3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which is to be performed.
FIELD OF THE INVENTION
The present invention relates to compounds of Formula (I) which are useful as anti¬bacterial agents. The present invention also relates to the preparation of compounds of Formula (I) and their use for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder associated where there is an advantage in inhibiting UPPS activity.
BACKGROUND OF THE INVENTION
Bacterial undecaprenyl pyrophosphate synthase (UPPS), also known as undecaprenyl diphosphate synthase, is a z-type prenyltransferase that catalyzes the sequential condensation of eight molecules of isoprenyl pyrophosphate (IPP) with trans, trans-farnesyl pyrophosphate (FPP) to produce the 55-carbon molecule termed undecaprenyl pyrophosphate. Undecaprenyl pyrophosphate is released from the synthase and dephosphorylated to form undecaprenyl phosphate that serves as the essential carbohydrate and lipid carrier in bacterial cell wall and lipopolysaccharide biosynthesis.
Emerging resistance to currently used antibacterial agents has generated an urgent need for antibiotics acting by different mechanisms. Undecaprenyl pyrophosphate synthase exists ubiquitously in bacteria and plays an essential and critical role in the cell wall biosynthesis pathway. Thus, undecaprenyl pyrophosphate synthase is essential for cell viability and provides a valid and unexploited molecular target for antibacterial drug discovery.
SUMMARY OF THE INVENTION
The present invention relates to compounds of Formula (I) which inhibit the activity of UPPS, the use of these compounds as anti-bacterial agents and pharmaceutical compositions comprising these compounds.
The first embodiment of the present invention provides the structure of compounds as set forth in Formula (I):


or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein

R.2 is hydrogen, optionally substituted monocyclic or fused bicyclic aryl or arylalkyl or optionally substituted monocyclic heteroarylalkyl, wherein the optional substituent at each occurrence is selected from halogen, hydroxyl or alkyl;
R3 is hydrogen or alkyl;
R4 at each occurrence is independently selected from alkyl or alkoxy;
Ring Het is 5-6 membered heteroaryl, 5- to 6-membered heteroaryl fused to a phenyl or phenyl fused to a 5- to 6-membered heteroaryl;

In another embodiment of the present invention, it provides the pharmaceutical composition comprising compound of Formula (I) and processes for preparing thereof.
In yet further another aspect of the present invention, it relates to the use of compounds of Formula (I), its pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, including mixtures thereof in all suitable ratios wherever applicable as a medicament for the treatment and prevention of disorder or diseases by inhibitory action on enzymes- UPPS.

DETAILED DESCRIPTION OF THE INVENTION
There is much interest in targeting enzymes involved in isoprenoid biosynthesis for use as anti-infective and anti-cancer agents. UPPS is present in E coli and S. aureus and is a verified drug target of interest. Compounds that inhibit UPPS are of significant interest to pharmaceutical companies and researchers developing anti-infective drugs. The compounds provided by the present invention are inhibitors of UPPS. In various embodiments, the compounds described herein are not bisphosphonates, nor tetramic acids, both of which have problems with distribution about the body. Various genera and examples of the compounds are novel, and to the best of our knowledge not described as inhibitors of UPPS anywhere in the literature. Several of the compounds described herein have been tested via inhibition assays against UPPS with favorable results. Additionally, some compounds have been tested and have demonstrated effectiveness in cellular assays of bacterial cell growth. The compounds are therefore important leads for drug development.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present invention.
As used herein, the term "optionally substituted" refers to replacement of one or more hydrogen radicals in a given structure with a radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic. It is understood that the substituent may be further substituted.
As used herein the term "alkyl" refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, and which is attached to the rest of the molecule by a single bond. The alkane radical may be straight or branched. For example, the term "C1-C4 alkyl" refers to a monovalent, straight, or branched

aliphatic group containing 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and the like).
"Alkoxy" as used herein refers the radical -O-alkyl, wherein the alkyl is as defined above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and heptyloxy. The alkyl portion of the alkoxy may be optionally substituted.
As used herein, the term "aryl" alone or in combination with other term(s) means a carbocyclic aromatic system containing one or more rings wherein such rings may be fused. The term "fused" means that the second ring is attached or formed by having two adjacent atoms in common with the first ring. The term "fused" is equivalent to the term "condensed". Unless otherwise specified, an aryl group typically has from 6 to about 14 carbon atoms but the invention is not limited in that respect. (C6-C12) aryl refers to an aryl group having six to twelve carbon atoms. Examples of aryl groups include but are not limited to phenyl, naphthyl, indanyl, and the like. Unless otherwise specified, all aryl groups described herein may be optionally substituted.
"Arylalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with an aryl group as defined above. Examples of arylalkyl group include, but are not limited to benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl and the like. An arylalkyl group can be unsubstituted or substituted with one or more suitable groups.
As used herein, the term "halo" or "halogen" alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.
"Hydroxy" or "hydroxyl" refers to -OH group.
The term "heteroaryl" unless otherwise specified refers to substituted or unsubstituted 5 to 14 membered aromatic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, and the like. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.

The term "heterocycloalkyl" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocycloalkyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocycloalkyl groups described or claimed herein may be substituted or unsubstituted. Examples of heterocycloalkyl include, but are not limited to aziridinyl, pyrrolidinyl, piperdinyl, piperazinyl, morpholinyl, 2-oxopyridyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl and the like.
The term "heterocyclic ring" includes the definitions of "heterocycloalkyl" and "heteroaryl".
"Hetero atom" refers to a sulfur, nitrogen or oxygen atom.
The term "fused" as used herein with respect to two polyatomic, cyclic rings means that such rings have two adjacent atoms thereof common to both rings. The two adjacent atoms can be C or N. The fused ring can be 4-6 membered ring inclusive of the fused bond.
The term "membered ring" can embrace any cyclic structure. The term"membered" is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5-membered rings.
"Optionally substituted or substituted" as used herein means that at least one or two hydrogen atoms of the optionally substituted group has been substituted with suitable groups as exemplified but not limited to alkyl, alkenyl, alkoxy, alkynyl, aryl, amido, amino, carboxy, cyano, cycloalkyl, guanidine, halogen, imidamide, hydroxy, nitro, haloalkyl, haloalkoxy, heterocyclyl,

or two substituents on the same carbon atom combined together to form an optionally substituted 3-8 member ring containing 0-3 heteroatoms independently selected form N, O and S in any stable combination;
"Comprise" or "Comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

The term "pharmaeeutieally acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, potassium, sodium and zinc.
As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions {e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For example carriers, stabilizers and adjuvants known in literature.
The term "stereoisomers" refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of Formula (I), wherever they are chiral or when they bear one or more double bond. When the compounds of the Formula (I) and related formulae are chiral, they can exist in racemic or in optically active form. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis.
The term "treat", "treating" or "treatment" of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition

or at least one of its clinical or subclinical symptoms. The terms "treat," "treating" or "treatment", include, but are not limited to, prophylactic and/or therapeutic treatments.
The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
As used herein, the term "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
As used herein, the term 'compound(s)' comprises the compounds disclosed in the present invention.
As used herein, the term "comprise" or "comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
As used herein, the term "including" as well as other forms, such as "include", "includes" and "included" is not limiting.
In our endeavor to provide an inhibitors of UPPS, the first embodiment of the present invention provides compounds as set forth in Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein


R.2 is hydrogen, optionally substituted monocyclic or fused bicyclic aryl or arylalkyl or optionally substituted monocyclic heteroarylalkyl, wherein the optional substituent at each occurrence is selected from halogen, hydroxyl or alkyl;
R.3 is hydrogen or alkyl;
R4 at each occurrence is independently selected from alkyl or alkoxy;
Ring Het is 5-6 membered heteroaryl, 5- to 6-membered heteroaryl fused to a phenyl or phenyl fused to a 5- to 6-membered heteroaryl;

The embodiment below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment of the present invention, specifically provided are compounds of Formula (I), in which Ri and R3 are hydrogen.
According to another embodiment of the present invention, specifically provided are compounds of Formula (I), in which R\ is arylalkyl for example benzyl or phenylethyl.
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (I), in which R2 is optionally substituted monocyclic aryl, for example phenyl and the optional substituent is halo (for example bromo).
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (I), in which R2 is optionally substituted monocyclic arylalkyl, for example benzyl and the optional substituent is hydroxyl or halo (for example bromo).
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (I), in which R2 is bicyclic arylalkyl, for example napthylmethyl.
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (I), in which R2 is optionally substituted monocyclic

heteroarylalkyl, for example imidazol-5-yl-methyl and the optional substituent is alkyl (for example methyl).
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (I), in which Z is aryl for example phenyl.
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (I), in which ring Het is 6-membered heteroaryl for example pyridyl.
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (I), in which ring Het is phenyl fused to a 5-membered heteroaryl for example indolyl,
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (I), in which ring Het is 5- membered heteroaryl fused to a phenyl for example benzofuranyl.
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (I), in which R4 is alkyl, preferably C1-C4 alkyl for example methyl and 'p' is 1.
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (I), in which R4 is alkoxy for example isopropoxy and 'p' is 1.
According to yet another embodiment of the present invention, the compound of Formula (I) is a compound of Formula (la):


or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein


According to yet another embodiment of the present invention, specifically provided are compounds of Formula (la), in which ring Het is pyridyl, indolyl or benzofuranyl.
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (la), in which R4 is C1-C4 alkyl, preferably methyl.
According to yet another embodiment of the present invention, specifically provided are compounds of Formula (la), in which Ra is C1-C4 alkyl, preferably methyl.
In yet another particular embodiment of the present invention, the compound of Formula (I) is selected from the group listed in Table 1:

or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof.
In further yet another particular embodiment, the definition of "compounds of Formula (I)" inherently includes all stereoisomers of the compound of Formula (I) either as pure stereoisomer or as amixture of two or more stereomers. The word stereoisomers includes enantiomers, diasteroisomers, racemates, cis isomers, trans isomers and mixture thereof.
The absolute configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1% of the other isomers. Thus when a compound of Formula (I) is for instance specified as (R), this means that the compound is substantially free of (S) isomer; when the compound of Formula (I) is for instance specified as E, this means that the compound is free of the Z isomer; when the compound of Formula (I) is for istance specified as cis isomer, this means that the compound is free of the trans isomer.

