CA2532403A1 - Ppar active compounds - Google Patents

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
[0001] The present invention relates to the field of agonists for the family of nuclear receptors identified as peroxisome proliferator-activated receptors.

[0002] The following description is provided solely to assist the understanding of the reader. None of the references cited or. information provided is admitted to be 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.

[0003] The peroxisome proliferator-activated receptors (PPARs) form a subfamily in the nuclear receptor superfamily. Three isoforms, encoded by separate genes, have been identified thus far: PPARy, PPARa, and PPARB.

(0004] There are two PPARy isoforms expressed at the protein level in mouse and human, y1 and y2. They differ only in that the latter has 30 additional amino acids at its N
terminus due to differential promoter usage within the same gene, and subsequent alternative RNA processing. PPARy2 is expressed primarily in adipose tissue, while PPARyl is expressed in a broad range of tissues.

[0005] Murine PPARa was the first member of this nuclear receptor subclass to be cloned; it has since been cloned from humans. PPARa is expressed in numerous metabolically active tissues, including liver, kidney, heart, skeletal muscle, and brown fat.
It is also present in monocytes, vascular endothelium, and vascular smooth muscle cells.
Activation of PPARa induces hepatic peroxisome proliferation, hepatomegaly, and hepatocarcinogenesis in rodents. These toxic effects are lost in humans, although the same compounds activate PPARa across species.

[0006] Human PPARB was cloned in the early 1990s and subsequently cloned from rodents. PPARB is expressed in a wide range of tissues and cells with the highest levels of expression found in digestive tract, heart, kidney, liver, adipose, and brain.
Thus far, no PPARB-specific gene targets have been identified.

(0007] The PPARs are ligand-dependent transcription factors that regulate target gene expression by binding to specific peroxisome proliferator response elements (PPREs) in enhancer sites of regulated genes. PPARs possess a modular structure composed of functional domains that include a DNA binding domain (DBD) and a ligand binding domain (LBD). The DBD specifically binds PPREs in the regulatory region of PPAR-responsive 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 heterodimer with a retinoid X receptor (RXR). Upon binding an agonist, the conformation of a PPAR is altered and stabilized such that a binding cleft, made up in part of the AF-2 domain, is created and recruitment of transcriptional coactivators occurs.
Coactivators augment the ability of nuclear receptors to initiate the transcription process. The result of the agonist-induced PPAR-coactivator interaction at the PPRE is an increase in gene transcription. Downregulation of gene expression by PPARs appears to occur through indirect mechanisms. (Bergen & Wagner, 2002, Diabetes Tech. 8~ Then, 4:163-174).

[0008] The first cloning of a PPAR (PPARa) occurred in the course of the search for the molecular target of rodent hepatic peroxisome proliferating agents. Since then, numerous fatty acids and their derivatives including a variety of eicosanoids and prostaglandins have been shown to serve as ligands of the PPARs. Thus, these receptors may play a central role in the sensing of nutrient levels and in the modulation of their metabolism. In addition, PPARs are the primary targets of 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 to the development and utilization of drugs used to treat metabolic disorders. In addition, due to the great interest within the research community, a wide range of additional roles for the PPARs have been discovered; PPARa and PPARy may play a role in a wide range of events involving the vasculature, including atherosclerotic plaque formation and stability, thrombosis, vascular tone, angio-genesis,and cancer.

[0009] Among the synthetic ligands identified for PPARs are Thiazolidinediones (TZDs). These compounds were originally developed on the basis of their insulin-sensitizing effects in animal pharmacology studies. Subsequently, it was found that TZDs induced adipocyte differentiation and increased expression of adipocyte genes, including the adipocyte fatty acid-binding protein aP2. Independently, it was discovered that PPAR~y interacted with a regulatory element of the aP2 gene that controlled its adipocyte-specific expression. On the basis of these seminal observations, experiments were performed that determined that TZDs were PPARy ligands and agonists and demonstrate a definite correlation between their in vitro PPARy activities and their ih vivo insulin-sensitizing actions. (Bergen & Wagner, 2002, Diabetes Tech. & Ther., 4:163-174).

[0010] Several TZDs, including troglitazone, rosiglitazone, and pioglitazone, have insulin-sensitizing and anti-diabetic activity in humans with type 2 diabetes and impaired glucose tolerance. Farglitazar is a very potent non-TZD PPAR-y-selective agonist that was recently shown to have antidiabetic as well as lipid-altering efficacy in humans. In addition to these potent PPAR~y ligands, a subset of the non-steroidal antiinflammatory drugs (NSAIDs), including indomethacin, fenoprofen, and ibuprofen, have displayed weak PPARy and PPARa activities. (Bergen & Wagner, 2002, Diabetes Tecl2. c~ Ther., 4:163-174).

[0011] The fibrates, amphipathic carboxylic acids that have been proven useful in the treatment of hypertriglyceridemia, are PPARa ligands. The prototypical member of this compound class, clofibrate, was developed prior to the identification of PPARs, using i~z vivo assays in rodents to assess lipid-lowering efficacy. (Bergen & Wagner, 2002, Diabetes Tech. ~ Ther., 4:163-174).

[0012] Fu et al., Nature, 2003, 425:9093, demonstrated that the PPARa binding compound, oleylethanolamide, produces satiety and reduces body weight gain in mice.

[0013] Clofibrate and fenofibrate have been shown to activate PPARa with a 10-fold selectivity over PPARy. Bezafibrate acted as a pan-agonist that showed similar potency on all three PPAR isoforms. Wy-14643, the 2-arylthioacetic acid analogue of clofibrate, was a potent murine PPARa agonist as well as a weak PPARy agonist. In humans, all of the fibrates must be used at high doses (200-1,200 mg/day) to achieve efficacious lipid-lowering activity.
_3_ [0014] TZDs and non-TZDs have also been identified that are dual PPARy/a agonists.
By virtue of the additional PPARa agonist activity, this class of compounds has potent lipid-altering efficacy in addition to antihyperglycemic activity in animal models of diabetes and lipid disorders. KRP-297 is an example of a TZD dual PPARyIa agonist (Fajas, 1997, J. Biol. Claerra., 272:18779-18789) DRF-2725 and AZ-242 are non-TZD dual PPARy/a agonists. (Lohray, et al., 2001, J. Med. Ghem., 44:2675-2678; Cronet, et al., 2001, Structure (Camb.) 9:699-706).

[0015] In order to define the physiological role of PPAR~, efforts have been made to develop novel compounds that activate this receptor in a selective manner.
Amongst the a-substituted carboxylic acids previously described, the potent PPARB ligand L-demonstrated approximately 30-fold agonist selectivity for this receptor over PPARy; it was inactive on marine 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 potent, highly-selective PPAR~ agonist that produced beneficial changes in serum lipid parameters in obese, insulin-resistant rhesus monkeys.
(Oliver et al., 2001, Proc. Natl. Aced. Sci., 98:5306-5311). . ' [0016] In addition to the compounds above, certain thiazole derivatives active on PPARs have been described. (Cedilla et al., Internet. Appl. PCTfLJS01/149320, Internet. Publ. W) 021062774, incorporated herein by reference in its entirety.) [0017] Some tricyclic-a-alkyloxyphenylpropionic acids were described as dual PPARoc/y agonists. Sauerberg et al., 2002, J. Med. Chem. 45:789-804.) [0018] A group of compounds that were stated to have equal activity on PPARa/y/8 was described in Morgensen et al., 2002, Bioorg. & Med. Cher~a. Lett. 13:257-260.

[0019] Oliver et al., described a selective PPARB agonist that promotes reverse cholesterol transport. (Oliver et al., 2001, PNAS 98:5306-5311.) [0020] Yamamoto et al., U.S. Patent 3,489,767 describes "1-(phenylsulfonyl)-indolyl aliphatic acid derivatives" that are stated to have "antiphlogistic, analgesic and antipyretic actions." (Col. 1, lines 16-19.) [0021] Kato et al., European patent application 94101551.3, Publication No. 0 Al, describes the use of 3-(5-methoxy-1-p-toluenesulfonylindol-3-yl)propionic acid (page 6) and 1-(2,3,6-triisopropylphenylsulfonyl)-indole-3-propionic acid (page 9) as intermediates in the synthesis of particular tetracyclic morpholine derivatives.
SUMMARY OF THE INVENTION

[0022] In the present invention, compounds were identified that were only weakly active on PPARs. Identification of such compounds led to the identification of molecular scaffolds that allows for convenient ligand development utilizing structural information about the PPARS, and the preparation of compounds based on that scaffold that have greatly enhanced activity on PPARs as compared to the compounds initially identified.
Included are compounds that have significant pan-activity across the PPARs, PPARa, PPARb, and PPARy, as well as compounds that have significant specificity (at least 5-, 10-, or 20-fold greater activity) on a single PPAR, or on two of the three PPARs.

[0023] A molecular scaffold is represented below by the structure of Formula I, but with n=1, Y=CH, the R substituents except for Rl as H, and with Rl as -COOH.
Similar scaffolds with each of the alternate selections for the indicated moieties (e.g., Y=N and/or n=0 or 2 and/or Rl as one of the other indicated substituents) are also provided. The present invention concerns 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 the PPARs, PPARa, PPARB, and PPARy, where Formula I is:
R~

( )n V %U~ R8 X
Ws ~~Ns Y

Formula I
where:

[0024] U, V, W, X, and Y are independently substituted N or CRg, where there are no more than 4, and preferably no more than 3, nitrogens in the bicyclic ring structure shown in Formula I, and there are no more than 2 nitrogens in either of the rings;

(0025] Rl is a carboxyl group (or ester thereof) or a carboxylic acid isostere such as optionally substituted thiazolidine dione, optionally substituted hydroxamic acid, optionally substituted acyl-cyanamide, optionally substituted tetrazole, optionally substituted isoxazole, optionally substituted sulphonate, optionally substituted sulfonamide, and optionally substituted acylsulphonamide;

[0026] R2 is hydrogen, optionally substituted lower alkyl, -CHz-CR12= CR13R14, -CHZ-C---CRIS, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)NRl°Rn, _C(Z)R2°, -S(O)2NRioRll; or-S(~)2Rai;

[0027] R6 and R' 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 R~ combine to form a mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;

[0028] R$ is hydrogen, halo, optionally substituted lower alkyl, -CH2-CRIa=
CR13R14~
optionally substituted cycloalkyl, optionally substituted monofluoroalkyl, optionally substituted difluoroalkyl, optionally substituted trifluoroalkyl, trifluoromethyl, -CHZ-C=CRl$, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR9, -SR9, y oRi i ~ -C(Z)y oRi i ~ -C(Z)Rao~ -S (~)2y oRi i ~ or -S (O)2Ra i;

[0029] R9 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarallcyl;

[0030] Rl° and Rl 1 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 Rl° and Rll combine to form a mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;

[0031] Rlz, R13, Ri4, and Rls are independently 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;

[0032] R2° is optionally substituted monofluoroalkyl, trifluoromethyl, optionally substituted difluoroalkyl, -CH2-CRl2= CR13R14, -CHZ-C-CRIS, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

[0033] R21 is optionally substituted lower alkoxy, -CH2-CR12= CR13R14, -CH2-C=CRIB
optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

[0034] Z is O or S; and [0035] n = 0, 1, or 2.

[0036] In specifying a compound or compounds of Formula I, unless indicated to the contrary, specification of such compounds) includes pharmaceutically acceptable salts of the compound(s).

[0037] In connection with compounds of Formula I, various chemical structures and moieties have the following meanings.

[0038] "Halo" or "Halogen" - alone or in combination means all halogens, that is, chloro (C1), fluoro (F), bromo (Br), iodo (I).

[0039] "Hydroxyl" refers to the group -OH.

[0040] "Thiol" or "mercapto" refers to the group -SH.

[0041] "Alkyl" - alone or in combination means an alkane-derived radical containing ,from 1 to 20, preferably 1 to 15, carbon atoms (unless specifically defined).
It is a straight chain alkyl, branched alkyl, or cycloalkyl. In many embodiments, an alkyl is a straight or branched alkyl group containng 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 the straight chain alkyl groups of 1-6, 1-4, or 1-2 carbon atoms.
Preferably, cycloalkyl groups are monocyclic, bicyclic or tricyclic ring systems of 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, and the like, but can also include larger ring structures such as adamantyl.
Alkyl also includes a straight chain or branched alkyl group that contains or is interrupted by a 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, or cycloalkyl group defined previously, independently 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, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like.

[0042] "Alkenyl" - alone or in combination means a straight, branched, or cyclic hydrocarbon containing 2-24, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2-4, carbon atoms and at least one, preferably 1-3, more preferably 1-2, most preferably one, carbon to carbon double bond. In the case of a cycloalkenyl group, conjugation of more than one carbon to carbon double bond is not such as to confer aromaticity to the ring. Carbon to carbon double bonds may be either contained within a cycloalkenyl portion, with the exception of cyclopropenyl, or within a straight chain or 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 defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, allcylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally _g_ 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-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, or the like attached at any available point to produce a stable compound.

[0043] "Alkynyl" - alone or in combination means a straight or branched hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2-4, carbon atoms containing at least one, preferably one, carbon to carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl and the like.
A substituted alkynyl refers to the straight chain alkynyl or branched alkynyl defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfmyl, 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-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like attached at any available point to produce a stable compound.

[0044] "Alkyl alkenyl" refers to a group -R-CR'=CR"' R"", where R is lower alkylene, or substituted lower alkylene, R', R"', R"" may independently be hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.

[0045] "Alkyl alkynyl" refers to a groups -RCCR' where R is lower alkylene or substituted lower alkylene, R' is hydrogen, lower alkyl, substituted lower alkyl, aryl, aryl, substituted aryl, hetaryl, or substituted hetaxyl as defined below.

[0046] "Alkoxy" denotes the group -OR, where 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.
_g_ [0047] "Alkylthio" or "thioalkoxy" denotes the group -SR, -S(O)"-1_Z-R, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl as defined herein.

[0048] "Acyl" denotes groups -C(O)R, where R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl and the like as defined herein.

[0049] "Aryloxy" denotes groups -OAr, where Ar is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group as defined herein.

[0050] "Amino" or substituted amine denotes the group -NRR', where R and R' may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, or substituted heteroaryl as defined herein, acyl or sulfonyl.

[0051] "Amido" denotes the group -C(O)NRR', where R and R' may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl as defined herein.

(0052] "Carboxyl" denotes the group -C(O)OR, where R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, and substituted hetaryl as defined herein.

[0053] The term "carboxylic acid isostere" refers to a group selected from optionally substituted thiazolidine dione, optionally substituted hydroxamic acid, optionally substituted acyl-cyanamide, optionally substituted tetrazole, optionally substituted isoxazole, optionally substituted sulphonate, optionally substituted sulfonamide, and optionally substituted acylsulphonamide [0054] "Carbocyclic" refers to a saturated, unsaturated, or aromatic group having a single ring (e.g., phenyl) or multiple condensed rings where all ring atoms are carbon atoms, which can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0055] "Aryl" - alone or in combination means phenyl or naphthyl optionally carbocyclic fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members and/or 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, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like.

[0056] "Substituted aryl" refers to aryl optionally substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, vitro, cyano, thiol, sulfamido and the like.

(0057] "Heterocycle" refers to a saturated, unsaturated, or aromatic group having a single ring (e.g., morpholino, pyridyl or furyl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo[b]thienyl) and having carbon atoms and at least one hetero atom, such as N, O or S, within the ring, which can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, vitro, cyano, thiol, sulfamido and the like.

[0058] "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, containing 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, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A
carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such 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, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl and the like. A substituted heteroaryl contains a substituent attached at an available carbon or nitrogen to produce a stable compound.

[0059] "Heterocyclyl" - alone or in combination means a non-aromatic cycloalkyl group having from 5 to 10 atoms in which 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 ring members and/or are optionally substituted as in the case of cycloalkyl.
Heterocycyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attaclunent is at a carbon or nitrogen atom.
Examples of heterocyclyl groups are tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, dihydroindolyl, and the like. A substituted hetercyclyl group contains a substituent nitrogen attached at an available carbon or nitrogen to produce a stable compound.

[0060] "Substituted heteroaryl" refers to a heterocycle optionally mono or poly substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, vitro, cyano, thiol, sulfamido and the like.

[0061] "Aralkyl" refers to the group -R-Ar where Ar is an aryl group and R is lower alkyl or substituted lower alkyl group. Aryl groups can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, vitro, cyano, thiol, sulfamido and the like.

(0062] "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 unsubstituted or substituted with e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, vitro, cyano, thiol, sulfamido and the like.

w0 2005/009958 PCT/US2004/023234 [0063] "Heteroarylalkyl" refers to the group -R-HetAr where HetAr is an heteroaryl group and R is lower alkylene or substituted lower alkylene. Heteroarylalkyl groups can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, vitro, cyano, thiol, sulfamido and the like.

[0064] "Cycloalkyl" refers to a cyclic or polycyclic alkyl group containing 3 to 15 carbon atoms.

[0065] "Substituted cycloalkyl" refers to a cycloalkyl group comprising one or more substituents with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, vitro, cyano, thiol, sulfamido and the like.

[0066] "Cycloheteroalkyl" refers to a cycloalkyl group wherein one or more of the ring carbon atoms is replaced with a heteroatom (e.g., N, O, S or P).

[0067] Substituted cycloheteroalkyl" refers to a cycloheteroalkyl group as herein defined 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, vitro, cyano, thiol, sulfamido and the like.

[0068] "Alkyl cycloalkyl" denotes the group -R-cycloalkyl where cycloalkyl is a cycloalkyl group and R is a lower alkylene or substituted lower alkylene.
Cycloalkyl groups can optionally be unsubstituted or substituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, vitro, cyano, thiol, sulfamido and the like.

[0069] "Allcyl cycloheteroalkyl" denotes the group -R-cycloheteroalkyl where R
is a lower alkylene or substituted lower alkylene. Cycloheteroalkyl groups can optionally be unsubstituted or substituted with e.g. halogen, lower alkyl, lower alkoxy, allcylthio, amino, amido, carboxyl, acetylene, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, vitro, cyano, thiol, sulfamido and the like.

[0070] 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:
iii u-~N ~ ~ ~ Ni ~ ~
~ N~ v \\ N \\ \
\\N \\N ~~N
N~ ~ NA N ~ N~
,, N i v ~ i v ~~ i v N/N /N
\\N \\N
N ~N
\N N ~ N~ N ~ N

/N N /
~N -N
~N N~ ~N N

(0071] Thus, in particular embodiments involving compounds of Formula I, the compound includes a bicyclic core as shown above. Such compounds can include substitutents as described for Formula I, with the understanding that ring nitrogens other than the nitrogen corresponding to position 1 of the indole structure are unsubstituted. In particular embodiments, the compounds have one of the bicyclic cores shown above and substitution selections as shown herein for compounds having an indolyl core;
the compounds have one of the bicyclic cores above, and the substituents shown at the S-position are instead attached at the 6-position.

[0072] In certain embodiments involving compounds of Formula I, the compounds have a structure of Formula I-1, namely R~
Y

R~

R4 y X Rs R3 ~ N
Formula I-1 where:

[0073] R3, R4, and RS are independently hydrogen, halo, trifluoromethyl, optionally substituted lower alkyl, -CHI-CR12= CR13R14, optionally substituted monofluoroalkyl, optionally substituted difluoroalkyl, optionally substituted trifluoroalkyl, -CHI-C---CRIS, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR9, -SR9, NRioRi 1, -C(Z)NRIORI, _C(Z)RZO, -S(O)2NR1oR11, or-S(O)2Ray [0074] In particular embodiments of the different aspects of the invention, including in certain embodiments, the compounds of Formula I are compounds of Formulas Ia, Ib, Ic, Id, X, or XIV as shown in the Detailed Description. Also in particular embodiments, such compounds are compounds of Formula I with Y=N; with Y=CRB; with Y=CH; with all R
substituents other than Rl, RZ, and R4 as H (for each of X as N, X as CH, and X as CR8);
with R6 and R~ as H (for each of X as N, X as CH, and X as CR$).

[0075] In certain embodiments, n=l; n=1 and X and/or Y is CH; n=1, X and/or Y
is CH, and R6 and R' are H; n=1 and X and/or Y=CRB.

(0076] In certain embodiments, n=1, R2 is -S(O)2R21, with RZl being optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, in which n=1, and RZ is -S(O)aRzl, 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 further embodiments in which 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 heteroaryl substituted alkyl, and aryl or heteroaryl substituted alkoxy; in further embodiments in which a 6-membered ring is substituted with halo or alkoxy, the ring is substituted at the 3-position (mete), 4-position (pare), or 3- and 4-positions (mete and pare); in further embodiments in which a 6-membered ring is substituted at the 4-position, or 3- and 4-positions, the 4-position substitutent is lower alkyl, the 4-position substituent is not alkyl, the 4-position substituent is halo (e.g., fluoro or chloro), the 3- and 4-position substituents are fluoro, the 3- and 4-position substitutents are chloro, one of the 3- and 4-position substituents is fluoro and the other is chloro, the 3-position is halo (e.g., fluoro or chloro) and the 4-position is alkoxy (e.g., methoxy or ethoxy), the 3-position is alkoxy (e.g., methoxy or ethoxy) and the 4-position is halo (e.g., fluoro or chloro), the 3-position is chloro and the 4-position is alkoxy, the 3-position is alkoxy and the 4-position is chloro; the 6-membered ring is fused with a second 5- or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring. In further embodiments in which the aryl group is a 5-membered ring, the ring is substituted with one or two groups located at ring positions not adjacent to the ring atom linked to the -S(O)2- group; the 5-membered ring is substituted with one or two ring substituents selected from the group consisting of halo, alkoxy, cycloalkyl, axyl, aryloxy, heteroaryl, heteroaryloxy, aryl or heteroaxyl substituted alkyl, and aryl or heteroaryl substituted alkoxy; the ring is substituted with chloro; the ring is substituted 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 5- or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring.

[0077] In certain embodiments in which n=1, and Ra is -S(O)ZR21, 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.

[0078] In certain embodiments, n=2; n=2 and Xand/or Y is CH; n=2, X and/or Y
is CH, and R6 and R~ are H; n=2 and X and/or Y is CRB; n=2 and X and/or Y is N.

[0079] In certain embodiments in which n=2, R4 is different from H, halo, alkyl, alkoxy, alkylthio; R4 is different from H, halo, Cl_3 alkyl, Cl_~ alkoxy, Cl_3 alkylthio; R4 is different from Cl_3 alkoxy; R4 is not methoxy.

[0080] In certain embodiments, n=2, R2 is -S(O)aR2l, with R21 being optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, in which n=2, 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 further embodiments in which 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, aryl or heteroaryl substituted alkyl, and aryl or heteroaryl substituted alkoxy; in further embodiments in which a 6-membered ring is substituted with halo or alkoxy, the ring is substituted at the 3-position (meta), 4-position (para), or 3- and 4-positions (mete and para); in further embodiments in which a 6-membered ring is substituted at the 4-position, or 3- and 4-positions, the 4-position substitutent is lower alkyl, the 4-position substituent is not alkyl, the 4-position substituent is halo (e.g., fluoro or chloro), the 3- and 4-position substituents are fluoro, the 3- and 4-position substitutents are chloro; one of the 3- and 4-position substituents is fluoro and the other is chloro, the 3-position is halo (e.g., fluoro or chloro) and the 4-position is alkoxy (e.g., methoxy or ethoxy), the 3-position is alkoxy (e.g., methoxy or ethoxy) and the 4-position is halo (e.g., fluoro or chloro), the 3-position is chloro and the 4-position is alkoxy, the 3-position is alkoxy and the 4-position is chloro; the 6-membered ring is fused with a second 5- or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring. In further embodiments in which the axyl group is a 5-membered ring, the ring is substituted with one or two groups located at ring positions not adjacent to the ring atom linked to the -S(O)2- group; the 5-membered ring is substituted with one or two ring substituents selected from the group consisting of halo, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aryl or heteroaryl substituted alkyl, and aryl or heteroaryl substituted alkoxy; the ring is substituted with chloro; the ring is substituted 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 5- or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring.

[0081] In certain embodiments, in which n=2, and R2 is -S(O)ZR21, with R21 being a substituted aryl group with a 6-membered, the substitution on the aryl group is not methoxy, the substitution on the aryl group is not alkoxy; the substitution on the aryl group is not alkoxy; R4 and the substitution on the aryl group are not both alkoxy; R4 and the substitution on the aryl group are not both methoxy; R4 is not alkoxy; R4 is not methoxy.

[0082] Certain further embodiments include compounds described for corresponding embodiments as described above for both n=1 and n=2.

[0083] In certain embodiments, compounds of Formula I have a structure of Formula Ie as shown below:

[0084] where Formula Ie [0085] R" 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, -ORS (e.g., optionally substituted alkoxy, for example, methoxy, ethoxy) -SR9, NRIORn, -C(z)yoRy -C(z)Rao~ _s(O)aNRI°Rn, or-S(O)2Rai;

[0086] R24 is H, halo, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryloxy, or optionally substituted aralkoxy (e.g., Aryl-O(CH2)pO-, where p is 1-4);

[0087] R25 is H, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, or R24 and R25 together form a fused ring with the phenyl group, e.g., benzofuran.

[0088] In particular embodiments, R4 is optionally substituted alkoxy (e.g., ~nethoxy, ethoxy, propoxy, isopropoxy), optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl (e.g., methyl or ethyl), optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or halo.

[0089] In particular embodiments, R4 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.

[0090] In particular embodiments, compounds of Formula I can be as specified for Formula Ie, but with the phenyl ring to which R24 and RZS are attached as a heteroaryl ring.
If the heteroaxyl ring is a 5-membered ring, R24 and Ras are attached at the ring positions that are not adj acent to the atom linking to the sulfonyl group shown in Formula Ie.

[0091] In particular embodiments of compounds of Formula Ie, R4 is alkoxy and R24 and Rzs are chloro; R4 is alkoxy and R24 and RZS are fluoro; R4 is alkoxy and R24 is alkoxy; R4 is alkoxy and Rz4 is alkyl; R4 is methoxy or ethoxy and R24 and R25 are chloro; R4 is methoxy or ethoxy and R24 is alkoxy; R4 is methoxy or ethoxy and R24 is alkyl.

[0092] In particular embodiments of compounds of Formula Ie, both of Rz4 and RZS axe not alkyl; neither of R24 and R25 axe alkyl; with R24 as H, R25 is not alkyl;
with RZS as H, R24 is not alkyl.

[0093] Exemplary compounds include those listed in Table 1 and in Table 4.
Reference to compounds of Formula I herein includes specific reference to sub-groups and species of compounds of Formula I described herein (e.g., particular embodiments as described above) unless indicated to the contrary.

[0094] In particular embodiments, any one or more of the sub-groups of compounds of Formula I or any one or more of the exemplary compounds is excluded from one of the specified compound groups or sub-groups of Formula I that would otherwise include such sub-group or sub-groups.

[0095] In particular embodiments of aspects involving compounds of Formula I, the compound is specific for PPARa; specific for PPARS; specific for PPARy;
specific for PPARa and PPARB; specific for PPARa, and PPARy; specific for PPARB and PPARy.
Such specificity means that the compound has at least 5-fold greater activity (preferably at least 1-, 20-, 50-, or 100-fold or more greater activity) on the specific PPAR(s) than on the other PPAR(s), where the activity is determined using a biochemical assay suitable for determining PPAR activity, e.g., an assay as described herein.

[0096] A first aspect of the invention concerns novel compounds of Formula I
and sub-groups of Formula I, e.g., as described above or otherwise described herein.

(0097] A related aspect of this invention concerns pharmaceutical compositions that include a compound of Formula I and at least one pharmaceutically acceptable carrier, excipient, or diluent. The composition can include a plurality of different pharmacalogically active compounds.

[0098] In another related aspect, compounds of Formula I can be used in the preparation of a medicament for the treatment of a PPAR-mediated disease or condition.

(0099] In another aspect, the invention concerns a method of 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 compound, or a pharmaceutically acceptable salt of such compound or prodrug. The compound can be alone or can be part of a pharmaceutical composition.

[0100] In aspects and embodiments involving treatment or prophylaxis of a disease or conditions, the disease or condition is obesity, overweight condition, hyperlipidemia, dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia, hypoalphalipoproteinemia, Syndrome X, Type II diabetes mellitus, Type I
diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, a diabetic complication (e.g., 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), cancer, and conditions associated with the lung and gut and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia and anorexia nervosa.

[0101] The identification of compounds of Formula I active on PPARs also provides a method for identifying or developing additional compounds active on PPARs, e.g., improved modulators, by determining whether any of a plurality of test compounds of Formula I active on at least one PPAR provides an improvement in one or more desired pharmacologic properties relative to a reference compound active on such PPAR, and selecting a compound if any, that has an improvement in the desired pharmacologic property, thereby providing an improved modulator.

[0102] In particular embodiments of aspects of modulator development, the desired pharmacologic property is PPAR pan-activity, PPAR selectivity for any individual PPAR
(PPARa, PPARB, or PPARy), selectivity on any two PPARs (PPARa and PPARB, PPARa and PPARy, or PPARB and PPARy), serum half life longer than 2 hr or longer than 4 hr or longer than 8 hr, aqeous solubility, oral bioavailability more than 10%, oral bioavailability more than 20%.

[0103] Also in particular embodiments of aspects of modulator development, the reference compound is a compound of Formula I. The process can be repeated multiple times, i.e., multiple rounds of preparation of derivatives and/or selection of additional related compounds and evaluation of such further derivatives of related compounds, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more additional rounds.

[0104] In additional aspects, structural information about one or more of the PPARs is utilized, e.g., in conjunction with compounds of Formula I or a molecular scaffold or scaffold core of Formula I.

[0105] Thus, in another aspect, the invention provides a method of designing a ligand that binds to at least one member of the PPAR protein family (PPARa, PPARb, and PPARy), by identifying as molecular scaffolds one or more compounds that bind to a binding site of a PPAR with low affinity; determining the orientation of the one or more molecular scaffolds at the binding site of the PPAR by obtaining co-crystal structures of the molecular scaffolds in the binding site; identifying one or more structures of at least one scaffold molecule that, when modified, provide a ligand having altered binding affinity or binding specificity or both for binding to the PPAR as compared to the binding of the scaffold molecule. The designed ligand(s) can then be provided, e.g., 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.

[0106] In particular embodiments, a plurality of distinct compounds are assayed for binding to the binding site of the PPAR; co-crystals of the molecular scaffolds bound to the PPAR are isolated, and the orientation of the molecular scaffold is determined by performing X-ray crystallography on the co-crystals; the method further involves identifying common chemical structures of the molecular scaffolds, placing the molecular scaffolds into groups based on having at least one common chemical structure, and determining the orientation of the one or more molecular scaffolds at the binding site of the PPAR for at least one representative compound from a plurality of groups;
the ligand binds to the target molecule with greater binding affinity or greater binding specificity or both than the molecular scaffold; the orientation of the molecular scaffold is determined by nuclear magnetic resonance in co-crystal structure determination; the plurality of distinct compounds are each assayed for binding to a plurality of members of the PPAR
family.

[0107] Also in particular embodiments, after the identification of common chemical structures of the distinct compounds that bind, the compounds are grouped into classes based on common chemical structures and a representative compound from a plurality of the classes is selected for performing X-ray crystallography on co-crystals of the compound and target molecule; the distinct compounds are selected based on criteria selected from molecular weight, clogP, and the number of hydrogen bond donors and acceptors; the clog P is less than 2, and the number of hydrogen bond donors and acceptors is less than 5.

[0108] In certain embodiments, the distinct compounds have a molecular weight of from about 100 to about 350 daltons, or more preferably from about 150 to about 350 daltons or from 150 to 300 daltons, or from 200 to 300 daltons. The distinct compounds can be of a variety of structures. In some embodiments, the distinct compounds can have a ring stntcture, either a carbocyclic or heterocyclic ring, such as for example, a phenyl ring, a pyrrole, imidazole, pyridine, purine, or any ring structure.

[0109] In various embodiments, a compound or compounds binds 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 (andlor has low activity), or at least about 10%, 15%, or 20% of the compounds bind with low affinity (or very low or extremely low). After the identification of common chemical structures of the distinct compounds that bind, 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 classes selected for performing orientation determination, e.g., by X-ray crystallography and/or NMR analysis.

[0110] In selecting the distinct compounds for assay in the present invention, the selection can be based on various criteria appropriate for the particular application, such as molecular weight, clogP (or other method of assessing lipophilicity), Polar Surface Area (PSA) (or other indicator of charge and polarity or related properties), and the number of hydrogen bond donors and acceptors. Compounds can also be selected using the presence of specific chemical moieties which, based on information derived from the molecular family, might be indicated as having predisposing some affinity for members of the family. 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 150 to 300 daltons. The clog P is preferably less than 2, the number of hydrogen bond donors and acceptors is preferably less than 5 and the PSA less than 100. Compounds can be selected that include chemical structures of drugs having acceptable pharmacalogical properties and/or lacking chemical strutures that are known to result in undesirable pharmacological properties, e.g., excessive toxicity and lack of solubility.

[0111] In some embodiments, the assay is an enzymatic assay, and the number of groups of molecular scaffolds formed can conveniently be about 500. In some embodiments, the assay is a competition assay, e.g., a binding competition assay. Cell-based assays can also be used. As indicated above, compounds can be used that have low, very low, or extremely low activity in a biochemical or cell-based assay.

[0112] The modification of a molecular scaffold can be the addition, subtraction, or substitution of a chemical group. The modification may desirably cause the scaffold to be actively transported to or into particular cells and/or a particular organ. In various embodiments, the modification of the compound includes the addition or subtraction of a chemical atom, substituent or group, such as, for example, a hydrogen, alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenylthio, phenyl, phenylallcyl, phenylalkylthio, hydroxyalkyl-thio, alkylthiocarbbamylthio, cyclohexyl, pyridyl, piperidinyl, alkylamino, amino, nitro, mercapto, cyano, hydroxyl, a halogen atom, halomethyl, an oxygen atom (e.g., forming a ketone, ether or N-oxide), and a sulphur atom (e.g., forming a thiol, thione, sulfonamide or di-alkylsulfoxide (sulfone)).

[0113] In certain embodiments, the information provided by performing X-ray crystallography on 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 scaffold and the protein that result from specific modifications to the molecular scaffold, and the molecular scaffold is chemically modified 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 docking of the compound to the protein, shape-based matching, molecular dynamics simulations, free energy perturbation studies, and similarity to a three-dimensional pharmacophore. A variety of such programs axe well-known in the art.

[0114] Chemical modification of a chemically tractable structure can result, or be selected to provide one or more physical changes, e.g., to result, in a ligand that fills a void volume in the protein-ligand complex, or in an attractive polar interaction being produced in the protein-ligand complex. The modification can also result in a sub-structure of the ligand being present in a binding pocket of the protein binding site when the protein-ligand complex is formed. After common chemical structures of the compounds that bind are identified, the compounds can be grouped based on having a common chemical sub-structure and a representative compound from each group (or a plurality of groups) can be selected for co-crystallization with the protein and performance of the X-ray crystallography. The X-ray crystallography is preferably perfornzed on the co-crystals under at least 20, 30, 40, or 50 distinct enviromnental conditions, or more preferably under about 96 distinct environmental conditions. The X-ray crystallography and the modification of a chemically tractable structure of the compound can each be performed a plurality of times, e.g., 2, 3, 4, or more rounds of crystallization and modification.

[0115] Also in certain embodiments, one or more molecular scaffolds are selected to have binding to a plurality of members of the PPAR family.

[0116] The method can also include the identification of conserved residues in a binding sites) of a PPAR protein that interact with a molecular scaffold, ligand or other binding compound. Conserved residues can, for example, be identified by sequence alignment of different members of the PPAR family, and identifying binding site residues that are the same or at least similar between multiple member of the family. Interacting residues can be characterized as those within a selected distance from the binding compound(s), e.g., 3, 3.5, 4, 4.5, or 5 angstroms.

[0117] In a related aspect, the invention provides a method of 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 binding sites of a plurality of members of the PPAR family, determining the orientation of one or more molecular scaffolds at the binding site of a PPAR(s) to identify chemically tractable structures of the scaffolds) that, when modified, alter the binding affinity or binding specificity between the scaffolds) and the PPAR(s), and synthesizing a ligand wherein one or more of the chemically tractable structures of the molecular scaffolds) is modified to provide a ligand that binds to the PPAR with altered binding affinity or binding specificity.

[0118] Particular embodiments include those described for the preceding aspect.

[0119] The invention also provides a method to identify properties that a likely binding compound will possess, thereby allowing, for example, more efficient selection of compounds for structure activity relationship determinations and/or for selection for screening. Thus, another aspect concerns a method for identifying binding characteristics of a ligand of a PPAR protein, by identifying at least one conserved interacting residue 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 location with respect to the structure of the binding compound defines the binding characteristic.

[0120] In various embodiments, the identification of conserved interacting residues involves comparing (e.g., by sequence alignment) a plurality of amino acid sequences in the PPAR family and identifying binding site residues conserved in that family;
identification of binding site residues by determining a co-crystal structure;
identifying interacting residues (preferably conserved residues) within a selected distance of the binding compounds, e.g., 3, 3.5, 4, 4.5, or 5 angstroms; the interaction property involves hydrophobic interaction, charge-charge interaction, hydrogen bonding, charge-polar interaction, polar-polar interaction, or combinations thereof.

[0121] Another related aspect concerns a method for developing ligands for a PPAR
using a set of scaffolds. The method involves selecting a PPAR or plurality of PPARs, selecting a molecular scaffold, or a compound from a scaffold group, from a set of at least 3 scaffolds or scaffold groups where each of the scaffolds or compounds from each scaffold group are known to bind to the target. In particular embodiments, the set of scaffolds or scaffold groups is at least 4, 5, 6, 7, 8, or even more scaffolds or scaffold groups.

[0122] Another aspect concerns a method for identifying structurally and energetically allowed sites on a binding compound for attachment of an additional components) by analyzing the orientation of the binding compounds) in a PPAR binding site (e.g., by analyzing co-crystal structures), thereby identifying accessible sites on the compound for attachment of the separate component. In particular embodiments, the binding compound is a compound of Formula I.

[0123] In various embodiments, the method involves calculating the change in binding energy on attachment of the separate 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, bead, plate, chip, or well.

(0124] In a related aspect, the invention provides a method for attaching a PPAR binding compound to an attachment component(s), by identifying energetically allowed sites for attachment of such an attachment component on a binding compound (e.g., as described for the preceding aspect), and attaching the compound or derivative thereof to the attachment components) at the energetically allowed site(s). In particular embodiments, the binding compound is a compound of Formula I.

[0125] In various embodiments, the attachment component is a linker (which can be a traceless linker) for attachment to a solid phase medium, and the method also involves attaching the compound or derivative to a solid phase medium through the linker attached at the energetically allowed site; the binding compound or derivative thereof is synthesized on a linker attached to the solid phase medium; a plurality of compounds or derivatives are synthesized in combinatorial synthesis; the attachment of the compounds) to the solid phase medium provides an affinity medium [0126] A related aspect concerns a method for making an affinity matrix for a PPAR, where the method involves identifying energetically allowed sites on a PPAR
binding compound for attachment to a solid phase matrix; and attaching the PPAR
binding compound to the solid phase matrix through the energetically allowed site. In particular embodiments, the binding compound is a compound of Formula I.

[0127] Various embodiments are as described for attachment of a separate component above; identifying energetically allowed sites for attachment to a solid phase matrix is performed for at least 5, 10, 20, 30, 50, 80, or 100 different compounds;
identifying energetically allowed sites is performed for molecular scaffolds or other PPAR
binding compounds having different core ring structures.

[0128] 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), PPARB (also referred to as PPARd or PPARdelta), and PPARy (also referred to as PPARg or PPARgamma). The individual PPARs can be identified by their sequences, where exemplary reference sequence accession numbers are: NM 005036 (cDNA sequence for hPPARa), NP_005027 (protein sequence for hPPARa), NM 015869 (cDNA sequence for hPPARg isoform 2), NP 056953 (protein sequence for hPPARg isoform 2), NM 006238 (cDNA sequence for hPPARd), and NP_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, which have been identified or can be readily identified using sequence alignment and confirmation of activity, can also be used. One of ordinary skill in the art will also recognize that modifications can be introduced in a PPAR sequence without destroying PPAR activity. Such modified PPARs can also be used in the present invention, e.g., if the modifications do not alter the binding site conformation to the extent that the modified PPAR lacks substantially normal ligand binding.

[0129] As used herein in connection with the design or development of ligands, the term "bind" and "binding" and like terms refer to a non-convalent energetically favorable association between the specified molecules (i.e., the bound state has a lower free energy than the separated state, which can be measured calorimetrically). For binding to a target, the binding is at least selective, that is, the compound binds preferentially to a particular target or to members of a target family at a binding site, as compared to non-specific binding to unrelated proteins not having a similar binding site. For example, BSA is often used for evaluating or controlling for non-specific binding. ' In addition, for an association to be regarded as binding, the decrease in free energy going from a separated state to the bound state must be sufficient so that the association is detectable in an biochemical assay suitable for the molecules involved.

[0130] By "assaying" is meant the creation of experimental conditions and the gathering of data regarding a particular result of the experimental conditions. For example, enzymes can be assayed based on their ability to act upon a detectable substrate.
Likewise, for example, a compound or ligand can be assayed based on its ability to bind to a particular target molecule or molecules and/or to modulate an activity of a target molecule.

[0131] 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, molecular scaffold, or ligand that binds to the target molecule.
Persons of ordinary skill in the art will realize that accepted methods exist and are widely available for determining background signal.

[0132] When a decision is described as "based on" particular criteria, it is meant that the criteria selected are parameters of the decision and guide its outcome. A
substantial change in the parameters is likely to result in a change in the decision.

[0133] By "binding site" is meant an area of a taxget molecule to which a ligand can bind non-covalently. Binding sites embody particular shapes and often contain multiple binding pockets present within the binding site. The particular shapes are often conserved within a class of molecules, such as a molecular family. Binding sites within a class also can contain conserved structures such as, for example, chemical moieties, the presence of a binding pocket, and/or an electrostatic charge at the binding site or some portion of the binding site, all of which can influence the shape of the binding site.

[0134] By "binding pocket" is meant a specific volume within a binding site. A
binding pocket is a particular space within a binding site at least partially bounded by target molecule atoms. Thus a binding pocket is a particular shape, indentation, or cavity in the binding site. Binding pockets can 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 ionic, hydrogen bonding, van der Waals, or hydrophobic interactions between the molecules.

[0135] °By "chemical structure" or "chemical substructure" is meant any definable atom or group of atoms that constitute a part of a molecule. Normally, chemical substructures of a scaffold or ligand can have a role in binding of the scaffold or ligand to a target molecule, or can influence the three-dimensional shape, electrostatic charge, and/or conformational properties of the scaffold or ligand.

[0136] By "orientation", in reference to a binding compound bound to a target molecule is meant the spatial relationship of the binding compound and at least some of its consitituent atoms to the binding pocket and/or atoms of the target molecule at least partially defining the binding pocket.

[0137] In the context of target molecules in the present invention, the term "crystal"
refers to an ordered complex of target molecule, such 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 do not produce such a diffraction pattern. Preferably a crystal is of sufficient order and size to be useful for X-ray crystallography. A crystal may be formed only of target molecule (with solvent and ions) or may be a co-crystal of more than one molecule, for example, as a co-crystal of target molecule and binding compound, and/or of a complex of proteins (such as a holoenzyme).

[0138] In the context of this invention, unless otherwise specified, by "co-crystals" is meant an ordered complex of the compound, molecular scaffold, or ligand bound non-covalently to the target molecule that produces a diffraction pattern when placed in an N-ray beam. Preferably the co-crystal is in a form appropriate for analysis by X-ray or protein crystallography. In preferred embodiments the target molecule-ligand complex can be a protein-ligand complex.

[0139] By "clog P" is meant the calculated log P of a compound, "P" referring to the partition coefficient of the compound between a lipophilic and an aqueous phase, usually between octanol and water.

[0140] By "chemically tractable structures" is meant chemical structures, sub-structures, or sites on 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 can be, for example, that the ligand binds with greater affinity to a target molecule, binds with more specificity, or binds to a larger or smaller number of target molecules in a molecular family, or other desirable properties as needs require.

[0141] By "designing a ligand," "preparing a ligand," "discovering a ligand,"
and like phrases is meant the process of considering relevant data (especially, but not limited to, any individual or combination of binding data, X-ray co-crystallography data, molecular weight, clogP, and the number of hydrogen bond donors and acceptors) and making decisions about advantages that can be achieved with resort to specific structural modifications to a molecule, and implementing those decisions. This process of gathering data and making decisions about structural modifications that can be advantageous, implementing those decisions, and determining the result can be repeated as many times as necessary to obtain a ligand with desired properties.

[0142] By "docking" is meant the process of attempting to fit a three-dimensional configuration of a binding pair member into a three-dimensional configuration of the binding site or binding pocket of the partner binding pair member, which can be a protein, and determining the extent to which a fit is obtained. The extent to which a fit is obtained can 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 representative configuration of the binding pair member, e.g., an in silico representation or other model.

[0143] In the context of development of modulators using molecular scaffolds, by "ligand" is meant a molecular scaffold that has been chemically modified at one or more chemically tractable structures to bind to the target molecule with altered or changed Binding affinity or binding specificity relative to the molecular scaffold.
The ligand can bind with a greater specificity or affinity for a member of the molecular family relative to the molecular scaffold. A ligand binds non-covalently to a target molecule, which can preferably be a protein or enzyme.

[0144] By binding with "low affinity" is meant binding to the target molecule with a dissociation constant (kd) of greater than 1 wM under standard conditions. In particular cases, low affinity binding is in a range of 1 ~,M -10 mM, 1 ~,M -1 mM, 1 ~,M -500 p.M, 1 ~,M - 200 ~,M, 1 ~,M -100 ~,M. By binding with "very low affinity" is meant binding with a kd of above about 100 ~,M under standard conditions, e.g., in a range of 100 ~M -1 mM, 100 ~,M - 500 ~,M, 100 ~,M - 200 ~,M. By binding with "extremely low affinity" is meant binding at a ka of above about 1 mM under standard conditions. By "moderate affinity" is meant binding with a ka of from about 200 nM to about 1 ~M under standard conditions. By "moderately high affinity" is meant binding at a ka of from about 1 nM to about 200 nM. By binding at "high affinity" is meant binding at a ka of below about 1 nM
under standard conditions. For example, low affinity binding can occur because of a poorer fit into the binding site of the target molecule or because of a smaller number of non-covalent bonds, or weaker covalent bonds present to cause binding of the scaffold or ligand to the binding site of the target molecule relative to instances where higher affinity binding occurs. The standard conditions for binding are at pH 7.2 at 37°C for one hour.
For example, 100 ~,1/well can be used in HEPES 50 mM buffer at pH 7.2, NaCI 15 mM, ATP 2 p.M, and bovine serum albumin 1 ug/well, 37°C for one hour.

[0145] 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 (ICso) (for inhibitors or antagonists) or effective concentration (ECso) (applicable to agonists) of greater than 1 ~M under standard conditions. By "very low activity" is meant an ICso or ECso of above 100 ~,M under standard conditions. By "extremely low activity"
is meant an ICso or ECso of above 1 mM under standard conditions. By "moderate activity" is meant an ICSO or ECso of 200 nM to 1 ~.M under standard conditions. By "moderately high activity" is meant an ICso or ECso of 1 nM to 200 nM. By "high activity"
is meant an ICso or ECso of below 1 nM under standard conditions. The ICso (or ECso) is defined as the concentration of compound at which 50% of the activity of the target molecule (e.g., enzyme or other protein) activity being measured is lost (or gained) relative to activity when no compound is present. Activity can be measured using methods known to those of ordinary skill in the art, e.g., by measuring any detectable product or signal produced by occurrence of an enzymatic reaction, or other activity by a protein being measured. For PPAR agonists, activities call be determined as described in the Examples, or using other such assay methods known in the art.

(0146] By "molecular scaffold" or "scaffold" is meant a small target binding molecule to which one or more additional chemical moieties can be covalently attached, modified, or eliminated to form a plurality of molecules with common structural elements.
The moieties can include, but are not limited to, a halogen atom, a hydroxyl group, a methyl group, a nitro group, a carboxyl group, or any other type of molecular group including, but not limited to, those recited 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., protein family), and the target molecule is preferably an enzyme, receptor, or other protein. Preferred characteristics of a scaffold include molecular weight of less than about 350 daltons; binding at a target molecule binding site such that one or more substituents on the scaffold are situated in binding pockets in the target molecule binding site; having chemically tractable structures that can be chemically modified, particularly by synthetic reactions, so that a combinatorial library can be easily , constructed; having chemical positions where moieties can be attached that do not interfere with binding of the scaffold to a protein binding site, such that the scaffold or library members can be modified to form ligands, to achieve additional desirable characteristics, e.g., enabling the ligand to be actively transported into cells and/or to specific organs, or enabling the ligand to be attached to a chromatography column for additional analysis. Thus, a molecular scaffold is a small, identified target binding molecule prior to modification to improve binding affinity and/or specificity, or other pharmacalogic properties.

[0147] The term "scaffold core" refers to the core structure of a molecular scaffold onto which various substituents can be attached. Thus, for a number of scaffold molecules of a particular chemical class, the scaffold core is common to all the scaffold molecules. In many cases, the scaffold core will consist of or include one or more ring structures.

[0148] The term "scaffold group" refers to a set of compounds that share a scaffold core and thus can all be regarded as derivatives of one scaffold molecule.

[0149] By "molecular family" is meant groups of molecules classed 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. Molecules can also be classed together into a family based on, for example, homology. The person of ordinary slcill in the art will realize many other molecules that can be classified as members of a molecular family based on similarities in chemical structure or biological function.

[0150] By "protein-ligand complex" or "co-complex" is meant a protein and ligand bound non-covalently together.

[0151] By "protein" is meant a polymer of amino acids. The amino acids can be naturally or non-naturally occurring. Proteins can also contain adaptations, such as being glycosylated, phosphorylated, or other common modifications.

[0152] By "protein family" is meant a classification of proteins based on structural and/or functional similarities. For example, kinases, phosphatases, proteases, and similar groupings of proteins are protein families. Proteins can be grouped into a protein family based on having one or more protein folds in common, a substantial similarity in shape among folds of the proteins, homology, or based on having a common function.
In many cases, smaller families will be specified, e.g., the PPAR family.

[0153] "Protein folds" are 3-dimensional shapes exhibited by the protein and defined by the existence, number, and location in the protein of alpha helices, beta-sheets, and loops, i.e., the basic secondary structures of protein molecules. Folds can be, for example, domains or partial domains of a particular protein.

[0154] By "ring structure" is meant a molecule having a chemical ring or sub-structure that is a chemical ring. In most cases, ring strutures 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.

(0155] By "specific biochemical effect" is meant a therapeutically significant biochemical change in a biological system causing a detectable result. This specific biochemical effect can 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 alleviation of symptoms of a disease or condition or another desirable effect. The detectable result can also be detected through an intermediate step.

[0156] By "standard conditions" is meant conditions under which an assay is performed to obtain scientifically meaningful data. Standard conditions are dependent on the particular assay, and can be generally subjective. Normally the standard conditions of an assay will be those conditions that are optimal for obtaining useful data from the particular assay. The standard conditions will generally minimize background signal and maximize the signal sought to be detected.

[0157] By "standard deviation" is meant the square root of the variance. The variance is a measure of how spread out a distribution is. It is computed as the average squared deviation of each number from its mean. For example, for the numbers 1, 2, and 3, the mean is 2 and the variance is:
az = (1-2)Z + (2-2) 2 + (3-2) 2 = 0.667 [0158] By a "set" of compounds is meant a collection of compounds. The compounds may or may not be structurally related.

[0159] In the context of this invention, by "target molecule" is meant a molecule that a compound, molecular scaffold, or ligand is being assayed for binding to. The target molecule has an activity that binding of the molecular scaffold or ligand to the target molecule will alter or change. The binding of the compound, scaffold, or 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, animal, plant, or insect. In most but not all cases, the target molecule will be a protein or nucleic acid molecule.

[0160] By "pharmacophore" is meant a representation of molecular features that are considered to be responsible for a desired activity, such as interacting or binding with a receptor. A pharmacophore can include 3-dimensional (hydrophobic groups, charged/ionizable groups, hydrogen bond donors/acceptors), 2D (substructures), and 1D
(physical or biological) properties.

[0161] As used herein in connection with numerical values, the terms "approximately"
and "about" mean ~10% of the indicated value.

[0162] Additional embodiments will be apparent from the Detailed Description and from the claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0163] As indicated in the Summary above, the present invention concerns the peroxisome proliferator-activated receptors (PPARs), which have been identified in humans and other mammals. A group of compounds have been identified, corresponding to Formula I, that axe active on one or more of the PPARs, in particular compounds that are active one or more human PPARs.

[0164] The identification of these compound provides compounds that can be used as agonists on PPARs, as well as for identification or development of additional active compounds, for example, compounds within Formula I.
I. Applications of PPAR Agonists [0165] The PPARs have been recognized as suitable targets for a number of different disease and conditions. Some of those applications are described briefly below.
Additional applications are known and the present compounds can also be used for those diseases and conditions.

[0166] (a) Insulin resistance and diabetes: In connection with insulin resistance and diabetes, PPARy is necessary and sufficient for the differentiation of adipocytes ira vitro and ira vivo. In adipocytes, PPARy increases the expression of numerous genes involved in lipid metabolism and lipid uptake. In contrast, PPARy down-regulates leptin, a secreted, adipocyte-selective protein that has been shown to inhibit feeding and augment catabolic lipid metabolism. This receptor activity could explain the increased caloric uptake and storage noted in vivo upon treatment with PPARy agonists.
Clinically, TZDs, including troglitazone, rosiglitazone, and pioglitazone, and non-TZDs, including farglitazar, have insulin-sensitizing and antidiabetic activity. (Berger et al., 2002, Diabetes Tech. And They. 4:163-174.) [0167] PPARy has been associated with several genes that affect insulin action. TNFa, a proinflammatory cytokine that is expressed by adipocytes, has been associated with insulin resistance. PPARy agonists inhibited expression of TNFa in adipose tissue of obese rodents, and ablated the actions of TNFa in adipocytes in vitro. PPARy agonists were shown to inhibit expression of 11 /3-hydroxysteroid dehydrogenase 1 (11 (3-HSD-1), the enzyme that converts cortisone to the glucocorticoid agonist cortisol, in adipocytes and adipose tissue of type 2 diabetes mouse models. This is noteworthy since hypercortico-steroidism exacerbates insulin resistance. Adipocyte Complement-Related Protein of 30 kDa (Acrp30 or adiponectin) is a secreted adipocyte-specific protein that decreases glucose, triglycerides, and free fatty acids. In comparison to normal human subjects, patients with type 2 diabetes have reduced plasma levels of Acrp30. Treatment of diabetic mice and nondiabetic human subjects with PPARy agonists, increased plasma levels of Acrp30. Induction of Acrp30 by PPARy agonists might therefore also play a key role in the insulin-sensitizing mechanism of PPARy agonists in diabetes. (Berger et al., 2002, Diabetes Tech. AfZd Thef-. 4:163-1T4.) [0168] PPARy is expressed predominantly in adipose tissue. Thus, it is believed that the net ih vivo efficacy of PPARy agonists involves direct actions on adipose cells with secondary effects in key insulin responsive 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.
Furthermore, in vivo treatment'of insulin resistant rats produces acute (<24 h) normalization of adipose tissue insulin action whereas insulin-mediated glucose uptake in muscle was not improved until several days after the initiation of therapy. This is consistent with the fact that PPARy agonists can produce an increase in adipose tissue insulin action after direct in vitYO incubation, whereas no such effect could be demonstrated using isolated i~z vitro incubated skeletal muscles. The beneficial metabolic effects of PPARy agonists on muscle and liver may be mediated by their ability to (a) enhance insulin-mediated adipose tissue uptake, storage (and potentially catabolism) of free fatty acids; (b) induce the production of adipose-derived factors with potential insulin sensitizing activity (e.g., Acrp30); and/or (c) suppress the circulating levels and/or actions of insulin resistance-causing adipose-derived factors such as TNFa or resistin. (Berger et al., 2002, Diabetes Tech.
And Tl2er.
4:163-174.) (0169] (b) Dyslipidemia and atherosclerosis: In connection with dyslipidemia and atherosclerosis, PPARa has been shown to play a critical role in the regulation of cellular uptake, activation, and (3-oxidation of fatty acids. Activation of PPARa induces expression of fatty acid transport proteins and enzymes in the peroxisomal (3-oxidation pathway. Several mitochondria) enzymes involved in the energy-harvesting catabolism of fatty acids are robustly upregulated by PPARa agonists. Peroxisome proliferators also activate expression of the CYP4As, a subclass of cytochrome P450 enzymes that catalyze the w-hydroxylation of fatty acids, a pathway that is particularly active in the fasted and diabetic states. In sum, it is clear that PPARa is an important lipid sensor and regulator of cellular energy-harvesting metabolism. (Berger et al., 2002, Diabetes Tech.
Arid They.
4:163-174.) [0170] Atherosclerosis is a very prevalent disease in Westernized societies.
In addition to a strong association with elevated LDL cholesterol, "dyslipidemia"
characterized by elevated 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% were found to have low HDL
(<35 mg/dL) and 33% had elevated triglycerides (>200 mg/dL). In such patients, treatment with fibrates resulted in substantial triglyceride lowering and modest HDL-raising efficacy. More importantly, a recent large prospective trial showed that treatment with gemfibrozil produced a 22% reduction in cardiovascular events or death. Thus PPARa agonists can effectively improve cardiovascular risk factors and have a net benefit to improve cardiovascular outcomes. In fact, fenofibrate was recently approved in the United States for treatment of type IIA and IIB hyper-lipidemia. Mechanisms by which PPARa activation cause triglyceride lowering axe likely to include the effects of agonists to suppress hepatic apo-CIII gene expression while also stimulating lipoprotein lipase gene expression. Dual PPAR~y/a agonists, including KRP-297 and DRF 2725, possess potent lipid-altering efficacy in addition to antihyperglycemic activity in animal models of diabetes and lipid disorders.

