HRP20050335A2 - Substituted tetralins and indanes - Google Patents

Abstract

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

Description

Reviews of related applications

This application is a non-provisional U.S. patent application. provisional patent application no. 60/419,935 filed Oct. 21, 2002 and U.S. Pat. provisional patent application no. 60/495,270 filed Aug. 15, 2003 entitled “SUBSTITUTED TETRALINES AND INDANES”.

The field of invention

The invention provides substituted derivatives of tetralin and indan, preparations containing them and methods of their use.

Background

A member of the nuclear receptor family of ligand-activated transcription factors, peroxisome proliferator-activated receptor alpha (PPAR alpha) is an essential transcription factor that regulates genes related to fatty acid metabolism and insulin action.

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

Examples of known PPAR alpha agonists that can be used variously 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).

Abstract

The invention provides compounds of formula (I) below:

[image]

or a pharmaceutically acceptable salt, C1-6 ester or C1-6 amide thereof, wherein

each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8, or (CH2)mCO2R8, wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl, or R1 and R2 taken together with the carbon atom to which they are attached form C3-7cycloalkyl;

m is between 1 and 6;

n is 1 or 2;

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

R 3 is H, phenyl, C 1-3 alkoxy, C 1-3 alkylthio, halo, cyano, C 1-6 alkyl, nitro, NR 9 R 10 , NHCOR 10 , CONHR 10 ; and COOR10; and R 3 is ortho or meta to X;

R4 is H or -(C1-5alkylene)R15, wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene), (C1-3 alkoxyacyl) (C1-6alkylene), C1- 6-Alkoxy, C3-7alkenyl or C3-8alkynyl, wherein R4 has no more than 9 carbon atoms; R4 can also be -(C1-5alkylene)R15 where R15 is C3-6cycloalkyl, phenyl, phenyl-O-, phenyl-S-, or 5-6-membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

Y is NH, NH-CH2 or O;

each R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR, COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 , and 5-6-membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 and 5-6-membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

additionally, either R5 and R6 or R6 and R7 may be taken together and be a divalent group, saturated or unsaturated, selected from -(CH2)3-, -(CH2)4-, and (CH1-2)pN(CH1-2 )q,

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

each of R 9 and R 10 is independently C 1-6 alkyl;

each of R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl;

wherein each of the above hydrocarbyl and heterocarbyl groups 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 provides compositions that include one or more compounds of formula (I) and a pharmaceutical carrier or excipient.

These compositions and 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 PPAR alpha mediated diseases. Examples of PPAR alpha mediated diseases include dyslipidemia and atherosclerosis.

Dyslipidemia includes hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL-cholesterolemia. For example, dyslipidemia can 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. Concepts

The following terms are defined below and by their application in this filing.

“Alkyl” includes optionally substituted straight or branched chain hydrocarbons with at least one hydrogen removed to form a radical. 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 or branched chain hydrocarbon radicals as above with at least one carbon-carbon (sp2) double bond. Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyl, pentenyl, 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 here as alkynyls.

Alkenyl includes cycloalkenyl. Included in the invention are cis and trans or (E) and (Z) forms.

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

"Alkoxy" an optionally substituted straight or branched chain 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, with replacement of the terminal oxygen atom from the 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 forth, each of which may be substituted. Aryl also includes arylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Aryl includes a ring system containing a 6-membered carbocyclic aromatic ring, said system may be bicyclic, bridged, and/or fused. The system may include rings that are aromatic, or partially or fully 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 non-aromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom group (SO2, CO, CONH, COO) in the ring. Unless otherwise stated, the heterocyclic radical may have a valence that binds it to the rest of the molecule via a carbon atom, such as 3-furyl or 2-imidazolyl, or via a heteroatom, such as N-piperidyl or 1-pyrazolyl. Advantageously, the monocyclic heterocyclyl has between 5 and 7 ring atoms, or between 5 and 6 ring atoms; may be between 1 and 5 heteroatoms or heteroatom groups in the ring, and preferably between 1 and 3, or between 1 and 2. Heterocyclyl may be saturated, unsaturated, aromatic (eg, heteroaryl), non-aromatic, or fused.

Heterocyclyl also includes fused, eg, bicyclic, rings, such as those optionally fused 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 fused to an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring. Said heterocyclic five- or six-membered aromatic ring may contain 1, 2 or 3 nitrogen atoms when it is a six-membered ring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur when it is a five-membered ring.

Examples of heterocyclyl include thiazolyl, 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 group attached either to a hydrogen atom (ie, 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 the alkyl group, with one or more halo atoms, such as trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethoxy, or fluoromethylthio.

"Alkanediyl" or "alkylene" represents optionally substituted divalent straight or branched chain alkane radicals such as, for example, methylene, ethylene, propylene, butylene, pentylene or hexylene.

"Alkenedyl" represents, analogously to the above, possibly substituted divalent straight- or branched-chain alkene radicals such as, for example, propenylene, butenylene, pentenylene or hexenylene. In such radicals, it is preferable that the carbon atom connecting the nitrogen is not saturated.

"Aroyl" refers to a carbonyl group attached to an optionally substituted aryl or heteroaryl group, wherein aryl and heteroaryl are as defined 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 5- to 6-membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic. Said rings may be as defined in the summary of the invention section. Certain 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 that are within an acceptable benefit/risk ratio, pharmacologically effective, and suitable for contact with patient tissues without undue toxicity, irritation, or allergic response. These salts, esters and amides can be, for example, C1-8alkyl, C3-8cycloalkyl, aryl,

C2-10 heteroaryl, or C2-10 non-aromatic heterocyclic salts, esters, and amides. Salts, free acids, and esters are more favorable than amides on the terminal part of the carboxylate/

carboxylic acid groups to the left in 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, lacthiobionate, and lauryl sulfonate. These may include alkali and alkaline earth metal cations such as sodium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See for 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 amides derived from ammonia, primary C 1-6 alkyl amines and secondary di(C 1-6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring groups containing at least one nitrogen atom and possibly between 1 and 2 additional heteroatoms. Favorable amides are obtained from ammonia, C1-3 alkyl primary amines, and di(C1-2 alkyl)amines.

Representative pharmaceutically acceptable esters of the invention include C1-7alkyl, C5-7cycloalkyl, phenyl and phenyl(C1-6)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) for observation, experimentation, treatment or prevention of a particular disease or condition. Advantageously, the patient or subject is a human being.

"Preparation" includes a product containing specified ingredients in specified quantities as well as any product resulting from a combination of specified ingredients in specified quantities.

"Therapeutically effective amount or "effective amount" means that amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, animal or human system that is sought by an investigator, veterinarian, physician or other clinician, which includes alleviating the symptoms of a condition or disorder being heals.

Regarding the various radicals in this disclosure and in the claims, three general remarks are made. The first remark refers to valence. As with all hydrocarbon radicals, whether saturated, unsaturated or aromatic, and whether or not they are 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 request. The context will indicate whether 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 that connects two parts of the molecule is Y in formula (I) that connects phenyl substituted with R5, R6 and R7 to the rest of the molecule.

Second, radicals or structural fragments as defined herein are understood to include substituted radicals or structural 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 multivalent) radicals such as alkylene, alkenylene, phenylene, and so forth. Heterocarbyls include monovalent and divalent (or multivalent) radicals containing carbon, possibly hydrogen, and at least one heteroatom. Examples of monovalent heterocarbyls include acyl, acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl, and the like. Taking "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. Substituents can 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.

The di(C1-6 alkyl)amino group includes independently selected alkyl groups, to form, for example, methylpropylamino and isopropylmethylamino, in addition to dialkylamino groups having two of the same alkyl group such as dimethylamino or diethylamino.

Third, only stable compounds are taken. For example, where there is an NR 11 R 12 group, and R may 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- may be unsaturated, suitable hydrogen atom(s) are included or omitted, as shown in -(CH2)-N=(CH )-(CH2)- or -(CH2)-NH-(CH)=(CH)-.

The compounds of the invention are further described in the following section.

B. Compounds

The present invention provides compositions containing and methods of using the compounds of formula (I) as described in the Summary section above.

Examples include those compounds where:

(a) one of R1 and R2 is methyl or ethyl; (b) wherein each of R 1 and R 2 is methyl; (c) R 1 and R 2 taken together form cyclobutyl or cyclopentyl; (d) R 3 is H; (e) R 4 is H or C 2-7 alkyl; (e) R 4 is H or C 2-5 alkyl; (f) R 4 is ethyl; (g) R 4 is H; (h) n is 1; (i) n is 2; (j) Y is NHCH 2 ; (k) Y is NH; (l) X is S; (m) X is O; (n) at least one of R5 and R7 is H; (o) R 6 is C 1-4 alkyl, halomethoxy, or halothiomethoxy; (p) R 6 is t-butyl, isopropyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethoxy, difluoromethoxy, or dimethylamino; (q) R 3 is H, R 4 is C 2-7 alkyl, and Y is NH; (r) R 4 is C 2-5 alkyl; (s) R 6 is cyclopropylmethyl, isopropyl, isobutyl, methylethylamino, or diethylamino; (t) (S) enantiomer at C-2 position on indane or tetralin; (u) (R) enantiomer at C-2 position on indane or tetralin; (v) where R 15 is C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene), (C 1-3 alkoxyacyl) (C 1-6 alkylene), C 1-6 alkoxy, C 3-7 alkenyl, or C 3-8 alkynyl ; (w) R 6 is trifluoromethylthio or trifluoromethoxy; or (x) combinations of the above.

Additional beneficial compounds include the following:

[image]

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

[image]

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

[image]

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

[image]

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

[image]

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

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

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

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

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

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

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

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

The most favorable compounds are chosen from the following:

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

2-{6-[3-(4-trifluoromethoxyphenyl)ureido-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid;

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

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

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

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

Related compounds

The invention provides the listed and related compounds, pharmaceutically acceptable forms of the listed compounds, such as their salts, esters, amides, acids, hydrated or solvated forms; masked or protected forms; and racemic mixtures, or enantiomeric or optically pure forms. Related compounds also include compounds of the invention that have been modified to be detectable, eg isotopically labeled with 18F for use as probes in positron emission tomography (PET) or single photon emission computed tomography (SPECT).

The invention also encompasses the disclosed compounds having one or more functional groups (eg, hydroxyl, amino, or carboxyl) masked by a protecting group. See, eg, Greene and Wuts, Protective Groups in Organic Synthesis,3. edition, (1999) John Wiley & Sons, NY. Some of these masked or protected compounds are pharmaceutically acceptable; the rest will be useful as intermediaries. The 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, substituted benzyl ethers, and silyl ethers.

Substituted methyl ethers

Examples of substituted methyl ethers include methoxymethyl, 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-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, diphenylmethyl.

Esther

In addition to ethers, the hydroxyl group can 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 protecting groups.

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

Carbamates

Exemplary 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 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-dioxane and 5-methylene-1,3-dioxane.

PROTECTION FOR THE CARBOXYLIC GROUP

Esther

Substituted Methyl Esters

Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, α-methylphenacyl, and p-methoxyphenacyl. Examples of esters also include straight or branched chain 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.

Silil Esther

Examples of silyl esters include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl and di-t-butylmethylsilyl.

C. Synthesis procedures

The invention provides procedures for the preparation of the listed compounds according to traditional organic synthesis procedures as well as basic or combinatorial synthesis procedures. Schemes 1 to 10 describe the proposed synthetic routes. Using these schemes, the guidelines below and the examples, one skilled in the art can develop analogous or similar procedures for a given compound that are within the scope of the invention.

A person skilled in the art will recognize that the synthesis of the compounds of the proposed invention can be accomplished by purchasing the intermediate or protected intermediate compounds described in any of the schemes presented herein. One skilled in the art will further recognize that during any of the processes for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any contemplated molecule. This can be accomplished using conventional protecting groups, such as those described in "Protective Groups in Organic Synthesis", John Wiley & Sons, 1991. These protecting groups can be removed at a suitable stage by methods known in the art.

