UA80297C2 - Substituted tetralins and indanes - Google Patents

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

Description of the invention

This application is not prior |US patent application Mob0/419935, filed Oct. 21, 2002|, and 2 prior |US patent application Mob0/495270, filed Aug. 15, 2003, entitled "Substituted Tetralins and Indanes"|.

The invention relates to substituted tetralin and indane derivatives, compositions containing them, and methods of their use.

Peroxisomal proliferator-activated receptor alpha (PRAK-alpha), a member of the nuclear receptor family 70, a group of ligand-activated transcription factors, is an essential transcription factor that regulates genes related to fatty acid metabolism and insulin action.

PRAK-alpha receptors are present mainly in the liver. Genes regulated by PRAC-alpha include enzymes involved in beta-oxidation of fatty acids, hepatic fatty acid transport protein, and apo-A1, an important component of high-density lipoprotein (HDL). Selective high-affinity PRAC-alpha 79 agonists enhance hepatic fatty acid oxidation, which in turn lowers levels of circulating triglycerides and free fatty acids. A reduction in circulating triglycerides may mediate the observed reduction or improvement in insulin resistance in insulin-resistant or diabetic animals treated with agonists

PRAK-alpha. A course of treatment with such substances in animal models of obesity is associated with weight loss.

Fibrates, which are well-known treatments for hyperlipidemia, are weak PRAK-alpha agonists.

Examples of known PRAK-alpha agonists used for various purposes in hyperlipidemia, diabetes, or atherosclerosis include fibrates such as fenofibrate (Royschpieg), gemfibrozil (Ragke-Oamiz/Rijgeg, Muiap,

MUaizop), clofibrate (U/ue(p-Auegwi, Momorpagt), bezafibrate and ciprofibrate and ureidofibrates such as ZUU 7647, SUU 9578 and SMU 9820 (SiakhoztiyKiYiipe).

The invention relates to compounds of the following formula (1): p

K; What about

Co. GT

Fo about sch -- X--th about

I a d) no kt I still M. "

C - c :» Formula (I) or its pharmaceutically acceptable salt, C..b-ester or C..5-amide, where each of K. and Co independently denotes H, C..b-alkyl, (СНо )lchKak, (СНо)тОКа, (СНодпчнН(СОв» в or (СНо)тСО»Ра, where each of Ka, K, and Ka o independently denotes H or C..v-alkyl, or Ki and Ko together with an atom carbon, to which they are attached, form C3-cycloalkyl; («c) t has a value from 1 to 6;

HF n is equal to 1 or 2;

X stands for O or 5; and X is in position 5 or b, if n is equal to 1; and X is in se) position 6 or 7, if n is equal to 2; "m Kz denotes H, phenyl, C. 3-alkyl group, C. 3-alkylthio group, halide, cyano group, C. 3-alkyl, nitro group,

MEKoKchio, MNSOK o, SOMNK o and SOOK 0; and Kz is in the ortho- or meta-position in relation to X;

K. denotes H or -(C.4 in-alkylene)-Ki5, where Kv denotes H, C.7-alkyl, |di-«C4 o-alkyl)amino|-(C 4 in-alkylene), (C ..3-Alkoxyacyl)-(C..C-alkylene), C-.C-Alkoxy group, C3.C-Alkenyl or C3.C-Alkynyl, and K; contains no more than 9 carbon atoms; K. can also denote -(C..5-alkylene)-Ki5, where Ki5 denotes C3-5-cycloalkyl, phenyl, (F) phenyl-O-, phenyl-5- or 5-6-ene monovalent heterocyclic radical with 1 -2 heteroatoms selected from M, g O and 5;

ХУ denotes МН, МН-СН» or 0; in each of K5 and Co independently choose from H, C. γ-alkyl, halide, cyano group, nitro group, SOK.4, SOOK..,

C. d-Alkoxy group, S. -Alkylthio group, hydroxyl group, phenyl, MKK. and a 5-6-ene monovalent heterocyclic radical with 1-2 heteroatoms selected from M, O and 5;

Ke is chosen from C.i.v.-alkyl, halide, cyano group, nitro group, SOK.z, SOOK.z, C..4-alkyl group,

Si d-alkylthio group, hydroxyl group, phenyl, MK.z3K.i4 and 5-6-ene monovalent heterocyclic radical with 1-2 heteroatoms selected from M, O and 5; in addition, Ke5 and Ke or Ke and K; can together form a divalent fragment, saturated or unsaturated, selected from -"("СН")з-, "("СНа)д- and СН.2)BM(СН у.2)9; p equals 0-2 and d equals 1-3, where the sum (ra) is at least 2; each of K»e and Co independently denotes C. 5-alkyl; each of K44, Ku", Kiz and K.4 independently denotes H or C. 6-alkyl; where each of the above hydrocarbyl and heterocarbyl fragments can be substituted with 1-3 substituents independently selected from EK, SI, Bg, I, amino group, methyl, ethyl, hydroxyl group, nitro group, cyano group and methoxy group.

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

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

Another aspect of the invention includes methods of using the disclosed compounds or compositions in various methods of preventing, treating, or inhibiting the development of PRAK-alpha mediated disease. Examples

PRAC-alpha-mediated diseases include dyslipidemia and atherosclerosis. Dyslipidemia includes hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-NOI cholesterolemia. For example, dyslipidemia can be one or more of the following conditions: low NOI ("35 or 4Omg/dl), high triglycerides (220Omg/dl) and high I0. ("15Omg/dl).

Additional features and advantages of the invention will be apparent from the following detailed description, examples and claims.

A. Terms

The following terms are defined below and as used in this description. "Alkyl" includes optionally substituted linear and branched hydrocarbons in which at least one hydrogen has been removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, etc. Alkyl includes cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. i) "Alkenyl" includes optionally substituted linear and branched hydrocarbon radicals, such as those named above, with at least one carbon-carbon double bond (cf. 7). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa- 2,4-dienyl, etc. Hydrocarbon radicals having mixed double bonds and triple bonds, such as 2-penten-4-ynyl, are considered herein to belong to the alkynyl group. Alkenyl includes cycloalkenyl. The cis- and trans- or (E)- and (2)-forms are within the scope of the invention. He "Alkynyl" includes optionally substituted linear and branched hydrocarbon radicals, such as those named above, with at least one carbon-carbon triple bond (z). Alkynyls include ethynyl, propynyl, o-butynyl, and pentynyl. Hydrocarbon radicals having mixed double bonds and triple bonds, such as c 2-penten-4-ynyl, are considered herein to belong to the alkynyls. Alkynyl does not include cycloalkynyl. "Alkoxy" includes an optionally substituted linear or branched alkyl group with a terminal oxygen that connects the alkyl group to the rest of the molecule. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, etc. "Aminoalkyl", "thioalkyl" and "sulfonylalkyl" are analogous to the alkoxy group, with the terminal oxygen atom of the oxy group substituted, and c, respectively, by МН (or MK), 5 and 50». Heteroalkyl includes alkoxy group, aminoalkyl, thioalkyl, etc. "Aryl" includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, indenyl, etc., any of which may be optionally substituted. Aryl also includes arylalkyl groups such as benzyl, phenethyl, and phenylpropyl.

Aryl includes a ring system that contains an optionally substituted b--linked carbocyclic aromatic ring, and said system may be bicyclic, bridged, and/or fused. The system may include o rings that are aromatic or partially or fully saturated. Examples of ring systems include indenyl, pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl, o isoquinolinyl, etc. co "Monovalent heterocyclic radical" includes optionally substituted aromatic and non-aromatic

Rings that contain carbon atoms in the ring and at least one heteroatom (0, 5, M) or a fragment containing one or more heteroatoms (505, СО, СОМН, СОО). Unless otherwise specified, the heterocyclic radical may have a valence "I" bond connecting it to the rest of the molecule through a carbon atom, as in 3-furyl or 2-imidazolyl, or through a heteroatom, as in M-piperidyl or 1-Pyrazolyl Preferably, the monocyclic monovalent heterocyclic radical has from 5 to 7 ring atoms, or 5 to 6 ring atoms; the ring may have from 1 to 5 heteroatoms or

Heteroatomic fragments, preferably from 1 to 3, or 1-2. A monovalent heterocyclic radical may be saturated, unsaturated, aromatic (eg, heteroaryl), non-aromatic, or fused. iF) A monovalent heterocyclic radical also includes fused, for example, bicyclic, rings such as those optionally fused with an optionally substituted carbocyclic or heterocyclic five- or six-membered aromatic ring. For example, "heteroaryl" includes an optionally substituted six-membered or heteroaromatic ring containing 1, 2, or 3 nitrogen atoms fused to an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring. Said heterocyclic five- or six-membered aromatic ring fused with said five- or six-membered aromatic ring 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. 65 Examples of monovalent heterocyclic radicals include thiazolyl, furyl, thienyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl,

pyridazinyl, indolizinyl, isoiindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. For example, preferred monovalent heterocyclic radicals or heterocyclic radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, thienyl, and more preferably piperidyl or morpholinyl.

Illustrative examples of heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl. "Acyl" refers to a carbonyl group attached to a hydrogen atom (ie, a formyl group) or to an optionally substituted alkyl or alkenyl chain, or to a monovalent heterocyclic radical. "Halide" or "halogen" includes fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine as a substituent on an alkyl group with one or more halide atoms, such as trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethoxy or fluoromethylthio. "Alkanediyl" or "alkylene" refers to optionally substituted divalent linear or branched chain alkane radicals such as, for example, methylene, ethylene, propylene, butylene, pentylene or hexylene. "Alkenediyl" denotes, similarly to the above, optionally substituted divalent linear or branched chain alkene radicals, such as, for example, propenylene, butenylene, pentenylene or hexenylene. In such radicals, the carbon atom connected to nitrogen should preferably not be unsaturated. "Aroyl" refers to a carbonyl group attached to an optionally substituted aryl or heteroaryl group, where aryl and heteroaryl are as defined above. Specifically, benzoyl is a phenyl carbonyl.

As used herein, the two radicals, together with the atom(s) to which they are attached, may form an optionally substituted 4-7-, 5-7-, or 5-6-membered carbocyclic or heterocyclic ring which can be saturated, unsaturated or aromatic. Said rings may correspond to the definitions given above in the section on the essence of the invention. Specific examples of such rings are given in the next section. "Pharmaceutically acceptable salts, esters and amides" include carboxylate salts, addition salts of i) amino acids, esters and amides that provide an acceptable benefit/risk ratio, are pharmacologically effective and suitable for introduction into contact with patient tissues without undue toxicity, irritation or allergic reaction. These salts, esters, and amides can be, for example, M 2 salts, esters, and amides containing C 1-8 alkyl, C 1-8 cycloalkyl, aryl,

Co 10-heteroaryl or Co 40-non-aromatic heterocyclic radical. Salts, free acids and esters are better than amides formed by the terminal carboxylate group/carboxylic acid group on the left side of formula (I). Examples of salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate , mesylate, glucoheptonate, lactobionate and lauryl sulfonate. These may include alkali and alkaline earth metal co-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, 5.M. Vegde, et al., "Rpagtaseciisa! Zai85, 9. Riagt. Zsi., 1977, 66:1-19), which is incorporated herein by reference. Examples of pharmaceutically acceptable amides of the invention include "470 ammonia derivatives, primary S..v -alkylamines and secondary di-(C-.6-alkyl)amines. Secondary amines include 5- or b-membered 6-membered heterocyclic or heteroaromatic ring fragments containing at least one nitrogen atom and, optionally, 1-2 additional heteroatoms. The best amides are derivatives of ammonia, primary C 4.3 -alkylamines, and di-(C1-0-alkyl)amines. Examples of pharmaceutically acceptable esters according to the invention include esters that contain C 4-7 -alkyl, C 1-7 -cycloalkyl, phenyl and phenyl-(C 1-7 )-alkyl radicals. esters include methyl and ethyl esters.

Go! "Patient" or "subject" includes mammals such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates) in need of observation, experimentation, treatment or prevention in connection with associated with the relevant disease or condition. Preferably, the patient or subject is a human. co "Composition" includes a product that contains specified ingredients in a specified amount, as well as any product formed by combinations of specified ingredients in a specified amount. "Therapeutically effective amount" or "effective amount" means that amount of an active compound or "M pharmaceutical agent that produces a biological or medical response in a tissue system, animal, or human that is desirable to the researcher, veterinarian, physician, or other clinician, which includes relief symptoms of the condition or disorder being treated.

Let's make three general remarks about the various radicals in this description and claims. The first observation concerns valence. As with all hydrocarbon radicals, be they saturated, unsaturated or

F) aromatic, whether cyclic or not, linear or branched, as well as, similarly, all heterocyclic radicals, and each radical includes substituted radicals of this type and monovalent, bivalent and multivalent radicals, as indicated in the context of the claims. The context indicates that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more hydrogen atoms (polyvalent). An example of a bivalent radical connecting two parts of a molecule is XU in formula (I), which attaches phenyl substituted by Kb, Ko, and K7 to the rest of the molecule.

Second, radicals or structural fragments as used herein are understood to include substituted radicals or structural fragments. Hydrocarbyls include monovalent radicals containing 65 carbon and hydrogen, such as alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromatic or unsaturated), as well as corresponding divalent (or polyvalent) radicals such as alkylene, alkenylene,

phenylene, etc. Heterocarbyls include monovalent and divalent (or multivalent) radicals that contain carbon, optionally hydrogen, and at least one heteroatom. Examples of monovalent heterocarbyls include acyl, acyloxy, alkoxyacyl, monovalent heterocyclic radical, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl, etc. When using "alkyl" as an example, "alkyl" should be understood to include substituted alkyl having one or more substituents, for example, from 1 to 5, from 1 to 3, or from 2 to 4 substituents. Substituents can be the same (two hydroxyl groups, dimethyl), similar (xXchlorofluorine), or different (chlorobenzyl- or aminomethyl-substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromomethyl, trifluoromethyl, and 70 C- iodocyclopentyl), hydroxyalkyl (such as hydroxy methyl, hydroxyethyl, 2-hydroxypropyl, aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl and 2-aminopropyl), nitroalkyl, alkylalkyl, etc. di-(C. c- alkyl)amino includes independently selected alkyl groups such as methylpropylamino and isopropylmethylamino, as well as dialkylamino groups having two identical alkyl groups, such as dimethylamino or diethylamino.

Third, only stable compounds are predicted. For example, in the case of the presence of the MK 44K.o-group, where K can denote an alkenyl group, the double bond is distant from nitrogen by at least one carbon atom to avoid enamine formation. Similarly, if "(CH 2)p-M-(CH")d- may be unsaturated, the corresponding hydrogen atom(s) may be included or omitted, as, for example, in -(CH 52)-M-A(CH )(CH")- or -"CH2.)-MH-(CH)-(CH)-.

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

V. Compounds

The present invention discloses compositions containing, and methods of using, compounds of formula (I), which are described above in the section on the essence of the invention. Examples include compounds in which: (a) one of Ku and Co is methyl or ethyl; (B) in which each of K. and Co represents methyl; (c) Ku and Co together denote cyclobutyl or cyclopentyl; (а) сч з denotes H; (e) K. denotes H or C10-7-alkyl; (e) Ki denotes H or C»0.6-alkyl; (Her) K. denotes ethyl; (9) K/ denotes H; (P) n equals 1; (i) n equals 2; |) X stands for INN"; (K) U denotes MH; (I) X denotes 5; (t) X i) denotes O; (n) at least one of K5 and K7 denotes H; (0) Ke represents C 1-4 -alkyl, a halomethoxy group or a halothiomethoxy group; (p) Ke represents t-butyl, isopropyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethoxy, difluoromethoxy or dimethylamino; (4) Kz denotes H, K denotes M.

So-tpalkil, Her M stands for MN; (d) K. denotes C-alkyl; (5) Co denotes cyclopropylmethyl, isopropyl, isobutyl, methylethylamino or diethylamino; (0 (5)-enantiomer in the C-2 position of indane or tetralin; (y) Me (K)-enantiomer in the Cb-2 position of indane or tetralin; (M) in which K 345 denotes cC..-alkyl, c

Idi-(Ci-o-alkyl)amino|-(C.4-c-alkylene), (C.i.-c-alkoxyacyl)-(C-i-c-alkylene), C.i.5-alkyl group, C3U-7-alkenyl or

C-alkynyl; (mu) Ke denotes a trifluoromethylthio group or a trifluoromethoxy group; or (x) combinations of the above

Зз5 above signs. co

In addition to the best compounds include: with "

Y - s M n. 2-16-[1-ethyl-3-(4--rifluoromethoxyphenyl)ureido!|-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-m ethylpropionic acid, so o E o z z Her o 50 r) m that 2-i4-chloro-6-/1-ethyl-3--4--rifluoromethoxyphenyl)ureido|-1-fluoro-5,6,7 , 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid, o (F) H Z ime) and 60 r n 2-I3-ethyl-6-(/1-ethyl-3--4--rifluoromethoxyphenyl)ureido !|-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid, b5 b vro " Z o F A o A mn

Ethyl ester of 3-(1-carboxy-1-methylethylsulfanyl)-7-(/1-ethyl-3--4-trifluoromethoxyphenyl)ureido!|-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid, o o z sho 2-(6-(ethyl-(4-trifluoromethoxyphenoxycarbonyl)amino|-3-fluoro-5,6,7 8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid, 2-16-/1- Ethyl-3-(4--rifluoromethoxyphenyl)ureido|-3-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methylpropionic acid, 2-16-/1-ethyl-3 -"4--rifluoromethoxyphenyl)ureido|-3-chloro-5,6,7 8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methylpropionic acid, c 2-(6-/1-ethyl-3-" 4-trifluoromethoxyphenyl)ureido|-3-bromo-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methylpropionic acid, 2-16-/1-ethyl-3--(4- -rifluoromethoxyphenyl)ureido|-3-methyl-5,6,7,8-tetrahydro-naphthalene-2-ylsulfanyl)-2-methyl propionic acid, 2-16-/1-ethyl-3-«4--rifluoromethoxyphenyl) ureido|-3-trifluoromethoxy-5,6,7,8-tetrahydronaphthalene-2-ylsulfa-nil-2-methylpropionic acid, 2-16-/1-ethyl-3-(4-hydroxyphenyl)ureido!|-5, 6,7,8-tetrag hydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid, F 2-16-(4-aminophenyl)-1-ethylureido|-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid. Ge

The best compounds are selected from: 2-16-[1-ethyl-3-(4--rifluoromethoxyphenyl)ureido!|-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropiono

ZB VVOI ACID; (ee) 2-16-I(3--4-rifluoromethoxyphenyl)ureido!|-5,6,7-8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid; 2-2-(1-ethyl-3-(4-rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methyl-propionic acid; "2-2-(1-ethyl-3-4-rifluoromethylsulfanylphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid; 2-16-[1-ethyl-3-(4--rifluoromethoxyphenyl)ureido|-3-fluoro-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methyl-c lpropionic acid; and a 2-methyl-2-(2-(11-propyl-3-(4-trifluoromethoxyphenyl)ureido|indan-5-ylsulfanylpropionic acid. "» Related compounds

The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as their salts, esters, amides, acids, hydrates or solvated forms; masked or protected forms; (ee) and racemic mixtures, or enantiomerically or optically pure forms. Related compounds also include compounds of the invention that have been modified to enable their detection, e.g., isotopically labeled with "ZE for use as a probe in positron emission tomography (PET) or single-photon emission computed tomography (PET) ). o 20 The invention also includes disclosed compounds having one or more functional groups (eg, hydroxyl, amino or carboxyl) masked by a protecting group. Z'Ya eid., (1999) doip Uuieu 85: Zopv, MU). Some of these masked or protected compounds are pharmaceutically acceptable; others are useful as intermediates. The synthesized intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention. 59 Hydroxyl protective groups

GF) Protection for hydroxyl groups includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers and silyl ethers. where Substituted methyl ethers

Examples of substituted simple methyl ethers include methoxymethyl, methylthiomethyl, t-butylthiomethyl, 60 benzoxy methyl, p-methoxybenzoxymethyl, (4-methoxyphenoxy)methyl, t-butoxymethyl.

