Type 1 diacylglycerol o-acyltransferase enzyme inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or a pharmaceutically acceptable salt thereof, wherein G1 is phenyl or pyridyl, each of which is optionally additionally substituted by one substitute presented by T; G2 is phenyl, 1,3-thiazolyl or 1,3-oxazolyl, wherein G2 is bound to G1 in the para position in relation to a place of attachment of G1 to group NH in formula (I), wherein G2 means phenyl, G3 is bound to G2 in the para position of G2 in relation to G1, and wherein provided G2 represents 1,3-thiazolyl or 1,3-oxazolyl, G2 is bound to G1 in the position of 5 G2 and G3 is bound to G2 in the position of 2 G2; T in each case is independently specified in a group containing C1-6alkyl and halogen; G3 is presented by formula or by formula ; W1 is -C(R3)(R4)-C(R3)(R4)-, and W2 represents N; or W3 represents O; W4 is -C(R3)(R4) -; each R3 and R4 is hydrogen; each R5 and R6 kis hydrogen; Rc and Rd together with a carbon atom whereto attached, are a 4-5-member cycloalkyl or monocyclic heterocycle of formula ; wherein one hydrogen atoms attached to the carbon atom of the cycloalkyl ring and monocyclic heterocycle is optionally substituted by a radical specified in a group -C(O)O(R8); W5 is -CH2- or -CH2-CH2-; W6 is O or N(RX), wherein Rx is hydrogen, C1-6alkyl or -C(O)O(Rz); RZ in each case is independently C1-6alkyl; R8 is hydrogen; L1 is O; and X is hydrogen, C1-6alkyl, or - (CRgRh)u-C(O)O(R10); or L1 is -CH2- and X is -C(O)OH; R10 is hydrogen; or Q is G4 or Y1-Y3; or Q is described for formula wherein Z is phenyl; G4 is benzothiazole or benzoxazole optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of C1-6alkyl, halogen and -OR1; Y1 in each case is independently -C(O)-, -C(O)O- or -C(O)N(Rw)-, wherein the right side -C(O)O- and -C(O)N(Rw)- of the groups is attached to Y3 or (CRJRk)v, Y3 in each case is independently phenyl, benzyl, piperidinyl or bicyclo[4.2.0]octa-1,3,5-triene, wherein the phenyl and benzyl residues are optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of halogen and haloC1-6alkyl; Rg and Rh in each case is independently hydrogen, or C1-6alkyl; R1 in each case is independently halogenC1-6alkyl; Rw is hydrogen; and u means 1.

EFFECT: compounds being the type 1 diacylglycerol O-acyltransferase (DGAT-1) enzyme inhibitors.

7 cl, 1 tbl, 61 ex

 

The technical field

Described compounds, which are inhibitors of the enzyme diacylglycerol O-acyltransferase type 1 (DGAT-1). Also described ways 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 are the main storage form of energy in eukaryotes, and disorder or imbalance of the metabolism triacylglycerides involved in the pathogenesis and increased risk of obesity, insulin resistance, type II diabetes, nonalcoholic fatty liver disease and coronary heart disease (Lewis, et al., Endocrine Reviews 23:201, 2002). The storage of excess triacylglycerides in non-fat tissues, such as liver, muscle and other peripheral tissues, leads to caused by fats dysfunction in these tissues; thus, reducing the accumulation of fat in the skim sites is favorable for the treatment of lipotoxicity (Unger, R. H. Endocrinology, 144: 5159-5165, 2003). Accumulation of excess triacylglycerides in white adipose tissue (bzht) leads to obesity, a condition that is associated with a lower standard of living, type II diabetes, 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 widely distributed is in modern society, modern pharmacological treatment is severely limited, which creates the need to develop pharmaceuticals for the treatment of obesity that are safe and effective.

The diacylglycerol O-acyltransferase (DGAT) are membrane-bound enzymes that catalyze the final stage of the biosynthesis triacylglycerides. It was characterized by two enzymes, which have DGAT activity: DGAT-1 (diacylglycerol O-acyltransferase type 1) (U.S. patent 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 are identical, only 12% of the sequence. Largely DGAT-1 null mice are more resistant to caused by nutrition 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 lacking DGAT-1, protected from fatty hepatosis, demonstrate increased energy consumption and reduced levels triacylglycerides in the tissue. In addition to improved metabolism triacylglycerides deprived DGAT-1 mice have improved glucose metabolism, with lower levels of glucose and insulin after glucose load compared with wild-type mice. Partial deficiency of DGAT-1 heterozygous On the at-1+/- animals sufficient for the transmission of an intermediate phenotype in body weight, obesity and metabolism of insulin and glucose compared to wild type and homozygous pups from the same litter (Chen and Farese, Arterioscler. Thromb. Vase. Biol. 25:482-486, 2005), and has been described that the low molecular weight inhibitors DGAT-1 cause weight loss in mice with induced food obesity (VPO) (US 2004/0224997). Phenotypes deprived DGAT-1 mice and pharmacological activity described for inhibitors DGAT-1, suggest that the discovery of small molecules that effectively block the conversion of diacylglycerol in triacylglyceride through inhibition of the enzyme DGAT-1, can be used in the treatment of obesity and other diseases associated with an imbalance of triacylglycerides.

The invention

One aspect of this invention relates to compounds of formula (I)or their pharmaceutically acceptable salts, prodrug, salt of a prodrug, or their combination,

where

G1is a phenyl or a monocyclic heteroaryl, each of which is optionally additionally substituted with 1, 2, 3 or 4 substituents represented by T;

G2is a phenyl or a monocyclic heteroaryl, each of which is optionally further substituted by 1, 2, 3 or 4 substituents represented by T;

T in each case independently selected from the group including, but not limited to, alkyl, alkenyl, alkyne is, halogen, -CN, -NO2, -OR1, -OC(O)(R2), -N(RW)(R1), -N(RW) (O)(R1), -N(RW)-C(O)O(R1), -N(RW)-C(O)N(RW)(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), -(CRaRb)r-CN, -(CRaRb)r-NO2, -(CRaRb)r-OR1, -(CRaRb)r-OC(O)(R2), -(CRaRb)r-N(Rw)(R1), -(CRaRb)r-N(Rw)C(O)(R1), -(CRaRb)r-N(Rw)-C(O)O(R1), -(CRaRb)r-N(Rw)-C(O)N(Rw)(R1), -(CRaRb)r-N(Rw)-S(O)2(R2), -(CRaRb)r-C(O)O(R1), -(CRaRb)r-C(O)N(Rw)(R1), -(CRaRb)r-C(O)R1, -(CRaRb)r-SR1, -(CRaRb)r-S(O)R2, -(CRaRb)r-S(O)2R2, -(CRaRb)r-S(O)2N(Rw)(R1and halogenated; or

two neighboring substituent T together with the carbon atoms to which they are attached, form a monocyclic ring selected from the group including, but not limited to, phenyl, heterocycle and heteroaryl, where each ring is optionally substituted by 1, 2 or 3 substituents, selected and from the group including, but not limited by them, 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(Rw)(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), -(CRaRb)r-CN, -(CRaRb)r-NO2, -(CRgRh)t-OR1, -(CRaRb)r-OC(O)(R2), -(CRaRb)r-N(Rw)(R1), -(CRaRb)r-N(Rw)C(O)(R1), -(CRaRb)r-N(Rw)-C(O)O(R1), -(CRaRb)r-N(Rw)-C(O)N(Rw)(R1), -(CRaRb)r-N(Rw)-S(O)2(R2), -(CRaRb)r-C(O)O(R1), -(CRaRb)r-C(O)N(Rw)(R1), -(CRaRb)r-C(O)R1, -(CRaRb)r-SR1, -(CRaRb)r-S(O)R2, -(CRaRb)r-S(O)2R2, -(CRaRb)r-S(O)2N(Rw)(R1and halogenated;