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

General guidelines

A convenient synthesis of formula 14, when X is S (and R 3 is H) is shown in Schemes 1-5.

Abbreviations or acronyms as 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

[image]

According to Scheme 1, tetralins can be made by converting compound 1 to compound 2. For example, methoxy-2-tetralone, such as 6-methoxy-2-tetralone, can be treated with a reagent such as ammonium acetate or ammonia, or hydroxylamine . 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 catalytically reduced with palladium or platinum in a polar protic solvent, such as methanol, ethanol, or ethyl acetate, as a racemic compound 2 would be obtained. A person skilled in the art can easily prepare the hydrochloride salt.

Scheme 2

[image]

According to Scheme 2, indanes can be prepared by converting compound 3 to 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, gives keto-oxime 4. Reduction of compound 4 can be achieved using suitable reducing agents, such as lithium aluminum hydride or hydrogen, and a catalyst , such as palladium or platinum, in a suitable solvent, such as acetic acid-sulfuric acid, THF, or methanol at a suitable temperature. A person skilled in the art can easily select a process for forming the salt.

Scheme 3

[image]

According to Scheme 3, compound 2 or 5 can be converted to compound 12. For example, when the 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 further reacted with an anhydride, such as phthalic anhydride at elevated temperatures, the cyclic imide 6 can be obtained. Cleavage of the methyl aryl ether of formula 6 to the compound of formula 7 can be achieved using a Lewis acid such as boron tribromide, boron trichloride, aluminum chloride or trimethylsilyl iodide in nonpolar, aprotic solvents such as toluene, dichloromethane, or dichloroethane with or without cooling. Acylation of a phenol of formula 7 to a compound of formula 8 can be accomplished using a thiocarbamoyl chloride, such as dimethylaminothiocarbamoyl chloride or diethylthiocarbamoyl chloride, and an unreactive, 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 thermally rearranged into compounds of formula 9 at temperatures between 180°C to 350°C, either neat as a melt or using a high-boiling solvent such as DOWTHERM ® A (a mixture of biphenyl and biphenyl ether solids from, 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 treatment with a suitable nucleophile, such as hydrazine, disodium sulphide or methylamine in a suitable polar solvent such as ethanol or THF at elevated temperatures. Conversion of formula 10 to compounds of formula 11 can be accomplished using an appropriate reagent, such as potassium hydroxide in an alcoholic solvent, such as ethanol or methanol, or lithium aluminum hydride in THF or ether, followed by alkylation with an appropriately substituted alkyl halide, such as which is 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 give compounds of formula 12 using a carboxylic acid or acid chloride and a suitable reducing agent such as borane-THF or borane-dimethylsulfide, using aprotic solvents such as THF, dichloromethane, or hexane. 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

[image]

According to Scheme 4, compounds of formula 13 can be prepared from compounds of formula 12 by acylation of the secondary amine with aryl acetic acid, using neat thionyl chloride or oxalyl chloride in either toluene or dichloromethane with or without a catalytic amount of DMF. Alternatively, ligation can be accomplished using standard peptide conditions, such as EDC, DCC, or DIC in dichloromethane. When Y = NH or O, the aryl isocyanate or aryl chloroformate can be changed, respectively, in a non-polar aprotic solvent, such as THF, dichloromethane or hexane, to obtain compounds of formula 13. A person skilled in the art can easily choose a deprotection procedure to give compounds of formula 14.

Scheme 5

[image]

Likewise, compounds of formula 16 can be prepared from compounds of formula 11 by acylation of the primary amine as shown in Scheme 5 to give compounds 15. One skilled in the art can easily choose a deprotection procedure to give compounds of formula 16.

Scheme 6

[image]

A compound of formula 18 can be prepared from a compound of formula 10 as shown in Scheme 6. For example, a 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 give 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 an appropriate solvent such as THF or ether followed by alkylation with 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

[image]

A convenient synthesis of formula 21, when X is O (and R3 is H) is shown in Scheme 7. For example, when compounds of formula 2 or 5 are acylated with a carboxylic acid or acid chloride as described above, compounds of formula 19 are prepared. aryl ether of formula 19 to a compound of formula 20 can be achieved using a Lewis acid such as boron tribromide, boron trichloride, aluminum chloride, or trimethylsilyl iodide 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 treatment 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

[image]

Compounds of formula 24 can be prepared from compounds of formula 22 as shown in Scheme 8. For example, a compound of formula 22 can be treated with a suitable base, such as butyllithium or sec-butyllithium in a suitable solvent, such as ether or THF, with or without TMEDA and cooling, and a suitable electrophile, such as alkyl halides, aldehydes, or disulfides to give 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 conversion of compound 8 in compound 9.

Scheme 9

[image]

An alternative synthesis of compounds of formula 32 is shown in Scheme 9. For example, when 4-methylthiophenyl acetic acid of Formula 26 was treated with oxalyl chloride or thionyl chloride in the presence of methanol, compound of formula 27 was obtained. Treatment of compounds of formula 27 with 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, affords tetralones of formula 28. Using the procedure shown in Scheme 1, tetralones of formula 29 can be prepared. Compounds of formula 29 may be substituted to give compounds of formula 30 by means of a carboxylic acid under the above binding conditions 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 be converted to a compound of formula 31 using an oxidizing agent such as mCPBA or hydrogen peroxide in a suitable solvent such as methylene chloride followed by further 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, to give compounds of formula 31. Alternatively, deprotection of the thioether in compounds of formula 30 can be accomplished with 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 chemical reactions analogous to those described in Scheme 3 to convert compound 10 to compound 11, compounds of formula 31 can easily be converted into compounds of formula 32.

Scheme 10

[image]

According to Scheme 10, compounds of formula 22 can be easily converted to compounds of formula 32a, where R 3 = OCH 3 . For example, compounds of formula 22 can be treated with an appropriate base, such as butyllithium or sec-butyllithium in an appropriate solvent, such as ether or THF, with or without TMEDA and cooling, and an appropriate disulfide, such as dimethyl disulfide or dibenzyl disulfide to give compounds of formula 33. Removal of dimethylamino thiocarbamate from compounds of formula 33 was accomplished using potassium or sodium hydroxide in a suitable solvent, such as water, methanol, or ethanol with or without cooling, to give compounds of formula 34. Compounds of formula 34 can be methylated to give compounds of formula 19a using methyl iodide, dimethylsulfate, or diazomethane in a suitable solvent, such as DMF, methanol, or dichloromethane, with or without a base, such as cesium carbonate or potassium carbonate. Using chemical reactions analogous to those described in Scheme 9 to convert compounds of formula 30 to compounds of formula 32, compounds of formula 32a can be readily synthesized from compounds of formula 19a.

Method 1

[image]

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

Compound 1.0 (Example 1)

A. 6-Methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride.

Scheme 1. Ammonium acetate (65 g; 0.84 mol) was added to a solution of 6-methoxy-2-tetralone (10.0 g; 56.7 mmol) dissolved in MeOH (400 mL) and the reaction was stirred for 30 min at RT. Sodium cyanoborohydride (17.8 g; 0.28 mol) was then added to the reaction and the reaction was refluxed for 1-2 h. The reaction was cooled, the solvent was removed under reduced pressure, the residue was diluted with EtOAc, and 1 N NaOH was added to quench the reaction. The aqueous phase was separated and the organic phase washed with H2O, brine, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to give a crude residue which was purified by flash chromatography (SiO2) eluting with CH2Cl2/MeOH:NH4OH (10%) which gave 5.0 g (50%) of 6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine as a dark oil. HCl (g) was bubbled into a solution of the title compound in ether (100 mL) cooled to 0oC until the solution became saturated. The suspension was stirred for an additional 30 min at RT and the solvent was evaporated under reduced pressure. The remaining solid was triturated with ether, filtered, washed with ether and dried under reduced pressure to give 4.9 g of 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride as a white solid.

LC/MS: C11H15NO: 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) was added 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine (30 g; 0.140 mol), in meals at 0oC. The reaction mixture was warmed to RT and stirred for an additional 1 h. Phthalic anhydride (20.7 g; 0.139 mol) was added in 1 portion at RT, after which the reaction mixture was stirred for an additional 1 h, then 18 h at 120oC. The reaction was allowed to cool to RT, diluted with H2O and extracted several times with EtOAc. The combined organic extracts were washed with water, brine, dried over Na 2 SO 4 , and the solvent removed under reduced pressure. The crude solid was triturated with MeOH, filtered, and dried under vacuum to give 29.1 g (67%) of 2-(6-methoxy-1,2,3,4-tetrahydro naphthalen-2-yl)isoindole-1,3- dione as an off-white solid.

1H NMR (300 MHz, CDCl3): δ 7.83-7.86 (m, 2H), 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, 1H), 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: C19H17NO3: m/z 308 (M+1)

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

Scheme 3. In 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)isoindole-1,3-dione (29 g; 94.3 mmol) dissolved in anhydrous CH2Cl2 (500 mL), cooled to -60oC, 1.0 M boron tribromide-CH2Cl2 solution (471 mL) was added dropwise to maintain the reaction temperature between -50 to -60oC. Upon completion of the addition, the reaction mixture was allowed to warm to RT and stirred for an additional 4 h. The reaction was cooled to 0°C, quenched with saturated NaHCO3 (400 mL) and stirred for an additional 0.5 h at RT. The precipitate was filtered off, thoroughly washed with H2O, suspended in ether, filtered and dried under vacuum to give 25.4 g (92%) of 2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)isoindol- 1,3-dione as an off-white solid.

1H NMR (300 MHz, DMSO-d6): δ 9.11 (bs, 1H), 7.82-7.89 (m, 4H), 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: C18H15NO3: 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-yl] ester.

Scheme 3. 1 ,4-diazabicyclo[2.2.2]octane (48.5 g; 4.32 mol) then dimethylaminothiocarbamoyl chloride (53.4 g; 4.32 mol) and the solution was stirred at RT for 4 h. The reaction was poured over ice water (1 L) and stirred for 18 h. The precipitate was filtered, washed with H2O and dried under vacuum. The crude solid was purified by flash chromatography (SiO2) eluting with a hexane-EtOAc gradient to give 30 g (91%) of O-[6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5 ,6,7,8-tetrahydro-naphthalen-2-yl] dimethyl-thiocarbamic acid ester as a white solid.

1H NMR (300 MHz, CDCl3): δ 7.83-7.86 (m, 2H), 7.70-7.73 (m, 2H), 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: C21H20N2O3S: m/z 381 (M+1)

E. Dimethylthiocarbamic acid S-[6-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]ester.

Scheme 3. O-[6-(1,3-dioxo-1,3-) was added in 1 portion to a 50 mL round-bottom flask equipped with a reflux condenser and a stirring rod, preheated to 330oC in a sand bath. dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl] dimethyl-thiocarbamic acid ester (5.32 g; 13.9 mmol). The melt was stirred for 7-8 min. at 330oC, then it was rapidly cooled to RT with a flow of N2. The crude residue was purified by flash chromatography (SiO2) eluting with a hexane-EtOAc gradient to give 3.1 g (58%) of S-[6-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-5,6 ,7,8-Tetrahydronaphthalen-2-yl]dimethylthiocarbamic acid ester as a white solid.

