Ppar active compounds, pharmaceutical compositions comprising them and uses thereof for preparing medicaments

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 PPAR5.

[0004] There are two PPARy isoforms expressed at the protein level in mouse and human, γΐ and γ2. 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 PPAR5 was cloned in the early 1990s and subsequently cloned from rodents. PPAR5 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 PPARresponsive 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 PP.RE as a heterodinier 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. & Ther., 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 peioxisome 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, hi 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, angiogenesis,and cancer.

WO 2005/00995:

[0009] Among the synthetic ligands identified for PPARs are Thiazolidinediones (TZDs). These compounds were originally developed on the basis of their insulinsensitizing 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 PPARy interacted with a regulatory element of the aP2 gene that controlled its adipocytespecific expression. On the basis of these seminal observati ons, 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 in vivo insulinsensitizing 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 PPARy 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 Tech. & Ther., 4:163174).

[00.11] The fibrates, amphipathic carboxylic acids that have been proven useful in the treatment of hypertriglyceridemia, arePPARa ligands. The prototypical member of this compound class, clofibrate, was developed prior to the identification of PPARs, using in **‘יvivo assays in rodents to assess lipid-lowering efficacy. (Bergen & Wagner, 2002, Diabetes Tech. & Ther., ΑΛΝΙΛΊA).

[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 lipidlowering activity.

WO 2005/009958 PCT/US2004/023234

[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 PPARy/a agonist (Fajas, 1997, J. Biol. Chem., 272:18779-18789) DRF-2725 and AZ-242 are non-TZD dual PPARy/a agonists. (Lohray, et al., 2001, J. Med. Chem., 44:2675-2678; Cronet, et al., 2001, Structure (Camb.) 9:699-706).

[0015] In order to define the physiological role of PPAR5, efforts have been made to develop novel compounds that activate this receptor in a selective maimer. Amongst the a-substituted carboxylic acids previously described, the potent ΡΡΑΚδ ligand L-165041 demonstrated approximately 30-fold agonist selectivity for this receptor over PPARy; it was inactive on murine PPARa (Liebowitz, et al/ 2000, FEBSLett., 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 PPAR5 agonist that produced beneficial changes in serum lipid parameters in obese, insulin-resistant rhesus monkeys. (Oliver et al., 2001, Proc. Natl. Acad. Sci., 98:5306-5311).

[0016] In addition to the compounds above, certain thiazole derivatives active on PPARs have been described. (Cadilla et al., Ihtemat. Appl. PCT/US01/149320, Ihtemat. Publ. W) 02/062774, incorporated herein by reference in its entirety.) *ft'

[0017] Some tricyclic-a-alkyloxyphenylpropionic acids were described as dual

.«.‘יי

PPARa/γ 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/γ/δ was described in Morgensen et al., 2002, &Med. Chem. Lett. 13:257-260.

[0019[ Oliver et al., described a selective PPAR8 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. !,lines 16-19.)

[0021] Kato et al., European patent application 94101551.3, Publication No. 0 610 793

Al, describes the use of 3-(5-methoxy-l-p- toluenesulfonylindol-3-yl)propionic acid (page 6) and 1-(2,3,6- triisopropylphenylsulfonyl)-indole-3-propionic acid (page 9) as the intermediates in the synthesis of particular tetracyclic morpholine derivatives.

SUMMARY OF THE INVENTION

In one aspect of the invention there is provided a compound of Formula I,

R¹

<img file="IL173079A_D0001.tif" />

Formula I or a pharmaceutically acceptable salt thereof, wherein:

U, V, W, X, and Y are independently CR⁸;

R¹ is -C(O)OR or a carboxylic acid isostere, wherein R is hydrogen, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl wherein substituted lower alkyl is a straight chain alkyl, branched alkyl, or cycloalkyl group substituted with 1 to 3 groups or substituents selected from the group -------consisting—of—hater־hydroxyl—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 and heteroarylcarbonylamino;

R²is -S(O)2R²¹;

R⁶ and R⁷ are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally

01646801\81-01 substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, or R⁶ and R⁷ combine to form a monocarbocyclic 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=CR¹⁵, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR⁹, -SR⁹, -NR¹⁰Rⁿ, -C(Z)NR¹⁰R״, -C(Z)R²⁰, -S(O)2NR¹⁰Rⁿ, 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, R³׳, R⁴׳, 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^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-OCR^1־, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or aryl, wherein aryl is optionally substituted with 1 to 3 groups or substituents independently selected from the group consisting of halo, hydroxyl, optionally substituted lower alkoxy, optionally substituted lower alkyl, alkylthio, acetylene, amido, carboxyl, optionally substituted aryl, a 173079/1 optionally substituted aryloxy, optionally substituted aralkoxy, heterocycle, optionally substituted heteroaryl, nitro, cyano, thiol, sulfamido, alkylsulfinyl, alkylsulfonyl, acyloxy, heteroaryloxy, amino mono-substituted with aryl or heteroaryl groups 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, and heteroarylcarbonylamino;

Z is O or S; and n= 1, wherein said compound is different from 3-(5-methoxy-l-p-toluenesulfonylindol-3yl)propionic acid and l-(2,4,6-triisopropylphenylsulfonyl)indole-3-propionic acid.

In another aspect there is provided a pharmaceutical composition comprising a compound according to the invention and a pharmaceutically acceptable carrier.

In a further aspect there is provided a kit comprising a pharmaceutical composition according to the invention.

Yet in a further aspect there is provided a compound of Formula I,

<img file="IL173079A_D0002.tif" />

or a pharmaceutically acceptable salt thereof, wherein:

X, and Y are independently CR⁸;

U is CR⁸, wherein R⁸ is R⁵;

V is CR⁸, wherein R⁸ is R⁴;

b173079/1

W is CR⁸, wherein R⁸ is R³;

R¹ is a carboxyl group or ester thereof or a carboxylic acid isostere;

R² is-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 monocarbocyclic or mono-heterocyclic 5- or 6-membered ring system;

R³, R⁵ and each R⁸ are independently hydrogen, halo, optionally substituted lower alkyl, -CH2-CR¹²=CR^I3R¹⁴, optionally substituted cycloalkyl, optionally substituted monofluoroalkyl, optionally substituted difluoroalkyl, optionally substituted trifluoroalkyl, trifluoromethyl, -CH2-O=CR¹⁵, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR⁹, SR⁹, -NR¹⁰R^״, -C(Z)NR¹⁰R”, -C(Z)R²⁰, -S(O)2NR¹⁰R^״, or -S(O)₂R²¹;

R⁴ is halo, optionally substituted lower alkyl, -CH2־CR¹²=CR^I3R¹⁴, optionally substituted cycloalkyl, optionally substituted monofluoroalkyl, optionally substituted difluoroalkyl, optionally substituted trifluoroalkyl, trifluoromethyl, CH2־C=CR¹⁵, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR⁹, -SR⁹, -NR¹⁰Rⁿ, -C(Z)NR^1OR^U, -C(Z)R²⁰, -S(O)₂NR׳°R¹¹, 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 R^1:> 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;

c 173079/1

R²⁰ is optionally substituted monofluoroalkyl, trifluoromethyl, optionally substituted difluoroalkyl, -CH2־CR¹²=CR^I3R¹⁴, -CH2־C^CR¹⁵, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

R²¹ is optionally substituted lower alkoxy, -CH2־CR¹²=CR¹³R¹⁴, -CH2־C^CR¹⁵, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or aryl, wherein aryl is optionally substituted with 1 to 3 groups or substituents independently selected from the group consisting of halo, hydroxyl, optionally substituted lower alkoxy, optionally substituted lower alkyl, alkylthio, acetylene, amido, carboxyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aralkoxy, heterocycle, optionally substituted heteroaryl, nitro, cyano, thiol, sulfamido, alkylsulfinyl, alkylsulfonyl, acyloxy, heteroaryloxy, amino mono-substituted with aryl or heteroaryl groups 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, and heteroarylcarbonylamino;

Z is 0 or S; and n= 1, wherein said compound is different from 3-(5-methoxy-l-p-toluenesulfonylindol-3yl)propionic acid and l-(2,4,6-triisopropylphenylsulfonyl)indole-3-propionic acid.

In a further aspect there is provided the use of a PPAR modulator having the chemical structure of Formula I in the preparation of a medicament for treating a patient suffering from or at risk of a disease or condition for which PPAR modulation provides a therapeutic benefit.

DETAILED DESCRIPTION OF EMBODIMENTS

[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 d173079/2 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, PPAR6, 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=l, Y=CH, the R substituents except for R¹ as H, and with R¹ as -COOR. Similar scaffolds with each of the alternate selections for the indicated moieties (e.g., Y=N and/or n=0 or 2 and/or R¹ 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, PPAR6, and PPARy, where Formula I is:

<img file="IL173079A_D0003.tif" />

Formula I where:

5e

[0024] U, V, W, X, and Y are independently substituted N or CR^S, 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] R¹ 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, -CH2-CR¹²= CR^!3R¹⁴, -CH2CsCR¹⁵, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -C(Z)NR¹⁰R^״, -C(Z)R²⁰, -S(O)2NR¹⁰R^u; orS(O)2R²¹;

[0027] R 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 R⁷ combine to form a mono-carbocyclic or mono-heterocyclic 5- or 6-niembered ring system;

[0028] R^s is hydrogen, halo, optionally substituted lower allcyl, -CH2-CR¹²= CR¹³R¹⁴, optionally substituted cycloalkyl, optionally substituted monofluoroalkyl, optionally substituted difluoroalkyl, optionally substituted trifluoroalkyl, trifluoromethyl, -CH2CsCR¹⁵, optionally substituted hetero cyclo alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted hetero aralkyl, -OR⁹, -SR⁹, -NR¹⁰R^״, -Ο(Ζ)ΝΚ¹⁰Κ^1], -C(Z)R²⁰, -S(O)2NR¹⁰R^״, or-S(O)2R²¹;

[0029] R⁹is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo alkyl, optionally substi tuted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally s ubstituted hetero aralkyl;

[0030] R¹⁰ and R¹¹ are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or

WO 2005/009958 optionally substituted hetero aralkyl, or R¹⁰ and R¹¹ combine to form a mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;

[0031] R¹², R¹³, R^14, and R¹⁵ are independently optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted monofluoro alkyl, trifluoromethyl, optionally substituted difluoro allcyl, optionally substituted heterocycloalkyl, opti onally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted hetero aralkyl;

[0032] R is optionally substituted mono fluoroalkyl, trifluoromethyl, optionally substituted difluoroalkyl, -CH₂-CR¹²= CR¹³R¹⁴, -CH₂-C=CR¹⁵, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

[0033] R²¹ is optionally substituted lower alkoxy, -CH2-CR^I2=: CR¹³R¹⁴, -CH2-C^CR¹⁵, optionally substituted cycloalkyl, optionally substituted heterocyclo alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted hetero ar allcyl;

[0034] Z is O or S; and

[0035] n = 0,1,012־.

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

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

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

[0039] “Hydroxyl” refers to the group -OH.

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

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[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 containing from 1-15,1 to 8, 1-6,1-4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. The term “lower alkyl” is used herein to describe 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. Allcyl also includes a straight chain or branched alkyl group that contains or is interrupted by a cycloalkyl portion. The straight chain or branched allcyl grojrp 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, ammo optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with allcyl, 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” - alon® or in combination means a straight, branched, or cyclic hydrocarbon containing 2-20, 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 12, most preferably one, carbon to carbon double bond. Tn 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, alkylsulfmyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally -8WO 2005/009958 mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, amino sulfonyl optionally Nmono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, hetero arylsulfonyl amino, 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 01־ substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, hetero aryloxy, 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, 01־ 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, ^וor 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, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.

[0046] “Alkoxy” denotes the group -OR, where R is lower allcyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl as defined.

WO 2005/009958

[0047] “Alkylthio” or “thioalkoxy” denotes the group -SR, -S(O)_n=1-2־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 allcyl, 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, v־f״.

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 allcyl, substituted lower allcyl, 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-cyanamitfe, 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, -10WO 2005/009958 alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, hetero aryloxy, amino optionally mono- or di-substituted with alkyl, aryl or hetero aryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, amino sulfonyl optionally Nmono- or N,N-di-substiiuted with allcyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylammo, 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, nitro, cyano, thiol, sulfamido and the like.

*Φυ,

[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, nitro, cyano, thiol, sulfamido and the like.

[0058] “Heteroaryl” - alone or in combination means a monocyclic aromatic ring structure containing 5 or 6 ring atoma, 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, hetero aryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-disubstituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylammo, 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,

WO 2005/009958 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 subs tituted 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 attachment 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 01־ poly substituted with one or more functional groups, e.g., halogen, lower allcyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

>

[0061] “Aralkyl” refers to the group -R-Ar where At־ 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, nitro, 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, nitro, cyano, thiol, sulfamido and the like.

WO 2005/009958

[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, nitro, 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,dietaryl, substituted hetaryl, nitro, 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, nitro, 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, nitro, cyano, thiol, sulfamido and the like.

[0069] “Alkyl 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, alkylthio, amino, amido, carboxyl, acetylene, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

WO 2005/009958

[0070] hi certain embodiments involving compounds of Formula I, the compounds have a structure of Formula I in wlrich the bicyclic core shown for Formula I has one of the following structures:

<img file="IL173079A_D0004.tif" />

<img file="IL173079A_D0005.tif" />

<img file="IL173079A_D0006.tif" />

<img file="IL173079A_D0007.tif" />

<img file="IL173079A_D0008.tif" />

<img file="IL173079A_D0009.tif" />

WO 2005/009958

<img file="IL173079A_D0010.tif" />

[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 havin'g‘־an indolyl core; the compounds have one of the bicyclic cores above, and the substituents shown at the 5position are instead attached at the 6-position.

[0072] In certain embodiments involving compounds of Formula I, the compounds have a structure of Formula 11־, namely

<img file="IL173079A_D0011.tif" />

where:

[0073] R³, R⁴, and R⁵ are independently hydrogen, halo, trifluoromethyl, optionally substituted lower alkyl, -CH2־CR¹²= CR¹³R¹⁴, optionally substituted monofluoroalkyl, optionally substituted difluoroalkyl, optionally substituted trifluoroalkyl, -CH2-C=CR¹⁵, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted hetero aralkyl, -OR⁹, -SR⁹, -NR¹⁰Rⁿ, -C(Z)NR¹⁰Rⁿ, -C(Z)R²⁰, S(O)2NR¹⁰R^!i,or״S(O)₂R²¹.

[0074] In particular embodiments of the different aspects of the invention, including in certain embodiments, the compounds of Formula I are compounds of Formulas la, lb, Ic,

WO 2005/009958

Id, X, or XIV as shown in the Detailed Description. Also in particular embodiments, such compounds are compounds of Fonnula I with Y=N; with Y=CR⁸; with Y=CH; with all R substituents other than R¹, R², and R⁴ as H (for each of X as N, X as CH, and X as CR⁸);

with R⁶ and R⁷ as H (for each of X as N, X as CH, and X as CR⁸).

[0075] In certain embodiments, n=l; n=l and X and/or Y is CH; n=l, X and/or Y is CH, and R⁶ and R⁷ are H; n=l and X and/or Y=CR⁸.

[0076] In certain embodiments, n=l, R² is -S(O)2R²¹, with R²¹ being optionally substituted aryl or optionally substituted heteroaryl, hi certain embodiments, in which n=l, 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 ting; the aryl group is a 6membered 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 (meta), 4position (para), or 3- and 4-positions (meta 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 allcyl, the 4-position substituent is halo (e.g., fluoro or chloro), the 3- and 4-position substituents are fluoro, the 3- and 4position substitutents are chloro, one*of the 3- and 4-position substituents is fluoro and the other is chloro, the 3-posjtion 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 4position 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, hi 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, aryl, aryloxy, heteroaryl, hetero aryloxy, 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

WO 2005/009958 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] hi certain embodiments in which n=l, and R² is -S(O)2R²¹, with R²¹ being optionally substituted aryl or optionally substituted heteroaryl, R⁴ is different from H and alkoxy, or R⁴ is different from ΙΊ and OR⁹.

[0078] hi certain embodiments, n=2; n=2 and Xand/or Y is CH; n=2, X and/or Y is CH, and R⁶ and R^z are H; 11=2 and X and/or Y is CR⁸; n=2 and X and/or Y is N.

[0079] hi certain embodiments in which n=2, R⁴ is different from H, halo, alkyl, alkoxy, alkylthio; R⁴ is different from H, halo, C!_3 alkyl, C!_3 alkoxy, C!_3 alkylthio; R⁴ is different from C]_3 alkoxy; R⁴ is not methoxy. k

[0080] hi certain embodiments, 11=2, R² is -S(O)2R²¹, with R²¹ being optionally substituted aryl or optionally substituted heteroaryl. hi certain embodiments, in which 11=2, and R^ 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 6membered 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, hetero aryloxy, aryl 01־ heteroaryl substituted allcyl, and aryl or heteroaryl substituted alkoky; in further embodiments in which a 6-membered ring is substituted with halo or alkoxy, the ring is substituted at the 3-position (meta), 4position (para), or 3- and 4-positions (meta 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 4position 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 4position 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

WO 2005/009958 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 allcyl, 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 nng 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)₂R²¹, with R²¹ being a substituted aryl group with a 6-membe1־ed, 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=l and n=2.

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

<img file="IL173079A_D0012.tif" />

Formula le

[0084] where

WO 2005/009958

[0085] R‘¹ 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 (e.g., optionally substituted alkoxy, for example, methoxy, ethoxy) -SR⁹, -NR¹⁰Rⁿ,

-C(Z)NR¹⁰R^״, -C(Z)R²⁰, -SiOhKR‘!¹¹, or-S(O)₂R²¹;

[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 (!,fused ring with the phenyl group, e.g., benzofuran.

[0088] In particular embodiments, R⁴ is optionally substituted alkoxy (e.g., methoxy, 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] hi particular־ embodiments, R⁴ is optionally substituted alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy), optionally substituted allcyl (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 le, but with the phenyl ring to which Rⁱ⁴ and R²⁵ are attached as a heteroaryl ring. If the heteroaryl ring is a 5-membered ring, R²⁴ and R²⁵ are attached at the ring positions that are not adjacent to the atom linking to the sulfonyl group shown in Formula le.

[0091] In particular embodiments of compounds of Formula le, R⁴ is alkoxy and R²⁴ and R²־’ are chloro; R⁴ is alkoxy and R²⁴ and R²⁵ are fluoro^R⁴ is alkoxy and R²⁴ is alkoxy; R⁴is alkoxy and R²⁴ is alkyl; R⁴ is methoxy or ethoxy and R²⁴ and R²⁵ are chloro; R⁴ is methoxy 01־ ethoxy and R²⁴ is alkoxy; R⁴ is methoxy or ethoxy and R²⁴ is allcyl.

WO 2005/009958

[0092] In particular embodiments of compounds of Formula le, both of R²⁴ and R²⁵ are not alkyl; neither of R²⁴ and R²⁵ are allcyl; with R²⁴ as H, R²⁵ is not allcyl; with R²⁵ as H,

R²⁴ is not allcyl.

[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 thafijyould otherwise include such sub-group or sub-groups.

[0095] la particular embodiments of aspects involving compounds of Formula I, the compound is specific for PPARa; specific for PPAR5; specific for PPARy; specific for PPARa and PPAR5; specific for PPARa, and PPARy; specific for PPARS 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 subgroups of Formula I, e.g.״־»as described above or otherwise described herein.

[0097] A related aspect of tins 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] hi 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 io the mammal a therapeutically effective amount of a compound of Formula I, a prodrug of such compound, or a

WO 2005/009958 pharmaceutically acceptable salt of such compound or prodrag. 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, h}׳poalphalipoproteinemia, 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, PPAR5, or PPARy), selectivity on any two PPARs (PPARa and PPAR5, PPARa and PPARy, or PPAR5 and PPARy), serum half-life longer than 2 hr or longer than 4 hr or longer than 8 hi־, 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

WO 2005/009958 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, PPAR5, 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). hr 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.

WO 2005/009958

[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] .’ hi 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, hi some embodiments, the distinct compounds can have a ring structure, either a carbocyclic dr 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 (and/or has low activity), or at least about 10%, 15%, 0120%־ 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 compoundsscan be grouped into classes based on common chemical structures and at least one representative compound from at least one, or

«►‘י 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

WO 2005/009958 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 axe reported in the literature and can be used, e.g.:

(1) CAVEAT: Bartlett et al.,(1989), in Chemical ancfjriological 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. AidedMolec. Design 8:153.

(3) PRO Modulator: Clark et al., (1995), J. Comp. AidedMolec. Design 9:13.

(4) MCSS: Miranker and Karplus, (1991), Proteins: Structure, Function, and

Genetics 11:29.

(5) AUTODOCK: Goodsell and Olson, (1990), Proteins: Structure, Function, and

Genetics 8:195.

(6) GRID: Goodford, (1985), J. Med. Chem. 28:849.

2. Design 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 -44WO 2005/009958 favorable complementary interactions are attained. Compounds that have favorable scores are potential modulators.

3. Design by Modifying the Structure of Compounds that Bind a PPAR

[0196] A third method of structure-based modulator design is to screen compounds designed by a modulator building or modulator searciting 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 ISIS/HOST, ISIS/BASE, ISIS/DRAW) 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 searciting 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).

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[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] hi 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 are low molecular weight molecules that bind with low or very low affinity to the target and typically have low or very low activity on that target and/or act broadly across families of target molecules. The ability of a scaffold or other compound to act broadly across multiple members of a target family is advantageous 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.

