyceridemia, are PPARa ligands. The prototypical member of this class of compounds, clofibrate, was developed prior to the identification of PPARs, using in vivo tests in rodents to evaluate lipid-lowering efficacy. (Bergen &Wagner, 2002, Diabetes Tech. &Ther., 4: 163-174). Fu et al., Nature, 2003, .425: 9093, demonstrated that the PPARa binding compound, oleylethanolamide, produces satiety and reduces body weight gain in mice. Clofibrate and fenofibrate have been shown to activate PPARa with a 10-fold selectivity over PPAR ?. Bezafibrate acts as a total agonist that demonstrated similar potential in all three PPAR isoforms. Wy-14643, the 2-arylthioacetic acid analogue of clofibrate, was a potent murine PPARα agonist as well as a PPARα agonist. weak. In humans, all fibrates can be used in high doses (200-1,200 mg / day) to achieve effective lipid lowering activity. TZDs and without TZD have been identified as dual PPAR? Agonists. By virtue of the additional PPARα agonist activity, this class of compounds has potent lipid-altering efficacy in addition to anti-hyperglycemic activity in animal models of diabetes and lipid disorders. KRP-297 is an example of a TZD dual PPARα agonist (Fajas, 1997, J. Biol. Chem., 272: 18779-18789) DRF-2725 and AZ-242 are dual PPARα / a agonists without TZD (Lohray, et al., 2001, J. Med. Chem., 44: 2675-2678; Cronet, et al., 2001, Structure (Camb.) 9: 699-706). In order to define the physiological role of PPARd, efforts have been made to develop novel compounds that activate this receptor in a selective manner. Among the a-substituted carboxylic acids previously described, the potent PPARd ligand L-165041 demonstrated approximately 30-fold agonist selectivity for this receptor on the PPARα; it was inactive in murine PPARa (Liebowitz, et al., 2000, FEBS Lett., 473: 333- 336). This compound was found to increase high density lipoprotein levels in rodents. It was also reported that GW501516 was a highly selective, potent PPARd agonist that produces beneficial changes in serum lipid parameters in Indian monkeys, resistant to insulin, obese. (Oliver et al., 2001, Proc. Nati, Acad. Sci., 98: 5306-5311). In addition to the above compounds, certain thiazole derivatives that are activated in the PPARs have been described. (Cadilla et al., International, Appl. PCT / US01 / 149320, International Publication WO 02/062774, incorporated herein by reference in its entirety). Some tricyclic-α-alkyloxyphenylpropionic acids were described as PPARa /? Agonists. dual.

Sauerberg et al., 2002, J. Med. Chem. 45: 789-804). A group of compounds that were established to have equal activity in PPARa /? / D is described in Morgensen et al., 2002, Bioorg. & Med. Chem. Lett. 13: 257-260. Oliver et al., Describe a selective PPARd agonist that promotes the transport of inverse cholesterol (Oliver et al., 2001, PNAS 98: 5306-5311). Yamamoto et al., US Patent 3,489,767 discloses "derivatives of '1- (phenylsulfonyl) indolyl-lactic acid" which are established by having "antiphlogistic, analgesic and antipyretic actions". (Col. 1, lines 16-19). Kato et al., European patent application 94101551.3.

Publication No. 0 610 793 A1, describes the use of 3- (5-methoxy-1-p-toluenesulfonylindol-3-yl) propionic acid (page 6) and the acid 1- (2,3,6-triisopropylphenylsulfonyl) - indole-3-propionic (page 9) as intermediates in the synthesis of particular tetracyclic morpholine derivatives.

COMPENDIUM OF THE INVENTION In the present invention, compounds that are only weakly active in PPARs were identified. The identification of such compounds leads to the identification of molecular scaffolds that allows the development of conventional ligand using the structural information about PPARs, and the preparation of compounds based on that scaffolding that has greatly improved activity in PPAR, when compared to the compounds initially identified. Compounds that have significant total activity are included through PPARs, PPARa, PPARd, and PPAR ?, as well as compounds that have significant specificity (at least 5, 10, or 20 times greater activity) in a single PPAR, or in two of the three PPARs. A molecular scaffold is then represented by the structure of Formula I, but with n = 1, Y = CH, the R substituents except for R1 as H, and with R1 as -COOH. Similar scaffolds with each of the alternative sections for the indicated portions (for example, Y = N and / or n = 0 or 2 and / or R1 as one of the other indicated substituents) are also provided.

The present invention relates to molecular scaffolds of Formula I and the use of such molecular scaffolds, and the use of compounds with the structure of Formula I as modulators of PPARs, PPARa, PPARd and PPAR ?, where Formula I is: U, V, W, X and Y are independently substituted N or CR8, wherein there are no more than 4, and preferably no more than 3, nitrogens in the bicyclic ring structure shown in Formula I, and no more than 2 nitrogens in any of the rings; R1 is a carboxyl group (or ester thereof) or a carboxylic acid ester such as the optionally substituted thiazolidinedione, the optionally substituted hydroxamic acid, the optionally substituted acyl-cyanamide, the optionally substituted tetrazole, the optionally substituted isoxazole, the sulfonate optionally substituted, the optionally substituted sulfonamide and the optionally substituted acyl sulfonamide; R 'is hydrogen, optionally substituted lower alkyl, -CH2-CR12 = CR13R14, -CH2-C = CR15, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C (Z) NR 10 R 1 -C (Z) R 20, -S (O) 2 NR 10 R 11; or -S (O) 2R21; R6 and R7 are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl, or R6 and R7 are fused to form a ring system 5 or 6 mono-carbocyclic or mono-heterocyclic members; R8 is hydrogen, halo, optionally substituted lower alkyl, -CH2-CR12 = CR13R14, optionally substituted cycloalkyl, optionally substituted monofluoroalkyl, optionally substituted difluoroalkyl, optionally substituted trifluoroalkyl, trifluoromethyl, -CH2-C = CR15, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR9, -SR9, -NR10R11, -C (Z) NR10R11, -C (Z) R20, -S (O) 2 NR 10 R 11 or -S (O) 2 R 21; R9 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl; R 10 and R 11 are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl, or R 10 and R 11 combine to form a ring system. 5 or 6 mono-carbolytic or mono-heterocyclic members. R12, R13, R14 and R15 are independently and optionally substituted lower alkyl, optionally substituted cycloalkyl optionally substituted monofluoroalkyl, trifluoromethyl, optionally substituted difluoroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R10 is optionally substituted monofluoroalkyl, trifluoromethyl, optionally substituted difluoroalkyl, -CH2-CR12 = CR13R14, -CH2-C = CR15, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl; R? is optionally substituted lower alkoxy. -CH2-CR12 = CR13.R14, -CH2-C = CR15, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; Z is O or S; and n = 0, 1 or 2. In specification a compound or compounds of the Form I, unless otherwise indicated, the specification of such compound or compounds includes pharmaceutically acceptable salts of the compounds. In relation to the compounds of Formula I, various structures and chemical moieties have the following meanings. "Halo" or "Halogone" - alone or in combination mean all halogens, ie, chlorine (Cl), fluoro (F), bromine (Br), iodine (I). "Hydroxy" refers to the -OH group. "Tiol" or "mercapto" refers to the SH group. "Alkyl" - alone or in combination means a radical derived from alkane containing from 1 to 20, preferably 1 to , carbon atoms (unless specifically defined).

This is a straight chain alkyl, branched alkyl or cycloalkyl. In many embodiments, an alkyl is a linear or branched alkyl group containing from 1-15, 1 to 8, 1-6, 1-4 or 1-2 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl , t-butyl and the like. The term "lower alkyl" is used herein to describe straight chain alkyl groups of 1-6, 1-4 or 1-2 carbon atoms. Preferably, the cycloalkyl groups are monocyclic, bicyclic or tricyclic ring systems of 3-8, most preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl and the like, but may also include larger rings which contain or are interrupted by a portion of cycloalkyl such as adamantyl. The alkyl also includes a straight or branched chain alkyl group which contains or is interrupted by the cycloalkyl portion. The straight chain or branched alkyl group is attached at any available point to produce a stable compound. Examples of this include, but are not limited to 4- (isopropyl) -cyclohexylethyl or 2-methyl-cyclopropylpentyl. A substituted alkyl is a straight chain alkyl, branched alkyl, a previously defined cycloalkyl group, independently substituted with 1 to 3 halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino groups or substituents or substituents. , optionally mono or di substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclic groups, aminosulfonyl optionally N-mono or N, N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulphonylamino, arylsulfonylamino, heteroaryl sulphonyl, lamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino or the like. "Alkenyl" -single or in combination means a linear, branched or cyclic hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferred 2-8, most preferably 2-4, carbon atoms and at least one, preferably 1-3, more preferably 1-2 more preferably an atom of a carbon-carbon double bond. In the case of a cycloalkenyl group, the conjugation of more than one carbon-to-carbon double bond is not such as to confer aromaticity to the ring. The carbon-carbon double bonds may be contained within either a cycloalkenyl portion, with the exception of cyclopropenyl, or within a straight chain or a branched portion. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl and the like. A substituted alkenyl is the straight chain alkenyl, branched alkenyl or cycloalkenyl group previously defined, independently substituted with 1 to 3 halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono or substituents or substituents. di substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heteroarylocyclyl, aminosulfonyl optionally N-mono or N, N-disubstituted with alkyl, aryl or heteroaryl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino groups , alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl or the like attached to any available site to produce a stable compound. "Alkyl" -single or in combination means a linear or branched hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferred 2-8, more preferably 2-4 carbon atoms containing at least one, preferably a triple bond of carbon to carbon. Examples of afkynyl groups include ethynyl, propynyl, butynyl, and the like. A "substituted alkynyl" refers to straight-chain alkynyl or branched alkynyl previously defined, independently substituted with 1 to 3 halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino groups optionally mono- or di-substituted groups or substituents alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, optionally N-mono or N, N-disubstituted aminosulfonyl with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, a rylsulfon i lamino, heteroacylsulfon Lamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like attached at any available point to produce a stable compound. "Alkylalkenyl" refers to a group -R-CR '= CR' "R" ", wherein R is lower alkylene or substituted lower alkylene, R ', R'", R "" may independently be hydrogen, halogen, alkyl lower, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below. "Alkylalkyl" refers to groups -RCCR ', wherein R is lower alkylene or substituted lower alkylene, R 'is hydrogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl or substituted hetaryl as defined below. "Alkoxy" designates the group -OR, wherein R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl as defined. "Alkylthio" or "thioalkoxy" designates the group -SR, -S (O) n =? - 2-R, wherein R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl as defined herein. "Acyl" designates groups -C (O) R, wherein R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, and the like as defined herein. "Aryloxy" designates -OAR groups, wherein Ar is an aryl, substituted aryl, heteroaryl or substituted heteroaryl group as defined herein. "Amino" or substituted amine designates the group -NRR ', wherein R and R' may independently be hydrogen, lower alkyl, substituted lower alkyl, substituted aryl, hetaryl or substituted heteroaryl as defined herein, acyl or sulfonyl. "Amido" designates the group -C (O) NRR \ wherein R and R 'can independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl as defined herein. "Carboxyl" designates the group -C (O) OR, wherein R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl and hetaryl? substituted as defined herein. The term "carboxylic acid isostere" refers to a group selected from optionally substituted thiazolidinedione, optionally substituted hydroxamic acid, optionally substituted acyl cyanamide, optionally substituted tetrazole, optionally substituted isoxazole, optionally substituted sulfonate, optionally substituted sulfonamide, and optionally acylsulfonamide. replaced. "Carbocyclic" refers to a saturated, unsaturated or aromatic group having a single ring (e.g., phenyl) or multiple fused rings wherein all the ring atoms are carbon atoms, which may optionally be substituted or unsubstituted with, example, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like. "Aryl" -single or in combination means phenyl or naphthyl, carbocyclic optionally fused with a cycloalkyl or preferably 5-7, most preferably 5-6, members in the ring and / or optionally substituted with 1 to 3 substituent groups of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono or di substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N -mono or N, N-disubstituted with alkyl, aryl or heteroaryl, alkylsulfonylamino, arylsulf or nylamino, heteroaryl sulphonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino or the like groups. "Substituted aryl" refers to aryl optionally substituted with one or more functional groups, for example, halogen, eg, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle. , heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like. "Heterocycle" refers to a saturated, unsaturated or aromatic group having a single ring (eg, morpholino, pyridyl or furyl) or multiple fused rings (eg, napthyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo [b] thienyl) and having carbon atoms and at least one heteroatom, such as N, O or S, within the ring, which may optionally be substituted or unsubstituted, with for example, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like. "Heteroaryl" - alone or in combination means a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, which contains one or more preferably 1-4, more preferably 1-3, even more preferably 1-2 heteroatoms independently selected from the group O, S and N, and optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono or di-substituted with alkyl, aryl or heteroaryl groups, aminosulfonyl optionally N-mono or N, N-disubstituted with alkyl, aryl or heteroaryl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino and the like. Heteroaryl is also intended to include oxidized S or N such as sulfinyl, sulfonyl and N-oxide of a nitrogen in the tertiary ring. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure so that a stable aromatic ring is retained. Examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, midazolyl, triazinyl, furanyl, benzofuryl, indolyl and the like. A substituted heteroaryl contains a substituent- attached to an available carbon or nitrogen that produces a stable compound. "Heterocyclyl" - alone or in combination means a non-aromatic cycloalkyl group having from 5 to 10 atoms wherein from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally benzo fused or fused heteroaryl of 5-6 members in the ring and / or optionally substituted as in the case of cycloalkyl. Heterocyclyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a nitrogen in the tertiary ring. The point of attachment is in a carbon or nitrogen atom. Examples of heterocyclyl groups are tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, dihydroindolyl and the like. A substituted heterocyclyl group contains a nitrogen substituent attached to an available carbon or nitrogen that produces a stable compound. "Substituted heteroaryl" refers to the group -R-Het where Het is a heterocycle group and R is a lower alkylene group. Heterocycle groups optionally mono or poly substituted with one or more functional groups, for example, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, hetaryl substituted, cyano, thiol, sulfamido and the like. "Aralkyl" refers to the group -R-Ar wherein Ar is an aryl group and R is lower alkyl or a substituted lower alkyl group. The aryl groups may optionally be substituted or unsubstituted with, for example, halogen, lower alkyl, alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like. "Heteroalkyl" refers to the group -R-Het where Het is a heterocycle group and R is a lower alkylene group. Heteroalkyl groups can optionally be substituted or unsubstituted with, for example, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and similar. "Heteroarylalkyl" refers to the group -R-HetAr where HetAr is a heteroaryl group and R is lower alkylene or substituted lower alkyl. Heteroarylalkyl groups may optionally be substituted or unsubstituted with, for example, halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Cycloalkyl" refers to a cyclic or polycyclic alkyl group containing 3 to 15 carbon atoms. "Substituted cycloalkyl" refers to a cycloalkyl group comprising one or more substituents with for example, halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro , cyano, thiol, sulfamido and the like. "Cycloheteroalkyl" refers to a cycloalkyl group in which one or more of the carbon atoms in the ring is replaced with a heteroatom (e.g., N, O, S or P). "Substituted cycloheteroalkyl" refers to a cycloheteroalkyl group as defined herein, which contains one or more substituents, such as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy , heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like. "Alkylcycloalkyl" denotes the group -R-cycloalkyl wherein cycloalkyl is a cycloalkyl group and R is a lower alkylene or substituted lower alkylene. Cycloalkyl groups may optionally be substituted or unsubstituted with, for example, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano , thiol, sulfamido and the like.

"Alkylcycloheteroalkyl" denotes the group -R-cycloheteroalkyl wherein R is a lower alkylene or substituted lower alkylene. Cycloheteroalkyl groups may optionally be substituted or unsubstituted with, for example, halogen, lower alkyl, lower alkoxy, alkylthio, amino, amido, carboxyl, acetylene, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano , thiol, sulfamido and the like. In certain embodiments involving compounds of Formula I, the compounds have a structure of Formula I in which the bicyclic core shown for Formula I has one of the following structures: Thus, in particular embodiments involving compounds of Formula I, the compound includes a bicyclic core as shown above. Such compounds may include substituents as described for Formula I, with the understanding that the ring nitrogens other than the nitrogen corresponding to position 1 of the indole structure are not substituted. In particular embodiments, the compounds have one of the bicyclic cores shown above and substitution selections as shown herein for compounds having an indolyl nucleus; the compounds have one of the bicyclic cores above, and the substituents shown at position 5 are rather linked in position 6. In certain embodiments involving compounds of Formula I, the compounds have a structure of Formula 1-1, mainly Formula 1-1 - wherein: R3, R4 and R5 are independently hydrogen, halo, trifluoromethyl, optionally substituted lower alkyl, -CH2-CH12 = CR13R14, optionally substituted monofluoroalkyl, optionally substituted difluoroalkyl, optionally substituted trifluoroalkyl, -CH2-C = CR15, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR9, -SR9, -NR10R11i-C (Z) NR10R11, -C (Z) R20, S (O) 2NR10R11 or ~ S (O) 2R21. In the particular embodiments of the various aspects of the invention, including in certain embodiments, the compounds of Formula I are compounds of Formulas a, Ib, le, Id, X or XIV as shown in the Detailed Description. Also the particular embodiments, such compounds are compounds of Formula I with Y = N; with Y = CR8; with Y = CH; with all R substituents different from R1, R2 and R4 as H (for each of X as N, X as CH, and X as CR8); with R6 and R7 as H (for each of X as N, X as CH and X as CR8). In certain modalities, n = 1; n = 1 and X and / or Y is CH; n = 1, X and / or Y is CH, and R6 and R7 are H; n = 1 and X and / or Y = CR8. In certain embodiments, n = 1, R2 is -S (O) 2R21, with R21 being optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, wherein n = 1, and R2 is -S (O) 2R21, with R21 being optionally substituted aryl or optionally substituted heteroaryl, the aryl group is a 5- or 6-membered ring; the aryl group is a 6-membered ring; in the further embodiments wherein the aryl group is a 6-membered ring, the ring is substituted with one or two groups independently selected from halo, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aryl or substituted heteroarylalkyl, and aryl or substituted heteoarylalkoxy; in the additional embodiments wherein a 6-membered ring is substituted with halo or alkoxy, the ring is substituted at the 3 (meta) position, 4 (para) position, or 3 and 4 (meta and para) positions; in the further embodiments, wherein a 6-membered ring is substituted at the 4-position, or the 3 and 4-positions, the substituent at the 4-position is lower alkyl, the substituent at the 4-position is not alkyl, the substituent at the 4-position is position 4 is halo (for example, fluoro or chloro), substituents at position 3 and 4 are fluoro, substituents at position 3 and 4 are chlorine, one of the substituents in position 3 and 4 is fluoro and the other it is chlorine, position 3 is halo (for example, fluoro or chloro) and position 4 is alkoxy (for example methoxy or ethoxy), position 3 is alkoxy (for example, methoxy or ethoxy) and position 4 is halo ( for example, fluoro or chloro), position 3 is chloro and position 4 is alkoxy, position 3 is alkoxy and position 4 is chloro; the 6-membered ring is fused with a second aromatic or non-aromatic 5- or 6-membered carbocyclic or heterocyclic ring. In additional embodiments wherein the aryl group is a 5-membered ring, the ring is substituted with one or two groups located at the positions on the ring not adjacent to the ring atom linked to the -S (O) 2- group; the 5-membered ring is substituted with one or two substituents on the ring selected from the group consisting of halo, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aryl or substituted heteroarylalkyl, and substituted aryl or heteroarylalkoxy; the ring is replaced with chlorine; the ring is replaced with alkoxy; the ring is substituted with alkyl; the ring is substituted with optionally substituted aryl or heteroaryl; the ring is substituted with optionally substituted aryloxy or heteroaryloxy; the 5-membered ring is fused to a 5- or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring. In certain embodiments wherein n = 1, and R2 is -S (O) 2R21, with R21 being optionally substituted aryl or optionally substituted heteroaryl, R4 is different from H and alkoxy, or R4 is different from H and OR9. In certain modalities, n = 2; n = 2 and X and / or Y is CH; n = 2, X and / or Y is CH, and R6 and R7 are H; n = 2 and X and / or Y is CR8; n = 2 and X and / or Y is N. / In certain embodiments where n = 2, R4 is different from H, halo, alkyl, alkoxy, alkylthio; R 4 is different from H, halo, C 3-13 alkyl, C. 3 alkoxy, C 1 .3 alkylthio; R4 is different from C? -3 alkoxy; R4 is not methoxy. In certain embodiments, n = 2, R2 is -S (O) 2R21, with R21 being optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, wherein n = 2, and R2 is -S (O) 2 R 21, with R .21 which is optionally substituted aryl or optionally substituted heteroaryl, the aryl group is a 5- or 6-membered ring; the aryl group is a 6-membered ring; in further embodiments, wherein the aryl group is a 6-membered ring, the ring is substituted with one or two groups independently selected from halo, alkyl, cycloalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, substituted aryl or heteroarylalkyl, and aryl or substituted heteroarylalkoxy; in the additional embodiments wherein a 6-membered ring is substituted with halo or alkoxy, the ring is substituted at the 3 (meta) position, 4 (para) position, or 3 and 4 (meta and para) positions; in further embodiments wherein a 6-membered ring is substituted at the 4-position, or the 3 and 4-positions, the substituent at the 4-position is lower alkyl, the substituent at the 4-position is not alkyl, the substituent in the 4-position is halo (for example, fluoro or chloro), the substituents at position 3 and 4 are fluoro, the substituents at position 3 and 4 are chlorine, one of the substituents at position 3 and 4 is fluoro and the other is clear , position 3 is halo (for example, fluoro or chloro) and position 4 is alkoxy (for example, methoxy or ethoxy), position 3 is alkoxy (for example, methoxy or ethoxy) and position 4 is halo (for example, methoxy or ethoxy). example, fluoro or chloro), position 3 is chloro and position 4 is alkoxy, position 3 is alkoxy and position 4 is chloro; the 6-membered ring is fused with a second aromatic or non-aromatic 5- or 6-membered carbocyclic or heterocyclic ring. In additional embodiments wherein the aryl group is a 5-membered ring, the ring is substituted with one or two groups located at the positions on the ring not adjacent to the ring atom linked to the -S (O) 2- group; the 5-membered ring is substituted with one or two substituents on the ring selected from the group consisting of halo, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aryl or substituted hetearylalkyl, and substituted aryl or heteroarylalkoxy; the ring is replaced with chlorine; the ring is replaced with alkoxy; the ring is substituted with alkyl; the ring is substituted with optionally substituted aryl or heteroaryl; the ring is substituted with optionally substituted aryloxy or heteroaryloxy; the 5-membered ring is fused with a second aromatic or non-aromatic 5- or 6-membered carbocyclic or heterocyclic ring. In certain embodiments, where n = 2, and R2 is -S (O) 2R21, with R21 being an aryl group substituted with 6 members, the substitution in the aryl group is not methoxy, the substitution in the aryl group is not alkoxy; the substitution in the aryl group is not alkoxy; R 4 and the substitution in the aryl group are not alkoxy; R 4 and the substitution in the aryl group are not methoxy; R4 is not alkoxy; R4 is not methoxy. Certain additional embodiments include compounds described for corresponding embodiments as described above for n = 1 and n = 2. In certain embodiments, the compounds of Formula I have a structure of Formula I as shown below: Formula you wherein R 4 is hydrogen, halo, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR 9 (e.g., optionally substituted alkoxy, e.g. methoxy, ethoxy) -SR9, -NR10R11, -C (Z) R10R11, -C (Z) R20, -S (O) 2NR10R11 or -S (O) 2R21; R 24 is H, halo, optionally substituted alkyl, optionally substituted alkoxy or aryloxy. optionally substituted, or optionally substituted aralkoxy (e.g., Aril-O (CH2) pO-, wherein p is 1-4); R25 is H, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, or R24 and R25 together form a ring fused with the phenyl group, for example, benzofuran. In particular embodiments, R 4 is optionally substituted alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy), optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl (eg, methyl or ethyl), optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl , optionally substituted aryl, optionally substituted heteroaryl, or halo. In particular embodiments, R 4 is optionally substituted alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy), optionally substituted alkyl (e.g., methyl or ethyl), optionally substituted aryl, optionally substituted heteroaryl, or halo. In particular embodiments, the compounds of Formula I can be as specified for Formula I, but with the phenyl ring to which R24 and R25 are attached as a heteroaryl ring. If the heteroaryl ring is a 5-membered ring, R24 and R25 are attached to the positions on the ring that are not adjacent to the atom that bind to the sulfonyl group shown in Formula LE. In particular embodiments of the compounds of Formula I, R 4 is alkoxy and R 24 and R 25 are chloro; R4 is alkoxy and R24 and R25 are fluoro; R4 is alkoxy and R24 is alkoxy; R4 is alkoxy and R24 is alkyl; R 4 is methoxy or ethoxy and R 24 and R 25 are chloro; R 4 is methoxy or ethoxy and R 24 is alkoxy; R 4 is methoxy or ethoxy and R 24 is alkyl. In particular embodiments of the compounds of Formula I, both of R 24 and R 25 are not alkyl; neither R24 nor R25 are alkyl; with R24 as H, R25 is not alkyl; with R25 as H, R24 is not alkyl. Exemplary compounds include those listed in Table 1 and Table 4. Reference to compounds of Formula I herein includes the specific reference to subgroups and species of compounds of Formula I described herein (e.g., particular modalities as described above) unless otherwise indicated. In particular embodiments, any one or more of the sub-groups of the compounds of Formula I or any one or more of the exemplary compounds is excluded from one of the groups or subgroups of the specified compound of Formula 1 that otherwise would include such a sub-group or sub-groups. In particular embodiments of the aspects involving compounds of Formula I, the compound is specific for PPARa; specific for PPARd; specific for PPAR ?; specific for PPARa and PPARd; specific for PPARa and PPAR ?; specific for PPARd and PPAR ?. Such specificity means that the compound has at least 5 times greater activity (preferably at least 1, 20, 50, or 100 times or greater activity) in the specific PPAR (s) than in the other PPAR, where the activity is determined using a suitable biochemical assay to determine PPAR activity, eg, an assay as described herein. A first aspect of the invention relates to novel compounds of Formula I and to subgroups of Formula I, for example, as described above or otherwise described herein. A related aspect of this invention relates to pharmaceutical compositions which include a compound of the Formula I and at least one pharmaceutically acceptable carrier, excipient or diluent. The composition may include a plurality of different pharmacologically active compounds. In another related aspect, the compounds of Formula I can be used in the preparation of a medicament for the treatment of a disease or condition mediated by PPAR. In another aspect, the invention relates to a method for treating or prophylaxis of a disease or condition in a mammal, by administering to the mammal a therapeutically effective amount of a compound of Formula I, a prodrug of such a compound, or a pharmaceutically acceptable salt of such compound or prodrug. The compound may be alone or may be part of a pharmaceutical composition. In aspects and modalities that involve the treatment or prophylaxis of a disease or conditions, the disease or condition is obesity, overweight condition, hyperlipidemia, dyslipidemia that include diabetic dyslipidemia associated and mixed dyslipidemia, hypoalphalipoproteinemia, Syndrome X, diabetes mellitus type II , type I diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, a diabetic complication (eg, neuropathy, nephropathy, retinopathy or cataracts), hypertension, coronary heart disease, heart failure, hypercholesterolemia, inflammation, thrombosis, failure congestive heart disease, cardiovascular disease (including atherosclerosis, arteriosclerosis and hypertriglyceridemia), epithelial hyperproliferative diseases (such as eczema and psoriasis), cancer and conditions associated with the lung and intestine and the regulation of appetite and food intake in subjects suffering from disorders such c ome obesity, anorexia, bulimia and anorexia nervosa. The identification of compounds of Formula I active in the PPARs also provides a method for identifying or developing additional active compounds in PPAR, eg, improved modulators, determining as much as any of a plurality of the test compounds of Formula 1 active in at least one PPAR that provides an improvement in one or more desired pharmacological properties relative to the active reference compound in such a PPAR sample, and selecting a compound if any, which has an improvement in the desired pharmacological property, thereby providing an improved modulator.

In particular embodiments of aspects of modular development, the desired pharmacological property is a total activity of PPAR, selectivity of PPAR for any individual PPAR (PPARa, PPARd or PPAR?), Selectivity in either of the two PPARs (PPARa and PPARd, PPARa and PPAR? or PPARd and PPAR?), longer serum half-life of 2 hours or longer of 4 hours or longer of 8 hours, aqueous solubility, oral bioavailability greater than 10%, oral bioavailability greater than 20%. Also, in the particular embodiments of the aspects of the development of the modulator, the reference compound makes a compound of Formula I. The process may be repeated multiple times, ie multiple cycles of preparation of derivatives and / or the selection of additional related compounds. and the evaluation of such additional derivatives of the related compounds, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more additional cycles. In additional aspects, the structural information of the PPARs is used, for example together with the compounds of Formula I or a molecular scaffold or scaffolding core of Formula I. Thus, in another aspect, the invention provides a method for design a ligand that binds to at least one member of the PPAR protein family (PPARa, PPARd and PPAR?), identifying as molecular scaffolds one or more compounds that bind to a binding site of a PPAR with low affinity; determining the orientation of one or more molecular scaffolds at the PPAR binding site, obtaining the co-crystal structures of the molecular scaffolds at the binding site; identifying one or more structures of at least one scaffold molecule that, when modified, provides a ligand that has altered binding affinity or binding specificity or both binds to PPAR when compared to the binding of the scaffold molecule. The designed ligand (s) can then be provided, for example by synthesizing or otherwise obtaining the ligand (s). In particular embodiments, the molecular scaffold is a compound of Formula I, or contains a bicyclic core as shown above for Formula I. In particular embodiments, a plurality of different compounds is evaluated by binding to the binding site of the PPAR; the co-crystals of the molecular scaffolds attached to the PPAR are isolated, and the orientation of the molecular scaffolding is determined by performing X-ray crystallography in the co-crystals; the method also involves identifying common chemical structures of the molecular scaffolds, placing the molecular scaffolds within the groups based on having at least one common chemical structure, and determining the orientation of one or more molecular scaffolds at the PPAR binding site by minus a representative compound from a plurality of groups; the ligand binds to the target molecule with higher binding affinity or greater binding specificity or both than the molecular scaffold; the orientation of the molecular scaffolding is determined by nuclear magnetic resonance in the determination of co-crystal molecular structure; the plurality of different compounds are each evaluated by binding to a plurality of members of the PPAR family. Also, in the particular embodiments, after the identification of the common chemical structures of the different compounds that are bound together, the compounds are grouped into classes based on common chemical structures and a representative compound from a plurality of the classes is selected by performing X-ray crystallography in co-crystals the compound and the target molecule; the various compounds are selected based on criteria selected from the molecular weight, clogP, and the number of hydrogen bonding and acceptor donors; the clog P is less than 2, and the number of the hydrogen bonding and acceptor donors is less than 5. In certain embodiments, the various compounds have a molecular weight of from about 100 to about 350 daltons, or more preferably from about 150 to approximately 350 daltons or from 150 to 300 daltons, or from 200 to 300 daltons. The different compounds can be a variety of structures. In some embodiments, the various compounds can have a ring structure, either a carbocyclic or heterocyclic ring, such as for example a phenyl ring, a pyrrole, imidazole, pyridine, purine or any ring structure. In various embodiments, a compound or compounds bind with extremely low affinity, very low affinity, low affinity, moderate affinity, or high affinity; at least about 5% of the binding compounds bind with low affinity (and / or have low activity), or at least about 10%, 15% or 20% of the compounds bind with low affinity (or very low or extremely low). After identification of the common chemical structures of the different compounds that are bound together, the compounds can be grouped into classes based on common chemical structures and at least one representative compound from at least one, or preferably a plurality, of the selected classes performing targeting determination, for example by X-ray crystallography and / or NR analysis. In selecting the different compounds for testing in the present invention, the selection may be based on several criteria appropriate for the particular application, such as molecular weight, clogP (or another method to evaluate lipophilic properties), the Polar Surface Area (PSA) (or other indicator of charge and polarity or related properties), and the number of hydrogen bonding donors and acceptors. The compounds can also be selected using the presence of specific chemical moieties which, based on the information derived from the molecular family, could be indicated as having a predisposition to some affinity for family members. Compounds with highly similar structures and / or properties can be identified and grouped using computational techniques to facilitate the selection of a representative subset of the group. As indicated above, in preferred embodiments, the molecular weight is from about 150 to about 350 daltons, more preferably from 50 to 300 daltons. The Clog P is preferably less than 2, the number of hydrogen bonding donors and acceptors is preferably less than 5 and the PSA is less than 100. The compounds can be selected to include chemical structures of drugs that have pharmacological properties acceptable and / or lacking chemical structures that are known to result in pharmacological and desirable properties, eg, excessive toxicity and lack of solubility. In some embodiments, the assay is an enzymatic assay and the number of molecular scaffolding groups formed can conveniently be about 500. In some embodiments, the assay is a competition assay, for example a binding competition assay. Cell-based assays can also be used. As indicated above, the compounds can be used in a manner that has low, very low or extremely low activity in a cell-based or biochemical assay. The modification of a molecular scaffold can be the addition, subtraction or substitution of a chemical group. The modification may desirably cause scaffolding to be actively transported to, or within, particular cells and / or a particular organ. In various embodiments, the modification of the compound includes the addition or subtraction of a chemical atom, a substituent or a group, such as, for example, a hydrogen, alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenylthio, phenyl, phenylalkyl, phenylalkylthio, hydroxyalkylthio, alkylthiocarbamylthio, cyclohexyl, pyridyl, piperidinyl, alkylamino, amino, nitro, mercapto, cyano, hydroxyl, a halogen atom, halomethyl, an oxygen atom (e.g. , forming a ketone, an ether or an N-oxide), and a sulfur atom (for example, forming a thiol, thione, sulfonamide or di-alkyldisulfoxide (sulfone)). In certain embodiments, the information provided by performing X-ray crystallography in the co-crystals is provided to a computer program, wherein the computer program provides a measure of the interaction between the molecular scaffold and the protein and a prediction. of changes in the interaction between the molecular scaffolding and the protein that results from the specific modifications to the molecular scaffolding, and the molecular scaffolding is modified chemically based on the prediction of the biochemical result. The computer program can provide the prediction based on a virtual assay such as, for example, virtual binding of the compound to the protein, form-based coupling, molecular dynamic simulations, free energy perturbation studies, and similarity to a three-dimensional pharmacophore. A variety of such programs are well known in the art. The chemical modification of a chemically treatable structure can result, or be selected to provide one or more physical changes, for example, to result in a ligand that fills an empty volume in the protein-ligand complex, an attractive polar interaction that occurs in the protein-ligand complex. The modification may also result in a sub-structure of the ligand that occurs in a binding pocket of the protein binding site when the protein-ligand complex is formed. After that the common chemical structures of the compound that binds are identified, the compounds can be grouped based on having a common chemical sub-structure and a representative compound of each group (a plurality of the group) can be selected for co-crystallization with the protein and the performance of the X-ray crystallography. X-rays are preferably performed in co-crystals under at least 20, 30, 40 or 50 different environmental conditions, most preferably under approximately 96 different environmental conditions. X-ray crystallography and the modification of a chemically treatable structure of the compound can each perform a plurality of times, for example 2, 3, 4 or more cycles of crystallization and modification. Also, in certain embodiments, one or more molecular scaffolds are selected to have a binding to a plurality of members of the PPAR family. The method may also include the identification of conserved residues at one or a few PPAR protein binding sites that interact with a molecular scaffold, a ligand or other binding compound. The conserved residues can, for example, be identified by sequence alignment of different members of the PPAR family, and identifying residues from the binding site that are the same or at least similar among the multiple member of the family. The residues of the interaction can be characterized as those of a distance selected from the binding compound (s), for example 3, 3.5, 4, 4.5 or 5 angstroms. In a related aspect, the invention provides a method for designing a ligand that. binds to at least one PPAR that is a member of the PPAR family, identifying as molecular scaffolds one or more compounds that bind to the binding sites of a plurality of members of the PPAR family, determining the orientation of one or more molecular scaffolds in the binding site of the PPAR or to identify the chemically treatable structures of the scaffold or scaffolds that, when modified, alter the binding affinity or the binding specificity between the scaffold (s) and the PPARs, and synthesizing a ligand wherein one or more of the chemically treatable structures or molecular scaffolds are modified to provide a ligand that binds to PPAR with altered binding affinity or binding specificity. Particular modalities include those described by the present aspect. The invention also provides a method for identifying properties that a binding compound will likely possess, whereby for example, the most efficient selection of compounds for determinations of structural activity ratio and / or selection is allowed. Thus, another aspect relates to a method for identifying binding characteristics of a ligand or a PPAR protein, identifying at least one interaction residue conserved in the PPAR that interacts with at least two binding molecules; and identifying at least one common interaction property of those binding molecules with the conserved residue (s). The interaction property and the location with respect to the structure of the binding compound define the binding characteristic. In various embodiments, the identification of conserved interaction residues involves comparing (eg, by sequence alignment) a plurality of amino acid sequences in the PPAR family and identifying residues of binding sites conserved in that family; the identification of residues of binding sites by determining a co-crystal structure; identifying interaction residues (preferably conserved residues) within a selected distance of the binding compounds, for example 3, 3.5, 4, 4.5 angstroms; the interaction property involves hydrophobic interaction, charge-charge interaction, hydrogen bonding, polar charge interaction, polar-polar interaction, or combinations thereof. Another related aspect is related to a method to develop ligands for a PPAR using a set of scaffolds. The method involves selecting a PPAR or a priority of the PPARs, selecting a molecular scaffolding, or a composite from a scaffolding group, from a set of at least three scaffolds or groups of scaffolds where each of the scaffolds or compounds from each scaffolding group are known to join the target. In the particular embodiments, the set of scaffolds or scaffolding groups is at least 4, 5, 6, 7, 8 or even more scaffolds or groups of scaffolds. Another aspect relates to a method for identifying structural and energetically permitted sites in a binding compound for the binding of one or more additional components by analyzing the orientation of the binding compound (s) at a PPAR binding site (eg by analyzing the structures co-crystal), whereby accessible sites are identified in the compound for attachment of the separated component. In particular embodiments, the binding compound is a compound of Formula I. In various embodiments, the method involves calculating the change in binding energy at the junction of the separated component at one or more of the accessible sites; the orientation is determined by co-crystallography; the separate component includes a linker, a label such as a fluorophore, a solid phase material such as a gel, a bead, a plate, a chip or a well. In a related aspect, the invention provides a method for the adhesion of a PPAR binding compound to an adhesion component or components by identifying energetically permitted sites for the adhesion of such adhesion component in a binding compound (eg as described for the preceding aspect), and the adherence of the compound or derivative thereof to the adhesion component (s) at the energetically permitted site (s). In particular embodiments, the binding compound is a compound of Formula I. In various embodiments, the adhesion component is a linker (which may be a linker without trace) for adhesion to a solid phase medium, and the method it also involves the adhesion of the compound or derivative to a solid phase medium through the linker attached to the energetically permitted site; the binding compound or derivative thereof is synthesized in a linker attached to the solid phase medium; a plurality of compounds or derivatives are synthesized in combinatorial synthesis; the adhesion of the compound (s) to the solid phase medium provides an affinity medium. A related aspect relates to a method for making an affinity matrix for a PPAR, wherein the method involves identifying energetically permitted sites in a PPAR binding compound for adhesion to a solid phase matrix; and adhesion to the PPAR binding compound to the solid phase matrix through the energetically permitted site. In particular embodiments, the binding compound is a compound of Formula I. Various embodiments are as described for the attachment of a previous separate component.; identifying energetically permitted sites for the binding of a solid phase matrix was performed for at least 5, 10, 20, 30, 50, 80 or 100 different compounds; identify energetically permitted sites for molecular scaffolds or other PPAR binding compounds that have different core ring structures. As used herein, the term "PPAR" refers to a peroxisome proliferator-activated receptor as recognized in the art. As indicated above, the PPAR family includes PPARa (also referred to as PPARa or PPARalpha), PPARd (also referred to as PPARd or PPARdelta), and PPAR4 (also referred to as PPARg and PPARgamma). Individual PPARs can be identified for their sequences, where the access numbers of the exemplary reference sequence are: NM_005036 (cDNA sequence for hPPARa), NP_005027 (protein sequence for hPPARa), NM_015869 (cDNA sequence for isoform 2 from h PPARg), N P_056953 (protein sequence for isoform 2 hPPARg), NM_006238 (cDNA sequence for hPPARd), and N P_006229 (protein sequence for hPPARd). One of ordinary skill in the art will recognize that sequence differences will exist due to allelic variation, and will also recognize that other animals, particularly other mammals have corresponding PPARs, that have been identified or can be easily identified using sequence alignment and confirmation. activity, can also be used. One of ordinary skill in the art will also recognize that modifications can be introduced into a PPAR sequence without destroying the PPAR activity. Such modified PPARs can also be used in the present invention, for example, if the modifications do not alter confirmation of the binding site to the extent that the modified PPAR substantially lacks the normal ligand binding.