1H NMR (300 MHz, CDCl3): δ 7.82-7.86 (m, 2H), 7.72-7.75 (m, 2H), 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: C21H20N2O3S: m/z 381 (M+1)

F. Dimethylthiocarbamic acid S-[6-Amino-5,6,7,8-tetrahydronaphthalen-2-yl)ester.

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

LC/MS: C13H18N2OS: m/z 251 (M+1)

G. tert-Butyl ester of 2-(6-amino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropanoic acid.

Scheme 3. To S-[6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)ester of dimethylthiocarbamic acid (6.1 g; 24.4 mmol), dissolved in MeOH (25 mL) was added KOH solution (4.1 g ; 73.2 mmol) in MeOH (25 mL) at RT. The solution was stirred at reflux for 5 h and cooled to RT. tert-Butyl 2-bromoisobutyrate (16.3 g; 73.2 mmol) was added to the solution and the solution was stirred for 16 h at RT. NaBH4 (9.2 g; 2.44 mol) was added and the reaction was stirred for an additional 48 h at RT. The reaction was quenched with H2O, the solvent evaporated under reduced pressure, and the crude residue partitioned between H2O and CH2Cl2. The aqueous phase was extracted with CH2Cl2 and the combined organic extracts dried over Na2SO4, filtered and evaporated under reduced pressure to give 4.7 g (60%) of tert-butyl ester 2-(6-amino-5,6,7,8-tetrahydronaphthalene- 2-ylsulfanyl)-2-methylpropanoic acid as a brown oil.

LC/MS: C181H27NO2S: m/z 266 (M+1)

H. tert-butyl ester of 2-(6-acetylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methyl propanoic acid.

Scheme 3. In 2-(6-amino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropanoic acid tert-butyl ester (4.7 g; 14.6 mmol), dissolved in CH2Cl2 (25 mL), DIEA (3.3 mL; 18.9 mmol) was added and the reaction mixture was cooled to 0°C. Acetyl chloride (1.25 mL; 17.5 mmol) was added dropwise at a rate to maintain the temperature between 0-5°C. The reaction was allowed to warm to RT and stir for 16 h. The reaction was diluted with CH2Cl2, washed with H2O, dried over Na2SO4 and evaporated under reduced pressure. The crude oil was purified by flash chromatography (SiO2) eluting with a gradient of hexane-EtOAc, which gave 1.7 g (32%) of tert-butyl ester 2-(6-acetylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)- 2-methyl propanoic acid as a light brown solid.

1H NMR (300 MHz, CDCl3): δ 7.23-7.26 (m, 2H), 6.99-7.01 (d, 1H), 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 ( with, 15H)

LC/MS: C20H29NO3S: m/z 308 (M+1)

I. tert-Butyl ester of 2-(6-ethylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropanoic acid.

Scheme 3. To a solution of 2-(6-acetylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methyl propanoic acid tert-butyl ester (1.7 g; 4.64 mmol) in THF (42 mL) was added is 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 evaporated under reduced pressure. The remaining oil was further azeotroped with MeOH (3x) to obtain 1.9 g (100%) of a mixture of tert-butyl ester 2-(6-ethylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropane acid and its complex with borane as oil.

LC/MS: C20H31NO2S·BH3: m/z 308 ((M+BH3)+1)

J. tert-Butyl ester of 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropanoic acid.

Scheme 4. Into a mixture of 2-(6-ethylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropanoic acid tert-butyl ester and its complex with borane (1.9 g; 5.2 mmol) dissolved in CH2Cl2 (15 mL) was 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 hexane-EtOAc gradient to give 1.66 g (58%) of tert-butyl ester 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl) )ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropanoic acid as a white foam.

LC/MS: C28H35F3N2O4S: m/z 497 ((M-C4H8)+1)

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

Scheme 4. 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropanoic acid tert-butyl ester (1.66 g ; 3.0 mmol) dissolved in CH2Cl2 (15 mL), TFA (15 mL) was added 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 hexane-EtOAc gradient to give 0.643 g (43%) of 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5 ,6,7,8-tetrahydro naphthalen-2-ylsulfanyl}-2-methylpropanoic 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, 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: C24H27F3N2O4S: m/z 497 (M+1)

Method 2

[image]

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

Compound 2.0 (Example 2)

A. 5-Methoxindan-1,2-dione-2-oxime.

Scheme 2. Solutions of 5-methoxyindan-1-one (75.8 g; 0.467 mol)

in MeOH (1.4 L) at 45oC, butyl nitrite (81 mL; 0.693 mol) was added dropwise over 45 min. Concentrated HCl (45 mL) was 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 was then cooled, the precipitate filtered, washed several times with cold MeOH, and dried under vacuum to give 55.8 g (62%) of 5-methoxyindan-1,2-dione-2-oxime as a beige solid.

1H NMR (300 MHz, CD3OD): δ 7.80-7.83 (m, 1H), 6.95 (bs, 2H), 3.92 (s, 3H), 3.78 (s, 2H), 3.47 (bs, 1H)

LC/MS: C10H9NO3: m/z 192 (M+1)

B. 5-Methoxyindan-2-ylamine hydrochloride.

Scheme 2. To 5-methoxyindane-1,2-dione-2-oxime (55.7 g; 0.291 mol), suspended in glacial acetic acid (0.99 L) was added concentrated H2SO4 (67 mL) and then 10% Pd-C (27 g) and the reaction was stirred on a Parr apparatus under H 2 at 60 psi for 18 h. The reaction was purged with N2, filtered through a pad of celite and washed with AcOH. The solvent was removed under reduced pressure to 1/5 volume and the remaining solvent was diluted with H2O (500 mL), cooled to 0°C, and neutralized to pH 10 with 50% aqueous NaOH. The aqueous phase was extracted extensively with CHCl3 several times and the extracts were combined, washed with H2O, brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give 77.3 g (66%) of crude oil. The oil was subjected to flash chromatography (SiO2) eluting with 40 : 2.2 : 0.2 CHCl3 : MeOH : NH4OH, which yielded 43.8 g (37%) of a dark oil. The oil was dissolved in ether (1 L), cooled to 0°C, and the solution saturated with HCl (g). The solvent was removed under reduced pressure and the solid triturated with ether, filtered, and washed with ether to give 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, 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: C10H9NO3: m/z 192 (M+1)

tt. = 240-241o 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 0o C, 5-methoxyindan-2-ylamine hydrochloride (40.0 g; 0.2 mol) was added and the suspension was stirred for 1 h at CAPE. Phthalic anhydride (30 g; 0.2 mol) was added in one portion and the suspension was stirred for an additional 1-1.5 h at RT followed by stirring at 120° C. for 96 h. The reaction was cooled and diluted with EtOAc. The organic phase was washed with H2O, the resulting precipitate was filtered, washed with EtOAc, MeOH and dried under vacuum to give 25.2 g (43%) of 2-(5-methoxyindan-2-yl)isoindole-1,3-dione as a white solid . The organic phase was washed with H2O, evaporated under reduced pressure and the solid was triturated with MeOH, filtered and dried to give 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, 1H), 3.79 (s, 3H), 3.48-3.65 (m, 2H), 3.07-3.18 (m, 2H)

LC/MS: C18H15NO3: m/z 294 (M+1)

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

Scheme 3. 1.0 M boron tribromide-CH2Cl2 solution was added to 2-(5-methoxyindan-2-yl)isoindole-1,3-dione (19.7 g; 67 mmol) dissolved in anhydrous CH2Cl2 (350 mL) and cooled to 60oC. (340 mL), dropwise at such a rate as to maintain the internal temperature between -50o and -60o C. The reaction mixture was allowed to warm to RT and was stirred for an additional 5 h. The reaction was cooled to 0o C, quenched with saturated NaHCO3 (500 mL) d and stirred for an additional 0.5 h at RT. The precipitate was filtered, washed with H2O, suspended in ether, filtered and dried under vacuum to give 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, 1H), 7.82-7.91 (m, 4H), 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: C17H13NO3: m/z 280 (M+1)

F. Dimethylthiocarbamic acid O-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)indan-5-yl] ester.

Scheme 3. 2-(5-hydroxyindan-2-yl) isoindole-1,3-dione (

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

1H NMR (300 MHz, CDCl3): δ 7.82-7.87 (m, 2H), 7.69-7.75 (m, 2H), 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. Dimethylthiocarbamic acid S-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)indan-5-yl] ester.

Scheme 3. O-[2-(1,3-dioxo-1,3-dihydroisoindole-2- yl)indan-5-yl] dimethylthiocarbamic acid ester (6.30 g; 18.7 mmol) in one portion. The melt was stirred for 12 min. at 338oC, rapidly cooled to RT with a stream of N2 and the crude residue was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to give 3.88 g (61%) of S-[2-(1,3-dioxo-1,3- dihydroisoindol-2-yl)indan-5-yl] dimethylthiocarbamic acid ester as an off-white solid.

1H NMR (300 MHz, CDCl3): δ 7.81-7.87 (m, 2H), 7.69-7.74 (m, 2H), 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: C20H18N2O3S: m/z 367 (M+1)

H. Dimethylthiocarbamic acid S-(2-aminoindan-5-yl) ester.

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

1H NMR (300 MHz, CDCl3): δ 7.15-7.33 (m, 3H), 3.80-3.88 (m, 1H), 3.05-3.22 (m, 8H), 2.64-2.72 (m, 1H), 2.17 (bs, 2H)

LC/MS: C12H16N2OS: m/z 237(M+1)

I. tert-Butyl ester of 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropanoic acid.

Scheme 3. A solution of KOH (11.8 g; 0.210 mol) in MeOH (110 mL) was added to dimethylthiocarbamic acid S-(2-aminoindan-5-yl) ester (4.9 g; 20.9 mmol), dissolved in MeOH (60 mL). CAPE. The solution was stirred at reflux for 5 h and cooled to RT. Tert-butyl 2-bromoisobutyrate (7.0 g; 31.3 mmol) was added to the solution and stirred for 18 h at RT. The solvent was evaporated under reduced pressure and the crude residue was partitioned between H2O and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with H2O, brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give 4.9 g (76%) of 2-(2-aminoindan-5-ylsulfanyl) tert-butyl ester )-2 methylpropane acid as a brown oil.

LC/MS: C17H25NO2S: m/z 308 (M+1)

J. tert-Butyl ester of 2-(2-acetylaminoindan-5-ylsulfanyl)-2-methylpropanoic acid.

Scheme 3. TEA (8.6 mL; 61.7 mmol) was added to 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropanoic acid tert-butyl ester (14.6 g; 47.4 mmol), dissolved in CH2Cl2 (100 mL) and the reaction mixture was cooled to 0oC. Acetyl chloride (4.1 mL; 57.6 mmol) was 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 CH2Cl2, washed with H2O, dried over Na2SO4 and evaporated under reduced pressure. The crude oil was purified by flash chromatography (SiO2) eluting with a hexane-EtOAc gradient to give 11.7 g (71%) of 2-(2-acetylaminoindan-5-ylsulfanyl)-2-methylpropanoic acid tert-butyl ester as a beige solid.

1H NMR (300 MHz, CDCl3): δ 7.31-7.35 (m, 2H), 7.15-7.18 (d, 1H), 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. tert-Butyl ester of 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methylpropanoic acid.

Scheme 3. A 1.0 M borane-THF solution (226 mL) was added to a solution of 2-(2-acetylamino indan-5-ylsulfanyl)-2-methylpropanoic acid tert-butyl ester (11.7 g; 33.5 mmol) in THF (280 mL) ), drop by drop 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 remaining oil was further azeotroped with MeOH (3x), which gave 11 g (100%) of a mixture of tert-butyl ester of 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methylpropane acid and its complex with borane as an oil.

LC/MS: C19H29NO2S BH3: m/z 336 ((M+BH3)+1)

L. tert-Butyl ester of 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl-2-methylpropanoic acid.

Scheme 4. 4-trifluoromethoxyphenyl was added to a mixture of tert-butyl ester of 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methylpropanoic acid and its complex with borane (11.0 g; 33 mmol), dissolved in CH2Cl2 (100 mL). isocyanate (10.2 g; 50.2 mmol) and the reaction was left to stir 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 hexane-EtOAc gradient to give 11.2 g (62%) of tert-butyl ester 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl) ) of ureido]indan-5-ylsulfanyl-2-methylpropane acid as white foam.

