Inhibitors of diacylglycerol o-acyltransferase type 1 enzyme

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, where Q is phenyl or pyridinyl; A is pyrazolyl or triazolyl, where each A is independently additionally unsubstituted or substituted with 1 or 2 substitutes represented by Ra, or A is formula (a); Va is C(R4), Vb is N or C(R5) and Vc is N; or Va is N, Vb is C(R5) and Vc is N or C(R6); R4 is hydrogen, R5 is hydrogen, C1-6alkyl, -ORb, -SRb, aryl, selected from phenyl, heteroaryl, selected from thienyl, or cycloalkyl, selected from cyclopropyl; R6 is hydrogen or aryl, selected from phenyl; R7 is hydrogen or C1-6alkyl; R3 is hydrogen, C1-3alkyl, -OH, -S(O)2R1, or heteroaryl, selected from tetrazolyl, where the heteroaryl is bonded to a nitrogen atom through a ring carbon atom; Rb, Rx, Ry, Rza, Rzb, Rw, Re, Rk, Rm, Rn, Rq and R1, in each case, are independently hydrogen, C1-3alkyl or C1-3haloalkyl; and Rf, in each case, is independently hydrogen, C1-3alkyl or -OH (the rest of the substitutes assume values given in the claim). The invention also relates to a pharmaceutical composition, having inhibiting action on DGAT-1, which contains a compound of formula (I), and a treatment method.

EFFECT: compounds of formula (I) as DGAT-1 inhibitors are provided.

16 cl, 9 dwg, 1 tbl, 127 ex

 

This application claims the priority of U.S. patent application No. 60/867695, issued November 29, 2006, the contents of which is given here by reference.

The technical field to which the invention relates

The present invention relates to compounds that are inhibitors of the enzyme diacylglycerol O-acyltransferase type 1 (DGAT-1). The invention also includes methods of using such compounds for inhibiting the activity of diacylglycerol O-acyltransferase type 1 and pharmaceutical compositions containing such compounds.

The level of technology

Triacylglyceride represent the main form of energy storage in eukaryotes and disturbance or imbalance in the metabolism of triacylglyceride involved in the pathogenesis and increase the risk of obesity, insulin resistance, type II diabetes, nonalcoholic fatty infiltration of the liver and coronary heart disease (Lewis, et al, Endocrine Reviews 23:201, 2002). The accumulation of excess triacylglycerides in lean tissues, such as liver, muscle and other peripheral tissues, leads to induced lipid dysfunction in these tissues, in reducing the accumulation of fat in the skim sections that, obviously, is a positive factor in the treatment of lipotoxicity (Unger, R. H. Endocrinology, 144: 5159-5165, 2003). The accumulation of excess triacylglycerides in white LM is new tissue (WAT) leads to obesity, the condition, which leads to reduced life expectancy, diabetes type II, coronary artery disease, hypertension, stroke and some types of cancer (Grundy, S. M. Endocrine 13(2): 155-165, 2000). Obesity is a chronic disease that is most prevalent in modern society and for which there is currently limited options for pharmacological treatment that requires the development of safe and effective pharmaceuticals for the treatment of obesity.

The diacylglycerol O-acyltransferases (DGATs) are membrane-associated enzymes that catalyze the final stage of the biosynthesis of triacylglycerides. Were characterized by two enzymes, which are active in DGAT: DGAT-1 (diacylglycerol O-acyltransferase type 1) (patent document U.S. Pat. No. 6100077; Cases et al., Proc. Nat. Acad. Sci. 95:13018-13023, 1998) and DGAT-2 (diacylglycerol O-acyltransferase type 2) (Cases et al., J. Biol. Chem. 276:38870-38876, 2001). DGAT-1 and DGAT-2 share only 12% sequence identity. It is essential that mice with absence of DGAT-1 are resistant to induced by diet obesity and have increased sensitivity to insulin and leptin (Smith, et al, Nature Genetics 25:87-90, 2000; Chen and Farese, Trends Cardiovasc Med. 10:188, 2000; Chen et al., J. Clin. Invest. 109:10049, 2002). Mice with deficiency of DGAT-1 is protected from fatty hepatosis and are characterized by high power consumption is reduced levels of triglycerides in tissues. In addition to improved metabolism triacylglycerides, mice with deficiency of DGAT-1 also have improved glucose metabolism, with lower levels of glucose and insulin after glucose load compared to wild type mice. Partial deficiency of DGAT-1 in heterozygous DGAT-1 +/- animals is sufficient to produce an intermediate phenotype of body weight, obesity and metabolism of insulin and glucose compared to wild type and homozygous animals odnopolnymi animals (Chen and Farese, Arterioscler. Thromb. Vase. Biol. 25:482-486, 2005) and it was reported that small molecule inhibitors of DGAT-1 cause weight loss in mice with obesity induced by diet (DIO) (patent document US 2004/0224997). The phenotypes of mice with deficiency of DGAT-1 and described in the publications of the pharmacological activity of inhibitors of DGAT-1 suggests that the discovery of small molecules that effectively block the conversion of diacylglycerol in triacylglyceride by the inhibition of DGAT-1 enzyme can be used in the treatment of obesity and other diseases associated with an imbalance of triacylglycerides.

The invention

One aspect of the invention relates to compounds of formula (I) or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof,

where:

Q is phenyl or mo is cyclicism heteroaryl, optionally substituted by 1, 2 or 3 substituents, denoted as T, where each T is independently an alkyl, alkenyl, quinil, halogen, -CN, -NO2, -OR1, -OC(O)(R2), -N(Rw)(R1), -N(Rw)C(O)(R1), -N(Rw)-C(O)O(R1), -N(Rw)-C(O)N(R1)2, -N(Rw)-S(O)2(R2), -C(O)O(R1), -C(O)N(Rw)(R1), -C(O)R1, -SR1, -S(O)R2, -S(O)2R2, -S(O)2N(Rw)(R1), -(CRgRh)t-CN, -(CRgRh)t-NO2, -(CRgRh)tOR1, -(CRgRh)t-OC(O)(R2), -(CRgRh)t-N(Rw)(R1), -(CRgRh)t-N(Rw)C(O)R1, -(CRgRh)t-N(Rw)-C(O)O(R1), -(CRgRh)t-N(Rw)-C(O)N(R1)2, -(CRgRh)t-N(Rw)-S(O)2(R2), -(CRgRh)t-C(O)O(R1), -(CRgRh)t-C(O)N(Rw)(R1) -(CRgRh)t-C(O)R1, -(CRgRh)t-SR1, -(CRgRh)t-S(O)R2, -(CRgRh)t-S(O)2R2, -(CRgRh)t-S(O)2N(Rw)(R1or halogenation; alternatively, two adjacent T Deputy together with the carbon atoms to which they are attached, form a monocyclic ring selected from the group consisting of phenyl, heterocycle and heteroaryl, where each ring is optionally additionally substituted with 1, 2 or 3 substituents selected from the group consisting of oxo, alkyl, alkenyl, quinil, halogen, -CN, -NO2, -OR1, -OC(O)(R2), -N(Rw)(R1), -N(Rw)C(O)(R1), -N(Rw)-C(O)O(R1), -N(Rw)-C(O)N(R1)2, -N(Rw)-S(O)2(R2), -C(O)O(R1), -C(O)N(Rw)(R1), -C(O)R1, -SR1, -S(O)R2, -S(O)2R2, -S(O)2N(Rw)(R1), -(CRgRh)t-CN, -(CRgRh)t-NO2, -(CRgRh)tOR1, -(CRgRh)t-OC(O)(R2), -(CRgRh)t-N(Rw)(R1), -(CRgRh)t-N(Rw)C(O)R1, -(CRgRh)t-N(Rw)-C(O)O(R1), -(CRgRh)t-N(Rw)-C(O)N(R1)2, -(CRgRh)t-N(Rw)-S(O)2(R2), -(CRgRh)t-C(O)O(R1), -(CRgRh)t-C(O)N(Rw)(R1), -(CRgRh)t-C(O)R1, -(CRgRh)t-SR1, -(CRgRh)t-S(O)R2, -(CRgRh)t-S(O)2R2, -(CRgRh)t-S(O)2N(Rw)(R1and halogenoalkane;

A is a phenyl or a 4-, 5-, 6 - or 7-membered monocyclic ring selected from the group, with the standing of heteroaryl and heterocycle, where each A is independently optionally unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents represented by Raand Raselected from the group consisting of oxo, -N(Rw)C(O)H, alkyl, alkenyl, quinil, halogen, -NO2, -CN, halogenoalkane, G1, -(CReRf)q-G1, -Y1-Y3, -Y1-(CReRf)q-Y3, -Y1-(CReRf)q-Y2-Y3and-Y1-(CReRf)q-Y2-(CReRf)q-Y3; or

A is formula (a)

where:

Vais C(R4), Vbis N or C(R5and Vcis N or

Vais N, Vbis C(R5and Vcis N or C(R6);

R4is hydrogen, halogen, alkyl, halogenation, -CN, -ORb, -SRb, -S(O)Rc, -S(O)2Rc, -N(Rb)(Rdor heterocycle,

R5is hydrogen, alkyl, halogen, halogenation, -CN, -ORb, -SRb, -S(O)Rc, -S(O)2Rc, aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycle;

R6is hydrogen, alkyl, halogen, halogenation, aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycle; or

R4and R5together with the carbon atoms to which the output they are attached, form a phenyl ring, which is optionally unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, halogen, -CN, -ORb, -SRband halogenoalkane;

R7is hydrogen, alkyl, halogen, -CN or halogenation;

G1is cycloalkyl, cycloalkenyl, heterocycle, heteroaryl or aryl;

Y1and Y2in each case, is each independently O, S, S(O), S(O)2N(Rw), -C(O), -OC(O)-, -N(Rw)C(O)-, -N(Rw)S(O)2-, -N(Rw)C(O)N(Rw)-, -OC(O)N(Rw)-, -N(Rw)C(O)O-, -C(O)O-, -C(O)N(Rw)- or-S(O)2N(Rw)-; where the right-hand side-OC(O)-, -N(Rw)C(O)-, -N(Rw)S(O)2-, -N(Rw)C(O)N(Rw)-, -OC(O)N(Rw)-, -N(Rw)C(O)O-, -C(O)O-, -C(O)N(Rw)- and-S(O)2N(Rw)fragments connected with -(CReRf)qor Y3;

Y3in each case, is independently hydrogen, alkyl, halogenation, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl or aryl;

r and s are independently 1 or 2;

X is the X1, -(CRkRm)u-X1-(CRkRm)u-C(O)-X2or-C(O)-X2,

X1in each case, is independently a heterocycle or heteroaryl;

X2in each case, is independent heteroaryl, heterocycle, -OR11, -N(Rw)(R3 ), -N(Rw)-(CRnRq)w-C(O)OR11, -N(Rw)-(CRnRq)w-OR11or-N(Rw)-(CRnRq)w-S(O)2R12;

R11in each case, is independently hydrogen, alkyl, halogenation, arylalkyl or heterogenisation;

R12in each case, is alkyl, halogenation, arylalkyl or heterogenisation where cycloalkenyl, cycloalkyl, heterocycle, heteroaryl, aryl, aryl fragment of arylalkyl and heteroaryl movie heteroallyl represented as G1, Y3X1X2, R4, R5, R6, R11and R12each optionally additionally substituted 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, quinil, halogen, oxo, Ethylenedioxy, methylenedioxy, -CN, -NO2, -OR1, -OC(O)(R2), -N(Rw)(R1), -N(Rw)C(O)(R1), -N(Rw)-C(O)O(R1), -N(Rw)-S(O)2(R2), -C(O)O(R1), -C(O)N(Rw)(R1), -C(O)R1, -SR1, -S(O)R2, -S(O)2R2, -S(O)2N(Rw)(R1), halogenoalkane, -(CRgRh)v-CN, -(CRgRh)v-NO2, -(CRgRh)v-OR1, -(CRgRh)v-OC(O)(R2), -(CRgRh)v-N(Rw)(R1), -(CRgRh)v-N(Rw)C(O)(R1gRh)v-N(Rw)C(O)O(R1) -(CRgRh)v-N(Rw)-S(O)2(R2), -(CRgRh)v-C(O)O(R1), -(CRgRh)v-C(O)N(Rw)(R1), -(CRgRh)v-C(O)R1, -(CRgRh)v-SR1, -(CRgRh)v-S(O)R2, -(CRgRh)v-S(O)2R2, -(CRgRh)v-S(O)2N(Rw)(R1and halogenoalkane;

q, t, u, v and w, in each case, is each independently 1, 2, 3, 4, 5 or 6;

R3is hydrogen, alkyl, halogenation, -OH, -S(O)2R1, -C(O)OR1, heterocycle or heteroaryl where heteroaryl connected to the nitrogen atom through a carbon atom of the ring, and the heterocycle and heteroaryl optionally additionally substituted with 1 or 2 substituents selected from the group consisting of alkyl, halogen, halogenoalkane, -C(O)OR1, -OR1and-N(Rw)(R1);

Rb, Rd, Rx, Ry, Rza, Rzb, Rw, Re, RgRh, Rk, Rm, Rn, Rqand R1in each case, are independently hydrogen, alkyl or halogenation;

Rcand R2in each case, are independently an alkyl or halogenation; and

Rfin each case, is independently hydrogen, alkyl, halogen, halogenation, -OH, -O(Ala the scrap) or-O(halogenation).

Another aspect of the invention provides methods of treating various diseases or conditions in a mammal, such as man, where these methods include administration to a mammal, nuzhdayushevia is disclosed here, the compound of the invention or its pharmaceutically acceptable salt or pharmaceutical composition comprising the described connection of the invention or salt compound and a pharmaceutically acceptable carrier. In another aspect, the invention provides methods for prevention or treatment of a disease or condition associated with elevated levels of lipids, such as lipid levels in plasma or elevated levels of triglycerides, a mammal suffering from such elevated levels. The invention also relates to new compounds with therapeutic ability to reduce lipid levels in a mammal, for example, levels of triglycerides. In an additional aspect, the invention provides pharmaceutical compositions comprising revealed here is the link of the invention, its pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier. In addition, the present invention provides various methods of treatment of various conditions in a patient, comprising the stage of introduction to the patient a pharmaceutical composition comprising the compound image is etenia, its pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier.

Detailed description of the invention

In the case of a variable that appears more than once in any Deputy, its definition in each case depends on its definition at every other case. Combinations of substituents allowed only if such combinations result in stable compounds. Stable compounds are compounds that can be selected with the desired degree of purity from a reaction mixture.

If not indicated otherwise, the following terms when used in the description and claims have the meanings specified below.

Used herein, the term "alkenyl" means a hydrocarbon with a linear or branched chain containing from 2 to 10 carbons and containing at least one double bond in the carbon-carbon formed in the removal of two hydrogens. Typical examples of alkenyl include, but are not limited to, ethynyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-Heptene and 3-decenyl.

Used herein, the term "alkyl" means a hydrocarbon with a linear or branched chain containing from 1 to 10 carbon atoms, preferably having from 1 to 6 carbon atoms. The term "lower alkyl" or "C-6 alkyl" means a hydrocarbon with a linear or branched chain containing from 1 to 6 carbon atoms. The term "C1-3alkyl" means a hydrocarbon with a linear or branched chain containing from 1 to 3 carbon atoms. Typical examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-etylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

The term "alkylene" denotes a divalent group derived from a hydrocarbon with a linear or branched chain containing from 1 to 10 carbon atoms. Typical examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- and-CH2CH(CH3)CH2-.

Used herein, the term "quinil" means a hydrocarbon group with a linear or branched chain containing from 2 to 10 carbon atoms and containing at least one triple bond of carbon-carbon. Typical examples of quinil include, but are not limited to, acetylenyl, 1-PROPYNYL, 2-PROPYNYL, 3-butynyl, 2-pentenyl and 1-butynyl.

Used herein, the term "aryl" means phenyl or bicyclic aryl. Bicyclic aryl is naphthyl or phenyl fused with Monaci the symbolic cycloalkyl or phenyl, condensed with a monocyclic cycloalkenyl. Phenyl and bicyclic aryl groups of the present invention are unsubstituted or substituted. Bicyclic aryl is connected with the main molecular fragment through any carbon atom contained within the bicyclic aryl. Typical examples of aryl groups include, but are not limited to, dihydroindeno, indenyl, naphthyl, dihydronaphthalene and 5,6,7,8-tetrahydronaphthalene.

Used herein, the term "arylalkyl" here means certain aryl group attached to the primary slice through certain there alkyl group.

Used herein, the term "cycloalkyl" or "cycloalkyl" means a monocyclic or bicyclic cycloalkyl. Monocyclic cycloalkyl has from three to eight carbon atoms and no heteroatoms and double bonds. Monocyclic cycloalkyl can be attached to the main molecular fragment through any capable of substitution atom contained within the monocyclic cycloalkyl. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Bicyclic cycloalkyl is a monocyclic cycloalkyl condensed with a monocyclic cycloalkyl or a monocyclic cycloalkyl, in which two nesmin the x carbon atoms, monocyclic cycloalkyl connected alkilinity bridge, consisting of one, two, three or four carbon atoms. Bicyclic cycloalkyl can be attached to the main molecular fragment through any capable of substitution atom contained in the ring of a bicyclic cycloalkyl and it may contain additional Allenby bridge, consisting of one, two, three or four carbon atoms connected to two non-adjacent carbon atoms (the same or different rings). Typical examples of bicyclic cycloalkyl include, but are not limited to, substituted. Monocyclic and bicyclic cycloalkyl group of the present invention can be unsubstituted or substituted.

Used herein, the term "cycloalkenyl" or "cycloalkyl" means a monocyclic or bicyclic hydrocarbon ring system. Monocyclic cycloalkenyl has four, five, six, seven, or eight carbon atoms and no heteroatoms. Four-membered ring systems have one double bond, five - or six-membered ring systems have one or two double bonds and seven - or eight-membered ring systems have one, two or three double bonds. Monocyclic cycloalkenyl can be attached to the main molecular fragment through any capable of substitution atom contained within the monocyclic cycloalkenyl. Type cnie examples of monocyclic cycloalkenyl groups include, but not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctanol. Bicyclic cycloalkenyl is a monocyclic cycloalkenyl condensed with a monocyclic cycloalkyl group or a monocyclic cycloalkenyl condensed with a monocyclic cycloalkenyl group or a monocyclic cycloalkenyl, in which two non-adjacent carbon atoms of the monocyclic cycloalkenyl connected alkilinity bridge of one, two, three or four carbon atoms. Bicyclic cycloalkenyl can be attached to the main molecular fragment through any capable of substitution atom contained in the bicyclic cycloalkenyl. Representative examples of bicyclic cycloalkenyl groups include, but are not limited to, 4,5,6,7-tetrahydro-3aH-inden, octahydronaphthalene and 1,6-dihydroindole. Monocyclic and bicyclic cycloalkenyl group of the present invention can be unsubstituted or substituted.

Used herein, the term "halogen" means-Cl, -Br, -I or-F.

Used herein, the term "halogenated" means certain higher alkyl group in which one, two, three, four, five or six hydrogen atoms are substituted with halogen. Typical examples of halogenoalkane include, but are not limited to, chloromethyl, deformity, 2-ft is ratil, trifluoromethyl, pentafluoroethyl and 2-chloro-3-terpencil.

Used herein, the term "heterocycle" or "heterocyclic" means a monocyclic heterocycle or the bicyclic heterocycle. Monocyclic heterocycle is a three-, four-, five-, six - or semiclean ring containing at least one heteroatom independently selected from the group consisting of O, N and S. the Three - or four-membered ring does not contain or contains one double bond and one heteroatom selected from the group consisting of O, N and S. the five-Membered ring does not contain or contains one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. the six-membered ring does not contain or contains one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. Semiline ring does not contain or contains one, two or three double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. the Monocyclic heterocycle is connected to the main molecular fragment through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Typical examples of monocyclic heterocycle include, but are not limited to, azetidine, azepane, aziridinyl, diazepan, 2,5-dihydro-1H-pyrazolyl (including 2,5-dihydro-1H-pyrazole-3-yl), 1,3-dioxane, 1,3-dioxolane is l, 1,3-dithiolane, 1,3-ditional, imidazolines, imidazolidinyl, isothiazolines, isothiazolinones, isoxazolyl, isoxazolidine, morpholine, oxadiazolyl, oxadiazolidine, oxazolines, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolyl, pyrazolidine, pyrrolidyl, pyrrolidinyl, tetrahydrofuranyl (including tetrahydrofuran-2-yl), tetrahydrofuranyl, tetrahydropyranyl (including tetrahydro-2H-Piran-2-yl, tetrahydro-2H-Piran-4-yl), thiadiazolyl, thiadiazolidine, thiazolyl, diazolidinyl, thiomorpholine, 1,1-dioxythiophene (thiomorpholine), tiopronin and tritional. The bicyclic heterocycle is a monocyclic heterocycle fused to the phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle. The bicyclic heterocycle is connected to the main molecular fragment through any carbon atom or a nitrogen atom contained in a bicyclic heterocycle. Monocyclic and the bicyclic heterocycle of the present invention can be unsubstituted or substituted. Representative examples of bicyclic heterocycle include, but are not limited to, 2,3-dihydro-1,4-benzodia inil (including 2,3-dihydro-1,4-benzodioxin-2-yl), 1,3-benzodithiol, benzopyranyl, benzothiophene, 2H-chromen-2-yl, 2H-chromen-3-yl, 2H-chromen-4-yl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-isoindole-2-yl, 2,3-dihydroindol-3-yl, 1,3-dioxo-1H-isoindolyl and 1,2,3,4-tetrahydroquinoline.

Used herein, the term "heteroaryl" means monocyclic heteroaryl or bicyclic heteroaryl. Monocyclic heteroaryl is a five - or six-membered ring. Five-membered ring contains two double bonds and one, two, three or four nitrogen atom and optionally one oxygen atom or one sulfur atom. Six-membered ring contains three double bonds and one, two, three or four nitrogen atom. Typical examples of monocyclic heteroaryl include, but are not limited to, furanyl (including furan-2-yl) imidazolyl, isoxazolyl (including isoxazol-3-yl), isothiazolin, oxadiazolyl, oxazolyl (including 1,3-oxazol-4-yl), pyridinyl (including pyridine-2-yl, pyridin-3-yl, pyridine-4-yl), pyridazinyl, pyrimidinyl, pyrazinyl (including pyrazin-2-yl), pyrazolyl (including 1H-pyrazole-3-yl, 1H-pyrazole-5-Il), pyrrolyl, tetrazolyl (including 2H-tetrazol-5-yl), thiadiazolyl, thiazolyl (including 1,3-thiazol-4-yl), thienyl (including Tien-2-yl), triazolyl (including 1,2,4-triazole-5-yl) and triazinyl. Bicyclic heteroaryl includes monocyclic heteroaryl condensed with phenyl, or monoc Klionsky heteroaryl, condensed with a monocyclic cycloalkyl, or monocyclic heteroaryl condensed with a monocyclic cycloalkenyl, or monocyclic heteroaryl condensed with a monocyclic heteroaryl or monocyclic heteroaryl condensed with a monocyclic heterocycle. Monocyclic and bicyclic heteroaryl groups of the present invention can be substituted or unsubstituted. Monocyclic and bicyclic heteroaryl connected to the main molecular fragment through any carbon atom or any nitrogen atom contained in the group. Representative examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothiazol, benzoxazolyl, benzimidazolyl, benzoxazolyl, 6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazoles, indolyl, isoindolyl, ethenolysis, naphthyridine, predominately, chinoline, thiazolo[5,4-b]pyridine-2-yl, thiazolo[5,4-d]pyrimidine-2-yl and 5,6,7,8-tetrahydroquinolin-5-yl.

Used herein, the term "heteroaromatic" means specified above heteroaryl group attached to the primary molecular fragment through a higher alkyl group.

Used herein, the term "heteroatom" means nitrogen atom, an oxygen atom or a sulfur atom.

The preferred value of alternating the groups in compounds of formula (I) are as follows. These values can be used where appropriate with any of the other values, definitions, claims or variants of implementation defined above or hereinafter in the description.

In one embodiment, Q is phenyl, unsubstituted or optionally substituted as described in the section "summary of the invention". In another embodiment, Q is a monocyclic heteroaryl, optionally additionally substituted as described in the section "summary of the invention". Example Q is pyridinyl. When Q is phenyl or 6-membered heteroaryl, it is preferable that A was in the 4-position of ring Q, relative to the point of attachment between Q and cycloalkenyl ring of formula (I).

Optional substituents Q, represented as T have the meanings described in the section "summary of the invention". For example, T is a halogen.

In an additional embodiment, A is phenyl, unsubstituted or optionally substituted as described in the section "summary of the invention". Alternatively, A is A 4-, 5-, 6 - or 7-membered monocyclic ring selected from the group consisting of heteroaryl and heterocycle, each of which is independently unsubstituted or optionally substituted as described in the section "summary of the invention".

In another the embodiment, A is 5 - or 6-membered monocyclic heteroaryl, unsubstituted or additionally substituted, as stated in the section "summary of the invention". Examples of A as heteroaryl rings include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolin, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. Preferably, A was pyrazolyl, triazolyl, thiazolyl, oxazolyl or pyrazinium. More preferably, A was pyrazolyl (for example, 1H-pyrazole-3-yl, 1H-pyrazole-5-yl) or triazolam (for example, 1,2,4-triazole-5-yl). In each example A is independently optionally unsubstituted or substituted as described in the section "summary of the invention".

In yet another embodiment, A is optionally substituted monocyclic heterocyclic ring. For example, A is optionally substituted 2,5-dihydro-1H-pyrazole-3-yl.

A can be unsubstituted or optionally substituted by 1, 2, 3, 4, or 5 substituents as described in the section "summary of the invention". Preferably, A was optionally substituted by 1, 2 or 3 substituents. Examples of the substituents A include, but are not limited to, oxo, N(Rw)C(O)H, halogen, alkyl (for example, C1-6 alkyl, such as methyl, ethyl, isopropyl, n-propyl, n-butyl and other similar alkali), halogenated (for example, C1-6halogenated, such as deformity or trifluoromethyl), -(CReRf)q-G1, -Y1-Y3, -Y1-(CReRf)q-Y3and-Y1-(CReRf)q-Y2-Y3.

In one embodiment, where A is substituted by -(CReRf)q-G1, q is 1 or 2, Reand Rfare hydrogen or alkyl, such as C1-6the alkyl (preferably, stands) and G1described in the section "summary of the invention". Preferably, Reand Rfwas the hydrogen and G1was cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), aryl (e.g. phenyl) or heteroaryl, such as, but not limited to, TuranAlem, imidazolium, isoxazolyl, isothiazolines, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinium, pyrazolyl, pirrallo, tetrazolium, thiadiazolyl, thiazolyl, teinila, triazolam and triazinyl, preferably, TuranAlem, where each G1is independently unsubstituted or optionally substituted as described in the section "summary of the invention". For example, G1is phenyl, cyclobutyl or TuranAlem, where each ring t is aetsa independently unsubstituted or optionally substituted, as described in the section "summary of the invention". Examples of the substituents on G1include, but are not limited to, alkyl (e.g. methyl, ethyl), halogen, halogenated (for example, deformity, trifluoromethyl and other similar halogenated) and-OR1(where R1is hydrogen, stands, ethyl, deformation or trifluoromethyl). Preferably, each G1was independently unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of trifloromethyl triptoreline.

In another embodiment, where A is replaced by-Y1-Y3, Y1is O, N(Rw), -N(Rw)C(O)-, -N(Rw)C(O)N(Rw)- or-C(O)O-, where the right side of fragments-N(Rw)C(O)- and-C(O)O - is connected to the Y3, Rwis hydrogen and Y3is hydrogen, alkyl, cycloalkyl, heteroaryl, such as furanyl, imidazolyl, isoxazolyl, isothiazolin, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl, heterocycle or aryl. Examples of Y include, but are not limited to, hydrogen, C1-6alkyl, cycloalkyl, furanyl, isoxazolyl, pyridinyl, phenyl or heterocycle, such as 2,3-dihydro-1,4-benzodioxin-2-yl, 2H-chromen-4-yl, tetrahydrofuranyl or tetrahydropyranyl. Preferably, Ysup> 3was hydrogen, stands, ethyl, adamantium, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydrofuranyl or tetrahydropyranyl. Each ring represented Y3is independently unsubstituted or optionally substituted as described in the section "summary of the invention". Examples of substituents for Y3include, but are not limited to, oxo, -OR1(where R1is hydrogen, C1-6the alkyl or C1-6halogenation), halogenated (for example, trifluoromethyl, deformity), halogen and alkyl, such as C1-6alkyl. In one embodiment, each ring represented Y3is independently unsubstituted or optionally substituted one, two or three substituents selected from the group consisting of oxo, -OH, -O(methyl), -O(ethyl), -O(deformity), -O(trifluoromethyl)diformate, trifloromethyl, Cl, Br, F, I, methyl and ethyl.

Additional variant of implementation refers to compounds where A is substituted for Y1-(CReRf)q-Y3, Y1is O, Reis hydrogen or alkyl, such as C1-6alkyl (preferably, methyl), Rfis hydrogen, alkyl, such as C1-6alkyl (preferably methyl) or-OH; q is 1, 2, 3 or 4, preferably, q is 1 or 2 and Y3is cycloalkyl a heterocycle, heteroaryl or aryl, each of which is independently unsubstituted or substituted as described in the section "summary of the invention". Examples Y3include, but are not limited to, adamantyl, C1-6cycloalkyl, heterocycle, heteroaryl, such as furanyl, imidazolyl, isoxazolyl, isothiazolin, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl or phenyl. Preferably, Y3was adamantium, phenyl, TuranAlem, pyridinyl, isoxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1,4-benzodioxin-2-yl, 2H-chromen-4-yl, tetrahydrofuranyl or tetrahydro-2H-piranian, where each ring can be unsubstituted or optionally substituted as described in the section "summary of the invention". Examples of substituents for Y3include, but are not limited to, oxo, -OR1(where R1is hydrogen, C1-6the alkyl or C1-6halogenation), halogenated (for example, C1-6halogenated, such as deformity, trifluoromethyl), halogen and alkyl, such as C1-6alkyl. For example, each ring represented Y3is independently unsubstituted or optionally substituted one, two or three substituents selected from groups who, consisting of oxo, -OH, -O(methyl), -O(ethyl), -O(deformity), -O(trifluoromethyl)diformate, trifloromethyl, Cl, Br, F, I, methyl and ethyl.

In another embodiment, where A is replaced by-Y1-(CReRf)q-Y2-Y3, q is 1, 2, 3 or 4, Reis hydrogen or alkyl, such as C1-6alkyl (preferably, methyl) and Rfis hydrogen, alkyl, such as C1-6alkyl (e.g. methyl) or-OH, Y1is O, Y2is O or C(O) and Y3is hydrogen, alkyl, such as C1-6alkyl, cycloalkyl, heterocycle, heteroaryl or aryl, each ring represented Y3is independently unsubstituted or substituted as described in the section "summary of the invention". Examples Y3include, but are not limited to, hydrogen, C1-6alkyl, adamantyl, C1-6cycloalkyl, heterocycle, heteroaryl, such as furanyl, imidazolyl, isoxazolyl, isothiazolin, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl or phenyl. Preferably, Y3was hydrogen, stands, ethyl, adamantium, phenyl, TuranAlem, pyridinyl, isoxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3-dihydro-1,4-benzodioxin-ILOM, 2H-chromen-4-yl, tetrahydrofuranyl or tetrahydro-2H-piranian, where each ring is independently unsubstituted or optionally substituted as described in the section "summary of the invention". Examples of substituents for Y3include, but are not limited to, oxo, -OR1(where R1is hydrogen, C1-6the alkyl or C1-6halogenation), halogenated (for example, C1-6halogenated, such as deformity, trifluoromethyl and other similar halogenated), halogen and alkyl, such as C1-6alkyl. Each ring represented Y3may be unsubstituted or substituted one, two or three substituents selected from the group consisting of oxo, -OH, -O(methyl), -O(ethyl), -O(deformity), -O(trifluoromethyl)diformate, trifloromethyl, Cl, Br, F, I, methyl and ethyl.

In one embodiment, A is unsubstituted.

In yet another embodiment, A is formula (a)

where VaVbVcand R7defined in section "summary of the invention". In one embodiment, Vais N, Vbis C(R5and Vcis C(R6). In another embodiment, Vais N, Vbis C(R5and Vcis N. In another embodiment, Vais C(R4), Vb is one who by C(R 5and Vcis N. Examples R4include, but are not limited to, hydrogen, and a heterocycle, such as morpholinyl. Examples R5include, but are not limited to, hydrogen, C1-6alkyl, such as methyl, -ORbsuch-OH and-O(C1-6alkyl), -SRb(where Rbis C1-6by alkyl such as methyl), aryl such as phenyl, heteroaryl, such as thienyl and cycloalkyl, such as cyclopropyl. Examples R6include, but are not limited to, hydrogen, and aryl, such as phenyl. Examples R7include, but are not limited to, hydrogen, and C1-6alkyl (e.g. methyl, ethyl). Alternatively, R4and R5together with the carbon atoms to which they are attached, form a phenyl ring, unsubstituted or substituted as described in the section "summary of the invention". Each of the aryl, cycloalkyl, heterocycle and heteroaryl for R4, R5and R6are independently optionally optionally substituted as described in the section "summary of the invention". Examples of optional substituents include, but are not limited to, C1-6alkyl (e.g. methyl), halogen, C1-6halogenated (for example, trifluoromethyl, deformity), OH, -O(methyl), -O(trifluoromethyl)- O(deformity).

Rx, Ry, Rzaand Rzbin each case, are independently hydrogen, alkyl or halogenated the m In one embodiment, Rx, Ry, Rzaand Rzbare hydrogen or C1-6the alkyl (for example, the stands). In another embodiment, Rzais hydrogen and Rx, Ryand Rzbare hydrogen or stands. In an additional embodiment, Rx, Ry, Rzaand Rzbare hydrogen.

r and s are independently 1 or 2. In one embodiment, r and s are 2. Accordingly, one alternative embodiment of the invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts,

where A, Q, Rx, Ry, X, Rzaand Rzbhave the meanings described in the section "summary of the invention" and "Detailed description of the invention".

X is the X1, -(CRkRm)u-X1, -(CRkRm)u-C(O)-X2or-C(O)-X2where Rk, Rm, u, X1and X2described in the section "summary of the invention".