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[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 common features can then be tested to determine if they retain binding and/or 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 200500־ 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 cocrystals 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 homolog is available for use in a homology model. Preferably the cocrystals 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, and/or (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 homology 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

01646801X85-01 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 tojsimplify 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 A².; 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 banner 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 prope1־ties to the library members, for example, causing the library

WO 2005/009958 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

WO 2005/009958 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 aid, 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

WO 2005/009958 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. 121:31321, 2000; Liparoto et al., Biosensor analysis of the interleukin-2 receptor complex, Journal of Molecular Recognition. 12:316-21, 1999; Lipschultz et al., Experimental design for analysis of complex kinetics using surface plasmon resonance, Methods. 20(3):310-8, 2000; Malmqvist., BIACORE: an affinity biosensor system for characterization of biomolecular interactions, Biochemical Society Transactions 27:33540,1999; Alfthan, Surface plasmon resonance biosensors as a tool in antibody engineering, Biosensors &amp; 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 MUC1 mucin. Tumour Biology 19 Suppl 1:1-20,1998; Malmqvist et al, Biomolecular interaction analysis: affinity biosensor technologies for functional analysis of proteins, Current Opinion in Chemical Biology’. 1:378-83, 1997; O’Shannessy et al., Interpretation of deviations from pseudo-first-order kinetic behavior in the characterization of ligand binding by biosensor technology, rtzzaZpizczz/BzOcAez/zzVzgr 236:275-83,1996; . Malmborg et al., BIAcore as a tool in antibody engineering, Journal of Immunological Methods. 183:7-13, 1995; VanRegenmortel, Use of biosensors to characterize recombinant proteins. Developments in Biological Standardization. 83:143-51, 1994; and O’Shannessy, Determination of kinetic rate and equilibrium binding constants for macromolecular interactions: a critique of the surface plasmon resonance literature, Current Opinions in Biotechnology. 5:65-71, 1994.

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[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 film, 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/mm . These changes are displayed with respect to time along the y-axis of a sensorgrani, 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 multi container earner 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 !mown in the art and commercially available.

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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 are 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 Suring Screening Assays

[0226] Techniques for measuring the progression of enzymatic and binding reactions, e.g., in multicontamer carriers, are !mown 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 Companion: A Handbook Of Practical Data, Techniques, Aid References, John Wiley and Sons, N.Y., 1972, Page 437.

[0228] Fluorescence spectrometry may be used to monitor the generation of reaction products. Fluorescence methodology is generally more sensitive than the absorption methodology. The use of fluorescent probes is well !mown to those skilled in the art. For reviews, see Bashford et al., Spectrophotometry and Spectrofluorometry: A Practical Approach, pp. 91-114, IRL Press Ltd. (1987); and Bell, Spectroscopy In Biochemistry, Vol. I, pp. 155-194, CRC Press (1981).

[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

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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, Η₂Ο₂, 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, tracerreceptor reagent. For a review, see Owickiet al., Application of Fluorescence Polarization Assays in High-Throughput Screening, Genetic 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 Enzymology 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.

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[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-difluoro5,7-dimethyl4־-bora-3a,4a-diaza-s-indacene- 3-pentanoyl)sphingosyl phosphocholine (BODIPY® FL C5-sphingomyelin); N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-sindacene- 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 C5־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, Hdmbrechtikon, 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. Enzymol. 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. Lipid Res. 38:2365-2373 (1997); Kahl et al., Anal. Biochem. 243:282-283 (1996); Undenfriend et al, Anal. Biochem. 161:494-500 (1987)). See also U.S. Patent Nos. 4,626,513 and 4,568,649, and European Patent No.

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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 Conn.). If a radiolabeled expression product binds to the target molecule, the radiolabel remains in proximity to the scintillant long 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 molebule. 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: AlphaScreen, Handbook of Drag Screening, Marcel Dekkar Pub. 2001, pp. 106-110.

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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 for 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 protein(s) of interest but do cause the scaffold to achieve 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 higli 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

WO 2005/009958 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, hi addition, cluster analysis based on relationships between the compounds, or structural components of the compound, can also be earned out to the same end; see Lance and Williams Computer Journal 9 (1967) 373380, 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 *bl* 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, hr 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. Ih 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 structure of previously characterized compounds and/or pharmacophores.

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[0245] Compound libraries may contain molecules isolated from natural sources, artificially synthesized molecules, or molecules synthesized, isolated, or otherwise prepared in such a maimer so as to have one 01־ 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, 6378-6382; Houghten et al., Nature 1991, 354, 84-86; Lam et al., Nature 1991, 354, 8.2-84; 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, 171183; 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, Combinatorial Chemistry &amp;High Throughput Screening. 2:299-318, 1999).

[0247] Libraries of a variety of types of molecules are 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

WO 2005/009958 al., Mol Divers 1998-99;4(1):318־, Solution-phase combinatorial chemistry, Sun, Comb Chem High Throughput Screen 1999 2(6):299-318, Recent advances in liquid-phase combinatorial chemistry); synthesis on soluble polymer (Gravert et al., Curr Opin Chem 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., J Comb Chem 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., Prog Drug Res 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):6339, Solid-phase combinatorial chemistry and novel tagging methods for identifying leads).

Ml׳«.

[0248] The combinatorial synthesis of carbohydrates and libraries containing oligosaccharides have been described (Schweizer et al., Curr Opin Chem Biol 1999 3(3):291-8, Combinatorial synthesis of carbohydrates). The synthesis of natural-product based compound libraries has been described (Wessjohann, Curr Opin Chem Biol 2000 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 then־ 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. Martinez 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 &amp; High Throughput 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 &amp; High Throughput Screening 3:167-83,2000; al-Obeidi, Mol

WO 2005/009958

Biotechnol 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 !mown 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 &amp; 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 TD. 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 ID., Selection of tumorspecific internalizing human antibodies from phage libraries. Source Journal of Molecular Biolog)>. 301:1149-61, 2000; Amersdorfer P. Marks JD., Phage libraries for generation of anti-botulinum scFv antibodies, Methods in Molecular Biology. 145:219-40, 2001;

Hughes-Jones NC. Bye JM. Gorick BD. Marks JD. Ouwehand WH., Synthesis of Rh Fv phage-antibodies using VH and VL germline genes, British Journal of Haematology.

105:811-6, 1999; McCall AM. Amoroso AR. Sautes C. Marks JD. Weiner LM., Characterization of anti-mouse Fc gamma RII single-chain Fv fragments derived from human phage display libraries, Immunotechnology. 4:71-87, 1998; Sheets MD. Amersdorfer P. Finnem R. Sargent P. Lindquist E. Schier R. Hemingsen G. Wong C. Gerhart JC. Marks JD. Lindquist E., Efficient construction of a large nonimmune phage antibody library: the production of high-affinity human single-chain antibodies to protein antigens (published erratum appears in Proc Natl Acad Sci US AT 999 96:795), Proc Natl Acad Sci USA 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

WO 2005/009958 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 ding design and estimation of ligand binding affinities (Joseph-McCarthy D., Computational approaches to structure-based ligand design, Pharmacology &amp; Therapeutics 84:179-91, 1999;

Kirkpatrick DL. Watson S. Ulhaq S., Structure-based drug design: combinatorial chemistry and molecular modeling, Combinatorial Chemistry & High Throughput Screening. 2:211-21, 1999; Eliseev AV. Lehn JM., Dynamic combinatorial chemistry: evolutionary formation and screening of molecular libraries, Current Topics in Microbiolog)> & 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 Journal 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 !mown desirable

WO 2005/009958 effects, such as iifoibiting 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.,

WO 2005/009958 both 4 and 20 degrees. In preferred embodiments, about 96 crystallization screening conditions can be performed in order to obtain sufficient information about the cocomplexation 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 medfttinal 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

WO 2005/009958 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 affinities.

[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, winch 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 coniplexation and concentration steps can conveniently be performed using a 96 well formatted concentration apparatus (e.g., A mi con 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 μΐ) 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

WO 2005/009958 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 f target, (e.g. Insight!!®, 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 crystallographic structure deteimination 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-67WO 2005/009958 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:

AGbmd = AGtr + AG'hb + AGion + AGlipo + AGarom + AGrot where: AGtr is a constant term that accounts for the overall loss of rotational and translational entropy of the lignand, AGlib accounts for hydrogen bonds formed between the ligand and protein, AGon accounts for the ionic interactions between the ligand and protein, AGlipo accounts, for the lipophilic interaction that corresponds to the proteinligand contact surface, AGarom accounts for interactions between aromatic rings in the protein and ligand, and AGrot 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 ofthe 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 biotin:

streptavidin complex.

[0271] Another exemplary method for calculating binding energies is the MM-PBSA technique (Massova and Kollman, Journal of the American Chemical Society 121:813343,1999; Chong et al, Proceedings of the National Academy of Sciences 96:14330-5,1999; Donini and Kollman, Journal of Medicinal Chemistry 43:4180-8,2000). This method uses a Molecular Dynamics approach to generate many sample configurations of the compound and complexed target molecule, then calculates an interaction energy using the well-known AMBER force field (Cornell, et al Journal of the American Chemical Society 117:5179-97 1995) with corrections for 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 cocrystal 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 samp- 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

01646801\85-01 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 discoveiy and design of dmgs 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. hi 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

WO 2005/009958 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. SitelD, 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 greatei־ 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 silica 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 modification 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, afkyloxy, alkylthio, alkenylthio, phenyl, phenylalkyl, phenylalkylthio, hydroxyalkyl-thio, alkylthiocarbamylthio, cyclohexyl, pyridyl, piperidinyl alkylamino, aminn, 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, dialkylsulfoxide 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 -ΝΧ2Χ3» where X2 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 -(X₅)_nCOOH or ester of formula (X₆)nCOOX7, where X₅, X6, and X₇ and are independently selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1; an alcohol of formula (Xg)_nOH or an alkoxy moiety of formula -(X8)_nOX9, where Xg and X₉ are independently selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more

01646801X85-01 substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester and where n is 0 or 1; an amide of formula NHCOX10, where X!_o 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; SO?, NXn X!₂, where X_nand X!2 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 allcyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; an aldehyde of fonnula ־COH; a sulfone of formula -SO2X13, where X₁₃ is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties; and a nitro of fonnula -NO2-

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 tins 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

WO 2005/009958 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. Tn 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 bin ding compound. Energetic cd’fts 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 maybe 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 CombiLibMaker, 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

WO 2005/009958 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 Journal 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 of Medicinal 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 Charifson, Journal of Medicinal Chemistr)/ 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).

י׳יו^,'’ (1) Linkers

[0285] Linkers suitable for use in the invention can be of many different type's. 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., 1995,7. Org. Chem., 60:6006.

WO 2005/009958

[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 Vol. 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 perfonnedaising 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, oyines, and pets such as dogs and cats.

WO 2005/009958

[0290] 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 kno wn 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, 18^th 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 d’fa compound without preventing it from exerting its physiological effect. Usefol 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, ptoluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric^cid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethaneSulfonic acid, benzenesulfonic acid,/)-toluenesulfonic acid,

^‘י.

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 Remington's Pharmaceutical Sciences, 19^th 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 -77WO 2005/009958 aqueous or aqueous-alcoliol 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-chlorotheophyllme complex (analogous to, e.g., dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrin inclusion complexes.

[0296] , Camers or excipients can be used to produce pharmaceutical compositions. The earners 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 injection (WEI), 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 sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, !־ice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/01 polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents maybe added, such as the cross—linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate.

[0299] Dragee cores are provided with suitable coatings. For this pufose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments maybe 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/or subcutaneous. 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. In 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 IC50, the biological half-life of the compound, the age, size, and weight of the patient, and the disorder

01646801\81-01 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.

*Gw

[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 Π 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 R⁵ are as specified for Formula I or a sub-generic description within Formula I. In synthetic Scheme la 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:

<img file="IL173079A_D0013.tif" />

Step !-Preparation of compound of formula IV:

[0307] Compound IV was prepared by reacting commercially available aldehyde ΙΠ 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. Pharm, 1988, 321, 377-83). Compound III, in turn, can be prepared by reacting compound V under Vilsmeier (POC13 and DMF) conditions as described by in March's Advanced Organic Chemistry, 5^th Edition, p.715.

Step 2 - Preparation of intermediate II:

[0308] Key intermediate Π 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, 37783).

Scheme lb:

[0309] Key intermediate II compounds can also be prepared in accordance with Scheme lb as shown below.

<img file="IL173079A_D0014.tif" />

Step 1 - Preparation of formula VI:

[0310] Compound VI was prepared conventionally by a reacting commercially available compound of formula V with an Ν,Ν-dialkyl amine hydrochloride in a polar solvent (e.g. iPropanol), in the presence of formaldehyde and heated, typically near 90 degrees centigrade, typically for 24h, as described by Snyder et al, JACS, 73, 970.

01646801\81-01

Step 2 - Preparation of formula VH:

[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 - Preparation of formula. la:

[0312] , Compound of formula la 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 II:

[0313] Intermediate II was prepared by Fisher esterification of compound la with alcohol (e. g. Methanol) and catalytic amount of an acid (e.g. HC1) under reflux, typically for 16-2411.

Scheme 1c:

[0M4] Compounds of Key Intermediate Π can also be prepared according to Scheme 1c as shown below.

<img file="IL173079A_D0015.tif" />

<img file="IL173079A_D0016.tif" />

<img file="IL173079A_D0017.tif" />

<img file="IL173079A_D0018.tif" />

!V ii

Step 1 - Preparation of formula VIII:

[0315] Compound VIII can be prepared by a reacting commercially available of a compound 01 formula V with bromine in an inert solvent (e.g. DMF) (Bocchi and Palla;

Synthesis, 1982, pl096).

Step 2 - Preparation of formula IV:

[0316] Compound IV can be prepared by a reacting compound of formula VIII with methacrylate under Heck coupling conditions as described by Sznaidman et. at, in 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 Aarati et. al in Arch. Pharm, 321,1988, 377- 83.

Synthesis of Compound la

[0318] Compounds of Formula la can be prepared by hydrolysis of Key Intermediate II as shown in Scheme Π.

Scheme 2

<img file="IL173079A_D0019.tif" />

« _________________________________________ la

[0319] Compound of formula la 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 Chemistry, 5^th Edition, p. 715.

Synthesis of Compound lb

[0320] Compounds of Formula lb, in which the indole ring is substituted at the 3- position (or corresponding position of the other bi-cyclic rings of Formula I), can be prepared according to Scheme 3.

01646801\81-01

Scheme 3

<img file="IL173079A_D0020.tif" />

II

<img file="IL173079A_D0021.tif" />

Step 1 - Preparation of compound offormula IXa:

[0321] Compound of formula IXa was prepared by treating intermediate of formula II with a base (e. g. sodium hydride) in an inert solvent Ν,Ν-Dimethylformamide, followed by the addition of R²W, where W is a leaving group (e.g. chloro, bromo), and stirring at RT, typically for 16 to 24 h (Jerry March in March 's Advanced Organic Chemistry, 5^th Edition, p576). The product was obtained by column chromatography (e. g. silica gel) after workup using conventional methods.

Step 2 - Preparation of compound offormula lb:

[0322] Compound of formula lb 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 1c

[0323] Compounds of Formula Ic, in which R² is R^I0R^״NCZ, can be prepared according to Scheme 4.

Scheme - 4

<img file="IL173079A_D0022.tif" />

__________01646801X76-01

Step 1 - Preparation of compound offormula IXb:

[0324] Compound of formula IXb was prepared by treating intermediate of formula Π 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 Marc 's Advanced Organic Chemistry, 5^th Edition, p 1191). 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 R¹⁰R¹¹NCZ.

Synthesis of Compound Id

Compounds of Formula Id can be prepared according to Scheme 5a.

Scheme - 5a

<img file="IL173079A_D0023.tif" />

<img file="IL173079A_D0024.tif" />

--------01646801X76-01

Step 1 - Preparation of compound of formula 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, 5^th Edition, p8) and heating the reaction mixture, typically 90° C, for 24 and isolating the product by conventional methods (e.g. aqueous Avork up and purification by chromatography).

[0329] . Compound of formula IXc Avas in turn prepared from commercially available compound of formula V, where “R⁴” is bromine, using the synthetic steps described in Scheme lb, 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 Avith 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 5b

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PCT/US2004/G23234

<img file="IL173079A_D0025.tif" />

Step 1 - Preparation of compound of formula V

[0331] Compound of fonnula V was prepared from commercially available compound of formula Va by reacting it with aryl boronic acids under Kumada reaction conditions as described by Hayashi, et. al, JACS, 106(1984), 158 —163, and heating the reaction mixture, typically 90° C, for 24 and isolating the product by conventional methods (e.g. aqueous *I work up and purification by chromatography).

Step 2 - Preparation of formula VI:

[0332] Compound VI was prepared conventionally by a reacting commercially available compound of formula V with an Ν,Ν-dialkyl amine hydrochloride in a polar solvent (e.g. i-Propanol), in the presence of formaldehyde and heated, typically near 90 °C, typically for 2411, as described previously for compound VI.

Step 3 - Preparation of formula HI:

[0333] Compound of fonnula VII was prepared by heating compound VI with diethyl malonate and a catalytic amount of sodium metal, typically at 120° C as described previously,, foil owed by flash chromatography purification.

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PCI7US2004/023234

Step 4 - Preparation of formula la:

[0334] Compound of formula la was prepared by hydrolyzing compound VII using aqueous base (e.g. NaOH) followed by the decarboxylation under reflux conditions as described previously.

Step 5 - Preparation of intermediate II:

[0335] , Intermediate II was prepared by Fisher esterification of compound la with alcohol (e. g. Methanol) and catalytic amount of an acid (e.g. HCI) under reflux, typically for 16-24h.

י.\י4ייי

Step 6 - Preparation of compound of formula IXd:

[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 “R²W”, 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 compound of formula. Ib:

[0337] Compound of fojjnula 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 . chromato graphy).

Synthesis of Compound X

Scheme 6

<img file="IL173079A_D0026.tif" />

Step -1 Preparation of Intermediate XI

[0338] Compound XI was prepared from the compound V reacting with γ-butyrolatone in an inert solvent with potassium hydroxide under reflux conditions, usually 4 to 24 hours, as described by Fritz et al, (J. Org. Chem., 1963, 28,1384-1385).

Step 2 - Preparation of Intermediate XII

[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 XIII

[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 R²W, where W is a leaving group (e.g. chloro, bromo), and stirring at RT, typically for 16 to 24 h (Jerry March in March ^,s Advanced Organic Chemistry, 5^th Edition, p576). The product was obtained by column chromatography (e. g. silica gel) after workup using conventional methods.

Step 4 - Preparation of intermediate X

-----------01646801\76-01

[0341] Compound of formula X was prepared by the hydrolysis of compound of formula ΧΙΠ with aqueous base (e. g. aq. NaOH), typically for 6-15 h and isolating the product by conventional methods (e.g. aqueous workup and purification by chromatography).

Synthesis of compound XIV

Scheme 7

<img file="IL173079A_D0027.tif" />

Step 1: Preparation of Intermediate XV

[0342] Compound XV can be prepared from the corresponding aldehyde HI reacting with a reducing 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 Tetrahedron Letters (1997,35,26452648־).

Step 3: Preparation of Intermediate XVII

01646801\85-01

[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 R²W, where W is a leaving group (e.g. chloro, bromo), and stirring at RT, typically for 16 to 24 h (Jerry March in

March's Advanced Organic Chemistry, 5^th Edition, p576). The product was obtained by column chromatography (e. g. silica gel) after workup using conventional methods.

Step 4 Preparation of intermediate XIV

[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 compounds 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-l -(4-methoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid,

- [5 -Ethyl-1 -(4-methoxy-benzenesulfonyl)- lH-indol-3-yl] -propionic acid, Indazole-3־propionic acid, 5-Isopropoxy-3-(l-Benzene-sulfonyl-indol-3-yl)-propionic acid, Indole-3 -propionic acid,

3-(1 -Benzenesulfonyl-5-methoxy-1 H-indol-3 -yl)-propionic acid,

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

-[ 1 -(3 -Chloro-benzyl)-5 -methoxy- 1 H-indol-3 -yl] -propionic acid, 3-[l-(4-Fluoro-benzyl)-5-methoxy-lH-indol-3-yl]-propionicacid, 3-[l-(4-Chloro-benzyl)-5-methoxy-lH-mdol-3-yl]-propionic acid,

- [5 -Methoxy-1 -(2-methoxy-benzyl)-1 H-indol-3 -yl] -propionic acid, 3-[5-Methoxy-l-(2-trifluoromethoxy-benzyl)-lH-indol-3-yl]-propionicacid, 3-[5-Methoxy-l-(3-trifh1oromethoxy-benzyl)-lH-indol-3-yl]-propionicacid, 3-(l-Ethylthiocarbamoyl5־-methoxy-lH-indol-3-yl)-propionic acid, 3-[5־Methoxy-l-(toluene-4-sulfonyl)־lH־indol3־-yl]־propionicacid, 3-(l-Benzenesulfonyl-lH-indazol-3-yl)-propionic acid,

- [ 1 -(4-Isopropyl-benzenesulfonyl)-5 -methoxy-1 H-indol-3 -yl] -propionic acid methyl ester,

01646801\85-01

3-[l-(4-Isopropyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid, 3-(l-(4-Butoxy-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester, 3-(l-(4-Butoxy-benzenesuIfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid, 3-[5-Methoxy־l-(4-trifluoromethoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid methyl ester, 3-[5-Methoxy-l-(4-trifluoromethoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid, 3-[5-Methoxy-l-(4-phenoxy-benzenesulfonyl)-lH-indol-3-yl]-propiomc acid methyl ester, 3-[5-Methoxy-l-(4-phenoxy-benzenesulfonyl)“lH-indol-3-yl]-propionic acid, 3-[l-(4-Chloro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester, 3-[l-(4-Chlor0-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid, 3-[l-(4-Cyano-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester, 3 - [ 1 - (4-Cyano-benzenesulfonyl)-5 -methoxy-1 H-indol-3-yl]-propionic acid, 3-(l-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-i^;H-indol-3-yl]-propionic acid methyl ester,

3-(1-(3,4-Dichloro-benzenesulfony 1)-5-methoxy-1.H-indol-3-yl]-propionic acid, 3-[5-Methoxy־l-(4-trifluoromethyl-benzenesulfonyl)-lH-indol-3-yl]-propionic acid methyl ester,

- [5 -Methoxy-1 -(4-trifluoromethyl-benzenesulfonyl)-1 H-indol-3 -yl] -propionic acid, 3-[l-(4-Fluoro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester, 3-(1 -(4-Fluoro-'benzenesulfonyl)-5-methoxy-1 H-indol-3 -yl] -propionic acid,

