EA009553B1

EA009553B1 - Substituted tetralins and indanes

Info

Publication number: EA009553B1
Application number: EA200500515A
Authority: EA
Inventors: Сяоли Чен; Кит Т. Демарест; Джанг Ли; Джей М. Мэттьюз; Филип Рибжински
Original assignee: Янссен Фармацевтика Н.В.
Priority date: 2002-10-21
Filing date: 2003-10-17
Publication date: 2008-02-28
Also published as: WO2004037778A1; NO20052199L; NZ539510A; EA200500515A1; AU2003277441A1; JP2006503916A; TW200418773A; PL376325A1; CA2502661A1; HRP20050335A2; MXPA05004191A; EG24842A; AU2003277441B2; EP1569897A1; RS20050318A; CR7795A; KR20050055773A; BR0315596A

Abstract

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

Description

The invention relates to compounds of formula (I) below

or a pharmaceutically acceptable salt thereof, a C1 _-6 ester or a C1 _-6 amide, wherein each of T and B ₂ independently is H, C1 _-6 alkyl, _(CH2) _m B _and the IR _s, _(CH2) _t S ₈ , (CH ₂ ) _t IN (CO) B ₈ or (CH ₂ ) _t CO ₂ B ₈ , where each of B _a , B _|:, and B _{8 is} independently H or _C1-6 alkyl, or

R | and B ₂ , taken together with the carbon atom to which they are attached, form C _3-7 cycloalkyl; t is from 1 to 6;

n is 1 or 2;

X is O or 8; if X is in position 5 or 6, then n is 1; if X is in position 6 or 7, then n is 2;

is H, phenyl, C1 _-3 alkoxy, C1 _-3 alkylthio, halogen, cyano, C1 _-6 alkyl, nitro, ΝΚ ₉ Β ₁₀ , INSO4, COINV ₁₀ and СООВ ₁₀ ; and B ₃ is in the position of ortho or meta relative to X;

B ₄ is H or - (C _1-5 alkylene) B ₁ 5 where B ₁₅ 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, C _3-7 alkenyl or C _3-8 alkynyl, where B ₄ contains no more than 9 carbon atoms; At ₄ can also be - (C _1- 5alkilen) ₁₅ where ₁₅ is C _3-6 cycloalkyl, phenyl, phenyl-O-, phenyl-8- or 5-6 membered heterocyclyl containing 1 or 2 heteroatoms, selected from Ν, O and 8;

Υ is ΝΉ, ΝΉ-Ssch or O;

each of B ₅ and B ₇ are independently selected from H, C _1-6 alkyl, halogen, cyano, nitro, SOC _11, SOOV _11, C _1-4 alkoxy, C _1-4 alkylthio, hydroxy, phenyl, _M ₁₂ It.V. and a 5-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from, O, and 8;

B _{6 is} selected from C _1-6 alkyl, halogen, cyano, nitro, COB ₁₃ , COOB ₁₃ , C _1-4 alkoxy, C _1-4 alkylthio, hydroxy, phenyl, ΝΡρ, Ρρι and 5-6-membered heterocyclyl containing 1 or 2 heteroatoms selected from Ν, O and 8;

in addition, either B ₅ and B <5, or B ₆ and B ₇ can be taken together to form a divalent group, saturated or unsaturated, selected from - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ - and (CH _1-2 ) ^ (CH _1-2 ) _H , p is 0-2 and μ is 1-3, where the sum (p + d) is at least 2;

each of B ₉ and B _{10 is} independently C _1-6 alkyl;

- 1 009553 each of Itz, And ₁₂ , And _13, and And ₁₄ independently is H or C1_alkyl;

wherein each of the above hydrocarbyl and heterocarbyl groups may be substituted with 1-3 substituents independently selected from E, C1, Br, I, amino, methyl, ethyl, hydroxy, nitro, cyano, and methoxy.

The invention also relates to compositions that include one or more compounds of formula (I) and a pharmaceutical carrier or excipient.

These compounds and methods presented below may also include additional pharmaceutically acceptable agents, such as lipid lowering agents, blood pressure lowering agents, or both.

Another aspect of the present invention includes methods of using the described compounds or compositions in various methods of preventing, treating or inhibiting the development of diseases mediated by APPR alpha. Examples of diseases mediated by APPR alpha include dyslipidemia and atherosclerosis. Dyslipidemia includes hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL cholesterol. For example, dyslipidemia may include one or more of the following characteristics: low levels of IIP (<35 or 40 mg / dl), high triglycerides (> 200 mg / dl), and high LDL (> 150 mg / dl).

Additional characteristics and advantages of this invention will be visible from the detailed description, examples and claims below.

Detailed description

A. Terms.

Below are definitions of terms and their use in the description.

"Alkyl" includes optionally substituted straight and branched chain hydrocarbons containing at least one hydrogen atom removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-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 and branched chain hydrocarbons, such as those described above, containing at least one carbon-carbon double bond (paragraph ² ). Alkenyl include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyl, hexa-2, 4-dienyl and so on. Hydrocarbon radicals containing a mixture of double bonds and triple bonds, such as 2-pentene-4-ynyl, are represented as alkynyls. Alkenyl includes cycloalkenyl. The invention also includes cis and trans, or (E) and (Ζ) forms.

"Quinil" includes optionally substituted hydrocarbons with a straight and branched chain, such as described above, containing at least one carbon-carbon triple bond (g). Alkynyls include ethynyl, propynyl, butynyl, and pentynyl. Hydrocarbon radicals containing a mixture of double bonds and triple bonds, such as 2-pentene-4-ynyl, are represented as alkynyls. Quinil does not include cycloalkynyl.

"Alkoxy" includes optionally substituted straight and branched-chain alkyl groups containing an oxygen atom at the end that binds the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, and so on. "Aminoalkyl", "thioalkyl" and "sulfonylalkyl" are analogues of alkoxy, where the final oxygen atom of alkoxy is replaced by, respectively, ΝΗ (or), 8 and 8О ₂ . Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl, and so on.

“Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, indenyl, etc., any of which may be optionally substituted. Aryl also includes an arylalkyl group such as benzyl, phenethyl, and phenylpropyl. Aryl includes ring systems containing an optionally substituted 6-membered carbocyclic aromatic ring, where the system may be bicyclic, bridged, and / or condensed. 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 containing carbon atoms in the ring and at least one heteroatom (O, 8, Ν) or a group with a heteroatom (8O ₂ , CO, CONN, COO). Unless otherwise indicated, the heterocyclic radical can have a valency that binds it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a hetero-atom, such as Ν-piperidyl or 1-pyrazolyl. Preferably, the monocyclic heterocyclyl contains from 5 to 7 ring atoms or from 5 to 6 ring atoms; can be from 1 to 5 heteroatoms or groups, including a heteroatom, in the ring and preferably from 1 to 3 or 1-2. Heterocyclyl can be saturated, unsaturated, aromatic (for example, heteroaryl), non-aromatic or condensed.

Heterocyclyl also includes fused, for example, bicyclic rings, such as

- 2 009553 necessarily condensed with an optionally substituted carbocyclic or heterocyclic five or six membered aromatic ring. For example, “heteroaryl” includes an optionally substituted six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms fused with an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring. Such heterocyclic five- or six-membered aromatic rings condensed with said five- or six-membered aromatic rings may contain 1, 2 or 3 nitrogen atoms, if it is a six-membered ring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, if it is a five-membered ring.

Examples of heterocycles are thiazolyls. , 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 include thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl.

“Acyl” refers to a carbonyl group attached to either a hydrogen atom (ie, a formyl group), or an optionally substituted alkyl or alkenyl chain, or heterocyclyl.

“Halogen” includes fluorine, chlorine, bromine and iodine, and preferably fluorine or chlorine, as a substituent for an alkyl group containing one or more halogen atoms, such as trifluoromethyl, trifluoromethoxy, trofluoromethylthio, difluoromethoxy, or fluoromethylthio.

“Alcandiyl” or “alkylene” include optionally substituted straight or branched divalent alkane radicals, such as, for example, methylene, ethylene, propylene, butylene, pentylene or hexylene.

“Alkenediyl” includes, as described above, optionally substituted straight or branched divalent alkene radicals, such as, for example, propenylene, butenylene, pentenylene or hexenylene. In such radicals, the carbon atom bound to the nitrogen atom should preferably not be unsaturated.

“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 above, two radicals together with the atom (s) to which they are attached can form optionally substituted 4-7, 5-7 or 5-6 membered rings, carbocyclic or heterocyclic rings, where such rings can be saturated , unsaturated or aromatic. These rings may be as defined above in the summary of the invention. Specific examples of such rings are presented in the next section.

“Pharmaceutically acceptable salts, esters and amides” include carboxylate salts, acid addition salts of amino acids, esters and amides, which, within a reasonable benefit / risk ratio, are pharmacologically effective and suitable for contact with the patient’s tissues without causing toxicity, irritation or allergic reaction. Such salts, esters, and amides can be, for example, C ₁ -C alkyl, C _3-8 cycloalkyl, aryl, C _2-10 heteroaryl, or C _2-1 hetero-aromatic heterocyclic salts, esters and amides. Salts, free acids and esters are more preferable than amides formed on the terminal group of the carboxylate / carboxylic acid in the left part of the formula (I). Examples of salts include hydrobromide, hydrochloride, sulphate, bisulphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, softenate, tartrate, acetate, citrate, tartrate, fumarate, succinate, tartrate; , glucoheptonate, lactiobionate and lauryl sulfonate. These may include alkali metal and alkaline earth metal cations, such as sodium, potassium, calcium and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as tetramethylammonium, methylamine, trimethylamine and ethylamine. See, for example, δ.Μ. Vegde, e1 a1., Ryatshaseiysak 8a1k, I. Ryatsh. 8st, 1977, 66: 1-19, which is incorporated here by reference. Examples of pharmaceutically acceptable amides of the invention include amides derived from ammonia, primary C1 _-6 alkyl amines and secondary di (C1 _-6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic rings containing at least one nitrogen atom and optionally from 1 to 2 additional heteroatoms. Preferred amides are derived from ammonia, C1 _-3 alkyl primary amines and di (C1 _-2 alkyl) amines. Examples of pharmaceutically acceptable esters of the invention include _C1-7 alkyl, _C5-6 cycloalkyl, phenyl, and phenyl ( _C1-6 ) alkyl esters.

Preferred esters are methyl and ethyl esters.

“Patient” or “object” refers to mammals, such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates), who have the need for observation, experiment, treatment or prevention of relevant diseases or conditions.

- 3 009553

Preferably, the patient or object is a human.

"Composition" includes a product containing certain ingredients in certain quantities, as well as any product that is obtained by combining certain ingredients in certain quantities.

A “therapeutically effective amount” means that amount of an active compound or pharmaceutical agent that causes a biological or medical response in an animal or human tissue system that is expected by a researcher, veterinarian, physician or other clinician who includes relief of symptoms of the condition or disorder being treated.

With regard to the various radicals presented in this description and in the claims, it is necessary to make three main points. The first remark concerns valency. As with all hydrocarbon radicals, whether they are saturated, unsaturated or aromatic, or whether they are non-cyclic, straight or branched, as well as all heterocyclic radicals, each radical includes substituted radicals of this type and monovalent, divalent and multi-valent radicals, as noted in the context of the claims. In the context, it is said that a substituent is alkylene or a hydrocarbon radical with at least two hydrogen atoms removed (divalent) or a large number of hydrogen atoms removed (multivalent).

An example of a bivalent radical that binds two parts of a molecule is Υ in formula (I), which binds phenyl substituted by B ₅ , B ₆ and B- with the rest of the molecule.

Secondly, it is believed that radicals or fragments of the structure, such as those described herein, include substituted radicals or fragments of the structure. Hydrocarbyls include monovalent radicals containing carbon atoms and hydrogen atoms, such as alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (aromatic or unsaturated), as well as corresponding divalent (or multivalent) radicals, such as alkylene, alkenylene, phenylene, etc. Heterocarbils include monovalent and bivalent (or multivalent) radicals containing carbon, optionally hydrogen, and at least one heteroatom. Examples of monovalent heterocarbyls include acyl, acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl, etc. If "alkyl" is used as an example, it is believed that "alkyl" includes substituted alkyl having one or more substituents, for example, from 1 to 5, from 1 to 3, and from 2 to 4 substituents. Substituents may be the same (dihydroxy, dimethyl), similar (chlorofluor) or different (chlorobenzyl or aminomethyl substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perhlormetil, 2-bromoethyl, trifluoromethyl, and 3-yodtsiklopentil), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl), aminoalkyl (such as aminomethyl, 2aminoetil, 3- aminopropyl and 2-aminopropyl), nitroalkyl, alkylalkyl, etc. The di (C _1-6 alkyl) amino group includes independently selected alkyl groups that form, for example, methylpropylamino and isopropylmethylamino, as well as dialkylamino groups having two identical alkyl groups, such as dimethylamino or diethylamino.

Third, only stable compounds are included.

For example, if there is a group of _{ΝΒ 1Ρ} Β ₁₂ and B may be an alkenyl group, the double bond is separated from the nitrogen atom by at least one carbon atom, to prevent the formation of enamine. Also, if - (CH ₂ ) _P- N (CH ₂ ) _H - is unsaturated, the corresponding hydrogen atom (s) is included or excluded, as shown in - (CH ₂ ) ^ = (CH) - (CH ₂ ) - or (CH ₂ ) -NH- (CH) = (CH) -.

Compounds in accordance with this invention are described in the following section.

B. Compounds.

This invention provides compositions and methods for using the compounds of formula (I) described in the Summary of the Invention section above. Examples include compounds in which: (a) one of B ₁ and B ₂ is methyl or ethyl; (B) each of B ₁ and B ₂ is methyl; (c) B ₁ and B ₂ , taken together, form cyclobutyl or cyclopentyl; (ά) B ₃ is H; (e) B ₄ is H or C _2-- alkyl; (e) B ₄ is H or C _2-5 alkyl; (D) B ₄ is ethyl; (e) B ₄ is H; (11) η is 1; (ί) η is 2; (|) Υ is ΝΗΟΗ _; ; (k) Υ is ΝΗ; (1) X is 8; (t) X is O; (η) at least one of B ₅ and B- is H; (o) B ₆ is C _1-4 alkyl, halogenmethoxy or halogeniomethoxy; (p) B ₆ is t-butyl, isopropyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethoxy, difluoromethoxy or dimethylamino; (with |) B ₃ is H, B ₄ is C _2-- alkyl and Υ is ΝΗ; (g) B ₄ is C _2-5 alkyl; (§) B ₆ is cyclopropylmethyl, isopropyl, isobutyl, methylethylamino or diethylamino; (ΐ) (8) the enantiomer in the C-2 position of indane or tetralin; (and) (B) the enantiomer in the C-2 position of indane or tetralin; (ν) ₁₅ is C _1-7 alkyl, [di _(C1-2 alkyl) amino] _(C1-6 alkylene), (C _1-3 alkoksiatsil) (C _1-6 alkylene), C _1-6 alkoxy, C _3-- alkenyl or C ₃ -alkynyl; (te) B ₆ is trifluoromethylthio or trifluoromethoxy; or (x) combinations of the above.

Additional preferred compounds include

- 4 009553

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

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

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

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

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

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

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

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

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

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

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

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

The most preferred compounds are selected from 2- {6- [1-ethyl-3- (4-trifluoromethoxyphenyl) ureido] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2methylpropionic acid;

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

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

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

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

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

- 5 009553

Related compounds.

The present invention provides the described compounds and closely related pharmaceutically acceptable forms of the described compounds, such as salts, esters, amides, acids, hydrates or solvated forms; masked or protected forms; and racemic mixtures or enantiomerically or optically pure forms. Related compounds also include compounds in accordance with this invention that have been modified to detect, for example, labeled with ¹⁸ E isotopes for use as a probe in positron emission tomography (PET) or single photon emission computed tomography (SPECT).