Use of compounds as above and pharmaceutically acceptable salts or stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and prevention in diseases or disorder, where there is an advantage in inhibiting enzymes- UPPS.
Use of compounds as above and pharmaceutically acceptable salts or stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and prevention of bacterial diseases, where there is an advantage in inhibiting enzymes- UPPS.
Use of compounds as above wherein there is an advantage in inhibiting enzymes-UPPS for anti-bacterial or antimicrobial diseases.
A compound having Formula described above or a specific compound described or illustrated herein can be used to inhibit UPPS. The compounds can also kill or inhibit the growth of bacteria. In one embodiment, a compound described herein can inhibit an isoprenoid biosynthesis enzyme in vitro. The Ki of the compound can be, for example, less than about 10 uM, less than about 5 uM, less than about 2 uM, less than about 1.5 uM, less than about 1 uM.
The invention thus provides methods of inhibiting the activity UPPS wherein the compound binds to the enzyme, thereby inhibiting the activity of the enzyme. The invention also provides methods of treating a bacterial infection in a mammal such as a human, wherein the bacterial infection is caused by a bacteria that has the UPPS enzyme, wherein the method comprises administering to a mammal in need of such treatment an effective amount of a compound described herein, wherein the compound binds to the enzyme, thereby inhibiting the activity of the enzyme, thereby treating the bacterial infection or parasitic infection. These methods can include treating the bacterium with a compound described herein, wherein the compound binds to UPPS, thereby killing or inhibiting the growth of the bacterium. The bacterial infection may be associated with, for example, a gram negative bacterium; a gram positive bacterium, e.g., hospital gram positive infection; or in particular embodiments, a bacterium selected from the group consisting of S. aureus, Group A Streptococcus, E. faecalis; with E. coli, S. aureus, E. faecalis, or S. pneumoniae. The bacterial infection may be an outpatient skin infection or a skin structure infection, e.g., wherein the bacterial infection is associated with a bacterium selected from the group consisting of S. aureus and Group AStreptococcus. The bacterial infection may be community-acquired methicillin-

resistant Staphylococcus aureus (CA-MRSA), e.g., wherein the bacterial infection is associated with methicillin-resistant Staphylococcus aureus (MRSA). The bacterial infection can also be an antibiotic-associated colitis infection, e.g., wherein the bacterial infection is associated with C. difficile or nosocomial pneumonia, e.g., wherein the bacterial infection is associated with S. aureus or wherein the bacterial infection is associated with gram negative bacterium, e.g., P. aeruginosa, Klebsiella, Enterobacter, E. coli, or Acinetobacter. The compounds of the invention are useful in treating bacterial infection wherein said bacterial infection is resistant to other antibiotics.
Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s).
A therapeutically effective amount of a compound of the Formula (1) and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet. However, an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to l0mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.
In a further aspect, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All

isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as
Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
Experimental
The procedure for the preparation of compounds of general Formula (I) are detailed herein below, including the general synthesis of various intermediates involved in process of manufacture of the compounds according to the present invention.

3-|4-(l-Methyl-lH-indol-5-yl)-phenyl]-propionic acid (2): A solution of 3-(4-Bromo-phenyI)-propionic acid (1) (10 g, 43.6 mmol) and l-Methyl-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indole (11.2 g, 43.6 mmol) in Dioxane:H20 (120 mL : 30 mL) was degassed and backfilled with N2 at room temperature. To this reaction mixture was added CS2CO3 (42.57 g, 131.0 mmol) and again degassed. Then added 2.18 mmol) into the reaction mixture and degassed twice and refiuxed for 15 h under nitrogen. Reaction mixture was allowed to cool at room temperature and acidify up to pH3

with dil HC1. Reaction mixture was diluted with H2O (25 mL) and extracted with ethyl acetate (4 x 100 mL). Combined organic layer was dried over sodium sulfate and evaporated to get crude residue which was purified by Silica gel (100-200 mesh) column chromatography eluted with 30% ethyl acetate in hexane provided 4.0 g (32.8% yield) of 3-[4-(l-Methyl-lH-indol-5-yl)-phenyl]-propionic acid (2) as light yellow viscous liquid. 3-[4-(l-Methyl-lH-indol-5-yl)-phenyl]-propan-l-ol (3): To a stirred solution of 3-[4-(l-Methyl-lH-indol-5-yl)-phenyl}-propionic acid (2) (7.56 g, 28.48 mol) in dry THF (40 mL) was added BH3-DMS solution (5.2 mL, 54.0 mol) drop wise at 0 °C under nitrogen and then stirred at room temperature for 14 h. After completion, monitored by TLC, reaction mixture was cooled to 0 °C and quenched with MeOH (10 mL) and H20 (10 mL) slowly. THF was distilled under rotary evaporator and reaction mixture was extracted with EtOAc (3 x 25 mL). Combined organic layer was dried over sodium sulfate and evaporated to give 4.6 g (64.4% yield) of 3-[4-(l-Methyl-lH-indol-5-yl)-phenyl]-propan-l-ol (3) as yellow solid. Methanesulfonic acid 3-[4-(l-methyI-lH-indol-5-yl)-phenyl]-propyl ester (4): To a solution of solution of 3-[4-(l-Methyl-lH-indol-5-yl)-phenyl]-propan-l-ol (3) (1.5 g, 6.0 mmol) in Dichloromethane (15 mL) was added Methanesulfonyl chloride (1.03 g, 9.0 mmol) and Et3N (1.8 g, 15.10 mmol) at 0 °C and stirred at room temperature for 1 h. Reaction mixture was diluted with H20 (25 mL), extracted with dichloromethane (3 x 25 mL). Combined organic layer was washed with brine dried over sodium sulfate and evaporated to give 1.8 g (92.7% yield) of Methanesulfonic acid 3-[4-(l-methyl-lH-indol-5-yl)-phenyl]-propyl ester (4) as yellow solid.
6-{3-[4-(l-Methyl-lH-indol-5-yl)-phenyll-propoxy}-pyridine-2-carboxylic acid methyl ester (5): To a solution of solution of 6-Hydroxy-pyridine-2-carboxylic acid methyl ester (0.89 g, 5.80 mmol) in DMF (10 mL) was added K2C03 (2.41 g, 17.00 mmol) and stirred at room temperature for 30 min followed by addition of Methanesulfonic acid 3-[4-(l-methyl-lH-indol-5-yl)-phenyl]-propyl ester (4) (2.0 g, 5.80 mmol). Reaction mixture was stirred at room temperature for overnight. After completion, monitored by TLC, reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organic layer was dried over sodium sulfate and evaporated. Crude residue was purified by Silica gel (100-200 mesh) column chromatography eluted with 20% ethyl acetate in hexane provided 1.5 g (64.3% yield) of 6-{3-[4-(l-Methyl-lH-indol-5-yl)-phenyl]-propoxy}-pyridine-2-carboxylic acid methyl ester (5) as light yellow solid.
6-{3-[4-(l-MethyI-lH-indol-5-yl)-phenyl]-propoxy}-pyridine-2-carboxylic acid (6): To a solution of solution of 6-{3-[4-(l-Methyl-lH-indol-5-yl)-phenyl]-propoxy}-pyridine-2-

carboxylic acid methyl ester (5) (0,8 g, 1.90 mmol) in 20 mL of THF:H20 (1:1) was added LiOH (0.42 g, 9.50 mmol) and stirred at room temperature for overnight. After completion, reaction mixture was acidified with citric acid solution and extracted with ethyl acetate (3 x 25 mL). Combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 0.7 g (90.0% yield) of 6-{3-[4-(l-Methyl-lH-indol-5-yl)-phenyl]-propoxy}-pyridine-2-carboxylic acid (6) as light yellow solid.

