WO2004037778A1

WO2004037778A1 - Substituted tetralins and indanes

Info

Publication number: WO2004037778A1
Application number: PCT/US2003/033090
Authority: WO
Inventors: Xiaoli Chen; Jay M. Matthews; Keith T. Demarest; Jung Lee; Philip Rybczynski
Original assignee: Janssen Pharmaceutica, N.V.
Priority date: 2002-10-21
Filing date: 2003-10-17
Publication date: 2004-05-06
Also published as: NZ539510A; EG24842A; NO20052199L; KR20050055773A; AU2003277441B2; TW200418773A; MXPA05004191A; JP2006503916A; EP1569897A1; EA009553B1; RS20050318A; CR7795A; HRP20050335A2; PL376325A1; AU2003277441A1; CA2502661A1; EA200500515A1; BR0315596A

Abstract

The invention features tetralin and indane compounds, compositions containing them, and methods of using them as PPAR alpha modulators to treat or inhibit the progression of, for example, dyslipidemia.

Description

SUBSTITUTED TETRALINS AND INDANES

Cross-References to Related Applications This application is a non-provisional patent application of U.S. provisional patent application No. 60/419,935 filed on October 21 , 2002 and U.S. provisional patent application No. 60/495,270 filed on August 15, 2003 entitled, "SUBSTITUTED TETRALINS AND INDANES"

Field of the Invention The invention features substituted tetralin and indane derivatives, compositions containing them, and methods of using them.

Background A member of the nuclear receptor family, a group of ligand-activated transcription factors, the peroxisome proliferator-activated receptor alpha (PPAR alpha) is a necessary transcription factor regulating genes relating to fatty acid metabolism and insulin action.

PPAR alpha receptors are found predominantly in the liver. The genes regulated by PPAR alpha include enzymes involved in the beta-oxidation of fatty acids, the liver fatty acid transport protein, and apo A1 , an important component of high density lipoproteins (HDL). Selective, high affinity PPAR alpha agonists increase hepatic fatty acid oxidation, which in turn decreases circulating triglycerides and free fatty acids. The reduction of circulating triglycerides may mediate the observed decrease, or improvement, in insulin resistance in insulin resistant or diabetic animals when treated with PPAR alpha agonists. Such treatment in animal obesity models is associated with weight loss. Known as treatments for hyperlipidemia, fibrates are weak PPAR alpha agonists.

Examples of known PPAR alpha agonists variously useful for hyperlipidemia, diabetes, or atherosclerosis include fibrates such as fenofibrate (Fournier), gemfibrozil (Parke-Davis/Pfizer, Mylan, Watson), clofibrate (Wyeth- Ayerst, Novopharm), bezafibrate, and ciprofibrate and ureidofibrates such as GW 7647, GW 9578, and GW 9820 (GiaxoSmithKline).

Summarv

The invention features compounds of formula (I) below:

Formula (I)

or a pharmaceutically acceptable salt, C 1-₆ ester or C ₁-₆ amide thereof, wherein

each of R^ and R₂ is independently H, C ι_-6 alkyl, (CH₂)_mNR_aR_b, (CH₂)_mOR₈, (CH₂)mNH(CO)R₈, or (CH₂)_mCO₂R8, where each of R_a, Rb, and R₈ is independently H or C ₁-₆ alkyl, or R^ and R₂ taken together with the carbon atom to which they are attached are a C _3-7 cycloalkyl;

m is between 1 and 6;

n is 1 or 2; X is O or S; wherein X is at the 5 or 6 position when n is 1 ; and wherein X is at the 6 or 7 position when n is 2;

R₃ is H, phenyl, C ι_-3 alkoxy, C ι_-3 alkylthio, halo, cyano, C ₁-₆ alkyl, nitro, NR9R₁0, NHCOR10, CONHR₁0; and COOR₁0; and R₃ is ortho or meta to X;

R₄ is H or -(C 1-5 alkylene)Rιs, where R15 is H, Cι_₇ alkyl, [di(C ι_-2 alkyl)amino](C 1-6 alkylene), (C ι_-3 alkoxyacyl)(C ₁-₆ alkylene), C 1-6 alkoxy, C ₃.₇ alkenyl, or C _3-a alkynyl, wherein R₄ has no more than 9 carbon atoms; R can also be -(C ι_-5 aIkylene)Ri₅ wherein R₁₅ is C _3-6 cycloalkyl, phenyl, phenyl-O-, phenyl-S-, or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

Y is NH, NH-CH₂, or O;

each of R₅ and R₇ is independently selected from H, C ι_-6 alkyl, halo, cyano, nitro, COR₁₁, COOR₁₁, C ι-₄ alkoxy, C ι- alkylthio, hydroxy, phenyl, NRnR-ι₂ and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

Re is selected from C ι_-6 alkyl, halo, cyano, nitro, CORι₃, COORι₃, C ι_-4 alkoxy, C ι- alkylthio, hydroxy, phenyl, NRi₃R-i and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

in addition, either R₅ and Re or Re and R₇ may be taken together to be a bivalent moiety, saturated or unsaturated, selected from -(CH₂)₃- -(CH₂) -, and (CH_1-2)_PN(CH_1-2)_q,

p is 0-2 and q is 1-3, where the sum (p + q) is at least 2;

each of R₉ and R₁₀ is independently C ι_-6 alkyl; each of R₁₁, Rι₂, Rι₃ and Rι is independently H or C ₁-₆ alkyl;

wherein each of the above hydrocarbyl and heterocarbyl moieties may be substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy, nitro, cyano, and methoxy. The invention also features compositions that include one or more compounds of formula (I) and a pharmaceutical carrier or excipient.

These compositions and the methods below may further include additional pharmaceutically active agents, such as lipid-lowering agents or blood-pressure lowering agents, or both.

Another aspect of the invention includes methods of using the disclosed compounds or compositions in various methods for preventing, treating, or inhibiting the progression of, a disease mediated by PPAR alpha. Examples of PPAR alpha-mediated diseases include dyslipidemia and atherosclerosis. Dyslipidemia includes hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL-cholesterolemia. For example, dyslipidemia may be one or more of the following: low HDL (< 35 or 40 mg/dl), high triglycerides ( > 200 mg/dl), and high LDL (> 150 mg/dl).

Additional features and advantages of the invention will become apparent from the detailed discussion, examples, and claims below.

Detailed Description

A. Terms

The following terms are defined below and by their usage throughout this disclosure.

"Alkyl" includes optionally substituted straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isoprdpyl, butyl, isobutyl, t-butyl, 1- methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on. Alkyl includes cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

"Alkenyl" includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon double bond (sp²). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyI), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkenyl includes cycloalkenyl. Cis and trans or (E) and (Z) forms are included within the invention.

"Alkynyl" includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon triple bond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4- ynyl, are grouped as alkynyls herein. Alkynyl does not include cycloalkynyl.

"Alkoxy" includes an optionally substituted straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on. "Aminoalkyl", "thioalkyl", and "sulfonylalkyl" are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and SO₂. Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl, and so on.

"Aryl" includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, indenyl, and so on, any of which may be optionally substituted. Aryl also includes arylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Aryl includes a ring system containing an optionally substituted 6-membered carbocyclic aromatic ring, said system may be bicyclic, bridge, and/or fused. The system may include rings that are aromatic, or partially or completely saturated. Examples of ring systems include indenyl, pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on.

"Heterocyclyl" includes optionally substituted aromatic and nonaromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom moiety (SO₂, CO, CONH, COO) in the ring. Unless otherwise indicated, a heterocyclic radical may have a valence connecting it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or 1-pyrazolyI. Preferably a monocyclic heterocyclyl has between 5 and 7 ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5 heteroatoms or heteroatom moieties in the ring, and preferably between 1 and 3, or between 1 and 2. A heterocyclyl may be saturated, unsaturated, aromatic (e.g., heteroaryl), nonaromatic, or fused.

Heterocyclyl also includes fused, e.g., bicyclic, rings, such as those optionally condensed with an optionally substituted carbocyclic or heterocyclic five- or six-membered aromatic ring. For example, "heteroaryl" includes an optionally substituted six-membered heteroaromatic ring containing 1 , 2 or 3 nitrogen atoms condensed with an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring. Said heterocyclic five- or six- membered aromatic ring condensed with the said five- or six-membered aromatic ring may contain 1 , 2 or 3 nitrogen atoms where it is a six-membered ring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur where it is a five- membered ring.

Examples of heterocyclyls include thiazoylyl, furyl, thienyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. For example, preferred heterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, thienyl.and more preferably, piperidyl or morpholinyl.

Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzόxazolyl, benzothiazolyl.

"Acyl" refers to a carbonyl moiety attached to either a hydrogen atom (i.e., a formyl group) or to an optionally substituted alkyl or alkenyl chain, or heterocyclyl.

"Halo" or "halogen" includes fluoro, chloro, bromo, and iodo, and preferably fluoro or chloro as a substituent on an alkyl group, with one or more halo atoms, such as trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethoxy, or fluoromethylthio.

"Alkanediyl" or "alkylene" represents straight or branched chain optionally substituted bivalent alkane radicals such as, for example, methylene, ethylene, propylene, butylene, pentylene or hexylene. "Alkenediyl" represents, analogous to the above, straight or branched chain optionally substituted bivalent alkene radicals such as, for example, propenylene, butenylene, pentenylene or hexenylene. In such radicals, the carbon atom linking a nitrogen preferably should not be unsaturated.

"Aroyl" refers to a carbonyl moiety attached to an optionally substituted aryl or heteroaryl group, wherein aryl and heteroaryl have the definitions provided above. In particular, benzoyl is phenylcarbonyl.

As defined herein, two radicals, together with the atom(s) to which they are attached may form an optionally substituted 4- to 7-, 5 - to 7-, or a 5- to 6- membered ring carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic. Said rings may be as defined above in the Summary of the Invention section. Particular examples of such rings are as follows in the next section.

"Pharmaceutically acceptable salts, esters, and amides" include carboxylate salts, amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. These salts, esters, and amides may be, for example, C ι-β alkyl, C _3-s cycloalkyl, aryl, C 2-10 heteroaryl, or C ₂-₁0 non-aromatic heterocyclic salts, esters, and amides. Salts, free acids, and esters are more preferable than amides on the terminal carboxylate/carboxylic acid group on the left of formula (I). Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C ι-β alkyl amines and secondary di (C ι-₆ alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C ι_-3 alkyl primary amines, and di (C ι_-2alkyl)amines. Representative pharmaceutically acceptable esters of the invention include C ι_₇ alkyl, C _5-7cycloalkyl, phenyl, and phenyl(C ι_-6 )alkyl esters. Preferred esters include methyl and ethyl esters.

"Patient" or "subject" includes mammals such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates) in need of observation, experiment, treatment or prevention in connection with the relevant disease or condition. Preferably, the patient or subject is a human.

"Composition" includes a product comprising the specified ingredients in the specified amounts as well as any product which results from combinations of the specified ingredients in the specified amounts.

"Therapeutically effective amount" or "effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the condition or disorder being treated.

Concerning the various radicals in this disclosure and in the claims, three general remarks are made. The first remark concerns valency. As with all hydrocarbon radicals, whether saturated, unsaturated or aromatic, and whether or not cyclic, straight chain, or branched, and also similarly with all heterocyclic radicals, each radical includes substituted radicals of that type and monovalent, bivalent, and multivalent radicals as indicated by the context of the claims. The context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more hydrogen atoms removed (multivalent). An example of a bivalent radical linking two parts of the molecule is Y in formula (I) which links a phenyl substituted with R₅, Re, and R to the rest of the molecule.

Second, radicals or structure fragments as defined herein are understood to include substituted radicals or structure fragments. Hydrocarbyls include monovalent radicals containing carbon and hydrogen such as alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromatic or unsaturated), as well as corresponding divalent (or multi-valent) radicals such as alkylene, alkenylene, phenylene, and so on. Heterocarbyls include monovalent and divalent (or multivalent) radicals containing carbon, optionally hydrogen, and at least one heteroatom. Examples of monovalent heterocarbyls include acyl, acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl, and so on. Using "alkyl" as an example, "alkyl" should be understood to include substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents may be the same (dihydroxy, dimethyl), similar (chlorofluoro), or different (chlorobenzyl- or aminomethyl- substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, trifluoromethyl, and 3-iodocyclopentyl), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and 2-aminopropyl), nitroalkyl, alkylalkyl, and so on. A di(C ι-₆ alkyl)amino group includes independently selected alkyl groups, to form, for example, methylpropylamino and isopropylmethylamino, in addition dialkylamino groups having two of the same alkyl group such as dimethyl amino or diethylamino. Third, only stable compounds are intended. For example, where there is an NRnRι₂ group, and R can be an alkenyl group, the double bond is at least one carbon removed from the nitrogen to avoid enamine formation. Similarly, where -(CH₂)_p-N-(CH₂)_q- can be unsaturated, the appropriate hydrogen atom(s) is(are) included or omitted, as shown in -(CH₂)-N=(CH)-(CH₂)- or -(CH₂)-NH- (CH)=(CH)-.

Compounds of the invention are further described in the next section.

B. Compounds

The present invention features compositions containing and methods of using compounds of formula (I) as described in the Summary section above. Examples include those compounds wherein: (a) one of Ri and R₂ is methyl or ethyl; (b) wherein each of Ri and R₂ is methyl; (c) Ri and R₂ taken together are cyclobutyl or cyclopentyl; (d) R₃ is H; (e) R₄ is H or C _2- alkyl; (e) R is H or C 2-5 alkyl; (f) R₄ is ethyl; (g) R is H; (h) n is 1 ; (i) n is 2; 0) Y is NHCH₂; (k) Y is NH; (I) X is S; (m) X is O; (n) at least one of R₅ and R₇ is H; (o) Re is C ι- alkyl, halomethoxy, or halothiomethoxy; (p) Re is t-butyl, isopropyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethoxy, difluoromethoxy, or dimethylamino; (q) R₃ is H, R is C ₂-₇ alkyl, and Y is NH; (r) R is C ₂-₅ alkyl; (s) Re is cyclopropylmethyl, isopropyl, isobutyl, methylethylamino, or diethylamino; (t) the (S) enantiomer at the C-2 position on the indane or tetralin; (u) the (R) enantiomer at the C-2 position on the indane or tetralin; (v) where R₁₅ is Cι_-7 alkyl, [di(C ι_-2 alkyl)amino](C ι_-6 alkylene), (C ι_-3 alkoxyacyl)(C i-β alkylene), C ι_-6 alkoxy, C _3-7 alkenyl, or C _3-s alkynyl; (w) R₆ is trifluoromethylthio or trifluoromethoxy; or (x) combinations of the above.

Additional preferred compounds include:

2-{6-[1-Ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-1 ,4-difluoro-5,6,7,8-tetrahydro- naphthalen-2-yIsu!fanyl}-2-methylpropionic acid

2-{4-Chloro-6-[1-ethyI-3-(4-trifluoromethoxyphenyl)ureido]-1-fluoro-5,6,7,8- tetrahydronaphthalen-2-y!sulfanyl}-2-methylpropionic acid

2-{3-EthyI-6-[1-ethyI-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid

3-(1 -Carboxy-1 -methyl-ethylsulfanyl)-7-[1 -ethyl-3-(4- trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid ethyl ester

2-{6-[Ethyl-(4-trifluoromethoxyphenoxycarbonyl)-amino]-3-fluoro-5, 6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyI)ureido]-3-methoxy-5, 6,7,8- tetrahydronaphthalen-2-ylsuIfanyl}-2-methylpropionic acid

2-{6-[1 -Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-5, 6,7,8- tetrahydronaphthalen-2-ylsuIfanyl}-2-methylpropionic acid

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-bromo-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-trifluoromethoxy-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid

2-{6-[1-Ethyl-3-(4-hydroxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyl}-2-methylpropionic acid

2-{6-[4-Aminophenyl)-1-ethyl-ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsuIfanyl}-

2-methylpropionic acid

The most preferred compounds are selected from:

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8- tetrahydronaphthalen-2-ylsuIfanyl}-2-methylpropionic acid;

2-{6-[3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyl}-2-methylpropionic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-yIsulfanyl}-2- methylpropionic acid;

2-{2-[1-Ethyl-3-(4-trifluoromethylsuIfanylphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid;

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8- tetrahydronaphthaIen-2-ylsulfanyl}-2-methyIpropionic acid; and

2-Methyl-2-{2-[1-propyI-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsuIfanyl}propionic acid.

Related Compounds

The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, acids, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms. Related compounds also include compounds of the invention that have been modified to be detectable, e.g., isotopically labelled with ¹⁸F for use as a probe in positron emission tomography (PET) or single-photon emission computed tomography (SPECT).

The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. See, e.g., Greene and Wuts, Protective Groups in Organic Synthesis. 3^rd ed., (1999) John Wiley & Sons, NY. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.

HYDROXYL PROTECTING GROUPS

Protection for the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substitute benzyl ethers, and silyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl, methylthiomethyl, t-butylthiomethyl, benzyloxymethyl, p- methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, t-butoxymethyl. Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl, 1-methyl-1- methoxyethyl, 1 -methyl- 1-benzyloxyethyl, 2,2,2-trichloroethyl, t-butyl, allyl, p- chlorophenyl, p-methoxyphenyl, and benzyl. Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4- dimethoxybenzyl, p-halobenzyl, 2,6-dichIorobenzyl, p-cyanobenzyl, p- phenylbenzyl, diphenylmethyl. Esters

In addition to ethers, a hydroxyl group may be protected as an ester. Examples of esters include formate, benzoylformate, acetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, benzoate.

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.