This invention also includes compounds having one or more functional groups (eg, hydroxyl, amino, or carboxyl) masked by a protecting group. See, for example, пе пе пе ап Ан Ан Ан Р Р Р Р Ог Ог Ог Ог уп 8 8 818, 3 ^| Some of these masked or protected compounds are pharmaceutically acceptable; others are used as intermediates. The synthetic intermediates and methods described herein and their minor modifications are also included in the scope of the present invention.

Hydroxyl protecting groups

Protection of the hydroxyl group includes methyl esters, substituted methyl esters, substituted ethyl esters, substituted benzyl esters, and silyl esters.

Substituted methyl esters.

Examples of substituted methyl ethers include methyloxymethyl, methylthiomethyl, tert-butylthiomethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, tertbutoxymethyl.

Substituted ethyl esters.

Examples of substituted ethyl esters include 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-methyl 1-benzyloxyethyl, 2,2,2-trichloroethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, and benzyl.

Substituted benzyl esters.

Examples of substituted benzyl esters include p-methoxybenzyl, 3,4-dimethoxybenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, diphenylmethyl.

Esters

In addition to the esters, the hydroxyl group can be protected by an ester. Examples of esters include formate, benzoyl formate, acetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, benzoate.

Sulfonates.

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

Amino protecting groups

Protection of amino groups includes carbamates, amides, and special —ΝΗ protective groups.

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

Carbamates

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

Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2-phenylethyl, tert-butyl, vinyl, allyl, 1-isopropyllyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4- dichlorobenzyl and diphenylmethyl.

Photolytically detachable protection.

Examples of photolytically cleavable protection include m-nitrophenyl, 3,5-dimethoxybenzyl, onitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl (o-nitrophenyl) methyl.

Amides.

Examples of amides include Ν-formyl, Ν-acetyl,-trichloroacetyl,-trifluoroacetyl,-phenylacetyl, Ν-3-phenylpropionyl, Ν-picolinoyl,-3-pyridylcarboxamide, Ν-benzoyl,-pyphenylbenzoyl and phtyloxy.

Carbonyl protection

Cyclic acetals and ketals.

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

Protection of the carboxyl group

Esters

Substituted methyl esters.

Examples of substituted methyl ethers 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 alkyl esters, such as tert-butyl, ethyl, propyl, isopropyl and butyl.

- 6 009553

Substituted benzyl esters.

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

Silyl esters.

Examples of silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, phenyldimethylsilyl and di-t-butylmethylsilyl.

C. Methods of synthesis.

The present invention provides methods for producing the described compounds according to traditional methods of organic synthesis, as well as matrix or combinatorial methods. Schemes 1-10 show the proposed synthesis methods. Using these schemes, the attached explanations and examples, a person skilled in the art can develop similar or similar methods for these compounds that are within the scope of this invention.

One skilled in the art will recognize that the synthesis of compounds in accordance with the present invention can be carried out using commercially available intermediates or protected intermediates described in any of the schemes presented here. One skilled in the art will also appreciate that during any process for making compounds in accordance with this invention, it may be necessary and / or desirable to protect sensitive or reactive groups of any molecules involved. This can be achieved by the use of conventional protective groups, such as those described in “Precedent Scoirs Огη Ogdash 8wiHe518”, οΐιη \ Upeu & 8op8. 1991. Such protective groups can be removed at an appropriate stage using methods known in the art.

Examples of the synthetic methods described include synthesis examples 1-57. Compounds similar to the target compounds of these examples can be, and in many cases, obtained by similar methods. The compounds described are used in baseline studies and as pharmaceutical agents described in the following section.

General leadership.

The preferred synthesis of the compound of formula 14, if X is δ (and K ₃ is H), is shown in Schemes 1-5.

Abbreviations or acronyms used below include: AcOH (glacial acetic acid);

ESS (1,3-dicyclohexylcarbodiimide);

ECE (1,2-dichloroethane);

E1C (2-dimethylaminoisopropyl chloride hydrochloride);

ΌΙΕΆ (diisopropylethylamine);

DMF (dimethylformamide);

EEC (1 - (3-dimethylaminopropyl) -3-ethylcarbodiimide);

EULS (ethyl acetate);

tsrva (3-chloroperoxybenzoic acid);

ΝΜΙ (1-methylimidazole);

TEA (triethylamine);

TEA (trifluoroacetic acid);

THF (tetrahydrofuran);

TMEEA (Ν, Ν, Ν ', Ν'-tetramethylethylenediamine).

Scheme 1

According to scheme 1, tetralines can be obtained 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, sodium triacetoxyborohydride, and the resulting oxime can be reduced by a catalytic method using palladium or platinum in a polar proton solvent, such as methanol, ethanol or ethyl acetate, to give the racemic compound 2. The preparation of hydrochloride can be easily carried out by a person skilled in the art.

- 7 009553

Scheme 2

---- * r0> *

According to scheme 2, indans can be obtained by converting compound 3 to compound 5. For example, when methoxyindanone, 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 an acid, such as hydrochloric acid acid or hydrobromic acid, in a polar solvent, such as methanol or ether, get keto-oxime 4. Reduction of compound 4 can be achieved using the appropriate reducing agent (s), such as lithium aluminum hydride or hydrogen and a catalyst such as palladium or platinum, in an appropriate solvent such as acetic acid-sulfuric acid, THF, or methanol at a suitable temperature. The choice of method for obtaining salt is determined by a person skilled in the art.

Scheme 3

According to scheme 3, compound 2 or 5 can be converted to compound 12. For example, when 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 is reacted with anhydride, such as phthalic anhydride, at elevated temperatures, cyclic imide 6 is obtained. The cleavage of methylaryl ethers of formula 6 to the compound of formula 7 can be carried out using Lewis acid, such as boron tribromide, boron trichloride, aluminum chloride Ia or trimethylsilyl iodide, in a nonpolar aprotic solvent such as toluene, dichloromethane, or dichloroethane with or without cooling. Acylation of the phenols of Formula 7 to the compound of Formula 8 can be carried out using thiocarbamoyl chlorides, such as dimethylaminothiocarbamoyl chloride or diethylthiocarbamoyl chloride, and a non-reactive tertiary amine, such as triethylamine, 1,8 diazabicyclo [5.4.0] undec-7-ε-δ-é-β-amines. diazabicyclo [2.2.2] octane, in an aprotic solvent such as dichloromethane, DMF or THF, with or without cooling. The compounds of formula 8 can be thermally rearranged into compounds of formula 9 at temperatures from 180 to 350 ° C, either in pure form or in a melt, or using high boiling point solvents such as EO \ UTNEVM® A (a mixture of biphenyl and biphenyl ether, commercially available from, for example, P1IKa Cisepa1 Sogr., Mitaekee, No. 1 (IL8),,-dimethylaniline, diphenyl ether or decalin. The compounds of formula 10 can be obtained from compounds of formula 9 by treatment with a suitable nucleophile, such as hydrazine, disodium sulfide or methylamine, in an appropriate polar solvent, such as ethanol or THF, at elevated temperatures. The conversion of a compound of formula 10 to a compound of formula 11 is carried out using an appropriate reagent, such as potassium hydroxide, in alcohol

- 8 009553 a solvent such as ethanol or methanol, or such as lithium aluminum hydride in 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. The compounds of formula 11 may be substituted to obtain compounds of formula 12 using a carboxylic acid or acid chloride, and an appropriate reducing agent, such as borane-THF or borane-dimethyl sulfide, using an aprotic solvent, such as THF, dichloromethane or hexane. Alternatively, the substitution can be carried out using an aldehyde and a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in a suitable aprotic solvent, such as THF, dichloromethane or dichloroethane.

Scheme 4

I * / H

YalyatRousogN about p- ⁷

O o ₁₃ or 13

Yavmtrammhoy

ABOUT

According to Scheme 4, compounds of formula 13 can be prepared from compounds of formula 12 by acylation of a secondary amine with arylacetic acid, using thionyl chloride or oxalyl chloride, pure or in toluene or dichloromethane, with or without catalytic DMF. Alternatively, the combination can be carried out using standard peptide conditions such as BFB, OCC or ΌΙί. ' in dichloromethane. If Υ is ΝΗ or O, aryl isocyanate or aryl chloroformate may be used, respectively, in a non-polar aprotic solvent, such as THF, dichloromethane or hexane, to give compounds of formula 13. The choice of deprotection method to obtain compounds of formula 14 is easily determined by a person skilled in the art .

Also, compounds of formula 16 can be obtained from compounds of formula 11 by acylation of the primary amine, as shown in Scheme 5, to obtain compounds of formula 15. It will be easy for the person skilled in the art to determine the choice of deprotection methods and to obtain compounds of formula 16.

- 9 009553

Scheme 6

The compound of formula 18 can be obtained from the 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, pure or in the presence of a suitable solvent, such as dichloromethane or dichloroethane, with or without heating obtaining compounds of formula 1-. Compounds of formula 1- can be converted to compounds of formula 18 with a suitable reagent, such as lithium aluminum hydride, in a suitable 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

Il * NzSgMD 2/5 20 HCS ^ About 21

The preferred synthesis of compounds of formula 21 when X is O (and B ₃ is H) is represented in the scheme: 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. Cleavage of the methylaryl ethers of formula 19 to compounds of formula 20 can be carried out using Lewis acid such as boron tribromide, boron trichloride, chloride aluminum or trimethylsilyl iodide, in a non-polar aprotic solvent, 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.

The compounds of formula 24 can be obtained from compounds of formula 22, as shown in Scheme 8. For example, a compound of formula 22 can be treated with an appropriate base, such as butyl lithium or sec-butyl lithium, in an appropriate solvent, such as ether or THF, using and cooling or without it, and the corresponding electrophilic, such as alkyl halides, aldehydes or disulfides, to obtain compounds of formula 23. Compounds of formula 23 can be converted into compounds of formula 24 according to the procedure described in scheme 3, for evrascheniya compound 8 to compound 9.

- 10 009553

An alternative synthesis of compounds of formula 32 is described in Scheme 9. For example, when 4-methylthiophenylacetic acid, formula 26, is treated with oxalyl chloride or thionyl chloride in the presence of methanol, a compound of formula 27 is obtained. Treatment of compounds of formula 27 with a Lewis acid, such as aluminum chloride, in a chlorinated solvent, such as chloroform or dichloroethane, in the presence of an alkene, such as ethylene, gives tetralones of formula 28. Using the procedure described in scheme 1, tetralins of formula 29 can be obtained. Compounds of formula 29 can be substituted to obtain compounds of Formula 30 using a carboxylic acid in the coupling conditions described above, 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 tsRBA or hydrogen peroxide, in a suitable solvent, such as methylene chloride, followed by treating the compounds of formula 30 with trifluoroacetic anhydride, with or without a solvent, such as chloroform, followed by by treating a tertiary amine, such as triethylamine or diisopropylethylamine, in a suitable solvent, such as methanol, to give compounds of formula 31. Alternatively, deprotect the thioether in compounds of formula 30 Can be achieved using a base, such as tert-butyl sodium sulfide, sodium, sodium methylthiol, in a suitable solvent, such as DMF, N-methyl-2-pyrrolidone or ammonia, to produce compounds of formula 31. Using a technique similar to that described in the scheme 3 to convert compound 10 to compound 11, compounds of formula 31 can be easily converted to compounds of formula 32.

According to scheme 10, compounds of formula 22 can be easily converted into compounds of formula 32a, where K ₃ is equal to OCH ₃ . For example, compounds of formula 22 may be treated with an appropriate base, such as butyl lithium or sec-butyl lithium, in a suitable solvent, such as ether or TTF, using TMEBA and with or without cooling, and an appropriate disulfide, such as dimethyl disulfide or dibenzyldisulfide, to give compounds of formula 33. Removal of dimethylaminothiocarbamate from compounds of formula 33 can be carried out using sodium hydroxide, in a suitable solvent, such as water, methanol or ethanol, with or without heating, with cheniem compounds of Formula 34. Compounds of Formula 34 can be methylated to afford compounds of formula 19a, by 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 a technique similar to that described in Scheme 9 to transform

- 11 009553 compounds of formula 30 in compounds of formula 32, compounds of formula 32a can be easily obtained from compounds of formula 19a.

Method 1.

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

Connection 1.0 (example 1).

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

Scheme 1. To a solution of 6-methoxy-2-tetralone (10.0 g; 56.7 mmol) dissolved in MeOH (400 ml), ammonium acetate (65 g; 0.84 mol) is added, and the reaction mixture is stirred in for 30 min at room temperature. Sodium cyanoborohydride (17.8 g; 0.28 mol) is then added to the reaction mixture and the reaction mixture is heated under reflux for 1-2 hours. The reaction mixture is cooled, the solvent is removed under reduced pressure, the residue is diluted with EALAc and 1N is added. ΝαΟΗ to stop the reaction. The aqueous phase is separated and the organic phase is washed with H ₂ O, brine, dried over Ν; · ι ₂ 8Ο ₄ . filtered and the solvent removed under reduced pressure to give a crude residue which was purified by flash chromatography (8ίΟ ₂₎ eluting with CH ₂ C1 ₂ / MeOH: MH ₄ OH (10%) to give 5.0 g (50%) of 6-methoxy -1,2,3,4-tetrahydronaphthalen-2-ylamine as a dark oil. HC1 (l) is bubbled into a solution of the title compound in ether (100 ml), cooled to 0 ° C, until the solution is saturated. The suspension is stirred for another 30 minutes at room temperature and the solvent is evaporated off under reduced pressure. The remaining solid is 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: SpN ^ O: t / ζ 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% No. 1H (6 g; 0.182 mmol) in DMF (400 ml) add 6methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine (30 g; 0.140 mol) in portions at 0 ° WITH. The reaction mixture is heated to room temperature and stirred for another 1 hour. Phthalic anhydride (20.7 g; 0.139 mol) is added in one portion at room temperature, the reaction mixture is stirred for another 1 h, followed by stirring for 18 hours at 120 ° s The reaction mixture is cooled to room temperature, diluted with H ₂ O, and extracted several times with EA. The combined organic extracts were washed with water, brine, dried over №8O ₄ and the solvent removed under reduced pressure. The crude solid is triturated with MeOH, filtered and dried in vacuo to give 29.1 g (67%) of 2- (6-methoxy-1,2,3,4-tetrahydronaphthalen-2yl) isoindole-1,3-dione as whitish solid.

-NMR (300 MHz, COCl ₃ ): 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: C1 ₉ H ₁₇ yes ₃ : t / ζ 308 (M + 1).

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

Scheme 3. To 2- (6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl) isoindole-1,3-dione (29 g; 94.3 mmol) dissolved in anhydrous CH ₂ C1 ₂ ( 500 ml), cooled to -60 ° C, add 1.0 M solution of tribromide boron-CH ₂ C1 ₂ (471 ml) dropwise, maintaining the reaction temperature from -50 to -60 ° C. After the addition is complete, the reaction mixture is warmed to room temperature and stirred for another 4 hours. The reaction mixture is cooled to 0 ° C, quenched with saturated NaHCΟ ₃ (400 ml) and stirred for another 0.5 h at room temperature. The precipitate is filtered, 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) isoindole-1,3 -dione as an off-white solid.

-NMR (300 MHz, DMSO-b ₆ ): δ 9.11 (brs, 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 (brs, 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: C1 ₈ H ^ O ₃ : t / ζ 294 (M + 1).

Ό. O- [6- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -5,6,7,8-tetrahydronaphthalen-2-yl) dimethylthiocarbamic acid ester.

Scheme 3. To 2- (6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl) isoindole-1,3-dione (25.4 g; 86.5 mmol) dissolved in anhydrous DMF (200 ml), add 1,4-diazabicyclo [2.2.2] octane (48.5 g; 4.32 mol), followed by treatment with dimethylaminothiocarbamoyl chloride (53.4 g; 4.32 mol), and the solution is stirred at room temperature in for 4 hours. The reaction mixture was poured into ice water (1 l) and

- 12 009553 is stirred for 18 h. The precipitate is filtered, washed with H ₂ O and dried in vacuum. The crude solid was purified by flash chromatography (81O ₂ ), eluting with a hexane-EULs gradient to give 30 g (91%) of O- [6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -5 compound , 6,7,8-tetrahydronaphthalen-2yl] dimethylthiocarbamic acid ester as a white solid.

