ZA200504065B - Substituted tetralins and indanes - Google Patents

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 (GlaxoSmithKline).

-3- i

Summary

The invention features compounds of formula (1) below:

R7 Re

Rs 0) 0 N Mv

X—p— N

HO Ry s Ri Re Rg n

Formula (I) ’ or a pharmaceutically acceptable salt, C 1.6 ester or C 1.6 amide thereof, wherein each of Ry and R; is independently H, C 1.6 alkyl, (CH2)mNRzRp, (CH2)mOR, (CH2)mNH(CO)Rg, or (CH2)mCO2Rs, where each of Rj, Rp, and Rgis independently H or C 1.6 alkyl, or Ry and R; taken together with the carbon atom to which they are attached are a C 3.7 cycloalkyl; m is between 1 and 6; nis 1 or 2;

Xis 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;

R; is H, phenyl, C 1.3 alkoxy, C 1.3 alkylthio, halo, cyano, C 1.6 alkyl, nitro,

NRgR10, NHCOR19, CONHR1o; and COOR1g; and Rj is ortho or meta to X;

Rs is H or -(C 1.5 alkylene)R1s, where Ris is H, Cq.7 alkyl, [di(C 12 alkyl)amino](C 1.6 alkylene), (C 1.3 alkoxyacyl)(C 1s alkylene), C 1.6 alkoxy, C 37 alkenyl, or C 3g alkynyl, wherein R4 has no more than 9 carbon atoms; Ry can also be -(C 1.5 alkylene)R4s wherein Rss 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-CH, or O; each of Rs and Ry is independently selected from H, C 1.5 alkyl, halo, cyano, nitro, COR41, COOR4, C 14 alkoxy, C 14 alkylthio, hydroxy, phenyl, NR{1R2 and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

Re is selected from C 1 alkyl, halo, cyano, nitro, COR;3, COOR43, C 14 alkoxy, C 1.4 alkylthio, hydroxy, phenyl, NR13R14 and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S; in addition, either Rs and Rs or Rs and R; may be taken together to be a bivalent moiety, saturated or unsaturated, selected from —(CH3z)3—, -(CH2)s-, and (CH41.2)pN(CH1.2),, pis 0-2 and q is 1-3, where the sum (p + q) is at least 2; each of Rg and Rg is independently C 1.6 alkyl; each of Ry1, R12, R13 and Ry4 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, 1, 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 5 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

S

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, isopropyl, 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 (sp®). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyis, 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, propynyis, 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 SO,. 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-dihydronaphthyi, 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 (SO,, 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-pyrazolyl. 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, benzoxazolyl, 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-,0r 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 1galkyl, C 3.8 cycloalkyl, aryl, C 2.10 heteroaryl, or C 5.49 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 M.

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 1. alkyl amines and secondary di (C 1.6 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 1.3 alkyl primary amines, and di (C 1.; alkyl)amines.

Representative pharmaceutically acceptable esters of the invention include C 1.7 alkyl, C s.7 cycloalkyl, phenyl, and phenyl(C 1 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 Rs, Rg, and Ry 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 muilti- valent) 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 (chiorobenzyl- 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), hitroalkyl, alkylalkyl, and so on. A di(C 1.5 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 NR44R2 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 —(CH:),-N-(CH.)¢- can be unsaturated, the appropriate hydrogen atom(s) is(are) included or omitted, as shown in -(CH;)-N=(CH)-(CHa)- 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 (l) as described in the Summary section above.

Examples include those compounds wherein: (a) one of Ry and R; is methyl or ethyl; (b) wherein each of Ry and Rz is methyl; (c) R1 and Rz taken together are cyclobutyl or cyclopentyl; (d) Raz is H; (e) Rs is H or C 27 alkyl; (e) Reis Hor C 25 alkyl; (f) Ry is ethyl; (g) Reis H; (h) nis 1; (i) nis 2; (j) Y is NHCHg; (k) Y is NH; (1)

X is S; (m) Xis O; (n) at least one of Rs and Ry is H; (0) Rg is C 1.4 alkyl, halomethoxy, or halothiomethoxy; (p) Rs is t-butyl, isopropyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethoxy, difluoromethoxy, or dimethylamino; (q) Rs is H, Ry is C 27 alkyl, and Y is NH; (r) Rs is C 2.5 alkyl; (s) Re is cyclopropyimethyl, 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 Rs is C17 alkyl, [di(C 12 alkyl)amino](C 1.5 alkylene), (C 1.3 alkoxyacyl)(C 16 alkylene), C 1.6 alkoxy, C 3.7 alkenyl, or C 3.5 alkynyl; (w) Rs is trifluoromethylthio or trifluoromethoxy; or (x) combinations of the above.

Additional preferred compounds include: ga eeR Von

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

Xs ] OCF.