[0171] The presence of PPARa and/or PPAR~y expression in vascular cell types, including macrophages, endothelial cells, and vascular smooth muscle cells, suggests that direct vascular effects might contribute to potential antiatherosclerosis efficacy. PPARa and PPARa activation have been shown to inhibit cytokine-induced vascular cell adhesion and to suppress monocyte-macrophage migration. Several additional studies have also shown that PPARy-selective compounds have the capacity to reduce arterial lesion size and attenuate monocyte-macrophage homing to arterial lesions in animal models of atherosclerosis. In addition, two recent studies have suggested that either PPARa or PPARy activation in macrophages can induce the expression of a cholesterol efflux "pump" protein.

[0172] It has been found that relatively selective PPARS agonists produce minimal, if any, glucose- or triglyceride-lowering activity in marine models of type 2 diabetes in comparison with efficacious PPARy or PPARa agonists. Subsequently, a modest increase in HDL-cholesterol levels was detected with PPARB agonists in db/db mice.
Recently, Oliver et al. reported that a potent, selective PPARB agonist could induce a substantial increase in HDL-cholesterol levels while reducing triglyceride levels and insulin resistance in obese rhesus monkeys.

[0173] Thus, via multifactorial mechanisms that include improvements in circulating lipids, systemic and local antiinflammatory effects, and, inhibition of vascular cell proliferation, PPARa, PPARy, and PPARB agonists can be used in the treatment or prevention of atherosclerosis. (Berger et al., 2002, Diabetes Teclz. Ahd Ther.
4:163-174.) [0174] (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 inducible nitric oxide synthase.
Rosiglitazone has been shown to induce apoptosis of macrophages at concentrations that paralleled its affinity for PPARy. This ligand has also been show to block inflammatory cytokine synthesis in colonic cell lines. This latter observation suggests a mechanistic explanation for the observed anti-inflammatory actions of TZDs in rodent models of colitis.

[0175) Anti-inflammatory actions have been described for PPARa ligands that can be important in the maintenance of vascular health. Treatment of cytokine-activated human macrophages with PPARa agonists induced apoptosis of the cells. It was reported that PPARa agonists inhibited activation of aortic smooth muscle cells in response to inflammatory stimuli. (Staels et al., 1998, Natuf°e 393:790-793.) In hyperlipidemic patients, fenofibrate treatment decreased the plasma concentrations of the inflammatory cytokine interleukin-6.

[0176] (d) Hypertension: Hypertension is a complex disorder of the cardiovascular system that has been shown to be associated with insulin resistance. Type 2 diabetes patients demonstrate a 1.5-2-fold increase in hypertension in comparison with the general population. Troglitazone, rosiglita.zone, and pioglitazone therapy have been shown to decrease blood pressure in diabetic patients as well as troglitazone therapy in obese, insulin-resistant subj ects. Since such reductions in blood pressure were shown to correlate with decreases in insulin levels, they can be mediated by an improvement in insulin sensitivity. However, since TZDs also lowered blood pressure in one-kidney one-clip Sprague Dawley rats, which are not insulin resistant, it was proposed that the hypotensive action of PPARy agonists is not exerted solely through their ability to improve insulin sensitivity. Other mechanisms that have been invoked to explain the antihypertensive effects of PPARy agonists include their ability to (a) downregulate expression of peptides that control vascular tone such as PAI-I, endothelin, and type-c natriuretic peptide C or (b) alter calcium concentrations and the calcium sensitivity of vascular cells.
(Berger et al., 2002, Diabetes Tech. And Ther. 4:163-174.) [0177) In accordance with the description above, 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 function to regulate a broad array of genes in a coordinate fashion. Important biochemical pathways that regulate insulin action, lipid oxidation, lipid synthesis, adipocyte differentiation, peroxisome function, cell apoptosis, and inflammation can be modulated through the individual PPAR isoforms. Strong therapeutic effects of PPARa and PPARy agonists to favorably influence systemic lipid levels, glucose homeostasis, and atherosclerosis risk (in the case of PPARa activation in humans) have recently been discovered. PPARa and PPARy agonists are presently used clinically to favorably alter systemic lipid levels and glucose homeostasis, respectively.
Recent observations made using PPARS ligands suggest that this isoform is also an important therapeutic target for dyslipidemia and insulin resistance, as well.

[0178] Thus, PPAR agonists, such as those described herein, can be used in the prophylaxix and/or therapteutic treatment of a variety of different disease and conditions, such as obesity, overweight condition, hyperlipidemia, dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia, hypoalphalipoproteinemia, Syndrome X, Type II diabetes mellitus, Type I diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, a diabetic complication (e.g., 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 gut and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia and anorexia nervosa.

[0179] (e) Cancer: PPAR modulation has also been correlated with cancer treatment.
(Burstein et al.; Breast Cancer Res. Treat. 2003 79(3):391-7; Alderd et al.;
Oracogene, 2003, 22(22):3412-6).

[0180] (f7 Weight Control: Administration of PPARoc agonists can induce satiety, and thus are useful in weight loss or maintenance. Such PPARa agonists can act preferentially on PPARa, or can also act on another PPAR, or can be PPAR pan-agonists. Thus, the satiety inducing effect of PPARa agonists can be used for weight control or loss.
II. PPAR Active Compounds [0181] As indicated in the Summary and in connection with 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 Summary above. Included within Formula I are sub-groups of compounds, for example, sub-groups shown by the structures Ia, Ib, Ic, Id, X, and XIV as shown in the synthetic schemes below. Included within such compounds of Formula I, are exemplary compounds provided in Table 1 below. Additional compounds within Formula I can also be prepared and tested to confirm activity using conventional methods and the guidance provided herein.
III. Development of PPAR Active Compounds A. Modulator identification and design [0182] A large number of different methods can be used to identify modulators and to design improved modulators. Some useful methods involve structure-based design.

(0183] Structure-based modulator design and identification methods are powerful techniques that can involve searches of computer databases containing a wide variety of potential modulators and chemical functional groups. The computerized design and identification of modulators is useful as the computer databases contain more compounds than the chemical libraries, often by an order of magnitude. For reviews of structure-based drug design and identification (see Kuntz et al. (1994), Acc. Claem. Res.
27:117; Guida (1994) CuYrent Opinion in Struc. Biol. 4: 777; Colinan (1994) Current Opinion in Stt~uc.
Biol. 4: 868).

[0184] The three dimensional structure of a polypeptide defined by structural coordinates can be utilized by these design methods, for example, the structural coordinates of a PPAR. In addition, the three dimensional structures of PPARs deternlined by the homology, molecular replacement, and NMR techniques can also be applied to modulator design and identification methods.

[0185] For identifying modulators, structural information for a PPAR, in particular, structural information for the active site of the PPAR can be used. However, it may be advantageous to utilize structural information from one or more co-crystals of the PPAR
with one or more binding compounds. It can also be advantageous if the binding compound has a structural core in common with test compounds.

[0186] Such modulator identification and design can, for example, be used to identify and/or develop additional active compounds within Formula I (a sub-group thereof).
1. Design by Searching Molecular Data Bases [0187] One method of rational design searches for modulators by docking the computer representations of compounds from a database of molecules. 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 (0188] One such data base (ACD distributed by Molecular Designs Limited Information Systems) contains compounds that are synthetically derived or are natural products.
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 are can be carried out using such computer programs as CONCORD from Tripos Associates or DE-Converter from Molecular Simulations Limited.

[0189] Multiple methods of structure-based modulator design are known to those in the art. (Kuntz et al., (192), J. Mol. Biol. 162: 269; Kuntz et aZ., (1994), Acc.
Chern. Res.
27: 117; Meng et al., (1992), J. Conapt. Chem. 13: 505; Bohm, (1994), J. Comp.
Aided Molec. Design ~: 623.) [0190] A computer program widely utilized by those skilled in the art of rational modulator design is DOCK from the University of California in San Francisco.
The general methods utilized by this computer program and programs like it are described in three applications below. 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 processes comprising the following steps or functions:
(a) remove the existing compound from the protein;
(b) dock the structure of another compound into the active-site using the computer program (such as DOCK) or by interactively moving the compound into the active-site;
(c) characterize the space between the compound and the active-site atoms;
(d) search libraries for molecular fragments which (i) can fit into the empty space between the compound and the active-site, and (ii) can be linked to the compound; and (e) link the fragments found above to the compound and evaluate the new modified compound.

[0191] 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 attained when a significant surface area is shared between the compound and active-site atoms without forming unfavorable steric interactions.One skilled in the art would note that the method can be performed by skipping parts (d) and (e) and screening a database of many compounds.

[0192] Structure-based design and identification of modulators of PPAR
function can be used in conjunction with assay screening. As large computer databases of compounds (around 10,000 compounds) can. be searched in a matter of hours or even less, the computer-based method can narrow the compounds tested as potential modulators of PPAR function in biochemical or cellular assays.

[0193] The above descriptions of structure-based modulator design are not all encompassing and other methods are reported in the literature and can be used, e.g.:
(1) CAVEAT: Bartlett et a1.,(1989), in Chemical and Biological Problems in Molecular Recognition, Roberts, S.M.; 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, arad (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 by Modifying Compounds in Complex with a PPAR

[0194] Another way of identifying compounds as potential modulators is to modify an existing modulator in the polypeptide active site. For example, the computer representation of modulators can be modified within the computer representation of a PPAR active site. Detailed instructions for this technique can be found, for example, in the Accelerys User Manual, 1995 in LUDI. The computer representation of the modulator is typically modified by the deletion of a chemical group or groups or by the addition of a chemical group or groups.

[0195] Upon each modification to the compound, the atoms of the modified compound and active site can be shifted in conformation and the distance between the modulator and the active-site atoms may be scored along with any complementary interactions formed between the two molecules. Scoring can be complete when a favorable geometric fit and favorable complementary interactions are attained. Compounds that have favorable scores are potential modulators.
3. Design by Modifying the Structure of Compounds that Sind a PPAR

(0196] A third method of structure-based modulator design is to screen compounds designed by a modulator building or modulator searching computer program.
Examples of these types of programs can be found in the Molecular Simulations Package, Catalyst.
Descriptions for using this program are documented in the Molecular Simulations User Guide (1995). Other computer programs used in this application are ISISBOST, ISISBASE, ISIS/DRA~ from Molecular Designs Limited and UNITY from Tripos Associates.

[0197] 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 on such a compound is preferable since it is in a biologically active conformation.

[0198] A modulator construction computer program is a computer program that may be used to replace computer representations of chemical groups in a compound complexed with a PPAR or other biomolecule with groups from a computer database. A
modulator searching computer program is a computer program that may be used to search computer representations of compounds from a computer data base that have similar three dimensional structures and similar chemical groups as compound bound to a particular biomolecule.

[0199] A typical program can operate by using the following general steps:
(a) map the compounds by chemical features 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 features; and (c) search databases with the model generated in (b).

[0200] Those skilled in the art also recognize that not all of the possible chemical features of the compound need be present in the model of (b). One can use any subset of the model to generate different models for data base searches.
B. Identification of Active Compounds Using PPAR Structure and Molecular Scaffolds [0201] W addition to the methods described above that are normally applied based on screening hits that have a substantial level of activity, the availability of crystal structures that include ligand binding sites for the various PPARs provides application of a scaffold method for identifying and developing additional PPAR active compounds. As an example, such a scaffold method can be applied using molecular scaffolds within Formula I, or having a scaffold core of Formula I, but can also be applied to other molecular scaffolds that are identified.

[0202] Thus, the present invention also concerns methods for designing ligands active on PPARs by using structural information about the ligand binding sites and identified PPAR binding compounds. While such methods can be implemented in many ways (e.g., as described above), highly preferably the process utilizes molecular scaffolds. Such development processes and related methods are described generally below, and can, as indicated by applied to the PPARs, individually and/or in any pair, or as a family.

[0203] Molecular scaffolds axe 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 andlor 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 in developing ligands. For example, a scaffold or set of scaffolds can serve as starting compounds for developing ligands with desired specificity or with desired cross-activity on a selected subset of members of a target family. Further, identification of a set of scaffolds that each bind with members of a target family provides an advantageous basis for selecting a starting point for ligand development for a particular target or subset of targets. In many cases, the ability of a scaffold to bind to and/or have activity on multiple members of a target family is related to active site or binding site homology that exists across the target family.

[0204] A scaffold active across multiple members of the target family interacts with surfaces or residues of relatively high homology, i. e., binds to conserved regions of the binding pockets. Scaffolds that bind with multiple members can be modified to provide greater specficity or to have a particular cross-reactivity, e.g., by exploiting differences between target binding sites to provide specificity, and exploiting similarities to design in cross-reactivities. Adding substituents that provide attractive interactions with the particular target typically increases the binding affinity, often increasing the activity. The various parts of the ligand development process are described in more detail in following sections, but the following describes an advantageous approach for scaffold-based ligand development.

[0205] Scaffold-based ligand development (scaffold-based drug discovery) can be implemented in a variety of ways, but large scale expression of protein is useful to provide material for crystallization, co-crystallization, and biochemical screening (e.g., binding and activity assays). For crystallization, crystallization conditions can be established for apo protein and a structure determined from those crystals. For screening, preferably a biased library selected for the particular target family is screening for binding and/or activity on the target. Highly preferably a plurality of members from the target family is screened. Such screening, whether on a single target or on multiple members of a target family provides screening hits. Low affinity and/or low activity hits are selected. Such low affinity hits can either identify a scaffold molecule, or allow identification of a scaffold molecule by analyzing common features between binding molecules.
Simpler molecules containing the cormnon features can then be tested to determine if they retain binding andlor activity, thereby allowing identification of a scaffold molecule.

[0206] When multiple members of a particular target family are used for screening, the overlap in binding and/or activity of compounds can provide a useful selection for compounds that will be subjected to crystallization. For example, for 3 target molecules from a target family, if each target has about 200-500 hits in screening of a particular library, much smaller subsets of those hits will be common to any 2 of the 3 targets, and a still smaller subset will be common to all 3 targets, e.g., 100-300. In many cases, compounds in the subset common to all 3 targets will be selected for co-crystallography, as they provide the broadest potential for ligand development.

[0207] Once compounds for co-crystallography are selected, conditions for forming co-crystals are determined, allowing determination of co-crystal structure and the orientation of binding compound in the binding site of the target is determined by solving the structure (this can be highly assisted if an apo protein crystal structure has been determined or if the structure of a close hoinolog is available for use in a homology model.
Preferably the co-crystals are formed by direct co-crystallization rather than by soaking the compound into crystals of apo protein.

[0208] From the co-crystals and knowledge of the structure of the binding compounds, additional selection of scaffolds or other binding compounds can be made by applying selection filters, e.g., for (1) binding mode, (2) multiple sites for substitution, andlor (3) tractable chemistry. A binding mode filter can, for example, be based on the demonstration of a dominant binding mode. That is, a scaffold or compounds of a scaffold group bind 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 for developing ligands for specific targets due to the greater capacity for appropriately modifying the structure of the scaffold. Filtering for tractable chemistry also facilitates preparation of ligands derived from a scaffold because the synthetic paths for making derivative compounds are available. Carrying out such a process of development provides scaffolds, preferably of divergent structure.

[0209] In some cases, it may be impractical or undesirable to work with a particular target for some or all of the development process. For example, a particular target may be difficult to express, by easily degraded, or be difficult to crystallize. In these cases, a surrogate target from the target family can be used. It is desirable to have the surrogate be as similar as possible to the desired target, thus a family member that has high homolgy in 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 sequence of the desired target can be inserted in the .. .
family member replacing the corresponding part of the sequence of the family member.

[0210] Once one or more scaffolds are identified for a target family, the scaffolds can be used to develop multiple products directed at specific members of the family, or at specific subsets of family members. Thus, starting from a scaffold that acts on multiple member of the target family, derivative compounds (ligands) can be designed and tested that have increasing selectivity. In addition, such ligands are typically developed to have greater activity, and will also typically have greater binding affinity. In this process, starting with the broadly acting scaffold, ligands are developed that have improved selectivity and activity profiles, leading to identification of lead compounds for drug development, leading to drug candidates, and final drug products.
C. Scaffolds [0211] Typically it is advantageous to select scaffolds (and/or compound sets or libraries for scaffold or binding compound identification) with particular types of characteristics, e.g., to select compounds that are more likely to bind to a particular target and/or to select compounds that have physical and/or synthetic properties to simplify preparation of derivatives, to be drug-like, and/or to provide convenient sites and chemistry for modification or synthesis.

[0212] Useful chemical properties of molecular scaffolds can include one or more of the following characteristics, but are not limited thereto: an average molecular weight below about 350 daltons, or between from about 150 to about 350 daltons, or from about 150 to about 300 daltons; having a clogP below 3; a number of rotatable bonds of less than 4; a number of hydrogen bond donors and acceptors below 5 or below 4; a Polar Surface Area of less than 100 ~2.; binding at protein binding sites in an orientation so that chemical substituents from a combinatorial library that are attached to the scaffold can be projected into pockets in the protein binding site; and possessing chemically tractable structures at its substituent attachment points that can be modified, thereby enabling rapid library construction.

[0213] The term "Molecular Polar Surface Area (PSA)" refers to the sum of surface contributions of polar atoms (usually oxygens, nitrogens and attached hydrogens) in a molecule. The polar surface area has been shown to correlate well with drug transport properties, such as intestinal absorption, or blood-brain barner penetration.

[0214] Additional useful chemical properties of distinct compounds for inclusion in a combinatorial library include the ability to attach chemical moieties to the compound that will not interfere with binding of the compound to at least one protein of interest, and that will impart desirable properties to the library members, for example, causing the library members to be actively transported to cells and/or organs of interest, or the ability to attach to a device such as a chromatography column (e.g., a streptavidin column through a molecule such as biotin) for uses such as tissue and proteomics profiling purposes.

[0215] A person of ordinary skill in the art will realize other properties that can be desirable for the scaffold or library members to have depending on the particular requirements of the use, and that compounds with these properties can also be sought and identified in like manner. Methods of selecting compounds for assay are known to those of ordinary skill in the art, for example, methods and compounds described in U.S. Patent No. 6,288,234, 6,090,912, 5,840,485, each of which is hereby incorporated by reference in its entirety, including all charts and drawings.

[0216] In various embodiments, the present invention provides methods of designing ligands that bind to a plurality of members of a molecular family, where the ligands contain a common molecular scaffold. Thus, a compound set can be assayed for binding to a plurality of members of a molecular family, e.g., a protein family. One or more compounds that bind to a plurality of family members can be identified as molecular scaffolds. When the orientation of the scaffold at the binding site of the target molecules has been determined and chemically tractable structures have been identified, a set of ligands can be synthesized starting with one or a few molecular scaffolds to arrive at a plurality of ligands, wherein each ligand binds to a separate target molecule of the molecular family with altered or changed binding affinity or binding specificity relative to the scaffold. Thus, a plurality of drug lead molecules can be designed to individually target members of a molecular family based on the same molecular scaffold, and act on them in a specific manner.
D. Binding Assays 1. Use of binding assays [0217] The methods of the present invention can involve assays that are able to detect the binding of compounds to a target molecule at 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. The assays can also include assaying 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) highly preferably allow for the identification of compounds that bind with low affinity, very low affinity, and extremely low affinity. Therefore, potency (or binding affinity) is not the primary, nor even the most important, indicia of identification of a potentially useful binding compound. Rather, even those compounds that bind with low affinity, very low affinity, or extremely low affinity can be considered as molecular scaffolds that can continue to the next phase of the ligand design process.

[0218] As indicated above, to design or discover scaffolds that act broadly across protein families, proteins of interest can be assayed against a compound collection or set. The assays, can preferably be enzymatic or binding assays. In some embodiments it may be desirable to enhance the solubility of the compounds being screened and then analyze all compounds that show activity in the assay, including those that bind with low affinity or produce a signal with greater than about three times the standard deviation of the background signal. These assays can be any suitable assay such as, for example, binding assays that measure the binding affinity between two binding partners. Various types of screening assays that can be useful in the practice of the present invention are known in the art, such as those described in U.S. Patent Nos. 5,763,198, 5,747,276, 5,877,007, 6,243,980, 6,294,330, and 6,294,330, each of which is hereby incorporated by reference in its entirety, including all charts and drawings.

[0219] In various embodiments of the assays 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 can show activity in the screening assay and these compounds can then be analyzed directly with high-throughput co-crystallography, computational analysis to group the compounds into classes with common structural properties (e.g., structural core and/or shape and polarity characteristics), and the identification of common chemical structures between compounds that show activity.

[0220] The person of ordinary skill in the art will realize that decisions can be based on criteria that are appropriate for the needs of the particular situation, and that the decisions -5'I -can be made by computer software programs. Classes can be created containing almost any number of scaffolds, and the criteria selected can be based on increasingly exacting criteria until an arbitrary number of scaffolds is arrived at for each class that is deemed to be advantageous.
2. Surface Plasmon Resonance [0221] 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 dissociation constants of reaction between an 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 ofMoleculanRecognition. 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, 1999; Alfthan, Surface plasmon resonance biosensors as a tool in antibody engineering, Bi~sensors & 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 MUCl mucin. TumouY Biology 19 Suppl 1:1-20, 1998; Malmqvist et al, Biomolecular interaction analysis: affinity biosensor technologies for functional analysis of proteins, CurYent Opiniora 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 BiochernistYy. 236:275-83, 1996; . .
Malmborg et al., BIAcore as a tool in antibody engineering, JouYnal of Imnzunological Methods. 183:7-13, 1995; Van Regenmortel, Use of biosensors to characterize recombinant proteins, Developments irz 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.

[0222] BIAcore° uses the optical properties of surface plasmon resonance (SPR) to detect alterations in protein concentration bound to a dextran matrix lying on the surface of a gold/glass sensor chip interface, a dextran biosensor matrix. In brief, 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 onto the opposite side of the sensor chip surface is reflected and also induces an evanescent wave in the gold filmi, which in turn, causes an intensity dip in the reflected light at a particular angle known as the resonance angle. If the refractive index of the sensor chip surface is altered (e.g., by ligand binding to the bound protein) a shift occurs in the resonance angle.
This angle shift can be measured and is expressed as resonance units (RUs) such that 1000 RUs is equivalent to a change in surface protein concentration of 1 ng/mm2.
These changes are displayed with respect to time along the y-axis of a sensorgram, which depicts the association and dissociation of any biological reaction.
E. High Throughput Screening (HTS) Assays [0223] HTS typically uses automated assays to search through large numbers of compounds for a desired activity. Typically HTS assays are used to find new drugs by screening for chemicals that act on a particular enzyme or molecule. For example, if a chemical inactivates an enzyme it might prove to be effective in preventing a process in a cell which causes a disease. High throughput methods enable researchers to assay thousands of different chemicals against each target molecule very quickly using robotic handling systems and automated analysis of results.

[0224] As used herein, "high throughput screening" or "HTS" refers to the rapid in vitro screening of large numbers of compounds (libraries); generally tens to hundreds of thousands of compounds, using robotic screening assays. Ultra high-throughput Screening (uHTS) generally refers to the high-throughput screening accelerated to greater than 100,000 tests per day.

[0225] To achieve high-throughput screening, it is advantageous to house samples on a multicontainer tamer or platform. A multicontainer carrier facilitates measuring reactions .
of a plurality of candidate compounds simultaneously. Multi-well microplates may be used as the carrier. Such multi-well microplates, and methods for their use in numerous assays, are both known in the art and commercially available.

Screening assays may include controls for purposes of calibration and confirmation of proper manipulation of the components of the assay. Blank wells that contain all of the reactants but no member of the chemical library axe usually included. As another example, a known inhibitor (or activator) of an enzyme for which modulators are sought, can be incubated with one sample of the assay, and the resulting decrease (or increase) in the enzyme activity used as a comparator or control. It will be appreciated that modulators can also be combined with the enzyme activators or inhibitors to find modulators which inhibit the enzyme activation or repression that is otherwise caused by the presence of the known the enzyme modulator. Similarly, when ligands to a target are sought, known ligands of the target can be present in control/calibration assay wells.
F. Measuring Enzymatic and Binding Reactions During Screening Assays [0226] Techniques for measuring the progression of enzymatic and binding reactions, e.g., in multicontainer carriers, are known in the art and include, but are not limited to, the following.

[0227] Spectrophotometric and spectrofluorometric assays are 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 Com anion: A
Handbook Of Practical Data, Techniques, And References, John Wiley and Sons, N.Y., 1972, Page 437.

[0228] Fluorescence spectrometry may be used to monitor the generation of xeaction products. 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., Spectrophotometr ay nd Spectrofluorometry A
Practical Approach, pp. 91-114, IRL Press Ltd. (19&7); and Bell, Spectroscopyln Biochemistry, Vol. I, pp. 155-194, CRC Press (191).

[0229] In spectrofluorometric methods, enzymes are exposed to substrates that change their intrinsic fluorescence when processed by the target enzyme. Typically, the substrate is nonfluorescent and is converted to a fluorophore through one or more reactions. As a non-limiting example, 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, SMase hydrolyzes sphingomyelin to yield ceramide and phosphorylcholine. Second, alkaline phosphatase hydrolyzes phosphorylcholine to yield choline. Third, choline is oxidized by choline oxidase to betaine. Finally, Hz02, in the presence of horseradish peroxidase, reacts with Amplex°
Red to produce the fluorescent product, Resorufin, and the signal therefrom is detected using spectrofluorometry.

[0230] Fluorescence polarization (FP) is based on a decrease in the speed of molecular rotation of a fluorophore that occurs upon binding to a larger molecule, such as a receptor protein, allowing for polarized fluorescent emission by the bound ligand. FP
is empirically determined by measuring the vertical and horizontal components of fluorophore emission following excitation with plane polarized light.
Polarized emission is increased when the molecular rotation of a fluorophore is reduced. A
fluorophore produces a larger polarized signal when it is bound to a larger molecule (i.e.
a receptor), slowing molecular rotation of the fluorophore. The magnitude of the polarized signal relates quantitatively to the extent of fluorescent ligand binding.
Accordingly, polarization of the "bound" signal depends on maintenance of high affinity binding.
FP is a homogeneous technology and reactions are very rapid, taking seconds to minutes to reach equilibrium. The reagents are stable, and large batches may be prepared, resulting in high reproducibility. Because of these properties, FP has proven to be highly automatable, often performed with a single incubation with a single, premixed, tracer-receptor reagent. For a review, see Owickiet al., Application of Fluorescence Polarization Assays in High-Throughput Screening, Gevretic Engineering News, 17:27, 1997.

[0231] FP is particularly desirable since its readout is independent of the emission intensity (Checovich, W. J., et al., Nature 375:254-256, 1995; Dandliker, W.
B., et al., Methods in Enzynaology 74:3-28, 1981) and is thus insensitive to the presence of colored compounds that quench 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 throughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase/phosphatase assays, J Biomol Screen 5:77-88, 2000.

[0232] Fluorophores derived from sphingolipids that may be used in FP assays are commercially available. For example, Molecular Probes (Eugene, OR) currently sells sphingomyelin and one ceramide flurophores. These are, respectively, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene- 3-pentanoyl)sphingosyl phosphocholine (BODIPY~ FL CS-sphingomyelin); N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene- 3-dodecanoyl)sphingosyl phosphocholine (BODIPY~ FL C12-sphingomyelin);
and N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene- 3-pentanoyl)sphingosine (BODIPY~ FL CS-ceramide). U.S. Patent No. 4,150,949, (Immunoassay for gentamicin), discloses fluorescein-labelled gentamicins, including fluoresceinthiocarbanyl gentamicin.
Additional fluorophores may be prepared using methods well known to the skilled artisan.

[0233] Exemplary normal-and-polarized fluorescence readers include the POLARION~
fluorescence polarization.system (Tecan AG, Hombrechtikon, Switzerland).
General multiwell plate readers for other assays are available, such as the VERSAMAX~
reader and the SPECTRAMAX~ multiwell plate spectrophotometer (both from Molecular Devices).

[0234] Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interaction and has been described. See, e.g., Heim et al., Curr.
Biol. 6:178-182, 1996; Mitra et al., Gene 173:13-17 1996; and Selvin et al., Meth. Erazymol.
246:300-345, 1995. FRET detects the transfer of energy between two fluorescent substances in close proximity, having 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 specifically interacts 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 shifts, which can be measured by a fluorometer, such as a fMAX multiwell fluorometer (Molecular Devices, Sunnyvale Calif.).

[0235] 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. Li~aid Res. 38:2365-2373 (1997);
Kahl et al., Anal. Biochena. 243:282-283 (1996); Undenfriend et al., Ataal. 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. One commercially available system uses FLASHPLATE°
scintillant-coated plates (NEN Life Science Products, Boston, MA).

[0236] The target molecule can be bound to the scintillator plates by a variety of well known means. Scintillant plates are available that are derivatized to bind to fusion proteins such as GST, His6 or Flag fusion proteins. Where the target molecule is a protein complex or a multimer, one protein or subunit can be attached to the plate First, then the other components of the complex added later under binding conditions, resulting in a bound complex.

[0237] In a typical SPA assay, the gene products in the expression pool will have been radiolabeled and added to the wells, and allowed to interact with the solid phase, which is the immobilized target molecule and scintillant coating in the wells. The assay can be measured immediately or allowed to reach equilibrium. Either way, when a radiolabel becomes sufficiently close to the scintillant coating, it produces a signal detectable by a device such as a TOPCOUNT NXT° microplate scintillation counter (Packard BioScience Co., Meriden Cornl.). If a radiolabeled expression product binds to the target molecule, the radiolabel remains in proximity to the scintillant Iong enough to produce a detectable signal.

[0238] In contrast, the labeled proteins that do not bind to the target molecule, or bind only briefly, will not remain near the scintillant long enough to produce a signal above background. Any time spent near the scintillant caused by random Brownian motion will also not result in a significant amount of signal. Likewise, residual unincorporated radiolabel used during the expression step may be present, but will not generate significant signal because it will be in solution rather than interacting with the target molecule. These non-binding interactions will therefore cause a certain level of background signal that can be mathematically removed. If too many signals are obtained, 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).

(0239] Additionally, the assay can utilize AlphaScreen (amplified luminescent proximity homogeneous assay) format, e.g., AlphaScreening system (Packard BioScience).
AlphaScreen is generally described in Seethala and Prabhavathi, Homogenous Assays:
Alp~2aScreen, Handbook of Drub Screening, Marcel Del~l~ar Pub. 2001, pp. 106-110.

Applications of the technique to PPAR receptor ligand binding assays are described, for example, in Xu et al., 2002, Nature 415:813-817.
G. Assay Compounds and Molecular Scaffolds [0240] As described above, preferred characteristics of a scaffold include being of low molecular weight (e.g., 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 scaffold is from -1 to 8, more preferably less than 6, 5, or 4, most 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 of 0 to an upper limit of 2,3, 4, 5, 6, or 8. Preferably the number of rotatable bonds is less than 5, more preferably less than 4. Preferably the number of hydrogen bond donors and acceptors is below 6, more preferably below 5. An additional criterion that can be useful is a Polar Surface Area of less than 100. Guidance that can be useful in identifying criteria fox a particular application can be found in Lipinski et al., Advanced Drug Delivery Reviews 23 (1997) 3-25, which is hereby incorporated by reference in its entirety.

[0241] A scaffold will preferably bind to a given protein binding site in a configuration that causes substituent moieties of the scaffold to be situated in pockets of the protein binding site. Also, possessing chemically tractable groups that can be chemically modified, particularly through synthetic reactions, to easily create a combinatorial library can be a preferred characteristic of the scaffold. Also preferred can be having positions on the scaffold to which other moieties can be attached, which do not interfere with binding of the scaffold to the proteins) of interest but do cause the scaffold to aclueve a desirable property, for example, active transport of the scaffold to cells and/or organs, enabling the scaffold to be attached to a chromatographic column to facilitate analysis, or another desirable property. A molecular scaffold can bind to a target molecule with any affinity, such as binding with an affinity measurable as about three times the standard deviation of the background signal, or at high affinity, moderate affinity, low affinity, very low affinity, or extremely low affinity.

[0242] Thus, the above criteria can be utilized to select many compounds for testing that have the desired attributes. Many compounds having the criteria described are available in the commercial market, and may be selected for assaying depending on the specific needs to which the methods are to be applied. In some cases sufficiently large numbers of compounds may meet specific criteria that additional methods to group similar compounds may be helpful. A variety of methods to assess molecular similarity, such as the Tanimoto coefficient have been used, see Willett et al, Journal of Chemical Information and Computer Science 38 (1998), 983-996. These can be used to select a smaller subset of a group of highly structurally redundant compounds. In addition, cluster analysis based on relationships between the compounds, or structural components of the compound, can also be carried out to the same end; see Lance and Williams Computer.Iournal 9 (I967) 373-380, Jarvis and Patrick IEEE Transactions in Computers 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 of deriving the chemical components of a large group of potential scaffolds is to virtually break up the compound at rotatable bonds so as to yield components of no less than 10 atoms. The resulting components may be clustered based on some measure of similarity, e.g. the Tanimoto coefficient, to yield the common component groups in the original collection of compounds. For each component group, all compounds containing that component may be clustered, and the resulting clusters used to select a diverse set of compounds containing a common chemical core structure.
In this fashion, a useful library of scaffolds may be derived even from millions of commercial compounds.

[0243] A "compound library" or "library" is a collection of different compounds having different chemical structures. A compound library is screenable, that is, the compound library members therein may be subject to screening assays. Iiz preferred embodiments, the library members can have a molecular weight of from about 100 to about 350 daltons, or from about 150 to about 350 daltons.

(0244] Libraries can contain at least one compound that binds to the target molecule at low affinity. Libraries of candidate compounds can be assayed by many different assays, such as those described above, e.g., a fluorescence polarization assay.
Libraries may consist of chemically synthesized peptides, peptidomimetics, or arrays of combinatorial chemicals that are large or small, focused or nonfocused. By "focused" it is meant that the collection of compounds is prepared using the stnicture of previously characterized compounds and/or pharmacophores.

[0245] Compound libraries 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 moieties variable, e.g., moieties that are independently isolated or randomly synthesized. Types of molecules in 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.
Compound libraries useful for the invention may be purchased on the commercial market or prepared or obtained by any means including, but not limited to, combinatorial chemistry techniques, fermentation methods, plant and cellular extraction procedures and the like (see, e.g., CWirla et al., Biochemistry 1990, 87, 63?8-6382; Houghten et al., Nature 1991, 354, 84-86; Lam et al., Nature 1991, 354, 82-84; Brenner et al., Proc. Natl.
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 noncommercial groups, natural products; extracts of marine organisms, fungi, bacteria, and plants.

[0246] Preferred libraries can be prepared in a homogenous reaction mixture, and separation of unreacted reagents from members of the library is not required prior to screening. Although many combinatorial chemistry approaches are based on solid state chemistry, liquid phase combinatorial chemistry is capable of generating libraries (Sun CM., Recent advances in liquid-phase combinatorial chemistry, Corrabinatorial Chemistry & High Throughput Screening. 2:299-318, 1999).

[0247] Libraries of a variety of types of molecules axe prepared in order to obtain members therefrom having one or more preselected 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 array and mixture-based synthetic combinatorial chemistry; solution-phase combinatorial chemistry (Merritt, Comb Chem High Throughput Screen 1998 1 (2):57-72, Solution phase combinatorial chemistry, Coe et al., Mol Divers 1998-99;4(1):31-8, Solution-phase combinatorial chemistry, Sun, Comb Chern Higla Throughput Screen 1999 2(6):299-318, Recent advances in liquid-phase combinatorial chemistry); synthesis on soluble polymer (Graven et al., Curr Opin Claem Biol 1997 1(1):107-13, Synthesis on soluble polymers: new reactions and the construction of small molecules); and the like. See, e.g., Dolle et al., JComb Chern 1999 1(4):235-82, Comprehensive survey of cominatorial library synthesis: 1998. Freidinger RM., Nonpeptidic ligands for peptide and protein receptors, Current Opinion in Chemical Biology; and Kundu et al., ProgDrugRes 1999;53:89-156, Combinatorial chemistry:
polymer supported synthesis of peptide and non-peptide libraries). Compounds may be clinically tagged for ease of identification (Chabala, Curr Opin Biotechnol 1995 6(6):633-9, Solid-phase combinatorial chemistry and novel tagging methods for identifying leads).

[0248] The combinatorial synthesis of carbohydrates and libraries containing oligosaccharides have been described (Schweizer et al., Curr Opin Chem Biol 3(3):291-8, Combinatorial synthesis of carbohydrates). The synthesis of natural-product based compound libraries has been described (Wessjohann, Curr Opin Chem Biol 4(3):303-9, Synthesis of natural-product based compound libraries).

[0249] Libraries of nucleic acids are prepared by various techniques, including by way of non-limiting example the ones described herein, for the isolation of aptamers. Libraries that include oligonucleotides and polyaminooligonucleotides (Markiewicz et al., Synthetic oligonucleotide combinatorial libraries and their applications, Farmaco.
55:174-7, 2000) displayed on streptavidin magnetic beads are known. Nucleic acid libraries are known that can be coupled to parallel sampling and be deconvoluted without complex procedures such as automated mass spectrometry (Enjalbal C. Martinet J. Aubagnac JL, Mass spectrometry in combinatorial chemistry, Mass Spectrometry Reviews. 19:139-61, 2000) and parallel tagging. (Perrin DM., Nucleic acids for recognition and catalysis: landmarks, limitations, and looking to the future, Combinatorial Chemistry & High Tlaroughput Screening 3:243-69).

[0250] 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 Throughput Screening 3:167-83, 2000; a1-Obeidi, Mol Biotechraol 1998 9(3):205-23, Peptide and peptidomimetric libraries. Molecular diversity and drug design). The synthesis may be entirely random or based in part on a known polypeptide.

[0251] Polypeptide libraries can be prepared according to various techniques.
In brief, phage display techniques 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 may be used as the basis for synthesis of peptidomimetics. Polypeptides, constrained peptides, proteins, protein domains, antibodies, single chain antibody fragments, antibody fragments, and antibody combining regions are displayed on filamentous phage for selection.

[0252] Large libraries of individual variants of human single chain Fv antibodies have been produced. See, e.g., Siegel RW. Allen B. Pavlik P. Marks JD. Bradbury A., Mass spectral analysis of a protein complex using single-chain antibodies selected on a peptide target: applications to functional genomics, Journal of Molecular Biology 302:285-93, 2000; Poul MA. Becerril B. Nielsen UB. Morisson P. Marks JD., Selection of tumor-specific internalizing human antibodies from phage libraries. Source Jou~ual ofMolecular Biology. 301:1149-61, 2000; Amersdorfer P. Marks JD., Phage libraries fox generation of anti-botulinum scFv antibodies, Methods i~c Moleculaf° Biology. 145:219-40, 2001;
Hughes-Jones NC. Bye JM. Gorick BD. Marks JD. ~uwehand WH., Synthesis of Rh Fv phage-antibodies using VH and VL germline genes, Bf°itish Jou~hal of Haematology.
105:811-6, 1999; McCall AM. Amoroso AR. Sautes C. Marks JD. Weiner LM., Characterization of anti-mouse Fc gamma RII single-chain Fv fragments derived from human phage display libraries, Immufzoteeh~rology. 4:71-87, 1998; Sheets MD.
Amersdorfer P. Finnern R. Sargent P. Lindquist E. Schier R. ~iemingsen G. Wong C.
Gerhart JC. Marks JD. Lindquist E., Efficient construction of a large nonimrnune phage antibody library: the production of high-affinity human single-chain antibodies to protein . .
antigens (published erratum appears in Proc Natl Acad Sci USA 1999 96:795), Proc Natl Acad Sci TISA 95:6157-62, 1998).

[0253] Focused or smart chemical and pharmacophore libraries can be designed with the help of sophisticated strategies involving computational chemistry (e.g., 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 database 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 Screenirag. 2:211-21, 1999; Eliseev AV. Lehn JM., Dynamic combinatorial chemistry:
evolutionary formation and screening of molecular libraries, Current Topics ira 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).

[0254] Selecting a library of potential scaffolds and a set of assays measuring binding to representative target molecules which are in a particular protein family thus allows the creation of a data set profiling binding of the library to the target protein family. Groups of scaffolds with different sets of binding properties can be identified using the information within this dataset. Thus, groups of scaffolds binding to one, two or three members of the family may be selected for particular applications.

[0255] In many cases, a group of scaffolds exhibiting binding to two or more members of a target protein family will contain scaffolds with a greater 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" which severely complicate the interpretation of screening assays (see McGovern et al .Iournal of Medicinal Chemistry 45:1712-22, 2002). Thus, in many preferred applications the property of displaying binding to multiple target molecules in a protein family may be used as a selection criteria to identify molecules with desirable properties.
In addition, groups of scaffolds binding to specific subsets of a set of potential target molecules may be selected. Such a case would include the subset of scaffolds that bind to any two of three or three of five members of a target protein family.

(0256] Such subsets may 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 inhibiting some members of a protein family had known desirable effects, such as inhibiting tumor growth, whereas inhibiting other members of the protein family which were found ~to be essential for normal cell function would have undesirable effects. A criteria that would be useful in such a case includes selecting the subset of scaffolds binding to any two of three desirable target molecules and eliminating from this group any that bound to more than one of any three undesirable target molecules.
H. Crystallography [0257] After binding compounds have been determined, the orientation of compound bound to target is determined. Preferably this determination involves crystallography on co-crystals of molecular scaffold compounds with target. Most protein crystallographic platforms can preferably be designed to analyze up to about 500 co-complexes of compounds, ligands, or molecular scaffolds bound to protein targets due to the physical parameters of the instruments and convenience of operation.

[0258] If the number of scaffolds that have binding activity exceeds a number convenient for the application of crystallography methods, the scaffolds can be placed into groups based on having at least one common chemical structure or other desirable characteristics, and representative compounds can be selected from one or more of the classes. Classes can be made with increasingly exacting criteria until a desired number of classes (e.g., 10, 20, 50, 100, 200, 300, 400, 500) is obtained. The classes can be based on chemical structure similarities between molecular scaffolds in the class, e.g., all possess a pyrrole ring, benzene ring, or other chemical feature. Likewise, classes can be based on shape characteristics, e.g., space-filling characteristics.

[0259] The co-crystallography analysis can be performed by co-complexing each scaffold with its target, e.g., at concentrations of the scaffold that showed activity in the screening assay. This co-complexing can, for example, be accomplished with the use of low percentage organic solvents with the target molecule and then concentrating the target with each of the scaffolds. In preferred embodiments these solvents are less than 5%
organic solvent such as dimethyl sulfoxide (DMSO), ethanol, methanol, or ethylene glycol in water or another aqueous solvent.

[0260] Each scaffold complexed to the target molecule can then be screened with a suitable number of crystallization screening conditions at appropriate temperature, e.g., both 4 and 20 degrees. In preferred embodiments, about 96 crystallization screening conditions can be performed in order to obtain Buff cient information about the co-complexation and crystallization conditions, and the orientation of the scaffold at the binding. site of the target molecule. Crystal structures can then be analyzed to determine how the bound scaffold is oriented physically within the binding site or within one or more binding pockets of the molecular family member.

[0261] It is desirable to determine the atomic coordinates of the compounds bound to the target proteins in order to determine which is a most suitable scaffold for the protein family. X-ray crystallographic analysis is therefore most preferable for determining the atomic coordinates. Those compounds selected can be further tested with the application of medicinal chemistry. Compounds can be selected for medicinal chemistry testing based on their binding position in the target molecule. For example, when the compound binds at a binding site, the compound's binding position in the binding site of the target molecule can be considered with respect to the chemistry that can be performed on chemically tractable structures or sub-structures of the compound, and how such modifications on the compound are expected to interact with structures or sub-structures on the binding site of the target. Thus, one can explore the binding site of the target and the chemistry of the scaffold in order to make decisions on how to modify the scaffold to arrive at a ligand with higher potency and/or selectivity.

[0262] The structure of the target molecule bound to the compound may also be superimposed or aligned with other structures of members of the same protein family. In this way modifications of the scaffold can be made to enhance the binding to members of the target family in general, thus enhancing the utility of the scaffold library. Different useful alignments may be generated, using a variety of criteria such as minimal RMSD
superposition of alpha-carbons or backbone atoms of homologous or structurally related regions of the proteins.

[0263] These processes allow for more direct design of ligands, by utilizing structural and chemical information obtained directly from the co-complex, thereby enabling one to more efficiently and quickly design lead 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, very low affinity, or extremely low affinity. It may also be advantageous to perform co-crystallography on a selection of scaffolds that bind with any combination of affnuties.

[0264] Standard X-ray protein diffraction studies such as by using a Rigaku RU-200~
(Rigaku, Tokyo, Japan) with an X-ray imaging plate detector or a synchrotron beam-line can be performed on co-crystals and the diffraction data measured on a standard X-ray detector, such as a CCD detector or an X-ray imaging plate detector.
Performing X-ray crystallography on about 200 co-crystals should generally lead to about 50 co-crystal structures, which should provide about 10 scaffolds for validation in chemistry, which should finally result in about 5 selective leads for target molecules.

[0265] Additives that promote co-crystallization can of course be included in the target molecule formulation in order to enhance the formation of co-crystals. In the case of proteins or enzymes, the scaffold to be tested can be added to the protein formulation, which is preferably present at a concentration of approximately 1 mg/ml. The formulation can also contain between 0%-10% (v/v) organic solvent, e.g. DMSO, methanol, ethanol, propane diol, or 1,3 dimethyl propane diol (MPD) or some combination of those organic solvents. Compounds are preferably solubilized in the organic solvent at a concentration of about 10 mM and added to the protein sample at a concentration of about 100 mM. The protein-compound complex is then concentrated to a final concentration of protein of from about 5 to about 20 mg/ml. The complexation and concentration steps can conveniently be performed using a 96 well formatted concentration apparatus (e.g., Amicon Inc., Piscataway, NJ). Buffers and other reagents present in the formulation being crystallized can contain other components that promote crystallization or are compatible with crystallization conditions, such as DTT, propane diol, glycerol.

[0266] The crystallization experiment can be set-up by placing small aliquots of the concentrated protein-compound complex (e.g., 1 ~,l) in a 96 well format and sampling under 96 crystallization conditions. (Other formats can also be used, for example, plates with fewer or more wells.) Crystals can typically be obtained using standard crystallization protocols that can involve the 96 well crystallization plate being placed at different temperatures. Co-crystallization varying factors other than temperature can also be considered for each protein-compound complex if desirable. For example, atmospheric pressure, the presence or absence of light or oxygen, a change in gravity, and many other variables can all be tested. The person of ordinary skill in the art will realize other variables that can advantageously be varied and considered. Conveniently, commercially available crystal screening plates with specified conditions in individual wells can be utilized.
I. Virtual Assays [0267] As described above, virtual assays or compound design techniques are useful for identification and design of modulators; such techniques are also applicable to a molecular scaffold method. Commercially available software that generates three-dimensional graphical representations of the complexed target and compound from a set of coordinates provided can be used to illustrate and study how a compound is oriented when bound to a target. (e.g., InsightII~, Accelerys, San Diego, CA; or Sybyl~, Tripos Associates, St.
Louis, MO). Thus, the existence of binding pockets at the binding site of the targets can be particularly useful in the present invention. These binding pockets are revealed by the crystallograpluc structure determination and show the precise chemical interactions involved in binding the compound to the binding site of the target. The person of ordinary skill will realize that the illustrations can also be used to decide where chemical groups might be added, substituted, modified, or deleted from the scaffold to enhance binding or another desirable effect, by considering where unoccupied space is located in the complex and which chemical substructures might have suitable size and/or charge characteristics to fill it. The person of ordinary skill will also realize that regions within the binding site can be flexible and its properties can change as a result of scaffold binding, and that chemical groups can be specifically targeted to those regions to achieve a desired effect. Specific locations on the molecular scaffold can be considered with reference to where a suitable chemical substructure can be attached and in which conformation, and which site has the most advantageous chemistry available.

[0268] An understanding of the forces that bind the compounds to the target proteins reveals which compounds can most advantageously be used as scaffolds, and which properties can most effectively be manipulated in the design of ligands. The person of ordinary skill will realize that steric, ionic, polar, hydrogen bond, and other forces can be considered for their contribution to the maintenance or enhancement of the target-compound complex. Additional data can be obtained with automated computational methods, such as docking and/or molecular dynamics simulations, which can afford a measure of the energy of binding. In addition, to account for other effects such as entropies of binding and desolvation penalties, methods which provide a measure of these effects can be integrated into the automated computational approach. The compounds selected can be used to generate information about the chemical interactions with the target or for elucidating chemical modifications that can enhance selectivity of binding of the compound.

[0269] 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 the Tripos software suite (Tripos Associates, St. Louis, MO). The form for that equation is shown below:
OGbind = Gtr + OGhb + OGion + ~Glipo + ~Garom + ~Grot where: OGtr is a constant term that accounts for the overall loss of rotational and translational entropy of the lignand, OGhb accounts for hydrogen bonds formed between the ligand and protein, OGion accounts for the ionic interactions between the ligand and protein, OGlipo accounts for the lipophilic interaction that corresponds to the protein-ligand contact surface, ~Garom accounts for interactions between aromatic rings in the protein and ligand, and OGrot accounts for the entropic penalty of restricting rotatable bonds in the ligand upon binding. The calculated binding energy for compounds that bind strongly to a given target will likely be lower than 25 kcal/mol, while the calculated binding affinity for a good scaffold or an unoptimized compound will generally be in the range of -15 to -20. The penalty for restricting a linker such as the ethylene glycol or hexatriene is estimated as typically being in the range of +5 to +15.

[0270] This method estimates the free energy of binding that a lead compound should have to a target protein for which there is a crystal structure, and it accounts for the entropic penalty of flexible linkers. It can therefore be used to estimate the penalty incurred by attaching linkers to molecules being screened and the binding energy that a lead compound must attain in order to overcome the penalty of the linker. The method does not account for solvation, and the entropic penalty is likely overestimated when the linkers are bound to the solid phase through an additional binding complex, e.g., a biotinatreptavidin complex.

[0271] Another exemplary method for calculating binding energies is the MM-PBSA
technique (Massova and Kollman, Journal of the Anzerican Chemical Society 121:8133-43,1999; Chong et al, Proceedings of theNational 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 complexed target molecule, then calculates an interaction energy using the well-known AMBER force field (Cornell, et al Jourtzal of the American Chemical Society 117:5179-97 1995) with corrections for desolvation and entropy of binding from the ensemble.

[0272] Use of this method yields binding energies highly correlated with those found experimentally. The absolute binding energies calculated with this method are reasonably accurate, and the variation of binding energies is approximately linear with a slope of 1+/-0.5. Thus, the binding energies of compounds interacting strongly with a given target will be lower than about -8 kcal/mol, while a binding energy of a good scaffold or unoptimized compound will be in the range of -3 to -7 kcal/mol.

[0273] Computer models, such as homology models (i.e., based on a known, experimentally derived structure) can be constructed using data from the co-crystal structures. A computer program such as Modeller (Accelrys, San Diego CA) may be used to assign the three dimensional coordinates to a protein sequence using an alignment of sequences and a set or sets of template coordinates. When the target molecule is a protein or enzyme, preferred co-crystal structures for making homology models contain high sequence identity in the binding site of the protein sequence being modeled, and the proteins will preferentially also be within the same class and/or fold family.
Knowledge of conserved residues in active sites of a protein class can be used to select homology models that accurately represent the binding site. Homology models can also be used to map structural information from a surrogate protein where an apo or co-crystal structure exists to the target protein.

[0274] Virtual screening methods, such as docking, can also be used to predict the binding configuration and affinity of scaffolds, compounds, and/or combinatorial library members to homology models. Using this data, and carrying out "virtual experiments"
using computer software can save substantial resources and allow the person of ordinary skill to make decisions about which compounds can be suitable scaffolds or ligands, without having to actually synthesize the ligand and perform co-crystallization. Decisions thus can be made about which compounds merit actual synthesis and co-crystallization.
An understanding of such chemical interactions aids in the discovery and design of drugs that interact more advantageously with target proteins and/or are more selective for one protein family member over others. Thus, applying these principles, compounds with superior properties can be discovered.
J. Ligand Design and Preparation (0275] The design and preparation of ligands can be performed with or without structural and/or co-crystallization data by considering the chemical structures in common between the active scaffolds of a set. In this process structure-activity hypotheses can be formed and those chemical structures found to be present in a substantial number of the scaffolds, including those that bind with low affinity, can be presumed to have some effect on the binding of the scaffold. 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 scaffolds can be tested to disprove the maximum number of binding and/or structure-activity hypotheses.
The remaining hypotheses can then be used to design ligands that achieve a desired binding.
and biochemical effect.

[0276] But in many cases it will be preferred to have co-crystallography data for consideration of how to modify the scaffold to achieve the desired binding effect (e.g., binding at higher affinity or with higher selectivity). Using the case of proteins and enzymes, co-crystallography data shows the binding pocket of the protein with the molecular scaffold bound to the binding site, and it will be apparent that a modification can be made to a chemically tractable group on the scaffold. For example, a small volume of space at a protein binding site or pocket might be filled by modifying the scaffold to include a small chemical group that fills the volume. Filling the void volume can be expected to result in a greater binding affinity, or the loss of undesirable binding to another member of the protein family. Similarly, the co-crystallography data may show that deletion of a chemical group on the scaffold may decrease a hindrance to binding and result in greater binding affinity or specificity.

[0277] Various software packages have implemented techniques which facilitate the identification and characterization of interactions of potential binding sites from complex structure, or from an apo structure of a target molecule, i.e. one without a compound bound (e.g. SiteID, Tripos Associates, St. Louis MO and SiteFinder, Chemical Computing Group, Montreal Canada, GRID, Molecular Discovery Ltd., London UK ). Such techniques can be used with the coordinates of a complex between the scaffold of interest and a target molecule, or these data in conjunction with data for a suitably aligned or superimposed related target molecule, in order to evaluate changes to the scaffold that would enhance binding to the desired target molecule structure or structures.
Molecular Interaction Field-computing techniques, such as those implemented in the program GRID, result in energy data for particular positive and negative binding interactions of different computational chemical probes being mapped to the vertices of a matrix in the coordinate space of the target molecule. These data can then be analyzed for areas of substitution around the scaffold binding site which are predicted to have a favorable interaction for a particular target molecule. Compatible chemical substitution on the scaffold e.g. 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 affinity of the scaffold.
Conversely, a scaffold could be made more selective for a particular target molecule by making such a substitution in a region predicted to have an unfavorable hydrophobic interaction in a second, related undesirable target molecule.

[0278] It can be desirable to take advantage of the presence of a charged chemical group located at the binding site or pocket of the protein. For example, a positively charged group can be complemented with a negatively charged group introduced on the molecular scaffold. This can be expected to increase binding affinity or binding specificity, thereby resulting in a more desirable ligand. In many cases, regions of protein binding sites or pockets 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 (e.g., hydrophobic, electrostatic, or entropic) that allow a compound to be more specific for one protein target over another or to bind with greater affinity, thereby enabling one to synthesize a compound with greater selectivity or affinity for a particular family member. Additionally, certain regions can contain amino acids that are known to be more flexible than others. This often occurs in amino acids contained in loops connecting elements of the secondary structure of the protein, such as alpha helices or beta strands. Additions of chemical moieties can also be directed to these flexible regions in order to increase the likelihood of a specific interaction occurring between the protein target of interest and the compound. Virtual screening methods can also be conducted in silico to assess the effect of chemical additions, subtractions, modifications, and/or substitutions on compounds with respect to members of a protein family or class.