Substituted ethyl ethers

Examples of substituted simple ethyl ethers include 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzoxyethyl, 2,2,2-trichloroethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl and benzyl.

Substituted Benzyl Ethers Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, p-halobenzyl,

2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, diphenylmethyl.

Complex ethers

In addition to simple esters, the hydroxyl group can be protected by an ester. Examples of esters

Include formate, benzoylformate, acetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, benzoate.

Sulfonates

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

Protection of amino groups 70 Protection for amino groups includes carbamates, amides, and special MH protecting groups.

Examples of carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, cleavable carbamates in the presence of auxiliary agents, photolytically cleavable carbamates, urea-type derivatives, and various carbamates.

Carbamates

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

Substituted ethyl

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

Photolytic cleavage

Examples of groups suitable for photolytic cleavage include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6b-nitrobenzyl and phenyl(o-nitrophenyl)methyl.

Amides sch

Examples of amides include M-formyl, M-acetyl, M-trichloroacetyl, M-trifluoroacetyl, M-phenylacetyl,

M-3-phenylpropionyl, M-picolinoyl, M-3-pyridylcarboxamide, M-benzoyl, M-p-phenylbenzoyl and phthaloyl. (8)

Protection for the carbonyl group

Cyclic acetals and ketals

Examples of cyclic acetals and ketals include 1,3-dioxane and 5-methylene-1,3-dioxane. M zo Protection for the carboxyl group

Complex esters of Me

Substituted methyl esters of

Examples of substituted methyl esters include 9-fluorenylmethyl, methoxy methyl, methylthiomethyl, methoxyethoxymethyl, 2-trimethylsilyl)ethoxymethyl, benzoxymethyl, phenacyl, p-bromophenacyl, x-methylphenacyl, and p-methoxyphenacyl. Examples of CO esters also include linear or branched alkyl esters such as tert-butyl, ethyl, propyl, isopropyl, and butyl.

Substituted benzyl esters

Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, 3-anthrylmethyl, 2,4,b-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, c p-methoxybenzyl, 2,6-dimethoxybenzyl, piperonyl, 4- picolyl and p-P-benzyl. and Silyl Esters Examples of silyl esters include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, phenyldimethylsilyl, and di-t-butylmethylsilyl.

C. Methods of synthesis o The invention offers methods of obtaining the disclosed compounds according to traditional methods of organic synthesis, as well as methods of matrix or combinatorial synthesis. Schemes 1-10 describe the proposed synthesis routes. Using these Schemes, the following description and examples, one skilled in the art can develop analogous or similar methods for a particular compound of the invention.

One of ordinary skill in the art will appreciate that the synthesis of the compounds of the present invention can be accomplished by obtaining an intermediate or protected intermediates described in any of the schemes disclosed herein. "And it will further be understood by one skilled in the art that during any of the processes for preparing the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules. This may be accomplished by conventional protecting groups , such as those described in Hrgoyesiime dgoyrz ip Ogdapis Zupipevziv, doip MUPeu 8 Zopv, 1991). These protective groups can be removed at a convenient stage using methods known to those skilled in the art. iF) Examples of the described synthesis routes include Synthesis Examples 1-57. Compounds analogous to the target compounds of these examples can be, and in many cases have been, prepared by analogous routes.The disclosed compounds are suitable for use in basic research and as pharmaceutical agents, as described in the next section.

General recommendations

A preferred synthesis of compounds of formula 14, where X is 5 (and Kz is H) is demonstrated in Schemes 1-5.

Abbreviations or acronyms used herein include: AcOH (glacial acetic acid); OSS (1,3-dicyclohexylcarbodiimide); OSE (1,2-dichloroethane); IC (2-dimethylaminoisopropyl chloride hydrochloride); OIEA 65 (diisopropylethylamine/; DMF (dimethylformamide); EOS (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide); EUAs (ethyl acetate); tSRBA (3-chloroperoxybenzoic acid); MMI (1-methylimidazole; TEA (triethylamine); TRA

(trifluoroacetic acid); THF (tetrahydrofuran); TMEBA (M,M,M',M'-tetramethylethylenediamine). and from Z. 4 2

According to Scheme 1, tetralins can be prepared by converting compound 1 to compound 2. For example, a methoxy-2-tetralone such as b-methoxy-2-tetralone can be treated with a reagent such as ammonium acetate or ammonia or hydroxylamine. The corresponding imine can be reduced with a suitable reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, and the resulting oxime can be reduced catalytically using palladium or platinum in a polar protic solvent such as methanol, ethanol or ethyl acetate to give the racemic compound 2. Preparation of the hydrochloride salt can be easily accomplished by one skilled in the art. ; he nko--50- chna inv vvi tn popy ny no, neo Seya Na sch schi 6) z 4 5

According to Scheme 2, indanes can be obtained by converting compound C to compound 5.

For example, when a 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 or hydrobromic acid in a polar solvent such as methanol or ether, receive ketoxime 4. e)

The reduction of compound 4 can be accomplished by using a suitable reducing agent(s) such as lithium aluminum hydride or hydrogen and a catalyst such as palladium or platinum in a suitable solvent such as acetic acid-sulfuric acid, THF or methanol, at suitable temperature. The choice of method of formation of the Ha») salt can be easily determined by a person skilled in the art. d) - . and? (ee) («c) has) se) that has) 60 b5

Scheme 3

Not on SY na no ), and 215 in 7 they rnya vo-yaya- M O- bbopuv" - p "on Y "

I 9 1; p ovsayakodi tu --- chChanniivruy. - Ki

Yes

M

(8) cha chn (22) hi ; and th Kh. --th sch o h2 o

According to Scheme 3, compound 2 or 5 can be converted to compound 12. For example, if the hydrochloride salt of a racemic amine is treated with a base such as sodium hydride or lithium hydride in a polar aprotic solvent such as DMF or THF and then reacted with with an anhydride such as phthalic anhydride at elevated temperature, cyclic imide 6 can be obtained. Cleavage of methyl aryl ethers of formula 6 to compounds of formula 7 can be accomplished using a Lewis acid such as boron bromide, boron chloride, aluminum chloride, or trimethylsilyl iodide, in non-polar aprotic solvents, such as toluene, dichloromethane 2-3) c or dichloroethane, with or without cooling. Acylation of phenols of formula 7 to compounds of formula 8 can be carried out using thiocarbamoyl chlorides, such as dimethylaminothiocarbamoyl chloride. and diethylthiocarbamoyl chloride, and a non-reactive tertiary amine such as triethylamine, 1,8-diazabicyclo|5,4,0undec-7-ene or 1,4-diazabicyclo|2,2,2doctane in an aprotic solvent such as dichloromethane, DMF or THF, with or without cooling. Compounds of formula 8 can be subjected to thermal

Go! rearrangement into compounds of formula 9 at a temperature in the range from 1802 to 35023, undiluted in the form of a melt or using high-boiling solvents, such as OOMUTNEKM Я A (a mixture of biphenyl and o biphenyl ether, sold, for example, by Rick SPpetis! Sogr., Mim /aKee, MUMI, ZA), ka M,M-dimethylaniline, diphenyl ether or decalin. Compounds of formula 10 can be obtained from compounds of formula

With by treatment with a suitable nucleophile such as hydrazine, disodium sulphide or methylamine in a suitable polar solvent such as ethanol or THF at elevated temperature. Conversion of compounds of formula 10"C to compounds of formula 11 can be accomplished using a suitable reagent, such as potassium hydroxide in an alcoholic solvent such as ethanol or methanol, or lithium aluminum hydride in THF or ether, followed by alkylation with an appropriately substituted alkyl halide , such as tert-butyl-2-bromoisobutyrate, ethyl bromoacetate or ethyl 2-bromobutyrate, and a reducing agent such as lithium borohydride or sodium borohydride. Compounds of formula 11 may be substituted to form compounds of formula 12 with carboxylic acid or (F, chloride acid and a suitable reducing agent such as borane-THF or borane-dimethylsulfide using aprotic solvents such as THF, dichloromethane or hexanes Alternatively, the substitution can be carried out using an aldehyde and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, in suitable aprotic solvents such as THF, dichloromethane or dichloroethane b5

Scheme 4 and 5 c

VeReVIRNUSOzN o a and vi yin; nav U-u otsey i - le

On) I YavAvAuRIMSO vir eh I like at 42 or 13

ReiavTRIEOYUI

On Ka is;

WITH

3- -- yuku cheh i o "4 Ge

According to Scheme 4, compounds of formula 13 can be prepared from compounds of formula 12 by H0) acylation of the secondary amine with arylacetic acid, using thionyl chloride or oxalyl chloride, neat or in toluene or dichloromethane, with or without a catalytic amount of DMF. Alternatively, conjugation can be carried out using standard peptide synthesis conditions, such as using m zo ES, OSS or IS in dichloromethane. If M is MH or 0, then aryl isocyanate or aryl chloroformate, respectively, in a nonpolar aprotic solvent such as He) can be used to prepare compounds of formula 13

THF, dichloromethane or hexanes. The choice of methods of deprotection to obtain compounds of formula 14 can be easily determined by a person skilled in the art.

Scheme 5 o d)

Re plyu Nevey; RYSOzN U. o) s v ve Yad" chi ia v --k h ay g" y va y VeyeyuRNMSO wah p cha 15 (ee) («c)

Kv ime) so 2 o i; "And now that I Mn gives x p 16

F) Similarly, compounds of formula 16 can be prepared from compounds of formula 11 by acylation of the primary coamine as depicted in Scheme 5 to give compounds of formula 15. The choice of deprotection methods to prepare compounds of formula 16 can be readily determined by one skilled in the art. in Scheme 6

Х M, ---- и Дю век Рсо аю пе В DO-tnsv te и: 5 ve b5 gg th tv

A compound of formula 18 can be prepared from a compound of formula 10 as demonstrated in Scheme 6.

For example, a compound of formula 10 can be treated with ethyl formate or ammonium formate, neat or in the presence of a suitable solvent such as dichloromethane or dichloroethane, with or without heating, to give a compound of formula 17. Compounds of formula 17 can be converted to compounds of formula 18 by using a suitable reagent such as lithium aluminum hydride in a suitable solvent such as

THF or ether, followed by alkylation using an appropriately substituted alkyl halide such as tert-butyl-2-bromoisobutyrate, ethyl bromoacetate or ethyl 2-bromobutyrate and a reducing agent such as lithium borohydride or sodium borohydride. tyu Scheme 7 about tissos Ua x-- ! MN. 0------e Mn - oz I Mn na po NO or No a p con 218 19 20 a

M- y Movy Z nn chn deni" from time to time! o o g

A preferred synthesis of a compound of formula 21 in which X is O (and Kz is H) is shown in Scheme 7.

For example, if compounds of formula 2 or 5 are acylated with carboxylic acid or acid chloride as described above, then compounds of formula 19 are obtained. Cleavage of methyl aryl ethers of formula 19 to compounds of formula 20 can be carried out using a Lewis acid such as boron bromide, chloride boron, aluminum chloride, or trimethylsilyl iodide in nonpolar aprotic solvents such as toluene, dichloromethane, or c dichloroethane, with or without cooling. Compounds of formula can be converted to compounds of formula 21 by treatment with a suitable base, such as potassium carbonate, cesium carbonate or potassium hydroxide, and accordingly with a 5-substituted alkyl halide such as tert-butyl-2-bromoisobutyrate, ethyl bromoacetate or ethyl 2-bromobutyrate, in a suitable solvent such as DMF or methanol.

Compounds of formula 24 can be prepared from compounds of formula 22, as shown in Scheme 8.

For example, a compound of formula 22 can be treated with a suitable base such as butyllithium or t-t-butyllithium in a suitable solvent such as ether or THF using TMEVA and with or without cooling and a suitable electrophile such as alkyl halides, aldehydes or disulfides, to obtain compounds 15 of formula 23. Compounds of formula 23 can be converted to compounds of formula 24 in a manner similar to that described in Scheme 3 to convert compound 8 to compound 9.

F) name) 60 b5

Scheme 9 p. sosnu 0 SNesn o - in Y nd nin nnnnnnnnnnnn yy 25 70 her 213 nche yo i

There are many things to do. mills Shk -- at 29 30 nn and.

M. .v, M. ot

DDT tu i s nz b 5) t) 31 z

An alternative synthesis of the compound of formula 32 is presented in Scheme 9. For example, if 4-methylthiophenylacetic acid, which is a compound of formula 26, is treated with oxalyl chloride or thionyl chloride in the presence of methanol, compounds of formula 27 are obtained. Treatment of compound 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, affords tetralones of formula 28. Using the procedure depicted in Scheme 1, tetralines of formula 29 can be prepared. Compounds of formula 29 can be substituted to give compounds of formula 30 using a carboxylic acid under the previously described coupling reaction conditions, or an acid chloride with a tertiary amine, such as diisopropylethylamine or triethylamine, in a suitable solvent, such as (ee) dichloromethane or dichloroethane. A compound of formula 30 can be converted to a compound of formula 31 using an oxidizing agent such as tCPBA or hydrogen peroxide in a suitable solvent such as methylene chloride followed by treatment of a compound of formula 30 with trifluoroacetic anhydride in a solvent such as chloroform with or without followed by treatment with a tertiary amine such as triethylamine or isopropylethylamine in a suitable solvent such as methanol to form a compound of formula 31. - c Alternatively, deprotection of the thioester group in compounds of formula 30 can be accomplished with and using a base such as tert-butyl sodium sulfide , sodium, sodium methylthiol, in a suitable solvent, such as DMF, M-methyl-2-pyrrolidone, or ammonia, to provide compounds of formula 31. Using chemistry analogous to that described in Scheme C to convert compound 10 to compound 11, compounds of formula 31 can be easily transformed into compounds of formula 32.

GO Mn t p p -4 | : n 22 33 m

Ge; about: with- with ke - pn itiny--- fa NN

En Z a bo 108 9 zga

According to Scheme 10, compounds of formula 22 can be readily converted to compounds of formula 32a, where

KBhOSN". For example, compounds of formula 22 may be treated with a suitable base such as butyllithium or sec-butyllithium in a suitable solvent such as ether or THF using TMEBBA and cooling and with or without a suitable disulfide such as dimethyldisulfide or dibenzyldisulfide to give compounds of formula 33. Removal of dimethylaminothiocarbamate from a compound of formula 33 is carried out using potassium or sodium hydroxide in a suitable solvent such as water, methanol or ethanol, with or without heating,

to form compounds of formula 34. Compounds of formula 34 may be methylated to give compounds of formula 19a with methyl iodide, dimethyl sulfate or diazomethane in a suitable solvent such as DMF, methanol or dichloromethane, with or without a base such as cesium carbonate or potassium carbonate her Using chemistry similar to that described in Scheme 9 to convert compounds of formula 30 to compounds of formula 32, compounds of formula 32a can be readily synthesized from compounds of formula 19a.

Path 1

OA

MOM p nn 2-16--1-Ethyl-3-«4--rifluoromethoxyphenylureido)|-5,6,7 8-tetrahydronaphthal-2-ylsulfanyl)-2-methylpropionic acid.

Compound 1.0 (Example 1)

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

Scheme 1. Ammonium acetate (65g;

O, in 4 mol) and the reaction is stirred for ЗОхв. at room temperature. Sodium cyanoborohydride (17.8 g; 0.28 mol) is then added to the reaction and the reaction is refluxed for 1-2 hours.

The reaction is cooled, the solvent is removed under reduced pressure, the residue is diluted with EtOAc and 1N s is added

Mahon for quenching the reaction. The aqueous phase is separated and the organic phase is washed with H 20, brine, dried (d) over NaCl 53O), filtered and the solvent is removed under reduced pressure, obtaining a crude residue, which is purified by flash chromatography (5lO) with CHCl 2 /Meon elution: -MnH.АОНн (1095), obtaining 5.0 g (50905) of b-methoxy-1,2,3,4-tetrahydronaphthalene-2-ylamine in the form of a dark oily liquid. Through a solution of the compound named in the title in ether (10 Oml), cooled to 02C, bubble NCI (gas.) until saturation of the solution. -

The suspension is stirred for another 30 minutes. at room temperature and the solvent is evaporated under reduced pressure. The remaining solid was triturated with ether, filtered, washed with ether, and dried under reduced pressure to give 4.9 g of b-methoxy-1,2,3,4-tetrahydronaphthalene-2-ylamine hydrochloride as a white solid. at

And С/М5 (Liquid chromatography/mass spectrometry): С.44Н45МО: t/: 178 (М 1).