¹ H-NMR (300 MHz, SES1 ₃ ): 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: C ₂₁ H ₂₀ ^ O ₃ 8: t / ζ 381 (M + 1).

E. An 8- [6- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -5,6,7,8-tetrahydronaphthalen-2-yl compound dimethylthiocarbamic acid ester.

Scheme 3. In a 50-ml round-bottom flask equipped with a reflux condenser and a stirrer, preheated to 330 ° C in a sand bath, add complex O- [6- (1,3-dioxo-1,3 dihydroisoindol-2-yl) -5 , 6,7,8-tetrahydronaphthalen-2-yl] ether of dimethylthiocarbamic acid (5.32 g; 13.9 mmol) in one portion. The melt is stirred for 7-8 minutes at 330 ° C, then rapidly cooled to room temperature with a flow of Ν ₂ . The crude residue is purified by flash chromatography (81O ₂ ), eluting with a hexane-EULs gradient to obtain 3.1 g (58%) of the complex 8- [6- (1,3 dioxo-1,3-dihydro-isoindol-2-yl) -5.6, 7,8-tetrahydronaphthalen-2-yl] dimethylthiocarbamic acid ester as a white solid.

¹ H-NMR (300 MHz, SES1 ₃ ): 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: C ₂ 1H _{2 (} C ₂ O ₃ 8: t / ζ 381 (M + 1).

R. Complex 8- [6-amino-5,6,7,8-tetrahydronaphthalen-2-yl] dimethylthiocarbamic acid ester.

Scheme 3. In a three-neck flask equipped with a reflux condenser and a mechanical stirrer, E1OH (115 ml) and a complex 8- [6- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -5,6,7 are charged. , 8-tetrahydronaphthalen-2-yl] ether of dimethylthiocarbamic acid (8.7 g; 23.5 mmol). Hydrazine (6.6 ml; 2.11 mol) is added in one portion at room temperature and the reaction mixture is heated under reflux with mechanical stirring for 40 minutes. The reaction mixture is cooled to room temperature and the gelatinous white solid is filtered and thoroughly washed with ether. The ether washes were combined, evaporated under reduced pressure and the crude residue was triturated with ether, filtered and the ether evaporated under reduced pressure to give 6.1 g (100%) of 8- [6-amino-5,6,7,8-tetrahydronaphthalene -2-silt] dimethylthiocarbamic acid ester as a yellow oil.

LC / MS: C1 ₃ H ₁₈ ^ O8: t / ζ 251 (M + 1).

C. 2- (6-Amino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl) -2-methyl propionic acid t-butyl ester.

Scheme 3. To the complex 8- (6-amino-5,6,7,8-tetrahydronaphthalen-2-yl) dimethylthiocarbamic acid ester (6.1 g; 24.4 mmol), dissolved in MeOH (25 ml), is added KOH solution (4.1 g; 73.2 mmol) in MeOH (25 ml) at room temperature. The solution is stirred at reflux for 5 hours and cooled to room temperature. Tert-butyl-2-bromoisobutyrate (16.3 g; 73.2 mmol) is added to the solution and stirred for 16 hours at room temperature. NaΒH ₄ (9.2 g; 2.44 mol) is added and the reaction mixture is stirred for another 48 h at room temperature. The reaction mixture was quenched with H ₂ O, the solvent was evaporated under reduced pressure, and the crude residue was partitioned between H ₂ O and CH ₂ Cl ₂ . The aqueous phase is extracted with CH ₂ Cl ₂ and the combined organic extracts are dried over No. ₂ 8O ₄ , filtered and evaporated under reduced pressure to give 4.7 g (60%) of t-butyl 2- (6-amino-5.6, 7.8 tetrahydronaphthalen-2-ylsulfanyl) -2-methylpropionic acid as a brown oil.

LC / MS: C1 ₈ 1H ^ O ₂ 8: t / ζ 266 (M + 1).

N. 2- (6-Acetylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl) -2-methyl propionic acid t-butyl ester.

Scheme 3. To tert-butyl ester of 2- (6-amino-5,6,7,8-tetrahydronaphthalen-2ylsulfanyl) -2-methylpropionic acid (4.7 g; 14.6 mmol) dissolved in CH ₂ Cl ₂ (25 ml), EHEA (3.3 ml; 18.9 mmol) is added and the reaction mixture is cooled to 0 ° C. Acetyl chloride (1.25 ml; 17.5 mmol) is added dropwise at such a rate as to maintain the temperature from 0 to 5 ° C. The reaction mixture is warmed to room temperature and stirred for 16 hours. The reaction mixture is diluted with CH ₂ Cl ₂ , washed with H ₂ O, dried over No. ₂ 8 O ₄ and evaporated under reduced pressure. The crude oil is purified by flash chromatography (81O ₂ ), eluting with a hexane-EYUA gradient to give 1.7 g (32%) of 2- (6-acetylamino-5,6,7,8-tetrahydronaphthalen-2ylsulfanyl) t-butyl ester -2-methylpropionic acid as a tan solid.

-NMR (300 MHz, SES1 ₃ ): 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),

- 13 009553

1.43 (s, 15H).

LC / MS: C ₂₀ H ₂ ^ O ₃ 8: t / ζ 308 (M + 1).

I. 2- (6-Ethylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl) -2-methyl propionic acid t-butyl ester.

Scheme 3. To a solution of tert-butyl ester of 2- (6-acetylamino-5,6,7,8 tetrahydronaphthalen-2-ylsulfanyl) -2-methylpropionic acid (1.7 g; 4.64 mmol) in THF (42 ml ) add a solution of 1.0 M borane-THF (42 ml) dropwise at room temperature. The reaction mixture is stirred for 18 hours at room temperature, carefully quenched with MeOH, and the solvent is evaporated off under reduced pressure. The residual oil is subjected to azeotropic distillation with MeOH (3x) to give 1.9 g (100%) of a mixture of 2- (6-ethylamino-5,6,7,8 tetrahydronaphthalen-2-ylsulfanyl) -2-methylpropionic acid t-ester and its borane complex as an oil.

LC / MS: C ₂₀ H ₃ ^ O ₂ 8-BH ₃ : t / ζ 308 ((M + BH ₃ ) +1).

I. 2- {6- [1-ethyl-3- (4-trifluoromethoxyphenyl) ureido] -5,6,7,8 tetrahydronaphthalen-2-ylsulfanyl} -2-methylpropionic acid t-butyl ester.

Scheme 4. To a mixture of tert-butyl ester of 2- (6-ethylamino-5,6,7,8-tetrahydronaphthalen-2ylsulfanyl) -2-methylpropionic acid and borane complex (1.9 g; 5.2 mmol), dissolved in CH ₂ Cl ₂ (15 ml), 4-trifluoromethoxyphenyl isocyanate (1.6 g; 7.8 mmol) is added and the reaction mixture is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and the crude residue is purified by flash chromatography ( 81O _2), eluting with a gradient geksanEYuAs to give 1.66 g (58%) of tert-butyl 2- {6- [1-ethyl-3- (4triftormetoksifenil) Ur to] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2-methylpropionic acid as a white foam.

LC / MS: SCh11 _; , 1 + Ν <+8: t / ζ 497 ((M-CHV) +1).

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

Scheme 4. To tert-butyl ester of 2- {6- [1-ethyl-3- (4-trifluoromethoxyphenyl) ureido] 5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2-methylpropionic acid (1, 66 g; 3.0 mmol) dissolved in CH ₂ Cl ₂ (15 ml), TEA (15 ml) is added and the reaction mixture is stirred at room temperature for 1.5 hours. The solvent is removed under reduced pressure and the residue is purified by flash chromatography ( 81O ₂ ), eluting with a hexane-EYUAc gradient to obtain 0.643 g (43%) of 2- {6- [1-ethyl-3- (4 trifluoromethoxyphenyl) ureido] -5,6,7,8-tetrahydronaphthal-2-ylsulfanyl} - 2-methylpropionic acid as white o solid matter.

-NMR (300 MHz, SOzOC): 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: C ₂₄ H ₂₇ E ^ ₂ O ₄ 8: t / ζ 294 (M + 1).

Method 2

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

Connection 2.0 (example 2).

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

Scheme 2. To a solution of 5-methoxyindan-1-one (75.8 g; 0.467 mol) in MeOH (1.4 l) at 45 ° C, butyl nitrite (81 ml; 0.693 mol) is added dropwise over 45 minutes. Then, concentrated HC1 (45 ml) is added to the hot solution for 20 minutes and the reaction mixture is stirred at 45 ° C for another 1.5-2 hours. The reaction suspension is cooled, the precipitate is filtered, washed several times with cold MeOH and dried under vacuum obtaining 55.8 g (62%) of 5-methoxyindan-1,2-dione-2-oxime as a beige solid.

¹ H-NMR (300 MHz, CO ₃ OP): δ 7.80-7.83 (m, 1H), 6.95 (brs, 2H), 3.92 (s, 3H), 3.78 (s, 2H), 3.47 (brs, 1H).

LC / MS: C ₁₀ N <^ O ₃ : t / ζ 192 (M + 1).

B. 5-Methoxyindan-2-ylamine hydrochloride.

Scheme 2. To 5-methoxyindan-1,2-dione-2-oxime (55.7 g; 0.291 mol) suspended in glacial acetic acid (0.99 l), add concentrated H ₂ O ₄ (67 ml) with followed by addition of 10% Ph-C (27 g) and the reaction mixture was stirred in a Parr apparatus under h ₂ at 60 lb / ⁱⁿ² for 18 h. The reaction mixture was purged with Ν _2, filtered through a pad of celite and pro

- 14 009553 wash AcOH. The solvent is removed under reduced pressure to 1/5 of the volume and the remaining solvent is diluted with H ₂ O (500 ml), cooled to 0 ° C and neutralized to pH 10 by the addition of 50% aqueous No. 1OH. The aqueous phase is extensively extracted with CHC1 ₃ several times and the extracts are combined, washed with H ₂ O, brine, dried over Ν ₂ 8Ο ₄ , filtered and evaporated under reduced pressure to obtain 77.3 g (66%) of crude oil. The oil is purified by flash chromatography (81O ₂ ), eluting with 40: 2.2: 0.2 CHC1 ₃ : MeOH: MH ₄ OH, to give 43.8 g (37%) of a dark oil. The oil is dissolved in ether (1 l), cooled to 0 ° C and the solution is saturated with HC1 (l). The solvent is removed under reduced pressure and the solid is triturated with ether, filtered and washed with ether to obtain 43.8 g (30%) of 5-methoxyindan-2-ylamine hydrochloride as a white solid.

-NMR (300 MHz, C1HO1)): 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: SyuN ^ O ₃ : t / ζ 192 (M + 1).

Mp = 240-241 ° C.

C. 2- (5-Methoxyindan-2-yl) isoindole-1,3-dione.

Scheme 3. To a suspension of 60% NaH (8 g; 0.240 mol) in DMF (250 ml), cooled to 0 ° C, add 5-methoxyindan-2-ylamine hydrochloride (40.0 g; 0.2 mol) and suspension stirred for 1 h at room temperature. Phthalic anhydride (30 g; 0.2 mol) is added in one portion and the suspension is stirred for another 1-1.5 h at room temperature, followed by stirring at 120 ° C for 96 h. The reaction mixture is cooled and diluted with ULF. The organic phase is washed with H ₂ O, the resulting precipitate is filtered, washed with EUAc, MeOH and dried in vacuo to give 25.2 g (43%) of 2- (5-methoxyindan-2-yl) isoindole-1,3-dione as white solid matter. The organic phase is washed with H2O, evaporated under reduced pressure and the solid is triturated with MeOH, filtered and dried to give another 19.7 g (33%) of 2- (5-methoxyindan-2-yl) isoindole-1,3-dione as white solid.

-NMR (300 MHz, C1HO1)): 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: C1 ₈ H ^ O ₃ : t / ζ 294 (M + 1).

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

Scheme 3. To 2- (5-methoxyindan-2-yl) isoindole-1,3-dione (19.7 g; 67 mmol), dissolved in anhydrous CH ₂ C1 ₂ (350 ml) and cooled to -60 ° C , add a 1.0 M solution of tribromide boron-CH ₂ C1 ₂ (340 ml) dropwise at such a rate as to maintain the temperature of the reaction mass from -50 to -60 ° C. The reaction mixture is heated to room temperature and stirred for another 5 hours. The reaction mixture is cooled to 0 ° C, quenched with saturated NaHCΟ ₃ (500 ml) and stirred for another 0.5 h at room temperature. The precipitate is filtered, washed with H2O, suspended in ether, filtered and dried in vacuo to give 14.8 g (79%) of 2- (5-hydroxyindan-2-yl) isoindole-1,3-dione as a beige solid.

-NMR (300 MHz, DMSO-6 ₆ ): 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: C-11- _; \ About _; : t / ζ 280 (M + 1).

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

Scheme 3. To 2- (5-hydroxyindan-2-yl) isoindole-1,3-dione (31 g; 0.11 mol) dissolved in anhydrous DMF (400 ml), add 1,4-diazabicyclo [2.2. 2] octane (62 g; 0.55 mol) followed by treatment with dimethylaminothiocarbamoyl chloride (68 g; 0.55 mol) and the solution is stirred at room temperature for 16 hours. The reaction mixture is poured into ice water (1L) and stirred for 18 h. The precipitate is filtered, washed with H2O and dried in vacuum to obtain 41.6 g (100%) of the O [2- (1,3-dioxo-1,3-dihydroisoindol-2-yl) indan-5-yl] ether complex dimethylthiocarbamic acid in the form of beige Verdi substances.

Я-NMR (300 MHz, SOS): 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).

C. Complex 8- [2- (1,3-dioxo-1,3-dihydroisoindol-2-yl) indan-5-yl] dimethylthiocarbamic acid ester.

Scheme 3. In a 50-ml round-bottom flask equipped with a reflux condenser and stirrer, preheated to 330 ° C in a sand bath, add complex O- [2- (1,3-dioxo-1,3 dihydro-isoindol-2-yl) indane- Dimethylthiocarbamic acid 5-sulphate] ester (6.30 g; 18.7 mmol) in one portion. The melt is stirred for 12 minutes at 338 ° C, then rapidly cooled to room temperature with a flow of Ν ₂ and the crude residue is purified by flash chromatography (81O ₂ ), eluting with a hexane-EYAA gradient to obtain 3.88 g (61%) of a complex 8- [2- (1,3-Dioxo-1,3dihydroisoindol-2-yl) dimethylthiocarbamic acid ester as an off-white solid.

Ή-NMR (300 MHz, SOS): 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),

- 15 009553

3.59-3.67 (m, 2H), 3.06-3.23 (m, 9H).

LC / MS: C ₂₀ N ₁₈ S ₂ O ₃ 8: t / ζ 367 (M + 1).

H. Complex 8- (2-aminoindan-5-ilovy) dimethylthiocarbamic acid ester.

Scheme 3. In a three-necked flask equipped with a reflux condenser and mechanical stirrer, EYUN (98 ml) and complex 8- [6- (1,3-dioxo-1,3-dihydroisoindol-2-yl) indan-5-yl] are loaded dimethylthiocarbamic acid ester (6.9 g; 20.6 mmol). Hydrazine (5.8 ml; 186 mmol) is added in one portion at room temperature and the reaction mixture is heated under reflux with mechanical stirring for 30 minutes. The reaction mixture is cooled to room temperature and the gelatinous white solid is filtered and washed with ether several times. The ether washes were combined, evaporated under reduced pressure and the crude residue was triturated with ether, filtered and the ether evaporated under reduced pressure to give 4.6 g (95%) of dimethylthiocarbamic acid 8- (2-aminoindan-5-yl) ether brown oil.