AMINO PROTECTING GROUPS

Protection for the amino group includes carbamates, amides, and special -NH protective groups.

Examples of carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, assisted cleavage carbamates, photolytic cleavage carbamates, urea-type derivatives, and miscellaneous carbamates.

Carbamates

Examples of methyl and ethyl carbamates include methyl and ethyl, 9- fluorenylmethyl, and 4-methoxyphenacyl.

Substituted Ethyl Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2- phenylethyl, t-butyl, vinyl, allyl, 1-isopropylallyl , benzyl, p-methoxybenzyl, p- nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl and diphenylmethyl. Photolytic Cleavage

Examples of photolytic cleavage include m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyI(o- nitrophenyl)methyl.

Amides

Examples of amides include N-formyl, N-acetyl, N-trichloroacetyl, N- trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3- pyridylcarboxamide, N-benzoyl, N-p-phenylbenzoyl, and phthaloyl.

PROTECTION FOR THE CARBONYL GROUP

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include 1 ,3-dioxanes and 5- methylene-1 ,3-dioxane.

PROTECTION FOR THE CARBOXYL GROUP

Esters

Substituted Methyl Esters

Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, benzyl oxymethyl, phenacyl, p-bromophenacyl, α- methylphenacyl, and p-methoxyphenacyl. Examples of esters also include straight chain or branched alkyl esters such as tert-butyl, ethyl, propyl, isopropyl, and butyl.

Substituted Benzyl Esters Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, 9-anthrylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o- nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, piperonyl, 4- picolyl and p-P-benzyl.

Silyl Esters

Examples of silyl esters include trimethylsilyl, triethylsilyl, f-butyldimethylsilyl, /^'-propyldimethylsilyl, phenyldimethylsilyl and di-f- butylmethylsilyl.

C. Synthetic Methods

The invention provides methods of making the disclosed compounds according to traditional organic synthetic methods as well as matrix or combinatorial synthetic methods. Schemes 1 through 10 describe suggested synthetic routes. Using these Schemes, the guidelines below, and the examples, a person of skill in the art may develop analogous or similar methods for a given compound that are within the invention.

One skilled in the art will recognize that synthesis of the compounds of the present invention may be effected by purchasing an intermediate or protected intermediate compounds described in any of the schemes disclosed herein. One skilled in the art will further recognize that during any of the processes for preparation of the compounds in the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in "Protective Groups in Organic Synthesis", John Wiley & Sons, 1991. These protecting groups may be removed at a convenient stage using methods known from the art.

Examples of the described synthetic routes include Synthetic Examples 1 through 57. Compounds analogous to the target compounds of these examples can be, and in many cases, have been, made according to similar routes. The disclosed compounds are useful in basic research and as pharmaceutical agents as described in the next section.

General Guidance

A preferred synthesis of Formula 14, when X is S (and R₃ is H) is demonstrated in Schemes 1-5.

Abbreviations or acronyms used herein include: AcOH (glacial acetic acid); DCC (1 ,3-dicycIohexylcarbodiimide); DCE (1 ,2-dichloroethane); DIG (2-dimethylaminoisopropyl chloride hydrochloride); DIEA (diisopropylethylamine); DMF (dimethylformamide); EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide); EtOAc (ethyl acetate); mCPBA (3-chloroperoxybenzoic acid); NMI (1-methylimidazole); TEA (triethylamine);TFA (trifluoroacetic acid); THF (tetrahydrofuran);TMEDA (N, N, N', N'-tetramethyl- ethylenediamine).

Scheme 1

In accordance with Scheme 1 , the tetralins can be made by conversion of compound 1 to compound 2. For example, a methoxy-2-tetralone, such as 6- methoxy-2-tetralone, can be treated with a reagent such as ammonium acetate or ammonia, or hydroxyl amine. The corresponding imine can be reduced with an appropriate reducing agent, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride and the resulting oxime can be reduced catalytically using palladium or platinum in a polar protic solvent, such as methanol, ethanol or ethyl acetate, to obtain a racemic compound 2. Preparation of the hydrochloride salt may be easily accomplished by one skilled in the art. Scheme 2

In accordance with Scheme 2, the indanes can be prepared by conversion of a compound 3 to a compound 5. For example, when a methoxy indanone, such as 5-methoxy-1 -indanone, is treated with an acylating agent, such as butyl nitrite or isoamyl nitrite in the presence of a catalytic amount of acid, such as hydrochloric acid or hydrobromic acid in a polar solvent, such as methanol or ether, a keto-oxime 4 is obtained. Reduction of a compound 4 can be achieved by using the appropriate reducing agent(s), such as lithium aluminum hydride or hydrogen and a catalyst, such as palladium or platinum, in an appropriate solvent, such as acetic acid-sulfuric acid, THF, or methanol at an appropriate temperature. The choice of salt formation methods may be easily determined by one skilled in the art.

Scheme 3

2/5

10fr _NHz BrCR^jRzC^QzRzo

In accordance with Scheme 3, a compound 2 or 5 can be converted to a compound 12. For example, when a racemic amine hydrochloride is treated with a base, such as sodium hydride or lithium hydride in a polar aprotic solvent, such as DMF or THF and consequently reacted with an anhydride, such as phthalic anhydride at elevated temperatures, a cyclic imide 6 can be furnished. Cleavage of methyl aryl ethers of Formula 6 to a compound of the Formula 7 can be accomplished using a Lewis acid such as boron tribromide, boron trichloride, aluminum chloride or trimethylsilyliodide in nonpolar, aprotic solvents such as toluene, dichloromethane, or dichloroethane with or without cooling., Acylation of phenols of Formula 7 to a compound of Formula 8 can be achieved using thiocarbamoyl chlorides, such as dimethylaminothiocarbamoyl chloride or diethylthiocarbamoyl chloride and a non-reactive, tertiary amine, such as triethylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, or 1 ,4- diazabicyclo[2.2.2.]octane in an aprotic solvent such as dichloromethane, DMF, or THF with or without cooling. Compounds of Formula 8 can be rearranged thermally to compounds of Formula 9 at temperatures between 180 °C to 350 °C, either neat as a melt or using high-boiling solvents such as DOWTHERM ® A (a mixture of biphenyl and biphenyl ether sold by, for example, Fluka Chemical Corp., Milwaukee, Wl USA), N,N-dimethylaniline, diphenyl ether or decalin. Compounds of Formula 10 can be prepared from compounds of Formula 9 by treating with a suitable nucleophile, such as hydrazine, disodium sulfide or methylamine in appropriate polar solvent such as ethanol or THF at elevated temperatures. Conversion of Formula 10 to compounds of Formula 11 can be achieved using an appropriate reagent, such as potassium hydroxide in an alchoholic solvent, such as ethanol or methanol, or lithium aluminum hydride in THF or ether, followed by alkylation using an appropriately substituted alkyl halide, such as terf-butyl 2-bromoisobutyrate, ethyl bromoacetate, or ethyl 2- bromobutyrate and a reducing agent, such as lithium borohydride or sodium borohydride. Compounds of Formula 11 can be substituted to provide compounds of Formula 12 using a carboxylic acid or an acid chloride and an appropriate reducing agent such as borane-THF or borane-dimethylsulfide, using aprotic solvents such as THF, dichloromethane, or hexanes. Alternatively, substitution can be accomplished using an aldehyde and a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in appropriate aprotic solvents, such as THF, dichloromethane or dichloroethane.

Scheme 4

In accordance to Scheme 4, compounds of Formula 13 can be prepared from compounds of Formula 12 by acylating a secondary amine with an aryl acetic acid, using thionyl chloride or oxalyl chloride neat or in toluene or dichloromethane with or without catalytic DMF. Alternatively, the coupling can be achieved using standard peptide conditions, such as EDC, DCC, or DIG in dichloromethane. When Y = NH or O, an aryl isocyanate or aryl chloroformate, respectively, in a non-polar aprotic solvent, such as THF, dichloromethane or hexanes can be used to provide compounds of Formula 13. The choice of deprotection methods may be easily determined by one skilled in the art to provide compounds of Formula 14.

Scheme 5

Likewise, compounds of Formula 16 can be prepared from compounds of

Formula 11 by acylating the primary amine as delineated in Scheme 5 to afford compounds of Formula 15. The choice of deprotection methods may be easily determined by one skilled in the art to provide compounds of Formula 16.

Scheme 6

^NHCH'

A compound of Formula 18 can be prepared from a compound of Formula

10 as demonstrated in Scheme 6. For example, compound of Formula 10 can be treated with ethyl formate or ammonium formate either neat or in the presence of a suitable solvent, such as dichloromethane or dichloroethane with or without heating to provide a compound of Formula 17. Compounds of Formula 17 can be converted to compounds of Formula 18 by using an appropriate reagent, such as lithium aluminum hydride in a suitable solvent, such as THF or ether followed by alkylation using an appropriately substituted alkyl halide, such as terf-butyl 2- bromoisobutyrate, ethyl bromoacetate, or ethyl 2-bromobutyrate and a reducing agent, such as lithium borohydride or sodium borohydride.

Scheme 7

BrGR₁R₂G0₂R₂o

A preferred synthesis of Formula 21, when X is O (and R₃ is H) is demonstrated in Scheme 7. For example, when compounds of Formula 2 or 5 are acylated with a carboxylic acid or an acid chloride as described previously, compounds of Formula 19 are prepared. Cleavage of methyl aryl ethers of Formula 19 to a compound of the Formula 20 can be accomplished using a Lewis acid such as boron tribromide, boron trichloride, aluminum chloride or trimethylsilyliodide in nonpolar, aprotic solvents such as toluene, dichloromethane, or dichloroethane with or without cooling. Compounds of Formula 20 can be converted to compounds of Formula 21 by treating with an appropriate base, such as potassium carbonate, cesium carbonate or potassium hydroxide and an appropriately substituted alkyl halide, such as terf-butyl 2- bromoisobutyrate, ethyl bromoacetate, or ethyl 2-bromobutyrate in a suitable solvent, such as DMF or methanol. Scheme 8

22 23 24

Compounds of Formula 24 can be prepared from compounds of Formula

22 as demonstrated in Scheme 8. For example, compound of Formula 22 can be treated with an appropriate base, such as butyl lithium or sec-butyl lithium in an appropriate solvent, such as ether or THF, with or without TMEDA and cooling, and the appropriate electrophile, such as alkyl halides, aldehydes, or disulfides to provide compounds of Formula 23. Compounds of Formula 23 can be converted to compounds of Formula 24 in a manner analogous to that described in Scheme 3 for the transformation of compound 8 to compound 9.

Scheme 9

26 27 28

29 30

An alternative synthesis toward compounds of Formula 32 is outlined in Scheme 9. For example, when 4-methylthiophenyl acetic acid, Formula 26, is treated with oxalyl chloride or thionyl chloride in the presence of methanol, a compound of Formula 27 is afforded. Treatment of compounds of Formula 27 with a Lewis acid, such as aluminum chloride, in a chlorinated solvent such as chloroform or dichloroethane, in the presence of an alkene, such as ethylene, provides tetralones of Formula 28. Using the procedure outlined in Scheme 1 , the tetralins of Formula 29 can be prepared. Compounds of Formula 29 can be substituted to provide compounds of Formula 30 using a carboxylic acid under coupling conditions outlined previously or an acid chloride with a tertiary amine, such as diisopropylethylamine or triethylamine in a suitable solvent, such as dichloromethane or dichloroethane. A compound of Formula 30 can converted to a compound of Formula 31 using with an oxidizing agent, such as mCPBA or hydrogen peroxide in a suitable solvent, such as methylene chloride, followed by subsequent treatment of compounds of Formula 30 with trifluoroacetic anhydride with or without a solvent, such as chloroform, followed by treatment with a tertiary amine, such as triethylamine or diisopropylethylamine in a suitable solvent, such as methanol affords compounds of Formula 31. Alternatively, deprotection of the thio ether in compounds of Formula 30 can be achieved using a base, such as tert-butyl sodium sulfide, sodium, sodium methyl thiol in a suitable solvent, such as DMF, N-methyl-2-pyrrolidone or ammonia to provide compounds of Formula 31. Using chemistry analogous to that described in Scheme 3 for the transformation of compound 10 to compound 11, compounds of Formula 31 can be readily converted to compounds of Formula 32.

Scheme 10

In accordance to Scheme 10, compounds of Formula 22 can be readily converted to compounds of Formula 32a, where R₃ = OCH₃. For example, compounds of Formula 22 can be treated with an appropriate base, such as butyl lithium or sec-butyl lithium in an appropriate solvent, such as ether or THF, with or without TMEDA and cooling, and the appropriate disulfide, such as dimethyl disulfide or dibenzyl disulfide provide compounds of Formula 33. Removal of the dimethylamino thiocarbamate from compounds of Formula 33 is achieved using potassium or sodium hydroxide in an appropriate solvent, such as water, methanol, or ethanol with or without heating, to afford compounds of Formula 34. Compounds of Formula 34 can be methylated to provide compounds of Formula 19a by using methyl iodide, dimethylsulfate, or diazomethane in an appropriate solvent, such as DMF, methanol, or dichloromethane, with or without base, such as cesium carbonate or potassium carbonate. Using chemistry analogous to that described in Scheme 9 for the transformation of compounds of Formula 30 to Compounds of Formula 32, Compounds of Formula 32a can be readily synthesized from Compounds of Formula 19a. Route 1

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyIureido]-5,6,7,8-tetrahydronaphthal-2- ylsulfanyl}-2-methyI-propionic acid. Compound 1.0 (Example 1)

A. 6-Methoxy-1 ,2.3.4-tetrahvdronaphthalen-2-ylamine hydrochloride.

Scheme 1. To a solution of 6-methoxy-2-tetraIone (10.0 g; 56.7 mmol) dissolved in MeOH (400 mL) is added ammonium acetate (65 g; 0.84 mol) and the reaction was stirred for 30 min. at RT. To the reaction is then added sodium cyanoborohydride (17.8 g; 0.28 mol) and the reaction was refluxed for 1-2 h. The reaction is cooled, the solvent removed under reduced pressure, the residue diluted with EtOAc and 1 N NaOH added to quench the reaction. The aqueous phase is separated and the organic phase washed with H₂O, brine, dried over Na₂SO₄, filtered, and the solvent removed under reduced pressure to afford a crude residue which was purified by flash chromatography (Siθ₂) eluting with CH₂CI₂ / MeOH : NH₄OH (10%) to provide 5.0 g (50%) of 6-methoxy-1 ,2,3,4- tetrahydro-naphthalen-2-ylamine as a dark oil. To a solution of titled compound in ether (100 mL) cooled to 0 °C is bubbled HCI (g) until the solution is saturated. The suspension is stirred for an additional 30 min at RT and the solvent evaporated under reduced pressure. The remaining solid is triturated with ether, filtered, washed with ether and dried under reduced pressure to provide 4.9 g of 6-methoxy-1 ,2,3,4-tetrahydronaphthaIen-2-ylamine hydrochloride as a white solid.

LC/MS: C₁₁H₁₅NO: m/z 178 (M+1)

B. 2-(6-Methoxy-1 ,2,3.4-tetrahvdronaphthalen-2-yl)isoindole-1 ,3-dione. Scheme 3. To a stirred suspension of 60% NaH (6 g; 0.182 mmol) in

DMF (400 mL) is added 6-methoxy-1 ,2,3,4-tetrahydronaphthalen-2-ylamine (30 g; 0.140 mol), portionwise at 0 °C. The reaction mixture is warmed to RT and stirred for an additional 1 h. Phthalic anhydride (20.7 g; 0.139 mol) is added in 1 -portion at RT, upon which the reaction mixture is stirred for an additional 1 h followed by 18 h at 120 °C. The reaction was allowed to cool to RT, diluted with

H₂O and extracted several times with EtOAc. The combined organic extracts are washed with water, brine, dried over Na₂SO₄, and the solvent removed under reduced pressure. The crude solid was triturated with MeOH, filtered, and dried under vacuo to afford 29.1 g (67%) of 2-(6-methoxy-1 ,2,3,4-

) tetrahydronaphthalen-2-yl)isoindole-1 ,3-dione as an off-white solid.

¹H NMR (300 MHz, CDCI₃): δ 7.83-7.86 (m, 2 H), 7.70-7.73 (m, 2H), 6.96-

6.99 (d, 1H), 6.67-6.72 (m, 2H), 4.50-4.59 (m, 1H), 3.78 (s, 3H), 3.52-3.61 (m, 1

H), 2.95-2.98 (m, 2H), 2.81-2.88 (m, 1 H), 2.65-2.76 (m, 1 H), 1.97-2.01 (m, 1 H) LC/MS: Cι₉Hι₇NO₃: m/z 308 (M+1)

C. 2-(6-Hydroxy-1 ,2,3,4-tetrahvdronaphthalen-2-yl)isoindole-1 ,3,dione.

Scheme 3. To 2-(6-methoxy-1 ,2,3,4-tetrahydronaphthaIen-2-yl)isoindole- 1 ,3-dione (29 g; 94.3 mmol) dissolved in anhydrous CH2CI2 (500 mL), cooled to - 60 °C, is added a 1.0 M solution of boron tribromide-C^C (471 mL), dropwise to maintain reaction temperature between -50 to -60 °C. Upon completion of the addition, the reaction mixture is allowed to warm to RT and stirred for an additional 4 h. The reaction is cooled to 0 °C, quenched with saturated NaHCO₃ (400 mL) and stirred for an additional 0.5 h at RT. The precipitate is filtered, washed thoroughly with H2O, suspended in ether, filtered and dried under vacuo to afford 25.4 g (92%) of 2-(6-hydroxy-1 ,2,3,4-tetrahydronaphthalen-2- yl)isoindole-1 ,3-dione as an off-white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 9.11 (bs, 1 H), 7.82-7.89 (m, 4 H), 6.84- 6.87 (d, 1H), 6.52-6.56 (m, 2H), 4.29-4.37 (m, 1 H), 3.45 (bs, 1 H), 3.25-3.34 (m, 1 H), 2.73-2.84 (m, 3H), 2.37-2.47 (m, 1 H), 1.94-1.98 (m, 1 H) LC/MS: C₁₈H₁₅NO₃: m/z 294 (M+1) P. Dimethyl-thiocarbamic acid-O-f6-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-5,6,7,8- tetrahvdro-naphthalen-2-yll ester.