To a solution of 6-{3-[4-(l-Methyl-lH-indol-5-yl)-phenyl]-propoxy}-pyridine-2-carboxylic acid (6) (0.2 g, 0.50 mmol) and (S)-phenylalanine ethyl ester (0.1 g, 0.50 mmol) in DCM (5 mL) was added was added EDC.HC1 (0.15 g, 0.80 mmol) and stirred at room temperature for 15 min. Then added DMAP (0.094 g, 0.80 mmol) and resulting mixture was stirred at room temperature for overnight. After completion, H2O (20 mL) was added into reaction mixture and extracted with ethyl acetate (3 x 25 mL). Combined organic layer was dried over sodium sulfate and evaporated. Crude residue was purified by Silica gel (100-200 mesh) column chromatography eluted with 10% ethyl acetate in hexane provided 0.14 g (48.2% yield) of (S)-2-[(6-{3-[4-(l-Methyl-lH-indol-5-yl)-phenyl]-propoxy}-pyridine-2-carbonyl)-amino]-3-phenyl-propionic acid ethyl ester (7) as light brown solid.


To a solution of (L)-2-[(6-{3-[4-(l-Methyl-lH-indoI-5-yl)-phenyl]-propoxy}-pyridine-2-carbonyl)-amino]-3-phenyl-propionic acid ethyl ester (7) (0.15 g, 0.26 mmol) in 15 mL of THF:H20 (1:1) was added LiOH (0.056 g, 1.30 mmol) and stirred at room temperature for overnight. After completion, reaction mixture was acidified with citric acid solution and extracted with ethyl acetate (3 x 25 mL). Combined organic layer was dried over sodium sulfate, evaporated under reduced pressure and resulting solid was purified by washing with warm hexane (5 x 15 mL) provided 0.03 g (21.4% yield) of (S)-2-[(6-{3-[4-(l-Methyl-lH-indol-5-yI)-phenyl]-propoxy}-pyridine-2-carbonyl)-amino]-3-phenyl-propionic acid (RDP-1081) as a light yellow solid; 1H NMR (400 MHz, DMSO-d6): 8 13.04 (s, 1H), 8.36 (d, J= 8.08 Hz, 1H), 7.87 (t, J= 7.8 Hz, 1H), 7.79 (s, 1H), 7.60-7.56 (m, 3H), 7.50-7.42 (m, 2H), 7.34 (d, J= 2.88 Hz, 1H), 7.30 (d, J= 8.0 Hz, 2H), 7.23-7.12 (m, 5H), 7.05 (d, J= 8.28 Hz, 1H), 6.46 (d, J= 2.72 Hz, 1H), 4.66-4.62 (m, 1H), 4.36-4.28 (m, 2H), 3.80 (s, 3H), 3.18 (d, J = 6.32 Hz, 2H), 2.77 (t, J= 7.32 Hz, 2H), 2.11-2.06 (m, 2H); LC-MS: [M+H]+ = 534.1 m/z

The below compounds were prepared using similar procedure as described above for RDP-1081 with appropriate variation in reactants, quantities of reagent and reaction conditions.


(Benzyl-(3-{3-[4-(l-methyl-lH-indol-5-yl)phenyl]propoxy}beiizoyl)amino]acetic acid (RDP 1079):
!H NMR (400 MHz, DMSO-d6): 8 12.94 (bs, IH), 9.06 (d, J= 7.36 Hz, 1H), 7.49-7.44 (m, 5H), 7.39-7.34 (m, 4H), 7.31-7.25 (m, 4H), 7.13-7.11 (m, 1H), 7.60 (d, J= 8.32 Hz, 1H), 5.58 (d, J = 7.32 Hz, IH), 5.29-5.25 (m, 1H), 4.05 (t, J = 5.56 Hz, 2H), 2.80 (t, J= 7.04 Hz, 2H), 2.33 (s, 3H), 2.07 (t, J = 6.32 Hz, 2H), 1.297 (d, J = 6.0 Hz, 6H); LC-MS: [M*H]+ = 539.1 m/z
(R)-[(6-{3-I4-(l-Methyl-lH-indol-5-yl)phenyl)propoxy}pyridine-2-carbonyl)amino] phenylacetic acid (RDP 1080):
'H NMR (400 MHz, DMSO-d6): 8 13.34 (s, 1H), 8.95 (d, J= 7.12Hz, 1H), 7.90 (t, 7= 7.76 Hz, IH), 7.78 (s, 1H), 7.61-7.56 (m, 3H), 7.50-7.41 (m, 4H), 7.37-7.34 (m, 3H), 7.31-7.29 (m, 3H), 7.10 (d, J= 8.28 Hz, IH), 6.46 (d, J= 2.80 Hz, IH), 5.51 (d, /= 7.08 Hz, IH), 4.42 (t, J = 6.4 Hz, 2H), 3.80 (s, 3H), 2.80 (t, J = 7.32 Hz, 2H), 2.13-2.08 (m, 2H); LC-MS: [M+H]+ = 520.1 m/z
(S)-2-[(6-{3-[4-(l-Methyl-lH-indol-5-yl)phenyl]propoxy}pyridine~2-carbonyl)amino]-3-phenylpropionic acid (RDP 1081):
'H NMR (400 MHz, DMSO-d*): 8 13.04 (s, IH), 8.36 (d, J= 8.08 Hz, IH), 7.87 (t, J= 7.8 Hz, IH), 7.79 (s, IH), 7.60-7.56 (m, 3H), 7.50-7.42 (m, 2H), 7.34 (d, J= 2.88 Hz, IH), 7.30 (d, J= 8.0 Hz, 2H), 7.23-7.12 (m, 5H), 7.05 (d, J= 8.28 Hz, IH), 6.46 (d, J= 2.72 Hz, IH), 4.66-4.62 (m, IH), 4.36-4.28 (m, 2H), 3.80 (s, 3H), 3.18 (d, J= 6.32 Hz, 2H), 2.77 (t, J = 7.32 Hz, 2H), 2.11-2.06 (m, 2H); LC-MS: [M+H]+ = 534.1 m/z
(S)-[(6- {3-[4-(l-Methyl-1 H-indol-5-yl)-phenyl] propoxy}pyridine-2-carbonyl)amino] phenylacetic acid (RDP 1082):
1H NMR (400 MHz, DMSO-de): 8 13.52 (s, IH), 8.97 (d, J= 6.92 Hz, IH), 7.89 (t, J= 7.76 Hz, IH), 7.78 (s, IH), 7.61-7.56 (m, 3H), 7.50-7.48 (m, IH), 7.43 (d, J- 6.72 Hz, 3H), 7.34-7.28 (m, 6H), 7.10 (d, J = 8.28 Hz, IH), 6.46 (d, J = 2.80 Hz, IH), 5.45 (d, J= 7.08 Hz, IH),

4.42 (t, J= 6.4 Hz, 2H), 3.80 (s, 3H), 2.80 (t, J= 7.32 Hz, 2H), 2.13-2.09 (m, 2H); LC-MS: [M+H]+ = 520.0 m/z


!H NMR (400 MHz, DMSO-d6): S 8.56 (d, J= 6.56 Hz, 1H), 7.85 (t, J= 7.12 Hz, 1H), 7.78 (s, 1H), 7.59-7.56 (m, 3H), 7.50-7.42 (m, 2H), 7.34 (d, J= 2.72 Hz, 1H), 7.28 (d, J = 7.88 Hz, 2H), 7.11-6.98 (m, 6H), 6.46 (d, J- 2.68 Hz, 1H), 4.28-4.23 (m, 2H), 4.13-4.12 (m, 1H), 3.80 (s, 3H), 3.13 (d, J = 6.12 Hz, 2H), 2.74 (t, J- 7.24 Hz, 2H), 2.04-2.0 (m, 2H); LC-MS: [M+H]+ = 533.9 m/z
(R)-({6-I3-(4-Benzofuran-2-yl-phenyl)propoxy]pyridine-2-carbonyl}amino)phenylacetic acid (RDP 1084):
*H NMR (400 MHz, DMSO-d*): 5 13.34 (s, 1H), 8.91 (d, J= 7.16 Hz, 1H), 7.90 (t, J= 7.84 Hz, 1H), 7.83 (d, J= 7.88 Hz, 2H), 7.65-7.59 (m, 3H), 7.44-7.42 (m, 2H), 7.39-7.33 (m, 5H), 7.31-7.19 (m, 3H), 7.07 (d, J= 8.48 Hz, 2H), 5.51 (d, J= 7.08 Hz, 1H), 4.42 (t, J = 6.4 Hz, 2H), 2.82 (t, J= 7.32 Hz, 2H), 2.14-2.10 (m, 2H); LC-MS: [M+Hf = 507.0 m/z
(S)-({6-|3-(4-Benzofuran-2-yl-phenyl)propoxy]pyridine-2-carbonyl}amino)phenylacetic acid (RDP 1086):
'H NMR (400 MHz, DMSO-d6): 8 13.38 (s, 1H), 8.92 (d, J= 7.16 Hz, 1H), 7.90 (t, J= 7.84 Hz, 1H), 7.83 (d, J = 8.04 Hz, 2H), 7.65-7.59 (m, 3H), 7.44-7.42 (m, 2H), 7.39-7.35 (m, 4H), 7.33-7.27 (m, 4H), 7.07 (d, J = 8.44 Hz, 1H), 5.50 (d, J= 7.08 Hz, 1H), 4.42 (t, J = 6.4 Hz, 2H), 2.82 (t, J= 7.32 Hz, 2H), 2.15-2.12 (m, 2H); LC-MS: [M+Hf = 507.0 m/z
(R,S)-2-{3-[3-(4-Benzofuran-2-yl-phcnyl)propoxylbenzoylamino}-3-phenylpropionic acid (RDP 1089):
JH NMR (400 MHz, DMSO-d*,): 5 12.81 (s, 1H), 8.70 (d, J= 8.08 Hz, 1H), 7.86 (d, J= 7.88 Hz, 2H), 7.65-7.60 (m, 2H), 7.38-7.22 (m, 12H), 7.15-7.13 (m, 1H), 7.10-7.09 (m, 1H), 4.62-4.57 (m, 1H), 4.01 ): 5 13.15 (bs, 1H), 7.90 (d, J= 7.2 Hz, 1H), 7.84 (d, J= 8.16 Hz, 2H), 7.65-7.56 (m, 4H), 7.47-7.43 (m, 4H), 7.39-7.36 (m, 3H), 7.30-7.25 (m, 2H), 7.14-7.11 (m, 1H), 5.54 (d, J= 7.24 Hz, 1H), 4.03 (t, J= 6.4 Hz, 2H), 2.81 (t, J= 7.32 Hz, 2H), 2.09-2.06 (m, 2H); LC-MS: [M+Hf = 586.1 m/z
(R, S)-{3-[3-(4-Benzofuran-2-yl-phenyI)propoxy]benzoylamino}-(3-bromophenyl)acctic acid (RDP 1105):
1HNMR(400MHz,DMSO-d6):5 13.17 (bs, 1H), 9.09 (d, J =7.36 Hz, 1H), 7.84 (d,J= 8.08 Hz, 2H), 7.70 (s, 1H), 7.65-7.60 (m, 2H), 7.53-7.44 (m, 4H), 7.40-7.35 (m, 4H), 7.33-7.30 (m, 1H), 7.28-7.23 (m, 2H), 7.14-7.12 (m, 1H), 5.58 (d, J= 7.36 Hz, 1H), 4.04 (t, J= 6.4 Hz, 2H), 2.82 (t, J= 7.32 Hz, 2H), 2.09-2.05 (m, 2H); LC-MS: pVfHf = 586.4 m/z