[0279] The addition, subtraction, or modif cation of a chemical structure or sub-structure to a scaffold can be performed with any suitable chemical moiety. For example the following moieties, which are provided by way of example and are not intended to be limiting, can be utilized: hydrogen, alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenylthio, phenyl, phenylalkyl, phenylalkylthio, hydroxyalkyl-thio, alkylthiocarbbamylthio, cyclohexyl, pyridyl, piperidinyl, alkylamino, amino, nitro, mercapto, cyano, hydroxyl, a halogen atom, halomethyl, an oxygen atom (e.g., forming a ketone or N-oxide) or a sulphur atom (e.g., forming a thiol, thione, di-alkylsulfoxide or sulfone) are all examples of moieties that can be utilized.

[0280] Additional examples of structures or sub-structures that may be utilized 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 moieties; an amine of formula -NX2X3, where Xa and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties; halogen or trihalomethyl; a ketone of formula -COX4, where X4 is selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties; a carboxylic acid of formula -(XS)"COOH or ester of formula (X6)nCOOX~, where X5, X6, and X~ and are independently selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or l; an alcohol of formula (X8)"OH or an alkoxy moiety of formula -(X8)"OX9, where Xg and X~ are independently selected from the group consisting of,saturated or unsaturated allcyl and homocyclic or heterocyclic ring moieties, wherein said 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 where n is 0 or l; an amide of formula NHCOXIO, where Xlo is selected from the group consisting of alkyl, hydroxyl, and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester; SOz, NXII Xlz, where Xl and XIZ are selected from the group consisting of hydrogen, alkyl, and homocyclic or heterocyclic ring moieties; a homocyclic or heterocyclic ring moiety 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 formula -COH; a sulfone of formula -SO2Xl3, where Xi3 is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties;
and a nitro of formula -NOz.
K. Identification of Binding Characteristics of Binding Compounds [0281] It can also be beneficial in selecting compounds for testing to first identify binding characteristics that a ligand should advantageously possess. This can be accomplished by analyzing the interactions that a plurality of different binding compounds have with a particular target, e.g., interactions with one or more conserved residues in the binding site. These interactions are identified by considering the nature of the interacting moieties. 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 Allowed Sites for Attachment [0282] In addition to the identification and development of ligands, determination of the orientation of a molecular scaffold or other binding compound in a binding site allows identification of energetically allowed sites for attachment of the binding molecule to another component. For such sites, any free energy change associated with the presence of the attached component should not destablize the binding of the compound to the target to an extent that will disrupt the binding. Preferably, the binding energy with the attachment should be at least 4 kcal/mol., more preferably at least 6, 8, 10, 12, 15, or 20 kcal/mol. Preferably, the presence of the attachment at the particular site reduces binding energy by no more than 3, 4, 5, 8, 10, 12, or 15 kcal/mol.
In many cases, suitable attachment sites will be those that are exposed to solvent when the binding compound is bound in the binding site. In some cases, attachment sites can be used that will result in small displacements of a portion of the enzyme without an excessive energetic cost. Exposed sites can be identified in various ways. For example, exposed sites can be identified using a graphic display or 3-dimensional model. In a grahic display, such as a computer display, an image of a compound bound in a binding site can be visually inspected to reveal atoms or groups on the compound that are exposed to solvent and oriented such that attachment at such atom or group would not preclude binding of the enzyme and binding compound. Energetic costs of attachment can be calculated based on changes or distortions that would be caused by the attachment as well as entropic changes.

[0283] Many different types of components can be attached. Persons with skill are familiar with the chemistries used for various attachments. Examples of components that can be attached include, without limitation: solid phase components such as beads, plates, chips, and wells; a direct or indirect label; a linker, which may be a traceless linker; among others. Such linkers can themselves be attached to other components, e.g., to solid phase media, labels, and/or binding moieties.
The binding energy of a compound and the effects on binding energy for attaching the molecule to another component can be calculated approximately by manual calculation, or by using any of a variety of available computational virtual assay techniques, such as docking or molecular dynamics simulations. A virtual library of compounds derived from the attachment of components to a particular scaffold can be assembled using a variety of software programs (such as Afferent, MDL Information Systems, San Leandro, CA
or CombiLibMalcer, Tripos Associates, St. Louis, MO). This virtual library can be assigned 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 may then be submitted to the appropriate computational technique for evaluation of binding energy to a particular target molecule. This information can be used for purposes of prioritizing compounds for synthesis, for selecting a subset of chemically tractable compounds for synthesis, and for providing data to correlate with the experimentally determined binding energies for the synthesized compounds.

[0284] The crystallographic determination of the orientation of the scaffold in the binding site specifically enables more productive methods of assessing the likelihood of the attachment of a particular component resulting in an improvement in binding energy.
Such an example is shown for a docking-based strategy in Haque et al .lout raal of Medicinal Chemistry 42:1428-40, 1999, wherein an "Anchor and Grow" technique which relied on a crystallographically determined fragment of a larger molecule, potent and selective inhibitors were rapidly created. The use of a crystallographically characterized small molecule fragment in guiding the selection of productive compounds for synthesis has also been demonstrated in Boehm et al, Journal ofMedicinal Chemistry 43:2664-74, 2000. An illustration of the use of crystallographic data and molecular dynamics simulations in the prospective assessment of inhibitor binding energies can be found in Pearlman and Chaxifson, Journal of Medicinal Chemistry 44, 3417-23, 2001.
Another important class of techniques which rely on a well defined structural starting point for computational design is the combinatorial growth algorithm based systems, such as the GrowMol program (Bohacek and McMartin, Journal of the American Chemical Society 116:5560-71, 1994. These techniques have been used to enable the rapid computational evolution of virtual inhibitor computed binding energies, and directly led to more potent synthesized compounds whose binding mode was validated crystallographically (see Organic Letters (2001) 3(15):2309-2312).
(1) Linkers [0285] Linkers suitable for use in the invention can be of many different types. Linkers can be selected for particular applications based on factors such as linker chemistry compatible for attachment to a binding compound and to another component utilized in the particular application. Additional factors can include, without limitation, linker length, linker stability, and ability to remove the linker at an appropriate time.
Exemplary linkers include, but are not limited to, hexyl, hexatrienyl, ethylene glycol, and peptide linkers.
Traceless linkers can also be used, e.g., as described in Plunkett, M. J., and Ellman, J. A., 1995, J. Org. Chena., 60:6006.

[0286] Typical functional groups, that are utilized to link binding compound(s), include, but not limited to, carboxylic acid, amine, hydroxyl, and thiol. (Examples can be found in Solid-supported combinatorial and parallel synthesis of small molecular weight compound libraries; Tetrahedron organic chemistry series Vo1.17; Pergamon, 1998; p85).
(2) Labels [0287] As indicated above, labels can also be attached to a binding compound or to a linker attached to a binding compound. Such attachment may be direct (attached directly to the binding compound) or indirect (attached to a component that is directly or indirectly attached to the binding compound). Such labels allow detection of the compound either directly or indirectly. Attachment of labels can be performed using conventional chemistries. Labels can include, for example, fluorescent labels, radiolabels, light scattering particles, light absorbent particles, magnetic particles, enzymes, and specific binding agents (e.g., biotin or an antibody target moiety).
(3) Solid Phase Media [0288] Additional examples of components that can be attached directly or indirectly to a binding compound include various solid phase media. Similar to attachment of linkers and labels, attachment to solid phase media can be performed using conventional chemistries. Such solid phase media can include, for example, small components such as beads, nanoparticles, and fibers (e.g., in suspension or in a gel or chromatographic matrix).
Likewise, solid phase media can include larger objects such as plates, chips, slides, and tubes. In many cases, the binding compound will be attached in only a portion of such an objects, e.g., in a spot or other local element on a generally flat surface or in a well or portion of a well.
IV. Administration [0289] The methods and compounds will typically be used in therapy for human patients. However, they may also be used to treat similar or identical diseases in other vertebrates, e.g., mammals such as other primates, sports animals, bovines, equines, porcines, ovines, and pets such as dogs and cats.

[~02'9U] Suitable dosage forms, in part, depend upon the use or the route of administration, for example, oral, transdermal, transmucosal, or by injection (parenteral).
Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, PA, 1990 (hereby incorporated by reference herein).
[0291] Compounds can be formulated as pharmaceutically acceptable salts.
Pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
[0292] Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, malefic 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 quinic acid.
[0293] 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 acidic functional groups, such as carboxylic acid or phenol are present. For example, see Remin~ton'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.
[0294] 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 in 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 acid in an organic solvent.
[0295] The pharmaceutically acceptable salt of the different compounds may be present as a complex. Examples of complexes include 8-chlorotheophylline complex (analogous to, e.g., dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:l) complex;
Dramamine) and various cyclodextrin inclusion complexes.
[0296] Carriers or excipients can be used to produce pharmaceutical compositions. The Garners or excipients can 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 inj ection (WFI), saline solution, and dextrose.
[0297] The compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, or transdermal.
Oral administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.
[0298] Pharmaceutical preparations for oral use can be obtained, for example, by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugaxs, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize staxch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate.
_78_ [0'299] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[0300] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin ("gelcaps"), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler 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 may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGS). In addition, stabilizers may be added.
[0301] Alternatively, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and/orsubcutaneous. For injection, the compounds of the invention are formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
[0302] Administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated 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. Tn addition, detergents may be used to facilitate permeation.
Transmucosal administration, for example, may be through nasal sprays or suppositories (rectal or vaginal).
[0303] The amounts of various compound to be administered can be determined by standard procedures taking into account factors such as the compound ICSO, the biological half life of the compound, the age, size, and weight of the patient, and the disorder _79_ associated with the patient. The importance of these and other factors are well known to those of ordinary skill 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 may be used.
V. Synthesis of Compounds of Formula I
(0304] 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 utilized by one skilled in chemical synthesis.
[0305] Certain of the syntheses can utilize key intermediate II in the synthesis. Key intermediate II can be prepared as follows:
Synthesis of Key Intermediate II
[0306] One synthetic route for Intermediate II compounds is shown below. In these compounds, Y and Z (as well as U, V, and W) can be C as in indole, or can be other heteroatoms as specified for Formula I, and R3, R4, and RS are as specified for Formula I
or a sub-generic description within Formula I. In synthetic Scheme Ia and other synthetic schemes described herein for groups of compounds, it should be understood that generic formulas in the schemes (e.g., Formula III in Scheme la) describe a set of compounds, but are referenced in the text description of the synthesis in the singular.
Scheme la:
C02Me COZMe R5 O H o o R5 ~ R5 R4 Me~~~P. 4 4 s . I .,X ~ Ra i I . X LH~ Ra i I . X
R Y H R .Y H R Y H
III IV n Step 1- Preparation of compound of formula ITS

[0307] Compound IV was prepared by reacting commercially available aldehyde III
with an activated phosphonate ester in an inert solvent (e.g. tetrahydrofuran) under reflux conditions, typically for 16-24 h, as described by Garuti et al in Arch.
Pharzyz,1988, 321, 377-83). Compound III, in turn, can be prepared by reacting compound V under Vilsmeier (POC13 and DMF) conditions as described by izz May~ch's Advanced Organic Chezzistzy, Srh Editiozz, p. 71 S.
Step 2 - P~epa~atioh of izztez"mediate II:
[0308] Key intermediate II was prepared by the reduction of IV in an inert solvent (i.e.
tetrahydrofuran) by catalytic hydrogenation (typically 10% palladium on activated carbon and atmospheric hydrogen) as described by Garuti et al in Arch. Pharm,1988, 321, 377-83).
Scheme 1b:
[0309] Key Intermeidate II compounds can also be prepared in accordance with Scheme 1b as shown below.
R5 R5 f 5 CO2Et R4 4 Nv 4 R
I ~,X ~ R i I ~ X --~ R ~ . ~C02Et R3 Y H R3 Y H R3 ,Y I N X
H
V VI VII
C02H C02Me I ~ X --~- ~ I ~ X

la II
Step 1 - Pz~epa~atiozz of formula TEL
[0310] Compound VI was prepared conventionally by a reacting commercially available compound of formula V with an N,N-diall~yl amine hydrochloride in a polar solvent (e.g.
i-Propanol), in the presence of formaldehyde and heated, typically near 90 °C, typically for 24h, as described by SzzydeY et al, JACS, 73, 970.

Step 2 - Preparation of forrnula YIL
[0311] Compound of formula VII was prepared by heating compound VI with diethyl malonate and a catalytic amount of sodium metal, typically at 120° C as described by Robinson et. al, JACS, 78, 1247, followed by flash chromatography purification.
Step 3 - PreparatiotZ of fonmula Ia:
[0312] Compound of formula Ia was prepared by hydrolyzing compound VII using aqueous base (e.g. NaOH) followed by the decarboxylation under reflux conditions (JACS, 78, 1247).
Step 4 - Preparation of intermediate IL' [0313] Intermediate II was prepared by Fisher esterification of compound Ia with alcohol (e. g. Methanol) and catalytic amount of an acid (e.g. HCl) under reflux, typically for 16-24 h.
Scheme lc:
[0314] Compounds of I~ey Intermediate II can also be prepared according to Scheme 1 c as shown below.
C02Me C02Me R4 R Ra R Br 4 R5 ~ 4 R5 I ~X > . I v.X ~ R . I ~X IH-- > >R . I ~X

R Y H R3 Y H R3 Y~H R3 Y~H
V VIII IV
Step 1 - Preparation of forfraula- T~IIL
[0315] Compound VIII can be prepared by a reacting commercially available of a compound of formula V with bromine in an inert solvent (e.g. DMF) (Bocchi and Palla;
Synthesis, 1982, p10967.
Step 2 - Preparation of formula IY.

[0316] Compound IV can be prepared by a reacting compound of formula VIII with methacrylate under Heck coupling conditions as described by Sznaidman et. akin Bioorg.
Med. Chem. Lett., 13, 2003, 1517.
Step 3 - Preparation of intermediate II:
[0317] Key intermediate II was prepared by the reduction of IV in an inert solvent (i.e.
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 Ia [0318] Compounds of Formula Ia can be prepared by hydrolysis of Key Intermediate II
as shown in S cheme II.
Scheme 2 C02Me C02H

R4 R Hydrolysis R

. I .X i I .X

H
II la [0319] Compound of formula Ia was prepared by the hydrolysis of key intermediate of formula II with aqueous base (e. g. ~aq. NaOH), typically for 6-15 h and isolating the product by conventional methods (e.g. aqueous work up and purification by chromatography) Jerry March in March's Advanced Organic Chenistry, 5'h Edition, p. 71 S.
Synthesis of Compound Ib [0320] Compounds of Formula Ib, in which the indole ring is substituted at the position (or corresponding position of the other bi-cyclic rings of Formula I), can be prepared according to Scheme 3.

Scheme 3 C02Me C02Me CO2H
R5 Rs Rs R4 , R2W R4 , Hydrolysis R4.
3 ' ~ ~ X -'-~. s w ~ X -~- ' ~ X

II IXa Ib Step 1 - PrepaYation of compound of formula I~Ya:
[0321] Compound of formula IXa was prepared by treating intermediate of formula II
with a base (e. g. sodium hydride) in an inert solvent N,N-Dimethylformamide, followed by the addition of Rah, where "W" is a leaving group (e.g. chloro, bromo), and stirring at RT, typically for 16 to 24 h (Jerry Mach in March's Advanced Organic Chenistry, St'' Edition, p576~. The product was obtained by column chromatography (e. g.
silica gel) after workup using conventional methods.
Step 2 - Preparation of compound of fornaula Ib:
[0322] Compound of formula Ib was prepared by the hydrolysis of compound of formula V with aqueous base (e. g. aq. NaOH), typically for 6-15 h and isolating the product by conventional methods (e.g. aqueous work up and purification by chromatography).
Synthesis of Compound Ic [0323] Compounds of Formula Ic, in which R2 is Rl°Ri 1NCZ, can be prepared according to Scheme 4.
Scheme - 4 C02Me C02Me C02H
R5 Rs Rs R4 R~oR~~NCZ R4 , Hydrolysis R4 X a w X ~- w X

II IXb Ic Step 1 - Preparation of compound of fo>"rnula IXb:
[0324] Compound of formula IXb was prepared by treating intermediate of formula II
with a base (e. g. sodium hydride) in an inert solvent (DMF) followed by the addition of R16NCZ, where "Z" is oxygen or sulfur, and stirring at RT, typically for 16 to 24 h (Jerry March in March's Advanced Organic Chenistry, 5'h Edition, p1191). The product was obtained by column chromatography (e. g. silica gel) after workup using conventional methods.
[0325] Compound of formula IXb can also be prepared by treating intermediate of formula II with R16NCZ, where "Z" is oxygen or sulfur, in an inert solvent (THF) followed by the addition of catalytic amount of DMAP (N,N,-dimethylaminopyridine) and stirring at RT, typically for 16 to 24 h. The product can be obtained by column chromatography (e. g. silica gel) after workup using conventional methods.
Step 2 - Preparation of compound of formula Ic:
[0326] Compound of formula Ic was prepared by the hydrolysis of compound of formula IXb with aqueous base (e. g. aq. NaOH), typically for 6-15 h and isolating the product by conventional methods (e.g. aqueous work up and purification by chromatography}.
[0327] In compound of formula Ic, substituent R2 would then be Rl°R11NCZ.
Synthesis of Compound Id Compounds of Formula Id can be prepared according to Scheme Sa.
Scheme - 5a C02Me C02Me C02H
Br R5 R4B(OH)2 R4 R5 Hydrolysis R R5 ~~X ~ ~~~,X 4~I~X
R3 Y RZ R3 Y RZ R3 Y Ra IXc IXd Id Step 1 - Preparation of compound of fontnula IXd [0328] Compound of formula IXd was prepared from compound of formula IXc by reacting it with aryl boronic acids under Suzuki reaction conditions (March's Advanced Organic Chemistry, S'j' Edition, p8) and heating the reaction mixture, typically 90° C, for 24 and isolating the product by conventional methods (e.g. aqueous work up and purification by chromatography).
[0329] Compound of formula IXc was in turn prepared from commercially available compound of formula V, where "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 compound of formula Id [0330] Compound of formula Id was prepared by the hydrolysis of compound of formula IXd with aqueous base (e. g. aq. NaOH), typically for 6-15 h and isolating the product by conventional methods (e.g. aqueous work up and purification by chromatography).
Scheme Sb B r ~ R4 , ' R4 I X
R3 Y I H X -~ R3 Y N ~ R3 Y I N X
H H
Va V VI
. C02H
R5 C02Et R5 R4 , ~COZEt ' R i I , X
. I .X s , R3 y H R Y
VII la C02Me CO2Me C02H

R4 R Z R4 R Hydrolysis R R5 RW
w I ~ X ~ ~ I ~ X ---~ 4 ~ I ;X
R3 Y H Rs Y N 2 R3 Y N z R R
IXa Ib Step 1 - P~epaYation of compound of formula Y
[0331] Compound of formula V was prepared from commercially available compound of formula Va by reacting it with aryl boronic acids under I~umada reaction conditions as described by Hayashi et. al, JA CS, 106(1984), 158 -163, and heating the reaction mixture, typically 90° C, for 24 and isolating the product by conventional methods (e.g. aqueous work up and purification by chromatography).
Step 2 - P~epa~atiofa of fof°naula Vl.
[0332] Compound VI was prepared conventionally by a reacting commercially available compound of formula V with an N,N-dialkyl amine hydrochloride in a polar solvent (e.g.
i-Propanol), in the presence of formaldehyde and heated, typically near 90 °C, typically for 24h, as described previously for compound VI.
Step 3 - Prepa~~ation of formula ~'IL~
[0333] Compound of formula VII was prepared by heating compound Vl with diethyl malonate and a catalytic amount of sodium metal, typically at 120° C as described previously, followed by flash chromatography purification.

Step 4 - Preparation of forfraula Ia:
[0334] Compound of formula Ia was prepared by hydrolyzing compound VII using aqueous base (e.g. NaOH) followed by the decarboxylation under reflux conditions as described previously.
Step 5 - Preparatiora of intermediate IL~
[0335] Intermediate II was prepared by Fisher esterification of compound Ia with alcohol (e. g. Methanol) and catalytic amount of an acid (e.g. HCl) under reflux, typically for 16-24h.
Step 6 - Preparation of compound of formula IXa:
[0336] Compound of formula IXa was prepared by treating intermediate of formula II
with a base (e. g. sodium hydride, NaH) in an inert solvent (DMF) followed by the addition of "RZW", where "W" is a leaving group (e.g. chloro, bromo), and stirring at RT, typically for 16 to 24 h. The product was obtained by column chromatography (e. g. silica gel) after workup using conventional methods.
Step 7 - Preparation of eompourad of formula Ib:
[0337] Compound of formula Ib was prepared by the hydrolysis of compound of formula IXa with aqueous base (e. g. aq. NaOH), typically for 6-15 h and isolating the product by conventional methods (e.g. aqueous work up and purification by chromatography).
Synthesis of Compound X
Scheme 6 _88_ C02H COZMe Rs Rs Rs Ra Ra ~ I ~X ~ , I ~X ~ , I ~X
Ra Y H Rs Y... H R3 Y~ H
V XI XII
R5 C02Me R5 C02H
Ra _ Ra --~ . I ~X ~ , I ~X
R3 y N Rs y N
Rz Rz XIII X
Step - 1 Preparatiozz of Intermediate XI
[0338] Compound XI was prepared from the compound V reacting with y-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 - Prepaz°atiozz of Intermediate XII
[0339] Compound XII was prepared by the carboxylic acid XI reacting in either a catalytic amount of sulfuric acid in methanol under reflux conditions, or activated methylene moiety such as diazomethane.
Step 3 - Preparation of Intermediate 1~III
[0340] Compound XIII was prepared by treating intermediate of formula XII with a base (e. g. sodium hydride) in an inert solvent (DMF) followed by the addition of RZW, where "W" is a leaving group (e.g. chloro, bromo), and stirnng at RT, typically for 16 to 24 h (.ferry March in March's Advanced Organic Chenistry, 5'h Edition, p57c~.
The product was obtained by column chromatography (e. g. silica gel) after workup using conventional methods.
Step 4 - Preparation of intermediate X
_89_ [0341] Compound of formula X was prepared by the hydrolysis of compound of formula XIII with aqueous base (e. g. aq. NaOH), typically for 6-15 h and isolating the product by conventional methods (e.g. aqueous work up and purification by chromatography).
Synthesis of compound XIV
Scheme 7 COZMe Ra R5 H R4 R5 OH R

I ~X -~ , I ~X ~ ~ l ~X
Ra Y H Ra Y H Ra Y N
H
III XV XVI
C02Me C02H
Rs Rs . 1 .X --~ ~ l .X
Ra Y RZ Ra Y R2 XVII XIV
Step l: Preparation of Intermediate XV
[0342] Compound XV can be prepared from the corresponding aldehyde III
reacting with a reducting agent such as sodium borohydride in an inert solvent (e.g.
tetrahydrofuran~.
Step 2: Preparation of Intermediate XVI
(0343] Compound XVI can be prepared by reacting the methanol XV with silyl ketene acetal in presence of a catalyst such as magnesium triflimide or perchlorate at ambient temperature for 1-2 hours as described by Grieco et al in Tetraladron Letts (1997, 3~, 2645-2648).
Step 3: Preparation of Intermediate XVII

[0344) Compound XVII was prepared by treating intermediate of formula XVI with a base (e. g. sodium hydride) in an inert solvent (DMF) followed by the addition of RZW, where "W" is a leaving group (e.g. chloro, bromo), and stirring at RT, typically for 16 to 24 h (.Ierf y March in March's Advanced Organic Chenistry, 5'j2 Edition, p57~.
The product was obtained by column chromatography (e. g. silica gel) after workup using conventional methods.
Step 4 Preparation of intermediate ~YIIT~
[0345] Compound of formula XIV was prepared by the hydrolysis of compound of formula XVII with aqueous base (e. g. aq. NaOH), typically for 6-15 h and isolating the product by conventional methods (e.g. aqueous work up and purification by chromatography).
[0346] Using the synthetic schemes described above, a set of exemplary compound was prepared. Those compounds include those listed below, which are also listed in Table 1 along with the chemical structures, along with additional exemplary compounds.
3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid, 3-[5-ethyl-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid, Indazole-3-propionic acid, 5-isopropoxy-3-(1-Benzene-sulfonyl-indol-3y1)-propionic acid, Indole-3-propionic acid, 3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid, 3-[5-Methoxy-1-(3-methoxy-benzyl)-1H-indol-3-yl]-propionic acid, 3-[1-(3-Chloro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-[1-(4-Fluoro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-[1-(4-Chloro-benzyl)-5-methoxy-1H-indol-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-1H-indol-3-yl)-propionic acid, 3-[5-Methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-propionic acid, 3-(1-Benzenesulfonyl-1H-indazol-3-yl)-propionic acid, 3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester, -91 _ 3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester, 3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester, 3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid, 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-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester, 3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester, 3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester, 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester, 3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic acid, 3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester, 3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester, 3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid, 3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester, 3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid methyl ester, 3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid, 3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester, 3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester, 3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid, 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, _9 3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester, 3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid, 3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid methyl ester, 3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid, 3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid methyl ester, 3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid, 3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester, 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 methyl ester, 3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid, 3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester, 3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid, 3-(1-Benzenesulfonyl-5-ethoxy-1H-indol-3-yl)-propionic acid, 3-[1-(4-Isopropoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid methyl ester, 3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid, 3-[1-(4-Ethyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid, 3-(5-bromo-1H-indol-3-yl)-propionic acid, 3-(5-Bromo-1H-indol-3-yl)-propionic acid methyl ester, 3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid methyl ester, 3-(1-Benzenesulfonyl-S-bromo-1H-indol-3-yl)-propionic acid methyl ester, 3-(Benzenesulfonyl-5-thiophen-3-yl-1H-indol-3-yl)-propionic acid methyl ester, 3-(Benzenesulfonyl-5-thiophen-3-yl-1H-indol-3-yl)-propionic acid, 3-(1-Benzenesufonyl-5-pheyl-1H-indol-3-yl) propionic acid methyl ester, 3-(1-Benzenesufonyl-5-pheyl-1H-indol-3-yl) propionic acid, Preparation of 3-(1H-Pyrrolo[2,3-b]pyridine-3-yl)-propionic acid, 3-(5-Methoxy-1H-Indol-3-yl)-propionic acid, 3-(1-Benzenesulfonyl-1H-indol-3-yl)-propionic acid, 3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester, 3-[5-Methoxy-1-(thiophene-3-sulfonyl)-1H-indol-3-yl]-propionic acid, (1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-acetic acid.
EXAMPLES

Example l: Bio-chemical Screening [0347] The homogenous Alpha screen assay was used in the agonist mode to determine the ligand dependent interaction of the PPARs (a,S,y) with the coactivator peptides (SRC
or DRIP205). Briefly 15u1 of the reaction mix (SOmM Tris pH 7.S,SOmM Kcl, 0.05%
Tween 20,1mM DTT,0.1% BSA and lOnM-200nMPPAR and lOnM-200nM coactivator peptide) was added to the test compound (1u1 compound in DMSO) and preincubated for 1-6hr.Next, Sul of the Alpha screen beads were added. The reactions were incubated for 2 hrs before taking the reading in the Fusion alpha instrument. In the antagonist mode compounds were assayed for inhibition of the co-activator binding signal caused by the control agonists for each receptor.
[0348] The controls agonists used were WY-14643(PPAR(a), farglitazar (PPAR (y) and bezafibrate (PPAR (8).
[0349] Using the assay above, compounds from Table 1 were analyzed for activity.
Results for exemplary compounds are shown in Table 2. The data reported in Table 2 was generated via the alpha screen assay and expressed in ~,Mol/L. The data points from the Fusion alpha instrument were transferred to Assay Explorer~ (MDL) to generate a curve and calculate the inflection point of the curve as ECso.
(0350] Among those compounds, several have notable pan-activity at low micromolar or even sub-micromolar levels, for example, compounds 29, 43, and 53. In contrast, compound 6 is selective for PPARy, with activity on PPARy of approximately 8 micromolar and activity on PPARa and 8 of at least 200 micromolar.
Example 2: Co-transfection assay [0351] 293T cells were transfected for 4-Shr in serum free DMEM media using cell fectin reagent. Each well was transfected with lug each of the reporter plasmid ( pFR-Luc from stratagene)and PPAR constructs (Gal4-PPAR-LBD). After 24hrs of recovery in serum medium the cells were treated with compounds for 48 hrs then assayed for luciferase activity using luciferase reporter gene assay kit (Roche).
[0352] This assay serves to confirm the observed biochemical activity on the modulation of intended target molecules) at the cellular level.

Example 3: Synthesis of 3-[5-methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]- propionic acid 1 [0353] Indole-3-propionic acid 1 was synthesized from the commercially available 5-methoxyindole-3-carboxaldehye in four steps as shown in Scheme 7.
Scheme 7 C02Me C02Me O o 0 O H Me,p~F~, Etd oEt ,O ~ Pd-C/H2 ~O
I N ~ ~ I N ~ ~ I N
H H H

C02Me C02H
ArS02Cl ~O i ~ KOH ~O ~ v ~ I N ~ ~ I N

/ ~ /
~O ~O
Step 1 - Ps eparation of 3-(S-Methoxy-1 H ihdol-3 yl)-ac~ylie acid yraethyl ester 3 [0354] To a cold solution (ice bath) of methyl phosphonoacetate (13.74 g, 0.065 mol) in tetrahydrofuran (120 mL) under nitrogen, was added sodium hydride (2.6 g, 0.065 mol, 60%) in one portion, and stirred until hydrogen evolution ceased. A solution of commercially available 5-Methoxyindole-3-carboxyaldehyde 2 (5.2 g, 0.029 mol) in tetrahydrofuran (84 mL) was added, over a period of 60 minutes, to the phosphonate solution. The reaction mixture was heated to 55°C for 24 h 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 yellow-tinted oil and purified by filtering through a silica plug. The filtrate was evaporated to afford 3 as an off white solid (6.2 g;
78% yield; M + 1 = 232.0).
Step 2 - Preparation of 3-(5-Meth.oxy-1 H indol-3 yl) propionic acid »aethyl ester 4:

[0355] To a solution of 3-(5-Methoxy-1H indol-3-yl)-acrylic acid methyl ester 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 hydrogen was introduced to the reaction flask from a balloon filled with hydrogen. The process was repeated three times and the reaction mixture was stirred for 16 h at room temperature.
The mixture was filtered through celite and the filtrate was evaporated under reduced pressure to yield ester 4 as a while solid (2.78 g; 92% yield; M + 1 = 234.0).
Step 3-Preparation of 3-(S MetlZOxy-1-(4-methoxy-benzenesulfonyl)-IH indol-3 ylJ-propionic acid methyl ester 5:
[0356] To a cooled solution (0° C) of indole-3-propionic acid methyl ester 4 (0.797 g, 3.42mmo1) in DMF (20 mL) was added sodium hydride (60%; 0.25 g; 0.0625 mol) was added in one portion and stirred for 30 min followed by the addition of 4-methoxybenzenesulfonyl chloride (1.3 g; 6.31 mmol). The reaction was allowed to warm up to room temperature and stirred for 16 h, subjected to aqueous work up, and 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 afford the ester 5 as a white solid (0.83 g; 61% yield; M + 1 = 404.1).
Step 4 - Preparation of 3-(5-Methoxy-1-(4-rnethoxy-benzenesulfonyl)-1 H indol-3 ylJ-propi~nic acid 1:
[0357] To a solution of the 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 h. The acid 1 was isolated by neutralising the reaction mixture by 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 afford a white solid (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 [0358] Indole-3-propionic acid 6 was synthesized from the commercially available 5-bromo-indole 7 in eight steps as shown in Scheme 8.
Scheme 8 Br Br ~ I N ~ ~ I N ~ ~ I N
H TIPS TIPS
7 g g N
N ~ N
H H

COZEt CO~H
C02Et ' , I ' Cp2H
H . H H

-.
N ,O
S;.
O

Step I - P~~epaYation of 5-B~omo-1-triisopropylsilanyl-1 H indole 8.
[0359] 5-Bromoindole (2.5 g, 12.75 mmol) was dissolved in tetrahydrofuran (THF; 50 mL) and cooled to 0° C and Sodium Hydride NaH (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 (TIPSCI; 2.78 mL, 13.1 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was washed with 2.0 N H3P04, and the organic layer was dried over MgS04, 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-Preparatiorz of S-Ethyl-1-triisopropylsilarayl-IH indole 9.
[0360] The 1-triisopropyl-5-bromoindole ( 3.0 g, 8.51 mmol) was combined with PdCl2(dppf) at -78° C and stirred for 5 minutes before Ethylmagnesium bromide (EtMgBr; 12.8 mL, 12.81 mmol) was added. The mixture was allowed to warm to room temperature. Toluene (15 mL) was added to the reaction mixture and heated at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and was quenched with 2N H3P04. The mixture was extracted with EtOAc and washed with brine, dried over MgS04, filtered and evaporated to give compound 9 as an oil (5 %
EtOAc/Hexanes) to give (2.3 g;90% yield; M + 1 = 302.5).
Step 3 -Preparation of 5 Ethyl-1H indole 10.
[0361] The Indole 9 (2.2 g, 7.29 mmol) was dissolved in THF ( 20 mL) and a solution of ammonium fluoride (NH4F; 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 H3P04, dried over MgS04, filtered and evaporated to give compound 10 as an off white solid (1.06 g; M + 1 =146.2).
Step 4 - Preparation of (5-Ethyl-IH indol-3 ylmethyl)-dimethyl-amine 11.
[0362] 5-Ethylindole 10 (1.0 g, 6.89 mmol) was combined with isopropyl alcohol (200 mL), N,N-dimethylamine hydro chloride (718 mg, 6.95 mmol) and aqueous formaldehyde (37%, 589 mg, 6.95 mmol) and heated at reflux 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 NaHC03. The organic layer was dried over MgS04, filtered and evaporated to give compound 11 as a solid in (1.35 g for a 97%
yield; M + 1= 203.2) Step 5-Preparation oft-(S-Ethyl-1H indol-3 ylrrZethyl)-malonic acid diethyl ester 12.
_98_ [0363] The 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 was formed.
To this mixture was added sodium metal (100 mg, 4.36 mmol) and the mixture was stirred at 120° C for 24 hours. TLC indicated the completion of the reaction.
The reaction was allowed to cool to room temperature and a solution of 5% 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 sulafate, filtered and evaporated to give compound 12 as a white solid (1.67 g; 85% yield;
M + 1 = 318.4). The product was taken into the next step without purification.
Step 6-Preparation oft-(S-Ethyl-IH indol-3 ylnaethyl)-malohic acid 13.
[0364] The crude diethyl malonylindole 12 (1.67 g, 5.26 mmol) was dissolved in THF
(20 mL) and a solution of NaOH (1.0 g, 25.5 mmol) in HZO (20mL) was added.
MeOH (S
mL) was also added to the reaction to make the solution homogeneous. The mixture was warmed to 50° C and stirred overnight. The mixture was allowed to cool to room temperature, the organic layer was evaporated and the residue was acidified with 2N
H3PO4, and the product was extracted with a mixture of 3:1 / CHCI3:MeOH. The organic layer was washed with brine, dried over MgS04, filtered, and evaporated to give the crude diacid as a white solid (1.25 g; M -1 = 260.2). The product was taken into the next step without purification.
Step 7-Preparation of 3-(5-Ethyl-IIf iyadol-3 y1) pr~opioraic acid 14.
[0365] The crude malonic acid 13 (250 mg, 0.957 mmol) was placed in a round bottom flask under vacuum and slowly heated to between 150 and 200° C, as the evolution of CO2 occurred. As the bubbling ended, the reaction was heated for 2 more additional minutes, then allowed to cool to room temperature. The product was purified by flash chromatography three times using 0 to 10% MeOH in CHCl3 to give compound 14 as a solid (120 mg; 57.7 % yield; M - 1 = 216.3).
Step 8-Preparation of 3-(1-Behzehesulfortyl-S-ethyl-IH iyadol-3-yl) propiouic acid 6.
_99_ [0366] The indole propionic acid 14 (100 mg, 0.46 mmol) was dissolved in THF
(5.0 mL) and cooled to -78° C. To this solution was added n-butyllithium (n-BuLi; 0.4 mL, 1.0 mmol, 2.4 M in hexanes) dropwise 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 warm to room temperature. The mixture was poured into ice cold H3P04 and extracted with EtOAc. The organic layer was dried over MgS04, 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 Indazole-3 propionic acid 16 [0367] Indazole-3-propionic acid 16 was prepared from commercially available indazole-3-carboxylic acid 17 in 5 steps as described in Scheme 9.
Scheme 9 O OH OH O
H
~ I vN ~ I vN ~ 1 vN
N~ ~ N ~ N
H H H
17 18 1g COZH CO~Me C02Me ~I ~N ~I ~N't ~I ~N
N~ N ~ N
H H H

Step 1- Prepar,atiotz of (1H Indazo-3 yl)-metlzanole 18 [0368] 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 rnmol) was added in one portion. The resulting alcohol 17 was isolated through quenching the reactive LAH with water, until no hydrogen evolution was observed and the solution was then filtered, washed with THF, and concentrated to to give alcohol 18 as a light brown solid (2.63 g, 72%).
Step 2 - Preparation of Indazole-3-carboxyaldehyde 19 [0369] Manganese (II) oxide (6.4 g, 73 mmol) was added to a solution of (1H-indazol-3-yl)-methanol 18 (1.08 g, 7.4 mmol) in a mixture of DCM (40 ml) and THF (30m1).
The solution stirred for 16 hours at ambient temperature and filtered through celite and concentrated under reduced pressure to yield a white solid (0.65 g, 61 %).
Step 3 - Preparation of 3-(Indazo-3 yl) propehoic acid metlxyl ester 20 [0370] 3-(Indazo-3-yl)-propenoic acid methyl ester 20 was prepared from aldehyde 19, as described in Stepl, Example 3.
Step 4 - Preparation of Iradazole-3 pr~opio~ic acid methyl ester 21 [0371] Indazole-3-propionic acid methyl ester was prepared from compound 20 as described in Step 2, Example 3.
Step S-Preparation oflradazole-3 propionic acid 16.
[0372] Indazole-3-propionic acid was prepared through saponification of compound 21 as described in Step 4, Example 3 (M-1 = 197.1).
Example 6: Synthesis of 5-isopropoxy-3-(1-Benzene-sulfonyl-indol-3yl)-propionic acid 22 [0373] Propionic acid 22 was preparedfrom commercially available S-hydroxy-indole 23 in 5 steps as shown in Scheme 10.
Scheme 10 MeYMe MeYMe NMe HO O
O , llAe ~ I N ----N N
H H H

MeYMe C02H MeYMe C02H MeYMe COZEt O O O , ' C02Et ~ I ~ ~ I ~ .~; I
N
N ~ N
H
22 O=S'O 27 H 26 Step 1- Synthesis of 5-Isopropoxy-indole 24 [0374] 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 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 purifed with 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 - Syratlaesis of S Isopnopoxy g~amirae 25 [0375] The 5-Isopropoxy gramme 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-Isopf~opox,~-IH Ifadol-3 ylmethyl)-rnalonic acid diethyl ester 26 [0376] Compound 26 was prepared from 25 as described in Step 3, Example 4 (M+1 =
348.5).
Step 4 - Synthesis of 5 Isopropoxy-iradole-3 propionic acid 27 [0377] 5-Isopropoxy-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-(I-Benzene-sulfonyl-ifidol-3yl) p~opiohic acid 22 [0378] To a cooled (-78°C) solution of propionic acid (27) (96.3mg, 0.51 Ommol) in tetrahydrofuran (10 ml), n-butyl lithium (1.40m1, 2.24 mol) was added next and stirred for 30 minutes at -78°C. Benzene sulfonyl chloride (277 mg, 1.5 mmol) was added next, and the reaction was stirred for 16-24 hours, allowing 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 crude material was then purified by flash chromatography with silica, eluting with 5% methanol in dichloromethane to yield the desire product (22) as a white solid. (M -1 =
386.4) Example 7: Preparation of Indole-3-propionic acid 28 N
H

[0379] W dole-3-propionic acid 28 was prepared through the commercially available indole-3-carboxyaldehyde as described in Example 3. (M-1, 188.2) Example 8: Preparation of 3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid 29 Me'O
N
O SO

[0380] 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-methoxybenzene sulfonyl chloride with benzene sulfonyl chloride, (M-1 = 358.4) Example 9: Synthesis of 3-[5-Methoxy-1-(3-methoxy-benzyl)-1H-indol-3-yl]-propionic acid 30 Me'O
N
Me0 ~ 30 ~/
[0381] 3-[5-Methoxy-1-(3-methoxy-benzyl)-1H-indol-3-yl]-propionic acid 30 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with 3-methoxybenzyl bromide, (M-1= 336.4) Example 10: Synthesis of 3-[1-(3-Chloro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid 31 Me'O
N
C~ 31 ~ ~
[0382] 3-[1-(3-Chloro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid 3I was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with 3-chlorobenzyl bromide, (M-1 = 322.4).

Example 11: Synthesis of 3-[1-(4-Fluoro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid 32 Me O i I v N

\s F
[0383] 3-[1-(4-Fluoro-benzyl)-5-methoxy-1H-indol-3-yl]-propionic acid 32 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with 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 CO~H
M e'0 N

CI
[0384] 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-methoxybenzene sulfonyl 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 COZH
Me'~
N

~ O
IVI a [0385] 3-[5-Methoxy-1-(2-methoxy-benzyl)-1H-indol-3-yl]-propionic acid 34 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride 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 35 Me'o N
o OF
F~ F
[0386] 3-[5-Methoxy-1-(2-trifluoromethoxy-benzyl)-1H-indol-3-yl]-propionic acid 35 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride 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 Me'~
N

F~O
F
[0387] 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-methoxybenzene sulfonyl chloride with 3-trifluoromethoxybenzyl bromide, (M-1 = 392.4).
Example 16: Synthesis of 3-(1-Ethylthiocarbamoyl-5-methoxy-1H-indol-3-yl)-propionic acid 37 Me~~
N
37 ~N'~S
H
[0388] 3-(1-Ethylthiocarbamoyl-5-methoxy-1H-indol-3-yl)-propionic acid 37 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with ethyl isothiocyanate, (M-1 = 305.4).
Example 17: Synthesis of 3-[5-Methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-propiouc acid 38 Me'O
N 'O

~ /
[0389] 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-methoxybenzene sulfonyl chloride with 4-tolyl sulfonyl chloride, (M-1 = 373.4).
Example 18: Synthesis of 3-(1-Benzenesulfonyl-1H-indazol-3-yl)-propionic acid H
S' O

r ~ /
[0390] 3-(1-Benzenesulfonyl-1H-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-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-yl]-propionic acid methyl ester 40 CO2Me M e'0 N.O
S' 'O
[0391] 3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 40 was prepared using the same protocol as in example 3, substituting 4-methoxybenzenesulfonyl chloride with 4-isopropylbenzenesulfonyl chloride, (M +
1 =
416.6).
Example 20: Synthesis of 3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 41 Me'O i I
N ,O
S' O

[0392] 3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid was prepared through the saponification protocol with 3-[1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 41 as described in step 4 of example 3, (M -1 = 400.5).
Example 21: Synthesis of 3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 42 C02Me Me'O
N
SO

~ /
~O
[0393] 3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 42 was prepared using the same protocol as example 3, substituting 4-methoxybenzenesulfonyl chloride with 4-n-butoxybenznesulfonyl chloride (M + 1=
446.5) Example 22: Synthesis of 3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 43 CO~H
Me'O
N
~S

~ /
~O
[0394] 3-[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid was prepared through the saponification protocol with -[1-(4-Butoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 42 as described in step 4 of example 3, (M -1 = 430.5).
Example 23: Synthesis of 3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-indol-3-yl]-propionic acid methyl ester 44 C02Me Me'O ~ I
N.O
S' O

F
F~O
F
(0395] 3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester was prepared using the same protocol as in example 3, substituting 4-methoxybenzenesulfonyl chloride with 4-trifluoromethoxybenzene sulfonyl chloride, (M
+ 1 = 457.4).
Example 24: Synthesis of 3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 45 Me'O
N.O
S, O
~ /
F'I
FT O
F
[0396] 3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid was prepared through the saponification protocol with 3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 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 CO2Me Me'O
N.O
S:O

~ O
[0397] 3-[5-Methoxy-1-(4-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 45 as prepared using the same protocol as example 3, substituting methoxybenzenesulfonyl chloride with 4-phenoxybenzene sulfonyl chloride, (M+1 =
466.6).
Example 26: Synthesis of 3-[5-Methoxy-1-(4-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 47 CO~H
M e'0 N.O
S' O

~ /
O
[0398] 3-[5-Methoxy-1-(4-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid was prepared through the saponification protocol with 3-[5-Methoxy-1-(4-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 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 C02Me M e'0 N.O
. 48 S.O
~ /
CI
[0399] 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 4-methoxybenzene sulfonyl chloride with 4-chlorobenzene sulfonyl chloride (M+1 =
406.9).
Example 28: Synthesis of 3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 49 Me'O
N.O
S' O

CI
[0400] 3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid was prepared through the saponification protocol with 3-[1-(4-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 48 as described in step 4 of example 3, (M -1 = 392.9).
Example 29: Synthesis of 3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 50 C02Me Me'O
NO
SO
~ /
NC
[0401] 3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 50 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride with 4-cyanobenzene sulfonyl chloride. (M+1 =
399.4}
Example 30: Synthesis of 3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 51 M e'0 N
~ eO
51 Sp ~ /
NC
[0402] 3-[1-(4-Cyano-benzenesulfonyl}-5-methoxy-1H-indol-3-yl]-propionic acid was prepared through the saponification protocol with 3-[1-(4-Cyano-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 50 as described in step 4 of example 3, (M -1 = 383.4).
Example 31: Synthesis of 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 52 C02Me Me'O
NO
SO

~ /
CI CI
[0403] 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 52 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with 3,4-dichlorobenzene sulfonyl chloride, (M+1 =
443.3).
Example 32: Synthesis of 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 53 Me'O i I
NO
53 S p ~ /
CI~CI
[0404] 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 53 was prepared through the saponification with 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 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 C02Me Me'O
NO

~ /

[0405] 3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 54 was prepared using the same protocol as in example 3, substituting 4-methoxybenzenesulfonyl chloride with trifluoromethylbenzene sulfonyl chloride, (M+1 =
442.4).
Example 34: Synthesis of 3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 55 Me'O i [
NO
.e ~ /
r [0406] 3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 55 was prepared through the saponification of 3-[5-Methoxy-1-(4-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 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 ester56 C02Me Me'O
NO

~ /
i F
[0407] 3-[1-(4-Fluoro-benzenesulfonyl)-S-methoxy-1H-indol-3-yl]-propionic acid methyl ester 56 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride with 4-fluorobenzene sulfonyl chloride, (M+1 =
3 92.4).
Example 36: Synthesis of 3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 57 Me'O
NO
SO

~ /
F
[0408] 3-[1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid was prepared through the saponification of the 3-[1-(4-Fluoro-benzenesulfonyl)-methoxy-1H-indol-3-yl]-propionic acid methyl ester 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 CO~Me Me'O
NO

~ /
O
~ /
(0409] 3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 58 was prepared using the same protocol as in example 3, substituting 4-methoxybenzenesulfonyl chloride with 3-phenoxybenzene sulfonyl chloride, (M +
1 =
466.5}.
Example 38: Synthesis of 3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 59 Me'~
NO

~ /
O
~ /
[0410] 3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 59 was prepared through the saponification of 3-[5-Methoxy-1-(3-phenoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 58 as described in step 4 of example 3, (M -1 = 376.4).

Example 39: Synthesis of 3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 60 C02Me M e'0 NO
.s ~ /
F
[0411] 3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 60 was prepared using the same protocol as in example 3, substituting 4 methoxybenzene sulfonyl chloride with 3-fluorobenzene sulfonyl chloride, (M+1 =
392.3).
Example 40: Synthesis of 3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 61 M e'0 N
. s0 ~ /
F
[0412] 3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid was prepared through saponification of 3-[1-(3-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 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 C02Me Me'O
NO

~ /
Me [0413] 3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid methyl ester was prepared using the same protocol as in example 3, substituting 4-methoxybenzenesulfonyl chloride with 3-tolyl sulfonyl chloride, (M+1 = 388.5).
Example 42: Synthesis of 3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid 63 Me'O ~ I
NO

~ /
Me [0414] 3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid 63 was prepared through the saponification of 3-[5-Methoxy-1-(toluene-3-sulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 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 ester64 C02Me Me'O
NO

~ /
CI
[0415] 3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 64 was prepared using the same protocol as in example 3, substituting 4-methoxybenzenesulfonyl chloride with 3-chlorobenzene sulfonyl chloride, (M+1 =
408.9).
Example 44: Synthesis of 3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 65 Me'O
NO

~ /
CI
[0416] 3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid was prepared through the saponification of 3-[1-(3-Chloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 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 C02Me Me'O
N
.O

~ /
O-Me [0417] 3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 66 was prepared using the same protocol as in example 3, substituting 4-methoxybenzenesulfonyl chloride with 3-methoxybenzene sulfonyl chloride, (M+1 =
404.5).
Example 46: Synthesis of 3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 67 Me'O
N O

~ /
O-Me [0418] 3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 67 was prepared through the saponification of 3-[5-Methoxy-1-(3-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 66 as described in step 4 of example 3, (M -1 = 388.4).
Example 47: Synthesis of 3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-lII-indol-3-yl]-propionic acid methyl ester 68 C02Me Me'O
NO
6$ S O
~ /
F
FF
[0419] 3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 68 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with 3-trifluoromethylbenzene sulfonyl chloride, (M+1 = 442.4).
Example 48: Synthesis of 3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 69 Me'O
NO
SO

~ /
F
FF
(0420] 3-[5-Methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 69 was prepared through the saponifcation of 3-[5-Methoxy-1-(3-trifluoromethyl benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 68 as described in step 4 of example 3, (M -1 = 426.4).
Example 49: Synthesis of 3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester 70 C02Me Me'O
N
~ /
[0421] 3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester 70 was prepared using the same protocol as example 3, substituting 4-methoxybenzenesulfonyl chloride with benzyl bromide, (M+1= 324.4).
Example 50: Synthesis of 3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid Me O
N

~ /
[0422] 3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid 71 was prepared through the saponification of 3-(1-Benzyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester 70 as described in step 4 of example 3, (M+1 = 30.3).
Example 51: Synthesis of 3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 72 COZMe Me O
NO
72 _ S O
~ S

[0423] 3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 72 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride with 2-thiopene sulfonyl chloride, (M+1 =
380.5).
Example 52: Synthesis of 3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid 73 NO

~ S
[0424] 3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid was prepared through the saponification of 3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 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 CQ2Me Me'~ i I
N
~S

[0425] 3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid methyl ester 74 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride with phenyl isothiocyanate, (M+1 = 369.5).