As used herein in conjunction with the design or development of ligands, the term "join" and "link" and similar terms refers to an energetically favorable, non-covalent association between the specific molecules (i.e., the bound state has a free energy lower than the separate state, which can be measured calorimetrically). For binding to a target, the binding is at least selective, that is, the compound binds preferably to a particular target or to members of a target family at a binding site, when coed to non-specific binding to non-target proteins. related that do not have a similar binding site. For example, BSA is frequently used to evaluate or control non-specific binding. Furthermore, for an association that will be estimated as the binding, the decrease in free energy that comes from a separate state to the bound state should be sufficient so that the association is detectable in a suitable biochemical assay for the molecules involved. By "analyze" is meant the creation of experimental conditions and the gathering of data with respect to a particular result of the experimental conditions. For example, enzymes can be evaluated based on their ability to act on a detectable substrate. Likewise, for example, a compound or ligand can be evaluated based on its ability to bind to a target molecule or molecules and / or to modulate an activity of a target molecule. By "background signal" in reference to a binding assay is meant the signal that is recorded under standard conditions for the particular assay in the absence of a test compound, a molecular scaffold, or ligand that binds to the target molecule . Those of ordinary skill in the art will understand that there are accepted methods and are widely available to determine the background signal. When a decision is described as "based" on particular criteria, it means that the selected criteria are parameters of the decision and guide its outcome. A substantial change in the parameters would probably result in a change in the decision. By "binding site" is meant an area of a target molecule to which a ligand can be attached non-covalently. The binding sites incorporate particular forms and often contain multiple binding cavities present within the binding site. Particular forms are frequently conserved within a class of molecules, such as a molecular family. The binding sites within a class may also contain conserved structures such as, for example, chemical moieties, the presence of a binding cavity, and / or an electrostatic charge at the binding site or some portion of the binding site, all which can influence the shape of the binding site. By "joint cavity" is meant a specific volume within a binding site. A binding cavity is a particular space within a binding site at least partially bound by the atoms of the target molecule. Thus, a joint cavity is a particular shape, indentation, or cavity at the junction site. The binding cavities may contain particular chemical groups or structures that are important in the non-covalent binding of another molecule such as, for example, groups that contribute to hydrogen bonding, ionic, van der Waals or hydrophobic interactions between the molecules. By "chemical structure" or "chemical substructure" is meant any atom or definable group of atoms that constitutes a part of a molecule. Normally, the chemical substructures of a scaffold or ligand may have a role in binding the scaffold or the ligand to a target molecule, or they may influence the three-dimensional shape, electrostatic charge and / or conformational properties of the scaffold or the ligand. By "orientation", in reference to a binding compound attached to a target molecule is meant the spatial relationship of the binding compound and at least some of its constituent atoms to the binding cavity and / or atoms of the target molecule that defines at least partially the joint cavity. In the context of the target molecules in the present invention, the term "crystal" refers to an ordered complex of the target molecule, so that the complex produces an X-ray diffraction pattern when placed in an X-ray beam. Thus, a "crystal" is distinguished from a disordered or partially ordered complex or aggregate of molecules that does not produce such a diffraction pattern. Preferably, a crystal is of sufficient order and size to be useful for X-ray crystallography. A crystal can be formed only of a target molecule (with solvent and ions) or it can be a co-crystal of more than one molecule, for example , as a co-crystal of the target molecule and the binding compound, and / or of a protein complex (such as a holoenzyme). In the context of this invention, unless otherwise specified, by "co-crystals" is meant an ordered complex of the compound, a molecular scaffold, or ligand non-covalently bound to the target molecule that produces a diffraction pattern when placed in an X-ray beam. Preferably, the co-crystal is in the proper form for X-ray analysis or protein crystallography. In preferred embodiments, the target molecule-ligand complex can be a protein-ligand complex. By "clog P" is meant the calculated logarithm P of a compound, "P" refers to the coefficient of division of the compound between a lipophilic and an aqueous phase, usually between octanol and water. By "chemically treatable structures" is meant chemical structures, sub-structures, or sites in a molecule that can be covalently modified to produce a ligand with a more desirable property. The desirable property will depend on the needs of the particular situation. The property may be, for example, that the ligand binds with greater affinity to a target molecule, which binds with more specificity, or that binds to a larger or smaller number of target molecules in a molecular family, or other desirable properties when required. By "design a ligand", "prepare a ligand", "discovering a ligand" and similar phrases means the process for considering relevant data (especially, but not limited to, any individual type or combination of binding data, co-crystallography data of X-ray, molecular weight, clogP, and the number of hydrogen bond donors and acceptors) and make decisions about the advantages that can be achieved with resources for structural modifications specific to a molecule, and implement those decisions. This process to gather data and make decisions about the structural modifications that can be advantageous, implement those decisions, and determine that the result can be repeated as many times as necessary to obtain a ligand with desired properties. By "linking" is meant the process for attempting to establish a three-dimensional configuration of a binding pair member within a three-dimensional configuration of the binding site or attachment cavity of the associated binding pair member, which may be a protein, and determine the magnitude at which an adjustment is obtained. The magnitude at which an adjustment is obtained may depend on the amount of void volume in the resulting binding pair complex (or target molecule-ligand complex). The configuration can be physical or a configuration representative of the union pair member, for example, an in silico representation or another model. In the context of the development of modulators that use molecular scaffolds, by "ligand" is meant a molecular scaffold that has been chemically modified into one or more chemically treatable structures to bind to the target molecule with altered or changed binding affinity or specificity of union relative to molecular scaffolding. The ligand can bind with a higher specificity or affinity for a member of the molecular family relative to the molecular scaffold. A ligand does not bind covalently to a target molecule, which may preferably be a protein or enzyme. By "low affinity" binding is meant the binding to the target molecule with a dissociation constant (Kd) of more than 1 μM under standard conditions. In particular cases, the low affinity binding is in a range of 1 μM-10 mM, 1 μM-1 mM, 1 μM-500 μM, 1 μM-200 μM, 1 μM-100 μM. To be linked with "very low affinity" is meant binding with a kd of above about 100 μM under standard conditions, for example in a range of 100 μM-1 mM, 100 μM-500 μM, 100 μM-200 μM . By binding with "extremely low affinity" it is meant to bind in a kd of above about 1 mM under standard conditions. By "moderate affinity" is meant to bind with a kd from about 200 nM to about 1 μM under standard conditions. By "moderately high affinity" it is meant to bind in a kd from about 1 mM to about 200 nM. By "high affinity" binding it is meant to bind in a d below about 1 nM under standard conditions. For example, low affinity binding may occur due to a more poor fit at the binding site of the target molecule or due to a smaller number of non-covalent bonds, or weaker covalent bonds present to cause binding of the scaffolding or ligand to the binding site of the target molecule in relation to cases where the highest affinity binding occurs. The standard conditions for binding are at pH 7.2 at 37 ° C for one hour. For example, 100 μl / well in 50 mM HEPES of buffer at pH 7.2, 15 mM NaCl, 2 μM ATP, and bovine serum albumin 1 ug / poz.o, 37 ° C for one hour can be used. The binding compounds can also be characterized by their effect on the activity of the target molecule. Thus, a "low activity" compound has an inhibitory concentration (IC50) (for inhibitors or antagonists) or an effective concentration (EC50) (applicable to agonists) of more than 1 μM under standard conditions. By "very low activity" is meant an IC50 or EC50 of above 100 μM under standard conditions. By "emely low activity" is meant an IC5o or EC50 of above 1 mM under standard conditions. By "moderate activity" is meant an IC50 or EC50 of 200 nM to 1 μM under standard conditions. By "moderately elevated activity" is meant an IC50 or EC50 of 1 nM to 200 nM. By "high activity" is meant an IC50 or EC50 below 1 mM under standard conditions. The IC50 (or EC50) is defined as the concentration of the compound at which 50% of the activity of the target molecule (e.g., enzyme or other protein) that is measured is lost (or gained) in relation to the activity when no compound is present. The activity can be measured using methods known to those of ordinary skill in the art, for example, by measuring any detectable product or signal produced by the occurrence of an enzymatic reaction, or other activity by a protein being measured. For PPAR agonists, the activities can be determined as described in the Examples, or use other such assay methods known in the art. By "molecular scaffolding" or "scaffolding" is meant a small target binding molecule to which one or more additional chemical moieties can be covalently linked, modified or eliminated to form a plurality of molecules with common structural elements. The portions may include, but are not limited to, a halogen atom, a hydroxyl group, a methyl group, a nitro group, or any other type of molecular group including, but not limited to, those reported in this application. Molecular scaffolds bind to at least one target molecule with low or very low affinity and / or bind to a plurality of molecules in a target family (e.g., family of proteins) and the target molecule is preferably an enzyme, receptor , or another protein. The preferred features of a scaffold include the molecular weight of less than about 350 daltons; binding at a binding site of a target molecule so that one or more substituents on the scaffolding are located in the binding cavities at the binding site of the target molecule; having chemically treatable structures that can be chemically modified, particularly by synthetic reactions, so that a combinatorial library can be easily constructed; having chemical positions in which the portions can be linked so as not to interfere with the binding of scaffolding to a protein binding site, so that the scaffolding or library members can be modified to form ligands, to achieve additional desirable characteristics, example, allowing the ligand to be actively transported in the cells and / or to specific organs, or allowing the ligand to bind to a chromatography column for further analysis. Thus, a molecular scaffold is an identified target binding molecule, small before modification to improve affinity and / or binding specificity, or other pharmacological properties. The term "scaffolding core" refers to the core structure of a molecular scaffold upon which various substituents can be attached. Thus, for a number of scaffolding molecules of a particular chemical class, the scaffolding core is common to all scaffolding molecules. In many cases, the scaffolding core will consist of, or will include, one or more ring structures. The term "scaffolding group" refers to a set of compounds that share a scaffolding core and can thus be considered as derivatives of a scaffolding molecule. By "molecular family" is meant groups of class molecules together based on structural and / or functional similarities. Examples of molecular families include proteins, enzymes, polypeptides, receptor molecules, oligosaccharides, nucleic acids, DNA, RNA, etc. In this way, for example, a protein family. It is a molecular family. The molecules can also be classified together in a family based on, for example, homology. The person with ordinary skill in the art will understand many other molecules that can be classified as members of a molecular family based on similarities in chemical structure or biological function. By "protein-ligand complex" or "co-complex" is meant a non-covalently bound protein and ligand. By "protein" is meant a polymer of amino acids. The amino acids can be of natural or non-natural origin. The proteins may also contain adaptations, such as being glycosylated, phosphorylated or other common modifications. By "protein family" is meant a classification of proteins based on structural and / or functional similarities. For example, kinases, phosphatases, proteases and similar protein groupings are protein families. Proteins can be grouped into a family of proteins based on having one or more protein folds in common, a substantial similarity in shape between protein folding, homology, or on the basis of having a common function. In many cases, smaller families will be specified, for example, the PPAR family. "Protein Folds" are three-dimensional forms exhibited by the protein and defined by the existence, number and location in the protein of alpha helices, beta sheets, and loops, that is, the secondary secondary structures of protein molecules. Folds can be, for example, the domains or partial domains of a particular protein. By "ring structure" is meant a molecule that has a chemical ring or sub-structure that is a chemical ring. In most cases, the ring structures will be carbocyclic or heterocyclic rings. The chemical ring may be, but is not limited to, a phenyl ring, aryl ring, pyrrole ring, imidazole, pyridine, purine or any ring structure. By "specific biochemical effect" is meant a therapeutically significant biochemical change in a biological system that causes a detectable result. This specific biochemical effect may be, for example, the inhibition or activation of an enzyme, the inhibition or activation of a protein that binds to a desired target, or similar types of changes in the body's biochemistry. The specific biochemical effect can cause the relief of symptoms of a disease or a condition or other desirable effect. The detectable result can also be detected through an intermediate stage. By "standard conditions" is meant conditions under which an assay is performed to obtain scientifically meaningful data. Standard conditions are dependent on the particular test, and may be generally subjective. Normally, the standard conditions of a test will be those conditions that are optimal for obtaining useful data from the particular test.

Standard conditions will generally minimize the background signal and maximize the intended signal to be detected. By "standard deviation" we mean the square root of the variance. Variance is a measure of how a distribution is separated. This is calculated as the average square deviation of each number from its average. For example, for numbers 1, 2 and 3, the average is 2 and the variation is: s2 = (1-2) 2+ (2 + 2.2+ (3-2) 2 = 0.667 3 For a "set" of The term "target molecule" is intended to mean a molecule in which a compound, a molecular scaffold, or a ligand is being analyzed for the purpose of The target molecule has a binding activity so that the binding of the molecular scaffold or ligand to the target molecule will be altered or changed.The binding of the compound, the scaffold or the ligand to the target molecule can preferentially cause a biochemical effect specific when it occurs in a biological system A "biological system" includes, but is not limited to, a living system, such as a human being, an animal, a plant or an insect, in most, but not in all cases, the target molecule will be a protein or a nucleic acid molecule. By "pharmacophore" is meant a representation of molecular characteristics that are considered to be responsible for a desired activity, such as interaction or binding with a receptor. A pharmacophore can include three-dimensional properties (hydrophobic groups, charged / ionizable groups, hydrogen donors / acceptors), 2D (substructures) and 1D (physical or biological). As used herein, together with the numerical values, the terms "approximately" and "around" mean ± 10% of the indicated value. Additional modalities will be apparent from the Detailed Description and from the claims.

DETAILED DESCRIPTION OF THE MODALITIES PREFERRED As indicated in the previous Compendium, the present invention relates to receptors activated with a peroxisome proliferator (PPAR), which have been identified in humans and other mammals. A group of compounds have been identified, corresponding to Formula I, which are active in one or more of the PPARs, in the particular compounds so that one or more human PPARs are active. The identification of these compounds provides compounds that can be used as agonists in PPARs, as well as for the identification or development of additional active compounds, for example, compounds within the Formula I. Applications of PPAR Agonists PPARs have been recognized as suitable targets for a number of different diseases and conditions. Some of these applications are described briefly later. Additional applications are known and the present compounds can also be used for those diseases and conditions. (a) Insulin resistance and diabetes: Along with insulin resistance and diabetes, PPAR? it is necessary and sufficient for the differentiation of adipocytes in vitro and in vivo. In adipocytes, PPAR? increases the expression of numerous genes involved in lipid metabolism and lipid absorption. In contrast, the PPAR? it deregulates leptin, a secreted adipocyte selective protein that has been shown to inhibit feeding and increased metabolism of catabolic lipid. This receptor activity could explain the increased caloric absorption and storage observed in vivo in the PPAR? Agonist treatment. Clinically, TZDs, including troglitazone, rosiglitazone and pioglitazone and without TZD, including farglitazar, have insulin-sensitive and antidiabetic activity. (Berger et al., 2002, Diabetes Tech. And Ther. 4: 163-174). The PPAR? It has been associated with several genes that affect the action of insulin. TNFa a pro-inflammatory cytosine that is expressed by adipocytes, has been associated with insulin resistance. The PPAR agonists? inhibit the expression of TNFα in adipose tissue of obese rodents, and remove the actions of TNFα in adipocytes in vitro. The PPAR agonists? showed that they inhibit the expression of 11 β-hydroxysteroid dehydrogenase 1 (11β-HSD-1), the enzyme that converts cortisone to glucocorticoid agonist cortisol, in adipocytes and adipose tissue of mouse models with type 2 diabetes. This is remarkable that hypercorticosteroidism intensifies insulin resistance. The 30 kDa Adipocyte-Related Protein (Acrp30 or adiponectin) is a secreted adipocyte-specific protein that decreases glucose, triglycerides and free fatty acids. Compared with normal humans, patients with type 2 diabetes have reduced plasma levels of Acrp30. The treatment of diabetic mice and non-diabetic humans with increased plasma levels of PPAR agonists? of Acrip30. The induction of Acrp30 by PPAR agonists? Could it, therefore, play a key role in the insulin sensitization mechanism of PPAR agonists? in diabetes. (Berger et al., 2002, Diabetes Tech. And Ther.4: 163-174). The PPAR? it is expressed predominantly in adipose tissue. Thus, it is believed that the real in vivo efficacy of PPAR agonists? it involves direct actions on adipose cells with side effects in key insulin response tissues such as skeletal muscle and liver. This is supported by the lack of glucose-lowering efficacy of rosiglitazone in a mouse model of severe insulin resistance where white adipose tissue was essentially absent. In addition, in vivo treatment of insulin-resistant rats produces acute normalization (<24 hours) of adipose tissue insulin action while insulin-mediated glucose uptake in the muscle was not improved until several days after the start of therapy. This is consistent with the fact that PPAR agonists? they may produce an increase in the action of adipose tissue insulin after direct in vitro incubation, whereas no effect could be demonstrated using skeletal muscles incubated in vitro isolated. The beneficial metabolic effects of PPAR agonists? in muscle and liver it can be mediated by its ability to (a) improve insulin-mediated adipose tissue absorption, storage (and potentially catabolism) of free fatty acids; (b) inducing the production of factors derived from adiposis with potential insulin sensitization activity (eg, Acrp30); and / or (c) suppress circulating levels and / or actions of factors derived from adiposis that cause resistance such as TNFa or resistin. (Berger et al., 2002, Diabetes Tech. And Ther.4: 163-174). (b) Dyslipidemia and atherosclerosis: Along with dyslipidemia and atherosclerosis, PPARa has been shown to play a critical role in the regulation of cellular uptake, activation and ß-oxidation of fatty acids. Activation of PPARa induces the expression of fatty acid transport proteins and enzymes in the path of peroxisomal β-oxidation. Several mitochondrial enzymes involved in the catabolism of fatty acid energy harvest are over-regulated to a large extent by PPARa agonists. Peroxisome proliferators also activate the expression of CYP4A, a subclass of cytochrome P450 enzymes that catalyze the? -hydroxylation of fatty acids, a trajectory that is particularly active in fasting and diabetic states. In summary, it is clear that PPARa is an important lipid sensor and regulator of cellular energy harvest metabolism. (Berger et al., 2002, Diabetes Tech. And Ther.4: 163-174). Atherosclerosis is a very prevalent disease in Western societies. In addition to a strong association with elevated LDL cholesterol, "dyslipidemia" characterized by high triglyceride-rich particles and low levels of HDL cholesterol is commonly associated with others, aspects of a metabolic syndrome that includes obesity, insulin resistance, type 2 diabetes and an increased risk of coronary artery disease. Thus, in 8,500 men with known coronary artery disease, 38% had low HDL (<35 mg / dl) and 33% had high triglycerides (> 200 mg / dl). In such patients, treatment with fibrates resulted in a substantial decrease in triglycerides and the efficacy to produce modest HDL. More importantly, a recent large potential trial showed that treatment with gemfibrozil produced a 22% reduction in cardiovascular events or death. In this way, PPARa agonists can effectively improve cardiovascular risk factors and have a real benefit in improving cardiovascular outcomes. In fact, fenofibrate was recently approved in the United States for the treatment of hyperlipidemia of type HA and IIB. The mechanisms by which PPARa activation cause the triglyceride decrease likely to include the effects of agonists to suppress hepatic apo-Clll gene expression while also stimulating the lipoprotein lipase gene expression. Dual PPARα agonists, including KRP-297 and DRF 2725, possess the potent lipid-altering efficacy in addition to antihyperglycemic activity in animal models of diabetes and lipid disorders. The presence of expression of PPARa and / or PPAR? in vascular cell types, including macrophages, endothelial cells, and vascular smooth muscle cells, suggests that direct vascular effects may contribute to potential antiatherosclerosis efficacy. The activation of PPARa and PPARa has been shown to inhibit vascular cell adhesion that induces cytosine and to suppress the migration of monolith-macrophage. Several additional studies have also shown that selective PPAR? they have the capacity to reduce the size of arterial injury and attenuate the replacement of monocytes-macrophages to arterial lesions in animal models of atherosclerosis. In addition, two recent studies have suggested that the activation of PPARa or PPAR? in macrophages it can induce the expression of a cholesterol pump "pump" protein. It has been found that relatively selective PPARd agonists produce minimal glucose or triglyceride lowering activity, if any, in murine models of type 2 diabetes compared to PPARγ agonists. or PPARa effective. Subsequently, a modest increase in HDL cholesterol levels was detected with PPARd agonists in db / db mice. Recently, Oliver et al. , reported that a selective PPARd agonist, potent could induce a substantial increase in HDL-cholesterol levels although triglyceride levels and insulin resistance are reduced in obese diabetic monkeys. Thus, through multifactorial mechanisms that include improvements in circulating lipids, local systemic and anti-inflammatory effects, and the inhibition of vascular cell proliferation, PPARa agonists, PPAR? and PPARd can be used in the treatment or prevention of atherosclerosis (Berger et al., 2002, Diabetes Tech. And Ther.4: 163-174). (c) Inflammation: Monocytes and macrophages are known to play an important part in the inflammatory process through the release of inflammatory cytokines and the production of nitric oxide by nitric oxide of inducible synthase. Rosiglitazone has been shown to induce macrophage apoptosis in concentrations that are equivalent to its affinity for PPAR ?. This ligand has also been shown to block the synthesis of inflammatory cytosine in colonic cell lines. This last observation suggests a mechanistic explanation for the anti-inflammatory actions observed in TZDs in rodent models of colitis. Anti-inflammatory actions have been described for PPARa ligands that may be important in maintaining vascular health. The treatment of human macrophages activated with cytosine with PPARa agonists that induce apoptosis of cells. It was reported that PPARa agonists inhibit the activation of smooth aortic muscle cells in response to the inflammatory stimulus (Staels et al., 1998, Nature 393: 790-793). In hyperlipidemic patients, fenofibrate treatment decreases plasma concentrations of inflammatory cytokine interleukin-6. (d) Hypertension: Hypertension is a complex disorder of the cardiovascular system that has been shown to be associated with insulin resistance. Patients with type 2 diabetes demonstrate a 1.5-2-fold increase in hypertension compared to the general population. Therapy with troglitazon, rosiglitazon and pioglitazon have been shown to lower blood pressure in diabetic patients as well as troglitazon therapy in insulin-resistant, obese subjects. Since such reductions in blood pressure showed that they correlate with decreases in insulin levels, they can be mediated by an improvement in insulin sensitivity. However, since the TZDs also decreased blood pressure in Sprague Dawley rats from a kidney staple, which are not insulin resistant, it was proposed that the hypotensive action of the PPAR agonists be? Do not exercise only through your ability to improve the sensitivity of insulin. Other mechanisms that have been invoked to explain the antihypertensive effects of PPAR agonists? they include their ability to (a) deregulate the expression of peptides that control vascular tone such as PAI-I, endothelium and C-natriuretic peptide of type co (b) alter calcium concentrations and calcium sensitivity of vascular cells (Berger et al., 2002, Diabetes Tech. And Ther.4: 163-174). According to the above description, the isoforms of the PPAR family of nuclear receptors are clearly involved in the systemic regulation of lipid metabolism and serve as "sensors" for fatty acids, prostanoid metabolites, eicosanoids and related molecules. These receptors work to regulate a broad array of genes in a coordinated fashion. The important biochemical pathways resulting from insulin action, lipid oxidation, lipid synthesis, adipocyte differentiation, peroxisome function, cellular apoptosis, and inflammation can be modulated through the individual PPAR isoforms. The strong therapeutic effects of PPARa and PPAR agonists? They favorably influence systemic lipid levels, glucose homeostasis and the risk of atherosclerosis (in the case of activation of PPARa in humans) have recently been discovered. The PPARa and PPAR agonists? they are used at the moment clinically to favorably alter levels of systemic lipids and glucose homeostasis, respectively. Recent observations are made using PPAR ligands that suggest that this isoform is also an important therapeutic target for dyslipidemia and insulin resistance, as well. Thus, PPAR agonists, such as those described herein, can be used in prophylaxis and / or therapeutic treatment of a variety of different conditions and diseases, such as obesity, overweight condition, hyperlipidemia, dyslipidemia including diabetic dyslipidemia associated and mixed dyslipidemia, hypoalphalipoproteinemia, Syndrome X, Type II diabetes mellitus, Type I diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, a diabetic complication (eg, neuropathy, nephropathy, retinopathy or cataracts), hypertension , coronary heart disease, heart failure, hypercholesterolemia, inflammation, thrombosis, congestive heart failure, cardiovascular disease (including atherosclerosis, arteriosclerosis and hypertriglyceridemia), epithelial hyperproliferative diseases (such as eczema and psoriasis) and conditions associated with the lung and intestine and the ape regulation Tito and food consumption in subjects suffering from disorders such as obesity, anorexia, bulimia and anorexia nervosa. (e) Cancer: The modulation of PPAR has also been correlated with cancer treatment. (Burstein et al.; Breast Cancer Res. Treta. 2003 79 (3): 391-7; Alderd et al .; Oncogene, 2003, 22 (22): 3412-6). (f) Weight Control: The administration of PPARα agonists can induce satiety, and in this way they are useful in the loss or conservation of weight. Such PPARa agonists can preferentially act on PPARa, or they can also act on another PPAR, or they can be PPAR total agonists. Thus, the satiety-inducing effect of PPARa agonists can be used for control or weight loss.II. Active PPAR Compounds As indicated in the Compendium and together with the applicable diseases and conditions, a number of different PPAR agonists have been identified. In addition, the present invention provides PPAR agonist compounds described by Formula I as provided in the above Compendium. Included within Formula I are sub-groups of compounds, for example, the sub-groups by structures la, Ib, le, Id, X and XIV as shown in the synthetic schemes below. Included within such compounds of Formula I are exemplary compounds provided in Table I below. Additional compounds within Formula I can also be prepared and tested to confirm activity using conventional methods and the guidance provided herein. lll. Development of Active PPAR Compounds A. Identification and modulator design A large number of different methods can be used to identify modulators and to design improved modulators. Some useful methods involve design based on structure. Modulator design based on structures and identification methods are powerful techniques that can involve computer database records containing a wide variety of. Potential modulators and chemical functional groups. The computerized design and identification of modulators is useful because computer databases contain more compounds than chemical libraries, often by an order of magnitude. For design reviews and drug-based identification of structures (see Kuntz et al., (1994), Acc. Chem. Res. 27: 117; Guida (1994) Current Opinion in Struct. Biol. 4: 777; Colman (1994 ) Current Opinion in Struct. Biol. 4: 868). The three-dimensional structure of a polypeptide defined by the structural coordinates can be used by these design methods, for example, the structural coordinates of a PPAR. In addition, the three-dimensional structures of PPARs determined by homology, molecular replacement, and NMR techniques can also be applied to modulator design and identification methods. To identify modulators, the structural information for a PPAR, in particular, the structural information for the active site of the PPAR can be used. However, it may be advantageous to use the structural information from one or more PPAR co-crystals with one or more binding compounds. It may also be advantageous if the binding compound has a structural core in common with test compounds. Such identification and modulator design can for example be used to identify and / or develop additional active compounds within Formula I (a subgroup thereof). 1. Design when Investigating Molecular Databases A rational design research method for modulators by linking computer representations of compounds from the molecule database. Publicly available databases include, for example: a) ACD from Molecular Designs Limited b) NCI from National Cancer Institute c) CCDC from Cambridge Crystallographic Data Center d) CAST from Chemical Abstract Service e) Derwent from Derwent Information Limited f) Maybridge from Maybridge Chemical Company LTD g) Aldrich from Aldrich Chemical Company h) Directory of Natural Products from Chapman & Hall One of such database (ACD distributed by Molecular Designs Limited Information Systems) contains compounds that are derived synthetically or are natural products. The methods available to those skilled in the art can convert a data set represented in two dimensions to one represented in three dimensions. These methods can be carried out using such computer programs as CONCORD from Tripos Associates or DE-Converter from Molecular Simulations Limited. Multiple methods of structure-based modulator design are known to those skilled in the art (Kuntz et al., (1982), J. Mol. Biol. 62: 269; Kuntz et al., (1994), Acc. Chern. Res. 27: 117; Meng et al., (1992), J. Compt. Chem. 73: 505; Bohm, (1994), J. Comp. Aided Molec. Design 8: 623). A computer program widely used by those skilled in the art of rational modulator design is DOCK from the University of California at San Francisco. The general methods used by this computer program and programs similar to those described in three subsequent applications. More detailed information regarding some of these techniques can be found in the Accelerys User Guide, 1995. A typical computer program used for this purpose can perform a process that comprises the following stages or functions: (a) removing the existing compound to from the protein; (b) linking the structure of another compound within the active site using the computer program (such as DOCK) or interactively moving the compound within the active site; (c) characterizing the space between the compound and the active site atoms; (d) exploring libraries for molecular fragments that (i) can be adjusted within the empty space between the compound and the active site, and (ii) can be bound to the compound; and (e) linking the fragments found around the compound and evaluating the new modified compound. Part (c) refers to characterizing the geometry and the complementary interactions formed between the atoms of the active site and the compounds. A favorable geometric fit is achieved when a significant surface area is divided between the compound and the active site atoms without forming unfavorable spherical interactions. One skilled in the art would observe that the method can be performed by parts (d) and (e) of leakage and select a database of many compounds. The design and identification based on modulator structures of the PPAR function can be used together with the selection of tests. Since large computer databases of compounds (around 10,000 compounds) can be investigated in a matter of hours or even less, the computer-based method can contract compounds-proven potential modulators of PPAR function in biochemical assays or cell phones The above descriptions of the structure-based modulator design are not fully covered and other methods are reported in the literature and can be used, for example: (1) CAVEAT: Bartlett et al., (1989), in Chemical and Biological Problems in Molecular Recognition, Roberts, SM; Ley, S. V .; Campbell, M. M. eds .; Royal Society of Chemistry: Cambridge, pp. 182-196. (2) FLOG: Miller et al. , (1994), J. Comp. Aided Molec.

Design 8: 153. (3) PRO Modulator: Clark et al., (1995), J. Comp. Aided Molec. Design 9: 13. (4) MCSS: Miranker and Karplus, (1991), Proteins: Structure, Function, and Genetics 11:29. (5) AUTODOCK: Goodsell and Olson, (1990), Proteins: Structure, Function, and Genetics 8: 195. (6) GRID: Goodford, (1985), J Med. Chem. 28: 849. 2. Design Modifying Compounds in the Complex with a PPAR Another way to identify compounds as potential modulators is to modify an existing modulator in the active site of the polypeptide. For example, the representation of the computer in the modulators can be modified within the computer representation of an active PPAR site. Detailed instructions for this technique can be found, for example, in the Accelerys User Manual, 1995 in LUDÍ. The representation of the modulator computer is usually modified by the removal of the chemical group or groups or by the addition of a chemical group or groups. At each modification to the compound, the atoms of the modified compound and the active site can be changed into conformation and the distance between the modulator and the active site atoms can be classified together with any complementary interactions formed between the two molecules. The evaluation can be completed when a favorable geometric adjustment and favorable complementary interactions are achieved. Compounds that have favorable evaluations are potential modulators. 3. Design Modifying the Structure of the Compounds that Link to PPAR A third method of modulator-based structure design is to select compounds designed by a modulating construction or modulation search computer program. Examples of these types of programs can be found in the Molecular Simulations Packet, Catalyst.

The descriptions for using this program are documented in the Molecular Simulations User's Guide (1995). Other computer programs used in this application are ISIS / HOST, ISIS / BASE, ISIS / DRA.) Of Molecular Designs Limited and U N ITY of Tripos Associates. These programs can be operated on the structure of a compound that has been removed from the active site of the three-dimensional structure of a compound-PPAR complex.

Operating the prog ram in such a compound is preferable, since it is in a biologically active conformation. A modulating construction computer program is a computer program that can be used to replace computer representations of chemical groups in a compound fused with a PPAR or other biomolecule with groups from a computer database. A modulating search computer program is a computer program that can be used to look for computer representations of compounds from a computer database that have similar three-dimensional structures and similar chemical groups as a compound bound to a particular biomolecule. A typical program may operate using the following general steps: (a) mapping the compounds by chemical characteristics such as by hydrogen bond donors or acceptors, hydrophobic / lipophilic sites, positively ionizable sites, or negatively ionizable sites; (b) add geometric constraints to the mapped characteristics; and (c) search databases with the model generated in (b). Those skilled in the art also recognize that not all possible chemical characteristics of the compound need to be presented in the model of (b). Any subset of the model can be used to generate different models for database searches.

B. Identification of Active Compounds Using a PPAR Structure and Molecular Scaffolds In addition to the methods described above, which are normally applied based on selection hits that have a substantial level of activity, the availability of crystal structures that include ligand binding sites for the various PPARs provides the application of a scaffolding method to identify and develop additional PPAR active compounds. As an example, such a scaffolding method can be applied using molecular scaffolds within Formula I, or having a scaffolding core of Formula I, but can also be applied to other molecular scaffolds that are identified. Thus, the present invention also relates to methods for designing active ligands in PPARs using structural information about the ligand binding sites and the identified PPAR binding compounds. Although such methods can be implemented in many ways (e.g., as described above), preferably, the elevated process uses molecular scaffolds. Such developed processes and related methods are generally described below, and may, as indicated when applied to PPARs, individually and / or in any pair or as a family. Molecular scaffolds are low molecular weight molecules that bind with low or very low affinity to the target and typically have low or very low activity on that target and / or act broadly across families of target molecules. The ability of a scaffold or other compound to act broadly across multiple members of a target family is advantageous for developing ligands. For example, a scaffold or set of scaffolds can serve as starting compounds to develop ligands with desired specificity or desired cross-activity in a selected subset of members of a target family. In addition, the identification of a set of scaffolds that are each linked to members of a target family provides an advantageous basis for selecting a starting point for the development of ligands for a particular objective or subset of objectives. In many cases, the ability of a scaffold to join and / or to have activity in multiple members of a target family is related to an active site or homology of the binding site that exists through the target family. Active scaffolding through multiple members of the target family interacts with surfaces or residues of relatively high homology, that is, binds to conserved regions of the binding cavities. Scaffolds that bind with multiple members can be modified to provide greater specificity or to have a particular cross-reactivity, for example, exploiting differences between the target binding sites to provide specificity, and exploiting similarities to design cross-reactivities. Add substituents that provide attractive interactions with the particular objective of normally increasing binding affinity, often increasing activity. The various parts of the ligand development process are described in greater detail in the following sections, but the following describes an advantageous approach for the development of scaffold-based ligands. The development of scaffold-based ligands (scaffold-based drug discovery) can be implemented in a variety of ways, but large-scale expression is useful in providing material for crystallization, co-crystallization and biochemical selection (e.g. of union and activity). For crystallization, the crystallization conditions can be established for the apo protein and a structure determined from those crystals. For selection, a partial library selected for the particular target family is preferably selected for attachment and / or activity on the target. A highly preferable plurality of members is selected from the target family. Such selection, whether in a single objective or in multiple members of a target family, provides selection successes. Low affinity and / or low activity hits are selected. Such low affinity hits can identify a scaffolding molecule, or allow the identification of a scaffolding molecule by analyzing common characteristics between the binding molecules. The simplest molecules that contain the common characteristics can then be tested to determine if they retain the binding and / or the activity, so that the identification of a scaffolding molecule is allowed. When multiple members of a particular target family are used for selection, the overlap in binding activity and / or activity of compounds can provide a useful selection for compounds that will undergo crystallization. For example, for 3 target molecules of a target family, if each target has approximately 200-500 hits in the selection of a particular library, much smaller subsets of those hits will be common to any of 2 of the 3 targets, and a subset even smaller will be common to all 3 targets, for example, 100-300. In many cases, the compounds in the subset common to all 3 targets will be selected for co-crystallography, since they provide the broadest potential for the development of ligands. Once the compounds for co-crystallization are selected, the conditions for forming the co-crystals are determined, allowing the determination of a co-crystal structure and the orientation of the binding compound at the target binding site is determined solving the structure (this can be addressed highly if a crystal structure of apo protein has been determined or if the structure of a nearby homolog is available for use in a homology model.) Co-crystals are preferably formed by co-crystallization Directly instead of by impregnation of the compound into apo-protein crystals From the co-crystals and the knowledge of the structure of the binding compounds, the additional selection of scaffolds or other binding compounds can be done by applying the selection, for example, for (1) mode of attachment, (2) multiple sites for substitution and / or (3) treatable chemistry. The ion can, for example, be based on the demonstration of a dominant mode of union. That is, a scaffold or composite of a group of scaffolds are joined with a consistent orientation, preferably a consistent orientation across multiple members of a target family. Filtering scaffolds for multiple sites for substitution provides greater potential to develop ligands for specific targets due to the large capacity to appropriately modify the structure of the scaffolding. Filtering the treatable chemistry also facilitates the preparation of ligands derived from a scaffold because the synthetic trajectories making derivative compounds are available. Carrying out such a development process provides scaffolds, preferably of divergent structure. In some cases, it may be impractical or undesirable to work with a particular objective for some or all of the development process. For example, a particular goal may be difficult to express, be easily degraded, or difficult to crystallize. In these cases, a substitute goal can be used from the target family. It is desirable to have the substitute that is as similar as possible to the desired objective, thus a family member having high homology at the binding site should be used, or the binding site can be modified to be more similar to that of the desired target, or part of the desired target sequence can be inserted into the family member by replacing the corresponding part of the family member sequence. Once one or more scaffolds are identified for a target family, the scaffolds can be used to develop multiple products targeted at specific members of the family, or specific subsets of family members. In this way, from a scaffold, which acts on multiple members of the target family, the derivative compounds (ligands) can be designed and tested so that they have increased selectivity. In addition, such ligands are normally developed to have greater activity, as well as to have normally higher binding affinity. In this process, when starting with the action scaffold extensively, the ligands are developed in a way that have improved selectivity and activity profiles, leading to the identification of major compounds for drug development, leading drug candidates, and final drug products. . C. Scaffolds Normally, it is advantageous to select scaffolds (and / or assemblies or libraries of compounds for the identification of the scaffold or the binding compound) with particular types of characteristics, for example, to select compounds that are more likely to join a target. particular and / or to select compounds having physical and / or synthetic properties to simplify the preparation of derivatives, which are drug-like, and / or to provide convenient sites and chemistry for modification or synthesis. The useful chemical properties of molecular scaffolds may include one or more of the following characteristics, but are not limited thereto: an average molecular weight below about 350 daltons, or between about 150 to about 350 daltons, or from about 150 to about 300 daltons; having a ClogP below 3; a number of rotatable joints of less than 4; a number of hydrogen bonding donors and acceptors below 5 or below 4; a Polar Surface Area of less than 100 A2; binding at the protein binding sites in an orientation so that chemical substituents from a combinatorial library that bind to the scaffold can be projected into cavities at the protein binding site; and having chemically treatable structures at their substituent attachment points that can be modified, thereby allowing the rapid construction of the library. The term "Molecular Polar Surface Area (PSA)" refers to the sum of surface contributions of polar atoms (usually oxygens, nitrogens and bound hydrogens) in a molecule. The polar surface area has been shown to correlate well with drug transport properties, such as intestinal absorption, or penetration into the re-brain barrier. Additional chemical properties of compounds for inclusion in a combinatorial library include the ability to bind chemical moieties to the compound which will not interfere with the binding of the compound to at least one protein of interest, and which will impart desirable properties to the members of the library, for example, by causing members of the library to be actively transported to cells and / or organs of interest, or the ability to bind to a device such as a chromatography column (eg, a streptavidin column through a molecule such as biotin) for uses such as tissue and proteomic profile purposes. A person with ordinary skill in the art will understand other properties that may be desirable for scaffolding or library members that have to depend on the particular requirements of use, and so that compounds with these properties can also be searched and identified in a similar way. Methods for screening compounds for testing are known to those of ordinary skill in the art, for example, the methods and compounds described in US Patent No. 6,288,234, 6,090,912, 5,840,485, each of which is incorporated herein by reference in its entirety, including all graphics and drawings. In various embodiments, the present invention provides methods for designing ligands that bind to a plurality of members of the molecular family, wherein the ligands contain a common molecular scaffolding. Thus, a set of compounds can be evaluated to bind to a plurality of members of a molecular family, for example, a family of proteins. One or more compounds that bind to a plurality of family members can be identified as molecular scaffolds. When the orientation of the scaffolding at the binding site of the target molecules has been determined and the chemically treatable structures have been identified, a set of ligands can be synthesized by starting with one or a few molecular scaffolds to achieve a plurality of ligands, wherein each ligand binds to a target molecule separated from the molecular family with altered or changed binding affinity or a binding specificity relative to the scaffold. Thus, a plurality of main drug molecules can be designed to individually target members of a molecular family based on the same molecular scaffold, and to act them in a specific manner.

D. Binding Assays 1. Use of Binding Assays The methods of the present invention involve assays that are capable of detecting the binding of compounds of a target molecule to a signal of at least about three times the standard deviation of the background signal , or at least about four times the standard deviation of the background signal. Assays may also include analyzing compounds for low affinity binding to the target molecule. A large variety of assays indicative of binding are known for different target types and can be used for this invention. Compounds that act broadly across protein families are not likely to have a high affinity against individual targets, due to the broad nature of their binding. Thus, assays (e.g., as described herein) give high preference preference to the identification of compounds that bind with low affinity, very low affinity, and extremely low affinity. Therefore, the potency (or binding affinity) is not a major, or even the most important, sign of identification of a potentially useful binding compound. Rather, even those compounds that bind with low affinity, very low affinity, or extremely very low can be considered as molecular scaffolds that can continue to the next phase of the ligand design process. As indicated above, to design or discover scaffolds that act broadly across protein families, the proteins of interest can be evaluated against a collection or set of compounds. The assays may preferably be enzymatic or binding assays. In some embodiments, it may be desirable to improve the solubility of the compounds that are selected and then analyze all compounds that show activity in the assay, including those that bind with low affinity or produce a signal greater than about three times the standard deviation of the background signal. These assays can be any assay such as, for example, binding assays that measure the binding affinity between two binding partners. Various types of screening assays that may be useful in the practice of the present invention are known in the art, such as those described in US Patents Nos. 5,763,198, 5,747,276, 5,877,007, 6,243,980, 6,294,330 and 6,294,330, each of which it is incorporated herein by reference in its entirety, including all graphics and drawings. In several test modalities, at least one compound, al. less about 5%, at least about 10%, at least about 15%, at least about 20%, or at least about 25% of the compounds can be linked with low affinity. In many cases, up to about 20% of the compounds may show activity in the screening test and these compounds can be analyzed directly with high-throughput co-crystallography, computational analysis to group the compounds into classes with common structural properties (e.g. of structural core and / or shape and polarity), and the identification of common chemical structures among the compounds that show activity. The person with ordinary skill in the art will understand that decisions can be based on criteria that are appropriate for the needs of the particular situation, and that decisions can be made by computer software programs. Classes can be created that contain almost any number of scaffolds, and the selected criteria can be based on increasingly accurate criteria until an uncontrolled number of scaffolds arrive for each class that is conceptualized to be advantageous. 2. Surface Plasmon Resonance The binding parameters can be measured using surface plasmon resonance, for example, with a BIAcore® chip (Biacore, Japan) coated with immobilized binding components. Surface plasmon resonance is used to characterize the microscopic association and reaction dissociation constants between a sFv or other ligand directed against target molecules. Such methods are generally described in the following references which are incorporated herein by reference. Vely F. et al. , BIAcore® analysis to test phosphopeptide-SH2 domain interactions, Methods in Molecular Biology. 121: 313-21, 2000; Liparoto et al. , Biosensor analysis of the interleukin-2 receptor complex, Journal of Molecular Recognition. 12: 316-21, 1999; Lipschultz et al. , Experimental design for analysis of complex kinetics using surface plasmon resonance, Methods. 20 (3): 310-8, 2000; Malmqvist. , BIACORE: an affinity biosensor system for characterization of biomolecular interactions, Biochemical Society Transactions 27: 335-40, 1 999; Alfthan, Surface plasmon resonance biosensors as a tool in antibody engineering, Biosensors & Bioelectronics. 13: 653-63, 1998; Fivash et al. , BIAcore for macromolecular interaction, Current Opinion in Biotechnology. 9: 97-1 01, 1998; Price et al.; Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUCI mucin. Tumor Biology 19 Suppl 1: 1 -20, 1998; Malmqvist et al, Biomolecular interaction analysis: affinity biosensor technologies for functional analysis of proteins, Current Opinion in Chemical Biology. 1: 378-83, 1997; O'Shannessy et al. , Interpretation of deviations from pseudo-first-order kinetic behavior in the characterization of ligand binding by biosensor technology, Analytical Biochemistry. 236: 275-83, 1996; Malmborg et al., BIAcore as a tool in antibody engineering, Journal of immunological Methods. 183: 7-13, 1995; Van Regenmortel, Use of biosensors to characterize recombinant proteins, Developments in Biological Standardization. 83: 143-51, 1994; and O'Shannessy, Determination of kinetic rate and constant equilibrium binding for macromolecular interactions: a critique of the surface plasmon resonance literature, Current Opinions in Biotechnology. 5: 65-71,1994. BIAcore® uses the optical properties of surface plasmon resonance (SPR) to detect alterations in the concentration of proteins bound to a dextran matrix that are located on the surface of a gold / glass sensor chip interface, a biosensor matrix of dextran. In brief, the proteins are covalently bound to the dextran matrix at a known concentration and a ligand for the protein is injected through the dextran matrix. Near-infrared light, directed on the opposite side of the sensor chip surface, is reflected and also induces an evanescent wave in the gold film, which in turn, causes a reduction in intensity in light reflected at a particular angle known as the resonance angle. If the refractive index of the sensor chip surface is altered (for example, by ligand binding to the bound protein) a change in the resonance angle occurs. This angle change can be measured and expressed as resonance units (the RUs) so that 1000 RU is equivalent to a change in the surface protein concentration of 1 ng / mm2. These changes are displayed with respect to time along the y axis of a sensorgram, which describes the association and dissociation of any biological reaction. E. High Performance Selection Tests (HTS) The HTS normally uses automated tests to look for large direct numbers of compounds for a desired activity. Typically, HTS assays are used to find new drugs by selecting chemicals that act on a particular enzyme or molecule. For example, if a chemical inactivates an enzyme, it could prove effective in preventing a process in a cell that causes disease. High throughput methods allow researchers to evaluate thousands of different chemicals against each target molecule very quickly using robotic management systems and automated results analysis. As used herein, "high throughput selection" or "HTS" refers to the rapid in vitro selection of large numbers of compounds (libraries); it tends generally to hundreds of thousands of compounds, using robotic selection tests. The Ultra High Performance Selection (uHTS) generally refers to the selection of accelerated high performance to more than 100, 000 tests per day. In order to achieve high performance selection, it is advantageous to host samples in a multirecipient carrier or platform. A multi-container carrier facilitates measuring the reactions of a plurality of candidate compounds simultaneously. Multi-well microplates can be used as the carrier. Such multi-well microplates and methods for their use in numerous assays are known in the art and are commercially available. Selection tests may include control for calibration purposes and confirmation of proper handling of the test components. Blank wells containing all reagents, but not members of the chemical library are usually included. As another example, a known inhibitor (or activator) of an enzyme for which modulators are sought, can be incubated with a test sample, and the resulting decrease (or increase) in the enzymatic activity used as a comparator or a control. It will be appreciated that the modulators can also be combined with the enzyme activators or inhibitors to find modulators that inhibit the activation or enzymatic repression that is otherwise caused by the presence of the known enzymatic modulator. Similarly, when ligands to a target are searched, known ligands of the target can be presented in control / calibration test wells.