- (5-Methoxy-1 -(3 -phenoxy-benzene,sulfonyl)-1 H-indol-3 -yl]-propionic acid methyl ester, 3-(5-Methoxy-l-(3-phenoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid, 3-[l-(3-Fluoro-benzenesuifonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester, 3-(l-(3-Fluoro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid, 3-(5-Methoxy-l-(toluene-3-sulfonyl)-lH-indol-3-yl]-propionic acid methyl ester, 3-(5-Methoxy-l-(toluene-3-sulfonyl)-lH-indol-3-yl]-propionic acid, 3-(l-(3-Chlo1O-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester, 3-[l-(3-Chloro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid, 3-(5-Methoxy-l-(3-methoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid methyl ester, 3-[5-Methoxy-l-(3-methoxy-benzenesulfonyl)-lH־indol-3-yl]-propionic acid,

3-[5-Methoxy-1 -(3-trifluoromethyl-benzenesulfony 1)-1 H-indol-3-yl]-propionic acid methyl ester, 3-(5-Methoxy-l-(3-trifluoromethyl-benzenesulfonyl)-lH-indol-3-yl]-propionic acid, . 93 - 173079/3

3- (l-Benzyl-5-methoxy-lH-indol-3-yl)-propionic acid methyl ester, 3- (l-Benzyl-5 -methoxy- lH-indol-3-yl)-propionic acid, 3-[5-Methoxy-l-(thiophene-2-sulfonyl)-lH-indol-3-yl]-propionic acid methyl ester, 3-[5-Methoxy-l־(thiophene-2-sulfonyl)-lH-indol-3-yl]־propionic acid, 3-(5-Methoxy-l-phenylthiocarbamoyl-lH-indol-3-yl)-propionic acid methyl ester, 3-(5-Methoxy-1-phenylthiocarbamoyl-lH-indol-3-yl)-propionic acid, 3-[l.(4-Butyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester, 3.[l.(4-Butyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid, 3-[5-Methoxy-l-(3-trifluoromethoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid methyl ester, 3-[5-Methoxy-l-(3-trifluoromethoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid, 3-(l-Benzoyl-5-methoxy־lH-indol-3-yl)-propionic acid methyl ester, 3-(l-Benzoyl-5-methoxy-lH-indol-3-yl)-propionic acid, 3-(1 -Benzenesulfonyl-5-ethoxy-lH-indol-3-y !)-propionic acid, 3-[l-(44sopropoxy-benzenesulfonyl)-5-1nethoxy-lH-indol-3-yl]-propionicacid, 3-(5-Methoxy-l-phenylcarbamoyl-lH-indol-3-yl)-propionic acid me±yl ester, 3-(5-Methoxy-l-phenylcarbamoyl-lH-indol-3־yl)-propionic acid, 3-[l-(4-Ethyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid, 3-(5-Bromo-lH-indol-3-yl)-propionicacid, 3-(5-Bromo-lH-indol-3-yl)-propionic acid methyl ester, 3-(l-Benzenesulfonyl-5-bromo-lH-indol-3-yl)-propionic acid methyl ester, 3-(l-Benzenesulfonyl-5-bromo־lH-indol-3-yl)-propionic acid methyl ester, 3-(Benzenesulfonyl-5-thiophen-3-yl-lH-indol-3-yl)־propionic acid methyl ester, 3-(Benzenesulfonyl-5 -thiophen-3-yl-lH-indol-3-yl)-propionic acid, 3-(l-Benzenesulfonyl-5-phenyl-l H-indol-3-yl) propionic acid methyl ester, 3-(l-Benzenesulfonyl-5-phenyl-lH-indol-3-yl) propionic acid, 3-(lH-Pyrrolo[2,3 -b]pyridine-3-yl)-propionic acid, 3-(5-Methoxy-lH-Indol-3-yl)-propionicacid, 3-(l-Benzenesulfonyl-lH-indol-3-yl)-propionic acid, 3-(l-Benzenesulfonyl-5-methoxy-lH-indol-3-yl)-propionic acid methyl ester, 3-[5-Methoxy-l-(thiophene-3-sulfonyl)-lH-indol-3-yl]-propionic acid, (l-Benzenesulfonyl-5-methoxy-lH-indol-3-yl)-acetic acid.

EXAMPLES

01646801X88-01

Example 1: Bio-chemical Screening

[0347] The homogenous Alpha screen assay was used in the agonist mode to determine the ligand dependent interaction of tire PPARs (α,δ,γ) with the coactivator peptides (SRC or DRIP205). Briefly 15ul of the reaction mix (50mM Tris pH 7.5,50mM Kcl, 0.05% Tween 20,lmMDTT,0.1% BSA and 10nM-200nMPPAR and 1011M-200nM coactivator peptide) was added to the test compound (lul compound in DMSO) and preincubated for l-6hr.Next, 5ul of the Alpha screen beads were added. The reactions were incubated for 2 hrs before taking the reading in the Fusion alpha instrument, hi 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 (γ) and bezafibrate (PPAR (δ).

[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 μΜοΙ/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 EC50.

[0350] Anong those compounds, several have notable pan-activity at low micromolar or even sub-micromolar levels, for exarfiple, compounds 29, 43, and 53. In contrast, compound 6 is selective fpj PPARy, with activity on PPARy of approximately 8 micromolar and activity on PPARa and δ of at least 200 micromolar.

Example 2: Co-transfection assay

[0351] 293T cells were transfected for 4-5111111 ־ 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 molecule(s) at the cellular level.

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Example 3: Synthesis of

3-[5-methoxy-l-(4-methoxy-benzenesulfonyl)-lH-indol-3-yl]- propionic acid 1

[0353] Indole-3-propionic acid 1 was synthesized from the commercially available 5methoxyindole-3-carboxaldehye in four steps as shown in Scheme 7.

Scheme 7

<img file="IL173079A_D0028.tif" />

Step 1 - Preparation of 3-(5-Metho׳xy-lH-indol-3-yl)-acrylic acid methyl ester 3

[0354] To a cold solution (ice bath) of methyl phosphono acetate (13.74 g, 0.065 mol) in tetrahydro furan (120 mLJ'ttndei־ 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 tetrahydrofiiran (80 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 di chloromethane (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+l= 232.0).

Step 2 — Preparation of 3-(5-Methoxy-lH-indol-3-yl)~propionic acid methyl ester 4:

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[0355] To a solution of 3-(5-Methoxy-ll?-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 3f5-Methoxy-lf4-methoxy-benzenesulfonyl)-lH-indol-3~yl]propionic acid methyl ester 5:

[0356] To a cooled solution (0° C) of indole-3-propionic ac'i'd methyl ester 4 (0.797 g, 3.42mmol) 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 4methoxybenzenesulfonyl chloride (1.3 g; 6.31 mmol). The reaction was allowed to warm up to room temperahire 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 flashchromatography (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-l-(4-methoxy-benzenesulfonyl)-lH-indol-3-yl]~ propionic acid 1: ״*

[0357] To a solution of the methyl ester 5 (830 mg, 2.06 mmol) in tetrahydro furan (15 mL) was added an aqueous solution of potassium hydroxide (5 mL of IM) and stirred at room temperature for 5 h. The acid 1 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 (697.5 mg, 91%; M-l = 373.1).

Example 4: Synthesis of

3-[5-ethyl-l-(4-methoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid 6

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[0358] Indole-3-propionic acid 6 was synthesized from the commercially available 5bromo-indole 7 in eight steps as shown in Scheme 8.

Scheme 8

<img file="IL173079A_D0029.tif" />

Step 1 — Preparation of 5-Bromo-l-triisopropylsilaiiyl-lH-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 (T1PSC1; 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 H3PO4, and the organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash silica

chromatography (100% Hexanes) to give compound 8 as an oil (4.3 g; 96% yield; M+1 353.4)

Step 2 — Preparation of 5-Ethyl-l-triisopropylsHanyl-lH-indole 9.

[0360] The l-triisopropyl5־-bromoindole (3.0 g, 8.51 mmol) was combined with PdCl₂ (dppf) at -78°C and stirred for 5 minutes before Ethyl magnesium 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 H3PO4. The mixture was extracted with EtOAc and washed with brine, dried over MgSO4, 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-lH-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 H3PO4, dried over MgSO4, filtered and evaporated to give compound 10 as an off white solid (1.06 g; M + 1 = 146.2).

Step 4 —Preparation 0 f (5-Ethyl-lH-indol-3-ylmethyl)-dimethyl-amine 11.

[0362] 5-Ethylindole 10 (1.0 g, 6.89 mmol) was combined with isopropyl alcohol (200 mL), Ν,Ν-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 NaHCO₃. The organic layer was dried over MgSO4, 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 of 2-(5-Ethyl-lH-indol-3-ylmethyl)-malonic acid diethyl ester 12.

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[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% HCI (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 of 2-(5-Ethyl-lH-indol-3-ylmethyl)-malonic acid 13.

[0364] The crude diethyl malonylindole 12 (1.6,7 g, 5.26 mmol) was dissolved in THF (20 mL) and a solution of NaOH (1.0 g, 25.5 mmol) in ¾0 (20mL) was added. MeOH (5 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 / CHCfyMeOH. The organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated to give the erode diacid as a white solid (1.25 g; M -1 = 260.2). lire product was taken into the next step without purification.

Step 7 - Preparation of 3-.(f -Ethyl-lH-indol-3-y1)-propionic 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 CHC1₃ to give compound 14 as a solid (120 mg; 57.7 % yield; Μ- 1 = 216.3).

Step 8 - Preparation of 3-(l-Benzenesulfonyl-5-ethyl-lH-indol-3-yl)-propionic acid 6.

[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 H3PO4 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (5 % MeOH / CHCI3) 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-3carboxylic acid 17 in 5 steps as described in Scheme 9.

Scheme 9

<img file="IL173079A_D0030.tif" />

Step 1 - Preparation of (lH-Indazo-3-yl)-methanol 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,

01646801X76-01

50.5 mmol) 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 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 (lH-indazol-3- yl)methanol 18 (1.08 g, 7.4 mmol) in a mixture of DCM (40 ml) and THF (30ml). 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)-propenoic acid methyl ester 20

[0370] 3-(Indazoi-3-yl)-propenoic acid methyl ester 20 was prepared from aldehyde 19, as described in Step 1, Example 3.

Step 4 — Preparation of Indazole-3-propionic acid methyl ester 21

[0371] Indazole-3 -propionic acid methyl ester was prepared from compound 20 as described in Step 2, Example 3.

Step 5 - Preparation oflndazole-3-propionic acid 16.

[0372] Indazole-3 -propionic acid was prepared through saponification of compound 21 as described in Step 4, Example 3 (M-l = 197.1).

Example 6: Synthesis of 5-isopropoxy-3-(l-Benzene-sulfonyl-indol-3yl)-propionic acid 22

[0373] Propionic acid 22 was prepared from commercially available 5-hydroxy-indole 23 in 5 steps as shown in Scheme 10.

Scheme 10

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PCT7US2004/023234

<img file="IL173079A_D0031.tif" />

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 grains, 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).

**‘י.

Step 2 — Synthesis of 5-Isopropoxy gramine 25

[0375] The 5-Isopropoxy gramine 25 was prepared from 5-Isopropoxy-indole 24 as described in Step 2, Example 4 (M+l = 233.4).

Step 3 Synthesis of 2-(5-Isopropoxy-lH-Indol-3-ylmethyl)-malonic acid diethyl ester 26

[0376] Compound 26 was prepared from 25 as described in Step 3, Example 4 (M+l = 348.5).

Step 4 - Synthesis of 5-Isopropoxy-indole-3-propionic acid 27

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[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-l = 246.2).

Step 5- Synthesis of 5-isopropoxy-3-(l-Benzene-sulfonyl-indol-3yl)-p7'0pionic acid 22

[0378] To a cooled (-78°C) solution of propionic acid (27) (96.3mg, 0.510mmol) in tetrahydrofuran (10 ml), n-butyl lithium (1.40ml, 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 horns, allowing temperature to rise from -78°C to ambient conditions. The reaction was then diluted with ethyl acetate, and IM HCI was added to adjust the pEI 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

<img file="IL173079A_D0032.tif" />

[0379] Indole-3-propionic acid 28 was prepared through the commercially available indole-3-carboxyaldehyde as described in Example 3. (M-l, 188.2)

Example 8: Preparation of

3-(l-Benzenesulfonyl5־-methoxy-lH-mdol-3-yl)-propionic acid 29

<img file="IL173079A_D0033.tif" />

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[0380] The 3-(l-benzenesulfonyl-5-methoxy-lH-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-l = 358.4)

Example 9: Synthesis of

3-[5-Methoxy-l-(3-methoxy-benzyl)-lH-indol3־-yl]-propi0nic acid 30

<img file="IL173079A_D0034.tif" />

[0381] 3-[5-Methoxy-l-(3-methoxy-benzyl)-lH-indol-3-yl]-propiomc acid 30 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with 3-methoxybenzyl bromide, (M-l = 336.4)

Example 10: Synthesis of

- [ 1 - (3 - Chi or 0 -b enzyl) - 5 -methoxy-1 H-ind 01-3 -yl] -propionic acid 31

<img file="IL173079A_D0035.tif" />

[0382] 3-[l-(3-Chloro-benzyl)-5-methoxy-lH-mdol-3-yl]-propionic acid 31 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with 3-chlorobenzyl bromide, (M-l = 322.4).

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Example 11: Synthesis of

3-[l-(4-Fluoro-benzyl)-5-methoxy-lH-indol-3-yl]-propionic acid 32

<img file="IL173079A_D0036.tif" />

[0383] 3-| l-(4-Fluoro-benzyl)-5-methoxy-lH-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-l = 326.6).

Example 12: Preparation of

3-[l-(4-Chloro־benzyl)-5-methoxy-lH-indol-3-yl]-propionic acid 33

<img file="IL173079A_D0037.tif" />

[0384] 3-[l-(4-Chloro--benzyl)-5-methoxy-lH-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-l = 342.8)

Example 13: Synthesis of

3-[5-Methoxy-1 -(2-methoxy-benzyl)-1 H-indol-3-yl]-propionic acid 34

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<img file="IL173079A_D0038.tif" />

[0385] 3-[5-Methoxy-l-(2-metl1oxy-benzyl)-lH-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-l = 338.4)

Example 14: Synthesis of

3-[5-Methoxy-l-(2-trifluoromethoxy-benzyl)-lH-indol-3-yl]-propionic acid 35

<img file="IL173079A_D0039.tif" />

[0386] 3-[5-Methoxy-l-(2-trifluoromethoxy-benzyl)-lH-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-l = 392.3).

Example 15: Synthesis of

- [5 -Methoxy-1 -(3-trifluoromethoxy-b enzyl)-1 H-indol-3-yl]-propionic acid 3 6

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<img file="IL173079A_D0040.tif" />

[0387] 3-[5-Methoxy-l-(3־trifluoromethoxy-benzyl)-lH-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'-l = 392.4).

Example 16: Synthesis of

3-(1-Ethylthiocarbamoyl-5-methoxy-lH-indol-3-yl)-propionic acid 37

<img file="IL173079A_D0041.tif" />

$

[0388] 3-(l-Ethylthiocarbamoyl-5-methoxy-lH-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-l =305.4).

Example 17: Synthesis of

3-[5-Methoxy-l-(toluene-4-sulfonyl)-lH-indol-3-yl]-propionic acid 38

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<img file="IL173079A_D0042.tif" />

[0389] 3-[5-Methoxy-l-(toluene-4-sulfonyl)-lH-indol-3-yl]-propionic acid 3§ was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with 4-tolyI sulfonyl chloride, (M-l = 373.4).

*Gta

Example 18: Synthesis of 3-(1 -Benzenesulfonyl-1 H-indazol-3-yl)-propiomc acid 39

<img file="IL173079A_D0043.tif" />

[0390] 3-(l-Benzenesuribnyl-lH-mdazol-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-[l-(4-Isopropyl-benzenesulfonyl)-5-methoxy-lH-indoI-3yl]-propionic acid methyl ester 40

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<img file="IL173079A_D0044.tif" />

[0391] _ 3-[l-(4-Isopropyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester 40 was prepared using the same protocol as in example 3, substituting 4methoxybenzenesulfonyl chloride with 4-isopropylbenzenesulfonyl chloride, (M + 1 = 416.6).

Example 20: Synthesis of

3-[ 1 -(4-Isopropyl-beimenesulfony 1)-5-methoxy-1 H-indol-3-yl]-propionic acid 41

<img file="IL173079A_D0045.tif" />

[0392] 3-[l-(4-Isopropyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid was prepared through the saponification protocol with 3-[l-(4-Isopropylbenzenesulfonyl)-5-methoxy-lH-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-[l-(4-Butoxy-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]propionic acid methyl ester 42

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<img file="IL173079A_D0046.tif" />

[0393] 3-[l-(4-Butoxy-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester 42 was prepared using the same protocol as example 3, substituting 4methoxybenzenesulfonyl chloride with 4-n-butoxybenznesulfonyl chloride (M + 1 = 446.5)

Example 22: Synthesis of

3-(1 -(4-Butoxy-benzenesulfonyl)-5-methoxy-1 H-indol-3-yl]-propionic acid 43

<img file="IL173079A_D0047.tif" />

[0394] 3 [l-(4-Butoxy-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid was prepared through the saponification protocol with -[l-(4-Butoxy-benzenesulfonyl)-5methoxy-lH-indoI-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-l-(4-trifluoromethoxy-benzenesulfonyI)-lHindol-3-yl]-propionic acid methyl ester 44

WO 2005/009958

<img file="IL173079A_D0048.tif" />

[0395] . 3-[5-Methoxy-1 -(4-trifluoromethoxy-benzenesulfonyl)-1 H-indol-3-yl]-propionic acid methyl ester was prepared using the same protocol as in example 3, substituting 4methoxybenzenesulfonyl chloride with 4־trifluoromethoxybdt1zene sulfonyl chloride, (M + 1 =457.4).

Example 24: Synthesis of

3-[5-Methoxy-l-(4-trifluoromethoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid 45

<img file="IL173079A_D0049.tif" />

[0396] 3-[5-Methoxy-l-(4-trifluoron1ethoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid was prepared through, the saponification protocol with 3-[5-Methoxy-l-(4trifluoromethoxy-benzenesulfonyl)-lH-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-l-(4-phenoxy-benzenesulfonyl)-lH-indol-3-yl]propionic acid methyl ester 46

WO 2005/009958

PC17US2004/023234

<img file="IL173079A_D0050.tif" />

[0397] .3-[5-Metl1oxy-l-(4-phenoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid methyl ester 45 as prepared using the same protocol as example 3, substituting 4methoxybenzenesulfonyl chloride with 4-phenoxybenzene sulfonyl chloride, (M+l = 466.6).

Example 26: Synthesis of

3-[5-Methoxy-l-(4-phenoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid 47

<img file="IL173079A_D0051.tif" />

[0398] 3-[5-Methoxy-l-(4-phenoxy-benzenesulfonyl)-lH-indol-3-yI]-propionic acid was prepared through the saponification protocol with 3-[5-Methoxy-l-(4-phenoxybenzenesulfonyl)-lH-indoI-3-yl]-propionic acid methyl ester 46 as described in step 4 of example 3, (M - 1 = 450.5).

Example 27: Synthesis of 3-[l-(4-Chloro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]propionic acid methyl ester 48

WO 2005/009958

<img file="IL173079A_D0052.tif" />

[0399] 3-[l-(4-Chloro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester 48 was prepared using the same protocol as in example 3, substituting 4methoxybenzene sulfonyl chloride with 4-chlorobenzene sulfonyl chloride (M+l = 406.9). .

Example 28: Synthesis of

3-[l-(4-Chloro-benzenesulfo11yl)-5-methoxy-lH-indol-3-yl]-propionic acid 49

<img file="IL173079A_D0053.tif" />

[0400] 3-[l-(4-Chloro-benzenesulfonyl)-5-methoxy-lH-indol3־-yl]-propionic acid 49 was prepared through the saponification protocol with 3-[l-(4-ChIoro-benzenesulfonyl)-5methoxy-lH-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-[l-(4-Cyano-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester 50

<img file="IL173079A_D0054.tif" />

[0401] 3-[l-(4-Cyano-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester 50 was prepared using the same protocol as example 3, substituting 4methoxybenzene sulfonyl chloride with 4-cyanobenzene sulfonyl chloride. (M+l = 399.4)

Example 30: Synthesis of

3-[l-(4-Cyano-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid 51

<img file="IL173079A_D0055.tif" />

NC

[0402] 3-[l-(4-Cyano-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid 51 was prepared through the saponification protocol with 3-[l-(4-Cyano-benzen6sulfonyl)-5methoxy-lH-indol-3-yl]-propionic acid methyl ester 50 as described in step 4 of example 3, (M-l =383.4).

Example 31: Synthesis of 3-[l-(3,4-Dichloro-benzenesulfonyl)~5-methoxy-lH-mdol-3yl]-propionic acid methyl ester 52

WO 2005/00995:

<img file="IL173079A_D0056.tif" />

[0403] 3-[l-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester 52 was prepared using the same protocol as in example 3, substituting 4methoxybenzene sulfonyl chloride with 3,4-dichlorobenzene sulfonyl chloride, (M+l =

443.3).

Example 32: Synthesis of

3-[ 1 -(3>4-Dichloro-benzenesulfonyl)-5-methoxy-1 H-indol-3-yl]-propionic acid 53

<img file="IL173079A_D0057.tif" />

[0404] 3-[l-(3,4-Dichloro-benzenesulfonyl)-5-1nethoxy-lH-indol-3-yl]-propi0nic acid 53 was prepared through the_; saponification with 3-[l-(3,4-Dichloro-benzenesulfonyl)-5methoxy-lH~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-l-(4-trifluoromethyl-benzenesulfonyl)־lHindol-3-yl]-propionic acid methyl ester 54

WO 2005/009958

<img file="IL173079A_D0058.tif" />

[0405] 3-[5-Methoxy-l-(4-trifluoromethyl-benzenesulfonyl)-lH-indol-3-yl]-propionic acid methyl ester 54 was prepared using the same protocol as in example 3, substituting 4methoxybenzenesulfonyl chloride with trifluoromethylbenzene sulfonyl chloride, (M+1 =

442.4).

Example 34: Synthesis of

3-[5-Methoxy-1 -(4-trifluoromethyl-benzenesulfonyl)-1 H-indol-3-yl]-propionic acid 55

<img file="IL173079A_D0059.tif" />

[0406] 3-[5-Methoxy-l-(4-trifluoromethyl-benzenesulfonyl)-lH-indol-3-yl]-propionic acid 55 was prepared through the saponification of 3-[5-Methoxy-l-(4-trifluoromethylbenzenesulfonyl)-lH-i11dol-3-yl]-propionic acid methyl ester 54 as described in step 3 of examples, (M+1 = 404.5).