In one embodiment, X is X1or -(CRkRm)u-X1where u, Rkand Rmand X1described in the section "summary of the invention". Preferably, u were 1 or 2. Rkand Rmin each case, are independently hydrogen, alkyl, such as C1-6alkyl or halogenation, such as C 1-6halogenated, preferably, Rkand Rmwas hydrogen or stands. X1is heteroaryl, such as furanyl, imidazolyl, isoxazolyl, isothiazolin, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. For example, X1is tetrazolium, oxazolium or oxadiazolyl (including 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl). Each ring represent X1is optionally substituted as described in the section "summary of the invention".

In another embodiment, X is -(CRkRm)u-C(O)-X2where u is 1 or 2, Rkand Rmin each case, are independently hydrogen, alkyl, such as C1-6alkyl (e.g. methyl) or halogenation, such as C1-6halogenated. Examples Rkand Rminclude, but are not limited to, hydrogen and methyl. Preferably, Rkand Rmwas hydrogen. X2is-OR11(where R11is hydrogen, C1-6the alkyl, C1-6halogenation, arylalkyl or heteroallyl, for example, R11is hydrogen, stands, ethyl, n-propylene, isopropyl, tert-bootrom, trifluoromethyl or benzyl), -N(Rw)-(CRnRq)w-C(O)OR 11(where Rw, Rnand Rqis each independently hydrogen or stands, w is 1 and R11is hydrogen, C1-6the alkyl, C1-6halogenation, arylalkyl or heteroallyl, for example, R11is hydrogen, stands, ethyl, n-propylene, isopropyl, tert-bootrom, trifluoromethyl or benzyl), heterocycle (such as pyrrolidinyl substituted by one Deputy, selected from the group consisting of-C(O)NH2and-C(O)OR1where R1is hydrogen, stands, ethyl, n-propylene, isopropyl or tert-bootrom) or-N(Rw)(R3) (where Rwis hydrogen or stands, R3is hydrogen, C1-6the alkyl, such as methyl, ethyl, n-propyl or isopropyl, -OH, heteroaryl, such as tetrazolyl, which is unsubstituted or substituted as described in the section "summary of the invention" or-S(O)2R1where R1is C1-6the alkyl, such as methyl, ethyl, n-propyl or isopropyl, preferably, R1was the stands.

In yet another embodiment, X is-CH2C(O)OH.

In another embodiment, X is-C(O)-X2where X2is-OR11and R11defined in section "summary of the invention". Examples R11include, but are not limited to, hydrogen, C1-6alkyl, such as methyl, who Tyl, n-propyl isopropyl and tert-butyl, arylalkyl, such as benzyl and heteroallyl. Preferably, R11was hydrogen.

In another embodiment, X is-C(O)-X2where X2is-N(Rw)(R3and Rwand R3described in the section "summary of the invention". Examples Rwand R3include, but are not limited to, hydrogen, and C1-6alkyl, such as methyl or ethyl.

It should be borne in mind that the scope of the present invention includes compounds of formula (I)with combinations of the above embodiments, including the preferred and more preferred options for implementation.

Accordingly, one aspect of the invention relates to compounds of formula (I) or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations of these, which are the compounds where X is -(CRkRm)u-C(O)-X2or C(O)-X2and u, Rk, RmX2A, Q, Rx, Ry, Rza, Rzb, r and s are described in the section "summary of the invention" and "Detailed description of the invention". Rkand Rmare, for example, independently hydrogen or C1-6the alkyl (for example, the stands). Preferably, u were 1 or 2. X2for example, is-OR11, heterocycle (unsubstituted or substituted as described in R. stele "the invention"), -N(Rw)(R3or-N(Rw)-(CRnRq)w-C(O)OR11where w is 1, Rw, Rnand Rqare each independently hydrogen or stands, R3is hydrogen, C1-6the alkyl, such as methyl, ethyl, n-propyl or isopropyl, -OH, heteroaryl (unsubstituted or substituted as described in the section "summary of the invention") or-S(O)2R1where R1is C1-6the alkyl and R11is hydrogen, C1-6the alkyl, C1-6halogenation, arylalkyl or heterogenisation. More preferably, u were 1 or 2, X2was-OR11, pyrrolidinyl (unsubstituted or substituted as described in the section "summary of the invention"), -N(Rw)(R3or-N(Rw)-(CRnRq)w-C(O)OR11where w is 1, Rw, Rnand Rqare each independently hydrogen or stands, R3is hydrogen, C1-6the alkyl, such as methyl or ethyl, -OH, tetrazolium (unsubstituted or substituted as described in the section "summary of the invention") or-S(O)2R1where R1is stands and R11is hydrogen, stands, ethyl, n-propylene, isopropyl, tert-bootrom or benzyl. In one embodiment, X is -(CRkRm)u-C(O)-X2or C(O)-X2where u is 1 or 2, Rkand R are independently hydrogen or stands and X2is-OR11where R11is hydrogen.

Another aspect of the invention relates to a group of compounds of formula (I) or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations of these, where X is -(CRkRm)u-C(O)-X2Q is phenyl, optionally substituted by 1, 2 or 3, T and u, Rk, RmX2, A, T, Rx, Ry, Rza, Rzb, r and s are described in the section "summary of the invention" and "Detailed description of the invention". For example, Q is phenyl, unsubstituted or substituted 1, 2 or 3 Halogens. Preferably, u were 1 or 2. Examples X2include, but are not limited to, -OR11, heterocycle (unsubstituted or substituted as described in the section "summary of the invention"), -N(Rw)(R3or-N(Rw)-(CRnRq)w-C(O)OR11where w is 1, Rw, Rnand Rqare each independently hydrogen or stands, R3is hydrogen, C1-6the alkyl, such as methyl, ethyl, n-propyl or isopropyl, -OH, heteroaryl (unsubstituted or substituted as described in the section "summary of the invention") or-S(O)2R1where R1is C1-6the alkyl and R11is hydrogen, C1-6the alkyl, C1-6halogenation, arylalkyl the m or heterogenisation. More preferably, u were 1 or 2, X2was-OR11, pyrrolidinyl (unsubstituted or substituted as described in the section "summary of the invention"), -N(Rw)(R3or-N(Rw)-(CRnRq)w-C(O)OR11where w is 1, Rw, Rnand Rqare each independently hydrogen or stands, R3is hydrogen, stands, ethyl, -OH, tetrazolium (unsubstituted or substituted as described in the section "summary of the invention") or-S(O)2R1where R1is stands and R11is hydrogen, stands, ethyl, n-propylene, isopropyl, tert-bootrom or benzyl. In one embodiment, X is -(CRkRm)u-C(O)-X2where u is 1 or 2, Rkand Rmare independently hydrogen or stands and X2is-OR11where R11is hydrogen.

Within this group of compounds, A, Rx, Ry, Rzaand Rzbdescribed in the section "summary of the invention" and "Detailed description of the invention". Examples Rx, Ry, Rzaand Rzbinclude, but are not limited to, hydrogen or C1-6alkyl (e.g. methyl). In one embodiment, A is optionally substituted phenyl. In another embodiment, A is optionally substituted monocyclic heterotic the practical ring. For example, A is optionally substituted 2,5-dihydro-1H-pyrazole-3-yl. In yet another embodiment, A is optionally substituted 5 - or 6-membered monocyclic heteroaryl. Examples of A as heteroaryl rings include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolin, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. Preferably, A was pyrazolyl, triazolyl, thiazolyl, oxazolyl or pyrazinium. More preferably, A was pyrazolyl or triazolyl. Each A is optionally additionally substituted as described above. In an additional embodiment, A is formula (a), where VaVbVcand R7defined in section "summary of the invention". In one embodiment, Vais N, Vbis C(R5and Vcis C(R6). In another embodiment, Vais N, Vbis C(R5and Vcis N. In another embodiment, Vais C(R4), Vbis C(R5and Vcis N. Examples R4include, but are not limited to, hydrogen, and a heterocycle, such as morpholinyl. Examples R5on the hunger but not limited to, hydrogen, C1-6alkyl, such as methyl, -ORbsuch as-OH and-O(C1-6alkyl), -SRb(where Rbis C1-6by alkyl such as methyl), aryl such as phenyl, heteroaryl, such as thienyl and cycloalkyl, such as cyclopropyl. Examples R6include, but are not limited to, hydrogen, and aryl, such as phenyl. Examples R7include, but are not limited to, hydrogen, and C1-6alkyl (e.g. methyl, ethyl). Alternatively, R4and R5together with the carbon atoms to which they are attached, form a phenyl ring, unsubstituted or substituted as described in the section "summary of the invention". Each of the aryl, cycloalkyl, heterocycle and heteroaryl for R4, R5and R6are independently optionally optionally substituted as described in the section "summary of the invention" and "Detailed description of the invention".

From this group of compounds, examples of a subgroup include compounds where r is 2 and s is 2.

From this group of compounds, examples of a subgroup include compounds where r is 2 and s is 1.

From this group of compounds, examples of a subgroup include compounds where r is 1 and s is 2.

In another aspect of the invention provides compounds of formula (I) or their pharmaceutically acceptable salts, prodrugs, salts about is learning about your medicine or combinations thereof, where X is -(CRkRm)u-C(O)-X2, Q is a monocyclic heteroaryl, optionally additionally substituted with 1, 2 or 3 substituents represented by T and u, Rk, RmX2, A, T, Rx, Ry, Rza, Rzb, r and s are described in the section "summary of the invention" and "Detailed description of the invention". For example, Q is a pyridinyl, unsubstituted or optionally substituted by 1, 2 or 3 Halogens. Rkand Rmare, for example, independently hydrogen or C1-6the alkyl (for example, the stands). Preferably, u were 1 or 2. Examples X2include, but are not limited to, -OR11, heterocycle (unsubstituted or substituted as described in the section "summary of the invention"), -N(Rw)(R3or-N(Rw)-(CRnRq)w-C(O)OR11where w is 1, Rw, Rnand Rqare independently hydrogen or stands, R3is hydrogen, C1-6the alkyl, such as methyl, ethyl, n-propyl or isopropyl, -OH, heteroaryl (unsubstituted or substituted as described in the section "summary of the invention") or-S(O)2R1where R1is C1-6the alkyl and R11is hydrogen, C1-6the alkyl, C1-6halogenation, arylalkyl or heterogenisation. More preferably, u were 1 or 2, X2was-OR11 , pyrrolidinyl (unsubstituted or substituted as described in the section "summary of the invention"), -N(Rw)(R3or-N(Rw)-(CRnRq)w-C(O)OR11where w is 1, Rw, Rnand Rqare independently hydrogen or stands, R3is hydrogen, stands, ethyl, -OH, tetrazolium (unsubstituted or substituted as described in the section "summary of the invention") or-S(O)2R1where R1is stands and R11is hydrogen, stands, ethyl, n-propylene, isopropyl, tert-bootrom or benzyl. In one embodiment, X is -(CRkRm)u-C(O)-X2where u is 1 or 2, Rkand Rmare independently hydrogen or stands and X2is-OR11where R11is hydrogen.

Within this group of compounds, A, Rx, Ry, Rzaand Rzbdefined in section "summary of the invention". Examples Rx, Ry, Rzaand Rzbinclude, but are not limited to, hydrogen or C1-6alkyl (e.g. methyl). In one embodiment, A is optionally substituted phenyl. In another embodiment, A is optionally substituted monocyclic heterocyclic ring. For example, A is optionally substituted 2,5-dihydro-1H-pyrazole-3-yl. In yet another variant implementation of the population, A is optionally substituted 5 - or 6-membered monocyclic heteroaryl. Examples of A as heteroaryl rings include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolin, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. Preferably, A was pyrazolyl, triazolyl, thiazolyl, oxazolyl or pyrazinium. More preferably, A was pyrazolyl or triazolyl. Each A is optionally additionally substituted as described in the section "summary of the invention" and "Detailed description of the invention". In an additional embodiment, A is formula (a), where VaVbVcand R7defined in section "summary of the invention". In one embodiment, Vais N, Vbis C(R5and Vcis C(R6). In another embodiment, Vais N, Vbis C(R5and Vcis N. In another embodiment, Vais C(R4), Vbis C(R5and Vcis N. Examples R4include, but are not limited to, hydrogen, and a heterocycle, such as morpholinyl. Examples R5include, but are not limited to, hydrogen,C 1-6alkyl, such as methyl, -ORbsuch as-OH and-O(C1-6alkyl), -SRb(where Rbis C1-6by alkyl such as methyl), aryl such as phenyl, heteroaryl, such as thienyl and cycloalkyl, such as cyclopropyl. Examples R6include, but are not limited to, hydrogen, and aryl, such as phenyl. Examples R7include, but are not limited to, hydrogen, and C1-6alkyl (e.g. methyl, ethyl). Alternatively, R4and R5together with the carbon atoms to which they are attached, form a phenyl ring, unsubstituted or substituted as described in the section "summary of the invention". Each of the aryl, cycloalkyl, heterocycle and heteroaryl for R4, R5and R6are independently optionally optionally substituted as described in the section "summary of the invention" and "Detailed description of the invention".

From this group of compounds, examples of a subgroup include compounds where r is 2 and s is 2.

From this group of compounds, examples of a subgroup include compounds where r is 2 and s is 1.

From this group of compounds, examples of a subgroup include compounds where r is 1 and s is 2.

Another aspect of the invention provides compounds of formula (I), where X is-C(O)-X2Q is phenyl, optionally additionally substituted with 1, 2 or 3 T and X 2, r, s, T, Rx, Ry, Rza, Rzband A described in the section "summary of the invention" and "Detailed description of the invention". For example, Q is phenyl, unsubstituted or substituted 1, 2 or 3 Halogens. For example, X2is-OR11or N(Rw)(R3), where R11, Rwand R3disclosed in the section "summary of the invention" and "Detailed description of the invention". Examples R11include, but are not limited to, hydrogen, C1-6alkyl, such as methyl, ethyl, n-propyl, isopropyl and tert-butyl or arylalkyl, such as benzyl. Preferably, R11was hydrogen. Examples Rwand R3include, but are not limited to, hydrogen, and C1-6alkyl, such as, but not limited to, methyl and ethyl.

Within this group of compounds, A, Rx, Ry, Rzaand Rzbdefined in section "summary of the invention". Examples Rx, Ry, Rzaand Rzbinclude, but are not limited to, hydrogen or C1-6alkyl (e.g. methyl). In one embodiment, A is optionally substituted phenyl. In another embodiment, A is optionally substituted monocyclic heterocyclic ring. For example, A is optionally substituted 2,5-dihydro-1H-pyrazole-3-yl. In yet another embodiment, A is optional for emenim 5 - or 6-membered monocyclic heteroaryl. Examples of A as heteroaryl rings include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolin, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. Preferably, A was pyrazolyl, triazolyl, thiazolyl, oxazolyl or pyrazinium. More preferably, A was pyrazolyl or triazolyl. Each A is optionally additionally substituted as described in the section "summary of the invention" and "Detailed description of the invention". In an additional embodiment, A is formula (a), where VaVbVcand R7defined in section "summary of the invention". In one embodiment, Vais N, Vbis C(R5and Vcis C(R6). In another embodiment, Vais N, Vbis C(R5and Vcis N. In another embodiment, Vais C(R4), Vbis C(R5and Vcis N. Examples R4include, but are not limited to, hydrogen, and a heterocycle, such as morpholinyl. Examples R5include, but are not limited to, hydrogen, C1-6alkyl, such as methyl, -ORbsuch as-OH and-O(C1-6alkyl), -SRb bis C1-6by alkyl such as methyl), aryl such as phenyl, heteroaryl, such as thienyl and cycloalkyl, such as cyclopropyl. Examples R6include, but are not limited to, hydrogen, and aryl, such as phenyl. Examples R7include, but are not limited to, hydrogen, and C1-6alkyl (e.g. methyl, ethyl). Alternatively, R4and R5together with the carbon atoms to which they are attached, form a phenyl ring, unsubstituted or substituted as described in the section "summary of the invention". Each of the aryl, cycloalkyl, heterocycle and heteroaryl for R4, R5and R6is independently optionally optionally substituted as described in the section "summary of the invention" and "Detailed description of the invention".

From this group of compounds, examples of a subgroup include compounds where r is 2 and s is 2.

From this group of compounds, examples of a subgroup include compounds where r is 2 and s is 1.

From this group of compounds, examples of a subgroup include compounds where r is 1 and s is 2.

In another aspect of the invention provides compounds of formula (I) or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, where X is-C(O)-X2, Q is a monocyclic heteroaryl, optionally substituted 1, ili 3 substituents, introducing the T and X2, A, T, Rx, Ry, Rza, Rzb, r and s are described in the section "summary of the invention" and "Detailed description of the invention". For example, Q is a pyridinyl, unsubstituted or substituted 1, 2 or 3 Halogens. For example, X2is-OR11or N(Rw)(R3), where R11, Rwand R3disclosed in the section "summary of the invention" and "Detailed description of the invention". Examples R11include, but are not limited to, hydrogen, C1-6alkyl, such as methyl, ethyl, n-propyl, isopropyl or tert-butyl or arylalkyl, such as benzyl. Preferably, R11was hydrogen. Examples Rwand R3include, but are not limited to, hydrogen, and C1-6alkyl, such as, but not limited to, methyl and ethyl.

Within this group of compounds, A, Rx, Ry, Rzaand Rzbdefined in section "summary of the invention". Examples Rx, Ry, Rzaand Rzbinclude, but are not limited to, hydrogen or C1-6alkyl (e.g. methyl). In one embodiment, A is optionally substituted phenyl. In another embodiment, A is optionally substituted monocyclic heterocyclic ring. For example, A is optionally substituted 2,5-dihydro-1H-pyrazole-3-yl. In yet another variant domestic who, A is optionally substituted 5 - or 6-membered monocyclic heteroaryl. Examples of A as heteroaryl rings include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolin, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. Preferably, A was pyrazolyl, triazolyl, thiazolyl, oxazolyl or pyrazinium. More preferably, A was pyrazolyl or triazolyl. Each A is optionally additionally substituted as described in the section "summary of the invention" and "Detailed description of the invention". In an additional embodiment, A is formula (a), where VaVbVcand R7defined in section "summary of the invention". In one embodiment, Vais N, Vbis C(R5and Vcis C(R6). In another embodiment, Vais N, Vbis C(R5and Vcis N. In another embodiment, Vais C(R4), Vbis C(R5and Vcis N. Examples R4include, but are not limited to, hydrogen, and a heterocycle, such as morpholinyl. Examples R5include, but are not limited to, hydrogen, C 1-6alkyl, such as methyl, -ORbsuch as-OH and-O(C1-6alkyl), -SRb(where Rbis C1-6by alkyl such as methyl), aryl such as phenyl, heteroaryl, such as thienyl and cycloalkyl, such as cyclopropyl. Examples R6include, but are not limited to, hydrogen, and aryl, such as phenyl. Examples R7include, but are not limited to, hydrogen, and C1-6alkyl (e.g. methyl, ethyl). Alternatively, R4and R5together with the carbon atoms to which they are attached, form a phenyl ring, unsubstituted or substituted as described in the section "summary of the invention". Each of the aryl, cycloalkyl, heterocycle and heteroaryl for R4, R5and R6is independently optionally optionally substituted as described in the section "summary of the invention" and "Detailed description of the invention".

From this group of compounds, examples of a subgroup include compounds where r is 2 and s is 2.

From this group of compounds, examples of a subgroup include compounds where r is 2 and s is 1.

From this group of compounds, examples of a subgroup include compounds where r is 1 and s is 2.

An additional aspect of the invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, where A, Q, T, Rx, Ry, Rza, Rzband X in the formula (Ia) described in formula (I). One variant of implementation relates to compounds of formula (Ia), where Q is phenyl. Such compounds can exist as CIS-isomers or TRANS isomers. Therefore, one alternative embodiment of the invention relates to TRANS-isomers represented by the formula (Ib), it should be borne in mind that the structural formula (Ib) includes not only one TRANS-isomer represented by the formula (Ib), but also other TRANS-isomers (for example, (Ic)) and mixtures thereof including racemates).

where p is 0, 1, 2 or 3 and A, T, Rx, Ry, Rza, Rzband X in the formula (Ib) and (Ic) are described in the formula (I). It should be borne in mind that embodiments of variables and combinations of embodiments, including the preferred and more preferred embodiments of described in the formula (I)also apply to compounds of formula (Ia), (Ib) and (Ic).

Thus, examples of the group of compounds having the formula (Ia) or (Ib) or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof include compounds where X is -(CRkRm)u-C(O)-X2or C(O)-X2and u, T, Rk, RmX2, A, Rx, Ry, Rzaand Rzbdescribed in the section "summary of the invention" section and the "Detailed description of the invention". For example, T is a halogen. Preferably, u were 1 or 2. Rk, Rm, Rx, Ry, Rzaand Rzbare, for example, each independently hydrogen or C1-6the alkyl (for example, the stands). Examples X2include, but are not limited to, -OR11, heterocycle (unsubstituted or substituted as described in the section "summary of the invention"), -N(Rw)(R3and-N(Rw)-(CRnRq)w-C(O)OR11where w is 1, Rw, Rnand Rqare each independently hydrogen or stands, R3is hydrogen, C1-6the alkyl, such as, but not limited to, stands, ethyl, n-propylene or isopropyl, -OH, heteroaryl (unsubstituted or substituted as described in the section "summary of the invention") or-S(O)2R1where R1is C1-6by alkyl; and R11is hydrogen, C1-6the alkyl, C1-6halogenation, arylalkyl or heterogenisation. More preferably, u were 1 or 2, X2was-OR11, pyrrolidinyl (unsubstituted or substituted as described in the section "summary of the invention"), -N(Rw)(R3or-N(Rw)-(CRnRq)w-C(O)OR11where w is 1, Rw, Rnand Rqare each independently hydrogen or stands, R3is hydrogen, C1-6the alkyl, so the AK, but not limited to, methyl, ethyl, n-propyl or isopropyl, -OH, tetrazolium (unsubstituted or substituted as described in the section "summary of the invention") or-S(O)2R1where R1is stands and R11is hydrogen, stands, ethyl, n-propylene-isopropyl, tert-bootrom or benzyl. In one embodiment, X is -(CRkRm)u-C(O)-X2or C(O)-X2where u is 1 or 2, Rkand Rmare independently hydrogen or stands and X2is-OR11where R11is hydrogen.

Within this group, compounds of formula (Ia) or (Ib), examples of a subgroup include compounds where a is a phenyl, optionally substituted as described in the section "summary of the invention" and "Detailed description of the invention".

Examples of another subgroup include compounds where A is optionally substituted 5 - or 6-membered monocyclic heteroaryl ring. Examples of monocyclic heteroaryl ring and its optional substituents described in the section "summary of the invention" and "Detailed description of the invention".

Examples of another subgroup include compounds where A is optionally substituted 5 - or 6-membered monocyclic heterocyclic ring. Examples of monocyclic heterocyclic ring and its optional is part of the substituents described in the section "summary of the invention" and "Detailed description of the invention".

Examples of another subgroup include compounds where A is formula (a), where VaVbVcand R7described in the section "summary of the invention" and "Detailed description of the invention". In one embodiment, Vais N, Vbis C(R5and Vcis C(R6). In another embodiment, Vais N, Vbis C(R5and Vcis N. In another embodiment, Vais C(R4), Vbis C(R5and Vcis N. Examples R4include, but are not limited to, hydrogen, and a heterocycle, such as morpholinyl. Examples R5include, but are not limited to, hydrogen, C1-6alkyl, such as methyl, -ORbsuch as-OH and-O(C1-6alkyl), -SRb(where Rbis C1-6by alkyl such as methyl), aryl such as phenyl, heteroaryl, such as thienyl, and cycloalkyl, such as cyclopropyl. Examples R6include, but are not limited to, hydrogen, and aryl, such as phenyl. Examples R7include, but are not limited to, hydrogen, and C1-6alkyl (e.g. methyl, ethyl). Alternatively, R4and R5together with the carbon atoms to which they are attached, form a phenyl ring, unsubstituted or substituted as described in the section "summary of the invention". Each of the aryl, the CEC is of valkila, heterocycle and heteroaryl for R4, R5and R6is independently optionally optionally substituted as described in the section "summary of the invention" and "Detailed description of the invention".

Another aspect of the present invention relates to compounds of formula (I), where A is formula (a), Q is phenyl, r and s are 2. Accordingly, one alternative implementation of the present invention provides compounds of formula (II) or their pharmaceutically acceptable salts

where p is 0, 1, 2 or 3 and VaVbVc, R7, T, Rx, Ry, Rza, Rzband X are described in the section "summary of the invention" and "Detailed description of the invention for formula (I). It should be borne in mind that such compounds can exist in the form or CIS - or TRANS-isomers. One variant of implementation refers to the TRANS-isomer of such compounds represented by formula (IIa). It should be borne in mind that the structural formula (IIa) includes not only one TRANS-isomer represented by the formula (IIa), but also other TRANS-isomers (for example, (IIb)) and mixtures thereof (including the racemate).

where p is 0, 1, 2 or 3 and VaVbVc, R7, T, Rx, Ry, Rza, Rzband X in the formula (IIa) and (IIb) described in formula (I). Should have the mean what options exercise of VaVbVc, R7, T, Rx, Ry, Rza, Rzband X and combinations of embodiments, including the preferred and more preferred embodiments of described in the formula (I)also include compounds of formula (II), (IIa) and (IIb).

Accordingly, examples of the group of compounds having the formula (II) or (IIa) or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, are compounds where X is -(CRkRm)u-C(O)-X2or C(O)-X2and u, Rk, RmX2VaVbVc, R7, Rx, Ry, Rzaand Rzbdescribed in the section "summary of the invention" and "Detailed description of the invention". For example, R7, Rx, Ry, Rzaand Rzbare each independently hydrogen or C1-6the alkyl (for example, the stands). T, for example, is a halogen. Preferably, u were 1 or 2. Examples X2include-OR11, heterocycle (unsubstituted or substituted as described in the section "summary of the invention"), -N(Rw)(R3and-N(Rw)-(CRnRq)w-C(O)OR11where w is 1, Rw, Rnand Rqare each independently hydrogen or stands, R3is hydrogen, C1-6the alkyl, such as, but without whom ograniczenia, methyl, ethyl, n-propyl or isopropyl, -OH, heteroaryl (unsubstituted or substituted as described in the section "summary of the invention") or-S(O)2R1where R1is C1-6the alkyl and R11is hydrogen, C1-6the alkyl, C1-6halogenation, arylalkyl or heterogenisation. More preferably, u were 1 or 2, X2was-OR11, pyrrolidinyl (unsubstituted or substituted as described in the section "summary of the invention"), -N(Rw)(R3or-N(Rw)-(CRnRq)w-C(O)OR11where w is 1, Rw, Rnand Rqare each independently hydrogen or stands, R3is hydrogen, C1-6the alkyl, such as, but not limited to, methyl, ethyl, n-propyl or isopropyl, -OH, tetrazolium (unsubstituted or substituted as described in the section "summary of the invention") or-S(O)2R1where R1is stands and R11is hydrogen, stands, ethyl, n-propylene, isopropyl, tert-bootrom or benzyl. In one embodiment, X is -(CRkRm)u-C(O)-X2or C(O)-X2where u is 1 or 2, Rkand Rmare independently hydrogen or stands and X2is-OR11where R11is hydrogen.

Examples of another group of compounds of formula (II) or (IIa) include the response where X is -(CRkRm)u-X1where Rk, Rmu and X1described in the section "summary of the invention" and "Detailed description of the invention". For example, Rkand Rmare hydrogen. For example, u is 1 or 2. X1is, for example, optionally substituted heteroaryl, such as, but not limited to, optionally substituted 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl. Examples of optional substituents X1described in the section "Detailed description of the invention".

Within these two groups of compounds of formula (II) or (IIa), examples of a subgroup include compounds where Vais N, Vbis C(R5and Vcis C(R6), where R5and R6have the meanings given in the section "summary of the invention" and "Detailed description of the invention".

Examples of another subgroup include compounds where Vais N, Vbis C(R5and Vcis N, where R5has the values defined in the section "summary of the invention" and "Detailed description of the invention".

Another examples of a subgroup include compounds where Vais C(R4), Vbis C(R5and Vcis N, where R4and R5have the meanings given in the section "summary of the invention" and "Detailed description of what subramania".

Examples of compounds include, but are not limited to, the following connections:

TRANS [4-(4-{3-[2-(1-substituted)-2-hydroxyethoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid;

TRANS [4-(4-{3-[2-(1-substituted)-2-oksidoksi]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid;

TRANS [4-(4-{3-[2-(4-methoxyphenyl)-2-oksidoksi]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid;

TRANS {4-[4-(3-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl} acetic acid;

TRANS {4-[4-(3-{[5-(trifluoromethyl)-2-furyl]methoxy}-4-{[5-(trifluoromethyl)-2-furyl]methyl}-1H-pyrazole-5-yl)phenyl]-cyclohexyl}acetic acid;

TRANS {4-[4-(4-[2-(triptoreline)benzyl]-3-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;

TRANS (4-{4-[3-(cyclohexylmethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS {4-[4-(3-{[3-(triptoreline)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;

TRANS {4-[4-(3-{[5-(trifluoromethyl)-2-furyl]methoxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;

TRANS (4-{4-[3-(3-phenoxypropane)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS (4-{4-[3-(4-phenoxyethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS (4-{4-[3-(2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS {4-[4-(3-{[2-(deformedarse)benzyl]OK and}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;

TRANS (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS (4-{4-[3-(cyclobutylmethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS (4-{4-[3-(cyclohexyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS (4-{4-[3-(tetrahydro-2H-Piran-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS ethyl [4-(4-{3-[2-(1-substituted)-2-oksidoksi]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetate;

TRANS (4-{4-[5-(cyclobutylmethyl)-1-(cyclobutylmethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetic acid;

TRANS (4-{4-[3-(benzyloxy)-1H-pyrazole-5-yl]phenyl}cyclo-hexyl)acetic acid;

TRANS (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS {4-[4-(3-{[4-(trifluoromethyl)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;

TRANS [4-(4-{3-[(5-methylisoxazol-3-yl)methoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid;

TRANS {4-[4-(1H-1,2,4-triazole-5-yl)phenyl]cyclohexyl}acetic acid;

TRANS [4-(4-{5-[(5-methylisoxazol-3-yl)methoxy]-1-[(5-methylisoxazol-3-yl)methyl]-1H-pyrazole-3-yl}phenyl)cyclohexyl]acetic acid;

TRANS N-methyl-N-[(4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetyl]glycine;

TRANS (4-{4-[3-(cyclobutylamine)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS (4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}is illogical)acetic acid;

TRANS (4-{4-[3-(cyclopropylmethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS 2-(4-{4-[3-(cyclohexylmethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)-N-hydroxyacetamido ;

TRANS (4-{4-[3-(pyridine-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS (4-4-[3-(tetrahydrofuran-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS (4-{4-[4-bromo-3-(cyclobutylmethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS-N-hydroxy-2-(4-{4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)ndimethylacetamide;

TRANS-N-(methylsulphonyl)-2-(4-{4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)ndimethylacetamide;

TRANS 1-({4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetyl)-L-Proline;

TRANS {4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetic acid;

TRANS (4-{4-[4-bromo-3-(cyclopropylmethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS ethyl [4-(4-{3-[2-(1-substituted)-2-hydroxyethoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetate;

TRANS methyl N-methyl-N-[(4-{4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetyl]glycinate;

TRANS [4-(4-{3-[(6,7-dimethoxy-2-oxo-2H-chromen-4-yl)methoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid;

TRANS N-2H-tetrazol-5-yl-2-(4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)ndimethylacetamide;

TRANS methyl {4-[4-(3-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohex the l}acetate;

TRANS ethyl 5-{4-[4-(2-ethoxy-2-oxoethyl)cyclohexyl]phenyl}-1H-pyrazole-3-carboxylate;

TRANS [4-(4-{3-[(2-hydroxycyclohexyl)oxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid;

TRANS {4-[4-(3-hydroxy-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;

TRANS methyl (4-{4-[3-(cyclohexyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;

TRANS [4-(4-{2-[(3-methoxyphenyl)amino]-1,3-thiazol-4-yl}phenyl)cyclohexyl]acetic acid;

TRANS ethyl (4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetate;

TRANS 2-methyl-N-[(4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetyl]alanine;

TRANS {4-[4-(4-ethyl-1-methyl-1H-pyrazole-3-yl)phenyl]cyclohexyl}acetic acid;

TRANS (4-{4-[3-(tetrahydro-2H-Piran-4-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS (4-{4-[4-bromo-3-(tetrahydro-2H-Piran-4-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS {4-[4-(2-{[2-(trifluoromethyl)phenyl]amino}-1,3-thiazol-4-yl)phenyl]cyclohexyl}acetic acid;

TRANS [4-(4-{2-[(3,5-dichlorophenyl)amino]-1,3-thiazol-4-yl}phenyl)cyclohexyl]acetic acid;

TRANS methyl (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;

TRANS ethyl {4-[4-(3-{[5-(trifluoromethyl)-2-furyl]methoxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetate;

TRANS [4-(4-{2-[(2-chlorophenyl)amino]-1,3-thiazol-4-yl}phenyl)cyclohexyl]acetic acid;

TRANS (4-{4[l,2-bis(cyclobutylmethyl)-5-oxo-2,5-dihydro-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetic acid;

TRANS {4-[4-(2-{[3-(trifluoromethyl)phenyl]amino}-1,3-thiazol-4-yl)phenyl]cyclohexyl}acetic acid;

TRANS methyl (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;

TRANS ethyl (4-{4-[3-(2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;

TRANS methyl 1-({4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetyl)-L-prolinate have been obtained;

TRANS [4-(4-{2-[(2-were)amino]-1,3-thiazol-4-yl}phenyl)cyclohexyl]acetic acid;

TRANS [4-(4-{2-[(4-chlorophenyl)amino]-1,3-thiazol-4-yl}phenyl)cyclohexyl]acetic acid;

TRANS [4-(4-{2-[(3-chlorophenyl)amino]-1,3-thiazol-4-yl}phenyl)cyclohexyl]acetic acid;

TRANS ethyl (4-{4-[3-(pyridine-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;

TRANS ethyl (4-{4-[3-(tetrahydrofuran-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;

TRANS (4-{4-[3-(tetrahydro-2H-Piran-4-yloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;

TRANS ethyl (4-{4-[2-(formylamino)-1,3-oxazol-4-yl]phenyl}cyclohexyl)acetate;

TRANS 1-({4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetyl)L prolinamide;

TRANS ethyl (4-{4-[3-(cyclohexylmethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;

TRANS tert-butyl 2-methyl-N-[(4-{4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetyl]alanine;

TRANS (4-{4-[2-(formylamino)-1,3-oxazol-4-yl]phenyl}cyclohexyl)acetic acid;

TRANS [4-(4-{2-[(2-forfinal)amino]-1,3-thiazole-4-the l}phenyl)cyclohexyl]acetic acid;

TRANS ethyl {4-[4-(4-bromo-3-{[(2R)-3-hydroxy-2-methyl-propyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetate;

[4-(4'-hydroxy-1,1'-biphenyl-4-yl)cyclohexyl]acetic acid;

(4-{4'-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1,1'-biphenyl-4-yl}cyclohexyl)acetic acid;

[4-(4-pyrazin-2-ylphenyl)cyclohexyl]acetic acid;

(4-(4-[5-(trifluoromethyl)-1H-1,2,4-triazole-3-yl]phenyl}cyclohexyl)acetic acid;

3-(4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)propionic acid;

2-{4-[4-(1H-1,2,4-triazole-3-yl)phenyl]cyclohexyl}propionic acid;

TRANS {4-[4-(7-amino-3-phenylpyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;

{4-[4-(7-amino-5-methyl - [l,2,4]triazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;

TRANS (4-{4-[7-amino-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine-6-yl]phenyl}cyclohexyl)acetic acid;

TRANS {4-[4-(7-amino-2-Tien-2-alprazola[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;

TRANS {4-[4-(7-amino-2-cyclopropylethanol[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;

TRANS {4-[4-(7-amino[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;

TRANS ethyl {4-[4-(5-aminoimidazo[1,2-a]pyrimidine-6-yl)-phenyl]cyclohexyl}acetate;

TRANS (4-{4-[7-amino-2-(4-forfinal)pyrazolo[1,5-a]-pyrimidine-6-yl]phenyl}cyclohexyl)acetic acid;

TRANS {4-[4-(7-amino-2-methylp Rotolo[1,5-a]pyrimidine-6-yl)-phenyl]cyclohexyl}acetic acid;

TRANS {4-[4-(7-amino-2-hydroxypyrazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;

TRANS 2-{4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}-N-methylacetamide;

TRANS 2-{4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}ndimethylacetamide;

TRANS {4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;

{4-[5-(5-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-3-yl)pyridine-2-yl]cyclohexyl}acetic acid;

TRANS {4-[4-(7-amino-5-methylpyrazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;

TRANS 3-({4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}methyl)-1,2,4-oxadiazol-5(4H)-he; and

TRANS-5-({4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}methyl)-1,3,4-oxadiazol-2(3H)-he.