G3is formula (a) or formula (b)

or

W1is-C(R3)(R4)- or-C(R3)(R4)-C(R3)(R4)-, and W2is -(R 7)or N; or

W1is N(H), N(alkyl), O, S(O) or S(O)2and W2is-C(R7)-;

W3is N(H), N(alkyl) or O;

W4is-C(R3)(R4)- or-C(R3)(R4)-C(R3)(R4)-;

R3and R4in each case, independently are hydrogen or C1-6by alkyl;

R5and R6independently are hydrogen or C1-6by alkyl; or R5and R6together with the carbon atom to which they are attached, form a C(=O);

R7in each case, independently is hydrogen, C1-6the alkyl or-C(O)OH;

Rcand Rdtogether with the carbon atom to which they are attached, are 3-6-membered cycloalkyl or a monocyclic heterocycle of formula (c)

where 1, 2, 3 or 4 hydrogen atoms attached to the carbon atom of the ring cycloalkyl and monocyclic heterocycle, optionally substituted by radicals selected from the group including, but not limited to, alkyl, halogen, -CN, halogenated, -C(O)O(R8), -C(O)N(R8)(R9), -(CReRf)t-C(O)O(R8and -(CReRf)t-C(O)N(R8)(R9);

W5is-CH2- or-CH2-CH2-;

W6is O, S, S(O), S(O)2N(RX), -C(O)N(Ry)- or-N(Ry)C(O)-; where Rxis hydrogen is, the alkyl, halogenation, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylation, cycloalkylation, arylalkyl, heteroallyl, heterocyclical, -C(O)O(Rz), -C(O)Rzor-C(O)N(Rw)(Rm);

Ryand Rmin each case, each independently is hydrogen, alkyl, halogenation, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycle, arylalkyl, cycloalkylation, cycloalkylation, heteroallyl or heterocyclical;

Rzin each case, independently is an alkyl, halogenation, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycle, arylalkyl, cycloalkylation, cycloalkylation, heteroallyl or heterocyclical;

R8and R9in each case, independently are hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycle, halogenation, arylalkyl, cycloalkylation, cycloalkylation, heteroallyl or heterocyclization; or

R8and R9together with the nitrogen atom to which they are attached, form a heterocyclic ring, optionally substituted by 1, 2 or 3 substituents selected from the group comprising alkyl, halogen and halogenated;

L1is O, N(H) or N(alkyl); and X is -(CRgRh) -tetrazolium, heterocyclical, heteroallyl, hydrogen, alkyl, halogenation, -C(O)O(R10), -C(O)N(R10)(R11), -(CRgRh)u-OR10, -(CRgRh)u-N(R10)(R11), -(CRgRh)u-CN, -(CRgRh)u-C(O)O(R10or -(CRgRh)u-C(O)N(R10)(R11); or

L1is -(CRpRq)s- and X is-C(O)OH or tetrazolium;

R10and R11in each case, independently are hydrogen, alkyl, cycloalkyl, cycloalkenyl, heteroaryl, aryl, heterocycle, cycloalkylation, cycloalkylation, heteroallyl, arylalkyl, heterocyclical or halogenation; or

R10and R11together with the nitrogen atom to which they are attached, form a heterocyclic ring, optionally substituted by 1, 2 or 3 substituents selected from the group comprising alkyl, halogen and halogenated;

Q is alkyl, alkenyl, quinil, halogenation, G4, Y1-Y3or Y1-(CRjRk)V-Y2-Y4; or Q has the formula(d)

,

where

Z is alkyl, alkenyl, quinil, halogenation, G4, Y1-Y3or-Y1-(CRjRk)v-Y2-Y4;

G4is cycloalkyl, cyclo what keniam, a heterocycle, heteroaryl, aryl, cycloalkylation, cycloalkylation, heterocyclical, heteroallyl or arylalkyl;

Y1in each case, independently is-C(O)-, -C(O)O-, -C(O)N(RW)-, -S(O)2-, -S(O)2-N(RW)-where the right side is-C(O)O-, -C(O)N(Rw)- and-S(O)2-N(RW)groups attached to the Y3or (CRjRk)v,

Y2in each case, independently is O, N(RW), or C(O);

Y3in each case, independently is an alkyl, halogenation, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, aryl, cycloalkylation, cycloalkylation, heterocyclical, heteroallyl or arylalkyl;

Y4in each case, independently is hydrogen, alkyl, halogenation, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, aryl, cycloalkylation, cycloalkylation, heterocyclical, heteroallyl or arylalkyl;

where cycloalkenyl, cycloalkyl, heterocycle, heteroaryl, aryl, aryl group arylalkyl, heteroaryl group heteroallyl, cycloalkyl group cycloalkenyl, heterocyclyl group geterotsiklicheskikh and cycloalkenyl group cycloalkenyl represented by X, G4, Y3, Y4, Rx, Ry, Rz, Rm, R8, R9, R10and R11 each independently substituted by 1, 2, 3, 4 or 5 substituents selected from the group comprising 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)-C(O)N(Rw)(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), halogenated, -(CRaRb)r-CN, -(CRaRb)r-NO2, -(CRaRb)r-OR1, -(CRaRb)r-OC(O)(R2), -(CRaRb)r-N(Rw)(R1), -(CRaRb)r-N(Rw)C(O)(R1), -(CRaRb)r-N(Rw)-C(O)O(R1), -(CRaRb)r-N(Rw)-C(O)N(Rw)(R1), -(CRaRb)r-N(Rw)-S(O)2(R2), -(CRaRb)r-C(O)O(R1), -(CRaRb)r-C(O)N(Rw)(R1), -(CRaRb)r-C(O)R1, -(CRaRb)r-SR1, -(CRaRb)r-S(O)R2, -(CRaRb)r-S(O)2R2, -(CRaRb)r-S(O)2N(Rw)(R1), and halogenated;

Ra, Rb, Re, Rf, Rg, Rh, Rj, Rk, Rpand Rqin each case, regardless what about are hydrogen, halogen, alkyl or halogenation;

R1and Rwin each case, independently are hydrogen, alkyl or halogenation;

R2in each case, independently is an alkyl or halogenation; and

r, s, t, u and v, in each case, independently equal to 1, 2, 3, 4, 5 or 6.

In another aspect of the present invention presents methods of treatment of various diseases or conditions in a patient, preferably a human, where the methods include administration to a patient in need of such, a therapeutically or prophylactically effective amount of the compounds in accordance with this invention or its pharmaceutically acceptable salts, or pharmaceutical compositions containing the compound in accordance with this invention or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. In another aspect, the present invention presents methods of preventing or treating a disease or condition associated with elevated levels of fats such as the fat levels in the plasma, especially elevated levels of triacylglycerides, in a patient, preferably a human, having such elevated levels, including the introduction to the patient a therapeutically or prophylactically effective amount of a compound, its pharmaceutically acceptable salt or containing pharmaceutical is oppozitsii, as explained above. This invention also relates to compounds having therapeutic ability to reduce levels of fat in a patient (e.g. a mammal), especially the levels triacylglycerides. Therefore, the compounds and compositions in accordance with this invention, alone or in combination with one or more pharmaceutical agents selected from the group comprising DPPIV inhibitor, mimic incretin, Metformin, frobert, rimonabant, sibutramine, orlistat, nicotinic acid and a statin, used for the preparation of drugs for treatment or prevention of diseases and disorders described above, particularly for the treatment or prevention of type 2 diabetes, obesity, elevated levels of triglycerides in plasma, metabolic syndrome, non-alcoholic steatohepatitis and nonalcoholic fatty liver disease. Compounds in accordance with this invention or their pharmaceutically acceptable salt or composition, alone or in combination with one or more described in the present description of pharmaceuticals is also used for making medicines for lowering lipid levels in a patient (e.g. a mammal, including humans), especially levels of triglycerides. In another aspect of the present invention presents pharmaceutical compositions is AI, comprising one or more compounds in accordance with this invention, described above, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

Detailed description of the invention

For variables that occur more than once in any Deputy or in connection in accordance with this invention or any other presented in this description of the formula, its definition in each case is independent of its definition in any other case. Combinations of substituents are permissible only if such combinations provide for a stable connection. Stable compounds are compounds that can be selected with a useful degree of purity from a reaction mixture.