HO fo} 3

COL

”s a J H 2-{4-Chloro-6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-1-fluoro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid

A

S OCF;

HO o) or

ACL,

JH

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

[0]

H oP o or

A ICOLE, 0 JH 3-(1-Carboxy-1-methyl-ethylsuifanyl)-7-[1-ethyl-3-(4- trifluoromethoxyphenyl)ureido}-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid ethyl ester

[0]

HO [5 o OCF,

Ess oR Ee;

J

2-{6-[Ethyl-(4-trifluoromethoxyphenoxycarbonyl)-amino]-3-fluoro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic 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-chloro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid 2-{6-[1-Ethyl-3~(4-trifluoromethoxyphenyi)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-methyipropionic 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-ylsulfanyl}- 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)ureidolindan-5-ylsulfanyl}-2- methylpropionic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureidojindan-5-ylsuifanyl}-2- methylpropionic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid; and 2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureidolindan-5- ylsulfanyl}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 '®F 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" 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- chiorophenyl, p-methoxyphenyl, and benzyl.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4- dimethoxybenzyl, p-halobenzyl, 2,6-dichlorobenzyl, 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- phenyiethyl, 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 phenyl(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 S-fluorenylmethyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, 2- (trimethyisilyl)ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, a- 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, t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl and di-t- 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 Rs is H) is demonstrated in Schemes 1-5. : Abbreviations or acronyms used herein include:

AcOH (glacial acetic acid); DCC (1,3-dicyclohexylcarbodiimide);

DCE (1,2-dichloroethane); DIC (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

NH; wool IT Co col LT ~ 1 2

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

[0] 0} 4 AN yg EE 5), op SSPE co £2 8 he 3 4 5

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

[0]

Cle 0 0

PS NH __°. ! pe 1) _ 2 1 oor SI) Hei ico n J HO n J 2/5 6 7 0 0]

S _— 0 N _— ee LED wEsasee “ne "o ! © 9 8

Q BrCR4R,CO4R: Ry R2 NH : SAT NH, TER. on TO ’ lo) 10 1

Ry Ry NH

PLN —R, © 12

In accordance with Scheme 3, a compound 2 or § 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 trimethyisilyliodide 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 diethylthiocarbamoy! 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.]Joctane 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, WI 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 tert-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 . Rs Rs

RR as sRsR;PhYCO,H [0] : Rg oo Sv

Ry Ra sna or Ry Re [TOM

Res” X n RsRgR,PhNCO Rar Ox n “Ra © 12 or © 13

RsRgR;PhC(O)CI

Rs Rg ag

[0] - Ry “CI

Hox Jy © 14

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 DIC 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

Rs Rg as

RsRgR7PhYCOH 0} —_— ee Y

Ry fe [Ty or R1 one] 0 2 re

Reg eS n RsReR7PhNCO Rao Tx n ; 1 15

Rs Rg as 0, a. Ry ONE .

HOS x ]

[0] 16 :

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 lo] O BrCR{R,CO.R Ri Re -— NCHO 12 aRao NHCH

AJ JO - aro 0 3 10 17 ° 18

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 tert-butyl 2- bromoisobutyrate, ethyl bromoacetate, or ethyl 2-bromobutyrate and a reducing agent, such as lithium borohydride or sodium borohydride.

Scheme 7

AN " R4COCI ON Sr, ~ Sr, a > CE 5 215 RaCO2M 19 20 3

BrCR1R2CO,Rz 0 4 " CI Rs o 21

A preferred synthesis of Formula 21, when X is O (and Rz 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 tert-butyl 2- bromoisobutyrate, ethyl bromoacetate, or ethyl 2-bromobutyrate in a suitable solvent, such as DMF or methanol.

Scheme 8

OQ 0, [e]

I Co Nr s "NR 2 IS er whole, WAT — SAAT 2 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

COH CO,CHs ~~ CH2=CHy lo]

JO JO JOT

26 27 28

NR

NH» 4 — J — CO 29 30

N Rg 4 ) Sh Rig Re T J.

CT [0] Ra Os o [e} 32

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

Ayo Nr, (MeS), Ay Sn, HO Sor, 8 Ds R § 9s A, 22 33 3 penta Sent ~ 0. Io } ‘on Y 0 ) 22a

In accordance to Scheme 10, compounds of Formula 22 can be readily converted to compounds of Formula 32a, where R3 = OCHs. 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 ols ° OCF,

CELT

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenylureido]-5,6,7,8-tetrahydronaphthal-2- ylsulfanyl}-2-methyl-propionic acid.

Compound 1.0 (Example 1)

A. 6-Methoxy-1,2,3.4-tetrahydronaphthalen-2-ylamine hydrochloride.

Scheme 1. To a solution of 6-methoxy-2-tetralone (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 1S 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 1N NaOH added to quench the reaction. The aqueous phase is separated and the organic phase washed with H;O, brine, dried over

Na>SOyq, filtered, and the solvent removed under reduced pressure to afford a crude residue which was purified by flash chromatography (SiO) eluting with

CH2Clz / 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-tetrahydronaphthalen-2-ylamine hydrochloride as a white solid.