-NMR (300 MHz, SBS1 ₃ ): 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 (brs, 2H).

LC / MS: C ₁₂ H ₁₆ N ₂ O8: m / ζ 237 (M + 1).

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

Scheme 3. To the complex 8- (2-aminoindan-5-yl) dimethylthiocarbamic acid ester (4.9 g; 20.9 mmol) dissolved in MeOH (60 ml) add a solution of KOH (11.8 g; 0.210 mol) in MeOH (110 ml) at room temperature. The solution is stirred at reflux for 5 hours and cooled to room temperature. Tert-butyl 2-bromoisobutyrate (7.0 g; 31.3 mmol) is added to the solution and stirred for 18 hours at room temperature. The solvent is evaporated off under reduced pressure and the crude residue is partitioned between H ₂ O and EYAAc. The aqueous phase is extracted with EUAc and the combined organic extracts are washed with H ₂ O, brine, dried over A ₂ O ₄ , filtered, and evaporated under reduced pressure to give 4.9 g (76%) of t-butyl 2- (2- aminoindan-5-ylsulfanyl) -2methylpropionic acid as a brown oil.

LC / MS: C ₁₇ H ₂₅ CU ₂ 8: t / ζ 308 (M + 1).

1. 2- (2-acetylaminoindan-5-ylsulfanyl) -2-methylpropionic acid t-butyl ester.

Scheme 3. To 2- (2-aminoindan-5-ylsulfanyl) -2-methylpropionic acid tert-butyl ester (14.6 g; 47.4 mmol) dissolved in CH2Cl2 (100 ml) add TEA (8.6 ml 61.7 mmol) and the reaction mixture is cooled to 0 ° C. Acetyl chloride (4.1 ml; 57.6 mmol) is added dropwise at such a rate as to maintain the temperature from 0 to 5 ° C. The reaction mixture is warmed to room temperature and stirred for 16 hours, diluted with CH ₂ C ₁₂ , washed with H ₂ O, dried over A ₂ O ₈ O ₄ and evaporated under reduced pressure. The crude oil is purified by flash chromatography (8U ₂ ), eluting with a hexane-EYUA gradient to give 11.7 g (71%) of 2- (2-acetylaminoindan-5-ylsulfanyl) -2-methylpropionic acid tert-butyl ester as a beige solid.

-NMR (300 MHz, SBS1 ₃ ): δ 7.31-7.35 (m, 2H), 7.15-7.18 (d, 1H), 5.73 (m, 1H), 4.68 -4.78 (m, 1H), 3.253.39 (dd, 2H), 2.74-2.80 (d, 2H), 1.94 (s, 3H), 1.43 (s, 15H).

LC / MS: C1 ₉ H ₂₇ SO ₃ 8: t / ζ 294 (M + 1).

K. 2- (2-Ethylaminoindan-5-ylsulfanyl) -2-methylpropionic acid t-butyl ester.

Scheme 3. To a solution of tert-butyl ester of 2- (2-acetylaminoindan-5-ylsulfanyl) -2methylpropionic acid (11.7 g; 33.5 mmol) in THF (280 ml) add a 1.0 M solution of borane-THF (226 ml) drop by drop at room temperature. The reaction mixture is stirred for 5 hours at room temperature, cooled to 0 ° C., quenched with MeOH (100 ml) and evaporated under reduced pressure. The residual oil is subjected to azeotropic distillation with MeOH (3x) to give 11 g (100%) of a mixture of 2- (2-ethylaminoindan-5-ylsulfanyl) tert-butyl ester and -2-methyl propionic acid and its borane complex as an oil.

LC / MS: C1 ₉ H ₂₉ SO _{2 2} -BH ₃ : t / ζ 336 ((M + BH ₃ ) +1).

B. 2- {2- [1-ethyl-3- (4-trifluoromethoxyphenyl) ureido] indan-5ylsulfanyl} -2-methylpropionic acid t-butyl ester.

Scheme 4. To a mixture of 2- (2-ethylaminoindan-5-ylsulfanyl) tert-butyl ester and 2-methyl propionic acid and borane complex (11.0 g; 33 mmol) dissolved in CH ₂ Cl ₂ (100 ml), add 4 trifluoromethoxyphenyl isocyanate (10.2 g; 50.2 mmol) and the reaction mixture is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and the crude residue is purified by flash chromatography (8U ₂ ), eluting with a hexane-EYAc gradient to obtain 11 , 2 g (62%) of 2- {2- [1-ethyl-3- (4-trifluoromethoxyphenyl) ureido] indan5-ylsul tert-butyl ester Anil} -2-methylpropionic acid as a white foam.

- 16 009553

-NMR (300 MHz, SOS1 ₃ ): δ 7.30-7.36 (m, 4H), 7.10-7.19 (m, 3H), 6.31 (s, 1H), 4.97 -5.08 (m, 1H), 3.223.39 (m, 4H), 3.01-3.09 (dd, 2H), 1.42-1.44 (m, 15H), 1.23-1 , 28 (t, 3H).

LC / MS: C ₂₇ H ₃₃ P ₃ S ₂ O ₄ 8: t / ζ 483 ((M – C ₄ H ₈ ) +1).

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

Scheme 4. To t-butyl ester of 2- {2- [1-ethyl-3- (4-trifluoromethoxyphenyl) ureido] indan-5-ylsulfanyl} -2-methylpropionic acid (4.8 g; 8.91 mmol) dissolved in CH ₂ Cl ₂ (15 ml), TTL (15 ml) is added and the reaction mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (81O ₂ ), eluting with a gradient of hexane. EULS to yield 3.13 g (73%) of 2- {2- [1-ethyl-3- (4 trifluoromethoxyphenyl) ureido] indan-5-ylsulfanyl} -2-methylpropionic acid as a white solid.

-NMR (300 MHz, SOS1 ₃ ): δ 7.29-7.35 (m, 4H), 7.15-7.17 (d, 1H), 7.08-7.11 (d, 2H) , 6.45 (s, 1H), 4.945.04 (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: C ₂₃ H ₂₅ R ₃ S ₂ O ₄ 8: t / ζ 483 (M + 1).

Mp = 73-77 ° C.

The following 14 compounds are prepared according to the procedures presented in Schemes 3 and 4 and in Stages 1, K, L and M of Method 2, replacing the reagents and adjusting the reaction conditions as necessary.

(8) -2- {2- [1-Ethyl-3- (4-trifluoromethoxyphenyl) ureido] indan-5-ylsulfanyl} -2-methylpropionic acid.

Connection 2.1 (example 3).

Intermediate compound b (11 g) of method 2 was separated by chiral chromatography (syna1 c column; isocratic hexane / methanol / ethanol gradient: 92/4/4) to give (8) intermediate cc b (4.8 g). According to the method of stage M of method 2, compound 2.1 (3.1 g) is obtained.

LC / MS: C ₂₃ H ₂ 5p ₃ S ₂ O ₄ 8: t / ζ 483 (M + 1).

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

Compound 2.2 (Example 4).

Compound 2.2 (0.33 g; 57% from two stages; white solid) is obtained by method 2, replacing 4-trifluoromethoxyphenyl isocyanate with 4-trifluorothiomethoxyisocyanate.

-NMR (CO ₃ OP): 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: C ₂₃ H ₂ 5p ₃ S ₂ O ₃ 8 ₂ : t / ζ 4 99 (M + 1).

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

Connection 2.3 (example 5).

Compound 2.3 (0.22 g; 32% from two stages; white solid) is obtained by method 2 using compound 2.2, replacing acetyl chloride with valeryl chloride.

Ή-NMR (CO ₃ OE): 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).

- 17 009553

LC / MS: C ₂₆ H ₃₁ E ^ ₂ O ₃ 8 ₂ : t / ζ 541 (M + 1).

2- {2- [1-Ethyl-3- (4-isopropylphenyl) ureido] indan-5-ylsulfanyl} -2-methylpropionic acid. Connection 2.4 (example 6).

Compound 2.4 (0.18 g; 34% from two stages; white solid) was prepared by method 2, replacing 4-trifluoromethoxyphenyl isocyanate with 4-isopropylphenyl isocyanate.

Ή-NMR (CO ₃ OP): 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, 3Η), 7.23 -7.26 (m, 2H), 7.32-7.50 (m, 2H), 7.40 (s, 1H).

LC / MS: C-, 11 ₃ TO _; 8: t / ζ 441 (M + 1).

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

Connection 2.5 (example 7).

Compound 2.5 (0.34 g; 66% from two stages; white solid) is prepared by method 2, replacing 4-trifluoromethoxyphenyl isocyanate with 4-dimethylaminophenyl isocyanate.

Ή-NMR (CO ₃ OP): δ 1.15-1.20 (t, 3Η), 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, 3Η), 7.29-7.41 (m, 2H).

LC / MS: C ₂₄ H ₃ ^ ₃ O ₃ 8: t / ζ 442 (M + 1). 2-Methyl-2- {2- [1-pentyl-3- (4-trifluoromethoxyphenyl) ureido] indan-5-ylsulfanyl} -2methylpropionic acid.

Connection 2.6 (example 8).

Compound 2.6 (0.29 g; 77% from two stages; white solid) is prepared by method 2, replacing acetyl chloride with valeryl chloride.

Ή-NMR (CO ₃ OP): δ 0.847-0.893 (t, 3Η), 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, 3Η), 7.32-7.34 (m, 1H), 7.40-7.45 (m, 3Η).

LC / MS: C ₂₆ H ₃₁ P ^ ₂ O ₄ 8: t / ζ 525 (M + 1).

Connection 2.7 (example 9).

Compound 2.7 (0.25 g; 36% from two stages; white solid) is obtained by method 2 with the use of compound 2.5, replacing the acetyl chloride with valeryl chloride.

Ή-NMR (ΟΌ ₃ ΟΌ): 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: 0 ₂₇ Η ₃₇ ₃ ₃ 8: t / ζ 484 (M + 1). 2- {2- [3- (4-Isopropylphenyl) -1- (3-pentyl) ureido] indan-5-ylsulfanyl} -2-methylpropionic acid.

Connection 2.8 (example 10).

Compound 2.8 (5 mg; 14% from two stages; white solid) is obtained by method 2 using compound 2.4, replacing acetyl chloride with valeryl chloride.

LC / MS: 0 ₂₈ Η ₃₈ ₂ ₃ δ: t / ζ 483 (M + 1).

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

Connection 2.9 (example 11).

Compound 2.9 (4 mg; 9% from two stages; white solid) is obtained by method 2 using compound 2.3, replacing 4-trifluorothiophenyl isocyanate with 4-tert-butylphenyl isocyanate.

LC / MS: C ₂₉ H ₄₀ ) ₂ ₃ 8: t / ζ 497 (M + 1).

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

Compound 2.10 (3 mg; 7% from two stages; white solid) is obtained by method 2 using compound 2.3, replacing the 4-trifluorothiophenyl isocyanate with 4-biphenylyl isocyanate.

LC / MS: ^ ιΗ ₃₆ Ν ₂ ₃ 8: t / ζ 517 (M + 1).

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

Connection 2.11 (example 13).

- 19 009553

Compound 2.11 (13 mg; 44% from two stages; oil) is obtained by method 2 using the compound

2.4, replacing valerylchloride on caproyl chloride.

LC / MS: C ₂₉ H _{4 (} ) ₂ Θ ₃ 8: t / ζ 497 (M + 1).

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

Compound 2.12 (18 mg; 54% from two stages; white solid) is prepared by method 2, replacing valeryl chloride with caproyl chloride.

LC / MS: C ₂₇ H ₃₃ P ^ ₂ O ₄ 8: t / ζ 539 (M + 1). 2-Methyl-2- {2- [1-hexyl-3- (4-trifluoromethylsulfanylphenyl) ureido] indan-5-ylsulfanyl} propionic acid.

Connection 2.13 (example 15).

Compound 2.13 (14 mg; 36% from two stages; white solid) is obtained by method 2 using compound 2.2, replacing valeryl chloride with caproyl chloride.

LC / MS: C ₂₇ H ₃₃ P ^ ₂ O ₃ 8 ₂ : t / ζ 555 (M + 1).

Connection 2.14 (example 16).

Compound 2.14 (1.2 mg; 3% from two stages; oil) is obtained by method 2, replacing acetyl chloride with propionyl chloride.

LC / MS: C ₂₄ H ₂₇ P ^ ₂ O ₃ 8: t / ζ 4 97 (M + 1).

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

- 20 009553

Connection 2.15 (example 17).

Connection 2.15 (11 mg; 32% from two stages; oil) is obtained by method 2 using the compound

2.2, replacing acetyl chloride with butyryl chloride.

LC / MS: C ₂₅ H ₂₉ E ₃ ^ Oz8 ₂ : t / ζ 527 (Μ + 1).

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

Compound 2.16 (11 mg; 4 9% from two stages; oil) is obtained by method 2, acylating 4 trifluoromethoxyphenyl isocyanate.

LC / MS: C 1 H ₂₁ ₂ E ^ _s ₂ O 8: m / ζ 455 (M + 1).

Method 3

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

Connection 3.0 (example 19).

To the complex tert-butyl ester of 2- (2-aminoindan-5-ylsulfanyl) -2-methylpropionic acid (0,220 g; 0,72 mmol), dissolved in BSE (4 ml), add pent-4-enal (0,060 mg; 0.72 mmol) followed by addition of sodium triacetoxyborohydride (0.21 g; 1.0 mmol) and the reaction mixture is stirred for 18 hours at room temperature. The reaction mixture was diluted with CH2Cl2, washed with H ₂ O, brine, dried over Να ₂ 80. ₄ . filtered and the solvent is evaporated under reduced pressure to obtain the t-butyl ester of 2-methyl-2- (2-pent-4enylaminoindan-5-ylsulfanyl) propionic acid as a crude oil.

Compound 3.0 (0.149 mg; 40% from three stages; white solid) is obtained by Method 2, Stages B and M, by acylation of 4-trifluoromethoxyphenyl isocyanate.

LC / MS: C ₂₆ H ₂₉ E _c ^ O ₄ 8: t / ζ 522 (Μ + 1).

The following 2 compounds are obtained according to the methods presented in schemes 3 and 4, method 3, stages b and M of method 2, replacing the reagents and adjusting the reaction conditions if necessary:

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

Connection 3.1 (example 20).

Compound 3.1 (13 mg; 29% from three stages; white solid) is obtained by method 3, replacing pent-4-enal with isobutyraldehyde and acylating with 4-trifluoromethoxyphenyl isocyanate.

LC / MS: C ₂₆ H ₃₁ E _c ^ O ₄ 8: t / ζ 525 (M + 1).

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

- 21 009553 acid.

Compound 3.2 (Example 21).

Compound 3.2 (11 mg; 27% from three stages; white solid) is obtained by method 3 using compound 3.1, replacing the 4-trifluoromethoxyphenyl isocyanate with 4-isopropylphenyl isocyanate.

-NMR (SOZOO): 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: C ₂₈ H ₃₈ ^ O ₃ 8: t / ζ 483 (M + 1).

The following 3 compounds are obtained according to the methods presented in schemes 1 and 3, stages 1 and K of method 1, replacing the reagents and adjusting the reaction conditions, if necessary.

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

Compound 1.1 (Example 22).

Compound 1.1 (41 mg; 68% from two stages; white solid) is obtained by method 1, replacing acetyl chloride with butyryl chloride.

LC / MS: C ₂₆ N ₃₁ B ^ ₂ O ₄ 8: t / ζ 525 (M + 1).

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

Connection 1.2 (example 23).

ABOUT

Compound 1.2 (23 mg; 34% from two stages; white solid) is obtained by method 1 using compound 1.1, replacing acetyl chloride with butyryl chloride and 4-trifluoromethoxyphenyl isocyanate with 4-trifluorothiophenyl isocyanate.

LC / MS: C ₂₆ N ₃₁ B ₃ ^ O ₃ 8 ₂ : t / ζ 541 (M + 1).

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

Compound 1.3 (Example 24).