In this description and presents the claims, unless otherwise specified, the following terms have the indicated meanings:

The term "alkenyl" in this specification means a straight or branched hydrocarbon chain, comprising from 2 to 10 carbon atoms, and containing at least one double bond in the carbon-carbon bonds formed by removing two hydrogen atoms. 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.

The term "alkyl" in the present description, oznachaet is a straight or branched hydrocarbon chain, comprising from 1 to 10 carbon atoms. The term "lower alkyl" or "C1-6alkyl" means a straight or branched hydrocarbon chain, comprising from 1 to 6 carbon atoms. The term "C1-3alkyl" means a straight or branched hydrocarbon chain, comprising 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" means a divalent group derived from a straight or branched hydrocarbon chain, comprising from 1 to 10 carbon atoms. Typical examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- and-CH2CH(CH3)CH2-.

The term "quinil" in this specification means a straight or branched hydrocarbon chain, comprising 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.

The term "aryl" in the present description means a phenyl or bicyclic aryl. The bicyclic aryl is naphthyl or enil, condensed with a monocyclic cycloalkyl, or phenyl fused with a monocyclic cycloalkenyl. Phenyl and bicyclic aryl groups in accordance with this invention are substituted or unsubstituted. Bicyclic aryl attached to the main molecular group via any of the carbon atoms contained in the bicyclic aryl. Typical examples of aryl groups include, but are not limited to, bicyclo[4.2.0]OCTA-1,3,5-trien-7-yl, dihydroindeno, indenyl, naphthyl, dihydronaphthalene and 5,6,7,8-tetrahydronaphthalene.

The term "arylalkyl" in this description means an aryl group such as defined above, attached to the main molecular group through an alkyl group, such as defined above. Typical examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl and 3-phenylpropyl.

The term "cycloalkyl" or "cycloalkane" in this description means a monocyclic, bicyclic or tricyclic cycloalkyl. Monocyclic cycloalkyl represents a hydrocarbon system of rings containing from three to eight carbon atoms, and zero heteroatoms and zero double bonds. Examples of monocyclic systems of rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Bicyclic cycloalkyl is a monocyclic cycloalkyl, to denserank with monocyclic cycloalkyl ring, or bridged monocyclic cycloalkyl, in which two adjacent carbon atom monocyclic ring are linked alkilinity bridge containing one, two, three, or four carbon atoms. Typical examples of bicyclic systems of rings include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonan, bicyclo[3.3.1]nonan and bicyclo[4.2.1]nonan. Tricyclic cycloalkyl presents a bicyclic cycloalkyl condensed with a monocyclic cycloalkyl, or bridged bicyclic by cycloalkyl, in which two non-adjacent carbon atoms of the bicyclic system of rings connected alkilinity bridge comprising from one to four carbon atoms. Typical examples of tricyclic systems of rings include, but are not limited to, tricyclo[3.3.1.03,7]nonan and tricyclo[3.3.1.13,7]decane (adamantane). Monocyclic, bicyclic and tricyclic cycloalkyl can be attached to the main molecular group via any substitutable atom contained within the ring and may be substituted or not substituted.

The term "cycloalkenyl" in this description means cycloalkyl group, such as defined above, attached to the base molecule through an alkyl group, such as defined above. Typical examples of cycloalkenyl include, but are not limited to them is, cyclopropylmethyl, 2-cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

The term "cycloalkenyl" or "cycloalkene" in this description means a monocyclic or bicyclic system of rings. Monocyclic cycloalkenyl has four, five, six, seven, or eight carbon atoms and zero heteroatoms. Four-system ring has one double bond, five - or six-membered rings have one or two double bonds, and the seven - or eight-membered system of rings has two or three double bonds. Monocyclic cycloalkenyl can be attached to the main molecular group via any substitutable atom contained within the monocyclic cycloalkenyl. Typical examples of monocyclic cycloalkenyl groups include, but are 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. Monocyclic or bicyclic cycloalkenyl ring may contain one or two alkilinity bridge, each of which includes one, two, three, or four carbon atoms and each of which connects two adjacent or non-adjacent carbon atoms of monocyclic the tion or bicyclic system of rings. Cycloalkenyl in accordance with this invention can be attached to the main molecular group via any substitutable atom contained within the ring system. Typical 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 in accordance with this invention can be substituted or not substituted.

The term "cycloalkenyl" in this description means cycloalkenyl group, such as defined above, attached to the main molecular group through an alkyl group, such as defined above.

The term "Ethylenedioxy" in this description means-O-(CH2)2-O - group in which the oxygen atoms of Ethylenedioxy attached to two adjacent carbon atoms of the phenyl or naftilos group, forming a six-membered ring with two adjacent carbon atoms of the phenyl or naftilos group to which it is attached.

The term "halogen" in the present description means Cl, Br, I or F.

The term "halogenated" in this description means an alkyl group such as defined above, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. Typical examples of halogenoalkane include, but are not limited to, chloromethyl, 2-f is oratel, trifluoromethyl, deformity, pentafluoroethyl and 2-chloro-3-terpencil.

The term "heterocycle" or "heterocyclic" in this description means a monocyclic heterocycle, a bicyclic or tricyclic a heterocycle. Monocyclic heterocycle is a three-, four-, five-, six - or semiline ring containing at least one heteroatom independently selected from the group including, but not limited to them, O, N and S. the Three - or four-membered ring contains zero or one double bond and one heteroatom selected from the group including, but not limited by them, O, N and S. the five-Membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group including, but not limited by them, O, N and S. the six-membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group including, but not limited by them, O, N and S. Semiline ring contains zero, one, two or three double bonds, two or three heteroatoms selected from the group including, but not limited to them, O, N and S. examples of monocyclic heterocycles include, but are not limited to, azetidine, azepane, aziridinyl, diazepan, 1,3-dioxane, 1,3-DIOXOLANYL, 1,3-dithiolane, 1,3-ditional, imidazolines, imidazolidinyl, isothiazolines, isothiazolinones, isoxazolyl, isoxazole inil, morpholinyl, oxadiazolyl, oxadiazolidine, oxazolines, oxazolidinyl, piperazinil, piperidinyl (including piperidine-1-yl), pyranyl, pyrazolyl, pyrazolidine, pyrrolidyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuryl, 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, a monocyclic heterocycle condensed with a monocyclic heterocycle, or bridged monocyclic heterocyclic system of rings, in which two non-adjacent carbon atoms of the ring are connected alkilinity bridge containing one, two, three, or four carbon atoms. Typical examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiophene, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzofuranyl and 2,3-dihydro-1H-indolyl. Tricyclic heterocycles presents a bicyclic heterocycle condensed with a phenyl group, or a bicyclic heterocycle condensed with a monocyclic cyclo what Kilom, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle or bridged bicyclic-heterocycle, in which two non-adjacent carbon atoms of the bicyclic ring are connected alkilinity bridge, including, but not limited to, one, two, three or four carbon atoms. Examples of tricyclic heterocycle include, but are not limited to, oxyadamantane and saadamanty. Monocyclic, bicyclic and tricyclic heterocycles are linked with the main molecular group via any carbon atom or any nitrogen atom contained within the monocyclic, bicyclic and tricyclic heterocyclic ring and may not be protected or reserved.

The term "heterocyclyl" in this description means a heterocycle, such as defined above, connected with the main molecular group through an alkyl group, such as defined above.