'H NMR (400 MHz, DMSO-d6): 8 12.81 (s, 1H), 8.71 (d, J= 8.08 Hz, 1H), 7.79 (s, 1H), 7.59 (d, J= 7.96 Hz, 2H), 7.50-7.42 (m, 2H), 7.36-7.35 (m, 4H), 7.31-7.29 (m, 4H), 7.26-7.22 (m, 2H), 7.17-7.13 (m, 1H), 7.11-7.09 (m, 1H),6.46 (d, J =2.68 Hz, lH),4.60(m, lH),4.02(t,J = 6.4 Hz, 2H), 3.80 (s, 3H), 3.19-3.16 (m, 1H), 3.08-3.06 (m, 1H), 2.79 (t, J= 7.24 Hz, 2H), 2.09-2.06 (m, 2H); LC-MS: [M+Hf = 533.0 m/z

lH NMR (400 MHz, DMSO-d*): 6 12.83 (s, 1H), 8.70 (d, J= 8.0 Hz, 1H), 7.79 (s, 1H), 759 (d, J= 7.76 Hz, 2H), 7.50-7.42 (m, 2H), 7.36-7.34 (m, 4H), 7.31-7.29 (m, 4H), 7.26-7.22 (m, 2H), 7.17-7.13 (m, 1H), 7.11-7.10 (m, 1H), 6.46 (d, J- 2.60 Hz, 1H), 4.62-4.56 (m, 1H), 4.02 (t, J= 6.36 Hz, 2H), 3.80 (s, 3H), 3.20-3.15 (m, 1H), 3.08-3.02 (m, 1H), 2.79 (t, J= 7.24 Hz, 2H), 2.10-2.04 (m, 2H); LC-MS: [M+H]+ = 533.0 m/z
(R)-2-(3-{3-l4-(l-Methyl-lH-indol-5-yl)-phenyl]propoxy}benzoylamino)-3-naphthaleB-1-yl-propionic acid (RDP 1113):
lHNMR (400 MHz, DMSO-d6): 5 12.94 (bs, 1H), 8.80 (d, J = 8.16 Hz, 1H), 8.18 (d, J- 8.20 Hz, 1H), 7.91 (d, J = 8.04 Hz, 1H), 7.79-7.75 (m, 2H), 7.60-7.58 (m, 3H), 7.53-7.48 (m, 3H), 7.45-7.38 (m, 2H), 7.36-7.31 (m, 6H), 7.11-7.09 (m, 1H), 6.46 (d, J= 2.92 Hz, 1H), 4.74-4.73 (m, 1H), 4.04 (t, J- 6.56 Hz, 2H), 3.80 (s, 3H), 3.80-3.72(m, 1H), 3.49-3.42 (m, 1H), 2.79 (t, J= 7.28 Hz, 2H), 2.09-2.05 (m, 2H); LC-MS: [MrH]+ = 583.5 m/z
(S)-2-(3-{3-[4-(l-Methyl-lH-indoI-5-yl)-phenyl]propoxy}benzoylamino)-3-naphthalen-l-yl-propionic acid (RDP 1114):
lH NMR (400 MHz, DMSO-d*): 6 12.96 (bs, 1H), 8.80 (d, J= 8.16 Hz, 1H), 8.18 (d, J= 8.20 Hz, 1H), 7.90 (d, J= 8.12 Hz, 1H), 7.79-7.75 (m, 2H), 7.60-7.58 (m, 3H), 7.53-7.48 (m, 3H), 7.45-7.38 (m, 2H), 7.36-7.31 (m, 6H), 7.11-7.09 (m, 1H), 6.46 (d, J = 2.92 Hz, 1H), 4.74-4.73 (m, 1H), 4.04 (t, J= 6.56 Hz, 2H), 3.80 (s, 3H), 3.80-3.72(m, 1H), 3.49-3.42 (m, 1H), 2.79 (t, J= 7.28 Hz, 2H), 2.09-2.05 (m, 2H); LC-MS: [M+Hf = 583.5 m/z
[(3-{3-[4-(l-MethyI-lH-indol-5-yl)-phenyl]propoxy}bedzoyl)phenethyIainino]acetic acid (RDP 1136):

lH NMR (400 MHz, DMSO-d6): 8 7.78 (d, J = 8.0 Hz, 1H), 7.60-7.55 (m, 2H), 7.49-7.47 (m, 1H), 7.44-7.40 (m, 1H), 7.34-7.32 (m, 2H), 7.30-7.28 (m, 3H), 7.22-7.18 (m, 2H), 7.15-7.13 (m, 1H), 7.02-6.98 (m, 2H), 6.78-6.75 (m, 1H), 6.67 (s, 1H), 6.46 (d, J= 2.88 Hz, 1H), 4.15 (s, 1H), 3.98 (t, J= 6.04 Hz, 2H), 3.84 (s, 1H), 3.80 (s, 3H), 3.63-3.59 (m, 1H), 2.90-2.86 (m, 1H), 2.81-2.76 (m, 4H), 2.08-2.01 (m, 2H); LC-MS: [NfH]+ = 547.20 m/z
(R,S)-3-(4-Bromophenyl)-2-(3-{3-[4-(l-methyl-lH-indoI-5-yl)phenyl]propoxy} benzoylamino)propionic acid (RDP 1142):
'H NMR (400 MHz, DMSO-d*): 8 12.84 (s, 1H), 8.71 (d, J= 8.08 Hz, 1H), 7.79 (s, 1H), 7.59 (d, J= 7.88 Hz, 2H), 7.50-7.43 (m, 4H), 7.36-7.25 (m, 8H)> 7.11-7.10 (m, 1H), 6.46 (d, J = 2.80 Hz, 1H), 4.63-4.57 (m, 1H), 4.03 (t, J= 6.32 Hz, 2H), 3.80 (s, 3H), 3.18-3.13 (m, 1H), 3.06-3.00 (m, 1H), 2.81-2.77 (m, 2H), 2.09-2.05 (m, 2H); LC-MS: [M^f = 613.00 m/z
(R)-3-(3-Hydroxyphenyl)-2-(3-{3-l4-(l-methyl-lH-mdol-5-yl)phenyl]propoxy}beiizoyl amino)propionic acid (RDP 1144):
'H NMR (400 MHz, DMSO-d<>): 8 12.86 (s, 1H), 9.27 (s, 1H), 8.52 (s, 1H), 7.79 (s, 1H), 7.59 (d, J= 8.04 Hz, 1H), 7.50-7.42 (m, 2H), 7.36-7.34 (m, 3H), 7.30 (d, J= 8.12 Hz, 2H), 7.11-7.08 (m, 1H), 7.02-6.99 (m, 1H), 6.70-6.68 (m, 2H), 6.55-6.54 (m, 2H), 6.46 (d, J= 2.88 Hz, 1H), 4.49-4.45 (m, 1H), 4.03 (t, J= 6.08 Hz, 2H), 3.80 (s, 3H), 3.16-3.06 (m, 1H), 3.00-2.94 (m, 1H), 2.79 (t, J= 7.24 Hz, 2H), 2.10-2.04 (m, 2H); LC-MS: [M+Hf = 549.2m/z
(R)-3-(4-Hydroxyphenyl)-2-(3-{3-[4-(l-methyl-lH-indol-5-yl)phenyl]propoxy}benzoyl-amino)prop ionic acid (RDP 1145):
'H NMR (400 MHz, DMSO-dg): 8 9.15 (s, 1H), 8.46 (bs, 1H), 7.78 (s, 1H), 7.59 (d, J= 8.08 Hz, 2H), 7.55-7.40 (m, 2H), 7,35-7.29 (m, 6H), 7.10-7.04 (m, 3H), 6.61 (d, J= 8.36Hz, 2H), 6.46 (d, J= 2.88 Hz, 1H), 4.39 (m, 1H), 4.03 (t, J= 6.32 Hz, 2H), 3.80 (s, 3H), 3.14-3.03 (m, 1H), 2.96-2.90 (m, 1H), 2.79 (t, J= 7.20 Hz, 2H), 2.09-2.05 (m, 2H); LC-MS: [M4H]+ = 549.30 m/z
(S)-3-(3-Methyl-3H-imidazol-4-yl)-2-(3-{3-[4-(l-methyl-lH-indol-5-yl)phenyllpropoxy} benzoylamino)- propionic acid (RDP 1149):
'HNMR (400 MHz, DMSO-dg): 8 7.78 (s, 1H), 7.59 (d, J= 8.08 Hz, 2H), 7.50-7.42 (m, 3H), 7.38-7.29 (m, 6H), 7.11-7.10 (m, 1H), 6.81 (s, 1H), 6.46 (d, J= 2.88 Hz, 1H), 4.48-4.47 (m, 1H), 4.04 (t, J= 6.36 Hz, 2H), 3.80 (s, 3H), 3.54 (s, 3H), 3.97-2.96 (m, 2H), 2.79 (t, J= 7.20 Hz, 2H), 2.09-2.04 (m, 2H); LC-MS: [M+H]+ = 537.0 m/z