Compound 1.3 (36 mg; 57% from two stages; white solid) is obtained by method 1, replacing acetyl chloride with caproyl chloride.

LC / MS: C- ₈ 11 _; , GDO ₄ 8: t / ζ 553 (M + 1).

The following 2 compounds are prepared according to the procedures presented in Schemes 3 and 4 and the stages b and M of method 2, replacing the reagents and adjusting the reaction conditions as necessary.

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

- 22 009553

Connection 2.17 (example 25).

Compound 2.17 (0.018 g; 19% from three stages; white solid) is obtained by method 2, replacing the 4-trifluoromethoxyphenyl isocyanate with 3-bromo-4-trifluoromethoxyphenyl isocyanate. To 3-bromo-4 trifluoromethoxyaniline (0.214 g; 0.836 mmol) in THF (1 ml) was added di-tert-butyl dicarbonate (0.255 g; 1.17 mmol) followed by the addition of 4-dimethylaminopyridine (0.102 g; 0.835 mmol). After cessation of rapid foaming (30 minutes), a solution of 2- (2ethylaminoindan-5-ylsulfanyl) -2-methylpropionic acid t-butyl ester (0.058 g; 0.167 mmol) in THF (1 ml) is added and the reaction mixture is stirred for 18 h at room temperature.

The title compound is prepared according to the procedures of steps K and b of method 2.

LC / MS: C ₂₃ H ₂₄ Bg ^ ₂ O ₄ 8: t / ζ 563 (M + 1).

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

Connection 2.18 (example 26).

Compound 2.18 (13 mg; 12% from three stages; white solid) was prepared according to the procedure of Example 2.0, replacing 4-trifluoromethoxyphenyl isocyanate with 3-trifluoromethoxyphenyl isocyanate. To a solution of carbonyldiimidazole (0.454 g; 2.8 mmol) in THF (2 ml), heated to 50 ° C, add 3 trifluoromethoxyaniline (0.522 g; 2.94 mmol) dropwise. After 15 min, the reaction mixture is cooled and added to a solution of 2- (2-ethylaminoindan-5-ylsulfanyl) tert-butyl ester (2-ethyl-propionic acid (0.077 g; 0.22 mmol)) in THF (1 ml).

LC / MS: C ₂₃ H ₂₅ E ^ ₂ O ₄ 8: t / ζ 483 (M + 1).

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

Connection 2.19 (example 27).

A. Complex 8- (2-formylaminoindan-5-yl) dimethylthiocarbamic acid ester.

Scheme 6. To the complex 8- [2-aminoindan-5-yl) dimethylthiocarbamic acid ester (2.0 g; 8.46 mmol) in CHC1 ₃ (10 ml) add ethyl formate (50 ml) and the reaction mixture is heated to 55 ° C for 24 hours. The reaction mixture is cooled, the solvent is removed under reduced pressure and the crude oil is purified by flash chromatography (81O ₂ ), eluting with a gradient of ethyl acetate-methanol to give 0.77 g (35%) of a complex 8- (2-formyl-aminoindane). Dimethylthiocarbamic acid 5-sulphate ester as a white solid.

LC / MS: ^ ₃ Η ₁₆ Ν ₂ ₂ : t / ζ 264 (M + 1).

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

Scheme 6. To the complex 8- (2-formylaminoindan-5-yl) dimethylthiocarbamic acid ester (0.772 g; 2.9 mmol) in THF (9 ml) in an atmosphere of ₂ add a solution of 1.0 M lithium aluminum hydride (9 ml) at 0 ° C. The reaction mixture is heated to room temperature, then stirred at reflux for 24 hours. The reaction mixture is cooled to 0 ° C, quenched with Ο ₂ and the solvent is removed under reduced pressure. The residue is dissolved in MeOH (4 ml), to which C ₂ CO ₃ (0.304 g; 0.93 mmol), tert-butyl-2-bromoisobutyrate (0.311 ml; 1.39 mmol) and ΝαΒΗ ₄ (2.0 g; 52.8 mmol). The reaction mixture is stirred for 18 hours, removed under reduced pressure, and the residue is partitioned between EUAc and H ₂ O. The layers are separated, the aqueous phase is extracted with EUAc, the organic extracts are combined, washed with brine, dried over n ° ₂ 8O ₄ , filtered and evaporated at reduced pressure. The crude residue is purified by flash chromatography (8U ₂ ), eluting with a gradient of CH ₂ C1 ₂ -MeOH to give 0.186 g (20%) of t-butyl ester

- 23 009553

2-methyl-2- (2-methylaminoindan-5-ylsulfanyl) propionic acid as an oil.

LC / MS: C ₁₈ H ₂ ^ O ₂ 8: t / ζ 321 (M + 1).

Compound 2.19 (44 mg; 65% from two stages; white solid) is obtained by Method 2, Stages B and M, replacing the 4-trifluoromethoxyphenyl isocyanate with 4-dimethylaminophenyl isocyanate.

LC / MS: C ₂₃ H ₂ ^ ₃ O ₃ 8: t / ζ 428 (M + 1).

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

Compound 2.20 (39 mg; 49% from two stages; white solid) is obtained by method 2, replacing the acetyl chloride with 3-cyclopentylpropionyl chloride.

LC / MS: C11;, E; \ O ₄ 8: t / ζ 565 (M + 1).

2- [2- (3-Indan-5-yl-1-pentylureido) indan-5-ylsulfanyl] -2-methylpropionic acid.

Compound 2.21 (9.3 mg; 24% from two stages; white solid) is obtained by method 2 using compound 2.3, replacing acetyl chloride with valeryl chloride and 4-trifluoromethoxyphenyl isocyanate with indanyl isocyanate.

LC / MS: C ₂₈ H ₃₆ ^ O ₃ 8: t / ζ 481 (M + 1).

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

Connection 2.22 (example 30).

Compound 2.22 (5.0 mg; 12% from two stages; white solid) is obtained by method 2 using compound 2.3, replacing the 4-trifluoromethoxyphenyl isocyanate with 4-methyl-3-nitrophenyl isocyanate.

LC / MS: C ₂₆ H ₃₃ No., O ₅ 8: t / ζ 500 (M + 1).

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

Connection 3.4 (example 31).

Compound 3.4 (2.9 mg; 4% from two stages; white solid) is obtained by method 3, replacing

- 24 009553 pent-4-enal to 1-naphthalaldehyde.

LC / MS: C ₃₂ H ₂₉ R ₃ ^ O ₄ 8: t / ζ 595 (M + 1).

2- {2- [3- (4-Methoxyphenyl) -1-propylureido] indan-5-ylsulfanyl} -2-methylpropionic acid. Connection 2.23 (example 32).

Compound 2.23 (21 mg; 64% from two stages; white solid) is obtained by method 2 using compound 2.14, replacing 4-trifluoromethoxyphenyl isocyanate with 4-methoxyphenyl isocyanate.

LC / MS: C ₂₄ H ₂₇ P ^ ₂ O ₄ 8: t / ζ 443 (M + 1). 2- {2- [3- (3,5-Dimethylphenyl) -1-propylureido] indan-5-ylsulfanyl} -2-methylpropionic acid. Connection 2.24 (example 33).

Compound 2.24 (19 mg; 57% from two stages; white solid) is obtained by method 2 using compound 2.14, replacing the 4-trifluoromethoxyphenyl isocyanate with 3,5-dimethylphenyl isocyanate.

LC / MS: C ₂₅ H ₃₂ ^ O ₃ 8: t / ζ 441 (M + 1).

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

Compound 2.25 (Example 34).

Compound 2.25 (7.0 mg; 16% from two stages; oil) is obtained by method 2 using the compound

2.2, replacing acetyl chloride with methoxyacetyl chloride.

LC / MS: C ₂₄ H ₂₇ P ^ ₂ O ₄ 8 ₂ : t / ζ 529 (M + 1).

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

Compound 2.26 (20 mg; 56% from two stages; white solid) is obtained by method 2 using compound 2.14, replacing the 4-trifluoromethoxyphenyl isocyanate with 4-trifluoromethylphenyl isocyanate.

LC / MS: C ₂₄ H ₂₇ P ^ ₂ O ₃ 8 ₂ : t / ζ 481 (M + 1).

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

- 25 009553

Connection 2.27 (example 36).

Compound 2.27 (10 mg; 26% from two stages; oil) is obtained by method 2 using compound 2.0, replacing acetyl chloride with trifluoromethylbutyryl chloride.

LC / MS: ^ ₅ Η ₂₆ Ρ ₆ ₂ Ο ₃ 8: t / ζ 564 (M + 1).

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

Compound 2.28 (Example 37).

Compound 2.28 (38 mg; 56% from two stages; oil) is obtained by method 2 using compound 2.0, replacing acetyl chloride with cyclopentyl propionyl chloride and 4-trifluoromethoxy phenyl isocyanate with phenyl isocyanate.

LC / MS: ^ ₈ Η ₃₆ ₂ ₃ δ: t / ζ 481 (M + 1).

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

Connection 2.29 (example 38).

NASO ^ C

Compound 2.29 (12 mg; 38% from two stages; white solid) is obtained by method 2 using compound 2.4, replacing acetyl chloride with methyl ester of 5-chlorocarbonylpentanoic acid.

LC / MS: &, ₀ Η ₄₀ ₂ ₅ 8: t / ζ 541 (M + 1). 2-Methyl-2- [2- (3-naphthalen-2-yl-1-pentylureido) indan-5-ylsulfanyl] propionic acid. Connection 2.30 (example 39).

Compound 2.30 (15 mg; 39% from two stages; white solid) is obtained by method 2 using compound 2.3, replacing the 4-trifluorothiomethoxy phenyl isocyanate with 2 naphthyl isocyanate.

LC / MS: ^ ₉ Η ₃₄ ₂ ₃ 8: t / ζ 491 (M + 1).

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

- 26 009553

Connection 2.31 (example 40).

Compound 2.31 (15 mg; 25% from two stages; white solid) is obtained by method 2 using compound 2.0, replacing acetyl chloride with cyclohexylacetyl chloride.

LC / MS: C ₂₈ H ₃₃ P3 ^ O ₄ 8: t / ζ 551 (M + 1).

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

Connection 3.5 (example 41).

Compound 3.5 (10 mg; 12% from two stages; oil) was prepared by method 3 using compound 3.0, replacing pent-5-enal with 2-methylpropionaldehyde.

LC / MS: C ₂₅ H ₂₉ P ^ ₂ O ₄ 8: t / ζ 511 (M + 1). 2- {2- [3- (3,4-Dichlorophenyl) -1-heptylureido] indan-5-ylsulfanyl} -2-methylpropionic acid. Connection 2.32 (example 42).

Compound 2.32 (6.7 mg; 12% from two stages; oil) is obtained by method 2 using compound 2.0, replacing acetyl chloride with heptanoyl chloride and 4-trifluoromethoxyphenyl isocyanate with 3.4 dichlorophenyl isocyanate.

LC / MS: C ₂₇ H ₃₄ LSS ₃ 8: t / ζ 538 (M + 1).

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

Connection 2.33 (example 43).

Connection 2.33 (1.9 mg; 4% from two stages; oil) is obtained by method 2 using the compound

2.2, replacing acetyl chloride with dimethylaminoacetyl chloride and 4-trifluoromethoxyphenyl isocyanate with 4 trifluoromethylthiophenyl isocyanate.

LC / MS: C ₂₅ H ₃₀ R ₃ SchO ₃ 8 ₂ : t / ζ 542 (M + 1).

2- {2- [3- (3-Chlorophenyl) -1-heptylureido] indan-5-ylsulfanyl} -2-methylpropionic acid.

- 27 009553

Connection 2.34 (example 44).

Compound 2.34 (7.4 mg; 14% from two stages; white solid) is obtained by method 2 using compound 2.32, replacing 4-trifluoromethoxyphenyl isocyanate with 3-chlorophenyl isocyanate.

LC / MS: C ₂₇ N ₃₅ U.S. ₂ O _c 8: t / ζ 542 (M + 1).

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

Compound 2.35 (1.0 mg; 1.3% from two stages; white solid) is obtained by method 2 using compound 2.32, replacing tert-butyl-2-bromoisobutyrate with ethyl-1-bromocyclobutanecarboxylate.

LC / MS: C11 _; , 1 ^; _; \ <G8: t / ζ 565 (Μ + 1).

2-Methyl-2- {7- [1-propyl-3- (4-trifluoromethoxyphenyl) ureido] -5,6,7,8-tetrahydronaphthalen-2ylsulfanyl} propionic acid.

Compound 1.4 (53 mg; 25% from two stages; oil) is obtained by method 1 using compound 1.0, replacing acetyl chloride with propionyl chloride.

LC / MS: C ₂₅ H ₂₉ E _c ^ O ₄ 8: t / ζ 511 (M + 1).

The following 2 compounds are prepared according to the procedures presented in Schemes 10 and 4 and Stages I, 1 and K of Method 1, replacing the reagents and adjusting the reaction conditions as necessary.

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

Connection 1.5 (example 47).

ABOUT

Compound 1.5 (9.8 mg; oil) is prepared by method 1, stages I, 1 and K, and according to schemes 4 and 10.

Ή-NMR (300 MHz, SAT ₃ 0B): 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: C ₂₅ H ₂₉ E _c ^ O ₅ 8: t / ζ 527 (M + 1).

Method 4.

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

- 28 009553 methylpropionic acid

Connection 4.0 (example 48).

A. yl- (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 CH ₂ Cl ₂ (20 ml) add ΌΙΕΑ (3.4 ml ) and the reaction mixture is cooled to 0 ° C. Acetyl chloride (1.22 ml; 17.1 mmol) is added dropwise at 0 ° C and the reaction mixture is warmed to room temperature and stirred for 18 h. The reaction mixture is diluted with CH2Cl2, washed with H ₂ O, dried over Ma ₂ 8O ₄ , filtered and the solvent is removed under reduced pressure to obtain a crude solid. Purification by flash chromatography ₍₂ occupies 8), eluting with hexane-EYuAs gives 1.57 g (50%) of N- (6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl) acetamide as a white solid .

LC / MS: C1 ₃ H ₁₇ SO ₂ : t / ζ 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 CH ₂ C1 ₂ (70 ml) cooled to -60 ° C, add a solution of tribromide boron-CH ₂ C1 ₂ (36 ml) dropwise, maintaining the reaction temperature from -50 to -60 ° C. The gel-like suspension is heated to room temperature and stirred for 30 minutes. The reaction mixture is cooled to 0 ° C, quenched with saturated # 1CHO ₃ and stirred for 30 minutes at room temperature. The mixture was extracted with CH ₂ C1 ₂ (2X), the extracts were combined, dried over №8O _4. filtered and evaporated under reduced pressure to give a crude solid, which was purified by flash chromatography (8U ₂ ), eluting with a gradient of CH ₂ C1 ₂ -MeOH to give 1.13 g (76%) L- (6-hydroxy-1, 2,3,4 tetrahydronaphthalen-2-yl) acetamide as a beige solid.

LC / MS: C1 ₂ H ₁₅ SO ₂ : t / ζ 206 (M + 1).

C. 2- (6-Acetylamino-5,6,7,8-tetrahydronaphthalen-2-yloxy) -2-methyl propionic acid t-butyl ester.

Scheme 7. To a suspension of M- (6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl) acetamide (0.439 g; 2.1 mmol) in DMF (6 ml) C ₂ CO ₃ (1 , 7 g; 5.2 mmol) and tert-butyl-2-bromoisobutyrate (2.1 ml; 9.4 mmol) and the reaction mixture is stirred at 100 ° C for 18 hours. The reaction mixture is cooled to room temperature, diluted with EUTA , washed with H ₂ O, brine, dried over Na ₈ O ₄ . filter and remove the solvent under reduced pressure to obtain a crude oil, which is purified by flash chromatography (8U ₂ ), eluting with a gradient of hexane-EUAc, to give 0.51 g (69%) of t-butyl ester 2- (6-acetylamine- 5,6,7,8-tetrahydronaphthalen-2-yloxy) -2methylpropionic acid as an oil.