The term "heteroaryl" in this description means a monocyclic heteroaryl or bicyclic heteroaryl. Monocyclic heteroaryl is a five - or six-membered ring. Five-membered ring contains two double bonds. Five-membered ring may contain one heteroatom selected from O or S; or one, two or three nitrogen atom and, optionally, one updat the additional heteroatom, selected from oxygen or sulfur; or four nitrogen 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, imidazolyl, isoxazolyl, isothiazolin, oxadiazolyl, 1,3-oxazoles (including 1,3-oxazol-2-yl), pyridinyl (including pyridine-3-yl, pyridin-2-yl), pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl (including 1,3-thiazol-2-yl), thienyl, triazolyl and triazinyl. Bicyclic heteroaryl includes monocyclic heteroaryl condensed with a phenyl or monocyclic 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. Typical examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothiazol, benzoxazolyl (including 1,3-benzoxazol-2-yl), benzimidazolyl, benzoxazolyl, benzothiazolyl (including 1,3-benzothiazol-2-yl), 6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-α]pyridinyl, indazoles, indolyl, isoindolyl, ethenolysis, naphthyridine, predominately, quinoline is l, thiazolo[5,4-b]pyridine-2-yl, thiazolo[5,4-d]pyrimidine-2-yl and 5,6,7,8-tetrahydroquinolin-5-yl. Monocyclic and bicyclic heteroaryl groups in accordance with this invention can be substituted or not substituted, and connected to the main molecular group via any carbon atom or any nitrogen atom contained within the ring system.

The term "heteroaromatic" in this description means heteroaryl, such as defined above, attached to the main molecular group through an alkyl group, such as defined above.

The term "heteroatom" in this description means a nitrogen atom, oxygen or sulfur.

The term "methylenedioxy" in this description means-O-(CH2)-O-group in which the oxygen atoms of methylenedioxy attached to two adjacent carbon atoms of the phenyl or afternova ring, getting a five-membered ring with two adjacent carbon atoms with phenyl or naftilos the group to which they are attached.

The term "oxo" in this description means =O group.

"Mammal" includes humans and domestic animals such as cats, dogs, pigs, cattle, horses and the like.

Compounds in accordance with this invention have the formula (I)as described above.

Specific values of variable groups in the compounds of formula (I) as follows. Such values which may be applied, where applicable, with any of the other values, definitions, claims or options defined above or below.

In the compounds of formula (I) G1is a phenyl or a monocyclic heteroaryl (for example, pyridinyl, pyrimidinyl, pyrazinium, pyridazinyl, 1,3-thiazolyl, 1,3-oxazolyl and the like), each of which is optionally further substituted by 1, 2, 3 or 4 substituents represented by T, and T as defined in the section "summary of the invention".

In one embodiment, G1is phenyl, optionally substituted as described above.

In another embodiment, G1is a monocyclic heteroaryl, optionally further substituted as described above. For example, G1is pyridinyl, unsubstituted or further substituted as described in the section "summary of the invention".

G2is a phenyl or a monocyclic heteroaryl (for example, pyridinyl, pyrimidinyl, pyrazinium, pyridazinyl, 1,3-thiazolyl, 1,3-oxazolyl and the like), each of which is optionally further substituted by 1, 2, 3 or 4 substituents represented by T, and T as defined in the section "summary of the invention".

In one embodiment, G2is phenyl, optionally substituted as described above.

In another embodiment, G2is a monocyclic heteroaryl, long is Ino substituted, as explained above. Specific examples G2include 1,3-thiazolyl, 1,3-oxazolyl and pyridinyl, each of which is optionally substituted as described in the section "summary of the invention".

Examples of optional substituents G1and G2represented by T include, but are not limited to, halogen and C1-6alkyl, such as methyl, ethyl and the like.

G3is formula (a) or formula (b), where W1, W2, W3, W4, R3, R4, R5, R6, Rc, RdL1and X are such as defined in the section "summary of the invention".

In one embodiment, G3is formula (a), where W1, W2, W3, W4, R3, R4, R5and R6such as described in the section "summary of the invention". For example, G3is formula (a), where W1is-C(R3)(R4)- or-C(R3)(R4)-C(R3)(R4)-, and W2is N, and W3, W4, R3, R4, R5and R6such as described in the section "summary of the invention". Other examples G3from the formula (a) include those in which W1is-C(R3)(R4)- or-C(R3)(R4)-C(R3)(R4)-, and W2is-C(R7)-, and W3, W4, R3, R4, R5, R6and R7such as described in the section "summary of the invention". R34, R5and R6for example, are hydrogen.

In another embodiment, G3has the formula (b), where Rc, RdL1and X are such as defined in the section "summary of the invention".

In another embodiment, G3has the formula (b), where L1is O, N(H) or N(alkyl), and X is -(CRgRh)u-tetrazolium, heterocyclical, heteroallyl, hydrogen, alkyl, halogenation, -C(O)O(R10), -C(O)N(R10)(R11), -(CRgRh)u-OR10, -(CRgRh)u-N(R10)(R11), -(CRgRh)u-CN, -(CRgRh)u-C(O)O(R10or -(CRgRh)u-C(O)N(R10)(R11), where R10, R11, Rg, Rhand u such as defined in the section "summary of the invention". Examples of X include, without limitation, hydrogen, C1-6alkyl (e.g. methyl, ethyl and the like), and -(CRgRh)u-C(O)O(R10), where Rg, Rhand R10defined in section "summary of the invention". In one embodiment, R10is hydrogen, and Rgand Rhin each case, each independently selected from the group including, but not limited to, hydrogen, C1-6alkyl (e.g. methyl, ethyl and the like). In one embodiment, u is 1 or 2. Preferably, u is 1.

In another embodiment, G3has the formula (b) where L1is -(CR pRq)s- and X is-C(O)OH or tetrazolium, where Rp, Rqand s such as defined in the section "summary of the invention". In one embodiment, X is-C(O)OH. Examples Rpand Rqinclude hydrogen and C1-6alkyl (e.g. methyl, ethyl and the like). In one embodiment, Rpand Rqare hydrogen and s is 1.

In one embodiment, Rcand Rdtogether with the carbon atom to which they are attached, are 3-6-membered cycloalkyl (for example, cyclobutyl, cyclopentyl and the like), where 1, 2, 3 or 4 hydrogen atoms attached to the carbon atom of cycloalkyl, optionally substituted as described in the section "summary of the invention". For example, one of the hydrogen atoms attached to the carbon atom of the ring, optionally substituted-C(O)OH.

In another embodiment, Rcand Rdtogether with the carbon atom to which they are attached, form a monocyclic heterocycle of formula (c), as described in the section "summary of the invention". For example, Rcand Rdtogether with the carbon atom to which they are attached, form a monocyclic heterocycle of formula (c) where W5is-CH2- or-CH2-CH2and W6is O or N(RX); where Rxsuch as defined in the section "summary of the invention". For example, Rxis C1-6the alkyl (for example, stands the ethyl and the like), or-C(O)O(C1-6by alkyl).

Q is alkyl, alkenyl, quinil, halogenation, G4, Y1-Y3, -Y1-(CRjRk)v-Y2-Y4or formula (d) where G4, Y1, Y3, Rj, Rk, v, Y2, Y4and Z are such as defined in the section "summary of the invention". For example, Q is G4, Y1-Y3, -Y1-(CRjRk)v-Y2-Y4or formula (d) where G4, Y1, Y3, Rj, Rk, v, Y2, Y4and Z are such as defined in the section "summary of the invention".

In one embodiment, Q is G4where G4such as defined in the section "summary of the invention". For example, G4is aryl (e.g. phenyl) or heteroaryl (for example, 1,3-benzoxazolyl, 1,3-benzothiazolium), each of which is optionally substituted as described in the section "summary of the invention". Examples of optional substituents G4include, but are not limited to, C1-6alkyl (e.g. methyl, ethyl and the like), halogen, halogenated (e.g., trifluoromethyl) or-OR1where R1is C1-6the alkyl or halogenation (for example, trifluoromethyl).