Example 54: Synthesis of 3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid 75 Me'O
N
S

[0426] 3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid 75 was prepared through the saponification of 3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-yl)-propionic acid methyl ester 74 as described in step 4 of example 3, (M -1 = 353.4).
Example 55: Synthesis of 3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 76 C02Me Me'O
NO

~ /
(0427] 3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 76 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride with 4-n-butylbenzene sulfonyl chloride, (M+1 =
430.2).
Example 56: Synthesis of 3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 77 Me O ~ I
NO

~ /
V
[0428] 3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 77 was prepared through the saponification of 3-[1-(4-Butyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester 76 as described in step 4 of example 3, (M -1 =
414.1).
Example 57: Synthesis of 3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-indol-3-yl]-propionic acid methyl ester 78 C02Me Me'O
N
..O
S' 'O

~ /
O
F
~F
F
[0429] 3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 78 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride with 3-trifluorobenzene sulfonyl chloride (M+1 =
458.1).
Example 58: Synthesis of 3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 79 Me'O
NO
S, 79 'O
~ /
O
F
F F
[0430] 3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 79 was prepared through the saponification of 3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 4 as described in step 4 of example 3, (M -1 = 442.0).
Example 59: Synthesis of 3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester 80 CO2Me I
O ~
w I N~

~ /
[0431] 3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester 80 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride with benzoyl chloride, (M+1 = 338.1).
Example 60: Synthesis of 3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid (0432] 3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid 81 was prepared through the saponification of 3-(1-Benzoyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester 80 as described in step 4 of example 3, (M -1 = 322.1).
Example 61: Synthesis of 3-(1-Benzenesulfonyl-5-ethoxy-1H-indol-3-yl)-propionic acid 82 H
82 O;S=O
[0433] 3-(1-Benzenesulfonyl-5-ethoxy-1H-indol-3-yl)-propionic acid 83 was prepared using the same protocol as example 6, substituting 2-propyl iodide with ethyl iodide, (M
-1 = 372.4).
Example 62: Synthesis of 3-[1-(4-Isopropoxy-benzenesulfonyl)-S-methoxy-1H-indol-3-yl]-propionic acid 83 H
O:S:O

_~
O
[0434] 3-[1-(4-Tsopropoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 83 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride with 4-isopropoxybenzene sulfonyl chloride, (M - 1 = 416.5).
Example 63: Synthesis of 3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid methyl ester 84 84 O~NH
[0435] 3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid methyl ester 84 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride with phenyl isocyanate, (M+1 = 353.4).
Example 64: Synthesis of 3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid 85 OH
O~NH
I
[0436] 3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid 85 was prepared through the saponifcation of 3-(5-Methoxy-1-phenylcarbamoyl-1H-indol-3-yl)-propionic acid methyl ester 84 as described in step 4 of example 3, (M -1 =
337.4).
Example 65: Synthesis of 3-[1-(4-Ethyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid 86 N
O,S~O

[0437] 3-[1-(4-Ethyl-benzenesulfonyl)-5-methoxy-1H-indol-3-yl~-propionic acid 86 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride with 4-ethylbenzene sulfonyl chloride, (M -1 = 386.4).
Example 66: Synthesis of 3-(5-bromo-1H-indol-3-yl)-propionic acid 87 H

[0438] 3-(5-bromo-1H-indol-3-yl)-propionic acid 87 was prepared from 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-1H-indol-3-yl)-propionic acid methyl ester H

[0439] The 5-bromoindole-3-propionic acid 87 (4.0 g, 14.91 mmol) was dissolved in methanol (MeOH, 100 mL) and Trimethylsilyl chloride (TMSCI, 33.0 mL, 32.8 mmol, 1.0 M in CH2Cl2) was added dropwise 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-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid methyl ester 89 C
Br \
N
O=S=O

02C ~"~ 3 [0440] 3-(1-Benzenesulfonyl-5-bromo-IH-indol-3-yI)-propionic acid methyl ester prepared as described in step 3 of example 3 by suhstituting 4-methoxybenzenesulfonyl chloride with benzenesulfonyl chloride, (M + 1 = 424).
Example 69: Synthesis of 3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid methyl ester 90 C
Br \
N
O=S=O

[0441] 3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid 90 was prepared through the saponifcation methyl ester 89 using the procedure as described in step 4 of example 3, (M -1 = 406.0).
Example 70: Synthesis of 3-(Benzenesulfonyl-5-thiophen-3-yl-IH-indol-3-yl)-propionic acid methyl ester [0442] 3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid methyl ester (200 mg, 0.474 mmol) was combined with 3-thienyl boronic acid (67.0 mg, 0.52 mmol), triphenylphosphine (9.0 mg, 0.03 mmol), Pd(OAc)a (4.0 mg, 0.015 mmol), KaC03 (90 mg, 0.65 mmol), 1,2-Dimethoxyethane (DME, 4.0 mL) and HBO (0.4 mL) and was 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 MgS04, filtered, and evaporated. The residue was purified with flash silica gel chromatography (20% EtOAclHexanes) to obtain the ester 91 as a white solid, (110 mg, M + 1 = 426.1).
Example 71: Synthesis of 3-(Benzenesulfonyl-5-thiophen-3-yl-1H-indol-3-yl)-propionic acid 92 O=S=O
O=S=O

[0443] 3-(Benzenesulfonul-S-thiophen-3-yl-1H-indol-3-yl)-propionic acid 92 was prepared through the saponifcation of methyl ester 91 as described in step 4 of example 3, (M -1 = 410.1).
Example 72: Synthesis of 3-(1-Benzenesufonyl-5-pheyl-1H-indol-3-yl) propionic acid methyl ester 93 [0444] The ester 93 was prepared from the methyl ester 89 by following the procedure as described in example 70 by substituting 3-Thienyl boronic acid with Phenyl boronic acid, (M + 1 = 420).
Example 73: Synthesis of 3-(1-Benzenesufonyl-5-pheyl-1H-indol-3-yl) propionic acid 94 O=S=O .
O=S=O

[0445] 3-(1-Benzenesufonyl-5-pheyl-1H-indol-3-yl) propionic acid 94 was prepared through the saponifcation of methyl ester 94 as described in step 4 of example 3, (M -1 = 404.5).
Example 74: Preparation of 3-(1H-Pyrrolo[2,3-b]pyridine-3-yl)-propionic acid [0446] 3-(1H-Pyrrolo[2,3-b]pyridine-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-1H-Indol-3-yl)-propionic acid 96 H

[0447] 3-(5-Methoxy-1H-Indol-3-yl)-propionic acid 96 was prepared from 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-Benzenesulfonyl-1H-indol-3-yl)-propionic acid 97 N
O;g:O

[0448] 3-(1-Benzenesulfonyl-1H-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-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester 98 C02Me N
O:g:O
a (0449] 3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid methyl ester 98 was prepared using the same protocol as example 3, substituting 4-methoxybenzene sulfonyl chloride with benzene sulfonyl chloride. (M+1 = 374.4) Example 78: Synthesis of 3-[5-Methoxy-1-(thiophene-3-sulfonyl)-1H-indol-3-yl]-propionic acid 99 ,O
N O
..
S
O' S

(0450] 3-[5-Methoxy-1-(thiophene-3-sulfonyl)-1H-indol-3-yl]-propionic acid 99 was prepared from 3-(5-methoxy-1H-indol-3-yl)-propionic acid 96 and 3-thienyl-sulfonyl chloride using the same protocol as described in step 8, Example 4. (M - l, 364.4) Example 79: Synthesis of (1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-acetic acid 100 N
O:g:O

[0451] (1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-acetic acid 100 was prepared from commercially available (5-methoxy-1H-indol-3-yl)-acetic acid and benzene sulfonyl chloride using the protocol as described in step 8, example 4. (M -1 = 344.4) Scheme 11: Alternative synthesis methodology for Compounds of Formula Ib COZH
Ra Rs O H a Rs O H Ra Rs R
I ~X ~ . I ~X ~ ~ I ~,X 1 R3 Y H R3 Y N R3 Y Nv III XVIII R2 XIX R2 .w Step 1- Preparation of compound of formula XhIII:
[0452] Compound XVIII can be prepared through coupling of compound III with benzene sulfonyl chloride in a bi-phasic solvent condition e.g. toluene and water, in presence of a base, e.g. an aqueous potassium hydroxide solution with a phase transfer catalyst, e.g. tetrabutylammonium hydrogen sulfate, similar to conditions as described Gribble et al, in J. Org. ChenZ., 2002, 63, pg 1001-1003.
Step 2 - Preparation of compound XI~Y
(0453] Compound XIX was prepared through conventionally Knoevenagel reaction reacting compound XVIII with malonic acid piperidine in pyridine at 80°C for 3-4 hours, as described in Vangvera et al in J. Med. Chem.,1998, 41, pg 4995-5001.
Step 3 - Preparation of Compound Ib:
[0454] Compound Ia was prepared from compound XIX through reduction via catalytic hydrogenation (typically with 10% palladium on activated carbon in an inert solvent (see preparation of intermediate II, vide supra).
Example 80: Alternate synthesis of 3-[5-methoxy-1-(4-methoxy-benzenesulfonyl)-indol-3-yl]- propionic acid 1 Scheme 12 O C~~S ~ ~ O H
Me0 ~ ' H ~ OMe Me0 ~
~ 117 H Step 1 :S~0 O

O O
'-I I-I OMe HO~OH
Step 2 Me0 Me0 O~S;O Step 3 O:S=O

OMe OMe Step 1: P~-eparatiofz of l-(4 Methoxy behzerzesulfouyl)-5-metlzoxy-1H ihdole-3-ca~boxyaldehyde) (117) [0455] To 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 added next. After about 5 minutes of stirring, 4-methoxybenzene sulfonyl chloride (1.7 grams, 8.2 mmol) was added. Within 2-3 hours, solid began to precipitate out of the solution. This reaction was allowed to stir at ambient temperature for 2 hours, after which water (50 mL) and ethyl acetate (150 ml) was added to the reaction.
The layers were separated; the organic layer was washed with saturated bicarbonate (3 X
75 mL) and water (4X 75 mL) to ensure removal of the hydroxide and sulfonate salt, and washed with brine (1 X 75 ml) and dried over anhydrous sodium sulfate.
Evaporation under reduced pressure afforded 117 as a light brown solid. (1.86g, 94%) 1H
NMR(CDC13) 8 10.0 (s, 1H), 8.20(s, 1H ), 7.92(d, J = 9.2 Hz, 2H), 7.85 (d, J=
8.8, 1H), 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: P~~epaf-atiofa of 3-~l-(4-Methoxy befazehesulfonyl)-5-~raethoxy-1H
ifadol-3 ylJ-acYylic acid(118) [0456] To a solution of 1-(4-Methoxy benzenesulfonyl)-5-methoxy-1H- 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, (1mL) were combined in a reaction vessel. The yellow solution was heated for 3 hours at 80°C. The reaction was allowed to cool to ambient temperature and diluted with 150 mL of ethyl acetate. The organic layer was washed with 1N
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 product 118 as an off white solid. (0.521 g, 90%) 1HNMR
(CDCl3) 8 7.86 (m, SH), 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: PYepa~ation of 3-~l -(4-Methoxy behzenesulforZyl)-5-methoxy-1 H ihdol-3-~lJ-propionic acid (1) [0457] To a solution of 3-[1-(4-Methoxy benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-acrylic acid 118 (1.0 g, 2.6 mmol) dissolved in THF (14 mL), Pd/C (67 mg) was added in one portion. The solution was attached to the Parr hydrogenator. The reaction was allowed to proceed 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 washes/solution was evaporated under reduced pressure to afford straw colored oil that solidified after cooling under high vacuum. The crude was triturated with diethyl ether to leave behind off white solid as product 1. (0.6208, 62%) 1H NMR(DMSO) 8 7.86 (d, J= 9.2 Hz, 1H), 7.75 (d, J= 8.4Hz, 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 BSI
O C02Me Me CHO Me OH ' I
home O
I i N Step 1 I i N Step 2 I i N

O,.O
CI'S I ~ C02H
O
O I~
~ N
Step 3 Step 4 O;g~O

O O
Me Me Step 1 - Synthesis of 5-methoxy-IH indol-3yl-methanol 141 [0458] To a solution of sodium borohydride (2 grams, 0.05 mol) in methanol (15 ml), a solution of 5-methoxy-1H-indol-3-carboxaldehyde Z (1 gram, 0.006 mol) dissolved in THF (20 ml) and methanol (15m1) were combined and stirred at ambient temperature for 16 hours. The reaction was diluted with water and potassium carbonate (to saturation) and stirred to quench unreacted sodium borohydride. Diethyl ether was used to extract the product from the quenched solution. Following layers separation, the aqueous layer was further extracted (2X) with diethyl ether. The combined organic pats were dried over sodium sulfate and evaporated to dryness to yield a light colored solid 141 (736 mg, 70%).
Step 2 - Preparation of 3-(5 Methoxy-IH itadol-3 yl) p~~opionic acid methyl ester 142:
[0459] To a solution of 5-methoxy-1H-indol-3y1-methanol 141 (115 mg, 0.643 mmol) dissolved in dichloromethane (3m1), (1-methoxy-2-methyl-propenyloxy)-trimethylsilane (200 mg, 1 mmol) and magnesium perchlorate (164 mg, 0. 74 mmol) were added.
The reaction was allowed to stir at ambient temperature for 3-4 hours after after which the mixture was diluted with water (50m1) 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 with flash chromatography (silica with 80%hexane, 20% ethyl acetate to afford 142 as a light colored oil (150 mg; 88%
yield; M
+ 1 = 262.3).
Step 3 -Preparation of 3-~5-Metlzoxy-1-(4-methoxy-befzzenesulforzyl)-IH indol-3 ylJ-propionic acid methyl ester 120:
[0460] To a cooled solution (0° C) of indole-3-propionic acid methyl ester 142 (0.110 g, 0.42mmol) in DMF (3 mL) was added sodium hydride (60%; 0.030 g; 0.75 mmol) was added in one portion and stirred for 30 min followed by the addition of 4-methoxybenzenesulfonyl chloride (0.200 g; 1.Ommol). The reaction was allowed to warm up to room temperature and stirred for 16 h, subjected to aqueous work up, and 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 afford the methyl ester 120 as an oil (M + 1 = 432.4). The methyl ester 120 was then taken on toward generation of the product.
Step 4 - Preparation of 3-~5-Methoxy-1-(4-metho.~,y-beyzzenesulfonyl)-I H
indol-3 ylJ-2,2-diznethyl propionic acid 119:
[0461] To a solution of the methyl ester 120 in tetrahydrofuran (6 mL) was added an aqueous solution of potassium hydroxide (2 mL of 1M) and stirred at room temperature for 5 h. The acid 119 was isolated by neutralizing the reaction mixture by 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 afford a white solid (80 mg, 46% overall, M -1 = 416.5).
Example 82: Synthesis of 3-[1-(3,4-Dimethoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 101 CO2hi Me O
~ N
O;g:O
Me 101 ~ O
Me O
[0462] 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-methoxybenzene sulfonyl chloride with 3, 4-dimethoxybenzenesulfonyl chloride, (M -1 =
418.5).
Example 83: Synthesis of 3-[1-(3,4-Difluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 102 Me O
N>
O;g:O
s~
102 ~ F
F
[0463] 3-[1-(3,4-difluorobenzenesulfonyl)-S-methoxy-1H-indol-3-yl]-propionic acid 102 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with 3, 4-difluorobenzenesulfonyl chloride, (M -1 =395.3).
Example 84: Synthesis of 3-[1-(3-chloro-4-methyl-benzenesulfonyl)-5-methoxy-1H-.
indol-3-yl]-propionic acid 103 Me O
I~ N
O:g~O
103 ~ CI
Me [0464] 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 4-methoxybenzene sulfonyl chloride with 3-chloro-4-methylbenzenesulfonyl chloride, (M -1 =
406Ø
Example 85: 3-~l-(behzenesulfonyl)-S fZuo~o-IH indol-3 ylJ p~opiohic acid 104 F
I ~ N
O;g-O

[0465] 3-[1-(benzenesulfonyl)-5-fluoro-1H-indol-3-yl~-propionic acid 104 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with benzenesulfonyl chloride, (M -1 = 346.5).
Example 86: Synthesis of 3-[1-(benzenesulfonyl)-5-methyl-1H-indol-3-yl~-propionic acid 105 Me N
O;g:O

[0466] 3-[1-(benzenesulfonyl)-5-methyl-1H-indol-3-yl]-propionic acid 105 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with benzenesulfonyl chloride, (M -1 = 342.2).
Example 87: Synthesis of 3-[1-(benzenesulfonyl)-5-chloro-1H-indol-3-yl]-propionic acid CI
N
O;g:O

[0467] 3-[1-(benzenesulfonyl)-5-chloro-1H-indol-3-yl]-propionic acid 106 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with benzenesulfonyl chloride, (M -1 = 362.7).
Example 88: Synthesis of 3-[1-(3-fluoro4-methyl-benzenesulfonyl)-5-chloro-1H-indol-3-yl]-propionic acid 107 COZH
Me O
N
O;g:O
107 ~ F
(0468] 3-[1-(3-fluoro-4-methyl-benzenesulfonyl)-5-chloro-1H-indol-3-yl]-propionic acid 107 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride 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 COSH
Me O ' N
O;g:O

O
[0469] 3-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-S-methoxy-1H-indol-3-yl]-propionic acid 108 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl 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 Me CO~H

° ' .
N
r ~

Me [0470] 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-methoxybenzene sulfonyl chloride with 4-ethyl-benzenesulfonyl chloride, (M -1 = 400.5).
Example 91: Synthesis of 3-[1-(4-methoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid 110 Me COZH

N
O;g:O

110 ~
O' Me [0471] 3-[1-(4-methoxy-benzenesulfonyl)-5-ethoxy 1H-indol-3-yl]-propionic acid 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-1H-indol-3-yl]-propionic acid 111 Me1 COzH
O
N
O;g:O
111 ~ O
FF F
[0472] 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-methoxybenzene sulfonyl chloride with 3-trifluoromethoxy-benzenesulfonyl chloride, (M
-1 = 456.3).
Example 93: Synthesis of 3-[1-(4-butyl-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid 112 Me C02H

N
O;g~O

[0473] 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-methoxybenzene sulfonyl chloride 4-butyl-benzenesulfonyl chloride, (M -1 = 428.4).
Example 94: Synthesis of 3-[1-(4-butoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid 113 Me C02H

O;g:O

113 ~
O
[0474] 3-[1-(4-butoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride 4-butoxy-benzenesulfonyl chloride, (M -1 = 444.5).
Example 95: Synthesis of 3-[1-(3, 4-dichloro-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid 114 Mel COZH
O
N
O;g:O
114 ~ CI
CI

[0475] 3-[1-(3, 4-dichloro-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid 114 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride 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 Me, C02H
O
N
O;g;O
/\
115 ~_ O
IIAe [0476] 3-[1-(3-methoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride 3-methoxy-benzenesulfonyl chloride, (M -1 = 402.5).
Example 97: Synthesis of 3-[1-(4-phenoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid 116 COZH
Me O
~ N, O;g:O
~\

O
' \\ ~~
[0477] 3-[1-(4-phenoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-propionic acid was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride 4-phenoxy-benzenesulfonyl chloride, (M -1 = 464.3).
Example 98: Synthesis of 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-2,2-dimethyl-propionic acid methyl ester 122.

C02Me Me O
N
O;g:O
122 ~ CI
l CI
[0478] 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-2,2-dimethyl-propionic acid methyl ester 122 was prepared using the same protocol as 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 Me O v y N
O;g~O

121 ~ CI
CI
[0479] 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-2,2-dimethyl-propionic acid methyl ester 121 was prepared from the corresponding methyl ester 122, using the same protocol as example 3, step 4, (M + 1 = 469.2).
Example 100: Synthesis of (E)-3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-acrylic acid 123 Me O
~ N
O:g:O

CI
CI
[0480] (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-methoxybenzene sulfonyl chloride 3, 4-dichlorobenzenesulfonyl chloride in step - 1, (M -1=425.2).
Example 101: Synthesis of (E)-3-[1-(4-butyl-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-acrylic acid 124 Me O
~ N
O;g:O
124 ~ ~
[0481] (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 4-methoxybenzene sulfonyl chloride 4-butylbenzenesulfonyl chloride in step - l, (M -1 =426.4).
Example 102: Synthesis of (E)-3-[1-(4-butoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-acrylic acid 125 Me O
N
O;g:O

O
[0482] (E)-3-[1-(4-butoxy-benzenesulfonyl)-5-ethoxy-1H-indol-3-yl]-acrylic acid 125 was prepared using the same protocol as in Scheme 12, substituting 4-methoxybenzene sulfonyl chloride 4-butoxybenzenesulfonyl chloride in step - 1, (M -1 =442.4).
Example 103: Synthesis of 3-[1-(3-Chloro-4-methoxy-benzenesulfonyl)-5-methoxy-indol-3-yl]-propionic acid 126 Me O
~ N>
O;g:O

CI
Me O
[0483] 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 4-methoxybenzene sulfonyl chloride 3-chloro-4-methoxy-benzenesulfonyl chloride in step -1, (M -1 = 423.0). 3-Chloro-4-methoxy-benzenesulfonyl chloride was in turn prepared by reacting 2-chloroanisole with chlorosulfonic acid (neat at 0 °C, 4h) following the literature procedure (Cremlyn,R.J.W.; Hornby,R.; J.Chem.Soc.C; 1969; 1341-1345) Example 104: Synthesis of Synthesis of 3-[1-(4-Methoxy-benzenesulfonyl)-7-methyl-1H-indol-3-yl]-propionic acid 127 O
O
N
S;O
~O
O
I

[0484] Compound 127 is synthesized from commercially available 7-methy-lindole-carboxaldehyde following synthetic steps shown in Scheme 12.
Example 105: Synthesis of 3-[1-(4-Methoxy-benzenesulfonyl)-6-methyl-1H-indol-3-yl]-propionic acid 128 N
~ .,O
S;
O
O
I

[0485] Compound 128 is synthesized from commercially available 6-methyl-indole-carboxaldehyde following synthetic steps shown in Scheme 12.
Example 106: Synthesis of 3-[1-(4-Methoxy-benzenesulfonyl)-6-fluoro-1H-indol-3-yl]-propionic acid 129 I

[0486] Compound 129 is synthesized from commercially available 6-fluoro-indole-carboxaldehyde following synthetic steps shown in Scheme 12.
Example 107: Synthesis of 3-[1-(4-Methoxy-benzenesulfonyl)-7-fluoro-1H-indol-3-yl]-propionic acid 130 N
F S;O
O
O
I

(0487] Compound 130 is synthesized from commercially available 7-fluoro-indole-carboxaldehyde following synthetic steps shown in Scheme 12.
Example 108: Synthesis of 3-[1-(4-Methoxy-benzenesulfonyl)-4-chloro-7-fluoro-indol-3-yl]-propionic acid 131 N
F S;O
O
O
I

[0488] Compound 131 is synthesized from commercially available 4-chloro-7-fluoro- J
indole-3-carboxaldehyde following synthetic steps shown in Scheme 12.
Example 109: Synthesis of 3-[1-(4-Methoxy-benzenesulfonyl)-6-methoxy-1H-indol-yl]-propionic acid 132 O
I

[0489] Compound 132 is synthesized from 6-methoxy-indole-3-carboxaldehyde, which in turn is synthesized from commercially available 6-methoxy-indole using Vilsmeier-Haack reaction (Advanced organic chemistry, Jerry March, 2nd Ed. P715), following synthetic steps shown in Scheme 12.
Example 110: Synthesis of 3-[1-(4-Methoxy-benzenesulfonyl)-5,6-dimethoxy-1H-indol-3-yl]-propionic acid 133 \O \ N :O
S, O
O

[0490] Compound 133 is synthesized from 5,6-dimethoxy-indole-3-carboxaldehyde, which in turn is synthesized from commercially available 5,6-dimethoxy-indole using Vilsmeier-Haack reaction (Advanced organic chemistry, Jerry March, 2nd Ed.
P715), following synthetic steps shown in Scheme 12.
Example 111: Synthesis of 3-[1-(4-Methoxy-benzenesulfonyl)-6-bromo-1H-indol-3-yl]-propionic acid 134 O
O
I
B S;O
O
O

[0491] Compound 134 is synthesized from commercially available 6-bromo-indole-carboxaldehyde following synthetic steps shown in Scheme 12.
Example 112: Synthesis of 3-[1-(4-Methoxy-benzenesulfonyl)-5-methoxy-1H-indazol-3-yl]-propionic acid 135 o o o \\N
N
S;O
O
O

[0492] Compound 135 is synthesized from commercially available 5-methoxy indazole-3-carboxylic acid following synthetic steps shown in Scheme 9.
Example 113: Synthesis of 3-[1-(4-Methoxy-benzenesulfonyl)-6-methoxy-1H-indazol-3-yl]-propionic acid 136 O
S ; _.
O V

[0493] Compound 136 is synthesized from commercially available 6-methoxy-indazole-3-carboxylic acid following synthetic steps shown in Scheme 9.
Example 114: Synthesis of 3-[1-(4-Methoxy benzenesulfonyl)-S-methoxy-1H-7aza-indazol-3-yl]-propionic acid 137 I

[0494] Compound 137 is synthesized from aldehyde 138, prepared from commercially available 7-azainbdole as shown in Scheme 14, following synthetic steps shown in Scheme 12.
Scheme 14 H
O
$r I \
N N N N N N N N

[0495] Compound 139, 5-bromo-7-azaindole, was prepared from commercially available 7-azaindole by following the procedure published by Mazeas, Daniel;
Guillaumet, Gerald;

Marie-Claude Viaud, Heterocycles,1999, v50 (2), 1065-1080. Compound 140 is prepared by heating the bromide 139 with sodium methoxide in dimethyl formamide in presence of cuprous bromide as described by Mazeas, Daniel; Guillaumet, Gerald; Marie-Claude Viaud, Metef°ocycles, 1999, v50 (2), 1065-1080, from which the aldehyde 138 is prepared by Vilsmeier-Haack reaction.
Example 115: Synthesis of Analogs of Compound 1 [0496] Analogs of compound 1 can be synthesized, e.g., by using the commercially available compounds shown in Table 3 as described in Example 3 or Example 109.
Synthesis of carboxylic acid bioisosteres:
(0497] The carboxylic acid functional group of the propionic acid moiety at position 3 can advantageously be replaced with any of a number of carboxylic acid bioisosteres in compounds of Formula I. For example, the following moieties can be used, which are shown with respect to Formula I-1, but which can also be incorporated in other bicyclic rings systems within Formula I.
Thia.zolidione (TZD) and related analogs:
Scheme 14 R5 ~ R5 W~W R5 W~W

I ~X ~ I ~X W ' . I ~X W
R3 Y N R3 Y N Rs Y N
III R2 ~( R2 XXI R2 Step l:
[0498] Compound XX can be prepared through a Knoevenagel coupling. of thiazolidione or related compounds in presence of an inert solvent, e.g. ethanol, with catalytic amount of piperidine with starting compound III. (L. Sun. et al, J.Med Chem., 1999, 42, 5120-30.) Step 2:

[0499] Compound X~~I can be prepared from compound XX through a reduction process using palladium on activated carbon, or a metal reduction reaction (e.g.
magnesium). (B.C. Cantello, J. Med. Claefn.,1994, 37, 3977-85.) Hydroxamic acid:
Scheme 15 i I .X O H
R3 ~Y N N'OH

la or Ib R2 R4 I ~X
or C02Me R3 Y N
Rs R2 ~X
R3 y N
II or IXa RZ
[0500] Compound XXII can be prepared through either amide bond formation reaction with Ia or Ib or nucleophilic displacement of the ester II or IXa with n-hydroxyamine.
(Hard et al, J. Afn. Chem. Soc.,1954, 76, 2791 and Dinh, T.Q., Tet. Lett.
1996, 37; 1161-4).
Tetrazole:
Scheme 16 Rs Rs I .X . I .X

la or Ib R2 XXIII RZ
N,N.N
NH CN
Rs Rs I .X . I .X

[0501] Tetrazole isostere of the carboxylic acid can be prepared through 3 steps from the corresponding acetic or propanoic acid (depending on linker size).
Step l:
[0502] The conversion of the carboxylic acid moiety to the corresponding amide XXIII
with compound Ia or Ib can be done with ammonia (gas) with ethyl polyphosphate in an inert solvent such as chloroform (Imamoto, T. et al, Synthesis, 1983, 142-3).
Step 2:
[0503] The propionamide XXIII can be converted to the nitrite XXIV by treating the amide with methyl magnesium iodide (Wilson et al, J. Claena Soc.,1923, 123, 2615) or with formic acid in acetonitrile (Heck, M.-P., J. Org. Chem., 1996, 61, 6486-7).
Step 3:
[0504] The preparation of the tetrazole isostere involves 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. Claeyn.,1969, 12, 396-401).
Iso-oxazoles:

Scheme 17 N
<~ 1 N
R5 C02H R5 Cp2H R5 R4 ~ R4 R4 'O
3 . WX i I v X
R Y N Rs y N ~ R3 y I N X XXV I I I
H

O O
H O~O~
OH ~O
O O
5~ / 5~ /

R4 R4 ~ R4 I ~X . I .X i I ~X
R3 Y N R3 Y N R3 ~y N
XXXI R2 X~ R2 XXIX RZ
Method 1:
[0505] The hydroxyiso-oxazole compound XXVIII can be derived in 5 steps. Using starting material indole-3-acetic acid XXVI, compound XXVII can be prepared through reactions in Example 4. Activation of the acid group with bis-imidazole-carbonyl leads to compound XXVIII (Eils et al, S~ynthesis,1999, 275-81). The reaction with ethyl malonic acid affords XXIX. Cyclization with hydroxylamine provides the hydroxy protected iso-oxazole XXX. The deprotection of the hydroxy functionality arnves at the desired compound ~;XXI. (Frolund et al, J. Med. C7zem., 2002, 45, 2454-2468) Scheme 18 O'P
OH
O. N'~ N
R5 V 1 .N R5O ~ 50 /

~X P R ~ I ~X R4 i Rs Y H R3 'y H R3 Y ~ N X
V
XXXII XXXI RZ

Method 2:
(0506] The hydroxyiso-oxazole compound ~:.XXI can be derived in 4 steps. The first step involves direct coupling of the 3-unsubstituted indole V with a protected hydroxy iso-oxazole methyl halogen (chloride or bromide) with a base (e.g. sodium hydroxide) in an alcohol solvent (e.g. methanol) system. (Sholtz et al, Ghem. Ber., 1913, 46, 2145)Subsequent removal of the methoxy group under reductive conditions and deprotection of the protection group and protection of the indole nitrogenleads to the desired compound ~:XYI. (Oster, T.A., et al, J. O~g. Ghem. 1983, 48, 2454-68) Scheme 19 O O N.OH
4 Rs OH Rs Rs R . R4 _ H Ra. _ H
R3 Y~ NX ~ 3 . I ~X 3 . I ~X
R Y N R Y N
XXVII R2 XXXIII Rz XXXIV Rz O~ R OH
.OH N .
R5 N O.R 50 ~ N~/
O
R4 i ~ , CI ~~~ R4 R R4 R5 s . ~ X . ~ X I .X
R Y N R Ra Y N R3 ~Y N

Method 3:
[0507] An alternative synthetic approach to compound XXXI, starts with compound XXVII (prepared through reduction of 3-acetic acid) to generate the hydroxy imine X~XIV. Chlorination of XXXIV with chlorination reagents (e.g. NCS) arrive at intermediate ~:XXV. From the hydroxy iminium chloride, a cyclization with acetylene would afford the protected hydroxy iso-oxazole. The deprotection would provide the desired compound ~;XYI. (Weidner-Wells, M.A. et al, Bioo~g. & Med Glaefra.
Lett., 2004, 14, 3069-72) Acyl cyanamide:
Scheme 20 Rs Rs Rs w N
Ra Ra Ra R3 Y I NX Rs Y I NX Rs Y I NX
la or Ib R2 XXXVII R2 XXXVIII RZ
[0508] Compound X~XVIII can be prepared through a two step process starting from either Ia or Ib.
Step l:
[0509] The carboxylic acid group in Ia or Ib can be converted to aryl halide XXXVII
through the use of reagents (e.g. thionyl chloride, phosphorous pentachloride, or phosphorous trichloride) in an inert solvent (e.g. dichloromethane). (Cao, J.
et al, J. Med.
Chena., 2003, 46, 2589-98 and Kitamura, M. et al, Synthesis, 2003, 2415-26) Step 2:
[0510] The acyl cyanamide functionality can be introduced via coupling of the cyanamide with compound XXXVII to yield the desired product ~:XYVIII.
(Belletire, J.L. et al, Syn. Comnaun., 1988,18, 2063-72) Sulfonamides:
Scheme 21 SH

R ' I , X R4 R4 Rs Y N a . I .,X s . I .,X
R Y N R Y

R

Rs Rs Rs R4 > R4 ~ R4 i 3 . I ~ X 3 . I ~,X
R Y N R Y N R3 y~X

[0511] The sulfonamide bio-isostere for carboxylic acid can be prepared in 6 steps from from indolyl-3-acetic acid or propionic acid (if the linker is to be extended) Steps 1 &2:
[0512] Compound XXVII can be transformed to the corresponding alcohol ~;XXIX
through treatment with 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 proper reagents such as methane sulfonyl chloride or Phosphorous tribromide respectively.
Step 3:
(0513] Intermediate XL can be prepared by treating XXXIX with sodium hydrogen sulfide, hexabutyldistannathian, or 1-(2-hydroxyethyl)-4,6-diphenylpyridine-2-thione to get to the ethanethiol or propanethiol. (Gingras et al, Tet. Lett. 1990, 31,1397-1400, Maercker et al, Justus Liebigs Anh. Claerya., 1865, 136, 88, or Molina et al, TetfAahed~or~
Lett.,1985, 26 469-472.) Step 4:
[0514] The thiol XL can be oxidized to the corresponding sulfonic acid with oxidative reagents such as hydrogen peroxide to afford intermediate XLI.
Step 5:

[0515] Compound XL can be treated to reagents (e.g. thionyl chloride or phosphorous pentachloride) to convert the sulfonic acid to the corresponding sulfonyl chloride to arnve at intermediate XLII. (Scheme 20, step 1) Step 6:
[0516] Sulfonamide isosteres of the carboxylic acid is then generated through coupling of the sulfonyl chloride XLIIIa with amine reagents (e.g. sodium amide or methylamine).
Acetyl-sulfonamides:
Scheme 22 O ~O
S02CI S02NH2 O'S-NH
Rs R5 Rs R4 . I v,X Ra i Ra X I ~aC
R3 Y N R3 ~Y N' R3 ~Y N
XLII R2 XLlllb R2 XLIV R2 [0517] Acetyl-sulfonamides XLIV can be prepared through the sulfonyl chloride XLII
in two steps.
Step 1:
[0518] Compound XLII is treated to ammonia or sodium amide to yield XLIIIb.
Step ~:
[0519] Compound XXXIIIb is then deprotonated and treated to acetic anhydride to arrive at the acetyl-sulfonamide XLIV.
Exemplary general synthesis of compounds of Formula L, where W,Y, and Z are independently N or CH; n = 0,1, or 2.
Scheme 23a- Preparation of sulfonyl chloride XLVIII:

X n~ \ ~ ~ Z
W. , Z ,Z \ n ~ OH X~ \ O n.W y I ~ O n W.Y
H03S ~ HO S- v CIOZS

XLV XLVII XLVIII
Step l: Preparation of intermediate XLTIIL' [0520] Commerically available 4-hydroxy benzenesulfonic acid XLV, can be reacted with aryl halides, e.g., iodobenzene benzyl bromide etc., under Buckwald reaction conditions and SNZ reaction conditions respectively, or with alcohols, e.g.
benzyl alcohols under Mitsunobu reaction conditions, or other coupling reactions to afford XLVII.
Step 2: Preparation of intermediate XLT~IIl.-[0521] Compound of formula XI,VII can be converted to the corresponding sulfonly chloride with reagents such as PC13, PCIs, POC13, or SOCIa.
Scheme 2,3b- Preparation of Compound of Formula L
CO~R
p ~ XLVIII
LLR = H Me ~ ICOH(aq)/'FHF
E
~Z
O 'X,Y
I_In [0522] Compound of formula L can be prepared by reacting the sulfonyl chloride XLVIII with 5-methoxy-indole-3-propionic ester in presence of a base, e.g. aq.
Potassium hydroxide, in UHF.
Example 116: Synthesis of 3- f 5-Methoxy-1-[4-(pyridin-3-yloxy)-benzenesulfonyl]-1H-indol-3-yl~-propionic acid 143. , [0523] Compound 143 can be prepared through methods described in Scheme 23, using 4-hydroxybenzenesulfonic acid and 3-hydroxypyridine to prepare the corresponding sulfonyl chloride. The various coupling of the sulfonyl chloride to 5-methoxy-indole-3-p;ropionic ester or the corresponding acid as described in Scheme 7, 10, or 12.
Example 117: Synthesis of 3-{5-Methoxy-1-[4-(pyridin-4-yloxy)-benzenesulfonyl]-indol-3-yl]-propionic acid 144.

[0524] Compound 144 can be prepared through methods described in Scheme 23, using 4-hydroxybenzenesulfonic acid and 4-hydroxypyridine to prepare the corresponding sulfonyl chloride. The various coupling of the sulfonyl chloride to 5-methoxy-indole-3-p;ropionic ester or the corresponding acid as described in Scheme 7, 10, or 12.
Example 118: Synthesis of 3-~5-Methoxy-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-1H-indol-3-yl}-propionic acid 145.

[0525] Compound 145 can be prepared through methods described in Scheme 23, using 4-hydroxybenzenesulfonic acid and 4-pyridylcarbinol to prepaxe the corresponding sulfonyl chloride. The various coupling of the sulfonyl chloride to 5-methoxy-indole-3-p;ropionic ester or the corresponding acid as described in Scheme 7, 10, or 12.
Example 119: Synthesis of 3-[1-(3,5-Dichloro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 146 COZH
I
O
N
OIg~O
s~
~ci ci [0526] Compound 146 can be prepared by reacting 5-methoxy-indole-3-p;ropionic ester or the corresponding acid through methods with 3,5-dichlorobenzenesulfonyl chloride as described in Scheme 7, 10, or 12.
Example 120: Synthesis of 3-[1-(3,5-Dimethoxy-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic acid 147 CO~H
I
O o N' O;SaO
O
O \

[0527] Compound 147 can be prepared by reacting 5-methoxy-indole-3-p;ropionic ester or the corresponding acid through methods with 3,5-dimethoxybenzenesulfonyl chloride as described in Scheme 7, 10, or 12.
General synthesis of compounds of formula LIV and LV
Scheme 24 Step -1 O ~ C102S ~ I ~ v I N I ' N ~O
O=~
H a Br S
2. A = CHO LII
4. A = CH2CH2C02Me Br Step - 2 C02R w C02R
I H2N I i I
n O
O I ~ ~ LIII I ~ ~ LV R=He~KOH(aq}/TH
i N N
O:S:O O:S=O
LII
~
n Br N
H
Stepl: Pr°epa~~ation of intermediate LII
[0528] Compound LII can be prepared through coupling of indole (2 or 4) with sulfonyl chloride LI from methodologies described in Scheme 7 or 12.
Step 2: P~epar~atioya of compoufad LIT~or LT~
[0529] Compound LIV or LV can be prepared through nucleophilic displacement of the bromomethyl group under basic conditions, in an inert solvent such as DMF.

Example 121: Synthesis of 3- f 5-Methoxy-1-[4-(quinolin-7-ylaminomethyl)-benzenesulfonyl]-1H-indol-3-yl}-propionic acid 148 COZH
O
N
O,SoO
d NH
i N
i [0530] Compound 148 can be prepared via coupling of compound LII with the corresponding Quinol-7-ylamine with the bromomethyl moiety in Scheme 24.
Example 122: Synthesis of 3-~1-[4-(Isoquinolin-3-ylaminomethyl)-benzenesulfonyl]-5-methoxy-1H-indol-3-yl)-propionic acid 149 COZH

O
N
O=Ss0 ~NH

[0531] Compound 149 can be prepared via coupling of compound LII with the corresponding isoquinolin-3-yl-amine with the bromomethyl moiety in Scheme 24.
Example 123: Synthesis of 3-~5-Methoxy-1-[4-(quinolin-6-ylaminomethyl)-benzenesulfonyl]-1H-indol-3-yl~-propionic acid 150 COzH
O
N
O=S:O
' \ NH
i N~

[0532] Compound 149 can be prepared via coupling of compound LII with the corresponding quinolin-6-yl amine with the bromomethyl moiety 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 [0533] Compound 151 can be prepared via coupling of compound LII with the corresponding 7-azaindole with the bromomethyl moiety in Scheme 24.
Example 125: Synthesis of 3-[5-Methoxy-1-(4-phenoxymethyl-benzenesulfonyl)-1H-indol-3-yl]propionic acid 152 [0534] Compound 152 can be prepared via coupling of compound LII with the corresponding phenol with the bromomethyl moiety in Scheme 24.
General synthesis of compounds of formula LIX, LX, or LXI
Scheme 25 ' CN ~ CN ~ CN
OH X I ~ ~ O ~ I O ~ I
n LVI ' I ~ n I ~ n H03S ~ S

C02Me CO2H
I
I
O
O I w N N.O
O-S
o~
LIX ~ n LIX R = CN
LX R = CHZNHa LXI R = CONHZ
N R
Step l: Preparation of intermediate LVII:
[0535] The intermediate LVII can be prepared through either similar methods as described in step 1 of preparation of XLVII, or through nucleophilic displacement of a fluoro group.
Step2: Preparation of intermediate LT~IIZ
[0536] The sulfonic acid can be converted to the corresponding sulfonyl chloride with PCl3, POC13, PCIs, or SOCIa.
Step 3: Preparation of intermediate LIW
[0537] The sulfonyl chloride LVIII can be coupled to the indole intermediates 4 to arrive at LIX.

Step 4: Preparation of corrapourad LX ahd LXI
[0538] The nitrile moiety can be further converted to either amide through hydrolysis or amine through reduction.
Example 126: Synthesis of 3- f 5-Methoxy-1-[4-(pyridin-3-ylmethoxy)-benzenesulfonyl]-1H-indol-3-yl]-propionic acid 153 I
O
N
S:O
a ~~
a N
O

[0539] Compound 153 can be prepared through methods described in Scheme 23, using 4-hydroxybenzenesulfonic acid and 3-pyridinemethanol to prepare the corresponding sulfonyl chloride. The various coupling of the sulfonyl chloride to the indole-moiety are described in Scheme 7, 10, or 12.
Example 127: Synthesis of 3- f 1-[4-(4-Aminomethyl-benzyloxy)-benzenesulfonyl]-methoxy-1H-indol-3-yl}-propionic acid 154 [0540] Compound 154 can be prepared through reduction of the nitrile group, as described in Scheme 25. The nitrile functionality can be prepared through coupling of the sulfonyl chloride with the 5-methoxyindole-3-propionic acid methyl ester. The sulfonyl chloride can be prepared through coupling of the 4-hydroxy benzenesulfonic acid with 4-cyanobenzyl bromide.
Example 128: Synthesis of 3-~l-[4-(4-Carbamoyl-benzyloxy)-benzenesulfonyl]-5-methoxy-1H-indol-3-yl~-propionic acid 155 NHa [0541] Compound 155 can be prepared through hydrolysis of the nitrile group, as described in Scheme 25. The nitrite functionality can be prepared through coupling of the sulfonyl chloride with the 5-methoxyindole-3-propionic acid methyl ester. The sulfonyl chloride can be prepared through coupling of the 4-hydroxy benzenesulfonic acid with 4-cyanobenzyl bromide.
Example 129: Synthesis of compound 162:
Scheme 26 I CN
O N
I ' 158 I
O N COZH
N0~6 O N' O N CHO I
+ N. ~ I~ N --> I~ N ~ > I~ ~
H H N
/N ~~ 160 161 162 O:S:O

I
O N' ~ N~ O.
I i NO 159 Step 1: Preparation of 5 Methoxy-IH pyY~~olo~3,2-bJpyridine 160 [0542] The title compound can be prepared through:
1. 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 catalytic hydrogenation and cyclization under reflux conditions with C-tert-butoxy-tetra-N-methyl-methanediamine 157 (K-H. Buchheit et al, J.
Med. Chem., 1995, 2331-2338).
3. Reductive cyclization with 159 (S.A. Filla et al, J. Med. Chem., 2003, 46, 3060-71) Step 2: Preparation of 5-Methoxy-IH pyr~olo~3,2-bJpyridiTZe-3-carbaldehyde 161 [0543] The intermediate 161 can be prepared either through Vilsmeier reaction (I~-H.
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).
(0544] The subsequent conversion to introduce the propionic acid side chain and the sulfonamide can be achieve using methodologies as described in Scheme 7 or 12.
Example 130: Synthesis of compound 166:
Scheme 27 COZH
Siw ~ 1 CHO
N ~ NH2 N ~ N N ~ H ~ N ~ N
O:S=O

Step l: Preparation of intermediate 164, 5-Methoxy-IH pyrrolo~2,3-cJpyridine:
[0545] 5-Methoxy-1H-pyrrolo[2,3-c]pyridine 164 can be prepared through cyclization of 6-methoxy-4-trirnethylsilanylethylnyl-pyridin-3-ylamine 163 with cuprous iodide in DMF
(D. Mazeas et. al, Heterocycles, 1999, 50, 1065-80).
Step2: Preparation of intermediate 165, 5 Methoxy-1H pyrrolo~2,3-cJpyridine-3-carbaldehyde:
[0546] 5-Methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde can be prepared from using with 1,3,5,7-tetraaza-adamantane under refluxing conditions with DMF (D.
Mazeas et. al, Heterocycles, 1999, 50, 1065-80).
[0547] The subsequent conversion to introduce the propionic acid side chain and the sulfonamide can be achieve using methodologies as described in Scheme 7 or 12.
Example 131: Synthesis of compound 172 Scheme 28 HN % ' N % ~ N %
O H CI H p N
167 168 ~ 169H C02H
CHO
N ~ ~ N ~ ~ N ~
i i N ~ ~ i ~ -~ i , O O N O N
I 170 H ~ 171 H ~ O:S'd /O

Step 1: Preparation of 168, 6-ClZloro-2,3-dihydro-IH py~rolo~3,2-cJpyridine:
[0548] 1,2,3,5-Tetrahydro-pyrrolo[3,2-c]pyridin-6-one 167 can be converted to the 6-Chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine 168 with Phosphorous oxychloride (N.N.
Bychikhina et. al, Chem. Heterocycl. Compds., 1982, 18, 356-360) Step2: Preparation of 169, 6-Methoxy-2,3-dihydf°o-IH pyrrolo~3,2-cJpyridine:
[0549] 6-Methoxy-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine 169 can be prepared through direct displacement of the chloro group in 168 with sodium methoxide. (V.A.
Azimov et.al, Chem. Heterocycl.Compd. 1981, 17, 1648-1653) Step3: Preparation of170, 6-Methoxy-lHpyrrolo~3,2-cJpyYidine:
[0550] 6-Methoxy-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine 169 is oxidized to the corresponding 170 with the use of Mn02. (V.A. Azimov et.al, Chem.
Heterocycl.Compd.
1981, 17, 1648-1653) Step 4: Preparation of 171, 6 Methoxy-IH pyrrolo~3,2-cJpyridine-3-carbaldehyde:
[0551] 6-Methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde is prepared through Vilsmeier conditions with 170. (N.N. Bychikhina et. al, Chem. Heterocycl.
Compds., 1982, 18, 356-360) [0552] The subsequent conversion to introduce the propionic acid side chain and the sulfonamide can be achieve using methodologies as described in Scheme 7 or 12.
Example 132: Synthesis of compound 181 Scheme 29 ~ O
N . I I
CI~
N NH2 ~ ~ ' ~ ' ' N ' ' N ' v 170 I CI N H ~~ N H ~O~N H ~~~N
O' "O
p 175 176 177 178 O_ / 1 C02H ~ CO2H

N ' v ~ ' y--- N ' y < N w v <-- N ' v N ~O N N J:
O N ys;0 t OsS:O O N N O ~ N N .O ~ N Ss0 183 p 182 ~ p_5' p;S p.
/ ~ 181 / ' 180 / ~ 179 /O s0 .gyp /O /O
Step 1: preparation of 175 [0553] 2-chloro-7H-pyrrolo[2,3-d]pyrimidine 175 can be prepared from either 2-chloro-5-(2-ethoxy-vinyl)-pyrimidin-4-ylamine 173 or 2-chloro-5-(2,2-dimethoxy-ethyl)-pyrimidin-4-ylamine 174 (under reflex conditions in methanol with concentrated hydrochloric acid (M. Cheung et al, Tet. Lett., 2001, 42, 999-1002).
Step 2: Preparation of 176 [0554] The 2-chloro group in 2-chloro-7H-pyrrolo[2,3-d]pyrimidine 176 can be converted to the corresponding methoxy moiety 176 through nucleophilic displacement of the chloro group by sodium methoxide (F., Seela et. al, Liebigs Ann.Chem.
1985, 312-320.) Step3: Preparatiora of 177 (0555] Intermediate 177 can be prepared from 176 through iodination of 176 with Iodine, with base in N,N-dimethylformamide at ambient temperature. (T., Salcamoto, Takao et.al, J.Chem.Soc.Perkin Trans.l, 1996; 459-464) Step 4: Preparation of 178 [0556] Protection of the pyrrolopyrimidine 177 with 4-methoxybenzenesulfonyl chloride can be achieve through a bi-phasic coupling using aqueous sodium hydroxide solution or with sodium hydride in DMF.

Step 5: Preparation of 179 [0557] The 3-carboxylic acid functionality can be prepared through deprotonation with a grignard reaction, follow by COa addition and acidification to yield the desired intermediate from 177. (Y. Kondo, et.al Heterocycles, 1996, 42, 205-8.) [0558] The subsequent conversion to introduce the propionic acid side chain and the sulfonamide can be achieve using methodologies as described in Scheme 9 Example 133: Synthesis of compound 190 Scheme 30 w ~ , I ~ ~I Q2N , ~ H2N
I ~ ~ . I N ~ . 1 ~N
N CI N N
N H N H N N

I ~N~O ~ I ~N --> ~ I ~N --~ Q ~ I ~N
N H N H NON ~ N~N,O

H 190 Q' Step l: Synthesis of intermediate 184 [0559] Intermediate 184 can be prepared from 3-acetyl-2-chloropyridine, through cyclization with methylhyrazine. (B.M. Lynch et.al, Canadian Journal of Chemistry, 1988, 66, 420-8) Step2: Synthesis of intermediate 185 [0560] Intermediate 185 is prepared through nitration of the 5-position with nitric acid and sulfuric acid. (B.M. Lynch et.al, Canadian Journal of Chemistry, 1988, 66, 420-8) Step 3: Synthesis of intermediate 186 [0561] The nitro group is reduced the corresponding amine group through use of reagents such as palladium on activated carbon. (B.M. Lynch et.al, Canadian Journal of Chemistry, 1988, 66, 420-8) Step 4: Sy~tlaesis of intermediate 187 [0562] The amine group is then converted to diazonium salt with sodium nitrate and concentrated hydrochloric acid. The diazonium ion is then quenced with methanol to yield the corresponding methoxy functionality. (B.M. Lynch et.al, Canadian Journal of Chemistry, 1988, 66, 420-8) Step 5: Synthesis of intermediate 188 [0563] The 3-methyl group is oxidized through _K_M_n_04 oxidation to the carboxylic acid.
(B:M. Lynch et.al, Canadian Journal of Chemistry, 1988, 66, 420-8) [0564] The subsequent conversion to introduce the propionic acid side chain and the sulfonamide can be achieve using methodologies as described in Scheme 9 to arrive at the desired compound 190.
Example 134: Crystallization and Crystal Structures of PPARs [0565] PPARa, PPARB, and PPARy have each been crystallized and crystal structures determined and reported. Such structures and atomic coordinates are available at Protein Data Bank (PDB) (available on the Internet on the Web where the remainder of the address following www is rcsb.org). For PPARa deposited atomic coordinates are available under PDB code 1KKQ, Xu; 2001, Nature 41 S, p813; for PPARB under code 1 GWX, .Xu, 1999, Mol Cell, 3, p397; and for PPARy under code 1 PRG, Notle, et al, 1998, Nature, 395, p137. (Each of the references cited in connection with PPAR
structures is hereby incorporated by reference in its entirety.) Additional atomic coordinate deposits are available, where PDB codes of the deposited structures are: 1K7L, lI7G, and 1KKQ
for PPARalpha, 1PRG, 2PRG, 3PRG, 4PRG, 1K74, 1FM6, 1FM9, lI7I, and 1KNU for PPARgamma, 1GWX, 2GWX, and 3GWX for PPARdelta.

[0566] In addition, high quality crystals of the PPARs can be obtained by crystalization under conditions as described below. The structures can then be readily obtained by using published structures as references. Sequences encoding the individual PPARs can be readily obtained. Sequences encoding the individual PPARs were obtained from the NCBI LocusLink (on the Web where the remainder of the address following www is ncbi.nih.gov/LocusLink). The sequence accession numbers are: NM 005036 (cDNA
sequence for PPARa), NP_005027 (protein sequence for PPARa), NM 015869 (cDNA
sequence for PPARg isoform 2), NP_056953 (protein sequence for PPARg isoform 2), NM 006238 (cDNA sequence for PPARd), and NP_006229 (protein sequence for PPARd). Using these sequences, the coding sequences can be isolated from a cDNA
library using conventional cloning techniques. PPAR proteins can then be expressed and purified by conventional methods.
[0567] In the present case, PPAR polypeptides were obtained by PCR from a cDNA
library (Invitrogen), and sub-cloned to obtain constructs for expression.
Expressing those sequences thus provided PPAR polypeptides for crystallization.
[0568] In addition to the conditions published for crystallizing each of the PPARs, the following crystallization conditions have been used for producing co-crystals of each of the PPAR ligand binding domains with compounds of Formula I. The particular ligand binding domain sequence used for PPARalpha: GenBank accession: NP-005027 (protein sequence) and NM 005036 (mRNA sequence), ligand binding domain: amino acid residues 196-468.
[0569] For PPARgamma the ligand binding domain used corresponded to amino acid residues 174 475 of GenBank accession: NP-005028 (protein sequence) and NM

(mRNA sequence).
[0570] For PPARdelta the ligand binding domain used corresponded to amino acid 441 of GenBank accession: NP_006229 (protein sequence) and NM 006238 (mRNA
sequence).
[0571] Exemplary Crystallization conditions for PPARgarnma:
1. with Zx molar excess of SRC-1 and 1mM compound 0.2M Ammonium Acetate, O.1M Bistris, pH 6.5, 13-25%PEG4k, or 0.2M Ammonium Acetate, O.1M Hepes, pH 7.5, 13-25%PEG4k 2. with 0.3 - 1 mM compound 12-22% PEG 8k, 0.2M NaAcetate, O.1M Hepes pH 7.5; or 0.6M -1.OM NaCitrate, O.1M Hepes pH 7.5; or 0.9-1.4M Ammonium Sulfate, O.1M Hepes pH 7.5 [0572] Crystallization conditions for PPARalpha:
1. with 2x molar excess of SRC-1 and 1mM compound 9 - 30% PEG 4K, 0.2M Ammonium Acetate, O.1M Citrate, pH 5.6; or 17 - 30% PEG4k, 0.2M Lithium Sulfate, O.1M Tris/HCI, pH 8.5; or 22 - 30% PEG4k, 0.2M NaAcetate, O.1M Tris/HCI, pH 8.5 2. with co-concentrated compound 0.6-1.OM Lithium Sulfate, O.1M Tris/HCl pH 8.5 [0573] Crystallization conditions for PPARdelta:
1. with 2x molar excess of SRC-1 and co-concentrated compound 0.2-1.2M KNaTartrate, 2.5% 1,2 Propanediol, O.1M Mes pH 5.5-6.5 [0574] The X-ray diffraction data from such co-crystals were then collected from synchrotron radiation facilities. The useable diffraction data were of high resolution such as 1.9A-3.OA, preferably 2.5A or higher, more preferably 2.2A or higher, most preferably 2.0A or higher. The 3-dimensional structures of proteins were determined with the co-crystal diffraction data by molecular replacement method using the published structures as starting search model. The molecular replacement solutions of the protein structures were then refined and used for calculating difference Fourier maps. The difference Fourier maps provide basis for the determination of compound binding geometry. The compound orientation and structure within the protein ligand binding site were determined based on the information obtained from the co-crystal diffraction data. A skilled person in this art will be able to interpret the X-ray diffraction data according to the compound structures which were involved in the co-rystallization experiements. Water molecules that are tightly bound to the proteins are an integral part of the protein structures.
They can also be critical mediators of protein ligand interactions. Such water molecules are termed "structural water". The structural water molecules are built into the structure model based on difference Fourier maps through the iterative refinement process. The compound-protein complex structures including structural water molecules were refined against the co-crystal diffraction data using computational crystallography methods in an iterative manner to yield accurate atomic coordinates for further ligand design process.
Example 135: Exemplary Compounds of Formula I.
[0575] The structures, IUPAC names, and molecular weights for synthesized exemplary compounds of Structure I are shown below in Table 1.

Number Structure M. Wt IUPAC name O
w ~OH 3-(1H-Indol-3-yl)-propionic acid N
H
28 I 189.2 OH
3-(5-Methoxy-1 H-indol-3-yl)-propionic acid 96 I 219.2 O
O 3-(5-Methoxy-1 H-indol-3-yl)-H3C-O , ~ propionic acid methyl ester 4 H 233.3 OH

3-( 1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-propionic acid s~o 29 ~ ~ 359.4 O

3-[5-Methoxy-1-(3-methoxy-N
_ benzyl)-1H-indol-3-yl]-propionic \/
acid H,c' 339.4 I

O OH

~ ~ 3-[1-(3-Chloro-benzyl)-5-methoxy-~ N
_ 1H-indol-3-yl)-propionic acid \/
343.8 O OH

I ~ ~ 3-[1-(4-Fluoro-benzyl)-5-methoxy-N 1H-indol-3- 1 - ro ionic _ acid y] p p \ /.
F 327.3 O OH

3 -[1-(4-Chloro-benzyl)-5-methoxy-N 1H-indol-3-yl]-propionic acid \/
ci 343.8 OH

3-[5-Methoxy-1-(2-methoxy-benzyl)-1H-indol-3-yl]-propionic acid \

cH3 339.4 OH

o"' 3-[5-Methoxy-1-(2-~ N trifluoromethoxy-benzyl)-1H-indol-3-yl]-propionic acid \ / OF

F~F 393.4 O OH

oH'~ ~ 3-[5-Methoxy-1-(3-I

trifluoromethoxy-benzyl)-1H-indol-3-yl]-propionic acid F'F F 393.4 ci 3-(1-Ethylthiocarbamoyl-5-methoxy-1 H-indol-3-yl)-propionic acid 306.4 O OH

o"3 3-[5-Methoxy-1-(toluene-4-~

I sulfonyl)-1H-indol-3-yl]-propionic N ,o s.
acid H3~ 373.4 OH

3-(1-Benzenesulfonyl-1H-indol-3-N .,o yl)-propionic acid S~

_ o \ / 329.4 O OH

3-[ 1-(4-Isopropyl-I
N o benzenesulfonyl)-5-methoxy-1H-s:
o \ ~ indol-3-yl]-propionic acid "'0 401.5 cH, 3-[ 1-(4-Isopropyl-benzenesulfonyl)-5-methoxy-1 H-indol-3-yl]-propionic acid methyl 415.5 ester O OH

OH' 3-[1-(4-Butoxy-benzenesulfonyl)-5-I
methoxy-1 H-indol-3-yl]-propionic s;
acid 431.5 O CHs O

3-[1-(4-Butoxy-benzenesulfonyl)-5-I N methoxy-1H-indol-3-yl]-propionic .o s acid methyl ester "' U--o 445.5 O OH

0 3 3-[5-Methoxy-1-(4-trifluoromethoxy-benzenesulfonyl)-_s 0 1H-indol-3-yl]-propionic acid F \

F Fo 443.4 0H3 0 3-[5-Methoxy-1-(4-\ o N
,O
rifluoromethoxy-benzenesulfonyl)-S
- ''0 1H-indol-3-yl]-propionic acid F ~ /
k 457 methyl ester F .