(R, S)-2-{3-[3-(4-Benzofuran-2-yl-phenyl)propoxy]bcnzoylamino}-3-(4-bromophenyl) propionic acid (RDP 1150):
'H NMR (400 MHz, DMSO-d6>: 5 12.86 (bs, 1H), 8.68 (d, J= 8.16 Hz, 1H), 7.85 (d, J= 8.08 Hz, 2H), 7.65-7.60 (m, 2H), 7.43 (d, J= 8.42 Hz, 2H), 7.39-7.33 (m, 6H), 7.30-7.23 (m, 3H), 7.11-7.08 (m, 1H), 4.61-4.55 (m, 1H), 4.02 (t, J- 6.08 Hz, 2H), 3.18-3.14 (m, 1H), 3.05-3.02 (m, 1H), 2.82 (t, J = 7.32 Hz, 2H), 2.11-2.04 (m, 2H); LC-MS: [M+H]* = 600.20m/z
(R)-3-(3-Hydroxyphenyl)-2-(3-{3-[4-(l-methyl-lH-indol-5-yl)phenyllpropoxy}benzoyl-amino)propionic acid (RDP 1152):
'H NMR (400 MHz, DMSO-d*): 5 13.10 (bs, 1H), 9.21 (s, 1H), 8.31 (bs, 1H), 7.79 (s, 1H), 7.59 (d, J = 8.04 Hz, 2H), 7.50-7.42 (m, 2H), 7.34-7.29 (m, 6H), 7.10-7.04 (m, 1H), 7.70-6.96 (m, 1H), 6.68-6.66 (m, 2H), 6.54-6.45 (m, 2H), 4.44-4.43 (m, 1H), 4.02 (t, J= 6.02 Hz, 2H), 3.80 (s, 3H), 3.12-3.09 (m, 1H), 2.99-2.94 (m, 1H), 2.79 (t, /= 7.04 Hz, 2H), 2.09-2.05 (m, 2H); LC-MS: [M+H]+ = 549.10 m/z
(S)-3-(3-Methyl-3H-imidazol-4-yl)-2-(3-{3-[4-(l-methyl-lH-iiidol-5-yl)plienyllpropoxy} benzoylamino)-propionic acid (RDP 1153):
'H NMR (400 MHz, DMSO-cU): 5 8.60 (bs, 1H), 7.79 (s, 1H), 7.59 (d, J = 8.04 Hz, 2H), 7.50-7.44 (m, 3H), 7.38-7.29 (m, 5H), 7.13-7.10 (m, 1H), 6.86 (s, 1H), 6.46 (d, J= 2.80 Hz, 1H), 4,48-4.47 (m, 1H), 4.04 (t, J = 6.36 Hz, 2H), 3.80 (s, 3H), 3.54 (s, 3H), 3.97-2.96 (m, 2H), 2.79 (t, J= 7.16 Hz, 2H), 2.09-2.06 (m, 2H); LC-MS: [M+Hf = 537.1 m/z
(S)-2-{3-[3-(4-Benzofuran-2-yl-phenyl)propoxy]benzoylamino}-3-naphthalen-l-yl-prop ionic acid (RDP 1154):
'H NMR (400 MHz, DMSO-d6): 5 13.10 (bs, 1H), 8.78 (d, J= 8.12 Hz, 1H), 8.18 (d, J= 8.44 Hz, 1H), 7.91-7.89 (m, 1H), 7.85 (d, J= 8.16 Hz, 2H), 1.11-1.IS (m, 1H), 7.63-7.60 (m, 3H), 7.51-7.49 (m, 2H), 7.39-7.25 (m, 9H), 7.10-7.07 (m, 1H), 4.76-4.71 (m, 1H), 4.0 (t, J= 62A Hz, 2H), 3.77-3.72 (m, 1H), 3.48-3.42 (m, 1H), 2.81 (t, J= 7.24 Hz, 2H), 2.11-2.04 (m, 2H); LC-MS: [M+H]+ = 570.3 m/z
(R)-2-{3-[3-(4-Benzofuran-2-yl-phenyl)propoxy]benzoylamino}-3-naphthalen-l-yl-propionic acid (RDP 1155):

'HNMR (400 MHz, DMSO-d^): 5 13.10 (bs, 1H), 8.76 (d, J= 8.12 Hz, 1H), 8.19 (d, J= 8.44 Hz, 1H), 7.90-7.88 (m, 1H), 7.85 (d, J= 8.16 Hz, 2H), 7.77-7.74 (m, 1H), 7.63-7.60 (m, 3H), 7.51-7.49 (m, 2H), 7.39-7.25 (m, 9H), 7.10-7.07 (m, 1H), 4.75-4.69 (m, 1H), 4.0 (t, /= 6.24 Hz, 2H), 3.77-3.72 (m, 1H), 3.47-3.41 (m, 1H), 2.81 (t, J = 7.24 Hz, 2H), 2.09-2.05 (m, 2H); LC-MS: [M+H]+ = 570.3 m/z
(R,S)-2-({6-[3-(4-Benzofuran-2-yl-phenyl)-propoxy]-pyridine-2-carbonyl}-amino)-3-phenylpropionic acid (RDP 1204):
lH NMR (400 MHz, DMSO-d6): 8 12.99 (bs, 1H), 8.34 (t, J= 8.04 Hz, 1H), 7.88-7.84 (m, 3H), 7.65-7.56 (m, 3H), 7.41-7.36 (m, 3H), 7.32-7.13 (m, 7H), 7.04 (d, J= 8.24 Hz, 1H), 4.67-4.64 (m, 1H), 4.35-4.30 (m, 2H), 2.19-2.17 (m, 2H), 2.80 (t, J = 7.32 Hz, 2H), 2.09-2.06 (m, 2H); LC-MS: [M+H]+ = 521.00 m/z
(R,S)-2-[(6-{3-[4-(l-MethyHH-indoI-5-y[)phenyI]propoxy}pyridine-2-carbonyI)amino]-3-phenylpropionic acid (RDP 1213):
JH NMR (400 MHz, DMSO-d6): 8 8.40 (d, J= 7.24 Hz, 1H), 7.83 (t, /= 7.72 Hz, 1H), 7.75 (s, 1H), 7.57-7.53 (m, 3H), 7.47-7.45 (m, 1H), 7.41-7.39 (m, 1H), 731-7.25 (m, 3H), 7.15-7.03 (m, 5H), 7.00 (d, J= 8.12 Hz, 1H), 6.43 (d, / = 2.88 Hz, 1H), 4.42 (m, IH), 4.30-4.24 (m, 2H), 3.77 (s, 3H), 3.14 (s, 2H), 2.73 (t, J = 10.68 Hz, 2H), 2.04-2.00 (m, 2H); LC-MS: [M+H]+ = 534.20 m/z