1H NMR (300 MHz, CDCl3): δ 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: C27H33F3N2O4S: m/z 483 ((M-C4H8)+1)

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

Scheme 4. Into 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl-2-methylpropanoic acid tert-butyl ester (4.8 g; 8.91 mmol) dissolved in CH2Cl2 (15 mL) ) TFA (15 mL) was added and the reaction was stirred at RT for 2 h. The solvent was removed under reduced pressure and the precipitate was purified by flash chromatography (SiO2) eluting with a hexane-EtOAc gradient to give 3.13 g (73%) of 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indane- 5-ylsulfanyl}-2-methylpropanoic acid as a white solid.

1H NMR (300 MHz, CDCl3): δ 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: C23H25F3N2O4S: m/z 483 (M+1)

T.T. = 73-77oC

The following 14 compounds were prepared by following Schemes 3 and 4 and steps J, K, L, and M of Method 2, substituting reagents and adjusting reaction conditions as necessary:

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

Compound 2.1 (Example 3)

[image]

Intermediate L (11 g) from method 2 was resolved by chiral chromatography (Chiralpak AD column; isocratic gradient with hexane/methanol/ethanol: 92/4/4) to give (S)-intermediate L (4.8 g). Applying step M from method 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-methylpropanoic acid.

Compound 2.2 (Example 4)

[image]

Compound 2.2 (0.33 g; 57% over 2 steps; white solid) was prepared following method 2 by substituting 4-trifluorothiomethoxy isocyanate for 4-trifluoromethoxyphenyl 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-ylsulfanyl}propanoic acid

Compound 2.3 (Example 5)

[image]

Compound 2.3 (0.22 g; 32% over 2 steps; white solid) was prepared following method 2 and Compound 2.2 substituting valeryl chloride for acetyl 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, 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: C26H31F3N2O3S2: m/z 541 (M+1)

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

Compound 2.4 (Example 6)

[image]

Compound 2.4 (0.18 g; 34% over 2 steps; white solid) was prepared following method 2 replacing 4-trifluoromethoxyphenyl isocyanate with 4-isopropylphenyl 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, 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: C25H32N2O3S: m/z 441 (M+1)

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

Compound 2.5 (Example 7)

[image]

Compound 2.5 (0.34 g; 66% over 2 steps; white solid) was prepared following method 2 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, 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: C24H31N3O3S: m/z 442 (M+1)

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

Compound 2.6 (Example 8)

[image]

Compound 2.6 (0.29 g; 77% over 2 steps; white solid) was prepared following method 2 substituting valeryl chloride for acetyl 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, 1H), 7.14-7.17 (m, 3H), 7.32-7.34 (m, 1H), 7.40-7.45 (m, 3H)

LC/MS: C26H31F3N2O4S: m/z 525 (M+1)

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

Compound 2.7 (Example 9)

[image]

Compound 2.7 (0.25 g; 36% over 2 steps; white solid) was prepared following method 2 and compound 2.5 substituting valeryl chloride for acetyl 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-Isopropylphenyl)-1-(3-pentyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid

Compound 2.8 (Example 10)

[image]

Compound 2.8 (5 mg; 14% over 2 steps; white solid) was prepared following method 2 and compound 2.4 substituting valeryl chloride for acetyl chloride.

LC/MS: C28H38N2O3S: m/z 483 (M+1)

2-{2-[3-(4-tert-butylphenyl)-1-(3-pentyl)ureido]indan-5-ylsulfanyl)-2-methylpropanoic acid

Compound 2.9 (Example 11)

[image]

Compound 2.9 (4 mg; 9% over 2 steps; white solid) was prepared following method 2 and compound 2.3 by replacing 4-trifluorothiophenyl isocyanate with 4-tertbutylphenyl isocyanate.

LC/MS: C29H40N2O3S: m/z 497 (M+1)

2-[2-(3-(Biphenyl-4-yl-1-pentylureido)indan-5-ylsulfanyl]-2-methylpropanoic acid

Compound 2.10 (Example 12)

[image]

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

LC/MS: C31H36N2O3S: m/z 517 (M+1)

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

Compound 2.11 (Example 13)

[image]

Compound 2.11 (13 mg; 44% over 2 steps; oil) was prepared following method 2 and compound 2.4 substituting caproyl chloride for valeryl chloride.

LC/MS: C29H40N2O3S: m/z 497 (M+1)

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

Compound 2.12 (Example 14)

[image]

Compound 2.12 (18 mg; 54% over 2 steps; white solid) was prepared following method 2 substituting caproyl chloride for valeryl chloride.

LC/MS: C27H33F3N2O4S: m/z 539 (M+1)

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

Compound 2.13 (Example 15)

[image]

Compound 2.13 (14 mg; 36% over 2 steps; white solid) was prepared following method 2 and Compound 2.2 substituting caproyl chloride for valeryl chloride.

LC/MS: C27H33F3N2O3S2: m/z 555 (M+1)

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

Compound 2.14 (Example 16)

[image]

Compound 2.14 (1.2 mg; 3% over 2 steps; oil) was prepared following method 2 substituting propionyl chloride for acetyl chloride.

LC/MS: C24H27F3N2O4S: m/z 497 (M+1)

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

Compound 2.15 (Example 17)

[image]

Compound 2.15 (11 mg; 32% over 2 steps; oil) was prepared following Method 2 and Compound 2.2 substituting butyryl chloride for acetyl chloride.

LC/MS: C25H29F3N2O3S2: m/z 527 (M+1)

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

Compound 2.16 (Example 18)

[image]

Compound 2.16 (11 mg; 49% over 2 steps; oil) was prepared following method 2 by acylation with 4-trifluoromethoxyphenyl isocyanate.

LC/MS: C21H21F3N2O4S: m/z 455 (M+1)

Method 3

2-Methyl-2-{2-[1-pent-4-enyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propanoic acid

Compound 3.0 (Example 19)

[image]

Pent-4-enal (0.060 mg; 0.72 mmol) was added to 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropanoic acid tert-butyl ester (0.220 g; 0.72 mmol), dissolved in DCE (4 mL). ) then sodium triacetoxyborohydride (0.21 g; 1.0 mmol) and the reaction mixture was stirred for 18 h at RT. The reaction mixture was diluted with CH2Cl2, washed with H2O, brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to give tert-butyl ester 2-methyl-2-(2-pent-4-enylaminoindan-5-ylsulfanyl) propane acid as crude oil.

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

LC/MS: C26H29F3N2O4S: m/z 522 (M+1)

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

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

Compound 3.1 (Example 20)

[image]

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

LC/MS: C26H31F3N2O4S: m/z 525 (M+1)

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

Compound 3.2 (Example 21)

[image]

Compound 3.2 (11 mg; 27% over 3 steps; white solid) was prepared following method 3 and compound 3.1 substituting 4-trifluoromethoxyphenyl isocyanate for 4-isopropylphenyl 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, 1H), 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 by following Schemes 1 and 3 and Steps J and K of Method 1, substituting reagents and adjusting reaction conditions as necessary:

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

Compound 1.1 (Example 22)

[image]

Compound 1.1 (41 mg; 68% over 2 steps; white solid) was prepared following method 1 substituting butyryl chloride for acetyl chloride.

LC/MS: C26H31F3N2O4S: m/z 525 (M+1)

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

Compound 1.2 (Example 23)

[image]

Compound 1.2 (23 mg; 34% over 2 steps; white solid) was prepared following method 1 and compound 1.1 substituting butyryl chloride for acetyl chloride and 4-trifluoromethoxyphenyl isocyanate for 4-trifluorothiophenyl isocyanate.

LC/MS: C26H31F3N2O3S2: m/z 541 (M+1)

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

Compound 1.3 (Example 24)

[image]

Compound 1.3 (36 mg; 57% over 2 steps; white solid) was prepared following method 1 substituting caproyl chloride for acetyl chloride.

LC/MS: C28H35F3N2O4S: m/z 553 (M+1)

The following 2 compounds were prepared by following Schemes 3 and 4 and steps L and M of Method 2, substituting reagents and adjusting reaction conditions as necessary:

2-{2-[3-(3-Bromo-4-trifluoromethoxyphenyl)-1-ethylureido]indan-5-ylsulfanyl}-2-methylpropanoic acid

Compound 2.17 (Example 25)

[image]

Compound 2.17 (0.018 g; 19% over 3 steps; white solid)

was prepared following method 2 with replacement of 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) was added di-tert-butyl dicarbonate (0.255 g; 1.17 mmol) followed by 4-dimethylaminopyridine (0.102 g; 0.835 mmol). After the foaming stopped (30 min.), a solution of 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methylpropanoic acid tert-butyl ester (0.058 g; 0.167 mmol) in THF (1 mL) was added and the reaction mixture was stirred 6 p.m. on RT. Applying steps K and L of Method 2, the title compound was prepared.

LC/MS: C23H24BrF3N2O4S: m/z 563 (M+1)

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

Compound 2.18 (Example 26)

[image]

Compound 2.18 (13 mg; 12% over 3 steps; white solid) was prepared following Example 2.0 substituting 3-trifluoromethoxyphenyl isocyanate for 4-trifluoromethoxyphenyl isocyanate. To a solution of carbonyldiimidazole (0.454 g; 2.8 mmol) in THF (2 mL), heated to 50°C, 3-trifluoromethoxyaniline (0.522 g; 2.94 mmol) was added dropwise. After 15 min. the reaction was cooled and added to a solution of 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methylpropanoic 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-methylpropanoic acid

Compound 2.19 (Example 27)

[image]

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

Scheme 6. Ethyl formate (50 mL) was added to dimethylthiocarbamic acid S-[2-aminoindan-5-yl)ester (2.0 g; 8.46 mmol) in CHCl3 (10 mL) and the reaction was heated at 55oC for 24 h. The reaction was cooled, the solvent was removed under reduced pressure, and the crude oil was purified by flash chromatography (SiO2) eluting with an ethyl acetate-methanol gradient to give 0.77 g (35%) of dimethylthiocarbamine S-(2-formylamino-indan-5-yl)ester. acid as a white solid.

LC/MS: C13H16N2O2: m/z 264 (M+1)

B. tert-Butyl ester of 2-methyl-2-(2-methylaminoindan-5-ylsulfanyl)-propanoic acid.

Scheme 6. To dimethylthiocarbamic acid S-(2-formylamino-indan-5-yl)ester (0.772 g; 2.9 mmol) in THF (9 mL) under N2 was added a solution of 1.0 M lithium aluminum hydride (9 mL) at 0°C. The reaction was warmed to RT then stirred at reflux for 24 h. The reaction was cooled to 0°C, quenched with H2O, and the solvent removed under reduced pressure. The residue was dissolved in MeOH (4 mL), to which were added Cs2CO3 (0.304 g; 0.93 mmol), tert-butyl 2-bromoisobutyrate (0.311 mL; 1.39 mmol), and NaBH4 (2.0 g; 52.8 mmol). The reaction mixture was stirred for 18 h, (??) removed under reduced pressure and the residue partitioned between EtOAc and H2O. The layers were 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 was purified by flash chromatography (SiO2) eluting with a CH2Cl2-MeOH gradient, which gave 0.186 g (20%) of 2-methyl-2-(2-methylaminoindan-5-ylsulfanyl)propanoic acid tert-butyl ester as an oil.

LC/MS: C18H27NO2S: m/z 321 (M+1)

Compound 2.19 (44 mg; 65% over 2 steps; white solid) was prepared following Method 2 and Steps L and M substituting 4-trifluoromethoxyphenyl isocyanate for 4-dimethylaminophenyl isocyanate.