OH

o"3 3-[5-Methoxy-1-(4-phenoxy-~

I benzenesulfonyl)-1 H-indol-3-yl]-_ s:
propionic acid r \ 0 451.5 ~

c"3 3-[5-Methoxy-1-(4-phenoxy-cH' o I
benzenesulfonyl)-1 H-indol-3-yl]-_ s:
propionic acid methyl ester \r -0 465.5 O OH

cH3 3-[ 1-(4-Chloro-benzenesulfonyl)-5-I v N methoxy-1H-indol-3-yl]-propionic o . acid _s 'o ci 393.8 ~

c"3 3-[1-(4-Chloro-benzenesulfonyl)-5-cH3 I v N methoxy-1H-indol-3-yl]-propionic HS'O
'cH3 acid methyl ester \

~
c, 407.9 .

c"3 3-[ 1-(4-Cyano-benzenesulfonyl)-5-cH' I
r; ; methoxy-1H-indol-3-yl]-propionic _ s.
acid methyl ester N s 398.4 CH °~cH3 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1 H
' s:o indol-3-yl]-propionic acid methyl \ ~ ester ci ci 442.3 cH3 ~CH' 3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-.o propionic acid methyl ester \~
H3°_° 403.4 o-CHa .CHs 0 3-[5-Methoxy-1-(4-trifluoromethyl-N ,o benzenesulfonyl)-1H-indol-3-yl]-s.
° propionic acid methyl ester 441.4 ~cH' 3-[ 1-(4-Fluoro-benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-propionic .o s~ acid methyl ester 391.4 cH3 .cH3 3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1 H-indol-3-yl]-propionic s o acid methyl ester ~o s 379.4 3-[5-Methoxy-1-(thiophene-2-sulfonyl)-1H-indol-3-yl]-propionic acid 365.4 cH3 cH' 3-(5-Methoxy-1-I
phenylthiocarbamoyl-1H-indol-3-s yl)-propionic acid methyl ester 36.4 OH

a 3 3-(5-Methoxy-1-phenylthiocarbamoyl-1H-indol-3-"~ yl)-propionic acid \ 354.4 ~~, ~ ~ 3-[5-Methoxy-1-(3-phenoxy-y _ s:o benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 465.5 .

c"' 3-[1-(3-Fluoro-benzenesulfonyl)-5-c"' methoxy-1 H-indol-3-yl]-propionic s.
acid methyl ester 391.4 ~

CIi~
CH3 3-[5-Methoxy-1-(toluene-3-~

I sulfonyl)-1H-indol-3-yl]-propionic o s.

acid methyl ester c~ 387.4 .

c"' 3-[1-(3-Chloro-benzenesulfonyl)-5-c"' I
,o methoxy-1 H-indol-3-yl]-propionic _ s.
acid methyl ester 407.9 .

o"' ~ \ 3-[5-Methoxy-1-(3-methoxy-cH3 s:o benzenesulfonyl)-1H-indol-3-yl]-o propionic acid methyl ester H3~ 403.4 ~

o"' ~ \ 3-[5-Methoxy-1-(3-trifluoromethyl-I/
s:o benzenesulfonyl)-1H-indol-3-yl]-propionic acid methyl ester 441.4 HO
O

0"3 3-[ 1-(4-Cyano-benzenesulfonyl)-5-methoxy-1 H-indol-3-yl]-propionic s, \ A 0 aCId 384.4 Ho 0 0"3 3-[1-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-1 H-~.,o o indol-3-yl]-propionic \ acid o ci ci 428.3 Ho 0 0 3 3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-:
S

o propionic acid \

o H3c_o 389.4 0 3 3-[5-Methoxy-1-(4-trifluoromethyl-~

I benzenesulfonyl)-IH-indol-3-yI]-s , propionic acid F \

F 427.4 F

HO O

cH3 3-[ 1-(4-Fluoro-benzenesulfonyl)-5-t ~ N methoxy-IH-indol-3-yl]-propionic So acid \o 377.4 O O
3-(1-Benzenesulfonyl-5-methoxy-1H-indol-3- 1 - ro ionic I acid Y) p p / N methyl ester s;

_ \ o 373.4 HO
O

o ~ ~ 3-(1-Benzyl-5-methoxy-1H-indol-I~
3-yl)-propionic acid 309.4 HsC_O O

"3 0 3-(1-Benzyl-5-methoxy-1H-indol-~ ~

J
3-yl)-propionic acid methyl ester 323.4 HO
O

N, 3-[5-Methoxy-1-(3-phenoxy-s,-- benzenesulfonyl)-1 H-indol-3-yl]-propionic acid 451.5 v , HO
O

0 3 3-[1-(3-Fluoro-benzenesulfonyl)-5-~

v I methoxy-1 H-indol-3-yl]-propionic s \ ~ ~~ acid F 377.4 HO O

0 3 3-[5-Methoxy-1-(toluene-3-i rs ; sulfonyl)-1H-indol-3-yl]-propionic s , \ ~ acid c"3 373.4 HO O

0"3 3-[ 1-(3-Chloro-benzenesulfonyl)-5-~

I methoxy-1H-indol-3-yl]-propionic a N

,, s \ acid ~
ci 393.8 HO
O

o"' 3-[5-Methoxy-1-(3-methoxy-~

4 benzenesulfonyl)-1H-indol-3-yl]-s,, \ m propionic acid 389.4 HO
O

o"' 3-[5-Methoxy-1-(3-trifluoromethyl-s; benzenesulfonyl)-1H-indol-3-yl]-propionic acid F F 427.4 F

OH

3-( 1-B enzenesulfonyl-5-bromo-1 H-o=s=o indol-3-yl)-propionic acid .

OH

oN' ~ ~ 3-[5-Methoxy-1-(3-I/
s;o trifluoromethoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid 443.4 o~oH, 3-[5-Methoxy-1-(3-trifluoromethoxy-benzenesulfonyl)-N O
1H-indol-3-yl]-propionic acid FCC 457.4 methyl ester F F

O
OH

0 3 3-[1-(4-Butyl-benzenesulfonyl)-5-v p methoxy 1H-indol-3-yl]-propionic s.
acid 415.5 3-[ 1-(4-Butyl-benzenesulfonyl)-S-methoxy-1 H-indol-3-yl}-propionic acid methyl ester 429.5 o, 3-(1-Benzenesulfonyl-5-thiophen-v 3-Y

o=s=o 1-1H-indol-3-yl)-propionic acid met 425 hYl ester .

0 3-( 1-B enzenesulfonyl-5-phenyl-1 H-in dol-3-yl)-propionic acid methyl est 419 er .

o ~CH
oH3 ~ ~ 3 3-(1-Benzoyl-5-methoxy-1H-indol-I ~ N>
3-yl)-propionic acid methyl ester _ o \ / 337.4 3-(1-Benzoyl-5-methoxy-1H-indol 3-yl)-propionic acid 323.3 _ OH
S ~
( , N 3-(1-Benzenesulfonyl-5-thiophen-o=s=o 3-y w I 411.5 1-1H-indol-3-yl)-propionic acid O OH
I
I ~ ~ 3-(1-Benzenesulfonyl-5-phenyl-1H-N
o=s=o in 405.5 dol-3-yl)-propionic acid O OH
rCH3 o I ~ ~ 3-(1-Benzenesulfonyl-5-ethoxy-1H-N
',O
o=S in a\
373.4 dol-3-yl)-propionic acid 3-[1-(4-Isopropoxy-benzenesulfonyl) N
°°s~° -5-methoxy-1 H-indol-3 -yl]-ry propionic °
417.5 acid O O Ha cH, 3-(5-Methoxy-1-phenylcarbamoyl-° t , N ' 1H-i HN~° ndol-3-yl)-propionic acid methyl es 3 52.4 ter \ ° 0"
0"3 3-[1-(4-Ethyl-benzenesulfonyl)-5-s:o me thoxy-1 H-indol-3-yl]-propionic "3° 387.5 acid OH

O
3-(5-Methoxy-1-phenylcarbamoyl-1H-i 338.4 ndol-3-yl)-propionic acid 3-(1-Benzenesulfonyl-5-ethyl-1H-ind 357.4 ol-3-yl)-propionic acid OH
3-( 1-B enzenesulfonyl-5-isopropoxy-1 387.5 H-indol-3-yl)-propionic acid n 3-[5-Methoxy-1-(thiophene-3-sulfony 365.4 1)-1H-indol-3-yl]-propionic acid O
OH
\ \N
H 190.2 Indazole-3-propionic acid O OH
3-( 1-B enzenesulfonyl-1 H-indazol-N
s.o 3_Y

39 ~ / 330.4 1)-propionic acid OH
3-( 1 H-Pyrro to [2, 3-b]pyridin-3-yl)-p 95 ~ h 190.2 ~ ropionic acid ~OH
°H~~
O' ~ \
-° 3-[ 1-(3,4-Dimethoxy-o~
~H, benzenesulfonyl)-5-methoxy-1H-H,C
101 419.5 indol-3-yl]-propionic acid O OH
C
O ~~ _~~/\
3-[ 1-(3,4-Difluoro-v F
benzenesulfonyl)-5-methoxy-1H-F
102 396.4 indol-3-yl]-propionic acid °
~OH
CFI
O ~ ~ \
=° 3-[ 1-(3-chloro-4-methyl-G
benzenesulfonyl)-5-methoxy-1 H-103 407. indol-3-yl]-propionic acid O OH
F
_O s=o 3-[1-(benzenesulfonyl)-5-fluoro-104 ~ ' 347.5 1H-indol-3-yl]-propionic acid O OH
H,C
\
N
O gc0 3-[ 1-(benzenesulfonyl)-5-methyl-105 323.2 1H-indol-3-yl]-propionic acid O OH
CI
\
N
O=Se0 i 3-[ 1-(benzenesulfonyl)-S-chloro-106 363.7 1H-indol-3-yl]-propionic acid ° OH
C
~~\
° 5:° 3-[1-(3-fluoro-4-methyl-benzenesulfonyl)-5-methoxy-1H-107 391.3 indol-3-yl]-propionic acid Oyy OH
C
O I ~~\
° s=° 3-[1-(2,3-Dihydro-benzofuran-5-v sulfonyl)-5-methoxy-1H-indol-3-O
108 401.2 yl]-propionic acid ~OH
H,C ~1 ° ~ \ \
=° 3-[1-(4-ethyl-benzenesulfonyl)-5 ethoxy 1H-indol-3-yl]-propionic HOC
109 401.5 acid oyOH
H,C ~1 ° \
3-[ 1-(4-methoxy-benzenesulfonyl)-r\
5-ethoxy-IH-indol-3-yl]-propionic HOC
110 403.6 acid ° off o ~ \ \
H'O1 N
°- -O 3-[1-(3-trifluoromethoxy-benzenesulfonyl)-5-ethoxy-1H-111 indol-3-yl]-propionic acid ° OH
FhG1 OI
3-[ 1-(4-butyl-benzenesulfonyl)-5-° r \
~H, ethoxy-1H-indol-3-yl]-propionic 112 429.4 acid H
H,1 o ~

I \
s--[ 1-(4-butoxy-benzenesulfonyl)-5-m' ethox -1H-indol-3- 1 -N, ro ionic Y y ] p p 113 445.5 acid O
Q-OH
C

~1 O

( \
3-[1-(3,4-dichloro-' Ci benzenesulfonyl)-5-ethoxy-1H-114 442.2 indol-3-yl]-propionic acid OH
~C

, ~
O

N
=s= 3-[ 1-(3-methoxy-benzenesulfonyl)-\

",~ 5-ethoxy-1H-indol-3-yl]-propionic 115 403.5 acid ~ON

N
', 3-[1-(4-phenoxy-benzenesulfonyl)-5-ethoxy-1 H-indol-3-yl]-propionic 116 465.3 acid CO~H
I
O

N
'S 3- f 5-Methoxy-1-[4-(pyridin-3-yloxy)-benzenesulfonyl]-1 H-indol-452.583-yl~-propionic acid 3- ~ 5-Methoxy-1-[4-(pyridin-4-yloxy)-b enzenesulfonyl]
-1 H-indol-452.583-yl~-propionic acid COzH
I

O
\

I 3- f 5-Methoxy-1-[4-(pyridin-4-' N
oa~o r ~ N ylmethoxy)-benzenesulfonyl]-1H-r ' 145 0~ 466.51indol-3-yl}-propionic acid COZH -O

I \
3-[1-(3,5-Dichloro-o_S:o r benzenesulfonyl)-5-methoxy-1 ~ H-146 o~ 2 4 8.29mdol-3-yl]-propiomc acid COZH
I

O
\

I 3-[1-(3,5-Dimethoxy-'o S;o benzenesulfonyl)-5-methoxy-1 H-147 ~ ~ 419.45indol-3-yl]-propionic acid COZH
I
O

I
N
O_g;0 r 3- f S-Methoxy-1-[4-(quinolin-7-NH
ylaminomethyl)-benzenesulfonyl]-148 ~ 515.581H-indol-3-yl)-propionic acid COZH
I

' ~ N
O;gcO

r ' 3- f 1-[4-(Isoquinolin-3-NH ylaminomethyl)-benzenesulfonyl]-I 5-methoxy-1H-indol-3-yl}-149 ~ I 515.58propionic acid coZH
I

N
O~g:O

r -NH 3- { 5-Methoxy-1-[4-(quinolin-6-\ I ylaminomethyl)-benzenesulfonyl]-150 NJ 515.581H-indol-3-yl)-propionic acid COZH
O a N
o=s'° 3-[S-Methoxy-1-(4-pyrrolo[2,3-b]pyridin-1-ylmethyl-' N ~
benzenesulfonyl)-1H-indol-3-yl]-N~ ~ 489.54 ro ionic acid p p COzH
I
O
~o s:o 3-[5-Methoxy-1-(4 \ 1 ~ ' phenoxyrnethyl-benzenesulfonyl)-465.53 1H-indol-3-yl]propionic acid I
O
N 3-{5-Methoxy-1-[4-(pyridin-3 o S:o o ~ ylmethoxy)-benzenesulfonyl]-1H-W
o~N 466.51 indol-3-yl~-propionic acid 3-{ 1-[4-(4-Aminomethyl benzyloxy)-benzenesulfonyl]-5 methoxy-1 H-indol-3-yl~-propionic 494.57 acid 3- { 1-[4-(4-Carbamoyl-benzyloxy)-benzenesulfonyl]-5-methoxy-1H-508.55 indol-3-yl]-propionic acid [0576] Agonist activities for exemplary compounds from Table 1 were determined, and are shown in Table 2, where "+" indicates activity <_ 10 ~,M, and "-"
indicates > 10 ~M.
These activities were determined as described in Example 1.
Table 2 PPARa agonist PPAR8 Agonist PPARY Agonist Compound # (ixM) (pM) (~,M) 2g + + +

97 - _ _ 39 - _ _ 43 + + +

4g + + +

53 + + +

71 + _ 79 + + +

77 + + +

81 + _ -92 + - +

82 + + +

85 _ - _ 6 _ _ +

Table 3 MOLSTRUCTUR.E ~ molecular weight ~ MOLNAME
251.284 5-BENZYLOXYINDOLE-3-o I~ CARBOXALDEHYDE

N 159.187 4-METHYLINDOLE-3-ALDEHYDE
I
o~
~c N 159.187 6-METHYLINDOLE-3 ~ CH CARBOXALDEHYDE

o~ ~ N , 251.284 7-BENZYLOXYINDOLE-3-o ~ I CARBOXALDEHYDE
° 251.284 6-BENZYLOXYINDOLE-3-'I
° CARBOXALDEHYDE
179.605 2-CHLORO-1 H-INDOLE-3-CARBALDEHYDE
ci ~ I
N
251.284 4-BENZYLOXYINDOLE-3-° _° CARBOXALDEHYDE
a rv 0 0 203..196 3-FORMYLINDOLE-5-CARBOXYLIC ACID METHYL
N ESTER
-° 203.196 METHYL 3-FORMYLINDOLE-6-CARBOXYLATE
N
c o _0 204.184 3-FORMYL-2-METHYL-5-I I.
'N ~ I' NITROINDOLE

N
189.169 3-FORMYL-1H-INDOLE-7-CARBOXYLIC ACID
O OH
_0 231.25 TIMTEC-BB ST002282 N
O-Chl~

190.15? 7-NITROINDOLE-2-~ ~ N ~ CARBOXALDEHYDE
oW°
0 190.157 5-NITROINDOLE-3-i.
I I ~ CARBOXALDEHYDE
N
,0 170.17 5-CYANOINDOLE-3-ALDEHYDE
N\
' ~ N
249.268 6-BENZOYL-1 H-INDOLE-3-CARBOXALDEHYDE
N
O
o _0 249.268 5-BENZOYL-1H-INDOLE-3-i ( ~ CARBOXALDEHYDE
\ N
173.214 7-ETHYL-1H-INDOLE-3-CARBOXALDEHYDE
N
Fi~C
196.636 5-AMINO-1 H-INDOLE-3-HrN
CARBOXALDEHYDE
°~" HYDROCHLORIDE
207.252 5-METHYLSULPHINYLINDOLE-3-~ CARBOXALDEHYI?E
\ I N
° 163.15 7-FLUOROINDOLE-3 CARBOXALDEHYDE
N
F

191.145 6-NITRO-1 H-INDAZOLE-3-;N CARBALDEHYDE
0.N' \ ~ N
I I
O
a o.c~, 204.184 METHYL-3-AL-4-INDAZOLE
CARBOXYLATE
N
/ N
151.595 6-CHLOROINDOLE
CI
131.177 6-METHYLINDOLE
0 162.147 7-NITROINDOLE
i.
i ~ ~o / 142.16 6-CYANOINDOLE
\ I N~
//
N
o c~ 177.202 5,7-DIMETHOXY INDOLE
N \
\ ~ i .c~

147.176 6-METHOXY1NDOLE
~ I 1 H3C~0 \ N
253.299 5-BENZYLOXY-6-METHOXYINDOLE

N o_~~ 147.176 7-METHOXYINDOLE
N ~O 162.147 6-NITROINDOLE
\ ~ \

145.204 7-ETHYLINDOLE
I
NJ

HO 163.175 5-HYDROXY-6-METHOXYINDOLE
H3Cw0 \ N
0 175.186 METHYL INDOLE-5-~o'o \ I ~ CARBOXYLATE
N
175.186 METHYL INDOLE-6-o i N CARBOXYLATE

175.186 METHYL INDOLE-7-CARBOXYLATE
0 o'cH' 273.334 N-(4-MORPHOLINOETHYL)INDOLE-6-N
~N~' CARBOXAMIDE
204.228 N-METHOXY-N-METHYL-INDOLE-o ~ I I 6-CARBOXAMIDE
N
~CiNvO~CHa F
N
F F

0 159.187 5-ACETYLINDOLE
~ I
w N
241.044 5-BROMO-7-NITROINDOLE
\; I N
O .~O
196.046 7-BROMOINDOLE
~1 Br 135.14 7-FLUOROINDOLE
~~ J
N
F
H3C\ /N 174.202 5-ACETAMIDOINDOLE
/
O
151.595 7-CHLOROINDOLE
I
N
CI
HO / 147.176 INDOLE-5-METHANOL
N
147.176 INDOLE-6-METHANOL
/
HO
N
~ 147.176 INDOLE-7-METHANOL
\ I N
HO
0 179.242 5-METHYLSULPHINYLINDOLE
H,c~s i I \
N

179.242 6-METHYLSULPHINYLINDOLE
~ac.s w ~ \
N
I I
O
F F 185.147 5-(TRIFLUOROMETHYL)INDOLE
N
191.257 N-(1H-INDOL-6-YL)THIOUREA
N \ N- _Nti2 \ 226.072 7-BROMO-5-METHOXYINDOLE
Br 195.241 6-(METHYLSULFONYL)-1H-N INDOLE
HaC~SO
163.135 5-NITROINDAZOLE
N ' O
N ~ / N+._ O
NON ,O 163.135 6-NITROINDAZOLE

N-N Di 163.135 7-NITROINDAZOLE
I "~ o "~" 183.213 ACB-BLOCKS PYR-0331 I~

183.213 ACB-BLOCKS PYR-0332 I ~ N
\ N S 206.272 N-(6-METHYL-1H-INDAZOL-5-N; I YL)THIOUREA
NCH N~
192.245 N-(iH-INDAZOL-7-YL)THIOUREA
N N ~ ~ Nhlx 192.245 N-(1H-INDAZOL-6-YL)THIOUREA
/ ~ \ S
N\
N / N' -NFiz 197.035 6-BROMOINDAZOLE
\ \
~N
N
Br 0 190.201 ETHYL 1H-INDAZOLE-5-~N CARBOXYLATE
N
sr ~ 211.061 CBI-BB ZERO/005553 I \\N
N
CI-l3 148.164 5-HYDROXYMETHYL-1 H-HO ~ ~ \
'N INDAZOLE
N
[0577] Additional exemplary compounds of Formula I are described inTable 4.
Table 4 describes exemplary compounds by specifying substituents for each of the bicyclic cores shown in the Summary herein, except that substituents on a nitrogen (N) in the membered ring are excluded, and the 6-membered ring includes at least one allcoxy or thioether substituent at the 5-or 6-position. Thus, for example, for a bicyclic core that includes a N at the 5-position, only those substitutent combinations that do not have a substitutent at the 5 position and have an alkoxy or thioether at the 6-position apply to that bicylic core. Where no substituent is specified for a ring position, it is to be understood that there is no substituent if the ring atom at that position is a N, and as H if the ring atom at that position is a carbon (C). All compounds include a -CHZCH2- linker at the 3-position; the specification of the 3-substituent in Table 4 is thus the moiety attached to that linker.
[0578] The numbering of the ring atoms as referenced herein, including in Table 4, is shown in the following structure. This structure includes the indolyl ring structure, but as used herein, the numbering for the other bicyclic structures using the same numbering for corresponding atoms. In addition, this structure shows the 1-position substituents referenced in Table 4, where 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 on that aromatic group.
3\

6 8 1~
N
L
Ar A
Table 4 1~ 3 5 6 -.

L1 Ar A

SOz henyl COOH methoxy 502 phenyl CF3 COOH methoxy SOZ henyl CHZCF3 COOH methoxy SOZ henyl Halo substitutedCOOH methoxy alkyl SOZ henyl OCH3 COOH methoxy 502 henyl OCHZCH3 COOH methoxy SOZ henyl OCHZCHZCH3 COOH methoxy SOZ phenyl OCHZCHZCHZCH3 COOH methoxy SOZ henyl OCHZCHZCH2CHZGH3COOH methoxy SOZ henyl CS-C8 alkoxy COON methoxy SOZ henyl Halo substitutedCOOH methoxy alkoxy SOZ henyl CH3 COOH methoxy SOZ henyl CHZCH3 COOH methoxy SOZ henyl CHZCHzCH3 COOH methoxy SOZ phenyl CHZCHZCHzCH3 COOH methoxy SOZ phenyl CS-C8 alkyl COOH methoxy SOZ phenyl F COOH methoxy SOZ henyl F,F COOH methoxy SOZ hen F,CI COOH methoxy SOZ henyl Cl COOH methoxy SOZ henyl C1,C1 COOH methoxy SOZ phenyl -(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlyCOOH methoxy linked atom linker-optionally subst. heteroaryl SOZ yridinyl COOH methoxy SOZ PyridinylCF3 COOH methoxy SOZ PyridinylCHZCF3 COOH methoxy SOZ PyridinylHalo substitutedCOOH methoxy alkyl SOZ PyridinylOCH3 COOH methoxy SOZ PyridinylOCHZCH3 COOH methoxy SOz PyridinylOCHZCHZCH3 COOH methoxy SOZ PyridinylOCHZCHZCHZCH3 COOH methoxy SOZ PyridinylOCHZCHZCHZCHZCH3COOH methoxy SOZ PyridinCS-C8 allcoxy COOH methoxy SOZ PyridinylHalo substitutedCOOH methox alkoxy SOZ PyridinylCH3 COOH methoxy SOZ PyridinylCHaCH3 COOH methoxy SOZ PyridinylCH~CHzCH3 COOH methoxy SOZ P idinylCHZCHZCHZCH3 COOH methoxy SOZ PyridinylCS-C8 allcyl COOH methoxy SOZ PyridinylF COOH methoxy SOZ PyridinylF,F COOH methoxy SOZ PyridinylF,Cl COOH methoxy SOZ PyridinylCl COOH methoxy SOZ PyridinylCl,CI COOH methoxy SOZ Pyridinyl-(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. heteroaryl CO Phenyl COOH methoxy CO Phenyl CF3 COON methox CO Phenyl CHZCF3 COOH methoxy CO Phenyl Halo substitutedCOOH methox alkyl CO Phenyl OCH3 COOH methoxy CO Phenyl OCHZCH3 COOH methoxy CO Phenyl OCHZCHZCH3 COOH methoxy CO Phenyl OCHZCHZCHZCH3 COOH methoxy CO Phenyl OCHZCHZCHZCHZCH3COOH methoxy CO Phenyl CS-C8 alkoxy COOH methoxy CO Phenyl Halo substitutedCOOH methoxy alkoxy CO Phenyl CH3 COOH methoxy CO Phenyl CHZCH3 COOH methoxy CO Phenyl CHZCHzCH3 COOH methoxy CO Phenyl CHzCHZCHZCH3 COOH methoxy CO Phenyl CS-C8 alkyl COOH methoxy CO Phenyl F COOH methoxy CO Phenyl F,F COOH methoxy CO Phenyl F,Gl COOH methoxy CO Phenyl Cl COOH methoxy CO Phenyl C1,C1 COOH methoxy CO Phenyl -(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. heteroaryl CO yridinyl COOH methoxy CO PyridinylCF3 COOH methoxy CO PyridinylCHzCF3 COOH methoxy CO PyridinylHalo substitutedCOOH methoxy alkyl CO PyridinylOCH3 COOH methoxy CO PyridinylOCHZCH3 COOH methoxy CO PyridinylOCH2CHZCH3 COOH methox CO PyridinylOCHzCH2CHzCH3 COOH methoxy CO PyridinylOCHzCH2CHZCHZCH3COOH methoxy CO PyridinylC5-C8 allcoxy COOH methox CO PyridinylHalo substitutedCOOH methoxy alkoxy CO PyridinylCH3 COON methoxy CO PyridinylCHzCH3 COOH methoxy CO PyridinylCHzCH2CH3 ~ COOH methoxy CO PyridinylCHzCHzCHzCH3 COOH methoxy CO PyridinylCS-C8 alkyl COON methoxy CO PyridinylF COOH methoxy CO PyridinylF,F COOH methoxy CO PyridinylF,Cl COOH methoxy CO PyridinylCl COOH methoxy CO PyridinylC1,C1 COOH methoxy CO Pyridinyl-(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. heteroaryl SOz henyl COOH ethoxy SOz henyl CF3 COOH ethoxy SOz phenyl CHzCF3 COOH ethoxy SOz henyl Halo substitutedCOON ethox alkyl SOz henyl OCH3 COOH ethoxy SOz phenyl OCHzCH3 COOH ethoxy SOz henyl OCHZCHZCH3 COOH ethoxy SOz phenyl OCHzCHzCH2CH3 COOH ethoxy SOz phenyl OCHzCH2CHZCH2CH3COOH ethoxy SOz hen CS-C8 alkoxy COON ethoxy SOz phenyl Halo substitutedCOOH ethoxy alkoxy SOz henyl CHs COOH ethoxy SOz phenyl CHzCH3 COOH ethoxy f SOZ phenyl CHZCHZCH3 COON ethoxy SOZ henyl CHzCHZCHZCH3 COOH ethoxy SOZ henyl CS-C8 alkyl COOH ethoxy SOz henyl F COOH ethoxy SOZ henyl F,F COOH ethoxy SOZ henyl F,CI COOH ethoxy SOZ phenyl Cl COOH ethoxy SOZ henyl CI,CI COOH ethoxy SOz phenyl -(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. aryl SO2 phenyl -(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. heteroaryl SOZ yridinyl COON ethoxy SOZ PyridinylCF3 COOH ethoxy SOZ PyridinylCHZCF3 COOH ethoxy SOZ PyridinylHalo substitutedCOOH ethoxy alkyl SOZ PyridinylOCH3 COOH ethoxy SOZ PyridinylOCHZCH3 COON ethoxy SOZ PyridinylOCH2CHZCH3 COOH ethoxy SOZ PyridinylOCHZCHZCHZCH3 COON ethox SOZ PyridinylOCHZCHZCHZCHZCH3COOH ethoxy SOZ PyridinylCS-C8 alkoxy COOH ethoxy SOZ PyridinylHalo substitutedCOOH ethoxy alkoxy SOZ PyridinylCH3 COOH ethoxy SOZ PyridinylCHZCH3 COOH ethoxy SOZ PyridinylCHZCHZCH3 COON ethoxy SOZ PyridinylCHZCHZCHZCH3 COOH ethoxy SOZ PyridinylCS-C8 alkyl COOH ethoxy SOZ PyridinylF COOH ethoxy SOa PyridinylF,F COOH ethoxy S02 PyridinylF,CI COOH ethoxy SOZ PyridinylCI COOH ethoxy SOz PyridinylCI,CI COOH ethoxy SOZ Pyridinyl-(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. aryl SOz Pyridinyl-(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. heteroaryl CO Phen COOH ethoxy CO Phenyl CF3 COON ethox CO Phenyl CHZCF3 COOH ethoxy CO Phenyl Halo substitutedCOOH ethoxy alkyl CO Phenyl OCH3 COOH ethoxy CO Phenyl OCHaCH3 COOH ethoxy CO Phen OCHzCHZCH3 COOH ethox I

CO Phenyl OCHZCHZCHZCH3 COOH ethoxy CO Phenyl OCHZCHZCHZCHZCH3COOH ethoxy CO Phen CS-C8 alkoxy COOH ethoxy CO Phenyl Halo substitutedCOOH ethoxy alkoxy CO Phenyl CH3 COOH ethoxy CO Phenyl CHZCH3 COOH ethoxy CO Phenyl CHZCHZCH3 COOH ethoxy CO Phenyl CHZCHZCHZCH3 COOH ethoxy ~CO Phenyl CS-C8 allcyl COOH ethoxy ~ ~

CO Phenyl F COON ethoxy CO Phenyl F,F COOH ethoxy CO Phenyl F,Cl COOH ethoxy CO Phenyl Cl COOH ethoxy CO Phenyl CI,CI COOH ethoxy CO Phenyl -(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. heteroaryl CO yridinyl COOH ethoxy CO PyridinylCF3 COOH ethoxy CO PyridinylCHZCF3 COON ethoxy CO PyridinylHalo substitutedCOOH ethoxy alkyl CO PyridinylOCH3 COOH ethoxy CO PyridinylOCHZCH3 COON ethoxy CO PyridinylOCHZCHZCH3 COOH ethoxy CO PyridinylOCHZCHZCHZCH3 COOH ethoxy CO PyridinylOCHzCHzCHZCHZCH3COOH ethoxy CO PyridinylCS-C8 alkoxy COON ethoxy CO PyridinylHalo substitutedCOOH ethoxy alkoxy CO PyridinylCH3 COON ethoxy GO PyridinylCHzCH3 COOH ethoxy CO PyridinylCHzCHzCH3 COOH ethoxy CO PyridinylCH~CHZCHZCH3 COOH ethoxy CO PyridinylCS-C8 alkyl COON ethoxy CO PyridinylF COOH ethoxy CO PyridinylF,F COOH ethoxy CO PyridinylF,CI COOH ethoxy CO PyridinylCl COOH ethoxy CO PyridinylC1,C1 COOH ethox CO Pyridinyl-(1 to 4 linearlyCOON ethoxy linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. heteroaryl SOZ henyl COOH ro oxy SOz phenyl CF3 COOH ro oxy SOa phenyl CHZCF3 COOH pro oxy SOZ henyl Halo substitutedCOON ro oxy alkyl SOZ henyl OCH3 COOH ro oxy SOZ phenyl OCHzCH3 COOH ro oxy SOZ henyl OCHZCH2CH3 COOH ropoxy SOz phenyl OCHzCHZCH2CH3 COON ro oxy SOz henyl OCHZCHZCHZCHZCH3COOH pro oxy SOz henyl CS-C8 alkoxy COOH ropoxy SOZ phenyl Halo substitutedCOOH ro ox alkoxy SOZ henyl CH3 COOH pro oxy SOZ henyl CHzCH3 COOH ro oxy SOZ phenyl CHZCHZCH3 COOH ro oxy SO~ henyl CHZCHZCHZCH3 COOH ropoxy SOZ phenyl CS-C8 allcyl COON pro oxy SOZ henyl F COOH propoxy SOz henyl F,F COOH ro oxy ~- phenyl F,CI COON propoxy SOZ ~
~

SOZ henyl Cl COOH pro oxy SOZ phenyl C1,C1 COOH ro oxy SOZ phenyl -(1 to 4 linearlyCOOH propoxy linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlyCOOH propoxy linked atom linker)-optionally subst. heteroaryl SOz pyridinyl COON ro oxy SOZ PyridinylCF3 COOH ro oxy SOZ PyridinylCHZCF3 COOH ro oxy SOZ PyridinylHalo substitutedCOOH ro oxy alkyl SOZ PyridinylOCH3 COOH ro oxy SOZ PyridinylOCHZCH3 COOH ro oxy SOZ PyridinylOCHZCHZCH3 COOH ropoxy SOZ PyridinylOCHZCHZCHZCH3 COOH ropoxy SOZ PyridinylOCHZCHZCHzCH2CH3COOH ro oxy SOZ PyridinylCS-C8 alkoxy COOH ro oxy SOZ PyridinylHalo substitutedCOOH ro oxy alkoxy SOZ PyridinylCH3 COOH ro oxy SOz PyridinylCHZCH3 COOH ro oxy SOZ PyridinylCHaCH~CH3 COOH pro oxy SOZ PyridinylCHZCHzCHZCH3 COOH pro oxy SOa PyridinylCS-C8 alkyl COOH ropoxy SOZ PyridinylF COOH ro oxy SOz PyridinylF,F COOH ropoxy SOZ PyridinylF,CI COOH ropoxy SOZ PyridinylCl COOH ropoxy SOZ PyridinylCl,Cl COOH ro oxy SOZ Pyridinyl-(1 to 4 linearlyCOOH propoxy linked atom linker)-optionally subst. aryl SOz Pyridinyl-(1 to 4 linearlyCOOH propoxy linked atom linker)-optionally subst. heteroaryl CO Phenyl COOH pro oxy CO Phenyl CF3 COOH ro oxy CO Phenyl CHzCF3 COOH ro oxy CO Phenyl Halo substitutedCOOH pro oxy alkyl CO Phenyl OCH3 COOH ro oxy CO Phenyl OCHZCH3 COOH ro oxy CO Phen OCHzCHZCH3 COOH propoxy CO Phenyl OCHaCHZCHZCH3 COOH ro oxy CO Phenyl OCHZCHZCHZCH2CH3COON ro oxy CO Phenyl CS-C8 alkoxy COOH ro oxy CO Phenyl Halo substitutedCOON ro oxy alkox CO Phenyl CH3 COOH ro oxy CO Phen CHZCH3 COOH pro oxy CO Phenyl CHZCHZCH3 COOH ro oxy CO Phenyl CHZCHZCHZCH3 COON ro oxy CO Phenyl CS-C8 alkyl COOH ro oxy CO Phenyl F COON ro oxy CO Phenyl F,F COOH ro oxy CO Phenyl F,Cl COOH ro oxy CO Phenyl Cl COOH ro oxy CO Phenyl Cl,Cl COON ro oxy CO Phenyl -(1 to 4 linearlyCOON ro oxy linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyCOOH propoxy linked atom linker)-optionally subst. heteroaryl CO pyridinyl COOH ro oxy CO PyridinylCF3 ~ COOH ro oxy CO PyridinylCHZCF3 COOH ro oxy CO PyridinylHalo substitutedCOOH ropoxy alkyl CO PyridinylOCH3 COOH ro oxy CO PyridinylOCHZCH3 COOH ro oxy CO PyridinylOCHZCHZCH3 COOH ro oxy CO PyridinylOCHZCHaCHzCH3 COOH ro oxy CO PyridinylOCHZCHZCHzCH2CH3COOH ro oxy CO PyridinylCS-C8 alkoxy COOH pro oxy CO PyridinylHalo substitutedCOOH ropoxy alkoxy CO PyridinylCH3 COOH ro oxy CO PyridinylCHzCH3 COOH propoxy CO PyridinylCHZCHZCH3 COOH ro oxy CO PyridinylCHzCH2CH2CH3 COOH ro ox CO PyridinCS-C8 alkyl COOH ro oxy CO PyridinylF COOH ro oxy CO PyridinylF,F COOH ro oxy CO PyridinylF,Cl COOH ro oxy CO PyridinylCl COOH ro ox CO PyridinylCl,Cl COOH ro oxy CO Pyridinyl-(1 to 4 linearlyCOON propoxy linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyCOOH propoxy linked atom linker)-optionally subst. heteroaryl SOz henyl COOH -SCH3 SOZ henyl CF3 COOH -SCH3 SOZ henyl CHZCF3 COOH -SCH3 SOZ phenyl Halo substitutedCOON -SCH3 alkyl SOZ henyl OCH3 COOH -SCH3 SOZ phenyl OCHZCH3 COOH -SCH3 SOZ henyl OCH2CHZCH3 COOH -SCH3 SOZ henyl OCHZCHZCHZCH3 COOH -SCH3 SOZ hen OCHZCHZCHZCHZCH3COOH -SCH3 SOZ henyl CS-C8 allcoxy COOH -SCH3 SOZ henyl Halo substitutedCOOH -SCH3 alkoxy SOz henyl CH3 COON -SCH3 SO2 henyl CHZCH3 COOH ~ -SCH3 SOZ phenyl CHZCHZCH3 COOH -SCH3 SOZ phen CHZCHzCH2CH3 COOH -SCH3 SOZ henyl CS-C8 alkyl COOH -SCH3 SOz henyl F COOH -SCH3 SOZ henyl F,F COOH -SCH3 SOZ henyl F,CI COON -SCH3 SOZ henyl CI COOH -SCH3 SOZ henyl C1,C1 COOH -SCH3 SOZ phenyl -(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. ar 1 SOZ henyl -(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. heteroaryl SOz yridinyl COOH -SCH3 SOz PyridinylCF3 COOH -SCH3 SOz PyridinylCHzCF3 COOH -SCH3 SOz PyridinylHalo substitutedCOOH -SCH3 alkyl SOz PyridinylOCH3 COOH -SCH3 SOz PyridinylOCHZCH3 COOH -SCH3 SOz PyridinylOCHZCHZCH3 COOH -SCH3 SOz PyridinylOCHZCHzCH2CH3 COOH -SCH3 SOz PyridinylOCHZCHZCHZCHZCH3COOH -SCH3 SOz PyridinylCS-C8 alkoxy COOH -SCH3 SOz PyridinylHalo substitutedCOOH -SCH3 alkoxy SOz PyridinylCH3 COOH -SCH3 SOz PyridinylCHzCH3 COOH -SCH3 SOz PyridinylCH~CHZCH3 COOH -SCH3 SOz PyridinylCHzCH2CH2CH3 COOH -SCH3 SOz PyridinylCS-C8 alkyl COOH -SCH3 SOz PyridinylF COOH -SCH3 SOz PyridinylF,F COOH -SCH3 SOz PyridinylF,Cl COON -SCH3 SOz PyridinylCl COOH -SCH3 SOz PyridinylC1,C1 COOH -SCH3 SOz Pyridinyl-(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. aryl SOz Pyridinyl-(1 to 4 linearlyCOON -SCH3 linked atom linker)-optionally subst. heteroaryl CO Phenyl COOH -SCH3 CO Phenyl CF3 COOH -SCH3 CO Phenyl CHzCF3 COOH -SCH3 CO Phenyl Halo substitutedCOOH -SCH3 alkyl CO Phenyl OCH3 COOH -SCH3 CO Phenyl OCHZCH3 COOH -SCH3 CO Phenyl OCHzCH2CH3 COOH -SCH3 CO Phenyl OCHzCHzCH2CH3 COOH -SCH3 CO Phenyl OCHZCHZCH~CHZCH3COOH -SCH3 -CO Phenyl CS-C8 allcox COOH -SCH3 CO Phenyl Halo substitutedCOON -SCH3 alkoxy CO Phenyl CH3 COON -SCH3 CO Phen CHZCH3 COOH -SCH3 CO Phenyl CHzCH2CH3 COON -SCH3 CO Phenyl CH2CHZCHZCH3 COOH -SCH3 CO Phenyl CS-C8 alkyl COOH -SCH3 CO Phenyl F COOH -SCH3 CO Phenyl F,F COOH -SCH3 CO Phenyl F,Cl COOH -SCH3 CO Phen Cl COOH -SCH3 CO Phenyl Cl,Cl COOH -SCH3 CO Phenyl -(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. heteroaryl CO yridinyl COOH -SCH3 CO PyridinylCF3 COOH ~~ -SCH3 CO PyridinylCHZCF3 COOH -SCH3 CO PyridinylHalo substitutedCOOH -SCH3 alkyl CO PyridinylOCH3 COOH -SCH3 CO PyridinylOCHZCH3 COOH -SCH3 CO PyridinylOCHZCH~CH3 COON -SCH3 CO PyridinylOCH~CHzCH2CH3 COOH -SCH3 CO PyridinylOCHZCHZCHZCHzCH3COOH -SCH3 CO PyridinylCS-C8 allcoxy COOH -SCH3 CO PyridinylHalo substitutedCOOH -SCH3 alkoxy CO PyridinylCH3 COOH -SCH3 CO PyridinylGH~GH3 COOH -SCH3 CO PyridinylCHzCH2CH3 COOH -SCH3 CO PyridinylCHZCHZCHZCH3 COOH -SCH3 CO PyridinylCS-C8 allcyl COOH -SCH3 CO PyridinylF COOH -SCH3 CO PyridinylF,F COOH -SCH3 CO PyridinylF,CI COOH -SCH3 CO PyridinylCl COOH -SCH3 CO PyridinylC1,C1 COOH -SCH3 CO Pyridinyl-(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. heteroaryl SOz phenyl COOH -SCHZCH3 SOz phenyl CF3 COOH -SCHZCH3 SOZ phenyl CHZCF3 COOH -SCHZCH3 SOZ phenyl Halo substitutedCOON -SCHzCH3 alkyl SOZ henyl OCH3 COOH -SCHZCH3 SOZ henyl OCHZCH3 COOH -SCHZCH3 SOZ henyl OCHzCH2CH3 COOH -SCHZCH3 SOZ phenyl OCHZCHZCHZCH3 COON -SCHZCH;

SOZ henyl OCHZCHZCHZCHZCH3COOH -SCHZCH3 SOZ henyl CS-C8 alkoxy COON -SCHZCH3 SOZ phenyl Halo substitutedCOON -SCHZCH3 alkoxy SOZ henyl CH3 COOH -SCHzCH3 SOZ phenyl CHZCH3 COOH -SCHZCH3 SOZ phenyl CHZCHZCH3 COOH -SCHzCH3 SOz henyl CHZCHZCHZCH3 COOH -SCHzCH3 SOZ henyl CS-C8 ally 1 COOH -SCHzCH3 SOZ henyl F COOH -SCHZCH3 SOZ henyl F,F COOH -SCHZCH3 SOZ henyl F,Cl COON -SCH2CH3 SOZ phenyl Cl COOH -SCHZCH3 SOz henyl C1,C1 COOH -SCH2CH3 SOZ phenyl -(1 to 4 linearlyCOOH -SCHzCH3 linked atom linker)-optionally subst. aryl SO~ phenyl -(1 to 4 linearlyCOOH -SCHZCH3 linked atom linker)-optionally subst. heteroaryl SOZ yridin COOH -SCHZCH3 SOZ PyridinylCF3 COOH -SCHZCH3 SOZ PyridinCHZCF3 COOH -SCHZCH3 SOZ PyridinylHalo substitutedCOOH -SCHZCH3 alkyl SOz PyridinylOCH3 COON -SCHZCH3 SOZ PyridinylOCHZCH3 COOH -SCHZCH3 SOZ PyridinylOCHZCHZCH3 COON -SCHzCH3 SOZ PyridinylOCHZCHzCHzCH3 COOH -SCHzCH3 SOZ PyridinylOCHZCHZCHZCHZCH3COOH -SCHZCH3 SOZ PyridinylCS-C8 alkoxy COOH -SCHZCH3 SOZ PyridinylHalo substitutedCOOH -SCHzCH3 alkoxy SOZ PyridinylCH3 COOH -SCHZCH3 SOZ PyridinylCHZCH3 COOH -SCHZCH3 SOZ PyridinylCHZCHZCH3 COOH -SCHzCH3 SOZ PyridinylCH2CHzCH2CH3 COOH -SCHZCH3 SOz PyridinylCS-C8 alkyl COOH -SCHZCH3 SOZ PyridinylF COON -SCHZCH3 SOZ PyridinylF,F COOH -SCHZCH3 SOZ PyridinylF,CI COOH -SCHZCH3 SOZ PyridinylCl COOH -SCHZCH3 SOZ PyridinylC1,C1 COOH -SCHZCH3 SOZ Pyridinyl-(1 to 4 linearlyCOOH -SCHZCH3 linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearlyCOOH -SCHzCH3 linked atom linker)-optionally subst. heteroaryl CO Phenyl COOH -SCHZCH3 CO Phenyl CF3 COOH -SCHZCH3 CO Phenyl CHZCF3 COOH -SCHaCH3 CO Phenyl Halo substitutedCOOH -SCHaCH3 alkyl CO Phenyl OCH3 COOH -SCHZCH3 CO Phenyl OCHZCH; COOH -SCHZCH3 CO Phenyl OCHZCHZCH3 COOH -SCH2CH3 CO Phenyl OCHZCHZCHZCH3 COON -SCHZCH3 CO Phenyl OCHZCHZCHZCH~CH3COOH -SCHZCH3 CO Phenyl CS-C8 alkoxy COOH -SCHZCH3 CO Phenyl Halo substitutedCOOH -SCHZCH3 alkoxy CO Phenyl CH3 COON -SCHZCH3 CO Phenyl CHzCH3 COOH -SCHZCH3 CO Phenyl CHZCHZCH3 COOH -SCH2CH3 CO Phenyl CHZCHZCHZCH3 COOH -SCHZCH3 CO Phenyl CS-C8 alkyl COOH -SCHZCH3 CO Phenyl F COON -SCHzCH3 CO Phenyl F,F COOH -SCHZCH3 CO Phen F,CI COOH -SCHZCH3 CO Phenyl Cl COOH -SCHZCH3 CO Phenyl CI,Cl COON -SCHZCH3 CO Phenyl -(1 to 4 linearlyCOOH -SCHZCH3 linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyCOOH -SCHZCH3 linked atom linleer)-optionally subst. heteroaryl CO yridin COOH -SCHZCH3 CO PyridinylCF3 COON -SCHZCH3 CO PyridinylCHzCF3 COOH -SCHZCH3 CO PyridinylHalo substitutedCOON -SCHZCH3 alkyl CO PyridinylOCH3 COON -SCHZCH3 CO PyridinylOCHZCH3 COOH -SCHZCH3 CO PyridinylOCHZCHZCH3 COOH -SCHZCH3 CO PyridinylOCHZCHZCHZCH3 COON -SCHaCH3 CO PyridinylOCHZCHZCHZCHZCH3COOH -SCHZCH3 CO PyridinylCS-C8 alkoxy COOH -SCHZCH3 CO PyridinylHalo substitutedCOOH -SCHZCH3 alkoxy CO PyridinylCH3 COOH -SCHZCH3 CO PyridinylCHZCH3 COOH -SCHzCH3 CO PyridinylCHZCHZCH3 COOH -SCHZCH3 CO PyridinylCHZCHZCHZCH3 COOH -SCHZCH3 CO PyridinylCS-C8 alkyl COOH -SCHaCH3 CO PyridinylF COOH -SCHzCH3 CO PyridinylF,F COOH -SCHzCH3 CO PyridinylF,CI COOH -SCHZCH3 CO PyridinylCl ' COOH -SCHZCH3 CO PyridinylC1,C1 COOH -SCHZCH3 CO Pyridinyl-(1 to 4 linearlyCOOH -SCHZCH3 linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyCOOH -SCHZCH3 linked atom linker)-optionally ' subst. heteroaryl SOz henyl tetrazole methoxy SOZ phenyl CF3 Tetrazole methoxy SOZ henyl CHZCF3 Tetrazole methoxy SOz henyl Halo substitutedTetrazole methoxy alkyl SOZ phenyl OCH3 Tetrazole methoxy SOZ henyl OCHZCH3 tetrazole methoxy SOz phenyl OCHzCHZCH3 tetrazole methoxy SOZ hen OCHZCHZCHZCH3 Tetrazole methoxy SOz phenyl OCHZCHZCHZCHZCH3Tetrazole methoxy SOZ henyl CS-C8 alkoxy Tetrazole methoxy SOZ henyl Halo substitutedTetrazole methoxy alkoxy SOz henyl CH3 tetrazole methoxy SOZ henyl CH~CH3 tetrazole methoxy SO~ hen CHZCH~CH3 Tetrazole methoxy SOZ henyl CHZCHZCHZCH3 Tetrazole methoxy SOZ henyl CS-C8 alkyl Tetrazole methoxy SOZ henyl F Tetrazole methoxy SOZ henyl F,F tetrazole methoxy SOZ henyl F,Cl tetrazole methoxy SOZ henyl Cl Tetrazole methox SOZ henyl C1,C1 Tetrazole methoxy SOZ phenyl -(1 to 4 linearlyTetrazole methoxy linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlyTetrazole methoxy linked atom linker)-optionally subst. hetero~ryl SOZ pyridinyl tetrazole methox SOz PyridinylCF3 tetrazole methoxy SOZ PyridinylCHZCF3 Tetrazole methoxy SOZ PyridinHalo substitutedTetrazole methoxy 1 alkyl SOZ PyridinylOCH3 Tetrazole methoxy SOZ PyridinylOCHZCH3 Tetrazole methoxy SOa PyridinylOCHzCHZCH3 tetrazole methoxy SOZ PyridinylOCHzCHZCHZCH3 tetrazole methoxy SOZ PyridinylOCHZCHZCHZCHZCH3Tetrazole methoxy SOZ PyridinylCS-C8 alkoxy Tetrazole methoxy SOZ PyridinylHalo substitutedTetrazole methoxy alkoxy SOZ PyridinylCH3 Tetrazole methoxy SOZ PyridinylCHZCH3 tetrazole methoxy SOZ PyridinylCHzCHzCH3 tetrazole methoxy SOZ PyridinylCHZCHZCHZCH3 Tetrazole methoxy SOZ PyridinylCS-C8 alkyl Tetrazole methoxy SOZ PyridinylF Tetrazole methoxy SOZ PyridinylF,F Tetrazole methoxy SOZ PyridinylF,CI tetrazole methoxy SOZ PyridinylCl tetrazole methoxy SOZ PyridinylCI,Cl Tetrazole methoxy SOZ Pyridinyl-(1 to 4 linearlyTetrazole methoxy linked atom linker)-optionally subst, aryl S02 Pyridinyl-(1 to 4 linearlyTetrazole methoxy linked atom linker)-optionally subst. heteroaryl CO Phenyl Tetrazole methoxy CO Phenyl CF3 tetrazole methoxy CO Phenyl CHZCF3 tetrazole methoxy CO Phenyl Halo substitutedTetrazole methoxy alkyl CO Phenyl OCH3 Tetrazole methoxy CO Phenyl OCHZCH3 Tetrazole methoxy CO Phenyl OCHZCHZCH3 Tetrazole methoxy CO Phenyl OCHZCHZCHZCH3 tetrazole methoxy CO Phenyl OCHZCHZCHzCH2CH3tetrazole methoxy CO Phenyl CS-C8 alkoxy Tetrazole methoxy CO. Phenyl Halo substitutedTetrazole methoxy alkoxy CO Phenyl CH3 Tetrazole methoxy CO Phenyl CHZCH3 Tetrazole methoxy CO Phenyl CHZCHZCH3 tetrazole methoxy CO Phenyl CHZCHzCHZCH3 tetrazole methoxy CO Phenyl CS-C8 a 1 Tetrazole methoxy CO Phenyl F Tetrazole methoxy CO Phenyl F,F Tetrazole methoxy CO Phenyl F,CI Tetrazole methoxy CO Phenyl Cl tetrazole methoxy CO Phenyl C1,C1 tetrazole methoxy CO Phenyl -(1 to 4 linearlyTetrazole methoxy linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyTetrazole methoxy linked atom linker)-optionally subst. heteroaryl CO yridinyl Tetrazole methoxy CO PyridinylCF3 Tetrazole methoxy CO PyridinylCHZCF3 tetrazole methoxy CO PyridinylHalo substitutedtetrazole methoxy alkyl CO PyridinylOCH3 Tetrazole methoxy CO PyridinylOCHzCH3 Tetrazole methoxy CO PyridinylOCHZCHzCH3 Tetrazole methoxy CO PyridinylOCHzCH2CHZCH3 Tetrazole methoxy CO PyridinylOCHZCHZCHZCHZCH3tetrazole methoxy CO PyridinylCS-C8 alkoxy tetrazole methoxy CO PyridinylHalo substitutedTetrazole methoxy alkox CO PyridinCH3 Tetrazole methoxy CO PyridinylCHZCH3 Tetrazole methoxy CO PyridinylCHZCHZCH3 Tetrazole methoxy CO PyridinylCHZCHZCHZCH3 tetrazole methoxy CO PyridinylCS-C8 alkyl tetrazole methoxy CO PyridinylF Tetrazole methoxy CO PyridinylF,F Tetrazole methoxy CO PyridinylF,Cl Tetrazole methoxy CO PyridinylCl Tetrazole methoxy CO PyridinylC1,C1 tetrazole methoxy CO Pyridinyl-(1 to 4 linearlytetrazole methoxy linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyTetrazole methoxy linked atom linker)-optionally subst. heteroaryl SOZ phenyl Tetrazole ethoxy SOZ phenyl CF3 Tetrazole ethoxy SOZ henyl CHZCF3 Tetrazole ethoxy SOz henyl Halo substitutedtetrazole ethoxy alkyl SOZ henyl OCH3 tetrazole ethox SOZ henyl OCHZCH3 Tetrazole ethoxy SO~ henyl OCHZCHZCH3 Tetrazole ethoxy SOZ phenyl OCHZCHZCHZCH3 Tetrazole ethoxy SO~ phenyl OCH~CHZCHZCHZCH3Tetrazole ethoxy SOZ henyl CS-C8 alkoxy tetrazole ethoxy SOZ hen Halo substitutedtetrazole ethoxy 1 alkoxy SOZ henyl CH3 Tetrazole ethoxy SOZ henyl CHZCH3 Tetrazole ethoxy SOZ phenyl CHZCHZCH3 Tetrazole ethoxy SOZ phenyl CH2CHZCHZCH3 Tetrazole ethoxy SOZ phenyl CS-C8 allcyl tetrazole ethoxy SOZ phenyl F tetrazole ethoxy SOZ henyl F,F Tetrazole ethoxy SOZ henyl F,CI Tetrazole ethoxy SOZ phenyl Cl Tetrazole ethox SOZ henyl C1,C1 Tetrazole ethoxy SOZ phenyl -(1 to 4 linearlytetrazole ethoxy linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlytetrazole ethoxy linked atom linker)-optionally subst. heteroaryl SOZ yridinyl Tetrazole ethoxy SOZ PyridinylCF3 Tetrazole ethoxy SOZ PyridinCHZCF3 Tetrazole ethox SOZ PyridinylHalo substitutedTetrazole ethoxy alkyl SOZ PyridinylOCH3 tetrazole ethoxy SOz PyridinylOCHZCH3 tetraz0le ethoxy SOZ PyridinylOCHZCHZCH3 Tetrazole ethoxy SOZ PyridinylOCHZCHZCHZCH3 Tetrazole ethoxy SOz PyridinylOCHZCHZCHzCHZCH3Tetrazole ethoxy SOZ PyridinylCS-C8 alkoxy Tetrazole ethoxy SOZ PyridinylHalo substitutedtetrazole ethoxy alkoxy SOZ PyridinylCH3 tetrazole ethoxy SOZ PyridinylCHzCH3 Tetrazole ethoxy SOz PyridinylCHZCHZCH3 Tetrazole ethox SOZ PyridinylCHZCHZCHZCH3 Tetrazole ethoxy SOz PyridinylCS-C8 alkyl Tetrazole ethoxy SOZ PyridinylF tetrazole ethoxy ~~

SOZ PyridinylF,F tetrazole ethoxy SOz PyridinylF,Cl Tetrazole ethoxy SOz PyridinylCl Tetrazole ethoxy SOZ PyridinylC1,C1 Tetrazole ethoxy SOz Pyridinyl-(1 to 4 linearlyTetrazole ethoxy linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearlytetrazole ethoxy linked atom linker)-optionally subst. heteroaryl CO Phenyl tetrazole ethoxy CO Phenyl CF3 Tetrazole ethoxy CO Phenyl CHZCF3 Tetrazole ethoxy CO Phenyl Halo substitutedTetrazole ethoxy alkyl CO Phenyl OCH3 Tetrazole ethoxy CO Phenyl OCHZCH3 tetrazole ethoxy CO Phenyl OCHZCHZCH3 tetrazole ethoxy ~