B. 2-(6-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)isoindole-1,3-dione so

Scheme 3. b-Methoxy-1,2,3,4-tetrahydronaphthalene-2-ylamine (30 g; 0.14 mol) is added in portions at 02С to a stirred suspension of bObo Man (bg, 0.182 mmol) in DMF (400 mol). The reaction mixture is heated to room temperature and stirred for another 1 hour. Add phthalic anhydride (20.7 g; O0.139 mol) in 1 portion at room temperature, after which the reaction mixture is stirred for another 10 hours, and then kept at room temperature for 18 hours. at 1202C. The reaction is allowed to cool to room temperature, diluted with NaOH and extracted several times with EtOAc. The combined organic extracts are washed with water, brine, dried over NaCl, and the solvent is removed under reduced pressure. The crude solid was triturated with MeonH, filtered and dried under vacuum to give 29.1 g (67905) of 2-(b-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)isoindole-1,3-dione as whitish solid substance. so 175 TN nMR (Z0OMHC, SOSIv): 5 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, 71H), 3.78 (s, ЗН), 3.52-3.61 (m, 1H), 2, 95-2.98 (m, 2H), 2.81-2.88 (m, 1H), 2.65-2.76 (m, 1H), o 1.97-2.01 (m, 1H) . d) IIS/M8: С419Н47Моз: t/2 308 (M 1). 20 b. 2-(6-Hydroxy-1,2,3,4-tetrahydronaphthalene-2-yl)isoindole-1,3-dione is) Scheme 3. To 2-(6-methoxy-1,2,3,4-tetrahydronaphthalene) -2-yl)isoindole-1,3-dione (29g; 94.3mmol), dissolved

And in anhydrous СНоСИ" (500 ml), cooled to -60 "С, add a 1.0 M solution of boron bromide-СНСНСИИ" (471 ml) dropwise to maintain the reaction temperature in the range from -50 to -60 С. After the end of the addition, the reaction mixture the mixture is allowed to warm to room temperature and stirred for another 4 hours. Reaction 5c is cooled to 02С, quenched with saturated Manso with (400 ml) and stirred for another 0.5 h. at room temperature. The precipitate is filtered, thoroughly washed with NaO, suspended in ether, filtered and dried under i) vacuum, obtaining 25.4 g (9295) of 2-(b-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)isoindole-1 ,3-dione in the form of a whitish solid. "H NMR (300 MHz, DMSO-iv): 5 9.11 (b, 1H), 7.82-7.89 (m, 4H), 6.84-6.87 (d, 1H), 6 .52-6.56 (m, 2H), because 4.29-4.37 (m, 1H), 3.45 (width, 1H), 3.25-3.34 (m, 1H), 2.73-2.84 (m, ZN), 2.37-2.47 (m, 1H), 1.94-1.98 (m, 1H).

IIS/M8: Si8Ni5Moz: t/2 294 (M 1). r. O-16-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl|) ester of dimethylthiocarbamic acid.

Scheme 3. To 2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)isoyiindole-1,3-dione (25.4 g; 86.5 mmol), 65 dissolved in anhydrous DMF (200 ml) , add 1,4-diazabicyclo|(2.2.2)octane (48.5 g; 4.32 mol), and then dimethylaminothiocarbamoyl chloride (53.4 g; 4.32 mol) and stir the solution at room temperature for

4 hours The reaction is poured into ice water (1 L) and stirred for 18 hours. The precipitate is filtered and washed

BUT and dried under vacuum. The crude solid is purified by flash chromatography (5105) eluting with a hexanes-EOAc gradient to give Zog (91960)

O-I6-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl) ester of dimethylthiocarbamic acid in the form of a white solid.

TN nMR (30 MHz, SOSIv): 5 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, ЗН), 3.34 ( c, ZN), 2.88-3.09 (m, ZN), 2.64-2.78 (m, 1H), 1.97-2.01 (m, 1H).

And C/M8: C24NooM2Oz5: t/2 381 (M'1).

E. 5-16-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl| complex ester of dimethylthiocarbamic acid

Scheme 3. To a round-bottom flask on BOml, equipped with a reflux condenser and a stirring rod, preheated to 330 90 in a sand bath, add

O-16-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl| dimethylthiocarbamic acid ester 75 (5.32 g; 13.9 mmol) in 1 portion. The melt is stirred for 7-8 minutes. at 3302C, then quickly cooled to room temperature with a stream of Mo. The crude residue is purified by flash chromatography (5iO"), eluting with a gradient of hexanes-EtOAc, obtaining Zyg (5890) 5-I6-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-5,6,7, 8-tetrahydronaphthalene-2-yl| dimethylthiocarbamic acid ester as a white solid.

TN NMR (Z0OMHC, SOSIv): 5 7.82-7.86 (m, 2), 7.72-7.75 (m, 2H), 7.23-7.26 (m, 2), 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).

And C/M8: C24NooM2Oz5: t/2 381 (M'1).

E. 5-I6-amino-5,6,7,8-tetrahydronaphthalen-2-yl) ester of dimethylthiocarbamic acid

Scheme 3. A 3-necked flask, equipped with a reflux condenser and a mechanical stirrer, is loaded with ЕУН с (115 ml) and 5-I6-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-5,6,7, 8-tetrahydronaphthalene-2-yl| ester (U) of dimethylthiocarbamic acid (8.7g; 23.5mmol). Hydrazine (b,bml; 2.11mol) is added in one portion at room temperature and the reaction is refluxed with mechanical stirring for 40 minutes. The reaction is cooled to room temperature temperature and the gel-like white solid is filtered and washed thoroughly with ether. The ether washings are combined, evaporated under reduced pressure, and the crude residue is further triturated with ether, filtered and the ether is evaporated under reduced pressure to give a run of (10095) 5- (b-amino-5,6,7,8-tetrahydronaphthalen-2-yl) ester of dimethylthiocarbamic acid in the form of a yellow oily liquid.

And C/M8: C43N48M208: t/2251 (M'-1). Ha») b. Tert-butyl ester of 2-(6b-amino-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid with

Scheme 3. A KOH solution (4 ,1g; 73.2mmol) in MeOnH (25ml) at room temperature. The solution is stirred at reflux for 5 hours. and « cooled to room temperature. Add tert-butyl-2-bromoisobutyrate (16.3 g; 73.2 mmol) to the solution and stir for 1 h. at room temperature Mavn (92 g; 2.44 mol) is added and the reaction is stirred for another 48 hours. at room temperature. The reaction is quenched with Н 20, the solvent is evaporated under reduced pressure and the crude residue is distributed between HO and СНоСиИ». The aqueous phase is extracted

СНоСИ» and the combined organic extracts are dried over Ma»5O,), filtered and evaporated under reduced pressure, obtaining 4 7 g (6090) of tert-butyl ester of 2-(6-amino-5,6,7,8-tetrahydronaphthalene) -2-ylsulfanyl)-2-methylpropionic acid in the form of a brown oily liquid. av) IS/M8: Si81N27M05: t/2266 (M'1).

N. tert-butyl ester of di 2-(6-acetylamino-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid (se) 20 Scheme C. To tert-butyl ester. 2-(6-amino-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid (4.7 g; 14 mmol), dissolved in СНоСИ» (25 ml), add OIEA (3.3 ml ; 18.mmol) and the reaction mixture was cooled to 02. Acetyl chloride (1.25ml; 17.5mmol) was added dropwise at such a rate as to maintain the temperature in the range 0-50. The reactions are allowed to warm to room temperature and stirred for 1 hour. The reaction is diluted with 59 mL of CHCl, washed with HO, dried over NaCl5O, and evaporated under reduced pressure. Raw oily

HF) the liquid is purified by flash chromatography (5105), eluting with a gradient of hexanes-EUAs, obtaining 1.7 g (3290)

GF tert-butyl complex ester of 2-(6-acetylamino-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid in the form of a yellow-brown solid.

TN nMR (30 MHz, SOSIv): δ 7.23-7.26 (m, 2H), 6.99-7.01 (d, 1H), 546-548 (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, ЗН), 1.70-1.82 (m, 1H), 1.43 (s, 15H).

IIS/M8: SooNoMOz: t/2 308 (M 1). 65 I. Tert-butyl ester of 2-(6b-ethylamino-5.6.7.8-tetrahydronaphthalin-2-ylsulfanyl)-2-methylpropionic acid

Scheme C. To a solution of tert-butyl ester of 2-(6-acetylamino-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid (1.7 g; 4.64 mmol) in THF (42 ml) is added 1.0 M borane-THF solution (42 ml) dropwise at room temperature. The reaction is left with stirring for 18 hours. at room temperature, carefully quench the MeOH and evaporate the solvent under reduced pressure. The residue of the oily liquid is further subjected to azeotropic distillation with Meon (3x), obtaining 1.9 g (10096) of a mixture of tert-butyl ester 2-(b-ethylamino-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2- methylpropionic acid and its borane complex in the form of an oily liquid. 70 I S/M8: SooNaziMO»5.VNU: t/2 308 (M VN») 1). in. Tert-butyl ester of 2-16-(1-ethyl-3--4--rifluoromethoxyphenyl)ureido!|-5,6,7-8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid

Scheme 4. To a mixture of tert-butyl ester and borane complex 75. 2-(b-ethylamino-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid (1.9g; 5.2mMmMol), dissolved in SNHSA" (15 ml), add 4-trifluoromethoxyphenyl isocyanate (1.6 mg; 7.3 mmol) and stir the reaction at room temperature for 18 hours. The solvent is removed under reduced pressure and the crude residue is purified by flash chromatography (502), eluting with a gradient of hexanes-EtOAc, yielding 1.6 bg (58965) of tert-butyl ester 2-16-P1-ethyl-3--4--rifluoromethoxyphenyl) ureido)|-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid in the form of a white foam.

JIS/M8: SovNavEzM20.5: t/2497 (M-S)Nv) 1).

K. 2-16-[1-Ethyl-3-4--rifluoromethoxyphenyl)ureido!|-5,6,7,8-tetrahydro-naphthalene-2-ylsulfanyl)-2-methylpropionic acid

Acid

Scheme 4. To the tert-butyl ester of i) 2-16-[1-ethyl-3--4--rifluoromethoxyphenyl)ureido!|-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid (1.66g; 3.0mol), dissolved in СНоСИ» (15ml), add TPA (15ml) and stir the reaction at room temperature for 1.5h. The solvent is removed under reduced pressure and the residue is purified by RT-flash chromatography (500"), eluting with a gradient of hexanes-BYUAc, obtaining 0.643g (4396) of 2-16-[1-ethyl-3--4--rifluoromethoxyphenyl)ureido!| -5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid as a white solid. si

TN nMR (SO00MHz, CO53O0): δ 7.45-7.48 (m, 2H), 7.06-7.24 (m, 5H), 4.44 (m, 1H), 343-345 (m, 2H), about 2.96-3.02 (m, 4H), 2.00-2.05 (m, 2H), 1.41-1.46 (s, 6H), 1.21-1.29 (m, ZN).

And C/M8: SodNo; Ra3M20.5: t/2 497 (M'1). d)

Path 2 "

2--2-(11-Ethyl-3--4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methyl-propionic acid. ime) Compound 2.0 (Example 2) with 50 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 Meon (1.4 l) at 4593 m butyl nitrite (8 ml; 0.69 mol) is added dropwise over 45 min. Then to the hot solution concentrated NCI (45 ml) is added over 20 minutes and the reaction is left with stirring at 459 for another 1.5-2 hours. The reaction suspension is cooled, the precipitate is filtered, washed several times with cold Meon and dried under vacuum, obtaining 55.8 g (62965) 5 -Methoxyindan-1,2-dione-2-oxime in the form of a beige solid.

HF) TN NMR (Z00MGu, COzO0): 5 7.80-7.83 (m, 1H), 6.95 (sh.s, 2H), 3.92 (s, ZN), 3.78 (s, 2H), 3.47 (width, 1H). from IIS/M8: C4oNoMoOz: t/2 192 (M'1).

B. 5-Methoxyindan-2-ylamine hydrochloride

Scheme 2. To b5B-methoxyindan-1,2-dione-2-oxime (55.7g; 0.291mol) suspended in glacial 60 acetic acid (0.99L), concentrated NiSO (b7ml) is added, and then 1095 Ra -C (27g) and the reaction is stirred in the apparatus

Parra at a pressure of 414 kPa (bOrzi) for 18 hours. The reaction is purged with M", filtered through a pad of celite and washed with AcOH. The solvent is removed under reduced pressure to 1/5 of the volume and the remaining solvent is diluted with HO (500 ml), cooled to 0 °C and neutralized to pH 10 with 5095 aqueous MaonN. The aqueous phase was carefully extracted several times with HCl and the extracts were combined, washed with H2O, brine, dried over NaCl5O, filtered and evaporated under reduced pressure to give 77.3 g (6695) of a crude oily liquid.

The oily liquid was subjected to flash chromatography (5iO2), eluting with 40:2.2:0.2 CHCl3:Meon:MH.OnH, yielding 43.8 g (3790) of a dark colored oily liquid. The oily liquid is dissolved in ether (1 l), cooled to 02C and the solution is saturated with CARRIERS (gas). The solvent was removed under reduced pressure and the solid was triturated with ether, filtered and washed with ether to give 43.8 g (3095) of 5-methoxyindan-2-ylamine hydrochloride as a white solid.

TN nMR (SO0MHz, CO53O0): 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, ЗН), 3.08-3.19 (m, 2H), 2.57-2.68 (m, 2H), 1.51 (s, 2H) .

IIS/M8: C4oNoMoOz: t/2 192 (M'1).

T.pl.-240-24196. b. 2-(5-Methoxyindan-2-yl)isoindole-1,3-dione

Scheme 3. 5-Methoxyindan-2-ylamine hydrochloride (40.0g; O0.2mol) is added to a suspension of bOboy Man (8g; 0.240mol) in DMF (25Oml), cooled to 09С, and the suspension is stirred for an hour. at room temperature. Phthalic anhydride (30 g; 0.2 mol) is added in one portion and the suspension is stirred for another 72 1-1,Bh. at room temperature, and then stirred at 1202 for 9 h. The reaction is cooled and diluted with E(Ac. The organic phase is washed with HO, the precipitate formed is filtered, washed with EtOAc, Meon and dried under vacuum, obtaining 25.2 g (4395) of 2-(5-methoxyindan-2-yl)isoindole-1,3- dione as a white solid.The organic phase is washed with H2O, evaporated under reduced pressure and the solid triturated with meon, filtered and dried to give an additional 19.7 (3390) g of 2-(5-methoxyindan-2-yl)isoindole-1 ,3-dione as a white solid.

TN nMR (30MHz, CO5O0): 5 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, ЗН), 3.48-3.65 (m, 2H), 3.07- 3.18 (m, 2H).

IIS/M8: Si8Ni5Moz: t/2 294 (M 1). at. 2-(5-Hydroxyindan-2-yl)isoindole-1,3-dione c 29 Scheme 3. To 2-(5-methoxyindan-2-yl)isoindole-1,3-dione (19.7g; b7mmol), dissolved in anhydrous СНоСи»Го) (35О0ml) and cooled to -60oС, add dropwise a 1.0M solution of boron bromide-СНСИ» (34Омл) at such a rate as to maintain the internal temperature in the interval from -50 to -602С. The reaction mixture is allowed to warm to room temperature and stirred for another 5 hours. The reaction is cooled to 0 C, quenched with saturated MnSO 4 (500 ml) and stirred for another 0.5 h. at room temperature. The precipitate was filtered, washed with NaOH, suspended in ether, filtered and dried under vacuum to give 14.8 g (79905) of Me 2-(5-hydroxyindan-2-yl)isoindole-1,3-dione as a beige solid. with

TN nMR (SO0MGhC, DMSO-iv): δ 9.16 (s, 1), 7.82-7.91 (m, 4H), 6.98-7.01 (d, 71H), 6.56- 6.62 (m, 2H), 4.91-5.03 (m, 1H), 3.27-3.43 (m, ЗН), 2.99-3.10 (m, 2H). at

And S/M8: S.47N41z3MOzch: t/2 280 (M'-1). (uh)

E. O-(2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)indan-5-yl)| complex ester of dimethylthiocarbamic acid

Scheme 3. 1,4-diazabicyclo|2.2.2|- octane (62 g; 0.55 mol), and then dimethylaminothiocarbamoyl chloride (68 g; 0.55 mol) and the solution is stirred at room temperature for 16 hours. The reaction is poured into ice water 40. (Il) and stirred for 18 hours. The precipitate is filtered, washed with HO and dried under vacuum, obtaining - with 41.6 g (10096) of O-I(2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)indan-5-yl) ester of dimethylthiocarbamic acid in the form of a beige solid. i TN nMR (ZO0MHZc, SOSIv): 5 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, ЗН), 3.34 (c, ZN), 3.09-3.23 (m, 2H). in. 5-(2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)indan-5-yl| compound ester of dimethylthiocarbamic acid with Scheme 3. To a round-bottomed flask on BOml equipped with a reflux condenser and a stirring rod , preheated to 330 90 in a sand bath, is added

O-I(2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)indan-5-yl| dimethylthiocarbamic acid ester ko (6.30 g; 18.7 mmol) in 1 portion. The melt is stirred for 12 min at 33829С, quickly cool to

Ge) 20 room temperature with a flow of Mo and the crude residue is purified by flash chromatography (5105), eluting with a gradient of hexanes-ETOAc, obtaining 3.88 g (61905) of 3-(2-(1,3-dioxo-1,3-dihydroisoindole-2 -yl)indan-5-yl

What. dimethylthiocarbamic acid ester in the form of a whitish solid.

TN nMR (Z0OMHC, SOSIv): 5 7.81-7.87 (m, 2H), 7.69-7.74 (m, 2H), 7.22-7.36 (m, ЗН), 5, 10-5.22 (m, 1H), 3.59-3.67 (m, 2H), 3.06-3.23 (m, 9H). 59 |S/M8: SoonivMoO88: t/2367 (MA).

HF) N. 5-2-Aminoindan-5-yl) ester of dimethylthiocarbamic acid 7 Scheme 3. A 3-necked flask equipped with a reflux condenser and a mechanical stirrer is charged with EYN (9 ml) and 5-I(2-(1,3 -dioxo-1,3-dihydroisoindol-2-yl)indan-5-yl ester of dimethylthiocarbamic acid (6.9g; 20.b6mmol). Add hydrazine (5.8ml; 18bmmol) in 1 portion at room temperature and the reaction 60 is heated to reflux with mechanical stirring for 30 minutes. The reaction is cooled to room temperature and the gel-like white solid is filtered and washed several times with ether. The ether washings are combined, evaporated under reduced pressure and the crude residue is triturated with ether, filtered further and the ether is evaporated under reduced pressure to give 4.bg (95965) of 8-(2-aminoindan-5-yl) dimethylthiocarbamic acid ester as a brown oily liquid.

TN nMR (Z00MHZc, SOSIv): 5 7.15-7.33 (m, ЗН), 3.80-3.88 (m, 1Н), 3.05-3.22 (m, 8Н), 2, 64-2.72 (m, 1H),

2.17 (width p, 2H).

And C/M8: C412H46M2O: t/2 237 (M-1).

I. Tert-butyl ester of 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropionic acid

Scheme 3. A solution of KOH (11.8 g; 0.210 mol) in MesN ( 110 ml) at room temperature.

The solution is stirred at reflux for 5 hours. and cooled to room temperature. Add tert-butyl-2-bromoisobutyrate (7.0 g; 31.mmol) to the solution and stir for 18 hours. at room temperature. The solvent is evaporated under reduced pressure and the crude residue is partitioned 7/0 between H2O and EtOAc. The aqueous phase is extracted with EtOAc and the combined organic extracts are washed with HO, brine, dried over NaCl, filtered and evaporated under reduced pressure to give 4.9 g (76905) of tert-butyl ester 2-(2-aminoindan-5- ylsulfanyl)-2-methylpropionic acid in the form of a brown oily liquid.

And C/M8: C47Н25МО»: t/2 308 (M 1).