F. Measuring Enzymatic and Union Reactions During Screening Assays Techniques for measuring the progress of enzymatic reactions and binding, eg, in multi-container carriers, are known in the art and include, but are not limited to the following. Spectrophotometric and spectrofluorometric assays well known in the art. Examples of such assays include the use of colorimetric assays for the detection of peroxides, as described in Gordon, A.J. and Ford, R.A. , The Chemist's Companion: A Handbook of Practical Data, Techniques, And References, John Wiley and Sons, N .Y. , 1972, page 437. Fluorescence spectrometry can be used to monitor the generation of reaction products. The fluorescence methodology is generally more sensitive than the absorption methodology. The use of fluorescent probes is well known to those skilled in the art. For reviews, see Bashford et al. , Spectrophotometrv and Spectrofluorometrv: A Practical Approach. pp. 91 -1 14, I RL Press Ltd. (1987); and Bell, Spectroscopy I n Biochemistry, Vol. I, pp. 155-194, CRC Press (1981). In spectrofluorometric methods, enzymes are exposed to substrates that change their intrinsic fluorescence when processed by the target enzyme. Normally, the substrate is not fluorescent and is converted to a fluorophore through one or more reactions. As a non-limiting example, the Mase activity can be detected using the Amplex® Red reagent (Molecular Probes, Eugene, OR). In order to measure sphingomyelinase activity using Amplex® Red, the following reactions occur. First, SMase hydrolyzes spinfomyelin to produce ceramide and phosphorylcholine. Second, alkaline phosphatase hydrolyzes phosphorylcholine to produce choline. Third, the hill is oxidized to betaine. Finally, the H2O2, in the presence of horseradish peroxidase, reacts with Amplex® Red to produce the fluorescent product, Resorufina and the signal of the same is detected using spectrofluorometry. Fluorescence polarization (FP) is based on a decrease in the rate of molecular rotation of a fluorophore that occurs at binding to a larger molecule, such as a receptor protein, allowing fluorescence emission polarized by the bound ligand. FP is determined empirically by measuring the vertical and horizontal components of fluorophore emission following excitation with plane polarized light. Polarized emission increases when the molecular rotation of a fluorophore is reduced. A fluorophore produces a larger polarized signal when it binds to a larger molecule (i.e., a receptor), decreasing the molecular rotation of the fluorophore. The magnitude of the polarized signal is quantitatively related to the degree of fluorescent ligand binding. Accordingly, the polarization of the "bound" signal depends on the maintenance of high affinity binding. FP is a homogenous technology and the reactions are very fast, taking seconds to minutes to reach equilibrium. The reagents are stable, and large batches can be prepared, resulting in high reproducibility. Because of these properties, FP has been shown to be highly automated, often performed with a single incubation with a simple, pre-mixed receptor-tracer reagent. For a review, see Owickiet et al., Application of Fluorescence Polarization Assays in High-Troughput Screening Genetic Engineering News, 17:27, 1997. FP is particularly desirable since its reading is independent of emission intensity (Checovich, WJ , et al., Nature 375: 254-256, 1995, Dandliker, WB, et al., Methods in Enzymology 74: 3-28, 1981) and is thus insensitive to the presence of color compounds that extinguish the fluorescence emission. FP and FRET (see below) are well suited for identifying compounds that block interactions between sphingolipid receptors and their ligands. See, for example, Parker, et al., Development of high troughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase / phosphatase assays, J Biomol Screen 5: 77-88, 2000. Fluorophores derived from spinfolpides which can be used in FP trials are commercially available. For example, Molecular Probes (Eugene, OR) currently markets espingomyelin and fluorophores of a ceramide. These are, respectively, N- (4,4-difluoro-5,7-dimethyl-4-bora-3a, 4a-diaza-s-indacen-3-pentanoyl) espingosyl phosphocholine (BODI PY® FL C5-espingomyelin); N- (4,4-difluoro-5,7-dimethyl-4-bora-3a, 4a-diaza-s-indacen-3-dodecanoyl) espingosiI phosphocholine (BODI PY® FL C12-espingomyelin); and N- (4,4-difluoro-5,7-dimethyl-4-bora-3a, 4a-diaza-s-indacen-3-pentanoyl) espingosine (BODI PY® FL C5-ceramide). US Patent No. 4,150,949 (Immunoassay for gentamicin), describes gentamicins labeled with fluorescein, including fluoresceintiocarbanyl gentamicin. Additional fluorophores can be prepared using methods well known to those skilled workers. Exemplary normal and polarized fluorescence readers include the POLARION® fluorescence polarization system (Tecan AG, Hombrechtikon, Switzerland). General multi-well plate readers for other assays are available, such as the VERSAMAX® reader and the SPECTRAMAX® multi-well plate spectrophotometer (both from Molecular Devices). The fluorescence resonance energy transfer (FRET) is another useful assay to detect the interaction and has been described. See for example, I EM et al., Curr.

Biol. 6: 178-182, 1996; Mitra et al., Gene 173: 13-17 1996; and Selvin et al., Meth. Enzymol. 246: 300-345, 1995. The FRET detects the transfer of energy between two fluorescent substances in close proximity, which has known excitation and emission wavelengths. As an example, a protein can be expressed as a fusion protein with green fluorescent protein (GFP). When two fluorescent proteins are in proximity, such as when a protein interacts specifically with a target molecule, the resonance energy can be transferred from one excited molecule to the other. As a result, the emission spectrum of the sample changes, which can be measured by a fluorometer, such as a fMAX multipole fluorometer (Molecular Devices, Sunnyvale Calif.). The scintillation proximity assay (SPA) is a particularly useful assay for detecting an interaction with the target molecule. SPA is widely used in the pharmaceutical industry and has been described (Hanselman et al., J. Lipid Res. 38: 2365-2373 (1997); Kahl et al., Anal. Biochem. 243: 282-283 (1996); Undenfriend et al., Anal. Biochem. 161: 494-500 (1987)). See also U.S. Patent Nos. 4,626,513 and 4,568,649 and European Patent No. 0,154,734. A commercially available system uses FLASHPLATE® scintillation coated plates (NEN Life Science Products, Boston, MA). The target molecule can be attached to the scintillation plates by a variety of well-known means. Blinking plates are available so that they are derived to bind fusion proteins such as GST, His6 or Flag fusion proteins. Where the target molecule is a protein complex or a multimer, a protein or subunit can bind to the first plate, then the other components of the complex are then added under binding conditions, resulting in a bound complex. In a typical SPA assay, the genetic products in a pressure junction that have been radiolabelled and added to the wells are allowed to interact with the solid phase, which is the immobilized target molecule and the scintillation coating in the wells. The test can be measured immediately or allowed to reach equilibrium. Any way, when a radio tag becomes sufficiently narrowed to the scintillation coating, it produces a detectable signal by a device such as a TOPCOUNT NXT® microplate scintillation counter (Packard BioScience Co., Meriden Conn.). If a radiolabelled expression product binds to the target molecule, the radiolabel remains in proximity to the blinking lamp long enough to produce a detectable signal. In contrast, tagged proteins that do not bind to the target molecule, or bind only shortly, will not remain near the blinking enough time to produce a signal on the background. Any time spent near the blinking caused by random Brownian movement will not result in a significant amount of signal either. Likewise, the residual unincorporated radiolabel used during the expression stage may be present, but will not generate significant signal because it will be in solution instead of interacting with the target molecule. These non-union interactions will therefore cause a certain level of background signal that can be removed mathematically. If too many signals are obtained, the salt or other modifiers can be added directly to the assay plates until the desired specificity is obtained (Nichols et al., Anal. Biochem 257: 112-119, 1998). Additionally, the assay can use an AlphaScreen format (homogeneous luminescent proximity probe amplification), for example, the AlphaScreening system (Packard BioScience). AlphaScreen is generally described in Seethala and Prabhavathi, Homogenous Assays: AlphaScreen, Handbook of Drug Screening, Marcel Dekkar Pub. 2001, p. 106-110. Applications of the art to PPAR receptor ligand binding assays are described, for example, in Xu, et al., 2002, Nature 415: 813-817. G. Compound and Scaffolding Tests Molecular As described above, preferred scaffold features include the existence of low molecular weight (eg, less than 350 Da, or from about 100 to about 350 daltons, or from about 150 to about 300 daltons). Preferably clog P of a scaffolding is from -1 to 8, more preferably less than 6, 5 or 4, more preferably less than 3. In particular embodiments, the clogP is in a range -1 to an upper limit of 2, 3, 4, 5, 6 or 8; or is in a range from 0 to an upper limit of 2, 3, 4, 5, 6 or 8. Preferably, the number of rotatable joints is less than 5, more preferably less than 4. Preferably, the number of Donors and hydrogen bond acceptors are below 6, most preferably below 5. An additional criterion that may be useful is a Polar Surface Area less than 100. The guidance that may be useful to identify criteria for an application particular can be found in Lipinski et al., Advanced Drug Delivery Reviews 23 (1997) 3-25, which is incorporated herein by reference in its entirety. A scaffold will preferably be attached to a given protein binding site in a configuration that causes substituent portions of the scaffold to be located in cavities of the protein binding site. Also, having chemically treatable groups that can be chemically modified, particularly through synthetic reactions, to easily create a combinatorial library can be a preferred feature of scaffolding. Own positions can also be preferred in the scaffolding to which other portions can be attached, which do not interfere with the scaffolding junction of the protein or proteins of interest, but do not cause scaffolding to achieve a desirable property, for example, the active transport of the scaffold. Scaffolding to cells and / or organs, allowing scaffolding to be attached to a chromatographic column to facilitate analysis, or other desirable property. A molecular scaffold can bind to a target molecule with any affinity, such as binding with a measurable affinity as approximately three times the standard deviation of the background signal, or at high affinity, moderate affinity, low affinity, very low affinity, or extremely low affinity. In this way, the above criteria can be used to select many compounds to prove that they have the desired attributes. Many compounds having the described criteria are available in the commercial market, and can be selected by analysis depending on the specific needs to which the methods are to be applied. In some cases, sufficiently large numbers of compounds can meet the specific criteria so that additional methods that group similar compounds can be useful. A variety of methods to assess molecular similarity, such as the Tanimoto coefficient has been used, see Willett et al, Journal of Chemical Information and Computer Science 38 (1998), 938-996. These can be used to select a smaller subset of a group of highly structural redundant compounds. In addition, cluster analysis based on relationships between the compounds, or structural components of the compound, can also be carried out at the same end; see Lance and Williams Computer Journal 9 (1967) 373-380, Jarvis and Patrick IEEE Transactions in Computer C-22 (1973) 1025-1034, for clustering algorithms, and Downs et al., Journal of Chemical Information and Computer Sciences 34 (1994) 1094-1102 for a review of these methods applied to chemical problems. One method to derive the chemical components of a large group of potential scaffolds is to virtually break the compound into rotatable bonds so that components of no less than 10 atoms are produced. The resulting components can be grouped based on some measure of similarity, for example, the Tanimoto coefficient, which produces the groups of the common component in the original collection of compounds. For each group of the component, all compounds containing that component can be grouped, and the resulting groups used to select a diverse set of compounds that contain a common chemical core structure. In this way, a useful library of scaffolds can still be derived from millions of commercial compounds. A "compound library" or "library" is a collection of different compounds that have different chemical structures. A library of the compound is selectable, i.e., members of the library of the compound herein can be screened for selection. In preferred embodiments, the library members can have a molecular weight from about 100 to about 350 daltons, or from about 150 to about 350 daltons. Libraries may contain at least one compound that binds to the target molecule in low affinity. The libraries of the candidate compounds can be evaluated by many different assays, such as those described above, for example, a fluorescence polarization assay. Libraries may consist of chemically synthesized peptides, peptidomimetics, or combinatorial chemical arrays that are large or small, focused or unfocused. By "focus" it is meant that the collection of compounds is prepared using the structure of previously characterized compounds and / or pharmacophores. The libraries of the compound may contain molecules isolated from natural sources, artificially synthesized molecules, or molecules synthesized, isolated or otherwise prepared in such a form so that they have one or more variant portions, for example, They are isolated independently or synthesized randomly. The types of molecules in the libraries of the compound include, but are not limited to, organic compounds, polypeptides and nucleic acids, as those terms are used in the present, and derivatives, conjugates and mixtures thereof. The libraries of the compound useful for the invention can be purchased commercially or prepared or obtained by any means including, but not limited to, combinatorial chemistry techniques. Fermentation methods, plant and cell extraction procedures and the like (see for example, Cwirla et al., Biochemistry 1990, 87, 6378-6382; Houghten et al., Nature 1991, 354, 84-86; Lam et al., Nature 1991, 354, 82-84; Brenner et al., Proc. Nati Acad. Sci. USA 1992, 89, 5381-5383; R. A. Houghten, Trends Genet. 1993, 9, 235-239; E. R. Felder, Chimia 1994, 48, 512-541; Gallop et al., J. Med. Chem. 1994, 37, 1233-1251; Gordon et al., J. Med. Chem. 1994, 37, 1385-1401; Carell et al., Chem. Biol. 1995, 3, 171-183; Madden et al., Perspectives in Drug Discovery and Design 2, 269-282; Lebl et al., Biopolymers 1995, 37 177-198); small molecules assembled around a shared molecular structure; collections of chemicals that have been assembled by various commercial and non-commercial groups, natural products; extracts of marine organisms, fungi, bacteria and plants. Preferred libraries can be prepared in a homogeneous reaction mixture, and the separation of non-reactive reagents from members of the library is not required before selection. Although many combinatorial chemistry approaches are based on solid-state chemistry, combinatorial liquid-phase chemistry is capable of generating libraries (Sun CM., Recent advances in liquid-phase combinatorial chemistry, Combinatorial Chemistry &High Troughput Screening 2: 299 -318, 1999). Libraries of a variety of types of molecules are prepared in order to obtain members thereof having one or more pre-selected attributes that can be prepared by a variety of techniques, including, but not limited to, parallel array synthesis (Houghton , Annu Rev Pharmacol Toxicol 2000 40: 273-82, parallel disposition and synthetic combinatorial chemistry based on the mixture, combinatorial chemistry solution phase (Merritt, Comb Chem High Throughput Screen 1998 1 (2): 57-72, Chemistry Combinatorial Solution Phase, Coe et al., Mol Divers 1998-99, 4 (1): 31-8, Combinatorial Chemistry of Solution Phase, Sun, Comb Chem High Troughput Screen 1999 2 (6): 299-318, Recent advances in the combinatorial chemistry of liquid phase), synthesis in the soluble polymer (Gravert et al., Curr Opin Chem Biol 1997 1 (1): 107-13, Synthesis in soluble polymers: new reactions and the construction of small molecules) and similar, see for example, D Olle et al., J Comb Chem 1999 1 (4): 235-82, Integral Inspection of Combinatorial Library Synthesis: 1998. Freidinger RM., Non-Peptide Ligands for Peptide and Protein Receptors, Current Opinion in Chemical Biology; and Kundu et al., Prog Drug Res 1999; 53: 89-156, Combinatorial Chemistry: Sustained Polymeric Synthesis of Peptide and Non-Peptide Libraries). The compounds can be clinically oriented for ease of identification (Chabala, Curr Opin Biotechnol 1995 6 (6): 633-9, solid phase combinatorial chemistry and novel labeling methods for identifying instructions). Combinatorial synthesis of carbohydrates and libraries containing oligosaccharides have been described (Schweizer et al., Curr Opin Chem Biol 19993 (3): 291-8, the combinatorial synthesis of carbohydrates). The synthesis of compound libraries based on a product has been described (Wessjohann, Curr Opin Chem Biol 20004 (3): 303-9, Synthesis of natural-product based compound libraries). Nucleic acid libraries are prepared by various techniques, including by way of non-limiting example, the only ones described herein, for the isolation of aptamers. Libraries that include oligonucleotides and polyamino-oligonucleotides (Markiewicz et al., Synthetic oligonucleotide combinatorial libraries and their applications, Drug 55: 174-7, 2000) deployed in streptavidin magnetic beads are known. Nucleic acid libraries are known that can be coupled to sample in parallel and deployed without complex procedures such as automated mass spectrometry (Enjalbal C. Martinez J. Aubagnac JL, Mass spectrometry in combinatorial chemistry, Mass Spectrometry Reviews 19: 139-61 , 2000) and the labeling in parallel. (Perrin DM., Nucleic acids for recognition and catalysis: landmarks, limitations, and looking to the future, Combinatorial Chemistry &; ~ High Throughput Screening 3: 243-69). Peptidomimetics are identified using combinatorial chemistry and solid phase synthesis (Kim HO. Kahn M., A merger of rational drug design and combinatorial chemistry: development and application of peptide secondary structure mimetics, Combinatorial Chemistry &High Troughput Screening 3: 167 -83, 2000, al-Obeidi, Mol Biotechnol 1998 9 (3): 205-23, Peptide libraries and peptidomimetics, molecular diversity and drug design). The synthesis can be completely random or based in part on a known polypeptide. The polypeptide libraries can be prepared according to various techniques. In short, the techniques deployed can be used to produce polypeptide ligands (Gram H, Phage display in proteolysis and signal transduction, Combinatorial Chemistry &High Throughput Screening, 2: 19-28, 1999) that can be used as the basis for the synthesis of peptidomimetics. Polypeptides, restricted peptides, proteins, protein domains, antibodies, single chain antibody fragments, antibody fragments, and antibody combining regions are displayed in filamentous phage for selection. Large libraries of individual variants of human single chain Fv antibodies have been produced. See, for example, Siegel R. W. Alien B. Pavlik P. Marks JD. Bradbury A., Mass spectrum analysis of a protein complex using single chain antibodies selected in a peptide target: applications to functional genomes, Journal of Molecular Biology 302: 285-93, 2000; Poul MA. Becerril B. Nielsen UB. Morisson P. Marks JD., Selection of human antibodies for tumor-specific internalization from phage libraries. Source Journal of Molecular Biology 301: 1149-61, 2000; Amersdorfer P. Marks JD., Phage libraries for the generation of anti-botulinum scFv antibodies, Methods in Molecular Biology. 145: 219-40, 2001; Hughes-Jones NC. Bye JM. Gorick BD. Marks JD. Ouwehand WH., Synthesis of Rh Fv phage-antibodies using VH and VL germline genes, British Journal of Haematology. 105: 811-6, 1999; McCall AM. Amoroso AR. Sautes C. marks JD. Weiner LM., Characterization of single chain Fv fragments Rm Fc anti-mouse derived from human phage display libraries, Imunotechnology. 4: 71-87, 1998; Sheets MD. Amersdorfer P. Finnern R. Sargent P. Lindquist E. Schier R. Hemingsen G. Wong C. Gerhart JC. Marks JD. Lindquist E., Efficient construction of a large noimmune phage antibody library: the production of high-affinity human single-chain antibodies to protein antigens (the published errata appears in Proc Nati Acad Sci USA 1999 96: 795), Proc Nati Acad Sci? SA95. ^ Q ^ 57-62, 1998). Acute and focused chemical and pharmacophore libraries can be designed with the aid of sophisticated strategies involving computational chemistry (eg, Kundu B. Khare SK, Rastogi SK, Combinatorial chemistry: polymer supported synthesis of peptide and non-peptide libraries, Progress in Drug Research 53: 89-1 56, 1999) and the use of structure-based ligands using datábase searching and docking, de novo drug design and estimation of ligand binding affinities (Joseph-McCarthy D., Computational approaches to structure-based ligand design, Pharmacology & Therapeutics 84: 179-91, 1999, Kirkpatrick DL.Watson S. Ulhaq S., Structure-based drug design: combinatorial chemistry and molecular modeling, Combinatorial Chemistry &High Throughput Screening. 21 1 -21, 1999, Eliseev AV Lehn J M., Dynamic combinatorial chemistry: evolutionary formation and screening of molecular libraries, Current Topics in Microbiology &Immunology 243: 159-72, 1999; Bolger et al. , Methods Enz. 203: 21 -45, 1991; Martin, Methods Enz. 203: 587-613, 1 991; Neidle et al. , Methods Enz. 203: 433-458, 1 991; OR . S. Patent 6, 178, 384). Select a library of potential scaffolds and a set of dispositions that measure the binding to representative target molecules that are in a family of particular proteins that allows in this way the creation of data set that outline the union of the library to the protein family objective. Scaffolding groups with different sets of binding properties can be identified using the information within this data set. In this way, scaffolding groups that join one, two or three family members can be selected for particular applications. In many cases, a group of scaffolds that exhibit binding to two or more members of a target protein family will contain scaffolds with a higher likelihood that such binding results from specific interactions with the individual target proteins. This would be expected to substantially reduce the effect of so-called "promiscuous inhibitors" that severely complicate the interpretation of screening assays (see McGovern et al., Journal of Medicinal Chemistry 45: 1712-22, 2002). Thus, in many preferred applications, the binding property of deployment to multiple target molecules in a protein family can be used as a selection criterion to identify molecules with desirable properties. In addition, groups of scaffolds that bind to specific subsets of a set of potential target molecules can be selected. Such a case would include the subset of scaffolds that bind to either two or three or three of five members of a target protein family. Such subsets can also be used in combination or opposition to further define a group of scaffolds that have additional, desirable properties. This would be of significant utility in cases where some members of a family of proteins that had known desirable effects are inhibited, such as inhibiting tumor growth, while inhibiting other members of the protein family found to be essential for function. Normal cellular would have undesirable effects. One criterion that would be useful in such a case includes the selection of the subset of scaffolds that bind to any two or three desirable target molecules and eliminating from this group any one that binds to more than one of any three undesirable target molecules.

H. Crystallography After the binding compounds have been determined, the orientation of the compound bound to the target is determined. Preferably, this determination involves crystallography in co-crystals of molecular scaffolding compounds with the target. Most protein crystallographic platforms can be designed preferably by analyzing up to approximately 500 co-complexes of compounds, ligands or molecular scaffolds attached to the protein targets due to the physical parameters of the instruments and the convenience of operation. If the number of scaffolds that have binding activity exceeds a convenient number for the application of crystallography methods, the scaffolds may be placed within groups based on having at least one common chemical structure or other desirable characteristics and representative compounds may be selected from of one or more of the classes. Classes can be done with increasingly severe criteria until a desired number of classes is obtained (for example, 1 0, 20, 50, 100, 200, 300, 400, 500). Classes can be based on chemical structural similarities between the molecular scaffolds in the class, for example, they all have a pyrrole ring, a benzene ring or other chemical characteristic. Likewise, the classes can be based on shaped features, for example, space filling characteristics. Analysis by co-crystallography can be performed by co-fusing each scaffold with its objective, for example, in scaffold concentrations that showed activity in the selection trial. This co-combination can, for example, be achieved with the use of organic solvents of low percentage with the target molecule and then concentrating the objective with each of the scaffolds. In preferred embodiments, these solvents are less than 5% of the organic solvent such as dimethyl sulfoxide (DMSO), ethanol, methanol, or ethylene glycol in water or other aqueous solvent. Each scaffold fused to the target molecule can then be selected with an appropriate number of crystallization selection conditions at an appropriate temperature, for example, 4 and 20 degrees. In the preferred embodiments, approximately 96 crystallization selection conditions can be performed in order to obtain sufficient information about the co-combination and crystallization conditions, and the orientation of the scaffold at the binding site of the target molecule. The crystal structures can then be analyzed to determine how to find the scaffolding to be physically oriented within the binding site or within one or more of the molecular family member attachment cavities. It is desirable to determine the atomic coordinates of the compounds bound to the target proteins in order to determine which is the most suitable scaffold for the protein family. X-ray crystallographic analysis is therefore more preferable for determining atomic coordinates. Those selected compounds can also be tested with the application of medicinal chemistry. The compounds can be selected for medicinal chemistry testing based on their binding position in the target molecule. For example, when the compound binds to a binding site, the binding position of the compound at the binding site of the target molecule can be considered with respect to the chemistry that can be performed on chemically treatable structures or sub-structures of the compound, and how such modifications in the compound are expected to interact with structures or sub-structures at the target binding site. In this way, one can explore the binding site of the target and the chemistry of the scaffolding in order to make decisions on how to modify the scaffolding to arrive at a ligand with the highest potency and / or selectivity. The structure of the target molecule bound to the compound may also be superimposed or aligned with other member structures of the same protein family. In this way, the scaffolding modifications can be made to improve the union to members of the target family in general, thus improving the usefulness of the scaffolding library. Different useful alignments can be generated, using a variety of criteria such as minimum RASD superposition of alpha-carbons or structure atoms of homologous or structurally related regions of the proteins. These processes allow for greater direct design of ligands, using structural and chemical information obtained directly from! co-complex, so one is allowed more efficient and rapidly design main compounds that are likely to lead to beneficial drug products. In various modalities, it may be desirable to perform co-crystallography on all scaffolds that bind, or only those that bind with a particular affinity, for example, • only those that bind with high affinity, moderate affinity, low affinity, very low affinity or extremely low affinity. It may also be advantageous to perform the co-crystallography in a selection of scaffolds that bind with any combination of affinities. Standard X-ray protein diffraction studies such as when using a Rigaku RU-200® (Rigaku, Tokyo, Japan) with an X-ray imaging plate detector or a synchrotron beam line can be performed in the -crystals and diffraction data measured in a standard X-ray detector, such as a CCD detector or an X-ray imaging plate detector. When performing X-ray crystallography in approximately 200 co-crystals should generally lead to approximately 50 co-crystal structures, which must provide approximately 10 scaffolds for chemistry validity, which should ultimately result in approximately 5 selective indications for the target molecules. The additives that promote co-crystallization can of course be included in the target molecule formulation in order to improve co-crystal formation. In the case of proteins or enzymes, the scaffolding that is tested can be added to the protein formulation, which is preferably presented at a concentration of about 1 mg / ml. The formulation may also contain between 0% -10% (v / v) of the organic solvent, for example, DMSO, methanol, ethanol, propandiol or 1,3-dimethylpropanediol (MPD) or some combination of those organic solvents. The compounds are preferably solubilized in the organic solvent at a concentration of approximately 10 mM and added to the protein sample at a concentration of approximately 100 mM. The protein-compound complex is then concentrated to a final concentration of the protein from about 5 to about 20 mg / ml. The combining and concentration steps can be performed conveniently using a 96-well formatted concentration apparatus in the formulation that is crystallized can contain other components that promote crystallization or are compatible with the crystallization conditions, such as DTT, propandiol, glycerol. The crystallization experiment can be formed by placing small aliquots of the protein-compound complex (eg, 1 μl) in a 96-well format and the sample under 96 crystallization conditions. (Other formats can also be used, for example, plates with fewer or more wells). The crystals can usually be obtained using standard crystallization protocols that may involve the 96-well crystallization plate that is placed at different temperatures. Co-crystallization that varies factors other than temperature can also be considered for each protein-compound complex is desirable. For example, atmospheric pressure, the presence or absence of light or oxygen, a change in gravity, and many other variables can also be tested. The person with ordinary skill in the art will understand other variables that can be varied and advantageously considered. Conveniently, commercially available glass selection plates with specific conditions in individual wells can be used.

I. Virtual Essays As described above, virtual assay techniques or compound design techniques are useful for the identification and design of modulators; such techniques are also applicable to a molecular scaffolding method. Commercially available software that generates three-dimensional graphic representations of the lens and composite fused from a set of provided coordinates that can be used to illustrate and study how a compound is oriented when attached to an objective (for example, Insightll®, Accelerys, San Diego, CA; or Civil®, Tripos Associates, St. Louis, MO). Thus, the existence of the binding cavities at the binding site of the targets may be particularly useful in the present invention. These binding cavities are revealed by the determination of crystallographic structure and show the precise chemical interactions involved in the binding of the compound to the target binding site. The person with ordinary experience will understand that the illustrations can also be used to decide where the chemical groups could be added, replaced, modified or eliminated from the scaffolding to improve the union or other desirable effect, considering where the unoccupied space is located. the complex and whose chemical substructures could have adequate size and / or load characteristics to fill it. The person with ordinary experience will also understand that the regions within the binding site can be flexible and their properties can change as a result of joining scaffolds, and that the chemical groups can specifically target those regions to achieve a desired effect. The specific locations in the molecular scaffold can be considered with reference to where a suitable chemical substructure can be joined and in whose conformation, and whose site has the most advantageous chemistry available. An understanding of the forces that bind the compounds to the target proteins reveals that the compounds can be used more advantageously as scaffolds, and whose properties can be manipulated more effectively in the design of ligands. The person with ordinary experience will understand that steric, ionic, polar, hydrogen bonding and other forces can be considered for their contribution to the maintenance or improvement of the target-compound complex. Additional data can be obtained with automated computational methods, such as dynamic binding and / or molecular simulations, which can produce a measure of binding energy. In addition, to account for other effects such as union entropies and desolvation penalties, methods that provide a measure of these effects can be integrated into the automated computational approach. The selected compounds can be used to generate information about the chemical interactions with the target or to produce chemical modifications that can improve the binding selectivity of the compound. An exemplary calculation of binding energies between protein-ligand complexes can be obtained using the FlexX score (an implementation of the Bohm scoring function) within a software set Tripos (Tripos Associates, St. Louis, MO). The form for that equation is shown as follows:? Gbind =? Gtr +? Ghb +? Gion +? Glipo +? Garom +? Gro where:? Gtr is a constant term that counts for the total loss of rotational and transnational entropy of the ligand,? Ghb counts for hydrogen bonds formed between the ligand and the protein,? Gion counts for the ionic interactions between the ligand and the protein,? Glipo account for the lipophilic interaction that corresponds to the protein-ligand contact surface,? Garom account for interactions between aromatic rings in the protein and the ligand, and? Grot account for the entropic penalty of rotational restriction bonds in the ligand in the union. The binding energy calculated for compounds that bind strongly to a given target would probably be lower than -25 kcal / moles, while the big affinity calculated for a good scaffolding or a non-optimized compound will generally be in the range of -15 to -20. The penalty for restricting a linker such as ethylene glycol or hexatriene is estimated as being typically in the range of +5 to +15. This method estimates the big-free energy so that a major compound must have a target protein for which a crystal structure exists, and account for the entropic penalty of flexible linkers. It can therefore be used to estimate the penalty incurred by linking linkers to molecules that are selected and the big energy that a master compound must achieve in order to overcome the linker penalty. The method does not count for the formation of solvents, and the entropic penalty is probably overestimated when the linkers bind to the solid phase through an additional big complex, for example, a biotin: streptavidin complex. Another exemplary method for calculating big energies is the MM-PBSA technique (Massova and Kollman, Journal of the American Chemical Society 121: 8133-43,1999; Chong et al, Proceedings of the National Academy of Sciences 96: 14330-5, 1999; Donini and Kollman, Journal of Medicinal Chemistry 43: 4180-8, 2000). This method uses a Molecular Dynamics approach to generate many sample configurations of the compound and the fused target molecule, then calculates an interaction energy using the well-known AMBER force field (Cornell, et al., Journal of the American Chemical Society 117: 5179 -97 1995) with corrections for the desolvation and entropy of union from the set.

The use of this method produces union energies highly correlated with those found experimentally. The absolute bond energies calculated with this method are reasonably accurate, and the variation of the bonding energies is approximately linear with an inclination of 1 +/- 0.5. In this way, the binding energies of the compounds that strongly interact with a given target will be lower than about -8 kcal / moles, while a binding energy of a good scaffolding or a non-optimized compound will be in the range of -3. at -7 kcal / moles. Computer models, such as homology models (ie, based on an experimentally derived, known structure) can be constructed using data from co-crystal structures. A computer program such as Modeller (Accelrys, San Diego CA) can be used to assign the three-dimensional coordinates to a sequence of proteins using a sequence alignment and a set or sets of template coordinates. When the target molecule is a protein or an enzyme, the preferred co-crystal structures for homology modeling contain high sequence identity at the binding site of the protein sequence being modeled, and the proteins will also preferably be inside. of the same class and / or fold family. The knowledge of conserved residues in active sites of a protein class can be used to select models of homology that exactly represent the site of an ion. The homology models can also be used to discard the structural information from a replacement protein where there is a apo or co-crystal structure to the target protein. The methods of virtual selection, such as in lazamiento, can also be used to predict the configuration and binding affinity of scaffolds, compounds and / or combinatorial library libraries to homology models. Using these data, and carrying out "virtual experiments" using computer software, can save substantial resources and allow the person with ordinary experience to make decisions about which compounds can be suitable scaffolds, without having to actually synthesize them. the ligand and perform co-crystallization. Decisions can thus be made about which compounds deserve real synthesis and co-crystallization. An understanding of such chemical interactions helps in the discovery and design of drugs that interact more advantageously with target proteins and / or are more selective for one member of the protein family over the others. Thus, by applying these principles, compounds with superior properties can be discovered. J. Design and Preparation of the Ligand The design and preparation of ligands can be carried out with or without structural and / or co-crystallization data considering the chemical structures in common between the active scaffolds of a set. In this process, the structure-activity hypothesis can be formed and those chemical structures found to be present in a substantial number of the scaffolds, including those that join with low affinity, can be assumed to have some effect on the scaffolding junction. This binding can be presumed to induce a desired biochemical effect when it occurs in a biological system (e.g., a treated mammal). New or modified scaffolds or combinatorial libraries derived from the scaffolds can be tested to invalidate the maximum number of union and / or structure-activity hypothesis. The remaining hypothesis can then be used to design ligands that achieve a desired biochemical and binding effect. But in many cases, it will be preferred to have co-crystallography data for the consideration of how to modify the scaffolding to achieve the desired binding effect (e.g., the union in higher affinity or with higher selectivity). Using the case of co-crystallography data of protein and enzymes, they show the protein binding cavity with the molecular scaffold attached to the binding site, and it will be apparent that a modification can be made to a chemically treatable group in the scaffolding. For example, a small volume of space in a protein binding site or cavity could be filled by modifying the scaffolding that includes a small chemical group that fills the volume. Filling the void volume can be expected to result in a higher binding affinity, or loss of undesirable binding to another member of the protein family. Similarly, the co-crystallography data may show that the suppression of a chemical group in the scaffold can decrease an obstacle to binding and result in greater affinity or binding specificity. Several software packages have implemented techniques that facilitate the identification and characterization of interactions of potential binding sites from a complex structure, or from an apo structure of a target molecule, ie, one without a binding compound (e.g. , SiteID, Tripos Associates, St. Louis MO and SiteFinder, Chemical Computing Group, Montreal Canada, GRAIS, Molecular Discovery Ltd., London UK). Such techniques can be used with the coordinates of a complex between the scaffolding of interest and an objective molecule, or these data together with the data for a related target molecule superimposed or appropriately aligned, to evaluate changes to the scaffolding that would improve the binding to the structure or structures of the desired target molecule. Molecular Interaction Activity Field computation techniques, such as those implemented in the GRID program, result in energy data for particular positive and negative binding interactions of different chemical and computational probes that are mapped to the vertices of a matrix. in the coordinate space of the target molecule. These data can then be analyzed for substitution areas around the scaffold binding site that are predicted to have a favorable interaction for a particular target molecule. Chemical substitution compatible in the scaffold, for example a methyl, ethyl or phenyl group in a favorable interaction region computed from a hydrophobic probe, would be expected to result in an improvement in the affinity of the scaffolding. Conversely, a scaffold could be made more selective for a particular target molecule by making such substitution in a region intended to have an unfavorable hydrophobic interaction in a second undesirable related target molecule. It may be desirable to take advantage of the presence of a charged chemical group located in the protein binding site or cavity. For example, a positively charged group can be complemented by a negatively charged group introduced into the molecular scaffolding. This can be expected to increase binding affinity or binding specificity, resulting in a more desirable ligand. In many cases, the regions of the protein binding sites or cavities are known to vary from one family member to another based on the amino acid differences in those regions. Chemical additions in such regions can result in the creation or elimination of certain interactions (eg, hydrophobic, electrostatic, or entropic) that allow a compound to be more specific for one target protein over another or for binding with higher affinity, by what is allowed to synthesize a compound with greater selectivity or affinity for a member of the particular family. Additionally, certain regions may contain amino acids that are known to be more flexible than others. This occurs frequently in amino acids contained in loops that are connected to elements of the secondary structure of the protein, such as alpha helices or beta strands. Additions of the chemical moieties can also be directed to those flexible regions in order to increase the likelihood of a specific interaction occurring between the target protein of interest and the compound. Virtual selection methods can also be conducted in silico, to evaluate the effect of chemical additions, subtractions, modifications, and / or substitutions on the compounds with respect to the members of a family or class of proteins. The addition, subtraction or modification of a chemical structure or substructure to a scaffold can be done with any suitable chemical portion. For example, the following portions, which are provided by way of example and are not intended to be limiting, may be used: hydrogen, alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, alkyloxy, alkylthio , alkenylthio, phenyl, phenylalkyl, phenylalkythio, hydroxyalkylthio, alkythiocarbamothio, cyclohexyl, pyridyl, piperidinyl, alkylamino, amino, nitro, mercapto, cyano, hydroxyl, a halogen atom, halomethyl, an oxygen atom (for example, forming a ketone, an ether or an N-oxide), and a sulfur atom (for example, forming a thiol, thione, sulfonamide or di-alkyldisulfoxide (sulfone)). In certain embodiments, the information provided by performing X-ray crystallography in the co-crystals is provided to a computer program, wherein the computer program provides a measure of the interaction between the molecular scaffold and the protein and a prediction of changes. in the interaction between the molecular scaffolding and the protein that results from the specific modifications to the molecular scaffolding, and the molecular scaffolding is modified chemically based on the prediction of the biochemical result. The computer program can provide the prediction based on a virtual assay such as, for example, virtual binding of the compound to the protein, form-based coupling, molecular dynamic simulations, free energy perturbation studies, and similarity to a three-dimensional pharmacophore. A variety of such programs are fine. known in the art. The chemical modification of a chemically treatable structure can result, or be selected to provide one or more physical changes, for example, to result in a ligand that fills an empty volume in the protein-ligand complex, an attractive polar interaction that occurs in the protein-ligand complex. The modification may also result in a sub-structure of the ligand that occurs in a binding pocket of the protein binding site when the protein-ligand complex is formed. After the common chemical structures of the compound that binds are identified, the compounds can be grouped based on having a common chemical sub-structure and a representative compound of each group (a plurality of the group) can be selected for co-crystallization with the protein and the performance of X-ray crystallography. X-ray crystallography preferably performs in co-crystals under at least 20, 30, 40 or 50 different environmental conditions, most preferably under approximately 96 different environmental conditions. X-ray crystallography and the modification of a chemically treatable structure of the compound can each perform a plurality of times, for example 2, 3, 4 or more cycles of crystallization and modification. Also, in certain embodiments, one or more molecular scaffolds are selected to have a binding to a plurality of members of the PPAR family. The method can also include the identification of residues conserved in one or more binding sites of a PPAR protein that interact with a molecular scaffold, a ligand or another binding compound. The conserved waste can, for example, identified by sequence alignment of different members of the PPAR family, and identifying residues of the binding site that are the same or at least similar among the multiple member of the family. The residues of the interaction can be characterized as those of a distance selected from the binding compound (s), for example 3, 3.5, 4, 4.5 or 5 angstroms. In a related aspect, the invention provides a method for designing a ligand that binds to at least one PPAR that is a member of the PPAR family, by identifying as molecular scaffolds one or more compounds that bind to the binding sites of a plurality of members of the PPAR family, determining the orientation of one or more molecular scaffolds in the binding site of the PPAR or to identify the chemically treatable structures or scaffolds that, when modified, alter the binding affinity or the binding specificity between the scaffold (s) and the PPARs, and synthesizing a ligand wherein one or more of the chemically treatable structures or molecular scaffolds are modified to provide a ligand that binds to the PPAR with the altered binding affinity or the binding specificity. Particular modalities include those described by the present aspect. The invention also provides a method for identifying properties that a binding compound will likely possess, whereby for example, the most efficient selection of compounds for determinations of structural activity ratio and / or selection is allowed. Thus, another aspect relates to a method for identifying binding characteristics of a ligand or a PPAR protein, identifying at least one interaction residue conserved in the PPAR that interacts with at least two binding molecules; and identifying at least one common interaction property of those binding molecules with the conserved residue (s). The interaction property and the location with respect to the structure of the binding compound define the binding characteristic. In various embodiments, the identification of conserved interaction residues involves comparing (eg, by sequence alignment) a plurality of amino acid sequences in the PPAR family and identifying residues of binding sites conserved in that family; the identification of residues of binding sites by determining a co-crystal structure; identifying interaction residues (preferably conserved residues) within a selected distance of the binding compounds, for example 3, 3.5, 4, 4.5 angstroms; the interaction property involves hydrophobic interaction, charge-charge interaction, hydrogen bonding, polar charge interaction, polar-polar interaction, or combinations thereof. Another related aspect is related to a method to develop ligands for a PPAR using a set of scaffolds. The method involves selecting a PPAR or a priority of the PPARs, selecting a molecular scaffolding, or a composite from a scaffolding group, from a set of at least three scaffolds or scaffolding groups where each of the scaffolds Scaffolds or compounds from each scaffolding group are known to join the target. In the particular embodiments, the set of scaffolds or scaffolding groups is at least 4, 5, 6, 7, 8 or even more scaffolds or groups of scaffolds. Another aspect relates to a method for identifying structurally and energetically permitted sites in a binding compound for the binding of one or more additional components by analyzing the orientation of the binding compound (s) at a PPAR binding site (eg by analyzing the structures co-crystal), whereby accessible sites are identified in the compound for attachment of the separated component. In particular embodiments, the binding compound is a compound of Formula I. In various embodiments, the method involves calculating the change in binding energy at the junction of the separated component at one or more of the accessible sites; the orientation is determined by co-crystallography; the separate component includes a linker, a label such as a fluorophore, a solid phase material such as a gel, a bead, a plate, a chip or a well. In a related aspect, the invention provides a method for the adhesion of a PPAR binding compound to an adhesion component or components by identifying energetically permitted sites for the adhesion of such adhesion component in a binding compound (eg as described for the preceding aspect), and the adherence of the compound or derivative thereof to the adhesion component (s) at the energetically permitted site (s). In particular embodiments, the binding compound is a compound of Formula I. In various embodiments, the adhesion component is a linker (which may be a linker without a trace) for adhesion to a solid phase medium, and the method it also implies the adhesion of the compound or derivative to a solid phase medium through the linked linker to the energetically permitted site; the binding compound or derivative thereof is synthesized in a linker attached to the solid phase medium; a plurality of compounds or derivatives are synthesized in combinatorial synthesis; the adhesion of the compound (s) to the solid phase medium provides an affinity medium. A related aspect relates to a method for making an affinity matrix for a PPAR, wherein the method involves identifying energetically permitted sites in a PPAR binding compound for adhesion to a solid phase matrix; and adhesion to the PPAR binding compound to the solid phase matrix through the energetically permitted site. In particular embodiments, the binding compound is a compound of Formula I. Several modalities are as described for the joining of a previous separate component; identifying energetically permitted sites for the binding of a solid phase matrix was performed for at least 5, 10, 20, 30, 50, 80 or 100 different compounds; identify energetically permitted sites for molecular scaffolds or other PPAR binding compounds that have different core ring structures. As used herein, the term "PPAR" refers to a peroxisome proliferator-activated receptor as recognized in the art. As indicated above, the PPAR family includes PPARa (also referred to as PPARa or PPARalpha), PPARd (also referred to as PPARd or PPARdelta), and PPAR4 (also referred to as PPARg and PPARgamma). Individual PPARs can be identified for their sequences, where the access numbers of the exemplary reference sequence are: N M_005036 (cDNA sequence for hPPARa), NP_005027 (protein sequence for hPPARa), NM__015869 (cDNA sequence for isoform 2 of hPPARg), N P_056953 (protein sequence for isoform 2 hPPARg), NM_006238 (cDNA sequence for hPPARd), and N P_006229 (protein sequence for hPPARd). One of ordinary skill in the art will recognize that sequence differences will exist due to allelic variation, and will also recognize that other animals, particularly other mammals have corresponding PPARs, that have been identified or can be easily identified using sequence alignment and activity confirmation. , they can be used too. One of ordinary skill in the art will also recognize that modifications can be introduced into a PPAR sequence without destroying the PPAR activity. Such modified PPARs may also be used in the present invention, for example, if the modifications do not alter confirmation of the binding site to the extent that the modified PPAR substantially lacks normal ligand binding. As used herein in conjunction with the design or development of ligands, the term "join" and "link" and similar terms refers to an energetically favorable, non-covalent association between the specific molecules (i.e., the bound state has a free energy lower than the separate state, which can be measured calorimetrically). For binding to a target, the binding is at least selective, that is, the compound binds preferably to a particular target or to members of a target family at a binding site, when compared to non-specific binding to non-target proteins. related that do not have a similar binding site. For example, BSA is frequently used to evaluate or control non-specific binding. Furthermore, for an association that will be estimated as the binding, the decrease in free energy that comes from a separate state to the bound state should be sufficient so that the association is detectable in a suitable biochemical assay for the molecules involved. By "analyze" is meant the creation of experimental conditions and the gathering of data with respect to a particular result of the experimental conditions. For example, enzymes can be evaluated based on their ability to act on a detectable substrate. Likewise, for example, a compound or ligand can be evaluated based on its ability to bind to a target molecule or molecules and / or to modulate an activity of a target molecule. By "background signal" in reference to a binding assay is meant the signal that is recorded under standard conditions for the particular assay in the absence of a test compound, a molecular scaffold, or a ligand that binds to the molecule objective. Those of ordinary skill in the art will understand that there are accepted methods and are widely available to determine the background signal. When a decision is described as "based" on particular criteria, it means that the selected criteria are parameters of the decision and guide its outcome. A substantial change in the parameters would probably result in a change in the decision. By "binding site" is meant an area of a target molecule to which a ligand can be attached non-covalently. The binding sites incorporate particular forms and often contain multiple binding cavities present within the binding site. Particular forms are frequently conserved within a class of molecules, such as a molecular family. The binding sites within a class may also contain conserved structures such as, for example, chemical moieties, the presence of a binding cavity, and / or an electrostatic charge at the binding site or some portion of the binding site, all which can influence the shape of the binding site. By "joint cavity" is meant a specific volume within a binding site. A binding cavity is a particular space within a binding site at least partially bound by the atoms of the target molecule. Thus, a joint cavity is a particular shape, indentation, or cavity at the junction site. The binding cavities may contain particular chemical groups or structures that are important in the non-covalent binding of another molecule such as, for example, groups that contribute to hydrogen bonding, ionic, van der Waals or hydrophobic interactions between the molecules. By "chemical structure" or "chemical substructure" is meant any atom or definable group of atoms that constitutes a part of a molecule. Normally, the chemical substructures of a scaffold or ligand may have a role in binding the scaffold or the ligand to a target molecule, or they may influence the three-dimensional shape, electrostatic charge and / or conformational properties of the scaffold or the ligand. By "orientation", in reference to a binding compound attached to a target molecule is meant the spatial relationship of the binding compound and at least some of its constituent atoms to the binding cavity and / or atoms of the target molecule that defines at least partially the joint cavity. In the context of the target molecules in the present invention, the term "crystal" refers to an ordered complex of the target molecule, such that the complex produces an X-ray diffraction pattern when placed in an X-ray beam In this way, a "crystal" is distinguished from a disordered or partially ordered complex or aggregate of molecules that does not produce such a diffraction pattern. Preferably, a crystal is of sufficient order and size to be useful for X-ray crystallography. A crystal can be formed only of a target molecule (with solvent and ions) or it can be a co-crystal of more than one molecule, for example , as a co-crystal of the target molecule and the binding compound, and / or of a protein complex (such as a holoenzyme). In the context of this invention, unless otherwise specified, by "co-crystals" is meant an ordered complex of the compound, a molecular scaffold, or ligand non-covalently bound to the target molecule that produces a diffraction pattern when placed in an X-ray beam. Preferably, the co-crystal is in the proper form for X-ray analysis or protein crystallography. In preferred embodiments, the target molecule-ligand complex can be a protein-ligand complex. By "clog P" is meant the calculated logarithm P of a compound, "P" refers to the coefficient of division of the compound between a lipophilic and an aqueous phase, usually between octanol and water. By "chemically treatable structures" is meant chemical structures, sub-structures, or sites in a molecule that can be covalently modified to produce a ligand with a more desirable property. The desirable property will depend on the needs of the particular situation. The property may be, for example, that the ligand binds with greater affinity to a target molecule, which binds with more specificity, or that binds to a larger or smaller number of target molecules in a molecular family, or other desirable properties when required. By "designing a ligand", "preparing a ligand", "discovering a ligand" and similar phrases is meant the process to consider relevant data (especially, but not limited to, any single type or combination of binding data, X-ray co-crystallography data, molecular weight, clogP, and the number of hydrogen bonding donors and acceptors) and make decisions about the advantages that can be achieved with resources for structural modifications ~ specific to a molecule, and implement those decisions.