LC/MS: C11H1sNO: m/z 178 (M+1)

B. 2-(6-Methoxy-1,2,3 4-tetrahydronaphthalen-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

H20 and extracted several times with EtOAc. The combined organic extracts are washed with water, brine, dried over Na,SO4, 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. 'H NMR (300 MHz, CDCls): 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 (mM, 1

H), 2.95-2.98 (m, 2H), 2.81-2.88 (m, 1H), 2.65-2.76 (m, 1H), 1.97-2.01 (m, 1H)

LC/MS: C1gH17NO3: m/z 308 (M+1)

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

Scheme 3. To 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)isoindole- 1,3-dione (29 g; 94.3 mmol) dissolved in anhydrous CHCl, (500 mL), cooled to - 60 °C, is added a 1.0 M solution of boron tribromide-CH,Cl, (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 NaHCOj3 (400 mL) and stirred for an additional 0.5 h at RT. The precipitate is filtered, washed thoroughly with HO, 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. 'H NMR (300 MHz, DMSO-dg): 5 9.11 (bs, 1H), 7.82-7.89 (m, 4 H), 6.84- 6.87 (d, 1H), 6.52-6.56 (m, 2H), 4.29-4.37 (m, 1H), 3.45 (bs, 1H), 3.25-3.34 (m, 1H), 2.73-2.84 (m, 3H), 2.37-2.47 (m, 1H), 1.94-1.98 (m, 1H)

LC/MS: C1gH1sNO3: m/z 294 (M+1)

D._Dimethyl-thiocarbamic acid-O-[6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5.6.7.8- tetrahydro-naphthalen-2-vl] 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-diazabicyclo[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 H,O and dried under vacuo. The crude solid was purified by flash chromatography (SiO) eluting with a hexanes-EtOAc gradient to afford 30 g (91%) of dimethyithiocarbamic acid -O-[6-(1,3-dioxo-1,3,- dihydroisoindol-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl] ester as a white solid. 'H NMR (300 MHz, CDCl3): § 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, 1H), 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, 1H), 1.97-2.01 (m, 1H)

LC/MS: C21H20N203S: m/z 381 (M+1)

E. Dimethylthiocarbamic acid S-[6-(1,3-dioxo-1,3-dihydroisoindol-2-y1)-5.6,7.8- tetrahydronaphthalen-2-yl] 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 N3 stream. The crude residue is purified by flash chromatography (SiO,) 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. 'H NMR (300 MHz, CDCl3): & 7.82-7.86 (m, 2H), 7.72-7.75 (m, 2 H), 7.23- 7.26 (m, 2H), 7.07-7.10 (d, 1H), 4.52-4.63 (m, 1H), 3.61-3.70 (m, 1H), 2.89-3.09 (m, 9H), 2.61-2.75 (m, 1H), 1.97-2.04 (m, 1H) :

LC/MS: C21H20N203S: m/z 381 (M+1)

F. Dimethyithiocarbamic acid S-[6-amino-5.6,7,8-tetrahydronaphthalen-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-y1)-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-tetrahydronaphthalen-2-yl) ester as a yellow oil.

LC/MS: C13H1gN20S: m/z 251 (M+1) : G. 2-(6-Amino-5.6.7,8-tetrahydronaphthalen-2-yisulfanyl)-2-methylpropionic acid tert-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. NaBH, (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 H20, the solvent evaporated under reduced pressure, and the crude residue partitioned between

H20 and CH2Cl,. The aqueous phase is extracted with CH2Cl, and the combined organic extracts were dried over Na;SO;, 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: C1g1H27NO2S: m/z 266 (M+1)

H. 2-(6-Acetylamino-5,6.7 8-tetrahydronaphthalen-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 CH.Cl (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 CH,Cl,, washed with H,O, dried over Na;SO4 and evaporated under reduced pressure. The crude oil was purified by flash chromatography (SiO) eluting with a hexanes-EtOAc gradient to afford 1.7 g (32%) of 2-(6-acetylamino-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyl)-2-methylpropionic acid tert-butyl ester as a tan solid. 'H NMR (300 MHz, CDCl3): & 7.23-7.26 (m, 2 H), 6.99-7.01 (d, 1 H), 5.46- 5.48 (m, 1H), 4.25-4.29 (m, 1H), 3.08-3.15 (dd, 1H), 2.82-2.88 (m, 2H), 2.58-2.66 (m, 1H), 2.01-2.04 (m, 1H), 1.98 (s, 3H), 1.70-1.82 (m, 1H), 1.43 (s, 15H)

LC/MS: C20H2gNO3S: m/z 308 (M+1)

I. 2-(6-Ethylamino-5,6.7.8-tetrahydronaphthalen-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: Cz0H31NO,S'BH3: m/z 308 ((M+BHj3)+1)

J. 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureidol-5.6.7.8- tetrahydronaphthalen-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 CH,Cl, (15 mL) is added 4- trifiuoromethoxyphenyl 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 (SiO,) 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: CagHasF3N204S: m/z 497 ((M-C4Hg)+1)

K. 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7.8- tetrahydronaphthalen-2-yisulfanyl}-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 CHCl; (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 (SiOy) 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. 'H NMR (300 MHz, CD30D): & 7.45-7.48 (m, 2H), 7.06-7.24 (m, 5H), 4.44 (m, 1H), 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: CoaH27F3N204S: m/z 497 (M+1)