U. Tert-butyl ester of 2-(2-acetylaminoindan-5-ylsulPhanyl)-2-methylpropionic acid

Scheme 3. TEA (8.bml; 61.7 mmol) and the reaction mixture is cooled to 09C. Acetyl chloride (4.1 mL; 57.bmol) was added dropwise at such a rate as to maintain the temperature in the range of 0-59C. The reaction is left to warm to room temperature, stirred for 16 hours, diluted with CHCl, washed with NaO, dried over NaO, and evaporated under reduced pressure. The crude oily liquid is purified by flash chromatography (ZO 5), eluting with a gradient of hexanes-EtOAc, obtaining 11.7 g (71960) of 2-(2-acetylaminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester as a solid beige color

TN nMR (30 MHz, SOSIv): 85 7.31-7.35 (m, 2H), 7.15-7.18 (d, 1), 5.73 (m, 1H), 4.68-4, 78 (m, 1H), 3.25-3.39 (dd, 2H), 2.74-2.80 (d, 2H), 1.94 (s, ЗН), 1.43 (s, 15H) . with

IIS/M8: C19H27MOz38: t/2 294 (M '-1). at

K. Tert-butyl ester of 2-(2-ethylaminoindan-5-ylsulPhanyl)-2-methylpropionic acid

Scheme C. To a solution of tert-butyl ester of 2-(2-acetylaminoindan-5-ylsulfanyl)-2-methylpropionic acid (11.7g; 33.5mmol) in THF (280ml) is added dropwise at room temperature a 1.0M solution borane-THF (226 bml). The reaction is left with stirring for 5 hours. at room temperature, cooled to 02C, quenched with MeonN (100 ml) and evaporated under reduced Fo pressure. The residual oily liquid is further subjected to azeotropic distillation with Meon (3x), obtaining 11 g (100965) of a mixture of tert-butyl ester of 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methylpropionic acid and its borane complex in the form of an oily liquid. at

I C/M8: C19NooMO»5. VNU: t/2 336 (M 'VN») 1). d. Tert-butyl ester of 2-2-[1-ethyl-3--4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid

Scheme 4. 4-trifluoromethoxyphenyl isocyanate is added to a mixture of tert-butyl ester and borane complex of 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methylpropionic acid (11.0g; 33mmol) dissolved in SNCI" (10Oml) (10.2 g; 50.2 mmol) and the reaction is left under stirring at 740 room temperature for 18 hours. The solvent is removed under reduced pressure and the crude residue is purified by flash chromatography (505), eluting with a gradient of hexanes-E(Ac, yielding 11.2 g (62965) of tert-butyl ester of /2-2-(1-ethyl -3--4--rifyl-ioromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid in the form of a white foam.

TN nMR (30 MHz, SOSIv): 85 7.30-7.36 (m, 4H), 7.10-7.19 (m, ZN), 6.31 (s, 1), 4.97-5008 ( m, 1H), so 75 3.22-3.39 (m, 4H), 3.01-3.09 (dd, ?2H), 1.42-1.44 (m, 15H), 1.23 -1.28 (t, ZN).

And C/M8: C27NzzEzM2O045: t/2 483 ((M-SANv) 1). (ав) M. 2-2-P1-Ethyl-3-4-rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid from Scheme 4. To tert-butyl ester 2-2-/1 -ethyl-3--4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid (4, g; (Ce) 20 8.91 mmol), dissolved in СНоСі» (15 ml), add TPA (15 ml ) and the reaction is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (510 5), eluting with a gradient of hexanes-EtOAc, to give 3.13 g (7390) of 2-2-/1-ethyl-3-(4--rifluoromethoxyphenyl)ureido|indane -5-ylsulfanyl)-2-methyl-propionic acid as a white solid.

TN nMR (30 MHz, SOSIv): 85 7.29-7.35 (m, 4H), 7.15-7.17 (d, 1H), 7.08-7.11 (d, 2H), 6, 45 (c, MH), (F. 4.94-5.04 (m, 1H), 3.18-3.36 (m, 4H), 2.98-3.07 (m, 2H), 1 .48 (c, 6H), 1.19-1.28 (t, ЗН). ko ИС/М8: СозНовз3М20.5: t/2483 (М '-1).

T.pl.-73-7796. The following 14 compounds were prepared according to Schemes 3 and 4 and stages U, K, I, and M of Path 2, using the appropriate reagents instead of the indicated ones and adjusting the reaction conditions: (5)-2-42-(1-Ethyl-3- (4-trifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid

Compound 2.1 (Example 3) b5 with b)-yain /

The intermediate compound HER (11g) of path 2 is separated by the method of chiral chromatography (column SpPigaIrak AYU; isocratic gradient hexane/methanol/ethanol: 92/4/4), obtaining the (5)-isomer of intermediate compound 1! (4.8 Gh).

Using Stage M of pathway 2, compound 2.1 (3.1g) is obtained.

IS/M8: SozNovz3M20.5: t/2483 (M '-1). 2--2-11-Ethyl-3--4--rifluoromethylsulfanylphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid.

Compound 2.2 (Example 4)

SEZ o a,

Fo / sch o

Compound 2.2 (0.33g; 5790 for 2 steps; white solid) was prepared according to route 2, using 4-trifluoromethoxyisocyanate instead of 4-trifluoromethoxyphenylisocyanate.

IN NMR (СО300): δ 1.16-1.20 (t, ЗН), 1.38 (s, 6Н), 3.09-3.23 (m, 4Н), 3.37-3.44 ( sq, 2H), 4.95-5.06 (m, 1H)U, 7.14-7.17 (m, 1H), 7.32-7.35 (m, 1H), 7.40 (s , 1H), 7.55 (c, 4H). -

And S/M5: SozNovEzM2O55»9: t/272499 (Mn). Fu 2-Methyl-2-12-(1-pentyl-3--4--rifluoromethylsulfanylphenyl)ureido|-indan-5-ylsulfanyl)propionic acid

Compound 2.3 (Example 5) p

Z o d) o

З У в -2о- : - с ;» (ee) Compound 2.3 (0.22g; 3295 for 2 steps; white solid) was prepared according to route 2 and the synthesis of Compound 2.2 using valeryl chloride instead of acetyl chloride. "YAN NMR (СО300): 5 0.844-0.890 (t, ЗН), 1.20-1.31 (m, 4Н), 1.39 (s, 6Н), 1.45-1.58 (m, 2Н ), 3.07-3.22 (m, ime) 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).

Ge) 50 I S/M5: SovNaiiii EzM2O352: t/2541 (Mn). 2-2-(11-Ethyl-3-(4-isopropylphenyl)ureido|indan-5-ylsulfanyl)-2-methyl-propionic acid "m Compound 2.4 (Example 6) schi o ime) v! U. 60 u;

Compound 2.4 (0.18g; 3495 for 2 steps; white solid) was prepared according to route 2, using 4-isopropylphenylisocyanate instead of 4-rifluoromethoxyphenylisocyanate. for "YAN NMR (СО50О0): 5 1.16-1.23 (m, 9Н), 1.38 (s, 6Н), 2.82-2.87 (m, 1Н), 3.10-3, 21 (m, 4H), 3.37-3.39 (m,

2H), 4.99-5.04 (m, 1H), 7.14-7.17 (m, ЗН), 7.23-7.26 (m, 2H), 7.32-7.50 ( m, 2H), 7.40 (c, 1H).

IS/M8: SoBNaa2M2Oz35: t/2441 (M'-1). 2-12-(3--4-Dimethylaminophenyl)-1-ethylureido)indan-5-ylsulfanyl)-2-methylpropionic acid

Compound 2.5 (Example 7)

And U U /

Compound 2.5 (0.34g; 66905 for 2 steps; white solid) was prepared according to route 2, using 4-dimethylaminophenylisocyanate instead of 4-rifluoromethoxyphenylisocyanate. "YAN NMR (СО50О0): 5 1.15-1.20 (t, ЗН), 1.42 (s, 6Н), 2.88 (s, 1Н), 3.05-3.69 (m, 4Н ), 3.31-3.69 (m, 2H), 4.94-5.06 (m, 1H), 6.78-6.81 (m, 2H), 7.16-7.21 (m , ZN), 7.29-7.41 (m, 2H).

And C/M8: SodNaz4M3O035: t/2442 (M '-1). 2-Methyl-2-12-(1-pentyl-3-4-rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid

Compound 2.6 (Example 8) 2 c o

In that

Fo c "c)

Compound 2.6 (0.29g; 7790 for 2 steps; white solid) was prepared according to route 2 using valeryl chloride as co instead of acetyl chloride. "YAN NMR (СО5О0): 5 0.847-0.893 (t, ЗН), 1.20-1.29 (m, 4Н), 1.39 (s, 6Н), 1.58-1.60 (m, 2Н ), 3.04-3.29 (m, 6H), 4.89-4.99 (m, 1H), 7.14-7.17 (m, ZH), 7.32-7.34 (m . -Dimethylaminophenyl)-1-pentylureido|indan-5-ylsulfanyl)-2-methylpropionic acid

Compound 2.7 (Example 9) . ;" x (ee) 7 U un o) no

M se) what

HF) Compound 2.7 (0.25g; 3695 for 2 steps; white solid) was prepared according to route 2 and the synthesis of Compound 2.5 using valeryl chloride instead of acetyl chloride. "YAN NMR (СО5О0): 5 0.869-0.915 (t, ЗН), 1.17-1.31 (m, 4Н), 1.44 (с, 6Н), 1.57-1.65 (m, 2Н ), 2.91 (s, 6H), in 3.12-3.29 (m, 6H), 4.94-5.02 (m, 1H), 6.80-6.83 (d, 2H) , 7.17-7.23 (m, ZN), 7.32-7.38 (m, 2H).

And C/M8: C27Na7M3O535: t/2 484 (M'1). 2-12-I3-(4-Isopropylphenyl)-1-(3-pentyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid

Compound 2.8 (Example 10) b5 and sor 15 Compound 2.8 (Bmg; 1495 for 2 steps; white solid) was prepared according to route 2 and synthesis

Compounds 2.4, using valeryl chloride instead of acetyl chloride.

IS/M8: SovNzavM2O»5: t/2 483 (M'1). 2-(2-N-3-(4-tert-butylphenyl)-1-(3-pentyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid

Compound 2.9 (Example 11) 20 s 25 "oso ? cha 30 Fo s

Compound 2.9 (4 mg; 995 for 2 steps; white solid) was prepared according to route 2 and the synthesis of Compound (a) 2.3 using 4-tert-butylphenyl isocyanate instead of 4-trifluorothiophenyl isocyanate. so 35 1C/M8: SoeNaoMoO88: t/2497 (Ma). 2-(2-(3-(Biphenyl-4-yl-1-pentylureido)indan-5-ylsulfanyl|-2-methylpropionic acid)

Compound 2.10 (Example 12) "40 s;"

U in so no (in) name) o 50 what

Compound 2.10 (Zmg; 7906 for 2 steps; white solid) was obtained according to route 2 and synthesis

Compounds 2.3, using 4-biphenyl isocyanate instead of 4-trifluorothiophenyl isocyanate.

And C/M8: C34Nz6M2Oz35: t/2517 (M'-1).

HF) 2-12-I3-(4-Isopropylphenyl)-1-(3-hexyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid 7 Compound 2.11 (Example 13) 60 b5

And ns. at 7 p.m

Compound 2.11 (1Zmg; 4495 for 2 steps; oily liquid) was prepared according to route 2 and the synthesis of Compound 2.4 using caproyl chloride instead of valeryl chloride.

IIS/M8: SooNaoM2Oz5: t/2497 (M'-1). 2-Methyl-2-12-(1-hexyl-3--4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)propionic acid

Compound 2.12 (Example 14)

Ost, s o o)

From the nose book

M cha

Fo s "c) lo gud : . (uh)

Compound 2.12 (18 mg; 5495 for 2 steps; white solid) was prepared according to route 2 using caproyl chloride instead of valeryl chloride.

And C/M8: C27NazEz3M20.5: t/2 539 (M 1). 2-Methyl-2-12-(1-hexyl-3--4--rifluoromethylsulfanylphenyl)ureido|-indan-5-ylsulfanyl)propionic acid «

Compound 2.13 (Example 15 du U (Example 15) z с с З ;" v so Y Go-ya ("in) name) o 50 what

Compound 2.13 (14 mg; 3695 for 2 steps; white solid) was obtained according to route 2 and synthesis 259 of Compound 2.2 using caproyl chloride instead of valeryl chloride.

HF) and C/M5: C27NazEzM2O55»9: t/2 555 (Mn). 2-Methyl-2-12-P1-propyl-3--4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)propionic acid de Compound 2.14 (Example 16) 60 b5

OSR,

Compound 2.14 (1.2 mg; 395 for 2 steps; oily liquid) was prepared according to route 2 using propionyl chloride instead of acetyl chloride.

And C/M8: SodNo; Ra3M20.5: t/2 497 (M'1). t 2-Methyl-2-12-(1-butyl-3--4-trifluoromethylsulfanylphenyl)ureido|indan-5-ylsulfanyl)propionic acid

Compound 2.15 (Example 17)

From on U in s o

Compound 2.15 (11 mg; 32905 for 2 stages; oily liquid) was prepared according to route 2 and the synthesis of Compound 2.2 using butyryl chloride instead of acetyl chloride. b

And C/M5: SoBNoo with M2O5359: t/2 527 (Mn). 2-Methyl-2-12-I3--4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-propionic acid c

Compound 2.16 (Example 18) o d) and "n U-kn n shi s" from Compound 2.16 (11 mg; 4995 for 2 stages; oily liquid) are obtained according to the path 2 by acylation " with 4-trifluoromethoxyphenyl isocyanate.

And C/M8: C24Na4B53M20.5: t/2 455 (M '1).

Route C with 2-Methyl-2-12-(1-pent-4-enyl-3-(4-trifluoromethoxyphenyl)ureido)indan-5-ylsulfanylpropionic acid o Compound 3.0 (Example 19) d) C o 50 and jus in WHICH

F) name) 60

Pent-4-enal (0.06 mg; 0 .72 mmol), and then sodium triacetoxyborohydride (0.21 g; 1.0 mmol) and the reaction mixture was stirred for 18 hours. at room temperature. The reaction mixture is diluted with CH 2Si", washed with NaO, brine, dried over Ma»5O), filtered and the solvent 65 is evaporated under reduced pressure, obtaining tert-butyl ester

2-methyl-2-(2-pent-4-enylaminoindan-5-ylsulfanyl)propionic acid as a crude oily liquid.

Compound 3.0 (0.149 mg; 4095 for steps C; white solid) was prepared according to route 2 and steps Y and M by acylation with 4-trifluoromethoxyphenyl isocyanate.

IS/M8: SovNov3M20.5: t/2 522 (M'1).

The following 2 compounds were prepared according to Schemes 3 and 4, Path 3, Steps Y and M of Path 2, with proper substitution of reagents and adjustment of reaction conditions: 2-Methyl-2-12-(1-(3-methylbutyl)-3- (4-trifluoromethoxyphenyl)ureido|-indan-5-ylsulfanyl)-2-methylpropionic acid 70 Compound 3.1 (Example 20)

OSEz o and ooo u.

Compound 3.1 (1Zmg; 2995 for step C; white solid) was prepared according to route C using isobutyraldehyde instead of pent-4-enal and addition of 4-trifluoromethoxyphenylisocyanate.

JIS/M8: SovNayaRz3M20.5: t/2 525 (M'1). c 2-(2-3-(4-Isopropylphenyl)-1-(3-methylbutyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid o

Compound 3.2 (Example 21) part

Fo c "c) d)

Compound 3.2 (11 mg; 2796 for step C; white solid) was prepared according to route C and the synthesis of compound 3.1 using 4-isopropylphenyl isocyanate instead of 4-trifluoromethoxyphenyl isocyanate. c TN nMR (С0О500): 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), with 2.99-3.08 (m, 2H), 3.17-3.48 (m, 4H), 4.98-5.03 (m, 1H), 6.26 ( c, 1H), 7.10-7.22 (m, 5H), 7.32-7.35 (m, 2H).

IS/M8: SovNzavM2O»5: t/2 483 (M'1).

The following C compounds were prepared according to Schemes 1 and 3 and Steps )/ and K of Route 1, with appropriate substitution of reagents and adjustment of reaction conditions: 2-16-/1-Butyl-3-(«4--rifluoromethoxyphenyl)ureido! |-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methylpropion o ova acid g Compound 1.1 (Example 22) o se) with Ez "m i

Mn n

F) name)

Compound 1.1 (41 mg; 6895 for 2 steps; white solid) was prepared according to route 1, using butyryl chloride instead of acetyl chloride.

JIS/M8: SovNayaRz3M20.5: t/2 525 (M'1). 2-16-/1-Butyl-3-(«4--rifluoromethylsulfanylphenyl)ureido!|-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methyl propionic acid

Compound 1.2 (Example 23) b5

With ZSE oyi iy I i m- g

Compound 1.2 (23mg; 3495 for 2 steps; white solid) was obtained according to route 1 and synthesis

Compounds 1.1, using butyryl chloride instead of acetyl chloride and 4-trifluorothiophenyl isocyanate instead of 4-trifluoromethoxyphenyl isocyanate.

And S/M5: SovNaiiii EzM2O352: t/2541 (Mn). 2-16-(/1-Hexyl-3-(4-trifluoromethoxyphenyl)ureido!)-5,6,7,8-tetrahydro-naphthalene-2-ylsulfanyl)-2-methylpropionic acid

Compound 1.3 (Example 24) 7 ooeSsi, Her / vn

OHM

N s o

Compound 1.3 (Zbmg; 5795 for 2 stages; white solid) was prepared according to route 1, using caproyl chloride instead of acetyl chloride. (at)

JIS/M8: SovNavEzM20.5: t/2 553 (M 1). high school

The following 2 compounds were obtained according to Schemes C and 4 and Steps Y and M of Route 2, with proper substitution of reagents and adjustment of reaction conditions: (ав) 2-12-I3-(3-Bromo-4-trifluoromethoxyphenyl)-1-ethylureido (indan-5-ylsulfanyl)-2-methylpropionic acid d)

Compound 2.17 (Example 25) ve z i z kn 7 p

M

:» in;

Compound 2.17 (0.018g; 1995 for 3 steps; white solid) was prepared according to route 2, substituting 3-bromo-4-trifluoromethoxyphenylisocyanate for 4-trifluoromethoxyphenyl isocyanate. Di-tert-butyldicarbonate (0.255g; 1.17mmol) was added to o3-bromo-4-trifluoromethoxyaniline (0.214g; 0.83bmmol) in THF (ml), followed by 4-dimethylaminopyridine (0.102g; 0.835mmol). After the release of gas bubbles has stopped, a solution of tert-butyl 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methylpropionic ether is added

Ge) 20 acid (0.058 g; 0.167 mmol) in THF (1 ml) and the reaction mixture was stirred for 18 hours. at room temperature. Using Steps K and Y of Route 2, the title compound is obtained. "m I C/M8: SozNo"VgzM2O,: t/2 563 (M 1). 2-42-(11-Ethyl-3-(3-trifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid

Compound 2.18 (Example 26) about ; In Os 60 /

Compound 2.18 (1Zmg; 1295 for C stages; white solid) was prepared according to Example 2.0, using 3-trifluoromethoxyphenylisocyanate instead of 4-trifluoromethoxyphenyl isocyanate. To a solution of carbonyldiimidazole 65 (0.454g; 2.mmol) in THF (2ml) heated to 509C, add dropwise

Z-trifluoromethoxyaniline (0.522g; 2.94mmol). After 15 minutes the reaction is cooled and added to a solution of tert-butyl 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methylpropionic acid (0.077g; 0.22mmol) in THF (ml).