In another embodiment, Q is Y1-Y3where-Y1and Y3such as described in the section "summary of the invention". For example, Y1is-C(O)- -C(O)O - or-C(O)N(R w)-where the right side is-C(O)O - and-C(O)N(Rw)groups attached to the Y3and Rwsuch as described in the section "summary of the invention". Examples Y3include, but are not limited to, aryl (e.g. phenyl, bicyclo[4.2.0]OCTA-1,3,5-trien-7-yl and the like), a heterocycle (for example, piperidinyl), cycloalkyl (for example, cyclobutyl, cyclopentyl, cyclohexyl and the like) and arylalkyl (e.g., benzyl), where each of the aryl, heterocycle, cycloalkyl and aryl groups arylalkyl independently 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, and the like), halogen and halogenated (for example, trifluoromethyl). In certain embodiments, Rwis hydrogen.

In another embodiment, Q is formula (d), where Z as described in the section "summary of the invention". For example, Z is G4where G4such as described in the section "summary of the invention". In one embodiment, G4is aryl (e.g. phenyl), unsubstituted or substituted as described in the section "summary of the invention". In another embodiment, G4is heteroaryl, unsubstituted or substituted as described in the section "summary of the invention". Examples of optional substituents include, but are not limited to, halogen, 1-6alkyl (e.g. methyl) and halogenated (for example, trifluoromethyl).

It is clear that this invention covers compounds of formula (I) combinations of the above alternatives, including the preferred, more preferred and most preferred options.

Therefore, in one aspect this invention relates to compounds of the formula (II) or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or their combination,

where Q, G1, G2, R3, R4, R5, R6, W1, W2, W3and W4such as described in the section "summary of the invention". For example, W1is-C(R3)(R4)- or-C(R3)(R4)-C(R3)(R4)-, W2is N, and Q, G1, G2, W3, W4, R3, R4, R5and R6such as described in the section "summary of the invention". For example, R3, R4, R5and R6are hydrogen. W3, W4, G1, G2and Q have the meanings described above. G1and G2, each independently, is a phenyl or a monocyclic heteroaryl, optionally substituted as described in the section "summary of the invention". Examples G1include, but are not limited to, phenyl and pyridinyl, each of which independently is not a substituted or substituted, ka is described in the section "summary of the invention". Examples G2include, but are not limited to, phenyl, pyridinyl, 1,3-thiazolyl and 1,3-oxazolyl, each of which is optionally additionally substituted with 1, 2, 3 or 4 substituents represented by T, and T as described in the section "summary of the invention". Examples of optional substituents G1and G2represented by T include, but are not limited to, halogen and C1-6alkyl, such as methyl, ethyl and the like. Examples of Q include G4, Y1-Y3, -Y1-(CRJRk)v-Y2-Y4or formula (d), where G4, Y1, Y3, RJ, Rk, v, Y2, Y4and Z have the meanings described above. In certain embodiments, W1is CH2, W2is N, W3is O and W4is CH2.

Other examples of compounds of the formula (II) include, where W1is-C(R3)(R4)- or-C(R3)(R4)-C(R3)(R4)-, W2is-C(R7)and W3, W4, R3, R4, R5, R6and R7such as described in the section "summary of the invention". In one embodiment, R7is-C(O)OH. R3, R4, R5and R6are, for example, hydrogen. W3, W4, G1, G2and Q have the meanings described above. G1and G2each independently is phenyl or monocyclic heteroa the scrap, optionally substituted as described in the section "summary of the invention". Examples G1include, but are not limited to, phenyl and pyridinyl, each of which independently is not a substituted or substituted as described in the section "summary of the invention". Examples G2include, but are not limited to, phenyl, pyridinyl, 1,3-thiazolyl and 1,3-oxazolyl, each of which is optionally additionally substituted with 1, 2, 3 or 4 substituents represented by T, and T, such as described in the section "summary of the invention". Examples of optional substituents G1and G2represented by T include, but are not limited to, halogen and C1-6alkyl, such as methyl, ethyl and the like. Examples of Q include G4, Y1-Y3, -Y1-(CRJRk)v-Y2-Y4or formula (d), where G4, Y1, Y3, RJ, Rk, v, Y2, Y4and Z have the meanings described above.

Another aspect of this invention relates to compounds of the formula (III) or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or their combination,

,

where Q, G1, G2, Rc, RdL1and X have the meanings described above.

Another aspect of this invention relates to compounds of the formula (III) or their pharmaceutically acceptable salts, salts of prodrugs or their combined is Yu, where L1is O, and Q, G1, G2, Rc, Rdand X have the above meanings. Examples of X include, but are not limited to, hydrogen, alkyl, such as C1-6alkyl (e.g. methyl, ethyl and the like), and -(CRgRh)u-C(O)O(R10), where Rg, Rhu and R10such as described in the section "summary of the invention". In one embodiment, X is -(CRgRh)u-C(O)O(R10). Rgand Rhin each case, independently selected from the group including, without limitation, hydrogen, and C1-6alkyl (e.g. methyl, ethyl and the like). In one embodiment, u is 1 or 2. More specifically, u is 1. In another embodiment, X is hydrogen or C1-6the alkyl (for example, stands, ethyl and the like). G1and G2, each independently, is aryl or a monocyclic heteroaryl, optionally substituted as described in the section "summary of the invention". Examples G1include, but are not limited to, phenyl and pyridinyl, each of which independently is not a substituted or substituted as described in the section "summary of the invention". Examples G2include, but are not limited to, phenyl, pyridinyl, 1,3-thiazolyl and 1,3-oxazolyl, each of which is optionally further substituted by 1, 2, 3 or 4 substituents represented by T, and T as described in the section "summary of the invention" and in the section of the detailed description." Examples of Q include G4, Y1-Y3, -Y1-(CRjRk)v-Y2-Y4or formula (d), where G4, Y1, Y3, Rj, Rk, v, Y2, Y4and Z have the meanings described above.

From the group of compounds of the formula (III), examples of a subgroup include those where Rcand Rdtogether with the carbon atom to which they are attached, form a 3-6-membered cycloalkyl (for example, cyclobutyl, cyclopentyl and the like), where 1, 2, 3 or 4 hydrogen atoms are replaced by radicals, as described in the section "summary of the invention". For example, one of the hydrogen atoms attached to the carbon atom of the ring, optionally substituted-C(O)OH.

From this group of compounds of the formula (III) examples of another subgroup include those where Rcand Rdtogether with the carbon atom to which they are attached, form a monocyclic heterocycle of formula (c), where 1, 2, 3 or 4 hydrogen atoms attached to the carbon atom of the ring is monocyclic heterocycle, optionally substituted radicals, and the radicals W5and W6such as described in the section "summary of the invention". For example, Rcand Rdtogether with the carbon atom to which they are attached, form a monocyclic heterocycle of formula (c), where W5is-CH2- or-CH2-CH2and W6is O or N(RX); where Rxso is th, as described in the section "summary of the invention". For example, Rxis C1-6the alkyl (for example, stands, ethyl and the like) or-C(O)O(C1-6by alkyl).