Route 2

OCF3

Leen tt

HO CI NH

/

2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyi}-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, CD;0D): & 7.80-7.83 (m, 1H), 6.95 (bs, 2H), 3.92 (s, 3H), 3.78 (s, 2H), 3.47 (bs, 1H)

LC/MS: C1oHgNO3: m/z 192 (M+1)

B. 5-Methoxyindan-2-ylamine hydrochloride.

Scheme 2. To 5-methoxyindan-1,2-dione-2-oxime (55.7 g; 0.291mol), suspended in glacial acetic acid (0.99 L) is added concentrated H,SO4 (67 mL) followed by 10% Pd-C (27 g) and the reaction is mixed on a Parr apparatus under Hj at 60 psi for 18 h. The reaction is purged with Ny, 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 H,O (500 mL), cooled to 0 °C, and neutralized to pH 10 with 50% aqueous NaOH. The aqueous phase is extracted extensively with CHCIs several times and the extracts are combined, washed with HO, brine, dried over Na,S Oy, filtered and evaporated under reduced pressure to provide 77.3 g (66%) of a crude oil. The oil was subjected to flash chromatography (SiO) eluting with 40 : 2.2: 0.2 CHCl5 :

MeOH : NH4OH to provide 43.8 g (37%) of a dark oil. The oil is dissolved in ether (1L), 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. 'H NMR (300 MHz, CD3OD): & 7.08-7.11 (d, 1H), 6.77 (s, 1H), 6.69-6.72 (d, 1H), 3.78-3.85 (m, 1H), 3.77 (s, 3H), 3.08-3.19 (m, 2H), 2.57-2.68 (m, 2H), 1.51(s, 2H)

LC/MS: C1oHgNO3: m/z 192 (M+1)

M.P. = 240 —- 241°C

C. 2-(5-Methoxyindan-2-yl)isoindole-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 HO, 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 H20, 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. *H NMR (300 MHz, CD30D): § 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, 1H), 3.79 (s, 3H), 3.48-3.65 (m, 2H), 3.07-3.18 (m, 2H)

LC/MS: C1gH1sNO3: m/z 294 (M+1)

D. 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 CH,Cl, (350 mL) and cooled to -60 °C, is added a 1.0 M solution of boron tribromide-CH,Cl; (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 NaHCOs (500 mL) and stirred for an additional 0.5 h at RT. The precipitate is filtered, washed with H,O, 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. 'H NMR (300 MHz, DMSO-ds): 5 9.16 (s, 1H), 7.82-7.91 (m, 4 H), 6.98- 7.01 (d, 1H), 6.56-6.62 (m, 2H), 4.91-5.03 (m, 1H), 3.27-3.43 (m, 3H), 2.99-3.10 (m, 2H)

LC/MS: C47H13NO3: m/z 280 (M+1)

F. Dimethyithiocarbamic acid O-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)indan-5-yl] 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 H,O 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. 'H NMR (300 MHz, CDCls): & 7.82-7.87 (m, 2 H), 7.69-7.75 (m, 2 H), 7.17- 7.24 (d, 1H), 6.87-6.93 (m, 2H), 5.13-5.25 (m, 1H), 3.53-3.68 (m, 2H), 3.46 (s, 3H), 3.34 (s, 3H), 3.09-3.23 (m, 2H)

G. Dimethyithiocarbamic acid S-[2-(1,3-dioxo-1.3-dihydroisoindol-2-yl)indan-5-yl] 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 N; stream and the crude residue purified by flash chromatography (SiO) 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-yl] ester as an off-white solid. 'H NMR (300 MHz, CDCl3): 6 7.81-7.87 (m, 2H), 7.69-7.74 (m, 2 H), 7.22- 7.36 (m, 3H), 5.10-5.22 (m, 1H), 3.59-3.67 (m, 2H), 3.06-3.23 (m, 9H)

LC/MS: CzoH1sN203S: m/z 367 (M+1)

H. Dimethyithiocarbamic acid S-(2-aminocindan-5-yi) 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 dimethyithiocarbamic acid S-[2- aminoindan-5-yl) ester as a brown oil. "H NMR (300 MHz, CDCl3): § 7.15-7.33 (m, 3H), 3.80-3.88 (m, 1 H), 3.05- 3.22 (m, 8H), 2.64-2.72 (m, 1H), 2.17 (bs, 2H)

LC/MS: C12H1eN20S: 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 (110 mL) at RT. The solution is stirred at refiux 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 H,O and EtOAc. The aqueous phase is extracted with EtOAc and the combined organic extracts were washed with HO, brine, dried over Na>SQy,, 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: C47H25NO,S: 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 CH,Cl, (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

CHCl, washed with H;0, dried over Na,SO4 and evaporated under reduced pressure. The crude oil was purified by flash chromatography (SiO) eluting with a hexanes-EtOAc gradient to afford 11.7 g (71%) of 2-(2-acetylaminoindan-5- yisulfanyl)-2-methylpropionic acid tert-butyl ester as a beige solid. 'H NMR (300 MHz, CDCl3): 8 7.31-7.35 (m, 2 H), 7.15-7.18 (d, 1 H), 5.73 (m, 1H), 4.68-4.78 (m, 1H), 3.25-3.39 (dd, 2H), 2.74-2.80 (d, 2H), 1.94 (s, 3H), 1.43 (s, 15H)