Scheme 3. To 2-(6-hydroxy-1 ,2,3,4-tetrahydronaphthalen-2-yl)isoindole-

1 ,3-dione (25.4 g; 86.5 mmol) dissolved in anhydrous DMF (200 mL) is added 1 ,4-diazabicycIo[2.2.2]octane (48.5 g; 4.32 mol) followed by dimethylaminothio- carbamoyl chloride (53.4 g; 4.32 mol) and the solution was stirred at RT for 4 h.

The reaction is poured over ice-water (1 L) and stirred for 18 h. The precipitate was filtered, washed with H₂O and dried under vacuo. The crude solid was purified by flash chromatography (Siθ₂) eluting with a hexanes-EtOAc gradient to afford 30 g (91 %) of dimethylthiocarbamic acid -O-[6-(1 ,3-dioxo-1 ,3,- dihydroisoindol-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl] ester as a white solid.

¹H NMR (300 MHz, CDCI₃): δ 7.83-7.86 (m, 2 H), 7.70-7.73 (m, 2 H), 7.07-

7.10 (d, 1H), 6.83-6.86 (m, 2H), 4.54-4.65 (m, 1 H), 3.60-3.69 (m, 1H), 3.46 (s,

3H), 3.34 (s, 3H), 2.88-3.09 (m, 3H), 2.64-2.78 (m, 1 H), 1.97-2.01 (m, 1 H) LC/MS: C₂ιH₂oN₂O₃S: m/z 381 (M+1 )

E. Dimethylthiocarbamic acid S-[6-(1 ,3-dioxo-1 ,3-dihvdroisoindol-2-vQ-5,6,7,8- tetrahydronaphthalen-2-yll ester.

Scheme 3. To a 50 mL round-bottom flask equipped with a reflux condenser and stir bar, preheated to 330 °C in a sand-bath, is added dimethyl-thiocarbamic acid O-[6-(1 ,3-dioxo-1 ,3-dihydroisoindol-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl] ester (5.32 g; 13.9 mmol) in 1 -portion. The melt is stirred for 7-8 min. at 330 °C, then rapidly cooled to RT with a N₂ stream. The crude residue is purified by flash chromatography (Siθ₂) eluting with a hexanes-EtOAc gradient to provide 3.1 g (58%) of dimethylthiocarbamic acid S-[6-(1 ,3-dioxo-1 ,3-dihydroisoindol-2-yl)- 5,6,7,8-tetrahydronaphthalen-2-yl] ester as a white solid.

¹H NMR (300 MHz, CDCI₃): δ 7.82-7.86 (m, 2H), 7.72-7.75 (m, 2 H), 7.23- 7.26 (m, 2H), 7.07-7.10 (d, 1 H), 4.52-4.63 (m, 1 H), 3.61-3.70 (m, 1 H), 2.89-3.09 (m, 9H), 2.61-2.75 (m, 1 H), 1.97-2.04 (m, 1 H) LC/MS: C₂ιH2oN₂O₃S: m/z 381 (M+1 ) F. Dimethylthiocarbamic acid S-r6-amino-5.6.7.8-tetrahvdronaphthalen-2-yl) ester.

Scheme 3. A 3-neck flask, equipped with a reflux condensor and mechanical stirrer, is charged with EtOH (115 mL) and dimethylthiocarbamic acid S-[6-(1 ,3-dioxo-1 ,3-dihydroisoindol-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl] ester (8.7 g; 23.5 mmol). Hydrazine (6.6 mL; 2.11 mol) is added in 1 -portion at RT and the reaction was refluxed with mechanical stirring for 40 min. The reaction is cooled to RT and the gelatinous, white solid is filtered and washed thoroughly with ether. The ether washes are combined, evaporated under reduced pressure and the crude residue was further triturated with ether, filtered and the ether evaporated under reduced pressure to afford 6.1 g (100%) of dimethylthiocarbamic acid S-[6-amino-5,6,7,8-tetrahydronaphthaIen-2-yl) ester as a yellow oil.

LC/MS: C₁₃H₁₈N₂OS: m/z 251 (M+1 )

G. 2-(6-Amino-5,6,7.8-tetrahvdronaphthalen-2-ylsulfanvπ-2-methylpropionic acid ferf-butyl ester.

Scheme 3. To dimethylthiocarbamic acid S-[6-amino-5,6,7,8- tetrahydronaphthalen-2-yl) ester (6.1 g; 24.4 mmol), dissolved in MeOH (25 mL) is added a solution of KOH (4.1 g; 73.2 mmol) in MeOH (25 mL) at RT. The solution is stirred at reflux for 5 h and cooled to RT. tert-Butyl 2- bromoisobutyrate (16.3 g; 73.2 mmol) is added to the solution and stirred for 16 h at RT. NaBH₄ (9.2 g; 2.44 mol) is added and the reaction is stirred for an additional 48 h at RT. The reaction is quenched with H₂O, the solvent evaporated under reduced pressure, and the crude residue partitioned between H₂O and CH₂CI₂. The aqueous phase is extracted with CH₂CI₂ and the combined organic extracts were dried over Na₂SO , filtered and evaporated under reduced pressure to afford 4.7 g (60%) of 2-(6-amino-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester as a brown oil. LC/MS: C181H2 NO2S: m/z 266 (M+1) H. 2-(6-Acetylamino-5.6₁7.8-tetrahvdronaphthalen-2-ylsulfanyl)-2-methyl propionic acid tert-butyl ester.

Scheme 3. To 2-(6-amino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2- methylpropionic acid tert-butyl ester (4.7 g; 14.6 mmol), dissolved in CH₂CI₂ (25 mL), is added DIEA (3.3 mL; 18.9 mmol) and the reaction mixture is cooled to 0 °C. Acetyl chloride (1.25 mL; 17.5 mmol) is added dropwise at a rate to maintain the temperature between 0-5 °C. The reaction was allowed to warm to RT and stirred for 16 h. The reaction was diluted with CH₂CI₂, washed with H₂O, dried over Na₂SO and evaporated under reduced pressure. The crude oil was purified by flash chromatography (SiO₂) eluting with a hexanes-EtOAc gradient to afford 1.7 g (32%) of 2-(6-acetyIamino-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyl)-2-methylpropionic acid tert-butyl ester as a tan solid.

¹H NMR (300 MHz, CDCI₃): δ 7.23-7.26 (m, 2 H), 6.99-7.01 (d, 1 H), 5.46- 5.48 (m, 1 H), 4.25-4.29 (m, 1 H), 3.08-3.15 (dd, 1 H), 2.82-2.88 (m, 2H), 2.58-2.66 (m, 1 H), 2.01-2.04 (m, 1 H), 1.98 (s, 3H), 1.70-1.82 (m, 1 H), 1.43 (s, 15H)

LC/MS: C₂oH₂₉NO₃S: m/z 308 (M+1 )

I. 2-(6-Ethylamino-5₁6.7.8-tetrahvdronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester. < Scheme 3. To a solution of 2-(6-acetylamino-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl)-2-methylpoprionic acid tert-butyl ester (1.7 g; 4.64 mmol) in THF (42 mL) is added a solution of 1.0 M borane-THF (42 mL), dropwise at RT. The reaction was allowed to stir for 18 h at RT, carefully quenched with MeOH and the solvent was evaporated under reduced pressure. The residual oil was further azeotroped with MeOH (3x) to afford 1.9 g (100%) of a mixture of 2-(6-ethylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2- methylpropionic acid tert-butyl ester and it's borane complex as an oil. LC/MS: C20H31NO2S H3: m/z 308 ((M+BH₃)+1 )

J. 2-(6-ri-Ethyl-3-(4-trifluoromethoχyphenvnureidol-5.6.7.8- tetrahvdronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert butyl ester. Scheme 4. To a mixture of 2-(6-ethylamino-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester and borane complex (1.9 g; 5.2 mmol) dissolved in CH₂CI₂ (15 mL) is added 4- trifluoromethoxyphenyl isocyanate (1.6 g; 7.8 mmol) and the reaction was stirred at RT for 18 h. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (SiO₂) eluting with a hexanes- EtOAc gradient to provide 1.66 g (58%) of 2-{6-[1 -ethyl-3-(4- trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2- methylpropionic acid tert butyl ester as a white foam. LC/MS: C₂₈H₃₅F₃N₂O₄S: m/z 497 ((M-C₄H₈)+1 )

K. 2-{6-π-Ethyl-3-(4-trifluoromethoxyphenvnureidol-5.6.7.8- tetrahvdronaphthalen-2-ylsulfanyl}-2-methylpropionic acid. Scheme 4. To 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5, 6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert butyl ester (1.66 g; 3.0 mmol) dissolved in CH₂CI₂ (15 mL) is added TFA (15 mL) and the reaction was stirred at RT for 1.5 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (SiO₂) eluting with a hexanes-EtOAc gradient to afford 0.643 g (43%) of 2-{6-[1-ethyl-3-(4- trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2- methylpropionic acid as a white solid.

¹H NMR (300 MHz, CD₃OD): δ 7.45-7.48 (m, 2H), 7.06-7.24 (m, 5H), 4.44 (m, 1 H), 3.43-3.45 (m, 2H), 2.96-3.02 (m, 4H), 2.00-2.05 (m, 2H), 1.41- 1.46 (s, 6H), 1.21-1.29 (m, 3H) LC/MS: C₂₄H₂₇F₃N₂O₄S: m/z 497 (M+1 )

Route 2

2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid. Compound 2.0 (Example 2)

A. 5-Methoxyindan-1.2-dione-2-oxime.

Scheme 2. To a solution of 5-methoxyindan-1-one (75.8 g; 0.467 mol) in MeOH (1.4 L) at 45 °C is added butyl nitrite (81 mL; 0.693 mol) dropwise over 45 min. Concentrated HCI (45 mL) is then added to the hot solution over 20 min and the reaction was allowed to stir at 45 °C for an additional 1.5-2 h. The reaction suspension is cooled, the precipitate filtered, washed several times with cold MeOH, and dried under vacuo to afford 55.8 g (62%) of 5-methoxyindan- 1 ,2-dione-2-oxime as a beige solid. H NMR (300 MHz, CD₃OD): δ 7.80-7.83 (m, 1 H), 6.95 (bs, 2H), 3.92 (s, 3H), 3.78 (s, 2H), 3.47 (bs, 1 H) LC/MS: C₁₀H₉NO₃: m/z 192 (M+1)

B. 5-Methoxyindan-2-ylamine hydrochloride.

Scheme 2. To 5-methoxyindan-1 ,2-dione-2-oxime (55.7 g; 0.291 mol), suspended in glacial acetic acid (0.99 L) is added concentrated H₂SO (67 mL) followed by 10% Pd-C (27 g) and the reaction is mixed on a Parr apparatus under H₂ at 60 psi for 18 h. The reaction is purged with N₂, filtered through a pad of celite and washed with AcOH. The solvent is removed under reduced pressure to 1/5 volume and the remaining solvent is diluted with H₂O (500 mL), cooled to 0 °C, and neutralized to pH 10 with 50% aqueous NaOH. The aqueous phase is extracted extensively with CHCI₃ several times and the extracts are combined, washed with H₂O, brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to provide 77.3 g (66%) of a crude oil. The oil was subjected to flash chromatography (SiO₂) eluting with 40 : 2.2 : 0.2 CHCI3 : MeOH : NH₄OH to provide 43.8 g (37%) of a dark oil. The oil is dissolved in ether (1 L), cooled to 0 °C, and the solution is saturated with HCI (g). The solvent was removed under reduced pressure and the solid triturated with ether, filtered, and washed with ether to provide 43.8 g (30%) of 5-methoxyindan-2-ylamine hydrochloride as a white solid.

¹H NMR (300 MHz, CD₃OD): δ 7.08-7.11 (d, 1 H), 6.77 (s, 1 H), 6.69-6.72 (d, 1H), 3.78-3.85 (m, 1 H), 3.77 (s, 3H), 3.08-3.19 (m, 2H), 2.57-2.68 (m, 2H), 1.51 (s, 2H)

LC/MS: C₁₀H₉NO₃: m/z 192 (M+1)

M.P. = 240 - 241 °C

C. 2-(5-Methoxyindan-2-v0isoindole-1 ,3-dione. Scheme 3. To a suspension of 60% NaH (8 g; 0.240 mol) in DMF (250 mL), cooled to 0 °C, is added 5-methoxyindan-2-ylamine hydrochloride (40.0 g; 0.2 mol) and the suspension stirred for 1 h at RT. Phthalic anhydride (30 g; 0.2 mol) is added in 1 -portion and the suspension stirred for an additional 1-1.5 h at RT followed by stirring at 120 °C for 96 h. The reaction is cooled and diluted with EtOAc. The organic phase is washed with H₂O, the resultant precipitate filtered, washed with EtOAc, MeOH and dried under vacuo to afford 25.2 g (43%) of 2-(5- methoxyindan-2-yl)isoindole-1 ,3-dione as a white solid. The organic phase is washed with H₂O, evaporated under reduced pressure and the solid is triturated with MeOH, filtered, and dried to afford an additional 19.7 (33%) g of 2-(5- methoxyindan-2-yl)isoindole-1 ,3-dione as a white solid.

¹H NMR (300 MHz, CD₃OD): δ 7.83-7.87 (m, 2H), 7.68-7.74 (m, 2H), 7.10- 7.13 (d, 1H), 6.73-6.78 (m, 2H), 5.08-5.21 (m, 1 H), 3.79 (s, 3H), 3.48-3.65 (m, 2H), 3.07-3.18 (m, 2H)

LC/MS: Cι₈H₁₅NO₃: m/z 294 (M+1)

P. 2-(5-Hydroxyindan-2-yl)isoindole-1 ,3-dione.

Scheme 3. To 2-(5-methoxyindan-2-yl)isoindole-1 ,3-dione (19.7 g; 67 mmol) dissolved in anhydrous CH₂CI₂ (350 mL) and cooled to -60 °C, is added a 1.0 M solution of boron tribromide-CH₂CI₂ (340 mL), dropwise at a rate to maintain the internal temperature between -50 and -60 °C. The reaction mixture is allowed to warm to RT and stirred for an additional 5 h. The reaction is cooled to 0 °C, quenched with saturated NaHCO₃ (500 mL) and stirred for an additional 0.5 h at RT. The precipitate is filtered, washed with H₂O, suspended in ether, filtered and dried under vacuo to afford 14.8 g (79 %) of 2-(5-hydroxyindan-2- yl)isoindole-1 ,3-dione as a beige solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.16 (s, 1 H), 7.82-7.91 (m, 4 H), 6.98-

7.01 (d, 1 H), 6.56-6.62 (m, 2H), 4.91-5.03 (m, 1 H), 3.27-3.43 (m, 3H), 2.99-3.10 (m, 2H)

LC/MS: Cι₇Hι₃NO₃: m/z 280 (M+1)

F. Dimethylthiocarbamic acid O-[2-(1 ,3-dioxo-1 ,3-dihydroisoindol-2-vPindan-5-yl1 ester.

Scheme 3. To 2-(5-hydroxyindan-2-yl)isoindole-1 ,3-dione (31 g; 0.11 mol) dissolved in anhydrous DMF (400 mL) is added 1 ,4-diazabicyclo[2.2.2]-octane (62 g; 0.55 mol) followed by dimethylaminothiocarbamoyl chloride (68 g; 0.55 mol) and the solution was stirred at RT for 16 h. The reaction is poured over ice- water (1 L) and stirred for 18 h. The precipitate was filtered, washed with H₂O and dried under vacuo to afford 41.6 g (100 %) of dimethylthiocarbamic acid O- [2-(1 ,3-dioxo-1 ,3-dihydroisoindol-2-yl)indan-5-yl] ester as a beige solid.

¹H NMR (300 MHz, CDCI₃): δ 7.82-7.87 (m, 2 H), 7.69-7.75 (m, 2 H), 7.17- 7.24 (d, 1 H), 6.87-6.93 (m, 2H), 5.13-5.25 (m, 1 H), 3.53-3.68 (m, 2H), 3.46 (s, 3H), 3.34 (s, 3H), 3.09-3.23 (m, 2H)

G. Dimethylthiocarbamic acid S-I2-(1 ,3-dioxo-1 ,3-dihvdroisoindol-2-yl)indan-5-yll ester. Scheme 3. To a 50 mL round-bottom flask, equipped with a reflux condenser and stir bar, preheated to 330 °C in a sand-bath is added dimethylthiocarbamic acid O-[2-(1 ,3-dioxo-1 ,3-dihydroisoindol-2-yl)indan-5-yl] ester (6.30g; 18.7 mmol) in 1 -portion. The melt is stirred for 12 min. at 338 °C, rapidly cooled to RT with a N₂ stream and the crude residue purified by flash chromatography (SiO₂) eluting with a hexanes-EtOAc gradient to afford 3.88 g (61 %) of dimethylthiocarbamic acid S-[2-(1 ,3-dioxo-1 ,3-dihydroisoindol-2- yl)indan-5-yI] ester as an off-white solid.