In another aspect this invention relates to compounds of the formula (III) or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations, where L1is N(H) or N(alkyl), and Q, G1, G2, Rc, Rdand X have the above meanings. Examples of X include, but are not limited to, hydrogen, alkyl, such as C1-6alkyl (e.g. methyl, ethyl and the like), and -(CRgRh)u-C(O)O(R10), where Rg, Rhu and R10such as described in the section "summary of the invention". In one embodiment, X is -(CRgRh)u-C(O)O(R10). Rgand Rhin each case, each independently selected from the group including, but not limited to, hydrogen, C1-6alkyl (e.g. methyl, ethyl and the like). In another embodiment, u is 1 or 2. Preferably, u is 1. In another embodiment, X is hydrogen or C1-6the alkyl (for example, stands, ethyl and the like). G1and G2, each independently, is aryl or a monocyclic heteroaryl, optionally substituted as described in the section "summary of the invention". Examples G1include, but are not limited to, phenyl and pyridine is l, each of which independently is not a substituted or substituted as described in the section "summary of the invention". Examples G2include, but are not limited to, phenyl, pyridinyl, 1,3-thiazolyl and 1,3-oxazolyl, each of which is optionally further substituted by 1, 2, 3 or 4 substituents represented by T, and T as described in the section "summary of the invention". Examples of Q include G4, Y1-Y3, -Y1-(CRjRk)v-Y2-Y4or formula (d), where G4, Y1, Y3, Rj, Rk, v, Y2, Y4and Z have the meanings described above.

From the group of compounds of the formula (III), examples of a subgroup include those where Rcand Rdtogether with the carbon atom to which they are attached, form a 3-6-membered cycloalkyl (for example, cyclobutyl, cyclopentyl and the like), where 1, 2, 3 or 4 hydrogen atoms attached to the carbon atom of the ring cycloalkyl, optionally substituted radicals, as described in the section "summary of the invention". For example, one of the hydrogen atoms attached to the carbon atom of the ring, optionally substituted-C(O)OH.

From this group of compounds of the formula (III) examples of another subgroup include those where Rcand Rdtogether with the carbon atom to which they are attached, form a monocyclic heterocycle of formula (c), where 1, 2, 3 or 4 hydrogen atoms attached to acomplete ring monocyclic heterocycle, optionally substituted radicals, and the radicals W5and W6such as described in the section "summary of the invention". For example, Rcand Rdtogether with the carbon atom to which they are attached, form a monocyclic heterocycle of formula (c), where W5is-CH2- or-CH2-CH2and W6is O or N(RX); where Rxsuch as described in the section "summary of the invention". For example, Rxis C1-6the alkyl (for example, stands, ethyl and the like) or-C(O)O(C1-6by alkyl).

Another aspect of this invention relates to compounds of the formula (III), or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or their combination, where L1is -(CRpRq)s-, and Q, G1, G2, Rc, Rd, Rp, Rq, s, and X have the above values. In one embodiment, X is-C(O)OH. Rpand Rqin each case, each independently selected from the group including, but not limited to, hydrogen, C1-6alkyl (e.g. methyl, ethyl and the like). In one embodiment, s is 1. G1and G2, each independently, is aryl or a monocyclic heteroaryl, optionally substituted as described in the section "summary of the invention". Examples G1include, but are not limited to, phenyl and pyridinyl, each of which is independently researched and the performance is not substituted or substituted, as described in the section "summary of the invention". Examples G2include, but are not limited to, phenyl, pyridinyl, 1,3-thiazolyl and 1,3-oxazolyl, each of which is optionally further substituted by 1, 2, 3 or 4 substituents represented by T, and T as described in the section "summary of the invention". Examples of Q include G4, Y1-Y3, -Y1-(CRjRk)v-Y2-Y4or formula (d), where G4, Y1, Y3, Rj, Rk, v, Y2, Y4and Z have the meanings described above.

From this group of compounds of the formula (III), examples of a subgroup include those where Rcand Rdtogether with the carbon atom to which they are attached, form a 3-6-membered cycloalkyl (for example, cyclobutyl, cyclopentyl and the like), where 1, 2, 3 or 4 hydrogen atoms attached to the carbon atom of the ring cycloalkyl, optionally substituted radicals, as described in the section "summary of the invention". For example, one of the hydrogen atoms attached to the carbon atom of the ring, optionally substituted-C(O)OH.

From this group of compounds of the formula (III) examples of another subgroup include those where Rcand Rdtogether with the carbon atom to which they are attached, form a heterocycle of formula (c), where 1, 2, 3 or 4 hydrogen atoms attached to the carbon atom of the ring is monocyclic heterocycle, optionally for enemy radicals, and the radicals W5and W6such as described in the section "summary of the invention". For example, Rcand Rdtogether with the carbon atom to which they are attached, form a monocyclic heterocycle of formula (c), where W5is-CH2- or-CH2-CH2and W6is O or N(Rx); where Rxsuch as described in the section "summary of the invention". For example, Rxis C1-6the alkyl (for example, stands, ethyl and the like) or-C(O)O(C1-6by alkyl).

Examples of compounds in accordance with this invention include, but are not limited to, the following:

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}urea;

N-{4-[2-(1-ethyl-4-hydroxypiperidine-4-yl)-1,3-thiazol-5-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

4-(5-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]-3-forfinal}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol;

4-(5-{4-[(7-methyl-1,3-benzoxazol-2-yl)amino]phenyl}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol;

4-(5-{2-chloro-4-[(7-chloro-1,3-benzoxazol-2-yl)amino]phenyl}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol;

4-(5-{4-[(7-chloro-1,3-benzoxazol-2-yl)amino]-2-were}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol;

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{6-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]pyridine-3-yl}urea;

N-{4-[2-(1-ethyl-4-hydroxypiperidine-4-yl)-1,3-thiazol-5-yl]-2-CFT is henyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-(2,5-differenl)-N'-{4-[2-(1-ethyl-4-hydroxypiperidine-4-yl)-1,3-thiazol-5-yl]-2-forfinal}urea;

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{6-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]pyridine-3-yl}urea;

phenyl 4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenylcarbamate;

N-(4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}piperidine-1-carboxamide;

tert-butyl 3-(5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1,3-thiazol-2-yl)-3-hydroxypyrrolidine-1-carboxylate;

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(3-hydroxypyrrolidine-3-yl)-1,3-thiazol-5-yl]phenyl}urea;

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(3-hydroxy-1-methylpyrrolidine-3-yl)-1,3-thiazol-5-yl]phenyl}urea;

N-{4-[2-(1-ethyl-3-hydroxypyrrolidine-3-yl)-1,3-thiazol-5-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}urea;

N-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea;

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}urea;

N-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea;

(±)-CIS-3-hydroxy-3-{4'-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1,1'-biphenyl-4-yl}cyclopentanecarbonyl acid;

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(1-methoxycyclohexyl)-1,3-thiazole--yl]phenyl}urea;

{[1-(5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;

{[1-(5-{4-[(bicyclo[4.2.0]OCTA-1,3,5-triene-7-ylcarbonyl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutyl]oxy}acetic acid;

({1-[5-(4-{[(2-forfinal)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid;

{[1-(5-{4-[(anilinoacrolein)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;

{[1-(5-{4-[(anilinoacrolein)amino]phenyl}-1,3-thiazol-2-yl)cyclobutyl]oxy}acetic acid;

{[1-(5-{6-[(anilinoacrolein)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;

{[1-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;

{[1-(4-{6-[(anilinoacrolein)amino]pyridine-3-yl}phenyl)cyclopentyl]oxy}acetic acid;

(±)-CIS-3-(4'-{[(2-forfinal)acetyl]amino}-1,1'-biphenyl-4-yl)-3-hydroxycyclohexanecarboxylate acid;

[(1-{5-[4-({2-[(4-chlorophenyl)amino]-3,4-dioxocyclohex-1-EN-1-yl}amino)phenyl]-1,3-thiazol-2-yl}cyclobutyl)oxy]acetic acid;

{[1-(5-{4-[(anilinoacrolein)amino]phenyl}-4-methyl-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;

{[1-(4-methyl-5-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;

{[1-(5-{6-[(anilinoacrolein)amino]pyridine-3-yl}-4-methyl-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid the acid;

{[1-(4-methyl-5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;

{[1-(5-{6-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;

2-{[1-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}propanoic acid;

2-{[1-(5-{6-[(anilinoacrolein)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}propanoic acid;