3-[4-(6-Isopropoxy-2-methyl-pyridin-3-yI)-phenyl]-propan-l-ol(2):
A solution of 3-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-propan-l-ol (1) (5.0 g, 19.7 mmol) and 3-Bromo-6-isopropoxy-2-methyl-pyridine (4.8g, 20.9 mmol) in Dioxane:H20 (60 mL : 20 mL) was degassed and backfilled with N2 at room temperature. To this reaction mixture was added CS2CO3 (18.5 g, 56.9 mmol) and again degassed. Then added PdCl2(PPh3)2 (0.6 g, 0.91 mmol) into the reaction mixture and degassed twice and refluxed for 10 h under nitrogen. After completion, reaction mixture was filtered through celite and wash with EtOAc (2 x 50 mL). Filtrate EtOAc layer was washed with water (2 x 25 mL) and dried over sodium sulfate and evaporated to get crude residue which was purified by Silica gel (100-200 mesh) column chromatography eluted with 25% ethyl acetate in hexane provided 3.23 g (59.4% yield) of 3-[4-(6-Isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propan-l-ol (2) as light yellow solid.
Methanesulfonic acid 3-[4-(6-isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propyl ester (3): To a solution of solution of 3-[4-(6-Isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propan-l-ol (2) (3.23 g, 11.3 mmol) in Dichloromethane (15 mL) was added Methanesulfonyl chloride (1.94 g, 16.9 mmol) and Et3N (3.44 g, 33.9 mmol) at 0 °C and stirred at room temperature for 1 h. Reaction mixture was diluted with H2O (25 mL), extracted with dichloromethane (3 x 25 mL). Combined organic layer was dried over sodium sulfate and

evaporated to give 3.42 g (83.2% yield) of Methanesulfonic acid 3-[4-(6-isopropoxy-2-methyl-pyridin-3-yl)-phenyl] -propyl ester (3) as yellow solid.
3-{3-[4-(6-Isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propoxy}-benzoic acid methyl ester (4): To a solution of solution of 6-Hydroxy-pyridine-2-carboxylic acid methyl ester (0.20 g, 1.37 mmol) in dry DMF (4 mL) was added K2C03 (0.57 g, 4.13 mmol) and stirred at room temperature for 30 min followed by addition of Methanesulfonic acid 3-[4-(6-isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propyl ester (3) (0.5 g, 1.37 mmol). Reaction mixture was stirred at room temperature for overnight. After completion, monitored by TLC, reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organic layer was dried over sodium sulfate and evaporated. Crude residue was purified by Silica gel (100-200 mesh) column chromatography eluted with 20% ethyl acetate in hexane provided 0.15 g (26.3% yield) of 3-{3-[4-(6-Isopropoxy-2-methyl-pyridin-3 -yl)-phenyl]-propoxy} -benzoic acid methyl ester (4) as light brown solid. 3-{3-|4-(6-Isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propoxy}benzoicacid (5): To a solution of solution of 3-{3-[4-(6-Isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propoxy}-benzoic acid methyl ester (4) (0.13 g, 0.31 mmol) in 5 mL of THF:H20 (1:1) was added LiOH (0.066 g, 1.55 mmol) and stirred at room temperature for overnight. After completion, reaction mixture was acidified with citric acid solution and extracted with ethyl acetate (3 x 10 mL). Combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 0.12 g (96.0% yield) of 3-{3-[4-(6-Isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propoxy}-benzoic acid (5) as light yellow solid.
(R,S)-2-(3-{3-(4-(6-Isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propoxy}-benzoylamino)-3-phenyl-pr op ionic acid methyl ester (6):
To a solution of 3-{3-[4-(6-Isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propoxy}-benzoic acid (5) (0.07 g, 0.17 mmol) and DL-phenylalanine (0.037 g, 0.17 mmol) in DCM (2 mL) was added was added EDC.HC1 (0.049 g, 0.26 mmol) and stirred at room temperature for 15 min. Then added DMAP (0.025 g, 0.21 mmol) and resulting mixture was stirred at room temperature for overnight. After completion, H2O (10 mL) was added into reaction mixture and extracted with ethyl acetate (3 x 20 mL). Combined organic layer was dried over sodium sulfate and evaporated. Crude residue was purified by Silica gel (100-200 mesh) column chromatography eluted with 10% ethyl acetate in hexane provided 0.05 g (51.5% yield) of (R, S)- 2-(3-{3-[4-(6-Isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propoxy}-benzoylamino)-3-phenyl-propionic acid methyl ester (6) as light yellow solid.

{R,S)-2-(3-{3-[4-(6-Isopropoxy-2-iiiethyl-pyridiii-3-yl)-pheiiyl]-propoxy}-benzoylamino)-3-phenyl-propionic acid (RDP1076):
To a solution of solution of 2-(3-{3-[4-(6-Isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propoxy}-benzoylamino)-3-phenyl-propionic acid methyl ester (6) (0.05 g, 0.088 mmol) in 4 mL of THF:H20 (3:1) was added LiOH (0.018 g, 0.44 mmol) and stirred at room temperature for overnight. After completion, reaction mixture was acidified with citric acid solution and extracted with ethyl acetate (3x15 mL). Combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 0.02g (41.6% yield) of (R, S)-2-(3-{3-[4-(6-Isopropoxy-2-methyl-pyridin-3-yl)-phenyl]-propoxy}-benzoylamino)-3-phenyl-propionic acid (RDP1076) as light yellow solid. lH NMR (400 MHz, DMSO-de): 5 12.73 (bs, 1H), 8.65 (d, J= 7.76 Hz, 1H), 7.45 (d, J = 8.32 Hz, 1H), 7.33-7.19 (m, 11H), 7.14-7.11 (m, 1H), 6.99 (m, 1H), 6.63-6.56 (m, 1H), 5.28-5.22 (m, 1H), 4.56 (m, 1H), 4.00 (t, J= 5.56 Hz, 2H), 3.16-3.14 (m, 1H), 3.05-2.99 (m, 1H), 2.77 (t, J= 7.16 Hz, 2H), 2.30 (s, 3H), 2.05 (t, J= 6.32 Hz, 2H), 1.27 (d, J= 6.04 Hz, 6H); LC-MS: [M+Hf = 553.2 m/z.
Synthesis of (R, S)-(3-{3-[4-(6-Isopropoxy-2-methyl-pyridin-3-yl)phenyl]propoxy} benzoylamino)phcnylacetic acid (RDP1077):
The title compound was prepared by following similar procedure as described above for RDP-1076:
'H NMR (400 MHz, DMSO-dt): 5 12.94 (bs, 1H), 9.06 (d, J= 7.36 Hz, 1H), 7.49-7.44 (m, 5H), 7.39-7.34 (m, 4H), 7.31-7.25 (m, 4H), 7.13-7.11 (m, 1H), 7.60 (d, J= 8.32 Hz, 1H), 5.58 (d, J= 7.32 Hz, 1H), 5.29-5.25 (m, 1H), 4.05 (t, J- 5.56 Hz, 2H), 2.80 (t, J- 7.04 Hz, 2H), 2.33 (s, 3H), 2.07 (t, J = 6.32 Hz, 2H), 1.297 (d, /= 6.0 Hz, 6H); LC-MS: [M+H]+ = 539.1 m/z


Step-1: Synthesis of 4-(l-Methyl-lH-indol-5-yl)-phenol (2): To stirred solution of Dioxane:H20 (4:1) (50 mL) was degassed with nitrogen atmosphere for 15 min then added 4-hydroxyphenylboronic acid (1) (3.0 g, 21.73 mmol) and 5-Bromo-l-methyl-lH-indole (4.5 g, 21.73 mmol). Resulting mixture degassed with nitrogen atmosphere for 15 min and added PdCl2(PPh3)2 (0.76 g, 1.08 mmol) and again degassed for 15 min. The resulting reaction mixture stirred at 100 °C for 3 h. Reaction monitored on TLC, after consumption of starting material, solvent was evaporated under reduced pressure. Crude was diluted with water and acidify with dil HC1 and extracted with ethyl acetate (4 x 100 mL). Combined organic layer were dried over sodium sulfate and concentrated under vacuum. Crude compound was purified by combifiash column chromatography eluted in 15% ethyl acetate in hexane provided 4-(l-Methyl-lH-indol-5-yl)-phenol (2) 1.5 g (30.92% yield) as an off white solid. Step-2: Synthesis of 5-[4-(2-Bromo-ethoxy)-phenyl]-l-methyl-lH-indole (3): A mixture of 4-(l-Methyl-lH-indol-5-yl)-phenol (2) (2.5 g, 11.21 mmol) and K2C03 (4.6 g, 33.63 mmol) in DMF (20 mL) was stirred at room temperature for 15 min and then added 1,2-Dibromoethane (6.3 g, 33.63 mmol). Resulting mixture was stirred at room temperature for 30 min and at 50 °C for overnight. After consumption of starting material, monitored by TLC, reaction mixture poured in to ice and extracted with ethyl acetate (3 x 250 mL). Combined organic layer dried over sodium sulfate and concentrated under reduced pressure. Crude compound was purified by column chromatography using (100-200 mesh) silica gel eluted