Example 35: Synthesis of

3-[ 1 -(4-Fluoro-benzenesulfonyl)-5-methoxy-1 H-indol-3-yl]-propionic acid methyl ester56

WO 2005/009958

<img file="IL173079A_D0060.tif" />

[0407] 3-[l-(4-Fluoro-benzenesulfonyl)-5-metl10xy-lH-mdol-3-yl]-propionic acid methyl ester 56 was prepared using the same-protocol as example 3, substituting 4methoxybenzene sulfonyl chloride with 4-fluorobenzene sulfonyl chloride, (M+l =

392.4).

Example 36: Synthesis of

3-[l-(4-Fluoro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid 57

<img file="IL173079A_D0061.tif" />

[0408] 3-[l-(4-Fluoro-benzenesulfonyl)-5-methoxy-lH-indoI-3־yl]־propionic acid 57 was prepared through the saponification of the 3-[l-(4-Fluoro-benzenesulfonyl)-5methoxy-lH-indol-3-yl]-propiomc acid methyl ester 56 as described in step 4 of example

3, (Μ—1 = 376.4).

Example 37: Synthesis of 3-[5-Methoxy-l-(3-phenoxy-benzenesulfonyl)-lH-indol-3-yl]propionic acid methyl ester 58

WO 2005/009958

<img file="IL173079A_D0062.tif" />

[0409] 3-[5-Methoxy-l-(3-phenoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid methyl ester 58 was prepared using the same protocol as in example 3, substituting 4methoxybenzenesulfonyl chloride with 3-phenoxybenzene sulfonyl chloride, (M + 1 =

466.5).

Example 38: Synthesis of

3-[5-Methoxy-l-(3-phenoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid 59

<img file="IL173079A_D0063.tif" />

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

WO 2005/009958

Example 39: Synthesis of 3-[l-(3-Fluoro-benzenesulfonyl)-5-methoxy-lH־indol-3-yl]propionic acid methyl ester 60

<img file="IL173079A_D0064.tif" />

[0411] 3-[l-(3-Fluoro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propiomc acid methyl ester 60 was prepared using the same protocol as in example 3, substituting 4methoxybenzene sulfonyl chloride with 3-fluorobenzene sulfonyl chloride, (M+l = 392.3).

Example 40: Synthesis of

3-[l-(3-Fluoro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid 61

<img file="IL173079A_D0065.tif" />

[0412] 3-[l-(3-Fluoro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid 61 was prepared through saponification of 3-[l-(3-Fluoro-benzenesulfonyl)-5-methoxy-lHindol-3-yl]-propionic acid methyl ester 60 as described in step 4 of example 3, (Μ -1 = 376.4).

Example 41: Synthesis of

3-[5-Methoxy-l-(toluene-3-sulfonyl)-lH־mdol-3-yl]-propionic acid methyl ester 62

<img file="IL173079A_D0066.tif" />

[0413] 3-[5-Methoxy-l-(toluene-3-sulfonyl)-lH-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+l = 388.5).

Example 42: Synthesis of 3-[5-Methoxy-l-(toluene-3-sulfonyl)-lH-indol-3-yl]-propionic acid 63

<img file="IL173079A_D0067.tif" />

[0414] 3-[5-Methoxy-l־(toluene-3־sulfonyl)-lH-indol-3-yl]-propionic acid 63 was prepared through the saponification of 3-[5-Methoxy-l-(toluene-3-sulfonyl)-lH־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-[l-(3-Chloro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]propionic acid methyl ester 64

----01646801\76-01

<img file="IL173079A_D0068.tif" />

[0415] 3-[l-(3-Chloro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester 64 was prepared using the same protocol as in example 3, substituting 4metiioxybenzenesulfonyl chloride with 3-chlorobenzene sulfonyl chloride, (M+l = 408.9).

Example 44: Synthesis of

3-[l-(3-Chloro-benzenesulfonyl)-5-metl1oxy-lH-indol-3-yl]-propionic acid 65

<img file="IL173079A_D0069.tif" />

Cl

[0416] 3-[l-(3-Chloro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid 65 was prepared through the saponification of 3-[l-(3-Chloro-benzenesulfonyl)-5-methoxylH-ind.ol-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-l-(3-methoxy-benzenesulfonyl)-lH-indol-3-yl]propionic acid methyl ester 66

WO 2005/009958

<img file="IL173079A_D0070.tif" />

[0417] 3-[5-Methoxy-l-(3-methoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid methyl ester 66 was prepared using the same protocol as in example 3, substituting 4methoxybenzenesulfonyl chloride with 3-methoxybenzene sulfonyl chloride, (M+l =

404.5).

Example 46: Synthesis of

3-[5-Methoxy-l-(3-metboxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid 67

<img file="IL173079A_D0071.tif" />

O-Me

[0418] 3-[5-Methoxy-l-(3-methoxy-benzenesulfonyl)-lH-indol-3-yl]-propiohic acid 67 was prepared through the saponification of 3-[5-Methoxy-l-(3-methoxy-benzenesulfonyl)lH-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-l-(3-trifluoromethyl-benzenesulfonyl)־lHindol-3-yl]-propionic acid methyl ester 68

WO 2005/009958

<img file="IL173079A_D0072.tif" />

[0419] 3-[5-Methoxy-l-(3-trifluoromethyl-benzenesulfonyl)-lH-indol-3-yl]-propionic acid methyl ester 68 was prepared using the same protocol as in example 3, substituting 4methoxybenzene sulfonyl chloride with 3-trifluoromethylbenjgne sulfonyl chloride, (M+l = 442.4).

Example 48: Synthesis of

3-[5-Methoxy-l-(3-trifluoromethyl-benzenesulfonyl)-lH-indol-3-yl]-p1Opionic acid 69

<img file="IL173079A_D0073.tif" />

[0420] 3-[5-Methoxy-l-(3-trifluoromethyl-benzenesulfonyl)-lH-indol-3-yl]-propionic acid 69 was prepared through the saponifcation of 3-[5-Methoxy-l-(3-trifluoromethylbenzenesulfonyl)-lH-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-(l-Benzyl-5-methoxy־lH-indol-3-yl)-propionic acid methyl ester 70

WO 2005/009958

PCT7US2004/023234

<img file="IL173079A_D0074.tif" />

[0421] 3-(l-Benzyl-5-methoxy-lH-mdol-3-yl)-propionic acid methyl ester 70 was prepared using the same protocol as example 3, substituting 4-methoxybenzenesulfonyl chloride with benzyl bromide, (M+l = 324.4).

*S’u

Example 50: Synthesis of 3-(l-Benzyl-5-methoky-lH-indol-3-yl)-propionic acid 71

<img file="IL173079A_D0075.tif" />

[0422] 3 -(1 -B enzyl-5-methoxy-1 H-indol-3-yl)-p1־opionic acid 71 was prepared through the saponification of 3-(l-»Benzyl-5-methoxy-lH-indol-3-yl)-propionic acid methyl ester 70 as described in step 4 of example 3, (M+l = 308.3).

Example 51: Synthesis of

3-[5-Methoxy-l-(thiophene-2-sulfonyl)-lH-indol-3-yl]-propionic acid methyl ester 72

<img file="IL173079A_D0076.tif" />

WO 2005/009958

[0423] 3-[5-Metl1oxy־l-(thiophene-2-sulfonyl)-lH-indol-3-yl]-propionic acid methyl ester 72 was prepared using the same protocol as example 3, substituting 4methoxybenzene sulfonyl chloride with 2-thiopene sulfonyl chloride, (M+l = 380.5).

Example 52: Synthesis of

3-[5-Methoxy-l-(thiophene-2-sulfonyl)-lH-indol-3-yl]-propionic acid 73

<img file="IL173079A_D0077.tif" />

[0424] 3-[5-Methoxy-l-(thiophene-2-sulfonyl)-lH-indol-3-yl]-propionic acid was prepared through the saponification of 3-[5-Methoxy-l-(thiophene-2-sulfonyl)-lH-indol3-yl]-propionic acid methyl ester as described in step 4 of example 3, (M -1 = 364.4).

Example 53: Synthesis of

3-(5-Methoxy-l-phenylthiocarbamoyl-lH-indol-3-yl)-propionic acid methyl ester 74

׳1»

<img file="IL173079A_D0078.tif" />

[0425] 3-(5-Methoxy-l-phenylthiocarbamoyl-lH-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+l = 369.5).

WO 2005/009958

Example 54: Synthesis of

3-(5 -Methoxy-1 -phenylthiocarbamoyl-1 H-indol-3-yl)-propionic acid 75

<img file="IL173079A_D0079.tif" />

[0426] 3-(5-Methoxy-l-phenylthiocarbamoyl-lH-indol-3-yl)-propionic acid 75 was prepared through the saponification of 3-(5-Methoxy-l-phenylthiocarbamoyl-lH-indol-3yl)-propionic acid methyl ester 74 as described nfstep 4 of example 3, (M - 1 = 353.4).

Example 55: Synthesis of

3-[l-(4-Butyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester 76

<img file="IL173079A_D0080.tif" />

[0427] 3-[l-(4-Butyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid methyl ester 76 was prepared using the same protocol as example 3, substituting 4methoxybenzene sulfonyl chloride with 4-n-butylbenzene sulfonyl chloride, (M+l = 430.2).

Example 56: Synthesis of

3-[l-(4-Butyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid 77

WO 2005/009958

[0428] 3-[l-(4-Butyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid 77 was prepared, through the saponification of 3-[l-(4-Butyl־benzenesulfonyl)-5-methoxy-lHindol-3-yl]-propionic acid methyl ester 76 as described in step 4 of example 3, (M - 1 = ⁴¹⁴.I).

.׳ 'bv,

Example 57: Synthesis of 3-[5-Methoxy-l-(3-trifluoromethoxy-benzenesulfonyl)-lHindol-3-yl]-propionic acid methyl ester 78

<img file="IL173079A_D0081.tif" />

[0429] 3-[5-Methoxy-l-(3-trifluoromethoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid methyl ester 78 was prepared using the same protocol as example 3, substituting 4methoxybenzene sulfonyl chloride with 3-trifluorobenzene sulfonyl chloride (M+l = 458.1).

Example 58: Synthesis of

3-[5-Methoxy-l-(3-trifluoromethoxy-benzenesulfonyl)-lH-indol-3-yl]-propionic acid 79

WO 2005/009958

<img file="IL173079A_D0082.tif" />

[0430] 3-[5-Methoxy-l-(3-trifluoromethoxy-benzenesulfonyl)-lH-indol-3-yl]-propi0nic acid 79 was prepared through the saponification of 3-[5-Methoxy-l-(3-trifluoromethoxy-

״1׳ benzenesulfonyl)-lH-indol-3-yl]-propionic acid methyl ester 4 as described in step 4 of examples, (M-1 =442.0). /

Example 59: Synthesis of

3-(l-Benzoyl-5-methoxy-lH-indol-3-yl)-propionic acid methyl ester 80

<img file="IL173079A_D0083.tif" />

[0431] 3-(l-Benzoyl-5-methoxy-lH-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+l = 338.1).

Example 60: Synthesis of 3-(l-Benzoyl-5-methoxy־lH-indol-3-yl)־propionic acid 81

WO 2005/009958

<img file="IL173079A_D0084.tif" />

[0432] 3-(l-Benzoyl-5-methoxy-lH-indol-3-yl)-propionic acid 81 was prepared through the saponification of 3-(l-Benzoyl-5-methoxy-lH-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-1 H-indol-3-yl)-propionic aciif 82

<img file="IL173079A_D0085.tif" />

[0433] 3-(l-Benzenesulfonyl-5-ethQxy-lH-mdol-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-[l-(4-Isopropoxy-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid 83

WO 2005/009958

<img file="IL173079A_D0086.tif" />

[0434] 3-[l-(4-Isopropoxy-benzenesulfonyl)-5-methoxy-lH-indol3־-yl]-propionic acid 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-l-phenylcarbamoyl-lH-indol-3-yl)-propio11ic acid methyl ester 84

<img file="IL173079A_D0087.tif" />

[0435] 3-(5-Methoxy-l-phenylcarbamoyl-lH-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+l = 353.4).

Example 64: Synthesis of

3-(5-Methoxy-l-phenylcarbamoyl-lH-indol-3-yl)-propionic acid 85

WO 2005/009958

<img file="IL173079A_D0088.tif" />

<img file="IL173079A_D0089.tif" />

[0436] 3-(5-Methoxy-l-phenylcarbamoyl-lH-indol-3-yl)-propionic acid 85 was prepared through the saponifcation of 3-(5-Methoxy-l-phenylcar־bamoyl-lH-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-[l-(4-Ethyl-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-propionic acid 86

<img file="IL173079A_D0090.tif" />

[0437] 3-[l-(4-Ethyl-benzenesulfonyl)-5-n1ethoxy-lH-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-lH-indol-3-yl)-propionic acid 87

<img file="IL173079A_D0091.tif" />

WO 2005/009958

[0438] 3-(5-bromo-lH-mdol-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-l =268.0).

Example 67: Synthesis of 3-(5-Bromo-lH-indol-3-yl)־propionic acid methyl ester 88

[0439] The 5-bromoindole-3-propionic acid 87 (4.0 g, 14.91 mmol) was dissolved in.

methanol (MeOH, 100 mL) and Trimethylsilyl chloride (TMSC1, 33.0 mL, 32.8 mmol, 1.0 M in CH2C12) 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-(l־Benzenesulfonyl-5-bromo-lH-indol-3-yl)-propionic acid methyl ester 89

WO 2005/009958

[0440] ' 3-(l-Benzenesulfonyl-5-bro1no-lH-mdol-3-yl)-propionic acid methyl ester 89 prepared as described in step 3 of example 3 by substituting 4-methoxybenzenesulfonyl chloride with benzene sulfonyl chloride, (M 4424 = 1 ־).

Example 69: Synthesis of

3-(l-Benze11esulfonyl-5-bromo-lH-indol-3-yl)-propionic acid methyl ester 90

<img file="IL173079A_D0092.tif" />

[0441] 3-(l-Benzenesulfonyl-5-bromo-lH-indol-3-yl)-p1Opionic 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-lH-indol-3-yl)-propionic acid methyl ester 91

WO 2005/009958

<img file="IL173079A_D0093.tif" />

CO₂CH₃

N 0=s=0

<img file="IL173079A_D0094.tif" />

[0442] 3-(l-Benzenesulfonyl-5-bromo-lH-indol-3-yl)-propionic acid methyl ester 89 (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(OA׳iJ)₂ (4.0 mg, 0.015 mmol), K₂CO₃ (90 mg, 0.65 mmol), 1,2—Dimethoxyethane (DME, 4.0 mL) and H₂O (0.4 mL) 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 MgSO4, filtered, and evaporated. The residue was . purified with flash silica, gel chromatography (20% EtOAc/Hexanes) to obtain the ester 91 as a white solid, (110 mg, M + 1 = 426.1).

Example 71: Synthesis of

3-(Benzenes ulfonyl-5 -tinophen-3-yl-1 H-indol-3-yl)-propionic acid 92 co₂h

N oso

[0443] 3-(Ben2enesulfonyl5־-thiophen-3-yl-lH־indol3־-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-(l-Benzenesulfonyl-5-phenyl-lH־indol-3-yl) propionic acid methyl ester 93

<img file="IL173079A_D0095.tif" />

[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-(l-Benzenesulfonyl-5-phenyl-lH-indol-3-yl) propionic acid 94

<img file="IL173079A_D0096.tif" />

----------01646801X76-01136

[0445] 3-(l-Benzenesulfonyl-5-phenyl-lH-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-(lH-Pyrrolo[2,3-b]pyridine-3-yl)-propionic acid 95

<img file="IL173079A_D0097.tif" />

[0446] 3-(lH-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-lH-Indol-3-yl)-propionic acid 96

<img file="IL173079A_D0098.tif" />

[0447] 3-(5-Methoxy-lH-Indol-3-yl)-propionic acid 96 was prepared from saponification of 3 (5-methoxy-lH-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-(l-Benzenesulfonyl-lH־indol-3-yl)-propionic acid 97

-----------01646801X76-01

<img file="IL173079A_D0099.tif" />

[0448] 3-(l-BenzenesulfonyI-lH-indoI-3-yI)-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) *4׳u

Example 77: Synthesis of

3-(l-Benzenesulfonyl-5-methoxy-lEl-indol-3-yl)-propionic acid methyl ester 98

<img file="IL173079A_D0100.tif" />

[0449] 3-(l-Benzenesulfonyl-5-methoxy-lH-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+l = 374.4)

Example 78: Synthesis of

3-[5-Methoxy-l -(thiophene-3-sulfonyl)-lH-indol-3-yi]-propionic acid 99

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<img file="IL173079A_D0101.tif" />

[0450] 3-[5-Metl1oxy־l-(tl1iophene-3-sulfonyl)-lH-indol-3-yl]-propionic acid 99 was prepared from 3-(5-methoxy-lI־I-indol-3-yl)-propionic acid 96 and 3-thienyl-sulfonyl chloride using the same protocol as described in step 8, Example 4. (M — 1, 364.4)

Example 79: Synthesis of (l-Benzenesulfonyl-5-methoxy-lH-indol-3-yl)-acetic acid 100

<img file="IL173079A_D0102.tif" />

[0451] (l-Benzenesulfonyl-5-methoxy-lH-indol-3-yl)-acetic acid 100 was prepared from commercially available (5-methoxy-lH-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 lb

<img file="IL173079A_D0103.tif" />

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Step 1 — Preparation of compound offormula XVIII׳.

(0452] Compound XVIII can be prepared through coupling of compound III with benzene sulfonyl chloride in abi-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. Chem., 2002, 63, pg 1001-1003.

Step 2 — Preparation of compound XIX:

[0453] Compound XIX was prepared through conventionally Khoevenagel 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 lb:

[0454] Compound la 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-l-(4-methoxy-benzenesulfonyl)-lHindol-3-yl]-propionic acicQ

Scheme 12

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<img file="IL173079A_D0104.tif" />

Step 1: Preparation of l-(4-Methoxy benzenes1dfonyl)-5-methoxy-lH- indole-3carboxyaldehyde) (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 iiext. 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) δ 10.0 (s, 1H), 8.20(5,1H), 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).

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Step 2: Preparation of 3-[l-(4-Methoxy benzenesulfonyl)-5-methoxy-lH-indol-3-yl]acrylic acid(118)

[0456] To a solution of l-(4-Methoxy benzenesulfonyl)-5-methoxy-lH- indole-3carbaldehyde 5 (0.51 g, 1.5 mmol) dissolved in pyridine (10 mL), malonic acid (0.53 g, 5.1 mmol) and piperidine, (ImL) were combined in a reaction vessel. The yellow solution was heated for 3 hours at 80^QC. The reaction was allowed to cool to ambient temperature and diluted with 150 mL of ethyl acetate. The organic layer was washed with IN HCI (6 X 50 mL) and saturated sodium chloride solution (1 X 50 mL). After drying over sodium sulfate, the organic layei־ 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 (CDC13) δ 7.86 (m, 5H), 7.2 (d, J= 2.4 Hz, 1H), 7.0 (dd, J= 218 Hz, 9.2 Hz, 1H), 6.91 (d, J= 8.8 Hz, 2H), 6.46 ( d, J= 16, 1H), 3.87 (s,3H, CH3) (M - 1 = 386.2).

Step 3: Preparation of 3-[l-(4-Methoxy benzenesulfonyl)-5-methoxy-lH-indol-3-yl]propionic acid (1)

[0457] To a solution of 3-[l-(4-Methoxy benzenesulfonyl)-5-methoxy-lH-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 hydro genator. The reaction was allowed to proceed overnight at 20-22 psi. The solution was filtered over celite, and the palladium-cehte 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. (0.620g, 62%) ¹PI NMR(DMSO) δ 7.86 (d, J= 9.2 Hz, Π-Ι), 7.75 (d, J= 8.4Hz, 1H), 6.92 (dd, J= 2.4 PIz, 9.2 PIz, 1H), 6.88 (s, 1PI), 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) CM- 1 =388.6).

Example 81: Synthesis of 3-[5-Methoxy-l-(4-methoxy-benzenesulfonyl)-lH-indol-3-yl] 2,2-dimethyl-propionic acid 119

Scheme 13

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<img file="IL173079A_D0105.tif" />

<img file="IL173079A_D0106.tif" />

Step 1 - Synthesis of 5-methox)>-lH-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-lH-indol-3-carboxaldehyde 2 (1 gram, 0.006 mol) dissolved in THF (20 ml) and methanol (15ml) were combined and stirred at ambient temperature for 16 hour's. 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

.*‘י sodium sulfate and evaporated to dryness to yield a light colored solid 141 (736 mg, 70%).

Step 2 — Preparation of 3-(5-Methoxy-lH-indol-3~yl)-propionic acid methyl ester 142:

[0459] To a solution of 5-methoxy-lH-indol-3yl-methanol 141 (115 mg, 0.643 mmol) dissolved in di chloromethane (3ml), (l-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 (50ml) 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

WO 2005/009958 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-Methoxy-l-(4-methoxy-benzenesulfonyl)-lH-indol-3-yl]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 4methoxybenzenesulfonyl chloride (0.200 g; l.Ommol). The reaction was allowed to warm up to room temperature and stirred for 16 h, subjected to aqrrfeous 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 flashchromatography (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-Methaxy-l-(4-methoxy-benzenes1dfonyl)-lPI-indol-3-yl]-2,2dimethyl-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 IM) 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-lH-indol3-yl]-propionic acid 101

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<img file="IL173079A_D0107.tif" />

[0462] 3-[l-(3,4-dimethoxybenzenesulfonyl)-5-methoxy-lH-mdol-3-yl]-propionic acid 101 was prepared using the same protocol as in example 3, substituting 4methoxybenzene sulfonyl chloride with 3, 4-dimethoxybenzenesulfonyl chloride, (M —1 = 418.5).