Disclosed here are the links may contain asimmetricheskii substituted carbon atoms or sulfur and, therefore, may exist and be isolated in the form of an individual stereoisomer (e.g., individual enantiomer or of an individual diastereoisomer), mixtures of stereoisomers (e.g., any mixture of enantiomers or diastereomers) or their racemic mixtures. Individual optically active forms of the compounds can be obtained, for example, by synthesis from optically active starting materials, by chiral synthesis, by enzymatic selection by biota is farmacii or by chromatographic separation. It should be borne in mind that the scope of the present invention includes any racemic, optically active, stereoisomeric form, or mixtures thereof in various proportions, which has the property of inhibiting the activity of DGAT-1. When the stereochemistry of the chiral centers present in illustrated here chemical structures is not specified, it is assumed that the chemical structure includes compounds containing any stereoisomer of each chiral center present in the connection.

In these compounds may be present geometric isomers. The invention includes various geometric isomers and mixtures thereof resulting from the placement of substituents around the double bond carbon-carbon cycloalkyl group or geteroseksualnoe group. Substituents around the double bond carbon-carbon is called the Z or E configuration, and Vice-around cycloalkyl or geterotsiklicheskie referred to as CIS - or TRANS-configuration.

In the framework of the present invention it should be borne in mind that the compound of formula (I), (Ia), (Ib), (Ic), (II), (IIa) and (IIb) can exhibit the phenomenon of tautomerism and that the structural formula of this description can only represent one of the possible tautomeric forms. It should be borne in mind that the invention encompasses any tautomeric form and it is not due shall be limited to only any one tautomeric form, used the title compounds or their image in the form of structural formulas.

Methods synthesis

It is expected that this invention includes compounds of the invention obtained by synthetic methods or by metabolic processes. Obtaining compounds of the invention as a result of metabolic processes includes processes occurring in the body of a person or animal (in vivo) or the processes occurring in vitro.

The synthesis of compounds of formula (I), (Ia), (Ib), (Ic), (II), (IIa) or (IIb), where group VaVbVc, Q, A, Ra, Rx, Ry, Rza, Rzb, Rw, Re, Rf, r, s, T, X, Y1, Y2, Y3and q have the meanings given in the section "summary of the invention", if not specified otherwise, are illustrated by examples of schemes 1-9. When used in the descriptions of the schemes and examples, it is assumed that the specific abbreviations have the following meanings: CDI for carbonyldiimidazole, DMSO for dimethyl sulfoxide, Et for ethyl, TBTU for tetrafluoroborate O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea, MeOH for methanol RP-HPLC to preparative high performance liquid chromatography reverse phase.

The compounds of formula (I), where A is optionally substituted by Piazolla, can be obtained by the General methods shown in scheme 1.

Scheme 1

The condensation of the compounds (1), where R101is hydrogen, halogen or alkyl, with reagents of the formula C(OCH3)(OCH3)(N(CH3)2)(R102), where R102is hydrogen or alkyl, at elevated temperatures (for example, about 60°C to 110°C) in a solvent such as, but not limited to, N,N-dimethylformamide, provides intermediate compounds of the formula (2), where R103is N(CH3)2.

Alternatively, intermediate compounds of formula (1), where R101is Racan interact with allermuir reagent of formula R102C(O)Z, where Z is O-alkyl, and R102is alkyl and substrate at a temperature of from about room temperature to 100°C, with the formation of intermediate compounds of the formula (2), where R103is OH. The reaction can be carried out in a solvent such as, but not limited to, toluene, or methyl tertiary butyl ether. Non-limiting examples of bases suitable for the implementation of the reaction, include trebuchet potassium and sodium ethylate.

Intermediate compounds of formula (2), where R103is OH or N(CH3)2when communicating with a hydrazine of the formula NH2N(H)(R104or its salts, where R104is hydrogen, alkyl or phenyl, in a solvent such as, but not limited to, acetic kislota 1,4-dioxane, at a temperature of from about 35°C to 100°C, to give the compounds of formula (3), where R104connected to one of the nitrogen atoms. Non-limiting examples of hydrazine powered reagents include hydrazine, methylhydrazine and phenylhydrazine.

Scheme 2

Scheme 2 illustrates the synthesis of compounds of General formula (I), where A is optionally substituted by Piazolla and one of Rais the-O-Y3, -O-(CReRf)q-Y3, -O-(CReRf)q-Y2-Y3or-O-(CReRf)q-Y2-(CReRf)q-Y3and the other represented by R104is hydrogen, alkyl or phenyl.

The interaction of compounds of the formula (4) with oxalylamino in the presence of aluminium chloride in a solvent such as, but not limited to, dichloromethane, at a temperature from about 0°C to room temperature gives the compounds of formula (5).

The compounds of formula (5) can be converted into compounds of the formula (6), where R105is alkyl, as a result of interaction with an equivalent amount of acetate, such as, but not limited to, ethylmalonate magnesium or (trimethylsilyl)ethylmalonate, in the presence of a base such as, but not limited to, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), at a temperature from about 0°C to room temperature in a solvent such is AK, but not limited to, acetonitrile.

The compounds of formula (6) can be converted into compounds of formula (7), where R104connected to one of the nitrogen atoms in the ring, when using the reaction conditions for the conversion of compound (2) compound (3)described in scheme 1.

When interacting with an alkylating reagent of the formula R106X3where R106is Y3, -(CReRf)q-Y3, -(CReRf)q-Y2-Y3or -(CReRf)q-Y2-(CReRf)q-Y3and X3is a leaving group such as, but not limited to, halide, triptorelin, methanesulfonate, p-toluensulfonate or bansilalpet, in the main reaction conditions and optionally in the presence of 18-crown-6 in a solvent such as, but not limited to N,N-dimethylformamide, at a temperature from about room temperature to 180°C, the compounds of formula (7) can be converted into compounds of the formula (8). Non-limiting examples of bases include inorganic bases such as potassium carbonate or sodium carbonate and cesium hydride, potassium or sodium. The reaction can be carried out in a microwave oven.

Alternatively, the conversion of compound (7) compound (8) can also be carried out in the presence of a metal catalyst, such as, but unlimited, metallic copper, CuI or palladium acetate, optionally in the presence of a ligand such as, but not limited to, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or three-tert-butylphosphine and optionally in the presence of a base such as, but not limited to, pyridine, triethylamine, trebuchet sodium, cesium carbonate or sodium hydride. The reaction is usually carried out at a temperature from about room temperature to 180°C in a solvent such as, but not limited to, toluene or N,N-dimethylformamide.

The compounds of formula (7) may also interact with alkilany alcohol under the conditions of the Mitsonobu reaction by joining arylphosphine, such as, but not limited to, triphenylphosphine, with azodicarbonamide reagent, such as, but not limited to, diethylazodicarboxylate at a temperature of from about 70°C to 100°C with the formation of compounds of the formula (8), where R106is alkyl. The reaction can be carried out in a solvent such as, but not limited to, toluene or dichloromethane.

Compounds of General formula (I), where A is optionally substituted by oxazolyl or optionally substituted thiazolium, can be obtained using the General method depicted in scheme 3.

Scheme 3

As shown in scheme 3, compounds of formula (1), where R101is I, Br or Cl, can be evaluation of goty condensation with timeonline formula R 106N(H)C(=S)NH2where R106is Y3, -(CReRf)q-Y3, -(CReRf)q-Y2-Y3or -(CReRf)q-Y2-(CReRf)q-Y3at a temperature of from about 70°C to 100°C with the formation of compounds of the formula (9). The reaction can be carried out in a solvent such as, but not limited to, ethanol.

The compounds of formula (9) can be alkylated in the compounds of formula (10) with the help of many synthetic methods known from the literature for organic synthesis. For example, compound (9) can be converted into a compound (10) in the presence of a suitable base and a reagent of formula RwX3where X3is a leaving group such as, but not limited to, halide, triftorbyenzola, methanesulfonate, p-toluensulfonate or bansilalpet, at room or elevated temperature.

The compounds of formula (1), where R101is I, Br and Cl, may also interact with urea in N,N-dimethylformamide at a temperature from about 35°C to 100°C with the formation of compounds of the formula (11).

Compounds of General formula (I), where A is optionally substituted by triazolyl, can be obtained using the General methods shown in scheme 4.

Scheme 4

The intermediate form is s (5) can be converted into amides of formula (12) in collaboration with ammonium hydroxide (or other sources of ammonia, such as gaseous ammonia or ammonia in an appropriate solvent) at room temperature. Amides of the formula (12) can be subjected to condensation with reagents of the formula C(OCH3)(OCH3)(N(CH3)2)(R102), where R102is hydrogen or alkyl (for example, dimethylformamide by dimethylacetal or 1,1-dimethoxy-N,N-dimethylethanamine) at elevated temperatures (e.g., from 70°C to 100°C) to obtain the intermediate compounds of formula (13). The reaction can be carried out in a solvent such as, but not limited to, N,N-dimethylformamide.

When interacting with hydrazines of the formula NH2N(H)(R104), where R104is hydrogen, alkyl or phenyl, intermediate compounds of formula (13) can be transformed into compounds (14) under the reaction conditions described for the conversion of compound (2) compound (3) in scheme 1.

Scheme 5

As shown in scheme 5, the intermediate compounds of formula (15), where R107is hydrogen, halogen, benzyloxy, alkoxy or protected hydroxy, can interact with homologation reagent in a solvent such as, but not limited to, tetrahydrofuran, N,N-dimethylformamide or dioxane, at a temperature from about room temperature up to 75°C, with the formation of intermediate compounds form the crystals (16), where X2is-O(alkyl) or-O(arylalkyl). Non-limiting examples homologizing reagents include trimethylphosphate and metiltiofosfonata. Intermediate compounds of formula (16) can be gidrirovanny gaseous hydrogen at high pressure in the presence of catalysts, such as, but not limited to, palladium on charcoal, in a solvent such as, but not limited to, ethanol or ethyl acetate, to obtain the compounds of formula (17). The reaction is usually carried out at room temperature or at elevated temperatures.

Intermediate compounds of formula (17), where R107is hydrogen, can be subjected to interaction with aluminium chloride and allermuir reagent of formula R101CH2C(O)Z, where R101is hydrogen or Raand Z is halogen, in a solvent such as, but not limited to, dichloromethane and at a temperature from about 0°C to room temperature to obtain the intermediate compounds of formula (18). Non-limiting examples alleluya reagents include acetylchloride, butyrylcholine, 2-phenylacetylene and other similar substances.

Intermediate compounds of formula (17) or (18), where X2is-O(alkyl) or-O(arylalkyl) (e.g. benzyl), can be converted into a compound where X2is OH, by the acid is whether alkaline hydrolysis or by hydrogenation. This transformation is well known to specialists in this field. One example of alkaline hydrolysis is the use of lithium hydroxide or sodium.

The conversion of these acids into the corresponding amides can be converted by means of combination reaction with the appropriate amine. Standard conditions for the reaction of the combination is also known to any expert in this field. One such condition is the initial conversion of the acid into an activated ester, for example, by reacting the acid with N-hydroxysuccinimide or the hydrochloride of N-(3-dimethylamino-propyl)-N'-ethylcarbodiimide and a base, such as N-methylmorpholine, in a solvent such as dichloromethane and without isolating the activated ester by its subsequent interaction with amines of the formula where X2is N(H)(Rw)(R3), N(H)(Rw)-(CRnRq)w-C(O)OR11N(H)(Rw)-(CRnRq)w-OR11or N(H)(Rw-(CRnRq)w-S(O)2R11. These manipulations can also be carried out after introducing A different group.

Scheme 6

As shown in scheme 6, the intermediate compounds of formula (15), where R107is hydrogen, halogen, benzyloxy, alkoxy or protected hydroxy, can interact with homology is the missing reagent, such as (methoxymethyl)triphenyl-phosphonylated, in the presence of a base such as, but not limited to, n-utility, with the formation of intermediate compounds of formula (19). The reaction is usually conducted in a solvent such as, but not limited to, tetrahydrofuran, and at temperatures from about -78°C to 75°C. the Intermediate compounds of formula (19) can be subjected to contact with an aqueous acid solution, such as, but not limited to, hydrochloric acid, to obtain the intermediate compounds of formula (20) at temperatures from about room temperature to 90°C. the Intermediate compounds of formula (20), where R107is hydrogen, halogen, benzyloxy, alkoxy or protected hydroxy, can be converted into compounds of formula (22), where X2is-O(alkyl) or-O(arylalkyl) under the reaction conditions described for the conversion of compound (15) in the compound (17) in scheme 5.

The compounds of formula (23), where R101is hydrogen or Racan be obtained from compounds (22), where R107is hydrogen, by the reaction conditions described in scheme 5. Acids or amides of compounds of formula (22) or (23), where X2is OH, N(H)(Rw)(R3), N(H)(Rw)-(CRnRq)w-C(O)OR11N(H)(Rw)-(CRnRq)wOR11or N(H)(Rw)-(CRnR q)w-S(O)2R11can be obtained when the reaction conditions shown in scheme 5.

Scheme 7

Intermediate compounds of formula (24), where R107is halogen or triflate (obtained from the corresponding alcohol), can be transformed into intermediate compounds of formula (24), where R107is bronovil ether or Bronevoy acid, by interacting with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) in the presence of a palladium catalyst and base. Non-limiting examples of solvents include dioxane and tetrahydrofuran, and non-limiting examples of bases include potassium acetate, potassium carbonate, potassium fluoride, and other similar reasons. Can be used for more phosphine reagents. These intermediate compounds can then be subjected to interaction with reagents of the formula A-R108where R108is halogen, triflate or tosylate, under the conditions of the Suzuki reaction to obtain compounds of formula (25). It should also be borne in mind that the compounds of formula (25) can be obtained by the reaction of a combination of compounds (24), where R107is halogen, triflate or tosylate, with A-R108where R108is Bronevoy acid or baronowie esters (many of which are produced in industry is, or can be obtained from the corresponding above triflate or halide), under the conditions of the Suzuki reaction.

Alternatively, the compounds of formula (24), where R107is a halide or triflate, can be turned into stannane formula (24), where R107is-Sn(alkyl)3by interaction with hexadecyldimethylamine formula (alkyl)3Sn)2in the presence of a palladium source such as tetrakis-(triphenylphosphine)palladium(0). Alternatively, stannane formula (24) can be obtained by exchanging the metal-halogen in the compounds of formula (24), where R107is bromide, n-butyllithium at a temperature of about -78°C followed by reaction with a halide of anti-at a temperature of from about -78°C to room temperature in a solvent such as tetrahydrofuran. Stannane formula (24), where R107is-Sn(alkyl)3, can then be subjected to interaction with A-R108where R108is a halide, triflate or tosylate, in the presence of a palladium source such as Tris(dibenzylidineacetone)dipalladium, tetrakis(triphenylphosphine)palladium(0) and optionally in the presence of a ligand such as tri(2-furyl)phosphine or triphenylarsine, to obtain the compounds of formula (25). It should be borne in mind that a similar transformation can be carried out by reacting compounds of the formula (24), where R107is a halide, triple the om or tosylate, with A-R108where R108is-Sn(alkyl)3under the above reaction conditions. Reagents of formula A-R108where R108is-Sn(alkyl)3can also be produced in industry or received from the corresponding halides or triflates in the above-mentioned similar reaction conditions.

Scheme 8

Scheme 8 shows the synthesis of compounds of General formula (I), where A is formula (a) and R7is hydrogen or alkyl.

The compounds of formula (5) can be converted into compounds of formula (26) when interacting with a reducing agent, such as, but not limited to, sodium borohydride at room temperature in a solvent such as, but not limited to, tetrahydrofuran. The compounds of formula (29) can be subjected to interaction with an activating reagent, such as, but not limited to, methansulfonate and trichromacy phosphorus in alkaline conditions, in a solvent such as, but not limited to, dichloromethane, at a temperature of from about zero degrees to room temperature. The activated intermediate compound may be converted into compounds of formula (27) when communicating with a source of cyanide, such as, but not limited to, tetrabutylammonium, in a solvent such as, but not limited to, N,N-di is malformed, at temperatures from about room temperature to 50°C.

The condensation of compounds (27) with reagents of the formula C(OCH3)(OCH3)(N(CH3)2)(R102), where R102is hydrogen or alkyl, at elevated temperatures (for example, about 60°C to 110°C), in a solvent such as, but not limited to, N,N-dimethylformamide, provides intermediate compounds of formula (28), where R103is N(CH3)2.

Alternatively, intermediate compounds of formula (27) can interact with allermuir reagent of formula R102C(O)Z, where Z is O-alkyl, and R102is alkyl and a base at a temperature from about room temperature to 100°C with intermediate compounds of formula (28), where R103is OH. The reaction can be carried out in a solvent such as, but not limited to, toluene, or methyl tertiary butyl ether. Non-limiting examples of bases suitable for transformation include trebuchet potassium and sodium ethylate.

Intermediate compounds of formula (28), where R103is OH or N(CH3)2when communicating with laminirovannyy a heterocycle of formula (i) (for example, aminopyrazoles, aminotriazoles and aminobenzimidazole), in a solvent such as, but not limited to, acetic acid, and 1,4-dioxane, at a temperature of from about 35°C to 100 is C, give the compounds of formula (29).

Scheme 9

The compounds of formula (30) can interact with the compounds of the formula (31), where Z1and Z2are both either hydrogen or alkyl, or Z1and Z2together are-C(CH3)2-C(CH3)2in the presence of palladium catalyst, such as, but not limited to, Pd(II) acetate in the presence of a base such as, but not limited to, phosphate and potassium in the system of mixed solvent containing water and an organic solvent, such as, but not limited to, dioxane. The reaction can be carried out at elevated temperatures, from about 70 to 110°C. the Intermediate compounds of formula (32) can be gidrirovanny gaseous hydrogen at high pressure in the presence of catalysts, such as, but not limited to, palladium on charcoal, in a solvent such as, but not limited to, ethanol or ethyl acetate, to obtain the compounds of formula (33). The reaction is usually carried out at room temperature or at elevated temperatures.

The compounds of formula (33) can be converted into compounds of formula (34) in collaboration with ether of the formula R109OC(O)C(R101)(H)C(O)O(alkyl), where R109is alkyl or aryl, R101is hydrogen, alkyl, aryl or alkoxy, and base, such as, but is e limited litigationrelated and in a solvent such as, but not limited to, tetrahydrofuran. The reaction is usually carried out at a temperature of about -78°C and then warmed to room temperature.

The compounds of formula (34) can be converted into compounds of formula (35), where R111connected to one of the nitrogen atoms in the ring, when the reaction conditions for the conversion of compound (2) compound (3)described in scheme 1.

The compounds of formula (35) can be converted into compounds of formula (36) by reacting with an alkylating reagent of the formula R106X3where R112is Y3, -(CReRf)q-Y3, -(CReRf)q-Y2-Y3or -(CReRf)q-Y2-(CReRf)q-Y3and X3is a leaving group such as, but not limited to, halide, triptorelin, methanesulfonate, p-toluensulfonate or bansilalpet, when the main reaction conditions and optionally in the presence of 18-crown-6, in a solvent such as, but not limited to, N,N-dimethylformamide, at a temperature from about room temperature to 180°C. non-limiting examples of bases include inorganic bases such as potassium carbonate or sodium carbonate and cesium hydride potassium sodium. The reaction can also be carried out in a microwave oven.

With the unity of formula (36) can be converted into compounds of formula (37) in collaboration with Lewis acid and a system of mixed aqueous solvent, containing water and a solvent, such as, but not limited to, methanol, and at temperatures of from about 50 to 100°C. alternatively, compound (36) can be converted into compounds (37) by stirring in aqueous mixtures of acids, such as, but not limited to, aqueous HCl, at elevated temperatures.

Using the reaction conditions discussed in schemes 5 and 6, the compounds of formula (37) can be transformed into compounds of formula (38), where X2is-OH, N(H)(Rw)(R3), N(H)(Rw)-(CRnRq)w-C(O)OR11N(H)(Rw-(CRnRq)w-OR11or N(H)(Rw)-(CRnRq)w-S(O)2R11.

Optimal reaction conditions and reaction times for each stage can depend on the applicable preferred reagents and substituents present in the used reagents. Unless otherwise noted, solvents, temperatures and other reaction conditions may readily be selected by any conventional expert in this field. Specific methods are provided in the examples section syntheses. The reaction products can stand out with the use of traditional methods, for example by removing the solvent from the residue and further purification in accordance with techniques well known in the art, such as, but not limited to, crystallization, recti acacia, extraction grinding into powder and chromatography. Unless stated otherwise, starting materials and reagents or produced in industry, or can be obtained by any expert in this field of manufacture in the industry of materials using the methods described in the chemical literature.

The methodology of the experiments, including the appropriate mode of reaction conditions, reagents and the sequence of synthesis, protection of any chemical functionality, which may not be compatible with the reaction conditions, and the removal of protection at the right moment, the sequence of implementation of the reactions of the method are included in the scope of the invention. Suitable protective groups and methods of protection and unprotect different substituents, for which use such suitable protective groups are well known to specialists in this area; examples of which can be found in the monograph by T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rded.), John Wiley & Sons, NY (1999), the contents of which is given here by reference. The synthesis of compounds of the present invention can be carried out by methods that are similar to the methods described in the above schemes of synthesis in the specific examples.

Source materials if they are not issued by the industry, can be obtained by methods selected from the standard IU the odik organic synthesis, which are similar to the synthesis of known, structurally similar compounds, or techniques which are analogous to the methods described above schemes or techniques described in the examples section synthesis.

When you want optically active form of compounds of the invention, it can be obtained by implementing one of the methods described here by using optically active starting material (obtained, for example, by asymmetric induction of a suitable reaction stage), or by separating a mixture of stereoisomers of the compound or intermediates using a standard method (such as chromatographic separation, recrystallization or enzymatic separation).

Similarly, when the required compounds of the invention, they can be obtained by implementing one of the methods described herein, through the use of pure geometric isomer as a starting material or by separation of a mixture of geometric isomers of the compound or intermediates using a standard method such as chromatographic separation.

It should be borne in mind that the scheme syntheses and specific examples, see the examples of synthesis are only illustrative and are not to be considered as limitations of the scope of what bretania, which is defined by the attached claims. All alternatives, modifications and equivalents of the methods of synthesis and specific examples are included in the scope of the claims.

Biological data

Inhibition of DGAT-1

Identification of the compounds of the invention as inhibitors of DGAT-1 was reached quickly using high-throughput screening as a result of analysis on the tablet FlashPlate. In this analysis received recombinant human DGAT-1, containing the end of the N-terminal His6-epitope, in the expression system of baculovirus. Of insect cells (such as Sf9 or High Five) were infected during the time from 24 to 72 hours and collected by centrifugation. Precipitation cells resuspendable in the buffer for homogenization [250 mm sucrose, 10 mm Tris-HCl (pH of 7.4), 1 mm EDTA] and literally by setting for homogenization, such as fluidization Micro fluidizer (single-pass, 4°C). Cellular debris was removed by centrifugation at 10000×g for 30 minutes and collected microsomal membranes by centrifugation at 100000×g for 30 minutes.

The activity of DGAT-1 was determined as follows. Used in the analysis buffer [20 mm HEPES (pH 7.5), 2 mm MgCl2, 0,04% BSA]containing 50 μm of enzyme substrate (decanoylamino) and 7.5 μm radiolabelled acyl-CoA substrate [1-14C]decanoyl-CoA)was added in each is well phospholipid tablet FlashPlate (Perkin Elmer Life Sciences). To initiate the reaction, was added to a small aliquot of membranes (1 μg/well) and then reaction was performed for 60 minutes. The reaction was stopped by adding an equal volume (100 ál) of isopropanol. The tablets covered, incubated overnight and read the next morning on the scintillation tablet reader TopCount (PerkinElmer Life Science). Received radiolabelled tridecanoate (triapin) is mainly associated with hydrophobic phospholipid coating on the tablet FlashPlate. The proximity of the radiolabelled product to the solid scintillator entered in the lower part of the tablet FlashPlate, induced fluorescence from the scintillator, which was measured in the tablet reader TopCount. Different concentrations (for example, of 0.0001 μm to 0.001 μm, 0.01 µm, 0.1 ám, and 1.0 ám to 10.0 ám) typical compounds of the invention were added to specific wells before the addition of membranes. The efficiency of inhibition of DGAT-1 for the compounds of the present invention was determined by calculating the values of the IC50defined as the concentration of the inhibitor of the sigmoidal curve "dose-effect", in which the activity of the enzyme is inhibited by 50%. Compounds of the present invention were effective in the inhibition of the activity of DGAT-1 and therefore they can be used as therapeutic agents for the treatment comprising the s and diseases connected with the activity of DGAT-1.

td align="left"> 9,76121
Table 1
Inhibition of DGAT-1 typical compounds of the present invention(IC50μm)
0,0090,010,018220,046210,04853
0,048770,058370,06140,076240,08328
0,091870,118170,126580,148110,19452
0,21290,217960,22270,237640,25735
0,277790,307430,419020,430,45694
0,53490,662210,706730,732390,76144
0,784740,804720,875340,9934 0,92475
0,961941,173541,183771,272511,28722
1,367151,482641,67512,173732,21226
2,397562,510593,190254,27264,53091
4,660034,777265,047155,079585,11289
5,161785,162145,352925,894375,90296
6,040166,125516,239096,676936,76644
7,347,737,792437,9127,94302
8,032498,580218,952479,492259,64461
9,694629,944644,820,0569
0,07060,5150,3530,5240,0396
4,2100,09490,5976,2300,0452
0,02110,0100,21100,01900,014
0,0170

To estimate the effects of the compounds on the reduction of body weight of the mice with dietary obesity

The purpose of this Protocol was to determine the validity of long-term administration of compounds on body weight and other parameters of the metabolic disorders in mice with induced obesity as a result of any unlimited consumption of a diet high in fat. Alimentary obesity (DIO) in rodents mimics key aspects of obesity in humans and metabolic syndrome. It was shown that used in this study DIO mice are hyperinsulinemic and insulin resistant, hyperl phenemine and leptinresistance and have expressed visceral obesity (as a review in DIO mice, see Collins et al, Physiol. Behav. 81:243-248, 2004).

Separately contained in the cells of male C57BL/6J were given unlimited access to water and or diet with a low fat diet (D12450B) or a diet with a high fat diet (D12492, containing 60% kcal from fat, both diet company Research Diets Inc., New Brunswick, NJ), for approximately 18 weeks. The mice were injected imitation dose once a day used in the study of medicinal environment for 7 days before the introduction of the active doses, so they are accustomed to the corresponding manipulation and oral probe. One day prior to the dose of active compound, the mice were divided into groups with equal average body weight and the amount of deviation. A typical experiment consisted of 80-100 animals, 10 animals per dose, including the group of animals with a diet low in fat and high in fat, which was injected drug the environment. Body weight and absorption of food was measured by differential weighing.

Typical compounds of the invention generally injected in doses of 3, 10 or 30 mg/kg orally twice daily in the form of a dosage form in 1% Tween 80 in water and believed that the compounds are active when there has been a statistically significant decrease in body weight in exposed therapy animals after a period of therapy for at least seven days, against the control animals sustained fashion, which was introduced media. In this model, typical compounds caused a statistically significant decrease in body weight after a period of therapy for at least seven days, relative to control animals, which were injected media.

The levels of triglycerides in the liver in DIO-mice subjected to treatment by the compounds of the invention are typically administered at doses of 3, 10 or 30 mg/kg orally twice daily in the form of a dosage form in 1% Tween 80 in water for a period of therapy, at least seven days was measured in the ethanol extracts in liver samples using reagents Infinity™ (Thermo Electron Corporation, Louisville, CO, USA). Typical compounds of the invention gave a statistically significant decrease in the level of triglycerides in the liver in DIO mice after a period of therapy for at least seven days, relative to control animals, which were injected drug the environment.

Measured the levels of triglycerides in plasma in DIO-mice subjected to treatment by the compounds of the invention are typically administered at doses of 3, 10 or 30 mg/kg orally twice daily in the form of a dosage form in 1% Tween 80 in water for a period of therapy, at least seven days. 50 μl of the United plasma sample animals subjected to the treatment drug, was loaded into a column of Superose 6 PC 3.2/30 (Amersham Biosciences) and separated into fractions of lipoprotein with the use of the Finance system SMART FPLC (Pfizer) at a flow rate during elution of 40 µl/min in the movable buffer, containing 0.15 M NaCl and 0.05 M sodium phosphate, pH 7.0. Collected fractions of 40 ml and was determined by the content of triglycerides using a set of enzymatic analysis (Infinity). Typical compounds of the invention caused a statistically significant decrease in triglycerides fraction lipoprotein very low density (VLDL) lipoprotein profile in DIO mice after a period of therapy for at least seven days, relative to control animals, which were injected drug the environment.

At the end of the study was also conducted test of tolerance to insulin in DIO mice after a 4 hour fast. Carried out monitoring of glucose levels in the blood through the incision at the tail up and 30 minute intervals after a single intraperitoneally injection of 0.25 U/kg insulin (Humulin R, Lilly) using the monitor glucose levels Precision PCx (Abbott Laboratories, Abbott Park, IL). Typical compounds of the invention caused a statistically significant decrease in the concentration of blood glucose in animals after a period of therapy for at least seven days, relative to control animals, which were injected drug the environment.

In DIO-mice also assessed the effect of the joint introduction of typical compounds of the invention with rimonabant. Compounds of the invention generally injected in doses of 3, 10 or 30 mg/kg orally twice daily in the form of a dosage form B1% Tween 80 in water and rimonabant usually together was administered in doses of 1 or 3 mg/kg oral daily dosage forms in 1% Tween 80 in water. Compounds were considered active if they significantly lowered body weight or significantly reduced the content of triglycerides compared to DIO-mice, which were injected only rimonabant. In this model, typical compounds caused a statistically significant decrease in body weight or significantly reduced the concentration of triglycerides and/or caused a statistically significant decrease in the concentration of triglycerides after a period of therapy for at least seven days, relative to control animals, which were introduced only rimonabant.

In DIO-mice also assessed the effect of the joint introduction of typical compounds of the invention with sibutramine. Compounds of the invention generally injected in doses of 3, 10 or 30 mg/kg orally twice daily in the form of a dosage form in 1% Tween 80 in water and sibutramine is usually together was administered in doses of 3 or 5 mg/kg orally twice daily in the form of a dosage form in 1% Tween 80 in water. Compounds were considered active if they significantly lowered body weight or significantly reduced the content of triglycerides compared to DIO-mice, which were injected only sibutramine. In this model, typical compounds caused a statistically significant decrease in body weight and/or a statistically significant decrease in the concentration of triglycerides after a period of therapy for at least seven days, otnositel the control animals, which was introduced only sibutramine.

In DIO-mice also assessed the effect of the joint introduction of typical compounds of the invention with fenofibrate. Compounds of the invention generally injected in doses of 3, 10 or 30 mg/kg orally twice daily in the form of a dosage form in 1% Tween 80 in water and phenobarbital usually together was administered at a dose of 100 mg/kg orally twice daily in the form of a dosage form in 1% Tween 80 in water. Compounds were considered active if they significantly reduced the content of triglycerides compared to DIO-mice, which were injected only fenofibrate. In this model, typical compounds caused a statistically significant decrease in the concentration of triglycerides after a period of therapy for at least seven days, relative to control animals, which were introduced only fenofibrate.

Compounds of the present invention and their pharmaceutically acceptable salts can be used as therapeutic agents. Accordingly, a variant implementation of the invention includes a method of treating various conditions of the patient, if necessary (including mammals), which includes the introduction of the indicated patient a pharmaceutical composition comprising an amount of a compound of the present invention, which is effective in the treatment of this condition or its pharmaceutical is Eski acceptable salt, together with a pharmaceutically acceptable carrier.

Another aspect of the present invention provides a method of treatment or prevention of various conditions in a patient (such as a mammal and preferably, human), which are mediated by DGAT-1, which includes an introduction to the specified patient compounds of the present invention or its pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, or pharmaceutical compositions comprising them.

Another aspect of the present invention provides methods for preventing or treating obesity and inducing weight loss in a patient, which includes the introduction of a specified patient compounds of the invention or pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof. The invention also provides a method of prophylaxis or treatment of obesity and inducing weight loss in a patient, which includes the introduction of the indicated patient a pharmaceutical composition comprising a compound of the invention, its pharmaceutically acceptable salt, prodrug, salt of a prodrug, or combination thereof in an amount that is effective in the treatment of obesity or to induce weight loss and a pharmaceutically acceptable carrier. Another aspect of the invention provides a method of preventing an increase in the mass t is La patient by injection, at least one compound of the invention or pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, in an amount that is sufficient to prevent weight gain.