CO Phenyl OCHZCHZCHZCH3 Tetrazole ethoxy CO Phenyl OCHZCHZCHzCH2CH3Tetrazole ethoxy CO Phenyl CS-C8 allcoxy Tetrazole ethoxy CO Phenyl Halo substitutedTetrazole ethoxy alkoxy CO Phenyl CH3 tetrazole ethoxy CO Phenyl CHzCH3 tetrazole ethoxy CO Phenyl CHZCHZCH3 Tetrazole ethoxy CO Phenyl CHZCHZCHZCH3 Tetrazole ethoxy CO Phenyl CS-C8 alkyl Tetrazole ethoxy CO Phenyl F Tetrazole ethoxy CO Phenyl F,F tetrazole ethoxy CO Phenyl F,Cl tetrazole ethoxy CO Phenyl Cl Tetrazole ethoxy CO Phenyl Cl,Cl Tetrazole ethoxy CO Phenyl -(1 to 4 linearlyTetrazole ethoxy linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyTetrazole ethoxy linked atom linker)-optionally subst. heteroaryl CO yridinyl tetrazole ethoxy CO PyridinylCF3 tetrazole ethoxy CO PyridinylCHZCF3 Tetrazole ethoxy CO PyridinylHalo substitutedTetrazole ethoxy alkyl CO PyridinylOCH3 Tetrazole ethoxy CO PyridinylOCHZCH3 Tetrazole ethoxy CO PyridinylOCHZCHzCH3 tetrazole ethoxy CO PyridinylOCHZCHZCHZCH3 tetrazole ethoxy CO PyridinylOCHzCH2CHZCH2CH3Tetrazole ethoxy CO PyridinylCS-C8 allcoxy Tetrazole ethoxy CO PyridinylHalo substitutedTetrazole ethoxy alkoxy CO PyridinylCH3 Tetrazole ethoxy CO PyridinylCHZCH3 tetrazole ethoxy CO PyridinCHZCHZCH3 tetrazole ethoxy CO PyridinylCHZCHzCHZCH3 Tetrazole ethoxy CO PyridinylCS-C8 alkyl Tetrazole ethoxy CO PyridinylF Tetrazole ethoxy CO PyridinylF,F Tetrazole ethoxy CO PyridinylF,CI tetrazole ethoxy CO PyridinylCl tetrazole ethoxy CO PyridinylCI,Cl Tetrazole ethoxy CO Pyridinyl-(1 to 4 linearlyTetrazole ethoxy linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyTetrazole ethoxy linked atom linker)-optionally subst. heteroaryl SOZ phenyl tetrazole ro oxy SOZ henyl CF3 Tetrazole ro oxy SOZ henyl CHZCF3 Tetrazole propoxy SOZ henyl Halo substitutedTetrazole ro oxy alkyl SOZ henyl OCH3 Tetrazole ro oxy SOZ henyl OCHZCH3 tetrazole ro oxy SOZ henyl OCHZCHzCH3 tetrazole ro oxy SOZ phenyl OCHZCHZCHZCH3 Tetrazole ro oxy SOZ henyl OCHZCHZCHZCHZCH3Tetrazole propoxy SOz phenyl CS-C8 alkoxy Tetrazole ro oxy SOZ henyl Halo substitutedTetrazole propoxy alkoxy SOZ henyl CH3 tetrazole pro oxy SOa henyl CHzCH3 tetrazole ro oxy SOZ henyl CHZCHZCH3 Tetrazole ro oxy SOZ henyl CHZCH2CHZCH3 Tetrazole ro oxy SOZ hen CS-C8 allcyl Tetrazole ro ox SOZ henyl F Tetrazole ro oxy SOZ henyl F,F tetrazole ro oxy SOZ henyl F,CI tetrazole ro oxy SOZ henyl Cl Tetrazole ro oxy SO2 henyl C1,C1 Tetrazole ro oxy SOz phenyl -(1 to 4 linearlyTetrazole propoxy linked atom linker)-optionally subst. aryl SO~ phenyl -(1 to 4 linearlyTetrazole propoxy linked atom linker)-optionally subst. heteroaryl SOZ yridinyl tetrazole pro oxy SO~ PyridinylCF3 tetrazole ro oxy SOZ PyridinylCHZCF3 Tetrazole propoxy SOZ PyridinylHalo substitutedTetrazole propoxy alkyl SOZ PyridinylOCH3 Tetrazole ro oxy SOZ PyridinylOCHzCH3 Tetrazole ro oxy SOZ P idinylOCHZCHZCH3 tetrazole ro ox SOZ PyridinylOCHZCHZCHZCH3 tetrazole ro oxy SOZ PyridinylOCHZCHZCHZCHzCH3Tetrazole ro oxy SOZ PyridinylCS-C8 alkoxy Tetrazole ro oxy SOZ PyridinylHalo substitutedTetrazole ro oxy alkoxy SOZ PyridinylCH3 Tetrazole ro oxy SOZ PyridinylCHZCH3 tetrazole ro oxy SOZ PyridinylCHZCHZCH3 tetrazole ro oxy SOz PyridinylCHZCHZCHZCH3 Tetrazole ro oxy SOZ PyridinylCS-C8 alkyl Tetrazole ro oxy SOZ PyridinylF Tetrazole propoxy SOZ PyridinylF,F Tetrazole ro oxy SOZ PyridinylF,CI tetrazole ro oxy SOZ PyridinylCl tetrazole pro oxy SOZ PyridinylCl,Cl Tetrazole pro oxy SOZ Pyridinyl-(1 to 4 linearlyTetrazole ro oxy linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearlyTetrazole propoxy linked atom linker)-optionally subst. heteroaryl CO Phenyl Tetrazole ro oxy CO Phenyl CF3 tetrazole ro oxy CO Phenyl CH2CF3 tetrazole ro oxy CO Phenyl Halo substitutedTetrazole ro oxy alkyl CO Phenyl OCH3 ~ Tetrazole ropoxy CO Phenyl OCH~CH3 Tetrazole pro oxy CO Phenyl OCHZCHZCH3 Tetrazole propoxy CO Phenyl OCHZCHZCHZCH3 tetrazole pro oxy CO Phenyl OCHZCHZCHzCHZCH3tetrazole ro oxy CO Phenyl CS-C8 alkoxy Tetrazole ro oxy CO Phenyl Halo substitutedTetrazole pro oxy alkoxy CO Phenyl CH3 Tetrazole ro oxy CO Phenyl CHZCH3 Tetrazole propoxy CO Phenyl CHzCH2CH3 tetrazole ro oxy CO Phenyl CH2CHzCHaCH3 tetrazole ropoxy CO Phenyl CS-C8 alkyl Tetrazole pro oxy CO Phenyl F Tetrazole ro oxy CO Phenyl F,F Tetrazole pro oxy CO Phen F,CI Tetrazole ro ox CO Phenyl Cl tetrazole ro oxy CO Phen C1,C1 tetrazole pro oxy CO Phenyl -(1 to 4 linearlyTetrazole propoxy linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyTetrazole propoxy linked atom linker)-optionally subst. heteroaryl CO yridinyl Tetrazole ro oxy CO PyridinylCF3 Tetrazole ro oxy CO PyridinylCHZCF3 tetrazole propoxy CO PyridinylHalo substitutedtetrazole ro oxy alkyl CO PyridinylOCH3 Tetrazole ro ox CO PyridinylOCHZCH3 Tetrazole ropoxy CO PyridinylOCH~CHZCH3 Tetrazole propoxy CO PyridinylOCHZCHzCHZCH3 Tetrazole ro oxy CO PyridinOCHZCHaCH2CH2CH3tetrazole ro oxy CO PyridinylCS-C8 alkoxy tetrazole ro ox CO PyridinHalo substitutedTetrazole ro oxy 1 alkoxy CO PyridinylCH3 Tetrazole ro oxy CO PyridinylCHZCH3 Tetrazole pro oxy CO PyridinylCHZCHZCH3 Tetrazole propoxy CO PyridinCHzCH2CHZCH3 tetrazole ro oxy CO PyridinylCS-C8 alkyl tetrazole ropoxy CO PyridinylF Tetrazole propoxy CO PyridinylF,F Tetrazole ro oxy CO PyridinylF,Cl Tetrazole ro oxy CO PyridinylCl Tetrazole pro oxy CO PyridinylCl,Cl tetrazole ropoxy CO Pyridinyl-(1 to 4 linearlytetrazole propoxy linked atom linker)-optionally subst. aryl CO Pyridinyl- 1 to 4 linearlyTetrazole ro oxy linked atom linker)-optionally subst. heteroaryl SOZ henyl Tetrazole -SCH3 SOZ henyl CF3 Tetrazole -SCH3 SOZ henyl CHZCF3 Tetrazole -SCH3 SOZ henyl Halo substitutedtetrazole -SCH3 alkyl SOZ henyl OCH3 tetrazole -SCH3 SOZ henyl OCHZCH3 Tetrazole -SCH3 SOZ henyl OCHZCHzCH3 Tetrazole -SCH3 SOz henyl OCHzCHZCHZCH3 Tetrazole -SCH3 SOZ phenyl OCHZCHZCHZCHZCH3Tetrazole -SCH3 SOz henyl CS-C8 alkoxy tetrazole -SCH3 SOZ henyl Halo substitutedtetrazole -SCH3 alkoxy SOZ phenyl CH3 Tetrazole -SCH3 SOz phenyl CHZCH3 Tetrazole -SCH;

SOZ henyl CHZCHZCH3 , Tetrazole -SCH3 SOZ henyl CHZCHZCHZCH; Tetrazole -SCH3 SOZ henyl CS-C8 alkyl tetrazole -SCH3 SOZ phenyl F tetrazole -SCH3 SO2 henyl F,F Tetrazole -SCH3 SOZ henyl F,Cl Tetrazole -SCH3 SOZ phenyl Cl Tetrazole -SCH3 SOZ henyl Cl,Cl Tetrazole -SCH3 , SOZ phenyl -(1 to 4 linearlytetrazole -SCH3 linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlytetrazole -SCH3 linked atom linker)-optionally subst. heteroaryl SOZ yridinyl Tetrazole -SCH3 SOZ PyridinylCF3 Tetrazole -SCH3 SOZ PyridinylCH~,CF3 Tetrazole -SCH3 SOZ PyridinylHalo substitutedTetrazole -SCH3 . allcyl SOz PyridinylOCH3 tetrazole -SCH3 SOZ PyridinylOCH~CH3 tetrazole -SCH3 SOZ Pyridin OCHZCHZCH3 Tetrazole -SCH3 SOZ PyridinylOCHZCHZCHZCH3 Tetrazole -SCH3 SOZ PyridinylOCHaCHZCHZCH~CH3Tetrazole -SCH3 SOZ PyridinylCS-C8 alkoxy Tetrazole -SCH3 SOZ PyridinylHalo substitutedtetrazole -SCH3 alkoxy SOz- PyridinylCH3 - tetrazole -_SCH3 -SOZ PytidinylCHZCH3 -.Tetrazole _~CH3 SOZ PyridinylCHZCHZCH3 Tetrazole -SCH3 SOz PyridinylCHZCHZCHZCH3 Tetrazole -SCH3 SOZ PyridinylCS-C8 alkyl Tetrazole -SCH3 SOZ PyridinylF tetrazole -SCH3 SOz PyridinylF,F tetrazole -SCH3 SOZ PyridinylF,Cl Tetrazole -SCH3 S02 PyridinylCl Tetrazole -SCH3 SOz PyridinylCl,Cl Tetrazole -SCH3 SOZ Pyridinyl-(1 to 4 linearlyTetrazole -SCH3 linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearlytetrazole -SCH3 linked atom linker)-optionally subst. heteroaryl CO ~ Phenyl~ ~ tetrazole -SCH3 ( ~

CO Phenyl CF3 Tetrazole -SCH3 CO Phenyl CHZCF3 Tetrazole -SCH3 CO Phenyl Halo substitutedTetrazole -SCH3 alkyl CO Phenyl OCH3 Tetrazole -SCH3 CO Phenyl OCHZCH3 tetrazole -SCH3 CO Phenyl OCHZCHzCH3 tetrazole -SCH3 CO Phenyl OCHzCH2CH2CH3 Tetrazole -SCH3 CO Phenyl OCHZCHaCH2CHZCH3Tetrazole -SCH3 CO Phenyl CS-C8 allcoxy Tetrazole -SCH3 CO Phenyl Halo substitutedTetrazole -SCH3 alkoxy CO Phenyl CH3 tetrazole -SCH3 CO Phenyl CHZCH3 tetrazole -SCH3 CO Phenyl CHZCHZCH3 Tetrazole -SCH3 CO Phenyl CHZCHZCHaCH3 Tetrazole -SCH3 CO Phenyl CS-C8 allcyl Tetrazole -SCH3 CO Phenyl F Tetrazole -SCH3 CO Phenyl F,F tetrazole -SCH3 CO Phenyl F,Cl tetrazole -SCH3 CO Phenyl Cl Tetrazole -SCH3 CO Phenyl C1,C1 Tetrazole -SCH3 CO Phenyl -(1 to 4 linearlyTetrazole -SCH3 linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyTetrazole -SCH3 linked atom linker)-optionally subst. heteroaryl CO yridinyl tetrazole -SCH3 CO PyridinylCF3 tetrazole -SCH3 CO PyridinylCHZCF3 Tetrazole -SCH3 CO PyridinylHalo substitutedTetrazole -SCH3 alkyl CO PyridinylOCH3 Tetrazole -SCH3 CO PyridinylOCHZCH3 Tetrazole -SCH3 CO PyridinylOCHZCHZCH3 tetrazole -SCH3 CO PyridinylOCHZCHZCHZCH3 tetrazole -SCH3 CO P 'din OCHZCH2CHzCH2CH3Tetrazole -SCH3 CO PyridinylCS-C8 allcoxy Tetrazole -SCH3 CO PyridinHalo substitutedTetrazole -SCH3 1 alkoxy CO PyridinCH3 Tetrazole -SCH3 CO PyridinylCHZCH3 tetrazole -SCH3 CO PyridinylCHZCHZCH3 tetrazole -SCH3 CO PyridinylCHZCHZCH~CH3 Tetrazole -SCH3 CO PyridinylCS-C8 allcyl Tetrazole -SCH3 CO PyridinylF Tetrazole -SCH3 CO PyridinylF,F Tetrazole -SCH3 CO PyridinF,CI tetrazole -SCH3 CO PyridinylCl tetrazole -SCH3 CO PyridinylCl,CI Tetrazole -SCH3 CO Pyridinyl-(1 to 4 linearlyTetrazole -SCH3 linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyTetrazole -SCH3 linked atom linker)-optionally subst. heteroaryl SOZ phenyl Tetrazole -SCHzCH3 SOZ henyl CF3 tetrazole -SCHZCH3 SOZ phenyl CHZCF3 tetrazole -SCHZCH3 SOZ phenyl Halo substitutedTetrazole -SCHZCH3 ~ alkyl ~ ~ ( SOZ phenyl OCH3 Tetrazole -SCHZCH3 SOZ phenyl OCHZCH3 Tetrazole -SCHZCH3 SOZ henyl OCHZCHZCH3 Tetrazole -SCHZCH3 SOZ henyl OCHZCHzCHZCH3 tetrazole -SCHZCH3 SOz henyl OCHZCHZCHZCHZCH3tetrazole -SCHZCH3 SO~ henyl CS-C8 alkoxy Tetrazole -SCHzCH3 SO~ henyl Halo substitutedTetrazole -SCHZCH3 alkoxy SOZ henyl CH3 Tetrazole -SCHZCH3 SOZ phenyl CHZCH3 Tetrazole -SCHzCH3 SO~ phenyl CHZCHZCH3 tetrazole -SCHZCH3 SOZ henyl CHZCHZCHZCH3 tetrazole -SCHZCH3 SOZ henyl CS-C8 alkyl Tetrazole -SCHZCH3 SOZ henyl F Tetrazole -SCHzCH3 SOZ phen F,F Tetrazole -SCHzCH3 SOZ henyl F,Cl Tetrazole -SCHZCH3 SOZ phenyl Cl tetrazole -SCHZGH3 SOZ phenyl Cl,CI tetrazole -SCHZCH3 SOZ phenyl -(1 to4linearlylinkedTetrazole -SCHZCH3 atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlyTetrazole -SCHZCH3 linked atom linker)-optionally subst. heteroaryl SOZ yridinyl Tetrazole -SCHZCH3 SOZ PyridinylCF3 Tetrazole -SCH2CH3 SOZ PyridinylCHZCF3 tetrazole -SCHZCH3 SOa PyridinylHalo substitutedtetrazole -SCHZCH3 alkyl SQZ PyridinylOCH3 Tetrazole -SCHZCH3 SOZ PyridinylOCHZCH3 Tetrazole -SCHzCH3 SOZ PyridinOCHZCHZCH3 Tetrazole -SCHzCH3 SOZ PyridinylOCHZCHZCHZCH3 Tetrazole -SCHZCH3 SOZ PyridinylOCHzCHZCH2CH2CH3tetrazole -SCHZCH3 SOZ PyridinylCS-C8 alkoxy tetrazole -SCHZCH3 SOZ PyridinylHalo substitutedTetrazole -SCHZCH3 alkoxy SOZ PyridinylCH3 Tetrazole -SCHZCH3 SOZ PyridinylCHZCH3 Tetrazole -SCHZCH3 SOZ PyridinylCH2CHZCH3 Tetrazole -SCH2CH3 SOZ PyridinylCHZCHzCHzCH3 tetrazole -SCHZCH3 SOZ PyridinylCS-C8 alkyl tetrazole -SCHZCH3 SOZ PyridinylF Tetrazole -SCH2CH3 SOZ PyridinylF,F Tetrazole -SCHzCH3 SOZ PyridinylF,CI Tetrazole -SCHZCH3 SOZ PyridinylCl Tetrazole -SCHaCH3 SOZ PyridinylCl,CI tetrazole -SCHZCH3 S02 Pyridinyl-(1 to 4 linearlytetrazole -SCHzCH3 linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearlyTetrazole -SCHZCH3 linked atom linker)-optionally subst. heteroaryl CO Phenyl Tetrazole -SCHZCH3 CO Phenyl CF3 Tetrazole -SCHZCH3 CO Phenyl CHzCF3 Tetrazole -SCHZCH3 CO Phenyl Halo substitutedtetrazole -SCHzCH3 alkyl CO Phenyl OCH3 tetrazole -SCHZCH3 CO Phenyl OCHZCH3 Tetrazole -SCHZCH3 CO Phenyl OCHzCHZCH3 Tetrazole -SCHZCH3 CO Phenyl OCHZCHZCHzCH3 Tetrazole -SCHZCH3 CO Phenyl OGHZCHZCHZCHzCH3Tetrazole -SCHZCH3 CO Phenyl CS-C8 alkoxy tetrazole -SCHZCH3 CO Phenyl Halo substitutedtetrazole -SCHZCH3 alkoxy .

CO Phenyl CH3 Tetrazole -SCHZCH3 CO Phenyl CHZCH3 Tetrazole -SCHZCH3 CO Phenyl CHZCH2CH3 Tetrazole -SCHZCH3 CO Phenyl CHZCHZCHZCH3 Tetrazole -SCHZCH3 CO Phenyl CS-C8 allcyl tetrazole -SCHZCH3 CO Phenyl F tetrazole -SCHZCH3 CO Phenyl F,F Tetrazole -SCHZCH3 CO Phenyl F,Cl Tetrazole -SCH~CH3 CO Phenyl Cl Tetrazole -SCHzCH3 CO Phenyl C1,C1 Tetrazole -SCHZCH3 CO Phenyl -(1 to 4 linearlytetrazole -SCHZCH3 linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlytetrazole -SCHZCH3 linked atom linker)-optionally subst. heteroaryl CO yridinyl Tetrazole -SCHZCH;

CO PyridinylCF3 Tetrazole -SCHZCH3 CO PyridinylCHZCF3 Tetrazole -SCHzCH3 CO PyridinylHalo substitutedTetrazole -SCHZCH3 alkyl CO PyridinylOCH3 tetrazole -SCHZCH3 CO PyridinylOCHZCH3 tetrazole -SCHZCH3 CO PyridinylOCHZCH2CH3 Tetrazole -SCHZCH3 CO PyridinylOCHZCHzCHZCH3 Tetrazole -SCHZCH3 CO PyridinylOCHZGH~CHzCHZCH3Tetrazole -SCHZCH3 CO PyridinylCS-C8 alkoxy Tetrazole -SCHZCH3 CO PyridinylHalo substitutedtetrazole -SCHZCH3 alkox CO PyridinylCH3 tetrazole -SCHZCH3 CO PyridinylCHaCH3 Tetrazole -SCHZCH3 CO PyridinylCH~CHZCH3 Tetrazole -SCHZCH3 CO PyridinylCHZCHZCHZCH3 Tetrazole -SCHZCH3 CO PyridinylCS-C8 ally 1 Tetrazole -SCHZCH3 CO PyridinylF tetrazole -SCHZCH3 CO PyridinylF,F tetrazole -SCHzCH3 CO PyridinylF,Cl Tetrazole -SCHZCH3 ' CO PyridinylCl Tetrazole -SCHZCH3 CO PyridinCI,Cl Tetrazole -SCHzCH3 CO Pyridinyl-(1 to 4 linearlyTetrazole -SCHZCH3 linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlytetrazole -SCHZCH3 linked atom linker)-optionally subst. heteroaryl SOZ henyl 3-hydroxy methoxy isoxazole SOZ hen CF3 3-h droxy methox 1 isoxazole SOZ henyl CH~CF3 3-hydroxy methoxy isoxazole SOz henyl Halo substituted3-h droxy methox alkyl isoxazole SOZ henyl OCH3 3-hydroxy methoxy isoxazole SOZ henyl OCHZCH3 3-h droxy methoxy isoxazole SOZ hen OCHZCHZCH3 3-hydroxy methoxy 1 isoxazole SOz henyl OCHzCHZCHZCH3 3-hydroxy methoxy isoxazole SOZ phenyl OCHZCHZCHZCHZCH33-h droxy methoxy isoxazole SOZ phenyl CS-C8 alkoxy 3-h droxy methoxy isoxazole SOZ henyl Halo substituted3-hydroxy methoxy alkoxy isoxazole SOZ henyl CH3 3-hydroxy methoxy isoxazole SOZ henyl CHZCH3 3-hydroxy methoxy isoxazole SOZ henyl CHZCHZCH3 3-hydroxy methoxy isoxazole SOZ henyl CHZCHzCHZCH3 3-hydroxy methoxy isoxazole SOZ henyl CS-C8 alkyl 3-hydroxy methoxy isoxazole SOZ phenyl F 3-hydroxy methoxy isoxazole SOZ phenyl F,F 3-hydroxy methoxy isoxazole SOZ phenyl F,Cl 3-hydroxy methoxy isoxazole SOZ henyl Cl 3-hydroxy methoxy isoxazole SOz henyl Cl,Cl 3-hydroxy methoxy isoxazole SOZ phenyl -(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. heteroaryl SOz yridinyl 3-hydroxy methoxy isoxazole SOZ PyridinylCF3 3-hydroxy methoxy isoxazole SOZ PyridinylCHZCF3 3-hydroxy methoxy isoxazole SOz PyridinylHalo substituted3-hydroxy methoxy alkyl isoxazole SOZ PyridinylOCH3 3-hydroxy methoxy isoxazole SOZ PyridinylOCHZCH3 3-hydroxy methoxy isoxazole SOZ PyridinylOCHZCHZCH3 3-hydroxy methoxy isoxazole SOZ PyridinylOCHZCHZCHZCH3 3-hydroxy methoxy isoxazole SOZ PyridinylOCHZCHZCHzCHzCH33-hydroxy methoxy isoxazole SOZ PyridinylCS-C8 alkoxy 3-hydroxy methoxy isoxazole SOZ PyridinylHalo substituted3-hydroxy methoxy alkoxy isoxazole SOZ PyridinylCH3 3-hydroxy methoxy isoxazole SOZ PyridinylCHZCH3 3-hydroxy methoxy isoxazole SOZ PyridinylCHZCHZCH3 3-hydroxy methoxy isoxazole SOZ PyridinylCHZCHZCHZCH3 3-hydroxy methoxy isoxazole SOz PyridinylCS-C8 alkyl 3-hydroxy methoxy isoxazole SOZ P idinylF 3-hydroxy methoxy isoxazole SOZ PyridinylF,F 3-hydroxy methoxy isoxazole SOZ PyridinylF,Cl 3-h droxy methoxy isoxazole SOZ PyridinylCl 3-hydroxy methoxy isoxazole SOZ PyridinylC1,C1 3-hydroxy methoxy isoxazole SOZ Pyridinyl-(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. a 1 SOZ Pyridinyl-(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxy methoxy isoxazole CO Phenyl CF3 3-hydroxy methoxy isoxazole CO Phenyl CHZCF3 3-hydroxy methox isoxazole CO Phenyl Halo substituted3-hydroxy methoxy alkyl isoxazole CO Phenyl OCH3 3-hydroxy methoxy isoxazole CO Phenyl OCHZCH3 3-hydroxy methox isoxazole CO Phenyl OCHZCHZCH3 3-hydroxy methoxy isoxazole CO Phenyl OCHZCHZCHzCH3 3-hydroxy methoxy isoxazole CO Phenyl OCHZCHZCHZCHZCH33-hydroxy methoxy isoxazole CO Phenyl CS-C8 alkoxy 3-hydroxy methoxy isoxazole CO Phenyl Halo substituted3-hydroxy methoxy alkoxy isoxazole CO Phenyl CH3 3-hydroxy methoxy isoxazole CO Phenyl CHZCH3 3-hydroxy methoxy isoxazole CO Phenyl CHzCHZCH3 3-hydroxy methoxy isoxazole CO Phenyl CHZCHZCHZCH3 3-hydroxy methoxy isoxazole CO Phenyl CS-C8 alkyl 3-hydroxy methoxy isoxazole CO Phenyl F 3-hydroxy methoxy isoxazole CO Phenyl F,F 3-hydroxy methoxy isoxazole CO Phenyl F,CI 3-hydroxy methoxy isoxazole CO Phenyl Cl 3-hydroxy methoxy isoxazole CO Phenyl C1,C1 3-hydroxy methoxy isoxazole CO Phenyl -(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. heteroaryl CO yridinyl 3-hydroxy methoxy isoxazole CO PyridinylCF3 3-hydroxy methoxy isoxazole CO PyridinylCHZCF3 3-hydroxy methoxy isoxazole CO PyridinylHalo substituted3-hydroxy methoxy alkyl isoxazole CO PyridinylOCH3 3-hydroxy methoxy isoxazole CO PyridinylOGHZCH3 3-hydroxy methoxy isoxazole CO PyridinylOCHzCHZCH3 3-hydroxy methoxy isoxazole CO PyridinOCHzGHzCH2CH3 3-hydroxy methoxy 1 isoxazole CO PyridinylOCHZCHZCHZCHZCH33-hydroxy methoxy isoxazole CO P idinylC5-C8 alkoxy 3-hydroxy methox isoxazole CO PyridinylHalo substituted3-hydroxy methoxy alkoxy isoxazole CO PyridinylCH3 3-hydroxy methoxy isoxazole CO PyridinylCHZCH3 3-hydroxy methoxy isoxazole CO PyridinylCHZCHZCH3 3-hydroxy methoxy isoxazole CO PyridinylCHZCH~CHzCH3 3-hydroxy methoxy isoxazole CO PyridinylCS-C8 alkyl 3-hydroxy methoxy isoxazole CO PyridinylF 3-hydroxy methoxy isoxazole CO PyridinylF,F 3-hydroxy methoxy isoxazole CO PyridinylF,Cl 3-hydroxy methoxy isoxazole CO PyridinylCl 3-hydroxy methoxy isoxazole CO PyridinylCl,Cl 3-hydroxy methoxy isoxazole CO Pyridinyl-(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. heteroaryl SOZ henyl 3-hydroxy ethox isoxazole SOZ hen CF3 3-hydroxy ethoxy 1 isoxazole SOZ phenyl CHZCF3 3-hydroxy ethoxy isoxazole SOZ henyl Halo substituted3-hydroxy ethoxy alkyl isoxazole SOZ henyl OCH3 3-hydroxy ethoxy isoxazole SOZ phenyl OCHZCH3 3-hydroxy ethoxy isoxazole SOZ henyl OCH~CHzCH3 3-hydroxy ethoxy isoxazole SOZ henyl OCHZCH2CHZCH3 3-hydroxy ethoxy isoxazole SOZ phenyl OCHZCHZCHzCHZCH33-h droxy ethoxy isoxazole SOZ hen CS-C8 alkoxy 3-hydroxy ethoxy 1 isoxazole SOZ henyl Halo substituted3-hydroxy ethoxy alkox isoxazole SO~ henyl CH3 3-hydroxy ethoxy isoxazole SOZ henyl CHZCH3 3-hydroxy ethoxy isoxazole S02 henyl CHZCHZCH3 3-hydroxy ethoxy isoxazole SOZ henyl CHZCHZCHzCH3 3-hydroxy ethoxy isoxazole SOz phenyl CS-C8 allcyl 3-hydroxy ethoxy isoxazole SOZ phenyl F 3-hydroxy ethoxy isoxazole SOZ henyl F,F 3-hydroxy ethoxy isoxazole SOZ henyl F,Cl 3-hydroxy ethoxy isoxazole SOZ henyl Cl 3-hydroxy ethoxy isoxazole SOZ henyl Cl,Cl 3-hydroxy ethoxy isoxazole SOZ phenyl -(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. heteroaryl SOZ yridinyl 3-hydroxy ethoxy isoxazole SOZ PyridinylCF3 3-hydroxy ethoxy isoxazole SOZ PyridinylCHZCF3 3-hydroxy ethoxy isoxazole SOz PyridinylHalo substituted3-hydroxy ethoxy alkyl isoxazole SOZ PyridinylOCH3 3-hydroxy ethoxy isoxazole SOZ PyridinylOCHzCH3 3-hydroxy ethoxy isoxazole SOz PyridinylOCHZCHZCH3 3-hydroxy ethoxy isoxazole SOZ PyridinylOCHZCHZCHzCH3 3-hydroxy ethoxy isoxazole SOZ PyridinylOCHZCHZCHZCHZCH33-hydroxy ethoxy isoxazole SOZ PyridinylCS-C8 alkoxy 3-hydroxy ethoxy isoxazole SOZ PyridinylHalo substituted3-hydroxy ethoxy alkoxy isoxazole SOZ PyridinylCH3 3-hydroxy ethoxy isoxazole SOZ PyridinylCHZCH3 3-hydroxy ethoxy isoxazole SOz PyridinylCHZCHZCH3 3-hydroxy ethoxy isoxazole SOZ PyridinylCHaCHZCH2CH3 3-hydroxy ethoxy isoxazole SO~ PyridinylCS-C8 alkyl 3-hydroxy ethoxy isoxazole SOZ PyridinylF 3-hydroxy ethoxy isoxazole SO~ PyridinylF,F 3-hydroxy ethoxy isoxazole SOZ PyridinylF,Cl 3-hydroxy ethoxy isoxazole SOZ PyridinylCl 3-hydroxy ethoxy isoxazole SOZ PyridinylCl,CI 3-hydroxy ethoxy isoxazole SOZ Pyridinyl-(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxy ethoxy isoxazole CO Phenyl CF3 3-hydroxy ethoxy isoxazole CO Phenyl CHZCF3 3-hydroxy ethoxy isoxazole CO Phenyl Halo substituted3-hydroxy ethoxy alkyl isoxazole CO Phenyl OCH3 3-hydroxy ethoxy isoxazole CO Phenyl OCHZCH3 3-hydroxy ethoxy isoxazole CO Phenyl OCHZCHzCH3 3-hydroxy ethoxy isoxazole CO Phen OCHZCHzCH2CH3 3-hydrox isoxazoleethox CO Phenyl OCHZCHZCHZCHZCH33-hydroxy ethoxy isoxazole CO Phenyl CS-C8 alkoxy 3-hydroxy ethoxy isoxazole CO Phenyl Halo substituted3-hydrox isoxazoleethoxy alkoxy CO Phenyl CH3 3-hydroxy ethoxy isoxazole CO Phenyl CHzCH3 3-hydroxy ethoxy isoxazole CO Phenyl CHZCHZCH3 3-hydroxy ethoxy isoxazole CO Phenyl CHZCHZCHZCH3 3-hydroxy ethoxy isoxazole CO Phenyl CS-C8 alkyl 3-hydroxy ethoxy isoxazole CO Phenyl F 3-hydroxy ethoxy isoxazole CO Phenyl F,F 3-hydroxy ethoxy isoxazole CO Phenyl F,Cl ~ 3-hydroxy ethoxy ~ ~ isoxazole ~

CO Phenyl Cl 3-hydroxy ethoxy isoxazole CO Phenyl C1,C1 3-hydroxy ethoxy isoxazole CO Phenyl -(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. heteroaryl CO yridinyl 3-hydroxy ethoxy isoxazole CO PyridinylCF3 3-hydroxy ethoxy isoxazole CO PyridinylCHzCF3 3-hydroxy ethoxy isoxazole CO PyridinylHalo substituted3-hydroxy ethoxy alkyl isoxazole CO PyridinylOCH3 3-hydroxy ethoxy isoxazole CO PyridinylOCHZCH3 3-hydroxy ethoxy isoxazole CO PyridinylOCHZCHZCH3 3-hydroxy ethoxy isoxazole CO PyridinylOCHZCHZCHZCH3 3-hydroxy ethoxy isoxazole CO PyridinylOCHZCHZCHzCHzCH33-hydroxy ethoxy isoxazole CO PyridinylCS-C8 alkoxy 3-hydroxy ethoxy isoxazole CO PyridinylHalo substituted3-hydroxy ethoxy alkoxy isoxazole CO PyridinylCH3 3-hydroxy ethoxy isoxazole CO PyridinylCHZCH3 3-hydroxy ethoxy isoxazole CO PyridinylCHZCHZCH3 3-hydroxy ethoxy isoxazole CO PyridinylCHZCHzCH2CH3 3-hydroxy ethoxy isoxazole CO PyridinylCS-C8 alkyl 3-hydroxy ethoxy isoxazole CO PyridinylF 3-hydroxy ethoxy isoxazole CO PyridinylF,F 3-hydroxy ethoxy isoxazole CO PyridinylF,Cl 3-hydroxy ethoxy isoxazole CO PyridinylCl 3-hydroxy ethoxy isoxazole CO PyridinylC1,C1 3-hydroxy ethoxy isoxazole CO Pyridinyl-(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. heteroaryl SO~ henyl 3-hydroxy ropoxy isoxazole SOZ henyl CF3 3-h drox isoxazolero oxy SOZ phenyl GHZCF3 3-hydroxy pro oxy isoxazole SO~ henyl Halo substituted3-hydroxy ropoxy alkyl isoxazole SOZ phenyl OCH3 3-hydroxy ropoxy isoxazole SOz phenyl OCHZCH3 3-h droxy ro oxy isoxazole SOz henyl OCHZCHZCH3 3-hydroxy ro ox isoxazole SOZ hen OCHZCHzCHZCH3 3-hydroxy ro oxy 1 isoxazole SOZ hen OCHZCHZCHZCHZCH33-hydroxy ro oxy .1 isoxazole SOZ henyl CS-C8 alkoxy 3-hydroxy ro oxy isoxazole SOZ henyl Halo substituted3-hydroxy ro oxy alkoxy isoxazole SOZ phenyl CH3 3-hydroxy ro oxy isoxazole SOZ henyl CHZCH3 3-h droxy ro oxy isoxazole SOZ henyl CHzCH2CH3 3-hydroxy ro oxy isoxazole SOZ phenyl CHZCHzCH2CH3 3-hydroxy ro ox isoxazole SOZ henyl CS-C8 alkyl 3-hydroxy ro oxy isoxazole SOz henyl F 3-hydroxy pro ox isoxazole SOZ henyl F,F 3-h droxy ropoxy isoxazole SOZ henyl F,Cl 3-hydroxy ro oxy isoxazole SOz phenyl Cl 3-hydroxy propoxy isoxazole SOZ henyl C1,C1 3-hydroxy ro oxy isoxazole SOz phenyl -(1 to 4 linearly3-hydroxy ro oxy linked isoxazole atom linker)-optionally subst. aryl SOz phenyl -(1 to 4 linearly3-hydroxy propoxy linked isoxazole atom linker)-optionally subst. heteroaryl SOz yridinyl 3-hydroxy ro oxy isoxazole SOZ PyridinylCF3 3-hydroxy ro oxy isoxazole SOZ PyridinylCHZCF3 3-hydroxy ro oxy isoxazole SOZ PyridinylHalo substituted3-hydroxy ro oxy alkyl isoxazole SOZ PyridinylOCH3 ~ 3-hydroxy ro oxy isoxazole SOZ PyridinylOCHzCH3 3-hydroxy ro oxy isoxazole SOZ PyridinylOCHzCHZCH3 3-hydroxy ropoxy isoxazole SOZ PyridinylOGHzCH2CH2CH3 3-hydroxy propoxy isoxazole SO2 P 'dinylOCHZCHZCHZCHZCH33-hydroxy ropoxy isoxazole SOZ PyridinylCS-C8 alkoxy 3-hydroxy ro oxy isoxazole SO~ PyridinylHalo substituted3-hydroxy ro oxy alkoxy isoxazole SOZ PyridinylCH3 3-hydroxy ropoxy isoxazole SOZ PyridinylCHzCH3 3-hydroxy pro oxy isoxazole SOZ PyridinylCHZCHZCH3 3-hydroxy ropoxy isoxazole SOZ PyridinylCHZCHzCH2CH3 3-hydroxy propoxy isoxazole SOZ PyridinylCS-C8 alkyl 3-hydroxy pro oxy isoxazole SOz PyridinylF 3-hydroxy ro oxy isoxazole SOz PyridinylF,F 3-hydroxy ro oxy isoxazole SOZ PyridinylF,Cl 3-hydroxy ropoxy isoxazole S02 PyridinylCl 3-hydroxy ro oxy isoxazole SOZ PyridinylCl,CI 3-hydroxy ro oxy isoxazole SOZ Pyridinyl-(1 to 4 linearly3-hydroxy propoxy linked isoxazole atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearly3-hydroxy propoxy linked isoxazole atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxy ropoxy isoxazole CO Phenyl CF3 3-hydroxy ro oxy isoxazole CO Phenyl CHZCF3 3-hydroxy pro oxy isoxazole CO Phenyl Halo substituted3-hydroxy ropoxy alkyl isoxazole CO Phenyl OCH3 3-hydroxy ro oxy isoxazole CO Phen OCHZCH3 3-hydroxy ropoxy 1 isoxazole CO Phenyl OCHzCH2CH3 3-hydroxy ropoxy isoxazole CO Phenyl OCHZCHaCH2CH3 3-hydroxy ro oxy isoxazole CO Phen OCHZCHZCHZCHZCH33-hydroxy ro ox .
1 isoxazole CO Phenyl CS-C8 alkoxy 3-hydroxy ropoxy isoxazole CO Phenyl Halo substituted3-h droxy ro oxy alkoxy isoxazole CO Phenyl CH3 3-hydroxy ropoxy isoxazole CO Phenyl CHzCH3 3-hydroxy ro ox isoxazole CO Phenyl CH~CHZCH3 3-hydroxy ro oxy isoxazole CO Phenyl CHZCHZCHZCH3 3-hydroxy ropoxy isoxazole CO Phenyl CS-C8 allcyl 3-hydroxy ro oxy isoxazole CO Phenyl F 3-hydroxy ro ox isoxazole CO Phenyl F,F 3-hydroxy ro oxy isoxazole CO Phenyl F,Cl 3-hydroxy ro oxy isoxazole CO Phen Cl 3-hydroxy ro oxy 1 isoxazole CO Phenyl Cl,Cl 3-hydroxy ro oxy isoxazole CO Phenyl -(1 to 4 linearly3-hydroxy propoxy linked isoxazole atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly3-hydroxy ropoxy linked isoxazole atom linker)-optionally subst. heteroaryl CO yridinyl 3-hydroxy ro oxy isoxazole CO PyridinylCF3 3-hydroxy ropoxy isoxazole CO PyridinylCHZCF3 3-hydroxy ro oxy isoxazole CO PyridinylHalo substituted3-hydroxy ro oxy alkyl isoxazole CO PyridinylOCH3 3-hydroxy pro oxy isoxazole CO PyridinylOCHZCH3 3-hydroxy ropoxy isoxazole CO PyridinylOCHZCHZCH3 3-hydroxy ro oxy isoxazole CO PyridinylOCHZCHZCHZCH3 3-hydroxy ro oxy isoxazole CO PyridinylOCHZCHZCHZCHZCH33-hydroxy ro oxy isoxazole CO PyridinylCS-C8 allcoxy 3-hydroxy ro oxy isoxazole CO PyridinylHalo substituted3-hydroxy ro oxy alkoxy isaxazole CO PyridinCH3 3-hydroxy ro oxy 1 isoxazole CO PyridinylCHZCH3 3-hydroxy ro oxy isoxazole CO PyridinylCHZCHZCH3 3-hydroxy ro oxy isoxazole CO PyridinylCHZCHZCHZCH3 3-hydroxy ro oxy isoxazole CO PyridinylCS-C8 allcyl 3-hydroxy ro oxy isoxazole CO PyridinylF 3-hydroxy ro oxy isoxazole CO PyridinylF,F 3-hydroxy ropoxy isoxazole CO PyridinF,Cl 3-hydroxy ro oxy 1 isoxazole CO PyridinylCl 3-hydroxy propoxy isoxazole CO PyridinylC1,C1 3-hydroxy ro oxy isoxazole CO Pyridinyl-(1 to 4 linearly3-hydroxy propoxy linked isoxazole atom linker)-optionally subst. a 1 CO Pyridinyl-(1 to 4 linearly3-hydroxy propoxy linked isoxazole atom linker)-optionally subst. heteroa SOZ henyl 3-hydroxy -SCH3 isoxazole SOZ henyl CF3 3-hydroxy -SCH3 isoxazole SOZ henyl CHZCF3 3-hydroxy -SCH3 isoxazole SOZ phenyl Halo substituted3-hydroxy -SCH3 alkyl isoxazole SOz henyl OCH3 3-hydroxy -SCH3 isoxazole SOZ henyl OCHzCH3 3-hydroxy -SCH3 isoxazole SOZ henyl OCHZCHZCH3 3-hydroxy -SCH3 isoxazole SOZ henyl OCHZCHZCHzCH3 3-hydroxy -SCH3 isoxazole SOZ henyl OCHZCHZCHZCHZCH33-hydroxy -SCH3 isoxazole SOZ phenyl CS-C8 alkoxy 3-hydroxy -SCH3 isoxazole SOz henyl Halo substituted3-hydroxy -SCH3 alkoxy isoxazole SOZ henyl CH3 3-hydroxy -SCH3 isoxazole SOZ henyl CHZCH3 3-hydroxy -SCH3 isoxazole SOz henyl CHZCHzCH3 3-hydroxy -SCH3 isoxazole SOZ phenyl CHZCHZCHaCH3 3-hydrox isoxazole-SCH3 SOZ phenyl CS-C8 allcyl 3-h droxy -SCH3 isoxazole SOz henyl F 3-hydroxy -SCH3 isoxazole SOZ henyl F,F 3-hydroxy -SCH3 isoxazole SOZ henyl F,Cl 3-hydroxy -SCH3 isoxazole SOZ phen Cl 3-hydroxy -SCH3 1 isoxazole SOZ henyl C1,C1 3-hydroxy -SCH3 isoxazole SOZ phenyl -(1 to 4 linearly3-hydroxy -SCH3 linked isoxazole atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearly3-hydroxy -SCH3 linked isoxazole atom linker)-optionally subst. heteroaryl SOz yridinyl 3-hydroxy -SCH3 isoxazole SOz PyridinylCF3 3-hydroxy -SCH3 isoxazole SOZ PyridinylCHZCF3 3-hydroxy -SCH3 isoxazole SOZ PyridinylHalo substituted3-hydroxy -SCH3 alkyl isoxazole SOZ PyridinylOCH3 3-hydroxy -SCH3 isoxazole SOZ PyridinylOCHzCH3 3-hydroxy -SCH3 isoxazole SOZ PyridinylOCHzCH2CH3 3-hydroxy -SCH3 isoxazole SOZ PyridinylOCHzCHaCH2CH3 3-hydroxy -SCH3 isoxazole SOZ PyridinylOCHZCHZCHZCHZCH33-hydroxy -SCH3 isoxazole SOZ PyridinylCS-C8 alkoxy 3-hydroxy -SCH3 isoxazole SOZ PyridinylHalo substituted3-hydroxy -SCH3 alkoxy isoxazole SOZ PyridinylCH3 3-hydroxy -SCH3 isoxazole SO2 PyridinylCHZCH3 3-hydroxy -SCH3 isoxazole SOZ PyridinylCHZCHZCH3 3-hydroxy -SCH3 isoxazole SOZ PyridinylCHZCHzCH2CH3 3-hydroxy -SCH3 isoxazole SOZ PyridinylCS-C8 alkyl 3-hydroxy -SCH3 isoxazole SOZ PyridinylF 3-hydroxy -SCH3 isoxazole SOZ PyridinylF,F 3-hydroxy -SCH3 isoxazole SOZ PyridinylF,Cl 3-hydroxy -SCH3 isoxazole SO~ PyridinylCl 3-hydroxy -SCH3 isoxazole SOZ PyridinylC1,C1 3-hydroxy -SCH3 isoxazole SOZ Pyridinyl-(1 to 4 linearly3-hydroxy -SCH3 linked isoxazole atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearly3-hydroxy -SCH3 linked isoxazole atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydrox isoxazole-SCH3 CO Phenyl CF3 3-hydroxy -SCH3 isoxazole CO Phenyl CHZCF3 3-hydroxy -SCH3 isoxazole CO Phenyl Halo substituted3-hydroxy -SCH3 alkyl isoxazole CO Phenyl OCH3 3-hydroxy -SCH3 isoxazole CO Phenyl OCH~CH3 3-hydroxy -SCH3 isoxazole CO Phenyl OCHZCHZCH3 3-h droxy -SCH3 isoxazole CO Phenyl OCHZCHZCHaCH3 3-hydroxy -SCH3 isoxazole CO Phenyl OCHZCHZCHZCHZCH33-hydroxy -SCH3 isoxazole CO Phenyl CS-C8 alkoxy 3-hydroxy -SCH3 isoxazole CO Phenyl _ Halo substituted3-hydroxy -SCH3 alkoxy isoxazole CO Phenyl CH3 3-hydroxy -SCH3 isoxazole CO Phenyl CH~CH3 3-hydroxy -SCH3 isoxazole CO Phenyl CHZCHZCH3 3-hydroxy -SCH3 isoxazole CO Phenyl CHZCHZCHzCH3 3-hydroxy -SCH3 isoxazole CO Phenyl CS-C8 alkyl 3-hydroxy -SCH3 isoxazole CO Phenyl F 3-hydroxy -SCH3 isoxazole CO Phenyl F,F 3-hydroxy -SCH3 isoxazole CO Phenyl F,Cl 3-hydroxy -SCH3 isoxazole CO Phenyl Cl 3-hydroxy -SCH3 isoxazole CO Phenyl C1,C1 3-hydroxy -SCH3 isoxazole ~

CO Phenyl -(1 to 4 linearly3-hydroxy -SCH3 linked isoxazole atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly3-hydroxy -SCH3 linked isoxazole atom linker)-optionally subst. heteroaryl CO yridinyl 3-hydroxy -SCH3 isoxazole CO PyridinylCF3 3-hydroxy -SCH3 isoxazole CO PyridinylCHzCF3 3-hydroxy -SCH3 isoxazole CO P idinylHalo substituted3-hydroxy -SCH3 alkyl isoxazole CO PyridinylOCH3 3-hydroxy -SCH3 isoxazole CO PyridinylOCHzCH3 3-hydroxy -SCH3 isoxazole CO PyridinylOCHZCHZCH3 3-hydroxy -SCH3 isoxazole CO PyridinylOCHzCHZCH2CH3 3-hydroxy -SCH3 isoxazole CO PyridinylOCHZCHZCHZCHzCH33-hydroxy -SCH3 isoxazole CO PyridinylCS-C8 alkoxy 3-hydroxy -SCH3 isoxazole CO PyridinylHalo substituted3-hydroxy -SCH3 alkoxy isoxazole CO PyridinylCH3 3-hydroxy -SCH3 isoxazole CO PyridinylCHZCH3 3-hydroxy -SCH3 isoxazole CO PyridinylCHZCHZCH3 3-hydroxy -SCH3 isoxazole CO PyridinylCHZCHZCHZCH3 3-hydroxy -SCH3 isoxazole CO PyridinylCS-G8 alkyl 3-hydroxy -SCH3 isoxazole CO PyridinylF 3-hydroxy -SCH3 isoxazole CO PyridinylF,F 3-hydroxy -SCH3 isoxazole CO PyridinylF,Cl 3-hydroxy -SCH3 isoxazole CO PyridinylCl 3-hydroxy -SCH3 isoxazole CO PyridinylC1,C1 3-hydroxy -SCH3 isoxazole CO Pyridinyl-(1 to 4 linearly3-hydroxy -SCH3 linked isoxazole atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearly3-hydroxy -SCH3 linked isoxazole atom linker)-optionally subst. heteroaryl SOz henyl 3-hydroxy -SCHZCH3 isoxazole SOZ henyl CF3 3-hydroxy -SCHZCH3 isoxazole SOz henyl CHZCF3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl Halo substituted3-hydroxy -SCHZCH3 alkyl is0xazole SOZ phenyl OCH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl OCH~CH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl OCHZCH2CH3 3-hydroxy -SCHZCH3 isoxazole SOZ phenyl OCHzCHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOZ phenyl OCHaCH2CHZCHZCH33-hydroxy -SCHzCH3 isoxazole SOZ henyl CS-C8 alkox 3-hydroxy -SCHzCH3 isoxazole SOZ phenyl Halo substituted3-hydroxy -SCH~CH3 alkoxy isoxazole SOZ henyl CH3 3-hydroxy -SCHZCH3 isoxazole SOz henyl CHzCH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl CHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl CHZCHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl CS-C8 alkyl 3-h droxy -SCHZCH3 isoxazole SOZ phenyl F 3-hydroxy -SCHZCH3 isoxazole SOZ henyl F,F 3-hydroxy -SCHZCH3 isoxazole SOZ henyl F,CI 3-hydroxy -SCHZCH3 isoxazole SOZ phenyl Cl 3-hydroxy -SCHZCH3 isoxazole SOZ henyl C1,C1 3-hydroxy -SCHzCH3 isoxazole SOZ phenyl -(1 to 4 linearly3-hydroxy -SCHaCH3 linked isoxazole atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearly3-hydroxy -SCHzCH3 linked isoxazole atom linker)-optionally subst. heteroaryl SOZ yridin 3-hydroxy -SCHZCH3 1 isoxazole SOZ PyridinylCF3 3-hydrox isoxazole-SCHZCH3 S02 PyridinylCHZCF3 3-hydroxy -SCHZCH3 isoxazole SOz PyridinylHalo substituted3-hydroxy -SCHZCH3 alkyl isoxazole SOZ PyridinylOCH3 3-hydroxy -SCHzCH3 isoxazole SOz PyridinOCHZCH3 3-hydroxy -SCHZCH3 1 isoxazole SOZ PyridinylOCHZCHZCH3 3-hydroxy -SCHzCH3 ~ ~ isoxazole SOZ PyridinylOCHZCHzCH2CH3 3-hydroxy -SCHZCH3 isoxazole SOz PyridinylOCHZCHZCHZCHzCH33-hydroxy -SCHZCH3 isoxazole SOZ PyridinylCS-C8 alkoxy 3-hydroxy -SCHZCH3 isoxazole SO2 PyridinylHalo substituted3-hydroxy -SCHZCH3 alkoxy isoxazole SOZ PyridinylCH3 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOz PyridinylCHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylCHZCHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylCS-C8 alkyl 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylF 3-hydroxy -SCHaCH3 isoxazole SOZ PyridinylF,F 3-hydroxy -SCHZCH3 isoxazole SOz PyridinylF,Cl 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylCl 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylCI,CI 3-hydroxy -SCHzCH3 isoxazole SOZ Pyridinyl-(1 to 4 linearly3-hydroxy -SCH~CH3 linked isoxazole atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearly3-hydroxy -SCHzCH3 linked isoxazole atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxy -SCHZCH3 isoxazole CO Phenyl CF3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl CHZCF3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl Halo substituted3-hydroxy -SCHZCH3 alkyl isoxazole CO Phenyl OCH3 3-hydroxy -SCHzCH3 isoxazole CO Phenyl OCHzCH3 3-hydroxy -SCHzCH3 isoxazole CO Phenyl OCHZCHzCH3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl OCHZCHzCHaCH3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl OCHZCHzCH2CH2CH33-hydroxy -SCHZCH3 isoxazole CO Phenyl CS-C8 allcoxy 3-hydroxy -SCHzGH3 isoxazole CO Phenyl Halo substituted3-hydroxy -SCHzCH3 alkoxy isoxazole CO Phenyl CH3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl CHZCH3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl CHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl CHZCHzCHZCH3 3-hydroxy -SCHzCH3 isoxazole CO Phenyl CS-C8 alkyl 3-hydroxy -SCHZCH3 isoxazole CO Phenyl F 3-hydroxy -SCHZCH3 isoxazole CO Phenyl F,F 3-hydroxy -SCHzCH3 isoxazole CO Phenyl F,Cl 3-hydroxy -SCHZCH3 isoxazole CO Phenyl Cl 3-hydroxy -SCHZCH3 isoxazole CO Phenyl Cl,Cl 3-hydroxy -SCHZCH3 isoxazole CO Phenyl -(1 to 4 linearly3-hydroxy -SCHZCH3 linked isoxazole atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly3-hydroxy -SCHZCH3 linked isoxazole atom linker)-optionally subst. heteroaryl CO yridinyl 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCF3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCHZCF3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylHalo substituted3-hydroxy -SCHZCH3 alkyl isoxazole CO PyridinylOCH3 3-hydroxy -SCHzCH3 isoxazole CO PyridinylOCHZCH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylOCHZCHzCH3 3-hydroxy -SCHzCH3 isoxazole CO PyridinylOCHZCHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylOCHZCHZCHzCH2CH33-hydroxy -SGHZCH3 isoxazole CO PyridinylCS-C8 alkoxy 3-hydroxy -SCHZCH3 isoxazole CO PyridinylHalo substituted3-hydroxy -SCHZCH3 alkoxy isoxazole CO PyridinylCH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCHzCH3 3-hydroxy -SCHzCH3 isoxazole CO PyridinylCHzCHZCH3 3-hydroxy -SCHzCH3 isoxazole CO PyridinylCHZCHZCHzCH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCS-C8 alkyl 3-hydroxy -SCHZCH3 isoxazole CO PyridinylF 3-hydroxy -SCHZCH3 isoxazole CO PyridinylF,F 3-hydroxy -SCHZCH3 isoxazole CO PyridinylF,CI 3-hydroxy -SCHzCH3 isoxazole CO PyridinylCl 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCl,CI 3-hydroxy -SCHZCH3 isoxazole CO Pyridinyl-(1 to 4 linearly3-hydroxy -SCHzCH3 linked isoxazole atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearly3-hydroxy -SCHzGH3 linked isoxazole atom linker)-optionally subst. heteroaryl SOz henyl COOH ' methoxy SOz phenyl CF3 COOH methoxy SOz hen CHZCF3 COOH methoxy SOz henyl Halo substitutedCOOH methox alkyl SOz henyl OCH3 COON methoxy SOz hen OCHZCH3 COOH methoxy SOz henyl OCHzCHzCH3 COOH methoxy SOz henyl OCHZCHzCH2CH3 COOH methoxy SOz henyl OCHZCHzCHZCHZCH3COOH methoxy SOz henyl CS-C8 alkox COOH methoxy SOz phenyl Halo substitutedCOON methoxy alkoxy SOz henyl CH3 COOH methoxy SOz henyl CHZCH3 COOH methoxy SOz henyl CH2CHZCH3 COOH methoxy SOz henyl CH2CHzCH2CH3 COOH methoxy SOz henyl CS-C8 alkyl COOH methoxy SOz phenyl F COOH methoxy SOz phenyl F,F COOH methoxy SOz henyl F,Cl COOH methoxy SOz henyl Cl COOH methoxy SOz phenyl Cl,CI COOH methoxy SOz phenyl -(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. aryl SOz phenyl -(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. heteroaryl SOz yridinyl COOH methoxy SOz PyridinylCF3 COOH methoxy SOz PyridinylCHzCF3 COOH methoxy SOz PyridinylHalo substitutedCOOH methoxy alkyl SOa PyridinylOCH3 COOH methoxy SOz PyridinylOCHZCH3 COON methoxy SOz PyridinylOCHZCHZCH3 COOH methoxy SOz PyridinylOCHZCHZCHZCH3 COOH methoxy SOz PyridinylOCHZCHzCH2CH2CH3COOH methoxy SOz PyridinylCS-C8 alkoxy COOH methoxy SOz PyridinylHalo substitutedCOOH methoxy alkoxy SOz PyridinylCH3 COOH methoxy SOz PyridinylCHZCH3 COON methoxy SOZ PyridinylCHZCHZCH3 COOH methoxy SOZ PyridinylCHZCHzCH2CH3 COOH methoxy SOZ PyridinylCS-C8 alkyl COOH methoxy SOZ PyridinF COOH methoxy SOz PyridinF,F COOH methoxy SOZ PyridinylF,Cl COOH methoxy SOZ PyridinCl COOH methoxy SOZ PyridinC1,C1 COOH methoxy SOZ Pyridinyl-(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. heteroaryl CO Phenyl COOH methoxy CO Phenyl CF3 COOH methoxy CO Phenyl CHZCF3 COOH methoxy CO Phenyl Halo substitutedCOOH methoxy alkyl CO Phen OCH3 COOH methoxy CO Phenyl OCHZCH3 COON methoxy CO Phenyl OCHZCHZCH3 COOH methoxy CO Phenyl OCHZCHZCHZCH3 COOH methoxy CO Phenyl OGHZCHZCHZCHZCH3COON methoxy CO Phenyl C5-C8 alkoxy COOH methoxy CO Phenyl Halo substitutedCOOH methoxy alkoxy CO Phenyl CH3 COOH methoxy CO Phenyl CHzCH3 COOH methoxy CO Phenyl CHzCHZCH3 COOH methoxy CO Phenyl GH~CHZCHZCH3 COON methoxy CO Phenyl CS-C8 allcyl COOH methoxy CO Phenyl F COOH methox CO Phen F,F COOH methoxy CO Phenyl F,Cl COOH methoxy CO Phenyl Cl COOH methoxy CO Phenyl C1,C1 COOH methoxy CO Phenyl -(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyCOON methoxy linked atom linker)-optionally subst. heteroaryl CO yridinyl COOH methoxy CO PyridinylCF3 COOH methoxy CO PyridinylCHzCF3 COOH methoxy CO PyridinylHalo substitutedCOOH methoxy alkyl CO PyridinylOCH3 COOH methoxy CO PyridinylOCHZCH3 COOH methoxy CO PyridinylOCHzCHaCH3 COOH methoxy CO PyridinylOCHZCHZCHZCH3 COOH methoxy CO PyridinOCHZCHzCH2CHzCH3COOH methoxy CO PyridinylCS-C8 alkoxy COOH methoxy CO PyridinHalo substitutedCOOH methoxy 1 alkoxy CO PyridinylCH3 COOH methoxy CO PyridinylCHZCH3 COOH methoxy CO PyridinylCHZCHZCH3 COOH methox CO PyridinCHZCHZCH~CH3 COON methoxy CO PyridinylCS-C8 alkyl COOH ~ ~ methoxy CO PyridinylF COOH methoxy CO PyridinylF,F COOH methoxy CO PyridinylF,CI COOH methoxy CO PyridinylCl GOOH methoxy CO PyridinylC1,C1 COOH methoxy CO Pyridinyl-(1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. aryl CO Pyridinyl-( 1 to 4 linearlyCOOH methoxy linked atom linker)-optionally subst. heteroaryl SOZ phenyl COOH ethoxy SOZ henyl CF3 COOH ethoxy SOZ henyl CHZCF3 COOH ethoxy SOZ phenyl Halo substitutedCOON ethoxy alkyl SOz henyl OCH3 COON ethoxy SOZ phenyl OCHZCH3 COOH ethoxy SOZ henyl OCHZCHZCH3 COOH ethoxy SOZ henyl OCH~CHZCHZCH3 COOH ethoxy SOZ phenyl OCHZCHZCHZCHzCH3COON ethoxy SOZ henyl CS-C8 alkoxy COOH ethoxy SOZ henyl Halo substitutedCOOH ethoxy alkoxy SOZ henyl CH3 COOH ethoxy SOz henyl CHZCH3 COOH . ethoxy SOz phenyl CHZCHZCH3 COOH ethoxy SOZ henyl CHZCHZCHZCH3 COON ethoxy SOZ phenyl CS-C8 allcyl COOH ethoxy SOz henyl F COON ethoxy SOZ phenyl F,F COOH ethoxy SOZ phenyl F,CI COON ethoxy SOZ henyl Cl COOH ethoxy SOZ hen CI,Cl COON ethoxy SOZ phenyl -(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally v subst. heteroaryl SOZ yridinyl COON ethoxy SOZ PyridinylCF3 COOH ethoxy SOz PyridinylCHZCF3 COOH ethoxy SOZ PyridinylHalo substitutedCOOH ethoxy alkyl SO~ PyridinylOCH3 COOH ethoxy SOZ PyridinylOCHZCH3 COOH ethoxy SOZ PyridinylOCHZCHZCH3 COOH ethoxy SOZ PyridinylOCHzCHZCHzCH3 COOH ethoxy SOZ PyridinylOCHZCHzCHZCH~CH3COOH ethoxy SOZ PyridinylCS-C8 alkoxy COOH ethoxy SOZ PyridinylHalo substitutedCOOH ethoxy alkoxy SOZ PyridinylCH3 ' COOH ethoxy SOZ PyridinylCHzCH3 COOH ethoxy SOZ PyridinylCHZCHZCH3 COOH ethoxy SOz PyridinylCHZCH~CHzCH3 COOH ethoxy SOZ PyridinylCS-C8 alk 1 COOH ethoxy SOZ PyridinylF COOH ethoxy SOZ PyridinylF,F COOH ethoxy SOZ PyridinylF,CI ~ COOH ethoxy SOZ PyridinylCl COOH ethoxy SOZ PyridinylC1,C1 COOH ethoxy SOZ Pyridinyl-(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. aryl SOz Pyridinyl-(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. heteroaryl CO Phenyl COOH ethoxy CO Phenyl CF3 COOH ethoxy CO Phenyl CHZCF3 COOH ethoxy CO Phenyl Halo substitutedCOOH ethoxy alkyl CO Phenyl OCH3 COOH ethoxy CO Phenyl OCHZCH3 COOH ethoxy CO Phenyl OCHZCHZCH3 COOH ethoxy CO Phenyl OCHZCHZCHZCH3 COOH ethoxy CO Phenyl OCHZCHZCHZCHZCH3COOH ethoxy CO Phenyl CS-C8 alkoxy COOH ethoxy CO Phenyl Halo substitutedCOON ethoxy alkoxy CO Phenyl CH3 COON ethoxy CO Phenyl CHzCH3 COOH ethoxy CO Phenyl CHZCHZCH3 COOH ethoxy CO Phenyl CHZCHZCHZCH3 COOH ethoxy CO Phenyl CS-C8 allcyl COOH ethoxy CO Phenyl F COOH ethoxy CO Phenyl F,F COOH ethox CO Phenyl F,Cl COON ethoxy CO Phen Cl COOH ethoxy CO Phenyl C1,C1 COOH ethoxy CO Phenyl -(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. heteroaryl CO yridinyl COON ethoxy CO PyridinylCF3 COOH ethoxy CO PyridinylCHZCF3 COOH ethoxy CO PyridinylHalo substitutedCOOH ethoxy alkyl CO PyridinylOCH3 COOH ethoxy ~