LC/MS: C19H27NO3S: m/z 294 (M+1)

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

Scheme 3. To a solution of 2-(2-acetylaminoindan-5-ylsulfanyi)-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: C1gH29NO2,S BH3: m/z 336 ((M+BH3)+1)

L. 2-{2-[1-Ethvyi-3-(4-trifluoromethoxyphenyl)ureidolindan-5-ylsulfanyi}-2- methylpropionic acid tert butyl ester.

Scheme 4. To a mixture of 2-(2-ethylaminoindan-5-yisulfanyl)-2- methylpropionic acid tert-butyl ester and borane complex (11.0 g; 33 mmol), dissolved in CH,Cl, (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 (SiO.) eluting with a hexanes-EtOAc gradient to afford 11.2 g (62%) of 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureidolindan-5- vyisulfanyl}-2-methylpropionic acid tert butyl ester as a white foam. 'H NMR (300 MHz, CDCls): 8 7.30-7.36 (m, 4H), 7.10-7.19 (m, 3H), 6.31 (s, 1H), 4.97-5.08 (m, 1H), 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: Cz7H33F3N204S: m/z 483 ((M-C4Hg)+1)

M. 2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureidolindan-5-ylsulfanyl}-2- methylpropionic acid.

Scheme 4. To 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyljureidojindan-5- ylsulfanyl}-2-methylpropionic acid tert butyl ester (4.8 g; 8.91 mmol) dissolved in

CHCl; (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 (SiO) 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.

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

LC/MS: Co3HasF3N204S: 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-Ethyi-3-(4-trifluoromethoxyphenyl)ureidolindan-5-yisulfanyl}-2- methylpropionic acid.

Compound 2.1 (Example 3)

OCF; = .

HO Co- NH

N

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: CasH2sF3N204S: m/z 483 (M+1) 2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid.

Compound 2.2 (Example 4)

SCF, : LO

RCD

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.

HNMR (CD3OD); 6 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: C23H2sF 3N203S,: m/z 499 (M+1) 2-Methyl-2-{2-[1-pentyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5- yisulfanyl}propionic acid

Compound 2.3 (Example 5) . SCF

Leen dE

HO CD NH

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.

H NMR (CD3OD); 8 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, 1H), 7.15-7.18 (m, 1H), 7.33- 7.35 (m, 2H), 7.33-7.35 (m, 1H), 7.40 (s, 1H), 7.50-7.57 (m, 4H)

LC/MS: Ca6H31F3N203S,: m/z 541 (M+1) 2-{2-[1-Ethyl-3-(4isopropylphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid

Compound 2.4 (Example 6)

et E

HO Co NH )

Compound 2.4 (0.18 g; 34% for 2 steps; white solid) was prepared following

Route 2 by replacing 4-trifluoromethoxyphenyl isocyanate with 4-isopropylphenyl isocyanate. 'H NMR (CD3OD); § 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, 1H), 7.14-7.17 (m, 3H), 7.23- 7.26 (m, 2H), 7.32-7.50 (m, 2H), 7.40 (s, 1H)

LC/MS: CsH32N205S: m/z 441 (M+1) 2-{2-[3-(4-Dimethylaminophenyl)-1-ethylureido]indan-5-ylsulfanyl}-2- methylpropionic acid

Compound 2.5 (Example 7)

Ne

Leon tt

HO CI NH

/

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. 'H NMR (CD30D); § 1.15-1.20 (t, 3H), 1.42 (s, 6H), 2.88 (s, 1H), 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: C24H31N303S: 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)

OCF;

Sas &

HO TD- INH

N

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

Route 2 by replacing acetyl chloride with valeryl chloride. } 'H NMR (CD30D); § 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, 1H), 7.14-7.17 (m, 3H), 7.32- 7.34 (m, 1H), 7.40-7.45 (m, 3H)

LC/MS: CogH3z1F3N204S: m/z 525 (M+1) 2-{2-[3-(4-Dimethylaminophenyl)-1-pentylureido]indan-5-ylsulfanyl}-2- methylpropionic acid

Compound 2.7 (Example 9) \

N—

A 2

HO TD- NH

N

:

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. 'H NMR (CD30D); § 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: Co7Ha7N303S: m/z 484 (M+1)

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

Compound 2.8 (Example 10)

HO TD- PH

N

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. C7

LC/MS: CogH3gN-0O3S: m/z 483 (M+1) 2-{2-[3-(4-tert-butylphenyl)-1-(3-pentyl)ureidojindan-5-yisulfanyl}-2- methylpropionic acid

Compound 2.9 (Example 11)

Xe ie $ NH

Compound 2.9 (4 mg; 9% for 2 steps; white solid) was prepared following Route 1s 2 and compound 2.3 by replacing 4-trifluorothiophenyl isocyanate with 4-tert- butylphenyl isocyanate.