¹H NMR (300 MHz, CDCI₃): δ 7.81-7.87 (m, 2H), 7.69-7.74 (m, 2 H), 7.22- 7.36 (m, 3H), 5.10-5.22 (m, 1 H), 3.59-3.67 (m, 2H), 3.06-3.23 (m, 9H) LC/MS: C₂₀H₁₈N₂O₃S: m/z 367 (M+1 )

H. Dimethylthiocarbamic acid S-(2-aminoindan-5-vP ester.

Scheme 3. A 3-neck flask, equipped with a reflux condensor and mechanical stirrer, is charged with EtOH (98 mL) and dimethylthiocarbamic acid S-[2-(1 ,3-dioxo-1 ,3-dihydroisoindol-2-yl)indan-5-yl] ester (6.9 g; 20.6 mmol). Hydrazine (5.8 mL; 186 mmol) is added in 1 -portion at RT and the reaction was refluxed with mechanical stirring for 30 min. The reaction is cooled to RT and the gelatinous, white solid is filtered and washed with ether several times. The ether washes are combined, evaporated under reduced pressure and the crude residue was further triturated with ether, filtered and the ether evaporated under reduced pressure to afford 4.6 g (95%) of dimethylthiocarbamic acid S-[2- aminoindan-5-yl) ester as a brown oil.

¹H NMR (300 MHz, CDCI₃): δ 7.15-7.33 (m, 3H), 3.80-3.88 (m, 1 H), 3.05- 3.22 (m, 8H), 2.64-2.72 (m, 1 H), 2.17 (bs, 2H) LC/MS: C₁₂H₁₆N₂OS: m/z 237 (M+1 )

I. 2-(2-Aminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester.

Scheme 3. To dimethylthiocarbamic acid S-(2-aminoindan-5-yl) ester (4.9 g; 20.9 mmol), dissolved in MeOH (60 mL) is added a solution of KOH (11.8 g; 0.210 mol) in MeOH (1 10 mL) at RT. The solution is stirred at reflux for 5 h and cooled to RT. tert-Butyl 2-bromoisobutyrate (7.0 g; 31.3 mmol) is added to the solution and stirred for 18 h at RT. The solvent is evaporated under reduced pressure and the crude residue partitioned between H₂O and EtOAc. The aqueous phase is extracted with EtOAc and the combined organic extracts were washed with H₂O, brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure to afford 4.9 g (76%) of 2-(2-aminoindan-5-ylsulfanyl)-2- methylpropionic acid tert-butyl ester as a brown oil. LC/MS: C₁₇H25NO₂S: m/z 308 (M+1)

J. 2-(2-Acetylaminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester. Scheme 3. To 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropionic acid tert- butyl ester (14.6 g; 47.4 mmol), dissolved in CH₂CI₂ (100 mL), is added TEA (8.6 mL; 61.7 mmol) and the reaction mixture is cooled to 0 °C. Acetyl chloride (4.1 mL; 57.6 mmol) is added dropwise at a rate to maintain the temperature between 0 - 5 °C. The reaction was allowed to warm to RT, stirred for 16 h, diluted with CH2CI2, washed with H2O, dried over Na₂SO and evaporated under reduced pressure. The crude oil was purified by flash chromatography (SiO₂) eluting with a hexanes-EtOAc gradient to afford 11.7 g (71 %) of 2-(2-acetylaminoindan-5- ylsulfanyl)-2-methylpropionic acid tert-butyl ester as a beige solid. ¹H NMR (300 MHz, CDCI₃): δ 7.31-7.35 (m, 2 H), 7.15-7.18 (d, 1 H), 5.73

(m, 1 H), 4.68-4.78 (m, 1 H), 3.25-3.39 (dd, 2H), 2.74-2.80 (d, 2H), 1.94 (s, 3H), 1.43 (s, 15H)

LC/MS: Cι₉H₂₇NO₃S: m/z 294 (M+1)

K. 2-(2-Ethylaminoindan-5-ylsulfanv0-2-methylpropionic acid tert-butyl ester.

Scheme 3. To a solution of 2-(2-acetylaminoindan-5-yIsulfanyl)-2- methylpropionic acid tert-butyl ester (11.7 g; 33.5 mmol) in THF (280 mL) is added a solution of 1.0 M borane-THF (226 mL), dropwise at RT. The reaction was allowed to stir for 5 h at RT, cooled to 0 °C, quenched with MeOH (100 mL) and evaporated under reduced pressure. The residual oil was further azeotroped with MeOH (3x) to afford 11 g (100%) of a mixture of 2-(2-ethylaminoindan-5- ylsulfanyl)-2-methylpropionic acid tert-butyl ester and its borane complex as an oil.

LC/MS: C19H29NO2SBH3: m/z 336 ((M+BH₃)+1)

L. 2-(2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureidolindan-5-ylsulfanyl)-2- methylpropionic acid tert butyl ester.

Scheme 4. To a mixture of 2-(2-ethylaminoindan-5-ylsulfanyI)-2- methylpropionic acid tert-butyl ester and borane complex (11.0 g; 33 mmol), dissolved in CH₂CI₂ (100 mL), is added 4-trifluoromethoxyphenyl isocyanate (10.2 g; 50.2 mmol) and the reaction was allowed to stir at RT for 18 h. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (Siθ2) eluting with a hexanes-EtOAc gradient to afford 11.2 g (62%) of 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}-2-methylpropionic acid tert butyl ester as a white foam.

¹H NMR (300 MHz, CDCI₃): δ 7.30-7.36 (m, 4H), 7.10-7.19 (m, 3H), 6.31 (s, 1 H), 4.97-5.08 (m, 1 H), 3.22-3.39 (m, 4H), 3.01 -3.09 (dd, 2H), 1.42-1.44 (m, 15H), 1.23-1.28 (t, 3H)

LC/MS: C₂7H₃₃F₃N₂O₄S: m/z 483 ((M-C₄H₈)+1 )

M. 2-{2-ri-Ethyl-3-(4-trifluoromethoxyphenyl)ureido1indan-5-ylsulfanyl)-2- methylpropionic acid.

Scheme 4. To 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}-2-methylpropionic acid tert butyl ester (4.8 g; 8.91 mmol) dissolved in CH₂CI₂ (15 mL) is added TFA (15 mL) and the reaction was stirred at RT for 2 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (Siθ2) eluting with a hexanes-EtOAc gradient to afford 3.13 g (73%) of 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}-2-methylpropionic acid as a white solid.

¹H NMR (300 MHz, CDCI₃): δ 7.29-7.35 (m, 4H), 7.15-7.17 (d, 1H), 7.08- 7.11 (d, 2H), 6.45 (s, 1 H), 4.94-5.04 (m, 1 H), 3.18-3.36 (m, 4H), 2.98-3.07 (m, 2H), 1.48 (s, 6H), 1.19-1.28 (t, 3H)

LC/MS: C₂₃H2₅F₃N₂O₄S: m/z 483 (M+1)

M.P. = 73-77 °C

The following 14 compounds were prepared following Schemes 3 and 4 and Steps J, K, L and M of Route 2, substituting reagents and adjusting reaction conditions as needed:

(S)-2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid.

Compound 2.1 (Example 3)

Intermediate L (11 g) of Route 2 was resolved by chiral chromatography (Chiralpak AD column; isocratic gradient with hexane/methanol/ethanol: 92/4/4) to provide (S)-intermediate L (4.8 g). Using Step M of Route 2, Compound 2.1 (3.1 g) was prepared.

LC/MS: C₂3H25F₃N₂O₄S: m/z 483 (M+1)

2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid. Compound 2.2 (Example 4)

Compound 2.2 (0.33 g; 57% for 2 steps; white solid) was prepared following Route 2 by replacing 4-trifluoromethoxyphenyl isocyanate with 4- trifluorothiomethoxy isocyanate. ¹H NMR (CD₃OD); δ 1.16-1.20 (t, 3H), 1.38 (s, 6H), 3.09-3.23 (m, 4H),

3.37-3.44 (q, 2H), 4.95-5.06 (m, 1H), 7.14-7.17 (m, 1H), 7.32-7.35 (m, 1H), 7.40 (s, 1H), 7.55 (s, 4H)

LC/MS: C₂₃H₂₅F₃N₂O₃S₂: m/z 499 (M+1)

2-Methyl-2-{2-[1-pentyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5- ylsulfanyljpropionic acid Compound 2.3 (Example 5)

Compound 2.3 (0.22 g; 32% for 2 steps; white solid) was prepared following Route 2 and Compound 2.2 by replacing acetyl chloride with valeryl chloride.

¹H NMR (CD₃OD); δ 0.844-0.890 (t, 3H), 1.20-1.31 (m, 4H), 1.39 (s, 6H), 1.45-1.58 (m, 2H), 3.07-3.22 (m, 6H), 4.89-4.99 (m, 1 H), 7.15-7.18 (m, 1H), 7.33- 7.35 (m, 2H), 7.33-7.35 (m, 1 H), 7.40 (s, 1H), 7.50-7.57 (m, 4H)

LC/MS: 6H31F3N2O3S2: m/z 541 (M+1)

2-{2-[1-Ethyl-3-(4isopropylphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid

Compound 2.4 (Example 6)

Compound 2.4 (0.18 g; 34% for 2 steps; white solid) was prepared following Route 2 by replacing 4-trifluoromethoxyphenyl isocyanate with 4-isopropyl phenyl isocyanate.

¹H NMR (CD₃OD); δ 1.16-1.23 (m, 9H), 1.38 (s, 6H), 2.82-2.87 (m, 1H), 3.10-3.21 (m, 4H), 3.37-3.39 (m, 2H), 4.99-5.04 (m, 1 H), 7.14-7.17 (m, 3H), 7.23- 7.26 (m, 2H), 7.32-7.50 (m, 2H), 7.40 (s, 1H)

LC/MS: C₂₅H₃₂N₂O₃S: m/z 441 (M+1)

2-{2-[3-(4-Dimethylaminophenyl)-1-ethylureido]indan-5-ylsuIfanyl}-2- methylpropionic acid

Compound 2.5 (Example 7)

Compound 2.5 (0.34 g; 66% for 2 steps; white solid) was prepared following Route 2 by replacing 4-trifluoromethoxyphenyl isocyanate with 4- dimethylaminophenyl isocyanate.

¹H NMR (CD₃OD); δ 1.15-1.20 (t, 3H), 1.42 (s, 6H), 2.88 (s, 1 H), 3.05-3.69 (m, 4H), 3.31-3.69 (m, 2H), 4.94-5.06 (m, 1H), 6.78-6.81 (m, 2H), 7.16-7.21 (m, 3H), 7.29-7.41 (m, 2H)

LC/MS: C₂₄H₃ιN₃O₃S: m/z 442 (M+1)

2-Methyl-2-{2-[1-pentyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid Compound 2.6 (Example 8)

Compound 2.6 (0.29 g; 77% for 2 steps; white solid) was prepared following

Route 2 by replacing acetyl chloride with valeryl chloride.

¹H NMR (CD₃OD); δ 0.847-0.893 (t, 3H), 1.20-1.29 (m, 4H), 1.39 (s, 6H),

1.58-1.60 (m, 2H), 3.04-3.29 (m, 6H), 4.89-4.99 (m, 1 H), 7.14-7.17 (m, 3H), 7.32-

7.34 (m, 1 H), 7.40-7.45 (m, 3H) LC/MS: C₂₆H₃ιF₃N₂O₄S: m/z 525 (M+1 )

2-{2-[3-(4-Dimethylaminophenyl)-1-pentylureido]indan-5-ylsulfanyI}-2- methylpropionic acid Compound 2.7 (Example 9)

Compound 2.7 (0.25 g; 36% for 2 steps; white solid) was prepared following Route 2 and compound 2.5 by replacing acetyl chloride with valeryl chloride.

¹H NMR (CD₃OD); δ 0.869-0.915 (t, 3H), 1.17-1.31 (m, 4H), 1.44 (s, 6H), 1.57-1.65 (m, 2H), 2.91 (s, 6H), 3.12-3.29 (m, 6H), 4.94-5.02 (m, 1H), 6.80-6.83 (d, 2H), 7.17-7.23 (m, 3H), 7.32-7.38 (m, 2H) LC/MS: C₂₇H₃7N₃O₃S: m/z 484 (M+1) 2-{2-[3-(4-lsopropylphenyl)-1-(3-pentyI)ureido]indan-5-ylsulfanyI}-2- methylpropionic acid Compound 2.8 (Example 10)

Compound 2.8 (5 mg; 14% for 2 steps; white solid) was prepared following Route 2 and compound 2.4 by replacing acetyl chloride with valeryl chloride. LC/MS: C₂₈H₃₈N₂O₃S: m/z 483 (M+1 )

2-{2-[3-(4-tert-butylphenyl)-1-(3-pentyl)ureido]indan-5-ylsulfanyI}-2- methylpropionic acid

Compound 2.9 (Example 11)

Compound 2.9 (4 mg; 9% for 2 steps; white solid) was prepared following Route 2 and compound 2.3 by replacing 4-trifluorothiophenyl isocyanate with 4-tert- butylphenyl isocyanate.

LC/MS: C₂₉H₄oN₂O₃S: m/z 497 (M+1)

2-[2-(3-(Biphenyl-4-yl-1-pentylureido)indan-5-ylsulfanyl]-2-methylpropionic acid Compound 2.10 (Example 12)

Compound 2.10 (3 mg; 7% for 2 steps; white solid) was prepared following Route 2 and compound 2.3 by replacing 4-trifluorothiophenyl isocyanate with 4- biphenylyl isocyanate.

LC/MS: C₃ιH₃₆N₂O₃S: m/z 517 (M+1)

2-{2-[3-(4-lsopropylphenyl)-1-(3-hexyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid Compound 2.11 (Example 13)

Compound 2.11 (13 mg; 44% for 2 steps; oil) was prepared following Route 2 and Compound 2.4 by replacing valeryl chloride with caproyl chloride. LC/MS: C₂₉H₄₀N₂O₃S: m/z 497 (M+1)

2-Methyl-2-{2-[1-hexyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}propionic acid Compound 2.12 (Example 14)

Compound 2.12 (18 mg; 54% for 2 steps; white solid) was prepared following Route 2 by replacing valeryl chloride with caproyl chloride. LC/MS: C₂₇H3₃F₃N₂O₄S: m/z 539 (M+1 )

2-Methyl-2-{2-[1-hexyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5- ylsulfanyljpropionic acid Compound 2.13 (Example 15)

Compound 2.13 (14 mg; 36% for 2 steps; white solid) was prepared following Route 2 and Compound 2.2 by replacing valeryl chloride with caproyl chloride. LC/MS: C₂₇H33F₃N₂O₃S₂: m/z 555 (M+1)

2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}propionic acid Compound 2.14 (Example 16)

Compound 2.14 (1.2 mg; 3% for 2 steps; oil) was prepared following Route 2 by replacing acetyl chloride with propionyl chloride. LC/MS: C₂₄H27F3N2θ₄S: m/z 497 (M+1 )

2-Methyl-2-{2-[1-butyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5- ylsulfanyl}propionic acid Compound 2.15 (Example 17)

Compound 2.15 (11 mg; 32% for 2 steps; oil) was prepared following Route 2 and Compound 2.2 by replacing acetyl chloride with butyryl chloride. LC/MS: C₂₅H2₉F₃N₂O₃S₂: m/z 527 (M+1)

2-Methyl-2-{2-[3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propionic acid Compound 2.16 (Example 18)

Compound 2.16 (11 mg; 49% for 2 steps; oil) was prepared following Route 2 by acylating with 4-trifluoromethoxyphenyl isocyanate. LC/MS: C₂ιH₂ιF₃N₂O₄S: m/z 455 (M+1)

Route 3

2-Methy-2-{2-[1-pent-4-enyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}propionic acid Compound 3.0 (Example 19) PI

To 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester (0.220 g; 0.72 mmol), dissolved in DCE (4 mL), is added pent-4-enal (0.060 mg; 0.72 mmol) followed by sodium triacetoxyborohydride (0.21 g; 1.0 mmol) and the reaction mixture stirred for 18 h at RT. The reaction mixture was diluted with CH2CI2, washed with H₂O, brine, dried over Na₂SO₄, filtered and the solvent evaporated under reduced pressure to afford 2-methyl-2-(2-pent-4- enylaminoindan-5-ylsulfanyl)propionic acid tert-butyl ester as a crude oil.

Compound 3.0 (0.149 mg; 40% for 3 steps; white solid) was prepared following Route 2 and steps L and M by acylating with 4-trifluoromethoxyphenyl isocyanate.

LC/MS: C₂₆H₂₉F₃N₂O₄S: m/z 522 (M+1)

The following 2 compounds were prepared following Schemes 3 and 4, Route 3, Steps L and M of Route 2, substituting reagents and adjusting reaction conditions as needed:

2-MethyI-2-{2-[1-(3-methyIbutyl)-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}-2-methylpropionic acid Compound 3.1 (Example 20)

Compound 3.1 (13 mg; 29% for 3 steps; white solid) was prepared following Route 3 substituting pent-4-enal with isobutyraldehyde and acylating with 4- trifluoromethoxyphenyl isocyanate.

LC/MS: C₂₆H₃ιF₃N₂O₄S: m/z 525 (M+1)

2-{2-[3-(4-lsopropylphenyl)-1-(3-methylbutyl)ureido]indan-5-yIsulfanyI}-2- methylpropionic acid Compound 3.2 (Example 21)

Compound 3.2 (11 mg; 27% for 3 steps; white solid) was prepared following Route 3 and compound 3.1 by replacing 4-trifluoromethoxyphenyl isocyanate with 4-isopropyIphenyl isocyanate.