This process to gather data and make decisions about the structural modifications that can be advantageous, implement those decisions, and determine that the result can be repeated as many times as necessary to obtain a ligand with desired properties. By "linking" is meant the process for attempting to establish a three-dimensional configuration of a binding pair member within a three-dimensional configuration of the binding site or attachment cavity of the associated binding pair member, which may be a protein, and determine the magnitude at which an adjustment is obtained. The magnitude at which an adjustment is obtained may depend on the amount of void volume in the resulting binding pair complex (or target molecule-ligand complex). The configuration can be physical or a configuration representative of the union pair member, for example, an in silico representation or another model. In the context of the development of modulators that use molecular scaffolds, by "ligand" is meant a molecular scaffold that has been chemically modified into one or more chemically treatable structures to bind to the target molecule with altered or changed binding affinity or specificity of union relative to molecular scaffolding. The ligand can bind with a higher specificity or affinity for a member of the molecular family relative to the molecular scaffold. A ligand does not bind covalently to a target molecule, which may preferably be a protein or enzyme. . By "low affinity" binding is meant the binding to the target molecule with a dissociation constant (Kd) of more than 1 μM under standard conditions. In particular cases, the low affinity binding is in a range of 1 μM-10 mM, 1 μM-1 mM, 1 μM-500 μM, 1 μM-200 μM, 1 μM-100 μM. To be linked with "very low affinity" is meant the binding with a kd of above about 100 μM under standard conditions, for example in a range of 100 μM-1 mM, 100 μM-500 μM, 100 μM-200 μM . By binding with "extremely low affinity" it is meant to bind in a kd of above about 1 mM under standard conditions. By "moderate affinity" is meant to bind with a kd from about 200 nM to about 1 μM under standard conditions. By "moderately high affinity" it is meant to bind in a kd from about 1 mM to about 200 nM. By "high affinity" binding it is meant to bind in a kd below about 1 nM under standard conditions. For example, low affinity binding may occur due to a more poor fit at the binding site of the target molecule or due to a smaller number of non-covalent bonds, or weaker covalent bonds present to cause binding of the scaffolding or ligand to the binding site of the target molecule in relation to cases where the highest affinity binding occurs. The standard conditions for binding are at pH 7.2 at 37 ° C for one hour. For example, 100 μl / well in 50 mM HEPES of buffer at pH 7.2, 15 mM NaCl, 2 μM ATP, and bovine serum albumin 1 ug / well, 37 ° C for one hour can be used. The binding compounds can also be characterized by their effect on the activity of the target molecule. Thus, a "low activity" compound has an inhibitory concentration (IC5o) (for inhibitors or antagonists) or an effective concentration (EC50) (applicable to agonists) of more than 1 μM under standard conditions. By "very low activity" is meant an IC50 or EC50 of above 100 μM under standard conditions. By "extremely low activity" is meant an IC50 or EC50 of above 1 mM under standard conditions. By "moderate activity" is meant an IC50 or EC50 of 200 nM to 1 μM under standard conditions. By "moderately elevated activity" is meant an IC50 or EC50 of 1 nM to 200 nM. By "high activity" is meant an IC50 or EC50 below 1 mM under standard conditions. The IC50 (or EC50) is defined as the concentration of the compound at which 50% of the activity of the target molecule (e.g., enzyme or other protein) that is measured is lost (or gained) in relation to the activity when no compound is present. The activity can be measured using methods known to those of ordinary skill in the art, for example, by measuring any detectable product or signal produced by the occurrence of an enzymatic reaction, or other activity by a protein being measured. For PPAR agonists, the activities can be determined as described in the Examples, or use other such assay methods known in the art. By "molecular scaffolding" or "scaffolding" is meant a small target binding molecule to which one or more additional chemical moieties can be covalently linked, modified or eliminated to form a plurality of molecules with common structural elements. The portions may include, but are not limited to, a halogen atom, a hydroxyl group, a methyl group, a nitro group, or any other type of molecular group including, but not limited to, those reported in this application. Molecular scaffolds bind to at least one target molecule with low or very low affinity and / or bind to a plurality of molecules in a target family (e.g., family of proteins) and the target molecule is preferably an enzyme, receptor , or another protein. The preferred features of a scaffold include the molecular weight of less than about 350 daltons; binding at a binding site of a target molecule so that one or more substituents on the scaffolding are located in the binding cavities at the binding site of the target molecule; having chemically treatable structures that can be chemically modified, particularly by synthetic reactions, so that a combinatorial library can be easily constructed; having chemical positions in which the portions can be linked so as not to interfere with the binding of scaffolding to a protein binding site, so that the scaffolding or library members can be modified to form ligands, to achieve additional desirable characteristics, example, allowing the ligand to be actively transported in the cells and / or to specific organs, or allowing the ligand to bind to a chromatography column for further analysis. Thus, a molecular scaffold is an identified target binding molecule, small before modification to improve affinity and / or binding specificity, or other pharmacological properties. The term "scaffolding core" refers to the core structure of a molecular scaffold upon which various substituents can be attached. In this way, for a number of scaffolding molecules of one. Particular chemical class, the scaffolding core is common to all scaffolding molecules. In many cases, the scaffolding core will consist of, or will include, one or more ring structures. The term "scaffolding group" refers to a set of compounds that share a scaffolding core and can thus be considered as derivatives of a scaffolding molecule. By "molecular family" is meant groups of class molecules together based on structural and / or functional similarities. Examples of molecular families include proteins, enzymes, polypeptides, receptor molecules, oligosaccharides, nucleic acids, DNA, RNA, etc. Thus, for example, a protein family is a molecular family. The molecules can also be classified together in a family based on, for example, homology. The person with ordinary skill in the art will understand many other molecules that can be classified as members of a molecular family based on similarities in chemical structure or biological function. By "protein-ligand complex" or "co-complex" is meant a non-covalently bound protein and ligand. By "protein" is meant a polymer of amino acids. The amino acids can be of natural or non-natural origin. The proteins may also contain adaptations, such as being osylated, phosphorylated or other common modifications. By "protein family" is meant a classification of proteins based on structural and / or functional similarities. For example, kinases, phosphatases, proteases and similar protein groupings are protein families. Proteins can be grouped into a family of proteins based on having one or more protein folds in common, a substantial similarity in shape between protein folding, homology, or on the basis of having a common function. In many cases, smaller families will be specified, for example, the PPAR family. "Protein Folds" are three-dimensional forms exhibited by the protein and defined by the existence, number and location in the protein of alpha helices, beta sheets, and loops, that is, the secondary secondary structures of protein molecules. Folds can be, for example, the domains or partial domains of a particular protein. By "ring structure" is meant a molecule that has a chemical ring or sub-structure that is a chemical ring. In most cases, the ring structures will be carbocyclic or heterocyclic rings. The chemical ring may be, but is not limited to, a phenyl ring, aryl ring, pyrrole ring, imidazole, pyridine, purine or any ring structure. By "specific biochemical effect" is meant a therapeutically significant biochemical change in a biological system that causes a detectable result. This specific biochemical effect may be, for example, the inhibition or activation of an enzyme, the inhibition or activation of a protein that binds to a desired target, or similar types of changes in the body's biochemistry. The specific biochemical effect can cause the relief of symptoms of a disease or a condition or other desirable effect. The detectable result can also be detected through an intermediate stage. By "standard conditions" is meant conditions under which an assay is performed to obtain scientifically meaningful data. Standard conditions are dependent on the particular trial, and may be generally subjective. Normally, the standard conditions of a test will be those conditions that are optimal for obtaining useful data from the particular test. Standard conditions will generally minimize the background signal and maximize the intended signal to be detected. By "standard deviation" we mean the square root of the variance. Variance is a measure of how a distribution is separated. This is calculated as the average square deviation of each number from its average. For example, for numbers 1, 2 and 3, the average is 2 and the variation is: s = (1-2.2 + (2 + 2) 2 + (3-2) 2 = 0.667 3 For a "set" of The term "target molecule" is intended to mean a molecule in which a compound, a molecular scaffold, or a ligand is being analyzed for the purpose of The target molecule has a binding activity so that the binding of the molecular scaffold or ligand to the target molecule will be altered or changed.The binding of the compound, the scaffold or the ligand to the target molecule can preferably cause a specific biochemical effect when it occurs in a . biological system A "biological system" includes, but is not limited to a living system, such as a human being, an animal, a plant or an insect. In most, but not in all cases, the target molecule will be a protein or a nucleic acid molecule. By "pharmacophore" is meant a representation of molecular characteristics that are considered to be responsible for a desired activity, such as interaction or binding with a receptor. A pharmacophore can include three-dimensional properties (hydrophobic groups, charged / ionizable, hydrogen donors / acceptors), 2D (substructures) and 1D (physical or biological). As used herein, together with the numerical values, the terms "approximately" and "around" mean ± 10% of the indicated value. Additional modalities will be apparent from the Detailed Description and from the claims.

DETAILED DESCRIPTION OF THE MODALITIES PREFERRED As indicated in the previous Compendium, the present invention relates to receptors activated with a peroxisome proliferator (PPAR), which have been identified in humans and other mammals. A group of compounds have been identified, corresponding to Formula I, which are active in one or more of the PPARs, in the particular compounds so that one or more human PPARs are active. The identification of these compounds provides compounds that can be used as agonists in PPARs, as well as for the identification or development of additional active compounds, for example, compounds within Formula I.

I. Applications of PPAR Agonists PPARs have been recognized as suitable targets for a number of different diseases and conditions.

Some of these applications are described briefly later.

Additional applications are known and the present compounds can also be used for those diseases and conditions. (a) Insulin resistance and diabetes: Along with insulin resistance and diabetes, PPAR? it is necessary and sufficient for the differentiation of adipocytes in vitro and in vivo. In adipocytes, PPAR? increases the expression of numerous genes involved in lipid metabolism and lipid absorption. In contrast, the PPAR? it deregulates leptin, a secreted adipocyte selective protein that has been shown to inhibit feeding and increased metabolism of catabolic lipid. This receptor activity could explain the increased caloric absorption and storage observed in vivo in the PPAR? Agonist treatment. Clinically, TZDs, including troglitazone, rosiglitazone and pioglitazone and without TZD, including farglitazar, have insulin-sensitive and antidiabetic activity. (Berger et al., 2002, Diabetes Tech. And Ther.4: 163-174). The PPAR? It has been associated with several genes that affect the action of insulin. TNFa, a pro-inflammatory cytosine that is expressed by adipocytes, has been associated with insulin resistance. The PPAR agonists? inhibit the expression of TNFα in adipose tissue of obese rodents, and remove the actions of TNFα in adipocytes in vitro. The PPAR agonists? showed that they inhibit the expression of 11 β-hydroxysteroid dehydrogenase 1 (11β-HSD-1), the enzyme that converts cortisone to glucocorticoid agonist cortisol, in adipocytes and adipose tissue of mouse models with type 2 diabetes. This is remarkable that hypercorticosteroidism intensifies insulin resistance.

The 30 kDa Adipocyte-Related Protein (Acrp30 or adiponectin) is a secreted adipocyte-specific protein that decreases glucose, triglycerides and free fatty acids. Compared with normal humans, patients with type 2 diabetes have reduced plasma levels of Acrp30. The treatment of diabetic mice and non-diabetic humans with increased plasma levels of PPAR agonists? of Acrip30. The induction of Acrp30 by PPAR agonists? could it therefore play a key role in the insulin sensitization mechanism of PPAR agonists? in diabetes. (Berger et al., 2002, Diabetes Tech. And Ther.4: 163-174). The PPAR? it is expressed predominantly in adipose tissue. Thus, it is believed that the real in vivo efficacy of PPAR agonists? it involves direct actions on adipose cells with side effects in key insulin response tissues such as skeletal muscle and liver. This is supported by the lack of glucose-lowering efficacy of rosiglitazone in a mouse model of severe insulin resistance where white adipose tissue was essentially absent. In addition, in vivo treatment of insulin-resistant rats produces acute normalization (<24 hours) of adipose tissue insulin action while insulin-mediated glucose uptake in the muscle was not improved until several days after the start of therapy. This is consistent with the fact that PPAR agonists? they may produce an increase in the action of adipose tissue insulin after direct in vitro incubation, whereas no effect could be demonstrated using skeletal muscles incubated in vitro isolated. The beneficial metabolic effects of PPAR agonists? in muscle and liver it can be mediated by its ability to (a) improve insulin-mediated adipose tissue absorption, storage (and potentially catabolism) of free fatty acids; (b) inducing the production of factors derived from adiposis with potential insulin sensitization activity (eg, Acrp30); and / or (c) suppress circulating levels and / or actions of factors derived from adiposis that cause resistance such as TNFa or resistin. (Berger et al., 2002, Diabetes Tech. And Ther.4: 163-174). (b) Dyslipidemia and atherosclerosis: Along with dyslipidemia and atherosclerosis, PPARa has been shown to play a critical role in the regulation of cellular uptake, activation and ß-oxidation of fatty acids. Activation of PPARa induces the expression of fatty acid transport proteins and enzymes in the path of peroxisomal β-oxidation. Several mitochondrial enzymes involved in the catabolism of fatty acid energy harvest are over-regulated to a large extent by PPARa agonists. Peroxisome proliferators also activate the expression of CYP4A, a subclass of cytochrome P450 enzymes that catalyze the? -hydroxylation of fatty acids, a trajectory that is particularly active in fasting and diabetic states. In summary, it is clear that PPARa is an important lipid sensor and regulator of cellular energy harvest metabolism. (Berger et al., 2002, Diabetes Tech. And Ther.4: 163-174). Atherosclerosis is a very prevalent disease in Western societies. In addition to a strong association with elevated LDL cholesterol, "dyslipidemia" characterized by high triglyceride-rich particles and low levels of HDL cholesterol is commonly associated with other aspects of a metabolic syndrome that includes obesity, insulin resistance, type 2 diabetes, and an increased risk of coronary artery disease. Thus, in 8,500 men with known coronary artery disease, 38% had low HDL (<35 mg / dl) and 33% had high triglycerides (> 200 mg / dl). In such patients, treatment with fibrates resulted in a substantial decrease in triglycerides and the efficacy to produce modest HDL. More importantly, a recent large potential trial showed that treatment with gemfibrozil produced a 22% reduction in cardiovascular events or death. In this way, PPARa agonists can effectively improve cardiovascular risk factors and have a real benefit in improving cardiovascular outcomes. In fact, fenofibrate was recently approved in the United States for the treatment of hyperlipidaemia of type HA and IIB. The mechanisms by which PPARa activation cause the triglyceride decrease likely to include the effects of agonists to suppress genetic expression of hepatic apo-Clll while also stimulating the genetic expression of lipoprotein lipase. Dual PPARα agonists, including KRP-297 and DRF 2725, possess the potent lipid-altering efficacy in addition to antihyperglycemic activity in animal models of diabetes and lipid disorders. The presence of expression of PPARa and / or PPAR? in vascular cell types, including macrophages, endothelial cells, and vascular smooth muscle cells, suggests that direct vascular effects may contribute to potential antiatherosclerosis efficacy. The activation of PPARa and PPARa has been shown to inhibit vascular cell adhesion that induces cytosine and to suppress the migration of monolith-macrophage. Several additional studies have also shown that selective PPAR? they have the capacity to reduce the size of arterial injury and attenuate the replacement of monocytes-macrophages to arterial lesions in animal models of atherosclerosis. further, two recent studies have suggested that the activation of PPARa or PPAR? in. macrophages can induce the expression of a "pump" cholesterol flow protein. It has been found that relatively selective PPARd agonists produce minimal glucose or triglyceride lowering activity, if any, in murine models of type 2 diabetes compared to PPARγ agonists. or PPARa effective. Subsequently, a modest increase in HDL cholesterol levels was detected with PPARd agonists in mice. db / db. Recently, Oliver et al. Reported that a selective, potent PPARd agonist could induce a substantial increase in HDL-cholesterol levels although triglyceride levels and insulin resistance in obese Indian monkeys are reduced. In this way, through multifactorial mechanisms which include improvements in circulating lipids, systemic and local anti-inflammatory effects, and inhibition of vascular cell proliferation, PPARa agonists, PPAR? and PPARd can be used in the treatment or prevention of atherosclerosis (Berger et al., 2002, Diabetes Tech. And Ther.4: 163-174). 1.5 (c) Inflammation: Monocytes and macrophages are known to play an important part in the inflammatory process through the release of inflammatory cytokines and the production of nitric oxide by nitric oxide of inducible synthase. Rosiglitazone has been shown to induce apoptosis of macrophages in concentrations that are equivalent to their affinity for PPAR ?. This ligand has also been shown to block the synthesis of inflammatory cytosine in colonic cell lines. This last observation suggests a mechanistic explanation for the observed anti-inflammatory actions of the TZD in rodent models of colitis.

Anti-inflammatory actions have been described for PPARa ligands that may be important in maintaining vascular health. The treatment of human macrophages activated with cytosine with PPARa agonists that induce cell apoptosis. It was reported that PPARa agonists inhibit the activation of smooth aortic muscle cells in response to the inflammatory stimulus (Staels et al., 1998, Nature 393: 790-793). In hyperlipidemic patients, the treatment of fenofibrate d reduces the plasma concentrations of the inflammatory cytokine interleukin-6. (d) Hypertension: Hypertension is a complex disorder of the cardiovascular system that has been shown to be associated with insulin resistance. Patients with type 2 diabetes demonstrate a 1.5-fold increase in hypertension compared to the general population. Therapy with troglitazon, rosig litazon and pioglitazon have been shown to lower blood pressure in diabetic patients as well as troglitazon therapy in insulin-resistant, obese subjects. Since such reductions in blood pressure showed that they correlate with decreases in insulin levels, they can be mediated by an improvement in insulin sensitivity. However, since the TZDs also decreased blood pressure in Sprague Dawley rats from a kidney staple, which are not insulin resistant, it was proposed that the hypotensive action of the PPAR agonists be? Do not exercise only through your ability to improve the sensitivity of insulin. Other mechanisms that have been invoked to explain the antihypertensive effects of PPAR agonists? they include their ability to (a) deregulate the expression of peptides that control vascular tone such as PAI-I, endothelium and C-natriuretic peptide of type co (b) alter calcium concentrations and calcium sensitivity of vascular cells (Berger et al., 2002, Diabetes Tech. And Ther.4: 163-174). According to the above description, the isoforms of the PPAR family of nuclear receptors are clearly involved in the systemic regulation of lipid metabolism and serve as "sensors" for fatty acids, prostanoid metabolites, eicosanoids and related molecules. These receptors work to regulate a broad array of genes in a coordinated fashion. The important biochemical trajectories resulting from insulin action, lipid oxidation, lipid synthesis, adipocyte differentiation, peroxisome function, cellular apoptosis, and inflammation can be modulated through the individual PPAR isoforms. The strong therapeutic effects of PPARa and PPAR agonists? they favorably influence systemic lipid levels, glucose homeostasis and the risk of atherosclerosis (in the case of the activation of PPARa in humans) have recently been discovered. The PPARa and PPAR agonists? they are used at the moment clinically to favorably alter levels of systemic lipids and glucose homeostasis, respectively. Recent observations are made using PPAR ligands that suggest that this isoform is also an important therapeutic target for dyslipidemia and insulin resistance, as well. Thus, PPAR agonists, such as those described herein, can be used in prophylaxis and / or therapeutic treatment of a variety of different conditions and diseases, such as obesity, overweight condition, hyperlipidemia, dyslipidemia including diabetic dyslipidemia associated and mixed dyslipidemia, hypoalphalipoproteinemia, Syndrome X, Type II diabetes mellitus, Type 1 diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, a diabetic complication (eg, neuropathy, nephropathy, retinopathy or cataracts), hypertension , coronary heart disease, heart failure, hypercholesterolemia, inflammation, thrombosis, congestive heart failure, cardiovascular disease (including atherosclerosis, arteriosclerosis and hypertriglyceridemia), epithelial hyperproliferative diseases (such as eczema and psoriasis) and conditions associated with the lung and intestine and the apeti regulation to and the consumption of food in suffering subjects. of disorders such as obesity, anorexia, bulimia and anorexia nervosa. (e) Cancer: The modulation of .PPAR has also been correlated with cancer treatment. (Burstein et al.; Breast Cancer Res. Treta. 2003 79 (3): 391-7; Alderd et al .; Oncogene, 2003, 22 (22): 3412-6). (f) Weight Control: The administration of PPARα agonists can induce satiety, and in this way they are useful in the loss or conservation of weight. Such PPARa agonists can preferentially act on PPARa, or they can also act on another PPAR, or they can be PPAR total agonists. Thus, the satiety-inducing effect of PPARa agonists can be used for control or weight loss.

II. Active PPAR Compounds As indicated in the Compendium and together with the applicable diseases and conditions, a number of different PPAR agonists have been identified. In addition, the present invention provides PPAR agonist compounds described by Formula 1 as provided in the above Compendium. Included within Formula I are sub-groups of compounds, for example, the sub-groups by structures la, Ib, le, Id, X and XIV as shown in the synthetic schemes below. Included within such compounds of Formula I are exemplary compounds provided in Table I below. Additional compounds within the. Formula I can also be prepared and tested to confirm activity using conventional methods and the guidance provided herein. lll. Development of Active PPAR Compounds A. Identification and modulator design A large number of different methods can be used to identify modulators and to design improved modulators. Some useful methods involve design based on structure. The structure-based modulator design and identification methods are powerful techniques that can involve computerized database records that contain a wide variety of potential modulators and chemical functional groups. The computerized design and identification of modulators is useful because computer databases contain more compounds than chemical libraries, often by an order of magnitude. For design reviews and drug-based identification of structures (see Kuntz et al., (1994), Acc. Chem. Res. 27: 117; Guida (1994) Current Opinion in Struct. Biol. 4: 777; Colman (1994 ) Current Opinion in Struct. Biol. 4: 868). The three-dimensional structure of a polypeptide defined by the structural coordinates can be used by these design methods, for example, the structural coordinates of a PPAR. In addition, the three-dimensional structures of PPARs determined by homology, molecular replacement, and NMR techniques can also be applied to modulator design and identification methods. To identify modulators, the structural information for a PPAR, in particular, the structural information for the active site of the PPAR can be used. However, it may be advantageous to use the structural information from one or more PPAR co-crystals with one or more binding compounds. It may also be advantageous if the binding compound has a structural core in common with test compounds. Such identification and modulator design can for example be used to identify and / or develop additional active compounds within Formula I (a subgroup thereof). 1. Design when Investigating Molecular Databases A rational design research method for modulators by linking computer representations of compounds from the molecule database. Publicly available databases include, for example: a) ACD from Molecular Designs Limited b) NCI from National Cancer Institute c) CCDC from Cambridge Crystallographic Data Center d) CAST from Chemical Abstract Service e) Derwent from Derwent Information Limited f) Maybridge from Maybridge Chemical Company LTD g) Aldrich from Aldrich Chemical Company h) Directory of Natural Products from Chapman & Hall One of such database (ACD distributed by Molecular Designs Limited Information Systems) contains compounds that are derived synthetically or are natural products. The methods available to those skilled in the art can convert a data set represented in two dimensions to one represented in three dimensions. These methods can be carried out using such computer programs as CONCORD from Tripos Associates or DE-Converter from Molecular Simulations Limited. It is known to those skilled in the art, multiple methods of modulator design based on structures (Kuntz et al., (1982), J. Mol. Biol. 762: 269; Kuntz et al., (1994), Acc. Chern. Res. 27: 117; Meng ef al., (1992), J. Compt. Chem. 73: 505; Bohm, (1994), J. Comp. Aided Molec. Design 8: 623). A computer program widely used by those skilled in the art of rational modulator design is DOCK from the University of California at San Francisco. The general methods used by this computer program and programs similar to those described in three subsequent applications. More detailed information regarding some of these techniques can be found in the Accelerys User Guide, 1995. A typical computer program used for this purpose can perform a process that comprises the following stages or functions: (a) removing the existing compound to from the protein; (b) link the structure of another compound within the active site using the computer program (such as DOCK) or by interactively moving the compound within the active site; (c) characterizing the space between the compound and the active site atoms; (d) exploring libraries for molecular fragments that (i) can be adjusted within the empty space between the compound and the active site, and (ii) can be bound to the compound; and (e) linking the fragments found around the compound and evaluating the new modified compound. Part (c) refers to characterizing the geometry and the complementary interactions formed between the atoms of the active site and the compounds. A favorable geometric fit is achieved when a significant surface area is divided between the compound and the active site atoms without forming unfavorable spherical interactions. One skilled in the art would observe that the method can be performed by parts (d) and (e) of leakage and select a database of many compounds. The design and identification based on modulator structures of the PPAR function can be used together with the selection of tests. Since large computer databases of the compounds (around 10,000 compounds) can be investigated in a matter of hours or even less, the computer-based method can contract the tested compounds as potential modulators of the PPAR function in biochemical assays or cell phones. The above descriptions of the structure-based modulator design are not fully covered and other methods are reported in the literature and can be used, for example: (1) CAVEAT: Bartlett et al., (1989), in Chemical and Biological Problems in Molecular Recognition, Roberts, SM; Law, S. V .; Campbell, M. M. eds .; Royal Society of Chemistry. Cambridge, pp. 182-196. (2) FLOG: Miller et al. , (1994), J. Comp. Aided Molec. Design 8: 153. (3) PRO Modulator: Clark et al., (1995), J. Comp. Aided Molec. Design 9: 13. (4) MCSS: Miranker and Karplus, (1991), Proteins: Structure, Function, and Genetics 11:29. (5) AUTODOCK: Goodsell and Olson, (1990), Proteins: Structure, Function, and Genetics 8: 195. (6) GRID: Goodford, (1985), J Med. Chem. 28: 849. 2. Design Modifying Compounds in the Complex with a PPAR Another way to identify compounds as potential modulators is to modify an existing modulator in the active site of the polypeptide. For example, the representation of the computer in the modulators can be modified within the computer representation of an active PPAR site. Detailed instructions for this technique can be found, for example, in the Accelerys User Manual, 1995 in LUDÍ. The representation of the modulator computer is usually modified by the removal of the chemical group or groups or by the addition of a chemical group or groups. At each modification to the compound, the atoms of the modified compound and the active site can be changed into conformation and the distance between the modulator and the active site atoms can be classified together with any complementary interactions formed between the two molecules. The evaluation can be completed when a favorable geometric adjustment and favorable complementary interactions are achieved. Compounds that have favorable evaluations are potential modulators. 3. Design Modifying the Structure of the Compounds that join PPAR A third method of modulator-based structure design is to select compounds designed by a modulating or modulating search computer program. Examples of these types of programs can be found in the Molecular Simulations Package, Cataiyst. The descriptions for using this program are documented in the Molecular Simulations User's Guide (1995). Other computer programs used in this application are ISIS / HOST, ISIS / BASE, ISIS / DRA.) Of Molecular Designs Limited and UNITY of Tripods Associates. These programs can be operated on the structure of a compound that has been removed from the active site of the three-dimensional structure of a compound-PPAR complex. Operating the program in such a compound is preferable, since it is in a biologically active conformation. A modulating construction computer program is a computer program that can be used to replace computer representations of chemical groups in a compound fused with a PPAR or other biomolecule with groups from a computer database. A modulating search computer program is a computer program that can be used to look for computer representations of compounds from a computer database that have similar three-dimensional structures and similar chemical groups as a compound bound to a particular biomolecule. A typical program can operate using the following general steps: (a) mapping the compounds by chemical characteristics such as by hydrogen bond donors or acceptors, hydrophobic / lipophilic sites, positively ionizable sites, or negatively ionizable sites; (b) add geometric constraints to the mapped characteristics; and (c) search databases with the model generated in (b). Those skilled in the art also recognize that not all possible chemical characteristics of the compound need to be presented in the model of (b). Any subset of the model can be used to generate different models for database searches.

B. Identification of Active Compounds Using a PPAR Structure and Molecular Scaffolds In addition to the methods described above, which are normally applied based on selection hits that have a substantial level of activity, the availability of crystal structures that include sites Ligand binding for the various PPARs provides the application of a scaffolding method to identify and develop additional active PPAR compounds. As an example, such a scaffolding method can be applied using molecular scaffolds within Formula I, or having a scaffolding core of Formula I, but can also be applied to other molecular scaffolds that are identified. Thus, the present invention also relates to methods for designing active ligands in PPARs using structural information about the ligand binding sites and the identified PPAR binding compounds. Although such methods can be implemented in many ways (e.g., as described above), preferably, the elevated process uses molecular scaffolds. Such developed processes and related methods are generally described below, and may, as indicated when applied to PPARs, individually and / or in any pair or as a family. Molecular scaffolds are low molecular weight molecules that bind with low or very low affinity to the target and typically have low or very low activity on that target and / or act broadly across families of target molecules. The ability of a scaffold or other compound to act broadly across multiple members of a target family is advantageous for developing ligands. For example, a scaffold or set of scaffolds can serve as starting compounds to develop ligands with desired specificity or desired cross-activity in a selected subset of members of a target family. In addition, the identification of a set of scaffolds that are each linked to members of a target family provides an advantageous basis for selecting a starting point for the development of ligands for a particular objective or subset of objectives. In many cases, the ability of a scaffold to join and / or to have activity in multiple members of a target family is related to an active site or homology of the binding site that exists through the target family. Active scaffolding through multiple members of the target family interacts with surfaces or residues of relatively high homology, that is, binds to conserved regions of the binding cavities. Scaffolds that bind with multiple members can be modified to provide greater specificity or to have a particular cross-reactivity, for example, exploiting differences between target binding sites to provide specificity, and exploiting similarities to design cross-reactivities. Add substituents that provide attractive interactions with the particular objective of normally increasing binding affinity, often increasing activity. The various parts of the ligand development process are described in greater detail in the following sections, but the following describes an advantageous approach for the development of scaffold-based ligands. The development of scaffold-based ligands (scaffold-based drug discovery) can be implemented in a variety of ways, but large-scale expression is useful in providing material for crystallization, co-crystallization, and biochemical selection (e.g. of union and activity). For crystallization, the crystallization conditions can be established for the apo protein and a structure determined from those crystals. For selection, a partial library selected for the particular target family is preferably selected for attachment and / or activity on the target. A highly preferable plurality of members is selected from the target family. Such selectioneither in a single objective or in multiple members of a target family provides selection successes. Low affinity and / or low activity hits are selected. Such low affinity hits can identify a scaffold molecule, or allow the identification of a scaffold molecule by analyzing common characteristics between the binding molecules. The simplest molecules that contain the common characteristics can then be tested to determine if they retain the binding and / or the activity, so that the identification of a scaffolding molecule is allowed. When multiple members of a particular target family are used for selection, the overlap in binding activity and / or activity of compounds can provide a useful selection for compounds that will undergo crystallization. For example, for 3 target molecules of a target family, if each target has approximately 200-500 hits in the selection of a particular library, much smaller subsets of those hits will be common to any of 2 of the 3 targets, and a subset even smaller will be common to all 3 targets, for example, 100-300. In many cases, the compounds in the subset common to all 3 targets will be selected for co-crystallography, since they provide the broadest potential for the development of ligands. Once the compounds for co-crystallization are selected, the conditions for forming the co-crystals are determined, allowing the determination of a co-crystal structure and the orientation of the binding compound at the target binding site is determined solving the structure (this can be addressed highly if a crystal structure of apo protein has been determined or if the structure of a close homolog is available for use in a homology model.) Co-crystals are preferably formed by co-crystallization Directly instead of by impregnation of the compound within protein crystals • apo. From the co-crystals and the knowledge of the structure of the binding compounds, the additional selection of scaffolds or other binding compounds can be done by applying the filters selection, for example, for (1) binding mode, (2) multiple sites for substitution and / or (3) treatable chemistry. The union can, for example, be based on the demonstration of a dominant mode of union. That is, a scaffold or composite of a group of scaffolds are joined with a consistent orientation, preferably a consistent orientation across multiple members of a target family. Filtering scaffolds for multiple sites for substitution provides greater potential to develop ligands for specific targets due to the large capacity to appropriately modify the structure of the scaffolding. Filtering the treatable chemistry also facilitates the preparation of ligands derived from a scaffold because the synthetic trajectories making derivative compounds are available. Carrying out such a development process provides scaffolds, preferably of divergent structure. In some cases, it may be impractical or undesirable to work with a particular objective for some or all of the development process. For example, a particular goal may be difficult to express, be easily degraded, or difficult to crystallize. In these cases, a substitute goal can be used from the target family. It is desirable to have the substitute that is as similar as possible to the desired objective, thus a family member having high homology at the binding site should be used, or the binding site can be modified to be more similar to that of the desired target, or part of the desired target sequence can be inserted into the family member by replacing the corresponding part of the family member sequence.

Once one or more scaffolds are identified for a target family, the scaffolds can be used to develop multiple products targeted at specific members of the family, or specific subsets of family members. Thus, from a scaffold, which acts on multiple members of the target family, the derivative compounds (ligands) can be designed and tested so that they have increased selectivity. In addition, such ligands are normally developed to have greater activity, as well as to have normally higher binding affinity. In this process, when initiating the action scaffold extensively, ligands are developed in a manner that have improved selectivity and activity profiles, leading to the identification of major compounds for drug development, leading drug candidates, and final drug products. .

C. Scaffolds Normally, it is advantageous to select scaffolds (and / or assemblies or libraries of compounds for identification of the scaffold or the binding compound) with particular types of features, for example, to select compounds that are more likely to bind to a target. particular and / or to select compounds having physical and / or synthetic properties to simplify the preparation of derivatives, which are drug-like, and / or to provide convenient sites and chemistry for modification or synthesis. The useful chemical properties of molecular scaffolds may include one or more of the following characteristics, but are not limited thereto: an average molecular weight below about 350 daltons, or between about 150 to about 350 daltons, or from about 150 to about 300 daltons; having a ClogP below 3; a number of rotatable joints of less than 4; a number of hydrogen bonding donors and acceptors below 5 or below 4; a Polar Surface Area of less than 100 A2; binding at the protein binding sites in an orientation so that chemical substituents from a combinatorial library that bind to the scaffold can be projected into cavities at the protein binding site; and having chemically treatable structures at their substituent attachment points that can be modified, thereby allowing the rapid construction of the library. The term "Molecular Polar Surface Area (PSA)" refers to the sum of surface contributions of polar atoms (usually oxygens, nitrogens and bound hydrogens) in a molecule. The polar surface area has been shown to correlate well with drug transport properties, such as intestinal absorption, or penetration into the blood-brain barrier.

Additional chemical properties of different compounds for inclusion in a combinatorial library include the ability to bind chemical moieties to the compound which will not interfere with the binding of the compound to at least one protein of interest, and which will impart desirable properties to the members of the library. , for example, by causing members of the library to be actively transported to cells and / or organs of interest, or the ability to bind to a device such as a chromatography column (eg, a streptavidin column through such a molecule). as biotin) for uses such as tissue and proteomic profile purposes. A person with ordinary skill in the art will understand other properties that may be desirable for scaffolding or library members that have to depend on the particular requirements of use, and so that compounds with these properties can also be searched and identified in a similar way. Methods for screening compounds for testing are known to those of ordinary skill in the art, for example, the methods and compounds described in US Pat. No. 6., 288,234, 6,090,912, 5,840,485, each of which is incorporated herein by reference in its entirety, including all graphics and drawings. In various embodiments, the present invention provides methods for designing ligands that bind to a plurality of members of the molecular family, wherein the ligands contain a common molecular scaffolding. Thus, a set of compounds can be evaluated to bind to a plurality of members of a molecular family, for example, a family of proteins. One or more compounds that bind to a plurality of family members can be identified as molecular scaffolds. When the orientation of the scaffolding at the binding site of the target molecules has been determined and the chemically treatable structures have been identified, a set of ligands can be synthesized by starting with one or a few molecular scaffolds to achieve a plurality of ligands, wherein each ligand binds to a target molecule separated from the molecular family with altered or changed binding affinity or a binding specificity relative to the scaffold. Thus, a plurality of drug master molecules can be designed to individually target members of a molecular family based on the same molecular scaffold, and to act them in a specific manner.

D. Binding Assays 1. Use of Binding Assays The methods of the present invention involve assays that are capable of detecting the binding of compounds of a target molecule in a signal of at least about three times the standard deviation of the background signal , or at least about four times the standard deviation of the background signal. Assays may also include analyzing compounds for low affinity binding to the target molecule. A large variety of assays indicative of binding are known for different target types and can be used for this invention. Compounds that act broadly across protein families are not likely to have a high affinity against individual targets, due to the broad nature of their binding. Thus, assays (e.g., as described herein) give high preference preference to the identification of compounds that bind with low affinity, very low affinity, and extremely low affinity. Therefore, the potency (or binding affinity) is not a major, or even the most important, sign of identification of a potentially useful binding compound. Rather, even those compounds that bind with low affinity, very low affinity, or extremely very low can be considered as molecular scaffolds that can continue to the next phase of the ligand design process. As indicated above, to design or discover scaffolds that act broadly across protein families, the proteins of interest can be evaluated against a collection or set of compounds. The assays may preferably be enzymatic or binding assays. In some embodiments, it may be desirable to improve the solubility of the compounds that are selected and then analyze all compounds that show activity in the assay, including those that bind with low affinity or produce a signal greater than about three times the standard deviation of the background signal. These assays can be any assay such as, for example, binding assays that measure the binding affinity between two binding partners. Various types of screening assays that may be useful in the practice of the present invention are known in the art, such as those described in US Patents Nos. 5,763,198, 5,747,276, 5,877,007, 6,243,980, 6,294,330 and 6,294,330, each of which it is incorporated herein by reference in its entirety, including all graphics and drawings. In various assay modalities, at least one compound, at least about 5%, at least about 10%, at least about 15%, at least about 20%, or at least about 25% of the compounds can bind with low affinity . In many cases, up to about 20% of the compounds may show activity in the screening test and these compounds can be analyzed directly with high performance co-cronography, computational analysis to group the compounds into classes with common structural properties (e.g. , characteristics of structural core and / or shape and polarity), and the identification of common chemical structures among the compounds that show activity. The person with ordinary skill in the art will understand that decisions can be based on criteria that are appropriate for the needs of the particular situation, and that decisions can be made by computer software programs. Classes can be created that contain almost any number of scaffolds, and the selected criteria can be based on increasingly accurate criteria until an uncontrolled number of scaffolds arrive for each class that is conceptualized to be advantageous. 2. Surface Plasmon Resonance The binding parameters can be measured using surface plasmon resonance, for example, with a BIAcore® chip (Biacore, Japan) coated with immobilized binding components. Surface plasmon resonance is used to characterize the microscopic association and reaction dissociation constants between a sFv or other ligand directed against target molecules. Such methods are generally described in the following references which are incorporated herein by reference. Vely F. et al., BIAcore® analysis to test phosphopeptide-SH2 domain interactions, Methods in Molecular Biology. 121: 313-21,2000; Liparoto et al., Biosensor analysis of the interleukin-2 receptor complex, Journal of Molecular Recognition. 12: 316-21, 1999; Lipschultz et al., Experimental design for analysis of complex kinetics using surface pl.asmon resonance, Methods. 20 (3): 310-8, 2000; Malmqvist., BIACORE: an affinity biosensor system for characterization of biomolecular interactions, Biochemical Society Transactions 27: 335-40,1999; Alfthan, Surface plasmon resonance biosensors as a tool in antibody engineering, Biosensors & Bioelectronics. 13: 653-63,1998; Fivash et al. , BIAcore for macromolecular interaction, Current Opinion in Biotechnology. 9: 97-101, 1998; Price et al .; Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUCI mucin. Tumor Biology 19 Suppl 1: 1-20, 1998; Malmqvist et al, Biomolecular interaction analysis: affinity and biosensor technologies for functional analysis of proteins, Current Opinion in Chemical Biology. 1: 378-83, 1997; O'Shannessy et al., Interpretation of deviations from pseudo-first-order kinetic behavior in the characterization of ligand binding by biosensor technology, Analytical Biochemistry. 236: 275-83, 1996; Malmborg et al., BIAcore as a tool in antibody engineering, Journal of Immunological Methods. 183: 7-13, 1995; Van Regenmortel, Use of biosensors to characterize recombinant proteins, Developments in Biological Standardization. 83: 143-51, 1994; and O'Shannessy, Determination of kinetic rate and equilibrium binding constants for macromolecular interactions: a critique of the surface plasmon resonance literature, Current Opinions in Biotechnology. 5: 65-71,1994. BIAcore® uses the optical properties of surface piasmon resonance (SPR) to detect alterations in the concentration of proteins bound to a dextran matrix that are located on the surface of a gold / glass sensor chip interface, a biosensor matrix of dextran. In brief, the proteins are covalently bound to the dextran matrix at a known concentration and a ligand for the protein is injected through the dextran matrix. Near-infrared light, directed on the opposite side of the sensor chip surface, is reflected and also induces an evanescent wave in the gold film, which, in turn, causes a reduction in intensity in the reflected light at a particular angle known as the resonance angle. If the refractive index of the sensor chip surface is altered (for example, by ligand binding to the bound protein) a change in the resonance angle occurs. This angle change can be measured and expressed as resonance units (the RUs) so that 1000 RU is equivalent to a change in the surface protein concentration of 1 ng / mm2. These changes are displayed with respect to time along the y axis of a sensorgram, which describes the association and dissociation of any biological reaction.