LC/MS: Ca9H4oN203S: m/z 497 (M+1) 2-[2-(3-(Biphenyl-4-yl-1-pentylureido)indan-5-ylsulfanyl]-2-methylpropionic acid

Compound 2.10 (Example 12)

Aer

S

HO TO NH

N

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: C31H36N203S: m/z 517 (M+1) 2-{2-[3-(4-Isopropylphenyl)-1-(3-hexyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid

Compound 2.11 (Example 13)

Xe &

S NH

HO TI

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: CogH4oN-O3S: 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)

OCF; er &

HO “To- P—NH

N

Compound 2.12 (18 mg; 54% for 2 steps; white solid) was prepared following

Route 2 by replacing valeryl chloride with caproy! chloride. :

LC/MS: Co7H33F3N204S: m/z 539 (M+1) 2-Methyl-2-{2-[1-hexyl-3-(4-trifluoromethylsulfanylphenyl)ureidojindan-5- yisulfanyl}propionic acid

Compound 2.13 (Example 15)

SCF; -~ .

S NH

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: Co7H33F3N>03S0): m/z 555 (M+1) 2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureidojindan-5- ylsulfanyl}propionic acid

Compound 2.14 (Example 16)

OCF;

Ae §

S NH

Compound 2.14 (1.2 mg; 3% for 2 steps; oil) was prepared following Route 2 by replacing acetyl chloride with propiony! chloride.

LC/MS: Co4Ho7F3N204S: m/z 497 (M+1) 2-Methyl-2-{2-[1-butyl-3-(4-trifluoromethylsulfanylphenyl)ureidojindan-5- ylsulfanyl}propionic acid

Compound 2.15 (Example 17)

SCF, ; LO

OC

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: CasH2gF3N203S5: m/z 527 (M+1) 2-Methyl-2-{2-[3-(4-trifluoromethoxyphenyl)ureido}indan-5-ylsulfanyl}propionic acid

Compound 2.16 (Example 18)

OCF;

HO TD- NH

NH

Compound 2.16 (11 mg; 49% for 2 steps; oil) was prepared following Route 2 by acylating with 4-trifluoromethoxyphenyl isocyanate.

LC/MS: Co1H21F3N204S: 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)

Pl

OCF3;

Lor &

HO “To- P--NH

N

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

CHCl, washed with HO, brine, dried over Na>SOQ,, 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: CasH2gF3N204S: 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-Methyl-2-{2-[1-(3-methylbutyl)-3-(4-trifluoromethoxyphenyljureido]indan-5- ylsulfanyi}-2-methylpropionic acid

Compound 3.1 (Example 20)

OCF,

Ae >

S. NH

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: CxH31F3N204S: m/z 525 (M+1) 2-{2-[3-(4-Isopropylphenyl)-1-(3-methylbutyl)ureidolindan-5-ylsulfanyl}-2- methylpropionic acid

Compound 3.2 (Example 21) est

HO CD NH

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-isopropylphenyl isocyanate. ' 'H NMR (CD30D); § 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, 1H), 7.10-7.22 (m, 5H), 7.32-7.35 (m, 2H)

LC/MS: CzgH3sN203S: 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- ylsulfanyl}-2-methylpropionic acid

Compound 1.1 (Example 22)

Ae

HO Ss o OCF,

TOT

J

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: CosH31F3aN2-04S: m/z 525 (M+1) 2-{6-[1-Butyl-3-(4-trifluoromethylsuifanylphenyl)ureido]-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyi}-2-methylpropionic acid

Compound 1.2 (Example 23)

Oo

Ss. SCF;

HO o

RQ, OF

J

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: C6H31F3N203S2: m/z 541 (M+1) 2-{6-[1-Hexyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen- 2-ylsuifanyl}-2-methylpropionic acid

Compound 1.3 (Example 24)

[0]

S OCF3

HO [0]

Ee COL

J

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: CogH3s5F3N204S: 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-yisulfanyi}-2- methylpropionic acid

Compound 2.17 (Example 25)

Br, OCF;

Ae &

N . /

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 15g; 0.836 mmol) in THF (1 mL) is added di-tert-butyi 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: Ca3H24BrFaN204S: m/z 563 (M+1) 2-{2-[1-Ethyl-3-(3-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid

Compound 2.18 (Example 26)

OCF;

Ae el

S NH

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-trifluoromethoxyaniline (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-methylpropionic acid tert- butyl ester (0.077 g; 0.22 mmol) in THF (1 mL).