CO PyridinylOCHZCH3 COOH ethoxy CO PyridinylOCHZCHzCH3 COOH ethoxy CO P idinylOCHZCHZCHZCH3 COOH ethox CO PyridinylOCHZCHZCHZCHZCH3COOH ethoxy CO PyridinylCS-C8 alkoxy COON ethoxy CO PyridinylHalo substitutedCOOH ethoxy alkoxy CO PyridinylCH3 COOH ethoxy CO PyridinylCHZCH3 COON ethoxy CO PyridinylCHzCHZCH3 COOH ethoxy CO PyridinylCHZCHZCHZCH3 COOH ethoxy CO PyridinylCS-C8 alkyl COOH ethoxy CO PyridinylF COOH ethoxy CO PyridinylF,F COOH ethoxy CO PyridinylF,Cl COOH ethoxy CO P 'dinylCl COOH ethox CO PyridinylC1,Cl COOH ethoxy CO Pyridinyl-(1 to 4 linearlyCOON ethoxy ~ ~ linked atom linker)-optionally subst. aryl CO Pyridinyl-( 1 to 4 linearlyCOOH ethoxy linked atom linker)-optionally subst. heteroaryl SOZ henyl COOH ro oxy SOZ henyl CF3 COOH ro oxy SOZ henyl CHzCF3 COOH ro oxy SOZ phenyl Halo substitutedCOOH pro oxy alkyl SOZ phenyl OGH3 COON pro oxy SOZ henyl OCHZCH3 COOH ropoxy SOZ henyl OCHZCHZCH3 COOH pro oxy SOZ henyl OCHZCHZCHzCH3 COOH ro oxy SOZ henyl OCHZCHZCHZCH2CH3COOH pro oxy SOZ henyl CS-C8 alkoxy COOH ro oxy SOZ henyl Halo substitutedCOON ro oxy alkoxy SOZ henyl CH3 COOH propoxy SOZ henyl CHzCH3 COOH ro oxy SOZ henyl CHZCHZCH3 COOH ro oxy SOZ henyl CHZCHZCH2CH3 COOH ropoxy SOZ henyl CS-C8 alkyl COON ro oxy SOZ phenyl F COOH ro oxy SOZ phenyl F,F COOH ropoxy SOZ henyl F,Cl COOH ro oxy SOZ henyl Cl COOH ro oxy SOz phenyl C1,C1 COOH ro oxy SOZ phenyl -(1 to 4 linearlyCOOH propoxy linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlyCOOH propoxy linked atom linker)-optionally subst. heteroaryl SOZ yridinyl COOH ro oxy SOZ PyridinylCF3 COOH ropoxy SOZ PyridinylCHZCF3 COOH ro oxy SOZ PyridinylHalo substitutedCOOH ro oxy alkyl SOZ PyridinylOCH3 COOH propoxy SOZ PyridinylOCHZCH3 COOH ro oxy SOZ PyridinylOCHZCHZCH3 COOH ro oxy SOZ PyridinylOCHZCHZCHzCH3 COOH pro oxy SOZ P idin OCHZCH~CHZCHzCH3COOH ro ox .l SOZ P idinylCS-C8 alkox COOH propoxy SOZ PyridinylHalo substitutedCOOH ro oxy alkox SOz PyridinylCH3 COOH ro oxy SOz PyridinylCHZCH3 COON ro oxy SOZ PyridinylCHZCH2CH3 COON ro oxy SOZ PyridinylCHZCHzCH2CH3 COOH ro oxy SOZ P 'dinylCS-C8 alkyl COOH ro oxy SOz PyridinylF COOH propoxy SOZ PyridinylF,F COOH ro oxy SOZ PyridinylF,Cl COOH r0 oxy SOz PyridinylCl COOH ro oxy SOZ PyridinylCI,CI COOH ro oxy SOZ Pyridinyl-(1 to 4 linearlyCOOH propoxy linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearlyCOOH ro oxy linked atom linker)-optionally subst. heteroaryl CO Phenyl COOH ro oxy CO Phen CF3 COON propoxy CO Phenyl CHZCF3 COOH propoxy CO Phenyl Halo substitutedCOOH ro oxy alkyl CO Phenyl OCH3 COOH pro oxy CO Phenyl OCHZCH3 COOH propoxy CO Phenyl OCHZCHZCH3 COOH propoxy CO Phenyl OCHZCHZCHZCH3 COOH ropoxy CO Phenyl OCHzCHzCHZCHZCH3COOH ro oxy CO Phenyl CS-C8 alkoxy COOH ro oxy CO Phenyl Halo substitutedCOOH propoxy alkoxy CO Phenyl CH3 COOH ro oxy CO Phenyl CHZCH3 COOH ro oxy CO Phenyl CHZCHZCH3 COOH ropoxy CO Phenyl CHZCHZCHZCH3 COOH ro oxy CO Phenyl CS-C8 alkyl COOH ropoxy CO Phenyl F COOH ropoxy CO Phenyl F,F COOH ro oxy CO Phenyl F,CI COOH propoxy CO Phenyl Cl COOH ro oxy CO Phenyl C1,C1 COOH ropoxy CO Phenyl -(1to41inearlylinkedCOOH propoxy atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyCOOH propoxy linked atom linker)-optionally subst. heteroaryl CO pyridinyl COOH propoxy CO PyridinylCF3 COOH propoxy CO PyridinylCHzCF3 COOH ro oxy CO PyridinylHalo substitutedCOOH ro oxy alkyl CO PyridinylOCH; COOH ro oxy CO PyridinylOCHZCH3 COOH pro oxy CO PyridinOCHZCHZCH3 COOH ro ox CO PyridinylOCHZCHZCHZCH3 COOH pro oxy CO PyridinylOCH2CHZCHZCHZCH3COON pro oxy CO PyridinCS-C8 alkoxy COOH ro oxy CO PyridinylHalo substitutedCOON ro oxy alkoxy CO PyridinylCH3 COOH ro oxy CO PyridinylCHZCH3 COOH ro oxy CO PyridinylCHZCHZCH3 COOH ro oxy CO PyridinylCHZCHZCH2CH3 COOH ro ox CO P idinylCS-C8 ally .1 COOH ro ox CO PyridinylF COOH ro oxy CO PyridinylF,F COOH pro oxy CO PyridinF,Cl COOH ro oxy CO PyridinylCl COOH ro oxy CO PyridinylCI,CI COOH pro oxy CO Pyridinyl-(1 to 4 linearlyCOOH propoxy linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyCOON propoxy linked atom linker)-optionally subst. heteroary1 SOZ phenyl ~ COOH . ~ ~ -SCH3 SOZ henyl CF3 COON -SCH3 SOZ henyl CHZCF3 COOH -SCH3 SOZ henyl Halo substitutedCOOH -SCH3 alkyl SOZ henyl OCH3 COOH -SCH3 SOZ henyl OCHZCH3 COOH -SCH3 SOZ henyl OCHzCH2CH3 COOH -SCH3 SOZ henyl OCHZCHZCHZCH; COOH -SCH3 SOZ phenyl OCHZCHZCHZCH~CH3COOH -SCH3 SOZ phenyl CS-C8 alkoxy COOH -SCH3 SOZ henyl Halo substitutedCOOH -SCH3 alkoxy SOZ henyl CH3 COOH -SCH3 SOZ henyl CHzCH3 COOH -SCH3 SOZ henyl CHaCHzCH3 COOH -SCH3 SOZ phenyl CHZCHZCHZCH3 COOH -SCH3 SOZ henyl CS-C8 alkyl COON -SCH3 SOz henyl F COOH -SCH3 SOZ henyl F,F COOH -SCH3 SOz henyl F,Cl COON -SCH3 SOz phenyl Cl COOH -SCH3 SOZ phenyl C1,C1 COOH -SCH3 SOZ phenyl -(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. aryl SOz phenyl -(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst, heteroaryl SOz pyridinyl COOH -SCH3 SOZ Pyridin CF3 COOH -SCH3 S02 PyridinylCHZCF3 COOH -SCH3 SOZ PyridinylHalo substitutedCOOH -SCH3 alkyl SOz PyridinylOCH3 COOH -SCH3 SOZ P 'dinylOCHZCH3 COOH -SCH3 SOZ PyridinylOCHZCHZCH3 COOH -SCH3 SOZ PyridinylOCHZCHZCHzCH3 COOH -SCH3 SOZ PyridinylOCHZCHZCHZCHZCH3COOH -SCH3 SOZ PyridinylCS-C8 alkoxy COOH -SCH3 SOZ PyridinylHalo substitutedCOOH -SCH3 alkoxy SOz PyridinylCH3 COOH -SCH3 SOz P idinylCHZCH3 COOH -SCH3 SOZ Pyridin CHZCHZCH3 COOH -SCH3 SOZ PyridinylCHZCHZCHzCH3 COOH -SCH3 SOZ PyridinylCS-C8 alkyl COOH -SCH3 SOZ PyridinylF COOH -SCH3 SOZ PyridinylF,F COOH -SCH3 SOz PyridinylF,CI COOH -SCH3 SOa PyridinylCl COOH -SCH3 SOZ PyridinylC1,C1 COON -SCH3 SOZ Pyridinyl-(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. aryl SOz Pyridinyl-(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. heteroaryl CO Phenyl COOH -SCH3 CO Phenyl CF3 COOH -SCH3 CO Phenyl CHZCF3 COOH -SCH3 CO Phenyl Halo substitutedCOOH ~ ~ -SCH3 alkyl CO Phenyl OCH3 COOH ~ ~ -SCH3 CO Phenyl OCHZCH3 COOH -SCH3 CO Phenyl OCHZCHzCH3 COOH -SCH3 CO Phenyl OCHZCHZCHZCH3 COOH -SCH3 CO Phenyl OCHZCHZCHZCHZCH3COOH -SCH3 CO Phenyl CS-C8 alkoxy COOH -SCH3 CO Phenyl Halo substitutedCOOH -SCH3 alkoxy CO Phenyl CH3 COOH -SCH3 CO Phenyl CHZCH3 COOH -SCH3 CO Phenyl CHZCHZCH3 COOH -SCH3 CO Phenyl CHZCHzCHZCH3 COOH -SCH3 CO Phenyl CS-C8 alkyl COOH -SCH3 CO Phenyl F COON -SCH3 CO Phenyl F,F COOH -SCH3 CO Phenyl F,CI COOH -SCH3 CO Phenyl Cl COOH -SCH3 CO Phenyl C1,C1 COOH -SCH3 CO Phenyl -(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. heteroaryl CO pyridinyl COOH -SCH3 CO PyiidinylCF3 COOH -SCH3 _ CO PyridinylCH~CF3 COOH -SCH3 CO PyridinylHalo substitutedCOOH -SCH3 alkyl CO PyridinOCH3 COOH -SCH3 CO PyridinylOCHzCH3 COOH -SCH3 CO PyridinylOCHZCHZCH3 COOH -SCH~

CO PyridinylOCHZCHZCHZCH3 COOH -SCH3 CO PyridinylOCHzCHZCH2CHzCH3COOH -SCH3 CO PyridinylCS-C8 alkoxy COOH -SCH3 CO PyridinylHalo substitutedCOOH -SCH3 alkoxy CO PyridinCH3 COOH -SCH3 CO PyridinylCHZCH3 COOH -SCH3 CO PyridinylCHzCH2CH3 COOH -SCH3 CO PyridinylCH~CHZCHZCH3 COOH -SCH3 CO PyridinylCS-C8 alkyl COOH -SCH3 CO P 'din F COOH -SCH3 CO PyridinylF,F COOH -SCH3 CO PyridinylF,Cl COOH -SCH3 CO PyridinylCl COOH -SCH3 CO PyridinylC1,C1 COOH -SCH3 CO Pyridinyl-(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyCOOH -SCH3 linked atom linker)-optionally subst. heteroaryl SOZ henyl COOH -SCHZCH3 SOZ phenyl CF3 COOH -SCHZCH3 SOZ henyl CHZCF3 COOH -SCHZCH3 SOZ henyl Halo substitutedCOOH -SCHZCH3 alkyl SOZ phenyl OCH3 COOH -SCHZCH3 SOZ henyl OCHZCH3 COON -SCH2CH3 SOZ henyl OCHZCHZCH3 COON -SCHzCH3 SOZ henyl OCHZCHZCHZCH3 COOH -SCHZCH3 SO~ henyl OCHZCHaCHzCHZCH3COOH -SCHZCH3 SOZ henyl CS-C8 allcoxy COOH -SCHZCH3 SOZ henyl Halo substitutedCOOH -SCHZCH3 alkoxy SOZ henyl CH3 COOH -SCHZCH3 SOZ henyl CHZCH3 COON -SCHZCH3 SOZ henyl CHZCHZCH3 COOH -SCHZCH3 SOZ henyl CHZCHZCHZCH3 COOH -SCHZCH3 SOZ henyl CS-C8 alkyl COOH -SCHZCH3 SOZ henyl F COON -SCHZCH3 SOz henyl F,F COOH -SCHZCH3 SOZ henyl F,Cl COOH -SCHzCH3 SOZ henyl Cl COOH -SCHZCH3 SOZ henyl CI,CI COOH -SCHZCH3 SOz phenyl -(1 to 4 linearlyCOON -SCH2CH3 linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlyCOOH -SCHZCH3 linked atom linker)-optionally subst. heteroaryl SOZ yridinyl COOH -SCHZCH3 SOZ PyridinylCF3 COOH -SCHzCH3 SOz PyridinylCHzCF3 COOH -SCHZCH3 SOZ PyridinylHalo substitutedCOOH -SCHZCH3 alkyl SOZ PyridinylOCH3 COOH -SCHzCH3 SOZ PyridinylOCHZCH3 COOH -SCHZCH3 SOZ PyridinylOCHZCHZCH3 COOH -SCHZCH3 SOZ PyridinOCHZCH~CHZCH3 COOH -SCHZCH3 .1 SOZ PyridinylOCHZCH2CHZCHaCH3COOH -SCHzCH3 SOZ PyridinylCS-C8 alkoxy COON -SCHZCH3 SOZ PyridinylHalo substitutedCOOH -SCHZCH3 alkoxy SOZ PyridinylCH3 COOH -SCHZCH3 SOZ ~ PyridinylCHZCH3 COOH -SCHZCH3 SOZ PyridinylCHZCHZCH3 COOH -SCHZCH3 SOZ PyridinylCHZCH~CHZCH3 COOH -SCHZCH3 SOZ PyridinylCS-C8 allcyl COOH -SCHZCH3 SOZ PyridinylF COOH -SCHZCH3 SOZ PyridinylF,F COOH -SCHZCH3 SOZ PyridinylF,Cl COOH -SCHZCH3 SOZ PyridinylCl COOH -SCHZCH3 SOz PyridinylCI,Cl COOH -SCHZCH3 SOz Pyridinyl-(1 to 4 linearlyCOOH -SCHZCH3 linked atom linker)-optionally subst. aryl SOz Pyridinyl-(1 to 4 linearlyCOOH -SCHZCH3 linked atom linker)-optionally subst. heteroaryl CO Phen COOH -SCHZCH3 CO Phenyl CF3 COOH -SCHZCH3 CO Phen CHZCF3 COOH -SCHzCH3 CO Phenyl Halo substitutedCOOH -SCHZCH3 alkyl CO Phenyl OCH3 COOH -SCHZCH3 CO Phenyl OCHZCH3 COOH -SCHZCH3 CO Phenyl OCHZCHZCH3 COON -SCHZCH3 CO Phen OCHZCHZCHZCH3 COOH -SCHZCH3 CO Phenyl OCH~CHZCHZCHZCH3COOH -SCHZCH3 CO Phenyl CS-C8 alkoxy COOH -SCHZCH3 ' ' CO Phenyl Halo substitutedCOOH -SCHZCH3 alkoxy CO Phenyl CH3 COOH -SCHZCH3 CO Phenyl CHZCH3 COOH -SCHZCH3 CO Phenyl CHZCHZCH3 COOH -SCHZCH3 CO Phenyl CHZCHzCHZCH3 COOH -SCHZCH3 CO Phenyl CS-C8 alkyl COOH -SCHZCH3 CO Phenyl F COOH -SCHZCH3 CO Phenyl F,F COOH -SCHZCH3 CO Phenyl F,Cl COON -SCHZCH3 CO Phen Cl COOH -SCHzCH3 CO Phenyl Cl,Cl COOH -SCHZCH3 CO Phenyl -(1 to 4 linearlyCOOH -SCHZCH3 linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyCOOH -SCHZCH3 linked atom linker)-optionally subst. heteroaryl CO pyridinyl COON -SCHZCH3 CO PyridinylCF3 COON -SCHZCHs CO PyridinylCHZCF3 COOH -SCHZCH3 CO PyridinylHalo substitutedCOON -SCHZCH3 alkyl CO PyridinylOCH3 COOH -SCHZCH3 CO PyridinylOCHZCH3 COOH -SCHZCH3 CO P 'dinylOCHzCH2CH3 COOH -SCHZCH3 CO PyridinylOCHZCHZCHzCH3 COOH -SCH2CH3 CO PyridinylOCHZCHZCHzCH2CH3COON -SCHZCH3 CO PyridinylCS-C8 alkoxy COOH -SCHZCH3 CO P idinylHalo substitutedCOOH -SCH2CH3 alkoxy CO PyridinylCH3 COOH -SCHZCH3 CO PyridinylCHZCH3 COOH -SCHZCH3 CO PyridinylCHZCHZCH3 COON -SCHZCH3 CO PyridinylCHZCHZCHZCH3 COOH -SCHZCH3 CO PyridinylCS-C8 alkyl COOH -SCHZCH3 CO PyridinylF COOH -SCHZCH3 CO PyridinylF,F COOH -SCHZCH3 CO PyridinylF,Cl COOH -SCHZCH3 CO PyridinylCl COOH -SCHzCH3 CO PyridinylCl,Cl COOH -SCHZCH3 CO Pyridinyl-(i to 4 linearlyCOOH -SCHzCHs linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyCOOH -SCHZCH3 linked atom linker)-optionally subst. heteroaryl SOZ henyl tetrazole methoxy SOZ henyl CF3 Tetrazole methoxy SOZ phenyl CHZCF3 Tetrazole methoxy SOZ henyl Halo substitutedTetrazole methox alkyl SOZ hen OCH3 Tetrazole methoxy SOZ phenyl OCHZCH3 tetrazole methoxy SOZ henyl OCHZCHzCH3 tetrazole methoxy SOZ phenyl OCHZCHZCHZCH3 Tetrazole methoxy SOZ phenyl OCHZCHZCHZCHZCH3Tetrazole methoxy SOZ henyl CS-C8 allcoxy Tetrazole methoxy SOZ phenyl Halo substitutedTetrazole methoxy alkoxy SOZ henyl CH3 tetrazole methoxy SOZ phenyl CHZCH3 tetrazole methoxy SOZ hen CHzCHZCH3 Tetrazole methoxy SOZ phenyl CHZCHZCHZCH3 Tetrazole methoxy SOZ phenyl CS-C8 alkyl Tetrazole methoxy SOZ phenyl F Tetrazole methoxy SOZ henyl F,F tetrazole methoxy SOZ henyl F,Cl tetrazole methoxy SOZ henyl Cl Tetrazole methoxy SOZ henyl C1,C1 Tetrazole methoxy SOZ phenyl -(1 to 4 linearlyTetrazole methoxy linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlyTetrazole methoxy linked atom linker)-optionally subst. heteroaryl SOZ yridinyl tetrazole methoxy SOZ PyridinylCF3 tetrazole methoxy SOZ PyridinylCHZCF3 Tetrazole methoxy SOZ PyridinylHalo substitutedTetrazole methoxy alkyl SOZ PyridinylOCH3 Tetrazole methoxy SOZ PyridinylOCHZCH3 Tetrazole methoxy SOZ PyridinylOCHZCHZCH3 tetrazole methoxy SOZ PyridinylOCHZCHZCH2CH3 tetrazole methoxy SOZ PyridinylOCHZCHZCHZCHZCH3Tetrazole methoxy SOZ PyridinylCS-C8 alkoxy Tetrazole methoxy SOZ PyridinylHalo substitutedTetrazole methoxy alkoxy SOZ PyridinylCH3 Tetrazole methoxy S02 PyridinylCHZCH3 tetrazole methoxy SOZ PyridinylCHZCHZCH3 tetrazole methoxy SOZ PyridinylCHzCH2CH2CH3 Tetrazole methoxy SOZ PyridinylCS-C8 alkyl Tetrazole methoxy SOZ PyridinylF Tetrazole methoxy SOZ PyridinylF,F Tetrazole methoxy SOz PyridinylF,Cl tetrazole methoxy SOZ PyridinCl tetrazole methoxy SOZ PyridinylC1,C1 Tetrazole rnethoxy S02 Pyridinyl-(1 to 4 linearlyTetrazole methoxy linked .
atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearlyTetrazole methoxy linked atom linker)-optionally subst, heteroaryl CO Phenyl Tetrazole methoxy CO Phenyl CF3 tetrazole methoxy CO Phenyl CHZCF3 tetrazole methoxy CO Phen Halo substitutedTetrazole methoxy 1 alkyl CO Phenyl OCH3 Tetrazole methoxy CO Phenyl OCHzCH3 Tetrazole methoxy CO Phenyl OCHzCH2CH3 Tetrazole methoxy CO Phenyl OCH~CHzCHZCH3 tetrazole methoxy CO Phenyl OCHzCH2CH2CHZCH3tetrazole methoxy CO Phenyl CS-C8 alkoxy Tetrazole methoxy CO Phenyl Halo substitutedTetrazole methox alkox CO Phenyl CH3 Tetrazole methoxy CO Phenyl CHZCH3 Tetrazole methoxy CO Phenyl CHZCHZCH3 tetrazole methoxy CO Phenyl CHzCH2CHzCH3 tetrazole methoxy CO Phenyl CS-C8 alkyl Tetrazole methoxy CO Phenyl F Tetrazole methoxy CO Phenyl F,F Tetrazole methoxy CO Phenyl F,Cl Tetrazole methoxy CO Phenyl Cl tetrazole methoxy CO Phenyl C1,C1 tetrazole methoxy CO Phenyl -(1 to 4 linearly linked Tetrazole methoxy atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly linked Tetrazole methoxy atom linker)-optionally subst. heteroaryl CO pyridinylTetrazole methoxy CO PyridinylCF3 Tetrazole methoxy CO PyridinylCHZCF3 tetrazole methoxy CO PyridinylHalo substituted alkyl tetrazole methoxy CO PyridinylOCH3 Tetrazole methoxy CO PyridinylOCHZCH3 Tetrazole methoxy CO PyridinylOCHZCHZCH3 Tetrazole methoxy CO PyridinylOCHZCHZCHZCH3 Tetrazole methoxy CO PyridinylOCHzCHzCHZCHZCH3 tetrazole methoxy CO PyridinylCS-C8 alkoxy tetrazole methoxy CO Pyridinyl. Halo substituted alkoxy methoxy Tetrazole CO PyridinylCH3 Tetrazole methoxy CO PyridinylCH2CH3 Tetrazole methoxy CO PyridinylCHZCHZCH3 Tetrazole methoxy CO PyridinylCH2CHZCHZCH3 tetrazole methoxy CO PyridinylCS-C8 alkyl tetrazole methoxy CO PyridinylF Tetrazole methoxy CO PyridinylF,F Tetrazole methoxy CO PyridinylF,Cl Tetrazole methoxy CO PyridinylCl Tetrazole methoxy CO PyridinylCl,Cl tetrazole methoxy CO Pyridinyl-(1 to 4 linearly linked tetrazole methoxy atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearly linked Tetrazole methoxy atom linker)-optionally subst. heteroaryl SOZ henyl Tetrazole ethoxy SOZ henyl CF3 Tetrazole ethoxy SOZ henyl CHZCF3 Tetrazole ethoxy SOz henyl Halo substituted alkyl tetrazole ethoxy SOZ henyl OCH3 tetrazole ethoxy SOZ henyl OCHZCH3 Tetrazole ethoxy SOZ henyl OCHZCHZCH3 Tetrazole ethoxy SOZ henyl OCHZCHzCH2CH3 Tetrazole ethoxy SOZ henyl OCHZCHZCHZCHZCH3 Tetrazole ethoxy SOZ henyl CS-C8 allcoxy tetrazole ethoxy SOZ henyl Halo substituted alkoxy tetrazole ethoxy SOZ phenyl CH3 Tetrazole ethoxy SOZ henyl CHZCH3 Tetrazole ethoxy SOZ phen CHZCHZCH3 Tetrazole ethoxy SO~ henyl CHZCHZCHzCH3 Tetrazole ethoxy SOZ hen CS-C8 alkyl tetrazole ethoxy SOZ henyl F tetrazole ethoxy SOZ hen F,F Tetrazole ethoxy SOZ henyl F,CI Tetrazole ethoxy SOZ henyl Cl ~ Tetrazole ethoxy SOZ phenyl CI,CI Tetrazole ethoxy SOZ phenyl -(1 to 4 linearlytetrazole ethoxy linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlytetrazole ethoxy linked atom linker)-optionally subst. heteroaryl SOZ yridinyl Tetrazole ethoxy SOZ PyridinylCF3 Tetrazole ethoxy SOz PyridinylCHZCF3 Tetrazole ethoxy SOZ PyridinylHalo substitutedTetrazole ethoxy alkyl SOZ PyridinylOCH3 tetrazole ethoxy SOZ PyridinylOCHZCH3 tetrazole ethoxy SOZ PyridinylOCHZCHZCH3 Tetrazole ethoxy SOZ PyridinylOCHzCHzCH2CH3 Tetrazole ethoxy SOZ PyridinylOCHZCHzCHZCHZCH3Tetrazole ethoxy SOZ PyridinylC5-C8 alkoxy Tetrazole ethoxy SOz PyridinylHalo substitutedtetrazole ethoxy alkoxy SOZ PyridinylCH3 tetrazole ethoxy SOZ PyridinylCHaCH3 Tetrazole ethoxy SOZ PyridinylCHZCHZCH3 Tetrazole ethoxy SOz PyridinylCHZCHZCHzCH3 Tetrazole ethoxy SOZ PyridinylCS-C8 alkyl Tetrazole ethoxy SOZ PyridinylF tetrazole ethoxy SOZ PyridinylF,F tetrazole ethoxy SOZ PyridinylF,Cl Tetrazole ethoxy SOZ PyridinylCl Tetrazole ethoxy SOZ PyridinylCl,Cl Tetrazole ethoxy SOZ Pyridinyl-(1 to 4 linearlyTetrazole ethoxy linked atom linker)-optionally subst. aryl SOz Pyridinyl-(1 to 4 linearlytetrazole ethoxy linked atom linker)-optionally subst. heteroaryl CO Phenyl tetrazole ethoxy CO Phenyl CF3 Tetrazole ethoxy CO Phenyl CHzCF3 Tetrazole ethoxy CO Phenyl Halo substitutedTetrazole ethoxy alkyl CO Phen OCH3 Tetrazole ethoxy CO Phenyl OCHzCH3 tetrazole ethoxy CO Phenyl OCHZCHZCH3 tetrazole ethoxy CO Phenyl OCHZCHZCHZCH3 Tetrazole ethoxy CO Phenyl OCHZCHZCHZCHZCH3Tetrazole ethoxy CO Phenyl CS-C8 alkoxy Tetrazole ethoxy CO Phen Halo substitutedTetrazole ethoxy 1 alkoxy CO Phenyl CH3 tetrazole ethoxy CO Phenyl CHZCH3 tetrazole ethoxy CO Phenyl CHZCHZCH3 Tetrazole ethoxy CO Phenyl CHZCHZCHZCH3 Tetrazole ethoxy CO Phenyl CS-C8 alkyl Tetrazole ethoxy CO Phenyl F Tetrazole ethoxy CO Phenyl F,F tetrazole ethoxy CO Phenyl F,Cl tetrazole ethoxy CO Phenyl Cl Tetrazole ethoxy CO Phenyl Cl,Cl Tetrazole ethoxy CO Phenyl -(1 to 4 linearlyTetrazole ethoxy linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyTetrazole ethoxy linked atom linker)-optionally subst. heteroaryl CO yridinyl tetrazole ethoxy CO PyridinylGF3 tetrazole ethoxy CO PyridinylCHZCF3 Tetrazole ethoxy CO PyridinylHalo substitutedTetrazole ethoxy alkyl CO PyridinylOCH3 Tetrazole ethoxy CO PyridinylOCHZCH3 Tetrazole ethoxy CO PyridinylOCHZCHZCH3 tetrazole ethoxy CO PyridinylOCHzCHZCHzCH3 tetrazole ethoxy CO PyridinylOCHZCHZCHZCHZCH3Tetrazole ethoxy CO PyridinylCS-C8 alkoxy Tetrazole ethoxy CO PyridinylHalo substitutedTetrazole ethoxy alkoxy CO PyridinylCH3 Tetrazole ethoxy CO PyridinylCHZCH3 tetrazole ethoxy CO PyridinylCHZCHzCH3 tetrazole ethoxy CO P.yridinylCHZCHzCH2CH3 Tetrazole ethoxy CO PyridinylCS-C8 alkyl Tetrazole ethoxy CO PyridinylF Tetrazole ethoxy CO PyridinylF,F Tetrazole ethoxy CO PyridinylF,CI tetrazole ethoxy CO P 'dinylCl tetrazole ethoxy CO P idinylC1,C1 Tetrazole ethoxy CO Pyridinyl-(1 to 4 linearlyTetrazole ethoxy linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyTetrazole ethoxy linked atom linker)-optionally subst. heteroaryl SOZ henyl tetrazole ro oxy SOZ phenyl CF3 Tetrazole pro oxy SOZ henyl CHZCF3 Tetrazole ropoxy SOZ henyl Halo substitutedTetrazole xo oxy alkyl SOZ phenyl OCH3 Tetrazole pro oxy SOZ henyl OCHZCH3 tetrazole ropoxy SOZ henyl OCHZCHZCH3 tetrazole ro oxy SOZ phenyl OCHaCHzCH2CH3 Tetrazole pro oxy SOZ hen OCHZCHZCHZCHZCH3Tetrazole ro ox SOZ phenyl CS-C8 alkoxy Tetrazole pro oxy SOZ phenyl Halo substitutedTetrazole ro oxy alkoxy SO~ henyl CH3 tetrazole ro oxy SOZ hen CHZCH3 tetrazole ro oxy SOZ henyl CHZCHZCH3 Tetrazole ropoxy SOZ henyl CHZCHZCHZCH3 Tetrazole ro oxy SOz henyl CS-C8 allcyl Tetrazole ropoxy SO~ henyl F Tetrazole ropoxy SOZ henyl F,F tetrazole ro oxy SOz phenyl F,Cl tetrazole propox SOZ henyl Cl Tetrazole ro oxy SOZ henyl C1,C1 Tetrazole ro ox SOZ phenyl -(1 to 4 linearlyTetrazole propoxy linked atom linker)-optionally subst. ar 1 SOZ henyl -(1 to 4 linearlyTetrazole pro oxy linked atom linker)-optionally subst. heteroaryl SOZ yridinyl tetrazole pro oxy SOZ PyridinylCF3 tetrazole pro oxy SOZ PyridinylCHZCF3 Tetrazole pro oxy SOZ PyridinylHalo substitutedTetrazole ro oxy alkyl SOZ PyridinylOCH3 Tetrazole ro oxy SOZ PyridinylOCHZCH3 Tetrazole ro oxy SOZ PyridinylOCHZCHzCH3 tetrazole ro oxy SOZ PyridinylOCHZCHzCHzCH3 tetrazole ro oxy SOZ PyridinylOCHZCHZCHZCHZCH3Tetrazole ro oxy SOZ PyridinylCS-C8 allcoxy Tetrazole ro oxy SOZ PyridinylHalo substitutedTetrazole ro oxy alkoxy SOZ PyridinylCH3 Tetrazole ro oxy SOZ PyridinylCHZCH3 tetrazole propoxy SOZ PyridinylCHZCHzCH3 tetrazole ropoxy SOZ PyridinylCHZCHZCHzCH3 Tetrazole ro oxy SOZ PyridinylCS-C8 alkyl Tetrazole ro oxy SOZ PyridinylF Tetrazole ro oxy SOZ PyridinylF,F Tetrazole pro oxy SOZ PyridinylF,Cl tetrazole ro oxy SOZ PyridinylCl tetrazole ro oxy SOZ PyridinylC1,C1 Tetrazole ro oxy SOZ Pyridinyl-(1 to 4 linearlyTetrazole propoxy linked atom linker)-optionally subst. aryl SOz Pyridinyl-(1 to 4 linearlyTetrazole propoxy linked atom linker)-optionally subst. heteroaryl CO Phenyl Tetrazole propoxy CO Phenyl CF3 tetrazole ro oxy CO Phenyl CHZCF3 ' tetrazole ro oxy CO Phenyl Halo substitutedTetrazole ro oxy alkyl CO Phenyl OCH3 Tetrazole ro oxy CO Phenyl OCHZCH3 Tetrazole ro oxy CO Phenyl OCHZCHZCH3 _ Tetrazole ro oxy CO Phenyl ' OCHZCHZCHZCH3 tetrazole ro oxy CO Phenyl OCHZCHaCHZCHZCH3tetrazole ro oxy CO Phenyl CS-C8 alkoxy Tetrazole pro oxy CO Phenyl Halo substitutedTetrazole ro oxy alkoxy CO Phenyl CH3 Tetrazole ro oxy CO Phenyl CHzCH3 Tetrazole propoxy CO Phenyl CHZCHZCH3 tetrazole ropoxy CO Phenyl CHZCHZCH2CH3 tetrazole ropoxy CO Phen CS-C8 alkyl Tetrazole ro oxy CO Phenyl F Tetrazole ro ox CO Phenyl F,F Tetrazole ro oxy CO Phenyl F,Cl Tetrazole ro oxy CO Phenyl Cl tetrazole ro oxy CO Phenyl Cl,Cl tetrazole ro oxy CO Phenyl -(1 to 4 linearlyTetrazole propoxy linked atom linker)-optionally subst. aryl CO Phenyl -( 1 to 4 linearlyTetrazole propoxy linked atom linker)-optionally subst. heteroaryl CO pyridinyl- - ~--Tetrazole _. I propox~
~ I - - I

CO PyridinylCF3 Tetrazole pro oxy CO PyridinylCHZCF3 _ pro oxy tetrazole CO P 'dinylHalo substitutedtetrazole propoxy alkyl CO PyridinylOCH3 Tetrazole pro oxy CO PyridinylOCHzCH3 Tetrazole ro oxy CO PyridinylOCHzCH~CH3 Tetrazole r0 oxy CO PyridinylOCHZCHZCHZCH3 Tetrazole ropoxy CO PyridinylOCHZCHZCHZCHZCH3tetrazole ro oxy CO PyridinylCS-C8 alkoxy tetrazole ro oxy CO PyridinylHalo substitutedTetrazole pro oxy alkoxy CO PyridinylCH3 Tetrazole ro oxy CO PyridinylCHZCH3 Tetrazole ropoxy CO PyridinylCHZCHZCH3 Tetrazole ro oxy CO PyridinylCHzCH2CHZCH3 tetrazole pro oxy ~

CO PyridinylCS-C8 allcyl tetrazole ro oxy CO PyridinylF Tetrazole pro oxy CO PyridinylF,F Tetrazole ro oxy CO PyridinylF,Cl Tetrazole pro oxy CO PyridinylCl Tetrazole ropoxy CO PyridinylC1,C1 tetrazole ropoxy CO Pyridinyl-(1 to 4 linearlytetrazole propoxy linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyTetrazole propoxy linked atom linker)-optionally subst. heteroaryl SOZ henyl Tetrazole -SCH3 SOZ hen CF3 Tetrazole -SCH3 SOZ henyl CHZCF3 Tetrazole -SCH3 SOZ henyl Halo substitutedtetrazole -SCH3 alkyl SOZ phenyl OCH3 tetrazole -SCH3 SOZ henyl OCHZCH3 Tetrazole -SCH3 SOZ henyl OCHZCHZCH3 Tetrazole -SCH3 SOZ hen OCHZCH~CH2CH3 Tetrazole -SCH3 SOZ phenyl OCH~CHzCH2CH2CH3Tetrazole -SCH3 SOZ henyl CS-C8 allcoxy tetrazole -SCH3 SO2 phenyl Halo substitutedtetrazole -SCH3 alkoxy SOz henyl CH3 Tetrazole -SCH3 SOZ henyl CHzCH3 Tetrazole -SCH3 SOZ henyl CHZCHZCH3 Tetrazole -SCH3 SOZ henyl CHZCHzCH2CH3 Tetrazole -SCH3 SOZ phenyl CS-C8 alkyl tetrazole -SCH3 SOz henyl F tetrazole -SCH3 SOZ henyl F,F Tetrazole -SCH3 SOZ henyl F,Cl Tetrazole -SCH3 SOZ henyl Cl Tetrazole -SCH3 SOZ henyl CI,Cl Tetrazole -SCH3 SO~ phenyl -(1 to 4 linearlytetrazole -SCH3 linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlytetrazole -SCH3 linked atom linker)-optionally subst. heteroaryl SOZ yridinyl Tetrazole -SCH3 SOZ PyridinylCF3 Tetrazole -SCH3 SOZ PyridinylCHZCF3 Tetrazole -SCH3 SOZ PyridinylHalo substitutedTetrazole -SCH3 alkyl SOZ PyridinylOCH3 tetrazole -SCH3 SOz PyridinylOCHzCH3 tetrazole -SCH3 SOZ PyridinylOCHZCHzCH3 Tetrazole -SCH3 SOZ PyridinylOCHZCHZCHZCH3 Tetrazole -SCH3 SOZ PyridinylOCHZCHZCHZCHZCH3Tetrazole -SCH3 SOZ PyridinylCS-C8 alkoxy Tetrazole -SCH3 SOZ PyridinylHalo substitutedtetrazole -SCH3 alkoxy SOZ PyridinylCH3 tetrazole -SCH3 SOz PyridinylCHzCH3 Tetrazole -SCH3 SOz PyridinylCHzCH2CH3 Tetrazole -SCH3 SOZ PyridinylCHZCHZCHZCH3 Tetrazole -SCH3 SOz PyridinylCS-C8 allcyl Tetrazole -SCH3 SOZ PyridinylF tetrazole -SCH3 SOZ PyridinylF,F tetrazole -SCH3 SOZ PyridinylF,Cl Tetrazole -SCH3 SOZ PyridinylCl Tetrazole -SCH3 SOZ PyridinylC1,C1 Tetrazole -SCH3 SOZ Pyridinyl-(i to 4 linearlyTetrazole -SCH3 linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearlytetrazole -SCH3 linked atom linker)-optionally subst. heteroaryl CO Phenyl tetrazole -SCH3 CO Phenyl CF3 Tetrazole -SCH3 CO Phenyl CH2CF3 Tetrazole -SCH3 CO Phenyl Halo substitutedTetrazole -SCH3 alkyl CO Phenyl OCH3 Tetrazole -SCH3 CO Phenyl OCHZCH3 tetrazole -SCH3 CO Phenyl OCHZCHZCH3 tetrazole -SCH3 CO Phenyl OCHZCHzCHZCH3 Tetrazole -SCH3 CO Phenyl OCHZCHZCHZCHZCH3Tetrazole -SCH3 CO Phenyl C5-C8 alkoxy Tetrazole -SCH3 CO Phenyl Halo substitutedTetrazole -SCH3 alkoxy CO Phenyl CH3 tetrazole -SCH3 CO Phenyl CHZCH3 tetrazole -SCH3 CO Phenyl CHZCHZCH3 Tetrazole -SCH3 CO Phenyl CHZCHZCHZCH3 Tetrazole -SCH3 CO Phen CS-C8 alkyl Tetrazole -SCH3 CO Phen F Tetrazole -SCH3 CO Phenyl F,F tetrazole -SCH3 CO Phenyl F,CI tetrazole -SCH3 CO Phenyl Cl Tetrazole -SCH3 CO Phenyl Cl,Cl Tetrazole -SCH3 CO Phenyl -(1 to 4 linearlyTetrazole -SCH3 linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlyTetrazole -SCH3 linked atom linker)-optionally subst. heteroaryl CO yridinyl tetrazole -SCH3 CO PyridinylCF3 tetrazole -SCH3 CO PyridinylCHzCF3 Tetrazole -SCH3 CO PyridinylHalo substitutedTetrazole -SCH3 alkyl CO PyridinylOCH3 Tetrazole -SCH3 CO PyridinylOCHZCH3 Tetrazole -SCH3 CO PyridinylOCHZCHzCH3 tetrazole -SCH3 CO PyridinylOCHZCHZCHZCH3 tetrazole ~ -SCH3 CO PyridinylOCHZCHzCH2CHZCH3Tetrazole -SCH3 CO PyridinylCS-C8 alkoxy Tetrazole -SCH3 CO PyridinylHalo substitutedTetrazole -SCH3 alkoxy CO PyridinylCH3 Tetrazole -SCH3 CO PyridinylCHZCH3 tetrazole -SCH3 CO PyridinylCH2CH2CH3 tetrazole -SCH3 CO PyridinylCHZCHZCHZCH3 Tetrazole -SCH3 CO PyridinylCS-C8 alkyl Tetrazole -SCH3 CO PyridinylF Tetrazole -SCH3 CO PyridinylF,F Tetrazole -SCH3 CO PyridinylF,CI tetrazole -SCH3 CO PyridinylCl tetrazole -SCH3 CO PyridinylCl,Cl Tetrazole -SCH3 CO Pyridinyl-(1 to 4 linearlyTetrazole -SCH3 linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlyTetrazole -SCH3 linked atom linker)-optionally subst. heteroaryl SOZ henyl Tetrazole -SCHZCH3 SOZ phenyl CF3 tetrazole -SCHZCH3 SOZ henyl CHZCF3 tetrazole -SCHZCH3 SOz henyl Halo substitutedTetrazole -SCHaCH3 alkyl SOZ henyl OCH3 Tetrazole -SCHZCH3 SOZ henyl OCHzCH3 Tetrazole -SCHzCH3 SOZ henyl OCHZCHZCH3 Tetrazole -SCHzCH3 SOZ henyl OCHZCHZCHzCH3 tetrazole -SCHZCH3 SOZ henyl OGH2CHZCHZCHZCH3tetrazole -SCHzCH3 SOZ henyl CS-C8 alkoxy Tetrazole -SCH2CH3 SOZ henyl Halo substitutedTetrazole -SCHZCH3 alkoxy SOZ henyl CH3 Tetrazole -SCHZCH3 SOZ henyl CHZCH3 Tetrazole -SCHZCH3 SOZ phenyl CHZCHZCH3 tetrazole -SCHzCH3 SOZ henyl CHZCHZCHzCH3 tetrazole -SCHZCH3 SOZ henyl CS-C8 alkyl Tetrazole -SCHZCH3 SOZ phenyl F Tetrazole -SCHZCH3 SOZ henyl F,F Tetrazole -SCHzCH3 SOZ phenyl F,CI Tetrazole -SCHZCH3 SOZ phenyl Cl tetrazole -SCHZCH3 SOZ henyl Cl,CI tetrazole -SCHZCH3 SOZ phenyl -(1 to 4 linearlyTetrazole -SCHZCH3 linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearlyTetrazole -SCHzCH3 linked atom linker)-optionally subst. heteroaryl SOZ yridinyl Tetrazole -SCHZCH3 SOZ PyridinylCF3 Tetrazole -SCHZCH3 SOZ PyridinylCH2CF3 tetrazole -SCHZCH3 SOz PyridinylHalo substitutedtetrazole -SCHZCH3 alkyl SOZ PyridinylOCH3 Tetrazole -SCHZCH3 SOZ PyridinylOCHZCH3 Tetrazole -SCHZCH3 SOZ PyridinylOCHZCHZCH3 Tetrazole -SCHzCH3 SOZ PyridinylOCHzCH2CH2CH3 Tetrazole -SCHZCH3 SOZ P idinylOCHZCHZCHZCHZCH3tetrazole -SCHZCH3 SOZ PyridinylCS-C8 alkoxy tetrazole -SCHzCH3 SOz PyridinHalo substitutedTetrazole -SCHZCH3 1 alkoxy SOZ PyridinylCH3 Tetrazole -SCHZCH3 SOZ PyridinylCHZCH3 Tetrazole -SCHZCH3 S02 PyridinylCHZCHZCH3 Tetrazole -SCHZCH3 SOz PyridinylCHZCHZCHZCH3 tetrazole -SCHzCH3 SOZ PyridinylCS-C8 alkyl tetrazole -SCHZCH3 SOZ PyridinylF Tetrazole -SCHZCH3 SOZ PyridinylF,F Tetrazole -SCHzCH3 SOZ PyridinylF,Gl Tetrazole -SCHZCH3 SOZ PyridinylCl Tetrazole -SCHaCH3 SOZ PyridinylC1,C1 tetrazole -SCHZCH3 SOZ Pyridinyl-(1 to 4 linearlytetrazole -SCHzCH3 linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearlyTetrazole -SCHZCH3 linked atom linker)-optionally subst. heteroaryl CO Phenyl Tetrazole -SCHZCH3 CO Phenyl CF3 Tetrazole -SCHZCH3 CO Phenyl CHzCF3 Tetrazole -SCHzCH3 CO Phenyl Halo substitutedtetrazole -SCHZCH3 alkyl CO Phenyl OCH3 tetrazole -SCHZCH3 CO Phenyl OCHZCH3 Tetrazole -SCHZCH3 CO Phenyl OCHZCHzCH3 Tetrazole -SCHZCH3 CO Phenyl OCHZCHZCHZCH3 Tetrazole -SCHZCH3 CO Phenyl OCHZCHZCHZCHZCH3Tetrazole -SCHzCH3 CO Phenyl CS-C8 alkoxy tetrazole -SCHZCH3 CO Phenyl Halo substitutedtetrazole -SCHZCH3 alkoxy CO Phenyl CH3 Tetrazole -SCHZCH3 CO Phenyl CHZCH3 Tetrazole -SCHZCH3 CO Phenyl CHzCH2CH3 Tetrazole -SCHZCH3 CO Phenyl CHxCH2CHZCH3 Tetrazole -SCHZCH3 CO Phenyl CS-C8 alkyl tetrazole -SCHZCH3 CO Phenyl F tetrazole -SCHZCH3 CO Phenyl F,F Tetrazole -SCHzCH3 CO Phenyl F,Cl Tetrazole -SCHZCH3 CO Phen Cl Tetrazole -SCHZCH3 CO Phenyl Cl,Cl Tetrazole -SCHZCH3 CO Phenyl -(1 to 4 linearlytetrazole -SCHaCH3 linked atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearlytetrazole -SCHZCH3 linked atom linker)-optionally subst. heteroaryl CO yridinyl Tetrazole -SCHaCH3 CO PyridinylCF3 Tetrazole -SCHZCH3 CO PyridinylCH~CF3 Tetrazole -SCHZGH3 CO PyridinylHalo substitutedTetrazole -SCHZCH3 alkyl CO PyridinylOCH3 tetrazole -SCHZCH3 CO PyridinylOCHZCH3 tetrazole -SCHzCH3 CO PyridinylOCHaCHZCH3 Tetrazole -SCHZCH3 CO PyridinylOCHZCH~CH2CH3 Tetrazole -SCHzCH3 CO P idinylOCHZCHZCHZCHZCH3Tetrazole -SCHZCH3 CO PyridinylCS-C8 alkoxy Tetrazole -SCHzCH3 CO PyridinylHalo substitutedtetrazole -SCHZCH3 alkoxy CO PyridinylCH3 tetrazole -SCHZCH3 CO PyridinylCHZCH3 Tetrazole -SCHZGH3 Cb PyridinylCHZCHZCH3 Tetrazole -SCHZCH3 CO PyridinylCHzCH2CH2CH3 Tetrazole -SCHzCH3 CO PyridinylCS-C8 alkyl Tetrazole -SCHZCH3 CO PyridinylF tetrazole -SCHZCH3 CO PyridinylF,F tetrazole -SCHzCH3 CO PyridinylF,Cl Tetrazole -SCHZCH3 CO PyridinylCl Tetrazole -SCHZCH3 CO PyridinylC1,C1 Tetrazole -SCHzCH3 CO Pyridinyl-(1 to 4 linearlyTetrazole -SCHZCH3 linked atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearlytetrazole -SCHZCH3 linked atom linker)-optionally subst. heteroaryl SOz phenyl 3-hydroxy methoxy isoxazole SOZ henyl CF3 3-hydroxy methoxy isoxazole SOZ henyl CHZCF3 3-hydroxy methoxy isoxazole SOZ henyl Halo substituted3-hydroxy methoxy alkyl isoxazole S02 henyl OCH3 3-hydroxy methoxy isoxazole SOZ phenyl OCHZCH3 3-hydroxy methoxy isoxazole SOZ phenyl OCHZCHzCH3 3-hydroxy methoxy isoxazole SOZ henyl OCHZCHzCH2CH3 3-hydroxy methoxy isoxazole SOZ henyl OCHaCH2CH2CH2CH33-hydrox isoxazolemethoxy ~