The present invention also relates to the use of compounds of the invention for the treatment of obesity-related diseases, including concomitant dyslipidemia and others associated with obesity and overweight complications, such as cholesterol gallstones, gallbladder disease, gout, cancer (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gall bladder and bile duct), menstrual disorders, infertility, polycystic ovaries, osteoarthritis and sleep apnea during sleep, as well as for a number of other pharmaceutical applications, for example, with the regulation of appetite and food intake, dyslipidemia, hypertriglyceridemia, metabolic syndrome or syndrome X, type 2 diabetes (leisureservices diabetes), atherosclerotic diseases such as heart failure, hyperlipidemia, hypercholesterolemia, low levels of alpha high density lipoprotein, hypertension, cardiovascular disease (including atherosclerosis, ischemic pain is in June of the heart, coronary artery disease and hypertension), cerebrovascular disease such as stroke and peripheral vascular disease. The compounds of this invention can also be used for the treatment of physiological disorders associated with, for example, regulation of insulin sensitivity, inflammatory reaction, hepatic steatosis, elevated levels of triglycerides in the liver, non-alcoholic fatty infiltration of the liver, non-alcoholic fatty hepatitis, levels of triglycerides, high density lipoprotein, low-density lipoprotein and cholesterol and other similar violations. Metabolic syndrome is a group of metabolic risk factors of the patient. Such factors include, but are not limited to, abdominal obesity, atherogenic dyslipidemia (blood disease due to the presence of fat, such as high triglycerides, low high-density lipoprotein cholesterol and high levels of low-density lipoprotein cholesterol), elevated blood pressure, insulin resistance or glucose tolerance), prothrombinase condition (e.g., high fibrinogen or inhibitor of plasminogen activator-1 in the blood), and proinflammatory state (e.g., elevated C-reactive protein in the blood). In one vari is NTE implementation the present invention provides methods for treatment of the above diseases, comprising the administration to a patient in need this, the compounds of the invention or its pharmaceutically acceptable salt or including their pharmaceutical compositions. The compounds of this invention or its pharmaceutically acceptable salts, and including their pharmaceutical compositions can also be used to reduce the levels of triglycerides in the plasma. Thus, in one embodiment, the present invention provides a method of reducing the level of triglycerides in the plasma of a patient (including a mammal) if it is necessary, including placing the patient in need this, the compounds of the invention or its pharmaceutically acceptable salt or including their pharmaceutical compositions.

The term "therapy" or "treatment" includes any method, act, use, drug action, or similar action, when the patient, including humans, providing medical care to improve the patient's condition, directly or indirectly, or slow down the progression of the condition or disease in a patient.

Compounds of the invention or their pharmaceutically acceptable salts can be entered by themselves or in combination (i.e., introduced jointly) with one or more additional pharmacist is ical means. Combination therapy includes the introduction of a single dose of a pharmaceutical preparation, which comprises the compound of the present invention and one or more additional pharmaceutical agents, as well as introducing the compound of the invention and each additional pharmaceutical agents in its own separate pharmaceutical form. For example, the compound of the invention and one or more pharmaceutical agents can be administered to the patient together in a single oral dosage forms with a fixed ratio of each active ingredient, such as a tablet or capsule, or each agent can be introduced in the form of a separate single oral dosage forms.

When using separate dosage forms, the compounds of the invention and one or more additional pharmaceutical agents can be introduced essentially in one and the same time (e.g., simultaneously) or separate moments of time step (e.g., one after the other).

For example, the compounds of the invention can be used in combination with one or more of the following pharmaceutical agents, including, but not limited to, drugs against obesity, including β-3 agonists such as CL-316,243; CB-1 antagonists and/or inverse agonists (e.g., rimonabant); inhibitors of neuropeptide Y5; ven the drugs to suppress appetite, such as, for example, sibutramine (By® / Reductil®); MCHr1 antagonists and lipase inhibitors, such as orlistat (Xenical) and medicinal compound that modulates digestion and/or metabolism, such as drugs that modulate thermogenesis, lipolysis, peristalsis, absorption of fat and saturation.

In addition, the compounds of the invention can be introduced in combination with one or more of the following pharmaceutical products, including PPAR ligands (agonists, antagonists), tools that enhance insulin secretion (e.g., sulfonylurea drugs and stimulants secretion that does not contain a sulfonylurea), inhibitors of α-glucosidase, insulin sensitizers, connections, decreasing hepatic glucose production, and insulin and derivatives of insulin. Such funds may be entered before, concurrently or after administration of the compounds of the invention. Insulin and derivatives of insulin include both forms and formulations of insulin long-acting and short-acting. The PPAR ligands may include agonists and/or antagonists of any of PPAR or a combination of both. For example, PPAR ligands may include ligands of PPAR-α, PPAR-γ, PPAR-δ, or any combination of two or three PPAR. The PPAR ligands include, for example, rosiglitazone, troglitazone and pioglitazone. Sulfonylurea among the CTB include, for example, glyburide, glimepiride, hlorpropamid, tolbutamide, and glipizide; inhibitors of α-glucosidase include acarbose, miglitol and voglibose. The insulin sensitizers include agonists of PPAR-γ, such as glitazone (for example, troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and other such glitazone) and other thiazolidinedione and non - thiazolidinedione compounds; biguanides, such as Metformin and phenformin; inhibitors of protein tyrosine fosfotazy-1B (PP-1B); inhibitors of dipeptidyl peptidases IV (DPP-IV) and inhibitors of 11β-HSD. Connections, decreasing hepatic glucose production, include antagonists of glucagon and Metformin, such as glucophage and glucophage XR. Tools that enhance insulin secretion include sulfonylurea and desulfonylation drugs: GLP-1, GIP, PACAP, secretin and its derivatives; nateglinide, meglitinide, Repaglinide, glibenclamide, glimepiride, hlorpropamid, glipizide. GLP-1 includes derivatives of GLP-1 with longer times the half-life than natural GLP-1, such as, for example, derivatives of GLP-1 and fatty acids and basis.

Compounds of the invention can also be applied in the methods of the invention in combination with one or more pharmaceutical means, including, but not limited to inhibitors of HMG-CoA reductase inhibitors, nicotinic acid (for example, Niaspan®), compounds lowering the soda is Jania fatty acids (for example, acipimox); lipid-lowering drugs (for example, esters of stanol, styrene glucosides, such as tiqueside and azetidinone, such as ezetimibe) ACAT inhibitors (such as avasimibe), biliary acids, inhibitors of reuptake of bile acids, inhibitors of microsomal transport triacylglycerides and derivatives fibroeva acid. Inhibitors of HMG-CoA reductase inhibitor include, for example, a statin such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, mevastatin, pitavastatin, tseriwastatina and ZD-4522. Derivatives fibroeva acid include, for example, clofibrate, fenofibrate, bezafibrat, ciprofibrate, becovered, etofibrate and gemfibrozil. Substances that increase the excretion include, for example, cholestyramine, colestipol and dialkylaminoalkyl derivatives of cross-linked dextran.

Compounds of the invention can also be used in combination with antihypertensive agents, such as, for example, β-blockers and ACE inhibitors. Examples of additional antihypertensive drugs for use in combination with compounds of the present invention include calcium channel blockers (L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mibefradil), diuretics (for example, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlor teased, polythiazide, benzthiazide, ethacrynic acid, ticrynafen, chlorthalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g. captopril, zofenopril, fosinopril, enalapril, ceronapril, cilazapril, delapril, pentopril, inapril, ramipril, lisinopril), antagonists of the receptor AT-1 (e.g., losartan, irbesartan, valsartan), antagonists of ET receptor (for example, sitaxsentan, atrsentan inhibitors of neutral endopeptidase (NEP)inhibitors vasopeptidase (inhibitors (dual NEP-ACE) (for example, omapatrilat and gemopatrilat) and nitrates.

The compounds of this invention can be used to achieve the desired pharmacological effect by introducing them to a patient in need of volume, composition suitably prepared pharmaceutical composition. The patient, for example, may be a mammal, including man, in need of treatment to improve the condition or disease. Therefore, the present invention includes pharmaceutical compositions that include a therapeutically effective amount of a compound identified by the methods described herein, or its pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable carrier. Compounds identified by the methods described herein, can be introduced with pharmaceuticas is acceptable carrier using any effective conventional dosage forms of single doses for example, preparations immediate-release and prolonged action, oral, parenteral, local, and other similar drugs.

The pharmaceutical compositions can be prepared for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.

Used herein, the term "pharmaceutically acceptable carrier" means a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or auxiliary agent of any type. Examples of therapeutically acceptable excipients include sugar, cellulose and its derivatives; oil; glycols; solutions; substances for buffering, coloring, release coating, sweetening, improve taste and smell and flavoring; and other similar substances. These therapeutic compositions may be introduced parenterally, intracisternally, orally, rectally, intravenously or administered intraperitoneally.

Liquid dosage forms for oral administration of the present compounds include forms such as emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds, the liquid dosage forms may contain diluents and/or solubilizer or emulsifier. Besides inert diluents, the oral compositeimage include moisturizing, emulsifying, sweetening, improves the taste and aromatic smell and tools.

Injectable preparations of the present compounds include sterile injectable aqueous or oily solutions, suspensions or emulsions, any of which may be optionally prepared with parenterally acceptable diluents, dispersing, wetting or suspendresume substances. These injectable preparations can be sterilized by filtering through inhibiting bacteria filter or cooked with sterilizing substances that dissolve or disperse in injectable environment.

Inhibition of DGAT-1 using the compounds of the present invention can be slowed by using a liquid suspension of crystalline or amorphous material with poor water-solubility. The speed of absorption of the compounds depends on their rate of dissolution which, in turn, depends on their crystallinity. Delayed absorption of parenteral entered the connection may be effected by dissolution or suspension of the compounds in the oil. Injectable depot forms of the compounds can also be prepared by microencapsulation compounds in biodegradable polymers. Depending on the relationship of connection to polymer and the nature of the polymer can be adjusted SC is the rate of release. Injectable pharmaceutical depot forms are also prepared by seizing compounds in liposomes or microemulsions that are compatible with body tissues.

Solid dosage forms for oral administration of the present compounds include capsules, tablets, pills, powders and granules. In such forms, the compound is mixed, with at least one inert, therapeutically acceptable excipient such as a carrier, filler, extender, a disintegrator, a dissolution retarder, humidifier, the absorbent material or substance that increases the slip. In the case of capsules, tablets and pills, the filler may also contain buferiruemoi substances. Suppositories for rectal injection can be prepared by mixing the compounds with acceptable non-irritating excipient which is solid at ordinary temperature but becomes liquid in the rectum.

These compounds may be microcapsulated with one or more discussed above fillers. Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared with coatings and shells, such as intersolubility and controlled release. These compounds may be mixed with at least one inert diluent, and may optionally include a means of polychrystalline and adjuvants during pelletizing. Capsules may also optionally contain substances that delay the release of compounds into the desired part of the intestine.

Transdermal patches have the added advantage of providing controlled delivery of these compounds in the body. Such dosage forms are prepared by dissolving or distribution of the compounds in an appropriate environment. To increase the flow of compounds through the skin can also be used to promote absorption of the substance and the speed of absorption can be controlled by providing a speed control membrane or by dispersing the compounds in a polymer matrix or gel.

Compounds of the invention can be used in the form of pharmaceutically acceptable salts, esters or amides derived from inorganic or organic acids. Used herein, the term "pharmaceutically acceptable salts, esters and amides" include salt, zwitterion, esters and amides disclosed here connections that are within reasonable medical conclusion acceptable for use in contact with the tissues of humans and lower animals without nonspecific toxicity, irritation, allergic reactions and other reactions, meet the proper ratio of benefit/risk and effective for their intended used the I.

Pharmaceutically acceptable salts are well known in the art. Salts can be obtained during the final isolation and purification of the compounds or separately by reacting amino compounds with the appropriate acid. Typical salts include acetate, adipate, alginate, citrate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, comfort, camphorsulfonate, digluconate, glycyrrhizinate, polysulfate, heptanoate, hexanoate, formate, isetionate, fumarate, lactate, malate, maleate, methanesulfonate, naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, pivalate, propionate, succinate, tartrate salt of trichloroacetic acid, salt triperoxonane acid, glutamate, para-toluensulfonate, undecanoate, salt, hydrochloric acid salt, Hydrobromic acid and salt , sulfuric acid salt, phosphoric acid, and other similar salts. The amino compounds may also be quaternization using alkylchloride, bromides and iodides, such as methyl, ethyl, propyl isopropyl, butyl, lauryl, myristyl, stearyl and other such compounds.

Salt accession bases can be obtained during the final isolation and purification of these compounds by reacting the carboxyl group with a suitable base such as the hydroxide, carbonate or bi is arbonet metal cation, such as lithium, sodium, potassium, calcium, magnesium or aluminum, or an organic primary, secondary or tertiary amine. It is assumed that the salt of the Quaternary amine derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylethylenediamine, 1 ethanamine and N,N'-dibenziletilendiaminom, Ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and other similar amines, are included in the scope of the present invention.

Used herein, the term "pharmaceutically acceptable ester" refers to esters of the compounds of the invention, which is hydrolyzed in vivo and include esters, which easily break down in the human body on the original compound or its salt. Examples of pharmaceutically acceptable non-toxic esters of the invention include C1-6alkalemia esters and C5-7cycloalkyl esters, although C1-4alkalemia esters are preferred. Esters of compounds of the invention can be obtained by traditional methods. Pharmaceutically acceptable esters can be attached by a hydroxyl group by reaction of a compound that contains a hydroxyl group, acid and alkalicarbonate acid, such as acetic Ki the lot, or with acid and arylcarbamoyl acid, such as benzoic acid. In the case of compounds containing carboxylic acid group, pharmaceutically acceptable esters derived from compounds containing the carboxylic acid group by reaction of the compound with base such as triethylamine and alkylhalogenide, alkylacrylate, for example, methyliodide, benzimidazol, cyclopenthiazide. They can also be obtained by reaction of the compound with an acid, such as hydrochloric acid and alkalicarbonate acid, such as acetic acid, or with acid and arylcarbamoyl acid, such as benzoic acid.

Used herein, the term "pharmaceutically acceptable amide" refers to non-toxic Amida of the invention derived from ammonia, primary C1-6alkylamines followed and secondary C1-6dialkylamino. In the case of secondary amines, the amine may be in the form of a 5 - or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, primary C1-3alkylamide and secondary C1-2dialkylamide are preferred. Amides of the compounds of formula (I), (Ia) or (IIa) can be obtained by traditional methods. Pharmaceutically acceptable amides can be obtained from compounds containing primary or secondary amino group by reaction of compounds containing the amino group, with alkylamides, arrangedwith, acelga what agenda or arilgalogenide. In the case of compounds containing carboxylic acid group, pharmaceutically acceptable esters derived from compounds containing the carboxylic acid group by reaction of the compound with base such as triethylamine, dehydrating agent, such as dicyclohexylcarbodiimide or carbonyldiimidazole and alkylamino, dialkylamino, for example, methylamine, diethylamine, piperidine. They can also be obtained by reaction of compounds with acid, such as sulfuric acid and alkalicarbonate acid, such as acetic acid, or with acid and arylcarbamoyl acid, such as benzoic acid under dehydrating conditions as in the case of adding molecular sieves. The composition may contain the compound of the invention in the form of pharmaceutically acceptable prodrugs.

Used herein, the term "pharmaceutically acceptable prodrug" or "prodrug" represents those prodrugs of the compounds of the invention that are, within reasonable medical conclusion acceptable for use in contact with the tissues of humans and lower animals without nonspecific toxicity, irritation, allergic reactions and other reactions, meet the proper ratio of benefit/risk and effective for their intended use. Prodrugs of the invention can be l the GKO converted in vivo into the parent compound of the invention, for example, by hydrolysis in blood. A detailed discussion of prodrugs is provided in the monographs T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

Treatment or prevention of diseases in a patient by injection to a patient a therapeutically effective amount of the compounds of the present invention in such amount and within such time, which are necessary to achieve the desired result. The term "therapeutically effective amount" refers to sufficient amounts of the compounds of the invention to effectively improve the condition of a patient in the inhibition of DGAT-1 with the proper ratio of risk-to-benefit, applicable to any medical treatment. The specific therapeutically effective dose level for any preferred patient will depend upon a number of factors, including being treated with disease and disease severity; the activity of the used compounds; used concrete composition; the age, body weight, General health, sex and diet of the patient; the time of administration, route of administration, rate of excretion; the duration of the treatment; drugs used in combination or when conducting the same time therapy.

Su the total daily dose of the compounds of the present invention, required for inhibition of the actions of DGAT-1 in a single dose or divided doses can be, for example, from about 0.01 to 50 mg/kg of body weight. In a more preferred range, the compounds of the present invention inhibit the action of DGAT-1 in a single dose or divided doses of from about 0.05 to 25 mg/kg of body weight. Composition single dose or its component fractions may contain such amounts of the compounds of the present invention that make up the daily dose. Usually, the treatment regimen comprises administration to a patient in need of such treatment, from about 1 mg to 1000 mg of the compounds per day as a single dose or multiple doses.

Compounds identified by the methods described herein, can be introduced in the form of a single pharmaceutical agents or in combination with one or more other pharmaceutical means when the combination causes no unacceptable adverse action. For example, the compounds of this invention can be combined with anti-obesity or with known antidiabetic drugs or drugs for other indications and other similar tools. Thus, the present invention also includes pharmaceutical compositions that include a therapeutically effective amount of a compound identified as described here m is today or its pharmaceutically acceptable salt, pharmaceutically acceptable carrier and one or more disclosed above pharmaceuticals.

EXAMPLES

Preparative high-performance liquid chromatography with reversed phase (RP-HPLC) was performed using column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (CH3CN with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, unless otherwise specified.

Example 1

TRANS [4-(4-{3-[2-(1-substituted)-2-hydroxyethoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid

Example 1A

ethyl 2-(4-phenylcyclohexylamine)acetate

In a three-neck flask with a volume of 250 ml, equipped with a magnetic stirrer, additional funnel, bubbling device with mineral oil, loaded 4-phenylcyclohexanone (6,01 g, 34.5 mmol) and N,N-dimethylformamide (17 ml) and cooled to 0°C in an ice bath. Then portions was added NaH (1.55 g, 60% dispersion, and 38.6 mmol) and the mixture was stirred for 30 minutes. Then was added dropwise triethylphosphate (7,8 ml of 38.7 mmol) in 6 ml N,N-dimethylformamide. After stirring for 40 minutes, the reaction mixture was poured into a 5% solution of NaHSO4and was extracted with dichloromethane (×3). The organic layers were combined, with the sewed over Na 2SO4was filtered and evaporated the solvent under vacuum. The precipitate was then dissolved in a mixture of 8:1 hexane/ethyl acetate and was purified using column chromatography using the same solvent system, obtaining 7.2 g of the named compound with 85% yield.1H NMR (300 MHz, CDCl3) δ ppm 1.28 (in t, 3H), 1,55-1,75 (m, 2H), 2.00 in to 2.15 (m, 3H), 2,24-2,48 (m, 2H), 2,67-is 2.88 (m, 1H), 3,88-a 4.03 (m, 1H), 4,17 (kV, J=7,12 Hz, 2H), of 5.68 (s, 1H), 7,17-7,24 (m, 3H), 7,27-7,34 (m, 2H); MS (ESI) m/z 245 [M+H]+.

Example 1B

TRANS ethyl 2-(4-phenylcyclohexyl)acetate

The product from example 1A (6,00 g of 24.7 mmol) was dissolved in 60 ml of ethanol was added 10% Pd/C (600 mg). The reaction mixture was placed in a shaking device Par at 60 psi for 2 hours. Then the catalyst was filtered and evaporated the solvent, to obtain the titled compound.1H NMR (300 MHz, CDCl3) δ ppm of 1.05 to 1.22 (m, 2H), 1,22-of 1.30 (m, 3H), 1,43-to 1.59 (m, 2H), 1,64 is 1.75 (m, 2H), 1,86 is 1.96 (m, 3H), 2,24 (d, J=6,44 Hz, 2H), 2.40 a-2,49 (m, 1H), 4,15 (kV, J=7,35 Hz, 2H), 7,17-of 7.23 (m, 3H), 7.24 to 7,33 (m, 2H); MS (ESI) m/z 247 [M+H]+.

Example 1C

TRANS ethyl 2-(4-(4-(chlorocarbonyl)phenyl)cyclohexyl)acetate

To the solution containing the product of example 1B (2,46 g, 10.0 mmol) and AlCl3(2.66 g, 20.0 mmol) in 30 ml dichloromethane at 0°C, was added oxalicacid (5 ml, 2 M solution in dichloromethane, 10 mmol). The mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was poured the chilled in ice solution containing calcium chloride (3 g) in 100 ml of water. The reaction mixture was stirred for 2 hours and was extracted with dichloromethane (2×100 ml). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, solvent was removed under reduced pressure and the resulting oil was purified flash chromatography (ethyl acetate/hexane, 1/8) to give the titled compound as a colorless oil.1H NMR (500 MHz, DMSO-d6) δ ppm to 1.15 (m, 2H), 1,19 (t, J=7,06 Hz, 3H), of 1.47 (m, 2H), 1,57-of 1.85 (m, 5H), 2,22 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), 4,07 (kV, J=7,06 Hz, 2H), 7,35 (d, J=8,29 Hz, 2H), a 7.85 (d, J=8,29 Hz, 2H).

Example 1D

TRANS ethyl 3-(4-((1s,4s)-4-(2-ethoxy-2-oxoethyl)-cyclohexyl)phenyl)-3-oxopropanoic

To a solution of 3-ethoxy-3-oxopropanoic acid (264 mg, 2.00 mmol) in 10 ml of tetrahydrofuran at 0°C was added magnesium ethylate (456 mg, 4.00 mmol). The mixture was stirred at room temperature overnight in an atmosphere of N2. The solvent was then removed by rotary evaporator and the resulting white powder was dried in vacuum for 2 hours and then poured into 20 ml of tetrahydrofuran. To the resulting suspension at 0°C was added the product of example 1C (310 mg, 1.00 mmol) in 5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 2 hours. Was added water (50 ml) to the reaction mixture and then extracted with ethyl acetate (2×100 ml). Merge the nnye organic layers were washed with brine, dried over Na2SO4and concentrated. The residue was purified column flash chromatography, elwira 0-5% ethyl acetate in hexano, obtaining these compounds.1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 a-1,22 (m, 8H), to 1.48 (m, 2H), 1,57 is 1.86 (m, 5H), 2,22 (d, J=6.75 Hz, 2H), has 2.56 (m, 1H), was 4.02 - to 4.15 (m, 6H), 7,40 (d, J=8,29 Hz, 2H), 7,87 (d, J=8,29 Hz, 2H); MS (ESI) m/z 361,1 [M+H]+.

Example 1E

TRANS ethyl 2-((1s,4s)-4-(4-(5-hydroxy-1H-pyrazole-3-yl)-phenyl)cyclohexyl)acetate

A mixture of the product of example 1D (70 mg, 0.20 mmol), acetic acid (0.1 ml) and hydrazine (35 % in water, 0.2 ml) in 1,4-dioxane (5 ml) was heated at 90-95°C for 2 hours. The reaction mixture was concentrated and the residue triturated in ethyl acetate. The named product was collected by filtration as a white precipitate was washed with ethyl acetate.1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 in (m, 2H), of 1.18 (t, J=7,06 Hz, 3H), of 1.47 (m, 2H), 1,53-to 1.87 (m, 5H), of 2.21 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), 4,06 (kV, J=7,06 Hz, 2H), 5,79 (s, 1H), 7,24 (d, J=of 8.28 Hz, 2H), 7,54 (d, J=of 8.28 Hz, 2H); MS (ESI) m/z 329,1 [M+H]+.

Example 1F

TRANS ethyl [4-(4-{3-[2-(1-substituted)-2-oksidoksi]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetate

A mixture of the product of example 1E (33 mg, 0.10 mmol), 1-adamantylamine (26 mg, 0.1 mmol) and potassium carbonate (14 mg, 0.10 mmol) in N,N-dimethylformamide was heated at 75°C in an atmosphere of N2within 6 hours. The reaction mixture was filtered through celite, washed with ethyl acetate, concentrated and is imali using column flash chromatography (elwira 15% ethyl acetate in hexano) to obtain the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 in (m, 2H), 1,19 (t, J=7,02 Hz, 3H), of 1.48 (m, 2H), 1,66-1,89 (m, 17H), 2,00 (m, 3H), 2,22 (d, J=of 6.71 Hz, 2H), 2,47 (m, 1H), 4,06 (kV, J=of 6.71 Hz, 2H), is 5.06 (s, 2H), the 6.06 (s, 1H), 7,28 (d, J=8,24 Hz, 2H,), EUR 7.57 (d, J=8,24 Hz, 2H), 12,12 (USS, 1H); MS (ESI) m/z 505,3 [M+H]+.

Example 1G

TRANS ethyl [4-(4-{3-[2-(1-substituted)-2-hydroxyethoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetate

Sodium borohydride (38 mg, 0.1 mmol) was added to a solution of the product of example 1F (25 mg, 0.05 mmol) in tetrahydrofuran (3 ml) and ethanol (3 ml) maintaining the temperature of 0°C. the Reaction mixture was allowed to warm to room temperature for 30 minutes and then it was stirred at room temperature for 1 hour. Then the reaction was stopped by adding water (5 ml) and was extracted with ethyl acetate. The organic extracts were combined and washed with water, brine, dried (MgSO4), filtered and concentrated to a brown oil, which was purified using flash column-chromatography (elwira 15% ethyl acetate in hexano) to obtain the titled compound.1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 in (m, 2H), 1,19 (t, J=to 7.32 Hz, 3H), 1,42 of 1.99 (m, 22H), 2,22 (d, J=of 6.71 Hz, 2H), 2,47 (m, 1H), 3,89 (DD, J1=10,38 Hz, J2=7,94 Hz, 1H), was 4.02 (m, 1H), 4,06 (kV, J=to 7.32 Hz, 2H), 4,24 (DD, J1=10,37 Hz, J2=2,74 Hz, 1H), 4,71 (s, 1H), 6,07 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), to 7.59 (d, J=8,24 Hz, 2H), 12,21 (USS, 1H); MS (ESI) m/z 507,4 [M+H]+.

Example 1H

TRANS [4-(4-{3-[2-(1-ad is mantel)-2-hydroxyethoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid

In scintillation vessel had downloaded the product from example 1G (18 mg, being 0.036 mmol), monohydrate of lithium hydroxide (5 mg, 0.12 mmol) and a mixed solvent (2 ml of tetrahydrofuran, 1 ml of H2O). The reactor was placed in a shaking device at room temperature over night. Then the mixture was acidified with 10% HCl, concentrated and purified using RP-HPLC (preparative high-performance liquid chromatography with reversed phase) using column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm (preparative method: water with 0.1% triperoxonane acid and CH3CN with 0.1% triperoxonane acid, gradient 5-95% CH3CN for 30 minutes at 15 ml/min) to give the named product.1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 in (m, 2H), 1,42 is 1.86 (m, 19H), was 1.94 (m, 3H), and 2.14 (d, J=7.01 Hz, 2H), 2,47 (m, 1H), 3,89 (DD, J1=10,38 Hz, J2=7,94 Hz, 1H), 4,24 (DD, J1=is 10.68 Hz, J2=2,74 Hz, 1H), 4,70 (d, J=5,49 Hz, 2H), 6,07 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), to 7.59 (d, J=8,24 Hz, 2H), 12,13 (USS, 2H); MS (ESI) m/z 479,3 [M+H]+.

Example 2

TRANS [4-(4-{3-[2-(1-substituted)-2-oksidoksi]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid

The named compound was obtained using the method described in example 1H, substituting the product from example 1G product from example 1E.1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 in (m, 2H), 1,44-of 1.88 (m, 19H), 2,00 (m, 3H), and 2.14 (d, J=7,02 Hz, 2H), 2,47 (m, 1H), is 5.06 (2H), the 6.06 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), EUR 7.57 (d, J=8,24 Hz, 2H), 12,02 (USS, 1H), 12,21 (USS, 1H); MS (ESI) m/z 477,3 [M+H]+.

Example 3

TRANS [4-(4-{3-[2-(4-methoxyphenyl)-2-oksidoksi]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid

A mixture of the product from example 1E (33 mg, 0.10 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (26 mg, 0.1 mmol) and potassium carbonate (14 mg, 0.10 mmol) in N,N-dimethylformamide was heated at 75°C in an atmosphere of N2within 6 hours. The reaction mixture was cooled, filtered through celite, washed with ethyl acetate and concentrated. The residue was purified column flash chromatography, elwira 15% ethyl acetate in hexano. The selected product is hydrolyzed in accordance with the method described in example 1H, obtaining these compounds.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,43-to 1.87 (m, 7H), of 2.15 (d, J=7.01 Hz, 2H), 2,47 (m, 1H), 3,86 (s, 3H), 5,46 (s, 2H), 6,13 (s, 1H), was 7.08 (d, J=9,16 Hz, 2H), 7,28 (d, J=8,24 Hz, 2H), EUR 7.57 (d, J=8,24 Hz, 2H), 7,98 (d, J=9,16 Hz, 2H), 12,25 (USS, 2H); MS (ESI) m/z 449,2 [M+H]+.

Example 4

TRANS {4-[4-(3-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid

The named compound was obtained in accordance with the procedure described in example 3, by replacing 2-bromo-1-(4-methoxyphenyl)-ethanone 1-(methyl bromide)-2-(triptoreline)benzene.1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 in (m, 2H), 1,47 (m, 2H), 1,68-to 1.87 (m, 5H), and 2.14 (d, J=7,06 Hz, 2H), 2,47 (m, 1H), 5.25 in (s, 2H), 6,14 (s, 1H), 7,29 (d, J=8,29 Hz, 2H), 7,38-7,53 (m, 3H), 7,58 (d, J=8,24 Hz, 2H), 7,66 (DD, J1=7,37 Hz, J2=1,85 Hz, 1H), 12,32 (USS, 1H); MS (ESI) m/z 475,2 [M+H]+.

Example 5

TRANS {4-[4-(3-{[5-(trifluoromethyl)-2-furyl]methoxy}-4-{[5-(trifluoromethyl)-2-furyl]methyl}-1H-pyrazole-5-yl)phenyl]-cyclohexyl}acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)Etalon 2-(methyl bromide)-5-(trifluoromethyl)furan.1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 in (m, 2H), 1,47 (m, 2H), 1,68-to 1.87 (m, 5H), and 2.14 (d, J=7,06 Hz, 2H), 2,47 (m, 1H), 3,83 (s, 2H, in), 5.25 (s, 2H), between 6.08 (m, 1H), of 6.71 (m, 1H), 6,98 (m, 1H), 7,19 (m, 1H), 7,32 (d, J=8,29 Hz, 2H), 7,40 (d, J=8,29 Hz, 2H), 11,98 (USS, 1H), of 12.26 (USS, 1H); MS (ESI) m/z 597,3 [M+H]+.

Example 6

TRANS {4-[4-(4-[2-(triptoreline)benzyl]-3-{[2-(three-formatosi)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)-alanon 1-(methyl bromide)-2-(triptoreline)benzene.1H NMR (500 MHz, DMSO-d6) δ ppm 1,11 (m, 2H), 1,47 (m, 2H), 1,66-to 1.87 (m, 5H), 2.13 in (d, 2H, J=6,76 Hz), 2,47 (m, 1H), 3,83 (s, 2H), 5,27 (s, 2H), 7,05-of 7.48 (m, 12H), 12,21 (USS, 1H); MS (ESI) m/z 649,4 [M+H]+.

Example 7

TRANS (4-(4-[3-(cyclohexylmethoxy)-1H-pyrazole-5-yl]phenyl} cyclohexyl)acetic acid

The named product was obtained from the product of example 72 using the method described in example 1H.1H NMR (500 MHz,DMSO-d 6) δ ppm 0,98-of 1.85 (m, 20H), and 2.14 (d, J=7,02 Hz, 2H), 2,47 (m, 1H), 3,88 (m, 2H), x 6.15 (s, 1H), 7,29 (d, J=8,24 Hz, 2H), to 7.59 (d, J=8,24 Hz, 2H), 12,11 (USS, 2H); MS (ESI) m/z 397,2 [M+H]+.

Example 8

TRANS {4-[4-(3-{[3-(triptoreline)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)Etalon 1-(methyl bromide)-3-(triptoreline)benzene.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,42-of 1.85 (m, 7H), and 2.14 (d, J=7,02 Hz, 2H), 2,47 (m, 1H), 5,24 (s, 2H), 6,16 (s, 1H), 7,29 (d, J=8,24 Hz, 2H), 7,30-7,34 (m, 1H), 7,43-of 7.55 (m, 3H), 7,58 (d, J=8,24 Hz, 2H), 12,00 (USS, 1H), 12,34 (USS, 1H); MS (ESI) m/z 475,2 [M+H]+.

Example 9

TRANS {4-[4-(3-{[5-(trifluoromethyl)-2-furyl]methoxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid

The named product was obtained from the product of example 57 using the method described in example 1H.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,40-to 1.87 (m, 7H), and 2.14 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), total of 5.21 (s, 2H), x 6.15 (s, 1H), 6,79 (d, J=3,68 Hz, 1H), 7,22 (m, 1H), 7,29 (d, J=of 8.28 Hz, 2H), to 7.59 (d, J=of 8.28 Hz, 2H), 12,40 (USS, 1H); MS (ESI) m/z 449,2 [M+H]+.

Example 10

TRANS (4-{4-[3-(3-phenoxypropane)-1H-pyrazole-5-yl]-phenyl}cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-l-(4-methoxyphenyl)Etalon to (3 bromopropane)benzene.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,43-,87 (m, 7H), of 2.15 (m, 4H), 2,47 (m, 1H), 4,11 (t, J=6,44 Hz, 2H), 4,25 (t, J=6,44 Hz, 2H), between 6.08 (s, 1H), 6.90 to-6,97 (m, 3H), 7,26-7,31 (m, 4H), to 7.59 (d, J=of 8.28 Hz, 2H), 12,40 (USS, 1H); MS (ESI) m/z 435,2 [M+H]+.