E. High Performance Selection Tests (HTS) The HTS normally uses automated tests to look for large direct numbers of compounds for a desired activity. Typically, HTS assays are used to find new drugs by selecting chemicals that act on a particular enzyme or molecule. For example, if a chemical inactivates an enzyme, it could prove effective in preventing a process in a cell that causes disease. High throughput methods allow researchers to evaluate thousands of different chemicals against each target molecule very quickly using robotic management systems and automated results analysis. As used herein, "high throughput selection" or "HTS" refers to the rapid in vitro selection of large numbers of compounds (libraries); it tends generally to hundreds of thousands of compounds, using robotic selection tests. The Ultra High Performance Selection (uHTS) generally refers to the selection of accelerated high performance to more than 100,000 tests per day. In order to achieve high performance selection, it is advantageous to host samples in a multirecipient carrier or platform. A multi-container carrier facilitates measuring the reactions of a plurality of candidate compounds simultaneously. Multi-well microplates can be used as the carrier. Such multi-well microplates and methods for their use in numerous assays are known in the art and are commercially available. Selection tests may include control for calibration purposes and confirmation of proper handling of the test components. Blank wells containing all reagents, but not members of the chemical library are usually included. As another example, a known inhibitor (or activator) of an enzyme for which modulators are sought, can be incubated with a test sample, and the resulting decrease (or increase) in the enzymatic activity used as a comparator or a control. It will be appreciated that the modulators can also be combined with the enzyme activators or inhibitors to find modulators that inhibit the activation or enzymatic repression that is otherwise caused by the presence of the known enzymatic modulator. Similarly, when ligands to a target are searched, known ligands of the target can be presented in control / calibration test wells.

F. Measuring Enzymatic and Union Reactions During Screening Assays Techniques for measuring the progress of enzymatic reactions and binding, eg, in multi-container carriers, are known in the art and include, but are not limited to the following. Spectrophotometric and spectrofluorometric assays well known in the art. Examples of such assays include the use of colorimetric assays for the detection of peroxides, as described in Gordon, A.J. and Ford, R.A., The Chemist's Companion: A Handbook of Practical Data, Techniques, and References, John Wiley and Sons, N.Y., 1972, page 437. Fluorescence spectrometry can be used to monitor the generation of reaction products. The fluorescence methodology is generally more sensitive than the absorption methodology. The use of fluorescent probes is well known to those skilled in the art. For reviews, see Bashford et al., Spectrophotometry and Spectrofluorometrv: A Practical Approach. pp. 91-114, IRL Press Ltd. (1987); and Bell, Spectroscopy In Biochemistry, Vol. I, pp. 155-194, CRC Press (1981). In spectrofluorometric methods, enzymes are exposed to substrates that change their intrinsic fluorescence when processed by the target enzyme. Normally, the substrate is not fluorescent and is converted to a fluorophore through one or more reactions. As a non-limiting example, the SMase activity can be detected using the Amplex® Red reagent (Molecular Probes, Eugene, OR). In order to measure sphingomyelinase activity using Amplex® Red, the following reactions occur. First, SM.se hydrolyzes spinfomyelin to produce ceramide and phosphorylcholine. Second, alkaline phosphatase hydrolyzes phosphorylcholine to produce choline. Third, the hill is oxidized to betaine. Finally, the H2O2, in the presence of horseradish peroxidase, reacts with Amplex® Red to produce the fluorescent product, Resorufina and the signal thereof is detected using spectrofluorometry. Fluorescence polarization (FP) is based on a decrease in the rate of molecular rotation of a fluorophore that occurs at binding to a larger molecule, such as a receptor protein, allowing fluorescence emission polarized by the bound ligand. FP is determined empirically by measuring the vertical and horizontal components of fluorophore emission following excitation with plane polarized light. Polarized emission increases when the molecular rotation of a fluorophore is reduced. A fluorophore produces a larger polarized signal when it binds to a larger molecule (i.e., a receptor), decreasing the molecular rotation of the fluorophore. The magnitude of the polarized signal is quantitatively related to the degree of fluorescent ligand binding. Accordingly, the polarization of the "bound" signal depends on the maintenance of high affinity binding. FP is a homogenous technology and the reactions are very fast, taking seconds to minutes to reach equilibrium. The reagents are stable, and large batches can be prepared, resulting in high reproducibility. Because of these properties, FP has been shown to be highly automated, often performed with a single incubation with a simple, pre-mixed receptor-tracer reagent. For a review, see Owickiet et al., Application of Fluorescence Polarization Assays in High-Troughput Screening Genetic Engineering News, 17:27, 1997. FP is particularly desirable since its reading is independent of emission intensity (Checovich, W. J., Et al., Nature 375: 254-256, 1995; Dandliker, W. B., et al. , Methods in Enzymology 74: 3-28, 1981) and is thus insensitive to the presence of colored compounds that extinguish the emission of fluorescence. FP and FRET (see below) are well suited for identifying compounds that block interactions between sphingolipid receptors and their ligands. See, for example, Parker, et al. , Development of high troughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase / phosphatase assays, J Biomol Screen 5: 77-88, 2000. Fluorophores derived from spinfolipids that can be used in FP assays are commercially available. available For example, Molecular Probes (Eugene, OR) currently markets espingomyelin and fluorophores of a ceramide. These are, respectively, N- (4,4-difluoro-5,7-dimethyl-4-bora-3a, 4a-diaza-s-indacen-3-pentanoi Respingos i lo phosphocholine (BOD1PY® FL C5-espingomyelin); N- (4,4-difluoro-5,7-dimethyl-4-bora-3a, 4a-diaza-s-indacen-3-dodecanoyl) espingosyl phosphocholine (BODI PY® FL C12-espingomyelin); and N- (4,4-difluoro-5,7-d imethyl-4-bora-3a, 4a-diaza-s-indacen-3-pentanoyl) espingosine (BODI PY® FL C5-ceramide). US Patent No. 4,150,949 (Immunoassay for gentamicin), describes gentamicins labeled with fluorescein, including fluoresceintiocarbanyl gentamicin. Additional fluorophores can be prepared using methods well known to those skilled workers. Exemplary normal and polarized fluorescence readers include the POLARION® fluorescence polarization system (Tecan AG, Hombrechtikon, Switzerland). General multi-well plate readers for other assays are available, such as the VERSAMAX® reader and the SPECTRAMAX® multi-well plate spectrophotometer (both from Molecular Devices). The fluorescence resonance energy transfer (FRET) is another useful assay to detect the interaction and has been described. See, for example, IEM et al. , Curr. Biol. 6: 178-1 82, 1996; Mitra et al. , Gene 173: 13-17 1 996; and Selvin et al. , Meth. Enzymol. 246: 300-345, 1995. The FRET detects the transfer of energy between two fluorescent substances in close proximity, which has known excitation and emission wavelengths. As an example, a protein can be expressed as a fusion protein with green fluorescent protein (GFP). When two fluorescent proteins are in proximity, such as when a protein interacts specifically with a target molecule, the resonance energy can be transferred from one excited molecule to the other. As a result, the emission spectrum of the sample changes, which can be measured by a fluorometer, such as a fMAX multipole fluorometer (Molecular Devices, Sunnyvale Calif.). The scintillation proximity assay (SPA) is a particularly useful assay for detecting an interaction with the target molecule. SPA is widely used in the pharmaceutical industry and has been described (Hanselman et al., J. Lipid Res. 38: 2365-2373 (1997); Kahl et al., Anal. Biochem. 243: 282-283 (1996); Undenfriend et al., Anal. Biochem. 161: 494-500 (1987)). See also U.S. Patent Nos. 4,626,513 and 4,568,649 and European Patent No. 0,154,734. A commercially available system uses FLASHPLATE® scintillation coated plates (NEN Life Science Products, Boston, MA). The target molecule can be attached to the scintillation plates by a variety of well-known means. The scintillation plates are available so that they are derived to bind to fusion proteins such as GST, Hisd or Flag fusion proteins. Where the target molecule is a protein complex or a multimer, a protein or subunit can bind to the first plate, then the other components of the complex are then added under binding conditions, resulting in a bound complex. In a typical SPA assay, the genetic products in a pressure junction that have been radiolabelled and added to the wells are allowed to interact with the solid phase, which is the immobilized target molecule and the scintillation coating in the wells. The test can be measured immediately or allowed to reach equilibrium. Any way, when a radio tag becomes sufficiently narrowed to the scintillation coating, it produces a detectable signal by a device such as a TOPCOUNT NXT® microplate scintillation counter (Packard BioScience Co., Meriden Conn.). If a radiolabelled expression product binds to the target molecule, the radiolabel remains in proximity to the blinking lamp long enough to produce a detectable signal. In contrast, tagged proteins that do not bind to the target molecule, or bind only shortly, will not remain near the blinking enough time to produce a signal on the background. Any time spent near the blinking caused by random Brownian movement will not result in a significant amount of signal either. Likewise, the residual unincorporated radiolabel used during the expression stage may be present, but will not generate significant signal because it will be in solution instead of interacting with the target molecule. These non-union interactions will therefore cause a certain level of background signal that can be removed mathematically. If too many signals are obtained, the salt or other modifiers can be added directly to the assay plates until the desired specificity is obtained (Nichols et al., Anal. Biochem 257: 112-119, 1998). Additionally, the assay can use an AlphaScreen format (homogeneous luminescent proximity probe amplification), for example, the AlphaScreening system (Packard BioScience). AlphaScreen is generally described in Seethala and Prabhavathi, Homogenous Assays: AlphaScreen, Handbook of Drug Screening. Marcel Dekkar Pub. 2001, pp. 106-110. Applications of the art to PPAR receptor ligand binding assays are described, for example, in Xu, et al., 2002, Nature 415: 813-817.

G. Molecular Compound and Scaffold Assays As described above, preferred scaffold features include the existence of low molecular weight (eg, less than 350 Da, or from about 100 to about 350 daltons, or from about 150 to about 300 daltons). Preferably clog P of a scaffolding is from -1 to 8, more preferably less than 6, 5 or 4, more preferably less than 3. In particular embodiments, the clogP is in a range -1 to an upper limit of 2, 3, 4, 5, 6 or 8; p is in a range from 0 to an upper limit of 2, 3, 4, 5, 6 or 8. Preferably, the number of rotatable joints is less than 5, more preferably less than 4. Preferably, the number of Donors and hydrogen bond acceptors are below 6, most preferably below 5. An additional criterion that may be useful is a Polar Surface Area less than 100. The guidance that may be useful to identify criteria for an application particular can be found in Lipinski et al., Advanced Drug Delivery Reviews 23 (1997) 3-25, which is incorporated herein by reference in its entirety. A scaffold will preferably be attached to a given protein binding site in a configuration that causes substituent portions of the scaffold to be located in cavities of the protein binding site. Also, having chemically treatable groups that can be chemically modified, particularly through synthetic reactions, to easily create a combinatorial library can be a preferred feature of scaffolding. Own positions can also be preferred in the scaffolding to which other portions can be attached, which do not interfere with the scaffolding junction of the protein or proteins of interest, but do not cause scaffolding to achieve a desirable property, for example, the active transport of the scaffold. Scaffolding to cells and / or organs, allowing scaffolding to be attached to a chromatographic column to facilitate analysis, or other desirable property. A molecular scaffold can bind to a target molecule with any affinity, such as binding with a measurable affinity as approximately three times the standard deviation of the background signal, or at high affinity, moderate affinity, low affinity, very low affinity, or extremely low affinity.

In this way, the above criteria can be used to select many compounds to prove that they have the desired attributes. Many compounds having the described criteria are available in the commercial market, and can be selected by analysis depending on the specific needs to which the methods are to be applied. In some cases, sufficiently large numbers of compounds can meet the specific criteria so that additional methods that group similar compounds can be useful. A variety of methods to assess molecular similarity, such as the Tanimoto coefficient has been used, see Willett et al, Journal of Chemical Information and Computer Science 38 (1998), 938-996. These can be used to select a smaller subset of a group of highly structural redundant compounds. In addition, cluster analysis based on relationships between the compounds, or structural components of the compound, can also be carried out at the same end; see Lance and Williams Computer Journal 9 (1967) 373-380, Jarvis and Patrick IEEE Transactions in Computer C-22 (1973) 1025-1034, for clustering algorithms, and Downs et al., Journal of Chemical Information and Computer Sciences 34 (1994) 1094-1102 for a review of these methods applied to chemical problems. One method to derive the chemical components of a large group of potential scaffolds is to virtually break the compound into rotatable bonds so that components of no less than 10 atoms are produced. The resulting components can be grouped based on some measure of similarity, for example, the Tanimoto coefficient, which produces the groups of the common component in the collection, original of compounds. For each group of the component, all compounds containing that component can be grouped, and the resulting groups used to select a diverse set of compounds that contain a common chemical core structure. In this way, a useful library of scaffolds can still be derived from millions of commercial compounds. A "composite library" or "library" is a - Collection of different compounds that have different chemical structures. A library of the compound is selectable, i.e., members of the library of the compound herein can be screened for selection. In preferred embodiments, the library members may have a molecular weight of from about 100 to about 350 daltons, or from about 150 to about 350 daltons. The libraries may contain at least one compound that binds to the target molecule at low affinity. Libraries of candidate compounds can be evaluated by many different assays, such as those described above, for example, a fluorescence polarization assay. Libraries may consist of chemically synthesized peptides, peptidomimetics, or combinatorial chemical arrays that are large or small, focused or unfocused. By "focused" it is meant that the collection of compounds is prepared using the structure of previously characterized compounds and / or pharmacophores. The libraries of the compound may contain molecules isolated from natural sources, artificially synthesized molecules, or molecules synthesized, isolated or otherwise prepared in such a manner so as to have one or more variable portions, for example, portions that are independently isolated or they are synthesized randomly. The types of molecules in the compound libraries include, but are not limited to, organic compounds, polypeptides and nucleic acids as those terms are used herein, and derivatives, conjugates and mixtures thereof. The libraries of the compound useful for the invention may be purchased in the commercial market or prepared or obtained by any means including, but not limited to, combinatorial chemistry techniques. Fermentation methods, plant and cell extraction procedures and the like (see for example, Cwirla et al., Biochemistry 1990, 87, 6378-6382; Houghten et al., Nature 1991, 354, 84-86; Lam et al. al., Nature 1991, 354, 82-84; Brenner et al., Proc. Nati, Acad. Sci. USA 1992, 89, 5381-5383; RA Houghten, Trends Genet., 1993, 9, 235-239; ER Felder , Chimia 1994, 48, 512-541; Gallop et al., J. Med. Chem. 1994, 37, 1233-1251; Gordon et al., J. Med. Chem. 1 994, 37, 1385-1401; ) et al. , Chem. Biol. 1 995, 3, 171-1 83; Madden et al. , Perspectives in Drug Discovery and Design 2, 269-282; Lebl et al. , Biopolymers 1995, 37 177-198); small molecules assembled around a shared molecular structure; collections of chemicals that have been assembled by various commercial and non-commercial groups, natural products; extracts of marine organisms, fungi, bacteria and plants. Preferred libraries can be prepared in a homogeneous reaction mixture, and the separation of non-reactive reagents from members of the library is not required before selection. Although many combinatorial chemistry approaches are based on solid-state chemistry, combinatorial liquid-phase chemistry is capable of generating libraries (Sun CM., Recent advances in liquid-phase combinatorial chemistry, Combinatorial Chemistry &High Troughput Screening 2: 299 -318, 1999). Libraries of a variety of types of molecules are prepared in order to obtain members thereof having one or more pre-selected attributes that can be prepared by a variety of techniques, including, but not limited to, parallel array synthesis (Houghton , Annu Rev Pharmacol Toxicol 2000 40: 273-82, parallel disposition and synthetic combinatorial chemistry based on the mixture, combinatorial chemistry solution phase (Merritt, Comb Chem High Throughput Screen 1998 1 (2): 57-72, Chemistry Combinatorial Solution Phase, Coe et al., Mol Divers 1998-99, 4 (1): 31-8, Combinatorial Chemistry of Solution Phase, Sun, Comb Chem High Troughput Screen 1999 2 (6): 299-318, Recent advances in liquid phase combinatorial chemistry); synthesis in the soluble polymer (Gravert et al., Curr Opin Chem Biol 1997 1 (1): 107-13, Synthesis in soluble polymers: new reactions and the construction of small molecules); and similar. See for example, Dolle et al., J Comb Chem 1999 1 (4): 235-82, Integral inspection of combinatorial library synthesis: 1998. Freidinger RM., Non-peptidic ligands for peptide and protein receptors, Current Opinion in Chemical Biology; and Kundu et al., Prog Drug Res 1999; 53: 89-156, Combinatorial Chemistry: Sustained Polymeric Synthesis of Peptide and Non-Peptide Libraries). The compounds can be clinically oriented for ease of identification (Chabala, Curr Opin Biotechnol 1995 6 (6): 633-9, solid phase combinatorial chemistry and novel labeling methods for identifying instructions). Combinatorial synthesis of carbohydrates and libraries containing oligos.accharides have been described (Schweizer et al., Curr Opin Chem Biol 19993 (3): 291-8, the combinatorial synthesis of carbohydrates). The synthesis of compound libraries based on a product has been described (Wessjohann, Curr Opin Chem Biol 20004 (3): 303-9, Synthesis of natural-product based compound libraries). Nucleic acid libraries are prepared by various techniques, including by way of non-limiting example, the only ones described herein, for the isolation of aptamers. Libraries that include oligonucleotides and polyamino-oligonucleotides (Markiewicz et al., Synthetic oligonucleotide combinatorial libraries and their applications, Drug 55: 174-7, 2000) deployed in streptavidin magnetic beads are known. Nucleic acid libraries are known that can be coupled to sample in parallel and deployed without complex procedures such as automated mass spectrometry (Enjalbal C. Martinez J. Aubagnac JL, Mass spectrometry in combinatorial chemistry, Mass Spectrometry Reviews 19: 139-61 , 2000) and the labeling in parallel. (Perrin DM., Nucleic acids for recognition and catalysis: landmarks, limitations, and looking to the future, Combinatorial Chemistry &High Throughput Screening 3: 243-69). Peptidomimetics are identified using combinatorial chemistry and solid phase synthesis (Kim HO. Kahn M., A merger of rational drug design and combinatorial chemistry: development and application of secondary structure mimetics, Combinatorial Chemistry &High Troughput Screening 3 : 167-83, 2000, al.-Obeidi, Mol Biotechnol 1998 9 (3): 205-23, Peptide libraries and peptidomimetics, molecular diversity and drug design). The synthesis can be completely random or based in part on a known polypeptide. The polypeptide libraries can be prepared according to various techniques. In short, the techniques deployed can be used to produce polypeptide ligands (Gram H., Phage display in proteolysis and signal transduction, Combinatorial Chemistry &High Throughput Screening, 2: 19-28, 1999) which can be used as the basis for the synthesis of peptidomimetics. The polypeptides, the restricted peptides, the proteins, the protein domains, the antibodies, the single-chain antibody fragments, the antibody fragments, and the antibody-combining regions unfold in filamentous phage for selection. Large libraries of individual variants of human single chain Fv antibodies have been produced. See, for example, Siegel R. W. Alien B. Pavlik P. Marks JD. Bradbury A., Mass spectrum analysis of a protein complex using single chain antibodies selected in a peptide target: applications to functional genomes, Journal of Molecular Biology 302: 285-93, 2000; Poul MA. Becerril B. Nielsen UB. Morisson P. Marks JD., Selection of human antibodies for tumor-specific internalization from phage libraries. Source Journal of Molecular Biology 301: 1149-61, 2000; Amersdorfer P. Marks JD., Phage libraries for the generation of anti-botulinum scFv antibodies, Methods in Molecular Biology. 145: 219-40, 2001; Hughes-Jones NC. Bye JM.

Gorick BD. Marks JD. Ouwehand WH., Synthesis of Rh Fv phage-antibodies using VH and VL germline genes, British Journal of Haematology. 105: 811-6, 1999; McCall AM. Amoroso AR. Sautes C. marks JD. Weiner LM., Characterization of single chain Fv fragments Rm Fc anti-mouse derived from human phage display libraries, Imunotechnology. 4: 71-87, 1998; Sheets MD. Amersdorfer P. Finnern R. Sargent P. Lindquist E. Schier R. Hemingsen G. Wong C. Gerhart JC. Marks JD. Lindquist E.,. Efficient construction of a large noimmune phage antibody library: the production of high-affinity human single-chain antibodies to protein antigens (the published errata appears in Proc Nati Acad Sci USA 1999 96: 795), Proc Nati Acad Sci LSA95: 6157-62 , 1998). Acute and focused chemical and pharmacophore libraries can be designed with the aid of sophisticated strategies involving computational chemistry (eg, Kundu B. Khare SK, Rastogi SK, Combinatorial chemistry: polymer supported synthesis of peptide and non-peptide libraries, Progress in Drug Research 53: 89-156,1999) and the use of structure-based ligands using datábase searching and docking, de novo drug design and estimation of ligand binding affinities (Joseph-McCarthy D., Computational approaches to structure-based ligand design , Pharmacology & Therapeutics 84: 179-91, 1999; Kirkpatrick DL, Watson S. Ulhaq S., Structure-based drug design: Combinatorial chemistry and molecular modeling, Combinatorial Chemistry &High Throughput Screening, 2: 211 -21, 1999, Eliseev AV, Lehn JM, Dynamic combinatorial chemistry: evolutionary formation and screening of molecular libraries, Current Topics in Microbiology &Immunology 243: 159-72, 1999; Bolger et al., Methods Enz. 203: 21-45, 1991; Martin, Methods Enz. 203: 587-613, 1991; Neidle et al., Methods Enz. 203: 433-458, 1991; U. S. Patent 6,178, 384). Select a library of potential scaffolds and a set of dispositions that measure the binding to representative target molecules that are in a family of particular proteins that allows in this way the creation of data set that outline the union of the library to the protein family objective. Scaffolding groups with different sets of binding properties can be identified using the information within this data set. In this way, the scaffolding groups that join one, two or three members of the family can be selected for particular applications. In many cases, a group of scaffolds that exhibit binding to two or more members of a target protein family will contain scaffolds with a higher likelihood that such binding results from specific interactions with the individual target proteins. This would be expected to substantially reduce the effect of so-called "promiscuous inhibitors" that severely complicate the interpretation of screening assays (see McGovern et al., Journal of Medicinal Chemistry 45: 1712-22, 2002). Thus, in many preferred applications, the binding property of deployment to multiple target molecules in a protein family can be used as a selection criterion to identify molecules with desirable properties. In addition, groups of scaffolds that bind to specific subsets of a set of potential target molecules can be selected. Such a case would include the subset of scaffolds that bind to either two or three or three of five members of a target protein family. Such subsets can also be used in combination or opposition to further define a group of scaffolds that have additional desirable properties. This would be of significant utility in cases where some members of a family of proteins that had known desirable effects are inhibited, such as inhibiting tumor growth, while inhibiting other members of the protein family found to be essential for function. Normal cellular would have undesirable effects. One criterion that would be useful in such a case includes the selection of the subset of scaffolds that bind to any two or three desirable target molecules and eliminating from this group any one that binds to more than one of any three undesirable target molecules.

H. Crystallography After the binding compounds have been determined, the orientation of the compound bound to the target is determined. Preferably, this determination involves crystallography in co-crystals of molecular scaffolding compounds with the target. Most protein crystallographic platforms can be designed preferably by analyzing up to approximately 500 co-complexes of compounds, ligands or molecular scaffolds attached to the protein targets due to the physical parameters of the instruments and the convenience of operation. If the number of scaffolds that have binding activity exceeds a convenient number for the application of crystallography methods, the scaffolds may be placed within groups based on having at least one common chemical structure or other desirable characteristics and representative compounds may be selected from of one or more of the classes. Classes can be done with increasingly severe criteria until a desired number of classes is obtained (for example, 10, 20, 50, 100, 200, 300, 400, 500). Classes can be based on chemical structural similarities between the molecular scaffolds in the class, for example, they all have a pyrrole ring, a benzene ring or other chemical characteristic. Likewise, the classes can be based on shaped features, for example, space filling characteristics. Analysis by co-crystallography can be performed by co-fusing each scaffold with its objective, for example, in scaffold concentrations that showed activity in the selection assay. This co-combination can, for example, be achieved with the use of organic solvents of low percentage with the target molecule and then concentrating the objective with each of the scaffolds. In preferred embodiments, these solvents are less than 5% of the organic solvent such as dimethyl sulfoxide (DMSO), ethanol, methanol, or ethylene glycol in water or other aqueous solvent. Each scaffold fused to the target molecule can then be selected with an appropriate number of crystallization selection conditions at an appropriate temperature, for example, 4 and 20 degrees. In the preferred embodiments, approximately 96 crystallization selection conditions can be performed in order to obtain sufficient information about the co-combination and crystallization conditions, and the orientation of the scaffolding at the binding site of the target molecule. The crystal structures can then be analyzed to determine how to find the scaffolding to be physically oriented within the binding site or within one or more joint cavities of the limb. molecular family. It is desirable to determine the atomic coordinates of the compounds bound to the target proteins in order to determine which is the most suitable scaffold for the protein family. X-ray crystallographic analysis is therefore more preferable for determining atomic coordinates. Those selected compounds can also be tested with the application of medicinal chemistry. The compounds can be selected for medicinal chemistry testing based on their binding position in the target molecule. For example, when the compound binds to a binding site, the binding position of the compound at the binding site of the target molecule can be considered with respect to the chemistry that can be performed on chemically treatable structures or sub-structures of the compound, and how such modifications in the compound are expected to interact with structures or sub-structures at the target binding site. In this way, the target binding site and scaffold chemistry can be explored in order to make decisions on how to modify scaffolding to arrive at a ligand with the highest potency and / or selectivity. The structure of the target molecule bound to the compound can also be superimposed or aligned with other member structures of the same protein family. In this way, the scaffolding modifications can be made to improve the union to members of the target family in general, thus improving the usefulness of the scaffolding library. Different useful alignments can be generated, using a variety of criteria such as minimal RASD superposition of alpha-carbons or structure atoms of homologous or structurally related regions of the proteins.

These processes allow for greater direct design of ligands, using structural and chemical information obtained directly from the co-complex, by allowing one to more efficient and rapidly designing major compounds that are likely to lead to beneficial drug products. . In various embodiments, it may be desirable to perform co-crystallography on all scaffolds that bind, or only those that bind with a particular affinity, for example, only those that bind with high affinity, moderate affinity, low affinity, affinity very low or extremely low affinity. It may also be advantageous to perform co-crystallography in a selection of scaffolds that bind with any combination of affinities. Standard X-ray protein diffraction studies such as when using a Rigaku RU-200® (Rigaku, Tokyo, Japan) with an X-ray imaging plate detector or a synchrotron beam line can be performed in the -crystals and diffraction data measured in a standard X-ray detector, such as a CCD detector or an X-ray imaging plate detector. When performing X-ray crystallography in approximately 200 co-crystals should lead generally to approximately 50 co-crystal structures, which must provide approximately 10 scaffolds for validity in chemistry, which should eventually result in approximately 5 selective indications for the target molecules. The additives that promote co-crystallization can of course be included in the target molecule formulation in order to improve co-crystal formation. In the case of proteins or enzymes, the scaffolding that is tested can be added to the protein formulation, which is preferably presented at a concentration of about 1 mg / ml. The formulation may also contain between 0% -10% (v / v) of the organic solvent, for example, DMSO, methanol, ethanol, propandiol or 1,3-dimethylpropanediol (MPD) or some combination of those organic solvents. The compounds are preferably solubilized in the organic solvent at a concentration of approximately 10 mM and added to the protein sample at a concentration of approximately 100 mM. The protein-compound complex is then concentrated to a final concentration of the protein from about 5 to about 20 mg / ml. The combining and concentration steps can be performed conveniently using a 96-well formatted concentration apparatus in the formulation that is crystallized can contain other components that promote crystallization or are compatible with the crystallization conditions, such as DTT, propandiol, glycerol. The crystallization experiment can be formed by placing small aliquots of the protein-compound complex (eg, 1 μl) in a 96-well format and the sample under 96 crystallization conditions. (Other formats can also be used, for example, plates with fewer or more wells). The crystals can usually be obtained using standard crystallization protocols that may involve the 96-well crystallization plate that is placed at different temperatures. Co-crystallization that varies factors other than temperature can also be considered for each protein-compound complex is desirable. For example, atmospheric pressure, the presence or absence of light or oxygen, a change in gravity, and many other variables can also be tested. The person with ordinary skill in the art will understand other variables that can be varied and advantageously considered. Conveniently, commercially available glass selection plates with specific conditions in individual wells can be used.

I. Virtual Tests As described above, virtual testing techniques or compound design techniques are useful for the identification and design of modulators; such techniques are also applicable to a molecular scaffolding method. Commercially available software that generates three-dimensional graphical representations of the lens and composite fused from a set of provided coordinates that can be used to illustrate and study how a compound is oriented when attached to an objective (for example, InsightlI®, Accelerys, San Diego, CA; or Civil®, Tripos Associates, St. Louis, MO). Thus, the existence of the binding cavities at the binding site of the targets may be particularly useful in the present invention. These binding cavities are revealed by the determination of crystallographic structure and show the precise chemical interactions involved in the binding of the compound to the target binding site. The person with ordinary experience will understand that the illustrations can also be used to decide where the chemical groups could be added, replaced, modified or eliminated from the scaffolding to improve the union or other desirable effect, considering where the unoccupied space is located. the complex and whose chemical substructures could have adequate size and / or load characteristics to fill it. The person with ordinary experience will also understand that the regions within the binding site can be flexible and their properties can change as a result of joining scaffolds, and that the chemical groups can specifically target those regions to achieve a desired effect. The specific locations in the molecular scaffold can be considered with reference to where a suitable chemical substructure can be joined and in whose conformation, and whose site has the most advantageous chemistry available. An understanding of the forces that bind the compounds to the target proteins reveals that the compounds can be used more advantageously as scaffolds, and whose properties can be manipulated more effectively in the design of ligands. The person with ordinary experience will understand that spherical, ionic, polar, hydrogen bonding and other forces can be considered for their contribution to the maintenance or improvement of the target-compound complex. Additional data can be obtained with automated computational methods, such as dynamic binding and / or molecular simulations, which can produce a measure of binding energy. In addition, to account for other effects such as union entropies and desolvation penalties, methods that provide a measure of these effects can be integrated into the automated computational approach. The selected compounds can be used to generate information about the chemical interactions with the target or to produce chemical modifications that can improve the binding selectivity of the compound. An exemplary calculation of binding energies between protein-ligand complexes can be obtained using the FlexX score (an implementation of the Bohm scoring function) within a software set Tripos (Tripos Associates, St. Louis, MO). The form for that equation is shown as follows:? Gbind =? Gtr +? Ghb +? Gion +? Glipo +? Garom +? Grot where:? Gtr is a constant term that counts for the total loss of rotational and transnational entropy of the ligand,? Ghb account for hydrogen bonds formed between the ligand and the protein,? Gion account for the ionic interactions between the ligand and the protein,? Glipo account for the lipophilic interaction that corresponds to the protein-ligand contact surface,? Garom account for interactions between aromatic rings in the protein and the ligand, and? Grot account for the entropic penalty of rotational restriction bonds in the ligand at the junction. The binding energy calculated for compounds that bind strongly to a given target would probably be lower than -25 kcal / moles, while the binding affinity calculated for good scaffolding or a non-optimized compound will generally be in the range of -15. to 20. The penalty for restricting a linker such as ethylene glycol or hexatriene is estimated as being typically in the range of +5 to +15. This method estimates the binding-free energy so that a major compound must have a target protein for which a crystal structure exists, and account for the entropic penality of flexible linkers. It can therefore be used to estimate the penalty incurred by linking linkers to molecules that are selected and the binding energy that a master compound must achieve in order to overcome the linker penalty. The method does not count for the formation of solvents, and the entropic penalty is probably overestimated when the linkers bind to the solid phase through an additional binding complex, for example, a biotin: streptavidin complex. Another exemplary method for calculating binding energies is the MM-PBSA technique (Massova and Kollman, Journal of the American Chemical Society 121: 8133-43,1999; Chong et al, Proceedings of the National Academy of Sciences 96: 14330-5, 1999; Donini and Kollman, Journal of Medicinal Chemistry 43: 4180-8, 2000). This method uses a Molecular Dynamics approach to generate many sample configurations of the compound and the fused target molecule, then calculates an interaction energy using "the well-known AMBER force field (Cornell, et al., Journal of the American Chemical Society 117: 5179-97 1995) with corrections for the desolvation and entropy of union from the set.The use of this method produces binding energies highly correlated with those found experimentally.The absolute bond energies calculated with this method are reasonably accurate, and the The variation of the bonding energies is approximately linear with an inclination of 1 +/- 0.5 Thus, the binding energies of the compounds that interact strongly with a given target will be lower than approximately -8 kcal / moles, while a binding energy of a good scaffolding or a non-optimized compound will be in the range of -3 to -7 kca l / moles Computer models, such as homology models (ie, based on an experimentally derived, known structure) can be constructed using data from co-crystal structures. A computer program such as Modeller (Accelrys, San Diego CA) can be used to assign the three-dimensional coordinates to a sequence of proteins using a sequence alignment and a set or sets of template coordinates. When the target molecule is a protein or an enzyme, the preferred co-crystal structures for homology modeling contain high sequence identity at the binding site of the protein sequence being modeled, and the proteins will also preferably be inside. of the same class and / or family. The knowledge of residues conserved in active sites of a protein class can be used to select models of homology that exactly represent the binding site. Homology models can also be used to map structural information from a replacement protein where there is an apo or co-crystal structure to the target protein. Virtual selection methods, such as binding, can also be used to predict the configuration and binding affinity of scaffolds, compounds and / or combinatorial library members to homology models. By using these data, and conducting "virtual experiments" using computer software, they can save substantial resources and allow the person with ordinary experience to make decisions about which compounds can be suitable scaffolds or ligands, without actually having to synthesize the ligand and perform co-crystallization. Decisions can thus be made about which compounds deserve real synthesis and co-crystallization. An understanding of such chemical interactions helps in the discovery and design of drugs that interact more advantageously with target proteins and / or are more selective for one member of the protein family over the others. Thus, by applying these principles, compounds with superior properties can be discovered.

J. Design and Preparation of Ligand The design and preparation of ligands can be carried out with or without structural and / or co-crystallization data considering the chemical structures in common between the active scaffolds of a set. In this process, the structure-activity hypothesis can be formed and those chemical structures found to be present in a substantial number of the scaffolds, including those that join with low affinity, can be assumed to have some effect on the scaffolding junction. This binding can be presumed to induce a desired biochemical effect when it occurs in a biological system (e.g., a treated mammal). New or modified scaffolds or combinatorial libraries derived from the scaffolds can be tested to invalidate the maximum number of union and / or structure-activity hypothesis. The remaining hypothesis can then be used to design ligands that achieve a desired biochemical and binding effect. But in many cases, it will be preferred to have co-crystallography data for consideration of how to modify the scaffolding to achieve the desired binding effect (e.g., higher affinity binding or higher selectivity). Using the case of co-crystallography data of protein and enzymes, they show the protein binding cavity with the molecular scaffold attached to the binding site, and it will be apparent that a modification can be made to a chemically treatable group in the scaffolding. For example, a small volume of space in a protein binding site or cavity could be filled by modifying the scaffolding that includes a small chemical group that fills the volume. Filling the empty volume can be expected to result in a higher binding affinity, or the loss of undesirable binding to another member of the protein family. Similarly, the co-crystallography data may show that the suppression of a chemical group in the scaffold can decrease an obstacle to binding and result in greater affinity or binding specificity. Several software packages have implemented techniques that facilitate the identification and characterization of interactions of potential binding sites from a complex structure, or from an apo structure of a target molecule, ie, one without a binding compound (e.g. , SiteID, Tripos Associates, St. Louis MO and SiteFinder, Chemical Computing Group, Montreal Canada, GRAIS, Molecular Discovery Ltd., London UK). Such techniques can be used with the coordinates of a complex between the scaffolding of interest and an objective molecule, or these data together with the data for a related target molecule superimposed or appropriately aligned, to evaluate changes to the scaffolding that would improve the binding to the structure or structures of the desired target molecule. Molecular I nteraction Activity Field computation techniques, such as those implemented in the GRI D program, result in energy data for particular positive and negative binding interactions of different chemical and computational probes that are mapped to the vertices of a matrix in the coordinate space of the target molecule. These data can then be analyzed for substitution areas around the scaffold binding site that are predicted to have a favorable interaction for a particular target molecule. Chemical substitution compatible in the scaffold, for example a methyl, ethyl or phenyl group in a favorable interaction region computed from a hydrophobic probe, would be expected to result in an improvement in the affinity of the scaffolding. Conversely, a scaffold could be made more selective for a particular target molecule by making such substitution in a region intended to have an unfavorable hydrophobic interaction in a second undesirable related target molecule. It may be desirable to take advantage of the presence of a charged chemical group located in the protein binding site or cavity. For example, a positively charged group can be complemented by a negatively charged group introduced into the molecular scaffolding. This can be expected to increase binding affinity or binding specificity, resulting in a more desirable ligand. In many cases, the regions of the protein binding sites or cavities are known to vary from one family member to another based on the amino acid differences in those regions. Chemical additions in such regions can result in the creation or elimination of certain interactions (eg, hydrophobic, electrostatic, or entropic) that allow a compound to be more specific for one target protein over another or for binding with higher affinity, for what is allowed to synthesize a compound with greater selectivity or affinity for a member of the particular family. Additionally, certain regions may contain amino acids that are known to be more flexible than others. This frequently occurs in amino acids contained in loops that connect to elements of the secondary structure of the protein, such as alpha helices or beta strands. The additions of the chemical portions can also be directed to those flexible regions in order to increase the likelihood of a specific interaction occurring between the target protein of interest and the compound. Virtual selection methods can also be conducted in silico, to evaluate the effect of chemical additions, subtractions, modifications, and / or substitutions on the compounds with respect to members of a family or class of proteins. The addition, subtraction or modification of a chemical structure or substructure to a scaffold can be done with any suitable chemical portion. For example, the following portions, which are provided by way of example and are not intended to be limiting, may be used: hydrogen, alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenylthio phenyl, phenylalkyl, phenylalkythio, hydroxyalkylthio, alkylthiocarbamylthio, cyclohexyl, pyridyl, piperidinyl, alkylamino, amino, nitro, mercapto, cyano, hydroxyl, a halogen atom, halomethyl, an oxygen atom (for example forming a ketone or N-oxide) ) or a sulfur atom (e.g., forming a thiol, a thione, a di-alkylsulfoxide or a sulfone) are all examples of portions that can be used. Additional examples of structures or sub-structures that may be used are an aryl optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester portions; an amine of the formula -NX2X3 wherein X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and portions on the homocyclic or heterocyclic ring; halogen or trihalomethyl; a ketone of the formula -COX4. wherein X 4 is selected from the group consisting of alkyl and portions on the homocyclic or heterocyclic ring; a carboxylic acid of the formula - (X5) nCOOH or ester of the formula (X6) nCOOX7, wherein X5, Xβ and X7 are independently selected from the group consisting of alkyl and portions on the homocyclic or heterocyclic ring and wherein n is 0 or 1; an alcohol of the formula (X8) nOH or an alkoxy moiety of the formula - (XβinOXg, wherein X8 and X9 are independently selected from the group consisting of saturated or unsaturated alkyl and portions on the homocyclic or heterocyclic ring, wherein the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester and wherein n is 0 or 1: an amide of the formula NHCOX10, wherein X10 is selected from the group consisting of alkyl, hydroxyl and portions on the homocyclic or heterocyclic ring, wherein the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester, SO2, NXn, X-? 2, wherein Xn and X.2 are selected from the group consisting of hydrogen, alkyl and portions in the homocyclic ring clico or heterocyclic; a moiety in the homocyclic or heterocyclic ring optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester moieties; an aldehyde of the formula -COH; a sulfone of the formula -SO2X? 3, wherein X.3 is selected from the group consisting of saturated or unsaturated alkyl and portions on the homocyclic or heterocyclic ring; and a nitro of the formula -NO2.

K. Identification of Binding Characteristics of Binding Compounds This can be beneficial in selecting compounds for experimentation to first identify binding characteristics that a ligand must advantageously possess. This can be achieved by analyzing the interactions that a plurality of different binding compounds have for a particular purpose, for example, interactions with one or more residues conserved at the binding site. These interactions are identified considering the nature of the interaction portions. In this way, atoms or groups that can participate in hydrogen bonding, polar interactions, charge-charge interactions, and the like are identified based on known structural and electronic factors.

L. Identification of Energetically Permitted Sites for Inclusion In addition to the identification and development of ligands, the determination of the orientation of a molecular scaffold or other binding compound in a binding site allows the identification of energetically permitted sites for the inclusion of the molecule binding to another component. For such sites, any free energy change associated with the presence of the included component should not destabilize the binding of the compound to the target to a magnitude that will disrupt the binding. Preferably, the binding energy with the inclusion should be at least 4 kcal / moles, more preferably at least 6, 8, 10, 12, 15 or 20 kcal / moles. Preferably, the presence of the adhesion at the particular site reduces the binding energy by not more than 3, 4, 5, 8, 10, 12 or 15 kcal / moles. In many cases, suitable inclusion sites will be those that are exposed to solvents when the binding compound binds at the binding site. In some cases, the inclusion sites may be used in a manner that will result in small displacements of a portion of the enzyme without excessive energy cost. The exposed sites can be identified in several ways. For example, exposed sites can be identified using a graphical display or three-dimensional model. In a graphic display, such as a computer display, an image of a compound bound at a binding site can be visually inspected to reveal atoms or groups in the compound which are exposed to a solvent and oriented so that inclusion to a such an atom or group would not preclude the binding of the enzyme and the binding compound. Energetic costs of inclusion can be calculated based on changes or distortions that would be caused by inclusion as well as entropic changes. Many different types of components can join. Experienced people are familiar with the chemistries used for several inclusions. Examples of components that may be attached include, without limitation: solid phase components such as beads, plates, chips and wells; a direct or indirect label; a linker, which can be a linker without a trace; among others. Such linkers can be attached by themselves to other components, for example to solid phase media, labels and / or binding portions. The binding energy of a compound and the effects on the binding energy to bind the molecule to another component can be calculated approximately by manual calculation, or by using any of a variety of available virtual computational assay techniques, such as binding or molecular dynamic simulations . A virtual library of compounds derived from the inclusion of compounds to a particular scaffolding can be assembled using a variety of software programs (such as Afferent, MDI Information Systems, San Leandro, CA or CombiLibMaker, Tripos Associates, St. Louis, MO ). This virtual library can assign appropriate three-dimensional coordinates using software programs (such as Concord, Tripos Associates, St. Louis, MO or Omega, Openeye Scientific Software, Santa Fe, NM). These structures can then be subjected to the appropriate computational technique for evaluating binding energy to a particular target molecule. This information can be used for purposes of priority compounds for the synthesis, selecting a subset of chemically treatable compounds for synthesis, and providing data to correlate with the binding energies experimentally determined for the synthesized compounds. The crystallographic determination of the orientation of the scaffold at the binding site specifically allows more productive methods to evaluate the probability of the inclusion of a particular component resulting in an improvement of binding energy. Such an example is shown for a strategy based on binding in Haque et al Journal of Medicinal Chemistry 42: 1428-40, 1999, where a "Fastening and Growth" technique is based on a crystallographically determined fragment of one more molecule large, selective and potent inhibitors were created quickly. The use of a crystallographically characterized small molecule fragment to guide the selection of productive compounds for synthesis has also been demonstrated in Boehm et al, Journal of Medicinal Chemistry 43: 2664-74, 2000. An illustration of the use of crystallographic data and Molecular dynamic simulations and prospective evaluation of inhibitory binding energies can be found in Pearlman and Charifson, Journal of Medicinal Chemistry 44, 3417-23, 2001. Another important class of techniques that is based on a well-defined structural starting point for design computational is the system-based combinatorial growth algorithm, such as the GrowMol program (Bohacek and McMartin, Journal of the American Chemical Society 116: 5560-71, 1994). These techniques have been used to allow the rapid computational evolution of energy junction computed by the virtual inhibitor, and leads directly to synthesized compounds more po whose binding mode was validated crystallographically (see Organic Letters (2001) 3 (15): 2309-2312). (1) Linkers Linkers suitable for use in the invention can be of many different types. The linkers can be selected for particular applications based on factors such as compatible linker chemistry for inclusion to a binding compound and to another component used in the particular application. Additional factors may include, without limitation, linker length, linker stability, and the ability to remove the linker at an appropriate time. Exemplary linkers include, but are not limited to, hexyl, hexatrienyl, ethylene glycol, and peptide linkers. Linkers without trace may also be used, for example, as described in Plunkett, M.J., and Ellman, J.A. 1995, J. Org. Chem. 60: 6006. Typical functional groups that are used to bind the binding compound (s), include but are not limited to carboxylic acid, amine, hydroxyl and thiol. (Examples can be found in the combinatorial and parallel synthesis supported by solids from the libraries of the small molecular weight compound, Tetrahedron organic chemistry series vol.17, Pergamon, 1998, p85). (2) Labels As indicated above, labels can also be attached to a binding compound or a linker attached to a binding compound. Such inclusion may be direct (bound directly to the binding compound) or indirect (linked to a component that directly or indirectly binds to the binding compound). Such labels allow the detection of the compound either directly or indirectly. The inclusion of labels can be done using conventional chemistries. Labels may include, for example, fluorescent labels, radiolabels, light scattering particles, light absorbing particles, magnetic particles, enzymes and specific binding agents (for example biotin or a target portion of the antibody). (3) Solid Phase Means Additional examples of components that can be linked directly or indirectly to a binding compound include various solid phase media. Similar to the inclusion of linkers and labels, inclusion in solid phase media can be done using conventional chemistries. Such solid phase media can include, for example, small components such as beads, nanoparticles and fibers (for example in suspension or in a gel or chromatographic matrix). Likewise, the solid phase media may include larger objects such as plates, chips, slides and tubes. In many cases, the binding compound will be bound in only a portion of such objects, for example at a point or other local element on a generally flat surface or in a well or portion of a well.