' ¹H NMR (CD₃OD); δ 0.877-0.895 (dd, 6H), 1.19-1.22 (dd, 6H), 1.42-1.53 (m, 9H), 2.80-2.89 (m, 1H), 2.99-3.08 (m, 2H), 3.17-3.48 (m, 4H), 4.98-5.03 (m, 1H), 6.26 (s, 1 H), 7.10-7.22 (m, 5H), 7.32-7.35 (m, 2H) LC/MS: C₂₈H₃₈N₂O₃S: m/z 483 (M+1)

The following 3 compounds were prepared following Schemes 1 and 3 and Steps J and K of Route 1 , substituting reagents and adjusting reaction conditions as needed:

2-{6-[1-Butyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyI}-2-methylpropionic acid Compound 1.1 (Example 22)

Compound 1.1 (41 mg; 68% for 2 steps; white solid) was prepared following Route 1 by replacing acetyl chloride with butyryl chloride. LC/MS: C₂₆H₃ιF₃N₂O₄S: m/z 525 (M+1)

2-{6-[1-Butyl-3-(4-trifluoromethylsuIfanyIphenyl)ureido]-5, 6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid Compound 1.2 (Example 23)

Compound 1.2 (23 mg; 34% for 2 steps; white solid) was prepared following Route 1 and compound 1.1 by replacing acetyl chloride with butyryl chloride and 4-trifluoromethoxyphenyl isocyanate with 4-trifluorothiophenyl isocyanate. LC/MS: C₂6H₃ιF₃N2θ3S₂: m/z 541 (M+1)

2-{6-[1-Hexyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen- 2-ylsulfanyl}-2-methylpropionic acid Compound 1.3 (Example 24)

Compound 1.3 (36 mg; 57% for 2 steps; white solid) was prepared following Route 1 by replacing acetyl chloride with caproyl chloride. LC/MS: C₂₈H₃₅F3N₂O₄S: m/z 553 (M+1)

The following 2 compounds were prepared following Schemes 3 and 4 and Steps L and M of Route 2, substituting reagents and adjusting reaction conditions as needed:

2-{2-[3-(3-Bromo-4-trifluoromethoxyphenyl)-1-ethylureido]indan-5-ylsuIfanyl}-2- methylpropionic acid Compound 2.17 (Example 25)

Compound 2.17 (0.018 g; 19% for 3 steps; white solid) was prepared following Route 2 by replacing 4-trifluoromethoxy phenyl isocyanate with 3-bromo-4- trifluoromethoxyphenyl isocyanate. To 3-bromo-4-trifluoromethoxy aniline (0.214 g; 0.836 mmol) in THF (1 mL) is added di-tert-butyl dicarbonate (0.255 g; 1.17 mmol) followed by 4-dimethylaminopyridine (0.102 g; 0.835 mmol). After the effervesence ceases (30 min.), a solution of 2-(2-ethylaminoindan-5-ylsulfanyl)-2- methylpropionic acid tert-butyl ester (0.058 g; 0.167 mmol) in THF (1 mL) is added and the reaction mixture stirred for 18 h at RT. Using Steps K and L of Route 2, the titled compound was prepared. LC/MS: C₂₃H₂₄BrF₃N₂O₄S: m/z 563 (M+1)

2-{2-[1-Ethyl-3-(3-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid Compound 2.18 (Example 26)

Compound 2.18 (13 mg; 12% for 3 steps; white solid) was prepared following Example 2.0 by replacing 4-trifluoromethoxyphenyl isocyanate with 3- trifluoromethoxyphenyl isocyanate. To a solution of carbonyldiimidazole (0.454 g; 2.8 mmol) in THF (2 mL), heated to 50 °C, is added 3-trifluoromethoxyaniIine (0.522 g; 2.94 mmol), dropwise. After 15 min. the reaction is cooled and added to a solution of 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methyIpropionic acid tert- butyl ester (0.077 g; 0.22 mmol) in THF (1 mL). LC/MS: C₂₃H₂₅F₃N₂O₄S: m/z 483 (M+1 )

2-{2-[3-(4-Dimethylaminophenyl)-1-methylureido]indan-5-ylsulfanyl}-2- methylpropionic acid

Compound 2.19 (Example 27)

A. Dimethylthiocarbamic acid S-(2-formylamino-indan-5-yl)ester.

Scheme 6. To dimethylthiocarbamic acid-S-[2-aminoindan-5-yl) ester (2.0 g; 8.46 mmol) in CHCI₃ (10 mL) is added ethyl formate (50 mL) and the reaction heated at 55 °C for 24 h. The reaction is cooled, the solvent removed under reduced pressure, and the crude oil purified by flash chromatography (Siθ₂) eluting with an ethyl acetate-methanol gradient to afford 0.77 g (35%) of dimethylthiocarbamic acid-S-(2-formylaminoindan-5-yl)ester as a white solid. LC/MS: Cι₃Hι₆N₂O₂: m/z 264 (M+1)

B. 2-Methyl-2-(2-methylaminoindan-5-ylsulfanvQ-propionic acid tert-butyl ester. Scheme 6. To dimethylthiocarbamic acid S-(2-formylaminoindan-5- yl)ester (0.772 g; 2.9 mmol) in THF (9 mL) under N₂ is added a solution of 1.0 M lithium aluminum hydride (9 mL) at 0 °C. The reaction is warmed to RT then stirred at reflux for 24 h. The reaction is cooled to 0 °C, quenched with H₂O, and the solvent removed under reduced pressure. The residue is dissolved in MeOH (4 mL), to which is added Cs₂CO₃ (0.304 g; 0.93 mmol), terf-butyl 2- bromoisobutyrate (0.311 mL; 1.39 mmol), and NaBH₄ (2.0 g; 52.8 mmol). The reaction mixture is stirred for 18 h, the removed under reduced pressure and the residue partitioned between EtOAc and H₂O. The layers are separated, the aqueous phase extracted with EtOAc, the organic extracts combined, washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue is purified by flash chromatography (SiU₂) eluting with a CH₂CI₂-MeOH gradient to afford 0.186 g (20%) of 2-methyl-2-(2- methylaminoindan-5-yIsulfanyI)propionic acid tert-butyl ester as an oil. LC/MS: C₁₈H₂7NO₂S: m/z 321 (M+1 )

Compound 2.19 (44 mg; 65% for 2 steps; white solid) was prepared following Route 2 and Steps L and M by replacing 4-trifluoromethoxyphenyl isocyanate with 4-dimethylaminophenyl isocyanate. LC/MS: C₂₃H₂₉N₃O₃S: m/z 428 (M+1 )

2-{2-[1-(3-Cyclopentylpropyl)-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}-2-methylpropionic acid

Compound 2.20 (Example 28)

Compound 2.20 (39 mg; 49% for 2 steps; white solid) was prepared following Route 2 by replacing acetyl chloride with 3-cyclopentylpropionyl chloride. LC/MS: C2₉H₃₅F₃N₂O₄S: m/z 565 (M+1)

2-[2-(3-lndan-5-yl-1-pentyIureido)indan-5-yIsulfanyl}-2-methyIpropionic acid Compound 2.21 (Example 29)

Compound 2.21 (9.3 mg; 24% for 2 steps; white solid) was prepared following Route 2 and Compound 2.3 by replacing acetyl chloride with valeryl chloride and 4-trifluoromethoxyphenyl isocyanate with indanyl isocyanate. LC/MS: C₂₈H₃₆N₂O₃S: m/z 481 (M+1)

2-Methyl-2-{2-[3-(4-methyl-3-nitrophenyl)-1-pentylureido]indan-5-ylsulfanyl} propionic acid Compound 2.22 (Example 30)

Compound 2.22 (5.0 mg; 12% for 2 steps; white solid) was prepared following Route 2 and compound 2.3 by replacing 4-trifluoromethoxyphenyl isocyanate with 4-methyl-3-nitrophenyl isocyanate.

LC/MS: C₂₆H₃₃N₃O₅S: m/z 500 (M+1)

2-Methyl-2-{2-[1-naphthalen-1ylmethyl-3-(4-trilfuoromethoxyphenyl)-ureido]indan- 5-ylsulfanyl}-propionic acid Compound 3.4 (Example 31)

Compound 3.4 (2.9 mg; 4% for 2 steps; white solid) was prepared following Route 3 by replacing pent-4-enal with 1-naphthaldehyde. LC/MS: C₃₂H₂₉F₃N2θ₄S: m/z 595 (M+1 )

2-{2-[3-(4-Methoxyphenyl)-1-propylureido]indan-5-ylsulfanyl}-2-methylpropionic acid

Compound 2.23 (Example 32)

Compound 2.23 (21 mg; 64% for 2 steps; white solid) was prepared following Route 2 and Compound 2.14 by replacing 4-trifluoromethoxyphenyl isocyanate with 4-methoxyphenyI isocyanate.

LC/MS: C₂₄H₂₇F₃N₂O₄S: m/z 443 (M+1)

2-{2-[3-(3,5-DimethylphenyI)-1-propylureido]indan-5-ylsulfanyl}-2-methylpropionic acid Compound 2.24 (Example 33)

Compound 2.24 (19 mg; 57% for 2 steps; white solid) was prepared following Route 2 and Compound 2.14 by replacing 4-trifluoromethoxyphenyl isocyanate with 3,5-dimethylphenyl isocyanate.

LC/MS: C₂₅H₃₂N₂O₃S: m/z 441 (M+1)

2-{2-[1-(2-MethoxyethyI)-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5- ylsulfanyI}-2-methyIpropionic acid

Compound 2.25 (Example 34)

Compound 2.25 (7.0 mg; 16% for 2 steps; oil) was prepared following Route 2 and Compound 2.2 by replacing acetyl chloride with methoxyacetyl chloride. LC/MS: C₂₄H₂₇F₃N₂O₄S₂: m/z 529 (M+1)

2-Methyl-2-{2-[1-propyI-3-(4-trifluoromethylphenyl)ureido]indan-5-ylsulfanyl}- propionic acid Compound 2.26 (Example 35)

Compound 2.26 (20 mg; 56% for 2 steps; white solid) was prepared following Route 2 and Compound 2.14 by replacing 4-trifluoromethoxyphenyl isocyanate with 4-trifluoromethylphenyl isocyanate.

LC/MS: C₂₄H₂₇F₃N₂O₃S₂: m/z 481 (M+1) 2-Methyl-2-{2-[1-(4,4,4-trifluorobutyI)-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}propionic acid Compound 2.27 (Example 36)

Compound 2.27 (10 mg; 26% for 2 steps; oil) was prepared following Route 2 and Compound 2.0 by replacing acetyl chloride with trifluoromethylbutyryl chloride.

LC/MS: C₂₅H₂₆F₆N₂O₄S: m/z 564 (M+1 )

2-{2-[1-(3-Cyclopentylpropyl)-3-phenylureido]indan-5-ylsulfanyl}-2- methylpropionic acid Compound 2.28 (Example 37)

Compound 2.28 (38 mg; 56% for 2 steps; oil) was prepared following Route 2 and Compound 2.0 by replacing acetyl chloride with cyclopentylpropionyl chloride and 4-trifluoromethoxyphenyl isocyanate with phenyl isocyanate. LC/MS: C₂₈H₃₆N₂O₃S: m/z 481 (M+1 )

6-[1 -[5-(1 -Carboxy-1 -methylethylsulfanyl)indan-2-yl]-3-(4-isopropylphenyl)- ureidojhexanoic acid methyl ester Compound 2.29 (Example 38)

Compound 2.29 (12 mg; 38% for 2 steps; white solid) was prepared following Route 2 and Compound 2.4 by replacing acetyl chloride with 5-chlorocarbonyl- pentanoic acid methyl ester.

LC/MS: C₃oH₄oN₂O₅S: m/z 541 (M+1)

2-Methyl-2-[2-(3-naphthalen-2-yl-1-pentyIureido)indan-5-ylsulfanyl]propionic acid Compound 2.30 (Example 39)

Compound 2.30 (15 mg; 39% for 2 steps; white solid) was prepared following Route 2 and Compound 2.3 by replacing 4-trifluorothiomethoxyphenyl isocyanate with 2-naphthyl isocyanate.

LC/MS: C2₉H₃₄N₂O₃S: m/z 491 (M+1)

2-{2-[1-Cyclohexylmethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsuIfanyl]- 2-methylpropionic acid Compound 2.31 (Example 40)

Compound 2.31 (15 mg; 25% for 2 steps; white solid) was prepared following Route 2 and Compound 2.0 by replacing acetyl chloride with cyclohexylacetyl chloride.

LC/MS: C₂₈H₃₃F₃N₂O₄S: m/z 551 (M+1)

2-{2-[1-lsobutyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid Compound 3.5 (Example 41)

Compound 3.5 (10 mg; 12% for 2 steps; oil) was prepared following Route 3 and Compound 3.0 by replacing pent-5-enal with 2-methylpropionaldehyde. LC/MS: C₂₅H₂₉F₃N₂O₄S: m/z 511 (M+1)

2-{2-[3-(3,4-Dichlorophenyl)-1-heptylureido]indan-5-ylsulfanyl}-2-methyIpropionic acid e 42)

Compound 2.32 (6.7 mg; 12% for 2 steps; oil) was prepared following Route 2 and Compound 2.0 by replacing acetyl chloride with heptanoyl chloride and 4- trifluoromethoxyphenyl isocyanate with 3,4-dichlorophenyl isocyanate. LC/MS: C₂₇H₃₄CI₂N₂O₃S: m/z 538 (M+1)

2-{2-[1-(2-DimethyIaminoethyl)-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5- ylsulfanyl}-2-methylpropionic acid

Compound 2.33 (Example 43)

Compound 2.33 (1.9 mg; 4% for 2 steps; oil) was prepared following Route 2 and Compound 2.2 by replacing acetyl chloride with dimethylamino acetyl chloride and 4-trifluoromethoxyphenyl isocyanate with 4-trifluoromethylthiophenyl isocyanate. LC/MS: C₂₅H₃₀F₃N₃O₃S₂: m/z 542 (M+1)

2-{2-[3-(3-ChlorophenyI)-1-heptylureido]indan-5-ylsulfanyI}-2-methylpropionic acid

Compound 2.34 (Example 44)

Compound 2.34 (7.4 mg; 14% for 2 steps; white solid) was prepared following Route 2 and Compound 2.32 and 4-trifluoromethoxyphenyl isocyanate with 3- chlorophenyl isocyanate. LC/MS: C₂₇H3₅CIN₂O₃S: m/z 542 (M+1)

1-{2-[1-HeptyI-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}- cyclobutanecarboxylic acid Compound 2.35 (Example 45)

Compound 2.35 (1.0 mg; 1.3% for 2 steps; white solid) was prepared following Route 2 and Compound 2.32 by replacing tert-butyl 2-bromoisobutyrate with ethyl 1-bromocyclobutanecarboxylate.

LC/MS: C29H₃₅F3N₂O₄S: m/z 565 (M+1 )

2-Methyl-2-{7-[1-propyl-3-(4-trifluoromethoxyphenyl)ureido}-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}propionic acid Compound 1.4 (Example 46)

Compound 1.4 (53 mg; 25% for 2 steps; oil) was prepared following Route 1 and Compound 1.0 by replacing acetyl chloride with propionyl chloride. LC/MS: C₂₅H₂9F₃N₂O₄S: m/z 511 (M+1)

The following two compounds can be prepared following Schemes 10 and 4, Steps I, J and K of Route 1 , substituting reagents and adjusting reaction conditions as needed: 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8- tetrahydronaphthale-2-ylsulfanyl}-2-methylpropionic acid. Compound 1.5 (Example 47)

Compound 1.5 (9.8 mg; oil) can be prepared following Route 1 , steps I, J, and K and Schemes 4 and 10. ¹H NMR (300 MHz, CD₃OD): δ 7.45-7.48 (d, 2H), 7.15-7.18 (m, 3H), 6.71

(s, 1 H), 4.43-4.79 (m, 1 H), 3.75 (s, 3H), 3.43-3.45 (m, 2H), 2.88-3.08 (m, 4H), 1.99-2.03 (m, 2H), 1.38 (s, 6H), 1.25-1.52 (t, 3H) LC/MS: C₂₅H₂₉F₃N₂O₅S: m/z 527 (M+1 )

Route 4

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2- yloxy}-2-methylpropionic acid. Compound 4.0 (Example 48)

A. N-(6-Methoxy-1 ,2,3,4-tetrahydronaphthalen-2-v0acetamide. Scheme 7. To a stirred suspension of 6-methoxy-1 ,2,3,4- tetrahydronaphthalen-2-ylamine (2.54 g; 14.3 mmol) in CH₂CI₂ (20 mL) is added

DIEA (3.4 mL) and the reaction mixture was cooled to 0 °C. Acetyl chloride (1.22 mL; 17.1 mmol) is added dropwise at 0 °C and the reaction is allowed to warm to RT and stirred for 18 h. The reaction mixture was diluted with CH₂CI₂, washed with H₂O, dried over Na₂SO₄, filtered and the solvent removed under reduced pressure to provide a crude solid. Purification by flash chromatography (SiO₂) eluting with hexanes-EtOAc affords 1.57 g (50%) of N-(6-methoxy-1 ,2,3,4- tetrahydronaphthalen-2-yl)acetamide as a white solid. LC/MS: C₁3H17NO2: m/z 220 (M+1)

B. N-(6-Hvdroxy-1 ,2,3,4-tetrahvdronaphthalen-2-yl)acetamide.

Scheme 7. To a suspension of N-(6-methoxy-1 ,2,3,4- tetrahydronaphthalen-2-yl)acetamide (1.57 g; 7.2 mmol) in CH₂CI₂ (70 mL), cooled to -60 °C, is added a solution of boron tribromide-CH₂Cl2 (36 mL), dropwise to maintain the reaction temperature between -50 to -60 °C. The gelatinous suspension is allowed to warm to RT and stir for 30 min. The reaction is cooled to 0 °C, quenched with satd NaHCO₃ and stirred for 30 min at RT. The mixture is extracted with CH₂CI₂ (2X), the extracts combined, dried over Na₂SO₄, filtered and evaporated under reduced pressure to provide a crude solid, which was purified by flash chromatography (SiO₂) eluting with a CH₂CI₂-MeOH gradient to afford 1.13 g (76%) of N-(6-hydroxy-1 ,2,3,4-tetrahydronaphthalen-2- yl)acetamide as a beige solid. LC/MS: Cι₂H₁₅NO₂: m/z 206 (M+1 )

C. 2-(6-Acetylamino-5,6,7,8-tetrahvdronaphthalen-2-yloxy)-2-methylpropionic acid tert-butyl ester.

Scheme 7. To a suspension of N-(6-hydroxy-1 ,2,3,4- tetrahydronaphthalen-2-yl)acetamide (0.439 g; 2.1 mmol) in DMF (6 mL) is added Cs₂CO₃ (1.7 g; 5.2 mmol) and tert-butyl 2-bromoisobutyrate (2.1 mL; 9.4 mmol) and the reaction mixture was stirred at 100 °C for 18 h. The reaction was cooled to RT, diluted with EtOAc, washed with H₂O, brine, dried over Na₂SO₄, filtered, and the solvent removed under reduced pressure to provide a crude oil, which was purified by flash chromatography (SiO₂) eluting with a hexanes-EtOAc gradient to afford 0.51 g (69%) of 2-(6-acetylamino-5,6,7,8-tetrahydronaphthalen- 2-yloxy)-2-methyIpropionic acid tert-butyl ester as an oil.