-NMR (300 MHz, COC1 ₃ ): 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: C ₂₀ N ₂₉ SO ₄ : t / ζ 292 (M + 1).

The following compounds are obtained according to the methods presented in schemes 3 and 4 and stages I, 1 and K of method 1, replacing the reagents and adjusting the reaction conditions if necessary.

Connection 4.0 (0,0168 g; 23% from two stages; oil) is obtained by method 1 using compound 1.0.

LC / MS: C ₂₄ H ₂₇ P ₃ S ₂ O ₅ : t / ζ 481 (M + 1).

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

Connection 1.6 (example 49).

Compound 1.6 (10 mg; oil) is obtained by replacing 4-trifluoromethoxyphenyl isocyanate with 4-tert-butylphenyl isocyanate using method 1, stage I, 1 and K, and schemes 4 and 10.

LC / MS: C ₂₈ N ₃₈ S ₂ O ₄ 8: t / ζ 499 (M + 1).

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

Connection 1.7 (example 50).

Compound 1.7 (16 mg; 30% from two stages; white solid) is obtained by method 1, stages I, 1 and K, and according to schemes 4 and 10.

- 29 009553

-NMR (300 MHz, SBS1 ₃ ): 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, 1H), 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: C-, 1 E. + LOL: t / ζ 515 (M + 1). 2- {6- [1-Ethyl-3- (4-trifluoromethoxyphenyl) ureido] -3-chloro-5,6,7,8-tetrahydronaphthalen-2ylsulfanyl} -2-methylpropionic acid.

Connection 1.8 (example 51).

Compound 1.8 (15 mg; 22% from two stages; white solid) is obtained by method 1, stages I, 1 and K, and according to schemes 4 and 10.

LC / MS: C.111 ^; _; \ Oh, 8: t / ζ 532 (M + 1). 2- {6- [1-Ethyl-3- (4-trifluoromethoxyphenyl) ureido] -3-bromo-5,6,7,8-tetrahydronaphthalen-2ylsulfanyl} -2-methylpropionic acid.

Connection 1.9 (example 52).

Compound 1.9 (55 mg; 43% from two stages; white solid) is obtained by method 1, stages I, 1 and K, and according to schemes 4 and 10.

-NMR (300 MHz, SBS1 ₃ ): δ 7.45-7.48 (m, 3H), 7.36 (s, 1H), 7.15-7.18 (d, 2H), 4.41 -4.79 (m, 1H), 3.403.47 (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: C.111 ^; _; \ Oh, 8: t / ζ 576 (M + 1).

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

Connection 1.10 (example 53).

Compound 1.10 (73 mg; 26% from two stages; white solid) is obtained by method 1, stages I, 1 and K, and according to schemes 4 and 10.

-NMR (300 MHz, SBS1 ₃ ): 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: C _; , 11; .1 ^; _; \ OU: t / ζ 511 (M + 1).

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

Connection 1.11 (example 54).

Compound 1.11 (118 mg; 58% from two stages; white solid) is obtained by method 1, stages I, 1 and K, and according to schemes 4 and 10.

-NMR (300 MHz, SBS1 ₃ ): 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: C.11E; \ O, 8: t / ζ 580 (M + 1). 2- {6- [1-Ethyl-3- (4-trifluoromethoxyphenyl) ureido] -3-phenyl-5,6,7,8-tetrahydronaphthalen-2ylsulfanyl} -2-methylpropionic acid.

Connection 1.12 (example 55).

Compound 1.12 (118 mg; 58% from two stages; white solid) is obtained by method 1, stage

- 30 009553

I, I and K, and according to schemes 4 and 10.

Ή-NMR (300 MHz, SOS): 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: C; NE _; \ Oh, 8: t / ζ 573 (M + 1). 2- {6- [1-Ethyl-3- (4-hydroxyphenyl) ureido] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2methylpropionic acid (Example 56).

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

> ^H

Method 5.

2- [3-Chloro-6- (ethyl-p-tolyloxycarbonylamino) -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl] -2-methylpropionic acid t-butyl ester.

Connection 5.0 (example 58).

To a mixture of 2- (3-chloro-6-ethylamino-5,6,7,8-tetrahydronaphthalen-2ylsulfonyl) -2-methylpropionic acid tert-butyl ester and its borane complex (80 mg; 201 μmol) dissolved in CH 2 C 12 (2 ml) at 0 ° C add p-tolylchloroformate (35 μl; 241 μmol). The reaction mixture is slowly warmed to room temperature and stirred at room temperature for 6 days. The solvent is removed under reduced pressure and the crude residue is purified by flash chromatography (§1O ₂ ), eluting with a hexane-EYAA gradient, to give 30 mg (29%) of 2- [3-chloro-6- (ethyl-p-tolyloxycarbonylamino) t-butyl ether - 5,6,7,8-tetrahydronaphthalen-2ylsulfanyl] -2-methylpropionic acid as a clear oil.

-NMR (300 MHz, SOS): 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 according to the method of Step M of method 2.

-NMR (300 MHz, SOZOO): 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: C; ₄ N; ₈ C1 \ O ₄ 5: t / ζ 462 (M + 1).

2- {3-Chloro-6 - [(4-chlorophenoxycarbonyl) ethylamino] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2methylpropionic acid.

Connection 5.1 (example 59).

Compound 5.1 (34 mg; 35% for two stages; white solid) is prepared by method 5, replacing p-tolyl chloroformate with 4-chlorophenyl chloroformate, and using stage M of method 2.

-NMR (300 MHz, SSO1)): 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: C _;; 11; C1; \ OA: t / ζ 482 (M + 1).

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

Connection 5.2 (example 60).

Compound 5.2 is prepared by method 5, replacing p-tolyl chloroformate with 1-chloroethyl ester

- 31 009553 rum, complex 4-trifluoromethoxyphenyl carbonate, and using stage M of method 2.

Alternatively, compound 5.2 can be obtained by the following method:

A. 1-Chloroethyl ester is a 4-trifluoromethoxyphenyl carbonate.

Scheme 1. A solution of 1-chloroethyl chloroformate (1.03 g; 7.20 mmol) in CH ₂ C1 ₂ (10 ml) is cooled to 0 ° C, trifluoromethoxyphenol (1.09 g; 6.0 mmol) and triethylamine are added and the resulting the solution is heated to room temperature. After stirring for 3 hours, quench the reaction mixture with saturated NaHΟΟ ₃ and extract with EUTAc (3 times). The combined organic extracts are washed with water, brine, dried over n ° ₂ 8O _4, and the solvent is removed under reduced pressure. The crude residue is purified by flash chromatography, eluting with hexane-EUAc (10: 1), to give 1.54 g (90%) of 4-trifluoromethoxyphenyl carbonic acid 1-chloroethyl ester as a colorless oil.

-NMR (400 MHz, SES1 ₃ ): δ 7.26 (m, 4H), 6.49 (q, 1H), 1.91 (d, 3H).

B. Ethyl- (6-methoxy-1,2,3,4-tetrahydronaphthalen-2yl) carbamic acid 4-trifluoromethoxyphenyl ester.

Scheme 1. To a mixture of 6-methoxy-2-tetralone (950 mg; 5.39 mmol), 2 M ethylamine in THF (5.4 ml; 10.78 mmol) and acetic acid (648 mg; 10.78 mmol) sodium triacetoxyborohydride (2.29 g; 10.78 mmol) is added to CH ₂ Cl ₂ (5 ml). The reaction mixture is stirred at room temperature for 3 hours, then 1N solution is added. No. UN and extracted with ether (3 times). The combined organic extracts were dried over №8O ₄ and the solvent removed under reduced pressure to give a pale yellow oil. This oil is added to a solution of 1-chloroethyl 4-trifluoromethoxyphenyl carbonate (1.23 g; 4.31 mmol) in toluene (8 ml) and the reaction mixture is stirred for 1 h at room temperature, followed by stirring for 1 h at 90 ° C. The reaction mixture is cooled to room temperature, diluted with EtO and washed with 1N. aqueous HC1 and saturated NaHΟΟ ₃ . The organic extract is dried over Na8O ₄ and the solvent is removed under reduced pressure. Flash chromatography of the residue using a hexane-CH ₂ Cl ₂ gradient gives 1.05 g (48%) of ethyl 4- trifluoromethoxyphenyl ethyl- (6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl) -carbamic acid in the form white solid.

-NMR (300 MHz, SES1 ₃ ): 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: C ₂ 1H ₂₃ P ^ O ₄ : t / ζ 410 (M + 1).

C. Ethyl- (6-hydroxy-1,2,3,4-tetrahydronaphthalen-2yl) carbamic acid 4-trifluoromethoxyphenyl ester.

Scheme 1. A solution of ethyl- (6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl) -carbamic acid complex 4-trifluoromethoxyphenyl ester (898.6 mg; 2.19 mmol) in anhydrous CH2C12 (8 ml) is cooled to -78 ° C, slowly add 1 M solution of boron tribromide-CH2Cl2 (6.57 ml; 6.57 mmol). After the addition is complete, the reaction mixture is warmed to room temperature, quenched with MeOH (10 ml) and stirred for another 2 hours. The solvents are evaporated and the residue is purified by flash chromatography, eluting with hexane-EUTAc (2.5: 1), to give 649.4 mg (75%) of ethyl- (6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl) carbamic acid 4-trifluoromethoxyphenyl ester as a white solid.

-NMR (300 MHz, SES1 ₃ ): 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: C ₂₀ H ₂₁ P ^ O ₄ : t / ζ 396 (M + 1).

Ό. Ethyl- (6-triisopropylsilanylsulfanyl-1,2,3,4-tetrahydronaphthalen-2-yl) carbamic acid 4-trifluoromethoxyphenyl ester.

Scheme 1. Solution of ethyl- (6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl) -carbamic acid complex 4-trifluoromethoxyphenyl ester (245.1 mg; 0.62 mmol) in anhydrous CH2Cl2 (3 ml) and THF (3 ml) is cooled to -30 ° C, then triethylamine (216 μl; 1.55 mmol) and trifly anhydride (125 μl, 0.74 mmol) are added successively. The resulting mixture was stirred at room temperature for 2 hours, then quenched with water and extracted with EO (3 times). The combined organic extracts were washed with water, brine, dried over №8O ₄ and the solvent removed under reduced pressure. Flash chromatography of the residue using hexane-EYUAc (5: 1) yields 301.6 mg (92%) of triflate. Triflate (279.8 mg; 0.53 mmol) and tetrakis (triphenylphosphine) palladium (61.2 mg; 0.053 mmol) are added to a toluene solution prepared from triisopropylsilanthiol (126 μl; 0.58 mmol) and No. 1H (13, 9 mg; 0.58 mmol) at room temperature. The resulting mixture is vacuumed twice, heated under reflux for 4 hours and concentrated under reduced pressure. Flash chromatography of the residue using hexane-EYUAc (10: 1) gives 261.8 mg (87%) of ethyl- (6-triisopropylsilane-sulfonyl-1,2,3,4-tetrahydronaphthalen-2-yl) carbamic acid 4-trifluoride in the form of a slightly colored oil .

-NMR (300 MHz, SES1 ₃ ): δ 6.82-7.29 (m, 7H), 4.32 (m, 1H), 3.40 (m, 2H), 2.81-3.05 (m, 4H), 2.05 (m,

- 32 009553

2H), 1.12-1.34 (m, 6H), 1.03-1.10 (m, 18H).

LC / MS: C ₂₉ H ₄₁ P ^ O ₃ 881: t / ζ 568 (M + 1).

E. 2- {6- [ethyl- (4-trifluoromethoxyphenoxycarbonyl) amino] -5,6,7,8 tetrahydronaphthalen-2-ylsulfanyl} -2-methylpropionic acid t-butyl ester.

Scheme 1. A solution of ethyl- (6-triisopropylsilanylsulfanyl-1,2,3,4-tetrahydronaphthalen-2-yl) carbamic acid complex 4-trifluoromethoxyphenyl ester (260.0 mg; 0.46 mmol) and tert-butyl bromoisobutyrate (130 μl, 0.69 mmol) in anhydrous THF (2 ml) is cooled to 0 ° C, add 1.0 M solution of CATAR (690 μl, 0.69 mmol), then the reaction mixture is heated to room temperature, stirred for 1 h and then diluted with water, extracted with EtO (3 times). The combined organic extracts are dried over No. ₂ 8O ₄ and the solvent is removed under reduced pressure. The crude residue is purified by flash chromatography, eluting with hexane-EUAc (7: 1), to give 229.2 mg (90%) of 2- {6- [ethyl- (4-trifluoromethoxyphenoxycarbonyl) amino] tert-butyl ester] 5,6 , 7,8-tetrahydronaphthalen-2-ylsulfanyl} -2-methylpropionic acid in the form of a slightly colored oil.

-NMR (300 MHz, COC1 ₃ ): 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: C ₂₈ N ₃₄ P ^ O ₅ 8G t / ζ 576 (M + No.).

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

Scheme 1. A solution of 2- {6- [ethyl- (4-trifluoromethoxyphenoxycarbonyl) amino] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2-methylpropionic acid (120.8 mg; 0.22 mmol) in CH ₂ C1 ₂ (4 ml) is cooled to -78 ° C and trifluoroacetic acid (4 ml) is slowly added. The reaction mixture is warmed to room temperature and stirred for 1.5 hours. The solvents are evaporated and the residue is purified by flash chromatography with CH ₂ Cl ₂ -MeOH (94: 6) to give 2- {6- [ethyl- (4-trifluoromethoxyphenoxycarbonyl) amino] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2-methylpropionic acid as a white solid.

-NMR (400 MHz, SOS1 ₃ ): 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: C ₂₄ H ₂₇ P ^ O ₅ 8: t / ζ 498 (M + 1).

Ό. Pharmaceutical compositions and administration.

The compounds of this invention may be in the form of various pharmaceutical compositions for administration. To prepare such pharmaceutical compositions, an effective amount of a specific compound, in the form of a base or an acid addition salt, as an active ingredient, is thoroughly mixed with a pharmaceutically acceptable carrier.

The carrier can have many varieties, depending on the formulation desired for administration. Such pharmaceutical compositions preferably have a unit dosage form suitable, preferably, for oral administration or parenteral administration. For example, in preparing the compositions in the form of oral dosage forms, any conventional pharmaceutical medium may be used. Such media include water, glycols, oils, alcohols and the like, when preparing liquid oral compositions such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binding agents, disintegrating agents and the like, in the preparation of powders, pills, capsules and tablets. From the point of view of ease of use, tablets and capsules are the most preferred oral unit dosage form, they are usually used solid pharmaceutical carriers. For parenteral compositions, carriers typically include sterile water, at least in most cases, although other ingredients can also be used, for example, to impart solubility. For example, injection solutions can be prepared in which the carrier comprises saline solution, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which suitable liquid carriers, suspending agents and the like are used. In compositions suitable for subcutaneous administration, the carrier optionally includes penetration enhancing agents and / or suitable moisturizing agents, optionally combined with suitable additives of any nature in minor proportions where the additives do not have a significant hazardous effect on the skin. Such additives may contribute to the introduction into the skin and / or may be useful in obtaining the desired compositions. Such compositions can be administered in various ways, for example, by means of a transdermal patch, as a spot-on or as an ointment. Acid additive salts of compounds of the formula I, due to their increased solubility in water compared with the corresponding bases, are more suitable for the preparation of aqueous compositions.

It is particularly preferable to obtain the above pharmaceutical compositions in unit dosage forms to facilitate the administration and uniformity of dosage. Standard dosage forms in this specification include physically separate forms suitable for single

- 33 009553 of administration, where each form contains a predetermined amount of the active ingredient, calculated in such a way as to have the desired therapeutic effect in combination with the desired pharmaceutical carrier. Examples of such unit dosage forms include tablets (including notched tablets and coated tablets), capsules, pills, bags of powders, lozenges, injection solutions or suspensions, dosage forms with special spoons, and so on, as well as their segregated sets .