Example 11

TRANS (4-{4-[3-(4-phenoxyethoxy)-1H-pyrazole-5-yl]phenyl}-cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)Etalon to (4 bromobutoxy)benzene.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,47 (m, 2H), 1,68-1,90 (m, 9H), of 2.15 (d, J=7,02 Hz, 2H), 2,47 (m, 1H), was 4.02 (m, 2H), 4,14 (m, 2H), between 6.08 (s, 1H), 6,92 (m, 3H), 7,27 (m, 4H), EUR 7.57 (d, J=8,24 Hz, 2H), of 12.26 (USS, 1H); MS (ESI) m/z 449,2 [M+H]+.

Example 12

TRANS (4-{4-[3-(2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-1H-pyrazole-5-yl]phenylcyclohexyl)acetic acid

The named compound was obtained from the product of example 62 using the method described in example 1H.1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 in (m, 2H), 1,47 (m, 2H), 1,67-of 1.88 (m, 5H), and 2.14 (d, J=7,06 Hz, 2H), 2,47 (m, 1H), 4,12 (DD, J1=11,66 GC J2=7,06 Hz, 1H), 4,34 (m, 2H), to 4.41 (DD, J1=11,66 Hz, J2=at 2.45 Hz, 1H), 4,57 (m, 1H), 6,14 (s, 1H), 6,82-6,94 (m, 4H), 7,29 (d, J=of 8.28 Hz, 2H), to 7.59 (d, J=of 8.28 Hz, 2H), 12,3 (USS, 2H); MS (ESI) m/z 449,2 [M+H]+.

Example 13

TRANS {4-[4-(3-{[2-(deformedarse)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)Etalon 1-(methyl bromide)--(deformedarse)benzene. 1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,48 (m, 2H), 1,57 is 1.86 (m, 5H), and 2.14 (d, J=7,02 Hz, 2H), 2,47 (m, 1H), total of 5.21 (s, 2H), 6,14 (s, 1H), 7,22-7,31 (m, 5H), 7,39 was 7.45 (m, 1H), 7,56-to 7.61 (m, 3H), 12,25 (USS, 2H); MS (ESI) m/z 457,2 [M+H]+.

Example 14

TRANS (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]-phenyl}cyclohexyl)acetic acid

The named compound was obtained from the product of example 56 using the method described in example 1H.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,31 (m, 2H), 1,44 of-1.83 (m, 13H), and 2.14 (d, J=7,02 Hz, 2H), to 2.29 (m, 1H), 2,47 (m, 1H), 3,97 (d, J=7,02 Hz, 2H), 6,07 (s, 1H), 7,29 (d, J=8,24 Hz, 2H), 7,68 (d, J=8,24 Hz, 2H), 12,11 (USS, 2H); MS (ESI) m/z 383,2 [M+H]+.

Example 15

TRANS (4-{4-[3-(cyclobutylmethyl)-1H-pyrazole-5-yl]phenyl} cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)alanon (methyl bromide)CYCLOBUTANE.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,48 (m, 2H), 1,68-of 1.95 (m, 10H), was 2.05 (m, 1H), and 2.14 (d, J=6,67 Hz, 2H), 2,47 (m, 1H), 2,70 (m, 1H), 4,05 (d, J=6.75 Hz, 2H), the 6.06 (s, 1H), 7,28 (d, J=8,29 Hz, 2H), 7,58 (d, J=8,29 Hz, 2H,), 12,25 (USS, 1H); MS (ESI) m/z 369,1 [M+H]+.

Example 16

TRANS (4-{4-[3-(cyclohexyloxy)-1H-pyrazole-5-yl]phenyl}-cyclohexyl)acetic acid

The named compound was obtained from the product of example 47 using the method described in example 1H.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,2-and 1.56 (m, 9H), 1,67 is 1.86 (m, 7H), of 1.97 (m, 1H), and 2.14 (d, J=7,02 Hz,2H), 2,47 (m, 1H), 4,39 (m, 1H), the 6.06 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H), 12,20 (USS, 1H); MS (ESI) m/z 383,2 [M+H]+.

Example 17

TRANS (4-{4-[3-(tetrahydro-2H-Piran-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)Etalon 2-(methyl bromide)-tetrahydro-2H-Piran.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,30 (m, 1H), 1,42 is 1.86 (m, 12H), was 2.05 (m, 1H), and 2.14 (d, J=6,67 Hz, 2H), 2,47 (m, 1H), 3,61 (m, 1H), 3,88 (m, 1H), 4.00 points (d, J=5,49 Hz, 2H), 6,07 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H), 12,21 (USS, 2H); MS (ESI) m/z 399,2 [M+H]+.

Example 18

TRANS ethyl [4-(4-{3-[2-(1-substituted)-2-oksidoksi]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetate

The named compound was obtained in accordance with the procedure described in example 1F.1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 in (m, 2H), 1,19 (t, J=7,02 Hz, 3H), of 1.48 (m, 2H), 1,66-1,89 (m, 17H), 2,00 (m, 3H), 2,22 (d, J=of 6.71 Hz, 2H), 2,47 (m, 1H), 4,06 (kV, J=of 6.71 Hz, 2H), is 5.06 (s, 2H), the 6.06 (s, 1H), 7,28 (d, J=8,24 Hz, 2H,), EUR 7.57 (d, J=8,24 Hz, 2H), 12,12 (USS, 1H); MS (ESI) m/z 505,3 [M+H]+.

Example 19

TRANS (4-{4-[5-(cyclobutylmethyl)-1-(cyclobutylmethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)alanon (methyl bromide)CYCLOBUTANE.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,47 (m, 2H), 1,66-2,12 (who, 17H), 2,22 (d, J=7,02 Hz, 2H), 2,45 (m, 1H), 2,72 (m, 2H), 3,92 (d, J=6,72 Hz, 2H), 4,08 (d, J=6,72 Hz, 2H), 6,09 (s, 1H), 7,21 (d, J=8,24 Hz, 2H), 7.62mm (d, J=8,24 Hz, 2H), 11,77 (USS, 1H); MS (ESI) m/z 437,3 [M+H]+.

Example 20

TRANS (4-{4-[3-(benzyloxy)-1H-pyrazole-5-yl]phenyl}-cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)Etalon on benzylbromide.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,48 (m, 2H), 1,65-to 1.87 (m, 5H), and 2.14 (d, J=7,06 Hz, 2H), 2,47 (m, 1H), 5,17 (s, 2H), 6,13 (s, 1H), 7,28 (d, J=8,29 Hz, 2H), 7,31-7,47 (m, 5H), 7,60 (d, J=8,29 Hz, 2H), 12,22 (USS, 1H); MS (ESI) m/z 391,2 [M+H]+.

Example 21

TRANS (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]phenyl}-cyclohexyl)acetic acid

The named compound was obtained from the product of example 61 using the method described in example 1H.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,48 (m, 2H), 1,53 is 1.91 (m, 13H), and 2.14 (d, J=7.01 Hz, 2H), 2,47 (m, 1H), 4,89 (m, 1H), 6,04 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H), 12,12 (USS, 2H); MS (ESI) m/z 369,2 [M+H]+.

Example 22

TRANS {4-[4-(3-{[4-(trifluoromethyl)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)Etalon 1-(methyl bromide)-4-(trifluoromethyl)benzene.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,48 (m, 2H), 1,65-to 1.87 (m, 5H), and 2.14 (d, J=7.01 Hz, 2H), 2,47 (m, 1H), from 5.29 (s, 2H) 6,16 (s, 1H), 7,29 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H), 7,66 (d, J=8,24 Hz, 2H), of 7.75 (d, J=8,24 Hz, 2H), a 12.03 (USS, 1H), of 12.33 (USS, 1H); MS (ESI) m/z 459,2 [M+H]+.

Example 23

TRANS [4-(4-{3-[(5-methylisoxazol-3-yl)methoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)Etalon 4-(methyl bromide)-5-methylisoxazol.1H NMR (500 MHz, DMSO-d6) δ ppm 1.13 (m, 2H), 1,48 (m, 2H), 1,65-to 1.87 (m, 5H), and 2.14 (d, J=6.75 Hz, 2H), 2.40 a (s, 3H), 2,47 (m, 1H), 5,19 (s, 2H), 6,14 (s, 1H), of 6.31 (s, 1H), 7,29 (d, J=8,24 Hz, 2H), to 7.59 (d, J=8,24 Hz, 2H), 12,02 (USS, 1H), 12,36 (USS, 1H); MS (ESI) m/z 396,2 [M+H]+.

Example 24

TRANS {4-[4-(1H-1,2,4-triazole-5-yl)phenyl]cyclohexyl}acetic acid

Example 24 A

TRANS ethyl 2-(4-(4-carbamoylphenoxy)cyclohexyl)acetate

Ammonium hydroxide (large excess) was added to the product of example 1C (8,43 g and 27.3 mmol) at room temperature. The white solid precipitate was filtered and washed with water to obtain the above compound (7.9 g, 100%) as a white solid, which was used in the next stage without additional purification. MS (DCI) m/z 290,1 [M+H]+.

Example 24B

TRANS {4-[4-(1H-1,2,4-triazole-5-yl)phenyl]cyclohexyl}acetic acid

Stage A:

The product of example 24A (250 mg, crude) was mixed with excess N,N-dimethylformamide of dimethylacetal and was heated at 110 the C for 1.5 hours. After cooling to room temperature the volatile components were removed using a rotary evaporator and the residue was kept under high vacuum for 1 hour to obtain these compounds in the form of a brown oil (200 mg). This material was used in the next stage without additional purification.

Stage B:

The product from step A (200 mg, about to 0.60 mmol) was mixed with glacial acetic acid (2.9 ml) in a vessel capable of withstanding high pressure and added hydrazine hydrate (34 μl, 0.70 mmol). The vessel was closed and the reaction mixture was heated to 70°C for 1.5 hours. Volatile components were removed using a rotary evaporator and the residue was passed through a layer of silica gel and then was dissolved in ethanol at room temperature. Was added aqueous NaOH solution (1N.) and the solution became turbid. The reaction mixture was heated at 60°C for 1.5 hours until until the solution became transparent. Volatile components were removed using a rotary evaporator and the aqueous portion was transferred into a separating funnel. The alkaline solution was washed with diethyl ether and the aqueous layer was acidified using 1N. HCl. Precipitated white solid precipitate and the aqueous layer was extracted with ethyl acetate (3×15 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated using a mouth is REGO evaporator to obtain a white solid. The solid is triturated with a mixture of ethyl acetate/hexane and filtered to obtain these compounds in the form of a white solid.1H NMR (300 MHz, methanol-d4) δ ppm 1,11-of 1.30 (m, 2H), 1,49-of 1.66 (m, 2H), 1.70 to 1,99 (m, 5H), of 2.23 (d, J=is 6.78 Hz, 1H), 2,43-of 2.64 (m, 1H), was 7.36 (d, J=8,14 Hz, 2H), of 7.90 (d, J=8,14 Hz, 2H), 8,31 (s, 1H); MS (ESI) m/z 286 [M+H]+.

Example 25

TRANS [4-(4-{5-[(5-methylisoxazol-3-yl)methoxy]-1-[(5-methylisoxazol-3-yl)methyl]-1H-pyrazole-3-yl}phenyl)cyclohexyl]-acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)Etalon 3-(methyl bromide)-5-methylisoxazol.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,48 (m, 2H), 1,65-to 1.87 (m, 5H), and 2.14 (d, J=6.75 Hz, 2H), 2,31 (m, 3H), 2.40 a (s, 3H), 2,47 (m, 1H), 5,19 (s, 2H), 5,26 (s, 2H), 5,95 (s, 1H), 6,27 (s, 1H), of 6.31 (s, 1H), 7,32 (d, J=8,24 Hz, 2H), 7,45 (d, J=8,24 Hz, 2H), 12, 20 (USS, 1H); MS (ESI) m/z 491,32 [M+H]+.

Example 26

TRANS N-methyl-N-[(4-(4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]-phenyl}cyclohexyl)acetyl]glycine

Example 26A

TRANS ethyl 2-(4-(4-acetylphenyl)cyclohexyl)acetate

In a round bottom flask 500 ml with a magnetic stirrer was loaded the product of example 1B (3 g, 12.2 mmol) and 60 ml of dichloromethane. The reaction solution was cooled to 0°C was added in portions AlCl3(a 4.86 g of 36.5 mmol). The mixture was stirred for 20 minutes and then was added dropwise acetylchloride (954 μl, of 13.4 mmol). After p is remesiana within 15 minutes the reaction mixture is slowly poured into the chemical glass with ice water and diluted with 120 ml of ethyl acetate. The layers were separated and the organic layer was washed for 1H. NaHCO3(×2), brine (×2), dried over Na2SO4and filtered. Evaporation of solvents gave a named connection.1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 million-1,17 (m, 2H), of 1.18 (t, 3H), 1,39-of 1.62 (m, 3H), 1,68-of 1.88 (m, 5H), 2,17-of 2.26 (m, 2H), 2,52-to 2.57 (s, 3H), 4,07 (kV, J=7,12 Hz, 2H), 7,25-7,46 (m, 2H), to 7.77-7,94 (m, 2H); MS (ESI) m/z 247 [M+H]+.

Example 26B

TRANS ethyl (4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetate

In a flask with a capacity of 50 ml was loaded with 6.6 ml of methyl tertiary butyl ether and ethyltryptamine (520 μl, 3,47 mmol). To this solution is then slowly added 533 μl ethylate sodium (21% in ethanol) and then the product of example 26A (1,00 g, 3,47 mmol) in 3 ml of methyl tertiary butyl ether for 5 minutes. After stirring overnight the reaction was stopped with saturated solution of NH4Cl and extracted with ethyl acetate (×2). Then an ethyl acetate layers were evaporated to dryness and the residue was dissolved in ethanol (5 ml). Added two equivalents of hydrazine hydrate (35% in water) and the solution was heated to 70°C during the night. Then the solution was cooled to room temperature and the solvent was evaporated in vacuum. The residue was dissolved in a mixture of 1:1 methanol/DMSO and purified using RP-HPLC with getting this product.1H NMR (300 MHz, DMSO-d6) δ ppm 1,03-1,15 (m, 1H), 1,19 (t, J=7,12 Hz, 3H), 1,37 is 1.60 (m, 2H), 1,69 is 1.86 (m, 5H), 2,15-of 2.27 (m, 2H), 4,07 (kV, J=7,12 Hz,2H), of 6.96-7,22 (m, 1H), 7,26-the 7.43 (m, 2H), 7,63-7,80 (m, 2H), 13,98 (s, 1H); MS (ESI) m/z 381 [M+H]+.

Example -26 C

TRANS (4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}-cyclohexyl)acetic acid

In a round bottom flask was loaded the product of example 26B (0,520 g of 1.36 mmol) and 6 ml of 20% aqueous tetrahydrofuran. Was added lithium hydroxide (114 mg, of 2.72 mmol) and the reaction mixture was stirred at room temperature overnight. After 16 hours the reaction was stopped with 1N. HCl and the mixture was filtered through a layer of celite. Evaporation of solvents and purification by chromatography on silica gel (10-30% ethyl acetate/hexane with 1% acetic acid) gave the titled compound.1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 million is 1.23 (m, 2H), 1.41 to of 1.57 (m, 2H), 1,58-to 1.67 (m, 1H), 1,69-to 1.77 (m, 1H), 1,78-of 1.88 (m, 4H), 2,12-of 2.20 (m, 2H), 7,05-7,17 (m, 1H), 7,26-7,41 (m, 2H), 7,62-of 7.82 (m, 2H), 12,00 (s, 1H), 13,89-14,07 (m, 1H) ; MS (ESI) m/z 354 [M+H]+.

Example 26D

TRANS methyl N-methyl-N-[(4-(4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetyl]glycinate

In scintillation vessel with a capacity of 20 ml was added the product from example -26 C (30 mg, of 0.085 mmol), methyl 2-(methylamino)acetate (10.0 mg, 0,097 mmol) and N,N-dimethylformamide (0,85 ml) and then O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium sexafter-phosphate (from 39.0 mg, is 0.102 mmol) and diisopropylethylamine (30,0 μl, 0,176 mmol). After 4 hours stirring at room temperature, the solvent was evaporated and the residue was purified by OSU RP-HPLC with getting this product. The NMR spectrum consists of a mixture of rotamers, and registered home rotamer.1H NMR (500 MHz, DMSO-d6) δ ppm 0,98-1,20 (m, 2H), 1,38-of 1.55 (m, 2H), 1.70 to of 1.93 (m, 5H), 2,20-of 2.33 (m, 2H), 2,78-is 2.88 (m, 1H), 3,01-3,10 (m, 3H), of 3.64 (s, 3H), 4,08 (s, 2H), 7.03 is-7,19 (m, 1H), 7,28-7,41 (m, 2H), 7,66-7,76 (m, 2H), 13,80-14,09 (m, 1H); MS (ESI) m/z 438 [M+H]+.

Example 26E

TRANS N-methyl-N-[(4-(4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]-phenyl}cyclohexyl)acetyl]glycine

In scintillation vessel with a capacity of 20 ml was downloaded the product from example 26D (12 mg, or 0.027 mmol), 80% tetrahydrofuran in water and lithium hydroxide (2.00 mg, 0,048 mmol) and was shaken for 6 hours. Then the reaction mixture was acidified using 1N. HCl, filtered and evaporated to dryness to obtain this product. The NMR spectrum consists of a mixture of rotamers, and registered home rotamer.1H NMR (500 MHz, DMSO-d6) δ ppm 1,02-1,20 (m, 2H), 1.41 to 1.55V (m, 2H), 1,74 is 1.91 (m, 5H), 2,22-2,31 (m, 2H), 2,78 is 2.80 (m, 1H), 2,96-3,10 (m, 3H), 3,98 (s, 2H), 7,05-7,19 (m, 1H), 7,27 was 7.45 (m, 2H), 7,60 is 7.85 (m, 2H), 13,98 (s, 1H); MS (ESI) m/z 424 [M+H]+.

Example 27

TRANS (4-{4-[3-(cyclobutylamine)-1H-pyrazole-5-yl]phenyl}-cyclohexyl)acetic acid

A mixture of the product from example 1E (40 mg, 0.12 mmol), cyclobutanol (15 mg, 0.15 mmol), 1,1'-(azodicarbon)- dipiperidino (ADDP) (30 mg, 0.12 mmol) and tributylphosphine (20 mg, 0.1 mmol) in toluene (2 ml) was heated at 90°C in an atmosphere of N2within 6 hours. The mixture was concentrated and purified using RP-HPLC. Granted the military the product is hydrolyzed in accordance with the methodology described in example 1H, obtaining these compounds.1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 in (m, 2H), 1,48 (m, 2H), 1,53 is 1.86 (m, 7H), 2,03 (m, 2H), and 2.14 (d, J=7.01 Hz, 2H), a 2.36 (m, 2H), 2,47 (m, 1H), and 4.75 (m, 1H), 6,02 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H), 12,19 (USS, 2H); MS (ESI) m/z 355,1 [M+H]+.

Example 28

TRANS (4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}-cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example -26 C.1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 million is 1.23 (m, 2H), 1.41 to of 1.57 (m, 2H), 1,58-to 1.67 (m, 1H), 1,69-to 1.77 (m, 1H), 1,78-of 1.88 (m, 4H), 2,12-of 2.20 (m, 2H), 7,05-7,17 (m, 1H), 7,26-7,41 (m, 2H), 7,62-of 7.82 (m, 2H), 12,00 (s, 1H), 13,89-14,07 (m, 1H) ; MS (ESI) m/z 354 [M+H]+.

Example 29

TRANS (4-{4-[3-(cyclopropylmethoxy)-1H-pyrazole-5-yl]-phenyl}cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)alanon (methyl bromide)cyclopropane.1H NMR (500 MHz, DMSO-d6) δ ppm 0.31 in (m, 2H), 0,55 (m, 2H), 1,13 (m, 2H), 1,23 (m, lH), to 1.48 (m, 2H), 1.56 to to 1.86 (m, 5H), and 2.14 (d, J=7,02 Hz, 2H), 2,47 (m, 1H), 3,90 (d, J=7,02 Hz, 2H), the 6.06 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H), 12,20 (USS, 1H); MS (ESI) m/z 355,1 [M+H]+.

Example 30

TRANS 2-(4-{4-[3-(cyclohexylmethoxy)-1H-pyrazole-5-yl]-phenyl}cyclohexyl)-N-hydroxyacetamido

In scintillation vessel had downloaded the product from example 72 (16 mg, of 0.038 mmol), sodium hydroxide (40 mg, 0.10 mmol), hydroxyl which (33 mg, 0.1 mmol) and 4 ml of methanol. The vial was placed in a shaking device at room temperature over night. The mixture was acidified with 10% HCl, concentrated and purified using RP-HPLC with obtaining these compounds.1H NMR (500 MHz, DMSO-d6) δ ppm 0,97-of 1.84 (m, 20H), a 1.88 (d, J=of 6.71 Hz, 2H), 2,47 (m, 1H), 3,88 (m, 2H), the 6.06 (s, 1H), 7,29 (d, J=8,24 Hz, 2H), to 7.59 (d, J=8,24 Hz, 2H), 8,67 (USS, 1H), 10,35 (s, 1H), 12,21 (USS, 1H); MS (ESI) m/z 412,2 [M+H]+.

Example 31

TRANS (4-{4-[3-(pyridine-2-ylethoxy)-1H-pyrazole-5-yl]-phenyl}cyclohexyl)acetic acid

The named compound was obtained from the product of example 67 using the method described in example 1H.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,48 (m, 2H), 1,65-to 1.87 (m, 5H), and 2.14 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), from 5.29 (s, 2H), 6,17 (s, 1H), 7,28 (d, J=8,29 Hz, 2H), 7,41 (m, 1H), 7,58 (m, 1H), 7,60 (d, J=8,29 Hz, 2H), 7,92 (m, 1H), at 8.60 (m, 1H), 12,20 (USS, 1H); MS (ESI) m/z 392,1 [M+H]+.

Example 32

TRANS (4-{4-[3-(tetrahydrofuran-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid

The named compound was obtained from the product of example 68 using the method described in example 1H.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,48 (m, 2H), 1,61 is 1.91 (m, 8H), to 1.98 (m, 1H), and 2.14 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), 3,66 (m, 1H), 3,78 (m, 1H), Android 4.04 (m, 2H), 4,14 (m, 1H), between 6.08 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), 7,60 (d, J=8,24 Hz, 2H), 12,21 (USS, 2H); MS (ESI) m/z 385,2 [M+H]+.

Example 33

TRANS (4-{4-[4-bromo-3-(cyclobutylmethyl)-1H-pyrazole-5-yl]phenyl}qi is logical)acetic acid

Stage A:

A mixture of the product of example 1E (65 mg, 0.20 mmol), bromelicola (30 mg, 0.20 mmol) and potassium carbonate (28 mg, 0.20 mmol) in N,N-dimethylformamide was heated at 75°C in atmosphere N2within 6 hours. The reaction mixture was then acidified with 4n. HCl, filtered through celite and concentrated.

Stage B:

The product from step A hydrolyzed using the method described in example 1H, getting a named product.1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 in (m, 2H), 1,50 (m, 2H), 1,68-of 1.95 (m, 10H)2,07 (m, 1H), 2,15 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), 2,73 (m, 1H), 4.16 the (d, J=6.75 Hz, 2H), 7,35 (d, J=of 8.28 Hz, 2H), 7.62mm (d, J=of 8.28 Hz, 2H), 12,56 (USS, 1H), 12,56 (USS, 1H); MS (ESI) m/z 447,0 [M+H]+.

Example 34

TRANS-N-hydroxy-2-(4-{4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)ndimethylacetamide

In scintillation vessel had downloaded the product from example 28 (38 mg, 0.1 mmol), sodium hydroxide (40 mg, 0.1 mmol), hydroxylamine hydrochloride (33 mg, 0.1 mmol) and 4 ml of methanol. The reaction vessel was placed in a shaking device at room temperature over night. Then the mixture was acidified with 10% HCl, concentrated and purified using RP-HPLC with obtaining these compounds.1H NMR (500 MHz, DMSO-d6) δ ppm 1,10 (m, 2H), 1,48 (m, 2H), 1,67-of 1.85 (m, 5H), of 1.88 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), 7,12 (s, 1H), 7,34 (d, J=of 8.28 Hz, 2H), 7,72 (d, J=8,24 Hz, 2H), 8,63 (USS, 1H), 10,34 (s, 1H), 13,96 (USS, 1H); MS (ESI) m/z 366,1 [M-H]+.

Example 35

TRANS-N-(methylsulphonyl)-2-(4-{4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)ndimethylacetamide

In scintillation vessel with a capacity of 20 ml was added the product from example -26 C (30 mg, of 0.085 mmol), methanesulfonamide (9,00 mg, 0,088 mmol) and N,N-dimethylformamide (0,85 ml) and then O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium sexafter-phosphate (from 39.0 mg, is 0.102 mmol) and diisopropylethylamine (30 μl, 0,176 mmol). After 4 hours of stirring the solvent was evaporated and the residue was purified using RP-HPLC with obtaining these compounds.1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 a-1,20 (m, 2H), 1,43-of 1.57 (m, 2H), 1,74 is 1.91 (m, 5H), 2,17-of 2.26 (m, 2H), 2,41 is 2.46 (m, 1H), 6,95-7,22 (m, 1H), 7.23 percent-7,44 (m, 2H), of 7.64-of 7.82 (m, 2H), 11,68 (s, 1H), 13,98 (s, 1H); MS (ESI) m/z 430 [M+H]+.

Example 36

TRANS 1-({4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetyl)-L-Proline

The monohydrate of lithium hydroxide (0,022 g, 0.5 mmol) was added to a stirred solution of the product from example 63 (0,065 g, 0.16 mmol) in tetrahydrofuran (5 ml) and water (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 12 hours and then stopped the reaction by adding 1N. HCl. Then extraction was performed with ethyl acetate (3×25 ml), the organic extracts were washed with water, brine, dried (MgSO4), concentrated and purified using RP-HPLC with obtaining these compounds are in the form of a white solid.1H NMR (400 MHz, D IS the CO-d 6) δ ppm 1,05-of 1.18 (m, 2H), 1,40-is 1.51 (m, 2H), 1.70 to 1,95 (m, 8H), 2,11-of 2.27 (m, 3H), 2.40 a-2,49 (m, 1H), 3,50 is 3.57 (m, 2H), 4,22 (DD, J=8,9, 4 Hz, 1H), 6,62 (d, J=2,15 Hz, 1H), 7,25 (d, J=8,3 Hz, 2H), 7,65-of 7.69 (m, 3H); MS (ESI) m/e 382,2 (M+H).

Example 37

TRANS {4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetic acid

Example 37A

TRANS (E)-ethyl 2-(4-(4-(3-(dimethylamino)acryloyl)-phenyl)cyclohexyl)acetate

The product from example 26A (2.14 g, 7,42 mmol) and N,N-dimethylformamide, dimethylacetal (1.42 g, to 11.9 mmol) in N,N-dimethylformamide (20 ml) was heated at 100°C for 16 hours. The solution was cooled to room temperature and added water (20 ml) for 10 minutes. The precipitate was collected by filtration, washed with water (3×20 ml) and dried in vacuum at 50°C techenie 24 hours to obtain the crude product.1H NMR (500 MHz, DMSO-d6) δ ppm 1,11-to 1.21 (m, 5H), 1,43-of 1.55 (m, 2H), 1,63-to 1.82 (m, 5H), 2,22 (d, J=6,76 Hz, 2H), 2,43-2,47 (m, 1H), 2,90 (s, 3H), of 3.12 (s, 3H), 4,07 (kV, J=7,06 Hz, 2H), 5,79 (d, J=12,27 Hz, 1H), 7,27 (d, J=8,59 Hz, 2H), to 7.67 (d, J=12,27 Hz, 1H), 7,79 (d, J=8,59 Hz, 2H); MS (ESI) m/z 344,1,0 [M+H]+.

Example 37B

TRANS ethyl 2-(4-(4-(1H-pyrazole-3-yl)phenyl)cyclohexyl)acetate

The product of example 37B (1.2 g, 3.5 mmol) was dissolved in ethanol (20 ml), then was added 35% aqueous hydrazine (2.0 g, 22 mmol). The solution was heated at 80°C for 2 hours and then evaporated to dryness. The crude product was re-dissolved in ethyl acetate (100 ml), washed with H2O (2×10 ml), brine (10 ml) and dried over Na2 SO4. Removal of solvent gave the crude product which was then purified using flash column-chromatography, elwira a mixture of 1:1 ethyl acetate/hexane with obtaining these compounds are in the form of a cream solid color.1H NMR (500 MHz, DMSO-d6) δ ppm 1,11-to 1.21 (m, 5H), 1,43-of 1.52 (m, 2H), 1.70 to to 1.82 (m, 5H), 2,22 (d, J=6.75 Hz, 2H), 2,46-2,49 (m, 1H), 4,07 (kV, J=7,06 Hz, 2H), 6,63 (d, J=1,84 Hz, 1H), 7,25 (d, J=of 7.36 Hz, 2H), 7,62-to 7.77 (m, 3H), 12,77(USS, 1H); MS (ESI) m/z 313,0 [M+H]+.

Example 37C

TRANS {4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetic acid

In scintillation vessel had downloaded the product from example 37B (31,3 mg, 0,100 mmol), lithium hydroxide (21 mg, 0.50 mmol) and 10 ml of a mixture of 4:1 tetrahydrofuran/water and placed in a shaking device over night at room temperature. The reaction mixture neutralize by adding 4M HCl and the resulting mixture was concentrated and purified using RP-HPLC with getting this product.1H NMR (500 MHz, DMSO-d6) δ ppm 1,07-1,17 (m, 2H), 1,42-of 1.53 (m, 2H), 1.70 to a 1.88 (m, 5H), and 2.14 (d, J=6.75 Hz, 2H), 2,44-2,48 (m, 1H), 6,63 (d, J=2,15 Hz, 1H), 7,26 (d, J=7,97 Hz, 2H), 7,65 (d, J=2,15 Hz, 1H), 7,68 (d, J=7,97 Hz, 2H), 12,46 (USS, 2H); MS (ESI) m/z 285,0 [M+H]+.

Example 38

TRANS (4-{4-[4-bromo-3-(cyclopropylmethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 33, substituting (methyl bromide)cycle is butane (methyl bromide)cyclopropane. 1H NMR (500 MHz, DMSO-d6) δ ppm 0,34 (m, 2H), 0,56 (m, 2H), 1.14 in (m, 2H), 1.27mm (m, 1H), 1,48 (m, 2H), 1,68-to 1.87 (m, 5H), and 2.14 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), was 4.02 (d, J=7,06 Hz, 2H), 7,38 (d, J=8,24 Hz, 2H), 7.62mm (d, J=8,24 Hz, 2H,), 12,00 (USS, 1H), 12,55 (USS, 1H); MS (ESI) m/z 433,0 [M+H]+.

Example 39

TRANS ethyl [4-(4-{3-[2-(1-substituted)-2-hydroxyethoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetate

The named compound was obtained in accordance with the procedure described in example 1G.1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 in (m, 2H), 1,19 (t, J=to 7.32 Hz, 3H), 1,42 of 1.99 (m, 22H), 2,22 (d, J=of 6.71 Hz, 2H), 2,47 (m, 1H), 3,89 (DD, J1=10,38 Hz, J2=7,94 Hz, 1H), was 4.02 (m, 1H), 4,06 (kV, J=to 7.32 Hz, 2H), 4,24 (DD, J1=10,37 Hz, J2=2,74 Hz, 1H), 4,71 (s, 1H), 6,07 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), to 7.59 (d, J=8,24 Hz, 2H), 12,21 (USS, 1H); MS (ESI) m/z 507,4 [M+H]+.

Example 40

TRANS methyl N-methyl-N-[(4-{4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetyl]glycinate

In scintillation vessel with a capacity of 20 ml was added the product of example 26B (30 mg, of 0.085 mmol), methyl 2-(methylamino)acetate (10.0 mg, 0,097 mmol) and N,N-dimethylformamide (0,85 ml) and then O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium sexafter-phosphate (from 39.0 mg, is 0.102 mmol) and diisopropylethylamine (30 μl, 0,176 mmol). After 4 hours of stirring the solvent was evaporated and the residue was purified using RP-HPLC with getting this product. MS (ESI) m/z 438 [M+H]+.

Example 41

TRANS [4-(4-{3-[(6,7-dimethoxy-2-oxo-2H-chromen-4-yl)-methoxy]-1H-feast of the ol-5-yl}phenyl)cyclohexyl]acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)Etalon 4-(methyl bromide)-6,7-dimethoxy-2H-chromen-2-it.1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 in (m, 2H), 1,48 (m, 2H), 1,54 is 1.86 (m, 5H), and 2.14 (d, J=7,02 Hz, 2H), 2,47 (m, 1H), 3,84 (s, 3H), 3,88 (s, 3H), 5,51 (s, 2H), 6,28 (m, 1H), 6,33 (s, 1H), 7,12 (s, 1H), 7,21 (s, 1H), 7,30 (d, J=8,24 Hz, 2H), to 7.61 (d, J=8,24 Hz, 2H), KZT 12.39 (USS, 1H); MS (ESI) m/z 519,4 [M+H]+.

Example 42

TRANS N-2H-tetrazol-5-yl-2-(4-(4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)ndimethylacetamide

In scintillation vessel with a capacity of 20 ml was added the product from example 28 (30 mg, of 0.085 mmol), 2H-tetrazol-5-amine (8,00 mg, 0,088 mmol) and N,N-dimethylformamide (0,85 ml) and then O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium sexafter-phosphate (from 39.0 mg, is 0.102 mmol) and diisopropylethylamine (30 μl, 0,176 mmol). After 4 hours of stirring the solvent was evaporated and the residue was purified using RP-HPLC with getting this product.1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 a-1,26 (m, 2H), 1,43-of 1.57 (m, 2H), 1,76-of 1.92 (m, 5H), 2,36-to 2.41 (m, 2H), of 6.96-of 7.23 (m, 1H), 7.23 percent-7,46 (m, 2H), EUR 7.57-7,80 (m, 2H), 11,99 (s, 1H), 13,98 (s, 1H), 15,83 (s, 1H); MS (ESI) m/z 420 [M+H]+.