¹H NMR (300 MHz, CDCI3): δ 6.89-6.92 (d, 1 H), 6.58-6.65 (m, 2H), 5.85- 5.88 (m, 1H), 4.24-4.30 (m, 1H), 2.99-3.06 (dd, 1H), 2.76-2.86 (m, 2H), 2.51-2.59 (dd, 1 H), 2.04 (s, 2H), 1.98-2.02 (m, 1 H), 1.74-1.79 (m, 1 H), 1.54 (s, 6H), 1.46 (s, 9H)

LC/MS: C₂oH₂₉NO₄: m/z 292 (M+1) The following compound was completed following Schemes 3 and 4 and Steps I, J and K of Route 1 , substituting reagents and adjusting reaction conditions as needed:

Compound 4.0 (0.0168 g; 23% for 2 steps; oil) was prepared following Route 1 and Compound 1.0.

LC/MS: C₂₄H₂₇F₃N2O₅: m/z 481 (M+1)

2-{6-[3-(4-tert-ButyIphenyl)1-ethylureido]-3-methoxy-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid.

Compound 1.6 (10 mg; oil) can be prepared by replacing 4- trifluoromethoxyphenyl isocyanate with 4-tert-butyl phenyl isocyanate and using Route 1 , steps I, J, and K and Schemes 4 and 10. LC/MS: C₂sH₃₈N₂O₄S: m/z 499 (M+1)

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid Compound 1.7 (Example 50)

Compound 1.7 (16 mg; 30% after 2 steps; white solid) can be prepared following Route 1 , steps I, J, and K and Schemes 4 and 10.

¹H NMR (300 MHz, CDCI₃): δ 7.46-7.51 (m, 2H), 7.25-7.28 (d, 1 H), 7.17- 7.20 (d, 2H), 6.92-6.95 (d, 1 H), 4.43 (m, 1 H), 3.42-3.49 (m, 2H), 2.90-3.11 (m, 4H), 2.02-2.07 (m, 2H), 1.45 (s, 6H), 1.25-1.31 (t, 3H)

LC/MS: C₂5H2₉F₃N2θ5S: m/z 515 (M+1 ) 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid Compound 1.8 (Example 51)

Compound 1.8 (15 mg; 22% after 2 steps; white solid) can be prepared following Route 1 , steps I, J, and K and Schemes 4 and 10. LC/MS: C₂₅H₂₉F₃N₂O₅S: m/z 532 (M+1 )

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-bromo-5, 6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid Compound 1.9 (Example 52)

Compound 1.9 (55 mg; 43% for 2 steps; white solid) can be prepared following Route 1 , steps I, J, and K and Schemes 4 and 10.

¹H NMR (300 MHz, CDCI₃): δ 7.45-7.48 (m, 3H), 7.36 (s, 1 H), 7.15-7.18 (d, 2H), 4.41-4.79 (m, 1 H), 3.40-3.47 (m, 2H), 2.90-3.07 (m, 4H), 2.01-2.03 (m, 2H), 1.45 (s, 6H), 1.24-1.29 (t, 3H)

LC/MS: C₂₅H₂₉F₃N₂O₅S: m/z 576 (M+1)

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid

Compound 1.10 (Example 53)

Compound 1.10 (73 mg; 26% for 2 steps; white solid) can be prepared following Route 1 , steps I, J, and K and Schemes 4 and 10.

¹H NMR (300 MHz, CDCI₃): δ 7.45-7.48 (m, 2H), 7.22 (s, 1 H), 7.15-7.18 (d, 2H), 7.02 (s, 1H), 4.41-4.79 (m, 1 H), 3.40-3.47 (m, 2H), 2.85-3.03 (m, 4H), 2.39 (s, 3H), 2.01-2.03 (m, 2H), 1.41 (s, 6H), 1.24-1.29 (t, 3H)

LC/MS: C₂₅H₂₉F₃N₂O₅S: m/z 511 (M+1)

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-trifluoromethoxy-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methyIpropionic acid Compound 1.11 (Example 54)

Compound 1.11 (118 mg; 58% for 2 steps; white solid) can be prepared following Route 1 , steps I, J, and K and Schemes 4 and 10.

¹H NMR (300 MHz, CDCI₃): δ 7.45-7.48 (d, 2H), 7.37 (s, 1 H), 7.12-7.18 (m, 3H), 4.44 (m, 1 H), 3.43-3.48 (m, 2H), 2.97-3.21 (m, 4H), 2.03-2.05 (m, 2H), 1.42 (s, 6H), 1.25-1.30 (t, 3H)

LC/MS: C₂₅H₂₉F₃N₂O₅S: m/z 580 (M+1)

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-phenyl-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid Compound 1.12 (Example 55)

Compound 1.12 (118 mg; 58% for 2 steps; white solid) can be prepared following Route 1 , steps I, J, and K and Schemes 4 and 10. ¹H NMR (300 MHz, CDCI₃): δ 7.45-7.48 (d, 2H), 7.29-7.38 (m, 6H), 7.15- 7.18 (d, 2H), 7.10 (s, 1 H), 4.46 (m, 1 H), 3.44-3.49 (m, 2H), 2.98-3.06 (m, 4H), 2.04-2.06 (m, 2H), 1.26-1.30 (t, 3H), 1.14 (s, 6H)

LC/MS: C₂₅H₂₉F₃N₂O₅S: m/z 573 (M+1)

2-{6-[1-Ethyl-3-(4-hydroxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyl}-2-methylpropionic acid (Example 56)

2-{6-[4-Aminophenyl)-1-ethylureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2- methylpropionic acid (Example 57)

Route 5

2-[3-Chloro-6-(ethyl-p-tolyloxycarbonyl-amino)-5,6,7,8-tetrahydro-naphthalen-2- ylsulfanyl]-2-methyl-propionic acid tert-butyl ester. Compound 5.0 (Example 58)

To a mixture of 2-(3-chloro-6-ethylamino-5,6,7,8-tetrahydro-naphthalen-2- ylsulfanyl)-2-methyl-propionic acid tert-butyl ester and borane complex (80 mg; 201 μmol), dissolved in CH₂CI₂ (2 mL), at 0°C is added p-tolyl chloroformate (35μL; 241 μmol). The reaction was slowly warmed to RT and allowed to stir at RT for 6 days. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (SiU2) eluting with a hexanes- EtOAc gradient to afford 30 mg (29%) of 2-[3-chloro-6-(ethyl-p-tolyloxycarbonyl- amino)-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl]-2-methyl-propionic acid tert- butyl ester as a clear oil.

¹H NMR (300 MHz, CDCI₃): δ 6.67-7.29 (m, 6H), 4.28 (m, 1 H), 3.40 (m, 2H), 2.87-2.97 (m, 4H), 2.33 (s, 3H), 1.89-2.06 (m, 2H), 1.39-1.46 (m, 15H), 1.21- 1.31 (m, 3H)

Compound 5.0 (23 mg; 59%) was prepared following Step M of Route 2.

¹H NMR (300 MHz, CD₃OD): δ 6.96-7.34 (m, 6H), 4.27 (m, 1 H), 3.49 (m,

2H), 2.91-3.14 (m, 4H), 2.32 (s, 3H), 2.10 (m, 2H), 1.45 (m, 6H), 1.28 (m, 3H)

LC/MS: C₂₄H₂₈CINO₄S: m/z 462 (M+1)

2-{3-Chloro-6-[(4-chloro-phenoxycarbonyl)-ethyl-amino]-5,6,7,8-tetrahydro- naphthalen-2-ylsulfanyl}-2-methyI-propionic acid. Compound 5.1 (Example 59)

Compound 5.1 (34 mg; 35% for 2 steps; white solid) was prepared following Route 5, substituting 4-chlorophenyl chloroformate for p-tolyl chloroformate and Step M of Route 2. ¹H NMR (300 MHz, CD₃OD): δ 7.11-7.39 (m, 6H), 4.30 (m, 1 H), 3.47 (m,

2H), 2.91-3.15 (m, 4H), 2.06 (m, 2H), 1.45 (m, 6H), 1.28 (m, 3H) LC/MS: C₂₃H₂₅CI₂NO₄S: m/z 482 (M+1 )

2-{6-[Ethyl-(4-trifluoromethoxy-phenoxycarbonyl)-amino]-5,6,7,8-tetrahydro- naphthalen-2-ylsulfanyl}-2-methyl-propionic acid. Compound 5.2 (Example 60)

Compound 5.2 can be prepared prepared following Route 5, substituting carbonic acid 1 -chloro-ethyl ester 4-trifluoromethoxy phenyl ester for p-tolyl chlroroformate and Step M of Route 2.

Alternatively, compound 5.2 can be prepared using the following procedure:

A. Carbonic acid 1 -chloro-ethyl ester 4-trifluoromethoxy-phenyl ester.

Scheme 1. A solution of 1 -chloroethyl chloroformate (1.03 g; 7.20 mmol) in CH₂CI₂ (10 mL) was cooled to 0 °C, trifluoromethoxyphenol (1.09 g; 6.0 mmol) and triethylamine were added, and the resulting solution was warmed to RT. After stirred for3 h, the reaction was quenched with saturated NaHCO₃, and extracted with EtOAc (3 times). The combined organic extracts were washed with water, brine, dried over Na₂SO₄, and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography eluting with Hexane-EtOAc (10:1) to provide 1.54 g (90%) of carbonic acid 1- chloro-ethyl ester 4-trifluoromethoxy-phenyl ester as a colorless oil.

¹H NMR (400 MHz, CDCI₃): δ 7.26 (m, 4 H), 6.49 (q, 1 H), 1.91 (d, 3H)

B. Ethyl-(6-methoxy-1 ,2,3,4-tetrahvdro-naphthalen-2-yl)-carbamic acid 4- trifluoromethoxy-phenyl ester

Scheme 1. To a mixture of 6-methoxy-2-tetralone (950 mg; 5.39 mmol), 2 M of ethylamine in THF (5.4 mL; 10.78 mmol) and acetic acid (648 mg; 10.78 mmol) in CH₂CI₂ (5 mL) was added sodium triacetoxyborohydride ( 2.29 g; 10.78 mmol). The reaction mixture was stirred at RT for 3 h, then 1 N solution of NaOH was added, and extracted with ether (3 times). The combined organic extracts were dried over Na₂SO₄, and the solvent was removed under reduced pressure to give a light-yellow oil. This oil was added to a solution of carbonic acid 1- chloro-ethyl ester 4-trifluoromethoxy-phenyl ester (1.23g; 4.31 mmol) in toluene(8 mL), and the reaction mixture was stirred for 1 h at RT followed by 1 h at 90 °C. The reaction was allowed to cool to RT, diluted with Et₂O and washed with 1 N of aqueous HCI and saturated NaHCO₃. The organic extract was dried over Na₂SO₄, and the solvent was removed under reduced pressure. Flash chromatography of the residue with a gradient of hexane-CH₂CI₂ gave 1.05 g (48%) of ethyl-(6-methoxy-1 ,2,3,4-tetrahydro-naphthalen-2-yI)-carbamic acid 4- trifluoromethoxy-phenyl ester as a white solid. ¹H NMR (400 MHz, CDCI₃): δ 7.10-7.30 (m, 4 H), 6.99 (d, 1H), 6.71 (d, 1H),

6.64 (s, 1 H), 4.33 (m, 1 H), 3.77 (s, 3H), 3.41 (m, 2 H), 2.93 (m, 4H), 2.04 (m, 2H), 1.31 (m, 3H)

LC/MS: C₂ιH₂₃F3NO₄: m/z 410 (M+1)

C. Ethyl-(6-hydroxy-1 ,2,3,4-tetrahvdro-naphthalen-2-vD-carbamic acid 4- trifluoromethoxy-phenyl ester.

Scheme 1. A solution of ethyl-(6-methoxy-1 ,2,3,4-tetrahydro-naphthalen- 2-yl)-carbamic acid 4-trifluoromethoxy-phenyl ester (898.6 mg; 2.19 mmol) in anhydrous CH2CI2 (8 mL) was cooled to -78 °C, a 1.0 M solution of boron tribromide-CH₂CI₂ (6.57 mL, 6.57 mmol) was added slowly. Upon completion of the addition, the reaction mixture was allowed to warm to RT, quenched with MeOH (10 mL) and stirred for an additional 2 h. The solvents were evaporated, and the residue was purified by flash chromatography with hexane-EtOAc (2.5:1) to give 649.4 mg (75%) of ethyl-(6-hydroxy-1 ,2,3,4-tetrahydro-naphthalen-2-yl)- carbamic acid 4-trifluoromethoxy-phenyl ester as a white solid.

¹H NMR (300 MHz, CDCI₃): δ 7.05-7.30 (m, 4 H), 6.90 (m, 1 H), 7.41-7.60 (m, 2H), 5.05 (s, 1H), 4.30 (m, 1 H), 3.41 (m, 2H), 2.90 (m, 4H), 1.99 (m, 2H), 1.31 (m, 3H)

LC/MS: C₂₀H₂ιF₃NO₄: m/z 396 (M+1)

P. Ethyl-(6-triisopropylsilanylsulfanyl-1 ,2,3,4-tetrahvdro-naphthalen-2-yl)- carbamic acid 4-trifluoromethoxy-phenyl ester.

Scheme 1. A solution of ethyl-(6-hydroxy-1 ,2,3,4-tetrahydro-naphthalen- 2-yI)-carbamic acid 4-trifluoromethoxy-phenyl ester (245.1 mg; 0.62 mmol) in anhydrous CH₂CI₂ (3 mL) and THF (3 mL) was cooled to -30 °C, triethylamine (216 uL,1.55 mmol) and triflic anhydride (125 uL, 0.74 mmol) were successively added. The resulting mixture was stirred at RT for 2 h, then quenched with water, and extracted with Et₂O (3 times). The combined organic extracts were washed with water, brine, dried over Na₂SO₄, and the solvent was removed under reduced pressure. Flash chromatography of the residue with hexane- EtOAc (5:1 ) yielded 301.6 mg (92%) of the triflate. This triflate (279.8 mg; 0.53 mmol) and tetrakis(triphenyIphosphine)palladium (61.2 mg; 0.053 mmol) were added to a toluene solution generated from triisopropylsilanethiol (126 uL, 0.58 mmol) and NaH (13.9 mg; 0.58 mmol) at RT. The resulting mixture was vacuumed twice, and refluxed for 4 h, and concentrated under reduced pressure. Flash chromatography of the residue with hexane-EtOAc (10:1 ) afforded 261.8 mg (87%) of ethyl-(6-triisopropylsilanylsulfanyl-1 ,2,3,4-tetrahydro-naphthalen-2- yl)-carbamic acid 4-trifluoromethoxy-phenyl ester as a light-color oil.