Example 83: Synthesis of 3-[l-(3,4-Difluoro-benzenesulfonyl)-5-methoxy-lH-indol-3 yl]-propionic acid 102

<img file="IL173079A_D0108.tif" />

[0463] 3-[l-(3,4-difluorobenzenesulfonyl)-5-methoxy-lH-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-[l-(3-chloro-4-methyl-benzenesulfonyl)-5-methoxy-lHindol-3-yl]-propionic acid 103

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<img file="IL173079A_D0109.tif" />

[0464] 3-[l-(3-chloro-4-methyl)-5-methoxy-lH-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 = 406.8).

Example 85: 3-[l-(benzenesulfonyl)-5-fluoro-lH-indol-3-yl]-propionic acid 104 co₂h

<img file="IL173079A_D0110.tif" />

[0465] 3-[l-(benzenesulfonyl)-5-fluoro־lH-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-[l-(benzenesulfonyl)5־-methyl-lH-indol-3-yl]-propionic acid 105

<img file="IL173079A_D0111.tif" />

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[0466] 3-[l־(benzenesulfonyl)-5-metl1yl-lH-indol-3-yl]-propionic acid 105 Avas prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with benzenesulfonyl chloride, (Μ -I = 342.2).

Example 87: Synthesis of 3-[l-(benzenesulfonyl)-5-chloro-lH־indol-3-yl]-propionic acid 106

<img file="IL173079A_D0112.tif" />

[0467] 3-[l-(benzenesulfonyl)-5-cl1101O-lH-indol-3-yl]-propionic acid 106 was prepared using the same protocol as in example 3, substituting 4-methoxybenzene sulfonyl chloride with benzenesulfonyl chloride, (Μ -1 = 362.7).

Example 88: Synthesis of 3-[l-(3-fluoro4-methyl-benzenesulfonyl)-5-chlo1O-lH-indol-3yl]-propionic acid 107

<img file="IL173079A_D0113.tif" />

[0468] 3-[l-(3-fluoro-4-methyl-benzenesulfonyl)-5-chloro-lH-indol-3-yl]-propionic acid 107 was prepared using the same protocol as in example 3, substituting 4methoxybenzene sulfonyl chloride with 3-fluoro-4-methyl-benzenesulfonyl chloride, (M -1 =390.3).

Example 89: Synthesis of 3-[l-(2,3-Dihydro-benzofuran-5-sulfonyl)-5-methoxy-lHindol-3-yl]-propionic acid 108

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<img file="IL173079A_D0114.tif" />

[0469] 3-[l-(2,3-Dil1ydro-benzofuran-5-sulfonyl)-5-meth0xy-lH-mdol-3-yl]-propionic acid 108, was prepared using the same protocol as in example 3, substituting 4methoxybenzene sulfonyl chloride with 2,3-Dihydro-benzofuran-5-sulfonyl chloride, (M -1 = 400.2).

Example 90: Synthesis of 3-[l-(4-ethyl-benzenesulfonyl)-5-ethoxy-lH-indol-3-yl]propionic acid 109

<img file="IL173079A_D0115.tif" />

[0470] 3-[l-(4-ethyl-benzenesulfonyl)-5-ethoxy-lH-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-[l-(4-methoxy-benzenesulfonyl)-5-ethoxy-lH-indol-3-yl]propionic acid 110

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<img file="IL173079A_D0116.tif" />

[0471] 3-[l-(4-methoxy-benzenesulfonyl)-5-ethoxy-lH-indol-3-yl]-propionic acid 110 was prepared.using the same protocol as in example 3, (M -1 = 402.6).

Example 92: Synthesis of 3-[l-(3-trifluoromethoxy-benzeriesulfonyl)-5-ethoxy-lH-indol.

3-yl]-propionic acid 111

<img file="IL173079A_D0117.tif" />

si

[0472] 3 -[1 -(3 -trifluoromethoxy-benzenesulfonyl)-5-ethoxy-1 H-indol-3 -yl] -propionic acid 111 was prepared usjpg the same protocol as in example 3, substituting 4methoxybenzene sulfonyl chloride with 3-trifluoromethoxy-benzenesulfonyl chloride, (M -1 = 456.3).

Example 93: Synthesis of 3-[l-(4-butyl-benzenesulfonyl)-5-ethoxy-lH-indol-3-yl]propionic acid 112

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<img file="IL173079A_D0118.tif" />

[0473] 3-[l-(4-butyl-benzenesulfonyl)-5-etl1oxy-lH-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-[l-(4-butoxy-benzenesulfonyl)-5-ethoxy-lH-indol-3-yl]propionic acid 113

<img file="IL173079A_D0119.tif" />

£

[0474] 3-[l-(4-butoxy-benzenesulfonyl)-5-ethoxy-lH-indol-3-yl]-propionic acid 113 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-[l-(3, 4-dichloro-benzenesulfonyl)-5-ethoxy-lH-indol-3-yl]propionic acid 114

<img file="IL173079A_D0120.tif" />

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[0475] 3-(1-(3,4-dichloro-benzenesulfonyl)-5-ethoxy-lH-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-l = 441.2).

Example 96: Synthesis of 3-[l-(3-methoxy-benzenesuIfonyl)-5-ethoxy-lH-indol-3-yl]propionic acid 115

<img file="IL173079A_D0121.tif" />

[0476] 3-[l-(3-methoxy-benzenesulfonyl)-5-etl1oxy-lH-indol-3-yl]-propionic acid 115 was prepared using the same protocol as in example 3, substitutmg 4-methoxybenzene sulfonyl chloride 3-methoxy-benzenesulfonyl chloride, (M -1 = 402.5).

Example 97: Synthesis of 3-[l-(4-phenoxy-benzenesulfonyl)-5-ethoxy-lH-indol-3-yl]propionic acid 116

<img file="IL173079A_D0122.tif" />

[0477] 3-[l-(4-phenoxy-benzenesulfonyl)-5-ethoxy-lH-indol-3-yl]-propionic acid 116 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-lH-indol-3yl]-2,2-dimethyl-propionic acid methyl ester 122.

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PCI7US2004/023234

<img file="IL173079A_D0123.tif" />

[0478] 3-[l-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-2,2-dimethylpropionic 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-[l-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-lH-indol-3yl]-2,2-dimethyl-propionic acid 121

<img file="IL173079A_D0124.tif" />

[0479] 3-[ 1 -(3,4-Dichloro-benzenesulfonyl)-5-m ethoxy-1 H-indol-3-yl]-2,2-dimethylpropionic 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-[l-(3,4-Dichloro-benzenesulfonyl)-5-methoxy-lHindol-3-yl]-acrylic acid 123

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<img file="IL173079A_D0125.tif" />

[0480] (E)-3-[l-(3,4-Dichlo1O-benzenesulfonyl)-5-methoxy-lH-indol-3-yl]-acrylic acid

123 was prepared using the same protocol as in Scheme 12, substituting 4methoxybenzene sulfonyl chloride 3, 4-dichlorobenzenesulfonyl chloride in step - 1, (M 1 =425.2).

Example 101: Synthesis of (E)-3-[l-(4-butyl-benzenesulfonyl)-5-ethoxy-lH-indol-3-yl]acrylic acid 124

<img file="IL173079A_D0126.tif" />

[0481] (E)-3-[l-(4-butyl-benzenesulfonyl)-5-ethoxy-lH-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 -1, (M-l =426.4).

Example 102: Synthesis of (E)-3-[l-(4-butoxy-benzenesuIfonyl)-5-ethoxy-lH-indol-3yl]-acrylic acid 125

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<img file="IL173079A_D0127.tif" />

[0482] (E)-3-[ 1 -(4-butoxy-benzenesulfonyl)-5-ethoxy-lH-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-[l-(3-Chloro-4-methoxy-benzenesulfonyl)-5-methoxy-lH-

<img file="IL173079A_D0128.tif" />

[0483] 3-[l-(3-Chloro-4-methoxy-benzenesulfonyl)-5-methoxy-lH-indol-3־yl]propionic acid 126 was prepared using the same protocol as in Scheme 12, substituting 4methoxybenzene 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-[l-(4-Methoxy-benzenesulfonyl)-7-methyllH-indol-3-yl]-propionic acid 127

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<img file="IL173079A_D0129.tif" />

[0484] Compound 127 is synthesized from commercially available 7-methy-lindole-3carboxaldehyde following synthetic steps shown in Scheme 12.

Example 105: Synthesis of 3-[l-(4-Methoxy-benzenesulfofiyl)-6-methyl-lH-indol-3-yl]propionic acid 128

<img file="IL173079A_D0130.tif" />

[0485] Compound 128 is synthesized from commercially available 6-methyl-indole-3carboxaldehyde following synthetic steps shown in Scheme 12.

Example 106: Synthesis of 3-[l-(4-Methoxy-benzenesulfonyl)-6-fluoro-lH-ihdol-3-yl]propionic acid 129

<img file="IL173079A_D0131.tif" />

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[0486] Compound 129 is synthesized from commercially available 6-fluoro-indole-3carboxaldehyde following synthetic steps shown in Scheme 12.

Example 107: Synthesis of 3-[l-(4-Methoxy-benzenesulfonyl)-7-fluoro-lH-indol-3-yl]propionic acid 130

<img file="IL173079A_D0132.tif" />

[0487] Compound 130 is synthesized from commercially available 7-fluoro־indole-3carboxaldehyde following synthetic steps shown in Scheme 12.

Example 108: Synthesis of 3-[l-(4-Methoxy-benzenesulfonyl)-4-chloro7־-fluoro-lHindol-3־yl]-propionic acid 131

<img file="IL173079A_D0133.tif" />

[0488] Compound 131 is synthesized from commercially available 4-chloro-7-fluoroindole-3-carboxaldehyde following synthetic steps shown in Scheme 12.

Example 109: Synthesis of 3-[l-(4־Methoxy-benzenesulfonyl)-6-methoxy-lH-indol-3yl]-propionic acid 132

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<img file="IL173079A_D0134.tif" />

[0489] Compound 132 is synthesized from 6-methoxy-indole-3-carboxaldehyde, which in turn is synthesized from commercially available 6-methoxy-indole using VilsmeierHaack reaction (Advanced organic chemistry, Jerry March, 2^nd Ed. P715), following synthetic steps shown in Scheme 12.

Example 110: Synthesis of 3-[l-(4-Methoxy-benzenesulfonyl)-5,6-dimethoxy-lH-indol3-yl]-propionic acid 133

<img file="IL173079A_D0135.tif" />

[0490] Compound 133 is synthesized from 5,6-dimethoxy-indole-3-carboxaldehyde, which m turn is synthesized from commeicially available 5,6-dimethoxy-indole using Vilsmeier-Haack reaction (Advanced organic chemistry, Jerry March, 2^nd Ed. P715), following synthetic steps shown in Scheme 12.

Example 111: Synthesis of 3-[l-(4-Methoxy-benzenesulfonyl)-6-bromo-lH-indol-3-yl]propionic acid 134

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<img file="IL173079A_D0136.tif" />

[0491] Compound 134 is synthesized from commercially available 6-bromo-indole-3 caiboxaldehyde following synthetic steps shown in Scheme 12.

Example 112: Synthesis of 3-[ 1 -(4-Methoxy-benzenesulfonyi)-5-methoxy-1 H-indazol-3 yl]-propionic acid 135

<img file="IL173079A_D0137.tif" />

[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-[l-(4-Methoxy-benzenesulfonyl)-6-methoxy-lH-indazol-3yl]-propionic acid 136

<img file="IL173079A_D0138.tif" />

<img file="IL173079A_D0139.tif" />

[0493] Compound 136 is synthesized from commercially available 6-methoxy-indazole- 3carboxylic acid following synthetic steps shown in Scheme 9.

Example 114: Synthesis of 3-[l-(4-Methoxy-benzenesulfonyl)-5-methoxy-lH-7aza- indazol-3yl] -propionic acid 137

[0494] Compound 137 is synthesized from aldehyde 138, prepared from commercially available 7-azaindole as shown in Scheme 14, following synthetic steps shown in Scheme 12.

Scheme 14

0.

o.

[0495] Compound 139,5-bromo-7-azaindole, was prepared from commercially available

7-azaindole by following the procedure published by Mazeas, Daniel; Guillaumet, Gerald;

_01646801.\7.6=01-_____________________________________-_________________________________________________________________________________________________________________

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; MarieClaude Viaud, Heterocycles, 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 1-1, but which can also be incorporated in other bicyclic rings systems within Formula I.

Thiazolidione (TZD) and related analogs:

Scheme 14

<img file="IL173079A_D0140.tif" />

<img file="IL173079A_D0141.tif" />

[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:

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[0499] Compound XXI 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. Chem., 1994, 37, 3977-85.)

Hydroxamic acid:

Scheme 15

<img file="IL173079A_D0142.tif" />

[0500] Compound XXII can be prepared through either amide bond formation reaction with la or lb or nucleophilic displacement of the ester II or IXa with n-hydroxyamine. (Hurd et al, J. Am. Chem. Soc., 1954, 76, 2791 and Dinh, T.Q., Tet. Lett. 1996, 37, 11614)Tetrazole:

Scheme 16

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<img file="IL173079A_D0143.tif" />

la or lb ^R2 XXIII R₂

<img file="IL173079A_D0144.tif" />

[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 1:

[0502] The conversion of the carboxylic acid moiety to the corresponding amide XXIII with compound la or lb can be done with ammonia (gas) with ethyl polyphosphate in an inert solvent such as chloroform (hnamoto, T. et al, Synthesis, 1983, 142-3).

Step 2:

[0503] The propionamide XXIII can be converted to the nitrile XXIV by treating the amide with methyl magnesium iodide (Wilson et al, J. Chem 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. Chem., 1969,12, 396-401).

Iso-oxazoles:

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Scheme 17

<img file="IL173079A_D0145.tif" />

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, Synthesis, 1999, 275-81). The reaction with ethyl malonic acid affords XXIX. Cyclization with hydroxylamine provides the hydroxy protected isooxazole XXX. The deprotection of the hydroxy functionality arrives at the desired compound XXXI. (Frolund et al, J. Med. Chem., 2002, 45, 2454-2468)

Scheme 18

<img file="IL173079A_D0146.tif" />

Method 2:

[0506] The hydroxyiso-oxazole compound XXXI 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, Chem. Ber., 1913, 46, 2145) Subsequent removal of the methoxy group under reductive conditions and deprotection of the protection group and protection of the indole nitrogen leads to the desired compound XXXI. (Oster, T.A., et al, J. Org. Chem. 1983,48,2454-68)

Scheme 19

<img file="IL173079A_D0147.tif" />

<img file="IL173079A_D0148.tif" />

XXXIII ^R2

<img file="IL173079A_D0149.tif" />

XXXIV R2

<img file="IL173079A_D0150.tif" />

<img file="IL173079A_D0151.tif" />

<img file="IL173079A_D0152.tif" />

XXXVI r₂

OH

<img file="IL173079A_D0153.tif" />

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 XXXIV. Chlorination of XXXTV with chlorination reagents (e.g. NCS) arrive at intermediate XXXV. From the hydroxy iminium chloride, a cyclization with acetylene would afford the protected hydroxy iso-oxazole. The deprotection would provide the desired compound XXXI. (Weidner- Wells, M.A. et al, Bioorg. and Med Chem. Lett., 2004, 14,3069-72)

01646801\76-01

Acyl cyanamide:

Scheme 20

<img file="IL173079A_D0154.tif" />

la or Ib ^R2 XXXVII ^R2 XXXVIII ^R2

[0508] Compound XXXVIII can be prepared through a two step process starting from either la or Ib.

Step A

[0509] The carboxylic acid group in la or Ib can be converted to acyl 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. Chem., 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 XXXVIII. (Belletire, J.L. et al, Syn. Commun., 1988,18, 2063-72)

Sulfonamides:

Scheme 21

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<img file="IL173079A_D0155.tif" />

Μ׳«.

[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&amp;2:

[0512] Compound XXVII can be transformed to the corresponding alcohol XXXIX 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 l-(2-hydroxyethyl)-4,6-diphenylpyridine-2-.thione to get to the ethanethiol or propanethiol. (Gingras et al, Tet. Lett. 1990, 37,1397-1400, Maercker et al, Justus Liebigs Ann. Chem., 1865,136, 88, or Molina et al, Tetrahedron Lett., 1985, 25 469-472.)

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:

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[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 arrive 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

<img file="IL173079A_D0156.tif" />

[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 2:

[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:

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<img file="IL173079A_D0157.tif" />

Step 1: Preparation of intermediate XLVII:

[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 SN9 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 XLVIII: *י

[0521] Compound of formula XLVII can be converted to the corresponding sulfonly chloride with reagents such as PC1_3־ PC1_5־POC13, or SOC1₂.

Scheme 23b- Preparation of Compound of Formula L

<img file="IL173079A_D0158.tif" />

XLIX R = Me —_r

L R = H I KOH(aq)/THF

[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 THF.

Example 116: Synthesis of 3-{5-Methoxy-l-[4-(pyridin-3-yloxy)-benzeriesulfonyI]-lHindol-3-yl}-propionic acid 143.

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<img file="IL173079A_D0159.tif" />

[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-3p;ropionic ester or the corresponding acid as described in Scheme 7, 10, or 12.

Example 117: Synthesis of 3-{5־Methoxy־l-[4-(pyridin-4-yloxy)-benzenesulfonyl]-lHindol-3-yl}-propionic acid 144.

<img file="IL173079A_D0160.tif" />

[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-methoxyrindole-3p;ropionic ester or the corresponding acid as described in Scheme 7, 10, or 12.

Example 118: Synthesis of 3-{5-Methoxy-l-[4-(pyridin-4-yhuethoxy)-benzenesulfonyl]lH-indol-3-yl}-propionic acid 145.

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<img file="IL173079A_D0161.tif" />

<img file="IL173079A_D0162.tif" />

[0525] Compound 145 can be prepared through methods described in Scheme 23, using 4-hydroxybenzenesulfonic acid and 4-pyridylcarbinol to prepare the corresponding sulfonyl chloride. The various coupling of the sulfonyl chloride to 5-methoxy-indole-3p;ropionic ester or the corresponding acid as described in Scheme 7, 10, or 12.

Example 119: Synthesis of 3-(1-(3,5-Dichloro-behzenesulfonyl)-5-methoxy-lH-indol-3yl]-propionic acid 146 co₂h

I 0

זו

0־4 ך=ס f \\ )¾=/ 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-lH-indol3-yl]-propionic acid 147

<img file="IL173079A_D0163.tif" />

<img file="IL173079A_D0164.tif" />

[0527] Compound 147 can be prepared by reacting 5-methoxy-indole-3-propionic ester or the conesponding 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

<img file="IL173079A_D0165.tif" />

2. A“CHO

4. A = CH₂CH₂CO₂Me

<img file="IL173079A_D0166.tif" />

<img file="IL173079A_D0167.tif" />

Stepl: Preparation 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: Preparation of compound LIV or LV

[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.

01646801X76-01

Example 121: Synthesis of 3-{5-Methoxy־l-[4-(quinolin-7-ylan1inomethyl)benzenesulfonyl]-lH-indol3־-yl}-propionic acid 148

<img file="IL173079A_D0168.tif" />

<img file="IL173079A_D0169.tif" />

[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-{l-[4-(Isoquinolin-3-ylaminomethyl)-benzenesulfonyl]-5methoxy-lH-indol-3-yl}-propionic acid 149

<img file="IL173079A_D0170.tif" />

co₂h

[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]-lH-indoI-3-yl}-propionic acid 150

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<img file="IL173079A_D0171.tif" />

[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-Meth0xy-l-(4-py1T010[2,3-b]pyridin-l-ylmethylbenzenesulfonyl)-lH-indol-3-yl]-propionic acid 151

<img file="IL173079A_D0172.tif" />

[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-l-(4-phenoxymethyl-benzenesulfonyl)-lHindol-3-yl]propionic acid 152

<img file="IL173079A_D0173.tif" />

[0534] Compound 152 can be prepared via coupling of compound LII with the conesponding phenol with the bromomethyl moiety in Scheme 24.

General synthesis of compounds of formula LIX, LX, or LXI

Scheme 25

<img file="IL173079A_D0174.tif" />

Step 1: 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 LVIH:

[0536] The sulfonic acid can be converted to the corresponding sulfonyl chloride with PC13, POC13, POC15, or SOC12.

Step 3: Preparation of intermediate LIX:

[0537] The sulfonyl chloride LVIII can be coupled to the indole intermediates 4 to arrive at LIX.

01646801V76-01

PCT7US2004/023234

Step 4: Preparation of compound LX and LXI

[0538] The nitrile moiety can be further converted to either amide through hydrolysis or amine through reduction.

Example 126: Synthesis of 3-{5-Methoxy-l-[4-(py1־idin-3-ylmethoxy)-benzenesulfonyl]lH-indol-3-yl}-propionic acid 153

<img file="IL173079A_D0175.tif" />

[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- {1 -[4-(4-Aminomethyl-benzyloxy)-benzenesulfonyl]-5methoxy-lH-indol-3-yl}-propionic acid 154

<img file="IL173079A_D0176.tif" />

[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

WO 2005/009958 chloride can be prepared through coupling of the 4־hydroxy benzenesulfonic acid with 4cyanobenzyl bromide.

Example 128: Synthesis of 3-{l-[4-(4-Carbamoyl-benzyloxy)-benzenesulfonyl]-5methoxy-lH-indol-3-yl}-propionic acid 155

<img file="IL173079A_D0177.tif" />

[0541] Compound 155 can be prepared through hydrolysis 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 4cyanobenzyl bromide.

Example 129: Synthesis of compound 162:

Scheme 26

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<img file="IL173079A_D0178.tif" />

Step 1: Preparation of 5-Methox\>-lH-pyrrolo[3,2-b]pyridine 160

[0542] The title compound can be prepared through:

1. Reductive Cyclization with 158 (M. Mieczyslaw et.al, Liebigs Aim. 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-lH-py1rolo[3,2-b]pyridine-3-carbaldehyde 161

[0543] The intermediate 161 can be prepared either through Vilsmeier reaction (K-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

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<img file="IL173079A_D0179.tif" />

<img file="IL173079A_D0180.tif" />

<img file="IL173079A_D0181.tif" />

<img file="IL173079A_D0182.tif" />

Step 1: Preparation of intermediate 164, 5-Methoxy-lH-pyrrolo[2,3-c]pyridine:

[0545] 5-Methoxy-lH-py1Tolo[2,3-c]pyridine 164 can be prepared through cyclization of 6-methoxy-4-trimethylsilanyl ethytayl-pyri din-3-ylamine 163 with cuprous iodide in DMF (D. Mazeas et. al, Heterocycles, 1999, 50, 1065-80).