LC/MS: Ca3Has5F3N204S: m/z 483 (M+1) 2-{2-[3-(4-Dimethylaminophenyl)-1-methylureidoljindan-5-ylsulfanyl}-2- methylpropionic acid

Compound 2.19 (Example 27)

Ne

WS

NH sta eos

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

Scheme 6. To dimethyithiocarbamic 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 (SiO,) 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: Cy3H1sN202: m/z 264 (M+1)

B. 2-Methyl-2-(2-methylaminoindan-5-ylsulfanyl)-propionic acid tert-butyl ester.

Scheme 6. To dimethylthiocarbamic acid S-(2-formylaminoindan-5- yhester (0.772 g; 2.9 mmol) in THF (9 mL) under N; 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 H,0, and the solvent removed under reduced pressure. The residue is dissolved in MeOH

Claims (51)

1. A compound of Formula R7 Rs a ®) X—w— N Hox lo R, S Ri Ro Rs n Formula or a pharmaceutically acceptable salt, C 1.5 ester or C 1. amide thereof, wherein each of Ry and R; is independently H, C 1.5 alkyl, (CH2)nNRaRb, (CH2)mORs, (CH2)mNH(CO)Rg, or (CH2)mCO2Rg, where each of Ra, Ry, and Rgis independently H or C 1 alkyl, or Ry and R; taken together with the carbon atom to which they are attached are a C 3.7 cycloalkyl; m is between 1 and 6; nis 1or2; Xis 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; Rs is H, phenyl, C 1.3 alkoxy, C 1.3 alkylthio, halo, cyano, C 1. alkyl, nitro, NRgR19, NHCOR 9, CONHR4p; and COOR 1p; and Rj is ortho or meta to X; Rs is Hor -(C 1.5 alkylene)R1s, where Ris is H, Ci.7 alkyl, [di(C 1-2 . 25 alkyl)amino](C 1.6 alkylene), (C 1.3 alkoxyacyl)(C 1s alkylene), C 1.5 alkoxy, C 37 alkenyl, or C 3.3 alkynyl, wherein R4 has no more than 9 carbon atoms; Rs can also be -(C 15 alkylene)R1s wherein Ris 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-CH>, and O; each of Rs and Ry is independently selected from H, C 1.¢ alkyl, halo, cyano, nitro, COR44, COOR14, C 14 alkoxy, C 1.4 alkylthio, hydroxy, phenyl, NRy1R12 and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S; Re is selected from C 15 alkyl, halo, cyano, nitro, COR{3, COOR13, C 14 alkoxy, C 1.4 alkylthio, hydroxy, phenyl, NR13R14 and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S; in addition, either Rs and Rg or Rg and R; may be taken together to be a bivalent moiety, saturated or unsaturated, selected from —(CHz)3—, -(CH2)4-, and (CH1.2)pN(CH1.2)q, pis 0-2 and q is 1-3, where the sum (p + q) is at least 2; each of Rg and Ry is independently C 1.5 alkyl; each of R11, R12, R13 and Ry4 is independently H or C 1 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 Ry and R; is methyl or ethyl.

3. A compound of claim 2, wherein each of Ry and R; is methyl.

4. A compound of claim 1, wherein Ry and R; taken together are cyclobutyl or - cyclopentyl.

’ 5. A compound of claim 1, wherein Rj is H.

6. A compound of claim 1, wherein Rs is C 1.3 alkoxy, C 1.3 alkylthio, halo, cyano, C 16 alkyl, nitro, NRgR19, NHCOR 9, CONHR 1g; or COOR yg.

7. A compound of claim 1, wherein Rs is H or C 2.7 alkyl. _

:

8. A compound of claim 7, wherein Rs is H or C 2.5 alkyl.

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

10. A compound of claim 8, wherein Ry is H.

11. A compound of claim 1, wherein nis 1.

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

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

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 Rs and Ry; is H.

18. A compound of claim 17, wherein Rg is C 14 alkyl, halomethoxy, } halomethylthio, or di(C 1.3 alkyl)amino. :

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

20. A compound of claim 3, wherein R3is H, Ry is C ».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 Ry is C 2.5 alkyl.

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

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

27. A compound of claim 1, wherein each of Ry and R; is independently H, C 14 alkyl, (CH2)mNRaRg, or (CH2)mORs, where each of Ra, Rp, and Rgis independently H or C 15 alkyl; m is between 1 and 6; nis 1or2; Xis O or S; wherein X is at the 5 or 6 position when nis 1; and wherein X is at the 6 or 7 position when n is 2;

Rais H, phenyl, C 1.3 alkoxy, C 1.3 alkylthio, halo, C 15 alkyl, or } NRgR19, and Rj is ortho or meta to X; : Rs is H or ~(C 1.5 alkylene)R1s, where Rs is H, Cq.7 alkyl, [di(C 12 alkyl)amino}(C 1. alkylene), (C 1.3 alkoxyacyl)(C 1.5 alkylene), C 1.5 alkoxy, or C 3-7 alkenyl, wherein Rs has no more than 9 carbon atoms: R4 can also be -(C 1.5 alkylene)R1s wherein Rs 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 NHCH_; each of Rs and Ry is independently selected from H, C 1 alkyl, halo, COR, COOR14, C 14 alkoxy, C 14 alkylthio, hydroxy, and NR{1R12; Rs is selected from C 1 alkyl, halo, COR13, COORy3, C 14 alkoxy, C 1.4 alkylthio, phenyl, NR13R14 and 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S; each of Rg and Ryo is independently C 15 alkyl; each of R11, R12, Riz and Rus is independently H or C 1. 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-yisulfanyl}-2-methylpropionic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureidolindan-5-yisulfanyl}-2- methylpropionic acid;