Example 43

TRANS methyl {4-[4-(3-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetate

A mixture of the product of example 1E (35 mg, 0.10 mmol), 1-(methyl bromide)-2-(triptoreline)benzene (26 mg, 0.10 mmol) and potassium carbonate (14 mg, 0.10 mmol) in N,N-Dimethylol amide ( ml) was heated at 75°C in an atmosphere of N 2within 6 hours. Then the reaction mixture was cooled to room temperature and filtered through celite, washed with ethyl acetate and then evaporated to obtain oil. The oil was directly processed by the monohydrate of lithium hydroxide (10 mg, 0.24 mmol) in a mixed solvent (2 ml of tetrahydrofuran, 1 ml of H2O) and was shaken at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in a mixture of 1:1 methanol/DMSO without acidification on the basis of which was formed methyl ester of the remaining non-hydrolyzed ethyl ester. Purification using RP-HPLC gave the product named.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,47 (m, 2H), 1.70 to to 1.87 (m, 5H), and 2.14 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), 3,60 (s, 3H), of 5.25 (s, 2H), 6,14 (s, 1H), 7,29 (d, J=of 8.28 Hz, 2H), 7,38-7,53 (m, 3H), 7,58 (d, J=of 8.28 Hz, 2H), 7,66 (DD, J1=7,37 Hz, J2=1,84 Hz, 1H), 12,32 (USS, 1H); MS (ESI) m/z 489,3 [M+H]+.

Example 44

TRANS ethyl 5-{4-[4-(2-ethoxy-2-oxoethyl)cyclohexyl]-phenyl}-1H-pyrazole-3-carboxylate

To a solution of the product from example 26A (0.9 g, 0.3 mmol) in 20 ml of tetrahydrofuran at -78°C was added diisopropylamide lithium (3 ml, 2M solution in tetrahydrofuran, 6 mmol). The mixture was stirred at -78°C for 30 minutes and then was added dropwise a solution of diethyloxalate (0.46 g, 30 mmol) in 5 ml of tetrahydrofuran. The reaction mixture was allowed to warm to room rate is ature for 30 minutes and then stirred at room temperature for 1 hour. Then the reaction mixture was poured into ice water (100 ml) and then extracted with ethyl acetate (2×100 ml). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting oil was treated with hydrazine (2 ml, 35% in water) in a mixed solvent (50 ml 1,4-dioxane, 0.5 ml of acetic acid under reflux for 2 hours. The reaction mixture was then filtered through celite, washed with ethyl acetate, concentrated and purified using flash column-chromatography, elwira 5% ethyl acetate in hexano, to obtain the titled compound as a colorless oil.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,19 (t, J=7,02 Hz, 3H), 1,32 (t, J=7,02 Hz, 3H), 1,49 (m, 2H), 1.70 to to 1.87 (m, 5H), 2,22 (d, J=of 6.71 Hz, 2H), 2,47 (m, 1H), 4,07 (kV, J=7,02 Hz, 2H), 4,80 (kV, J=7,02 Hz, 2H), 7,16 (s, 1H), 7,30 (d, J=8,24 Hz, 2H), 7,74 (d, J=8,24 Hz, 2H), 12,32 (USS, 1H); MS (ESI) m/z 385,2 [M+H]+.

Example 45

TRANS [4-(4-{3-[(2-hydroxycyclohexyl)oxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid

A mixture of the product from example 1E (40 mg, 0.12 mmol), cyclohexane-1,2-diol (15 mg, 0.15 mmol), 1,1'-(azodicarbon)dipiperidino (ADDP) (30 mg, 0.12 mmol) and tributylphosphine (20 mg, 0.1 mmol) in toluene (2 ml) was heated at 90°C in an atmosphere of N2within 6 hours. The mixture was concentrated and purified using RP-HPLC. The selected product gidrolizom is whether in accordance with the methodology described in example 1H, getting a named product.1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 a-to 1.87 (m, 17H), and 2.14 (d, J=6,72 Hz, 2H), 2,47 (m, 1H), 3,83 (m, 1H), 4,17 (m, 1H), the 6.06 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), 7,31 (m, 1H), 7,60 (d, J=8,24 Hz, 2H), 12,05 (USS, 1H); MS (ESI) m/z 399,2 [M+H]+.

Example 46

TRANS {4-[4-(3-hydroxy-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid

The named compound was obtained using the procedure described in example 1H, substituting the product from example 1G product from example 1E.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,46 (m, 2H), 1,53-to 1.87 (m, 5H), and 2.14 (d, J=7,02 Hz, 2H), 2,47 (m, 1H), 5,86 (s, 1H), 7,26 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H); MS (ESI) m/z 301,0 [M+H]+.

Example 47

TRANS methyl (4-{4-[3-(cyclohexyloxy)-1H-pyrazole-5-yl]-phenyl}cyclohexyl)acetate

A mixture of the product from example 1E (40 mg, 0.12 mmol), cyclohexanol (15 mg, 0.15 mmol), 1,1'-(azodicarbon)-dipiperidino (ADDP) (30 mg, 0.12 mmol) and tributylphosphine (20 mg, 0.1 mmol) in toluene (2 ml) was heated at 90°C in an atmosphere of N2within 6 hours. The reaction mixture was filtered through celite, washed with ethyl acetate and concentrated. The residue was then subjected to hydrolysis using monohydrate of lithium hydroxide (10 mg, 0.24 mmol) in a mixed solvent (2 ml of tetrahydrofuran, 1 ml of H2O). It was placed in a shaking device at room temperature over night. The reaction mixture was concentrated and osteoclastoma in a mixture of 1:1 methanol/DMSO without acidification, after which formed the methyl ether of the remaining non-hydrolyzed ethyl ester. Purification using RP-HPLC gave the product named.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,2-and 1.56 (m, 8H), 1,67 is 1.86 (m, 7H), of 1.97 (m, 2H), and 2.14 (d, J=of 6.71 Hz, 2H), 2,47 (m, 1H), 3,60 (s, 3H), 4,39 (m, 1H), the 6.06 (s, 1H), 7,27 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H), 12,20 (USS, 1H); MS (ESI) m/z 383,2 [M+H]+.

Example 48

TRANS [4-(4-{2-[(3-methoxyphenyl)amino]-1,3-thiazol-4-yl}-phenyl)cyclohexyl]acetic acid

Example 48A

TRANS ethyl {4-[4-(bromoacetyl)phenyl]cyclohexyl} acetate

To the solution containing the product from example 1B (1.5 g, 6.1 mmol) and AlCl3(2.4 g, 18 mmol) in 10 ml of dichloromethane, at 0°C was added bromacetyl bromide (0,55 ml, 6.2 mmol). The mixture was stirred at room temperature for a time from 30 minutes to one hour. After completion of the reaction, monitored by means of thin layer chromatography, the reaction mixture was poured into cooled with ice water (100 ml) and was extracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed under reduced pressure and the resulting oil was purified flash chromatography (ethyl acetate/hexane, 1/8) to give the titled compound as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,19 (t, J=7,06 Hz, 3H), 1,50 (m, 2), 1,70-of 1.85 (m, 5H), 2,22 (d, J=6.75 Hz, 2H), has 2.56 (m, 1H), 4,07 (kV, J=7,06 Hz, 3H), 4,88 (s, 2H), 7,41 (d, J=of 8.28 Hz, 2H), of 8.92 (d, J=of 8.28 Hz, 2H); MS (ESI) m/z 367,1 [M+H]+.

Example 48B

TRANS [4-(4-{2-[(3-methoxyphenyl)amino]-1,3-thiazol-4-yl}-phenyl)cyclohexyl]acetic acid

1-(3-Methoxyphenyl)-2-thiourea (0.01 g, 0,054 mmol) was added to a solution of the product from example 48A (0.02 g, 0,054 mmol) in ethanol (0.5 ml) and heated at 80°C for 1 hour. The solvent was then removed in vacuum and the residue was dissolved in tetrahydrofuran (1 ml) and water (0.5 ml). To the reaction mixture were added monohydrate of lithium hydroxide (0.005 g, 0.1 mmol) and stirred at 50°C for 3 hours. The solvents were then removed and the residue was purified using RP-HPLC with obtaining these compounds are in the form of a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm 1,09-of 1.18 (m, 2H), 1,45-and 1.54 (m, 2H), 1,62 was 1.69 (m, 1H), 1.70 to 1.77 in (m, 1H), 1,80-of 1.88 (m, 4H), 2,13 (d, J=7 Hz, 2H), of 3.78 (s, 3H), is 6.54 (DD, J=8,24 and 1.83 Hz, 1H), 7,10-7,16 (m, 1H), 7,20-7,27 (m, 1H), 7.29 trend (d, J=8,24 Hz, 2H), 7,51-7,56 (m, 1H), 7,79-7,83 (d, J=8,24 Hz, 2H), of 10.25 (s, 1H), 12,05 (s, 1H); MS (ESI) m/e 423,2 (M+H).

Example 49

TRANS ethyl (4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]-phenyl}cyclohexyl)acetate

The named compound was obtained using the procedure described in example 26B.

Example 50

TRANS 2-methyl-N-[(4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetyl]alanine

In scintillation vessel with a capacity of 20 ml was loaded product from the use of the and 73 (12.0 mg, or 0.027 mmol), dichloromethane (1 ml) and triperoxonane acid (0.5 ml) and the reactor was shaken for 6 hours at room temperature. Then the reaction solvent was evaporated and the residue was dissolved in toluene and evaporated to obtain the named product.1H NMR (500 MHz, DMSO-d6) δ ppm 1,02-of 1.15 (m, 2H), 1,23-of 1.30 (m, 1H), 1,31-of 1.35 (m, 6H), 1,40-of 1.53 (m, 2H), 1.70 to of 1.78 (m, 1H), 1,76-to 1.87 (m, 4H), 1,92-2,03 (m, 2H), 6,97-7,21 (m, 1H), 7.24 to 7,46 (m, 2H), 7,60-7,83 (m, 2H), 8,00 (s, 1H), 13,99 (s, 1H); MS (ESI) m/z 438 [M+H]+.

Example 51

TRANS (4-[4-(4-ethyl-1-methyl-1H-pyrazole-3-yl)phenyl] cyclohexyl)acetic acid

In a round bottom flask with a capacity of 100 ml with a magnetic stirrer was loaded the product of example 1B (0.5 g, 2.03 mmol) and 16 ml of dichloromethane. The reaction solution was cooled to 0°C was added in portions AlCl3(0,811 g 6,09 mmol). The mixture was stirred for 20 minutes and then was added dropwise butyrylcholine (251 μl, of 2.44 mmol). After stirring for 15 minutes the reaction mixture is slowly poured into the chemical glass cooled with ice water and diluted with 120 ml of ethyl acetate. Separated the layers and the organic layer was washed for 1H. NaHCO3(×2), brine (×2), dried over Na2SO4and filtered. Evaporation of solvents gave a clear oil. This material was then dissolved in N,N-dimethylformamide (2 ml) and was added to 140 μl of dimethylformamide dimethylacetal. The reaction solution was then heated to 95 the C and stirred at this temperature for 10 hours. Then the reaction solution was cooled to room temperature and the solvents evaporated. The residue was dissolved in 5 ml of ethanol was added methylhydrazine (108 μl, 2.03 mmol). The solution was boiled under reflux for 6 hours. After evaporation of the solvent and dissolved in a mixture of 4:1 tetrahydrofuran/H2O was added lithium hydroxide (100 mg, of 2.38 mmol). The reaction mixture was shaken at room temperature for 10 hours (completion of hydrolysis were determined using TECH) and then filtered. The solvents were evaporated and the residue was dissolved in a mixture of 1:1 DMSO/methanol and purified using RP-HPLC with getting this product.1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 a-1,12 (m, 1H), 1,12-of 1.18 (m, 3H), 1,37-of 1.55 (m, 2H), 1,55 by 1.68 (m, 1H), 1,69-of 1.78 (m, 1H), 1,78-of 1.88 (m, 4H), 2,09-2,19 (m, 2H), 2,41-2,48 (m, 1H), 2,53-2,62 (m, 2H), 3,76-a-3.84 (m, 3H), 7,20-7,28 (m, 2H,), 7,45-of 7.55 (m, 3H); MS (ESI) m/z 327 [M+H]+.

Example 52

TRANS (4-{4-[3-(tetrahydro-2H-Piran-4-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 33, substituting (methyl bromide)CYCLOBUTANE 4-(methyl bromide)tetrahydro-2H-Piran.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,31 (m, 2H), 1,48 (m, 2H), 1.55V is 1.86 (m, 7H), 2,00 (m, 1H), and 2.14 (d, J=of 6.71 Hz, 2H), 2,47 (m, 1H), 3,32 (m, 2H), a 3.87 (m, 2H), 3,94 (d, J=6,40 Hz, 2H), between 6.08 (s, 1H), 7,27 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H), 12,20 (USS, 1H); MS (ESI) m/z 383,2 [M+H]+.

Example 53

<> TRANS (4-{4-[4-bromo-3-(tetrahydro-2H-Piran-4-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 33, substituting (methyl bromide)CYCLOBUTANE 4-(methyl bromide)tetrahydro-2H-Piran.1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 in (m, 2H), of 1.34 (m, 2H), 1,48 (m, 2H), 1,61-of 1.88 (m, 7H), 2,03 (m, 1H), and 2.14 (d, J=7,06 Hz, 2H), 2,47 (m, 1H), 3,36 (m, 2H), a 3.87 (m, 2H), Android 4.04 (d, J=6,44 Hz, 2H), 7,37 (d, J=of 8.28 Hz, 2H), 7.62mm (d, J=of 8.28 Hz, 2H), 11,99 (USS, 1H), 12,57 (USS, 1H); MS (ESI) m/z 477,0 [M+H]+.

Example 54

TRANS {4-[4-(2-{[2-(trifluoromethyl)phenyl]amino}-1,3-thiazol-4-yl)phenyl]cyclohexyl}acetic acid

The named compound was obtained in accordance with the procedure described in example 48B, substituting 1-(3-methoxyphenyl)-2-thiourea, 1-(2-triptoreline)-2-thiourea.1H NMR (500 MHz, DMSO-d6) δ ppm 1,07-of 1.18 (m, 2H), 1,43-of 1.52 (m, 2H), 1,57-to 1.67 (m, IH), 1.70 to 1.77 in (m, IH), 1,80-of 1.88 (m, 4H), and 2.14 (d, J=6,7 Hz, 2H), 7,20-7,25 (m, 3H), 7,32 (t, J=8,24 Hz, 1H), 7.68 per to 7.75 (m, 4H), 8,13 (d, J=8,24 Hz, 1H), 9,46 (s, 1H), 12,02 (s, 1H); MS (ESI) m/e 461,2 (M+H).

Example 55

TRANS [4-(4-{2-[(3,5-dichlorophenyl)amino]-1,3-thiazol-4-yl}phenyl)cyclohexyl]acetic acid

The named compound was obtained in accordance with the procedure described in example 48B, substituting 1-(3-methoxyphenyl)-2-thiourea, 1-(3,5-dichlorophenyl)-2-thiourea.1H NMR (500 MHz, DMSO-d6) δ ppm 1,07-of 1.18 (m, 2H), 1,43-of 1.52 (m, 2H), 1,57 was 1.69 (m, 1H), 1.70 to 1.77 in (m, 1H), 1,80-of 1.88 (m, 4H), and 2.14 (d, J=7 G is, 2H), 7,14 (m, 1H), 7,32 (t, J=8,24 Hz, 1H), was 7.36-7,40 (m, 1H), 7,75-a 7.85 (m, 4H), for 10.68 (s, 1H), 12,02 (s, 1H); MS (ESI) m/e 461,1 (M+H).

Example 56

TRANS methyl (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate

The named compound was obtained in accordance with the procedure described in example 43, substituting 1-(methyl bromide)-2-(trifter-methoxy)benzene (methyl bromide)cyclopentane.1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 in (m, 2H), 1,31 (m, 2H), 1,44 of-1.83 (m, 13H), 2,24 (d, J=of 6.71 Hz, 2H), to 2.29 (m, 1H), 2,47 (m, 1H), 3,60 (s, 3H), 3,95 (d, J=7,02 Hz, 2H), 6,07 (s, 1H), 7,29 (d, J=8,24 Hz, 2H), 7,68 (d, J=8,24 Hz, 2H,), 12,11 (USS, 2H); MS (ESI) m/z 383,2 [M+H]+.

Example 57

TRANS ethyl {4-[4-(3-{[5-(trifluoromethyl)-2-furyl]methoxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetate

The named compound was obtained in accordance with the procedure described in example 1F, substituting 1-adamantylamine 2-(methyl bromide)-5-(trifluoromethyl)furan.1H NMR (500 MHz, DMSO-d6) δ ppm to 1.15 (m, 2H), 1,19 (t, J=7,06 Hz, 3H), of 1.48 (m, 2H), 1,71-of 1.85 (m, 5H), 2,22 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), 4,07 (kV, J=7,06 Hz, 2H), total of 5.21 (s, 2H), x 6.15 (s, 1H), 6,79 (d, J=3,68 Hz, 1H), 7,22 (m, 1H), 7,29 (d, J=of 8.28 Hz, 2H), to 7.59 (d, J=of 8.28 Hz, 2H), 12,35 (USS, 1H); MS (ESI) m/z 477,3 [M+H]+.

Example 58

TRANS [4-(4-{2-[(2-chlorophenyl)amino]-1,3-thiazol-4-yl}-phenyl)cyclohexyl]acetic acid

The named compound was obtained in accordance with the procedure described in example 48B, substituting 1-(3-methoxyphenyl)-2-thiourea, 1-(2-chlorophenyl)-2-thiourea.1H NMR (50 MHz, DMSO-d6) δ ppm 1,07-of 1.18 (m, 2H), 1,43-of 1.52 (m, 2H), 1,57-to 1.67 (m, 1H), 1.70 to 1.77 in (m, 1H), 1,80-of 1.88 (m, 4H), and 2.14 (d, J=7 Hz, 2H), 7,06 (dt, J=8, 1,53 Hz, 1H), 7,27 (d, J=8,24 Hz, 2H), 7,29 (s, 1H), 7,38 (dt, J=8, of 1.53 Hz, 1H), of 7.48 (DD, J=8, 1,53 Hz, 1H), 7,78 (d, J=8,24 Hz, 1H), of 8.47 (d, J=8,24 Hz, 1H), to 9.66 (s, 1H), 12,02 (s, 1H); MS (ESI) m/e 427,1 (M+H).

Example 59

TRANS (4-{4-[1,2-bis(cyclobutylmethyl)-5-oxo-2,5-dihydro-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 3, substituting 2-bromo-1-(4-methoxyphenyl)alanon (methyl bromide)CYCLOBUTANE.1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 in (m, 2H), 1,48 (m, 2H), 1,55-of 1.94 (m, 15H), 2,04 (m, 2H), 2,15 (d, J=of 6.71 Hz, 2H), 2,47 (m, 1H), 2,69-of 2.72 (m, 2H), 3,92 (d, J=7,02 Hz, 2H), was 4.02 (d, J=of 6.71 Hz, 2H), 5,71 (s, 1H), 7,33 (m, 4H), 12,00 (USS, 1H); MS (ESI) m/z 437,3 [M+H]+.

Example 60

TRANS {4-[4-(2-{[3-(trifluoromethyl)phenyl]amino}-1,3-thiazol-4-yl)phenyl]cyclohexyl}acetic acid

The named compound was obtained in accordance with the procedure described in example 48B, substituting 1-(3-methoxyphenyl)-2-thiourea, 1-(3-triptoreline)-2-thiourea.1H NMR (500 MHz, DMSO-d6) δ ppm 1,07-of 1.18 (m, 2H), 1,43-of 1.52 (m, 2H), 1,57-to 1.67 (m, 1H), 1.70 to 1.77 in (m, 1H), 1,80-of 1.88 (m, 4H), of 2.15 (d, J=7 Hz, 2H), 7,25-7,35 (m, 3H), 7,35 (s, 1H), EUR 7.57 (d, J=7.9 Hz, 1H), 7,80-of 7.90 (m, 3H), scored 8.38 (, 1H), 10,63 (s, 1H), 12,02 (s, 1H); MS (ESI) m/e 461,2 (M+H).

Example 61

TRANS methyl (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]-phenyl}cyclohexyl)acetate

The named compound was obtained according to the following method, described in example 47, substituting cyclohexanol to Cyclopentanol.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,48 (m, 2H), 1,53 is 1.91 (m, 13H), 2,24 (d, J=6,72 Hz, 2H), 2,47 (m, 1H), 3,60 (s, 3H), 4,89 (m, 1H), 6,04 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H), 12,00 (USS, 2H); MS (ESI) m/z 383,2 [M+H]+.

Example 62

TRANS ethyl (4-{4-[3-(2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate

The named compound was obtained in accordance with the procedure described in example 1F, substituting 1-adamantylamine 2-(methyl bromide)-2,3-dihydrobenzo[b][1,4]dioxin.1H NMR (500 MHz, DMSO-d6) δ ppm to 1.15 (m, 2H), 1,19 (t, J=7,06 Hz, 3H), of 1.48 (m, 2H), 1,71-of 1.85 (m, 5H), 2,24 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), 4,07 (kV, J=7,06 Hz, 2H), 4,12 (DD, J; = 11,35 Hz, J2 = 7,06 Hz, 1H), 4,34 (m, 2H), to 4.41 (DD, J1=11,35 Hz, J2=at 2.45 Hz, 1H), 4,57 (m, 1H), 6,14 (s, 1H), 6,82-6,94 (m, 4H), 7,29 (d, J=of 8.28 Hz, 2H), to 7.59 (d, J=of 8.28 Hz, 2H), of 12.33 (USS, 1H); MS (ESI) m/z 477,3 [M+H]+.

Example 63

TRANS methyl 1-({4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}-acetyl)-L-prolinate have been obtained

The hydrochloride of the methyl ester of L-Proline (0.03 g, 0.18 mmol) was added to a stirred solution of the product of example 37C (0.05 g, 0,17 mmol), hydrochloride of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (0,g, 0.22 mmol), hydrate of 1-hydroxybenzotriazole (0,g, 0.22 mmol) and N-methylmorpholine (0.1 ml, 0.87 mmol) in N,N-dimethylformamide (4 ml) at room temperature. The reaction mixture was stirred at room temperature for 12 hours and then stopped the reaction by adding water. The reaction mixture was then extracted with ethyl acetate (3×25 ml), the organic extracts were washed with water, brine, dried (MgSO4) and concentrated to obtain these compounds in the form of a clear oil.1H NMR (500 MHz, DMSO-d6) δ ppm 1,09-of 1.18 (m, 2H), 1,40-is 1.51 (m, 2H), 1,75 is 1.86 (m, 6H), 1,88-of 1.94 (m, 2H), 2,13-of 2.27 (m, 3H), 2.40 a-2,49 (m, 1H), 3,51-to 3.58 (m, 2H), 3,61 (s, 3H), 4,30 (DD, J=10, 5 Hz, 1H), only 6.64 (d, J=3 Hz, 1H), 7,27 (d, J=10 Hz, 2H), 7,66-7,72 (m, 3H).

Example 64

TRANS [4-(4-{2-[(2-were)amino]-1,3-thiazol-4-yl}-phenyl)cyclohexyl]acetic acid

The named compound was obtained in accordance with the procedure described in example 48B, substituting 1-(3-methoxyphenyl)-2-thiourea, 1-(2-were)-2-thiourea.1H NMR (500 MHz, DMSO-d6) δ ppm 1,07 is 1.16 (m, 2H), 1,43-of 1.52 (m, 2H), 1,57-to 1.67 (m, 1H), 1.70 to 1.77 in (m, 1H), 1,80-of 1.88 (m, 4H), and 2.14 (d, J=7 Hz, 2H), to 2.29 (s, 3H), 7,00-7,05 (m, 1H), 7,15-7,19 (m, 2H), 7,20-7,25 (m, 3H), of 7.75 (d, J=8,24 Hz, 2H), to 7.99 (d, J=8,24 Hz, 1H), of 9.30 (s, 1H), 12,02 (s, 1H); MS (ESI) m/e 407,2 (M+H).

Example 65

TRANS [4-(4-{2-[(4-chlorophenyl)amino]-1,3-thiazol-4-yl}phenyl)cyclohexyl]acetic acid

The named compound was obtained in accordance with the procedure described in example 48B, substituting 1-(3-methoxyphenyl)-2-thiourea, 1-(4-chlorophenyl)-2-thiourea.1H NMR (500 MHz, DMSO-d6) δ ppm 1,07-of 1.18 (m, 2H), 1,43-of 1.52 (m, 2H), 1,57-to 1.67 (m, 1H), 1.70 to 1.77 in (m, 1H), 1,80-of 1.88 (m, 4H), of 2.15 (d, J=7 Hz, 2H), 7,27-7,29 (m, 3H), 7,39 (d, J=9 Hz, 2H), of 7.75 (d, J=9 Hz, 2H), 7,81 (d, J=8,24 Hz, 2H), 10,4 (s, 1H), a 12.03 (s, 1H); MS (ESI) me 427,1 (M+H).

Example 66

TRANS [4-(4-{2-[(3-chlorophenyl)amino]-1,3-thiazol-4-yl}-phenyl)cyclohexyl]acetic acid

The named compound was obtained in accordance with the procedure described in example 48B, substituting 1-(3-methoxyphenyl)-2-thiourea, 1-(3-chlorophenyl)-2-thiourea.1H NMR (500 MHz, DMSO-d6) δ ppm 1,07-of 1.18 (m, 2H), 1,43-of 1.52 (m, 2H), 1,57-to 1.67 (m, 1H), 1.70 to 1.77 in (m, 1H), 1,80-of 1.88 (m, 4H), of 2.15 (d, J=7 Hz, 2H), 7,00 (DD, J=8, 1,53 Hz, IH), 7,30 (d, J=8,24 Hz, 2H), was 7.36 (t, J=8 Hz, 1H), EUR 7.57 (DD, J=8, 1,53 Hz, 1H), 7,80 (d, J=8,24 Hz, 2H), 7,98 (t, J=1,53 Hz, 1H), 10,48 (s, 1H), a 12.03 (s, 1H); MS (ESI) m/e 427,1 (M+H).

Example 67

TRANS ethyl (4-{4-[3-(pyridine-2-ylethoxy)-1H-pyrazole-5-yl]-phenyl}cyclohexyl)acetate

The named compound was obtained in accordance with the procedure described in example 1F, substituting 1-adamantylamine 2-(methyl bromide)pyridine.1H NMR (500 MHz, DMSO-d6) δ ppm 1.14 in (m, 2H), 1,19 (t, J=to 7.32 Hz, 3H), of 1.48 (m, 2H), 1,71-of 1.85 (m, 5H), 2,22 (d, J=of 6.71 Hz, 2H), 2,47 (m, 1H), 4,07 (kV, J=to 7.32 Hz, 2H), 5,80 (s, 2H), 6,18 (s, 1H), 7,29 (d, J=of 8.28 Hz, 2H), 7,43 (m, 1H), to 7.59 (m, 3H), 7,94 (m, 1H), 8,61 (m, 1H), of 12.33 (USS, 1H); MS (ESI) m/z 420,2 [M+H]+.

Example 68

TRANS ethyl (4-{4-[3-(tetrahydrofuran-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate

The named compound was obtained in accordance with the procedure described in example 1F, substituting 1-adamantylamine 2-(methyl bromide)tetrahydrofuran.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,19 (t, J=7,02 Hz, 3H), of 1.48 (m, 2H), 1,61 is 1.91 (m, 8H), to 1.98(m, 1H), 2,22 (d, J=6.75 Hz, 2H), 2,47 (m, 1H), to 3.67 (m, 1H), 3,78 (m, 1H), Android 4.04 (m, 2H), 4,07 (kV, J=7,02 Hz, 3H), 4,14 (m, 1H), between 6.08 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H), 12,21 (USS, 1H); MS (ESI) m/z 413,2 [M+H]+.

Example 69

TRANS (4-{4-[3-(tetrahydro-2H-Piran-4-yloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid

A mixture of the product from example 1E (40 mg, 0.12 mmol), tetrahydro-2H-Piran-4-ol (15 mg, 0.15 mmol), 1,1'-(azodicarbon)dipiperidino (ADDP) (30 mg, 0.12 mmol) and tributylphosphine (20 mg, 0.1 mmol) in toluene (2 ml) was heated at 90°C in an atmosphere of N2within 6 hours. The mixture was concentrated and purified using RP-HPLC and the selected product is hydrolyzed in accordance with the method described in example 1H, getting a named product.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,48 (m, 2H), 1,62 (m, 2H), 1,67 - of 1.88 (m, 5H), 2,02 (m, 2H), and 2.14 (d, J=7.01 Hz, 2H), 2,47 (m, 1H), 3.46 in (m, 2H), 3,85 (m, 2H), to 4.62 (m, 1H), 6,10 (s, 1H), 7,28 (d, J=8,24 Hz, 2H), 7,58 (d, J=8,24 Hz, 2H), 12,16 (USS, 2H); MS (ESI) m/z 385,1 [M+H]+.

Example 70

TRANS ethyl (4-{4-[2-(formylamino)-1,3-oxazol-4-yl]phenyl}-cyclohexyl)acetate

A mixture of the product from example 48A (100 mg, 0.27 mmol) and urea (33 mg, 0.54 mmol) in N,N-dimethylformamide (5 ml) was heated at 90-95°C in an atmosphere of N2within 2 hours. The mixture was concentrated and purified using RP-HPLC with getting this product.1H NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,19 (t, J=7,05 Hz, 3H), of 1.48 (m, 2H), 1,69-of 1.85 (m, 5H), 2,22 (d, J=6.75 Hz, 2H), 2,47 m, 1H), 4,07 (kV, J=7,05 Hz, 3H), 4,14 (m, 1H), 7,28 (d, J=8,29 Hz, 2H), 7,63 (d, J=8,29 Hz, 2H), 8,29 (s, 1H), 8,95 (USS, 1H), 11,50 (USS, 1H); MS (ESI) m/z 356,9 [M+H]+.

Example 71

TRANS 1-({4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetyl)-L-prolinamide

The named compound was obtained in accordance with the procedure described in example 63, substituting hydrochloride methyl ester of L-Proline to L-prolinamide.1H NMR (400 MHz, DMSO-d6) δ ppm 1,05-of 1.18 (m, 2H), 1,40-is 1.51 (m, 2H), 1.70 to 1,95 (m, 8H), 2,11-of 2.27 (m, 3H), 2.40 a-2,49 (m, 1H), 3,34-3,62 (m, 2H), 4,22 (DD, J=8,9, 4 Hz, 1H), 6,65 (d, J=2,15 Hz, 1H), 7,27 (d, J=8,3 Hz, 2H), 7,65-of 7.69 (m, 3H); MS (ESI) m/e 381,2 (M+H).

Example 72

TRANS ethyl (4-{4-[3-(cyclohexylmethoxy)-1H-pyrazole-5-yl]-phenyl}cyclohexyl)acetate

The named compound was obtained in accordance with the procedure described in example 1F, substituting 1-adamantylamine (methyl bromide)cyclohexane.1H NMR (500 MHz, DMSO-d6) δ ppm 0,96-of 1.84 (m, 23H), 2,22 (d, J=of 6.71 Hz, 2H), 2,47 (m, 1H), 3,89 (m, 2H), 4,06 (kV, J=7,02 Hz, 2H), the 6.06 (s, 1H), 7,29 (d, J=8,24 Hz, 2H), to 7.59 (d, J=8,24 Hz, 2H), 12,21 (USS, 1H); MS (ESI) m/z 425,2 [M+H]+.

Example 73

TRANS tert-butyl 2-methyl-N-[(4-(4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetyl]alanine

In scintillation vessel with a capacity of 20 ml was added the product from example 28 (30 mg, of 0.085 mmol), tert-butyl 2-amino-2-methylpropanoate (15,0 mg, 0,088 mmol) and N,N-dimethylformamide (0,85 ml), then O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate(39,0 mg, is 0.102 mmol) and diisopropylethylamine (30 μl, 0,176 mmol). After 4 hours of stirring the solvent was evaporated and the residue was purified using RP-HPLC with getting this product.1H NMR (500 MHz, DMSO-d6) δ ppm 1,01-of 1.16 (m, 2H), of 1.26 to 1.31 (m, 6H), of 1.35 (s, 9H), 1,40-of 1.53 (m, 2H), 1,68-to 1.77 (m, 1H), 1.77 in-1,90 (m, 4H), 1.93 and-2,02 (m, 2H), 8,01 (s, 1H), 13,98 (s, 1H); MS (ESI) m/z 494 [M+H]+.

Example 74

TRANS (4-{4-[2-(formylamino)-1,3-oxazol-4-yl]phenyl}- cyclohexyl)acetic acid

The named compound was obtained by hydrolysis of the product of example 70 using the method described in example 1H.1NMR (500 MHz, DMSO-d6) δ ppm of 1.13 (m, 2H), 1,48 (m, 2H), 1,63 is 1.91 (m, 5H), of 2.15 (d, J=7,06 Hz, 2H), 2,47 (m, 1H), 4,07 (kV, J=7,05 Hz, 3H), 4,14 (m, 1H), 7,28 (d, J=of 8.28 Hz, 2H), 7,63 (d, J=of 8.28 Hz, 2H), 8,29 (s, 1H), 8,96 (USS, 1H), 11,64 (USS, 2H); MS (ESI) m/z 329,0 [M+H]+.

Example 75

TRANS [4-(4-{2-[(2-forfinal)amino]-1,3-thiazol-4-yl}-phenyl)cyclohexyl]acetic acid

The named compound was obtained in accordance with the procedure described in example 48B, substituting 1-(3-methoxyphenyl)-2-thiourea, 1-(2-forfinal)-2-thiourea.1H NMR (500 MHz, DMSO-d6) δ ppm 1,07-of 1.18 (m, 2H), 1,43-of 1.52 (m, 2H), 1,57-to 1.67 (m, 1H), 1.70 to 1.77 in (m, 1H), 1,80-of 1.88 (m, 4H), of 2.15 (d, J=7 Hz, 2H), 7,00 (m, 1H), 7,20-7,26 (m, 2H), 7,27-7,33 (m, 3H), 7,79 (d, J=8,24 Hz, 2H), 8,59 (t, J=7,32 Hz, 1H), 10,04 (s, 1H), a 12.03 (s, 1H); MS (ESI) m/e 411,1 (M+H).

Example 76

TRANS ethyl {4-[4-(4-bromo-3-{[(2R)-3-hydroxy-2-methyl-propyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetate

<> The named compound was obtained in accordance with the procedure described in stage A of example 33, substituting (methyl bromide)CYCLOBUTANE (R)-3-bromo-2-methylpropan-1-ol.1H NMR (500 MHz, DMSO-d6) δ ppm of 0.95 (d, J=7,02 Hz, 2H), 1.14 in (m, 2H), 1,19 (t, J=7,02 Hz, 3H), 1,50 (m, 2H), 1,71-of 1.84 (m, 6H), for 2.01 (m, 1H), 2,23 (d, J=7,02 Hz, 2H), 2,47 (m, 1H), 3,39 (m, 1H), 3,42 (m, 1H), was 4.02 (DD, J1=10,06 Hz, J2=6,40 Hz, 1H), 4,07 (kV, J=7,02 Hz, 2H), 4,16 (DD, J1=10,06 Hz, J2=6,40 Hz, 1H), 7,37 (d, J=8,24 Hz, 2H), 7.62mm (d, J=8,24 Hz, 2H), 12,57 (USS, 1H); MS (ESI) m/z 481,0 [M+H]+.