JIS/M8: SozNovz3M20.5: t/2 483 (M 1). 2-2-(3--4-Dimethylaminophenyl)-1-methylureido|indan-5-ylsulfanyl)-2-methylpropionic acid.

Compound 2.19 (Example 27).

Scheme 6. To 5-(2-aminoindan-5-yl) ester of dimethylthiocarbamic acid (2.0 g; 8.4 mmol) in SNI (10 ml) add ethyl formate (5 ml) and heat the reaction at 559 for 24 hours. The reaction is cooled, the solvent is removed under reduced pressure, and the crude oily liquid is purified by flash chromatography (5105), eluting with an ethyl acetate-methanol gradient, yielding 0.77 g (35905)-(2-formylaminoindan-5-yl) dimethylthiocarbamic acid ester as white solid matter.

And С/М8: С43Н46М2О»: t/2 264 (M.1).

B. Tert-butyl ester of 2-methyl-2-(2-methylaminoindan-5-ylsulfanyl)propionic acid. Scheme 6. Dimethylthiocarbamic acid 5-(2-formylaminoindan-5-yl) ester (0.772 g; .9 mmol) in THF (9 ml) under Mo add a 1.0 M solution of lithium-aluminum hydride (d9 ml) at 02С. The reaction is heated to (o) room temperature, and then stirred at reflux for 24 hours. The reaction is cooled to 02C, quenched with NaO and the solvent is removed under reduced pressure. The residue is dissolved in MeOHnN (dml), to which are added Sv 2CO3 (0.304g; 0.9mmol), tert-butyl-2-bromoisobutyrate (0.311ml; 1.39mmol) and iso-Mavn (2.0g; 52, 8 mmol). The reaction mixture is stirred for 18 hours, the solvent is removed under reduced pressure and the residue is distributed between E(Ac) and H.O. at reduced su pressure. The crude residue is purified by flash chromatography (5105), eluting with a CHClCl-meon gradient, obtaining 0.186 g (2090) of tert-butyl ester of 2g-Methyl-2-(2-methylaminoindan-5-ylsulfanyl)propionic acid as an oily liquid co

IIS/M8: Si8No? MO": t/2 321 (M'-1).

Compound 2.19 (44 mg; 6595 for 2 steps; white solid) was prepared according to Route 2 and Steps I! and

M, using 4-dimethylaminophenylisocyanate instead of 4-rifluoromethoxyphenylisocyanate.

IS/M8: SozNooMZO085: t/2 428 (M-n1). 2-12-(11-(3-Cyclopentylpropyl)-3--4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic 8s acid and Compound 2.20 (Example 28) ,» Ost « ' s (F) Compound 2.20 (3 mg; 4995 for 2 steps; white solid) was prepared according to route 2, using 3-cyclopentylpropionyl chloride instead of acetyl chloride.

ИС/М8: СооНзвЕзМ20.5: t/2 565 (М 1). 2-(2-(3-Indan-5-yl-1-pentylureido)indan-5-ylsulfanyl)-2-methyl-propionic acid 60

Compound 2.21 (Example 29) b5 and o o

Compound 2.21 (9.Zmg; 2495 for 2 steps; white solid) was prepared according to Route 2 and the synthesis of Compound 2.3 79 using valeryl chloride instead of acetyl chloride and indanyl isocyanate instead of 4-trifluoromethoxyphenyl isocyanate.

IS/M8: SovNazeM2O»5: t/2 481 (M'1). 2-Methyl-2-12-13-4-methyl-3-nitrophenyl)-1-pentylureido(indan-5-ylsulfanyl)propionic acid

Compound 2.22 (Example 30) ; se ) o cha

Pho p

Compound 2.22 (5.0 mg; 1295 for 2 steps; white solid) was obtained according to route 2 and synthesis

Compounds 2.3, using 4-methyl-3-nitrophenyl isocyanate instead of 4-rifluoromethoxyphenyl isocyanate. at

JIS/M8: SovNazMz3O5: t/2,500 (M 1). 2-Methyl-2-12-P1-naphthalen-1-ylmethyl-3-(4-trifluoromethoxyphenyl)ureido|-indan-5-ylsulfanyl)propionic acid

Compound 3.4 (Example 31) - « shi s y U. dn (ee) («in) ime) o 50

Compound 3.4 (2.9 mg; 495 for 2 steps; white solid) was prepared according to route C using 1-naphthaldehyde instead of pent-4-enal.

JIS/M8: Sz2Novb3M20.5: t/2 595 (M 1). 2-12-I(3--4-Methoxyphenyl)-1-propylureido|indan-5-ylsulfanyl)-2-methyl-propionic acid 59 Compound 2.23 (Example 32)

F) name) 60 o nose?

M b5 /

Compound 2.23 (21 mg; 6495 for 2 steps; white solid) was obtained according to route 2 and synthesis

Compounds 2.14, using 4-methoxyphenylisocyanate instead of 4-rifluoromethoxyphenylisocyanate.

And C/M8: SodNo; Ra3M20.5: t/2 443 (M 1). 2-2-I3-(3,5-Dimethylphenyl)-1-propylureido|indan-5-ylsulfanyl)-2-methyl-propionic acid

Compound 2.24 (Example 33) 70 o

But yes-pl

Mn /

Compound 2.24 (19 mg; 5795 for 2 steps; white solid) was obtained according to route 2 and synthesis

Compounds 2.14, using 3,5-dimethylphenylisocyanate instead of 4-trifluoromethoxyphenylisocyanate.

IS/M8: SoBNaa2M2Oz35: t/2441 (M'-1). 2-12-(1--2-Methoxyethyl)-3-«4--rifluoromethylsulfanylphenyl)ureido|-indan-5-ylsulfanyl)-2-methylpropionic acid

Compound 2.25 (Example 34)

With s o ser i-

Fo c "c)

Compound 2.25 (7.0 mg; 1695 for 2 steps; oily liquid) was obtained according to route 2 and the synthesis of

Compounds 2.2, using methoxyacetyl chloride instead of acetyl chloride.

And C/M5: SodNo7RzM2Ou5: t/2 529 (Mn). 2-Methyl-2-42-P1-propyl-3--4--rifluoromethylphenyl)ureido|indan-5-ylsulfanyl)propionic acid

Compound 2.26 (Example 35) "shi s" With (ee) («c) ime)

He) 50 Compound 2.26 (20mg; 5695 for 2 steps; white solid) was obtained according to route 2 and synthesis

Compounds 2.14, using 4-trifluoromethylphenylisocyanate instead of 4-trifluoromethoxyphenylisocyanate. "m I C/M5: SodNo7PzM2O535»o: m/: 481 (Mn). 2-Methyl-2-12-(1-(4,4,4-trifluorobutyl)-3-(4--rifluoromethoxyphenyl)-ureido |indan-5-ylsulfanyl)ipropionic acid 59 Compound 2.27 (Example 36)

F) name) 60 b5 oso

IS

Compound 2.27 (1mg; 2695 for 2 steps; oily liquid) was prepared according to route 2 and the synthesis of Compound 2.0 using trifluoromethylbutyryl chloride instead of adethyl chloride. 19 1S/M8: SoNovEeMoOu: t/» 564 (Ma). 2-12-(1-(3-Cyclopentylpropyl)-3-phenylureido|indan-5-ylsulfanyl)-2-methylpropionic acid

Compound 2.28 (Example 37) - n "So X- nn s o cha

Fo

Compound 2.28 (ZVmg; 5690 for 2 steps; oily liquid) was prepared according to route 2 and the synthesis of Compound 2.0 using cyclopentylpropionyl chloride in place of acetyl chloride and phenyl isocyanate in place of C 4 -trifluoromethoxyphenyl isocyanate. at

IS/M8: SovNazeM2O»5: t/2 481 (M'1).

Methyl ester of 6-(1-(5-(1-carboxy-1-methylethylsulfanyl)-indan-2-yl|-3-(4-isopropylphenyl)ureido|hexanoic acid)

Compound 2.29 (Example 8) and p. » " 5 more (ee) («in) name) at 50 what

Compound 2.29 (12 mg; 3895 for 2 steps; white solid) was obtained according to route 2 and synthesis

Compounds 2.4, using 5-chlorocarbonylpentanoic methyl ester instead of acetyl chloride

ACIDS. o I S/M8: SzoNaoMoOB: t/2541 (M'-1). 2-Methyl-2-(2-(3-naphthalen-2-yl-1-pentylureido)indan-5-ylsulfanyl|-propionic acid ime) Compound 2.30 (Example 39) 60 b5 o a

Compound 2.30 (15 mg; 3995 for 2 steps; white solid) was obtained according to route 2 and synthesis

Compounds 2.3, using 2-naphthyl isocyanate instead of 4-trifluoromethoxyphenyl isocyanate.

And C/M8: SooNzaM2Oz5: t/2491 (M'-1). 2--2--/1-Cyclohexylmethyl-3-(4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl|-2-methylpropionic acid

Compound 2.31 (Example 40)

SEZ s o no so mn cha

Fo

Compound 2.31 (15 mg; 2595 for 2 steps; white solid) was obtained according to route 2 and the synthesis of

Compounds 2.0 using cyclohexylacetyl chloride instead of acetyl chloride. at

JIS/M8: SovNazEzM20.5: t/2551 (M'-1).

Zo 2-2-(1-Ixobutyl-3-(4-trifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid

Compound 3.5 (Example 41)

Compound 3.5 (10 mg; 1295 for 2 steps; oily liquid) was prepared according to route C and the synthesis of Compound 3.0 using 2-methylpropionaldehyde instead of pent-5-enal.

JIS/M8: SoBNov3M20.5: t/2511 (M'-1). 2-12-I3-(3,4-Dichlorophenyl)-1-heptylureido|indan-5-ylsulfanyl)-2-methyl-propionic acid "M Compound 2.32 (Example 42) s yu ob de) n cho 60 b5

Compound 2.32 (6.7 mg; 1295 for 2 steps; oily liquid) was obtained according to route 2 and synthesis

Compounds 2.0 using heptanoyl chloride instead of acetyl chloride and 3,4-dichlorophenyl isocyanate instead of 4-trifluoromethoxyphenyl isocyanate.

And C/M8: C27NazaSioM2Oz: t/2 538 (M'1). 2-2-11--2-Dimethylaminoethyl)-3--4--lifluoromethylsulfanylphenyl)-ureido|indan-5-ylsulfanyl)-2-methylpropionic acid

Compound 2.33 (Example 43)

Z yuyu A U vn

M

/

Compound 2.33 (1.9 mg; 495 for 2 steps; oily liquid) was prepared according to route 2 and the synthesis of Compound 2.2 using dimethylaminoacetyl chloride instead of acetyl chloride and 4-trifluoromethylthiophenyl isocyanate instead of 4-trifluoromethoxyphenyl isocyanate.

And S/M5: SoBNzobzMa5O559: t/2 542 (Mn). 2-12-I3-(3-Chlorophenyl)-1-heptylureido|indan-5-ylsulfanyl)-2-methyl-propionic acid c

Compound 2.34 (Example 44) about ay

Compound 2.34 (7 4 mg; 1495 for 2 steps; white solid) was prepared according to route 2 and the synthesis of Compound 2.32 using 3-chlorophenyl isocyanate instead of 4-rifluoromethoxyphenyl isocyanate. And C/M8: C27Na5CIM2Oz8: t/2 542 (M'-1). 1-2-1-Heptyl-3-(4-trifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-cyclobutanecarboxylic acid

Compound 2.35 (Example 45) (ee) se. ((c) name) i-o N Z, kn what

F) name) 60

Compound 2.35 (1.Omg; 1.395 for 2 steps; white solid) was obtained according to route 2 and synthesis

Compounds 2.32, using ethyl 1-bromocyclobutanecarboxylate instead of tert-butyl-2-bromoisobutyrate.

ИС/М8: СооНзвЕзМ20.5: t/2 565 (М 1). 65 2-Methyl-2-17-P1-propyl-3--4--rifluoromethoxyphenyl)ureido)-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)propionic acid

Compound 1.4 (Example 46)

Compound 1.4 (53 mg; 2595 for 2 steps; oily liquid) was prepared according to route 1 and the synthesis of Compound 1.0 using propionyl chloride instead of acetyl chloride.

JIS/M8: SoBNov3M20.5: t/2511 (M'-1).

The following two compounds can be prepared according to Schemes 10 and 4, Steps I, B, and K of Route 1, with proper substitution of reagents and adjustment of reaction conditions: 2-6-(1-Ethyl-3-(4--rifluoromethoxyphenyl)ureido |-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid

Compound 1.5 (Example 47) -Z-o chX in Hn p

Compound 1.5 (9.8 mg; oily liquid) can be prepared according to route 1, steps I, B, and

Schemes 4 and 10.

TN nMR (300 MHz, СО5300): δ 7.45-7.48 (d, 2H), 7.15-7.18 (m, ЗН), 6.71 (s, 1H), 4.43-4, 79 (m, 1H), 3.75 (s, ЗН), 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, ZN).

JIS/M8: SoBNovz3M2O55: t/2 527 (M'1). -

Path 4 Fos s ich z g) p, H 2-16--1-Ethyl-3-"4--rifluoromethoxyphenyl)ureido|-5,6,7 8-tetrahydro-naphthalene-2-yloxy)-2-methylpropion « acid

Compound 4.0 (Example 48) - with A. M-(6-Methoxy-1,2.3.4-tetrahydronaphthalene-2-yl)acetamide c Scheme 7. To a stirred suspension of b-methoxy-1,2,3,4-tetrahydronaphthalene -2-ylamine (2.54g; 14.3mmol) in "CHNOCl" (20ml) add OIEA (3.4ml) and the reaction mixture is cooled to 02С. Acetyl chloride (1.22ml; 17.1mmol) was added dropwise at 02C and the reaction was allowed to warm to room temperature and stirred for 18h. The reaction mixture is diluted with CH 5 Si , washed with Na 2 O , dried over Na 2 O ), filtered and the solvent is removed under reduced pressure to give a crude solid. Purification by flash chromatography (502) eluting with hexanes-EtOAc gives 1.57 g (50905) of M-(b-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide as a white solid. name) I S/M8: S43H47MO»: t/2220 (M '1). with 50 V. M-(6-Hydroxy-1.2.3.4-tetrahydronaphthalen-2-yl)uacetamide

Scheme 7. To a suspension of M-(b-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)ioacetamide (1.57 g; 7.2 mmol) in CHClCl (7 mL) cooled to -609С, add dropwise a solution of boron bromide-CH 5CI" (Zbml) in such a way as to maintain the reaction temperature in the range from -50 to -609С. The jelly-like suspension is allowed to warm to room temperature and stirred for 30 minutes. The reaction is cooled to 02С, quenched with sat. ManSOz and 29 are stirred for 30 minutes at room temperature. The mixture is extracted with CHCl" (2x), the extracts are combined,

HF) is dried over Ma»5ZO,, filtered and evaporated under reduced pressure, obtaining a crude solid, which is purified by flash chromatography (5IO5), eluting with a gradient of СНоСИ.-MeOH, obtaining 1.13 g (76905)

M-(b-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide as a beige solid.

IIS/M8: С42Н45МО»: t/2 206 (M 1). 60 C. Tert-butyl ester of 2-(b-acetylamino-5,6,7,8-tetrahydro-naphthalene-2-yloxy)-2-methylpropionic acid

Scheme 7. To a suspension of M-(6β-hydroxy-1,2,3,4-tetrahydronaphthalene-2-ylluacetamide) (0.439g; 2.1mmol) in DMF (bml) add Св82СО»z (1.7g; 5.2mmol) ) and tert-butyl-2-bromoisobutyrate (2.1ml; 9U4mmol) and the reaction mixture was stirred at 1009227 for 18 hours. The reaction was cooled to room temperature, diluted with EtOAc, washed with HO, brine, dried over NaCl, filtered and the solvent is removed under reduced pressure,

obtaining a crude oily liquid, which is purified by flash chromatography (ZO 5), eluting with a gradient of hexanes-EOAc, obtaining 0.51 g (6990) of tert-butyl ester 2-(6-acetylamino-5,6,7 8-tetrahydronaphthalene-2 -yloxy)-2-methylpropionic acid in the form of an oily liquid.

TN nMR (Z0OMHC, SOSIv): 5 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 (dc, 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).

IS/M8: SooNooMO,: t/2 292 (M 1).

The following compounds were prepared according to Schemes C and 4 and Steps I, C, and K of Route 1, with proper 70 substitution of reagents and adjustment of reaction conditions:

Compound 4.0 (0.0168g; 2395 for 2 steps; oily liquid) was obtained according to route 1 and synthesis

Compounds 1.0.

And S/M8: SodNoRzMoOv: t/2 481 (M'1). Ionic acid

Compound 1.6 (Example 49) and "oo zd

And h

Compound 1.6 (1mg; oily liquid) can be prepared by substituting 4-tert-butylphenylisocyanate for c 25 of 4-trifluoromethoxyphenylisocyanate, according to Route 1, steps I, ) and K, and Schemes 4 and 10. o

IS/M8: SovNzvM2O,5: t/2 499 (M'1). 2-16--1-Ethyl-3--«4--rifluoromethoxyphenyl)ureido|-33-fluoro-5,6,7,8-tetra-hydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid Compound 1.7 (Example 50) o (22) u, o Sg sch

Ah, oh

E Mn 35 r N g)

Compound 1.7 (1bmg; 3095 after 2 steps; white solid) can be prepared according to Route 1, Steps I, ) and K, and Schemes 4 and 10.

TN nMR (Z0OMHC, SOSIv): 85 7.46-7.51 (m, 2H), 7.25-7.28 (d, 1H), 7.17-7.20 (d, 2H), 6, 92-6.95 (d, 1H), with c 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, ZN).

JIS/M8: SoBNovz3M2O55: t/2 515 (M'1). ; t 2-16-1-Ethyl-3-(«4-trifluoromethoxyphenyl)ureido|-3-chloro-5,6,7-8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid

Compound 1.8 (Example 51) (ee) (ав) and Ost, : A c C M

And N what

Compound 1.8 (15 mg; 2295 after 2 steps; white solid) could be prepared according to Route 1, Steps I, ) and K, and Schemes 4 and 10.