2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureidolindan-5-ylsulfanyl}-2- } methylpropionic acid; 2-Methyl-2-{2-[1-pentyl-3-(4-trifluoromethylsulfanylphenyl)ureido)indan-5- . ylsulfanyl}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-Dimethylaminophenyl)-1-ethylureidolindan-5-yisulfanyl}-2- methylpropionic acid; 2-Methyl-2-{2-[1-(3-methylbutyl)-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}-2-methylpropionic acid; 2-{2-[3-(4-Isopropylphenyl)-1-(3-methylbutyl )ureido]indan-5-ylsulfanyl}-2- methylpropionic acid; 2-Methy-2-{2-[1-pent-4-enyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5- ylsulfanyl}propionic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyi}-2-methylpropionic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-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- tetrahydronaphthalen-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-trifluoromethylsulfanylphenyl)ureidolindan-5- ylsulfanyl}propionic acid ; 2-{2-[3-(4-Dimethylaminophenyl)-1-pentylureido)indan-5-yisulfanyi}-2- methylpropionic acid; 2-Methyl-2-{2-[3-(4-trifluoromethoxyphenyl)ureidolindan-5-ylsulfanyl}propionic acid; 2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureidojindan-5- ylsulfanyl}propionic acid; 2-Methyl-2-{2-[1-butyl-3-(4-trifluoromethylsulfanylphenyl)ureidojindan-5- vylsulfanyl}propionic acid; 2-{2-[3-(4-1sopropylphenyl)-1-(3-pentyl)ureidolindan-5-yisulfanyl}-2- methylpropionic acid; 2-{2-[3~(4-tert-Butylphenyl}-1-(3-pentyl )ureidolindan-5-ylsulfanyl}-2- methylpropionic acid; 2-[2-(3-(Biphenyl-4-yl-1-pentylureido)indan-5-ylsulfanyl]-2-methylpropionic acid, 2-{2-[3~(4-1sopropylphenyl)-1-(3-hexyl)ureido]indan-5-ylsulfanyl}-2- methylpropionic acid; 2-Methyl-2-{2-[1-butyl-3-(4-trifluoromethoxyphenyl)ureidolindan-5- ylsulfanyl}propionic 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-ylsulfanyl}-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- tetrahydronaphthalen-2-yisulfanyl}-2-methylpropionic acid; and

- 2-Methyl-2-{2-[1 -hexyl-3-(4-trifluoromethoxyphenyt)ureidolindan-5- yisulfanyl}propionic acid.

30. 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-{6-[3~(4-Trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyl}-2-methylpropionic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureidojindan-5-ylsulfany}-2- methylpropionic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-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-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureidolindan-5-ylsulfanyl}-2- methylpropionic acid; and 2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureidojindan-5- ylsulfanyl}propionic acid.

31. A compound of claim 1, selected from: 2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureidolindan-5-ylsulfanyl}-2- methylpropionic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyljureidojindan-5-ylsulfanyl}-2- methylpropionic acid; 2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureidolindan-5- ylsulfanyl}propionic acid; and 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido}-3-fluoro-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid.

111 PCT/US2003/033090

32. A pharmaceutical composition, comprising a compound of claims 1, 20, 27, 28, 30, or31.

33. Use of a compound of claim 1, 20, 27, 28 or 31 in the manufacture of a medicament for treating or inhibiting the progression of a PPAR-alpha mediated disease in a patient.

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

35. Use of claim 34, whercin said disease is dyslipidemia.

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

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

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

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

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

41. A substance or composition for use in a method of treatment of claim 40, wherein said PPAR-alpha mediated disease is selected from dyslipidemia and cardiovascular diseases.

112 PCT/US2003/033090

42. A substance or composition for use in a method of treatment of claim 41, wherein said disease is dyslipidemia.

43. A substance or composition for use in a method of treatment of claim 41, wherein said dyslipidemia is selected from phase I hyperlipidemia, pre-clinical hyperlipidemia, phase II hyperlipidemia, hypercholesteremia, hypo-HDL- cholesterolemia, and hypertriglyceridemia.

44. A substance or composition for use in a method of treatment of claim 41, wherein said cardiovascular disease is atherosclerosis, coronary artery disease, coronary heart disease, or hypertension.

45. A substance or composition for use in a method of treatment of claim 40, 42 or 43, further comprising administering to the patient a jointly-effective amount of a lipid- lowering agent.

46. A substance or composition for use in a method of treatment of claim 40, 42, 43 or 45, further comprising administering to the patient a jointly-effective amount of a blood-pressure lowering agent.

47. A compound according to any one of claims 1 to 31, substantially as herein described and illustrated.

48. A composition according to claim 32, substantially as hercin described and illustrated.

49. Use according to any one of claims 33 to 39, substantially as herein described and illustrated.

50. A substance or composition for use in a method of treatment according to any one of claims 40 to 46, substantially as herein described and illustrated.

113 PCT/US2003/033090

51. A new compound, a new composition, a new use of a compound as claimed in any one of claims 1 to 31, or a substance or composition for a new use in a method of treatment, substantially as herein described.