Example 77

[4-(4'-hydroxy-1,1'-biphenyl-4-yl)cyclohexyl]acetic acid

Example 77A

4-(4-benzyloxyphenyl)cyclohexanone

4-(4-Hydroxyphenyl)cyclohexanone (to 4.98 g, 26,18 mmol), benzylbromide ( 4,92 g, 28,79 mmol), K2CO3(of 5.06 g, 36,65 mmol) and 75 ml of acetone was mixed in a reaction vessel equipped with a reflux condenser. The mixture was heated under reflux and stirred overnight. The mixture was cooled to room temperature and added water. The mixture was extracted with ethyl acetate three times. The combined organic layers were dried over Na2SO4, filtered and concentrated. The obtained solid was recrystallized in ethyl acetate to obtain these compounds.1H NMR (300 MHz, CDCl3) δ ppm 1,80-2,00 (m, 2H), 2,13-of 2.26 (m, 2H), 2,43 is 2.55 (m, 4H), 2.91 in was 3.05 (m, 1H), of 5.05 (s, 2H), 6,94 (d, J=8,82 Hz, 2H), 7,16 (d, J=8,82 Hz, 2H), 7,28-of 7.48 (m, 5H); MS (DCI) m/z 298 (MNH 4)+.

Example 77B

ethyl 2-(4-(4-(benzyloxy)phenyl)cyclohexylidene)acetate

The named compound was obtained using the methods described in example 1A, substituting 4-phenylcyclohexanone the product from example 77A.1H NMR (300 MHz, CDCl3) δ ppm of 1.29 (t, J=7,12 Hz, 3H), 1,55 was 1.69 (m, 2H), 1,95-2,10 (m, 3H), 2,27 is 2.43 (m, 2H), 2,67-of 2.81 (m, 1H), 3,89-4,00 (m, 1H), 4,16 (kV, J=7,12 Hz, 2H), 5,04 (s, 2H), 5,67 (s, 1H), 6,91 (d, J=8,82 Hz, 2H), 7,12 (d, J=8,82 Hz, 2H), 7,28-7,46 (m, 5H); MS (DCI) m/z 368 (M+NH4)+.

Example 77C

ethyl [4-(4-hydroxyphenyl)cyclohexyl]acetate

The named compound was first made in the same manner as described in example 1B, substituting the product from example 1A of the product of example 77B. The product was a mixture of TRANS - and CIS-isomers with a ratio of 78:22.1H NMR (300 MHz, CDCl3) δ ppm 1.14 in and of 1.64 (m, 2H), of 1.27 and 1.26 (t, J=7,1 Hz, 3H), 1,84, and is 2.30 (m, 1H), 1,87 (m, 2H), 1,45 (m, 2H), and 1.67 to 1.87 (m, 2H), 1,84 and 2.3 (m, 1H), 2,23 and to 2.42 (d, J=6,7 Hz, 2H), 4,14 (kV, J=7,1 Hz, 2H), 6,76 (d, J=8,5 Hz, 2H), 7,06 (d, J=8.5 Hz, 2H); MS (DCI) m/z 280 (M+NH4)+.

Example 77D

ethyl 2-(4-(4-(tripterocalyx)phenyl)cyclohexyl)acetate

The product from example 77C (1,83 g of 6.99 mmol), 4-(dimethylamino)pyridine (85 mg, 0.7 mmol) and pyridine (15 ml) was mixed in a reaction vessel and cooled to 0°C. was Added via syringe triperoxonane anhydride (1,88 ml, 11,18 mmol). After completion of the reaction was added ethyl acetate and 1N. HCl. United an ethyl acetate is xtracta was dried over Na 2SO4and concentrated. The crude mixture was purified flash chromatography (5%, then 10-14% ethyl acetate/hexane) to obtain the titled compound.1H NMR (300 MHz, CDCl3) δ ppm 1,09-to 1.21 (m, 2H), 1.27mm (t, J=7,12 Hz, 3H), 1,48 (DD, J=12,38, of 2.54 Hz, 2H), 1,80 is 1.96 (m, 3H), 2,24 (d, J=is 6.78 Hz, 15H), 2,39 is 2.44 (m, 5H), 2,44-to 2.65 (m, 1H), 4,15 (kV, J=of 7.23 Hz, 2H), 7,15-7,21 (m, 2H), 7.23 percent-to 7.32 (m, 2H); MS (DCI) m/z 412 (M+NH4)+.

Example 77E

ethyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)cyclohexyl)acetate

Tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0,131 mmol) and tricyclohexylphosphine (1M, 313 ml, 0,313 mmol) were mixed in 2 ml of dioxane in a nitrogen atmosphere for 30 minutes. Then added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxa-borolane) (738 mg, of 3.13 mmol), potassium acetate (385 mg, to 3.92 mmol) and the product from example 77D (1,03 g, 2,61 mmol). The mixture was heated under reflux and stirred overnight. The mixture was then cooled to room temperature and diluted with 75% ethyl acetate/hexane and filtered. The filtrate was concentrated and then the obtained residue was purified flash chromatography (3% ethyl acetate/hexane) to obtain the titled compound. The product was contaminated 10-15% of unreacted source triflate material. MS (DCI) m/z 390 (M+NH4)+.

Example 77F

[4-(4'-hydroxy-1,1'-biphenyl-4-yl)cyclohexyl]acetic acid

The product from example 77E (65 mg, of) 0.157 mmol), [1,1'-bis(di is edelfosine)ferrocene]dichloropalladium(II) (9,9 mg, 0,0122 mmol), 4-itfinal (to 38.3 mg, 0,174 mmol) and Na2CO3(40,6 mg, 0,383 mmol) were mixed in 1.5 ml of a mixture of 7:2:3/1,2-dimethoxyethane:ethanol:H2O in the reaction tube with microwave heating. The mixture was heated to 100°C and was stirred for 20 minutes the Mixture was cooled to room temperature and then dissolved in about 2 ml of a mixture 1:1/DMSO:tetrahydrofuran. The mixture was filtered and the filtrate was purified using HPLC with reversed phase. This selected product is then hydrolyzed according to the method of example 1H obtaining these compounds.1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 a-1,19 (m, 4H), 1,38-of 1.53 (m, 2H), 1,55 was 1.69 (m, 2H), 1,68-to 1.87 (m, 3H), of 2.15 (d, J=7,02 Hz, 2H), 2,34-2,48 (m, 1H), PC 6.82 (d, J=8.54 in Hz, 2H), 7,21-7,34 (m, 2H), 7,39-rate of 7.54 (m, 2H), for 9.47 (s, 1H), 12,02 (, 1H); MS (ESI) m/z 309 (M-H)-.

Example 78

(4-{4'-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}-carbonyl)amino]-1,1'-biphenyl-4-yl}cyclohexyl)acetic acid

The named compound was obtained in accordance with the procedure described in example 77F, replacing itfinal 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-itfinal)urea, followed by hydrolysis, which was conducted in the same manner as described in example 1H.1H NMR (300 MHz, CF3COOD) δ ppm 1,29 is 1.48 (m, 3H), 1,49-of 1.81 (m, 2H), 1,80-to 1.98 (m, 2H), 2,11 (m Hz, 3H), 2,46-2,70 (m, 1H), 2,79, and 2,69 (d, J=7,81 Hz, 1H), 7,27-EUR 7.57 (m, 4H), 7,58-7,73 (m, 2H), 7,81 (DD, J=8,54, 2.20 Hz, 2H), of 8.09 (d, J=to 7.32 Hz, 1H); MS (ESI) m/z 515 (M+H)+.

Example 79

[4-(4-feast of the Jn-2-ylphenyl)cyclohexyl]acetic acid

The named compound was obtained in accordance with the procedure described in example 77F, replacing itfinal 2-chloropyrazine.1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 a is 1.23 (m, 2H), 1,44-of 1.57 (m, 2H), 1,59-1,90 (m, 5H), of 2.16 (d, J=7,02 Hz, 2H), 2,52-2,60 (m, 1H), 7,40 (d, J=8,24 Hz, 2H), with 8.05 (d, J=8,24 Hz, 2H), 8,58 (d, J=2,44 Hz, 1H), 8,69 (DD, J=2,59, 1,68 Hz, 1H), which 9.22 (d, J=1,53 Hz, 1H), a 12.03 (s, 1H); MS (ESI) m/z 297 (M+H)+.

Example 80

TRANS {4-[4-(7-amino-3-phenylpyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid

Example 80A

TRANS ethyl 2-4-(4-(hydroxymethyl)phenyl)cyclohexyl)acetate

Sodium borohydride (2.2 g, 58,32 mmol) was added in one portion to a stirred and cooled (0°C) solution of the product from example 1C (of 5.99 g, 19,44 mmol) in dry tetrahydrofuran (100 ml). The resulting solution followed an opportunity to warm to room temperature and was stirred for another 12 hours. The solution was cooled (0°C) and was interrupted by reaction with 0,1N. hydrochloric acid. The mixture was diluted with ether and water and the phases were separated. The organic phase was washed with brine and dried over magnesium sulfate. After filtration the solvent was evaporated and the residue was purified by chromatography on silica gel using 30% ethyl acetate in hexano with obtaining these compounds are in the form of a colorless oil.

Example 80B

TRANS ethyl 2-4-(4-(cyanomethyl)phenyl)cyclohexyl)acetate

Stage one

Tetrabromide carbon (5.3g, 15,86 mmol) in dichloromethane (10 ml) was added dropwise to a stirred and cooled (0°C) solution of example 80A (3,37 g, 12.20 mmol) and triphenylphosphine (4,2 g, 15,86 mmol) in dichloromethane (60 ml). The resulting solution was stirred for another 2 hours before evaporated solvent. Added ether to precipitate triphenylphosphine oxide and the mixture was filtered through a layer of silica gel using for washing the ether. The filtrate was concentrated and the product was used in step 2 without further purification.

Stage two

Sodium cyanide (3.50 g, 69,65 mmol) was added in one portion into a mixed solution of product from step 1 (12.20 mmol) in dry DMSO (30 ml). The obtained dark brown solution was heated (50°C) for 5 hours, then cooled and distributed between ether and water. The organic layer was washed with water and brine, dried (magnesium sulfate) and filtered. The residue was purified by chromatography on silica gel using 30% ethyl acetate in hexano with obtaining these compounds are in the form of a colorless oil which hardened on standing.

Example 80C

TRANS ethyl 2-(-4-(4-((Z)-1-cyano-2-(dimethylamino)vinyl)-phenyl)cyclohexyl)acetate

1-tert-butoxy-N,N,N',N'-tetramethylmethylenediamine (2.55 ml, 12,34 mmol) was added dropwise to a stirred and heated (120°C) Rast is oru example 80B (1,76 g, of 6.17 mmol) in dry toluene (30 ml). The resulting solution was heated for another 3 hours and then concentrated. The residue was purified by chromatography on silica gel using 50% ethyl acetate in hexano with obtaining these compounds are in the form of a light yellow oil which hardened on standing.

Example 80D

TRANS {4-[4-(7-amino-3-phenylpyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid

Example 80C (40 mg, 0,117 mmol) and 4-phenyl-1H-pyrazole-5-amine (56 mg, 0.351 mmol) was heated (microwave Personal Chemistry Microwave, 150°C, 20 minutes) in toluene (1 ml) and acetic acid (0.5 ml). The solvent was evaporated and the residue was dissolved in methanol (3 ml). Was added sodium hydroxide (1 ml, 1N.) and the solution was heated (50°C) for 1 hour. The solvent was evaporated and the residue was purified preparative high-performance liquid chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, unless otherwise specified. After evaporation of the titled compound was isolated as solid.1H NMR (300 MHz, methanol-d4) δ ppm 1,02-of 1.41 (m, 2H), 113-1,32 (m, 2H), 1,45-of 1.73 (m, 2H), 1,73-of 2.09 (m, J=12,21 Hz, 5H), 2,24 (d, J=7,12 Hz, 1H), 2,60 (t, J=12,21 Hz, 1H), 2,73 (s, 3H), 7,25-7,30 (m, 1H), 7,41-to 7.50 (m, 6H), 7,88 (s, 1H), to $ 7.91 (s, 1H), 8,15 (s, 1H), 8,46 (s, 1H). MS (ESI) m/z 247,3 [M+H].

Example 81

{4-[4-(7-amino-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid

Example 81 A

ethyl {4-[4-(7-amino-5-methyl[1,2,4]triazolo[1,5-a]-pyrimidine-6-yl)phenyl]cyclohexyl}acetate

6-Iodine-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-7-amine (205 mg, 0,745 mmol), the product from example 77E (308 mg, 0,745 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (128 mg, 0,149 mmol), sodium carbonate (174 mg, of 1.64 mmol) and 1,2-dimethoxyethane:ethanol:N,N-dimethylformamide:water (about 1.75:0,5: 0,75:0.3 ml) were mixed in the reaction the test tube with microwave heating and heated to 110°C (Personal Chemistry Microwave) for 15 minutes. The mixture was filtered through a layer of cellite and the filtrate was purified by using HPLC with a reversed phase column using Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min) to obtain the titled compound.

Example 81B

{4-[4-(7-amino-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)phenyl}cyclohexyl)acetic acid

The product p is the iMER 81 A was dissolved in methanol. Was added sodium hydroxide (excess, 1H.) and the solution was heated (50°C) for 1 hour. The solvent was evaporated and the residue was purified using preparative high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, unless otherwise specified. After evaporation of the titled compound was isolated as a mixture of isomers ~ 7:3/TRANS:CIS.1H NMR (400 MHz, methanol-d4) δ ppm 8,53 (s, 1H), 7,43-7,53 (m, 2H), 7,27-7,34 (m, 2H), 2,60-to 2.65 (m, 1H), 2.48 and of 2.25 (d, J=7,1 Hz, 2H), 2,30 (s, 3H), 1,96-to 1.98 (m, 3,3H), 1,76-to 1.79 (m, 2,3H), 1,58-of 1.64 (m, 1,7H), 1,20 of 1.28 (m, 1,7H). MS (ESI) m/z 366 (M+H)+.

Example 82

TRANS (4-{4-[7-amino-2-(methylthio)[1,2,4]triazolo[1,5-a]-pyrimidine-6-yl]phenyl}cyclohexyl)acetic acid

The product of example 80C (40 mg, 0,117 mmol) and 3-(methylthio)-1H-1,2,4-triazole-5-amine (50 mg, 0.35 mmol) was heated (microwave Personal Chemistry Microwave to 150°C, 20 minutes) in toluene (1 ml) and acetic acid (0.5 ml). The solvent was evaporated and the residue was dissolved in methanol (3 ml). Was added sodium hydroxide (1 ml, 1N.) and the solution was heated (50°C) for one hour. The solvent was evaporated and the residue was purified using drugs the active high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system, containing component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, unless otherwise specified. After evaporation of the titled compound was isolated as solid.1H NMR (300 MHz, methanol-d4) δ ppm of 1.16 to 1.31 (m, 2H), 1,71-of 1.81 (m, J=to 3.73 Hz, 2H), 1,89 is 2.01 (m, J=I to 1.87 Hz, 4H), 2,20-of 2.28 (m, 2H), of 2.44-2.50 (m, 2H), 2,68-a 2.71 (m, 1H), 2,73 (s, 3H), 7,31-7,41 (m, 3H), 7,33-7,41 (m, 1H), 7,44 (d, J=6,78 Hz, 2H), 8,18 (d, J=1.70 Hz, 1H). MS (ESI) m/z 278,2 [M+H].

Example 83

TRANS {4-[4-(7-amino-2-Tien-2-alprazola[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid

The product of example 80C (40 mg, 0,117 mmol) and 3-(thiophene-2-yl)-1H-pyrazole-5-amine (60 mg, 0.35 mmol) was heated (microwave Personal Chemistry Microwave to 150°C, 20 minutes) in toluene (1 ml) and acetic acid (0.5 ml). Then the solvent was evaporated and the residue was dissolved in methanol (3 ml). Was added sodium hydroxide (1 ml, 1N.) and the solution was heated (50°C) for one hour. The solvent was evaporated and the residue was purified using preparative high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% to mponent B, for 30 minutes at 15 ml/min, unless otherwise specified. After evaporation of the titled compound was isolated as solid.1H NMR (300 MHz, methanol-d4) δ ppm 1,09-to 1.38 (m, 2H), 1.41 to at 1.73 (m, 2H), 1,78-2,05 (m, J=12,21 Hz, 5H), of 2.25 (d, J=is 6.78 Hz, 2H), 2,48-2,69 (m, 1H), 7,20 (DD, J=5,09, to 3.73 Hz, 1H), was 7.36-7,53 (m, 5H), to 7.61 (DD, J=5,09, of 1.02 Hz, 1H), to 7.77 (DD, J=to 3.73, of 1.02 Hz, 1H), 8,16 (s, 1H). MS (ESI) m/z 433,3 [M+H].

Example 84

TRANS {4-[4-(7-amino-2-cyclopropylethanol[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid

The product of example 80C (40 mg, 0,117 mmol) and 3-cyclopropyl-1H-pyrazole-5-amine (42 mg, 0.35 mmol) was heated (microwave Personal Chemistry Microwave to 150°C, 20 minutes) in toluene (1 ml) and acetic acid (0.5 ml). The solvent is then evaporated and the residue was dissolved in methanol (3 ml). Was added sodium hydroxide (1 ml, 1N.) and the solution was heated (50°C) for one hour. The solvent was evaporated and the residue was purified using preparative high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, unless otherwise specified. After evaporation of the titled compound was isolated as solid. 1H NMR (300 MHz, methanol-d4) δ ppm 0,96-of 1.09 (m, 2H), 1,10-1,19 (m, 2H), 1,17-to 1.38 (m, 2H), 1,49 was 1.69 (m, 2H), 1.70 to 2.05 is (m, 5H), 2,22 (1H), is 2.09 to 2.35 (m, 3H), 2,49-a 2.71 (m, 1H), 6,28 (s, 1H), 7,27-to 7.61 (m, 4H), of 8.09 (s, 1H). MS (ESI) m/z 391,3 [M+H].

Example 85

TRANS {4-[4-(7-amino[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)-phenyl]cyclohexyl}acetic acid

The product of example 80C (57 mg, 0,167 mmol) and 1H-1,2,4-triazole-5-amine (42 mg, 0.50 mmol) was heated (microwave Personal Chemistry Microwave to 150°C, 20 minutes) in toluene (1 ml) and acetic acid (0.5 ml). The solvent was evaporated and the residue was dissolved in methanol (3 ml). Was added sodium hydroxide (1 ml, 1N.) and the solution was heated (50°C) for one hour. The solvent was evaporated and the residue was purified using preparative high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, unless otherwise specified. After evaporation, the named compound was isolated as solid.1H NMR (300 MHz, methanol-d4) δ ppm 1,02-to 1.38 (m, 2H) 1,50-1,72 (m, 2H) 1,79-of 2.08 (m, 7H) to 2.25 (d, J=7,12 Hz, 2H) of 2.51 is 2.80 (m, J=23,57, 11,02 Hz, 1H) 7,45 (s, 2H) to 8.34 (s, 1H) 8,72 (s, 1H). MS (ESI) m/z 352,2 [M+H].

Example 86

TRANS ethyl {4-[4-(5-what aminoimidazo[1,2-a]pyrimidine-6-yl)-phenyl]cyclohexyl}acetate

The product of example 80C (57 mg, 0,167 mmol), 2-aminoimidazole sulfate (130 mg, 0.50 mmol) and sodium acetate (0.2 g) was heated (microwave Personal Chemistry Microwave to 150°C, 20 minutes) in N,N-dimethylformamide (2 ml). The solvent was evaporated and the residue was purified using preparative high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, unless otherwise specified. After evaporation of the titled compound was isolated as solid.1H NMR (300 MHz, methanol-d4) δ ppm of 1.09 to 1.37 (m, 5H), 1,48 is 1.70 (m, 2H), 1,78-2,05 (m, 7H), and 2.27 (d, J=is 6.78 Hz, 2H), of 2.51-2,69 (m, J=12,21, 12,21 Hz, 1H), 4,14 (kV, J=7,12 Hz, 2H), 7,43 (s, 4H), to 7.93 (d, J=2,71 Hz, 1H), 8,07 (d, J=2,71 Hz, 1H), 8,31 (s, 1H). MS (ESI) m/z to 379.2 [M+H].

Example 87

TRANS (4-{4-[7-amino-2-(4-forfinal)pyrazolo[1,5-a]-pyrimidine-6-yl]phenyl}cyclohexyl)acetic acid

The product of example 80C (57 mg, 0,167 mmol) and 3-(4-forfinal)-1H-pyrazole-5-amine (90 mg, 0.50 mmol) was heated (microwave Personal Chemistry Microwave, 150°C, 20 minutes) in toluene (1 ml) and acetic acid (0.5 ml). The solvent is then evaporated and the residue was dissolved in methanol (3 ml). Was added sodium hydroxide (1 ml, 1 is.) and the solution was heated (50°C) for one hour. The solvent was evaporated and the residue was purified using preparative high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, unless otherwise specified. After evaporation of the titled compound was isolated as solid.1H NMR (300 MHz, methanol-d4) δ ppm of 1.03 to 1.37 (m, 2H), 1,48-1,72 (m, 2H), 1.70 to to 2.06 (m, 7H), of 2.25 (d, J=7,12 Hz, 2H), 2,53-to 2.74 (m, J=11,70, 11,70 Hz, 1H), 6,93 (s, 1H), 7,25 (t, J=8,82 Hz, 2H), was 7.36-7,58 (m, 4H), 8,01-of 8.27 (m, 4H). MS (ESI) m/z 445,3 [M+H].

Example 88

TRANS {4-[4-(7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid

The product of example 80C (57 mg, 0,167 mmol) and 3-methyl-1H-pyrazole-5-amine (50 mg, 0.50 mmol) was heated (microwave Personal Chemistry Microwave to 150°C, 20 minutes) in toluene (1 ml) and acetic acid (0.5 ml). The solvent is then evaporated and the residue was dissolved in methanol (3 ml). Was added sodium hydroxide (1 ml, 1N.) and the solution was heated (50°C) for one hour. The solvent was evaporated and the residue was purified using preparative high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV-de is the design wavelength at 220 and 254 nm and suirable using the solvent system, containing component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, unless otherwise specified. After evaporation of the titled compound was isolated as solid.1H NMR (300 MHz, methanol-d4) δ ppm 1.04 million-of 1.36 (m, 2H), 1,49 was 1.69 (m, J=12,66, 12,66, 12,66 Hz, 2H), 1,68-of 2.08 (m, 7H), 2,24 (d, J=7,12 Hz, 2H), 2,53 (s, 3H), 2,55-2,77 (m, 1H), 6,40 (s, 1H), 7,12-the 7.65 (m, 4H), to 8.12 (s, 1H). MS (ESI) m/z 365,2 [M+H].

Example 89

TRANS {4-[4-(7-amino-2-hydroxypyrazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid

The product of example 80C (57 mg, 0,167 mmol) and 5-amino-1H-pyrazole-3-ol (50 mg, 0.50 mmol) was heated (microwave Personal Chemistry Microwave to 150°C, 20 minutes) in toluene (1 ml) and acetic acid (0.5 ml). The solvent is then evaporated and the residue was dissolved in methanol (3 ml). Was added sodium hydroxide (1 ml, 1N.) and the solution was heated (50°C) for one hour. The solvent was evaporated and the residue was purified using preparative high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/m is h, if not stated otherwise. After evaporation of the titled compound was isolated as solid.1H NMR (300 MHz, methanol-d4) δ ppm 1,02-of 1.41 (m, 2H), 1,13-of 1.32 (m, 2H), 1,45-of 1.73 (m, 2H), 1,73-of 2.09 (m, J=12,21 Hz, 5H), 2,24 (d, J=7,12 Hz, 1H), 2,60 (t, J=12,21 Hz, 1H), of 6.52 (d, J=2,03 Hz, 1H), 7,38-7,51 (m, 4H), by 8.22 (s, 1H). MS (ESI) m/z 367,2 [M+H].

Example 90

TRANS 2-{4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)phenyl] cyclohexyl}-N-methylacetamide

To a solution of example 92 (40 mg, 0,114 mmol) and N,N-diisopropylethylamine (0.05 ml, 0.25 mmol) in dry N,N-dimethylformamide (2 ml) was added O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate (56 mg, 0,148 mmol). The resulting solution was stirred for 1 hour, then was added a solution of methylamine (0.5 ml, 2M in tetrahydrofuran). The resulting solution was stirred for another 1 hour, then evaporated the solvent and the residue was purified using preparative high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, if not specified otherwise. After evaporation of the titled compound was isolated as solid.1H NMR (300 MHz, methane is l-d 4) δ ppm 1,02-of 1.41 (m, 2H), 1,13-of 1.32 (m, 2H), 1,45-of 1.73 (m, 2H), 1,73-of 2.09 (m, J=12,21 Hz, 5H), 2,24 (d, J=7,12 Hz, 1H), 2,60 (t, J=12,21 Hz, 1H), 2,73 (s, 3H), of 6.52 (d, J=2,03 Hz, 1H), 7,38-7,51 (m, 4H), 8,16 (s, 1H), to 8.20 (d, J=2.37 Hz, 1H). MS (ESI) m/z 350,2 [M+H].

Example 91

TRANS 2-(4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)-phenyl] cyclohexyl}ndimethylacetamide

To a solution of example 92 (40 mg, 0,114 mmol) and N,N-diisopropylethylamine (0.05 ml, 0.25 mmol) in dry N,N-dimethylformamide (2 ml) was added O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate (56 mg, 0,148 mmol). The resulting solution was stirred for 1 hour, then was added a solution of ammonia (0.5 ml, 2M in isopropanol). The resulting solution was stirred for another 1 hour, then the solvent was evaporated and the residue was purified using preparative high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, if not specified otherwise. After evaporation of the titled compound was isolated as solid.1H NMR (300 MHz, methanol-d4) δ ppm 1,02-of 1.41 (m, 2H), 1,13-of 1.32 (m, 2H), 1,45-of 1.73 (m, 2H), 1,73-of 2.09 (m, J=12,21 Hz, 5H), 2,24 (d, J=7,12 Hz, 1H), 2,60 (t, J=12,21 Hz, 1H), of 6.52 (d, J=2,03 Hz, 1H), 7,38-,51 (m, 4H), 8,16 (s, 1H), to 8.20 (d, J=2.37 Hz, 1H). MS (ESI) m/z 350,2 [M+H].

Example 92

TRANS {4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)phenyl]-cyclohexyl}acetic acid

The product of example 80C (57 mg, 0,167 mmol) and 1H-pyrazole-5-amine (42 mg, 0.50 mmol) was heated (microwave Personal Chemistry Microwave to 150°C, 20 minutes) in toluene (1 ml) and acetic acid (0.5 ml). Then the solvent was evaporated and the residue was dissolved in methanol (3 ml). Was added sodium hydroxide (1 ml, 1N.) and the solution was heated (50°C) for one hour. The solvent was evaporated and the residue was purified using preparative high-performance chromatography with reversed phase (RP-HPLC) using a column Bond SB-C18 7 M of 21.2×250 mm, UV detection at a wavelength of 220 and 254 nm and suirable using the solvent system containing the component A (water with 0.1% triperoxonane acid) and component B (acetonitrile with 0.1% triperoxonane acid), gradient 5-95% component B, for 30 minutes at 15 ml/min, unless otherwise specified. After evaporation of the titled compound was isolated as solid.1H NMR (300 MHz, methanol-d4) δ ppm 1,02-of 1.41 (m, 2H), 1,13-of 1.32 (m, 2H), 1,45-of 1.73 (m, 2H), 1,73-of 2.09 (m, J=12,21 Hz, 5H), 2,24 (d, J=7,12 Hz, 1H), 2,60 (t, J=12,21 Hz, 1H), of 6.52 (d, J=2,03 Hz, 1H), 7,38-7,51 (m, 4H), 8,16 (s, 1H), to 8.20 (d, J=2.37 Hz, 1H). MS (ESI) m/z 351,2 [M+H].

Example 93

{4-[5-(5-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-3-yl)pyridine-2-yl]cyclohexyl}acetic acid

Example 93A

methyl 6-(1,4-dioxaspiro[4,5]Dec-7-EN-8-yl)nicotinate

Methyl 6-bromonicotinate (2,11 g, 9,78 mmol), 1,4-dioxaspiro[4,5]Dec-7-Yong-8-Voronova acid (2 g, 10,86 mmol), palladium(II) acetate (109 mg, 0.48 mmol), DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (0.40 g, 0.97 mmol) and potassium phosphate (6.2 g, of 29.1 mmol) were placed in a vessel Slanka in the vessel created a vacuum and fill it with argon. Added dioxane (30 ml) and water (4 ml) and the vessel was heated (80°C) during the night. The mixture was distributed between ether and water and the organic phase was washed with brine, dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography on silica gel using 30% ethyl acetate in hexano, to obtain the titled compound in the form of a slightly yellow oil which hardened on standing.

Example 93B

methyl 6-(1,4-dioxaspiro[4,5]Decan-8-yl)nicotinate

The palladium hydroxide on coal (1 g, 20 wt.% Pd) was added to a solution of example 93A (2.66 g, to 9.66 mmol) in methanol (40 ml) and ethyl acetate (10 ml). The mixture was subjected to vacuum and filled with hydrogen (balloon) and stirred for 3 hours, then filtered through a layer of cellica using methanol for washing. The solvent was evaporated and the product was dissolved in dichloromethane and dried over Na2SO4. After filtration and concentration was allocated a named connection in the form of a slightly yellow firmly what about the substance and used it in the next stage without additional purification.

Example 93C

tert-butyl 3-(6-(1,4-dioxaspiro[4,5]Decan-8-yl)pyridine-3-yl)-3-oxopropanoic

Tert-butyl acetate (2,40 ml, 17,82 mmol) was added to a stirred and cooled (-78°C) solution hexamethyldisilazide lithium (17,8 ml, 1M in tetrahydrofuran) in dry tetrahydrofuran (10 ml). After 30 minutes of stirring at -78°C the solution was added dropwise a solution of example 93B (2,47 g, 8.9 mmol) in tetrahydrofuran. The resulting mixture was stirred for one hour, then the reaction was stopped using ammonium chloride and allowed to warm the mixture to room temperature. The mixture was distributed between ether and water and the phases were separated. The organic phase was washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by chromatography on silica gel using 30% ethyl acetate in hexano with obtaining these compounds are in the form of a yellow oil.

Example 93D

3-(6-(1,4-dioxaspiro[4,5]Decan-8-yl)pyridine-3-yl)-1H-pyrazole-5-ol

The hydrazine hydrate (5 ml) was added to a solution of example 93C (1.07 g, 2,96 mmol) in dioxane (10 ml). The resulting solution was boiled under reflux for 3 hours, then cooled and distributed between tetrahydrofuran and brine. The aqueous phase was acidified with 6N hydrochloric acid to pH 2 and was extracted twice with a mixture of tetrahydrofuran/this is latitat. The combined organic phases were dried (magnesium sulfate), filtered and concentrated. The crude product is recrystallized from ethyl acetate and hexane to obtain a light brown solid.

Example 93E

2-(1,4-dioxaspiro[4,5]Decan-8-yl)-5-(5-(2-(trifter-methoxy)benzyloxy)-1H-pyrazole-3-yl)pyridine

1-(methyl bromide)-2-(triptoreline)benzene (0.4 g, 1.57 mmol) was added dropwise to a stirred solution of example 93D (0,43 g of 1.42 mmol) and potassium carbonate (0.16 g, 1.13 mmol) in dry acetone (7 ml) by boiling under reflux. The resulting solution was heated (50°C) for 1 hour, then the solvent was evaporated and the residue was distributed between brine and ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated. The residue was purified by chromatography on silica gel using 0 to 100% ethyl acetate in hexano, to obtain the titled compound as a yellow oil.

Example 93F

4-(5-(5-(2-(triptoreline)benzyloxy)-1H-pyrazole-3-yl)-pyridine-2-yl)cyclohexanone

Chloride India (0.11 g, 0,536 mmol) was added to a solution of example 93E (0,255 g, 0,536 mmol) in methanol (3 ml) and water (3 ml). The resulting solution was heated (85°C) for 5 hours, then the methanol was evaporated. The residue was distributed between ethyl acetate and water and the organic phase was washed with brine, dried (magnesium sulfate is), was filtered and concentrated. The crude product was used in the next stage without additional purification.

Example 93G

ethyl 2-(4-(5-(5-(2-(triptoreline)benzyloxy)-1H-pyrazole-3-yl)pyridine-2-yl)cyclohexylidene)acetate

Methyl 2-(dimethoxyphosphoryl)acetate (0,76 ml of 3.77 mmol) was added dropwise to a stirred and cooled (0°C) suspension of sodium hydride (0.15 g, 3,76 mmol) in dry N,N-dimethylformamide (10 ml). After 30 minutes stirring at room temperature was added a solution of example 93F (0,748 g, 1,71 mmol) in N,N-dimethylformamide at 0°C. After addition, the solution was allowed to warm to room temperature and was stirred overnight. The reaction was stopped with saturated solution of ammonium chloride and was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by chromatography on silica gel using 0 to 80% ethyl acetate in hexano, to obtain the titled compound as a white solid.

Example 93H

{4-[5-(5-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-3-yl)pyridine-2-yl]cyclohexyl}acetic acid

The product of example 93G (0,439 g, 0.87 mmol) was stirred in the presence of palladium hydroxide on coal (0.1 g, 20 wt.% Pd) and hydrogen (balloon) in methanol (10 ml) for 5 hours is impressive. The mixture was filtered, concentrated and the residue was dissolved in methanol (10 ml) and 1N. the sodium hydroxide (3 ml) and stirred at 50°C for 2 hours. The methanol was evaporated and the mixture was acidified (pH 2) and extracted with ethyl acetate. The combined organic phases were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography on silica gel using 0 to 15% methanol in dichloromethane, to obtain the titled compound in the form of butter.1NMR (500 MHz, methanol-d4) δ ppm of 1.18 to 1.37 (m, 2H), 1.60-to and 2.14 (m, 8H), 2,22-to 2.29 (m, 1H), 2,28-is 2.37 (m, 1H), 2,47 (d, J=7,63 Hz, 1H), 2,80-3,13 (m, 1H), 5,31 (s, 2H), 6,33 (s, 1H), 7,28-7,52 (m, 5H), 7,66 (d, J=7,63 Hz, 1H), 7,81 (DD, J=12,66, 8,39 Hz, 1H). MS (ESI) m/z 476,2 [M+H].