Step2: Preparation of intermediate 165, §*Methoxy-lH-pyrrolo[2,3-cJpyridine-3carbaldehyde:

[0546] 5-Methoxy-lH-pyrrolo [2,3-c]pyridine-3-carbaldehyde can be prepared from 165 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

<img file="IL173079A_D0183.tif" />

/°

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Step 1: Preparation of 168, 6-Chloro-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine:

[0548] l,2,3,5-Tetrahydro-pyrrolo[3,2-c]pyridin-6-one 167 can be converted to the 6Chl0r0-2,3-dihydr071H-pyrr010[3,2-c]pyridine 168 with Phosphorous oxychloride (N.N.

Bycliikhina et. al, Chem. Heterocycl. Compds., 1982, 18, 356-360)

Step2: Preparation of 169, 6-Methoxy-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine:

[0549] 6-Methoxy-2,3-dihydro-lH-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 of 170, 6-Methoxy-lH-pyrrolo[3J2-c]pyridine:

[0550] 6-Methoxy-2,3-dihydro-lH-pyrrolo[3,2ic]pyridine 169 is oxidized to the corresponding 170 with the use of MnO₂. (V.A. Azimov et.al, Chem. Heterocycl.Compd. 1981, 17,1648-1653)

Step 4: Preparation of 171, 6-Methoxy-lH-pyrrolo[3,2-c]pyridine-3carbaldehyde:

[0551] 6-Methoxy-lH-pyrrolo[3,2-c]pyndine-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

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<img file="IL173079A_D0184.tif" />

Step 1: preparation of 175

[0553] 2-chloro-7H-pyrrolo[2,3-d]pyrimidine 175 can be prepared from either 2-chloro5-(2-ethoxy-vinyl)-pyrimidin-4-ylamine 173 or 2-chloro-5-(2,2-dimetboxy-ethyl)pyrimidin-4-ylamine 174 (under reflux conditions in methanol with concentrated hydrochloric acid (M. Cheung et al, Tet. Lett., 2001, 42, 9991002־).

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, 312320.)

Step3: Preparation of 177

[0555] Intermediate 177 can be prepared from 176 through iodination of 176 with Iodine, with base mN,N־dimethylforman1ide at ambient temperature. (T., Sakamoto, Takao et.al, J.Chem.Soc.Perkin Trans.1, 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 CO2 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

<img file="IL173079A_D0185.tif" />

<img file="IL173079A_D0186.tif" />

<img file="IL173079A_D0187.tif" />

Step 1: Synthesis of intermediate 184

[0559] Intermediate 184 can be prepared from 3-acetyl-2-chloropyridine, through cyclization with methylhydrazine. (B.M. Lynch etal, 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.ab Canadian Journal of Chemistry, 1988,66,420-8)

Step 3: Synthesis of intermediate 186

01646801\76-01

[0561] The nitro group is reduced tine 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: Synthesis 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 KMnO4 oxidation to the carboxylic acid. (B.M. Lynch et.al, Canadian Journal of Chemistryfl 988, 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, PPAR8, 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 415, p813, for PPAR5 under code 1GWX, Xu, 1999, Mol Cell, 3, p397; and for PPARy under code 1PRG, Notle, et al, 1998, Nature, 395, pl 37. (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, 1I7G, and 1KK.Q for PPARalpha, 1PRG, 2PRG, 3PRG, 4PRG, 1K74, 1FM6, 1FM9, 1171, and IKNUfor PPARgamma, 1GWX, 2GWX, and 3 GWX for PPARdelta.

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[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 (frivitrogen), 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) andNM_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_005037 (mRNA sequence).

[0570] For PPARdelta the ligand binding domain used corresponded to amino acid 165441 of GenBank accession: NP_006229 (protein sequence) and NM_006238 (mRNA sequence).

[0571] Exemplary Crystallization conditions for PPARgamma:

1. Avith 2x molar excess of SRC-1 and ImM compound

0.2M Ammonium Acetate, 0.1M Bistris, pH 6.5,13-25%PEG4k, or -182WO 2005/009958

0.2M Ammonium Acetate, 0.1M Hepes, pH 7.5, 13-25%PEG4k

2. with 0.3 -1 mM compound

12-22% PEG 8k, 0.2M NaAcetate, 0.1M Hepes pH 7.5; or

0.6M- 1.0M NaCitrate, 0.1M Hepes pH 7.5; or

0.9-1.4M Ammonium. Sulfate, 0.IM Hepes pH 7.5

[0572] Crystallization conditions for PPARalpha:

1. with 2x molar excess of SRC-1 and ImM compound

- 30% PEG 4K, 0.2M Ammonium Acetate, 0.1M Citrate, pH 5.6; or

- 30% PEG4k, 0.2M Lithium Sulfate, 0.1M Tris/HCl, pH 8.5; or

- 30% PEG4k, 0.2M NaAcetate, 0.1M Tris/HCl, pH 8.5

2. with co-concentrated compound

0.6-1.0M Lithium Sulfate, 0.1M 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, 0.1M 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-3.0A, 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 cocrystal 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

WO 2005/009958 “structural water”. The structural water molecules are built into the structure model based on difference Fourier maps through the iterative refinement process. The compoundprotein 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.

TABLEI

<td> Number</td><td> Structure M. Wt</td><td> IUPAC name</td>

<td> 28</td><td> O N H 189.2</td><td> 3-(1 H-Indol-3 -yl)-propionic acid</td>

<td> 96</td><td> CH, 0. ό &gt;־OH N ^H 219.2</td><td> 3 -(5 -Methoxy-1 H-indol-3 -yl)propionic acid</td>

<td> 4</td><td> CH, O /¼ N 233.3</td><td> 3-(5-Methoxy-lH-indol-3-yl)propionic acid methyl ester</td>

<td> 29</td><td> Os 1r&gt; O °O 0-0</td><td> 3-(1 -Benzenesulfonyl-5-methoxy- lH-indol-3-yl)-propionic acid</td>

WO 2005/009958

<img file="IL173079A_D0188.tif" />

<td> 339.4</td><td> 3 - [ 5 -Methoxy-1-(3 -methoxybenzyl)-lH-indol-3-yl]-propionic acid</td>

<td> 343.8</td><td> 3-[l-(3-Chloro-benzyl)-5-methoxy- lH-indol-3-yl]-propionic acid</td>

<td> 327.3</td><td> 3-[ l-(4-Fluoro-benzyl)-5-methoxy- lH-indol-3-yl]-propionic acid</td>

<td> 343.8</td><td> 3-[ 1 -(4-Chloro-benzyI)-5-methoxylH-indoI-3-yl]-propionic acid</td>

<td> 339.4</td><td> 3-[5-Methoxy-1 -(2-methoxybenzyl)-lH-indol-3-yl]-propionic acid</td>

<td> 393.4</td><td> 3 -[5-Methoxy-1 -(2trifluoromethoxy-benzyl)-1 H-indol- 3-yl]-propionic acid</td>

<td> 393.4</td><td> 3 - [5 -Methoxy-1-(3trifluoromethoxy-benzyl)-1 H-indol- 3-yl]-propionic acid</td>

WO 2005/009958

<img file="IL173079A_D0189.tif" />

<td> 306.4</td><td> 3-(1 -Ethylthiocarbamoyl-5methoxy-1 H-indol-3-yl)-propionic acid</td>

<td> 373.4 •</td><td> 3-[5-Methoxy-1 -(toluene-4- sulfonyl)-1 H-indol-3-yl]-propionic acid</td>

<td> &lt; 329.4</td><td> 3-(1-Benzenesulfonyl-1 H-indol-3 yl)-propionic acid</td>

<td> 401.5</td><td> 3-(l-(4-Isopropyl- b enzenesulfonyl)- 5 -methoxy-1Hindol-3-yl]-propiomc acid</td>

<td> 415.5</td><td> 3-[l-(4-Isopropyl- benzenesulfonyl)-5-methoxy-1Hindol-3-yl]-propionic acid methyl ester</td>

<td> 431.5</td><td> 3-(1 -(4-Butoxy-benzenesulfonyl)- 5methoxy-1 H-indol-3-yl]-propionic acid</td>

<td> 445.5</td><td> 3-(1 -(4-Butoxy-benzenesulfonyl)5־methoxy-lH-indol-3-yl]-propionic acid methyl ester</td>

WO 2005/009958

<img file="IL173079A_D0190.tif" />

<td> 443.4</td><td> 3 - [5 -Methoxy-1 -(4trifluoromethoxy-benzenesulfonyl)lH-indol-3-yl]-propionic acid</td>

<td> 457.4</td><td> 3-[5-Methoxy-l-(4trifluoromethoxy-benzenesulfonyl)lH-indol-3-yl]-propionic acid methyl ester</td>

<td> &lt; ,4» 451.5</td><td> 3-[5,-:Methoxy-1 -(4-phenoxybenzenesulfonyl)-1 H-indol-3 -yl] propionic acid</td>

<td> 465.5</td><td> 3 - [ 5 -Methoxy-1 - (4-phenoxybenzenesulfonyl)-1 H-indol-3-yl]propionic acid methyl ester</td>

<td> 393.8</td><td> 3-[l-(4-Chloro-benzenesulfonyl)-5methoxy-1 H-indol-3 -yl] -propionic acid</td>

<td> 407.9</td><td> 3-[ 1 -(4-Chloro-benzenesulfonyl)-5methoxy-1 H-indol-3 -yl]-propionic acid methyl ester</td>

<td> 398.4</td><td> 3-[l-(4-Cyano-benzenesulfonyl)-5methoxy-1 H-indol-3-yl] -propionic acid methyl ester</td>

WO 2005/009958

<img file="IL173079A_D0191.tif" />

<td> 442.3</td><td> 3-(1-(3,4-Dichloro- benzenesulfonyl)-5-methoxy-1Hindol-3-yl]-propionic acid methyl ester</td>

<td> 403.4</td><td> 3-(5 -Methoxy-1 -(4-methoxyb enzenesulfonyl)1 ־ H-indol-3-yl] propionic acid methyl ester</td>

<td> t ,«V 441.4</td><td> 3-(5 -Methoxy-1 -(4-trifluoromethylb enzenesulfonyl)-1 H-indol-3 -yl] propionic acid methyl ester</td>

<td> 391.4</td><td> 3-(1 -(4-Fluoro-benzenesulfonyl)-5methoxy-1 H-indol-3 -yl] -propionic acid methyl ester</td>

<td> 379.4</td><td> 3 -(5-Methoxy-1 -(thiophene-2sulfonyl)-1 H-indol-3-yl] -propionic acid methyl ester</td>

<td> 365.4</td><td> 3-(5 -Methoxy-1 -(thiophene-2sulfonyl)-1 H-indol-3-yl] -propionic acid</td>

<td> 368.4</td><td> 3-(5-Methoxy־l- phenylthiocarbamoyl-lH-indol-3yl)-propionic acid methyl ester</td>

WO 2005/(109958

<td> 75</td><td> 0 I y-0H pu J I 3-(5-Methoxy-l- υύλ phenylthiocarbamoyl-lH-indol-3- hn' _n . . L yl)-prop1omc acid O 354.4</td>

<td> 58</td><td> 0 --—— -- V־° CH, J CH, °Y0 3-[5-Methoxy-l-(3-phenoxy- benzenesulfonyl)-lH-indol-3-yl]- 0 propionic acid methyl ester 0 465.5</td>

<td> 60</td><td> 0 y-0 CH —׳ CH₃ I 3-[l-(3«Fh10ro-benzenesulfonyl)-5- י methoxy-lH-indol-3-yI]-propionic 0) ° acid methyl ester V 391.4</td>

<td> 62</td><td> 0 l. --- V⁰־־ CH₃ J CH3 °ΥΥ( 3-[5-Methoxy-l-(toluene-3- sulfonyl)-lH-indol-3-yl]-propionic 0) acid methyl ester cu, 387.4</td>

<td> 64</td><td> c&gt; ¼-0 CH M CH₃ 3-[l-(3-Chloro-benzenesulfonyl)-5- methoxy-lH-1ndol-3-yl]-propiomc 01 ⁰ acid methyl ester b 407.9 ן</td>

<td> 66</td><td>₀ ' ־־-------'-----------ך----------------------- V⁰־. 9^H3 ^CH3 3-[5-Methoxy-l-(3-methoxy- benzenesulfonyl)- lH-indol-3-yl]propionic acid methyl ester h₃c403.4 °׳</td>

<td> 68</td><td> Q ־. .--—---- v־° CH3 ־ J ^CH3 3-[5-Methoxy-l-(3-trifluoromethyl- 1° benzenesulfonyl)-lH-indol-3-yl]- L? propionic acid methyl ester fV 441.4</td>

WO 2005/009958

HO

<img file="IL173079A_D0192.tif" />

<img file="IL173079A_D0193.tif" />

O

<img file="IL173079A_D0194.tif" />

<td> 384.4</td><td> 3-[ 1 -(4-Cyano-benzenesulfonyl)-5methoxy-1 H-indol-3-yl]-propionic acid</td>

<td> 428.3</td><td> 3-[l-(3,4-Dichloro- b enzenesulfonyl)-5 -methoxy-1Hindol-3-yl]-propionic acid</td>

<td> 389.4</td><td> 3-[§-Methoxy-l -(4-methoxybenzenesulfonyl)-1 H-indol-3 -yl] propionic acid</td>

<td> . 427.4</td><td> 3 - [5 -Methoxy-1 -(4-trifluoromethylbenzenesulfonyl)-1 H-indol-3 -yl] propionic acid</td>

<td> 377.4</td><td> 3 - [ 1 -(4-Fluoro-benzenesulfonyl)- 5 methoxy-1 H-indol-3-yl]-propionic acid</td>

<td> 373.4</td><td> 3-(1 -Benzenesulfonyl-5-methoxylH-indol-3-yl)-propionic acid methyl ester</td>

<td> 309.4</td><td> 3-(1 -Benzyl-5-methoxy-1 H-indol3-yl)-propionic acid</td>

WO 2005/009958

<img file="IL173079A_D0195.tif" />

HO

<img file="IL173079A_D0196.tif" />

<img file="IL173079A_D0197.tif" />

<img file="IL173079A_D0198.tif" />

<img file="IL173079A_D0199.tif" />

<img file="IL173079A_D0200.tif" />

<img file="IL173079A_D0201.tif" />

<img file="IL173079A_D0202.tif" />

<img file="IL173079A_D0203.tif" />

<img file="IL173079A_D0204.tif" />

<td> 323.4</td><td> 3-(l-Benzyl-5-methoxy-lH-indol3-yl)-propionic acid methyl ester</td>

<td> 451.5</td><td> 3-[5-Methoxy-l -(3-phenoxybenzenesuIfonyl)-lH-indol-3-yl]propionic acid</td>

<td> 377.4</td><td> 3-[ 1 -(3&lt;Fluoro-benzenesulfonyl)-5- methoxy-lH-indol-3-yl]-propionic acid</td>

<td> 373.4</td><td> 3-[5-Methoxy-l-(toluene-3sulfonyl)-1 H-indol-3-yl] -propionic acid</td>

<td> 393.8</td><td> 3-[l-(3-Chloro-benzenesulfonyl)-5methoxy-1 H-indol-3 -yl] -propionic acid</td>

<td> 389.4</td><td> 3 - [5-Metlioxy-1-(3 -methoxybenzenesulfonyl)-1 H-indol-3-yl] propionic acid</td>

<td> 427.4</td><td> 3 - [5-Methoxy-1-(3 -trifluorom ethylbenzenesulfonyl)-lH-indol-3-yl]~ propionic acid</td>

<img file="IL173079A_D0205.tif" />

<td> 408.3</td><td> 3-(1 -Benzenesulfonyl-5-bromo-lHindol-3-yl)-propionic acid</td>

<td> 443.4</td><td> 3-[5-Methoxy-l-(3trifluoromethoxy-benzenesulfonyl)lH-indol-3-yl]-propionic acid</td>

<td> 457.4</td><td> 3-[5-Methoxy-l-(3trifluoromethoxy-benzenesulfonyl)lH-indol-3-yl]-propiomc acid methyl ester</td>

<td> 415.5</td><td> 3-[l-(4-ButyI-benzenesulfonyl)-5- methoxy-lH-indol-3-yl]*propionic acid</td>

<td> 429.5</td><td> 3-[l-(4-Butyl-benzenesulfonyl)-5- methoxy-lH־indol~3-yl}־propionic acid methyl ester</td>

<td> 425.5</td><td> 3-(1 -Benzenesulfonyl-5-thiophen- 3-yl !-lH-indol-3-yl)-propionic acid methyl ester</td>

<td> 419.5</td><td> 3-(1 -Benzenesulfonyl-5-phenyl-lHindol .-3-yl)-propionic acid methyl ester</td>

01646801\76-01

<img file="IL173079A_D0206.tif" />

<td> 337.4</td><td> 3-(l-Benzoyl-5-methoxy-lH-indol3-yI)-propionic acid methyl ester</td>

<td> 323.3</td><td> 3-(l-Benzoyl-5-methoxy-lH-mdol- 3-yl)-propionic acid</td>

<td> 411.5</td><td> 3-(l-Benzenesulfonyl-5-thiophe11- 3-yl .-lH-indol3־-yl)-propionic acid</td>

<td> 405.5</td><td> 3-(l-Benzenesulfonyl-5-phenyl-lHindol -3-yl)-propionic acid</td>

<td> 373.4</td><td> 3-(1 -Benzenesulfonyl-5-ethoxy-lHindol -3־yl)-propionic acid</td>

<td> 417.5</td><td> 3-[l-(4-Isopropoxybenzenesulfonyl) -5-methoxy-lH-indol-3-yl]propionic acid</td>

0164680 676-01

<img file="IL173079A_D0207.tif" />

<td> 352.4</td><td> 3-(5־Methoxy-l-phenylcarbamoylΙΗ-indol -3-yl)-propio11ic acid methyl ester</td>

<td> 387.5</td><td> 3-[l-(4-Ethyl-benzenesulfonyl)-5methoxy -lH-indol3־-yl]-propiomc acid</td>

<td> 338.4</td><td> 3-(5-Methoxy-l-phenylcarbamoylIH-indol -3-yI)-propionic acid</td>

<td> 357.4</td><td> 3-(l-Benzenesulfonyl-5־ethyl-lHindol -3-yl)-propionic acid</td>

<td> 387.5</td><td> 3-(l-Benzenesulfonyl-5isopropoxy- IH-indol -3-yl)-propionic acid</td>

<td> 365.4</td><td> 3-[5-Methoxy- l-(thiophene-3sulfonyl -lH-indol-3-yl]-propio1nc acid</td>

<td> 190.2</td><td> Ihdazole-3-propionic acid</td>

01646801\76-01

<img file="IL173079A_D0208.tif" />

<td> 330.4</td><td> 3-(1 -Benzenesulfonyl-IH-indazol- 3-yl -propionic aoid</td>

<td> 190.2</td><td> 3-(lH-Pynolo[2j3-b]pyridin-3-yl)propionic acid</td>

<img file="IL173079A_D0209.tif" />

<td> 419.5</td><td> 3-(1-(3,4-Dimethoxybenzenesulfonyl)-5-methoxy-lH־ indol-3-yl]-propionic acid</td>

<td> 396.4</td><td> 3-(1 -(3,4-DifhiorobenzenesulfonyI)-5-methoxy-lHindol-3-yl]-propionic acid</td>

<td> 407.8</td><td> 3-(l-(3-cHoro-4-methylbenzenesuIfonyl)-5-methoxy-lHindol-3-yl]-propionic acid</td>

<td> 347.5</td><td> 3-(1 -(benzenesulfonyl)-5-fluorolH-indol-3-yl]-propionic acid</td>

<td> 323.2</td><td> 3-(l״(benzenesulfonyl)-5-methyl- LH-indol-3-yl]-propionic acid</td>

01646801X76-01

<img file="IL173079A_D0210.tif" />

<td> 363.7</td><td> 3-[l-(benzenesulfonyl)-5-chloro- lH-indol-3-yl]-propionic acid</td>

<td> 391.3</td><td> 3-[ 1 -(3-fluoro-4-methyl- benzenesulfonyl)-5-methoxy-1Hindol-3-yl]-propionic acid</td>

<td> ׳%, 401.2</td><td> 3- [ 1 -(2,3 -Dihydro-b enzofuran-5 sulfonyl)-5-methoxy- lH-indol-3 yl]-propionic acid</td>

<td> 401.5</td><td> 3-[ 1 -(4-etl1yl-benzenesulfonyl)-5ethoxy-lH-indol-3-yl]-propionic acid</td>

<td> 403.6</td><td> 3-(1 -(4-methoxy-benzenesulfonyl)5-ethoxy-lH-indol-3-yI]-propionic acid</td>

<td></td><td> 3-(1-(3 -trifluoromethoxybenzenesulfonyl)-5-ethoxy-1Hindol-3-yl]-propionic acid</td>

<td> 429.4</td><td> 3-[ 1 -(4-butyl-benzenesulfonyl)-5ethoxy-1 H-indol-3 -yl]-propionic acid</td>

WO 2005/009958

<img file="IL173079A_D0211.tif" />

<img file="IL173079A_D0212.tif" />

<td> 445.5</td><td> 3-[l-(4-butoxy-benzenesulfonyl)-5- ethoxy-1 H-indol-3-yl]-propionic acid</td>

<td> 442.2</td><td> 3-[l-(3,4-dichloro- benzenesulfonyl)-5-ethoxy-lH- indol-3-yl]-propionic acid</td>

<td> 403.5</td><td> 3-[ 1 -(3־tnethoxy-benzenesulfonyl)5-ethoxy- lH-indoI-3 -yl]-propionic acid</td>

<td> 465.3</td><td> 3-[l-(4-phenoxy-benzenesulfonyl)5-ethoxy-1 H-indoI-3 -yl] -propi onic acid</td>

<img file="IL173079A_D0213.tif" />

<img file="IL173079A_D0214.tif" />

<td> 452.58</td><td> 3-{5-Methoxy-l-[4-(pyridin-3yloxy)-benzenesulfonyl]-l H-indol3-yl}-propionic acid</td>

<td> 452.58</td><td> 3-{5-Methoxy-1-[4-(pyridin-4yloxy)-b enzenesulfonyl] -1 H-indol3-yl}-propionic acid</td>

WO 2005/009958

<img file="IL173079A_D0215.tif" />

Cl

<img file="IL173079A_D0216.tif" />

<img file="IL173079A_D0217.tif" />

<img file="IL173079A_D0218.tif" />

<td> 466.51</td><td> 3- {5-Methoxy-l -[4-(pyridin-4ylmethoxy)-b enzenesulfonyl] -1Hindol-3-yl}-propionic acid</td>

<td> 428.29'</td><td> 3-[l-(3,5-Dichlorobenzenesulfonyl)-5-methoxy-lHindol-3־yl]-propionic acid</td>

<td> ‘X 419.45</td><td> 3,5)-1 ] - ל-Dimethoxybenzenesulfony 1)-5 -methoxy-1Hindol-3-yl]-propionic acid</td>

<td> 515.58</td><td> 3- {5-Methoxy-1 -[4-(quinolin-7ylaminomethyl)־b enzenesulfonyl] IH-indo 1-3-yl}-propionic acid</td>

<td> 515.58</td><td> 3 - {1 -[4-(Isoquinolin-3ylaminomethyl)-b enzenesulfonyl] 5-methoxy-1 H-indol-3-yl} propionic acid</td>

<td> 515.58</td><td> 3- {5-Methoxy-1 -[4-(quinolin-6ylaminomethyl)-benzenesulfonyl]lH-indol-3-yl}-propionic acid</td>

WO 2005/009958

<img file="IL173079A_D0219.tif" />

<td> 489.54</td><td> 3-[5-Methoxy-l-(4-pyrrolo[2,3b]pyridin-1 -ylmethylbenzenesulfonyl)-lH-indol-3-yl]propionic acid</td>

<td> 465.53</td><td> 3 -[5-Methoxy-1 -(4phenoxymethyl-benzenesulfonyl)lH-indol-3-yl]propionic acid</td>

<td> &amp; 466.51</td><td> 3-{5“Methoxy-l-[4-(pyridin-3- . ylmethoxy)-benzenesulfonyl]-lHindo 1-3-yl}-propionic acid</td>

<td> 494.57</td><td> 3 - {1 - [4-(4-Aminomethylbenzyloxy)-benzenesulfonyl]-5methoxy-1 H-indol-3-yi} -propionic acid</td>

<td> 508.55</td><td> 3- {1 -[4-(4-Carbamoyl-benzyloxy)benzenesulfonyl]-5-methoxy-1Hindol-3-yl} -propionic acid</td>

[0576] Agonist activities for exemplary compounds from Table 1 were determined, and are shown in Table 2, where + indicates activity <10 μΜ, and indicates >10 μΜ. These activities were determined as described in Example 1.