with 10% ethyl acetate in hexane give 5-[4-(2-Bromo-ethoxy)-phenyl]-l-methyl-lH-indole (3) 1.8 g (48.78% yield) as a oily material.
Step-3: Synthesis of 3-{2-[4-(l-Methyl-lH-indol-5-yl)-phenoxy]-ethoxy}-benzoic acid methyl ester (4): A mixture of 3-Hydroxy-benzoic acid methyl ester (0.78 g, 5.15 mmol) and K2CO3 (2.13 g, 15.45 mmol) in DMF (15 mL) was stirred at room temperature for 10 min and then added 5-[4-(2-Bromo-ethoxy)-phenyl]-l-methyl-lH-indole (3) (1.7 g, 5.15 mmol). Resulting mixture was stirred at 50 °C for overnight. Reaction mass poured in to ice and stirred for 15 min. Resulting precipitated solid material was collected by filtration and dried to give 3-{2-[4-(l-Methyl-lH-indol-5-yl)-phenoxy]-ethoxy}-benzoic acid methyl ester (4) 1.6g (77.66% yield) as an off white solid.
Step-4: Synthesis of 3-{2-[4-(l-Methyl-lH-indol-5-yl)-phenoxy]-ethoxy}-benzoic acid (5): To stirred solution of 3-{2-[4-(l-Methyl-lH-indol-5-yl)-phenoxy]-ethoxy}-benzoic acid methyl ester (4) (1.6 g, 3.99 mmol) in THF:H20 (1:1) (25 mL) was added LiOH (0.84 g, 19.95 mmol) and stirred at room temperature for overnight. After consumption of starting material, monitored by TLC, solvent was concentrated under vacuum and diluted with water (10 mL) and acidify with citric acid solution. Resulting precipitated solid material was collected by filtration and dried to obtained 3-{2-[4-(l-MethyI-lH-indol-5-yl)-phenoxy]-ethoxy}-benzoic acid (5) 1.4g (90.90% yield) as a white solid.
Step-5: Synthesis of 2-(3-{2-[4-(l-MethyMH-indol-5-yl)-phenoxy]-ethoxy}-benzoylamino)-3-phenyl-propionic acid methyl ester (6): A solution of 3-{2-[4-(l-Methyl-lH-indol-5-yl)-phenoxy]-ethoxy}-benzoic acid (0.2 g, 0.516 mmol), DL-Phenylalanine (0.092 g, 0.516 mmol), EDC.HC1 (0.148 g, 0.775 mmol) and DMAP (0.094 g, 0.774 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. After consumption of starting material, monitored by TLC, reaction mass was diluted with water and extracted with DCM (3x10 mL). Combined organic layer were dried over sodium sulfate and concentrated under reduced pressure. Crude compound was purified by column chromatography using (100-200mesh) silica gel eluted with 30% ethyl acetate in hexane to give 2-(3-{2-[4-(l-Methyl-lH-indol-5-yl)-phenoxy]-ethoxy}-benzoylamino)-3-phenyl-propionic acid methyl ester (6) 0.1 g (35.71% yield) as a sticky material.
Step-6: Synthesis of 2-(3-{2-[4-(l-MethyHH-indol-5-yl)-phenoxyl-ethoxy}-benzoylamino)-3-phenyl-propionic acid (RDP-1224): To a stirred solution of 2-(3-{2-[4-(l-Methyl-lH-indol-5-yl)-phenoxy]-ethoxy}-benzoylamino)-3-phenyl-propionic acid methyl ester (6) (0.1 g, 0.18 mmol) in 10 mL THF:H20 (1:1) was added LiOH (0.038 g, 0.90 mmol) and stirred at room temperature for 16 h. After consumption of starting material, monitored

by TLC, solvent was concentrated under vacuum. Residue was diluted with water (10 mL), acidify with citric acid solution and extracted DCM (3x5 mL). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude compound was purified by Prep HPLC provided 0.02 g (20.61% yield) of 2-(3-{2-[4-(l-Methyl-lH-indol-5-yl)-phenoxy]-ethoxy}-benzoylamino)-3-phenyl-propionic acid (RDP-1224) as an off white solid; 1H NMR (400 MHz, DMSO-d6): 5 12.82 (bs, 1H), 8.67 (d, J= 6.04 Hz, 1H), 7.75 (s, 1H), 7.60 (d, J= 8.6 Hz, 2H), 7.49-7.47 (m, 1H), 7.41-7.37 (m, 4H), 7.35-7.27 (m, 5H), 7.23-7.16 (m, 2H), 7.06 (d, J= 8.16 Hz, 2H), 6.45 (d, J= 3.0 Hz, 1H), 4.59-4.55 (m, 1H), 4.37 (s, 4H), 3.80 (s, 3H), 3.21-3.16 (m, 1H), 3.08-3.02 (m, 1H); LC-MS: [M+H]+ = 535.2 m/z

Step-1: Synthesis of 4-Bcnzofuran-2-yl-phenol (2): To stirred solution of Dioxane:H20 (4:1) (15 mL) was degassed with nitrogen atmosphere for 15 min then added 4-hydroxyphenylboronic acid (1) (2.0 g, 14.50 mmol) and 2-Bromo-benzofuran (2.85 g, 14.50 mmol). Resulting mixture degassed with nitrogen atmosphere for 15 min and added PdCl2(PPh3)2 (0.50 g, 0.725 mmol) and again degassed for 15 min. The resulting reaction mixture stirred at 100 °C for 3 h. Reaction monitored on TLC, after consumption of starting material, solvent was evaporated under reduced pressure. Crude was diluted with water and acidify with dil HC1 and extracted with ethyl acetate (4 x 100 mL). Combined organic layer

were dried over sodium sulfate and concentrated under vacuum. Crude compound was purified by combiflash column chromatography eluted in 15% ethyl acetate in hexane provided 4-Benzofuran-2-yl-phenol (2) 1.5 g (49.83% yield) as an off white solid. Step-2: Synthesis of 2-[4-(2-Bromo-ethoxy)-phenylI-benzofuran (3): A mixture of 4-Benzofuran-2-yl-phenol (2) (2.5 g, 11.89 mmol) and K2C03 (4.92 g, 35.67 mmol) in DMF (20 mL) was stirred at room temperature for 15 min and then added 1,2-Dibromoethane (6.71 g, 35.67 mmol). Resulting mixture was stirred at room temperature for 30 min and at 50 °C for overnight. After consumption of starting material, monitored by TLC, reaction mixture poured in to ice and extracted with ethyl acetate (3 x 250 mL). Combined organic layer dried over sodium sulfate and concentrated under reduced pressure. Crude compound was purified by column chromatography using (100-200 mesh) silica gel eluted with 5% ethyl acetate in hexane give 2-[4-(2-Bromo-ethoxy)-phenyl]-benzofuran (3) 2.0 g (53.05% yield) as a oily material.
Step-3: Synthesis of 3-[2~(4-Benzofuran-2-yl-phenoxy)-ethoxy]-benzoic acid methyl ester (4): A mixture of 3-Hydroxy-benzoic acid methyl ester (0.96 g, 6.30 mmol) and K2CO3 (2.6 g, 18.91 mmol) in DMF (15 mL) was stirred at room temperature for 10 min and then added 2-[4-(2-Bromo-ethoxy)-phenyl]-benzofuran (3) (2.0 g, 6.30 mmol). Resulting mixture was stirred at 50 °C for overnight. Reaction mass poured in to ice and stirred for 15 min. Resulting precipitated solid material was collected by filtration and dried to give 3-[2-(4-Benzofuran-2-yl-phenoxy)-ethoxy]-benzoic acid methyl ester (4) 1.8g (73.77% yield) as an off white solid.
Step-4: Synthesis of 3-|2-(4-Benzofuran-2-yI-phenoxy)-ethoxy]-benzoic acid (5): To stirred solution of 3-[2-(4-Benzofuran-2-yl-phenoxy)-ethoxy]-benzoic acid methyl ester (4) (1.8 g, 4.63 mmol) in THF:H20 (1:1) (25 mL) was added LiOH (0.97 g, 23.17 mmol) and stirred at room temperature for overnight. After consumption of starting material, monitored by TLC, solvent was concentrated under vacuum and diluted with water (10 mL) and acidify with citric acid solution. Resulting precipitated solid material was collected by filtration and dried to obtained 3-[2-(4-Benzofuran-2-yl-phenoxy)-ethoxy]-benzoic acid (5) 1.5g (86.70% yield) as a white solid.
Step-5: Synthesis of {3-l2-(4-Benzofuran-2-yl-phenoxy)-ethoxy]-benzoylamino}-phenyl-acetic acid methyl ester (6): A solution of 3-[2-(4-Benzofuran-2-yl-phenoxy)-ethoxy]-benzoic acid (5) (0.2 g, 0.534 mmol), DL-Phenyl glycine methyl ester (0.088 g, 0.534 mmol), EDC.HC1 (0.153 g, 0.801 mmol) and DMAP (0.097 g, 0.801 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. After consumption of starting material, monitored by