LC/MS: C23H29N3O3S: m/z 428 (M+1)

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

Compound 2.20 (Example 28)

[image]

Compound 2.20 (39 mg; 49% over 2 steps; white solid) was prepared following method 2 by substituting 3-cyclopentylpropionyl chloride for acetyl chloride.

LC/MS: C29H35F3N2O4S: m/z 565 (M+1)

2-[2-(3-Indan-5-yl-1-pentylureido)indan-5-ylsulfanyl}-2-methylpropanoic acid

Compound 2.21 (Example 29)

[image]

Compound 2.21 (9.3 mg; 24% over 2 steps; white solid) was prepared following method 2 and Compound 2.3 substituting valeryl chloride for acetyl chloride and 4-trifluoromethoxyphenyl isocyanate for indanyl isocyanate.

LC/MS: C28H36N2O3S: m/z 481 (M+1)

2-Methyl-2-{2-[3-(4-methyl-3-nitrophenyl)-1-pentylureido]indan-5-ylsulfanyl}propanoic acid

Compound 2.22 (Example 30)

[image]

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

LC/MS: C26H33N3O5S: m/z 500 (M+1)

2-Methyl-2-{2-[1-naphthalen-1-ylmethyl-3-(4-trifluoromethoxy phenyl)-ureido]indan-5-ylsulfanyl}-propanoic acid

Compound 3.4 (Example 31)

[image]

Compound 3.4 (2.9 mg; 4% over 2 steps; white solid) was prepared following method 3 replacing pent-4-enal with 1-naphthaldehyde.

LC/MS: C32H29F3N2O4S: m/z 595 (M+1)

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

Compound 2.23 (Example 32)

[image]

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

LC/MS: C24H27F3N2O4S: m/z 443 (M+1)

2-{2-[3-(3,5-Dimethylphenyl)-1-propylureido]indan-5-ylsulfanyl}-2-methylpropanoic acid

Compound 2.24 (Example 33)

[image]

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

LC/MS: C25H32N2O3S: m/z 441 (M+1)

2-{2-[1-(2-Methoxyethyl)-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyl)-2-methylpropanoic acid

Compound 2.25 (Example 34)

[image]

Compound 2.25 (7.0 mg; 16% over 2 steps; oil) was prepared following method 2 and Compound 2.2 substituting methoxyacetyl chloride for acetyl chloride.

LC/MS: C24H27F3N2O4S2: m/z 529 (M+1)

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

Compound 2.26 (Example 35)

[image]

Compound 2.26 (20 mg; 56% over 2 steps; white solid) was prepared following method 2 and Compound 2.14 substituting 4-trifluoromethylphenyl isocyanate for 4-trifluoromethoxyphenyl isocyanate.

LC/MS: C24H27F3N2O3S2: m/z481 (M+1)

2-Methyl-2-{2-[1-(4,4,4-trifluorobutyl)-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propanoic acid

Compound 2.27 (Example 36)

[image]

Compound 2.27 (10 mg; 26% over 2 steps; oil) was prepared following method 2 and Compound 2.0 substituting trifluoromethylbutyryl chloride for acetyl chloride.

LC/MS: C25H26F6N2O4S: m/z 564 (M+1)

2-{2-[1-(3-Cyclopentylpropyl)-3-phenylureido]indan-5-ylsulfanyl}-2-methylpropanoic acid

Compound 2.28 (Example 37)

[image]

Compound 2.28 (38 mg; 56% over 2 steps; oil) was prepared following method 2 and Compound 2.0 substituting cyclopentylpropionyl chloride for acetyl chloride and phenyl isocyanate for 4-trifluoromethoxyphenyl isocyanate.

LC/MS: C28H36N2O3S: m/z 481 (M+1)

6-[1-[5-(1-carboxy-1-methylethylsulfanyl)indan-2-yl]-3-(4-isopropylphenyl)ureido]hexanoic acid methyl ester

Compound 2.29 (Example 38)

[image]

Compound 2.29 (12 mg; 38% over 2 steps; white solid) was prepared following method 2 and Compound 2.4 substituting 5-chlorocarbonylpentanoic acid methyl ester for acetyl chloride.

LC/MS: C30H40N2O5S: m/z 541 (M+1)

2-Methyl-2-[2-(3-naphthalen-2-yl-1-pentylureido)indan-5-ylsulfanyl]propanoic acid

Compound 2.30 (Example 39)

[image]

Compound 2.30 (15 mg; 39% over 2 steps; white solid) was prepared following Method 2 and Compound 2.3 substituting 2-naphthyl isocyanate for 4-trifluorothiomethoxyphenyl isocyanate.

LC/MS: C29H34N2O3S: m/z 491 (M+1)

2-{2-[1-Cyclohexylmethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl]-2-methylpropanoic acid

Compound 2.31 (Example 40)

[image]

Compound 2.31 (15 mg; 25% over 2 steps; white solid) was prepared following method 2 and Compound 2.0 substituting cyclohexylacetyl chloride for acetyl chloride.

LC/MS: C28H33F3N2O4S: m/z 551 (M+1)

2-{2-(1-Isobutyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid

Compound 3.5 (Example 41)

[image]

Compound 3.5 (10 mg; 12% over 2 steps; oil) was prepared following method 3 and Compound 3.0 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-methylpropanoic acid

Compound 2.32 (Example 42)

[image]

Compound 2.32 (6.7 mg; 12% over 2 steps; oil) was prepared following method 2 and Compound 2.0 substituting heptanoyl chloride for acetyl chloride and 4-trifluoromethoxyphenyl isocyanate for 3,4-dichlorophenyl isocyanate.

LC/MS: C27H34Cl2N2O3S: m/z 538 (M+1)

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

Compound 2.33 (Example 43)

[image]

Compound 2.33 (1.9 mg; 4% for 2 steps; oil) was prepared in the following manner 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-Chlorophenyl)-1-heptylureido]indan-5-ylsulfanyl}-2-methyl propanoic acid

Compound 2.34 (Example 44)

[image]

Compound 2.34 (7.4 mg; 14% over 2 steps; white solid) was prepared following method 2 and Compound 2.32 by replacing 4-trifluoromethoxyphenyl isocyanate with 3-chlorophenyl isocyanate.

LC/MS: C27H35ClN2O3S: m/z 542 (M+1)

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

Compound 2.35 (Example 45)

[image]

Compound 2.35 (1.0 mg; 1.3% over 2 steps; white solid) was prepared following Method 2 and Compound 2.32 substituting tert-butyl 2-bromoisobutyrate for 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}propanoic acid

Compound 1.4 (Example 46)

[image]

Compound 1.4 (53 mg; 25% over 2 steps; oil) was prepared following method 1 and Compound 1.0 substituting propionyl chloride for acetyl chloride.

LC/MS: C25H29F3N2O4S: m/z 511 (M+1)

The following two compounds can be prepared by following Schemes 10 and 4, steps 1, J and K of Method 1, substituting reagents and adjusting reaction conditions as necessary:

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

Compound 1.5 (Example 47)

[image]

Compound 1.5 (9.8 mg; oil) can be prepared following Method 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, 1H), 4.43-4.79 (m, 1H), 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)

Method 4

[image]

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

Compound 4.0 (Example 48)

A. N-(6-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide.

Scheme 7. To a stirred suspension of 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine (2.54 g; 14.3 mmol) in CH2Cl2 (20 mL) was added DIEA (3.4 mL) and the reaction mixture was cooled to 0°C. Acetyl chloride (1.22 mL; 17.1 mmol) was added dropwise at 0°C and the reaction was allowed to warm to RT and stirred for 18 h. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give a crude solid. Purification by flash chromatography (SiO2) eluting with hexanes-EtOAc afforded 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-Hydroxy-1,2,3,4-tetrahydronaphthalen-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 CH2Cl2 (70 mL), cooled to -60oC, a solution of boron tribromide- CH2Cl2 (36 mL), dropwise to maintain the reaction temperature between -50o to -60oC. The gelatinous suspension was allowed to warm to RT and stirred for 30 min. The reaction was cooled to 0o C, quenched with saturated NaHCO3 and stirred for 30 min at RT. The mixture was extracted with CH2Cl2 (2X), the extracts were combined, dried over Na2SO4, filtered and evaporated under reduced pressure to give a crude solid, which was purified by flash chromatography (SiO2) eluting with a CH2Cl2-MeOH gradient to give 1.13 g ( 76%) of N-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide as a beige solid. LC/MS: C12H15NO2: m/z 206 (M+1)

C. tert-Butyl ester of 2-(6-Acetylamino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-methylpropanoic acid

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) was 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 was removed under reduced pressure to give a crude oil, which was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient. which gave 0.51 g (69%) of 2-(6-acetylamino-5,6,7,8-tetrahydronaphthalen-2-yloxy)-2-methylpropanoic acid tert-butyl ester as an oil.

1H NMR (300 MHz, CDCl3): δ 6.89-6.92 (d, 1H), 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, 1H), 2.04 (s, 2H), 1.98-2.02 (m, 1H), 1.74-1.79 (m, 1H), 1.54 ( s, 6H), 1.46 (s, 9H)

LC/MS: C20H29NO4: m/z 292 (M+1)

The following compound was obtained by following Schemes 3 and 4 and steps I, J, and K of Method 1, substituting reagents and adjusting reaction conditions as necessary:

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

LC/MS: C24H27F3N2O5: m/z 481 (M+1)

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

Compound 1.6 (Example 49)

[image]

Compound 1.6 (10 mg; oil) can be prepared by replacing 4-trifluoromethoxyphenyl isocyanate with 4-tert-butylphenyl isocyanate and using Method 1, Steps I, J, and K and Schemes 4 and 10.

LC/MS: C28H38N2O4S: m/z 499 (M+1)

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-

5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid

Compound 1.7 (Example 50)

[image]

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

1H NMR (300 MHz, CDCl3): δ 7.46-7.51 (m, 2H), 7.25-7.28 (d, 1H), 7.17-7.20 (d, 2H), 6.92-6.95 (d, 1H), 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: C25H29F3N2O5S: m/z 515(M+1)

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-

5,6,7,8-tetrahydronaphthalene-2-i}-2-methylpropanoic acid

Compound 1.8 (Example 51)

[image]

Compound 1.8 (15 mg; 22% after 2 steps; white solid) can be prepared following Method 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-methylpropanoic acid

Compound 1.9 (Example 52)

[image]

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

1H NMR (300 MHz, CDCl3): δ 7.45-7.48 (m, 3H), 7.36 (s, 1H), 7.15-7.18 (d, 2H), 4.41-4.79 (m, 1H), 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-methylpropanoic acid

Compound 1.10 (Example 53)

[image]

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

1H NMR (300 MHz, CDCl3): δ 7.45-7.48 (m, 2H), 7.22 (s, 1H), 7.15-7.18 (d, 2H), 7.02 (s, 1H), 4.41-4.79 (m, 1H ), 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-methylpropanoic acid

Compound 1.11 (Example 54)

[image]

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

1H NMR (300 MHz, CDCl3): δ 7.45-7.48 (d, 2H), 7.37 (s, 1H), 7.12-7.18 (m, 3H), 4.44 (m, 1H), 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-methylpropanoic acid

Compound 1.12 (Example 55)

[image]

Compound 1.12 (118 mg; 58% over 2 steps; white solid) can be prepared following Method 1, Steps I, J and K and Schemes 4 and 10.

1H NMR (300 MHz, CDCl3): δ 7.45-7.48 (d, 2H), 7.29-7.38 (m, 6H), 7.15-7.18 (d, 2H), 7.10 (s, 1H), 4.46 (m, 1H) , 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-methylpropanoic acid (Example 56)

[image]

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

[image]

Method 5

tert-Butyl ester of 2-[3-chloro-6-(ethyl-p-tolyloxycarbonyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl]-2-methyl-propanoic acid.