IV. Administration The methods and compounds will normally be used in therapy for human patients. However, these can also be used to treat similar or identical diseases in other vertebrates, for example mammals such as other primates, recreational animals, bovines, horses, swine, sheep and pets such as dogs and cats.

The dosage forms suitable, in part, depend on the use or route of administration, for example, oral, transdermal, transmucosal or by injection (parenteral). Such dosage forms must allow the compound to reach the target cells. Other factors are well known in the art, include considerations such as toxicity and dosage forms that reject the compound or composition when exerting its effects. Techniques and formulations can generally be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, PA, 1990 (incorporated herein by reference herein). The compounds can be formulated as pharmaceutically acceptable salts. The pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations in which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of a compound without preventing it from its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate the administration of higher concentrations of the drug. Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, chlorohydrate, fumarate, maleate, phosphate, sulphamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexyl sulfamate, and quinate. The pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid , p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid and chemical acid. The pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine and zinc, when the groups functional such as carboxylic acid or phenol are present. For example, see Remington's Pharmaceutical Sciences. 19th ed., Mack Publishing Co., Easton PA, Vol. 2, p. 1457, 1995. Such salts can be prepared using the appropriate corresponding bases. The pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound is dissolved in a suitable solvent, such as an aqueous or aqueous alcohol solution containing the appropriate acid and then isolated by evaporating the solution. In another example, a salt is prepared by reacting the free base and an acid in an organic solvent. The pharmaceutically acceptable salt of different compounds can be presented as a complex. Examples of complexes include the 8-chlorotheophylline complex (analogs to for example dimenhydrinatin: diphenhydramine-8-chlorotheophylline complex (1: 1); Dramamine and several cyclodextrin inclusion complexes. The carriers or excipients can be used to produce pharmaceutical compositions. The carriers or excipients may be chosen to facilitate administration of the compound. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents. Examples of physiologically compatible solvents include sterile solutions of water for injection (WF1), saline and dextrose. The compounds can be administered by different routes including intravs, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal or transdermal. Oral administration is preferred. For oral administration, for example, the compounds may be formulated in conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops. Pharmaceutical preparations for oral use can be obtained, for example, by combining the active compounds with solid excipients, optionally grinding a reactant mixture, and spraying the mixture of greases, after adding suitable auxiliaries, if desired, to obtain tablets or nuclei of g rageas. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC) and / or polyvinylpyrrolidone (PVP: povidone). If desired, the disintegrating agents may be added, such as the crosslinked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate. Glycemic nuclei are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain, for example gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (P EG) and / or titanium dioxide, lacquer solutions and organic solvents. Suitable icos or mixtures of solvents. The coloring matters or pigments can be added to the coatings of tablets or dragees for identification or to characterize different combinations of the dose of active compounds. Pharmaceutical preparations which can be used orally include soft-setting capsules made of gelatin ("gelatin capsules"), as well as sealed soft capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The soft-fit capsules may contain the active ingredients 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 compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols (PEG's). In addition, the stabilizers can be added. Alternatively, an injection (parenteral administration), for example intramuscular, intravs, intraperitoneal and / or subcutaneous, may be used. For injection, the compounds of the invention are formulated in sterile liquid solutions, preferably in buffers or in physiologically compatible solutions, such as saline solution, Hank's solution or Ringer's solution. In addition, the compounds can be formulated in solid form and redissolved or suspended immediately before use. Lyophilized forms can also be produced. The administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, appropriate penetrants to the barrier to permeate are used in the formulation. Such penetrants are generally known in the art, and include, for example for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents can be used to facilitate the permeation. Transmucosal administration, for example, can be through nasal sprays or suppositories (rectal or vaginal). The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as compound IC5o. the biological half-life of the compound, the age, size and weight of the patient, and the disorder associated with the patient. The importance of these and other factors are well known to those with ordinary experience in the art. Generally, a dose will be between about 0.01 and 50 mg / kg, preferably 0.1 and 20 mg / kg of the patient being treated. Multiple doses can be used.

V. Synthesis of the Compounds of Formula I Compounds with the chemical structure of Formula I can be prepared in a number of different synthetic routes, including for example, the synthetic schemes described herein for groups of compounds within Formula I . Additional synthetic routes can be used by an expert in chemical synthesis. Certain of the syntheses can use the intermediary I I key in the synthesis. The key intermediary 11 can be prepared as follows: Synthesis of Intermediary II Clave A synthetic route for Intermediate II compounds are shown in the following. In these compounds, Y and Z (as well as U, V and W) may be C as in indole, or may be other heteroatoms as specified by Formula I, and R3, R4 and R5 are as specified by Formula I or a sub-generic description within Formula I. In the Scheme the synthetic and other synthetic schemes described herein by the groups of the compounds, it is to be understood that the generic formulas in the schemes (eg Formula lll in Scheme 1a) describe a set of compounds, but they are referenced in the description of the text of the synthesis in the singular.

Scheme 1a: III Step 1- Preparation of the compound of formula IV: Compound IV was prepared by reacting the commercially available aldehyde III with an activated ester phosphonate in an inert solvent (eg, tetrahydrofuran) under reflux conditions, typically for 16-24 hours, as described by Garuti et al in Arch. Pharm , 1988, 327, 377-83). He Compound III, in turn, can be prepared by reacting Compound V under Vilsmeier conditions (POCI3 and DMF) as described by in March's Advanced Organic Chemistry, 5th Edition p. 715. Step 2 - Preparation of intermediate II: The key intermediate II was prepared by reducing IV in an inert solvent (ie, tetrahydrofuran) by catalytic hydrogenation (usually 10% palladium on activated carbon and atmospheric hydrogen) as described by Garuti et al in Arch. Pharm., 1988, 327, 377-83).

Scheme 1b: The Compound II Intermediate compounds can also be prepared according to Scheme 1b as shown below.

Step 1 - Preparation of Formula VI: Compound VI was prepared conveniently by reacting a commercially available compound of the formula V with an N, N-dialkylamine hydrochloride in a polar solvent (eg, i-Propanol), in the presence of formaldehyde and heated normally to about 90 ° C, usually for 24 hours, as described by Snyder et al. al, JACS 73, 970. Step 2 - Preparation of the formula VII: The compound of the formula VII was prepared by heating the compound VI with diethyl malonate and a catalytic amount of sodium metal, usually 120 ° C as described by Robinson et. al., JACS, 78, 1247, followed by purification by flash chromatography. Step 3 - Preparation of formula la: The compound of the formula was prepared by hydrolyzing compound VII using an aqueous base (e.g., NaOH) followed by decarboxylation under reflux conditions (JACS, 78, 1247). Step 4 - Preparation of intermediate II: Intermediate II was prepared by esterification of Fisher of the compound with alcohol (for example, methanol) and a catalytic amount of an acid (for example, HCl) under reflux, usually for 16-24 hours.

Scheme 1c: The Compounds of the I I Key Intermediate can also be prepared according to Scheme 1 c as shown below.

HIV IV Step 1 - Preparation of Formula VIII: Compound VIII can be prepared by reacting a commercially available compound of the formula V with bromine in an inert solvent (for example, DM F) (Bocchi and Palla; Synthesis, 1982, p1096). Step 2 - Preparation of formula IV: Compound IV can be prepared by reacting a compound of formula VIII with methacrylate under Heck coupling conditions as described by Sznaidman et al., In Bioorg. Med. Chem. Lett. , 13, 2003, 1517. Step 3 - Preparation of intermediate II: The key intermediate II was prepared by reducing IV in an inert solvent (ie, tetrahydrofuran) by catalytic hydrogenation (typically 10% palladium on activated carbon and atmospheric hydrogen) as described by Aaruti et.

Al in Arch. Pharm. 321, 1988, 377-83.

Synthesis of Compound The compounds of the Formula can be prepared by hydrolysis of the Key Intermediary II as shown in Scheme II. Scheme 2 II the The compound of the formula la was prepared by hydrolysis of the key intermediate of formula II with an aqueous base (e.g., aqueous NaOH) typically for 6-15 hours and isolating the product by conventional methods (e.g., aqueous treatment and purification by chromatography) Jerry March in March's Advanced Organic Chemistry, 5th Edition, p.715.

Synthesis of Compound 1b The compounds of Formula Ib, wherein the indole ring is substituted at the 3-position (or corresponding position of the other bicyclic rings of Formula I), can be prepared according to Scheme 3.

Scheme 3 Step 1 - Preparation of the compound of the formula IXa: The compound of the formula IXa was prepared by treating the intermediate of the formula II with a base (for example, sodium hydride) in an inert solvent of N, N-dimethylformamide, followed by the addition of R2W, where "W" is a leaving group (eg, chlorine, bromine) and stirring at RT, typically for 16 to 24 hours (Jerry March in March's Advanced Organic Chemistry, 5th Edition, p576). The product was obtained by column chromatography (e.g., silica gel) after treating using conventional methods. Step 2 - Preparation of the compound of the formula Ib: The compound of the formula Ib was prepared by the hydrolysis of the compound of the formula V with an aqueous base (for example, aqueous NaOH), usually for 6-15 hours and isolating the product by conventional methods (for example, aqueous treatment and purification by chromatography).

Synthesis of the Compound The compounds of the Formula le, wherein R2 is R10R11NCZ, can be prepared according to Scheme 4.

Scheme 4 IXb Stage 1 - Preparation of the compound of the formula IXb: The compound of the formula IXb was prepared by treating the intermediate of the formula II with a base (for example, sodium hydride) in an inert solvent (DMF) followed by the addition of R1dNCZ, where "Z" is oxygen or sulfur, and stirring at RT, usually for 16 to 24 hours (Jerry March in March's Advanced Organic Chemistry, 5th Edition, p1191). The product was obtained by column chromatography (e.g., silica gel) after the treatment using conventional methods. The compound of formula IXb was also prepared by treating the intermediate of formula II with R16NCZ, wherein "Z" is oxygen or sulfur, in an inert solvent (THF) followed by the addition of a catalytic amount of DMAP (N, N , -dimethylaminopyridine) and stirring at RT, usually for 16 to 24 hours. The product can be obtained by column chromatography (eg, silica gel) after treating using conventional methods. Step 2- Preparation of the compound of the formula I: The compound of the formula I was prepared by hydrolysis of the compound of the formula IXb with an aqueous base (for example, aqueous NaOH), usually for 6-15 hours by isolating the product by conventional methods (eg, aqueous treatment and purification by chromatography). In the compound of the formula le, the substituent R2 would then be R10R11NCZ.

Synthesis of Compound Id The compounds of Formula Id can be prepared according to Scheme 5a. Scheme - 5a IXc IXd Id Step 1- Preparation of the compound of the formula IXd: The compound of the formula IXd was prepared from the compound of the formula lXc by reacting it with arylboronic acids under the conditions of. Suzuki reaction (march's Advanced Organic Chemistry, 5th Edition, p8) and heating the reaction mixture, usually 90 ° C for 24 hours and isolating the product by conventional methods (for example, aqueous treatment and purification by chromatography).

The compound of formula IXc was prepared in turn from the commercially available compound of formula V, wherein "R4" is bromine, using the synthetic steps described in Scheme 1b, followed by the reaction with "R16W" as described in step 1 of Synthetic Scheme 3, where "R4" is bromine. Step 2- Preparation of the compound of the formula Id: The compound of the formula Id was prepared by hydrolysis of the compound of the formula IXd with aqueous base (for example, aqueous NaOH), usually for 6-15 hours and isolating the product by conventional methods (eg, aqueous treatment and purification by chromatography).

Scheme 5b Step 1. Preparation of the compound of the formula V: The compound of the formula V was prepared from the commercially available compound of the formula Va by reacting it with arylboronic acids under Kumada reaction conditions as described by Hayashi et. al., JACS, 106 (1984), 158-163, and heating the reaction mixture, usually 90 ° C for 24 hours and isolating the product by conventional methods (e.g., accusative treatment and purification by chromatography). Step 2- Preparation of formula VI: Compound VI was prepared conventionally by reacting a commercially available compound of formula V with an N, N-dialkylamine hydrochloride in a polar solvent (eg, i-Propanol), in the presence of formaldehyde and heated normally to about 90 ° C, usually for 24 hours, as previously described for compound VI. Step 3 - Preparation of the formula VII: The compound of the formula VII was prepared by heating the compound V1 with diethyl malonate and a catalytic amount of sodium metal, usually at "120 ° C as previously described, followed by purification of the instant chromatography Step 2- Preparation of formula la: The compound of the formula was prepared by hydrolyzing compound VII using an aqueous base (e.g., NaOH) followed by decarboxylation under reflux conditions as previously described. of intermediate II: Intermediate II was prepared by Fisher esterification of the compound with alcohol (eg, methanol) and a catalytic amount of an acid (eg, HCl) under reflux usually for 16-24 hours. compound of the formula IXa: The compound of the formula IXa was prepared by treating the intermediate of the formula II with a base (for example, sodium hydride, NaH) in an inert solvent (DMF) followed by the addition of "R2W", wherein "W" is a leaving group (eg, chlorine, bromine) and stirring at RT, typically for 16 to 24 hours. The product was obtained by column chromatography (e.g., silica gel) after the treatment using conventional methods. Step 7- Preparation of the compound of the formula Ib: The compound of the formula Ib was prepared by hydrolysis of the compound of the formula IXa with an aqueous base (for example, aqueous NaOH), usually for 6-15 hours and isolating the product by conventional methods (for example, aqueous treatment and purification by chromatography).

Synthesis of Compound X E Step 1- Preparation of Intermediate XI: Compound XI was prepared from Compound V by reacting with β-butyrolatone in an inert solvent with potassium hydroxide under reflux conditions, usually 4 to 24 hours, as described by Fritz et al. , (J. Org. Chem., 1963, 28, 1384-1385). Step 2- Preparation of Intermediate XII: Compound XII was prepared by carboxylic acid XI by reacting in any catalytic amount of sulfuric acid in methanol under reflux conditions, or an activated methylene portion such as diazomethane. Step 3- Preparation of Intermediate Xlll: Compound Xlll was prepared by treating the intermediate of formula XII with a base (eg, sodium hydride) in an inert solvent (DMF) followed by the addition of R2W, where "W" is a leaving group (for example, chlorine, bromine) and stirring at RT, usually for 16 to 24 hours (Jerry March in March's Advanced Organic Chemistry, 5th Edition, p576). The product was obtained by column chromatography (for example, silica gel) after the treatment using conventional methods. Step 4 - Preparation of intermediate X: The compound of formula X was prepared by hydrolysis of the compound of formula XIII with an aqueous base (for example, aqueous NaOH), usually for 6-15 hours and isolating the product by conventional methods (for example, aqueous treatment and purification by chromatography).

Synthesis of compound XIV Scheme 7 Step 1- Preparation of Intermediate XV Compound XV was prepared from the corresponding aldehyde III by reacting with a reducing agent such as sodium borohydride in an inert solvent (for example, tetrahydrofuran). Step 2- Preparation of Intermediate XVI: Compound XVI can be prepared by reacting methanol XV with silyl ketene acetal in the presence of a catalyst such as magnesium trifluoride or perchlorate at room temperature for 1 -2 hours as described by Grieco et al in Tetrahedron Letts (1997, 38, 2645-2648). Step 3- Preparation of Intermediate XVll Compound XVII was prepared by treating the intermediate of formula XVI with a base (eg, sodium hydride) in an inert solvent (DMF) followed by the addition of R2W, where "W" is a leaving group (for example, chlorine, bromine) and stirring TA, normally for 16 to 24 hours (Jerry March in March's Advanced Organic Chemistry, 5thf Edition, p576). The product was obtained by column chromatography (e.g., silica gel) after the treatment using conventional methods. Step 4: Preparation of intermediate XIV: The compound of formula XIV was prepared by hydrolysis of the compound of formula XVII with an aqueous base (for example, aqueous NaOH), for 6-15 hours and isolating the product by conventional methods ( for example, aqueous treatment and purification by chromatography). Using the synthetic schemes described above, a set of an exemplary compound was prepared. Those compounds include those listed below, which are also listed in Table 1 along with the chemical structures, together with the additional exemplary compounds. 3- [5-Methoxy-1- (4-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid, 3- [5-ethyl-1- (4-methoxy-benzenesulfonyl) -1 H acid -indol-3-yl] -propionic acid, ldazol-3-propionic acid, 5-isopropoxy-3- (l-benzenesulfonyl-indol-3-yl) -propionic acid, indole-3-propionic acid, 3- (1-acid -Bencenesulfonyl-5-methoxy-1H-indol-3-yl) -propionic acid, 3- [5- M-ethoxy-1-H-indol-3-yl] -prop ion ion, 3- [1 - (3 -C lo ro-benzyl) -5-im ethoxy-1 H-indol-3-yl] -propionic, 3- [1- (4-Fluoro-benzyl) -5-methoxy-1 H-indole-3 -yl] -propionic acid, 3- [1- (4-chloro-benzyl) -5-methoxy-1H-indoi-3-yl] -propionic acid, 3- [5-methoxy-1- (2-methoxy) benzyl) -1H-indol-3-yl] -propionic acid, 3- [5-methoxy-1- (2-trifluoromethoxy-benzyl) -1H-indol-3-yl] -propionic acid, 3- [5-] Methoxy-1- (3-trifluoromethoxy-benzyl) -1H-indol-3-yl] -propionic acid, 3 ~ (1-Ethylthiocarbamoyl-5-methoxy-1 H-indol-3-yl) -propionic acid - [5 ~ Methoxy-1- (toluene-4-suifonyl) -1H-indol-3-yl] -propionic acid, 3- (1-ethylthiocarbamoyl-5) -methoxy-1H-indol-3-yl) -propionic acid, 3- [5-methoxy-1- (toluene-4-sulfonyl) -1H-indol-3-yl] -propionic acid, 3- [ 1-Benzylsulfonyl-1H-indazol-3-yl) propionic acid, 3- [1- (4-lsopropyl-benzenesulfonyl) -5-m-ethoxy-1H-indol-3-yl] -propionic acid methyl ester - [1- (4-lsopropyl-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid, 3- [I- (4-Butoxy-benzenesulfonyl) -5-m-ethoxy-] methyl ester. 1 H-indol-3-yl] -propionic acid, 3- [1- (4-Butoxy-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid, 3- [5-methyl ester] -Metoxy-1- (4-trifluoromethoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid, 3- [5-methoxy-1- (4-trifluoromethoxy-benzenesulfonyl) -1H-indol-3-yl ] -propionic, 3- [5-Methoxy-1- (4-phenoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid methyl ester, 3- [5-Methoxy-1- (4- phenoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid, 3- [l- (4-Chloro-benzenesulfonyl) -5-m-ethoxy-1H-indol-3-yl] -propionic acid methyl ester , 3- [1- (4-Chloro-benz ensulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic, 3- [1- (4-Cyano-benzenesulfonyl) -5-m-ethoxy-1 H-indol-3-yl] methyl ester -propionic, 3- [1- (4-Cyano-benzenesulfonyl) -5-m-ethoxy-1H-indol-3-yl] -propionic acid, 3- [l- (3,4-Dichloro- benzenesulfonyl) -5-m-ethoxy-1 H-indol-3-yl] -propionic, 3- [l- (3,4-Dichloro-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid, 3- [5-Methoxy-1- (4-trifluoromethyl) methyl ester -benzenesulfonyl) -1H-indol-3-yl] -propionic acid, 3- [5-methoxy-1- (4-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl] -prop ionic acid, methyl ester of the acid 3- [1- (4-Fluoro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid, 3- [1- (4-Fluoro-benzenesulfonyl) -5-methoxy-1H-indole -3-yl] -propionic acid methyl ester of the acid 3- [5-methoxy-1- (3-phenoxy-benzenesulfonyl) -1H-indol-3-yl] propionic acid, 3- [5-methoxy-1] - (3-phenoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid, 3- [1- (3-Fluoro-benzenesulfonyl) -5-m-ethoxy-1H-indole-3-methyl ester il] -propionic, 3- [l- (3-Fluoro-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid, 3- [5-Methoxy-l- (toluene) methyl ester -3-sulfonyl) -1 H-indol-3-yl] -propionic, 3- [5-Methoxy-1- (toluene-3-sulfonyl) -1 H -indol-3-yl] -propionic acid, Methyl ester 3- [1- (3-Chloro-benzenesulfonyl) acid ) -5-m-ethoxy-1 H-indol-3-yl] -propionic, 3- [l- (3-Chloro-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid, Methyl 3- [5-Methoxy-1- (3-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid ester, 3- [5-methoxy-1- (3-methoxy-benzenesulfonyl) -1] H-indol-3-yl] -propionic, 3- [5-Methoxy-1- (3-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl] -propionic acid methyl ester, 3- [5-Methoxy] -1- (3-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl-propionic acid, 3- (1-Benzyl-5-methoxy-1H-indol-3-yl) -propionic acid methyl ester, acid 3- (1-Benzyl-5-methoxy-1 H-indol-3-yl) -propionic acid, 3- [5-Methoxy-1- (thiophene-2-sulfonyl) -1H-indole-3-methyl ester -yl] -propionic acid, 3- [5-Methoxy-1- (thiophene-2-sulfonyl) -1H-indol-3-yl] -propionic acid, 3- (5-methoxy-1-phenylthiocarbamoyl) - methyl ester 1 H-indol-3-yl) -propionic acid, 3- (5-Methoxy-1-phenylthiocarbamoyl-1 H-indol-3-yl) -propionic acid, 3- [1- (4-Butyl- benzenesulfonyl) -5-methoxy-1 H-indol-3-i l] -propionic acid, 3- [1- (4-Butyl-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid, 3- [5-Methoxy-1- (3 -trifluoromethoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid, 3- [5- Methoxy-1- (3-trifluoromethoxy-benzenesulfon i I) -1H-indol-3-yl] -propionic acid, Methyl ester 3- (1-Benzoyl-5-methoxy-1 H-indol-3-yl) -propionic acid, 3- (1-Benzoyl-5-methoxy-1 H-indol-3-yl) -propionic acid, acid 3- (1-Benzylsulfonyl-5-ethoxy-1 H-indol-3-yl) -propionic acid, 3- [1- (4-lsopropoxy-benzenesulfonyl) -5-imethoxy-1 H-indol-3-yl] -propionic, 3- (5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl) -propionic acid methyl ester, 3- (5-Methoxy-1-phenylcarbamoyl-1 H-indol-3-yl) methyl ester ) -propionic, 3- [1- (4-Ethyl-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid, 3- (5-b-rom or-1 H-indole) -3-yl) -propionic, 3- (5-Bromo-1 H -indol-3-yl) -propionic acid methyl ester, 3- (1-Benzylsulfonyl-5-bromo-1 H-indole) methyl ester -3-il) -propionic, methyl ést 3- (1-Benzylsulfonyl-5-bromo-1 H-in-ol-3-yl) -propionic acid, 3- (Benzylsulfonyl-5-thiophen-3-yl-1 H-indole-3-methyl ester -yl) -propionic, 3- (Benzensulfonyl-5-thiophen-3-yl-H-indol-3-yl) -propionic acid, 3- (l-Benzensufonyl-5-phenyl-1 H-indole) methyl ester -3-yl) propionic, 3- (1-Benzylsulfonyl-5-phenyl-1 H-indol-3-yl) propionic acid, Preparation of 3- (1 H-Pyrrol [2,3-b] pyridin-3-yl) -propionic acid, 3- (5-M-ethoxy-1 H-lndol-3-yl) -propionic acid, 3- (1-Benzenesulfonyl-1H-indol-3-yl) -propionic acid, 3- (1-Benzylsulfonyl-5-methoxy-1H-indol-3-yl) -propionic acid methyl ester, - [5-Methoxy-1 - (thiophene o-3-sulfonyl) -1 H-indol-3-yl] -propionic acid (1-Benzylsulfonyl-5-methoxy-1 H-indol-3-yl) - acetic.

EXAMPLES Example 1: Biochemical Selection The homogeneous Alpha selection test was used in the agonist mode to determine the ligand-dependent interaction of the PPARs (a, d,) with the coactivating peptides (SRC or DRIP205). Briefly, 15 ul of the reaction mixture (50 mM Tris pH 7.5, 50 mM KCl, 0.05% Tween 20, 1 mM DTT, 0.1% BSA and 10 nM-200 nM PPAR and 10 nM-200 nM of the coactivator peptide) was added to the test compound (1 ul of the compound in DMSO) and pre-incubated for 1-6 hours. Then, 5 ul of the Alpha selection beads were added. The reactions were incubated for 2 hours before taking the reading in the Alpha Fusion instrument. In the antagonist compounds, they were evaluated for the inhibition of the co-activator binding signal elicited by the control agonists for each receptor. The control agonists used were WY-14643 (PPAR (a), farglitazar (PPAR (?) And bezafibrate (PPAR (d).) Using the previous test, the compounds in Table 1 were analyzed for activity. examples are shown in Table 2. The data reported in Table 2 were generated through the alpha selection test and expressed in μMoles / L Data points from the Fusion alpha instrument were transferred in Assay Explorer® ( MDL) to generate a curve and calculate the inflection point of the curve as EC5 (.. Among those compounds, several have remarkable total activity at low or even sub-micromolar micromolar levels, for example, compounds 29, 43 and 53. In contrast, compound 6 is selective for PPARα, with activity in PPARα of approximately 8 micromolar and activity in PPARa and d of at least 200 micromolar.

Example 2: Co-transfection assay 293T cells were transfected for 4-5 hours in serum-free DMEM medium using the cellular fectin reagent. Each well was transfected with 1 ug each of the reporter plasmid (pFR-Luc from stratagene) and the PPAR constructs (Gal4-PPAR-LBD). After 24 hours of recovery in a serum medium, the cells were treated with compounds for 48 hours, then evaluated for luciferase activity using luciferase reporter gene assay kit (Roche). This assay serves to confirm the biochemical activity observed in the modulation of the target molecule or molecules targeted at the cellular level.

Example 3: Synthesis of 3- [5-methoxy-1- (4-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 1 Indole-3-propionic acid 1 was synthesized from 5-methoxyindole -3-carboxaldehyde commercially available in four stages as shown in Scheme 7.

Scheme 7 Step 1 - Preparation of 3- (5-Methoxy-1 H-indol-3-yl) -acrylic acid methyl ester 3 To a cold (ice-bath) solution of methyl phosphonoacetate (13.74 g, 0.065 mol) in tetrahydrofuran (120 ml) under nitrogen, sodium hydride (2.6 g, 0.065 mole, 60%) was added in one portion, and stirred until the evolution of hydrogen ceased. A solution of the commercially available 5-methoxyindole-3-carboxyaldehyde 2 (5.2 g, 0.029 mole) in tetrahydrofuran (80 ml) was added, over a period of 60 minutes, to the phosphonate solution. The reaction mixture was heated at 55 ° C for 24 hours after which the mixture was diluted with dichloromethane (DCM, 500 mL), and washed with water (200 mL, 3X). The organic layer was washed once with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the oil stained yellow and purified by filtering through a silica plug. The filtrate was evaporated to yield 3 as an off-white solid (6.2 g.; 78% yield; M + 1 = 232.0). Step 2 - Preparation of 3- (5-Methoxy-1 H-indol-3-yl) -propionic acid methyl ester 4 To a solution of 3- (5-Methoxy-17-indol-3-yl) methyl ester Acrylic 3 (3 g, 0.013 mol) in tetrahydrofuran (THF, 70 mL) was added palladium on activated carbon (10%, 0.72 g). The solution was deoxygenated under vacuum and the hydrogen was introduced into the reaction flask from a balloon filled with hydrogen. The process was repeated three times and the reaction mixture was stirred for 16 hours at room temperature. The mixture was filtered through celite and the filtrate was evaporated under reduced pressure to yield ester 4 as a white solid (2.78 g, 92% yield, M + 1 = 234.0). Step 3 - Preparation of 3- [5-Methoxy-1- (4-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid methyl ester 5: To a cooled solution (0 ° C) of the methyl ester of the Indole-3-propionic acid 4 (0.797 g, 3.42 mmol) in DMF (20 mL) was added sodium hydride (60%, 0.25 g, 0.0625 mol) was added in one portion and stirred for 30 minutes followed by the addition of 4-methoxybenzenesulfonyl chloride (1.3 g, 6.31 mmol). The reaction was allowed to warm to room temperature and was stirred for 16 hours, subjected to aqueous work-up, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified by flash chromatography (silica gel, 80%, n-hexane-20% ethyl acetate). to produce ester 5 as a white solid (0.83 g, 61% yield, M + 1 = 404.1). Step 4 - Preparation of 3- [5-Methoxy-1- (4-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 1: To a solution of methyl ester 5 (830 mg, 2.06 mmol) in Tetrahydrofuran (15 mL) was added an aqueous solution of potassium hydroxide (5 mL of 1M) and stirred at room temperature for 5 hours. Acid 1 was isolated by neutralizing the reaction mixture with aqueous hydrochloric acid, extracting the product with ethyl acetate, drying over anhydrous magnesium sulfate, evaporating under reduced pressure, and purifying using flash chromatography with 5% methanol in dichloromethane to produce a solid white (697.5 mg, 91%, M-1 = 373.1).

Example 4: Synthesis of 3- [5-ethyl-1- (4-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 6 Indole-3-propionic acid 6 was synthesized from -bromo-indole 7 commercially available in eight stages as shown in Scheme 8.

Scheme 8 Step 1 - Preparation of 5-Bromo-1-triisopropylsilanyl-1 H-indole 8. 5-bromoindole (2.5 g, 12.75 mmoles) was dissolved in tetrahydrofuran (THF, 50 mL) and cooled to 0 ° C and NaH Hydride. Sodium (920 mg, 23 mmol, 60%) was added in portions. The mixture was allowed to warm to RT with stirring for 1 hour. The reaction mixture was again cooled to 0 ° C and triisopropylsilyl chloride (TIPSC1, 2.78 mL, 13.1 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was washed with 2.0 N H3PO4 and the organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash silica chromatography (100% Hexanes) to give compound 8 as an oil (4.3 g, 96% yield, M + 1 = 353.4) Step 2 - Preparation of 5-Ethyl-1-triisopropylsilanyl -1 H-indole 9. The 1-triisopropyl-5-bromoindole (3.0 g, 8.51 mmol) was combined with PdCI2 (dppf) at -78 ° C and stirred for 5 minutes before the addition of Ethylmagnesium bromide (EtMgBr). 12.8 mL, 12.81 mmol). The mixture was allowed to warm to room temperature. Toluene (15 mL) was added to the reaction mixture and heated to reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and quenched with 2N of H3PO4. The mixture was extracted with EtOAc and washed with brine, dried over MgSO 4, filtered and evaporated to give compound 9 as an oil (5% EtOAc / Hexanes) to give (2.3 g, 90% yield; + 1 = 302.5). Step 3 - Preparation of 5-EHI-1 H-indole 10. The indole 9 (2.2 g, 7.29 mmoles) was dissolved in THF (20 mL) and a solution of ammonium fluoride (NH F, 1.4 g, 37.8 mmol) in MeOH (20 mL) was added and stirred for 72 hours at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 2N H PO4, dried over MgSO, filtered and evaporated to give compound 10 as an off white solid (1.06 g, M + 1 = 146.2). Step 4 - Preparation of (5-EHI-1 H-indol-3-ylmethyl) -dimethyl-amine 11. Combine 5-Ethylindole 10 (1.0 g, 6.89 mmol) with isopropyl alcohol (200 mL), N-hydrochloride. , N-dimethylamine (718 mg, 6.95 mmol) and aqueous formaldehyde (37%, 589 mg, 6.95 mmol) and refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature, the solvent was evaporated and the resulting residue was dissolved in EtOAc and washed with saturated NaHCO3. The organic layer was dried over MgSO 4, filtered and evaporated to give compound 11 as a solid in (1.35 g for a yield of 97%; M + 1 = 203.2). Step 5 - Preparation of 2- (5-Ethyl-1 H-indol-3-ylmethyl) -malonic acid diethyl ester 12. 5-ethylgramine (1.25 g, 6.18 mmol) was combined with diethyl malonate (2.85 mL, 18.54 mmol) ) and heated to 120 ° C until a homogeneous solution formed. To this mixture was added sodium metal (100 mg, 4.36 mmol) and the mixture was stirred at 120 ° C for 24 hours. The FTA indicated the completion of the reaction. The reaction was allowed to cool to room temperature and a 5% solution of HCl (aqueous) was slowly added to the mixture and the resulting product was extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated to give compound 12 as a white solid (1.67 g, 85% yield, M + 1 = 318.4). The product was taken in the next step without purification. Step 6 - Preparation of 2- (5-Ethyl-1 H-indol-3-ylmethyl) -malonic acid. Diethylmalonylindole without purification 12 (1.67 g, 5.26 mmol) in THF (20 mL) and a solution of NaOH was dissolved. (1.0 g, 25.5 mmol) in H2O (20 mL) was added. MeOH (5 mL) was also added to the reaction to make the solution homogeneous. The mixture was heated to 50 ° C and stirred overnight. The mixture was allowed to cool to room temperature, the organic layer was evaporated and the residue acidified with 2 N of HsPO4, and the product was extracted with a mixture of 3: 1 / CHCl3: MeOH. The organic layer was washed with brine, dried over MgSO 4, filtered and evaporated to give the unpurified diacid as a white solid (1.25 g.; M - 1 = 260.2). The product was taken in the next step without purification. Step 7 - Preparation of 3- (5-Ethyl-1 H-indol-3-yl) -propionic acid 14. Malonic acid 13 was added without purification (250 mg, 0. 957 mmol) in a round bottom flask under vacuum and heated slowly between 150 and 200 ° C, when the CO 2 evolution occurred. When the bubbling was over, the reaction was heated for a further 2 minutes, then allowed to cool to room temperature. The product was purified by flash chromatography three times using 0 to 10% MeOH in CHCU to give compound 14 as a solid (120 mg, 57.7% yield, M-1 = 216.3). Step 8 - Preparation of 3- (1-Benzylsulfonyl-5-ethyl-1 H-indol-3-yl) -propionic acid 6. Indolepropionic acid 14 (100 mg, 0.46 mmol) was dissolved in THF (5.0 mL) and it was cooled to -78 ° C. To this solution was added n-butyllithium (n-BuLi, 0.4 mL, 1.0 mmol, 2.4 M in hexanes) in drops and the mixture was stirred at -78 ° C for 1 hour. To this mixture was added benzenesulfonyl chloride (0.13 mL, 1 mmol) and the reaction was allowed to stir overnight and warmed to room temperature. The mixture was poured into ice-cold HsPO4 and extracted with EtOAc. The organic layer was dried over MgSO, filtered and evaporated. The residue was purified by flash chromatography (5% MeOH / CHCl3) to give compound 6 as a white solid (10 mg, M-1 = 356.4).

Example 5: Synthesis of ldazol-3-propionic acid 16 Indazol-3-propionic acid 16 was prepared from commercially available indazole-3-carboxylic acid 17 in 5 steps as described in Scheme 9.

Scheme 9 Step 1 - Preparation of (1 H-lndazo-3-yl) -methanol 18 To a cooled solution of indazole-3-carboxylic acid 17 (3.95 g, 24.4 mmol) in tetrahydrofuran (THF, 300 mL) under nitrogen, lithium aluminum hydride (LAH; 1. 9 g, 50.5 mmol). The resulting alcohol 17 was isolated through the quenching of LAH reactive with water, until no evolution of hydrogen was observed and the solution was then filtered, washed with THF, and concentrated to give alcohol 18 as a brown solid. clear (2.63 g, 72%). Step 2 - Preparation of ldazol-3-carboxyaldehyde 19 Manganese oxide (II) (6.4 g, 73 mmol) was added to a solution of (1 H-indazol-3-yl) -methanol 18 (1.08 g, 7.4 mmol ) in a mixture of DCM (40 ml) and THF (30 ml). The solution was stirred for 16 hours at room temperature and filtered through celite and concentrated under reduced pressure to yield a white solid (0.65 g, 61%). Step 3 - Preparation of 3- (lndazo-3-yl) -propenoic acid methyl ester The 3- (lndazo-3-yl) -propenoic acid methyl ester 20 was prepared from aldehyde 19, as described in Step 1, Example 3. Step 4 - Preparation of the indazole-3-propionic acid methyl ester 21 The indazole-3-propionic acid methyl ester was prepared from compound 20 as described in Step 2, Example 3. Step 5 - Preparation of indazole-3-propionic acid 16. Indazole-3-propionic acid was prepared through the saponification of compound 21 as described in Step 4, Example 3 (M-1 = 197.1): Example 6: Synthesis of 5-isopropox? -3- (1-Benzenesulfonyl-indol-3-yl) -propionic acid 22 Propionic acid 22 was prepared from commercially available 5-hydroxy-indole 23 as shown in the scheme 10 Scheme 10 Step 1 - Synthesis of 5-lsopropoxy-indole 24 To a solution of 5-hydroxyindole 23 (2.0 g, 0.015 mol) in 20 ml of acetonitrile, anhydrous potassium carbonate (4 grams, 0.028 mol) was added and stirred vigorously before the isopropyl iodide (3 grams, 0.018 mol) was added. The reaction was stirred for 2 days at room temperature and the solid was washed with acetonitrile. The filtrate was concentrated and purified by flash chromatography (80% n-hexane / 20% ethyl acetate) to give the desired product 24 as a light yellowish oil (1.72 g, 83%, M + 1 = 176.1). Step 2 - Synthesis of 5-lsopropoxigramin 25 5-lsopropoxy gramine 25 was prepared from 5-Isopropoxy-indole 24 as described in Step 2, Example 4 (M + 1 = 233.4). Step 3 - Synthesis of 2- (5-lsopropoxy-1H-indol-3-ylmethyl) -malonic acid diethyl ester 26 Compound 26 was prepared from 25 as described in Step 3, Example 4 (M + 1 = 348.5). Step 4 - Synthesis of 5-lsopropoxy-indole-3-propionic acid 27 5-lsopropoxy-indole-3-propionic acid 27 was prepared from compound 26 through the same protocol as described in Step 4, Example 4 (M-1 = 246.2). Step 5 - Synthesis of 5-isopropoxy-3- (1-Benzenesulfonyl-indol-3-yl) -propionic acid 22 To a cooled solution (-78 ° C) of propionic acid (27) (96.3 mg, 0.510 mmol) in tetrahydrofuran (10 ml), n-butyllithium (1.40 ml, 2.24 mol) was added immediately and stirred for 30 minutes at -78 ° C. Benzenesulfonyl chloride (277 mg, 1.5 mmol) was added immediately and the reaction was stirred for 16-24 hours, allowing the temperature to rise from -78 ° C to ambient conditions. The reaction was then diluted with ethyl acetate, and 1M HCl was added to adjust the pH to 1-2. The layers were then separated, and the organic layer was placed over magnesium sulfate and concentrated under reduced pressure.

The unpurified material was then purified by flash chromatography on silica, eluting with 5% methanol in dichloromethane to yield the desired product (22) as a white solid. (M-1 = 386.4) Example 7: Preparation of lndo-3-propionic acid 28 Indole-3-propionic acid 28 was prepared through the commercially available indole-3-carboxaldehyde as described in Example 3. (M-1, 188.2).

Example 8: Preparation of 3- (1-Benzylsulfonyl-5-methoxy-1H-indol-3-yl) -propionic acid 29 The 3- (1-benzenesulfonyl-5-methoxy-1H-indol-3-yl) propionic acid 29 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with benzenesulfonyl chloride, ( M-1 = 358.4) Example 9: Synthesis of 3- [5-Methoxy-1- (3-methoxy-benzyl) -1H-indol-3-yl] -propionic acid 30 3- [5-Methoxy-1- (3-methoxy-benzyl) -1H-indol-3-yl] -propionic acid was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 3-methoxybenzyl bromide, (M-1 = 336.4).

Example 10: Synthesis of 3- [1- (3-cyoro-benzyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 31 3- [17 (3-Chloro-benzyl) -5-methoxy-1H-indol-3-yl] -propionic acid 31 was prepared using the same protocol as in Example 3, substituting the 4- methoxybenzenesulfonyl with 3-chlorobenzyl bromide, (M-1 = 322.4).

Example 11: Synthesis of 3- [1- (4-Fluoro-benzyl) -5-methoxy-1H-n-dol-3-yl] -propionic acid 32 3- [1- (4-Fluoro-benzyl) -5-methoxy-1H-indol-3-yl] -propionic acid was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride for 4-fluorobenzyl bromide, (M-1 = 326.6).

Example 12: Preparation of 3 ~ [1- (4-Chloro-benzyl) -5-methoxy-1H-indol-3-yl] -propionic acid 33 3- [1- (4-Chloro-benzyl) -5-methoxy-1H-indol-3-yl] -propionic acid 33 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 4-chlorobenzyl bromide. (M-1 = 342.8).

Example 13: Synthesis of 3- [5-Methoxy-1- (2-methoxy-benzyl) -1H-indol-3-yl] -propionic acid 34 3- [5-Methoxy-1- (2-methoxy-benzyl) -1H-indol-3-yl] -propionic acid 34 was prepared using the same protocol as in Example 3, substituting the chloride, 4- methoxybenzenesulfonyl with 2-methoxybenzyl bromide. (M-1 = 338.4).

Example 14: Synthesis of 3- [5-Methoxy-1- (2-trifluoromethoxy-benzyl) -1H-indol-3-yl] -propionic acid The 3- [5-Methoxy-1- (2-trifluoromethoxy-benzyl) -1H-indol-3-yl] -propionic acid was prepared using the same protocol as in Example 3, replacing the 4- methoxybenzenesulfonyl with 2-trifluoromethoxybenzyl bromide. (M-1 = 392.3).

Example 15: Synthesis of 3- [5-Methoxy-1- (3-trifluoromethoxy-benzyl) -1H-indol-3-yl] -propionic acid 36 2H 3- [5-Methoxy-1- (3-trifluoromethoxy-benzyl) -1H-indol-3-yl] -propionic acid 36 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 3-trifluoromethoxybenzyl bromide.

(M-1 = 392.4).

Example 16: Synthesis of 3- [1-ethylthiocarbamoyl-5-methoxy-1 H-indol-3-yl) -propionic acid 37 37 The 3- [1-ethylthiocarbamoyl-5-methoxy-1H-indol-3-yl) -propionic acid 37 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with ethyl isothiocyanate, ( M-1 = 305.4).

Example 17: Synthesis of 3- [5-methoxy-1- (toluene-4-sulfonyl) -1H-indol-3-yl] -propionic acid 3- [5-Methoxy-1- (toluene-4-sulfonyl) -1H-indol-3-yl] -propionic acid 38 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 4-tolylsulfonyl chloride. (M-1 = 373.4).

Example 18: Synthesis of 3- [1-Benzylsulfonyl-1 H-indazol-3-yl] -propionic acid 39 3- [1-Benzylsulfonyl-1 H-indazol-3-yl) -propionic acid 39 was prepared through the same protocol as in Step 5, Example 6. (M-1 = 329.4).

Example 19: Synthesis of 3- [1- (4-lsopropyl-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid methyl ester The 3- [1- (4-lsopropyl-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid methyl ester 40 was prepared using the same protocol as in Example 3, substituting 4-chlorocarbonyl chloride. -methoxybenzenesulfonyl with 4-isopropylbenzenesulfonyl chloride, (M + 1 = 416.6).

Example 20: Synthesis of 3- [1- (4-lsopropy-benzenesulfonyl) -5-m-ethoxy-1H-indol-3-yl] -propionic acid 41 The 3- [1- (4-lsopropyl-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid was prepared through the saponification protocol with the methyl ester of 3- [1-] (4-lsopropyl-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 41 as described in step 4 of example 3, (M-1 = 400.5).

Example 21: Synthesis of 3- [1- (4-Butoxy-benzenesuIfoniI) -5-methoxy-1H-indol-3-yl] -propionic acid methyl ester 42 The 3- [1- (4-Butoxy-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid methyl ester 42 was prepared using the same protocol as in Example 3, substituting the -methoxybenzenesulfonyl with 4-n-butoxybenzenesulfonyl chloride, (M + 1 = 446.5).

Example 22: Synthesis of 3- [1- (4-Butoxy-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 43 3- [1- (4-Butoxy-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid was prepared through the saponification protocol with the methyl ester of [1- (4-Butoxy] -benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic 42 as described in step 4 of example 3, (M-1 = 430.5).