Pharmaceutically acceptable acid addition salts include therapeutically active non-toxic acid addition salts, which the described compounds may form. They can be obtained by treating the base with an appropriate acid. Suitable acids include, for example, inorganic acids, such as hydrohalic acids, eg hydrochloric or hydrobromic acid; sulfuric, nitric; phosphoric and similar acids; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic syrup, syrup, syrup, malic, methanesulfonic, ethanesulfonic, propane, malic, succinic, hydroxyacetic, malic, tartaric - aminosalicylic, palm and similar acids. The term “acid addition salts” also includes solvates that the compounds described are capable of forming, as well as their salts. Such solvates include, for example, hydrates, alcoholates and the like. Conversely, the salt can be converted into the free base by treatment with alkali.

Stereoisomeric forms determine all possible isomeric forms that compounds of formula (I) may have. Unless otherwise indicated, chemical designations of compounds refer to mixtures of all possible stereochemical isomeric forms, where these mixtures contain all diastereomers and enantiomers of the basic molecular structure. More specifically, stereogenic centers can have (AND) - or (8) -configuration; bivalent cyclic radical substituents may have either the cis or trans configuration. The invention encompasses stereochemically isomeric forms, including diastereoisomers, as well as mixtures of the described compounds in any proportion. The compounds described may also exist in tautomeric forms. Such forms, although not described in detail in the description and claims, are included within the scope of this invention. For example, in compound 2.1 or example 3, there is a chiral center in the C-2 indane ring. For this compound, (8) -isomer is more active than (I) -isomer.

A specialist in the treatment of disorders or diseases mediated by ASR alpha can easily determine the effective daily amount using the test results presented below and other information. In general, it is assumed that a therapeutically effective dose is from 0.001 to 5 mg / kg body weight, more preferably from 0.01 to 0.5 mg / kg body weight. It may be convenient to administer a therapeutically effective dose in the form of two, three, four or more sub-doses at appropriate intervals throughout the day. Such subdose can be in the form of standard dosage forms, for example, containing from 0.05 to 250 mg or 750 mg, in particular from 0.5 to 50 mg of active ingredient per standard dosage form. Examples include 2, 4, 7, 10, 15, 25 and 35 mg dosage forms. Compounds in accordance with this invention can also be obtained in the form of prolonged release forms or in the form of transdermal patches. The described compounds may also be in the form of sprays or other compositions for topical administration and inhalation.

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical indicators of the particular patient, as well as other drugs that the patient can take; these parameters are well known to the person skilled in the art. It is further evident that these effective daily dosages may be reduced or increased depending on the response of the patient and / or depending on the assessment of the therapist who prescribed the compounds in accordance with this invention. Effective daily doses indicated in the description are exemplary only.

The following section provides detailed information regarding the use of the described compounds and compositions.

E. Application.

The compounds of the present invention are pharmaceutically active, for example, as agonists of the APPR alpha. According to one aspect of the present invention, the compounds are preferably selective agonists of APPR alpha, which have an activity index (for example, efficacy against APPR alpha compared with that against APPR gamma) of 10 or more, and preferably 15, 25, 30, 50 or 100 or more.

APPR alpha agonists are used in the treatment, prevention or inhibition of the development of one or more of the following conditions or diseases: stage I hyperlipidemia, preclinical hyperlipidemia, stage II hyperlipidemia, hypertension, ZKA (coronary artery disease), coronary disease and hypertriglyceridemia. Preferred compounds in accordance with this invention are used to reduce the serum level of low-density lipoprotein (LDL), XB and / or LDL of low density, and other atherogenic molecules, or molecules that cause athero

- 34 009553 sclerotic complications, and, thereby, reduce cardiovascular complications. Preferred compounds are also used to increase serum levels of high-density lipoprotein (HDL), to reduce serum levels of triglycerides, LDL and / or free fatty acids. It is also preferable to reduce PPC / HbA1c.

Combination therapy.

Compounds in accordance with this invention can be used in combination with other pharmaceutically active agents. Such agents include lipid lowering agents and blood pressure lowering agents.

Methods for determining effective doses for therapeutic and prophylactic purposes of the described pharmaceutical compositions or the described drug combinations, formulated or not in one composition, are known in the art. For therapeutic purposes, the term "joint effective amount" means that amount of each active compound or pharmaceutical agent, alone or in combination, that causes a biological or therapeutic response in an animal or human tissue system that is expected by a researcher, veterinarian, doctor or other clinician. which involves altering the symptoms of the disease or disorder being treated. For prophylactic purposes (for example, to inhibit the onset or development of a disorder), the term "joint effective amount" refers to that amount of each active compound or pharmaceutical agent, in pure form or in combination, that heals or inhibits in a patient the onset or development of the disease expected by the researcher , a veterinarian, a doctor or other clinician. Thus, the present invention provides combinations of two or more drugs, which, for example, (a) each drug is administered in an independent therapeutically or prophylactically effective amount; (B) at least one drug in combination is administered in an amount that is subtherapeutic or subprophylactic when administered in pure form, but is therapeutic or prophylactic when administered in combination with a second or additional drugs in accordance with this invention; or (c) both (or more) of the drug are administered in an amount that is subtherapeutic or subprophylactic when administered in its pure form, but which is therapeutic or prophylactic when administered together.

As agonists for APPR alpha, compounds in accordance with this invention may be more potent and effective for reducing triglycerides than known fibrates. These compounds can also increase the metabolism of fats and / or lipids, which provides methods for reducing weight, reducing fat, reducing body mass index, reducing lipids (such as reducing triglycerides), or treating obesity or overweight. Examples of lipid-lowering agents include bile acid sequestrants, fibrous acid derivatives, nicotinic acid, and HMCCoA reductase inhibitors. Specific examples include statins, such as RP1TOK ™, 2OSOK ™, RKAUASNO ™, BE8CUT ™ and MEWASOK ™, and pitavastatin (nisvastatin) (Νίδδαη. Kota Koduo, 8aikuo, ονατδ) and from the form of the stretch gauge, you can take out the use of the gauge to put on it and put out on it and put out on the –– –– –– –– ––––––––––––––– and pitavastatin (nisvastatin) (). lovastatin with prolonged secretion), as well as SolesT1b, LoBoleste, OieChish ΛΐΐΌΐηϋ Lo1b and Tpsog.

Examples of blood pressure lowering agents include antihypertensive agents such as angiotensin converting enzyme inhibitors (ACFs) (AssyrynH, Anasa, SarTorgP, LoP51i, Maνnk, MyorpP, RhMM1, iAAax, WaToTes and 2s1p1, Adrener, Adrener, Adrener Sagbiga, ^^ leiζu1 ^ ηе, Nu1oge1, NuTpi, M1shrge88 and M ^ η ^ ζ ^ be), alpha / beta adrenergic blockers (such as Soged, tsubuyi and TgaibaTe), calcium channel blockers (such as Absorbed blockers (such as Soged, tsubuiyi and TgaibaTe), calcium channel blockers (such as Absorbed blockers (such as Soged, tsubuyie and TgaibaTe), calcium channel blockers (such as Absorbed blockers (such as Soged, tsubuyie and TgaibaTe), calcium channel blockers (such as Soghed, blockbusters and calcium algae), calcium channel blockers (such as Absorbed blockers (such as Soged, tsubuyie and TgaibaTe), calcium channel blockers (such as Absorbed blockers (such as Soged, tsubuyi and TgaibaTe); , Sagl / et, Сoνe ^ a-Η8, Opasog, PuiaSLS, Portt, No.ToTor, Hothuas, Rleib11, Proslabta, Procausa, Xi, Sa, And cor and

Diuretics, diuretics, angiotensin II receptor antagonists (such as ATASAIB, Arden®, Sohaag, and O ^ ai), beta-adrenergic blockers (such as VeTarase, Vyusagbei, VEG ^ ZOs, SaGo go1, 1begara, Zeebe, Vyusagbei, Vse ^ ZYos, SaGo go1, 1begur, Zeebe, Vyusagbei, Vse ^ ZYos, Sahgoo1, 1 ibegara, Zebera, Vyusagbei, Vse ^ ZYos, Sahgoo1, 1begur, Zeebe, Vusagbei, Vge ^ ZYos, Sahagoo1, 1begara, Zeerabey, Vyusagbei, Vse ^ ayos, Austabe, β-adrenergic blockers. , Vorgezzog, 8TTG1, Teiogtt, Torgo1-XB and 2BeTa; MTgoTaT and Gog1TgT) and their combinations (such as lexhe1, bogee1, tagka, teset, hoTeizt NST, r ^^ ηζ ^ be, IshguTu, WazegeTu, 2eTogeIs).

R. Examples.

The following chemical and biological examples are given for illustration and do not limit the invention.

Example 1

2- {6- [1-ethyl-3- (4-trifluoromethoxyphenyl) ureido] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2 methylpropionic acid. EC ₅₀ = 0.023 μM.

- 35 009553

Example 2

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

EC ₅₀ = 0.027 μM.

Example 3

EC50 = 0.0002 μM.

Example 4

2- {2- [1-ethyl-3- (4-trifluoromethoxysulfanylphenyl) ureido] indan-5-ylsulfanyl} -2methylpropionic acid.

EC50 = 0.037 μM.

Example 5

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

EC50 = 0.053 μM.

Example 6

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

EC50 = 0.056 μM.

- 36 009553

Example 7

EC ₅₀ = 0.075 μM.

Example 8

2-methyl-2- {2- [1-pentyl-3- (4-trifluoromethoxyphenyl) ureido] indan-5-ylsulfanyl} -2methylpropionic acid. EC50 = 0.073 μM. Example 9

2- {2- [3- (4-dimethylaminophenyl) -1-pentylureido] indan-5-ylsulfanyl} -2-methylpropionic acid.

EC ₅₀ = 0.131 μM.

Example 10

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

EC ₅₀ = 0.165 μM.

Example 11

- 37 009553

EC ₅₀ = 0.173 μM.

Example 12

2- [2- (3 - (biphenyl-4-yl-1-pentyl) ureido) indan-5-ylsulfanyl] -2-methylpropionic acid. EC ₅₀ = 0.183 μM.

Example 13

EC ₅₀ = 0.184 μM.

Example 14

EC ₅₀ = 0.213 μM.

Example 15

2-methyl-2- {2- [1-hexyl-3- (4-trifluoromethylsulfanylphenyl) ureido] indan-5ylsulfanyl} propionic acid.

EC ₅₀ = 0.123 μM.

- 38 009553

Example 16

EC ₅₀ = 0.158 μM.

Example 17

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

EC50 = 0.160 μM.

Example 18

2-methyl-2- {2- [3- (4-trifluoromethoxyphenyl) ureido] indan-5-ylsulfanyl} propionic acid. EC ₅₀ = 0.135 μM.

Example 19

2-methyl-2- {2- [1-pent-4-enyl-3- (4-trifluoromethoxyphenyl) ureido] indan-5ylsulfanyl} propionic acid.

EC ₅₀ = 0.125 μM.

Example 20

EC50 = 0.106 μM.

- 39 009553

Example 21

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

EC ₅₀ = 0.106 μM.

Example 22

EC ₅₀ = 0.219 μM.

Example 23

EC ₅₀ = 0.244 μM.

Example 24

2- {6- [1-hexyl-3- (4-trifluoromethoxyphenyl) ureido] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2methylpropionic acid. EC ₅₀ = 0.235 μM. Example 47

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

EC ₅₀ = 0.045 μM.

Example 49

2- {6- [1-ethyl-3- (4-trifluoromethoxyphenyl) ureido] -5,6,7,8-tetrahydronaphthalen-2-yloxy} -2 methyl propionic acid. EC ₅₀ = 0.309 μM.

- 40 009553

Example 50

EC ₅₀ = 0.010 μM.

Example 51

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

EC5 ₀ = 0.027 μM.

Example 52

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

EC5 ₀ = 0.017 μM.

Example 53

EC5 ₀ = 0.042 μM.

Example 54

about

EC5 ₀ = 0.131 μM.

Example 55

ABOUT

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

EC5 ₀ = 0.545 μM.

Example 56.

o> ¹¹

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

- 41 009553

Example 57

2- {6 - [(4-aminophenyl) -1-ethyl-ureido] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2methylpropionic acid. Example 58

2- {3-chloro-6- [4-methylphenoxycarbonyl) ethylamino] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2methylpropionic acid EC50 = 0.340 μM. Example 59

2- {3-chloro-6 - [(4-chlorophenoxycarbonyl) ethylamino] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2methylpropionic acid EC50 = 0.390 μM. Example 60

EC50 = 0.002 μM.

Biological example 1.

BUT LODK study.

H411E rat hepatoma cell colony was obtained from ATCC. The cells are cultured in a 175 cm ² cell culture flask or seeded in a 96-well plate (high serum, 10% fetal bovine serum and 10% calf serum) with culture medium and kept at 37 ° C and 5% CO ₂ for whole study. 24 hours after the initial manual seeding in a 96-well plate (approximately 100,000 / cell), studies of inducing the BUT gene are initiated. The medium is removed and replaced with 100 μl of low serum culture medium (5% charcoal / dextran-treated calf serum) containing vehicle (DMSO) or a test compound or standard. The cells are returned to the incubator for 24-hour culture. At the end of the injection, 50 μl of the lysis buffer with the BUT gene-specific probes CE, BE, VB are added directly to each cell to initiate the cDNA BUT of the tRNA assay. Expanded DNA testing is carried out according to the manufacturer's protocol (Vaueg P1diokbsk; EteguuShe. SA). At the end of the study, the luminescence is counted on an Eupex MBC luminometer for microtiter plates. The EC _{50 is} determined by non-linear regression on the SgarNrab Rpct using a sigmoidal curve.

Biological example 2.

The transfection study for receptor L1P 1P <5.

HEK2 93 cells are grown in an EMEM / E-12 medium supplemented with 10% PBS and glutamine (C1BELF). Cells are transfected with DNA for the APPR-Ca14 receptor and the Ca14-luciferase reporter using the OMB1E-C reagent. The next day, the DNA-containing medium is replaced with growth medium containing 5% carbon treated FBS. After 6 h, the cells are seeded in a 96-well plate and incubated at 37 ° C in a CO ₂ incubator overnight. Test compounds are introduced into cells and incubated for 24 hours at 37 ° C in a 5% CO ₂ incubator. The luciferase activity is examined using 81e-6y-ClO biae Acqua Р from Rgothed. OMB1E-C reagent is commercially available from С1ВСО, catalog number 10459-014. The ORT1-MEM I Webikeb 8egit Mebsht medium is commercially available from С1ВСО, catalog number 31985. 81еа6у-С1о Leishegake Akkau Κίΐ is commercially available from Rgothed No. Е254В.

- 42 009553

Ίη νίίΓΟ data.

Example ΑΠΠΡα ESCC (µM) one 0.023 2 0.027 3 0,002 four 0.037 five 0.053 6 0.056 7 0.075 eight 0.073 9 0.131 ten 0.165 eleven 0.173 12 0.183 13 0.184 14 0,213 15 0.123 sixteen 0.158 17 0.160 18 0.135 nineteen 0.125 20 0.106 21 0.106 22 0.219 23 0.244 24 0.235 25 0.208 26 0.130 27 0.294 28 0.323 29 0.382 thirty 0.385 31 0.497 32 0.497

ΑΠΠΡδ gg ¹ [EU ₅₀ (μm)] ΑΠΠΡγ ΕΙ * ² [EC _L0 (µM) I 4.2 0.24 [> Yu] (> 10] 3.7 2, 5 4.0 3.6 1.9 0, 8 0 5, 9 1.9 1.0 2, 9 5.1 6, 1 eleven 1.2 1,3 0.3 1.2 0.37 0.43 0.31 1.4 0, 44 0.05 4.5 2.1 8.2 1.5

- 43 009553

33 0.537 0, 8 34 0.657 35 0.772 5, 6 36 0.796 37 0.838 1.9 38 0,950 39 1.00 9, 3 40 1.30 41 2.21 42 2, 34 43 2.99 44 2.09 45 0.780 46 1.39 6, 0 47 0.045 [> 3] 48 0.014 [> 3] 49 0,309 [> 3] 50 0,010 [> 3] [> 3] 51 0.027 [> y] 52 0,017 [> 3] 53 0.042 [0.873] 54 0.131 [> 3] 55 0, 545 [1.72] 58 0, 340 [0.613] [> 3] 59 0, 390 (0.655] [1,11] 60 0,002 [> 3] [> 3]

¹ degree of induction for A1111Rδ standard: P1 = 36.1 ² degree of induction for AHNRu standard: P1 = 70.3

Biological example 3.

aP2 study for agonists of the ASR gamma.