JIS/M8: SoBNovz3M2O55: t/2 532 (M 1). o 2-I6-1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido|-3-bromo-5,6,7,8-tetra-hydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid Compound 1.9 (Example 52) at 60

CO. / else

A n b5

Compound 1.9 (55mg; 4395 for 2 steps; white solid) can be prepared according to route 1, step

Y, U and K, and Schemes 4 and 10.

TN nMR (Z0OMHC, SOSIi): 5 7.45-748 (m, ЗН), 7.36 (s, 71Н), 7.15-7.18 (d, 2Н), 4.41-4.79 ( m, 1H), 3.40-3.47 (m, 2H), 2.90-3.07 (m, 4H), 2.01-2.03 (m, 2H), 1.45 (s, 6H), 1.24-1.29 (t, ZN).

JIS/M8: SoBNovz3M2O55: t/2 576 (M'1). 2-6--1-Ethyl-3-«4--rifluoromethoxyphenyl)ureido|-3-methyl-5,6,7,8-tetra-hydronaphthalene-2-ylsulfanyl)-2-methyl propionic acid

Compound 1.10 (Example 53) o Soon

Compound 1.10 (7Zmg; 2695 for 2 steps; white solid) can be prepared according to route 1, step

Y, U and K, and Schemes 4 and 10. "IN NMR (300 MHz, SOSIv): 5 7.45-7.48 (m, 2H), 7.22 (s, 1H), 7.15-7, 18 (d, 2H), 7.02 (s, 1H), 4(А41-4.79 (m, 1H), 3.40-3.47 (m, 2H), 2.85-3.03 ( m, 4H), 2.39 (s, ЗН), 2.01-2.03 (m, 2Н), 1.41 (s, 6Н), 1.24-1.29 (t, ЗН).

JIS/M8: SoBNovz3M2O55: t/2 511 (M'1). 2-16--1-Ethyl-3-«4--rifluoromethoxyphenyl)ureido|-3-trifluoromethoxy-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid

Compound 1.11 (Example 54) with 5 and rosh (5)

E M ri n y- sit y y

Compound 1.11 (118mg; 5895 for 2 steps; white solid) can be prepared according to Route 1, (o) steps I, ) and K, and Schemes 4 and 10. c

TN nMR (Z0OMHC, SOSIv): 5 7.45-7.48 (d, 2H), 7.37 (s, 1H), 7.12-7.18 (m, ЗН), 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, ZN). at

JIS/M8: SoBNovz3M2O55: t/2 580 (M 1). Ge) 2-6--1-Ethyl-3-"4--rifluoromethoxyphenyl)ureido|-3-phenyl-5,6,7,8-tetra-hydronaphthalene-2-ylsulfanyl)-2-methyl propionic acid

Compound 1.12 (Example 55) "o n OSE Z y X g" MS ran o that Compound 1.12 (118 mg; 5895 for 2 stages; white solid) can be obtained according to route 1, stages I, ) and K, and Schemes 4 and 10. o TN NMR (Z0OMHC, SOSIv): 5 745-748 (d, 2H), 7.29-7.38 (m, b6H), 7.15-7.18 (d, 2H), 7 ,10 (s, 1H), 446 ko (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, ЗН), 1.14 (c, 6H).

JIS/M8: SoBNovz3M2O55: t/2 573 (M'1). ee, 2-16-(/1-Ethyl-3-(4-hydroxyphenyl)ureido!|-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid (Example 56) in AND

Ф) ю L в 60 2-16-(4-Aminophenyl)-1-ethylureido)|-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid (Example 57) b5 o

N

Path 5

Tert-butyl ester of 2-3-chloro-6-(ethyl-p-tolyloxycarbonyl-amino)-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl|-2-methylpropionic acid.

Compound 5.0 (Example 58) and DI

To a mixture of tert-butyl ester and borane complex of 2-(3-chloro-b-ethylamino-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methyl-propionic acid (vOmg; 201μmol), dissolved in СНоСИ » (2 ml), add p-tolyl chloroformate (Zomcl; 241 μmol) at 09C. The reaction is slowly warmed to room temperature and left to saturate under stirring at room temperature

days The solvent is removed under reduced pressure and the crude residue is purified by flash chromatography (510 5), eluting with a gradient of hexanes-EHOAc, obtaining 30 mg (2995) of tert-butyl ester 2-III-chloro-6-(ethyl-p-tolyloxycarbonylamino)- 5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl|-2-methylpropionic acid in the form of a clear oily liquid.

TN NMR (300 MHz, SOSIz): 5 6.67-7.29 (m, 6H), 4.28 (m, 1H), 3.40 (m, 2H), 2.87-2.97 (m, 4Н), 2.33 (с, и- ЗН), 1.89-2.06 (m, 2Н), 1.39-1.46 (m, 15Н), 1.21-1.31 (m, ZN). Gee!

Compound 5.0 (233mg; 5995) was prepared according to step M of pathway 2.

TN nMR (300 MHz, CO53O0): δ 6.96-7.34 (m, 6H), 4.27 (m, 1H), 3.49 (m, 2H), 2.91-3.14 (m, 4H), 2.32 (p, p

ЗН), 2.10 (m, 2Н), 1.45 (m, 6Н), 1.28 (m, ЗН). (av)

And S/M8: So4NovSIMO,5: t/z: 462 (M-1). 2-(3-Chloro-6-((4-chlorophenoxycarbonyl)ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methylpropionic acid

Compound 5.1 (Example 59) but (1 - p

I" with r

Compound 5.1 (Zamg; 3595 for 2 steps; white solid) was prepared according to route 5 using 4-chlorophenylchloroformate instead of p-tolyl chloroformate and step M of route 2. av! TN nMR (300 MHz, CO3O0): 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, ЗН).

IIS/M8: Soz3No5SioMOud5: t/2482 (M '-1). (Ce) 50 2-I6--(Ethyl-4-trifluoromethoxyphenoxycarbonyl)amino)-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpr opionic acid

Compound 5.2 (Example 60)

E about E

F) t B) bo Compound 5.2 can be obtained according to route 5, using 4-trifluoromethoxyphenyl ester of 1-chloroethyl carbonic acid ester instead of p-tolyl chloroformate, and step M of route 2.

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

A. 4-Trifluoromethoxyphenyl ester of 1-chloroethyl ester of carbonic acid 65 Scheme 1. A solution of 1-chloroethyl chloroformate (1.03g; 7.20mmol) in SNSO" (100ml) is cooled to 02С, trifluoromethoxyphenol (1.09g; b, Ommol) and triethylamine and the resulting solution is heated to room temperature. After mixing during the Agreement. the reaction is quenched with saturated Manso's and extracted with EtOAc (Z times). The combined organic extracts were washed with water, brine, dried over NaCl, and the solvent was removed under reduced pressure. The crude residue is purified by flash chromatography, eluting with hexane-EtOAc (101), obtaining 1.54 g (9095) of 4-trifluoromethoxyphenyl ester of 1-chloroethyl ester of carbonic acid in the form of a colorless oily liquid. "IN NMR (400 MHz, SOSI"): 5 7.26 (m, 4H), 6.49 (sq, 1H), 1.91 (d, ZN).

B. 4-Trifluoromethoxyphenyl ester 70 of ethyl-(b-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)ucarbamic acid

Scheme 1. Sodium triacetoxyborohydride is added to a mixture of b-methoxy-2-tetralone (950 mg; 5.39 mmol), 2M ethylamine in THF (54 ml; 10.78 mmol) and acetic acid (648 mg; 10.78 mmol) in СНоСІ» (5 ml) (2.29g; 10.7v8mmol).

The reaction mixture is stirred at room temperature for 1 hour, then 1N Mahon solution is added and extracted with ether (3 times). The combined organic extracts were dried over NaCl, and the solvent was removed under reduced pressure to give a light yellow oily liquid. This oily liquid was added to a solution of 4-trifluoromethoxyphenyl 1-chloroethyl carbonic acid ester (1.23 g; 4.31 mmol) in toluene (mL), and the reaction mixture was stirred for 1 h. at room temperature, and then h. at 9020. The reaction is allowed to cool to room temperature, diluted with EC2O and washed with 1N aq. NOSE and saturated ManNnsSoO»z. The organic extract was dried over NaCl5O, and the solvent was removed under reduced pressure. Flash chromatography of the residue with a gradient of hexane-CHCl gives 1.05 g (4895) of 4-trifluoromethoxyphenyl ester of ethyl-(b-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbamic acid as a white solid .

TN nMR (400MHz, SOSIv): 5 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, ЗН), 3.41 (m, 2H), 2.93 (m, 4H), 2.04 (m, 2H), 1.31 (m, ZN). p 25 I C/M8: C24NozEzMO»: t/2410 (M '1). ge) p. 4-Trifluoromethoxyphenyl ester of ethyl-(b-hydroxy-1,2,3.4-tetrahydronaphthalen-2-yl)ucarbamic acid

Scheme 1. A solution of 4-trifluoromethoxyphenyl ester of ethyl-(b-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)ucarbamic acid (898.bmg; 2.19mmol) in anhydrous СНоСі» - 30 (vml) cool to -782C and slowly add 1.0M solution of boron bromide-CHClCl (6.57 ml, 6.57 mmol). After the addition is complete, the reaction mixture is allowed to warm to room temperature, quenched with Meon (1 Oml) and stirred for another 2 hours. Solvents were evaporated and the residue was purified by flash chromatography with c hexane-EFOAc (2.5:1) to give 649.4 mg (7596) of 4-trifluoromethoxyphenyl ester («3 ethyl-(b-hydroxy-1,2,3,4 -tetrahydronaphthalene-2-yl)carbamic acid as a white solid.

From TN nMR (Z0OMHC, SOSIv): 5 7.05-7.30 (m, 4H), 6.90 (m, 1), 7.41-7.60 (m, 2H), 5.05 (s , 1H), 4.30 (m, so 1H), 3.41 (m, 2H), 2.90 (m, 4H), 1.99 (m, 2H), 1.31 (m, ЗН).

And C/M8: SooN241BZMO,: t/2 396 (M'1). p. 4-trifluoromethoxyphenyl ester of ethyl-(b-triisopropyl-silanylsulfanyl-1,2.3.4-tetrahydronaphthalen-2-yl)carbamic acid with 70 Scheme 1. Solution of 4-trifluoromethoxyphenyl ester with ethyl-(b-hydroxy- 1,2,3,4-tetrahydronaphthalen-2-yl)ucarbamic acid (245.1mg; 0.62mmol) in anhydrous HNSSO (3ml) and THF (3ml) is cooled to -302C, triethylamine (21bml , 1.55 mmol) and trifluoromethanesulfonic anhydride (125 μl, 0.74 mmol). The resulting mixture is stirred at room temperature for 2 hours, then quenched with water and extracted with Ei 20 (3 times). The combined organic extracts were washed with water, brine, dried over NaCl, and the solvent was removed under reduced pressure.

Flash chromatography of the residue with hexane-EtOAc (5:11) gave 301.bmg (9295) of the triflate. This triflate (279.8 mg; (ab) 0.5 mmol) and tetrakis(triphenylphosphine)palladium (61.2 mg; 0.053 mmol) were added to a toluene solution of 7 formed from triisopropylsilanethiol (12 bml, 0.58 mmol) and Mann (13.9 mg ; O0.5v8mmol) at room temperature.

The resulting mixture is vacuumed twice and refluxed for 4 hours. and concentrated under (se) reduced pressure. Flash chromatography of the residue with hexane-EtOAc (10:11) gives 261.8 mg (87965) of 4-trifluoromethoxyphenyl ester of ethyl-(b-triisopropylsilanylsulfanyl-1,2,3,4-tetrahydro-naphthalen-2-yl) ucarbamic acid in the form of a light oily liquid.

TN nMR (30 MHz, SOSIv): δ 6.82-7.29 (m, 7H), 4.32 (m, 1H), 3.40 (m, 2H), 2.81-3.05 (m, 4H), 2.05 (m, 2H), 1.12-1.34 (m, 6H), 1.03-1.10 (m, 18H).

F) IS/M8: So9NAtRzMOz55i: t/2 568 (M 1). ka E. Tert-butyl ester of 2-(6-Hethyl-4--rifluoromethoxyphenoxycarbonyl)amino1|-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methyl-propyl new acid

Scheme 1. A solution of 4-trifluoromethoxyphenyl ester of ethyl-(b-triisopropylsilanylsulfanyl-1,2,3,4-tetrahydronaphthalen-2-yl)/ucarbamic acid (260.Omg; 0O.4bmmol) and tert-butyl-2-bromoisobutyrate (13Omcl, 0.69mmol) in anhydrous THF (2ml) is cooled to 09C, 1.0M TVA solution (b9Omcl, 0.b9mmol) is added, and then the reaction is heated to room temperature, b5 is stirred for Th. and diluted with water, extracted with E(2O (3 times). The combined organic extracts were dried over NaCl3O, and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography, eluting with hexane-EtOAc (7:1) to give 229 .2 mg (9095) tert-butyl ester of 2-(6-(ethyl-(4--rifluoromethoxyphenoxycarbonyl)amino)-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropio new acid in the form of a light oily liquid

TN nMR (Z00MHZc, SOSIv): 5 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, ZN).

And S/M8: SovNazaRzMOBZMa: t/2 576 (M'-Ma).

E. 70. 2-(6--Ethyl-(4-trifluoromethoxyphenoxycarbonyl)amino1-5.6.7.8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid

Scheme 1. Solution of tert-butyl complex ester of 2-(6-(ethyl-(4--rifluoromethoxyphenoxycarbonyl)amino)-5,6,7 8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropio new acid (120.8 mg; 0.22 mmol) in СНоСИ» (ml) is cooled to -782С and trifluoroacetic acid (4 ml) is slowly added. The reaction mixture is allowed to warm to room temperature and stirred for 1.5 hours.

The solvents are then evaporated and the residue is purified by flash chromatography with SNCI.-Meon (94:6) to give 2-(6-(ethyl-(4--rifluoromethoxyphenoxycarbonyl)amino)-5,6,7,8-tetrahydronaphthalene-2- yl-sulfanyl)-2-methylpropionic acid as a white solid.

TN nMR (400MHz, SOSIv): 5 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, ЗН).

I S/M8: SNU RzMO: t/2 498 (M '-1). r. Compositions and introduction

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

The carrier can take various forms depending on the form of the drug desired for administration. Such pharmaceutical compositions are preferably single dosage forms suitable for oral administration or parenteral injection. For example, in the manufacture of compositions in the form of dosage forms for oral administration, any suitable pharmaceutical medium can be used. Such F media include water, glycols, oils, alcohols, etc. in the case of liquid preparations for oral administration, such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents, etc., in the case of powders, pills, capsules and tablets. at

Because of their ease of administration, tablets and capsules are the best oral dosage forms

From the introduction, in which solid pharmaceutical carriers are usually used. For parenteral compositions, the carrier will usually include sterile water, at least mostly, although other ingredients may be included, for example, to improve solubility. Can be obtained, for example, solutions for injections, in which the carrier includes a saline solution, a glucose solution or a mixture of saline and glucose solutions. Suspensions for injections can also be prepared, in which suitable liquid carriers, suspending agents, etc. can be used. In compositions suitable for subcutaneous administration, the carrier optionally includes a penetration-enhancing agent and/or a suitable wetting agent, optionally together with suitable additives of any nature in small amounts that do not have a significant deleterious effect on skin. Such impurities may facilitate delivery to the skin and/or may be useful in the preparation of the desired composition. These compositions can be administered in various ways, for example, in the form of a transdermal patch, a topical agent, or a liquid ointment. Acid addition salts of compounds of formula I!, due to their increased solubility in water compared to the corresponding basic form, are more suitable for the production of aqueous compositions. o It is particularly convenient to produce the above-mentioned pharmaceutical compositions in the form of dosage forms due to the convenience of their administration and uniformity of doses. Dosage forms, as used in the description, refer to physically separate units suitable for use as single doses, each of which contains a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier . Examples of such single-use dosage forms are tablets (including score tablets or coated tablets), capsules, pills, sachets of powders, wafers, solutions or suspensions for injections, sachets containing 5 or 15 ml of suspension of the drug for oral administration etc., and multiples thereof.59 Pharmaceutically acceptable addition salts of acids include therapeutically active non-toxic forms of the salts

GF! addition of acids that can form open compounds. They can be conveniently obtained by treating the parent form with a suitable acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, for example, hydrochloric or hydrobromic acid; sulfur; nitrogen; phosphorous, etc. acids; or organic acids, such as, for example, acetic, propionic, glycolic, lactic, 60 pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic acid, pamoic acid, etc. acid The term acid addition salt also includes solvates that are capable of forming the disclosed compounds, as well as their salts. Such solvates are, for example, hydrates, alcohols, etc. Conversely, the salt form can be converted by treatment with alkalis to the free base form. for Stereoisomeric forms include all possible isomeric forms that compounds of formula (I) may have. Unless otherwise indicated or indicated, the chemical name of the compound denotes a mixture of all possible stereochemically isomeric forms, and the specified mixture contains all diastereomers and enantiomers of the basic molecular structure.

More specifically, stereogenic centers can have (K)- or (5)-configuration; substituents on bivalent cyclic saturated radicals can have cis- or trans-configuration. The invention covers stereochemically isomeric forms,

Including diastereoisomers, as well as mixtures thereof with any ratio of disclosed compounds. The disclosed compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the above description and in the following formulas, are to be considered as falling within the scope of the present invention. For example, in

Compound 2.1 or Example 3, the indane ring has a chiral center in the C-2 position. For this compound, the (5)-isomer is more active than the (K)-isomer. 70 Those skilled in the art of treating disorders or conditions mediated by PRAC-alpha can readily determine an effective daily amount from the best trial results and other information provided herein. In general, it is assumed that a therapeutically effective dose will be from 0.001 mg/kg to B5 mg/kg of body weight, preferably from 0.01 mg/kg to

About 5 mg/kg of body weight. It may be convenient to administer the therapeutically effective dose as two, three, four, or more subdoses at appropriate intervals throughout the day. These subdoses can be prepared as single dosage dosage forms, for example, those containing from 0.05mg to 250mg or 75Omg, in particular, from 0.5 to 5Omg, of the active ingredient per single dosage form. Examples include dosage forms containing 2mg, 4mg, 7mg, 10mg, 15mg, 25mg and 35mg. The compounds of the invention may also be formulated as sustained release compositions or compositions for subcutaneous administration or transdermal patches. The disclosed compound may also be incorporated into a spray composition or other composition for local administration or inhalation.

The exact dosages and frequency of administration depend on the particular compound of formula (I) being used, the particular condition being treated, the severity of the condition being treated, the age, weight, and general physical condition of the particular patient, as well as other medications that the patient may be taking, such as well known to specialists in this field.

In addition, it is obvious that the indicated effective daily amount can be reduced or increased depending on the reaction of the patient being treated and/or depending on the assessment of the physician who prescribed the compounds according to the present invention. The ranges of effective daily doses indicated here are therefore only indicative. i)

The following section includes detailed information regarding the use of the disclosed compounds and compositions.