¹H NMR (300 MHz, CPCI₃): δ 6.82-7.29(m, 7 H), 4.32 (m, 1 H), 3.40 (m, 2H), 2.81-3.05 (m, 4H), 2.05 (m, 2H), 1.12-1.34 (m, 6H), 1.03 -1.10 (m, 18H) LC/MS: C₂₉H₄₁F₃NO₃SSi: m/z 568 (M+1 )

E. 2-{6-fEthyl-(4-trifluoromethoxy-phenoxycarbonyl)-aminol-5,6,7,8- tetrahvdronaphthalen-2-ylsulfanyl)-2-methyl-propionic acid tert-butyl ester. Scheme 1. A solution of ethyl-(6-triisopropylsilanylsulfanyl-1 , 2,3,4- tetrahydro-naphthalen-2-yl)-carbamic acid 4-trifluoromethoxy-phenyl ester (260.0 mg; 0.46 mmol) and tert-butyl D-bromoisobutylrate (130 uL, 0.69 mmol) in anhydrous THF (2 mL) was cooled to 0 °C, a 1.0 M solution of TBAF (690 uL, 0.69 mmol) was added, then the reaction was warmed to RT, stirred for 1 h, and then diluted with water, extracted with Et₂O (3 times). The combined organic extracts were dried over Na₂SO₄, and the solvent removed under reduced pressure. The crude residue was purified by flash chromatography eluting with Hexane-EtOAc (7:1 ) to provide 229.2 mg (90%) of 2-{6-[ethyl-(4-trifluoromethoxy- phenoxycarbonyl)-amino]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methyl- propionic acid tert-butyl ester as a light-color oil. ¹H NMR (300 MHz, CPCI₃): δ 6.95-7.28 (m, 7 H), 4.34 (m, 1 H), 3.41 (m, 2H), 2.96 (m, 2H), 2.91 (m, 2H), 3.41 (m, 2H), 2.06 (m, 2H), 1.44 (s, 6H), 1.42 (s, 9H), 1.28 (m, 3H)

LC/MS: C₂₈H₃₄F₃NO₅SNa: m/z 576 (M+Na)

F. 2-{6-[Ethyl-(4-trifluoromethoxy-phenoxycarbonyl)-aminol-5,6,7,8-tetrahydro- naphthalen-2-ylsulfanyl)-2-methyl-propionic acid.

Scheme 1. A solution of 2-{6-[ethyl-(4-trifluoromethoxy-phenoxycarbonyI)- amino]-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyI}-2-methyl-propionic acid (120.8 mg; 0.22 mmol) in CH₂CI₂ (4 mL) was cooled to -78 °C, and trifluoroacetic acid (4 mL) was added slowly. The reaction mixture was allowed to warm to RT, and stirred for 1.5 h. The solvents were then evaporated, and the residue was purified by flash chromatography with CH₂CI₂-MeOH (94:6) to give 2-{6-[ethyl-(4- trifluoromethoxy-phenoxycarbonyl)-amino]-5,6,7,8-tetrahydro-naphthalen-2- ylsulfanyl}-2-methyl-propionic acid as a white solid.

¹H NMR (400 MHz, CPCI₃): δ 6.96-7.28 (m, 7H), 4.30 (m, 1 H), 3.39 (m, 2H), 2.85-3.10 (m, 4H), 2.06 (m, 2H), 1.49 (s, 6H), 1.28 (m, 3H) LC/MS: C₂₄H₂₇F₃NO₅S: m/z 498 (M+1)

P. Formulation and Administration

The compounds of the present invention may be formulated into various pharmaceutical forms for administration purposes. To prepare these pharmaceutical compositions, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is intimately mixed with a pharmaceutically acceptable carrier.

A carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral administration or parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. These include water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. In view of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are generally employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Such additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid addition salts of the compounds of formula I, due to their increased water solubility over the corresponding base form, are more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Posage unit form as used in the specification herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

Pharmaceutically acceptable acid addition salts include the therapeutically active non-toxic acid addition salt forms which the disclosed compounds are able to form. The latter can conveniently be obtained by treating the base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, palmoic and the like acids. The term addition salt also comprises the solvates which the disclosed componds, as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like. Conversely the salt form can be converted by treatment with alkali into the free base form. Stereoisomeric forms define all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the (R)- or (S)-configuration; substituents on bivalent cyclic saturated radicals may have either the cis- or trans-configuration. The invention encompasses stereochemically isomeric forms including diastereoisomers, as well as mixtures thereof in any proportion of the disclosed compounds. The disclosed compounds may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above and following formulae are intended to be included within the scope of the present invention. For example, in compound 2.1 or Example 3, there is a chiral center on the C-2 of the indane ring. For this compound, the (S) isomer is more active than the (R) isomer.

Those of skill in the treatment of disorders or conditions mediated by the PPAR alpha could easily determine the effective daily amount from the test results presented hereinafter and other information. In general it is contemplated that a therapeutically effective dose would be from 0.001 mg/kg to 5 mg/kg body weight, more preferably from 0.01 mg/kg to 0.5 mg/kg body weight. It may be appropriate to administer the therapeutically effective dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.05 mg to 250 mg or 750 mg, and in particular 0.5 to 50 mg of active ingredient per unit dosage form. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg, and 35 mg dosage forms. Compounds of the invention may also be prepared in time- release or subcutaneous or transdermal patch formulations. Pisclosed compound may also be formulated as a spray or other topical or inhalable formulations. The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the patient may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned herein are therefore only guidelines.

The next section includes detailed information relating to the use of the disclosed compounds and compositions.

E. Use

The compounds of the present invention are pharmaceutically active, for example, as PPAR alpha agonists. According to one aspect of the invention, the compounds are preferably selective PPAR alpha agonists, having an activity index (e.g., PPAR alpha potency over PPAR gamma potency) of 10 or more, and preferably 15, 25, 30, 50 or 100 or more.

PPAR alpha agonists are useful for the treatment, prevention, or inhibiting the progression of one or more of the following conditions or diseases: phase I hyperlipidemia, pre-clinical hyperlipidemia, phase II hyperlipidemia, hypertension, CAP (coronary artery disease), coronary heart disease, and hypertriglyceridemia. Preferred compounds of the invention are useful in lowering serum levels of low-density lipoproteins (LPL), IPL, and/or small-density LPL and other atherogenic molecules, or molecules that cause atherosclerotic complications, thereby reducing cardiovascular complications. Preferred compounds also are useful in elevating serum levels of high-density lipoproteins (HPL), in lowering serum levels of triglycerides, LPL, and/or free fatty acids. It is also desirable to lower FPG/HbA1c.

Combination therapy

The compounds of the present invention may be used in combination with other pharmaceutically active agents. These agents include lipid lowering agents, and blood pressure lowering agents.

Methods are known in the art for determining effective doses for therapeutic and prophylactic purposes for the disclosed pharmaceutical compositions or the disclosed drug combinations, whether or not formulated in the same composition. For therapeutic purposes, the term "jointly effective amount" as used herein, means that amount of each active compound or pharmaceutical agent, alone or in combination, that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. For prophylactic purposes (i.e., inhibiting the onset or progression of a disorder), the term " "jointly effective amount" refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that treats or inhibits in a subject the onset or progression of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician. Thus, the present invention provides combinations of two or more drugs wherein, for example, (a) each drug is administered in an independently therapeutically or prophylactically effective amount; (b) at least one drug in the combination is administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but is therapeutic or prophylactic when administered in combination with the second or additional drugs according to the invention; or (c) both (or more) drugs are administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but are therapeutic or prophylactic when administered together.

As PPAR alpha agonists, the compounds of the invention may be more potent and efficacious for lowering triglycerides than known fibrates. The present compounds also may increase fat and/or lipid metabolism, providing a method for losing weight, losing fat weight, lowering body mass index, lowering lipids (such as lowering triglycerides), or treating obesity or the condition of being overweight. Examples of lipid lowering agents include bile acid sequestrants, fibric acid derivatives, nicotinic acid, and HMGCoA reductase inhibitors. Specific examples include statins such as LIPITOR™, ZOCOR™, PRAVACHOL™, LESCOL™, and MEVACOR™, and pitavastatin (nisvastatin) (Nissan, Kowa Kogyo, Sankyo, Novartis) and extended release forms thereof, such as APX-159 (extended release lovastatin), as well as Colestid, Locholest, Questran, Atromid, Lopid, and Tricor.

Examples of blood pressure lowering agents include anti-hypertensive agents, such as angiotensin-converting enzyme (ACE) inhibitors (Accupril, Altace, Captopril, Lotensin ,Mavik, Monopril, Prinivil, Univasc, Vasotec, and Zestril), adrenergic blockers (such as Cardura, Pibenzyline, Hylorel, Hytrin, Minipress, and Minizide) alpha/beta adrenergic blockers (such as Coreg, Normodyne, and Trandate), calcium channel blockers (such as Adalat, Calan, Cardene, Cardizem, Covera-HS, Pilacor, PynaCirc, Isoptin, Nimotop, Norvace, Plendil, Procardia, Procardia XL, Sula, Tiazac, Vascor, and Verelan), diuretics, angiotensin II receptor antagonists (such as Atacand, Avapro, Cozaar, and Piovan), beta adrenergic blockers (such as Betapace, Blocadren, Brevibloc, Cartrol, Inderal, Kerlone, Lavatol, Lopressor, Sectral, Tenormin, Toprol-XL, and Zebeta), vasodilators (such as Peponit, Pilatrate, SR, Imdur, Ismo, Isordil, Isordil Titradose, Monoket, Nitro-Bid, Nitro-Pur, Nitrolingual Spray, Nitrostat, and Sorbitrate), and combinations thereof (such as Lexxel, Lotrel, Tarka, Teczem, Lotensin HCT, Prinzide, Uniretic, Vaseretic, Zestoretic).

F. Examples

The following chemical and biological examples are intended to illustrate, not limit, the invention.

Example 1

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyl}-2-methylpropionic acid _] EC₅o = 0.023 μM

Example 2

2-{2-[1-EthyI-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid

EC₅₀ = 0.027 μM

Example 3

(S)-2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid EC₅₀ = 0.0002 μM Example 4

2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyI}-2- methylpropionic acid EC₅₀ = 0.037 μM

Example 5

2-Methyl-2-{2-[1-pentyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5- ylsulfanyl}propionic acid

EC₅o = 0.053 μM

Example 6

) -{2-[1-Ethyl-3-(4-isopropylphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid

Example 7

2-{2-[3-(4-Pimethylaminophenyl)-1-ethylureido]indan-5-ylsulfanyl}-2- methylpropionic acid EC₅o = 0.075 μM

Example 8

-Methyl-2-{2-[1-pentyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid

EC₅₀ = 0.073 μM

Example 9

2-{2-[3-(4-Pimethylaminophenyl)-1-pentylureido]indan-5-ylsulfanyl}-2- methylpropionic acid EC₅₀ = 0.131 μM Example 10

2-{2-[3-(4-Isopropylphenyl)-1-(3-pentyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid EC₅₀ = 0.165 μM

Example 11

2-{2-[3-(4-tet -Butylphenyl)-1-(3-pentyl)ureido]indan-5-ylsuIfanyl}-2- methylpropionic acid

EC₅₀ = 0.173 μM

Example 12

-[2-(3-(Biphenyl-4-yI-1 -pentyIureido)indan-5-ylsulfanyl]-2-methylpropionic acid

EC₅₀ = 0.183 μM Example 13

2-{2-[3-(4-lsopropylphenyl)-1-(3-hexyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid EC₅₀ = 0.184 μM

Example 14

2-Methyl-2-{2-[1-hexyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyljpropionic acid

EC₅₀ = 0.213 μM

Example 15

-Methyl-2-{2-[1-hexyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5- ylsulfanyljpropionic acid EC₅o = 0.123 μM Example 16

2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}propionic acid

EC₅₀ = 0.158 μM

Example 17

2-MethyI-2-{2-[1-butyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5- ylsulfanyl}propionic acid EC₅o = 0.160 μM

Example 18

-Methyl-2-{2-[3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propionic acid EC₅₀ = 0.135 μM Example 19

2-Methy-2-{2-[1-pent-4-enyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}propionic acid EC₅₀ = 0.125 μM

Example 20

-Methyl-2-{2-[1-(3-methylbutyl)-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}-2-methylpropionic acid

EC₅o = 0.106 μM

Example 21

2-{2-[3-(4-lsopropylphenyl)-1-(3-methylbutyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid EC₅₀ = 0.106 μM Example 22

-{6-[1-Butyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyl}-2-methylpropionic acid EC₅₀ = 0.219 μM

Example 23

2-{6-[1-Butyl-3-(4-trifluoromethylsulfanylphenyl)ureido]-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid

ECso = 0.244 μM

Example 24

-{6-[1-Hexyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-

2-ylsulfanyl}-2-methylpropionic acid EC₅o = 0.235 μM Example 47

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8- tetrahydronaphthaIen-2-yIsulfanyl}-2-methylpropionic acid

Example 49

-{6-[1-Ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-5,6,7,8- ^■tetrahydro -naphthalen

2-yloxy}-2-methyl-propionic acid

EC50 = 0.309 μM

Example 50

.OCF₃

J H 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid EC₅₀ = 0.010 μM

Example 51

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyI}-2-methylpropionic acid

ECso = 0.027 μM Example 52

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-bromo-5,6,7,8- tetrahydronaphthalen-2-yIsulfanyl}-2-methyIpropionic acid

EC₅o = 0.017 μM

Example 53

OCF₃ *XXXXO

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5, 6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid

Example 54

-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-trifluoromethoxy-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid EC₅₀ = 0.131 μM

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-phenyl-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid

Example 56

2-{6-[1-EthyI-3-(4-hydroxyphenyI)ureido]-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyI}-2-methylpropionic acid

Example 57

-{6-[4-Aminophenyl)-1-ethyl-ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsuIfanyl}-

2-methylpropionic acid

Example 58

2-{3-Chloro-6-[(4-methyl-phenoxycarbonyl)-ethyl-amino]-5,6,7,8-tetrahydro- naphthalen-2-ylsulfanyl}-2-methyl-propionic acid EC₅o = 0.340 μM

Example 59

2-{3-Chloro-6-[(4-chloro-phenoxycarbonyl)-ethyl-amino]-5,6,7,8-tetrahydro- naphthalen-2-ylsulfanyl}-2-methyl-propionic acid

EC₅₀ = 0.390 μM

Example 60

-{6-[Ethyl-(4-trifluoromethoxy-phenoxycarbonyl)-amino]-5,6,7,8-tetrahydro- naphthalen-2-ylsulfanyl}-2-methyl-propionic acid

EC₅₀ = 0.002 μM

Biological Example 1

HP bPNA Assay H4IIE rat hepatoma cell line was obtained from ATCC. Cells were cultured in 175cm² tissue culture flask or seeded in 96-welI plate with (high serum content, 10% fetal bovine serum and 10% calf serum) culture medium and maintained at 37°C and 5% CO2 throughout study. Twenty-four hours after the initial seeding of the 96-well plate by hand (approximate 100,000/well), the HP gene induction assay was initiated. Media was removed and replaced with 100ul of low serum culture media (5% charcoal/dextran treated calf serum) containing vehicle (PMSO) or test compounds or standard. Cells returned to incubator for 24 hours culture. At the termination of the challenge, 50ul lysis buffer with HO gene specific CE, LE, BL probes was added directly into each well to initiate the bPNA HP mRNA assay. The branched PNA assay was performed according to the manufacturer's protocol (Bayer Piagnostics; Emeryville. CA.). At the end of the assay, the luminescence was quantitated in Pynex MLX microtiter plate luminometer. ECso's were determined by non-linear regression with a sigmoidal fit utilizing Graphpad Prism.

Biological Example 2 Transfection assay for PPARδ receptors

HEK293 cells were grown in PMEM/F-12 Media supplemented with 10% FBS and glutamine (GIBCOBRL). The cells were co-transfected with PNA for PPAR-Gal4 receptor and Gal4-Luciferase Reporter using the PMRIE-C Reagent. On the following day, the PNA-containing medium were replaced with 5% Charcoal treated FBS growth medium. After six hours, cells were seeded in 96well plate and incubated at 37 °C in CO2 incubator overnight. Cells were challenged by test compounds and incubated for 24 hours at 37°C in 5%CO₂ incubator. Luciferase activity was assayed using the Steady-Glo Luciferase Assay Kit from Promega. PMRIE-C Reagent was purchased from GIBCO Cat. No.10459-014. OPTI-MEM I Reduced Serum Medium was purchased from GIBCO Cat. No. 31985. Steady-Glo Luciferase Assay Kit was obtained from Promega Part# E254B.

In Vitro Data

ⁿ Fold induction for PPARδ standard: FI = 36.1 ^*2 Fold induction for PPARγ standard: FI = 70.3

Biological Example 3 aP2 Assay for PPAR gamma Agonists

The procedure is described in detail in Burris et al., Molecular Endocrinology, 1999, 13:410, which is hereby incorporated by reference in its entirety, and aP2 assay results of agonist intrinsic activity may be presented as fold increase over vehicle in induction of aP2 mRNA production.

Twenty-four hours after the initial seeding of the 96-weII plates by hand (around 20,000/well), the differentiation assay may be initiated. Medium may be removed and replaced with 150μl of differentiation medium containing vehicle (PMSO) or test compounds. Cells may be returned to incubator for 24 hours culture. At the termination of the challenge, medium may be removed and 100 ul of lysis buffer may be added to initiate the bPNA aP2 mRNA assay. The branched PNA assay may be performed according to the manufacturer's protocol (Bayer Piagnostics; Emeryville, CA). Result may be expressed as the fold increase of aP2 mRNA production activated over vehicle controls. EC₅₀'s and Emax may be determined by non-linear regression with a sigmoidal fit curve. Following the challenge of the preadipocytes, cells may be lysed with lysis buffer (Bayer Piagnostics) containing the aP2 oligonucleotides. After a 15 minute incubation at 53°C or 30 minutes at 37°C incubator, 70 ul of the lysis buffer from each well may be added to a corresponding capture well (preincubated with 70 ul of blocking buffer (Bayer Piagnostics)). The capture plate may be incubated overnight at 53°C in a plate incubator (Bayer Piagnostics). After this incubation, the bPNA and labeled probes may be annealed as directed by the manufacturer. Following a 30-minute incubation with the luminescent alkaline phosphatase substrate, dioxitane, the luminescence may be quantitated in a Pynex MLX microtiter plate luminometer.