Table!

<td> Compound #</td><td> PPARa agonist (μΜ)</td><td> PPARS Agonist (μΜ)</td><td> PPARy Agonist (μΜ)</td>

<td> 29</td><td> 4*</td><td> +</td><td> +</td>

<td> 97</td><td> •</td><td> M</td><td></td>

<td> 39</td><td> -</td><td> -</td><td> -</td>

<td> 43</td><td> +</td><td> +</td><td> +</td>

<td> 49</td><td> +</td><td> +</td><td> +</td>

<td> 75</td><td> -</td><td> •</td><td> -</td>

<td> 53</td><td> +</td><td> 4.</td><td> 4*</td>

<td> 71</td><td> 4.</td><td> *</td><td> *</td>

<td> 79</td><td> +</td><td> 4.</td><td> +</td>

<td> 77</td><td> +</td><td> +</td><td> +</td>

<td> 81</td><td> +</td><td> •</td><td> -</td>

<td> 92</td><td> +</td><td> M</td><td> +</td>

<td> 82</td><td> ״4</td><td> +</td><td> ז-</td>

<td> 85</td><td> •</td><td> -</td><td> -</td>

<td> 8</td><td> •</td><td> -</td><td></td>

Table 3

<td> MOLECULAR STRUCTURE</td><td> molecular weight</td><td> MOLECULAR NAME</td>

<td> ו</td><td> 251.284</td><td> 5-BENZYLOXYINDOLE-3- CARBOXALDEHYDE</td>

<td> 0/</td><td> 159.187</td><td> 4-METHYLINDOLE-3-ALDEHYDE</td>

01646801X81-01

<td> .N</td><td> 159.187</td><td> 6-METHYLINDOLE-3- CARBOXALDEHYDE</td>

<td> o h</td><td> 251.284</td><td> 7-BENZYLOXYINDOLE-3- CARBOXALDEHYDE</td>

<td> o '8</td><td> 251.284</td><td> 6-BENZYLOXYINDOLE-3- CARBOXALDEHYDE</td>

<td> o \ / o</td><td> 179.605 ,%</td><td> 2-CHLORO-1H-INDOLE-3- CARBALDEHYDE</td>

<td> qJE</td><td> 251.284</td><td> 4-BENZYLOXYINDOLE-3- CARBOXALDEHYDE</td>

<td> 0 '.¹׳ci</td><td> 203.196</td><td> 3-FORMYLINDOLE-5- CARBOXYLIC ACID METHYL ESTER</td>

<td> °^/ ΓΟ ס, H,C Vn^N 0</td><td> 203.196</td><td> METHYL 3-FORMYLINDOLE-6- CARBOXYLATE</td>

<td> ° /^° N. J 0־ YYy__CH3</td><td> 204.184</td><td> 3-FORMYL-2-METHYL-5- NITROINDOLE</td>

<td> /^==° to CTOH</td><td> 189.169</td><td> 3-FORMYL-1H-INDOLE-7- CARBOXYLIC ACID</td>

<td> y) T u I o 1 5</td><td> 231.25</td><td> TIMTEC-BB ST002282</td>

WO 2005/009958

<td></td><td></td><td></td>

<td> J Otj y^^N^ -Nk 0 ^XO</td><td> 190.157</td><td> 7-NITROINDOLE-2- CARBOXALDEHYDE</td>

<td> O z׳ z ¹o-z w o</td><td> 190.157</td><td> 5-NITROINDOLE-3- CARBOXALDEHYDE</td>

<td> hW / ' Vw'N</td><td> 170.17</td><td> 5-CYANOINDOLE-3-ALDEHYDE *4«u</td>

<td> o</td><td> 249.268</td><td> 6-BENZOYL-1H-INDOLE-3- CARBOXALDEHYDE</td>

<td> 0 ^-0 c/w</td><td> 249.268</td><td> 5-BENZOYL-1H-INDOLE-3- CARBOXALDEHYDE</td>

<td> o i cO Hfi''</td><td> 173.214</td><td> 7-ETHYL-1H-INDOLE-3- CARBOXALDEHYDE</td>

<td> r^° KN. J m CIH</td><td> 196.636</td><td> 5-AMINO-1H-INDOLE-3- CARBOXALDEHYDE HYDROCHLORIDE</td>

<td> 0 \י 0 / ח ΤΛ| ץ ^c%&lt;</td><td> 207.252</td><td> 5-METHYLSULPHINYLINDOLE-3- CARBOXALDEHYDE</td>

<td> 0 Od F</td><td> 163.15</td><td> 7-FLUOROINDOLE-3- CARBOXALDEHYDE</td>

WO 2005/009958

<td rowspan="8"></td><td> /^° - fT&gt; II 0</td><td> 191.145</td><td> 6-NITRO-1H-INDAZOLE-3- CARB ALDEHYDE</td>

<td> o MH d \^=j</td><td> 204.184</td><td> METHYL-3-AL-4-IND AZOLE CARBOXYLATE</td>

<td> o</td><td> 151.595</td><td> 6-CHLOROINDOLE</td>

<td> o A</td><td> 131.177 t</td><td> 6-METHYLINDOLE 1״4י</td>

<td> o 'o-A ry#</td><td> 162.147</td><td> 7-NITROINDOLE</td>

<td> jXO</td><td> 142.16</td><td> 6-CYANOINDOLE</td>

<td> / o \ Ω</td><td> 177.202</td><td> 5,7-DIMETHOXY INDOLE</td>

<td>^H3°X /׳CxL j ³ 0 .׳ N</td><td> 147.176</td><td> 6-METHOXYINDOLE</td>

<td colspan="2"> ”A 0 1 r־^</td><td> 253.299</td><td> 5-BENZYLOXY-6- METHOXYINDOLE</td>

WO 20(15/009958

<td> r^NV/⁰'^CH3</td><td> 147.176</td><td> 7-METHOXYINDOLE</td>

<td>_Z^N\_ 9׳</td><td> 162.147</td><td> 6-NITROINDOLE</td>

<td> 1/² J—I o</td><td> 145.204</td><td> 7-ETHYLINDOLE</td>

<td>^h3^cx ^{3 x}0 N</td><td> 163.175</td><td> 5-HYDROXY-6-METHOXYINDOLE</td>

<td> 0 H,CX JL ⁰ CFI</td><td> 175.186</td><td> METHYL INDOLE-5- CARBOXYLATE</td>

<td> 2f/=^O 0-0</td><td> 175.186</td><td> METHYL INDOLE-6- CARBOXYLATE</td>

<td> o /=\ pH-/ £ ^z\/</td><td> 175.186</td><td> METHYL INDOLE-7- CARBOXYLATE</td>

<td> ־JjO ^־־־^ n ^׳^ \־׳\ ✓N r n °X_^</td><td> 273.334</td><td> N-(4- MORPHOLINOETHYL)INDOLE-6- CARBOXAMIDE</td>

<td> ־²־ λ=Λ. 3Γ Μ &gt; λ—ζ 3Γ</td><td> 204.228</td><td> N-METHOXY-N-METHYL-INDOLE- 6-CARBOXAMIDE</td>

<td>^ργ00 F F</td><td></td><td></td>

WO 2005/009958

PC17US2004/023234

<td> 0</td><td> 159.187</td><td> 5-ACETYLINDOLE</td>

<td> מץ _.Ν&gt;. 0 0</td><td> 241.044</td><td> 5-BROMO-7-NITROINDOLE</td>

<td> Br</td><td> 196.046</td><td> 7-BROMOINDOLE</td>

<td> On '''p 'I'T F</td><td> 135.14 t</td><td> 7-FLUOROINDOLE</td>

<td> ח T1T&gt; ° w</td><td> 174.202</td><td> 5-ACETAMIDOINDOLE</td>

<td> Cl -----—___</td><td> 151.595</td><td> 7-CHLOROINDOLE</td>

<td></td><td> 147.176</td><td> INDOLE-5-METHANOL</td>

<td> ״no</td><td> 147.176</td><td> INDOLE-6-METHANOL</td>

<td> co Y^N HCj</td><td> 147.176</td><td> INDOLE-7-METHANOL</td>

<td> 0 II ^Ss, ^h3C VjfA WW ''N</td><td> 179.242</td><td> 5-METHYLSULPHINYLINDOLE</td>

WO 2005/009958

<td></td><td></td><td></td>

<td> h,c^ JLy II 0 ________</td><td> 179.242</td><td> 6-METHYLSULPHINYLINDOLE</td>

<td> F F ^F w/w-j</td><td> 185.147</td><td> 5-(TRIFLUOROMETHYL)INDOLE</td>

<td> &lt;11 A ^N '^x^^X־N^/XNH₂</td><td> 191.257</td><td> N-(lH-INDOL-6-YL)THIOUREA</td>

<td> fc ק |TA Br</td><td> 226.072</td><td> 7-BROMO-5-METHOXYINDOLE</td>

<td> Xo S^%W־-N H,C A ³ 0</td><td> 195.241</td><td> 6-(METHYLSULFONYL)-lH- INDOLE</td>

<td> N—\ .0 vA 0</td><td> 163.135</td><td> 5-NITROIND AZOLE</td>

<td> N ,0 vrv^N: —⁰</td><td> 163.135</td><td> 6-NITROIND AZOLE</td>

<td> N—N &lt;?־ &lt; ΧΛ u</td><td> 163.135</td><td> 7-NITROIND AZOLE</td>

<td> 0j r—N o</td><td> 183.213</td><td> ACB-B LOCKS PYR-0331</td>

WO 2005/009958

<td></td><td> 183.213</td><td> ACB-BLOCKS PYR-0332</td>

<td> /A/A Y!l l i'</td><td> 206.272</td><td> N-(6-METHYL-lH-INDAZOL-5- YL)THIOUREA</td>

<td> s N^NH, ^NOU</td><td> 192.245</td><td> N-( 1 H-INDAZOL-7-YL)THIOUREA</td>

<td> ΛΛ Λ N mi-L,</td><td> 192.245 t</td><td> N-(l H-INDAZOL-6-YL)THIOUREA</td>

<td> BC^^'N</td><td> 197.035</td><td> 6-BROMOINDAZOLE</td>

<td> 0 1 |l 1 ,n !!,c</td><td> 190.201</td><td> ETHYL 1H-INDAZOLE-5- CARBOXYLATE</td>

<td> ru m</td><td> 211.061</td><td> CBI-BB ZERO/005553</td>

<td> ho^/x/\־A ll׳^N</td><td> 148.164</td><td> 5-HYDROXYMETHYL-1H- INDAZOLE</td>

[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 6membered ring are excluded, and the 6-membered ring includes at least one alkoxy or -207WO 2005/009958 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 -CH2CH2- linker at the 3position; 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.

<img file="IL173079A_D0220.tif" />

L

Ar

A

Table 4

<td colspan="3"> 1</td><td> 3</td><td> 5</td><td> 6</td>

<td> L</td><td> Ar</td><td> A</td><td></td><td></td><td></td>

<td> so₂</td><td> phenyl</td><td></td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> CF₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch₂cf₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> OCH3</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> och,ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> och₂ch₂ch₃</td><td> COOH________</td><td> methoxy</td><td></td>

WO 2005/009958

<td> SO,</td><td> phenyl</td><td> OCH₂CH₂CH,CH₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> OCH₂CH₂CH₂CH₂CH₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> C5-CS alkoxy</td><td> COOH</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO,</td><td> phenyl</td><td> ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> CH₂CH₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> CH₂CH,CH₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> ch₂ch,ch₂ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> F</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> F,F</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> F,C1</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> Cl</td><td> COOH</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Cl,Cl</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)־optionally subst. aryl</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> pyridinyl</td><td></td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> cf₃</td><td> COOH?»</td><td> methoxy</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> ch,cf₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> OCH₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> och,ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och₂ch₂ch₃</td><td> ' COOH</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och₂ch,ch₂ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> och₂ch₂ch,ch₂ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> CH₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO₂</td><td> Pyridinyl</td><td> ch₂ch₂ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO₂</td><td> Pyridinyl</td><td> ch₂ch₂ch₂ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO,</td><td> Pyridinyl</td><td> F</td><td> COOH</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,F</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO,</td><td> Pyridinyl</td><td> F,C1</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO₂</td><td> Pyridinyl</td><td> Cl</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> Cl,Cl</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO₂</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> methoxy</td><td> •</td>

<td> so.</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td></td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> cf₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂cf₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och,ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch,ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl'</td><td> och₂ch,ch,ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch₂ch₂ch,ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> methoxy</td><td></td>

WO 2005/009958

<td> co</td><td> Phenyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH,</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₂CH₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₂ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₂CH,CH₂CH3</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ־C5-C8 alkyl</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,F</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,C1</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl</td><td> COOFI</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl,Cl</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> pyridinyl</td><td></td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CF₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH2CF3</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted allcyl</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH3</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH₂CH3</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH₂CH₂CH₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och,ch₂ch₂ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> 0CH₂CH₂CH₂CH₂CH3</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₂ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₂ch₂ch₃</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,F</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,C1</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl,Cl</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> methoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td></td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> CF₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch,cf₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted allcyl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> OCH₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> och₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> och₂ch₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> och₂ch₂ch₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> och₂ch₂ch₂ch₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> CH₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> CH2CH3</td><td> COOH</td><td> ethoxy</td><td></td>

WO 2005/009958

<td> SO2</td><td> phenyl</td><td> CH₂CH,CH₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> ch₂ch₂ch,ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> C5-C8 allcyl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> F</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,F</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,C1</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Cl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> C1,CI</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> -(1 to 4 linearly linked atom liriker)-optionally subst. aryl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> pyridinyl</td><td></td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> CF₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch,cf₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> 0CH3</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> OCH₂CH3</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och,ch,ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och₂ch₂ch₂ch₃</td><td> COOH;־</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och₂ch₂ch₂ch₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> CH₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch,ch₂ch,ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> SO₂.</td><td> Pyridinyl</td><td> F</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,F</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,C1</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Cl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Cl,CL</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionaUy subst. heteroaryl</td><td> COOH</td><td> ethoxy</td><td> .</td>

<td> co</td><td> Phenyl</td><td></td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CF₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch,cf₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH,CH,CH₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₂CH₂CH₂CH3</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₂CH₂CH₂CH,CH₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₂CH₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch,ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₂ch₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkyl</td><td> COOH |</td><td> ethoxy</td><td></td>

WO 2005/009958

<td> CO</td><td> Phenyl</td><td> F</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,F</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F.Cl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl,Cl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> pyridinyl</td><td></td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CF₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH₂CF3</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH3</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH2CH3</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH₂CH₂CH₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch,ch,ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch,ch₂ch₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH₂CH₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch,ch₂ch₂ch₃</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,F</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,C1</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl,Cl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> ethoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td></td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> CF₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch₂cf₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> OCH₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂ ־</td><td> phenyl</td><td> OCH₂CH₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> OCH₂CH,CH3</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> och₂ch₂ch,ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> OCH,CH₂CH₂CH₂CH3</td><td> COOH</td><td> propoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> propoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> CH3</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch,ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> ch₂ch₂ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> ch,ch,ch₂ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> C5-C8 allcyl</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> F</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> F,F</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> F,C1</td><td> COOH</td><td> propoxy</td><td></td>

WO 2005/009958

<td> so₂</td><td> phenyl</td><td> Cl</td><td> COOH</td><td> propoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> Cl,CI</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally sub st. aryl</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally sub st. heteroaryl</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> pyridinyl</td><td></td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> CF₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂cf₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Halo substituted allcyl</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> OCH₂CH3</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och,ch,ci-i₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och₂ch₂ch,ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och,ch₂ch₂ch,ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so_z</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> CH₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch,ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch,ch₃</td><td> cooft</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch,ch₂ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> F</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,F</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,C1</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Cl</td><td> COOH</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Cl,Cl</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> propoxy</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td></td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CF₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂cf₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted allcyl</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₂CH₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och,ch,ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och,ch,ch₂ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₂CH,CH_zCH,CH3</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch,ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₂ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch,ch,ch,ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,F</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,C1</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl,Cl</td><td> COOPI</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked</td><td> COOH</td><td> propoxy</td><td></td>

WO 2005/009958

<td></td><td></td><td> atom linker)-optionally subst. aryl</td><td></td><td></td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly Indeed atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> pyridinyl</td><td></td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> cf₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂cf₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> 0CH3</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH₂CH₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch₂ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch₂ch,ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch,ch,ch₂ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Plalo substituted alkoxy</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₂ch₃</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH,CH,CH,CH3</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,F</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,C1</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl,Cl</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td></td><td> COOH</td><td> -SCH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> cf₃</td><td> COOH</td><td> -SCH3</td><td></td>

<td> SO₂</td><td> phenyl</td><td> ch₂cf₃</td><td> COOH</td><td> -SCH3</td><td></td>

<td> so.</td><td> phenyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> -SCH₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> OCH3</td><td> COOH</td><td> -SCH₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> OCH2CH3</td><td> COOH</td><td> -SCH₃</td><td></td>

<td> so.</td><td> phenyl</td><td> OCFI,CH₂CH₃</td><td> COOH</td><td> -SCH3</td><td></td>

<td> so.</td><td> phenyl</td><td> och,ch,ch₂ch₃</td><td> COOH</td><td> -SCH3</td><td></td>

<td> so.</td><td> phenyl</td><td> och₂ch₂ch₂ch₂ch₃</td><td> COOH</td><td> -SCH₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO2</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> CH₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> ch,ch₃</td><td> COOH .</td><td> -SCH3</td><td></td>

<td> so.</td><td> phenyl</td><td> ch,ch₂ch₃</td><td> COOH</td><td> -SCH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch₂ch,ch₂ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> F</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,F</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,C1</td><td> COOH</td><td> -SCH3</td><td></td>

<td> so.</td><td> phenyl</td><td> Cl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> Cl,Cl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> -(1 to 4 linearly linked</td><td> COOH</td><td> -sch₃</td><td></td>

WO 2005/009958

<td></td><td></td><td> atom linker)-optionally subst. heteroaryl</td><td></td><td></td><td></td>

<td> so.</td><td> pyridinyl</td><td></td><td> COOH</td><td> -SCH₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> cf₃</td><td> COOFI</td><td> -SCH3</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> ch,cf₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> Halo substituted alkyd</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> OCH₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> OCH₂CH3</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> OCH₂CH₂CH3</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> OCH,CH,CH2CH₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO₂ ’</td><td> Pyndmyl</td><td> och,ch₂ch,ch,ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> CH₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> ch,ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> CH₂CH₂CH₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> CH₂CH,CH₂CH3</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> F</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> F,F</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> F,C1</td><td> COOH</td><td> -sch₃</td><td></td>

<td> SO,</td><td> Pyridinyl</td><td> Cl</td><td> COOH»’</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Cl,Cl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td></td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> cf₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₂CF₃</td><td> COOH</td><td> -SCH,</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> -SCH3</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH2CH₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch,ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch₂ch₂ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH2CH₂CH,CH,CH₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> ch,ch,ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> ch,ch₂ch,ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> F</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> F,F</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> F,C1</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl,Cl</td><td> COOH</td><td> -SCH3</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linkeij-optionally subst. heteroaryl</td><td> COOH</td><td> -SCH3</td><td></td>

<td> co</td><td> pyridinyl</td><td></td><td> COOH</td><td> -SCH3</td><td></td>

WO 2005/009958

<td> CO</td><td> Pyridniyl</td><td> cf₃</td><td> COOH</td><td> -SCH3</td><td> '</td>

<td> co</td><td> Pyridinyl</td><td> ch,cf₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> -SCH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och,ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch,ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och,ch₂ch₂ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch₂ch₂ch,ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> -SCH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> -SCH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch,ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₂ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch,ch,ch₂ch₃</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F</td><td> COOH</td><td> -SCH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,F</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,C1</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl</td><td> COOH «..</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C1,C1</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> -SCH3</td><td></td>