E. Uses of M zo The compounds of the present invention are pharmaceutically active, for example, as PRAK-alpha agonists. According to one aspect of the invention, the compounds are preferably selective PRAC-alpha agonists having a Me) activity (eg, the ratio of activity against PRAC-alpha to activity against PRAC-gamma) of 10 or more, preferably 15, 25, 30, 50 or 100 or more.

PRAC-alpha agonists are useful in the treatment, prevention, or inhibition of one or more of the

From such conditions or diseases: phase |! Hyperlipidemia, preclinical hyperlipidemia, phase |! hyperlipidemia, co hypertension, CHD (ischemic heart disease), coronary disease and hypertriglyceridemia. Preferred compounds of the invention are useful in reducing serum levels of low-density lipoprotein (01), intermediate-density lipoprotein (ILD), and/or low-density lipoprotein and other atherogenic molecules or molecules that cause atherosclerotic complications, thereby reducing cardiovascular complication. The best compounds are also "

Useful for increasing serum levels of high-density lipoproteins (HDL), for reducing serum levels of triglycerides, triglycerides, and/or free fatty acids. It is also desirable to reduce ERO/NBA1s.

Combined therapy;" The compounds of the present invention can be used in combination with other pharmaceutically active agents. Such agents include lipid-lowering agents and blood pressure-lowering agents.

Specialists in this field know methods of determining effective doses for therapeutic and prophylactic purposes

Go! the use of disclosed pharmaceutical compositions or disclosed combinations of drugs, regardless of whether they are part of the same composition or not. For therapeutic use, the term "total effective amount" as used herein means that amount of each active compound or pharmaceutical co-agent, alone or in combination, that produces a biological or medical response in a tissue system, animal or human being sought by a researcher, veterinarian, physician, or other clinician, which includes alleviating the symptoms of the disease or disorder being treated. For prophylactic use (ie, inhibition of the onset or development of an "M disorder"), the term "combined effective amount" refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that treats or inhibits the onset or development of the disorder in a subject, as sought by a researcher, veterinarian, physician, or other clinician.Thus, the present invention provides a combination of two or more drugs in which, for example, (a) each drug is administered in an independently therapeutically or prophylactically effective amount; (B) at least one medicine in

F) the combination is administered in an amount that is subtherapeutic or subprophylactic when it is administered separately, but is therapeutic or prophylactic when administered in combination with the second or additional medicinal products according to the invention; or (c) both drugs (or their greater quantity) are administered in amounts that are subtherapeutic or subprophylactic when administered separately, but are therapeutic or prophylactic when administered together.

As PRAC-alpha agonists, the compounds of the invention may be more active and effective in reducing triglycerides than known fibrates. Compounds of the present invention may also enhance fat and/or lipid metabolism, providing a method for weight loss, fat loss, body mass index reduction, b5 lipid reduction (such as triglyceride reduction), or treatment of obesity or overweight conditions.

Examples of lipid-lowering agents include bile acid excretory enhancers, fibric acid derivatives, nicotinic acid, and HMOCOOA reductase inhibitors. Specific examples include statins such as HIRITOK tm, 2OSOKtm, RKAMASNOI mm, | EBSOI tm ii MEMASOK m, pitavastatin (nisvastatin) (Mivzzap,

Kozha Koduo, ZapKuo, Momagiyiv) and their sustained-release forms, such as AYUOX-159 (sustained-release lovastatin), as well as Soieziia, I ospoievi, Ocevzigap, Agotiya, GI oria and Tgisog.

Examples of blood pressure-lowering agents include antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors (Assyrgii, Amase, Sariorgii, Ioepzip, Mamik, Moporgi, Rgipimi,

MOpimazs, Mazoies and 7ezigi), adrenoblockers (such as Sagatsga, Oirepliipe, Nuiogei, Nuigip, Mipirgez5 and

Mipigide), alpha/beta-adrenergic blockers (such as Soged, Mogtodupe and Tgapadaye), calcium channel 70 blockers (such as Adaiai, Saiap, Sagaepe, Sagaiguet, Somega-H5, Oiiasog, Oupasigs, Isoriip, Mitoior, Mogmase, Riepaiyi,

Rgosagaia, Rgosagaia XI, Zschia, Tiagas, Mazsog and Megeiap), diuretics, angiotensin II receptor antagonists (such as Abasapa, Amargo, Sogaag and Oiomap), beta-blockers (such as Veyarase, Viosadgep, Vgemirios,

Sapgoi, IpdegaIi, Kegpope, IamayiI, Iorgezzog, ZesigaI, Tepogtip, TorgoIi-XI, and 2ereifa), vasodilators (such as Oeropii Oaiai, BK, Itatsg, Ivto, IvogaiI, Ivogai Tiigadoze, MopoKei, Migo-Vii, Mygo-Juig .

І оиепвип НСТ, Ргипгиде, Опигеиис, Мазегеиис, 7евиогеиис).

E. Examples

The following chemical and biological examples are intended to illustrate the invention without limiting it.

Example 1 Fr

OS owl with su

And from (8) 2-16--1-Ethyl-3-"4--rifluoromethoxyphenyl)ureido|-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid

ECo-0.02Z3μM M 20 Example 2

Ez o s «c) zv s z | 2-42-(11-Ethyl-3--«4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methyl-propionic acid sshh with ECo-0.027μM

Example C;" ; ОСЕ, (ee) o 5 U m ime) o 50 "m (5)-2-42-(1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid

EC is 0.0002μM

Example 4

Seh

Ф) imi) full 2--2-(11-Ethyl-3--4-rifluoromethylsulfanylphenyl)ureido)indan-5-ylsulfanyl)-2-methylpropionic acid 65 ECx5o-0.037μM

Example 5 what? n 5 u kn n ) 2-Methyl-2-12-/1-pentyl-3--4--rifluoromethylsulfanylphenyl)ureido|indan-5-ylsulfanyl)ipropionic acid 19 ECo-0.053μM

Example 6

2-42-(11-Ethyl-3-(4-isopropylphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid

EC is 0.05bmM

Example 7 -

Fo c "c) d) more. « 2-2-(3--4-Dimethylaminophenyl)-1-ethylureido|indan-5-ylsulfanyl)-2-methyl-propionic acid З с ЕСє-0.075mМкM » Example 8 3 (ee) o 7 vno X-yan name) about 50 that 2-Methyl-2-12-[1-pentyl-3-4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid

Ф) ЕСє-0.073МКМ ka Example 9 60 b5 in o no ) MA

Mk t 2-12-(3--4-Dimethylaminophenyl)-1-pentylureido|indan-5-ylsulfanyl)-2-methyl-propionic acid

EC is 0.131μM

Example 10 no ) mn s o ; and

Fo 2-12-I3-(4-isopropylphenyl)-1-(3-pentyl)ureido|indan-5-ylsulfanyl)-2-methyl-propionic acid - c

EC is 0.165μM

Example 11 o d) "5 2 s ;" (ee) («c) 2-(2-I3-(4-Tert-butylphenyl)-1-(3-pentyl)ureido|indan-5-ylsulfanyl)-2-methyl-propionic acid about ESvo-0.173 µM so 020 Example 12 what

F; o yuyu 5 In other oh

M

60; bo 2-(2-(3-(Biphenyl-4-yl-1-pentylureido)indan-5-ylsulfanyl|-2-methylpropionic acid

EC is 0.183μM

Example 13 oxo 15 / 2-12-I3-(4-Isopropylphenyl)-1-(3-hexyl)ureido|indan-5-ylsulfanyl)-2-methyl-propionic acid

ESvo-0.184μM 20 Example 14 in s 25 (8) no So- and cha

Fo c «c) 2-Methyl-2-12-/1-hexyl-3--4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)propionic acid

ESvo-0.213μM

Example 15

SE, "shi s o x" 5 u-mn p n (ee) ((c) ime) ik 2-Methyl-2-12-/1-hexyl-3--4--rifluoromethylsulfanylphenyl)ureido|indan-5 -ylsulfanil|Ipropionic acid

And ECo-0.123μM

Example 16

WITH

Ф) imi) 2-Methyl-2-12-P1-propyl-3--4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)propionic acid b5 ECo-0.158μM

Example 17

AND

"Oso in the book

I

2-Methyl-2-12-(1-butyl-3--4-trifluoromethylsulfanylphenyl)ureido|indan-5-ylsulfanyl)ipropionic acid

EC5o-0.16O0μM

Example 18

Rz o n

МН с 2-Methyl-2-12-I3--4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-propionic acid o

Esho-0.135mMkM

Example 19

OSRa cha

Fo

70 2-Methyl-2-12-[1-pent-4-enyl-3-(4-trifluoromethoxyphenyl)ureido)indan-5-ylsulfanylpropionic acid as with ESvo-0.125MKM: with" Example 20

OSe. 2-Methyl-2-12-(1-(3-methylbutyl)-3-(4-trifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropion

F! acid

EC0-0.10bmM o Example 21 60 b5 in o no 2-(2-3-(4-Isopropylphenyl)-1-(3-methylbutyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid 19 EC0-0 ,10bmM

Example 22

Mn s (8) 2-16-[1-Butyl-3-(«4--rifluoromethoxyphenyl)ureido!|-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid

ECo-0.219μM m zo Example 23 (22) s vy i n g)

Kk « 2-16-(/1-Butyl-3-(4--rifluoromethylsulfanylphenyl)ureido!|-5,6,7 8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methyl-slpropionic acid in ESO- 0.244μM,» Example 24 o

And S

("in)

CH: o nn o 50 what 59 2-6-(1-Hexyl-3-(4-trifluoromethoxyphenyl)ureido!|-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropion

F! ova acid

ESvo-0.235mMKkM o Example 47 60 ooo o C

Azh p b5 2-16--1-Ethyl-3--4--rifluoromethoxyphenyl)ureido|-3-methoxy-5,6,7,8-tetrahydro-naphthalene-2-ylsulfanyl)-2-methylpropionic acid

EC is 0.045 mM

Example 49

Gi A ud i

M

170 g Н 2-16--1-Ethyl-3-«4--rifluoromethoxyphenyl)-ureido!|-5,6,7,8-tetrahydronaphthalene-2-yloxy)-2-methylpropionic acid

ESvo-0.309mMkM

Example 50 / o ver 2-16--1-Ethyl-3--«4--rifluoromethoxyphenyl)ureido|-33-fluoro-5,6,7,8-tetrahydro-naphthalene-2-ylsulfanyl)-2- methyl propionic acid p

ECo-0.010μM o

Example 51 and from

Fo

А НН сч 2-16--1-Ethyl-3-«4--rifluoromethoxyphenyl)ureido|-3Z-chloro-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methylpropionov acid so

EC is 0.027μM

Example 52 "from MO o-s AD." N

I» A n 2-I6-1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido|-3-bromo-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methyl pso 15 ropionic acid

ЕСє-0.017μM (ав) Example 53 име) и и "СС ува и "m Х мн

A m 59 2-6--1-Ethyl-3-«4--rifluoromethoxyphenyl)ureido|-3-methyl-5,6,7,8-tetrahydro-naphthalene-2-ylsulfanyl)-2-methyl

F! propionic acid

ECo-0.042μM o Example 54 60

And Go sh

E m Kk b5 r. N

2-16--1-Ethyl-3-«4--rifluoromethoxyphenyl)ureido|-3-trifluoromethoxy-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid

EC is 0.131μM

Example 55 5 b o z

M ran 2-6--1-Ethyl-3-"4--rifluoromethoxyphenyl)ureido|-3-phenyl-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methyl propionic acid

EC0-0.545 mM t Example 56 μM nm ra 2-16-(/1-Ethyl-3-(4-hydroxyphenyl)ureido!|-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid with

Example 57 2-16-(4-Aminophenyl)-1-ethylureido)|-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid

Example 58 o d) 0

2-(3-Chloro-6-((4-methylphenoxycarbonyl)ethylamino)-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid

Esho-0.340mMmkM

Example 59. -methylpropionic acid

EC5o-0.390μM

Example 60

F) o t EE 60 E

B) 2-(6-I-(Ethyl-4-trifluoromethoxyphenoxycarbonyl)amino1|-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methylpr 65 opionic acid

EC is 0.002μM

Biological Example 1

Analysis of BOMA (branched DNA) NO

Rat hepatoma NAIE cell line was obtained from ATSS. Are the cells cultured in a 175cm tissue culture flask? or plated on a 96-well plate with a culture medium (high serum content, 1096 fetal bovine serum and 1095 calf serum) and maintained at 372C and 596 СО" throughout the studies.

Twenty-four hours after the initial plating on a 9b-well plate by hand (approximately 100,000/well), the HO gene induction assay is initiated. The medium is removed and replaced with 100 µL of low-serum culture medium (595 charcoal/dextran-treated calf serum) containing 70 vehicle (DMSO) or test compound or standard. The cells are returned to the incubator for 24 hours for cultivation. At the end of the control infection, 5O0μl of lysis buffer with HO gene-specific CE-, IE-, VI-probes are added directly to each well to initiate the analysis of BOMA HO mRNA. Branched DNA analysis is performed according to the manufacturer's protocol (Vaueg Oiadpovziisv, EtegumShe, SA). At the end of the analysis, luminescence is quantitatively measured using a Supeh 75 MIH microtiter plate luminometer. ESvo values are determined by the method of nonlinear regression with sigmoidal approximation using the Ogarpraa Rgizt program.

Biological Example 2

Analysis of PPAK5 receptors with transfection

NEK293 cells are grown in OMEM/E-12 medium supplemented with 1095 fetal bovine serum (EV5) and glutamine (SIVSO VK). Cotransfection of cells with the DNA of the PRAMK-Cai4 receptor and the reporter is carried out

Side-luciferase using OMKIE-C reagent The next day, the DNA-containing medium is replaced with a medium for growth with 595 EB5, treated with charcoal. Six hours later, the cells are seeded on a 9b-well plate and incubated at 372C in a CO incubator overnight. Cells are subjected to the action of the studied compounds and incubated for 24 hours at 372C in an incubator with 595 CO. The activity of luciferase is evaluated with the C set of bieadu-sio I isitegase Azzau Kii company Rgoteda. Reagent OMAKIE-S was purchased from SIVSO, catalog number 10459-014. Reduced serum medium ORTI-MEM | was purchased from the company SIVSO, catalog number 31985. The kit for the analysis of luciferase bieadu-sio I isitegase Avzzau Kyi was obtained from the company Rgoteda, Mo product E254B. cha zo

F neEny nits Pon PO sch o in 11 so 6 1vyu|77111z611111le 1 v011v8010 « voy 11115111 z 81011618 ch - byum m 010005 x» yam 81 in vm 0100003 in mya 01179000 o 610110018 m 080 yam 0

FO in vmk 1741 -4 POET Sh U NNYA PON NOGU A shih ni nin o i 5v p nshsh z shshsh pi write: niny

F. vovi 1411 yu 5101 yav vo shi: nyny nyn vv byu vv0 pn lines nin vv de v vi 01v801

FOR 0.657 in 1otttt15601

VIT Sh S MON POL sl nie i PO

WE PI PO PO

ME tt PE PO yuyu 1 t NE t PO PO am 1 to yav 11 nyshe i i I PO shi shi niny po sh EE t PO TO PO jav i pos ng: no so po nshikh ni shshsh shi vvvvv 181 vvv 010 i me in cm

NO VO UI PO OVO PO PO o cha

Biological Example From Fo

Analysis of aP2 on PPRA-gamma agonists

The procedure is described in detail in |Vigtiz ei aiI., MoIesshag Epadoshypoiodu, 1999, 13:410), which is fully incorporated here by reference, and the results of the aP2 analysis of the agonist's own activity can be presented as a fold increase compared to the carrier when inducing the production of agg2 mRNA .

Twenty-four hours after initial seeding by hand into 9b-well plates (approximately 20,000 cells/well), the differentiation assay can be initiated. The medium can be removed and replaced with 150 µL of differentiation medium containing vehicle (DMSO) or test compounds. Cells can be returned to the incubator for 24 hours for cultivation. At the end of the control challenge, the medium can be removed and 100 µl of lysis buffer can be added to initiate the BOMA ag mRNA assay. Branched-chain DNA analysis can be performed according to the manufacturer's protocol (Vaugue Oiadpowiisv; Etegumie, CA). no) c The result can be expressed as a fold increase in the activated mRNA production of agRz2 compared to the control carrier. The values of ES Bo and Etakh can be determined by the method of nonlinear regression with a sigmoidal approximation of the curve.

After control infection of preadipocytes, cells can be lysed using a buffer for lysis (Vaueg Oiadpowiisv) containing oligonucleotides aP2. After 15 minutes of incubation at 53°C or 30 minutes in a 372°C incubator, 7µl of lysis buffer from each well can be added to the corresponding well for (a) immobilization (pre-incubated with 7µl of blocking buffer (Vaugue Oiadpoviisv)). The immobilization plate can be incubated overnight at 532 in a plate incubator (Vaugue Oiadpowiisv).

After this incubation, BOMA and labeled samples can be annealed according to the manufacturer's recommendations. (Ce) 20 After 30 minutes of incubation with the substrate of luminescent alkaline phosphatase - dioxytane, the luminescence -h can be quantitatively measured using a luminometer for microtitre tablets UOupeh MIH.

Oligonucleotide probes designed for annealing to aP2 mRNA and use in the mRNA detection system

LBOMA, developed with the help of the computer program RgoreJuOezidpeg (Vaueg Oiadpoviisv). This software package analyzes the desired target sequence using a series of algorithms to determine which 59 regions of the sequence can serve as annealing sites for immobilization, labeling, or spacers.

ГФ) The sequences of oligonucleotides are given below: име) 60 b5

5EOO MO1 SAT TOTOSASTITTSTAOOSATTATTSTTTTSTSTTOSADASADA

ZE MOH | SSsToTSOPTTSTSTTTATOOOTTTTTSSTTTOOAAASADAST

And AI

AST

ZEOIU MO 5 | ССАСОСТАСТАСАЛААОСАТСАСАТТТАСОСАТАССАСССОТО tst 5EOЙО МО.6 | OSSSASTOSTASTTSTTTSATATAATAATSATTTAOSSATAOOASOS

N stotst 7 ABSSASTTTTSSTOOTOOSADATTTAOOSATASOASSSOTOTST

ЗЕОИ0МО8 | САТССССАТСАСАСТОАТОАТСТГАСОСАТОСАСОСОТОТ рн Another 5Е0И0 МО | ОТАССАССАСССССАТСТААСОТТТТТАСОСАТОСАСССО totst zo | ZEO IO MO.10 | ОСТТОАТТТоСАТСССАТТТСТОСАСАТТТАООСАТАССАССС and sotTotTst сч

SSATTSSASSASSASSASTTTTATTSATTTTAOOSSATAOSASSSOSTOT o st (ee) 5EO 0 MO.12 | ОЗССААСТТСАСТССАОСТСААСОТСОСТТОТТТАОССАТАСОСА

SHY sssototst h - pee so | ZEO Yu MO.14 | ААААААААТАТСТТТТТОДАСААТАТТТАСОСАТАССАСС: ш АААСОТАСТTTСАСАТТТААТОСТОАТСА o 7 Biological Example 4 11-day administration of the compound according to Example C to female arB/ad mice at the age of 6-7 weeks

Female mice aB/aB (C57 AGE 5/)-t/n erg?, daskvop I ab", Vag Nagrog, ME) at the age of 6-7 weeks were kept four per cage in horseshoe-shaped cages with a solid bottom. Room temperature was maintained in the interval 65 20-22.22s (68-722P), and humidity - 50-6595. Room lighting was maintained on a 12-hour light/12-hour dark cycle. Mice were fed certified low-fat rat and mouse chow MIN Azio bE vo.