Example 23: Synthesis of 3- [5-Methoxy-1- (4-trifluoromethoxy-benzenesulfonyl) -1H-indol-3-yl] -propi onic acid methyl ester 44 The 3- (5-Methoxy-1- (4-trifluoromethoxy-benzenesulfonyl) -1H-indol-3-yl] -pro-ionic acid methyl ester was prepared using the same protocol as in Example 3, substituting the 4-methoxybenzenesulfonyl with 4-trifluoromethoxybenzenesulfonyl chloride, (M + 1 = 457.4).

Example 24: Synthesis of 3- [5-Methoxy-1- (4-trifluoromethoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 3- [5-Methoxy-1- (4 -trifluoromethoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic through the saponification protocol with the methyl ester of 3- [5-methoxy-1- (4-trifluoromethoxy-benzenesulfonyl) -1H- indole-3-yl] -propionic 45 as described in step 4 of example 3, (M-1 = 442.4).

Example 25: Synthesis of 3- [5-Methoxy-1- (4-phenoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid methyl ester 46 The 3- (5-Methoxy-1- (4-phenoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid methyl ester was prepared using the same protocol as in Example 3, substituting the 4-methoxybenzenesulfonyl with 4-phenoxybenzenesulfonyl chloride, (M + 1 = 466.6).

Example 26: Synthesis of 3- [5-Methoxy-1- (4-phenoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 47 The 3- [5-methoxy-1- (4-phenoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid was prepared through the saponification protocol with the methyl ester of 3- [5-Methoxy] 1- (4-phenoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 46 as described in step 4 of example 3, (M-1 = 450.5).

Example 27: Synthesis of 3- [1- (4-chloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid methyl ester 48 The 3- [1- (4-chloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid methyl ester 48 was prepared using the same protocol as in Example 3, substituting the chloride from 4-methoxybenzenesulfonyl with 4-chlorobenzenesulfonyl chloride, (M + 1 = 406.9).

Example 28: Synthesis of 3- [1- (4-Cioro-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 49 3- [1- (4-Chloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 49 was prepared through the saponification protocol with the methyl ester of 3- [1- ( 4-Chloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 48 as described in step 4 of example 3, (M-1 = 392.9).

Example 29: Synthesis of 3- [1- (4-Cyano-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid methyl ester 50 The 3- [1- (4-Cyano-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid methyl ester 50 was prepared using the same protocol as in Example 3, substituting the sodium chloride. -methoxybenzenesulfonyl with 4-cyanobenzenesulfonyl chloride, (M + 1 = 399.4).

Example 30: Synthesis of 3- [1- (4-cyano-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 51 3- [1- (4-Cyano-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 51 was prepared through the saponification protocol with the methyl ester of acid 3- [ 1- (4-Cyano-benzenesulfonyl) -5-methoxy-1H-indoI-3-yl] -propionic acid 50 as described in step 4 of example 3, (M-1 = 383.4).

Example 31: Synthesis of 3- [1- (3,4-dichloro-benzenesulfonyl) -5-m-ethoxy-1H-indol-3-yl] -propionic acid methyl ester 52 The methyl ester of 3- [1- (3,4-Dichloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 52 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 3,4-dichlorobenzenesulfonyl chloride, (M + 1 = 443.3).

Example 32: Synthesis of 3- [1- (3,4-Dichloro-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 53 3- [1- (3,4-Dichloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 53 was prepared through saponification with methyl ester of 3- [1- ( 3,4-dichloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 52 as described in step 4 of example 3, (M-1 = 427.3).

Example 33: Synthesis of 3- [5-Methoxy-1- (4-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl] propionic acid methyl ester 54 The methyl ester of 3- [5-methoxy-1- (4-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 54 was prepared using the same protocol as in example 3, substituting the -methoxybenzenesulfonyl with trifluoromethylbenzene chloride, (M + 1 = 442.4).

Example 34: Synthesis of 3- [5- (Methoxy-1- (4-trifluoromethyl-benzenesulfonyl) -1H-indol-3 -i I] -propionic acid 3- [5-Methoxy-1- (4-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 55 was prepared through saponification of the methyl ester of 3- [5-Methoxy-1] - (4-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl] -propionic 54 as described in step 3 of example 3, (M + 1 = 404.5).

Example 35: Synthesis of 3- [1- (4-Fluoro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid methyl ester The 3- [1- (4-methyl ester -Fluoro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic 56 using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 4-fluorobenzenesulfonyl chloride, (M + 1 = 392.4).

Example 36: Synthesis of 3- [1- (4-Fluoro-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 57 3- [1- (4-Fluoro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 57 was prepared through saponification of the methyl ester of 3- [1- (4- Fluoro-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic 56 as described in step 4 of example 3, (M-1 = 376.4).

Example 37: Synthesis of 3- [5-Methoxy-1- (3-phenoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid methyl ester 58 The methyl ester of 3- [5-methoxy-1- (3-phenoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 58 was prepared using the same protocol as in Example 3, substituting the -methoxybenzenesulfonyl with 3-phenoxybenzenesulfonyl chloride, (M + 1 = 466.5).

Example 38: Synthesis of 3- [5-Methoxy-1- (3-phenoxy-benzenesulfonyl) -1H-indoI-3-yl] -propionic acid 59. 3- [5-Methoxy-1- (3 -phenoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 59 through the saponification of 3- [5-methoxy-1- (3-phenoxy-benzenesulfonyl) -1H-indole-3-methyl ester. -il] -propionic 58 as described in step 4 of example 3, (M-1 = 376.4).

Example 39: Synthesis of 3- [1- (3-Fluorobenzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid methyl ester 60 The 3- [1- (3-Fluoro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid methyl ester was prepared using the same protocol as in Example 3, substituting the chloride -methoxybenzenesulfonyl with 3-fluorobenzenesulfonyl chloride, (M + 1 = 392.3).

Example 40: Synthesis of 3- [1- (3-Fluoro-benzenesulfonyl) -5-m-ethoxy-1H-indol-3-yl] -propionic acid 61 3- [1- (3-Fluoro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 61 was prepared through saponification of the methyl ester of 3- [1- (3-Fluoro acid -benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 60 as described in step 4 of example 3, (M-1 = 376.4).

Example 41: Synthesis of 3- [5-Methoxy-1- (toluene-3-sulfonyl) -1H-indol-3-yl] -propionic acid methyl ester 62 The methyl ester of 3- [5-methoxy-1- (toluene-3-sulfonyl) -1H-indol-3-yl] -propionic acid was prepared using the same protocol as in Example 3, substituting the 4- methoxybenzenesulfonyl with 3-tolylsulfonyl chloride, (M + 1 = 388.5).

Example 42: Synthesis of 3- [5-methoxy-1- (toluene-3-sulfonyl) -1H-indol-3-yl] -propionic acid 63 3- [5-Methoxy-1- (toluene-3-sulfonyl) -1H-indol-3-yl] -propionic acid 63 was prepared through saponification of 3- [5-Methoxy-1] methyl ester. - (toluene-3-sulfonyl) -1H-indol-3-yl] -propionic 62 as described in step 4 of example 3, (M-1 = 372.4).

Example 43: Synthesis of 3- [1- (3-chloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid methyl ester 64 The 3- [1- (3-chloro-benzenesulfonyl) -5-methoxy-1H-indoI-3-yl] -propionic acid methyl ester 64 was prepared using the same protocol as in Example 3, substituting the 4-methoxybenzenesulfonyl chloride with 3-chlorobenzenesulfonyl chloride, (M + 1 = 408.9).

Example 44: Synthesis of 3- [1- (3-Chloro-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 3- [1- (3-Chloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 65 was prepared through the saponification of the methyl ester of 3- [1- (3- Chloro-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic 64 as described in step 4 of example 3, (M-1 = 392.7).

Example 45: Synthesis of 3- [5-Methoxy-1- (3-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid methyl ester 66 The methyl ester of 3- [5-Methoxy-1- (3-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 66 was prepared using the same protocol as in Example 3, substituting the chloride of 4. -methoxybenzenesulfonyl with 3-methoxybenzenesulfonyl chloride, (M + 1 = 404.5).

Example 46: Synthesis of 3- [5-Methoxy-1- (3-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 67 3- [5-Methoxy-1- (3-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 67 was prepared through saponification of the methyl ester of 3- [5-Methoxy-1] - (3-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 66 as described in step 4 of example 3, (M-1 = 388.4).

Example 47: Synthesis of 3- [5-Methoxy-1- (3-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl] -propionic acid methyl ester 68 The methyl ester of 3- [5-Methoxy-1- (3-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 68 was prepared using the same protocol as in Example 3, substituting the 4-methoxybenzenesulfonyl with 3-trifluoromethylbenzenesulfonyl chloride, (M + 1 = 442.4).

Example 48: Synthesis of 3- [5-methoxy-1- (3-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 69 3- [5-Methoxy-1- (3-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 69 was prepared through saponification of 3- [5-Methoxy-1] methyl ester - (3-trifluoromethyl-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 68 as described in step 4 of example 3, (M-1 = 426.4).

Example 49: Synthesis of 3- (1-Benzyl-5-methoxy-1 H-indol-3-yl) -propionic acid methyl ester 70 The 3- (1-Benzyl-5-methoxy-1H-indol-3-yl) -propionic acid methyl ester 70 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with bromide benzyl, (M + 1 = 324.4).

Example 50: Synthesis of 3- (1-Benzyl-5-methoxy-1 H-indol-3-yl) -propionic acid 71 3- (1-Benzyl-5-methoxy-1H-indol-3-yl) -propionic acid was prepared through saponification of 3- (1-Benzyl-5-methoxy-1 H-indole) methyl ester -3-il) -propionic 70 as described in step 4 of example 3, (M + 1 = 308.3).

Example 51: Synthesis of 3- [5-Methoxy-1- (thiophene-2-sulfonyl) -1H-indol-3-yl] -propionic acid methyl ester 72 The 3- (5-Methoxy-1- (thiophene-2-sulfonyl) -1H-indol-3-yl] -propionic acid methyl ester was prepared using the same protocol as in Example 3, substituting the 4- methoxybenzenesulfonyl with 2-thiophenesulfonyl chloride, (M + 1 = 380. 5).

Example 52: Synthesis of 3- [5-Methoxy-1- (thiophene-2-sulfonyl) -1 H -indol-3-yl] -propionic acid 73 3- [5-Methoxy-1- (thiophene-2-sulfonyl) -1H-indol-3-yl] -propionic acid was prepared through the saponification of the methyl ester of 3- [5-Methoxy-1-] (thiophene-2-sulfonyl) -1H-indol-3-yl] -propionic acid as described in step 4 of example 3, (M-1 = 364.4).

Example 53: Synthesis of 3- (5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl) -propionic acid methyl ester 74 The 3- (5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl) -propionic acid methyl ester 74 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with phenyl isothiocyanate , (M + 1 = 369.5).

Example 54: Synthesis of 3- (5-Methoxy-1-phenylthiocarbamoyl-1 H-indol-3-yl) -propionic acid 75 2H 3- (5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl) -propionic acid 75 was prepared by saponification of 3- (5-Methoxy-1-phenylthiocarbamoyl-1 H-) methyl ester indol-3-yl) -propionic 74 as described in step 4 of example 3, (M-1 = 353.4).

Example 55: Synthesis of 3- [1- (4-Butylbenzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid methyl ester 76 The methyl ester of 3- [1- (4-Butyl-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 76 was prepared using the same protocol as in Example 3, substituting the 4-methoxybenzenesulfonyl with 4-n-butylbenzenesulfonyl chloride, (M + 1 = 430.2).

Example 56: Synthesis of 3- [1- (4-Butyl-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 77 3- [1- (4-Butyl-benzenesulfonyl) -5-methoxy-1 H -indole-3-yl] -propionic acid 77 was prepared through the saponification of the methyl ester of 3 ~ [1- ( 4-Butyl-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl-propionic acid 76 as described in step 4 of example 3, (M-1 = 414.1).

Example 57: Synthesis of 3- [5-Methoxy-1- (3-trifluoromethoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid methyl ester 78 The methyl ester of 3- [5-Methoxy-1- (3-trifluoromethoxy-benzenesulfonyl) -1H-in-1-3-yl] -proponic acid 78 was prepared using the same protocol as in Example 3 , substituting the 4-methoxybenzenesulfonyl chloride with 3-trifluorobenzenesulfonyl chloride, (M + 1 = 458.1).

Example 58: Synthesis of 3- [5-Methoxy-1- (3-trifluoromethoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 79 3- [5-Methoxy-1- (3-trifluoromethoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 79 was prepared through the saponification of the methyl ester of 3- [5-Methoxy-1] - (3-trifluoromethoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic 4 as described in step 4 of example 3, (M-1 = 442.0).

Example 59: Synthesis of 3- (1-Benzoyl-5-methoxy-1 H-indol-3-yl) -propionic acid methyl ester 80 The 3- (1-Benzoyl-5-methoxy-1H-indol-3-yl) -propionic acid methyl ester 80 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with benzoyl chloride , (M + 1 = 338.1).

Example 60: Synthesis of 3- (1-Benzoyl-5-methoxy-1 H-indol-3-yl) -propionic acid 81 The 3- (1-Benzoyl-5-methoxy-1 H-indol-3-yl) -propionic acid 81 was prepared through saponification of 3- (1-Benzoyl-5-methoxy-1 H-) methyl ester indol-3-yl) -propionic 80 as described in step 4 of example 3, (M-1 = 322.1).

Example 61: Synthesis of 3- (1-Benzylsulfonyl-5-ethoxy-1 H-indol-3-yl) -propionic acid 82 The 3- (1-Benzylsulfonyl-5-ethoxy-1H-indol-3-yl) -propionic acid 83 was prepared using the same protocol as in Example 6, substituting 2-propy iodide with ethyl iodide, ( M-1 = 372.4).

Example 62: Synthesis of 3- [1- (4-lsopropoxy-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 83 The 3- [1- (4-lsopropoxy-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 83 was prepared using the same protocol as in Example 3, substituting the 4-methoxybenzenesulfonyl chloride with 4-isopropoxybenzenesulfonyl chloride, (M-1 = 416.5).

Example 63: Synthesis of 3- (5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl) -propionic acid methyl ester 84 The methyl ester of 3- (5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl) -propionic acid 84 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with phenyl isocyanate , (M + 1 = 353.4).

Example 64: Synthesis of 3- (5-Methoxy-1-phenylcarbamoyl-1 H-indol-3-yl) -propionic acid 85 The 3- (5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl) -propionic acid 85 was prepared through the saponification of the methyl ester of 3- (5-Methoxy-1-phenylcarbamoyl-1 H- indole-3-yl) -propionic 84 as described in step 4 of example 3, (M-1 = 337. 4).

Example 65: Synthesis of 3- [1- (4-Ethyl-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 86 3- [1- (4-Ethyl-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 86 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 4-ethylbenzenesulfonyl chloride, (M-1 = 386.4).

Example 66: Synthesis of 3- (5-bromo-1 H-indol-3-yl) -propionic acid 87 87 3- (5-Bromo-1 H-indol-3-yl) -propionic acid 87 was prepared from the commercially available 5-Bromoindole, using the same protocol as in Example 6, to give a beige solid, ( M-1 = 268.0).

Example 67: Synthesis of 3- (5-Bromo-1 H-indol 3-yl) -propionic acid methyl ester 88 88 5-Bromoindol-3-propionic acid 87 (4.0 g, 14.91 mmol) was dissolved in methanol (MeOH, 100 mL), and Trimethylsilyl chloride (TMSC1, 33.0 mL, 32.8 mmol, 1.0 M) was added dropwise. CH2Cl2). The mixture was stirred for 24 hours, followed by refluxing for 1 hour. The reaction was allowed to cool to room temperature and the solvent was evaporated to ester as a white solid. (M + 1 = 284).

Example 68: Synthesis of 3- (1-Benzylsulfonyl-5-bromo-1 H -indol-3-yl) -propionic acid methyl ester 89 89 The methyl ester of 3- (1-Benzylsulfonyl-5-bromo-1 H-indol-3-yl) -propionic acid 89 was prepared as described in step 3 of Example 3 substituting 4-methoxybenzenesulfonyl chloride with benzenesulfonyl chloride , (M + 1 = 424).

Example 69: Synthesis of 3- (1-Benzylsulfonyl-β-rom or-1 H-indol-3-yl) -propyonic acid methyl ester 90 90 3- (1-Benzylsulfonyl-5-bromo-1H-indol-3-yl) -propionic acid was prepared through the saponification of methyl ester 89 using the procedure as described in step 4 of example 3, (M -1 = 406.0).

Example 70: Synthesis of 3- (Benzylsulfonyl-5-thiophen-3-yl-1 H-indol-3-yl) -propionic acid methyl ester 91 91 3- (1-Benzylsulfonyl-5-bromo-1 H-indol-3-yl) -propionic acid 89 methyl ester (200 mg, 0.474 mmol) was combined with 3-thienylboronic acid (67.0 mg, 0.52 mmol), triphenylphosphine (9.0 mg, 0.03 mmol), Pd (OAc) 2 (4.0 mg, 0.015 mmol), K2CO3 (90 mg, 0.65 mmol), 1,2-dimethoxyethane (DME, 4.0 ml) and H2O (0.4 ml) were added. heated at 90 ° C for 48 hours. The reaction was allowed to cool to room temperature and the solvent was evaporated. The resulting residue was dissolved in EtOAc and washed with brine. The organic layer was dried over MgSO, filtered and evaporated. The residue was purified with flash silica gel chromatography (20% EtOAc / Hexanes) to obtain ester 91 as a white solid, (110 mg, M + 1 = 426.1).

Example 71: Synthesis of 3- (Benzylsulfonyl-5-thiophen-3-yl-1H-indol-3-yl) -propionic acid 92 92 3- (Benzylsulfonyl-5-thiophen-3-yl-1 H-indol-3-yl) -propionic acid 92 was prepared through saponification of methyl ester 91 as described in step 4 of example 3, ( M-1 = 410.1).

Example 72: Synthesis of 3- (1-Benzenesulfonyl-5-phenyl-1H-indo! -3-yl) -propionic acid methyl ester 93 93 Ester 93 was prepared from methyl ester 89 following the procedure as described in Example 70 by substituting 3-thienylboronic acid with phenylboronic acid, (M + 1 = 420).

Example 73: Synthesis of 3- (1-B-Benzenesulfonyl-5-phenyl-1 H-indol-3-yl) -propionic acid 94 94 and prepared 3- (1-Benzylsulfonyl-5-phenyl-1 H-indol-3-yl) -propionic acid 94 through saponification of methyl ester 94 as described in step 4 of example 3, (M-1) = 404.5).

Example 74: Preparation of 3- (1 H-Pyrrolo [2,3-b] pyridin-3-yl) -propionic acid 95 95 3 -. (1H-Pyrrolo [2,3-b] pyridin-3-yl) -propionic acid 95 was prepared from commercially available 7-azaindole by the same protocol described in steps 4-6 of example 4, (M-1 = 189.2).

Example 75: Synthesis of 3- (5-Methoxy-1 H-indoI-3-yl) -propionic acid 96 96 3- (5-Methoxy-1H-indol-3-yl) -propionic acid 96 was prepared from the saponification of 3- (5-methoxy-1H-indol-3-yl) -propionic acid methyl ester. 4 as described in step 4 of Example 3. (M-1 = 218.2).

Example 76: Synthesis of 3- (1-Benzylsulfonyl-1 H-indol-3-yl) -propionic acid 97 97 3- (1-Benzylsulfonyl-1 H-indol-3-yl) -propionic acid 97 was prepared from indole-3-propionic acid 28 using the protocol as described in step 8, Example 4, (M -1 = 329.4).

Example 77: Synthesis of 3- (1-Benzylsulfonyl 5-methoxy-1H-indol-3-yl) -propionic acid methyl ester 98 98 3- (1-Benzylsulfonyl-5-methoxy-1H-indol-3-yl) -propionic acid methyl ester 98 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with benzenesulfonyl chloride , (M + 1 = 374.4).

Example 78: Synthesis of 3- [5-Methoxy-1- (thiophene-3-sulfonyl) -1H-indol-3-yl] -propionic acid 99 99 3- [5-Methoxy-1- (thiophene-3-sulfonyl) -1H-indol-3-yl] -propionic acid 99 was prepared from 3- (5-methoxy-1H-indole- 3-l) -propionic 96 and 3-thienyl-sulfonyl chloride using the same protocol as described in step 8, Example 4. (M-1, 364.4) Example 79: Synthesis of (1-Benzylsulfonyl-5-methoxy-1 H-indol-3-yl) -acetic acid 100 100 The (1-Benzylsulfonyl-5-methoxy-1H-indol-3-yl) -acetic acid 100 was prepared from the commercially available (5-methoxy-1H-indol-3-yl) -acetic acid and the chloride of benzenesulfonyl using the protocol as described in step 8, example 4. (M-1 = 344.4) Scheme 11: Alternative Synthesis Methodology for the Compounds of the Formula Ib Step 1 - Preparation of the compound of formula XVlll: Compound XVlll can be prepared by coupling compound III with benzenesulfonyl chloride in a biphasic solvent condition, for example, toluene and water, in the presence of a base, for example, a solution of aqueous potassium hydroxide with a phase transfer catalyst, for example, tetrabutylammonium acid sulfate, similar to conditions as those described in Gribble et al, in J. Org. Chem., 2002, 63, pages 1001-1003.

Step 2 - Preparation of compound XIX: Compound XIX was prepared via Knoevenagel reaction conventionally by reacting compound XVlll with a piperidine of malonic acid in pyridine at 80 ° C for 3-4 hours, as described in Vangvera et al. in J. Med. Chem., 1998, 41, pages 4995-5001.

Step 3- Preparation of Compound Ib: Compound 1 was prepared from compound XIX through reduction by catalytic hydrogenation (usually with 10% palladium on activated carbon in an inert solvent (see preparation of intermediate II, vide supra). ), Example 80: Alternative synthesis of 3- [5-methoxy-1- (4-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 1 Scheme 12 Step 1: Preparation of 1- (4-methoxy-benzenesulfonyl) -5-methoxy-1 H-indole-3-carboxaldehyde) (117) In a dry round bottom flask, 5-methoxy-indole-3-aldehyde 2 (1.0 g, 5.7 mmol) was dissolved with toluene (4 ml). Tetrabutylammonium iodide (10 mg) and 50% KOH solution (2 ml) were then added. After about 5 minutes of stirring, 4-methoxybenzenesulfonyl chloride (1.7 grams, 8.2 mmol) was added. Within 2-3 hours, the solid began to precipitate out of the solution. This reaction was allowed to stir at room temperature for 2 hours, after which water (50 ml) and ethyl acetate (150 ml) were added to the reaction. The layers separated; the organic layer was washed with saturated bicarbonate (3 X 75 ml) and water (4 X 75 ml) to insure removal of the hydroxide and sulfonate salt, and washed with brine (1 X 75 ml) and dried over sulfate. of sodium anhydrous. Evaporation under reduced pressure yielded 117 as a brown solid. (1.86 g, 94%) 1 H NMR (CDCl 3) d 10.0 (s, 1 H), 8.20 (s, 1 H), 7.92 (d, J = 9.2 Hz, 2 H), 7.85 (d, J = 8.8, 1 H), 7.74 (d, J = 2.4, 1H), 7.04 (dd, J = 2.8 Hz, 9.2 Hz, 1H), 6.97 (d, J = 9.2 Hz, 2H), 3.85 (s, 3H).

Step 2: Preparation of 3- [1- (4-Methoxy-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -acrylic acid (118) To a solution of 1- (4-methoxy-benzenesulfonyl) - 5-methoxy-1 H-indole-3-carbaldehyde 5 (0.51 g, 1.5 mmol) dissolved in pyridine (10 ml), malonic acid (0.53 g, 5.1 mmol) and piperidine (1 ml) were combined in a reaction vessel. The yellow solution was heated for 3 hours at 80 ° C. The reaction was allowed to cool to room temperature and diluted with 150 ml of ethyl acetate. The organic layer was washed with 1 N HCl (6 X 50 ml) and saturated sodium chloride solution (1 X 50 ml). After drying over sodium sulfate, the organic layer was filtered through a pad of sodium sulfate and evaporated under reduced pressure to yield the product 118 as an off-white solid. (0.521 g, 90%) 1HNMR (CDCI3) d 7.86 (m, 5H), 7.2 (d, J = 2.4 Hz, 1H), 7.0 (dd, J = 2.8 Hz, 9.2 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.46 (d, J = 16, 1H), 3.87 (s, 3H, CH3) (M-1 = 386.2).

Step 3: Preparation of 3- [1- (4-Methoxy-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid (1) To a solution of 3- [1- (4-Methoxy) benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -acrylic 118 (1.0 g, 2.6 mmol) dissolved in THF (14 ml), Pd / C (67 mg) was added in one portion. The solution was joined to the hydrogenator Parr. The reaction was allowed to develop overnight at 20-22 psi. The solution was filtered over celite, and the palladium-celite pad was washed with ethyl acetate (40 ml), and methanol (20 ml). The combined washings / solution were evaporated under reduced pressure to produce a straw-colored oil that solidified after cooling under high vacuum. The crude was triturated with diethyl ether to leave behind the off-white solid as product 1. (0.620g, 62%) 1H NMR (DMSO) d 7.86 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 2.4 Hz, 9.2 Hz, 1H), 6.88 (s, 1H), 6.83 (d, J = 9.2 Hz, 2H), 3.76 (s, 3H), 2.96 (t, J = 7.6 Hz, 14.8 Hz, 2H), 2.74 (t, J = 7.6 Hz, 14.8 Hz, 2H) (M-1 = 388.6).

Example 81: Synthesis of 3-_5-Methoxy-1- (4-methoxy-benzenesulfonyl) -1H-indol-3-yl] -2,2-dimethyl-propionic acid 119 Scheme 13 Step 1 - Synthesis of 5-methoxy-1 H-indole-3-yl-methanol 141 To a solution of sodium borohydride (2 grams, 0.05 mole) in methanol (15 ml), a solution of 5-methoxy-1 H-indole -3-carboxaldehyde 2 (1 gram, 0.006 moles) dissolved in THF (20 ml) and methanol (15 ml) were combined and stirred at room temperature for 16 hours. The reaction was diluted with water and potassium carbonate (for saturation) and stirred to quench the non-reactive sodium borohydride. Diethyl ether was used to extract the product from the extinguished solution. Following the separation of the layers, the aqueous layer was further extracted (2X) with diethyl ether. The organic layers were dried over sodium sulfate and evaporated to dryness to yield a clear solid 141 (736 mg, 70%). Step 2 - Preparation of 3- (5-Methoxy-1 H-indol-3-yl) -propionic acid 142-methyl ester: To a solution of 5-methoxy-1 H -indole-3-yl-methanol 141 (115 mg, 0.643 mmole) dissolved in dichloromethane (3 ml), (1-methoxy-2-methyl-profenyloxy) -trimethylsilane (200 mg, 1 mmol) and magnesium perchlorate (164 mg, 0.74 mmol) were added. The reaction was allowed to stir at room temperature for 3-4 hours after which the mixture was diluted with water (50 ml) and dichloromethane (DCM, 100 ml). The organic layer was separated and washed with water (50 ml, 3X). The organic layer was washed once with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give an oil and purified by flash chromatography (silica with 80% hexane, 20% ethyl acetate to produce 142 as a clear colorless oil (150 mg, 88% yield, M + 1 = 262.3).

Step 3 - Preparation of 3- [5-Methoxy-1- (4-methoxy-benzenesulfonyl) -1H-indol-3-yl] -propionic acid methyl ester 120: To a cooled (0 ° C) methyl ester solution indole-3-propionic acid 142 (0.110 g, 0.42 mmol) in DMF (3 ml) was added sodium hydride (60%); 0.030 g; 0.75 mmole) was added in one portion and stirred for 30 minutes followed by the addition of 4-methoxybenzenesulfonyl chloride (0.200 g, 1.0 mmoles). The reaction was allowed to warm to room temperature and was stirred for 16 hours, subjected to aqueous workup, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified by flash chromatography (silica gel: 85% n-hexane-15% ethyl acetate). to produce the methyl ester 120 as an oil (M-1 = 432.4). The methyl ester 120 was then taken for the generation of the product.

Step 4 - Preparation of 3- [5-Methoxy-1- (4-methoxy-benzenesulfonyl) -1H-indol-3-yl] -2,2-dimethyl-propionic acid 119: To a solution of methyl ester 120 in tetrahydrofuran (6 ml) an aqueous solution of potassium hydroxide (2 ml of 1 M) was added and stirred at room temperature for 5 hours. The acid 119 was isolated by neutralizing the reaction mixture with aqueous hydrochloric acid, extracting the product with ethyl acetate, drying over anhydrous magnesium sulfate, evaporating under reduced pressure, and purifying, using flash chromatography with 5% methanol in dichloromethane to produce a white solid (80 mg, 46% total, M-1 = 416.5).

Example 82: Synthesis of 3- [1- (3,4-dimethoxy-benzenesulfonyl) -5-m-ethoxy-1H-indol-3-yl] -propionic acid 101 3- [1- (3,4-Dimethoxybenzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 101 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 3,4-dimethoxybenzenesulfonyl chloride, (M-1 = 418.5).

Example 83: Synthesis of 3- [1- (3,4-Difluoro-benzenesulfonyl) -5-methoxy-1 H -indol-3-yl] -propionic acid 102 3- [1- (3,4-Difluorobenzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 102 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 3,4-difluorobenzenesulfonyl chloride, (M-1 = 395.3).

Example 84: Synthesis of 3- [1 - (3-chloro-4-methyl-benzenesulfonyl) -5-methoxy-1 H-indol-3-yl] -propionic acid 103 The 3- [1- (3-chloro-4-methyl) -5-methoxy-1H-indol-3-yl] -propionic acid 103 was prepared using the same protocol as in Example 3, substituting the 4-methoxybenzenesulfonyl with 3-chloro-4-methylbenzenesulfonyl chloride, (M-1 = 406.8).

Example 85: 3- [1- (Benzenesulfonyl) -5-fluoro-1 H-indol-3-yl] -propionic acid 104 3- [1 - (Benzenesulfonyl) -5-fluoro-1H-indol-3-yl] -propionic acid 104 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with benzenesulfonyl chloride , (M-1 = 346.5).

Example 86: Synthesis of 3- [1- (benzenesulfonyl) -5-methyl-1 H-indol-3-yl] -propionic acid 105 3- [1- (Benzenesulfonyl) -5-methyl-1H-indol-3-yl] -propionic acid 105 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with benzenesulfonyl chloride , (M-1 = 342.2).

Example 87: Synthesis of 3- [1- (benzenesulfonyl) -5-chloro-1 H-indol-3-yl] -propionic acid 106 H 3- [1- (Benzenesulfonyl) -5-chloro-1 H-indol-3-yl] -propionic acid 106 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with benzenesulfonyl chloride ., (M-1 = 362.7).

Example 88: Synthesis of 3- [1- (3-fluoro-4-methyl-benzenesulfonyl) -5-chloro-1 H -i ndol-3-H] -prop ionic acid 107 3- [1- (3-Fluoro-4-methyl-benzenesulfonyl) -5-chloro-1 H-indol-3-yl] -propionic acid 107 was prepared using the same protocol as in Example 3, substituting the chloride of 4-methoxybenzenesulfonyl with 3-fluoro-4-methyl-benzenesulfonyl chloride, (M-1 = 390.3).

Example 89: Synthesis of 3- [1- (2,3-Dihydro-benzofuran-5-sulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 108 The 3- [1- (2,3-Dihydro-benzofuran-5-sulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 108 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 2,3-Dihydro-benzofuran-5-sulfonyl chloride, (M-1 = 400.2).

Example 90: Synthesis of 3- [1- (4-ethyl-benzenesulfonyl) -5-ethoxy-1H-indol-3-yl] -propionic acid 109 3- [1- (4-Ethyl-benzenesulfonyl) -5-ethoxy-1H-indol-3-yl] -propionic acid 109 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 4-ethylbenzenesulfonyl chloride, (M-1 = 400.5).

Example 91: Synthesis of 3- [1- (4-methoxy-benzenesulfonyl) -5-ethoxy-1 H-indol-3-yl] -propionic acid 110 3- [1- (4-Methoxy-benzenesulfonyl) -5-ethoxy-1H-indol-3-yl] -propionic acid 110 was prepared using the same protocol as in Example 3, (M-1 = 402.6) .

Example 92: Synthesis of 3- [1- (3-trifluoromethoxy-benzenesulfonyl) -5-ethoxy-1 H-indol-3-yl] -propionic acid 111 3- [1- (3-Trifluoromethoxy-benzenesulfonyl) -5-ethoxy-1H-indol-3-yl] -propionic acid 111 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride for 3-trifluoromethoxy-benzenesulfonyl chloride, (M-1 = 456.3).

Example 93: Synthesis of 3- [1- (4-butyl-benzenesulfonyl) -5-ethoxy-1 H-indol-3-yl] -propionic acid 112 3- [1- (4-Butyl-benzenesulfonyl) -5-ethoxy-1H-indol-3-yl] -propionic acid 112 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 4-butyl-benzenesulfonyl chloride, (M-1 = 428.4).

Example 94: Synthesis of 3- [1- (4-butoxy-benzenesulfonyl) -5-ethoxy-1 H-indol-3-yl] -propionic acid 113 3- [1- (4-Butoxy-benzenesulfonyl) -5-ethoxy-1H-indol-3-yl] -propionic acid 113 was prepared using the same protocol as in Example 3, substituting 4-methoxy-benzenesulfonyl chloride with 4-butoxy-benzenesulfonyl chloride, (M-1 = 444.5).

Example 95: Synthesis of 3- [1- (3,4-dichloro-benzenesulfonyl) -5-ethoxy-1 H-indol-3-yl] -propionic acid 114 3- [1- (3,4-Dichloro-be-sulphonyl) -5-ethoxy-1H-indol-3-yl] -propionic acid 114 was prepared using the same protocol as in Example 3, replacing the -methoxybenzenesulfonyl with 3,4-dichloro-benzenesulfonyl chloride, (M-1 = 441.2).

Example 96: Synthesis of 3- [1- (3-methoxy-benzenesulfonyl) -5-ethoxy-1H-indol-3-yl] -propionic acid 115 3- [1- (3-Methoxy-benzenesulfonyl) -5-ethoxy-1H-indol-3-yl] -propionic acid 115 was prepared using the same protocol as in Example 3, substituting 4-methoxybenzenesulfonyl chloride with 3-methoxy-benzenesulfonyl chloride, (M-1 = 402.5).

Example 97: Synthesis of 3- [1- (4-phenoxy-benzenesulfonyl) -5-ethoxy-1 H-indol-3-yl] -propionic acid 116 The 3- [1- (4-phenoxy-benzenesulfonyl) -5-ethoxy-1H-indol-3-yl] -propionic acid 116 was prepared using the same protocol as in Example 3, substituting the 4-methoxybenzenesulfonyl chloride with 4-phenoxy-benzenesulfonyl chloride, (M-1 = 464.3), Example 98: Synthesis of 3- [1- (3,4-Dichloro-benzenesulfonyl) -5-m-ethoxy-1 H-indol-3-yl] -2,2-dimethyl-propionic acid methyl ester 122.

The methyl ester of 3- [1- (3,4-Dichloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -2,2-dimethyl-propionic acid 122 was prepared using the same protocol as in Example 3, step 3, substituting 4-methoxy-benzenesulfonyl chloride with 3,4-dichlorobenzenesulfonyl chloride, (M-1 = 457.2).

Example 99: Synthesis of 3- [1- (3,4-Dichloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -2,2-dimethyl-propionic acid 121 The methyl ester of 3- [1- (3,4-Dichloro-benzenesulfonyl) -5-methoxy-1Hyldol-3-yl] -2,2-d-methylpropionic acid 121 was prepared from methyl ester 122 corresponding, using the same protocol as in example 3, stage 4, (M + 1 = 469.2).

Example 100: Synthesis of (E) -3- [1- (3,4-Dichloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -acrylic acid The (E) -3- [1- (3,4-Dichloro-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -acrylic acid 123 was prepared using the same protocol as in Scheme 12, substituting 4-methoxybenzenesulfonyl chloride with 3,4-dichlorobenzenesulfonyl chloride in step 1, (M-1 = 425.2).

Example 101: Synthesis of (E) -3- [1- (4-Butyl-benzenesulfonyl) -5-ethoxy-1 H-indol-3-yl] -acrylic acid 124 2H The (E) -3- [1- (4-butyl-benzenesulfonyl) -5-ethoxy-1H-indol-3-yl] -acrylic acid 124 was prepared using the same protocol as in Scheme 12, substituting the 4-methoxybenzenesulfonyl with 4-butylbenzenesulfonyl chloride in step 1, (M-1 = 426.4).

Example 102: Synthesis of (E) -3- [1- (4-Butoxy-benzenesulfonyl) -5-ethoxy-1H-indol-3-yl] -acrylic acid N-sulphonyl) -5-ethoxy-1H-indol-3-yl] -acrylic 125 was prepared using the same protocol as in Scheme 12, substituting 4-methoxybenzenesulfonyl chloride with 4-butoxybenzenesulfonyl chloride in step 1, ( M-1 = 442.4).

Example 103: Synthesis of 3- [1- (3-Chloro-4-methoxy-benzenesulfonyl) -5-methoxy-1 H-indoi-3-yl] -propionic acid 126 3- [1- (3-Chloro-4-methoxy-benzenesulfonyl) -5-methoxy-1H-indol-3-yl] -propionic acid 126 was prepared using the same protocol as in scheme 12, substituting the chloride of 4-methoxybenzenesulfonyl, 3-chloro-4-methoxybenzenesulfonyl chloride in step 1, (M-1 = 423.0). The 3-chloro-4-methoxy-benzenesulfonyl chloride was prepared by reacting 2-chloroanisole with chlorosulfonic acid (almost at 0 ° C, 4 hours), following the literature procedure (Cremlyn, RJW, Hornby, R .; J. Chem. Soc. C; 1969; 1341-1345) Example 104: Synthesis of 3- [1- (4-Methoxy-benzenesulfonyl) -7-methyl-1H-indol-3-yl] -propionic acid Compound 127 is synthesized from 7-methyl-indole-3-carboxaldehyde following the synthetic steps shown in Scheme 12.

Example 105: Synthesis of 3- [1- (4-Methoxy-benzenesulfonyl) -6-methyl-1H-indol-3-yl] -propionic acid 128 Compound 128 is synthesized from commercially available 6-methyl-indole-3-carboxaldehyde following the synthetic steps shown in Scheme 12.

Example 106: Synthesis of 3- [1- (4-Methoxy-benzenesulfonyl) -6-fluoro-1 H-indol-3-yl] -propionic acid 129 Compound 129 is synthesized from commercially available 6-fluoro-indole-3-carboxaldehyde following the synthetic steps shown in Scheme 12.

Example 107: Synthesis of 3- [1- (4-methoxy-benzenesulfonyl) -7-fluoro-1 acid Compound 130 is synthesized from commercially available 7-fluoro-indole-3-carboxaIdehyde following the synthetic steps shown in Scheme 12.

Example 108: Synthesis of 3- [1- (4-methoxy-benzenesulfonyl) -4-chloro-7-fluoro-1 H-indol-3-yl] -propionic acid Compound 131 is synthesized from commercially available 4-chloro-7-fluoro-indole-3-carboxaldehyde following the synthetic steps shown in Scheme 12.

Example 109: Synthesis of 3- [1- (4-Methoxy-benzenesulfonyl) -6-methoxy-1 H-indol-3-yl] -propionic acid 132 Compound 132 is synthesized from 6-methoxy-indole-3-carboxaldehyde, which in turn is synthesized from commercially available 6-methoxy-indole using the Vilsmeier-Haack reaction (Advanced organic chemistry, Jerry March , 2pd Ed. P715), following synthetic steps shown in Scheme 12.

Example 110: Synthesis of 3- [1- (4-Methoxy-benzenesulfonyl) -5,6-dimethoxy-1 H-indol-3-yl] -propionic acid 133 Compound 133 is synthesized from 5,6-dimethoxy-indole-3-carboxaldehyde which in turn is synthesized from the 5,6-dimethoxy-indole commercially available using the Vilsmeier-Haack reaction (Advanced organic chemistry, Jerry March , 2nd Ed. P715), following the synthetic steps shown in Scheme 12.

Example 111: Synthesis of 3- [1- (4-Methoxy-benzenesulfonyl) -6-bromo-1H-indol-3-yl] -propionic acid 134 Compound 134 is synthesized from 6-bromo-indole-3- carboxaldehyde commercially available following the synthetic steps shown in Scheme 12.

Example 112: Synthesis of 3- [1- (4-Methoxy-benzenesulfonyl) -5-methoxy-1 H-indazol-3-yl] -propionic acid 135 Compound 135 is synthesized from commercially available 5-methoxy-indazole-3-carboxylic acid following the synthetic steps shown in Scheme 9.

Example 113: Synthesis of 3- [1- (4-Methoxy-benzenesulfonyl) -6-m-ethoxy-1 H-indazol-3-yl] -propionic acid Compound 136 is synthesized from commercially available 6-methoxy-indazole-3-carboxylic acid following the synthetic steps shown in Scheme 9.

Example 114: Synthesis of 3- [1- (4-Methoxy-benzenesulfonyl) -5-methoxy-1 H-7aza-indazol-3-yl] -propionic acid Compound 137 is synthesized from aldehyde 138, prepared from commercially available 7-azaindole as shown in Scheme 14, following the synthetic steps shown in Scheme 12.

Scheme 14 Compound 139, 5-bromo-7-azaindole was prepared from commercially available 7-azaindole following the procedure published by Mazeas, Daniel; Guillaumet, Gerald; Marie-Claude Viaud, Heterocycles, 1999, v50 (2), 1065-1080. Compound 140 is prepared by heating bromide 139 with sodium methoxide in dimethylformamide in the presence of cuprous bromide as described by Mazeas, Daniel; Guillaumet, Gerald; Marie-Claude Viaud, Heterocycles, 1999, v50 (2), 1065-1080, from which aldehyde 138 is prepared by Vilsmeier-Haack reaction.

Example 115: Synthesis of Analogs of Compound 1 Analogs of Compound I can be synthesized, for example, using the commercially available compounds shown in Table 3 as described in Example 3 or Example 109.

Synthesis of carboxylic acid bioisosters: The carboxylic acid functional group of the 3-position propionic acid moiety can be replaced with any of a number of carboxylic acid bioisosters in the compounds of Formula I. For example, the following portions can be used, which are shown with respect to Formula II, but which can also be incorporated into other systems of the bicyclic rings within Formula I. Thiazolidione (TZD) and related analogues: Step 1 Compound XX can be prepared through Knoevenagel coupling of thiazolidione or related compounds in the presence of an inert solvent, for example, ethanol, with a catalytic amount of piperidine with the starting compound III. (L. Sun. Et al, J. Med Chem., 1999, 42, 5120-30). Step 2: Compound XXI can be prepared from compound XX through a reduction process using palladium on activated carbon, or a metal reduction reaction (eg, magnesium). (B.C. Cantello, J. Med. Chem., 1994, 37, 3977-85). Hydroxamic acid: Scheme 15 Compound XXII can be prepared through any reaction of amide bond formation with the Ib or nucleophilic displacement of the ester II or IXa with n-hydroxyamine. (Hurd et al, J. Am. Chem. Soc, 1954, 76, 2791 and Dinh, T.Q., Tet. Lett., 1996, 37, 1161-4). Tetrazol: Scheme 16 The tetrazole isostere of the carboxylic acid can be prepared through 3 steps from the corresponding acetic or propanoic acid (depending on the size of the linker). Step 1: The conversion of the carboxylic acid portion to the corresponding amide XXIII with the compound Ia or Ib can be done with ammonia (gas) with ethyl polyphosphate in an inert solvent such as chloroform (Imamoto, T. ef al, Synthesis, 1983, 142-3). Step 2: Propionamide XXIII can be converted to nitrile XXIV by treating the amide with methylmagnesium iodide (Wilson et al., J. Chem Soc., 1923, 723, 2615) or with formic acid in acetonitrile (Heck, M.-P. , J. Org. Chem., 1996, 61, 6486-7). Step 3: The preparation of tetrazo isostere involves the coupling of the 2-cyano-alkyl group with sodium azide in a cyclization reaction to generate the desired compound XXV. (Juby et al, J. Med. Chem., 1969, 72, 396-401). Iso-oxazoles: Method 1: Compound XXVIII hydroxyisoxazole can be derived in 5 steps. When using the indole-3-acetic acid starting material XXVI, compound XXVII can be prepared through reactions in Example 4. Activation of the acidic group with bis-imidazole-carbonyl leads to compound XXVIII (Eils et al, Synthesis , 1999, 275-81). The reaction with ethylmalonic acid produces XXIX. Hydroxylamine cyclization provides the hydroxy-protected iso-oxazole XXX. The deprotection of the hydroxy functionality reaches the desired compound XXXI. (Frolund et al, J. Med. Chem., 2002, 45, 2454-2468).