<td> so₂</td><td> phenyl</td><td></td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> CF₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch₂cf₃</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so.</td><td> phenyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> och₃</td><td> COOH</td><td> -SCH2CH,</td><td></td>

<td> so₂</td><td> phenyl</td><td> OCH₂CH3</td><td> COOH</td><td> -SCH,CH3</td><td></td>

<td> so.</td><td> phenyl</td><td> OCH₂CH₂CH₃</td><td> COOH</td><td> -SCH₂CH3</td><td></td>

<td> so.</td><td> phenyl</td><td> 0ch,ch₂ch₂ch₃</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> och,ch₂ch₂ch,ch₃</td><td> COOH</td><td> -SCH,CH3</td><td></td>

<td> S02</td><td> phenyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so.</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> CH₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> CH₂CH₃</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> CH,CH₂CH₃</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so.</td><td> phenyl</td><td> ch₂ch₂ch₂ch₃</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> F</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so.</td><td> phenyl</td><td> F,F</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,C1</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so.</td><td> phenyl</td><td> Cl</td><td> COOH</td><td> -SCH₂CH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> Cl,Cl</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> SO2</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> SO₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linkerj-optionally subst. heteroaryl</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> pyridinyl</td><td></td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> CF3</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> CH2CF3</td><td> COOH</td><td> -SCH₂CH₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> COOH________</td><td> -SCH₂CH₃</td><td></td>

WO 2005/009958

<td> so₂</td><td> Pyridinyl</td><td> OCH3</td><td> COOH</td><td> -SCH₂CH₃</td><td> - ——</td>

<td> so.</td><td> Pyridinyl</td><td> OCH₂CH₃</td><td> COOH</td><td> -SCH,CH₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> OCH₂CH,CH₃</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och,ch,ch,ch₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och₂ch,ch₂ch₂ch₃</td><td> COOH</td><td> -SCH,CH3</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> ch₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch,ch₂ch₃</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch,ch₂ch₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,F</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> F,C1</td><td> COOH</td><td> -SCH,CH3</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Cl</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Cl,Cl</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td></td><td> . COOH</td><td> -SCH2CH3</td><td> •</td>

<td> co</td><td> Phenyl</td><td> CF3</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂cf₃</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH,CH₃</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> och,ch,ch₃</td><td> COOH</td><td> -SCH₂CH₃</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₂CH,CH,CH₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> och,ch,ch,ch₂ch₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> CHj</td><td> COOH</td><td> -SCH,CH₃</td><td></td>

<td> co</td><td> Phenyl</td><td> CH,CH₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₂ch₃</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch,ch₂ch₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkyl</td><td> COOH</td><td> -sch,ch.</td><td></td>

<td> co</td><td> Phenyl</td><td> F</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> F,F</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> F,C1</td><td> COOH</td><td> -SCH,CH₃</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl</td><td> COOH</td><td> -SCH,CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl,Cl</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> pyridinyl</td><td></td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CF3</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂cf₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> COOH</td><td> -SCH₂CH₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH3</td><td> COOH</td><td> -SCH₂CH₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och,ch₃</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch,ch₃__</td><td> COOH</td><td> -SCH₂CH3</td><td></td>

WO 2005/009958

<td> CO</td><td> Pyridinyl</td><td> OCH₂CH₂CH₂CH₃</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Pyiidinyl</td><td> och,ch₂ch₂ch₂ch₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> COOH</td><td> -SCH₂CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₃</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ־CH2CH3</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH₂CH,CH₃</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch,ch₂ch,ch₃</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alley]</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,F</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F.C1</td><td> COOH</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl</td><td> COOH</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl,CI</td><td> COOH</td><td> -SCH₂CH₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-oprionally subst. aryl</td><td> COOH</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> COOH</td><td> -SCH,CH₃</td><td></td>

<td> so₂</td><td> phenyl</td><td></td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> cf₃</td><td> Tetrazble</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> CH₂CF₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> OCH₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> och,ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> och₂ch₂ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> och,ch₂ch,ch₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> och,ch₂ch₂ch,ch₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch,ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch₂ch,ch₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> CH₂CH,CH,CH₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> C5-C8 alkyl</td><td> Tetr azole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> F</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> F,F</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,C1</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Cl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Cl,Cl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> pyridinyl</td><td></td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> CF₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch,cf₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridmyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> OCH₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> OCH2CH3</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> OCH₂CH₂CH3</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> OCH,CH₂CH,CH₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> OCH,CH,CH,CH₂CH₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> methoxy______</td><td></td>

WO 2005/009958

<td> so₂</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch,ch,ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch,ch,ch₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C5-C8 allcyl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> F</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,F</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,C1</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Cl</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Cl,Cl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally sub st. aryl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td></td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> cf₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂cf₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och₃</td><td> Tetr azo le</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och,ch₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch₂ch₃</td><td> Tetr azole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch₂ch₂ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch₂ch₂ch₂ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch,ch₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₂ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₂ch₂ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkyl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,F</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,C1</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl,Cl</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> pyridinyl</td><td></td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CF₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH₂CF₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkyd</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH3</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH,CH3</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och,ch₂ch₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och,ch₂ch₂ch₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch,ch,ch,ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

WO 2005/009958

<td> CO</td><td> Pyridinyl</td><td> CH,CH₂CH₃</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> CO</td><td> Pyridinyl</td><td> ch₂ch₂ch₂ch₃</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> CO</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> CO</td><td> Pyridinyl</td><td> F</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,F</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -F,C1</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl,Cl</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> tetrazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td></td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> CF₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> ch₂cf₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> Halo substituted alkyl</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> OCH₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> och,ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> och,ch,ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> och,ch₂ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> och₂ch₂ch₂ch,ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> C5-C8 alkoxy</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> CH₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> ch,ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch,ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch₂ch,ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> C5-C8 alkyl</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> F</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> f,f</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,C1</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> Cl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> 01,Cl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linkeij-optionally subst. aryl</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> pyridinyl</td><td></td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> cf₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂cf₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> 0ch₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och₂ch₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och,ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och,ch,ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och₂ch₂ch₂ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> CH₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch,ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch₂ch,ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> Tetrazole_____________1</td><td> ethoxy</td><td></td>

WO 2005/009958

<td> so.</td><td> Pyndinyl</td><td> F</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,F</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> F,Cl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂.</td><td> Pyridinyl</td><td> Cl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Cl,Cl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> 1)-־ to 4 linearly linked atom linker)-optionally subst. aryl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linkeij-optionally subst. heteroaryl</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td></td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CF₃</td><td> Tetr azole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₂CF₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH3</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH,CH₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> 0ch₂ch₂ch₃</td><td> tetrazole</td><td> . ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch,ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch₂ch,ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch,ch₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch,ch₂ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 allcyl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,F</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,C1</td><td> tet!׳ azole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C1,C1</td><td> Tetr azole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linkeij-optionally subst. and</td><td> Tetr azole</td><td> ethoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom lihker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> pyridinyl</td><td></td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CF₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch,cf₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH3</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> 0ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch₂ch₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och,ch₂ch₂ch₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch,ch,ch₂ch₃</td><td> Tetr azole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Flalo substituted alkoxy</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₂ch₃</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch,ch,ch₂ch₃</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,F</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,C1</td><td> tetrazole</td><td> ethoxy</td><td></td>

WO 2005/009958

<td> co</td><td> Pyridinyl</td><td> Cl</td><td> tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl,Cl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td></td><td> tetrazole .</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> CF₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch,cf₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> och₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> OCH₂CH₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> OCH₂CH₂CH₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> OCH,CH₂CH,CH3</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> OCH₂CH₂CH,CH,CH3</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> Tetrazole ״</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> CH3</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> CH₂CH₃</td><td> tetrazpie</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> CH,CH₂CH₃</td><td> TetrazOle</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> ch,ch₂ch₂ch₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> C5-C8 alkyl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> F</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,F</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,C1</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> Cl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> Cl,Cl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> pyridinyl</td><td></td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> CF₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> CH₂CF3</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ocfi₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> OCH,CH₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> OCH₂CH,CH3</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och₂ch,ch₂ch₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> OCH₂CH₂CH₂CH,CH3</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> CH₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> CH₂CH3</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch₂ch,ch₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> CH₂CH₂CH₂CH3</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> F,F</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,C1</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Cl</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Cl, Cl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked</td><td> Tetrazole</td><td> propoxy</td><td></td>

WO 2005/009958

<td></td><td></td><td> atom linker)-optionally subst. aryl</td><td></td><td></td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CF3</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂cf₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH3</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₂CH3</td><td> Tetr azole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₂CH₂CH₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₂CH₂CH₂CH₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch₂ch₂ch₂ch₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH3</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₂CH3</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₂CH₂CH₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₂ch₂ch₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkyl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,F</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,C1</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> c!a</td><td> tetr azole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> Tetr azole</td><td> propoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> pyridinyl</td><td></td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CF_S</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂cf₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted allcyl</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH2CH2CH3</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH₂CH₂CH₂CH₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH₂CH₂CH₂CH₂CH3</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl .</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₂ch₃</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₂ch₂ch₃</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-CS alkyl</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,F</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,C1</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl</td><td> Tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl,Cl</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> tetrazole</td><td> propoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked</td><td> Tetrazole</td><td> propoxy</td><td></td>

WO 2005/009958

<td></td><td></td><td> atom ln!ker)-optionally subst. heteroaryl</td><td></td><td></td><td></td>

<td> so₂</td><td> phenyl</td><td></td><td> Tetrazole</td><td> -SCH3</td><td></td>

<td> so.</td><td> phenyl</td><td> cf₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> ch₂cf₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> SO2</td><td> phenyl</td><td> Halo substituted alkyl</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> och₃</td><td> tetrazole</td><td> -SCFI3</td><td></td>

<td> so₂</td><td> phenyl</td><td> och,ch₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> och,ch₂ch₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> och₂ch,ch,ch₃</td><td> Tetrazole</td><td> -SCH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> och,ch₂ch₂ch,ch₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> C5-C8 alkoxy</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> CH₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> CH₂CH₃</td><td> Tetrazole</td><td> -SCH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> CH₂CH₂CH₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> ch₂ch,ch₂ch₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> C5-C8 alkyl</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> F</td><td> tetrazole »u</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> F,F</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,C1</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> Cl</td><td> Tetrazble</td><td> -sch₃</td><td></td>

<td> S02 .</td><td> phenyl</td><td> C1,C1</td><td> Tetrazole</td><td> -SCH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> tetr azole</td><td> -SCH3</td><td></td>

<td> so.</td><td> pyridinyl</td><td></td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> CF₃</td><td> Tetrazole</td><td> -SCH3</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch,cf₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so, .</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och₃</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och,ch₃</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och,ch₂ch₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och,ch,ch,ch₃</td><td> Tetr azole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och,ch,ch₂ch₂ch₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyndmyl</td><td> Halo substituted alkoxy</td><td> tetr azole</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch₃</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch,ch₃</td><td> Tetrazole</td><td> -sch₃</td><td> .</td>

<td> so.</td><td> Pyridinyl</td><td> ch,ch₂ch₃</td><td> Tetrazole</td><td> -SCH3</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch,ch,ch,ch₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> F</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> F,F</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> F,C1</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Cl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C1.C1</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> tetrazole</td><td> -SCH3</td><td></td>

<td> co</td><td> Phenyl</td><td></td><td> tetrazole</td><td> -sch₃</td><td></td>

WO 2005/009958

<td> co</td><td> Phenyl</td><td> CF₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> CO</td><td> Phenyl</td><td> ch,cf₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> CO</td><td> Phenyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> 0CH₂CH3</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₂CH,CH₃</td><td> tetrazole</td><td> -SCH3</td><td></td>

<td> co</td><td> Phenyl</td><td> och,ch,ch₂ch₃</td><td> Tetrazole</td><td> -SCH3</td><td></td>

<td> co</td><td> Phenyl</td><td> oci-i,ch₂ch,ch₂ch₃</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₃</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> ch,ch₃</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₂CH2CH3</td><td> Tetrazole</td><td> -SCH3</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch,ch₂ch₃</td><td> Tetrazole</td><td> -SCH3</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkyl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> F</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> F,F</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> F,C1</td><td> tetrazole</td><td> -SCH3</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl</td><td> Tetrazole</td><td> -SCH3</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl,Cl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> pyridinyl</td><td></td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CF3</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH2CF3</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH3</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH2CH3</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH₂CH,CH3</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH,CH,CH2CH3</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH2CH2CH2CH2CH3</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> -SCH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH3</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH2CH3</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₂ch₃</td><td> tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₂ch,ch₃</td><td> Tetr azole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 allcyl</td><td> Tetrazole</td><td> -sch₃</td><td> .״</td>

<td> co</td><td> Pyridinyl</td><td> F</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,F</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,C1</td><td> tetr azole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl</td><td> tetrazole</td><td> -SCH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl,Cl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linlceij-optionally subst. heteroaryl</td><td> Tetrazole</td><td> -sch₃</td><td></td>

<td> so.</td><td> phenyl</td><td></td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so.</td><td> phenyl</td><td> CF3</td><td> tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch,cf₃</td><td> tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted allcyl</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

WO 2005/009958

PC17US2004/023234

<td> so.</td><td> phenyl</td><td> och₃</td><td> Tetrazole</td><td> -sch,ch₃</td><td> ... </td>

<td> so₂</td><td> phenyl</td><td> och,ch₃</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> och,ch,ch₃</td><td> Tetrazole</td><td> -SCH₂CH₃</td><td></td>

<td> so.</td><td> phenyl</td><td> och₂ch,ch,ch₃</td><td> tetrazole</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> och,ch₂ch₂ch,ch₃</td><td> tetrazole</td><td> -SCH,CH₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> 'C5-C8 alkoxy</td><td> Tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> -SCH,CH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> CH₃</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch,ch₃</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch,ch₂ch₃</td><td> tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch₂ch₂ch,ch₃</td><td> tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> C5-C8 alkyl</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> phenyl</td><td> F</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,F</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,C1</td><td> Tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> Cl</td><td> tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> SO2</td><td> phenyl</td><td> Cl,Cl</td><td> tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linJker)-optionally subst. aryl</td><td> Tetrazole *in.</td><td> -sch₂ch₃</td><td></td>

<td> so₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> pyridinyl</td><td></td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> CF₃</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch,cf₃</td><td> tetr azole</td><td> -sch,ch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och₃</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och,ch₃</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och,ch₂ch₃</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och₂ch,ch₂ch₃</td><td> Tetrazole</td><td> -SCH,CH₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och,ch,ch,ch₂ch₃</td><td> tetrazole</td><td> -SCH,CH₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> CH₃</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch,ch₂ch₃</td><td> Tetrazole</td><td> -SCH,CH3</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch,ch,ch₃</td><td> tetrazole</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> tetrazole</td><td> -SCH,CH₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,F</td><td> Tetrazole</td><td> -SCH₂CH3</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> F,C1</td><td> Tetrazole</td><td> -SCH2CH₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Cl</td><td> Tetrazole</td><td> -SCH,CH₃</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Cl,Cl</td><td> tetrazole</td><td> -sch,ch₃</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom Inikerj-optionally subst. aryl</td><td> tetrazole</td><td> -sch,ch₃</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td></td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> CF₃</td><td> Tetrazole</td><td> -SCH2CH,</td><td></td>

<td> co</td><td> Phenyl</td><td> ch,cf₃</td><td> Tetrazole</td><td> -SCH,CH₃</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkyl</td><td> tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> och₃</td><td> tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH2CH3</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch,ch₃</td><td> Tetrazole____________</td><td> -sch,ch₃</td><td></td>

WO 2005/009958

<td> co</td><td> Phenyl</td><td> 0CH,CH₂CH₂CH₃</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> och₂ch,ch₂ch₂ch₃</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkoxy</td><td> tetrazole</td><td> -SCH₂CH₃</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkoxy</td><td> tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₃</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₃</td><td> Tetrazole</td><td> -SCH₂CH₃</td><td></td>

<td> co</td><td> Phenyl</td><td> ch,ch,ch₃</td><td> Tetrazole</td><td> -SCH₂CH₃</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₂ch₂ch₃</td><td> Tetrazole</td><td> -SCH₂CH₃</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 allcyl</td><td> tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> F</td><td> tetr azole</td><td> -SCH₂CH₃</td><td></td>

<td> co</td><td> Phenyl</td><td> F,F</td><td> Tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> F,C1</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl</td><td> Tetr azole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl,Cl</td><td> Tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> pyridinyl</td><td></td><td> Tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CF₃</td><td> Tetrazole</td><td> -sch,ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂cf₃</td><td> Tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> Tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH3</td><td> tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> 0CH,CH3</td><td> tetr azole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch,ch₃</td><td> Tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH,CH₂CH₂CH₃</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> OCH₂CH₂CH,CH₂CH₃</td><td> Tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> Tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH₃</td><td> tetr azole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> Tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch₂ch₃</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch,ch,ch₃</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-CS alkyl</td><td> Tetrazole</td><td> -SCH₂CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F</td><td> tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,F</td><td> tetrazole</td><td> -sch₂ch₃</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,C1</td><td> Tetrazole</td><td> -SCH₂CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl</td><td> Tetrazole</td><td> -SCH₂CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Cl,Cl</td><td> Tetrazole</td><td> -SCH₂CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> Tetrazole</td><td> -SCH2CH3</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> tetrazole</td><td> -SCH2CH3</td><td></td>

<td> so₂</td><td> phenyl</td><td></td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> cf₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch₂cf₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> Halo substituted alkyl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> OCH3</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> OCH₂CH₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO,</td><td> phenyl</td><td> och,ch,ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> och₂ch₂ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO,</td><td> phenyl</td><td> och₂ch₂ch,ch,ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> C5-CS alkoxy</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

WO 2005/009958

<td> so₂</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> ch₃ .</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> CH₂CH₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> CH₂CH₂CH₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch₂ch,ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> C5-C8 allcyl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> F</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> RF</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO2</td><td> phenyl</td><td> F,C1</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> Cl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> Cl,Cl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO₂</td><td> pyridinyl</td><td></td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> CF₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch,cf₃</td><td> '3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> OCH₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> 0ch,ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> .so₂</td><td> Pyridinyl</td><td> och₂ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> och₂ch₂ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> och₂ch,ch₂ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO2</td><td> Pyridinyl</td><td> Halo substituted alkoxy</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> CHj</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO₂</td><td> Pyridinyl</td><td> ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> SO₂</td><td> Pyridinyl</td><td> ch₂ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> ch₂ch₂ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> S02</td><td> Pyridinyl</td><td> F,F</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> F,C1</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> Cl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> Cl,Cl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. aryl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td> ׳</td>

<td> co</td><td> Phenyl</td><td></td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CF₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> CH₂CF₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkyl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> 0CH3</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> 0CH₂CH3</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> 0CH₂CH₂CH₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> och,ch,ch,ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> OCH₂CH,CH₂CH,CH3</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 aUcoxy</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Halo substituted alkoxy</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

WO 2005/009958

<td> CO</td><td> Phenyl</td><td> CH₂CH,CH₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td> ---------------—ן-</td>

<td> co</td><td> Phenyl</td><td> ch₂ch,ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> C5-C8 alkyl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> F,F</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -F,C1</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> Cl,Cl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td> —-</td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom Iinker)-optionally subst. aryl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> pyridinyl</td><td></td><td> ' 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CF₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> ch₂cf₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> Halo substituted alkyl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₃</td><td> 3-hydroxy isoxazolo.</td><td> methoxy</td><td> —</td>

<td> co</td><td> Pyridinyl</td><td> _och,ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch₂ch₃________</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td> ---</td>

<td> co</td><td> Pyridinyl</td><td> och,ch,ch,ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> och₂ch₂ch,ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkoxy</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td> ־</td>

<td> co</td><td> Pyridinyl</td><td> Jdalo substituted alkoxy</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> CH3</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td> ---—---</td>

<td> co</td><td> Pyridinyl</td><td> ch,ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td> .</td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch,ch₃__________</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td> -------—</td>

<td> co</td><td> Pyridinyl</td><td> ch₂ch,ch₂ch₃</td><td> 3-hydroxy isoxazole</td><td> methoxy_____</td><td></td>

<td> co</td><td> Pyridinyl</td><td> C5-C8 alkyl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,F</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> F,C1</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td> ' '״</td>

<td> co</td><td> Pyridinyl</td><td> Cl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridmyl</td><td> Cl,Cl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridmyl</td><td> -(1 to 4 linearly linked atom linker)-optionally _subst. aryl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> co</td><td> Pyridinyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> 3-hydroxy isoxazole</td><td> methoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td></td><td> 3-hydroxy isoxazole </td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> cf₃</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> ch₂cf₃</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> Halo substituted alkyl</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td> ---</td>

<td> so.</td><td> phenyl</td><td> och₃</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td> —</td>

<td> so₂</td><td> phenyl</td><td> och,ch₃____________</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl_____</td><td> OCH,CH₂CH₃</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td> — -------^-</td>

<td> so.</td><td> phenyl</td><td> OCH,CH,CH₂CH₃</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td> --</td>

<td> so₂</td><td> phenyl</td><td> och₂ch₂ch₂ch₂ch₃</td><td> 3-hydroxy. isoxazole</td><td> ethoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> C5-C8 alkoxy___________</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> SO₂</td><td> phenyl</td><td> Halo substituted alkoxy</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> ch₃</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td> --</td>

<td> SO₂</td><td> phenyl</td><td> CH₂CH₃</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl'</td><td> ch₂ch,ch₃__________</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td> —</td>

<td> so₂</td><td> phenyl</td><td> ch,ch₂ch,ch₃_______</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td> ----</td>

<td> SO2</td><td> phenyl</td><td> C5-C8 alkyl_____________</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

WO 2005/009958

<td> so₂</td><td> phenyl</td><td> F</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,F</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> F,C1</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> Cl</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> C1,C1</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> phenyl</td><td> 1)-־ to 4 linearly linked atom linker)-optionally subst. aryl</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> phenyl</td><td> -(1 to 4 linearly linked atom linker)-optionally subst. heteroaryl</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so₂</td><td> pyridinyl</td><td></td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> CF₃</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>

<td> so.</td><td> Pyridinyl</td><td> ch₂cf₃</td><td> 3-hydroxy isoxazole</td><td> ethoxy</td><td></td>