TLC, reaction mass was diluted with water and extracted with DCM (3 x 10 mL). Combined organic layer were dried over sodium sulfate and concentrated under reduced pressure. Crude compound was purified by column chromatography using (100-200mesh) silica gel eluted with 1% methanol in DCM to give 3-[2-(4-Benzofuran-2-yl-phenoxy)-ethoxy]-benzoylamino}-phenyl-acetic acid methyl ester (6) 0.15 g (53.95% yield) as a sticky material. Step-6: Synthesis of {3-[2-(4-Benzofuran-2-yl-phenoxy)-ethoxy|-benzoylamino}-phenyl-acetic acid (RDP-1236):
To a stirred solution of {3-[2-(4-Benzofuran-2-yl-phenoxy)-ethoxy]-benzoylamino}-phenyl-acetic acid methyl ester (6) (0.08 g, 0.153 mmol) in 10 mL THF:H20 (1:1) was added LiOH (0.032 g, 0.766 mmol) and stirred at room temperature for 16 h. After consumption of starting material, monitored by TLC, solvent was concentrated under vacuum. Residue was diluted with water (10 mL), acidify with citric acid solution and extracted DCM (3x5 mL). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude compound was purified by column chromatography using (100-200mesh) silica gel eluted with 5% methanol in DCM to give 0.06 g (77.92% yield) of {3-[2-(4-Benzofuran-2-yl-phenoxy)-ethoxy]-benzoylamino}-phenyl-acetic acid (RDP1236) as an off white solid; 1H NMR (400 MHz, DMSO-d6): 8 12.91 (bs, 1H), 8.97 (s, 1H), 7.86 (d, J= 8.56 Hz, 2H), 7.60 (t, J= 8.48 Hz, 2H), 7.54-7.47 (m, 4H), 7.42-7.22 (m, 7H), 7.18-7.16 (m, 1H), 7.13 (d, J- 8.60 Hz, 2H), 4.41 (s, 4H); LC-MS: [M-H]- = 511.9 m/z.
Biological Screening of the Compounds:
A compound having formula described above or a specific compound described or illustrated herein can be used to inhibit UPPS. The compounds can also kill or inhibit the growth of bacteria. In one embodiment, a compound described herein can inhibit an isoprenoid biosynthesis enzyme in vitro. The Ki of the compound can be, for example, less than about 10 uM, less than about 5 uM, less than about 2 uM, less than about 1.5 uM, less than about 1 uM.
UPPS enzyme purification and inhibition assay
The purification of UPPS from E. coli followed the published protocol (Pan et al, Biochemistry 2000, 39(35):10936-10942). The plasmid was transformed into E. coli BL21 (DE3) cells (Novagen) for expression. A single transformant was grown up overnight at 37 °C in LB medium containing 100 ug/mL ampicillin. The 50 mL overnight cultures were

transferred to 2 L fresh LB medium containing 100 ug/mL ampicillin and allowed to grow to OD6oo = 0.6 before induction with 1 mM IPTG. The cultures were induced for 4 h at 37 °C and harvested by centrifugation. Cell pellets were suspended in 60 mL buffer (25 mM Tris-HC1, pH 7.5 and 150 mM NaCl), followed by pulse sonication. The lysate was centrifuged and the cell debris discarded. For purification, the cell free extract was loaded into a 20 mL Ni-NTA column pre-equilibrated with 25 mM Tris-HCl (pH 7.5) and 150 mM NaCl. The column was washed with 30 mM imidazole-eontaining buffer. The His-tagged UPPS was eluted with a 0% to 100% gradient buffer (25 mM Tris-HCl, pH 7.5, 150 mM NaCl and 300 mM imidazole). The protein solution was dialyzed against 3 x 2 L buffer (25 mM Tris-HCl, pH 7.5 and 150 mM NaCl). The His-tagged UPPS was then digested with FXa protease to remove the His-tag. The solution was then loaded onto Ni-NTA. The UPPS in the flow through (25 mM Tris-HCl, pH 7.5, 150 mM NaCl and 30 mM imidazole) was pure as evidenced by to SDS-PAGE, and was dialyzed into buffer (25 mM Tris, pH 7.5 and 150 mM NaCl) for storage. The final concentration was determined by using a Bradford protein assay kit.
.The gene encoding UPPS was amplified from a plasmid containing the S. aureus UPPS gene. The forward primer was 5' GTA TTG AGG GTC GCA TGT TTA AAA AGC TAA TAA ATA AAA AGA ACA C 3 ' , and the reverse primer was 5 ' AGA GGA GAG TTA GAG CCC TAC TCC TCA CTC 3'. The amplified UPPS gene was purified and ligated into a pET-32 Xa LIC vector (Novagen, Madison, WI, USA). The plasmid with the S. aureus UPPS gene was subsequently expressed in E. coli BL21 (DE3) cells (Novagen). The protocol for expression and purification of S. aureus UPPS was similar to that for E. coli UPPS.
UPPS Inhibition Assays: E. coli UPPS and S. aureus UPPS inhibition assays were carried out as described previously (Durrant et al. , Chem Biol Drug Des 2011 , 78(3) :323 - 332). Briefly, the condensation of FPP with IPP catalyzed by UPPS was monitored by using a continuous spectrophotometric assay (Webb, Proc Natl Acad Sci U SA 1992, 89(11):4884-4887) in 96 well plates with 200 ut reaction mixtures containing 400 uM MESG, 350 [Jvl IPP, 35 uM FPP, 25 mM Tris-HCl (pH 7.5), 0.01% Triton X-100 and 1 mM MgCLz. The IC50 values for the most active hits were verified by using a radiometric assay (Li et al, JBiomol Screen 2003, 8(6):712-715) with 2.5 uM FPP, 25 uM [l4C] IPP and 0.01% Triton X-100.

Bacterial cell growth inhibition assays were carried out in Mueller-Hinton broth according to the prescribed protocol from NCCLS. Minimum Inhibitory Concentrations (MICs) were determined in 5 aureus ATCC 29213 strain.
E coli and S aureus UPPS potencies and MIC concentrations of representative compounds in ATCC 29213 are listed in Table 2.



The invention thus provides methods of inhibiting the activity UPPS wherein the compound binds to the enzyme, thereby inhibiting the activity of the enzyme. The invention also provides methods of treating a bacterial infection in a mammal such as a human, wherein the bacterial infection is caused by a bacteria that has the UPPS enzyme, wherein the method comprises administering to a mammal in need of such treatment an effective amount of a compound described herein, wherein the compound binds to the enzyme, thereby inhibiting the activity of the enzyme, thereby treating the bacterial infection or parasitic infection. These methods can include treating the bacterium with a compound described herein, wherein the compound binds to UPPS, thereby killing or inhibiting the growth of the bacterium. The bacterial infection may be associated with, for example, a gram negative bacterium; a gram positive bacterium, e.g., hospital gram positive infection; or in particular embodiments, a bacterium selected from the group consisting of S. aureus, Group A Streptococcus, E. faecalis; with E. coli, S. aureus, E. faecalis, or S. pneumoniae. The bacterial infection may be an outpatient skin infection or a skin structure infection, e.g., wherein the bacterial infection is associated with a bacterium selected from the group consisting of S. aureus and Group AStreptococcus. The bacterial infection may be community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), e.g., wherein the bacterial infection is associated with methicillin-resistant Staphylococcus aureus (MRSA). The bacterial infection can also be an antibiotic-associated colitis infection, e.g., wherein the bacterial infection is associated with C. difficile or nosocomial pneumonia, e.g., wherein the bacterial infection is associated with S. aureus or wherein the bacterial infection is associated with gram negative bacterium, e.g., P. aeruginosa, Klebsiella, Enterobacter, E. coli, orAcinetobacter. The

compounds of the invention are useful in treating bacterial infection wherein said bacterial infection is resistant to other antibiotics.

We Claim:
1. A compound of Formula (I):

or a pharmaceutical ly acceptable salt or a stereoisomer thereof; wherein

R2 is hydrogen, optionally substituted monocyclic or fused bicyclic aryl or arylalkyl or optionally substituted monocyclic heteroarylalkyl, wherein the optional substituent at each occurrence is selected from halogen, hydroxyl or alkyl;
R3 is hydrogen or alkyl;
R4 at each occurrence is independently selected from alkyl or alkoxy;
Ring Het is 5-6 membered heteroaryl, 5- to 6-membered heteroaryl fused to a phenyl or phenyl fused to a 5- to 6-membered heteroaryl;

2, The compound of claim 1 wherein the compound of Formula (I) is a compound of Formula (Ia)


or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein

3. The compound of claim 1, wherein Z is aryl.
4. The compound of claim 3, wherein aryl is phenyl.
5. The compound of claim 1, wherein Het is 6-membered heteroaryl, phenyl fused to a 5-membered heteroaryl or 5- membered heteroaryl fused to a phenyl.
6. The compound of claim 5, wherein heteroaryl is pyridyl.
7. The compound of claim 5, wherein phenyl fused to a 5-membered heteroaryl is indolyl and 5- membered heteroaryl fused to a phenyl is benzofuranyl.
8. A compound selected from the group consisting of

or a pharmaceutically acceptable salt or a stereoisomer thereof.
9. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I) according to any of claim 1 to 8, their pharmaceutically acceptable salts or individual isomers and mixtures of isomers thereof in admixture with at least one pharmaceutically acceptable carrier or excipient including mixtures thereof in all ratios, for use as a medicament.
10. A pharmaceutical composition for inhibiting undecaprenyl pyrophosphate synthase (UPPS) comprising the step of contacting UPPS with an activity-enhanced UPPS inhibitor such that UPPS is inhibited.