Scheme 18 Method 2: Compound XXXI of hydroxyisoxazole can be derived in 4 steps. The first step involves the direct coupling of the indole V 3-unsubstituted with a halogen of hydroxy iso-oxazolmethyl (chloride or bromide) with a base (e.g., sodium hydroxide) in an alcohol solvent system (e.g., methanol ). (Sholtz ef al, Chem. Ver., 1913, 46, 2145) Subsequent removal of the methoxy group under reduced conditions and deprotection of the protection group and protection of the indole nitrogen leads to the desired compound XXXI. (Ester, T.A., et al, J. Org. Chem. 1983, 48, 2454-68) Scheme 19 Method 3: A synthetic method alternative to compound XXXI, starts with compound XXVII (prepared through the reduction of 3-acetic acid) to generate hydroxyimine XXXIV. The chlorination of XXXIV with chlorination reagents (eg, NCS) reaches intermediate XXXV. From hydroxy iminium chloride, an acetylene cyclization would produce the protected hydroxy iso-oxazole. Deprotection would provide the desired compound XXXI. (Weidner-Wells, M.A. ef al, Bioorg. &Med Chem. Lett., 2004, 74, 3069-72). Acyl cyanamide: Scheme 20 Compound XXXVIII can be prepared through a two-step process starting from either Ib. Step 1: The carboxylic acid group in Ib can be converted to acyl halide XXXVII through the use of reagents (for example, thionyl chloride, phosphorous pentachloride or phosphorous trichloride) in an inert solvent (for example, dichloromethane). (Cao, J. ef al, J. Med. Chem., 2003, 46, 2589-98 and Kitamura, M. et al, Synthesis, 2003, 245-26) Stage 2 The functionality of acyl cyanamide can be introduced through of the coupling of cyanamide with compound XXXVII to produce the desired product XXXVIII. (Belletire, J.L. ef al, Syn.Commun., 1988, 78, 2063-72). Sulfonamides: Scheme 21 The bio-isoster sulfonamide for the carboxylic acid can be prepared in 6 steps from indolyl-3-acetic acid or propionic acid (if the linker is to be extended). Steps 1 and 2: Compound XXVII can be transformed to alcohol XXXIX corresponding to through treatment with a reducing reagent such as lithium-aluminum hydride in an inert solvent such as THF. The corresponding alcohol can be converted to mesylate or halogen with the appropriate reagents such as methanesulfonyl chloride or phosphorous tribromide respectively. Step 3: The intermediate XL can be prepared by treating XXXIX with sodium acid sulphide, hexabutyldistanatin, or 1- (2-hydroxyethyl) -4,6-diphenylpyridin-2-thione to obtain ethentiol or propantiol. (Griugas et al, Tet Lett., 1990, 37, 1397-1400, Maercker et al, Justus Liebigs Ann. Chem., 1865, 736, 88, or Molina ef al, Tetrahedron Lett., 1985, 26469-472). Step 4: Thiol XL can be oxidized to the corresponding sulfonic acid with oxidative reagents such as acid peroxide to produce intermediate XLI. Step 5: Compound XL can be treated with the reagents (for example, thionyl chloride or phosphorous pentachloride) to convert the sulfonic acid to the corresponding sulfonyl chloride to reach the intermediate XLII. (Scheme 20, stage 1). Step 6: The isosteric sulfonamide of the carboxylic acid is then generated through the coupling of the sulfonyl chloride XLIIIa with the amine reagents (for example, sodium amide or methylamine). Acetyl sulfon amides: Scheme 22 The acetyl sulfonamides XLIV can be prepared through the sulfonyl chloride XLII in two steps: Step 1: The XLII compound is treated in ammonia or sodium amide to produce XLIIIb. Step 2: Compound XXXIIIb is then deprotonated and acetic anhydride is treated to arrive at acetyl sulfonamide XLIV.

General exemplary synthesis of compounds of Formula L, wherein W, Y and Z are independently N or CH; n = 0, 1 or 2.

Scheme 23a - Preparation of sulfonyl chloride XLVIII XLV XLVI1 XLVHI Step 1 - Preparation of intermediate XLVII: Commercially available 4-hydroxybenzenesulfonic acid XLV can be reacted with aryl halides, for example, iodobenzene benzyl bromide, etc., under Buckwald reaction conditions and SN2 reaction conditions respectively, or with alcohols, for example , benzylic alcohols under Mitsunobu reaction conditions, or other coupling reactions to produce XLVII. Step 2: Preparation of intermediate XLVIII: The compound of formula XLVII can be converted to the corresponding sulfonyl chloride with reagents such as PCI3 > PCI5, POCI3 or SOCI2.

Scheme 23b - Preparation of the Compound of the Formula L The compound of the formula L can be prepared by reacting the sulfonyl chloride XLVIII with the 5-methoxy-indole-3-propionic ester in the presence of a base, for example, aqueous potassium hydroxide in THF.

Example 116: Synthesis of acid 3-. { 5-Methoxy-1- [4- (pyridin-3-yloxy) -benzenesulfonyl] -1H-indol-3-yl} -propionic 143. 143 Compound 143 can be prepared by methods described in Scheme 23, using 4-hydroxybenzenesulfonic acid and 3-hydroxypridine to prepare the corresponding sulfonyl chloride. The different couplings of the sulfonyl chloride to the 5-methoxy-indole-3-propionic ester of the corresponding acid as described in Scheme 7, 10 or 12.

Example 117: Synthesis of the acid 3-. { 5-Methoxy- [4- (pyridin-4-yloxy) -benzenesulfonyl] -1H-indol-3-yl} -propionic 144.

Compound 144 can be prepared by methods described in Scheme 23, using 4-hydroxybenzenesulfonic acid and 4-hydroxypyridine to prepare the corresponding sulfonyl chloride. The different coupling of the sulfonyl chloride to the 5-methoxy-indole-3-propionic ester or the corresponding acid as described in Scheme 7, 10 or 12.

Example 118: Synthesis of the acid 3-. { 5-Methoxy-1- [4- (pyridin-4-i-methoxy) -benzenesulfonyl] -1H-indol-3-yl} -propionic 145.

Compound 145 can be prepared by methods described in Scheme 23, using 4-hydroxybenzenesulfonic acid and 4-pyridylcarbinol to prepare the corresponding sulfonyl chloride. The different coupling of the sulfonyl chloride to the 5-metho? I-indo! -3-propionic ester or the corresponding acid as described in Scheme 7, 10 or 12.

Example 119: Synthesis of 3- [1- (3,4-Dichloro-benzenesulfonyl) -5-m-ethoxy-1H-indol-3-yl] -propionic acid 146.

Compound 146 can be prepared by reacting the 5-methoxy-indole-3-propionic ester or the corresponding acid by the methods with the 3,5-dichlorobenzenesulfonyl chloride as described in Scheme 7, 10 or 12.

Example 120: Synthesis of 3- [1- (3,5-dimethoxy-benzenesulfonyl) -5-m-ethoxy-1H-indol-3-yl] -propionic acid 147 147 Compound 147 can be prepared by reacting the 5-methoxy-indole-3-propionic ester or the corresponding acid through the methods with 3,5-dimethoxybenzenesulfonyl chloride as described in Scheme 7, 10 or 12. General Synthesis of the compounds of the formula LIV and LV Scheme 24 Step - 1 Step 1: Preparation of intermediate Lll Compound Lll can be prepared through the coupling of indole (2 or 4) with sulfonyl chloride Ll from the methodologies described in Scheme 7 or 12. Step 2: Preparation of compound LIV or LV Compound L1V or LV can be prepared through the nucleophilic displacement of the bromomethyl group under basic conditions, in an inert solvent such as DMF. Example 121: Synthesis of the acid 3-. { 5-Methoxy-1- [4- (quinolin-7-ylaminomethyl) -benzenesulfonyl] -1H-indol-3-yl} -propionic 148 148 Compound 148 can be prepared by coupling compound Lll with the corresponding quinol-7-ylamine with the bromomethyl portion in Scheme 24.

Example 122: Synthesis of the acid 3-. { 1- [4- (lsoquinolin-3-ylaminomethyl) -benzenesulfonyl] -5-methoxy-1H-indol-3-yl} -propionic 149 Compound 149 can be prepared by coupling compound Lll with the corresponding isoquinolin-3-ylamine with the bromomethyl portion in Scheme 24.

Example 123: Synthesis of acid 3-. { 5-Methoxy-1- [4- (quinolin-6-ylaminomethyl) -benzenesulfonyl] -1H-indol-3-yl} -propionic 150 150 Compound 149 can be prepared by coupling compound Lll with the corresponding quinolin-6-ylamine with the bromomethyl portion in Scheme 24.

Example 124: Synthesis of 3- [5-Methoxy-1- (4-pyrrolo [2,3-b] pyridin-1-ylmethyl-benzenesulfonyl) -1H-indol-3-yl] -propionic acid 151 Compound 151 can be prepared by coupling compound Lll with the corresponding 7-azaindole with the bromomethyl portion in Scheme 24.

Example 125: Synthesis of 3- [5-Methoxy-1- (4-phenoxymethyl-benzenesulfonyl) -1H-indol-3-yl] propionic acid 152 152 Compound 152 can be prepared through compound Lll with the corresponding phenol with the bromomethyl portion in Scheme 24.

General synthesis of compounds of the formula LIX, LX or LXI Step 1: Preparation of the intermediate LVII: The intermediate LVII can be prepared by any similar methods as those described in step 1 of preparation of XLVII, or through the nucleophilic displacement of a fluoro group. Step 2: Preparation of intermediate LVIII: The sulfonic acid can be converted to the corresponding sulfonyl chloride with PCI3, PQCI3, PCI5 or SOCI2. Step 3: Preparation of the LIX intermediate: The sulfonyl chloride LVIII can be coupled to the indole 4 intermediates to reach LIX. Step 4: Preparation of the compound LX and LXI The nitrile portion can be further converted to any amide through hydrolysis or amine through reduction.

Example 126: Synthesis of acid 3-. { 5-Methoxy-1- [4- (pyridin-3-ylmethoxy) -benzenesulfonyl] -1 H-ind or l-3-yl} -prop ion 153 Compound 153 can be prepared by methods described in Scheme 23, using 4-hydroxybenzenesulfonic acid and 3-pyridinemethanol to prepare the corresponding sulfonyl chloride. The various couplings of the sulfonyl chloride to the indole portion are described in Scheme 7, 10, or 12.

Example 127: Synthesis of acid 3-. { 1- [4- (4-Aminomethyl-benzyloxy) -benzenesulfonyl] -5-methoxy-1 H-indol-3-yl} -propionic 154 The compound 154 can be prepared through the reduction of the nitrile group, as described in Scheme 25. The functionality of the nitrile can be prepared through the coupling of the sulfonyl chloride with the methylester of 5-methoxyindole-3-propionic acid. The sulfonyl chloride can be prepared through the coupling of 4-hydroxy-benzenesulfonyl acid with 4-cyanobenzyl bromide.

Example 128: Synthesis of acid 3-. { 1- [4- (4-Carbamoyl-benzyloxy) -benzenesulfonyl] -5-methoxy-1 H-indol-3-yl} - propionic 155 155 Compound 155 can be prepared through hydrolysis of the nitrile moiety as described in Scheme 25. The nitrile functionality can be prepared through coupling of the sulfonyl chloride with the methylester of 5-methoxyindole-3-propionic acid. The sulfonyl chloride can be prepared through the coupling of 4-hydroxy-benzenesulfonic acid with 5-cyanobenzyl bromide.

Example 129: Synthesis of compound 162: Scheme 26 Step 1: Preparation of 5-Methoxy-1 H-pyrrole [3,2-bjpyridine 160 The title compound can be prepared by: 1. The reductive cyclization with 158 (M. Mieczyslaw et al., Liebigs Ann. Chem. 1988, 203-208, D. Mazeas et al., Heterocycles, 1999, 50, 1065-80). 2. Reduction through hydrogenation and catalytic cyclization under reflux conditions with C-tert-butoxy-tetra-N-methyl-methanediamine 157 (K-H, Buchheti et al, J. Med. Chem., 1995, 2331-2338). 3. Reductive cyclization with 159 (SA Filia et al, J. Med. Chem., 2003, 46, 3060-71) Step 2. Preparation of 5-Methoxy-1 H-pyrrolo [3,2-b] pyridin-3 -carbaldehyde 161 Intermediate 161 can be prepared either through Vilsmeier reaction (KH Buchheit et al, J. Med. Chem., 1995, 2331-2338) or with 1, 3,5,7-tetraaza-adamantane (D Mazeas et al., Heterocycles, 1999, 50, 1065-80). Subsequent conversion to introduce the side chain of propionic acid and sulfonamide can be achieved using methodologies as described in Scheme 7 or 12.

Example 130: Synthesis of! compound 166: Scheme 27 Step 1: Preparation of intermediate 164, 5-Methoxy-1H-pyrrolo [2, 3-c] pyridine: 5-Methoxy-1H-pyrrolo [2,3-c] pyridine 164 can be prepared by cyclization of the -methoxy-4-trimethylsilanylethynyl-pyridin-3-ylamine 163 with coprosodium iodide in DMF (D. Mazeas et al., Heterocycles, 1999, 50, 1065-80). Step 2. Preparation of intermediate 165, 5-Methoxy-1 H-pyrrolo [2,3-c] pyridine-3-carbaldehyde: 5-Methoxy-1 H-pyrrolo [2,3-c] pyridine-3 can be prepared -carbaldehyde from 165 using with 1, 3,5,7-tetraaza-adamantane under reflux conditions with DMF (D. Mazeas et al., Heterocycles, 1999, 50, 1065-80). The subsequent conversion to introduce the side chain of the propi 'acid. { One and the sulfonamide can be achieved using methodologies as described in Scheme 7 or 12.

Example 131: Synthesis of compound 172 Scheme 28 Step 1: Preparation of 168, 6-chloro-2,3-dihydro-1 H ~ pyrrolo [3,2-c] pyridine: 1, 2,3,5-tetrahydro-pyrrolo [3,2-c] pyridine -6-one 167 can be converted to 6-chloro-2,3-dihydro-1 H-pyrrolo [3,2-c] pyridine 168 with phosphorous oxychloride (NN Bychikhina et al., Chem. Heterocycl. 1982, 18, 356-360). Step 2: Preparation of 169, 6-Methoxy-2,3-dihydro-1H-pyrrolo [3,2-c] pyridine: 6-Methoxy-2,3-dihydro-1 H-pyrrolo [3, 2-cjpyridine 169 through direct displacement of the chloro group in 168 with sodium methoxide (VQ Azimov et., Chem. Heterocycl. Compd. 1981, 17m, 1648-1653). Step 3: Preparation of 170, 6-Methoxy-1 H-pyrrolo [3,2-cypyridine: The 6-methoxy-2,3-dihydro-1 H-pyrrolo [3,2-cjpyridine 169 to the corresponding 170 is oxidized with the use of MnO2. (V.A. Azimov et al., Chem. Heterocycl, Compd 1981, 17, 1648-1653). Step 4: Preparation of 171, 6-Methoxy-1 H -pyrrolo [3,2-c] pyrid i n-3-carb aldehyde: Prepare 6-Methoxy-1 H-pyrrolo [3,2-c] pyridine-3-carbaldehyde through Vilsmeier conditions with 170. (NN bychikhina et al., Chem. Heterocycl., Compass., 1982, 18, 356-360) Subsequent conversion to introduce the side chain of propionic acid and sulfonamide can be achieved using methodologies as described in Scheme 7 or 12.

Scheme 132: Synthesis of compound 181 Scheme 29 Stage 1: preparation of 175 The 2-chloro-7H-pyrrolo [2,3-d] pyrimidine can be prepared 175 from 2-chloro-5- (2-ethoxy-vinyl) -pyrimidin-4-ylamine 173 or 2-chloro-5- (2,2-dimethoxy-ethyl) -pyrimidin-4-ylamine 174 (low reflux conditions in methanol with concentrated hydrochloric acid (M. Cheung et al, Tet Lett., 2001, 42, 999-1002) Step 2: Preparation of 176 The 2-chloro group in 2-chloro-7H-pyrrolo [ 2,3-d] pyrimidine 176 can be converted to the corresponding methoxy moiety 176 through the nucleophilic displacement of the chloro group by sodium methoxide (f., Seela et al., Liebigs Ann. Chem. 1985, 312-320). 3: Preparation of 177 Intermediate 177 can be prepared from 176 through iodination of 176 with iodine, based on N, N-dimethylformamide at room temperature (T., Sakamoto, Takao et al., J. Chem. Soc. Perkin Trans. 1, 1996; 459-464) Step 4: Preparation of 178 The protection of pyrrolopyrimidine 177 with 4-methoxybenzenesulfonyl chloride can be achieved through a bi-phasic preparation using solution d and aqueous sodium hydroxide or with sodium hydride in DMF. Step 5: Preparation of 179 The functionality of 3-carboxylic acid can be prepared through deprotonation with a grignard reaction, followed by the addition of CO2 and acidification to produce the desired intermediate from 177. (Y. Kondo, et. to Heterocycles, 1996, 42, 205-8). Subsequent conversion to introduce the side chain of propionic acid and sulfonamide can be achieved using methodologies as described in Scheme 9 Example 133: Synthesis of compound 190 Scheme 30 Step 1: Synthesis of intermediate 184 Intermediate 184 can be prepared from 3-acetyl-2-chloropyridine, by cyclization with methylhirazine. (B.M. Lynch et al., Canadian Journal of Chemistry, 1988, 66, 420-8). Step 2: Synthesis of intermediate 185 Intermediate 185 is prepared by nitration of position 5 with nitric acid and sulfuric acid. (BM Lynch et al., Canadian Journal of Chemistry, 1988, 66, 420-8) Step 3: Synthesis of intermediate 186 The nitro group is reduced to the corresponding amine group through the use of reagents such as palladium on activated carbon . (B.M. Lynch et al., Canadian Journal of Chemistry, 1988, 66, 420-8). Step 4: Synthesis of the intermediate 187 The amino group is then converted to the diazonium salt with sodium nitrate and concentrated hydrochloric acid. The diazonium ion is then quenched with methanol to produce the corresponding methoxy functionality. (B.M. Lynch et al., Canadian Journal of Chemistry, 1988, 66, 420-8). Step 5: Synthesis of the intermediate 188 The 3-methyl group is oxidized through the oxidation KMnO 4 to the carboxylic acid. (B.M. Lynch et al., Canadian Journal of Chemistry, 1988, 66, 420-8). Subsequent conversion to introduce the side chain of propionic acid and sulfonamide can be achieved using methodologies as described in Scheme 9 to arrive at the desired compound 190.

Example 134: Crystallization and Crystal Structures of PPARs The PPARa, PPARd and PPAR? they have been each crystallized and the crystal structures determined and reported. Such structures and atomic coordinates are available in Protein Data Bank (PDB) (available on the Internet on the Web where the rest of the following www address is rcsb.org.). For atomic coordinates deposited in PPARa are available under PDB code 1KKQ, Xu, 2001, Nature 415, p813; for PPARd under code 1GWX, Xu, 1999, Mol Cell, 3, p397; and for PPAR? under code 1PRG, Notle, et al, 1998, Nature, 395, p137. (Each of the references cited together with the PPAR structures is therefore incorporated for reference in its entirety). Additional atomic coordinated repositories are available, where the PDB codes of the deposited structures are: 1K7L, 1I7G and 1KKQ for PPARalfa, 1PRG, 2PRg, 3PRg, 4PRG, 1K74, 1FM6, 1FM9, 1171, and 1KNU for PPARgama, 1GWX, 2GWX and 3GWX for PPARdelta. In addition, high quality crystals of PPARs can be obtained by crystallization under conditions as described below. The structures can then be obtained easily using published structures as references. The sequences encoding the individual PPARs can be easily obtained. The sequences that encode the individual PPARs were obtained from the NCBI LocusLinks (on the Web the rest of the following www address is ncbi.nih.gov/LocusLink). The sequence access numbers: NM_005036 (cDNA sequence for PPARa), NP_005027 (protein sequence for PPARa), NM_015869 (cDNA sequence for the PPARg 2 isoform), NP_05693 (protein sequence for PPARg 2 isoform), NM_006238 ( cDNA sequence for PPARd), and NP_006229 (protein sequence for PPARd). By using these sequences, the coding sequences can be isolated from a cDNA library using conventional cloning techniques. The PPAR proteins can then be expressed and purified by conventional methods. In the present case, the PPAR polypeptides were obtained by PCR from the cDNA library (Invitrogen) and sub-cloned to obtain constructs for expression. Those sequences provided in this way are expressed as PPAr polypeptides for crystallization. In addition to the published conditions for the crystallization of each of the PPARs, the following crystallization conditions have been used to produce co-crystals from each of the PPAR ligand binding domains with compounds of Formula I. Particular ligand binding used for PPARalpha: GenBank Access: NP_005027 (protein sequence) and NM_005036 (mRNA sequence), ligand binding domain; residues 196-468 amino acids. For PPARgamma the ligand binding domain used corresponds to residues 174_475 of amino acids from the GenBank access: NP_005028 (protein sequence) and NM_005037 (mRNA sequence). For PPARdelta, the ligand binding domain used corresponds to amino acids 165-441 of the GenBank access: NP_006299 (protein sequence) and NM_006238 (mRNA sequence). Exemplary Crystallization Conditions for PPARgamma: 1. with 2x molar excess of SRC-1 and 1mM compound 0.2M of ammonium acetate, 0.1M of Bistris, pH 6.5, 13-25% of PEG4k, or 0.2M of ammonium acetate , 0.1M Hepes, pH 7.5, 13-25% PEG4k 2. with compound 0.3-1 mM 12-22% PEG 8k, 0.2 mM Na acetate, 0.1 M hepes pH 7.5; or 0.6 M - 1.0 M Na Citrate, 0.1 M Hepes pH 7.5; or 0.9-1.4M Ammonium Sulfate, 0.1 M Hepes pH 7.5 Crystallization conditions for PPARalpha: 1. with 2x molar excess of SRC-1 and the compound 1mM 9-30% PEG 4K, 0.2M Ammonium Acetate, 0.1M Citrate, pH 5.6; or 17-30% PEG4k, 0.2 M Lithium Sulfate, 0.1M Tris / HCl, pH 8.5; or 22-30% PEG4k, 0.2 M Na Acetate, 0.1M Tris / Hcl, pH 8.5 2. with the co-concentrated compound 0.6-1.0M Lithium Sulfate, 0.1M Tris / Hcl pH 8.5 Conditions of crystallization for PPARdelta: 1. with 2x molar excess of SRC-1 and the co-concentrated compound 0.2-1.2M of Tartrate and KNa, 2.5% 1, 2-Propanediol, 0.1M Month pH 5.5-6.5 The diffraction data of X-rays from such co-crystals were then harvested from the synchrotron radiation facilities. The high resolution usable diffraction data were such as 1.9A-3.0A, preferably 2.5a or higher, more preferably 2.2A or higher, more preferably 2.0A or higher. The three-dimensional structures of the proteins were determined with the co-crystal diffraction data by the molecular replacement method using the published structures as a starting search model. The molecular replacement solutions of the protein structures were then retined and used to calculate Fourier difference maps. The different Fourier maps provide the basis for the determination of the binding geometry of the compound. The orientation of the compound and structure within the ligand-binding site of proteins were determined based on the information obtained from the co-crystal diffraction data. A person experienced in this technique will be able to interpret the X-ray diffraction data according to the structures of the compound that were involved in the co-crystallization experiments. Aqueous molecules that bind tightly to proteins are an integral part of protein structures. These can also be critical mediators of protein ligand interactions. Such aqueous molecules are called "structural water". The structural aqueous molecules are constructed in the structural model based on Fourier difference maps through the iterative refinement process. Compound-protein complex structures that include structural aqueous molecules were refined against co-crystal diffraction data using computational crystallography methods in an iterative manner to produce the exact atomic coordinates for additional ligand design processes.

Example 135: Exemplary Compounds of Formula I.

The structures, names, U PAC, and molecular weights for exemplified synthesized compounds of Structure I are shown below in Table 1. TABLE 1 ? » ? > , to 113 114 115 116 The agonist activities for the exemplary compounds to be determined from Table 1 were determined and are shown in Table 2, where "+" indicates the activity < .10 μM and "_" indicates > 10 μM. These activities were determined as described in Example 1. Table 2 Table 3 STRUCTURE MOL molecular weight NAME MOL 251,284 5-BENCILOXI1NDOL-3- CARBOXALDEHIDO 159. 187 4-METHYLINDOL-3-ALDEHYDE H_C H? " H, C Additional exemplary compounds of Formula I are described in Table 4. Table 4 describes exemplary compounds specifying substituents for each of the bicyclic cores shown in the Summary herein, except substituents on a nitrogen are excluded (N) in the 6-membered ring, and the 6-membered ring is included includes at least one alkoxy or thioether substituent in the 5 or 6 position. Thus, for example, for a bicyclic core that includes an N in at position 5, only those combinations of the substituent that do not have a substituent at the 5-position and have an alkoxy or thioether at the 6-position are applied to that bicyclic core. When no substituent is specified for a ring position, it will be understood that no substituent exists if the ring atom in that position is an N, and as H if the ring atom in that position is a carbon (C). All compounds include a linker -CH2CH2- in the 3-position; the specification of substituent 3 in Table 4 and in this way the portion binds to that linker. The numbering of the ring atoms as referenced herein, including in Table 4, is shown in the following structure. This structure includes the structure of the indolyl ring, but as used herein, the numbering for the other bicyclic structures that use the same numbering for corresponding atoms. In addition, this structure shows the substituents of position 1 referenced in Table 4, wherein L is a linker group attached to the bicyclic core, Ar is an aromatic group (i.e., aryl or heteroaryl), and A refers to a substituent or substituents in that aromatic group.

Table 4 With reference to the compounds described in Table 4 (and for each of the bicyclic cores), additional compounds are described for each of the substituent combinations herein, wherein the substituent shown in Table 4 in the position 5 is in place of an aryl group; a heteroaryl group; a monocyclic aryl group; a monocyclic heteroaryl group; a bicyclic aryl group; a heteroaryl group; a substituted aryl group, a heteroaryl group; a pyridinyl group; a pyrimidinyl group; a pyrazinyl group; a pyrrolyl group; a thiophenyl group. With reference to the compounds described in Table 4 and the preceding paragraph, additional compounds are described wherein L is CH2. With reference to the compounds described in Table 4 and the two preceding paragraphs, the additional compounds are described wherein the A portion is an acyl sulfonamide (-C (= 0) -N-SO 2 CH 3). All patents and other references cited in the specification are indicative of the level of experience of those skilled in the art to which the invention pertains, and are incorporated for reference in their totalities, including any tables and figures, to the same extent as if each reference would have been incorporated for reference in its entirety individually. One skilled in the art will readily appreciate that the present invention is well suited to obtain the ends and advantages mentioned, as well as those inherent herein. The methods, variations and compositions described herein as representative shortly of the preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes in the present and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims. It will be readily apparent to one skilled in the art that variable substitutions and modifications can be made to the invention described herein without departing from the scope and spirit of the invention. For example, variations can be made to exemplary compounds of Formula I to provide additional active compounds. Thus, such additional embodiments are within the scope of the present invention and the following claims. The invention described illustratively herein may be practiced in an adequate manner in the absence of any element or elements, limitation or limitations not specifically described herein. Thus, for example, in each case herein, any of the terms "comprising" "consisting essentially" and "consisting of" may be replaced with any of the other two terms. The terms and expressions that have been used are used as terms of description and not limitation, and there is no intention other than in the use of such terms and expressions to exclude any equivalents of the characteristics shown and described or portions thereof, but recognizes that several modifications are possible within the scope of the claimed invention. Thus, it should be understood that although the present invention has been specifically described by the preferred embodiments and optional features, the modification and variation of the concepts described herein may be assisted 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. In addition, when describing features and aspects of the invention in terms of the Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is therefore also described in terms of any individual member or subgroup of group members. Markush or another group. Also, unless otherwise indicated, when the various numerical values are provided for the modalities, the additional modalities are described by taking any of the 2 different values as the end points of a range. Such ranges are within the scope of the described invention. Thus, additional embodiments are within the scope of the invention and within the following claims.

Claims

CLAIMS 1. A compound that has the chemical structure of Formula I, particularly Formula I characterized in that: U, V, W, X and Y are independently N or CR 8, wherein there are no more than 4 nitrogens in the bicyclic ring structure shown in Formula I, and there are no more than 2 nitrogens in any of the rings of the structure of the bicyclic ring; R1 is a carboxyl group or ester thereof or an isostere of the carboxylic acid; R2 is hydrogen, optionally substituted lower alkyl, -CH2-CR12 = CR13R14, -CH2-C = CR15, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C ( Z) NR 10 R 11, -C (Z) R 20, -S (O) 2 NR 10 R 11; or -S (O) 2R21; R6 and R7 are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl, or R6 and R7 combine to form a ring system of or 6 mono-carbocyclic or mono-heterocyclic members; R8 is hydrogen, halo, optionally substituted lower alkyl, -CH2-CR12 = CR13R14, optionally substituted cycloalkyl, • CH2-C = optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, - OR 9, -SR 9, -NR 10 R 11, -C (Z) NR 10 R 1 -C (Z) R 20, -S (O) 2 NR 10 R 11 or -S (O) 2 R 21; R9 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl; R10 and R11 are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl or R10 and R11 combine to form a ring system of 5 or 6 mono-carbocyclic or mono-heterocyclic members; R12, R13, R14 and R5 are independently optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl; R20 is optionally substituted monofluoroalkyl, trifluoromethyl, optionally substituted difluoroalkyl, -CH2CR12 = CR13R14, -CH2-C = CR15, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl; R21 is optionally substituted lower alkoxy, -CH2CR12 = CR13R14, -CH2C = CR15, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl; Z is O or S; and n = 0, 1 or 2, wherein the compound is different from 3- (5-methoxy-1-p-toluenesulfonylindol-3-yl) propionic acid and 1- (2,4,6-triisopropylphenylsulfonyl) indole- 3-propionic.
2. The compound according to claim 1, characterized in that the compound has a structure of Formula 1-1, particularly Formula 1-1 wherein: X and Y are independently N or CR8; wherein R8 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR9, -SR9, -NR10R11, -C (Z) NR10R11 , -C (Z) R20, -S (O) 2NR10R11 or -S (O2) R21; each of U, V and W is CR8; wherein R8 at position 4 is R5; R8 at position 5 is R4; R8 at position 6 is R3; R2 is -S (O) 2R21; R3, R4 and R5 are independently hydrogen, halo, optionally substituted lower alkyl, -CH2CR12 = CR13R14, -CH2-C = CR15, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, heteroaralkyl optionally substituted, OR9, -SR9, -NR10R11, -C (Z) NR10R11, -C (Z) R20, -S (O) 2NR 0R11 or -S (O2) R21; R6 and R7 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and n = 1.
3. The compound according to claim 1, characterized in that R2 is SO2R21 and R21 is optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl.
The compound according to claim 3, characterized in that R21 is selected from the group consisting of substituted aryl, optionally substituted aralkyl, substituted heteroaryl or optionally substituted heteroaralkyl, wherein said substitution in R21 is 1 to 3 groups or substituents independently selected from the group consisting of halo, hydroxyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, optionally substituted aryl, aryloxy, heterocycle, optionally substituted heteroaryl, nitro, cyano, thiol, sulfamido, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono or disubstituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, optionally N-mono or N, N-disubstituted aminosulfonyl with alkyl, aryl or heteroaryl groups , alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbon ilamino, arylcarbonylamino, heteroarylcarbonylamino.
The compound according to claim 3, characterized in that R21 is selected from the group consisting of substituted aryl, optionally substituted aralkyl, substituted heteroaryl or optionally substituted heteroaralkyl, wherein said substitution at R21 is 1 to 3 independently selected groups or substituents of the group consisting of halo, hydroxyl, lower alkoxy, alkylthio, amino, amido and carboxyl.
6. The compound according to claim 1, characterized in that the compound has a structure of the Formula le, particularly: Formula where: each of U, V, W, X and Y is CR8; wherein R8 at position 5 is R4; R8 at positions 2, 4, 6 and 7 is H; R4 is hydrogen, halo, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, OR9, -SR9, -NR10R11, -C (Z) NR10R11, -C (Z) R20, -S (O) 2 NR 10 R 11 or -S (O 2) R 21; R24 is H, halo, optionally substituted alkyl, optionally substituted alkoxy or optionally substituted aryloxy, or optionally substituted aralkoxy; R25 is H, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, or R24 and R25 together form a ring combined with the phenyl ring.
7. The compound according to claim 6, characterized in that R 4 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, or -OR 9, wherein R 9 is optionally substituted lower alkyl, aryl optionally substituted or optionally substituted heteroaryl.
8. The compound according to claim 6, characterized in that R4 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, or -OR 9, wherein R 9 is optionally substituted lower alkyl.
9. The compound according to claim 6, characterized in that R4 is -OR9, wherein R9 is optionally substituted lower alkyl and R24 and R25 are chloro.
The compound according to claim 6, characterized in that R 4 is -OR 9, wherein R 9 is optionally substituted lower alkyl, and R 24 and R 25 are fluorine.
11. The compound according to claim 6, characterized in that R4 is -OR9, wherein R9 is optionally substituted lower alkyl, and R24 is alkoxy.
12. The compound according to claim 6, characterized in that R4 is -OR9, wherein R9 is optionally substituted lower alkyl and R24 is alkyl.
13. The compound according to claim 6, characterized in that R24 or R25 are both ethyl, propyl, butyl or pentyl.
14. The compound according to claim 6, characterized in that R4 is methoxy or ethoxy and R24 and R25 are chloro.
15. The compound in accordance with the claim 6, characterized in that R4 is methoxy or ethoxy and R24 is alkoxy.
16. The compound according to claim 6, characterized in that R4 is methoxy or ethoxy and R24 is alkyl.
17. The compound according to claim 6, characterized in that R24 and R25 are not both alkyl.
18. The compound according to claim 2, characterized in that Y and X are CH; R21 is optionally substituted heteroaryl, or optionally substituted heteroaralkyl; R3, R5, R6 and R7 are H and n = 1.
19. The compound according to the claim 18, characterized in that R21 is optionally substituted heteroaryl.
20. The compound according to the claim 19, characterized in that said optionally substituted heteroaryl is substituted with groups of 1 to 3 substituents selected from the group consisting of halo, lower alkyl, lower alkoxy, or said substituent groups together form a ring fused to said heteroaryl.
21. The compound according to claim 1, characterized in that said compound is a compound of the Formula la, Ib, le, Id, X or XIV.
22. A pharmaceutical composition, characterized in that: a compound has the chemical structure according to claim 1 and a pharmaceutically acceptable carrier.
23. The pharmaceutical composition according to claim 22, characterized in that R2 is SO2R21 and R21 is optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl.
The pharmaceutical composition according to claim 23, characterized in that R21 is selected from the group consisting of substituted aryl, optionally substituted aralkyl, substituted heteroaryl or optionally substituted heteroaralkyl, wherein said substitution at R21 is 1 to 3 groups or substituents independently selected from the group consisting of halo, hydroxyl, lower alkyl, lower alkoxy; alkylthio, acetylene, amino, amido, carboxyl, optionally substituted aryl, aryloxy, heterocycle, optionally substituted heteroaryl, nitro, cyano, thiol, sulfamido, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono or disubstituted with alkyl, aryl groups or heteroaryl, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, optionally N-mono or N, N-disubstituted aminosulfonyl with alkyl, aryl or heteroaryl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino groups .
The pharmaceutical composition according to claim 23, characterized in that R21 is selected from the group consisting of substituted aryl, optionally substituted aralkyl, substituted heteroaryl, or optionally substituted heteroaralkyl, wherein said substitution at R21 is 1 to 3 groups or substituents independently selected from the group consisting of halo, hydroxyl, lower alkyl, lower alkoxy, alkylthio, amino, amido and carboxyl.
26. The pharmaceutical composition according to claim 22, characterized in that said compound has a structure of the Formula le, particularly: Formula where: each of U, V, W, X and Y is CR8; wherein R8 at position 5 is R4; R8 at positions 2, 4, 6 and 7 is H; R 4 is optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or halo; R24 is H, halo, optionally substituted alkyl, optionally substituted alkoxy or optionally substituted aryloxy, or optionally substituted aralkoxy; R25 is H, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, or R24 and R25 together form a ring fused to the phenyl ring.
27. The pharmaceutical composition according to claim 26, characterized in that R4 is -OR9, wherein R9 is optionally substituted lower alkyl and R24 and R25 are chloro.
28. The pharmaceutical composition according to claim 26, characterized in that R4 is -OR9, wherein R9 is optionally substituted lower alkyl and R24 and R25 are fluorine.
29. The pharmaceutical composition according to claim 26, characterized in that R4 is -OR9, wherein R9 is optionally substituted lower alkyl and R24 is alkoxy.
30. The pharmaceutical composition according to claim 26, characterized in that R4 is -OR9, wherein R9 is optionally substituted lower alkyl and R24 is alkyl.
31. The pharmaceutical composition according to claim 26, characterized in that R24 or R25 or both are methyl, ethyl, propyl, butyl or pentyl.
32. The pharmaceutical composition according to claim 26, characterized in that R4 is methoxy or ethoxy and R24 and R25 are chloro.
33. The pharmaceutical composition according to claim 26, characterized in that R4 is methoxy or ethoxy and R24 is alkoxy.
34. The pharmaceutical composition according to claim 26, characterized in that R4 is methoxy or ethoxy and R24 is alkyl.
35. The pharmaceutical composition according to claim 26, characterized in that R24 and R25 are not both alkyl.
36. The pharmaceutical composition according to claim 22, characterized in that: Y and X are CH; R2 is -S (O) 2R21; R21 is optionally substituted heteroaryl, or optionally substituted heteroaralkyl; R6 and R7 are H; R8 at positions 4 and 6 is H and n = 1.
37. The compound according to claim 36, characterized in that R21 is optionally substituted heteroaryl.
38. The pharmaceutical composition according to claim 37, characterized in that said optionally substituted heteroaryl is substituted with 1-3 substituent groups selected from the group consisting of halo, lower alkyl, lower alkoxy, or said substituent groups together form a ring fused to said heteroaryl.
39. The pharmaceutical composition according to claim 36, characterized in that said compound is a compound of the Formula la, Ib, le, Id, le, X or XIV.
40. A method for treating a patient suffering from or at risk of a disease or condition for which the PPAR modulation provides a therapeutic benefit, characterized in that it comprises administering to the patient a PPAR modulator having the chemical structure in accordance with the claim 1.
The method according to claim 40, characterized in that said compound is a compound of the Formula la, Ib, le, Id, le, X or XIV.
42. The method according to claim 40, characterized in that said compound is a compound listed in Table 1.
43. The method according to claim 40, characterized in that said compound is approved for administration to a human being.
44. The method according to claim 40, characterized in that the disease or condition is a disease or condition mediated by PPAR.
45. The method according to claim 40, characterized in that said disease or condition is selected from the group consisting of obesity, overweight condition, hyperlipidemia, associated diabetic dyslipidemia, mixed dyslipidemia, hypoalphalipoproteinemia, Syndrome X, diabetes melllus type II, type I diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, a diabetic complication of neuropathy, nephropathy, retinopathy or cataracts, hypertension, coronary heart disease, heart failure, hypercholesterolemia, inflammation, thrombosis, congestive heart failure, disease cardiovascular, atherosclerosis, arteriosclerosis, hypertriglyceridemia, eczema, psoriasis, cancer and conditions associated with the lung and intestine and the regulation of appetite and food consumption in subjects suffering from disorders such as obesity, anorexia-bulimia and anorexia nervosa.
46. The method according to claim 40, characterized in that said disease or condition is selected from the group consisting of congestive heart failure, atherosclerosis, arteriosclerosis, obesity, overweight condition, hyperlipidemia, associated diabetic dyslipidemia, mixed dyslipidemia, hypoalphalipoproteinemia, Syndrome X, type II diabetes mellitus, type I diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance and cancer.
47. Equipment characterized in that it comprises a pharmaceutical composition according to claim 22.
48. The equipment according to claim 47, characterized in that said compound is a compound of Formula la, Ib, le, Id, le, X or XIV.
49. The equipment according to claim 47, characterized in that said compound is a compound listed in Table 1.
50. The equipment according to claim 47, further characterized in that it comprises a written indication that the composition is approved to be administered to a human.
51. The equipment according to claim 50, characterized in that said composition is approved for a medical indication selected from the group consisting of obesity, overweight condition, hyperlipidemia, associated diabetic dyslipidemia, mixed dyslipidemia, hypoalphalipoproteinemia, Syndrome X, diabetes mellitus type II, type I diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, a diabetic complication of neuropathy, nephropathy, retinopathy or cataracts, hypertension, coronary heart disease, heart failure, hypercholesterolemia, thrombosis, congestive heart failure, cardiovascular disease , atherosclerosis, arteriosclerosis, hypertriglyceridemia, eczema, psoriasis, cancer and conditions associated with the lung and intestine and the regulation of appetite and food consumption in subjects suffering from disorders such as obesity, anorexia-bulimia and anorexia nervosa.
52. The equipment according to claim 50, characterized in that the disease or condition is selected from the group consisting of congestive heart failure, atherosclerosis, arteriosclerosis, obesity, overweight condition, hyperlipidemia, associated diabetic dyslipidemia, mixed dyslipidemia, hypoalphalipoproteinemia, Syndrome X, type II diabetes mellitus, type I diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance and cancer.
53. A method for developing an improved active modulator in a PPAR comprising: determining whether any of a plurality of test compounds having the chemical structure according to claim 1, provides an improvement in one or more desired pharmacological properties in relation to to an active compound of reference in said PPAR and selecting that (those) compound (s) if there is one, that has an improvement in said desired pharmacological property, thus providing an improved modulator.
54. A method for designing a ligand that binds to at least one member of the PPAR protein family, characterized in that it comprises: identifying as molecular scaffolds one or more compounds that bind to a binding site of a PPAR with low affinity; determine the orientation of one or more molecular scaffolds at the PPAR binding site by obtaining co-crystal structures from the molecular scaffolds at the binding site, and identify one or more structures from at least one scaffolding molecule that, when they are modified, provide a ligand having altered binding affinity or binding specificity or both for binding to PPAR as compared to binding the scaffold molecule.
55. A method for designing a ligand that binds to at least one PPAR that is a member of the PPAR family, characterized in that it comprises: identifying as molecular scaffold one or more compounds that binds to link site (s) of a plurality of members of the PPAR family, determine the orientation of the one or more molecular scaffolds at the PPAR binding site to identify chemically treatable structures of the scaffolds that, when modified, alter the binding affinity or binding specificity between the scaffold and the PPAR, synthesize a ligand wherein one or more chemically treatable structures of the molecular scaffold is modified to provide a ligand that binds to the PPAR, with binding affinity or altered bond specificity.
56. A method for identifying binding characteristics of a ligand of a PPAR, characterized in that it comprises: identifying at least one conserved residue of interaction in said PPAR that interacts with at least two binding molecules, and identifying at least one common interaction property said at least two molecules of binding to said conserved residue, identifying at least one said characteristic.
57. A method for identifying energetically permitted sites in a PPAR binding compound to annex an additional component, characterized in that it comprises analyzing the orientation of said binding compound at a binding site PPAR, identifying accessible sites in said compound of said additional component.
58. A method for attaching a binding compound PPAR to an annex component in an energetically permitted site, characterized in that it comprises: identifying energetically permitted sites to annex said annexed component in a binding compound and annexing said compound or derivative thereof to said annexed component in said energetically permitted site.
59. A method for making an affinity matrix comprising a linking compound, characterized in that it comprises. identifying energetically permitted sites in a PPAR binding compound to be attached to a solid phase matrix and attaching said PPAR link compound to said solid phase matrix through said energetically permitted site.
60. The method according to claim 59, characterized in that it further comprises determining the orientation of said PPAR binding compound at a binding site in a PPAR to which said compound binds.
61. The method according to claim 59, wherein identifying energetically permitted sites comprises calculating the free energy change to attach said PPAR binding compound to said solid phase matrix.
62. The method according to claim 59, wherein said binding compound is attached to said solid phase matrix by a linker.
63. The method according to claim 59, wherein said solid phase matrix is selected from a group consisting of a gel, a bead, a chip and a well.
64. The method according to claim 59, wherein the identification of energetically permitted sites for the annex to said solid phase matrix is developed for at least 10 different compounds.