Compound 5.0 (Example 58)

[image]

Mixtures of 2-(3-chloro-6-ethylamino-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methyl-propanoic acid tert-butyl ester and borane complex (80 mg; 201 mol), dissolved in CH2Cl2 (2 mL), p-tolylchloroformate (35 L; 241 mol) was added at 0°C. 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 (SiO2) eluting with a hexanes-EtOAc gradient to give 30 mg (29%) of 2-[3-chloro-6-(ethyl-p-tolyloxycarbonyl) tert-butyl ester. -amino)-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl]-2-methyl-propanoic acid as a clear oil.

1H NMR (300 MHz, CDCl3): δ 6.67-7.29 (m, 6H), 4.28 (m, 1H), 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 method 2. 1H NMR (300 MHz, CD3OD): δ 6.96-7.34 (m, 6H), 4.27 (m, 1H), 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: C24H28ClNO4S: m/z 462 (M+1)

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

[image]

Compound 5.1 (34 mg; 35% over 2 steps; white solid) was prepared following Method 5, substituting 4-chlorophenylchloroformate for p-tolyl chloroformate and Step M of Method 2.

1H NMR (300 MHz, CD3OD): δ 7.11-7.39 (m, 6H), 4.30 (m,

1H), 3.47 (m, 2H), 2.91-3.15 (m, 4H), 2.06 (m, 2H), 1.45 (m, 6H), 1.28 (m, 3H)

LC/MS: C23H2Cl2NO4S: m/z 482 (M+1)

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

Compound 5.2 (Example 60)

[image]

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

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

A. 1-Chloro-ethyl ester 4-trifluoromethoxy phenyl ester of carbonic acid.

Scheme 1. A solution of 1-chloroethyl chloroformate (1.03 g; 7.20 mmol) in CH2Cl2 (10 mL) was cooled to 0oC, trifluoromethoxyphenol (1.09 g; 6.0 mmol) and triethylamine were added, and the resulting solution was warmed to RT.

After stirring for 3 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 Na 2 SO 4 , and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography eluting with hexane-EtOAc (10:1) to give 1.54 g (90%) of 1-chloro-ethyl ester of 4-trifluoromethoxy phenyl ester of carbonic acid as a colorless oil.

1H NMR (400 MHz, CDCl3): δ 7.26 (m, 4H), 6.49 (q, 1H), 1.91 (d, 3H)

B. 4-Trifluoromethoxy-phenyl ester of ethyl-(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid

Scheme 1. To a mixture of 6-methoxy-2-tetralone (950 mg; 5.39 mmol), 2M ethylamine in THF (5.4 mL; 10.78 mmol) and acetic acid (648 mg; 10.78 mmol) in CH2Cl2 (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 NaOH solution was added, and extracted with ether (3 times). The combined organic extracts were dried over Na 2 SO 4 and the solvent was removed under reduced pressure to give a light yellow oil. This oil was added to a solution of 1-chloro-ethyl ester of 4-trifluoromethoxy phenyl ester of carbonic acid (1.23 g; 4.31 mmol) in toluene (8 mL), and the reaction mixture was stirred for 1 h at RT, then at 90°C for 1 h. The reaction was allowed to cool to RT, diluted with Et 2 O and washed with 1 N aqueous HCl and saturated NaHCO 3 . The organic extract was dried over Na 2 SO 4 and the solvent was removed under reduced pressure. Flash chromatography of the precipitate with a hexane-CH2Cl2 gradient gave 1.05 g (48%) of ethyl-(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid 4-trifluoromethoxy-phenyl ester as white solids.

1H NMR (400 MHz, CDCl3): δ 7.10-7.30 (m, 4H), 6.99 (d, 1H), 6.71 (d, 1H), 6.64 (s, 1H), 4.33 (m, 1H), 3.77 (s , 3H), 3.41 (m, 2H), 2.93 (m, 4H), 2.04 (m, 2H), 1.31 (m, 3H)

LC/MS: C21H23F3NO4: m/z 410 (M+1)

C. 4-Trifluoromethoxy-phenyl ester of ethyl-(6-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid.

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 CH2Cl2 (8 mL) cooled is to –78o C, 1.0 M boron tribromide-CH2Cl2 solution (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 precipitate was purified by flash chromatography with hexane-EtOAc (2.5:1) to give 649.4 mg (75%) of 4-trifluoromethoxy-ester ethyl-(6-hydroxy-1,2,3,4-tetrahydro-naphthalene) -2-yl)-carbamic acid as a white solid.

1H NMR (300 MHz, CDCl3): δ 7.05-7.30 (m, 4H), 6.90 (m, 1H), 7.41-7.60 (m, 2H), 5.05 (s, 1H), 4.30 (m, 1H), 3.41 (m, 2H), 2.90 (m, 4H), 1.99 (m, 2H), 1.31 (m, 3H)

LC/MS: C20H21F3NO4: m/z 396 (M+1)

D. Ethyl-(6-triisopropyl-silanylsulfanyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid 4-trifluoromethoxy-ester.

Scheme 1. A solution of 4-trifluoromethoxy phenyl ester of ethyl-(6-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid (245.1 mg; 0.62 mmol) in anhydrous CH2Cl2 (3 mL) and THF (3 mL) was cooled to -30oC, triethylamine (216 μL, 1.55 mmol) and triflic anhydride (125 μL, 0.74 mmol) were added successively. 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 precipitate with hexane-EtOAc (5:1) gave 301.6 mg (92%) of the triflate. Ti triflate (279.8 mg; 0.53 mmol) and tetrakis(triphenylphosphine)palladium (61.2 mg; 0.053 mmol) were added to a toluene solution generated from triisopropylsilanethiol (126 μL, 0.58 mmol) and NaH (13.9 mg; 0.58 mmol) at RT. The resulting mixture was vacuumed twice, refluxed for 4 h and concentrated under reduced pressure. Flash chromatography of the precipitate with hexane-EtOAc (10:1) yielded 261.8 mg (87%) of ethyl-(6-triisopropyl-silanylsulfanyl-1,2,3,4-tetrahydro-naphthalen-2-yl) 4-trifluoromethoxy-phenyl ester )-carbamic acids as light colored oils.

1H NMR (300 MHz, CDCl3): δ 6.82-7.29 (m, 7H), 4.32 (m, 1H), 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. tert-Butyl ester of 2-{6-[ethyl-(4-trifluoromethoxy-phenoxycarbonyl)-amino]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methyl-propanoic acid.

Scheme 1. A solution of 4-trifluoromethoxy-phenyl ester of ethyl-(6-triisopropylsilanylsulfanyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid (260.0 mg; 0.46 mmol) and tert-butyl Γ-bromoisobutylate (130 μL, 0.69 mmol) in anhydrous THF (2 mL) was cooled to 0°C, 1.0 M TBAF solution (690 μL, 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 Na 2 SO 4 , and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography eluting with hexane-EtOAc (7:1) to give 229.2 mg (90%) of tert-butyl ester 2-{6-[ethyl-(4-trifluoromethoxy-phenoxycarbonyl)-amino]-5, 6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methyl-propanoic acid as a light colored oil.

1H NMR (300 MHz, CDCl3): δ 6.95-7.28 (m, 7H), 4.34 (m, 1H), 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)-amino]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methyl-propanoic acid.

Scheme 1. A solution of 2-{6-[ethyl-(4-trifluoromethoxy-phenoxycarbonyl)-amino]-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl}-2-methyl-propanoic acid (120.8 mg; 0.22mmol) in CH2Cl2 (4 mL) was cooled to -78°C, and trifluoroacetic acid (4 mL) was slowly added. 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 CH2Cl2-MeOH (94:6) to give 2-{6-[ethyl-(4-trifluoromethoxy-phenoxycarbonyl)-amino]-5,6,7,8-tetrahydro -naphthalen-2-ylsulfanyl}-2-methyl-propanoic acid as a white solid.

1H NMR (400 MHz, CDCl3):δ 6.96-7.28 (m, 7H), 4.30 (m, 1H), 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)

D. Formulation and Administration

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

The carrier can take a wide variety of forms depending on the form of the desired preparation for administration. These pharmaceutical compositions are preferably in unit dosage form suitable, preferably, for oral administration or parenteral injection. For example, in the preparation of compositions for oral dosage form, any of the conventional pharmaceutical agents can be used. 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 preparations such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like in the case of powders, pills, capsules and tablets. In terms of their ease of administration, tablets and capsules represent the most convenient unit form for oral dosage, in which case solid pharmaceutical carriers are generally used. For parenteral preparations, the vehicle will usually include sterile water, at least in large part, although other ingredients may be included, for example, to enhance solubility. Injectable solutions may be prepared, for example, in which the carrier comprises saline, glucose, or a mixture of saline or glucose. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents and the like can be used. In compositions suitable for percutaneous administration, the carrier may comprise a penetration-enhancing agent and/or a suitable wetting agent, possibly combined with suitable additives of any nature in minor proportions, which additives do not cause a significant adverse effect on the skin. Such additives may facilitate application to the skin and/or may be useful for the preparation of desired compositions. These preparations can be administered in different ways, eg as a transdermal patch, as a spot-on, as an ointment. Acid addition salts of compounds of formula I, due to their increased solubility in water compared to the corresponding basic form, are more suitable for the preparation of aqueous preparations.

It is particularly advantageous to formulate the above-mentioned pharmaceutical preparations in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein in the specification refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect together with the necessary pharmaceutical carrier.

Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, spoons, and the like, and divided multiples thereof. Pharmaceutically acceptable acid addition salts include therapeutically active non-toxic forms of acid addition salts that the above compounds can form. The latter can conveniently be obtained by treating the basic form with the appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, eg hydrochloric or hydrobromic acid; sulfate; nitrate; phosphoric and similar acids; or organic acids such as, for example, acetic, propane, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclaminic, salicylic, p-aminosalicylic, pamoic and similar acids. The term addition salt also includes solvates that the listed compounds, as well as their salts, can form. Such solvates are for example hydrates, alcoholates and the like. Conversely, the salt form can be converted to the free base form by treatment with alkali.

Stereoisomeric forms define all possible isomeric forms that compounds of formula (I) can have. If not mentioned or indicated otherwise, the chemical designation of the compounds means a mixture of all possible stereochemically isomeric forms, said mixtures contain all diastereomers and enantiomers of the basic molecular structure. In particular, chiral centers can have (R)- or (S)-configuration; substituents on divalent cyclic saturated radicals can have either cis- or trans-configuration. The invention includes stereochemically isomeric forms, including diastereoisomers, as well as their mixtures in any ratio of the listed compounds. The above compounds can also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above and following formulas, are within the scope of the proposed invention. For example, in compound 2.1 or Example 3, there is a chiral center at C-2 of the indane ring. For this compound, the (S) isomer is more active than the (R) isomer.

Persons skilled in the treatment of disorders or conditions mediated by PPAR alpha can easily determine the effective daily amount from the test results presented below and other information. It is generally believed that a therapeutically effective dose would be from 0.001 mg/kg to 5 mg/kg of body weight, more preferably from 0.01 mg/kg to 0.5 mg/kg of body weight. It may be convenient to administer a therapeutically effective dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses can be formulated as unit dosage forms, for example, containing 0.05 mg to 250 mg or 750 mg, and especially 0.5 to 50 mg of active ingredient per unit dosage form. Examples include dosage forms of 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg, and 35 mg. The compounds of the invention may also be prepared in time-release formulations either subcutaneously or as a transdermal patch. The present compound may also be formulated as a spray or other topical or inhalable formulation.

The exact dose 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, body weight and general physical condition of the particular patient as well as other drugs the patient may be taking, such as is known to persons skilled in the art. Furthermore, it is obvious that said effective daily dose can be lowered or raised depending on the response of the treated patient and/or depending on the judgment of the physician prescribing the compounds of this invention. Therefore, the effective daily dose ranges mentioned here are only guidelines.