Oligonucleotide probes designed to anneal to the aP2 mRNA and function in the bPNA mRNA detection system are designed with ProbePesigner software (Bayer Piagnostics). This software package analyzes a target sequence of interest with a series of algorithms in order to determine which regions of the sequence can perform as locations for capture, label, or spacer probe annealing. The sequences of the oligonucleotides are as follows:

SEQ ID NO.l CATTTTGTGAGTTTTCTAGGATTATTCTTTTCTCTTGGAAAGAAAGT

SEQ ID NO.2 ATGTTAGGTTTGGCCATGCCTTTCTCTTGGAAAGAAAGT

SEQ ID NO.3 CCTCTCGTTTTCTCTTTATGGTTTTCTCTTGGAAAGAAAGT

SEQ ID NO.4 GCTTATGCTCTCTCATAAACTCTCGTGGTTTCTCTTGGAAAGAAAGT

SEQ ID NO.5 CCAGGTACCTACAAAAGCATCACATTTAGGCATAGGACCCGTGTCT

SEQ ID NO.6 GCCCACTCCTACTTCTTTCATATAATCATTTAGGCATAGGACCCGTGTCT

SEQ ID NO.7 AGCCACTTTCCTGGTGGCAAATTTAGGCATAGGACCCGTGTCT

SEQ ID NO.8 CATCCCCATTCACACTGATGATCTTTAGGCATAGGACCCGTGTCT

SEQ ID NO.9 GTACCAGGACACCCCCATCTAAGGTTTTTAGGCATAGGACCCGTGTCT

SEQ ID NO.10 GGTTGATTTTCCATCCCATTTCTGCACATTTTAGGCATAGGACCCGTGTCT

SEQ ID NO.11 GCATTCCACCACCAGTTTATCATTTTAGGCATAGGACCCGTGTCT

SEQ ID NO.12 GCGAACTTCAGTCCAGGTCAACGTCCCTTGTTTAGGCATAGGACCCGTGTCT

SEQ ID NO.13 TCCCACAGAATGTTGTAGAGTTCAATTTTAGGCATAGGACCCGTGTCT

SEQ ID NO.14 AAAACAACAATATCTTTTTGAACAATATATTTAGGCATAGGACCCGTGTCT

SEQ ID NO.15 TCAAAGTTTTCACTGGAGACAAGTTT

SEQ ID NO.16 AAAGGTACTTTCAGATTTAATGGTGATCA

SEQ ID NO.17 CTGGCCCAGTATGAAGGAAATCTCAGTATTTTT

SEQ ID NO.18 TCTGCAGTGACTTCGTCAAATTC

SEQ ID NO.19 ATGGTGCTCTTGACTTTCCTGTCA SEQ ID NO . 0 AAGTGACGCCTTTCATGAC

Biological Example 4

11 Pay Posing of Example 3 in Female, 6-7 week Old db/db Mice

(Female db/db mice (C57 BLK S/J-m+/+Lepr^db, Jackson Labs, Bar Harbor, ME), 6-7 weeks of age, were housed four per cage in solid-bottomed shoe box cages. Room temperature was maintained at 68-72 °F and humidity at 50-65%. Room lighting was on a 12-hour light/12-hour dark cycle. Mice were fed a certified NIH Rat and Mouse/Auto 6F reduced fat diet #5K52 (P M I Nutrition Int'I, St. Louis, MO, via W. F. Fisher and Son, Inc., Bound Brook, NJ). Food and water were supplied ad libitum.

The compound was prepared as suspensions in 0.5% hydroxypropyl- methylcellulose (Pow Chemical, Midland, Ml). The dosing volume was 10 mL/kg of body weight. Female db/db diabetic mice (8/group) were orally gavaged once daily for 11 days with either 0.5% methylcellulose in dH₂O (vehicle) or PPARagonist at either 0.03, 0.1 , 0.3, 1 , 3, 10 mg/kg/day. Body weight was measured in the mornings on Pay 1 , prior to dosing, and on Pay 12 before bleeding. 18-24 hours after the final dose for each group, the mice were anesthetized with CO₂/O₂ (70:30) and bled by retro-orbital sinus puncture into micro-tubes containing clog activator and then put in ice. The serum samples were prepared by centrifugation. Serum glucose and triglycerides were determined by using COBAS Mira Plus blood chemistry analyzer (Roche Piagnostics, NJ). Serum insulin was measured by using ALPCO insulin ELISA kit. Statistical analysis was performed using the program Prism (Graphpad, Monrovia, CA) and performing one-way ANOVA with a Punnett's multiple comparison test.

In Vivo data

db/db Mice dosed @ 1.0 mpk. Data is represented as a % change compared to vehicle treated animals; NC = no change ² 10 day oral dosing ³ 11 day oral dosing ⁴ 5 day oral dosing

Biological Example 5 11 Pay Posing of Example in Female, 7 week Old ob/ob Mice

(Female ob/ob mice (C57 BL/6J-Lep^ob, Jackson Labs, Bar Harbor, ME), 7 weeks of age, were housed two per cage in solid-bottomed shoe box cages. Room temperature was maintained at 68-72 °F and humidity at 50-65%. Room lighting was on a 12-hour light/12-hour dark cycle. Mice were fed a certified NIH Rat and Mouse diet #5K50 (P M I Nutrition Int'I, St. Louis, MO, via W. F. Fisher and Son, Inc., Bound Brook, NJ). Food and water were supplied ad libitum.

The compound was prepared as suspensions in 0.5% hydroxypropyl- methylcellulose (Pow Chemical, Midland, Ml). The dosing volume was 10 mL/kg of body weight. Female ob/ob diabetic mice (8/group) were orally gavaged once daily for 11 days with either 0.5% methylcellulose in dH₂θ (vehicle) or PPAR agonist at 0.003, 0.01 , 0.03, 0.1 , 0.3, 1 mg/kg/day. Body weight was measured in the mornings on Pay 1 , prior to dosing, and on Pay 12 before bleeding. 18 hours after the final dose for each group, the mice were anesthetized with CO₂/O₂ (70%:30%) and bled by retro-orbital sinus puncture into micro-tubes containing clog activator and then put in ice. The serum samples were prepared by centrifugation. Serum glucose and triglycerides were determined by using COBAS Mira Plus blood chemistry analyzer (Roche Piagnostics, NJ). Serum insulin and free fatty acids were measured by using ALPCO insulin ELISA kit and Wako NEFA kit, respectively.

Statistical analysis was performed using the program Prism (Graphpad, Monrovia, CA) with one-way ANOVA and a Punnett's multiple comparison test.

In Vivo data

ob/ob Mice dosed @ 1.0 mpk. Data is represented as a % change compared to vehicle treated animals.

F. Other Embodiments

The features and principles of the invention are illustrated in the discussion, examples, and claims herein. Various adaptations and modifications of the invention will be apparent to a person of ordinary skill in the art and such other embodiments are also within the scope of the invention. Publications cited herein are incorporated in their entirety by reference.

What is claimed is:

Claims

1. A compound of Formula I

or a pharmaceutically acceptable salt, C ι_₆ ester or C ₁-₆ amide thereof, wherein

each of Ri and R₂ is independently H, C ι_-6 alkyl, (CH₂)_mNR_aRb, (CH₂)_mOR₈, (CH₂)mNH(CO)R₈, or (CH₂)mCO₂R8, where each of R_a, Rb, and R₈ is independently H or C ι_-6 alkyl, or Ri and R₂ taken together with the carbon atom to which they are attached are a C _3- cycloalkyl;

m is between 1 and 6;

n is 1 or 2;

X is O or S; wherein X is at the 5 or 6 position when n is 1 ; and wherein X is at the 6 or 7 position when n is 2;

R₃ is H, phenyl, C ι_₃ alkoxy, C ι-₃ alkylthio, halo, cyano, C ι-₆ alkyl, nitro, NR9R10, NHCOR10, CONHR10; and COOR₁0; and R₃ is ortho or meta to X;

R is H or -(C ι_-5 alkylene)Rιs, where R₁5 is H, C₁-7 alkyl, [di(C ι_-2 alkyI)amino](C ι_-6 alkylene), (C ι_-3 alkoxyacyl)(C ι_-6 alkylene), C ι_-6 alkoxy, C _3-7 alkenyl, or C _3-s alkynyl, wherein R₄ has no more than 9 carbon atoms; Ri can also be -(C ι_-5 alkylene)Rι₅ wherein R₁₅ is C _3-6 cycloalkyl, phenyl, phenyl-O-, phenyl-S-, or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

Y is NH, NH-CH₂, and O;

each of R₅ and R₇ is independently selected from H, C i-β alkyl, halo, cyano, nitro, COR₁₁, COOR₁₁, C ι_-4 alkoxy, C ι- alkylthio, hydroxy, phenyl, NR1₁R₁₂ and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

Re is selected from C 1-6 alkyl, halo, cyano, nitro, CORι₃, COORι₃, C ι- alkoxy, C ι_-4 alkylthio, hydroxy, phenyl, NRι₃R and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

in addition, either R₅ and Re or Re and R₇ may be taken together to be a bivalent moiety, saturated or unsaturated, selected from -(CH₂)3-, -(CH2)₄-, and (CH_1-2)pN(CH_1-2)_q,

p is 0-2 and q is 1-3, where the sum (p + q) is at least 2;

each of Rg and R₁0 is independently C ₁-6 alkyl; each of R₁₁, R₁₂, R₁₃ and R₁ is independently H or C ι_₆ alkyl;

wherein each of the above hydrocarbyl and heterocarbyl moieties may be substituted with between 1 and 3 substituents independently selected from F,

Cl, Br, I, amino, methyl, ethyl, hydroxy, nitro, cyano, and methoxy.

2. A compound of claim 1 , wherein one of Ri and R₂ is methyl or ethyl.

3. A compound of claim 2, wherein each of Ri and R₂ is methyl.

4. A compound of claim 1 , wherein Ri and R₂ taken together are cyclobutyl or cyclopentyl.

5. A compound of claim 1 , wherein R₃ is H.

6. A compound of claim 1 , wherein R₃ is C ι_-3 alkoxy, C ι_-3 alkylthio, halo, cyano, C ι-₆ alkyl, nitro, NR9R10, NHCOR10, CONHR10; or COOR10.

7. A compound of claim 1 , wherein R is H or C ₂-₇ alkyl.

8. A compound of claim 7, wherein R is H or C 2-5 alkyl.

9. A compound of claim 8, wherein * is ethyl.

10. A compound of claim 8, wherein R* is H.

11. A compound of claim 1 , wherein n is 1.

12. A compound of claim 1 , wherein n is 2.

13. A compound of claim 1 , wherein Y is NH-CH₂.

14. A compound of claim 1 , wherein Y is NH.

15. A compound of claim 1 , wherein X is S.

16. A compound of claim 1 , wherein X is O.

17. A compound of claim 1 , wherein at least one of R₅ and R is H.

18. A compound of claim 17, wherein R is C ι_-4 alkyl, halomethoxy, halomethylthio, or di(C ι_-3 alkyl)amino.

19. A compound of claim 18, wherein R₆ is trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethylthio, t-butyl, isopropyl, or dimethylamino.

20. A compound of claim 3, wherein R₃ is H, R₄ is C ₂-₇ alkyl, and Y is NH.

21. A compound of claim 20, wherein X is S.

22. A compound of claim 20, wherein n is 1.

23. A compound of claim 20, wherein n is 2.

24. A compound of claim 20, wherein R is C ₂-₅ alkyl.

25. A compound of claim 24, wherein R is ethyl.

26. A compound of claim 20, wherein Re is trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethylthio, t-butyl, isopropyl, or dimethylamino.

27. A compound of claim 1 , wherein each of Ri and R₂ is independently H, C ι_₆ alkyl, (CH₂)mNR_aRb, or (CH₂)mOR₈, where each of R_a, Rb, and R₈ is independently H or C ι_-6 alkyl;

m is between 1 and 6;

n is 1 or 2;

X is O or S; wherein X is at the 5 or 6 position when n is 1 ; and wherein X is at the 6 or 7 position when n is 2; R₃ is H, phenyl, C ι_-3 alkoxy, C ι_-3 alkylthio, halo, C ι-β alkyl, or NR9R10, and R₃ is ortho or meta to X;

R is H or -(C ₁.₅ alkylene)Rιs, where R₁₅ is H, C₁-₇ alkyl, [di(C ₁-₂ alkyl)amino](C ι_-6 alkylene), (C ι_-3 alkoxyacyl)(C ι_-6 alkylene), C ι_-6 alkoxy, or C ₃-7 alkenyl, wherein R₄ has no more than 9 carbon atoms; 4 can also be -(C ι_-5alkyIene)Rι₅ wherein R₁₅ is C _3-6 cycloalkyl, phenyl, phenyl-O-, phenyl-S-, or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

Y is NH or NHCH₂;

each of Rs and R₇ is independently selected from H, C i-β alkyl, halo, CORn, COOR₁₁, C ι_-4 alkoxy, C ι- alkylthio, hydroxy, and NR1₁R₁₂;

Re is selected from C ι-₆ alkyl, halo, CORι₃, COOR₁3, C ι_-4 alkoxy, C ι_ alkylthio, phenyl, NRι₃Rι and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

each of Rg and R10 is independently C -₆ alkyl; each of Rn , R12, R13 and R14 is independently H or C i-β alkyl;

wherein each of the above hydrocarbyl and heterocarbyl moieties may be substituted with between 1 and 3 substituents independently selected from F, Cl, amino, methyl, ethyl, hydroxy, and methoxy.

28. A compound of claim 1 , selected from:

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid; 2-{2-[1 -Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethylsuIfanylphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid;

2-Methyl-2-{2-[1-pentyl-3-(4-trifluoromethylsuIfanylphenyI)ureido]indan-5- y!sulfanyl}propionic acid; 2-{2-[1-Ethyl-3-(4-isopropylphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid;

2-Methyl-2-{2-[1-pentyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}- 2-methylpropionic acid;

2-{2-[3-(4-PimethylaminophenyI)-1-ethylureido]indan-5-ylsuIfanyI}-2- methylpropionic acid;

2-Methyl-2-{2-[1-(3-methylbutyI)-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}-2-methylpropionic acid;

2-{2-[3-(4-lsopropylphenyl)-1-(3-methylbutyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid; 2-Methy-2-{2-[1-pent-4-enyI-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyljpropionic acid;

2-{6-[1 -Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5, 6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid;

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8- tetrahydronaphthalen-2-yIsulfanyl}-2-methylpropionic acid;

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid;

2-{6-[1 -Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-bromo-5, 6,7,8- tetrahydronaphthalen-2-yIsulfanyl}-2-methylpropionic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8- tetrahydronaphtha!en-2-ylsulfanyl}-2-methylpropionic acid; and

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-trifluoromethoxy-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid.

29. A compound of claim 1 , selected from 2-Methyl-2-{2-[1 -hexyl-3-(4-trifluoromethylsulfanylphenyI)ureido]indan-5- ylsulfanyl}propionic acid ;

2-{2-[3-(4-Pimethylaminophenyl)-1-pentylureido]indan-5-ylsuIfanyl}-2- methylpropionic acid; 2-Methyl-2-{2-[3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propionic acid;

2-Methyl-2-{2-[1 -propyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsuIfanyl}propionic acid;

2-Methyl-2-{2-[1 -butyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5- ylsulfanyl}propionic acid;

2-{2-[3-(4-lsopropylphenyl)-1-(3-pentyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid;

2-{2-[3-(4-.etτ-Butylphenyl)-1-(3-pentyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid; 2-[2-(3-(Biphenyl-4-yl-1-pentylureido)indan-5-ylsulfanyl]-2-methylpropionic acid;

2-{2-[3-(4-lsopropylphenyl)-1-(3-hexyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid;

2-Methyl-2-{2-[1 -butyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyljpropionic acid;

2-{6-[1 -Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyI}-2-methylpropionic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyI)ureido]-3-chloro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid;

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-bromo-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid;

2-{6-[1 -Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methyIpropionic acid; and 2-Methyl-2-{2-[1-hexyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyljpropionic acid.

30. A compound of claim 1 , selected from: 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyI}-2-methylpropionic acid;

2-{6-[3-(4-Trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyl}-2-methylpropionic acid;

2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid;

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8- tetrahydronaphthaIen-2-ylsulfanyl}-2-methylpropionic acid;

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsuIfanyI}-2- methylpropionic acid; and

2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- y!sulfanyl}propionic acid.

31. A compound of claim 1 , selected from: 2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid;

2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsuIfanyl}-2- methylpropionic acid;

2-MethyI-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyljpropionic acid; and

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid. ill

32. A pharmaceutical composition, comprising a compound of claim 1 , 20, 27, 28, 30, or 31.

33. A method for treating or inhibiting the progression of a PPAR-alpha mediated disease, said method comprising administering to a patient in need of treatment a pharmaceutically-effective amount of a composition comprising a compound of claim 1 , 20, 27, 28 or 31.

34. A method of claim 33, wherein said PPAR-alpha mediated disease is selected from dyslipidemia and cardiovascular diseases.

35. A method of claim 34, wherein said disease is dyslipidemia.

36. A method of claim 34, wherein said dyslipidemia is selected from phase I hyperlipidemia, pre-clinical hyperlipidemia, phase II hyperlipidemia, hypercholesteremia, hypo-HPL-cholesterolemia, and hypertriglyceridemia.

37. A method of claim 34, wherein said cardiovascular disease is atherosclerosis, coronary artery disease, coronary heart disease, or hypertension.

38. A method of claim 33, 35, or 36, further comprising the step of administering to the patient a jointly-effective amount of a lipid-lowering agent.

39. A method of claim 33, 35, 36, or 38, further comprising the step of administering to the patient a jointly-effective amount of a blood-pressure lowering agent.