Example 94

TRANS {4-[4-(7-amino-5-methylpyrazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid

1H NMR (500 MHz, DMSO-d6) δ ppm 1.10 is to 1.21 (m, 2H), 1,46-to 1.59 (m, 2H), 1,62-1,71 (m, 1H), 1,72 and 1.80 (m, 1H), 1,83-of 1.92 (m, 3H), of 2.09 and 2.13 (m, 3H), 2,14-to 2.18 (m, 2H), 2,53-of 2.58 (m, 1H), 6,32 (d, J=2,14 Hz, 1H), to 6.88 (s, 2H), 7,17-7,31 (m, 2H), 7,33 was 7.45 (m, 2H), of 8.06 (d, J=2,14 Hz, 1H), 12,0 (s, 1H); MS (ESI) m/z 365 [M+H]+.

Example 95

TRANS 3-({4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)-phenyl]cyclohexyl}methyl)-1,2,4-oxadiazol-5(4H)-he

1H NMR (500 MHz, DMSO-d6) δ ppm 1,12-1,25 (m, 2H), 1,42-of 1.56 (m, 2H), 1.70 to of 1.78 (m, 1H), 1,79-of 1.92 (m, 4H), 2,44 (d, J=to 7.32 Hz, 2H), 2,53 at 2.59 (m, 1H), 6,44 (d, J=2,44 Hz, 1H), 7,29-7,49 (m, 6H), 8,05-8,16 (m, 2H), 12,0 (s, 1H); MS (ESI) m/z 391 [M+H]+.

Example 96

TRANS-5-({4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)-phenyl]cyclohexyl}methyl)-1,3,4-oxadiazol-2(3H)-he

1H NMR (300 MHz, DMSO-d6) δ ppm 1.06 a-1,32 (m, 2H), 1,42 is 1.60 (m, 2H), 1,65-to 1.79 (m, 2H), 1.77 in-of 1.92 (m, 4H), 2,37-2,47 (m, 1H), of 2.51 at 2.59 (m, 1H), 6,44 (d, J=2.37 Hz, 1H), 7,33-of 7.48 (m, 6H), 8,03-8,19 (m, 2H), 12,1 (s, 1H); MS (ESI) m/z 391 [M+H]+.

It should be borne in mind that the above detailed description of the invention and the accompanying examples are merely illustrations and should not be construed as limitations of the invention which is defined solely by the points of the attached claims and their equivalents. Various changes and modifications, including, but not limited to changes and modifications that pertain to the chemical structures, substituents, derivatives, intermediates compounds, synthesis, pharmaceutical forms and/or methods of use of the invention may be made without deviating from the essence and scope of the invention.

1. The compound having the formula (I)or its pharmaceutically acceptable salt

where Q is a phenyl or pyridinyl;
And is pyrazolyl or triazolyl, where each a is independently optionally unsubstituted or substituted by 1 or 2 substituents represented by Ra; and Rachoose from the group consisting and is oxo, -N(Rw)C(O)H, C1-6of alkyl, halogen, trifloromethyl, -(CReRf)q-G1, -Y1-Y3, -Y1-(CReRf)q-Y3, -Y1-(CReRf)-Y2-Y3and-Y1-(CReRf)q-Y2-(CReRf)q-Y3or
A is formula (a)
,
where Vais C(R4), Vbis N or C(R5and Vcis N; or
Vais N, Vbis C(R5and Vcis N or C(R6);
R4is hydrogen,
R5is hydrogen, C1-6by alkyl, -ORb, -SRb, aryl selected from phenyl, heteroaryl selected from tanila, or cycloalkyl selected from cyclopropyl;
R6is hydrogen or aryl selected from phenyl;
R7is hydrogen or C1-6by alkyl;
G1is cycloalkyl selected from cyclobutyl, heteroaryl selected from furanyl or isoxazolyl, or aryl selected from phenyl;
Y1and Y2in each case, are each independently O, -N(Rw), -C(O)- N(Rw)C(O)N(Rw)- or-C(O)O-;
where the right side is N(Rw)C(O)N(Rw)- and-C(O)O-fragments connected with -(CReRf)qor Y3;
Y3in each case is independently hydrogen, C1-6the alkyl,
sub> 3-10cycloalkyl, the heterocycle selected from tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-1,5-benzodioxepine and 2-N-chromene, heteroaryl selected from furanyl, isoxazolyl and pyridinyl, or aryl selected from phenyl;
r and s are independently 2;
X is the X1, -(CRkRm)u-X1or -(CRkRm)u-C(O)-X2,
X1in each case is independently a heterocycle selected from oxadiazolidine;
X2in each case is independently a heterocycle selected from pyrrolidinyl, -OR11, -N(Rw)(R3), -N(Rw)-(CRnRq)w-C(O)OR11or-N(Rw)-(CRnRq)w-S(O)2R12;
R11in each case, is independently hydrogen or C1-4by alkyl;
R12in each case, is C1-3by alkyl;
where cycloalkyl, heterocycle, heteroaryl and aryl fragment is represented as G1, Y3X1X2, R4, R5, R6, R11and R12are each optionally additionally substituted with 1 or 2 substituents selected from the group consisting of C1-6of alkyl, halogen, oxo, -OR1, -OC(O)(R1), trifloromethyl;
q, u, and w, in each case, are each independently 1, 2, 3, 4 or 5;
R3is hydrogen, C1-3by alkyl, -OH, -S(O)2R 1or heteroaryl selected from tetrazolyl where heteroaryl connected to the nitrogen atom through a carbon atom of the ring;
Rb, Rx, Ry, Rza, Rzb, Rw, Re, Rk, Rm, Rn, Rqand Rlin each case, are independently hydrogen, C1-3the alkyl or C1-3halogenation; and
Rfin each instance, is independently hydrogen, C1-3the alkyl or-OH.

2. The compound according to claim 1, having the formula (I)or its pharmaceutically acceptable salt, where X is - (CRkRm)u-C(O)-X2.

3. The compound according to claim 1, having the formula (I)or its pharmaceutically acceptable salt, where X is - (CRkRm)u-C(O)-X2and Q is phenyl.

4. The compound according to claim 1, having the formula (I)or its pharmaceutically acceptable salt, where
X is -(CRkRm)u-C(O)-X2;
Q is phenyl;
r and s are 2 and
And is pyrazolyl or triazolyl, optionally additionally substituted with 1 or 2 substituents represented by Ra.

5. The compound according to claim 1, having the formula (I)or its pharmaceutically acceptable salt, where
X is -(CRkRm)u-C(O)-X2,
Q is phenyl;
r and s are 2 and
A is formula (a).

6. The compound according to claim 1, having the formula (I)or its pharmaceutically acceptable whom I Sol, where
X is -(CRkRm)u-C(O)-X2,
Q is a pyridinyl,
r and s are 2 and
A is formula (a).

7. The compound according to claim 1, having the formula (I)or its pharmaceutically acceptable salt, where
X is - (CRkRm)u-C(O)-X2,
Q is pyridinyl;
r and s are 2 and
And is pyrazolyl or triazolyl, optionally additionally substituted with 1 or 2 substituents represented by Ra.

8. The compound according to claim 1, having the formula (I)selected from the group consisting of the following compounds:
TRANS [4-(4-{3-[2-(1-substituted)-2-hydroxyethoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid;
TRANS [4-(4-{3-[2-(1-substituted)-2-oksidoksi]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid;
TRANS [4-(4-{3-[2-(4-methoxyphenyl)-2-oksidoksi]-1H-pyrazole-5-yl} phenyl)cyclohexyl]acetic acid;
TRANS {4-[4-(3-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;
TRANS {4-[4-(3-{[5-(trifluoromethyl)-2-furyl]methoxy}-4-{[5-(trifluoromethyl)-2-furyl]methyl}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;
TRANS {4-[4-(4-[2-(triptoreline)benzyl]-3-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;
TRANS (4-{4-[3-(cyclohexylmethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS {4-[4-(3-{[3-(triptoreline)benzyl]oxy}-1H-feast of the ol-5-yl)phenyl]cyclohexyl}acetic acid;
TRANS {4-[4-(3-{[5-(trifluoromethyl)-2-furyl]methoxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;
TRANS (4-{4-[3-(3-phenoxypropane)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS (4-{4-[3-(4-phenoxyethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS (4-{4-[3-(2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS {4-[4-(3-{[2-(deformedarse)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;
TRANS (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS (4-{4-[3-(cyclobutylmethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS (4-{4-[3-(cyclohexyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS (4-{4-[3-(tetrahydro-2H-Piran-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS ethyl [4-(4-{3-[2-(1-substituted)-2-oksidoksi]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetate;
TRANS (4-{4-[5-(cyclobutylmethyl)-1-(cyclobutylmethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetic acid;
TRANS (4-{4-[3-(benzyloxy)-1H-pyrazole-1H-yl]phenyl}cyclohexyl)acetic acid;
TRANS (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS {4-[4-(3-{[4-(trifluoromethyl)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl} acetic acid;
TRANS [4-(4-{3-[(5-methylisoxazol-3-yl)methoxy]-1H-pyrazole--yl} phenyl)cyclohexyl]acetic acid;
TRANS {4-[4-(1H-1,2,4-triazole-5-yl)phenyl]cyclohexyl}acetic acid;
TRANS [4-(4-{5-[(5-methylisoxazol-3-yl)methoxy]-1-[(5-methylisoxazol-3-yl)methyl]-1H-pyrazole-3-yl}phenyl)cyclohexyl]acetic acid;
TRANS N-methyl-N-[(4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetyl]glycine;
TRANS (4-{4-[3-(cyclobutylamine)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS (4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetic acid;
TRANS (4-{4-[3-(cyclopropylmethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS 2-(4-{4-[3-(cyclohexylmethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)-N-hydroxyacetamido;
TRANS (4-{4-[3-(pyridine-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS (4-{4-[3-(tetrahydrofuran-2-ylethoxy)-1H-pyrazole-5-yl]fell}cyclohexyl)acetic acid;
TRANS (4-{4-[4-bromo-3-(cyclobutylmethyl)-1H-pyrazole-5-yl]-phenyl}cyclohexyl)acetic acid;
TRANS-N-hydroxy-2-(4-{4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)ndimethylacetamide;
TRANS-N-(methylsulphonyl)-2-(4-{4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)ndimethylacetamide;
TRANS 1-({4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetyl)-L-Proline;
TRANS {4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetic acid;
TRANS (4-{4-[4-bromo-3-(cyclopropylmethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS ethyl [4-(4-{3-[2-(1-substituted)-2-guide is acetoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetate;
TRANS methyl N-methyl-N-[(4-{4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetyl]glycinate;
TRANS [4-(4-{3-[(6,7-dimethoxy-2-oxo-2H-chromen-4-yl)-methoxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid;
TRANS N-2N-tetrazol-5-yl-2-(4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)ndimethylacetamide;
TRANS methyl {4-[4-(3-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetate;
TRANS ethyl 5-{4-[4-(2-ethoxy-2-oxoethyl)cyclohexyl]phenyl}-1H-pyrazole-3-carboxylate;
TRANS [4-(4-{3-[(2-hydroxycyclohexyl)oxy]-1H-pyrazole-5-yl}phenyl)cyclohexyl]acetic acid;
TRANS {4-[4-(3-hydroxy-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetic acid;
TRANS methyl (4-{4-[3-(cyclohexyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;
TRANS ethyl (4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetate;
TRANS 2-methyl-N-[(4-{4-[5-(trifluoromethyl)-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetyl]alanine;
TRANS {4-[4-(4-ethyl-1-methyl-1H-pyrazole-3-yl)phenyl]cyclohexyl} acetic acid;
TRANS (4-{4-[3-(tetrahydro-2H-Piran-4-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS (4-{4-[4-bromo-3-(tetrahydro-2H-Piran-4-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS methyl (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;
TRANS ethyl {4-[4-(3-{[5-(trifluoromethyl)-2-furyl]methoxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}aceta is;
TRANS (4-{4-[1,2-bis(cyclobutylmethyl)-5-oxo-2,5-dihydro-1H-pyrazole-3-yl]phenyl}cyclohexyl)acetic acid;
TRANS methyl (4-{4-[3-(cyclopentyloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;
TRANS ethyl (4-{4-[3-(2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;
TRANS methyl 1-({4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetyl)-L-prolinate have been obtained;
TRANS ethyl (4-{4-[3-(pyridine-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;
TRANS ethyl (4-{4-[3-(tetrahydrofuran-2-ylethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;
TRANS (4-{4-[3-(tetrahydro-2H-Piran-4-yloxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetic acid;
TRANS 1-({4-[4-(1H-pyrazole-3-yl)phenyl]cyclohexyl}acetyl)-L-prolinamide;
TRANS ethyl (4-{4-[3-(cyclohexylmethoxy)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetate;
TRANS tert-butyl 2-methyl-N-[(4-{4-[3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl}cyclohexyl)acetyl]alanine;
TRANS ethyl {4-[4-(4-bromo-3-{[(2R)-3-hydroxy-2-methylpropyl]oxy}-1H-pyrazole-5-yl)phenyl]cyclohexyl}acetate;
TRANS {4-[4-(7-amino-3-phenylpyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;
{4-[4-(7-amino-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;
TRANS (4-{4-[7-amino-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine-6-yl]phenyl}cyclohexyl)acetic acid;
TRANS {4-[4-(7-amino-2-Tien-2-alprazola[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}of the criminal code of Usna acid;
TRANS {4-[4-(7-amino-2-cyclopropylethanol[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;
TRANS {4-[4-(7-amino[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)-phenyl]cyclohexyl}acetic acid;
TRANS ethyl {4-[4-(5-aminoimidazo[1,2-a]pyrimidine-6-yl)-phenyl]cyclohexyl}acetate;
TRANS (4-{4-[7-amino-2-(4-forfinal)pyrazolo[1,5-a]-pyrimidine-6-yl]phenyl}cyclohexyl)acetic acid;
TRANS {4-[4-(7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;
TRANS {4-[4-(7-amino-2-hydroxypyrazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;
TRANS 2-{4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}-N-methylacetamide;
TRANS 2-{4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)-phenyl]cyclohexyl}ndimethylacetamide;
TRANS {4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;
{4-[5-(5-{[2-(triptoreline)benzyl]oxy}-1H-pyrazole-3-yl)pyridine-2-yl]cyclohexyl}acetic acid;
TRANS {4-[4-(7-amino-5-methylpyrazolo[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}acetic acid;
TRANS 3-({4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}methyl)-1,2,4-oxadiazol-5(4H)-he; and
TRANS-5-({4-[4-(7-aminopyrazole[1,5-a]pyrimidine-6-yl)phenyl]cyclohexyl}methyl)-1,3,4-oxadiazol-2(3H)-he;
or their pharmaceutically acceptable salt.

9. The compound according to claim 1, having formula (Ib), or its pharmaceutically acceptable salt,

where p is 0, 1, 2 or 3; and a, T, Rx, Ry, Rza, Rzband X are defined in claim 1.

10. The compound according to claim 1, having the formula (IIa), or its pharmaceutically acceptable salt,

where p is 0, 1, 2 or 3; and VaVbVc, R7, T, Rx, RY, Rza, Rzband X are defined in claim 1.

11. The method of treatment of a disease selected from the group consisting of type 2 diabetes, obesity, high level of triglycerides in plasma, metabolic syndrome, non-alcoholic steatohepatitis and alcahole fatty infiltration of the liver, comprising the administration to a patient in need this, the compounds according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

12. The method according to claim 11, further containing stage joint injection with one or more pharmaceutical selected from the group consisting of fenofibrate, rimonabant and sibutramine.

13. Pharmaceutical composition having inhibitory activity against DGAT-1, containing a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

14. Pharmaceutical composition having inhibitory activity against DGAT-1, containing a therapeutically effective amount of a compound according to claim 1 or f is rmaceuticals acceptable salt, one or more pharmaceutical agents selected from the group consisting of fenofibrate, rimonabant and sibutramine in combination with a pharmaceutically acceptable carrier.

15. The method of treatment of a disease selected from the group consisting of type 2 diabetes, obesity, high level of triglycerides in plasma, metabolic syndrome, non-alcoholic steatohepatitis and alcahole fatty infiltration of the liver, comprising the administration to a patient in need of this, the pharmaceutical composition according to item 13.

16. The method of treatment of a disease selected from the group consisting of type 2 diabetes, obesity, high level of triglycerides in plasma, metabolic syndrome, non-alcoholic steatohepatitis and nonalcoholic fatty infiltration of the liver, comprising the administration to a patient in need of this, the pharmaceutical composition 14.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a mTOR kinase inhibitor. In formula (I): A represents a 6-8-member mono- or bicyclic heterocyclic ring containing 1 to 2 heteroatoms optionally specified in N and O as apexes of the ring and having 0-2 double bonds; and wherein the ring A is additionally substituted by 0 to 2 substitutes RA specified in a group consisting of -ORa, -Rc and -(CH2)1-4-ORa wherein Ra is optionally specified in hydrogen and C1-6alkyl; Rc represents C1-6alkyl; G is specified in a group consisting of -C(O)-, -OC(O)-, -NHC(O)- and -S(O)0-2-; B is specified in a group consisting of phenylene and 5-6-member heteroarylene consisting 1-2 nitrogen heteroatom as apexes of the ring, and substituted by 0 to 1 substitutes RB specified in F, Cl, Br, I and Rp; wherein Rp represents C1-6 alkyl; D is specified in a group consisting of -NR3C(O)NR4R5, -NR4R5, C(O)NR4R5, -NR3C(=N-CN)NR4R5, -NR3C(O)R4, -NR3C(O)OR4 and -NR3S(O)2R4, and wherein the group D and a substitute placed on an adjoining atom in the ring B, optionally combined to form a 5-6-member heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms specified in N, O and S, as apexes of the ring and substituted by the substitute 0-1 RD. The R1-R5 radical values are presented in the patent claim.

EFFECT: invention also refers to a pharmaceutical composition containing said compounds, and to the use of the compounds for preparing a drug for treating a malignant tumour mediated by mTOR kinase activity.

33 cl, 13 dwg, 4 tbl, 498 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which is 7-methyl-5-(3-piperazin-1-ylmethyl-[1,2,4]oxadiazol-5-yl)-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition having potentiating activity on glutamate receptors, containing the compound described above; also described is use of the compound or a pharmaceutically acceptable salt in claim 1 in producing a medicinal agent for therapy of neurological and mental disorders associated with glutamate dysfunction.

EFFECT: novel compound which can be used in therapy of neurological and mental disorders is obtained and described.

5 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula II , where Q is (CR4R5)n3; n1 equals 1 or 2; n2 equals 1 or 2; n3 equals 1; R2 is R2-1 or R2-2 , Ar is phenyl or a heteroaryl ring consisting of 8-10 carbon atoms and 1-2 heteroatoms selected from O or S; X denotes 1-2 substitutes located on Ar, each independently selected from a group consisting of OR8, NR8R9, SR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9 and CN; R3-R5 denote H; R8 is H, alkyl, cyclopropyl, phenyl or pyridinyl; optionally substituted with one or more halogens or heteroatom-containing substitutes selected from a group consisting of OR11, NR11R12, CO2R11, CONR11R12, NRnC(=O)Ri2; R9 is H or alkyl; R11-R12 independently denote H, alkyl, pyridinyl or morpholinyl.

EFFECT: compounds are inhibitors of rho-associated protein kinase which can be used in medicine to prevent or treat diseases or conditions associated with cytoskeleton readjustment, specifically treat high intraocular pressure such as primary open angle glaucoma.

10 cl, 3 tbl, 226 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention describes specific compounds, namely pyridyl-piperidine compounds, which represent antagonists of orexin receptors and can be used for treatment or prevention of neurologic and psychiatric disorders and diseases, in development of which orexin receptors participate.

EFFECT: claimed invention relates to pharmaceutical compositions, containing said compounds, as well as to application of said compounds and compositions for prevention or treatment of diseases, in development of which orexin receptors participate.

5 cl, 1 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to dihydropyrazolone derivatives or of formula (I), where R1 denotes a heteroaryl group of formulae given below, where * denotes the linkage point with the dihydropyrazolone ring, A in each individual occurrence denotes C-R4 or N, wherein at most two ring members A represent N at the same time, E denotes O or S, R2, R3 and R4 are as defined in the claim. The invention also relates to a method of producing said compounds.

EFFECT: compounds of formula (I) inhibit HIF-propylhydroxylase activity and can be used to treat and/or prevent diseases, as well as for producing medicaments for treating and/or preventing diseases, particularly cardiovascular and haematologic diseases, kidney diseases, and for promoting the healing of wounds.

10 cl, 10 tbl, 178 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is oxazolidinone of general formula , where values of radicals are given in invention formula, and pharmaceutical antibiotic composition, which includes as active ingredient novel oxazolidinone derivative, its hydrate, solvate, isomer or pharmaceutically acceptable salt.

EFFECT: compounds are characterised by wide antibacterial spectrum and high antibacterial activity against gram-positive and gram-negative resistant bacteria, low toxicity and can be applied as antibiotic.

7 cl, 3 tbl, 106 ex

FIELD: medicine.

SUBSTANCE: described are novel heterocyclic compounds of general formulae and (values of radicals are given in invention formula), pharmaceutical compositions containing them and application of said heterocyclic compounds for treatment disorders mediated with MAP kinase cascade.

EFFECT: increase of compound efficiency.

67 cl, 106 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula , where A, Q, R1, R2, R3, R4, R5' are represented in i.1 of the formula, as well as to its hydrates, solvates and pharmaceutically acceptable salts, Also described are application of said compound and pharmaceutical composition, including such compound, for treatment of disease condition in mammals, which is sensitive to action of antagonists of vasopressin V1a, V1b or V2 receptors.

EFFECT: increase efficiency of compound application.

20 cl, 13 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel tetrahydroisoquinoline derivatives of general formula (I) or pharmacologically acceptable salts thereof, where R1 is a phenyl aminocarbonyl group which can be substituted with 1-3 groups independently selected from a substituting group A, a heteroaryl aminocarbonyl group, where the heteroaryl is pyridine, pyrazine, thiazole, pyrazole or isoxazole, which can be substituted with 1 group selected from a substituting group A, benzoxazol-2-yl group, which can be substituted with 1 group selected from a substituting group A, benzothiazol-2-yl group, (C1-C6 alkyl which can be monosubstituted with a C3-C6 cycloalkyl group), aminocarbonyl group, (C3-C6 cycloalkyl)aminocarbonyl group or adamantyl aminocarbonyl group; R2 independently represents a C1-C6 alkyl group; R3 is a heterocyclic group, where the heterocycle is oxazole, oxadiazole, pyrazole, isoxazole or tetrazole, which can be substituted with 1 group selected from a substituting group A, a group of formula -C(=O)-O-R4, or a group of formula -C(=O)-N(R5)R6; R4 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1-2 groups independently selected from a substituting group B; R5 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1 group selected from a substituting group B, a C3-C6 cycloalkyl group which is monosubstituted with a carboxyl group, or a heterocyclic group, where the heterocycle is tetrazole, which can be substituted with 1 group selected from a substituting group A; R6 is a hydrogen atom or a C1-C6 alkyl group; in those cases when both R5 and R6 represent a C1-C6 alkyl group, which can be substituted with 1 group selected from a substituting group B, their carbon atoms can be bonded to each other to form a 5-member saturated ring; X is an oxygen atom, a methylene group, a group of formula -NH-, a methylene group which is monosubstituted with a C1-C6 alkyl group, or a group of formula -N(R7)-; R7 is a C1-C6 alkyl group; L is a single bond, a methylene group, a 1,1-dimethylmethylene group, an ethylene group, a group of formula - CH=, or a methylene group which is monosubstituted with a C1-C6 alkyl group; … denotes a single bond or a double bond (however, … denotes a single bond when L is a group of formula -CH=); m equals 1 or 2; n equals 0 or 1; substituting group A is a group of substitutes selected from a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, a C1-C6 alkylthio group, a carboxyl group, a di-(C1-C6 alkyl)amino group, a cyano group, a hydroxy group, a C1-C6 alkylthionyl group and an oxo group; and substituting group B is a group of substitutes selected from a carboxyl group and a hydroxy group. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treating and/or preventing a disease.

EFFECT: obtaining novel tetrahydroisoquinoline derivatives, having excellent inhibiting action on acyl-coenzyme A: diacylglycerol-acyltransferase and excellent food intake suppression.

31 cl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A, J, R1, R4, X, Z are given in claim 1, and to a pharmaceutical composition containing such compounds, which modulate activity of store-operated calcium (SOC) channels. The present invention also describes methods of using such SOC channel modulators to treat diseases or conditions where inhibition of activity of SOC channels can be beneficial.

EFFECT: improved method.

17 cl, 5 tbl, 2 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) , where Ar denotes each of R2, R3, R4, R5, R4' and R5' denote hydrogen; A denotes C(O); D denotes oxygen or NR8; E denotes CR63R64CR65R66; R63 and R64 denote hydrogen; R65 and R66 independently denote hydrogen or C1-4alkyl; k equals 0; m equals 1; R6 denotes a group -(X)p-Y-(Z)q-R10, or R6 denotes α- or β-branched C3-6alkyl (optionally substituted with C6cycloalkyl); X and Z independently denotes a C1-4alkylene group; p and q are independently equal to 0 or 1; Y denotes a bond; R8 denotes hydrogen; R10 denotes hydrogen or a saturated 5-7-member ring system; R7 denotes a 6-member aromatic ring, optionally substituted with a halogen, carboxyl, C1-6alkyl, C1-2alkoxy or a 5-member heteroaromatic ring (which is optionally substituted with C1-6alkyl); or a pharmaceutically acceptable salt thereof. Compounds of formula (I) or a pharmaceutically acceptable salt thereof are used to produce a medicinal agent for treating respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma or rhinitis.

EFFECT: high efficiency of using said compounds.

7 cl, 1 tbl, 102 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to formula 1 compounds, possessing properties of Xa factor inhibitors, their pharmaceutically acceptable salts and based on them pharmaceutical compositions. In formula 1 cycle A stands for residue, selected from group, including the following structures: R1-R12 independently represents H, (C1-C7)alkyl or (C3-C7)cycloalkyl, R3 and R4 form cycle by binding (C3-C5)alkylene, alkylene carbon atom can be substituted with carbonyl; R13 stands for H, (C1-C7)alkyl or formyl.

EFFECT: obtaining compounds, possessing properties of Xa factor inhibitors.

8 cl, 5 ex, 3 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: described are novel heterocyclic compounds of general formulae and (values of radicals are given in invention formula), pharmaceutical compositions containing them and application of said heterocyclic compounds for treatment disorders mediated with MAP kinase cascade.

EFFECT: increase of compound efficiency.

67 cl, 106 ex, 2 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: in claimed invention described is compound of general formula 1, or its pharmaceutically acceptable salt, where in each case independently on each other m equals 0, 1; p equals 1 or 2; R1 is selected from group, including -OH, -OC(O)NHMe, -OC(O)NMe2, -OC(O)NH(CH2)2Ph and OC(O)NH(CH2)2NMe2; R2 stands for -OH, -OC(O)Me, -OCH2CO2H, -OCH2CO2Et, -N3, -N=C(NMe2)2, -NH2, -NMe2, -NHC(O)Me, -NHC(O)CF3, - NHC(O)Ph, -NHC(O)NHPh, -NHC(O)CH2CH2CO2H, -NHC(O)CH2CH2CO2Me, - NHCH2Ph, -NHCH2(4-pyridyl), -NHCH2(2-pyridyl), -NHCH2(4-(CO2H)Ph), - NHCH2(3-(CO2H)Ph), -NHEt, -NHCHMe2, -NHCH2CHMe2, -N(CH2CHMe2)2, - NHCH2(cyclopropyl) or -NHC(O)CH2CH2NMe2; R3 stands for -OMe, -OEt, - OCH2(cyclopropyl), F, -O(CH2)2NMe2 or -O(CH2)2(4-morpholino); R4 stands for -NMe2, -NEt2, -NHEt, -NHCH2CHMe2, -N(Me)CH2CHMe2, - N(Me)CH2CH2NHS(O)2Me, -N(Me)CH2CH2NHS(O)2CF3, -NHCH2CH2OH, - N(Me)CH2CH2OH, -N(Me)CH2CO2H, -N(Me)CH2C(O)NH2, N(Me)CH2C(O)NHMe, -N(Me)CH2C(O)NMe2, -NHC(O)Me, 1-piperidinyl, 4-morpholino, (R)-2-(hydroxymethyl)-1-pyrrolidinyl, -NH2, -NO2, Br, CI, F, -C(O)Me or -CH2NH2; R5 stands for -OH or -N(R17)(R18); R17 and R18 independently in each case stand for H, (C1-C6)-alkyl, (C5-C7)-aryl-(C1-C6)-alkyl, where said aryl contains from zero to two heteroatoms, (C1-C6)-alkoxy or -[C(R19)(R20)]P-R21 R19 and R20 independently in each case represent H, (C1-C6)-alkyl, (C1-C6)-alkoxy, amino-(C1-C6)-alkyl, acylamino, sulfonylamino, (C5-C7)-aryl, (C5-C7)-aryl-(C1-C6)-alkyl or 3-10-membered heterocyclyl-(C1-C6)-alkyl, containing in ring from one to two heteroatoms; R21 independently in each case represents H, 3-10-membered heterocyclyl, containing in ring one heteroatom, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfonamido or amido; R22 stands for halogen; R23 stands for methyl; R24 stands for methyl and R25 stands for methyl, where said aryl stands for 5-7-membered ring, containing from zero to two heteroatoms, and said aryl or said heterocyclyl can be non-substituted or substituted halogen, (C1-C6)-alkyl or amino. Also described is pharmaceutical composition, possessing inhibiting activity with respect to Bcl-2 and/or Bcl-XL proteins, which includes said compound, also described is method of treating disorder, mediated by Bcl-2 and/or Bcl-XL proteins, which lies in introduction of said compound to patient, who needs such treatment, in therapeutically efficient amount.

EFFECT: increased efficiency of compound application.

41 cl, 6 dwg, 125 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives having PGDS inhibiting properties. In formula (I): (I), R1 denotes phenyl or a 5- or 6-member heteroaryl containing 1-3 heteroatoms selected from N, O and S, each optionally having one or more of the following independent substitutes: halogen, (C1-C6)-alkyl, or (C1-C4)-haloalkyl; R2 denotes hydrogen or (C1-C6)-alkyl, which is optionally substituted with one or more halogens; R3 denotes hydrogen, (C1-C6)-alkyl or phenyl; R4 denotes C6-cycloalkyl, phenyl, a 6-member heterocyclyl containing one N heteroatom, a 6-member heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2, or -C(=O)-R5, where the phenyl, 6-member heteroaryl or 6-member heterocyclyl group optionally has one or more independent substitutes R6, or R3 and R4 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclyl containing one or two heteroatoms selected from N, O and S, a 6-member heterocyclenyl containing two or three N heteroatoms, a 5-member monocyclic or 9-member bicyclic heteroaryl containing one to three N heteroatoms, phenylheterocyclyl, where the heterocyclyl is 5- or 6-membered and contains one or two heteroatoms selected from N and O, each optionally having one or more independent substitutes R6. Values of R5, R6, Y1, Y2 are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds.

EFFECT: improved method.

15 cl, 227 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: it has been confirmed that the new azolcarboxamide compound or its pharmaceutically acceptable salt wherein a thiazole ring or an oxazole ring is bound to a benzene ring, a pyridine ring, a pyridazine ring, a thiophen ring, a pyrazole ring or a pyrrol ring through carboxamide or its ring possess high activity of receptor trkA inhibition; it has been found that they may be used as a therapeutic and/or preventive agent which is different in the fact concerning the effectiveness and safety for repeated urination, frequent micturate urge and urine incontinence associated with various urogenital diseases, including higher bladder activity, various lower bladder diseases accompanied with urogenital pain, such as interstitial cystitis, chronic prostatitis and others, and various diseases accompanied by pain; thereby the present invention has been created.

EFFECT: provided therapeutic and/or preventive agent for repeated urination, frequent micturate urge and urine incontinence associated with various urogenital diseases, including higher bladder activity, various lower bladder diseases accompanied with urogenital pain, such as interstitial cystitis, chronic prostatitis and others, and various diseases accompanied by pain on the basis of excellent inhibitory action on the receptor trkA.

24 cl, 1195 ex, 215 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a benzazepin compound of general formula (1) possessing the property of vasopressin antagonist, and to a based pharmaceutical composition. In general formula (1) R1 means a group (1-1) or (1-3) to (1-7): (1-1) represents a group -CO-(CH2)n-COR2 wherein n means an integer 1 to 4, R2 means (2-1) hydroxyl group; (2-2) lower alkoxy group if necessary substituted by hydroxyl group, lower alkanoyl group, lower alkanoyloxy group, lower alkoxycarbonyloxy group, cycloalkyloxycarbonyloxy group or 5-methyl-2-oxo-1,3-dioxol-4-yl; or (2-3) amino group if necessary substituted by hydroxyl lower alkyl; (1-3) represents a group -CO-(CH2)p-O-CO-NR5R6 wherein p means an integer 1 to 4, R5 means lower alkyl group, and R6 means a group of lower alkoxycarbonyl lower alkyl; (1-4) represents a group -CO-(CH2)q-X-R7 wherein q means an integer 1 to 4, X means an oxygen atom, a sulphur atom or a sulphonyl group, and R7 means a group of carboxy lower alkyl or a group of lower alkoxycarbonyl lower alkyl; (1-5) represents a group -CO-R8, (wherein R8 means (8-1) alkyl group if necessary substituted by a halogen atom, lower alkanoyloxy group or phenyl group (substituted by dihydroxyphosphoryloxy group wherein hydroxyl groups may be substituted by benzyl groups, and lower alkyl group), a (8-2) lower alkoxy group substituted by a halogen atom, lower alkanoyloxy group or dihydroxyphosphoryloxy group, (8-3) pyridyl group or (8-4) lower alkoxyphenyl group; (1-6) represents a lower alkyl group substituted by a group consisting of a lower alkylthio group, a dihydroxyphosphoryloxy group and a lower alkanoyloxy group; and (1-7) represents a peptide residue if necessary substituted by one or more protective groups.

EFFECT: compound of formula (1) is able to maintain the blood tolvaptan level for a long period of time that enables providing the desired pharmaceutical effects.

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