The following section includes detailed information relating to the use of the compounds and compositions set forth.

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 (eg, potency for PPAR alpha relative to potency for PPAR gamma) of 10 or more, and preferably 15, 25, 30, 50 or 100 or more. PPAR alpha agonists are useful for treating, preventing, or inhibiting the progression of one or more of the following conditions or diseases: stage I hyperlipidemia, pre-clinical hyperlipidemia, stage II hyperlipidemia, hypertension, CAD (coronary artery disease), coronary heart disease, and hypertriglyceridemia. Advantageous compounds of the invention are useful in lowering serum levels of low-density lipoprotein (LDL), IDL, and/or low-density LDL and other and atherogenic molecules, or molecules that cause atherosclerotic complications, thereby reducing cardiovascular complications. Advantageous compounds are also useful in increasing serum levels of high-density lipoprotein (HDL), in lowering serum levels of triglycerides, LDL, and/or free fatty acids. It is also desirable to lower FPG/HbA1c.

Combination treatment

The compounds of the proposed invention can be used in combination with other pharmaceutical 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 foregoing pharmaceutical compositions or combinations of drugs, whether or not they are formulated in the same composition. For therapeutic purposes, the term "combined effective amount" as used herein means the amount of any active compound or pharmaceutical agent, individually or in combination, that produces a biological or medical response in a tissue, animal or human system as examined by an investigator, veterinarian, physician medicine or other clinician, which involves alleviating the symptoms of the disease or disorder being treated. For prophylactic purposes (ie, inhibiting the onset or progression of a disorder), the term "combined effective amount" refers to that amount of each active compound or pharmaceutical agent, singly or in combination, that treats or inhibits the onset or progression of the disorder in a subject as examined researcher, veterinarian, medical doctor or other clinician. Accordingly, the present invention provides combinations of two or more drugs in which, for example, (a) each drug is administered in an amount that is independently therapeutically or prophylactically effective; (b) at least one drug in the combination is administered in an amount that is sub-therapeutic or sub-prophylactic when administered alone, but is therapeutic or prophylactic when administered in combination with other 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 when administered individually, but is therapeutic or prophylactic when administered together.

As PPAR alpha agonists, the compounds of the invention may be more potent and effective in lowering triglycerides than known fibrates. The proposed compounds may also increase fat and/or lipid metabolism, providing a method for weight loss, fat loss, lowering body mass index, lowering lipids (such as lowering triglycerides), or treating obesity or overweight conditions.

Examples of lipid-lowering agents include bile acid sequestrants, fibrates, nicotinic acid, and HMGCoA reductase inhibitors. Specific examples include statins such as LIPITORTM, ZOCORTM, PRAVACHOLTM, LESCOLTM, and MEVACORTM, and pitavastatin (nisvastatin) (Nissan, Kowa Kogyo, Sankyo, Novartis) and their extended-release forms, such as ADX-159 (lovastatin extended-release release), 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 blocking agents (such as is Cardura, Dibenziline, 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, Dilacor, DynaCirc, Isoptin, Nimotop, Norvace, Plendil, Procardia, Procardia XL, Sula, Tiazac, Vascor, and Verelan), diuretics, angiotensin II receptor antagonists (such as Atacand, Avapro, Cozaar, and Diovan), beta adrenergic blockers (such as Betapace, Blocadren, Brevibloc, Cartrol, Inderal, Kerlone, Lavatol, Lopressor, Sectral, Tenormin, Toprol-XL, and Zebeta), vasodilators (such as Deponit, Dilatrate, SR, Imdur, Ismo, Isordil, Isordil Titradose, Monoket, Nitro-Bid, Nitro-Dur, Nit rolingual Spray, Nitrostat, and Sorbitrate), and their combinations (such as Lexxel, Lotrel, Tarka, Teczem, Lotensin HCT, Prinzid, Uniretic, Vaseretic, Zestoretic).

F. Examples

The following chemical and biological examples are provided to illustrate the invention and not to limit it.

Example 1

[image]

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

EC50 = 0.023 μM

Example 2

[image]

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

EC50 = 0.027 μM

Example 3

[image]

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

EC50 = 0.0002 μM

Example 4

[image]

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

EC50 = 0.037 μM

Example 5

[image]

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

EC50 = 0.053 μM

Example 6

[image]

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

EC50 = 0.056 μM

Example 7

[image]

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

EC50 = 0.075 μM

Example 8

[image]

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

EC50 = 0.073 μM

Example 9

[image]

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

EC50 = 0.131 μM

Example 10

[image]

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

EC50 = 0.165 μM

Example 11

[image]

2-{2-[3-(4-tert-Butylphenyl)-1-(3-pentyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid

EC50 = 0.173 μM

Example 12

[image]

2-[2-(3-(Biphenyl-4-yl-1-pentylureido)indan-5-ylsulfanyl]-2-methylpropanoic acid

EC50 = 0.183 μM

Example 13

[image]

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

EC50 = 0.184 μM

Example 14

[image]

2-Methyl-2-{2-[1-hexyl-3-(4-trifluoro-methoxyphenyl)ureido]indan-5-ylsulfanyl}-propanoic acid

EC50 = 0.213 μM

Example 15

[image]

2-Methyl-2-{2-[1-hexyl-3-(4-trifluoro-methylsulfanylphenyl)ureido]indan-5-ylsulfanyl}-propanoic acid

EC50 = 0.123 μM

Example 16

[image]

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

EC50 = 0.158 μM

Example 17

[image]

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

EC50 = 0.160 μM

Example 18

[image]

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

EC50 = 0.135 μM

Example 19

[image]

2-Methyl-2-{2-[1-pent-4-enyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propanoic acid

EC50 = 0.125 μM

Example 20

[image]

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

EC50 = 0.106 μM

Example 21

[image]

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

EC50 = 0.106 μM

Example 22

[image]

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

EC50 = 0.219 μM

Example 23

[image]

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

EC50 = 0.244 μM

Example 24

[image]

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

EC50 = 0.235 μM

Example 47

[image]

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

EC50 = 0.045 μM

Example 49

[image]

2-{6-[1-Ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-5,6,7,8-tetrahydro-naphthalen-2-yloxy}-2-methyl-propanoic acid

EC50 = 0.309 μM

Example 50

[image]

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

EC50 = 0.010 μM

Example 51

[image]

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

EC50 = 0.010 μM

Example 52

[image]

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

EC50 = 0.017 μM

Example 53

[image]

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

EC50 = 0.042 μM

Example 54

[image]

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

EC50 = 0.131 μM

Example 55

[image]

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

EC50 = 0.545 μM

Example 56

[image]

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

Example 57

[image]

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

Example 58

[image]

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

EC50 = 0.340 μM

Example 59

[image]

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

EC50 = 0.390 μM

Example 60

[image]

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

EC50 = 0.002 μM

Biological example 1

HD bDNA assay

The rat hepatoma cell line H411E was obtained from ATCC. Cells were grown in a 175 cm2 tissue culture flask or plated in a 96-well plate with (high serum content, 10% fetal bovine serum and 10% calf serum) culture medium and kept at 37oC during the study and 5% CO2. Twenty-four hours after they were initially hand plated in a 96-well plate (approximately 100,000/well), the HD gene induction assay was initiated. The medium was removed and replaced with 100 μl of low-serum culture medium (calf serum treated with 5% charcoal/dextran) containing vehicle (DMSO) or test compounds or standard. The cells were returned to the incubator for 24 hours. Upon completion of the assay, 50 µl of assay buffer with HD gene specific CE, LE, BL probes was directly added to each well to initiate the bDNA HDmRNA assay. The branched DNA assay was performed according to the manufacturer's protocol (Bayer Diagnostics; Emeryville, CA.). At the end of the test, luminescence was measured in a Dynex MLX luminometer for microtiter plates. EC50s were determined by non-linear regression with sigmoid fitting using Graphpad Prism.

Biological example 2

Transfection assay for PPARδ receptors

HEK293 cells were grown in DMEM/F-12 medium containing 10% FBS and glutamine (GIBCOBRL). DNA for the PPAR-Gal4 receptor and the Gal4-Luciferase reporter gene were simultaneously transfected into the cells using the DMRIE-C reagent. The next day, the DNA-containing medium was replaced with 5% charcoal-treated FBS culture medium. After six hours, the cells were plated on a 96-well plate and incubated at 37oC in a CO2 incubator overnight. The cells were tested with test compounds and incubated for 24 hours at 37oC in an incubator with 5% CO2. Luciferase activity was assayed using the Steady-Glo Luciferase Assay Kit from Promega. DMRIE-C reagent was purchased from GIBCO cat. no. 10459-014. OPTI-MEM I Reduced Serum Medium was purchased from GIBCO cat. no. 31985. The Steady-Glo Luciferase Assay Kit was obtained from Promega part#; E254B.

In vitro data

[image]

[image]

¤ -fold induction for PPARδ standard: FI = 36.12

¤ -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 fully incorporated herein by reference, and the results of the aP2 intrinsic agonist activity assay can be shown as a -fold increase over vehicle in the induction of aP2 mRNA production .

Twenty-four hours after the initial hand-seeding in a 96-well plate (about 20,000/well), the differentiation assay can begin. The medium can be removed and replaced with 150 µl of differentiation medium containing vehicle (DMSO) or test compounds. Cells can be returned to the incubator for 24-hour culture. Upon completion of the assay, the medium can be removed and 100 µl of assay buffer can be added to initiate the bDNA aP2a mRNA assay. Branched DNA testing can be performed according to the manufacturer's protocol (Bayer Diagnostics; Emeryville, CA). The result can be expressed as a 2-fold activated increase in the production of aP2 mRNA compared to the vehicle control. EC50 and Emax can be determined by non-linear regression with a sigmoid fitting curve.

After examining preadipocytes, cells can be assayed with assay buffer (Bayer Diagnostics) containing aP2 oligonucleotides. After 15 minutes of incubation at 53oC or 30 minutes at 37oC in an incubator, 70 µl of assay buffer from each well can be added to the corresponding capture well (pre-incubated with 70 µl of blocking buffer (Bayer Diagnostics)). The capture plate can be incubated overnight at 53oC in a plate incubator (Bayer Diagnostics). After this incubation, bDNA and labeled probes can be annealed according to the manufacturer's instructions. After incubation for 30 minutes with the luminescent substrate of alkaline phosphatase, dioxytane, luminescence can be measured in a Dynex MLX luminometer for microtiter plates.

Oligonucleotide probes designed to anneal to aP2mRNA and function in the bDNA mRNA detection system were designed with ProbeDesigner software (Bayer Diagnostics). This software package analyzes the target sequence of interest with a series of algorithms to determine which regions of the sequence can serve as locations for capture, tagging, or spacer probe annealing.

The oligonucleotide sequences are as follows:

[image]

SEQ ID NO. 20 AAGTGACGCCTTTCATGAC

Biological example 4

Dosing of 11 days from the example to female mice, 6-7 weeks old db/db

Female db/db mice (C57 BLKS/J-m+/+Leprdb, Jackson Labs, Bar Harbor, ME), 6–7 weeks old, were housed four per cage in solid-bottomed shoebox cages. Room temperature was maintained at 68-72oF and humidity at 50-65%.

The room light was on a 12-hour light/12-hour dark cycle. Mice were fed a certified reduced-fat NIH Rat and Mouse/Auto 6F #5K52 diet (P M I Nutrition Int'l, St. Louis, MO, via W. F. Fisher and Son, Inc., Bound Brook, NJ). Food and water were given ad libitum.