The technique is described in detail in Wiggk E1 a1., Molescion Eu6osgshoda, 1999, 13: 410, which is fully included here, and the results of the aP2 study of the internal activity of the agonist can be in the form of an increase in the degree compared to the carrier when induction of aP2 tRNA production.

24 hours after the initial manual seeding in 96-well plates (about 20,000 / well), a differentiation study can be started. The medium can be removed and replaced with 150 μl of a differentiation medium containing vehicle (DMSO) or test compounds. Cells can be returned to the incubator for 24-hour culture. At the end of the injection, the medium can be removed and 100 μl of the lysis buffer can be added to start the LNNA aP2 tRNA study. Extended DNA testing is carried out according to the manufacturer’s protocol (Waueg O1-dio811c8; Eteguusche, CA) The results can be presented as an increase in the degree of activated production of aP2 tRNA in comparison with the carrier. EC ₅₀ and Etah can be determined by non-linear regression using a sigmoidal curve.

After the introduction of preadipocytes, the cells can be lysed with a lysis buffer (Waayer O1adio8Bsz) containing aP2 oligonucleotides. After 15 min of incubation at 53 ° C or 30 min of incubation at 37 ° C, 70 μl of lysis buffer from each well can be added to the appropriate cell for data collection (pre-incubated with 70 μl of blocking buffer (Woweg иηáibsbsb)). The data collection plate can be incubated overnight at 53 ° C in a plate incubator (Vaueg OhadiBsz). After incubation, the cDNA and labeled samples can be hybridized as prescribed by the manufacturer. After a 30-minute incubation with a luminescent alkaline phosphatase substrate, dioxitane, the luminescence can be counted on an Ewieb LX luminometer for microtiter plates. Oligonucleotide samples for the hybridization of aP2 tRNA and functioning in the LNNA tRNA determination system were developed using software

- 44 009553 of providing RgGoEekdpeg (Vaueg P1adpokksk). This software analyzes the target sequence using a number of algorithms to determine the region of the sequence, which can serve as a place to capture, tag, or hybridize the separation test. The sequences of oligonucleotides are as follows:

Zeo ΙΟ ΝΟ.1 8E0 ΙΟ Ko 2 Zeo ten N0.3 Zeo Yu N0.4 Zeo Yu N0.5 Zeo ten N0.6

SATTTTOTAAJT ^ STOOOATGATTSTTTTTTTSTOAAASAAASGG

ATSGGGASYUTTT0SSSATSSS1TTSG1'STTSaALAZAAST

Sstn

assisted

820

SA'GSSSSATTSASASTOATSGGTTASKhSSATAS-W ^. GSSSTSTST

Zeo YU N0.10 8E0 THAT N0.11 Zeo Yu N0.12 880 ten N0-13 Zeo Yu N0.14 Zeo that N0.15 Zeo Yu N0.16 Zeo Yu N0.17 JEO ten N0.13 Zeo ten N0.19 Zeo Yu N0.20

AZG'GSATLTSSSAKKSATTTTS'HGLSAAUTTPLESASLASASBLSSSGGSG

SSATTSSSASSASSGGTATSATTGGOSOSATAZ'ZSSSSSTS'G

S <ZAAS7TSAOTSOUSPGAAGATSOT ^ STTTLSLSAT;; СЛ .-- ССС-7СГ'СТ

TSSSLATSAATSTGOGAAOTOTOAATTTTA-ASSLTAOOASSSSSTS ^ ST

ALALSAGAATATSTPTTSAASAATATA '.- GGAZSZA'GLOZAS'SSSTST

TSLAAZTTTTSASTASAOASAAAS'GTT

AAASOTASTTTSAOAATTTAATOSTOATSA

STSSSSAOTATSAAOAAAATSTSASTATTLTT

TSTSSAOTPASTTOZTSLAAT'GS

ΛΤασι aetto ASGGTSStatsA

LAZTSAOZSSTTTSATOAS

Biological example 4.

days of dosing the compound of example 3 in female k / kb mice, age 6-7 weeks.

Females kL / kL mice (C57 VK 8/1-m + / + ^kL erg, 1askkop ak, Nagog Vah, ME) 6-7 weeks of age are placed in solid bottom cages with shaped shoe boxes, and 4 in the cell. Maintain a room temperature of 68-72 ° E and a humidity of 50-65%. The lighting of the room is a cycle of 12 hours of light / 12 hours of darkness. Mice were fed with certified food MN Ka1 apk Moike / Asho 6E with reduced fat content No. 5К52 (Р М I Мi1г1коп Σηΐ'1, 8ΐ. Bosch, MO through A.E. Food and water were given without restriction.

Compounds are prepared as suspensions in 0.5% hydroxypropylmethylcellulose (EO \\ Sket1ca1, M1k1apk, MTs. Dosing volume is 10 ml / kg of body weight. Female kb / kb mice with diabetes (8 / group) are orally administered once a day for 11 days, either 0.5% methylcellulose in kN2O (carrier), or the agonist AIRID in the amount of 0.03, 0.1, 0.3, 1, 3, 10 mg / kg / day. Body weight is measured in the morning on 1 day before dosing and on day 12 before blood collection.After 18-24 hours after the last dose for each group, mice are anaesthetized with CO ₂ / O ₂ (70:30) and retro-orbital blood is collected by puncture. serum samples are obtained by centrifugation. Glucose and triglycerides in serum are determined using COBA8 M1ga P1ik blood chemistry analyzer (Koske P1adpokksk, N1). Serum insulin is measured using the ALPO set tkikp ya8a.

Statistical analysis is carried out using the Rpct program (Sgarkrak, Mopgoula, SA) and conducting one-way AMOUA with the EippeI multiple comparison test.

- 45 009553

Data ίη νίνο.

¹ bb / bb mice are metered at 1.0 trk. Data are presented as% change compared to vehicle treated animals;

² 10-day oral dosing ³ 11-day oral dosing

5-day oral dosing

Biological example 5.

days of dosing of the compound in female mice of mice ob / ob, age 7 weeks.

Female ob / ob mice (C57 BL / ^ob LEP-61, 1askkop ak, Nagog Vah, ME) 7 weeks of age are placed in solid bottom cages with shaped shoe boxes 2 in the cell.

Maintain a room temperature of 68-72 ° B and a humidity of 50-65%. The lighting of the room is a cycle of 12 hours of light / 12 hours of darkness. Mice were fed with certified food ΝΜ Ka1 apb Moika No. 5К50 (Р М I МЦпбоп ШЛ, δί. Boshk, MO through ^. B. BBkeg apb Opop, Shs .. Voipb Vgook, N1). Food and water were given without restriction.

Compounds are prepared as suspensions in 0.5% hydroxypropyl methylcellulose (Bo Skeisisak M1b1apb, MC The volume of dosing is 10 ml / kg body weight. Female diabetic mice (8 / group) are orally administered once a day for 11 days or 0.5% methylcellulose in bN2O (carrier), or an ANHR agonist in an amount of 0.003, 0.01, 0.03, 0.1, 0.3, 1 mg / kg / day. Body weight is measured in the morning at 1 the day before dosing and on the 12th day before blood sampling.18 hours after the last dose for each group, mice are subjected to CO ₂ / O ₂ anesthesia (70%: 30%) and blood is collected by retroorbit puncture sinus in microtubes containing a delay activator and then placed on ice. Serum samples are obtained by centrifugation. Serum glucose and triglycerides are determined using COBA8 M1ga P1ik blood chemistry analyzer (Koske B1adpok11sk, Νί). Insulin and serum free fatty acids are measured with the use of the set АРРСО ткБп ЕЫ8А and the set \ Wako ΝΉ + Ά, respectively.

Statistical analysis is carried out with the use of the program Rpkt (Sgarkrab, Moigel / a, SA) and conducting one-sided A ^ UA with the test of multiple comparison Bippay.

Data w νί \ Ό.

Example ¹ Δ TG in plasma Δ glucose in plasma Δ insulin in plasma 50 -86% -74% -93%

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

B. Other options.

The characteristics and principles of the present invention are illustrated in the discussion, examples and claims. Various adaptations and modifications of this invention are obvious to a person skilled in the art, and such other options are also included in the scope of this invention. The publications mentioned in the description are included as references.

- 46 009553

Claims

CLAIM

1. The compound of formula I

Formula I or a pharmaceutically acceptable salt thereof, a C1 _-6 ester or a C1 _-6 amide, wherein each of Κ ₁ and R ₂ independently represent H, C1 _-6 alkyl or Κι and R _2, taken together with the carbon atom to to which they are attached are C _3-7 cycloalkyl;

η is 1 or 2;

X is O or 8; in which X is in 5 or 6 position, when η is 1; and in which X is in the 6 or 7 position when η is 2;

K ₃ is H, C 1 _-6 alkyl, C 1 _-3 alkoxy, halogen, phenyl; and K ₃ is in ortho or meta position with respect to X;

K ₄ is H or - (C1 _-5 alkylene) K1 ₅ , where Κι ₅ is H, C1 _-7 alkyl, C1 _-6 alkoxy, C _3-7 alkenyl, C _3-6 cycloalkyl, [di (C1 _{- 2} alkyl) amino] (C1 _-6 alkyl);

Υ represents or O;

each of R ₅ and R ₇ are independently selected from H, C1 _-6 alkyl, halogen, nitro, C1 _-4 alkoxy;

K _{6 is} selected from C _1-6 alkyl, halogen, hydroxy, C _{! -4} alkoxy, C 1 _-4 alkylthio, phenyl, ΝΚ ₁₃ ₁₄ ; Each of Κι ₃ and Κ _{14 is} independently H or C _1-6 alkyl;

Either K ₅ and K ₆ can be taken together to be a bivalent saturated residue - (- CHL-;

where each of the above hydrocarbyl residues may be substituted with substituents in an amount ranging between 1 and 3, independently selected from P, C1, Br, I, amino, methyl, ethyl, hydroxy, nitro, cyano and methoxy.

2. The compound according to claim 1, in which one of the Κ ₁ and K ₂ represents methyl or ethyl.

3. The compound according to claim 2, in which each of the Κ ₁ and K ₂ represents methyl.

4. The compound according to claim 1, in which Κ ₁ and Κ ₂ , taken together, represent cyclobutyl or cyclopentyl.

5. The compound according to claim 1, in which K ₃ represents N.

6. The compound according to claim 1, in which K ₃ represents C _1-3 alkoxy, halogen, C _1-6 alkyl.

7. The compound according to claim 1, in which K ₄ represents H or C _2-7 alkyl.

8. The compound according to claim 7, in which K ₄ is H or C _2-5 alkyl.

9. The compound of claim 8, in which K ₄ represents ethyl.

10. The compound of claim 8, in which K ₄ represents N.

11. The compound according to claim 1, in which η is 1.

12. The compound according to claim 1, in which η is 2.

13. The compound according to claim 1, in which Υ is a.

14. The compound according to claim 1, in which X represents 8.

15. The compound according to claim 1, in which X represents O.

16. The compound according to claim 1, in which at least one of K ₅ and K ₇ represents N.

17. The compound of claim 16, wherein K ₆ is C1 _-4 alkyl, halomethoxy, galogenmetiltio or di (C1-3alkyl) amino.

18. A compound of claim 17, wherein K ₆ is trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethylthio, tert-butyl, isopropyl, or dimethylamino.

19. The compound according to claim 3, in which K ₃ is H, K ₄ is C _2-7 alkyl, and Υ is.

20. The compound according to claim 19, in which X represents 8.

21. The compound according to claim 19, in which η is 1.

22. The compound according to claim 19, in which η is 2.

23. The compound according to claim 19 in which K ₄ is C _2-5 alkyl.

24. The compound according to claim 23, wherein K ₄ is ethyl.

25. The compound according to claim 19, wherein K ₆ is trifluoromethoxy, difluormethoxy, trifluoromethyl, trifluoromethylthio, tert-butyl, isopropyl or dimethylamino.

26. A compound according to claim 1, wherein each of Κι and R ₂ independently represent H, C1 _-6 alkyl;

- 47 009553 η is 1 or 2;

K ₃ is H, phenyl, C 1 _-3 alkoxy, halogen, C 1 _-6 alkyl, and K ₃ is in ortho or meta position with respect to X;

K ₄ is H or - (C1 _-5 alkylene) K1 ₅ , in which Κι ₅ represents H, C1 _-7 alkyl, C1 _-6 alkoxy, C _3-7 alkenyl, C _3-6 cycloalkyl, [di (C1 _-2 alkyl) amino] (C1 _-6 alkyl);

Υ is N4;

each of K ₅ and K _{7 is} independently selected from H, _C1-6 alkyl, halogen, C _4-4 alkoxy;

K _{6 is} selected from C1 _-6 alkyl, halogen, C1 _-4 alkoxy, C1 _-4 alkylthio, phenyl, ΝΚι ₃ Κι ₄ ;

each of K. | ₃ and _4, R1 independently represents H or C1 _-6 alkyl;

wherein each of the above hydrocarbyl residues may be substituted with substituents in an amount ranging between 1 and 3, independently selected from E, C1, amino, methyl, ethyl, hydroxy and methoxy.

27. The compound according to claim 1, selected from 2- {6- [1-ethyl-3- (4-trifluoromethoxyphenyl) ureido] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2-methylpropionic acid;

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

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

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

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

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

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

2-methyl-2- {2- [1-pent-4-enyl-3- (4-trifluoromethoxyphenyl) ureido] indan-5ylsulfanyl} propionic acid;

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

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

28. The compound according to claim 1, selected from 2-methyl-2- {2- [1-hexyl-3- (4-trifluoromethylsulfanylphenyl) ureido] indan-5-ylsulfanyl} propionic acid;

2- {2- [3- (4-dimethylaminophenyl) -1-pentylureido] indan-5-ylsulfanyl} -2-methylpropionic acid;

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

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

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

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

2- [2- (3- (biphenyl-4-yl-1-pentyl) ureido) indan-5-ylsulfanyl] -2-methylpropionic acid;

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

- 48 009553 slots;

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

29. The compound according to claim 1, selected from 2- {6- [1-ethyl-3- (4-trifluoromethoxyphenyl) ureido] -5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl} -2-methylpropionic acid;

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

30. The compound according to claim 1, selected from

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

31. Pharmaceutical composition having a HALF agonistic activity, containing a compound according to claims 1, 19, 26, 27, 29 or 30.

32. A method for treating or inhibiting the development of a disease mediated by ASR alpha, comprising administering to a patient in need of treatment a pharmaceutically effective amount of a composition comprising a compound according to claim 1, 19, 26, 27 or 30.

33. The method of claim 32, wherein said disease mediated by ASR alpha is selected from dyslipidemia and cardiovascular diseases.

34. The method according to p, in which the specified disease is dyslipidemia.

35. The method of claim 34, wherein said dyslipidemia is selected from stage I hyperlipidemia, preclinical hyperlipidemia, stage II hyperlipidemia, hypercholesterolemia, hypo-HDL cholesterolemia and hypertriglyceridemia.

36. The method of claim 33, wherein said cardiovascular disease is atherosclerosis, coronary artery disease, coronary heart disease, or hypertension.

37. The method of claim 32, 34 or 35, further comprising the step of administering to the patient a jointly effective amount of a fat reducing agent.

38. The method of claim 32, 34, 35, or 37, further comprising the step of administering to the patient a co-effective amount of an agent that lowers blood pressure.