{[1-(5-{4-[(7-methyl-1,3-benzoxazol-2-yl)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;

N-(4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}-2-[3-(trifluoromethyl)phenyl]ndimethylacetamide;

2-(2,4-differenl)-N-(4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}ndimethylacetamide;

2-(2,5-differenl)-N-(4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}ndimethylacetamide;

[(1-{5-[4-(benzoylamine)phenyl]-1,3-thiazol-2-yl}cyclobutyl)oxy]acetic acid;

({1-[5-(4-{[(3-forfinal)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid;

({1-[5-(4-{[4-(trifluoromethyl)benzoyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid;

[(1-{5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]acetyl}amino)phenyl]-1,3-thiazol-2-yl}cyclobutyl)oxy]acetic acid;

{[1-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-oxazol-2-yl)cyclopentyl]oxy}acetic acid to the slot;

({1-[5-(4-{[(2,5-differenl)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid;

({1-[5-(4-{[(3,5-differenl)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid;

({1-[5-(4-{[(3,4-differenl)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid;

{[1-(4-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}phenyl)cyclopentyl]oxy}acetic acid;

2-(1-(2-fluoro-4-(6-(3-(3-(trifluoromethyl)phenyl)ureido)pyridine-3-yl)phenyl)CYCLOBUTANE)acetic acid;

1-(5-(4-(4-oxa-1-azabicyclo[3.2.1]Octan-5-yl)phenyl)pyridin-2-yl)-3-phenylacetone;

2-(1-(3-fluoro-4-(6-(3-(3-(trifluoromethyl)phenyl)ureido)pyridine-3-yl)phenyl)cyclopentyloxy)acetic acid;

2-(1-(3-fluoro-4-(6-(3-(3-(trifluoromethyl)phenyl)ureido)pyridine-3-yl)phenyl)CYCLOBUTANE)acetic acid;

[(1-{5-[4-({[(2-forfinal)amino]carbonyl}amino)phenyl]pyridine-2-yl}cyclopentyl)oxy]acetic acid;

[1-(4-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}phenyl)cyclopentyl]acetic acid;

(1-{4-[6-({[(2-forfinal)amino]carbonyl}amino)pyridine-3-yl]phenyl}cyclopentyl)acetic acid;

{[1-(2-fluoro-4-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}phenyl)cyclobutyl]oxy}acetic acid;

[(1-{2-fluoro-4-[6-({[3-(trifluoromethyl)phenyl]acetyl}amino)pyridine-3-yl]phenyl}cyclobutyl)oxy]acetic acid; and

{[1-(3-fluoro-4'-{[6-(triptoreline)-1,3-Ben is thiazol-2-yl]amino}-1,1'-biphenyl-4-yl)cyclobutyl]oxy}acetic acid;

or their pharmaceutically acceptable salt, prodrug or salt of prodrug.

These compounds may contain asimmetricheskii substituted carbon atoms or sulfur and, therefore, may exist and be isolated in the form of single stereoisomers (for example, a single enantiomer or a single 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, enzymatic separation, biopreparation or chromatographic separation. It should be clear that the invention encompasses any racemic, optically active, stereoisomeric form, or mixtures thereof in various proportions, which may have properties that are useful for inhibiting the activity DGAT-1. If the stereochemistry of chiral centers contained in shown in the present description of chemical structures not indicated, it is assumed that the chemical structure covers compounds containing any stereoisomer of each chiral center present in the connection.

Geometric isomers may exist in the compounds in accordance with this invention. In this izopet who examines the various geometric isomers and mixtures thereof, get moving substituents around the double bond carbon-carbon cycloalkyl group or geteroseksualnoe group. Substituents around the double bond carbon-carbon designated as Z - or E-configuration, and Vice-around cycloalkyl or geterotsiklicheskie identified as CIS - or TRANS-configuration.

In this invention should be clearly described in the present description, the compounds may be characteristic of tautomerism and that the image of the formulas in this specification can represent only one of the possible tautomeric forms. It should be clear that the invention encompasses any tautomeric form and is not limited to only one tautomeric form, used when referring to compounds of the formula scheme.

Methods synthesis

This invention covers compounds derived synthetic methods or metabolic processes. Obtaining compounds in accordance with this invention by means of metabolic processes include processes in the human or animal (in vivo) or the processes in vitro.

The synthesis of compounds of formula (I), (II) or (III)where the group Rc, Rd, Rg, Rh, R3, R4, R10, G1, G2, G3, Q, W1, W3, X and u have the meanings described in the section "the Essence of izaberete the Oia", unless stated otherwise, presented in schemes 1-8.

In the description of the schemes and the examples, certain abbreviations are intended to refer to the following concepts: DMSO - dimethylsulfoxide, OF ghvd - preparative liquid chromatography high-pressure reversed-phase Boc - tert-butoxycarbonyl, and OTs - pair-toolswhat.

Compounds in accordance with this invention are named according to the standards of ACD/ChemSketch, version 5.06 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or they are given names in accordance with the nomenclature of the ACD.

Compounds of General formula (I) can be obtained using the General methods shown in scheme 1.

Scheme 1

As shown in scheme 1, compounds of formula (3), where X1is the NH2N(H)(Pg), NO2or N(H)(Q), where Pgis protective for nitrogen group can be obtained by palladium mediated reaction mix between compounds of formula (1) and compounds of formula (2)where one of X2and X3is halogen, triflate or tosylate, and the other is trialkyl(tin), Bronevoy acid or complex bronovil ether, for example 1,3,2-dioxaborolan-2-yl, or formula (4), where each X4is the same or different and each is C1-6the alkyl,

Suitable conditions is eacli and the appropriate values of X 1X2and X3can be easily selected for these reactions. For example, the compounds of formula (1), where X2is halogen, can be treated with compounds of the formula (2), where X3has the formula (4) and X4is stands, in the presence of a base, such as potassium iodide, triethylamine, cesium carbonate, sodium carbonate, potassium phosphate, potassium fluoride or cesium fluoride, palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), dichloride, 1,1'-bis(di-tert-butylphosphino)ferienparadies or source of palladium, modified with a suitable ligand. Examples of palladium sources include, but are not limited to, Tris(dibenzylideneacetone)dipalladium(0) and the product of the merger of chloroform. Suitable ligands include, but are not limited to, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and 2-dicyclohexylphosphino-2',6'-diisopropylphenyl. The reaction is usually carried out at a temperature from about 60°to about 120°C., in an organic solvent, such as toluene, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dimethoxyethane, dimethylsulfoxide, isopropanol, ethanol, water or a mixture thereof, and optionally in a microwave oven.

Intermediate compounds of formula (1) or (2) are either commercially available, known in the literature or can be obtained by modification of reaction conditions known to the literature.

Alternatively, the compounds of formula (3) can be obtained by treating compound (1) and (2)where one of X2and X3is hydrogen and the other is substituted by a functional group, such as halogen, triflate or tosylate. The reaction can be carried out first by litrownik compounds containing acidic hydrogen with the use of a base, such n-utility, at a temperature of about -78°C in a solvent such as tetrahydrofuran. Received litrovaya connection can then be processed zinc halides such as zinc chloride, at a temperature of -78°C followed by treatment of the compounds having a substituted functional group, in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0). The last reaction is usually carried out at a temperature from about 40°to about 100°C.

Intermediate compounds of formula (2), where X3is hydrogen or halogen, G3has the formula (b) and L1is O, can be obtained, for example, (a) the interaction of the aryl or heteroaryl groups containing acidic hydrogen with a strong base such as n-utility, or (b) the interaction of helgaleena or heteroarylboronic with alkyllithium or alkyl Grignard reagent and (c) treatment of the resulting anion with stage (a) or (b) a ketone of formula (5), as Asano in scheme 2. The reaction is usually carried out at a temperature of about -78°C and in an organic solvent such as tetrahydrofuran. The compounds of formula (7), where X5the same as defined for X in the formula (I)other than hydrogen, can be obtained by treating compounds of formula (6) base, such as lithium hydride, followed by treatment with a halide, such as alkylhalogenide or one compound of the formula X6-(CRgRh)u-C(O)O(R10), where X6is a halogen. The reaction can be carried out in an organic solvent such as N,N-dimethylformamide, and at a temperature from about 0°C. to about room temperature.