Mo5K52 (RMI Myyop Ipb, Z(IGotsiv, MO, through the firm M/.E. Rizpeg apa Zop, Ips., Voypa Vgook, MU). Food and water were given without restrictions (ad IiriSht).

Prepare suspensions of compounds in 0.595 hydroxypropyl methylcellulose (Yom/ Spetisai, Miailiapa, M). The dosage volume was 10 ml/kg of body weight. Female diabetic ar/46 mice (8/group) were administered orally by gavage once a day for 11 days with 0.595 methylcellulose in dist.H 20 (carrier) or the PRAK agonist in amounts of 0.03, 0.1, 0.3, 1, 3, 1Omg/kg/day. Body weight is measured in the morning on Day 1 before dosing, and on Day 12 before blood sampling. 18-24 hours after the last dose for each group, mice are anesthetized using

CO2O" (70:30) and take blood samples by puncturing the retroorbital sinus into microtubes containing /o coagulation activator, and then place on ice. Serum samples were obtained by centrifugation. Glucose and triglycerides of the serum were determined using a chemical blood analyzer SOVA5Z by Miga Riv (Cospe

Oiadpoviysv, MO). Serum insulin was measured using a solid-phase enzyme-linked immunosorbent assay (ELISA) kit for insulin A PSO.

Statistical analysis was performed using the Rgizt program (Sgarprad, Mopgomia, CA) and one-way analysis of variance (ANOVA) was performed using Dunnett's multiple comparison test (Yuyppey). sch z o mn z, popy sunday pot (poyu Don polo as zni u ovoyyan from pvryana poopnsnnalyu I wear 000 1 mice ar/ar, which were injected with 1.Omg/kg (trk). The data are given as 95 changes compared to animals, that received the carrier; MS - unchanged

Fsch o 325 Biological Example 5 so 11-day administration of the compound according to the Example to female ar/a mice at the age of 7 weeks

Female ar/a mice (C57 AGE VI/6.)-I ero?, daskvop I arz, Vag Nagbrog, ME) at the age of 7 weeks were kept two per cage in horseshoe-shaped cages with a solid bottom. Room temperature was maintained in the range of 20-22,296 "20 (68-722P), and humidity - 50-6595. Room lighting was maintained on a 12-hour light/12-hour dark cycle. with

Mice were fed with certified food for rats and mice with a reduced fat content MIN Mo5K5BO (RMI s My yshchop Iyb, ZK otsiv, MO, through the company MU.R. Rizpeg apa Zop, Ips., Voypa VgooK, Mu). food and water were given without :z» restrictions (aa Iirisht). 83

Prepare suspensions of compounds in 0.595 hydroxypropyl methylcellulose (Yom/ Spetisai, Miailipa, M). The dosage volume was TOml/kg of body weight. Female diabetic ob/ob mice (8/group) were injected orally through a gavage once a day for 11 days with 0.595 methyl cellulose in dist.H 20 (carrier) or PPRA agonist in the amount of 0.003, 0.01, ("in") 0.03 , 0.1, 0.3, Tmg/kg/day. Body weight is measured in the morning on Day 1 before the start of dosing, and on Day 12 before blood sampling. Eighteen hours after the last dose for each group, the mice were anesthetized using

CO" (7090:3090) and take blood samples by puncturing the retroorbital sinus into microtubes containing is), coagulation activator, and then placed on ice. Serum samples were obtained by centrifugation. Glucose and m triglycerides of the serum were determined using a chemical blood analyzer SOVAB Miga Riv (Cospe

Oiadpoviisv, M.)). Serum insulin and free fatty acids were measured using an enzyme-linked immunosorbent assay (ELISA) kit for insulin AG RSO and a U/aco MERA kit, respectively.

Statistical analysis was performed using the Rgizt program (Sgarprad, Mopgomia, CA) and one-way analysis of variance (ANOVA) was performed using Dunnett's multiple comparison test (Yuyppey).

F) yu yu

E. Other variants of implementation in 5 Features and principles of the invention are illustrated in the discussion, examples and claims. Various adaptations and modifications of the invention will be apparent to one of ordinary skill in the art, and such other embodiments are also within the scope of the invention.

The publications cited here are incorporated herein by reference in their entirety.

Claims (39)

The formula of the invention 1. The compound of the formula P, KE 70 ka Z s nok ke i y g; EZ " The formula or its pharmaceutically acceptable salt, C. 5-ester or C..5-amide, in which each of C. and Co independently means H, C.v.-alkyl, (СНо)lМКак, (СНо)tОкКеа , (СН) МН(СОк в or (СНо)тСО»Ра, where each of Ka, K and Ka independently means H or C..5-alkyl, or Ki and Ko together with the carbon atom to which they are attached form C3 -cycloalkyl, t has a value from 1 to 6, n is 1 or 2, c 29 X is O or 5, where X is in position 5 or 6, if n is 1, and where Ge) X is in position 6 or 7, if n is 2, Ez means H, phenyl, C. 3-alkyl group, C. 3-alkylthio group, halide, cyano group, C. 3-alkyl, nitro group, MKeKcho, МНСОКо, СОМНКо and SOOK.0о, and Kz is in an ortho- or meta-position in relation to X, K. means H or -(C.5-alkylene)-K/5, where K.5 means H, C.7-alkyl, (di-«C4 o-alkyl)amino|-(C.v-alkylene) , - (C..3-Alkoxyacyl)-(C..C-Alkylene), C.sub.3-Alkoxy group, C.sub.3-alkenyl or C.sub.3-Alkynyl, where K has no more than 9 carbon atoms, and K. can also mean -(C.4 5-alkylene)Ki5, where K/5 means C3.c-cycloalkyl, phenyl, phenyl-O-, phenyl-5- or 5-6--ene monovalent heterocyclic radical with 1-2 heteroatoms selected with M, c O and 5, o M means МН, МН-СН» and 0, each of Ко and К; are independently selected from H, C..6-alkyl, halide, cyano group, nitro group, SOK.4, SOOK.4, CO C d-alkyl group, C.-alkylthio group, hydroxyl group, phenyl, MKK. and a 5-6-ene monovalent heterocyclic radical with 1-2 heteroatoms selected from M, O and 5, "Ke selected from C.v-alkyl, halide, cyano group, nitro group, SOK.z, SOOK.z, S. .4-alkoxy group, C t0 C d-alkylthio group, hydroxyl group, phenyl, MK.zK.i4 and 5-6-ene monovalent heterocyclic radical with 1-2 heteroatoms selected from M, O and 5, in addition, Ko and Ko or Ke and K; can form together with" a divalent fragment, saturated or unsaturated, selected from "(СН2)з-, "СНо)уд- and (СН .2)BM(СН /.2)4, p equals 0-2 and 4 is equal to 1-3, and the sum (p and 4) is at least 2, each of Co and Clio independently means C 1 -alkyl, each of C 4 , Ki , Ki , and Ki 4 independently means H or C 6 -alkyl, each of the 75 above-mentioned hydrocarbyl and heterocarbyl fragments can be replaced by 1-3 substituents, Me independently selected from P, SI, Bg, I, amino group, methyl, ethyl, hydroxyl group, nitro group, cyano group and av) methoxy group. 2. The compound according to claim 1, in which one of Ku and Co is methyl or ethyl. at 3. Compound according to claim 2, in which each of the CC. and Co means methyl. (Se) 20 4. The compound according to claim 1, where Ku and Co together represent cyclobutyl or cyclopentyl. . 5. Compound according to claim 1, in which Kz means H. and 6. The compound according to claim 1, in which Kz means a C. 3-alkylthio group, a C. 3-alkylthio group, a halide, a cyano group, a C. . 7. Compound according to claim 1, in which Ku; means H or C»o.7-alkyl. 99 8. Compound according to claim 7, in which Ku; means H or C» c-alkyl. GF) 9. The compound according to claim 8, in which Ku means ethyl. 10. Compound according to claim 8, in which K; means N. name) that . 11. Compound according to claim 1, in which n is equal to 1. 12. Compound according to claim 1, in which n equals 2. 60 13. The compound according to claim 1, in which X means МН-СН»5. 14. The compound according to claim 1, in which M stands for МН. 15. The compound according to claim 1, in which X stands for 5. 16. The compound according to claim 1, in which X means 0. 17. Compound according to claim 1, in which at least one of Kv and K; means N. because 18. The compound according to claim 17, in which K 6 means C../-alkyl, halomethoxy group, halomethylthio group or di-(C.4 c-alkyl)amino group. 19. Compound according to claim 18, in which K; means trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethylthio, t-butyl, isopropyl or dimethylamino. 20. The compound according to claim 3, in which Kz means H, K, means Co 7-alkyl and M means MH. 21. The compound according to claim 20, in which X is 5. 22. The compound according to claim 20, in which n is equal to 1. 23. The compound according to claim 20, in which n is equal to 2. 24. The compound according to claim 20, in which Ku; means C»5-alkyl. 70 25. The compound according to claim 24, in which Ku; means ethyl. 26. The compound according to claim 20, in which Co represents a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, a trifluoromethylthio group, a t-butyl group, an isopropyl group, or a dimethylamino group. 27. The compound according to claim 1, in which each of K. and Ko independently means H, C.. 6-alkyl, (СНо)lМКакКъ or (СНо)тоКа, where each of Ка, Къ and Ка independently means H or С. c-alkyl, t is from 1 to 6, n is 1 or 2, X is O or 5, and X is in position 5 or b if n is 1, and X is in position 6 or 7 if n is 2, Ez means H, phenyl, C. 3-alkyl group, C. 3-alkylthio group, halide, C. 6-alkyl or MCoC.o, and Kz is in the ortho- or meta-position with respect to X, K. means H or -(C.5-alkylene)K/5, where Ku.v means H, C.7-alkyl, |di-"C.-.o-alkyl)amino1|-(C 4 c- alkylene), (C..3-Alkoxyacyl)-(C.4.C-Alkylene), C.C.-Alkoxy group or C.C.-Alkenyl, and K. contains no more than 9 carbon atoms, KK. can also mean -(C.5-alkylene)-C/5, where C/5 means C3-6-cycloalkyl, phenyl, phenyl-O-, phenyl-5- or C5-6-ene monovalent heterocyclic radical from 1 -2 heteroatoms selected from M, O and 5, U means МН or МНН", (8) each of K5 and K; are independently chosen from H, Si. 5-alkyl, halide, SOK.i, SOOMK.4, Si 4-alkyloxy group, Su d-alkylthio group, hydroxyl group and MK.4Kch2, Ke chosen from C..v-alkyl, halide, SOK.z, SOOK z, C.4-alkoxy group, C..4-alkylthio group, phenyl, MK.zK 14 M zo and 5-6-ene monovalent heterocyclic radical with 1-2 heteroatoms selected from M, O and 5, each from Ke and Ko independently means C.45-alkyl, each of K.44, Ki, Kis and Ki4 independently means H or C. 5-alkyl, Me and each of the above hydrocarbyl and heterocarbyl fragments can be substituted with 1-3 substituents, independently selected with E, SI, amino group, methyl, ethyl, hydroxyl group and methoxy group. 28. The compound according to claim 1, selected from: o 2-16-[1-ethyl-3-(4--rifluoromethoxyphenyl)ureido!|-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropion savoic acid, 2-2-/1-ethyl-3--(4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid, 2-2-/1-ethyl-3--4- -rifluoromethylsulfanylphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid, 2-methyl-2-(2-11-pentyl-3-(4--trifluoromethylsulfanylphenyl)ureido|indan-5-ylsulfanyl)propionic acid, " 2-2-(1-ethyl-3-(4-isopropylphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid, with 2-methyl-2-2-11-pentyl-3-(4-trifluoromethoxyphenyl) )ureido|indan-5-ylsulfanyl)-2-methylpropionic acid, . 2-12-(3--4-dimethylaminophenyl)-1-ethylureido|indan-5-ylsulfanyl)-2-methylpropionic acid, and? 2-methyl-2-12-(11-(3-methylbutyl)-3-(4--rifluoromethoxyphenyl)ureidoindan-5-ylsulfanyl)-2-methylpropionic acid, 2-(2-II3-(4-isopropylphenyl)- 1-(3-methylbutyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid, Ho! 2-methyl-2-(2-(11-pent-4-enyl-3--4-rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)propionic acid, 2-16-/1-ethyl-3--( 4--rifluoromethoxyphenyl)ureido|-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methyl o lpropionic acid, co 2-16-/1-ethyl-3--4-- Rifluoromethoxyphenyl)ureido|-33-fluoro-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methyl propionic acid, ik 2-16-/1-ethyl-3-(4--rifluoromethoxyphenyl)ureido| -3-Chloro-5,6,7-8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid, 2-I6-1-ethyl-3-(4-trifluoromethoxyphenyl)ureido-3-bromo- 5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid, 2-16-/1-ethyl-3-(4--rifluoromethoxyphenyl)ureido|-3-methyl-5,6,7 ,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methyl propionic acid and F) 2-16-[1-ethyl-3-"4--rifluoromethoxyphenyl)ureido|-3-trifluoromethoxy-5,6,7,8- tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid. 29. The compound according to claim 1, selected from: 2-methyl-2-(2-(1-hexyl-3-(4-trifluoromethylsulfanylphenyl)ureido|indan-5-ylsulfanyl)propionic acid, 2-12-(3- -4-dimethylaminophenyl)-1-pentylureido[indan-5-ylsulfanyl)-2-methylpropionic acid, 2-methyl-2-2-13--4--1-fluoromethoxyphenyl)ureido[indan-5-ylsulfanyl)-propionic acid, 2-methyl-2-(2-(11-propyl-3-(4-trifluoromethoxyphenyl)ureido|indan-5-ylsulfanylpropionic acid, 2-methyl-2-12-(/1-butyl-3-(4-trifluoromethylsulfanylphenyl) )ureido|indan-5-ylsulfanyl)propionic acid, 65 2-12-I3-(4-isopropylphenyl)-1-(3-pentyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid, 2-(2 -Y3-(4-tert-butylphenyl)-1-(3-pentyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid, 2-I(2-(3-(biphenyl-4-yl-1-pentylureido)indan-5-ylsulfanyl|-2-methylpropionic acid, 2-12-I3-(4-isopropylphenyl)-1-(3-hexyl )ureido|indan-5-ylsulfanyl)-2-methylpropionic acid, 2-methyl-2-12-(/1-butyl-3-(4-trifluoromethoxyphenyl)ureidoindan-5-ylsulfanylpropionic acid, 2-16-/1- ethyl-3--(4--rifluoromethoxyphenyl)ureido|-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid, 2-16-/1-ethyl-3- -4--rifluoromethoxyphenyl)ureido|-33-fluoro-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methyl propionic acid, 2-16-/1-ethyl-3-(4--rifluoromethoxyphenyl )ureido|-3-chloro-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpr 70 of opionic acid, 2-I6-1-ethyl-3-(«4-trifluoromethoxyphenyl)ureido|-3- bromo-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic acid, 2-16-/1-ethyl-3-(4--rifluoromethoxyphenyl)ureido|-3-methyl-5,6 ,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methyl propionic acid and 2-methyl-2-(2-(/1-hexyl-3-(4-trifluoromethoxyphenyl)ureido|indan-5-ylsulfanylpropio new acid. 30. The compound according to claim 1, selected from: 2-16-[1-ethyl-3-(4--rifluoromethoxyphenyl)ureido!|-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropion acid, 2-16-I(3--4--rifluoromethoxyphenyl)ureido!|-5,6,7 8-tetrahydronaphthalene-2-ylsulfanyl)-2-methylpropionic 2o ACIDS, 2-2-/1-ethyl-3 --(4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid, 2-16-/1-ethyl-3--4--rifluoromethoxyphenyl)ureido|-33-fluoro-5,6, 7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methyl propionic acid, 2-16-/1-ethyl-3-(4--rifluoromethoxyphenyl)ureido|-3-methyl-5,6,7,8-tetrahydronaphthalene -2-ylsulfanyl)-2-methyl propionic acid, 2-2-/1-ethyl-3--4--rifluoromethylsulfanylphenyl)ureido)indan-5-ylsulfanyl)-2-methylpropionic acid and i) 2-methyl- 2-(2-(11-propyl-3-(4-trifluoromethoxyphenyl)ureido|indan-5-ylsulfanylpropionic acid). 31. The compound according to claim 1, selected from: 2-2-/1-ethyl-3--(4--rifluoromethoxyphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid, M zo 2-2-/1 -ethyl-3--4--rifluoromethylsulfanylphenyl)ureido|indan-5-ylsulfanyl)-2-methylpropionic acid, 2-methyl-2-2-(11-propyl-3-(4-trifluoromethoxyphenyl)ureido|indan-5 -ylsulfanylpropionic acid and Me 2-16-(1-ethyl-3--4--rifluoromethoxyphenyl)ureido|-33-fluoro-5,6,7,8-tetrahydronaphthalene-2-ylsulfanyl)-2-methyl cpropionic acid . 32. Pharmaceutical composition, which contains as an active ingredient the compound according to claim 1, 20, 27, 28, 30 or 31. o 33. A method of treating or inhibiting the development of a PRAC-alpha-mediated disease, which includes administering to a patient in need of treatment a pharmaceutically effective amount of a composition containing a compound according to claim 1, 20, 27, 28 or 31. 34. The method according to claim 33, in which said PRAK-alpha-mediated disease is selected from dyslipidemia and cardiovascular diseases. " 35. The method according to claim 34, in which the specified disease is dyslipidemia. from the village 36. The method according to claim 34, in which the specified dyslipidemia is selected from hyperlipidemia of phase I, preclinical. hyperlipidemia, hyperlipidemia phase II, hypercholesterolemia, hypo-NOI -cholesterolemia and hypertriglyceridemia. and?" 37. The method according to claim 34, in which the specified cardiovascular disease is atherosclerosis, coronary heart disease, coronary disease or hypertension. 38. The method according to claim 33, 35 or Zb, which additionally includes the stage of administering to the patient a jointly effective Go! amount of lipid-lowering agent. 39. The method according to claim 33, 35, 3b or 38, which additionally includes the step of administering to the patient a jointly effective amount of the blood pressure lowering agent. ime) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated circuits and microcircuits", 2007, M 14, 10.09.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. Ф) име) 60 b5 -B4-