SOZ phenyl CS-C8 alkoxy 3-hydroxy methoxy isoxazole SOZ phenyl Halo substituted3-hydroxy methoxy alkoxy isoxazole SOZ henyl CH3 3-hydroxy methox .
isoxazole SOZ phenyl CHzCH3 3-hydroxy methox isoxazole SOZ phenyl CHZCHzCH3 3-hydroxy methoxy isoxazole SOZ henyl CHZCHZCHZCH3 3-hydrox isoxazolemethoxy SOZ phenyl CS-C8 allcyl 3-hydroxy methoxy isoxazole SOZ henyl F 3-hydroxy methox isoxazole SOZ phenyl F,F 3-hydroxy methoxy isoxazole SOz henyl F,CI 3-hydroxy methoxy isoxazole SOZ henyl Cl 3-hydroxy methoxy isoxazole SOZ phenyl Cl,Cl 3-hydrox isoxazolemethoxy SOZ phenyl -(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. heteroaryl SOZ yridinyl 3-hydroxy methoxy isoxazole SOZ PyridinylCF3 3-hydroxy methoxy isoxazole SOZ PyridinylCHZCF3 3-hydroxy methoxy isoxazole SOZ PyridinylHalo substituted3-hydroxy methoxy alk 1 isoxazole SOz PyridinylOCH3 3-hydroxy methoxy isoxazole SOZ PyridinylOCHZCH3 3-hydroxy methoxy isoxazole SOZ PyridinylOCHzCHzCH3 3-hydrox isoxazolemethox SOZ PyridinylOCHZCHZCHzCH3 3-h droxy methoxy isoxazole SOZ PyridinylOCHZCHZCHzCHZCH33-hydroxy methoxy isoxazole S02 PyridinylCS-C8 alkoxy 3-hydroxy methoxy isoxazole SOZ PyridinylHalo substituted3-hydroxy methoxy alkoxy isoxazole SOZ PyridinylCH3 3-hydroxy methoxy isoxazole SOZ PyridinylCHZCH3 3-hydroxy methoxy isoxazole SOZ PyridinylCHzCH2CH3 3-hydroxy methoxy isoxazole SOz PyridinylCHZCHzCHZCH3 3-hydroxy methoxy isoxazole SOZ PyridinylCS-C8 allcyl 3-hydroxy methoxy isoxazole SOZ PyridinylF ~ 3-hydroxy methoxy isoxazole SOZ PyridinylF,F 3-hydroxy methoxy isoxazole SOZ PyridinylF,CI 3-hydroxy methoxy isoxazole SOZ PyridinylCl 3-hydroxy methoxy isoxazole SOZ PyridinylC1,C1 3-hydroxy methoxy isoxazole SOZ Pyridinyl-(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxy methoxy isoxazole CO Phenyl CF3 3-hydroxy methoxy isoxazole CO Phenyl CHZCF3 3-hydroxy methoxy isoxazole CO Phenyl Halo substituted3-hydroxy methoxy alkyl isoxazole CO Phenyl OCH3 3-hydroxy methoxy isoxazole CO Phenyl OCHZCH3 3-hydroxy methoxy isoxazole CO Phenyl OCHZCHZCH3 3-hydroxy methoxy isoxazole CO Phenyl OCHZCHZCHzCH3 3-hydroxy methoxy isoxazole CO Phenyl OCHZCHZCHzCHZCH33-hydroxy methox isoxazole CO PlienylCS-C8 alkoxy 3-hydroxy methoxy isoxazole CO Phenyl Halo substituted3-hydroxy methoxy alkoxy isoxazole CO Phenyl CH3 3-hydroxy methoxy isoxazole CO Phenyl CHzCH3 3-hydroxy methoxy isoxazole CO Phenyl CHZCHZCH3 3-hydroxy methoxy isoxazole CO Phenyl CHZCHZCHZCH3 3-hydroxy methoxy isoxazole CO Phenyl CS-C8 alkyl 3-hydroxy methoxy isoxazole CO Phenyl F 3-hydroxy methoxy isoxazole CO Phenyl F,F 3-hydroxy methoxy isoxazole CO Phenyl F,CI 3-hydroxy methoxy isoxazole CO Phenyl Cl 3-hydroxy methoxy isoxazole CO Phenyl C1,C1 3-hydroxy methoxy isoxazole CO Phenyl -(i to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. heteroaryl CO yridinyl 3-hydroxy methoxy isoxazole CO PyridinylCF3 3-h droxy methoxy isoxazole CO PyridinylCHzCF3 3-hydroxy methoxy isoxazole CO PyridinylHalo substituted3-hydroxy methoxy alkyl isoxazole CO PyridinylOCH3 3-hydroxy methoxy isoxazole CO PyridinylOCH~CH3 3-hydroxy methoxy isoxazole CO PyridinylOCHZCHzCH3 3-hydroxy methoxy isoxazole CO PyridinylOCHZCHzCHZCH3 3-hydroxy methoxy isoxazole CO PyridinylOCHZCHZCHZCHZCH33-hydroxy methoxy isoxazole CO PyridinylCS-C8 alkoxy 3-hydroxy methoxy isoxazole CO PyridinHalo substituted3-hydroxy methoxy 1 alkoxy isoxazole CO PyridinylCH3 3-hydroxy methoxy isoxazole CO PyridinylCHZCH3 3-hydroxy methoxy is0xazole CO PyridinylCHzCH2CH3 3-hydroxy methox isoxazole CO PyridinylCHZCHZCHZCH3 3-hydroxy methoxy isoxazole CO PyridinylCS-C8 allcyl 3-hydroxy methox isoxazole CO PyridinylF 3-hydroxy methoxy isoxazole CO PyridinylF,F 3-hydroxy methoxy isoxazole CO PyridinylF,Cl 3-h droxy methoxy isoxazole CO PyridinylCl 3-hydroxy methoxy isoxazole CO PyridinylCI,CI 3-hydroxy methoxy isoxazole CO Pyridinyl-(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearly3-hydroxy methoxy linked isoxazole atom linker)-optionally subst. heteroaryl SOZ henyl 3-hydroxy ethoxy isoxazole SOZ phenyl CF3 3-hydroxy ethoxy isoxazole SOZ henyl CHZCF3 3-hydroxy ethoxy isoxazole SOZ henyl Halo substituted3-hydroxy ethoxy alkyl isoxazole SOZ henyl OCH3 3-hydroxy ethoxy isoxazole SOZ henyl OCHzCH3 3-hydroxy ethoxy isoxazole SOZ henyl OCHZCHZCH3 3-hydroxy ethoxy isoxazole SOZ henyl OCHZCHzCHZCH3 3-hydroxy ethoxy isoxazole SOz henyl OCHZCH2CHZCHZCH33-hydroxy ethoxy isoxazole SOZ henyl CS-C8 alkoxy 3-hydroxy ethoxy isoxazole SOz henyl Halo substituted3-hydrox isoxazole ethoxy alkoxy SOZ henyl CH3 3-hydroxy ethoxy isoxazole SOZ henyl CHzCH3 3-hydroxy ethoxy isoxazole SOZ henyl CHZCHzCH3 3-hydroxy ethoxy isoxazole SOZ henyl CHZCHZCHZCH3 3-hydroxy ethoxy isoxazole SOZ henyl CS-C8 alkyl 3-hydroxy ethoxy isoxazole SOa henyl F 3-hydroxy ethoxy isoxazole SOz phenyl F,F 3-hydroxy ethoxy isoxazole SOZ henyl F,Cl 3-hydroxy ethoxy isoxazole SOz phenyl Cl 3-hydroxy ethox .
isoxazole SOz henyl Cl,Cl 3-hydroxy ethoxy isoxazole SOz phenyl -(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. heteroaryl SOZ yridinyl 3-hydroxy ethoxy isoxazole SOZ PyridinCF3 3-hydroxy ethoxy 1 isoxazole SOZ PyridinylCH~CF3 3-hydroxy ethoxy isoxazole SOZ PyridinylHalo substituted3-hydroxy ethoxy alkyl isoxazole SOZ PyridinOCH3 3-hydroxy ethoxy 1 isoxazole SOZ PyridinylOCHzCH3 3-h droxy ethoxy isoxazole SOZ PyridinylOCHZCHZCH3 3-hydroxy ethoxy isoxazole SOz PyridinylOCH2CH~CHZCH3 3-hydroxy ethoxy isoxazole SOZ PyridinylOCHZCHzCHZCHZCH33-hydroxy ethoxy isoxazole SOZ PyridinCS-C8 alkox 3-hydroxy ethoxy 1 isoxazole SOZ PyridinylHalo substituted3-hydroxy ethoxy alkoxy isoxazole SOZ PyridinylCH3 3-hydroxy ethoxy isoxazole S02 PyridinylCHZCH3 3-hydroxy ethoxy isoxazole SOZ PyridinylCHZCHzCH3 3-hydroxy ethoxy isoxazole SOZ PyridinylCHZCHZCHzCH3 3-hydroxy ethoxy is0xazole SOZ PyridinylCS-C8 alkyl 3-hydroxy ethoxy isoxazole SOZ PyridinF 3-hydroxy ethoxy 1 isoxazole SOZ PyridinylF,F 3-hydroxy ethoxy isoxazole SOZ P idin F,Cl 3-hydroxy ethoxy 1 isoxazole SOZ PyridinylCl 3-hydroxy ethoxy isoxazole SOZ PyridinylCI,CI 3-hydroxy ethoxy isoxazole SOZ Pyridinyl-(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxy ethoxy isoxazole CO Phenyl CF3 3-hydroxy ethoxy isoxazole CO Phenyl CHZCF3 3-hydroxy ethoxy isoxazole CO Phenyl Halo substituted3-hydroxy ethoxy alkyl isoxazole CO Phenyl OCH3 3-hydroxy ethoxy isoxazole CO Phenyl OCHZCH3 3-hydroxy ethoxy isoxazole CO Phenyl OCH~CHZCH3 3-hydroxy ethoxy isoxazole CO Phenyl OCHZCHZCHZCH3 3-hydroxy ethoxy isoxazole CO Phenyl OCHZCHZCHZCHZCH33-hydroxy ethoxy isoxazole CO Phenyl CS-C8 alkoxy 3-hydroxy ethoxy isoxazole CO Phenyl Halo substituted3-hydroxy ethoxy alkoxy isoxazole CO Phenyl CH3 3-hydroxy ethoxy isoxazole CO Phenyl CHZCH3 3-hydroxy ethoxy isoxazole CO Phenyl CHZCHZCH3 3-hydroxy ethoxy isoxazole CO Phenyl CHZCH2CHZCH3 3-hydroxy ethoxy isoxazole CO Phenyl CS-C8 alkyl 3-hydroxy ethoxy isoxazole CO Phenyl F 3-hydroxy ethoxy isoxazole CO Phenyl F,F 3-hydroxy ethoxy isoxazole CO Phenyl F,Cl 3-hydroxy ethoxy isoxazole CO Phenyl Cl 3-hydroxy ethoxy isoxazole CO Phenyl C1,C1 3-hydroxy ethoxy isoxazole CO Phenyl -(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. heteroaryl CO yridinyl 3-hydroxy ethoxy isoxazole CO PyridinCF3 3-hydroxy ethoxy 1 isoxazole CO PyridinylCHzCF3 3-hydroxy ethoxy isoxazole CO PyridinylHalo substituted3-hydroxy ethoxy al 1 isoxazole CO PyridinylOCH3 3-hydroxy ethoxy isoxazole CO PyridinylOCHZCH3 3-hydroxy ethoxy isoxazole CO PyridinylOCHZCHZCH3 3-hydroxy ethoxy isoxazole CO P 'dinylOCH~CHZCHZCH3 3-h droxy ethoxy isoxazole CO PyridinOCHZCHZCHZCHZCH33-h drox isoxazole ethox CO PyridinylCS-C8 alkoxy 3-hydroxy ethoxy isoxazole CO P 'dinylHalo substituted3-hydroxy ethoxy alkoxy isoxazole CO PyridinylCH3 3-hydroxy ethoxy isoxazole CO PyridinylCHZCH3 3-hydroxy ethoxy isoxazole CO PyridinylCHZCHZCH3 3-hydroxy ethoxy isoxazole CO PyridinCHZCHZCHzCH3 3-hydroxy ethoxy 1 isoxazole CO PyridinylCS-C8 alkyl 3-hydroxy ethoxy isoxazole CO PyridinylF 3-hydroxy ethoxy isoxazole CO PyridinylF,F 3-hydroxy ethoxy isoxazole CO PyridinylF,Cl 3-hydroxy ethox isoxazole CO PyridinylCl 3-hydroxy ethoxy isoxazole CO PyridinylC1,C1 3-hydroxy ethoxy isoxazole CO Pyriduiyl-(1 to 4 linearly3-hydroxy ethoxy linked isoxazole atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearly3-hydrox isoxazole ethoxy linked atom linker)-optionally subst. heteroaryl SOZ henyl 3-hydroxy isoxazole ro oxy SOZ henyl CF3 3-hydroxy isoxazole ro oxy SOZ henyl CHZCF3 3-hydroxy isoxazole ro oxy SOZ henyl Halo substituted3-hydroxy isoxazole ro oxy alkyl SOZ henyl OCH3 3-hydroxy isoxazole ro oxy SOa henyl OCHZCH3 3-hydroxy isoxazole ro oxy SOZ henyl OCHZCHZCH3 3-hydroxy isoxazole ropoxy SOZ phenyl OCHzCHZCH2CH3 3-hydroxy isoxazole ropoxy SOz phenyl OCHzCHZCH2CH2CH33-hydroxy isoxazole ro oxy SOZ henyl CS-C8 alkoxy 3-hydrox isoxazole ro oxy SOz henyl Halo substituted3-hydroxy isoxazole pro oxy alkoxy SOZ henyl CH3 3-hydroxy isoxazole ropoxy SOZ henyl CHZCH3 3-hydrox isoxazole ro oxy SOZ henyl CHZCHZCH3 3-hydroxy isoxazole ro oxy SOZ phenyl CHzCHZCH2CH3 3-hydroxy isoxazole' ro oxy SOZ henyl CS-C8 alkyl 3-hydroxy isoxazole ro oxy SOZ henyl F 3-hydroxy isoxazole ro oxy SOZ henyl F,F 3-hydroxy isoxazole ro oxy SOZ henyl F,CI 3-hydroxy isoxazole ro oxy SOa henyl Cl 3-hydroxy isoxazole ro oxy SOZ phenyl CI,CI 3-hydroxy isoxazole ro oxy SOZ phenyl -(1 to 4 linearly3-hydroxy isoxazole propoxy linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearly3-hydroxy isoxazole propoxy linked atom linker)-optionally subst. heteroaryl SOZ yridinyl 3-hydroxy isoxazole ropoxy SOZ PyridinylCF3 3-hydroxy isoxazole ro oxy SO~ PyridinylCHzCF3 3-hydrox isoxazole ropoxy SOz PyridinylHalo substituted3-hydroxy isoxazole ro oxy alkyl SOZ PyridinylOCH3 3-hydroxy isoxazole pro oxy SOZ PyridinylOCHzCH3 3-h droxy isoxazole pro oxy SOZ PyridinylOCHzCH2CH3 3-hydroxy isoxazole ro oxy SOZ PyridinylOCHZCHZCHZCH3 3-hydroxy isoxazole pro oxy SOZ P 'dinylOCHZCHZCHzCHzCH33-hydroxy isoxazole ro oxy SOZ PyridinylCS-C8 alkoxy 3-hydroxy isoxazole ro oxy SOZ PyridinylHalo substituted3-hydroxy isoxazole ro oxy alkoxy SOZ PyridinylGH3 3-hydroxy isoxazole ro oxy SOa PyridinylCHZCH3 3-hydroxy isoxazole ro oxy SOZ PyridinylCHzCHZCH3 3-hydroxy isoxazole ro oxy SOZ PyridinylCHZCHZCHZCH3 3-hydroxy isoxazole ro oxy SOZ PyridinCS-C8 alkyl 3-hydroxy isoxazole ro ox SOz Pyridinyl' F 3-hydroxy isoxazole ro oxy SOZ PyridinylF,F 3-hydroxy isoxazole ro oxy SOZ PyridinylF,CI 3-hydroxy isoxazole propoxy SOZ PyridinylCl 3-hydroxy isoxazole ro ox SOZ PyridinylC1,C1 3-hydroxy isoxazole ro oxy SOZ Pyridinyl-(1 to 4 linearly3-hydroxy isoxazole propoxy linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearly3-hydroxy isoxazole propoxy linked atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxy isoxazole ropoxy CO Phenyl CF3 3-hydroxy ro oxy isoxazole CO Phenyl CHzCF3 3-hydroxy pro oxy isoxazole CO Phenyl Halo substituted3-hydroxy ro oxy alkyl isoxazole CO Phenyl OCH3 3-hydroxy ro oxy isoxazole CO Phenyl OCHzCH3 3-hydroxy ro oxy isoxazole CO Phenyl OCHzCHZCH3 3-hydroxy ro oxy isoxazole CO Phenyl OCHZCHzCH2CH3 3-hydroxy ro oxy isoxazole CO Phenyl OCHZCHzCHZCHZCH33-hydroxy ro oxy isoxazole CO Phenyl CS-C$ allcoxy 3-hydroxy ro oxy isoxazole CO Phenyl Halo substituted3-hydroxy ro oxy alkoxy isoxazole CO Phenyl CH3 3-hydroxy propoxy isoxazole CO Phenyl CHZCH3 3-hydroxy ro oxy isoxazole CO Phenyl CHzCH2CH3 3-hydroxy ro oxy isoxazole CO Phenyl CHZCHZCHZCH3 3-hydroxy ro oxy isoxazole CO Phenyl CS-C8 alkyl 3-hydroxy ro oxy isoxazole CO Phenyl F 3-hydroxy ro oxy isoxazole CO Phenyl F,F 3-hydroxy propoxy isoxazole CO Phenyl F,Cl 3-hydroxy ro oxy isoxazole CO Phenyl Cl 3-hydroxy ro oxy isoxazole CO Phenyl Cl,Cl 3-hydroxy ro oxy isoxazole CO Phenyl -(1 to 4 linearly3-hydroxy propoxy linked isoxazole atom linker)-optionally subst. aryl CO Phenyl -(1 to .4 linearly3-hydroxy propoxy linked isoxazole atom linker)-optionally subst. heteroaryl CO yridinyl 3-hydroxy ro oxy isoxazole CO PyridinylCF3 3-hydroxy ro oxy isoxazole CO PyridinylCH2CF3 3-hydroxy pro oxy isoxazole CO PyridinylHalo substituted3-hydroxy pro oxy alkyl isoxazole CO PyridinylOCH3 3-hydroxy ro oxy isoxazole CO PyridinylOCHZCH3 3-hydroxy ropoxy isoxazole CO PyridinylOCHZCH~CH3 3-h droxy ro oxy isoxazole CO PyridinylOCHZCHZCHZCH3 3-hydroxy ropoxy isoxazole CO P idinylOCHZCHZCHZCHZCH33-hydroxy pro oxy isoxazole CO PyridinCS-C8 alkoxy 3-hydrox isoxazole ropoxy CO PyridinylHalo substituted3-hydroxy ro oxy alkoxy isoxazole CO PyridinylCH3 3-hydroxy ro ox isoxazole CO PyridinCHZCH3 3-hydroxy ropoxy 1 isoxazole CO PyridinylCHZCHZCH3 3-hydroxy ro oxy isoxazole CO P idinylCHZCHZCHZCH3 3-hydroxy pro oxy isoxazole CO P idinylCS-C8 alkyl 3-hydrox isoxazole ro oxy CO P idinylF 3-hydroxy ro oxy isoxazole CO PyridinylF,F 3-hydroxy ro oxy isoxazole CO PyridinylF,CI 3-h droxy ro oxy isoxazole CO PyridinylCl 3-hydroxy ro oxy isoxazole CO P idinylC1,CI 3-hydroxy pro oxy isoxazole CO Pyridinyl-(1 to 4 linearly3-hydroxy propoxy linked isoxazole atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearly3-hydroxy propoxy linked isoxazole atom linker)-optionally subst. heteroaryl SOZ phenyl 3-hydrox isoxazole -SCH3 SOZ henyl CF3 3-hydroxy -SCH3 isoxazole SOZ phenyl CHZCF3 3-hydroxy -SCH3 isoxazole SOZ ~ phenylHalo substituted3-hydroxy ~ -SCH
alkyl isoxazole SOZ henyl OCH3 3-hydroxy isoxazole -SCH3 SOZ phenyl OCHZCH3 3-hydroxy isoxazole -SCH3 SOZ phenyl OCHZCHZCH3 3-hydroxy isoxazole -SCH3 SOZ henyl OCHZCHZCHZCH3 3-hydroxy isoxazole -SCH3 SOZ henyl OCHZCHZCHZCHZCH33-hydroxy isoxazole -SCH3 SOZ henyl CS-C8 alkoxy 3-hydroxy isoxazole -SCH3 SOZ henyl Halo substituted3-hydroxy isoxazole -SCH3 alkoxy SOZ henyl CH3 3-hydroxy isoxazole -SCH3 SOZ henyl CHZCH3 3-hydroxy isoxazole -SCH3 SOZ henyl CHZCHZCH3 3-hydroxy isoxazole -SCH3 SOZ phenyl CHzCH2CHZCH3 3-hydroxy isoxazole -SCH3 SOZ henyl CS-C8 alkyl 3-hydroxy isoxazole -SCH3 SOZ henyl F 3-hydroxy isoxazole -SCH3 SOZ henyl F,F 3-hydroxy isoxazole -SCH3 SOZ henyl F,CI 3-hydroxy isoxazole -SCH3 SOZ henyl Cl 3-hydroxy isoxazole -SCH3 SOZ henyl CI,CI 3-hydroxy isoxazole -SCH3 SOZ phenyl -(1 to 4 linearly3-hydroxy isoxazole -SCH3 linked atom linker)-optionally subst. aryl SOZ phenyl -(1 to 4 linearly3-hydroxy isoxazole -SCH3 linked atom linker)-optionally subst. heteroaryl SOZ yridinyl 3-hydroxy isoxazole -SCH3 SOZ PyridinylCF3 3-hydroxy isoxazole' -SCH3 SOZ PyridinylCHZCF3 3-hydroxy isoxazole -SCH3 SOZ PyridinylHalo substituted3-hydroxy isoxazole -SCH3 alkyl SOz PyridinylOCH3 3-hydroxy isoxazole -SCH3 SOZ PyridinylOCHZCH3 3-hydroxy isoxazole -SCH3 SOZ PyridinylOCHaCH2CH3 3-h droxy isoxazole -SCH3 SOZ PyridinylOCHZCHzCHzCH3 3-hydroxy isoxazole -SCH3 SOZ PyridinylOCH2CHZCHzCHZCH33-hydroxy isoxazole -SCH3 SOZ PyridinylCS-C8 alkoxy 3-hydroxy isoxazole -SCH3 SOZ P 'dinylHalo substituted3-hydroxy isoxazole -SCH3 alkoxy SOZ PyridinylCH3 3-hydroxy isoxazole -SCH3 SOZ PyridinylCHZCH3 3-hydroxy isoxazole -SCH3 SOZ P idinylCHZCHZCH3 3-hydroxy isoxazole -SCH3 SOZ PyridinylCH~CHZCHZCH3 3-h drox isoxazole -SCH3 SOZ PyridinylCS-C8 alkyl 3-hydroxy isoxazole -SCH3 SOZ PyridinylF 3-hydroxy isoxazole -SCH3 SOZ PyridinylF,F 3-hydroxy isoxazole -SCH3 SOZ PyridinylF,CI 3-hydroxy isoxazole -SCH3 SOZ PyridinylCl 3-hydroxy isoxazole -SCH3 SOZ PyridinylCl,Cl 3-hydroxy isoxazole -SCH3 SOa Pyridinyl-(1 to 4 linearly3-hydroxy isoxazole -SCH3 linked atom linker)-optionally subst. aryl SOZ Pyridinyl-(1 to 4 linearly3-hydroxy isoxazole -SCH3 linked atom linker)-optionally subst. heteroaryl CO Phen 3-hydroxy isoxazole -SCH3 CO Phenyl CF3 3-hydroxy isoxazole -SCH3 CO Phenyl CHZCF3 3-h droxy isoxazole -SCH3 CO Phenyl Halo substituted3-hydroxy isoxazole -SCH3 alkyl CO Phenyl OCH3 3-hydroxy isoxazole -SCH3 CO Phen OCHzCH3 3-hydroxy isoxazole -SCH3 CO Phenyl OCHZCHZCH3 3-hydroxy isoxazole -SCH3 CO Phenyl OCHzCHZCH2CH3 3-hydroxy -SCH3 isoxazole CO Phenyl OCHZCHZCHZCHZCH33-hydroxy -SCH3 isoxazole CO Phenyl C5-C8 alkoxy 3-hydroxy -SCH3 isoxazole CO Phenyl Halo substituted3-hydroxy -SCH3 alkoxy isoxazole CO Phenyl CH3 3-hydroxy -SCH3 isoxazole CO Phenyl CHZCH3 3-hydroxy -SCH3 isoxazole CO Phenyl CHZCHZCH3 3-hydroxy -SCH3 isoxazole CO Phenyl CHZCHZCHZCH3 3-hydroxy -SCH3 isoxazole CO Phenyl CS-C8 alkyl 3-hydroxy -SCH3 isoxazole CO Phenyl F 3-hydroxy -SCH3 isoxazole CO Phenyl F,F 3-hydroxy -SCH3 isoxazole CO Phenyl F,CI 3-hydroxy -SCH3 isoxazole CO Phenyl Cl 3-hydroxy -SCH3 isoxazole CO Phenyl CI,CI 3-hydroxy -SCH3 isoxazole CO Phenyl -(1 to 4 linearly3-hydroxy, -SCH3 linked isoxazole atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly3-hydroxy -SCH3 linked isoxazole atom linker)-optionally subst. heteroaryl CO yridinyl 3-hydroxy -SCH3 isoxazole CO PyridinylCF3 3-hydroxy -SCH3 isoxazole CO PyridinylCHZCF3 3-hydroxy -SCH3 isoxazole CO PyridinylHalo substituted3-hydrox isoxazole -SCH3 alkyl CO PyridinylOCH3 3-hydroxy -SCH3 isoxazole CO P 'dinylOCHZCH3 3-hydroxy -SCH3 isoxazole CO PyridinylOCHZCHzCH3 3-hydroxy -SCH3 isoxazole CO PyridinylOCHZCHzCH2CH3 3-hydroxy -SCH3 isoxazole CO PyridinylOCHZCHZCHZCHaCH33-hydroxy -SCH3 isoxazole CO PyridinylCS-C8 alkoxy 3-hydroxy -SCH3 isoxazole CO PyridinylHalo substituted3-hydroxy -SCH3 alkoxy isoxazole CO PyridinylCH3 3-hydroxy -SCH3 isoxazole CO PyridinylCHZCH3 3-hydroxy -SCH3 isoxazole CO PyridinylCHZCH~CH3 3-hydroxy -SCH3 isoxazole CO PyridinylCHZCHZCHZCH3 3-hydroxy -SCH3 isoxazole CO Pyridin CS-C8 alkyl 3-hydroxy -SCH3 1 isoxazole CO P 'dinylF 3-hydroxy -SCH3 isoxazole CO PyridinylF,F 3-hydroxy -SCH3 isoxazole CO Pyridin F,Cl 3-hydroxy -SCH3 1 isoxazole CO PyridinylCl 3-hydroxy -SCH3 isoxazole CO PyridinylCI,Cl 3-hydroxy -SCH3 isoxazole CO Pyridinyl-(1 to 4 linearly3-hydroxy -SCH3 linked isoxazole atom linker)-optionally subst. aryl CO Pyridinyl-(1 to 4 linearly3-hydroxy -SCH3 linked isoxazole atom linker)-optionally subst. heteroaryl SOZ henyl 3-hydroxy -SCHzCH3 isoxazole SOZ henyl CF3 3-hydroxy -SCHZCH3 isoxazole SOZ hen 1 CHZGF3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl Halo substituted3-hydroxy -SCHZCH3 alkyl isoxazole SOZ henyl OCH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl OCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl OCHZCHZCH3 3-hydroxy -SCHzCH3 isoxazole SOZ henyl OCHZCHZCHaCH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl OCHZCHZCHZCHZCH33-hydroxy -SCHzCH3 isoxazole SOZ henyl CS-C8 alkoxy 3-hydroxy -SCHzCH3 isoxazole SOZ henyl Halo substituted3-hydroxy -SCHZCH3 alkoxy isoxazole SOZ phenyl CH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl CHZCH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl CHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl CHZCHzCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOZ henyl CS-C8 alkyl 3-hydroxy -SCHZCH3 isoxazole SOZ henyl F 3-hydroxy -SCHZCH3 isoxazole SOZ henyl F,F 3-hydroxy -SCHZCH3 isoxazole SOZ phenyl F,Cl 3-hydroxy -SCHZCH3 isoxazole SOZ phenyl Cl 3-hydroxy -SCHZCH3 isoxazole SOZ henyl Cl,CI 3-hydroxy -SCH2CH3 isoxazole SOZ phenyl -(1 to 4 linearly3-hydroxy -SCHzCH3 linked isoxazole atom linker)-optionally subst. aryl SOz phenyl -(1 to 4 linearly3-hydroxy -SCHZCH3 linked isoxazole atom linker)-optionally subst. heteroaryl SOZ yridinyl 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylCF3 3-hydroxy -SCHzCH3 isoxazole SOZ PyridinylCHzCF3 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylHalo substituted3-hydroxy -SCHZCH3 alkyl isoxazole SOZ PyridinylOCH3 ~ 3-h droxy -SCHZCH3 isoxazole SOZ PyridinylOCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinOCH~CHZCH3 3-hydroxy -SCHZCH3 1 isoxazole SOZ PyridinylOCHZCHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOa PyridinOCH~CHZCHZCHZCH33-hydroxy -SCHZCH3 1 isoxazole SOZ PyridinylC5-C8 alkoxy 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylHalo substituted3-hydroxy -SCHzCH3 alkoxy isoxazole SOZ PyridinylCH3 3-hydroxy -SCHzCH3 isoxazole SOZ PyridinylCHZCH3 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylCHzCHZCH3 3-hydroxy -SCH2CH3 isoxazole SOZ PyridinylCHZCHZCHZCH3 3-hydroxy -SCHzCH3 isoxazole SOZ PyridinylCS-C8 alkyl 3-hydroxy -SCHzCH3 isoxazole SOZ PyridinylF 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylF,F 3-hydroxy -SCHzCH3 isoxazole SOZ PyridinylF,CI 3-hydroxy -SCHZCH3 isoxazole SOZ PyridinylCl 3-hydroxy -SCHZCH3 isoxazole -SOZ PyridinylCl,CI 3-hydroxy -SCHzCH3 isoxazole SOZ Pyridinyl-(1 to 4 linearly3-hydroxy -SCHzCH3 linked isoxazole atom linker)-optionally subst. aryl SOa Pyridinyl-(1 to 4 linearly3-hydroxy -SCHzCH3 linked isoxazole atom linker)-optionally subst. heteroaryl CO Phenyl 3-hydroxy -SCHZCH3 isoxazole CO Phenyl CF3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl CHZCF3 3-h droxy -SCHzCH3 isoxazole CO Phenyl Halo substituted3-hydroxy -SCHZCH3 alk 1 isoxazole CO Phenyl OCH3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl OCHZCH3 3-h droxy -SCHzCH3 isoxazole CO Phenyl OCHZCHzCH3 3-hydroxy -SCHzCH3 isoxazole CO Phenyl OCHZCHZCHzCH3 3-h droxy -SCHZCH3 isoxazole CO Phenyl OCHZCHZCHzCH2CH33-hydroxy -SCHZCH3 isoxazole CO Phenyl CS-C8 alkoxy 3-hydroxy -SCHZCH3 isoxazole CO Phenyl Halo substituted3-hydroxy -SCHZCH3 alkoxy isoxazole CO Phenyl CH3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl CHZCH3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl CHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl CHZCHZCHaCH3 3-hydroxy -SCHZCH3 isoxazole CO Phenyl CS-C8 alkyl 3-hydroxy -SCHZCH3 isoxazole CO Phenyl F 3-hydroxy -SCHZCH3 isoxazole CO Phenyl F,F 3-hydroxy -SCH~CH3 isoxazole CO Phenyl F,Cl 3-hydroxy -SCHZCH3 isoxazole CO Phenyl Cl 3-hydroxy -SCHZCH3 isoxazole CO Phenyl C1,C1 3-hydroxy -SCHZCH3 isoxazole CO Phenyl -(1 to 4 linearly3-hydroxy -SCH~CH3 linked isoxazole atom linker)-optionally subst. aryl CO Phenyl -(1 to 4 linearly3-hydroxy -SCHzCH3 linked isoxazole atom linker)-optionally subst. heteroaryl CO yridinyl 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCF3 3-hydroxy -SCH2CH3 isoxazole CO PyridinylCHZCF3 3-hydroxy -SCHzCH3 isoxazole CO PyridinylHalo substituted3-hydroxy -SCHZCH3 alkyl isoxazole CO PyridinylOCH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylOCHZCH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylOCHZCH~CH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylOCHzCHZCH2CH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylOCHZCHZCHzCHZCH33-hydroxy -SCHZCH3 isoxazole CO PyridinylCS-C8 alkox 3-hydroxy -SCHZCH3 isoxazole CO PyridinylHalo substituted3-hydroxy -SCHZCH3 alkoxy isoxazole CO PyridinylCH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCHZCH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCHZCHZCHZCH3 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCS-C8 alkyl 3-h droxy -SCHZCH3 isoxazole CO PyridinylF 3-hydroxy -SCHZCH3 isoxazole CO PyridinylF,F 3-hydroxy -SCHZCH3 isoxazole CO PyridinylF,CI 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCl 3-hydroxy -SCHZCH3 isoxazole CO PyridinylCl,Cl 3-hydroxy -SCHZCH3 isoxazole CO Pyridinyl-(1 to 4 linearly3-hydroxy -SCHzCH3 linked isoxazole atom linker}-optionally subst. aryl CO Pyridinyl-(1 to 4 linearly3-hydroxy -SCHZCH3 linked isoxazole atom linker)-optionally subst. heteroaryl [0579] With reference to the compounds described in Table 4 (and for each of the bicyclic cores), additional compounds are described for each of the substitutent combinations therein where the substituent shown in Table 4 at the 5-position is instead an aryl group; a heteroaryl group; a monocyclic aryl group; a monocyclic heteroaryl group; a bicyclic aryl group; a bicyclic heteroaryl group; a substituted aryl group; a substituted heteroaryl group; a pyridinyl group; a pyrimidinyl group; a pyradazinyl group;
a pyrrolyl group; a thiophenyl group.
[0580] With reference to the compounds described in Table 4 and the preceding paragraph, additional compounds are described in which L is CHZ.
[0581] With reference to the compounds described in Table 4 and the preceding two paragraphs, additional compounds are described in which the moiety A is an acyl sulphonamide (-C(=O)-N-S02CH3).
[0582] All patents and other references cited in the specification are indicative of the level of skill of those skilled in the art to which the invention pertains, and are incorporated by reference in their entireties, including any tables and figures, to the same extent as if each reference had been incorporated by reference in its entirety individually.
[0583] One skilled in the art would readily appreciate that the present invention is well adapted to obtain the ends and advantages mentioned, as well as those inherent therein.
The methods, variances, and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein 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.
[0584] It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed 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.
[0585] The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of and "consisting of may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
(0586] In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.
[0587] Also, unless indicated to the contrary, where various numerical values are provided for embodiments, additional embodiments are described by taking any 2 different values as the endpoints of a range. Such ranges are also within the scope of the described invention.
[0588] Thus, additional embodiments are within the scope of the invention and within the following claims.

Claims (147)

1. A compound having the chemical structure of Formula I, namely wherein U, V, W, X, and Y are independently N or CR8, where 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 either of the rings of said bicyclic ring structure;
R1 is a carboxyl group or ester thereof or a carboxylic acid isostere;
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)NR10R11, -C(Z)R20, -S(O)2NR10R11;
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 mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;
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.ident.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)2NR10R11, or -S(O)2R21;
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 mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;
R12, R13, R14, and R15 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, -CH2-CR12=CR13R14, -CH2-C.ident.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, -CH2-CR12=CR13R14, -CH2-C.ident.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 said compound is different from 3-(5-methoxy-1-p-toluenesulfonylindol-3-yl)propionic acid and 1-(2,4,6-triisopropylphenylsulfonyl)indole-3-propionic acid.

2. The compound of claim 1, wherein said compound has a structure of Formula I-1, namely wherein X and Y are independently N or CR8;
R1 is -COOH or an ester thereof or a carboxylic acid isostere;
R2 is -S(O)2R21;
R3, R4, and R5 are independently hydrogen, halo, optionally substituted alkyl, -CH2-CR12= CR13R14, -CH2-C.ident.CR15, 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(O)2R21;
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;
R8 is hydrogen, optionally substituted 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; and n=1.

3. The compound of claim 1, wherein R21 is optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl.

4. The compound of claim 3, wherein said R21 is selected from the group consisting of substituted aryl, optionally substituted aralkyl, substituted heteroaryl, or optionally substituted heteroaralkyl, wherein said substitution on 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 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-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino.

5. The compound of claim 3, wherein said R21 is selected from the group consisting of substituted aryl, optionally substituted aralkyl, substituted heteroaryl, or optionally substituted heteroaralkyl, wherein said substitution on R21 is 1 to 3 groups or substituents independently selected from the group consisting of halo, hydroxyl, lower alkoxy, alkylthio, amino, amido, and carboxyl.

6. The compound of claim 1, wherein said compound has a structure of Formula Ie, namely:
wherein 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)2NR10R11, or -S(O)2R21;

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 fused ring with the phenyl ring.

7. The compound of claim 6, wherein R4 is optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or halo.

8. The compound of claim 6, wherein R4 is optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or halo.

9. The compound of claim 6, wherein R4 is alkoxy and R24 and R25 are chloro.

10. The compound of claim 6, wherein R4 is alkoxy and R24 and R25 are fluoro.

11. The compound of claim 6, wherein R4 is alkoxy and R24 is alkoxy.

12. The compound of claim 6, wherein R4 is alkoxy and R24 is alkyl.

13. The compound of claim 6, wherein R24 or R25 or both are are ethyl, propyl, butyl, or pentyl.

14. The compound of claim 6, wherein R4 is methoxy or ethoxy and R24 and R25 are chloro.

15. The compound of claim 6, wherein R4 is methoxy or ethoxy and R24 is alkoxy.

16. The compound of claim 6, wherein R4 is methoxy or ethoxy and R24 is alkyl.

17. The compound of claim 6, wherein R24 and R25 are not both alkyl.

18. The compound of claim 1, wherein Y and X are CH;
R2 is R21, where R21 is optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R3, R5, R6, and R7 are H; and n=1.

19. The compound of claim 18, wherein R21 is optionally substituted heteroaryl.

20. The compound of claim 19, wherein 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.

21. The compound of claim 1, wherein said compound is a compound of Formula Ia, Ib, Ic, Id, X, or XIV.

22. A pharmaceutical composition comprising a compound having the chemical structure of Formula I, namely wherein U, V, W, X, and Y are independently N or CR8, where 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 either of the rings of said bicyclic ring structure;
R1 is a carboxyl group or ester thereof or a carboxylic acid isostere;
R2 is hydrogen, optionally substituted lower alkyl, -CH2-CR12= CR13R14, -CH2-C.ident.CR15, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)NR10R11, -C(Z)R20, -S(O)2NR10R11;
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 mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;
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.ident.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)2NR10R11, or -S(O)2R21;
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 mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;
R12, R13, R14, and R15 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, -CH2-CR12= CR13R14, -CH2-C.ident.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, -CH2-CR12= CR13R14, -CH2-C.ident.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 said compound is different from 3-(5-methoxy-1-p-toluenesulfonylindol-3-yl)propionic acid and 1-(2,4,6-triisopropylphenylsulfonyl)indole-3-propionic acid; and a pharmaceutially acceptable carrier.

23. The pharmaceutical composition of claim 22, wherein R2 is SO2R21; and R21 is optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl.

24. The pharmaceutical composition of claim 23, wherein R21 is selected from the group consisting of substituted aryl, optionally substituted aralkyl, substituted heteroaryl, or optionally substituted heteroaralkyl, wherein said substitution on 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 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-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino.

25. The pharmaceutical composition of claim 23, wherein said R21 is selected from the group consisting of substituted aryl, optionally substituted aralkyl, substituted heteroaryl, or optionally substituted heteroaralkyl, wherein said substitution on 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 of claim 22, wherein said compound has a structure of Formula Ie, namely:
wherein R4 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 fused ring with the phenyl ring.

27. The pharmaceutical composition of claim 26, wherein R4 is alkoxy and R24 and R25 are chloro.

28. The pharmaceutical composition of claim 26, wherein R4 is alkoxy and R24 and R25 are fluoro.

29. The pharmaceutical composition of claim 26, wherein R4 is alkoxy and R24 is alkoxy.

30. The pharmaceutical composition of claim 26, wherein R4 is alkoxy and R24 is alkyl.

31. The pharmaceutical composition of claim 26, wherein R24 or R25 or both are are methyl, ethyl, propyl, butyl, or pentyl.

32. The pharmaceutical composition of claim 26, wherein R4 is methoxy or ethoxy and R24 and R25 are chloro.

33. The pharmaceutical composition of claim 26, wherein R4 is methoxy or ethoxy and R24 is alkoxy.

34. The pharmaceutical composition of claim 26, wherein R4 is methoxy or ethoxy and R24 is alkyl.

35. The pharmaceutical composition of claim 26, wherein R24 and R25 are not both alkyl.

36. The pharmaceutical compositiion of claim 22, wherein Y and X are CH;
R21 is optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R3, R5, R6, and R7 are H; and n=1.

37. The compound of claim 36, wherein R21 is optionally substituted heteroaryl.

38. The pharmaceutical composition of claim 37, wherein 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 of claim 36, wherein said compound is a compound of Formula Ia, Ib, Ic, Id, Ie, X, or XIV.

40. A method for treating a patient suffering from or at risk of a disease or condition for which PPAR modulation provides a therapeutic benefit, comprising administering to said patient a PPAR modulator having the chemical structure of Formula I, namely wherein U, V, W, X, and Y are independently N or CR8, where 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 either of the rings of said bicyclic ring structure;
R1 is a carboxyl group or ester thereof or a carboxylic acid isostere;
R2 is hydrogen, optionally substituted lower alkyl, -CH2-CR12=CR13R14, -CH2-C.ident.CR15, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)NR10R11, -C(Z)R20, -S(O)2NR10R11;
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 mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;

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.ident.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)2NR10R11, or -S(O)2R21;
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 mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;
R12, R13, R14, and R15 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, -CH2-CR12= CR13R14, -CH2-C.ident.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, -CH2-CR12= CR13R14, -CH2-C.ident.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 said compound is different from 3-(5-methoxy-1-p-toluenesulfonylindol-3-yl)propionic acid and 1-(2,4,6-triisopropylphenylsulfonyl)indole-3-propionic acid.

41. The method of claim 40, wherein said compound is a compound of Formula Ia, Ib, Ic, Id, Ie, X, or XIV.

42. The method of claim 40, wherein said compound is a compound listed in Table 1.

43. The method of claim 40, wherein said compound is approved for administration to a human.

44. The method of claim 40, wherein said disease or condition is a PPAR-mediated disease or condition.

45. The method of claim 40, wherein said disease or condition is selected from the group consisting of 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, a diabetic complication of neuropathy, nephropathy, retinopathy or cataracts, hypertension, coronary heart disease, heart failure, hypercholesterolemia, inflammation, thrombosis, congestive heart failure, cardiovascular disease, atherosclerosis, arteriosclerosis, hypertriglyceridemia, eczema, psoriasis, cancer, and conditions associated with the lung and gut and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia and anorexia nervosa.

46. The method of claim 40, wherein 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. A kit comprising a pharmaceutical composition according to claim 22.

48. The kit of claim 47, wherein said compound is a compound of Formula Ia, Ib, Ic, Id, Ie, X, or XIV.

49. The kit of claim 47, wherein said compound is a compound listed in Table 1.

50. The kit of claim 47, further comprising a written indication that said composition is approved for administering to a human.

51. The kit of claim 50, wherein 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, Type II diabetes mellitus, 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 gut and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia and anorexia nervosa.

52. The kit of claim 50, wherein 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.

53. A method for developing an improved modulator active on a PPAR, comprising determining whether any of a plurality of test compounds having the chemical structure of Formula I, namely wherein U, V, W, X, and Y are independently N or CR8, where 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 either of the rings of said bicyclic ring structure;
R1 is a carboxyl group or ester thereof or a carboxylic acid isostere;
R2 is hydrogen, optionally substituted lower alkyl, -CH2-CR12= CR13R14, -CH2-C.ident.CR15, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)NR10R11, -C(Z)R20, -S(O)2NR10R11;
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 mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;
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.ident.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)2NR10R11, or -S(O)2R21;
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 mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;
R12, R13, R14, and R15 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, -CH2-CR12=CR13R14, -CH2-C.ident.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, -CH2-CR12=CR13R14, -CH2-C.ident.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 said compound is different from 3-(5-methoxy-1-p-toluenesulfonylindol-3-yl)propionic acid and 1-(2,4,6-triisopropylphenylsulfonyl)indole-3-propionic acid provides an improvement in one or more desired pharmacologic properties relative to a reference compound active on said PPAR; and selecting those compound(s) if any, that have an improvement in said desired pharmacologic property, thereby providing an improved modulator.

54. The method of claim 53, wherein said desired pharmacologic property is PPAR pan-activity.

55. The method of claim 54, wherein said desired property is PPAR pan-agonist activity.

56. The method of claim 55, wherein said reference compound is a compound of Formula I-1.

57. The method of claim 56, wherein at least one derivative of said improved modulator is used as a test compound and said determining and selecting are repeated.

58. A method of designing a ligand that binds to at least one member of the PPAR
protein family, comprising identifying as molecular scaffolds one or more compounds that bind to a binding site of a PPAR with low affinity;

determining the orientation of the one or more molecular scaffolds at the binding site of the PPAR by obtaining co-crystal structures of the molecular scaffolds in the binding site; and identifying one or more structures of at least one scaffold molecule that, when modified, provide a ligand having altered binding affinity or binding specificity or both for binding to the PPAR as compared to the binding of the scaffold molecule.

59. The method of claim 58, wherein said one or more molecular scaffolds bind with low affinity to a plurality of PPARs.

60. The method of claim 58, wherein said one or more molecular scaffolds bind with very low affinity to a plurality of PPARs.

61. The method of claim 58, wherein the ligand is prepared at least in part by chemical synthesis.

62. The method of claim 58, further comprising assaying a plurality of distinct compounds for binding to the binding site of the PPAR.

63. The method of claim 58, further comprising isolating co-crystals of the molecular scaffolds bound to the PPAR, and determining the orientation of the molecular scaffold by performing X-ray crystallography on the co-crystals.

64. The method of claim 58, further comprising identifying common chemical structures of the molecular scaffolds and placing the molecular scaffolds into groups based on having at least one common chemical structure; and determining the orientation of the one or more molecular scaffolds at the binding site of the PPAR for at least one representative compound from a plurality of groups.

65. The method of claim 58, wherein the ligand binds to the target molecule with greater binding affinity or greater binding specificity or both than the molecular scaffold.

66. The method of claim 58, wherein the orientation of the molecular scaffold is determined by nuclear magnetic resonance in co-crystal structure determination.

67. The method of claim 58, wherein the plurality of distinct compounds are each assayed for binding to a plurality of members of the PPAR family.

68. The method of claim 62, wherein the distinct compounds have a molecular weight of from about 100 to about 350 daltons.

69. The method of claim 62, wherein the distinct compounds have a molecular weight of from about 150 to about 350 daltons.

70. The method of claim 62, wherein the distinct compounds comprise a ring structure.

71. The method of claim 64, further comprising grouping the compounds into classes based on common chemical structures and selecting a representative compound from a plurality of the classes for performing X-ray crystallography on co-crystals of the compound and target molecule, after the identification of common chemical structures of the distinct compounds that bind.

72. The method of claim 69, wherein the distinct compounds are selected based on criteria selected from the group consisting of molecular weight, clogP, and the number of hydrogen bond donors and acceptors.

73. The method of claim 72, wherein the clog P is less than 2, and the number of hydrogen bond donors and acceptors is less than 5.

74. The method of claim 62, wherein the assay is an enzymatic assay.

75. The method of claim 71, wherein the number of classes is at least 200.

76. The method of claim 58, wherein the modification is the addition, subtraction, or substitution of a chemical group.

77. The method of claim 58, wherein the modification causes the ligand to be actively transported to particular cells and/or a particular organ.

78. The method of claim 58, wherein the modification of the compound comprises the addition or subtraction of a chemical group selected from the group consisting of:
hydrogen, alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, fluoroalkyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenylthio, phenyl, phenylalkyl, phenylalkylthio, hydroxyalkyl-thio, alkylthiocarbamylthio, cycloalkyl, pyridyl, piperidinyl, piperizinyl, morphinolinyl, alkylamino, amino, sulphonamide, urea, thiourea, nitro, mercapto, cyano, hydroxyl, a halogen atom, halomethyl, an oxygen atom (forming a ketone or N-oxide) and a sulphur atom (forming a thione).

79. The method of claim 63, further comprising providing information provided by performing X-ray crystallography on the co-crystals to a computer program, wherein the computer program provides a prediction of changes in the interaction between the molecular scaffold and the PPAR that result from specific modifications to the molecular scaffold, and chemically modifying the molecular scaffold based on the prediction of the biochemical result.

80. The method of claim 79, wherein the computer program provides the prediction based on a virtual assay selected from the group consisting of:
virtual docking of the compound to the protein, shape-based matching, free energy perturbations, and three-dimensional pharmacophore.

81. The method of claim 58, wherein a ligand is provided that fills a void volume in the protein-ligand complex when a chemically tractable structure of the compound is modified.

82. The method of claim 58, wherein an attractive ionic charge is produced in the protein-ligand complex when a chemically tractable structure of the compound is modified.

83. The method of claim 58, wherein the modification results in a sub-structure of the ligand being present in a binding pocket of the protein binding site when the protein-ligand complex is formed.

84. The method of claim 63, further providing that after identifying the common chemical structures of the compounds that bind, the compounds are grouped based on comprising a common chemical sub-structure and a representative compound from a plurality of groups is selected for co-crystallization with the protein and performance of the X-ray crystallography.

85. The method of claim 63, wherein the X-ray crystallography and the modification of a chemically tractable structure of the compound are each performed a plurality of times.

86. The method of claim 58, wherein said molecular scaffold binds to said PPAR
with very low affinity.

87. The method of claim 58, further comprising identifying conserved residues in said binding sites that interact with said molecular scaffold.

88. The method of claim 87, wherein identifying conserved residues comprises identifying binding site residues that are identical for a plurality of members of said PPAR
family in sequence alignments of said plurality of members.

89. The method of claim 88, wherein identifying conserved residues that interact with said molecular scaffold comprises identifying conserved residues within 5 angstroms of said molecular scaffold in a co-crystal of said molecular scaffold and PPAR.

90. The method of claim 58, further comprising providing at least one said ligand.

91. A method of designing a ligand that binds to at least one PPAR that is a member of the PPAR family, comprising, identifying as molecular scaffolds one or more compounds that bind to binding sites of a plurality of members of the PPAR family;

determining the orientation of the one or more molecular scaffolds at the binding site of the PPAR to identify chemically tractable structures of the scaffolds that, when modified, alter the binding affinity or binding specificity between the scaffold and the PPAR;

synthesizing a ligand wherein one or more of the chemically tractable structures of the molecular scaffold is modified to provide a ligand that binds to the PPAR
with altered binding affinity or binding specificity.

92. The method of claim 91, wherein said molecular scaffold binds to said PPAR
with low affinity.

93. The method of claim 91, wherein said molecular scaffold binds to said PPAR
with very low affinity.

94. The method of claim 91, wherein said molecular scaffold binds to said PPAR
with extremely low affinity.

95. The method of claim 91, wherein said molecular scaffold binds to said PPAR
with moderate affinity.

96. The method of claim 91, further comprising isolating co-crystals of the molecular scaffolds bound to the PPAR, and determining the orientation of a molecular scaffolds at the binding site of the protein by performing X-ray crystallography on the co-crystals.

97. The method of claim 91, further comprising identifying common chemical structures of the molecular scaffolds are identified and placing the molecular scaffolds into groups based on having at least one common chemical structure; and determining the orientation of the one or more molecular scaffolds at the binding site of the PPAR for at least one representative compound from each group.

98. The method of claim 91, wherein the ligand binds to the PPAR with greater binding affinity or binding specificity than the molecular scaffold.

99. The method of claim 91, wherein the orientation of the molecular scaffold is determined by nuclear magnetic resonance.

100. The method of claim 91, wherein a plurality of distinct compounds are each assayed for binding to a plurality of members of the PPAR family.

101. The method of claim 100, wherein the distinct compounds have a molecular weight of from about 100 to about 350 daltons.

102. The method of claim 100, wherein the distinct compounds have a molecular weight of from about 150 to about 350 daltons.

103. The method of claim 100, wherein the distinct compounds comprise a ring structure.

104. The method of claim 100, wherein at least about 5% of the compounds bind with low affinity.

105. The method of claim 100, wherein at least about 10% of the compounds bind with low affinity.

106. The method of claim 97, further comprising grouping the compounds into classes based on common chemical structures after the identification of common chemical structures of the distinct compounds that bind, and selecting a representative compound from a plurality of the classes for performing the X-ray crystallography.

107. The method of claim 100, wherein the distinct compounds are selected based on criteria selected from the group consisting of: molecular weight, clogP, and the number of hydrogen bond donors and acceptors.

108. The method of claim 107, wherein the molecular weight is from about 150 to about 350 daltons, the clog P is less than 2, and the number of hydrogen bond donors and acceptors is less than 5.

109. The method of claim 91, further comprising assaying the activity of said ligand.

110. The method of claim 106, wherein the number of groups is at least 200.

111. The method of claim 91, wherein the modification is the addition, subtraction, or substitution of a chemical group.

112. The method of claim 91, wherein the modification causes the scaffold to be actively transported to particular cells or a particular organ or both.

113. The method of claim 91, wherein the modification of the compound comprises the addition or subtraction of a chemical group selected from the group consisting of: hydrogen, alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenylthio, phenyl, phenylalkyl, phenylalkylthio, hydroxyalkyl-thio, alkylthiocarbbamylthio, cyclohexyl, pyridyl, piperidinyl, alkylamino, amino, nitro, mercapto, cyano, hydroxyl, a halogen atom, halomethyl, an oxygen atom (forming a ketone or N-oxide) and a sulphur atom (forming a thione).

114. The method of claim 96, further comprising providing information obtained by performing X-ray crystallography on the co-crystals to a computer program, wherein the computer program provides a prediction of changes in the interaction between the molecular scaffold and the protein that result from specific modifications to the molecular scaffold; and chemically modifying the molecular scaffold based on the prediction of the biochemical result.

115. The method of claim 114, wherein the computer program provides the prediction based on a virtual assay selected from the group consisting of virtual docking of the compound to the protein, shape-based matching, free energy perturbations, and three-dimensional pharmacophore.

116. The method of claim 91, wherein a ligand is provided that fills a void volume in the protein-ligand complex when a chemically tractable structure of the compound is modified.

117. The method of claim 91, wherein an attractive ionic charge is produced in the protein-ligand complex when a chemically tractable structure of the compound is modified.

118. The method of claim 91, wherein the modification results in a sub-structure of the ligand being present in a binding pocket of the protein binding site when the protein-ligand complex is formed.

119. The method of claim 97, wherein the compounds are grouped based on comprising a common chemical sub-structure after identifying the common chemical structures of the compounds that bind, and selecting a representative compound from each group for co-crystallization with the protein and performance of the X-ray crystallography.

120. The method of claim 97, wherein the X-ray crystallography and the modification of a chemically tractable structure of the compound are each performed a plurality of times.

121. The method of claim 91, further comprising identifying conserved residues in said binding sites that interact with said molecular scaffold.

122. The method of claim 91, wherein identifying conserved residues comprises identifying binding site residues that are identical for a plurality of members of said PPAR
family in sequence alignments of said plurality of members.

123. The method of claim 121, wherein identifying conserved residues that interact with said molecular scaffold comprises identifying conserved residues within 5 angstroms of said molecular scaffold in a co-crystal of said molecular scaffold and PPAR.

124. A method for identifying binding characteristics of a ligand of a PPAR, comprising identifying at least one conserved interacting residue in said PPAR that interacts with at least two binding molecules; and identifying at least one common interaction property of said at least two binding molecules with said conserved residue, thereby identifying at least one said characteristic.

125. The method of claim 124, wherein identifying at least one conserved interacting residue comprises comparing a plurality of amino acid sequences in the PPAR
family and identifying binding site residues conserved in said family.

126. The method of claim 124, wherein identifying at least one conserved interacting residue comprises identifying conserved residues within 5 angstroms of said at least two binding molecules in co-crystals of said binding molecules and PPAR.

127. The method of claim 124, wherein said interaction property is selected from the group consisting of hydrophobic interaction, charge-charge interaction, hydrogen bonding, charge-polar interaction, polar-polar interaction, and combinations thereof.

128. A method for identifying energetically allowed sites on a PPAR binding compound for attachment of an additional component, comprising analyzing the orientation of said binding compound in a PPAR binding site, thereby identifying accessible sites on said compound of said additional component.

129. The method of claim 128, further comprising calculating the free energy cost of attachment of said additional component at one or more of said accessible sites.

130. The method of claim 128, wherein said orientation is determined by co-crystallography.

131. The method of claim 128, wherein said additional component comprises a linker.

132. The method of claim 128, wherein said additional component comprises a label.

133. The method of claim 128, wherein said additional component comprises a solid phase material.

134. A method for attaching a PPAR binding compound to an attachment component at an energentically allowed site, comprising identifying energetically allowed sites for attachment of a said attachment component on a binding compound; and attaching said compound or derivative thereof to said attachment component at said energetically allowed site.

135. The method of claim 134, wherein said attachment component is a linker for attachment to a solid phase medium, and said method further comprises attaching said compound or derivative to a solid phase medium through said linker attached at a said energetically allowed site.

136. The method of claim 135, wherein said linker is a traceless linker.

137. The method of claim 134, wherein said binding compound or derivative thereof is synthesized on said linker attached to said solid phase medium.

138. The method of claim 137, wherein a plurality of said compounds or derivatives are synthesized in combinatorial synthesis.

139. The method of claim 135, wherein attachment of said compound to said solid phase medium provides an affinity medium.

140. The method of claim 134, wherein said attachment component comprises a label.

141. The method of claim 140, wherein said label comprises a fluorophore.

142. A method for making an affinity matrix comprising a PPAR binding compound, comprising identifying energetically allowed sites on a PPAR binding compound for attachment to a solid phase matrix; and attaching said PPAR binding compound to said solid phase matrix through a said energetically allowed site.

143. The method of claim 142, further comprising determining the orientation of said PPAR binding compound in a binding site in a PPAR to which said compound binds.

144. The method of claim 142, wherein identifying energetically allowed sites comprises calculating the change in free energy for attachment of said PPAR
binding compound to said solid phase matrix.

145. The method of claim 142, wherein said PPAR binding compound is attached to said solid phase matrix through a linker.

146. The method of claim 142, wherein said solid phase matrix is selected from the group consisting of gel, bead, plate, chip, and well.

147. The method of claim 142, wherein identifying energetically allowed sites for attachment to a solid phase matrix is performed for at least 10 different compounds.