The compound was prepared as a suspension in 0.5% hydroxypropyl methylcellulose (Dow Chemical, Midland, MI). The dose volume was 10 mL/kg body weight. Female diabetic db/db mice (8/group) were orally administered by gavage daily for 11 days either 0.5% methylcellulose in dH2O (vehicle) or a PPAR agonist at either 0.03, 0.1, 0.3, 1, 3, 10 mg/kg/day. Body mass was measured in the morning on day 1, before dosing, and on day 12, before bloodletting. 18-24 hours after the final dose for each group, mice were anesthetized with CO2/O2 (70:30) and bled by retro-orbital sinus puncture into microtubes containing clot activator and then placed on ice. Serum samples were prepared by centrifugation. Serum glucose and triglycerides were determined using the COBAS Mira Plus blood chemistry analyzer (Roche Diagnostics, NJ). Serum insulin was measured using an ALPCO ELISA insulin kit. Statistical analysis was performed using Prism software (Graphpad, Monrovia, CA) and performing one-way ANOVA with Dunnett's multiple comparison test.

In vivo data

[image]

1 db/db mice dosed at 1.0 mpk. Data are presented as % change compared to vehicle-treated animals;

NC = no change

210-day oral dosing

311-day oral dosing

45-day oral dosing

Biological example 5

11-day dosing from the example to female mice, 7 weeks old ob/ob

Female ob/ob mice (C57 BL/6J-Lepob, Jackson Labs, Bar Harbor, ME), 7 weeks old, were housed two per cage in solid-bottomed shoebox cages. Room temperature was maintained at 68-72oF and humidity at 50-65%.

The room light was switched on in a 12-hour light/12-hour dark cycle. Mice were fed a certified reduced fat NIH Rat and Mouse #5K50 diet (P M I Nutrition Int'l, St. Louis, MO, via W. F. Fisher and Son, Inc., Bound Brook, NJ). Food and water were given ad libitum. The compound was prepared as a suspension in 0.5% hydroxypropyl methylcellulose (Dow Chemical, Midland, MI). The dose volume was 10 mL/kg body weight. Female ob/ob mice with diabetes (8/group) were orally administered by gavage daily for 11 days either 0.5% methylcellulose in dH2O (vehicle) or a PPAR agonist at 0.003, 0.01, 0.03, 0.1, 0.3, 1 mg/kg/day. Body mass was measured in the morning on day 1, before dosing, and on day 12 before bloodletting. 18 hours after the final dose for each group, mice were anesthetized with CO2/O2 (70:30) and bled by retro-orbital sinus puncture into microtubes containing clot activator and then placed on ice. Serum samples were prepared by centrifugation. Serum glucose and triglycerides were determined using the COBAS Mira Plus blood chemistry analyzer (Roche Diagnostics, NJ). Serum insulin and free fatty acids were measured using ALPCO ELISA and Wako NEFA kits, respectively. Statistical analysis was performed using Prism software (Graphpad, Monrovia, CA) and performing one-way ANOVA with Dunnett's multiple comparison test.

In vivo data

[image]

1 db/db mice dosed at 1.0 mpk. Data are presented as % change compared to vehicle-treated animals.

F. Other achievements

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

Claims (39)

1. A compound of Formula I [image] or its pharmaceutically acceptable salt, C1-6 ester or C1-6 amide, wherein each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8, or (CH2)mCO2R8, wherein each of Ra, Rb, and R8 is independently H or C1-6alkyl, or R1 and R2 taken together with the carbon atom to which they are attached form C3-7cycloalkyl; m is between 1 and 6; n is 1 or 2; X is O or S; where X is at position 5 or 6 when n is 1; and wherein X is at position 6 or 7 when n is 2; R 3 is H, phenyl, C 1-3 alkoxy, C 1-3 alkylthio, halo, cyano, C1-6alkyl, nitro, NR9R10, NHCOR10, CONHR10; and COOR10; and R 3 is ortho or meta to X; R4 is H or -(C1-5alkylene)R15, wherein R15 is H, C1-7alkyl, [di(C1-2alkyl)amino](C1-6alkylene), (C1-3 alkoxyacyl) (C1-6alkylene), C1- 6-Alkoxy, C3-7alkenyl or C3-8alkynyl, wherein R4 has no more than 9 carbon atoms; R4 can also be -(C1-5alkylene)R15 where R15 is C3-6cycloalkyl, phenyl, phenyl-O-, phenyl-S-, or 5-6-membered heterocyclyl with 1 or 2 heteroatoms selected from N, O, and WITH; Y is NH, NH-CH2 or O; each R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR, COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 and 5-6-membered heterocyclyl with 1 or 2 heteroatoms selected between N, O and S; R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 and 5-6 membered heterocyclyl with 1 or 2 heteroatoms selected from N, O, and WITH; additionally, either R5 and R6 or R6 and R7 may be taken together and be a divalent group, saturated or unsaturated, selected from -(CH2)3-, -(CH2)4-, and (CH1-2)pN(CH1-2 )q, p is 0-2 and q is 1-3, where the sum of (p+q) is at least 2; each of R 9 and R 10 is independently C 1-6 alkyl; each of R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl; wherein each of the above hydrocarbyl and heterocarbyl groups may be substituted with 1 to 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy, nitro, cyano and methoxy. 2. The compound of claim 1, characterized in that one of R1 and R2 is methyl or ethyl. 3. The compound of claim 2, characterized in that each of R1 and R2 is methyl. 4. The compound of claim 1, characterized in that R1 and R2 taken together form cyclobutyl or cyclopentyl. 5. Spj according to claim 1, characterized in that R3 is equal to H. 6. The compound of claim 1, characterized in that R 3 is C 1-3 alkoxy, C 1-3 alkylthio, halo, cyano, C 1-6 alkyl, nitro, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 . 7. The compound of claim 1, characterized in that R4 is equal to H or is C2-7alkyl. 8. The compound of claim 7, characterized in that R4 is equal to H or is C2-5alkyl. 9. The compound of claim 8, characterized in that R4 is ethyl. 10. The compound of claim 8, characterized in that R4 is equal to H. 11. The compound of claim 1, characterized in that n is equal to 1. 12. The compound of claim 1, characterized in that n is equal to 2. 13. The compound of claim 1, characterized in that Y is equal to NH-CH2. 14. The compound of claim 1, characterized in that Y is NH. 15. The compound of claim 1, characterized in that X is equal to S. 16. The compound of claim 1, wherein X is O. 17. The compound of claim 1, characterized in that at least one of R5 and R7 is equal to H. 18. The compound of claim 17, characterized in that R6 is C1-4alkyl, halomethoxy, halomethylthio or di(C1-3alkyl)amino. 19. The compound of claim 18, characterized in that R6 is trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethylthio, t-butyl, isopropyl or dimethylamino. 20. The compound of claim 3, characterized in that R3 is H, R4 is C2-7 alkyl and Y is NH. 21. The compound of claim 20, characterized in that X is equal to S. 22. The compound of claim 20, characterized in that n is equal to 1. 23. The compound of claim 20, characterized in that n is equal to 2. 24. The compound of claim 20, characterized in that R4 is C2-5 alkyl. 25. The compound of claim 24, characterized in that R4 is ethyl. 26. The compound of claim 20, characterized in that R6 is trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethylthio, t-butyl, isopropyl or dimethylamino. 27. The compound of claim 1, characterized in that each of R1 and R2 is independently H, C1-6alkyl, (CH2)mNRaRb or (CH2)mOR8, wherein each of Ra, Rb and R8 is independently H or C1-6alkyl ; m is between 1 and 6; n is 1 or 2; X is O or S; wherein X is at position 5 or 6 when n is equal to 1; and wherein X is at position 6 or 7 when n is equal to 2; R 3 is H, phenyl, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl or NR 9 R 10 , and R 3 is ortho or meta to X; R4 is H or -(C1-5alkylene)R15, wherein R15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene), (C 1-3 alkoxyacyl) (C 1-6 alkylene), C 1-6 alkoxy or C 3-7 alkenyl, where R 4 has no more than 9 carbon atoms; R 4 can also be -(C 1-5 alkylene) R 15 where R 15 is C3-6cycloalkyl, phenyl, phenyl-O-, phenyl-S-, or 5-6 membered heterocyclyl with 1 or 2 heteroatoms selected from N,O and S; Y is NH or NHCH 2 ; each of R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, COR 11 , COON, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy and NR 11 R 12 ; R 6 is selected from C 1-6 alkyl, halo, COR 13 , COOR 13 , C 1-4 alkoxy, C1-4alkylthio, phenyl, NR13R14 and 5-6-membered heterocyclyl with 1 or 2 heteroatoms selected from N, O and S; each of R 9 and R 10 is independently C 1-6 alkyl; each of R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl; wherein each of the above hydrocarbyl and heterocarbyl groups may be substituted with 1 to 3 substituents independently selected from F, Cl, amino, methyl, ethyl, hydroxy and methoxy. 28. The compound of claim 1, characterized in that it is selected from the following: 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan- 5-ylsulfanyl}-2-methylpropanoic acid; 2-Methyl-2-{2-[1-pentyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyl}propanoic acid; 2-{2-[1-Ethyl-3-(4-isopropylphenyl)ureido]indan-5-ylsulfanyl)- 2-methylpropanoic acid; 2-Methyl-2-{2-[1-pentyl-3-(4-trifluoromethoxyphenyl)ureido] indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-{2-[3-(4-Dimethylaminophenyl)-1-ethylureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-Methyl-2-{2-[1-(3-methylbutyl)-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-{2-[3-(4-Isopropylphenyl)-1-(3-methylbutyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-Methyl-2-{2-[1-pent-4-enyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propanoic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-bromo-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; and 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-trifluoromethoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid. 29. The compound of claim 1, characterized in that it is selected from the following: 2-Methyl-2-{2-[1-hexyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyl}propanoic acid; 2-{2-[3-(4-Dimethylaminophenyl)-1-pentylureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-Methyl-2-{2-[3-(4-trifluoromethoxyphenyl)ureido]inda-5-ylsulfanyl}propanoic acid; 2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propanoic acid; 2-Methyl-2-{2-[1-butyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyl}propanoic acid; 2-{2-[3-(4-Isopropylphenyl)-1-(3-pentyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-{2-[3-(4-tert-Butylphenyl)-1-(3-pentyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-[2-(3-(Biphenyl-4-yl-1-pentylureido)indan-5-ylsulfanyl]-2-methylpropanoic acid; 2-{2-[3-(4-isopropylphenyl)-1-(3-hexyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-Methyl-2-{2-[1-butyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propanoic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-bromo-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; and 2-Methyl-2-{2-[1-hexyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propanoic acid. 30. The compound of claim 1, characterized in that it is selected from the following: 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{6-[3-(4-Trifluoromethoxyphenyl)ureido-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; and 2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propanoic acid. 31. The compound of claim 1, characterized in that it is selected from the following: 2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropanoic acid; 2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propanoic acid; and 2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropanoic acid. 32. Pharmaceutical preparation, characterized in that it contains the compound of claim 1, 20, 27, 28, 30 or 31. 33. A method for treating or inhibiting the progression of a disease mediated by PPAR-alpha, characterized in that said method comprises 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. The method of claim 33, characterized in that said disease mediated by PPAR-alpha is selected from dyslipidemia and cardiovascular diseases. 35. The method of claim 34, characterized in that said disease is dyslipidemia. 36. The method of claim 34, characterized in that said dyslipidemia is selected from phase I hyperlipidemia, preclinical hyperlipidemia, phase II hyperlipidemia, hypercholesteremia, hypo-HDL-cholesterolemia, and hypertriglyceridemia. 37. The method of claim 34, characterized in that said cardiovascular disease is atherosclerosis, coronary artery disease, coronary heart disease or hypertension. 38. The method of claim 33, 35 or 36, further comprising the step of administering to the patient a collectively effective amount of a lipid-lowering agent. 39. The method of claim 33, 35, 36 or 38, further comprising the step of administering to the patient a collectively effective amount of a blood pressure lowering agent.