The restoration of the nitro group that is attached to G1in the formula (1) or (3)can be carried out by standard reagents such as iron/acetic acid, or iron/ammonium chloride to obtain the corresponding-NH2connection.

Deriving-NH2that is attached to G1in the formula (1) or (3)to the corresponding carbamates, amides, ureas, secondary amines, sulfonamides, or the sulfonylureas, can be carried out using methods or their modifications known in the art. For example, the amides can be obtained by conducting the reaction in combination with a suitable carboxylic acids under standard conditions of combination reaction. Replacing K is included halides primary amino groups, which is attached to G1gives secondary amines of the formula (1) or (3). The reaction of primary amino groups with a suitable halogenfree in the presence of base gives the corresponding carbamates. Treatment of primary amines with a suitable isocyanate gives the corresponding urea.

Scheme 2

The compounds of formula (6) or (7), where G2is a phenyl or a monocyclic heteroaryl containing one or more hydrogen atoms in the ring can be galogenirovannyie conventional methods known to the person skilled in the art. For example, the iodides of the formula (2), where X is iodine, can be obtained by treating compounds of formula (6) n-butyllithium at -78°C, followed by adding dropwise the solution of iodine.

Alternatively, the compounds of formula (2), where X3is hydrogen, halogen, triflate or tosylate, G3has the formula (b), L1is O, and Rcand Rdtogether with the carbon atom to which they are attached, form cyclopentyl can be obtained by the General methods as shown in scheme 3.

Scheme 3

For example, esters of the formula (8) when processing 1,4-dibromobutane in the presence of magnesium and an organic solvent, such as tetrahydrofuran, at a temperature of about 0°C, give the is a group of formula (9).

Intermediate compounds of formula (2), where X3is hydrogen or halogen, and G3has the formula (b), where L1is-CH2- and X is-C(O)OH, can be obtained as shown in scheme 4.

Scheme 4

As shown in figure 4, the ketones of formula (5) can be processed by ethylcyanoacrylate in the presence hexamethyldisilazane obtaining compounds of formula (10). Treatment of compounds of formula (10) with Grignard reagents of the formula (11), where X3is hydrogen or halogen, and X7is halogen, in the presence of a salt of copper(I), such as, but not limited by them, Cu(I)I, Cu(I)Br and Cu(I)CN, in a solvent such as tetrahydrofuran, at a temperature from about 0°C. to about room temperature, provides compounds of formula (12). The compounds of formula (12) by treatment with base, such as sodium hydroxide or potassium hydroxide, in a solvent such as ethylene glycol, at a temperature of from about 100°to about 200°C gives the acid of formula (13).

Compounds of General formula (I), where G3has the formula (b) and L1is N(H) or N(alkyl), can be obtained using the General methods shown in scheme 5.

Scheme 5

Esters of the formula (14) can be converted into compounds of formula (15) by treatment with a halide of the formula X3-G2-X8where X 8is a halogen and X3is hydrogen or halogen, provided that X8is more reactive halogen, in the presence of triphenylphosphine, bases, such as dicyclohexylamine lithium and palladium catalyst such as bis(dibenzylideneacetone)palladium(0). Esters of the formula (15) can be transformed into amines of the formula (16) (a) by saponification with a base such as sodium hydroxide, to obtain the corresponding acid, (b) optional conversion of the acid into the acid chloride, (c) converting the acid or acid chloride to the corresponding azide by treatment of the acid diphenylphosphorylacetate at elevated temperature or by treatment of the acid chloride with sodium azide at ambient temperature, in the presence of a base, and (d) heating utilised from stage (c) with tert-butanol. The combination of compounds of the formula (16) with (1) using the reaction conditions described in scheme 1, gives the compounds of formula (17). Removal of the Boc group can be carried out by treatment with an acid, such as triperoxonane acid. The resulting primary amine may be subjected to reductive aminating with the aldehyde of formula XCHO using reaction conditions known in the art, to obtain the compounds of formula (18). For example, the transformation can be carried out in the presence of a reducing Agay is the such as triacetoxyborohydride sodium, and acid, such as acetic acid, in a solvent such as tetrahydrofuran. The reaction may be conducted at temperatures from about room temperature to about 50°C, optionally in the presence of molecular sieves, silica gel or in the conditions of the Dean-stark. The compounds of formula (19) can be obtained from compounds of formula (18) by treatment with the appropriate aldehyde using the above conditions amination.

Intermediate compounds of formula (2), where G3has the formula (a), where R5and R6are hydrogen, W1is-C(R3)(R4)- or-C(R3)(R4)-C(R3)(R4)-, W2is-C(R7)- or N, R7is-C(O)OH, and W4is-CH2-can be obtained by the General methods shown in scheme 6.

Scheme 6

The compounds of formula (20), where E is N(Boc) or C(H)COOH can be converted into compounds of formula (21), where X9is hydrogen or alkyl, the interaction of the compound (20) with halides of the formula X9OC(O)CH2X10where X10is halogen, in the presence of a base such as sodium hydride, in a solvent such as N,N-dimethylformamide. The compounds of formula (21), where E is C(H)COOH, can be methylated to compounds of the formula (21), where E javljaetsja(H)COO(CH 3) treatment trimethylsilyldiazomethane. Selective restore (21) soft regenerating agent such as sodium borohydride, followed by treatment with mozillateam in the presence of a base such as 4-dimethylaminopyridine, gives compounds of formula (22), where E is N(Boc) or C(H)COO(CH3). The compounds of formula (22), where E is N(Boc), may be converted into compounds of formula (23), where E is N(H), by treatment with an acid, such as triperoxonane acid. In the presence of a base such as potassium carbonate, sodium hydride or amide base, such as diisopropylamide lithium, compounds of formula (22), where E is N(H) or C(H)COO(CH3face-circuit rings with obtaining compounds of formula (23), where E is N or C-COO - (CH3). Saponification of the ester functional group may be at different stages of the synthesis, for example, after ring closure, or after combination of the compound (23) with (1), or after receiving amine derivatives attached to G1processing base, such as sodium hydroxide.

Scheme 7

Intermediate compounds of formula (1), where X1is-N(H)Q and Q is unsubstituted or substituted by benzoxazolium, can be obtained as shown in scheme 7. The aminophenols of the formula (24), where X11is substituents Q, is certain to formula (I), can be processed thioisocyanate formula (25), where X2is hydrogen or halogen, with the intermediate thiourea compounds of formula (26). The reaction is usually carried out in an inert organic solvent, such as tetrahydrofuran, at a temperature of from about -10°to about 50°C., preferably at about room temperature. The intermediate thiourea, with or without selection, handling lithium hydroxide/hydrogen peroxide give benzoxazole formula (27).

Scheme 8

Intermediate compounds of formula (1), where X1is-N(H)Q and Q is unsubstituted or substituted by benzothiazolium, can be obtained as shown in scheme 8. The halides of the formula (29), where X12is chlorine or bromine, and X11is Vice-Q, such as defined for formula (I)can be obtained from commercially available 2-aminobenzothiazole formula (28) (a) by treating compound (28) of tert-butylnitrite and (b) by the substitution of the diazonium salts formed at the stage of (a) copper chloride or copper bromide. Substitution of the halide (29) with a suitable amine of formula (30) in a similar reaction conditions known in the art, gives the compounds of formula (31).

Getting Baranovich esters of the formulas (27) and (31), where X2has the formula (4), from the corresponding the halide followed by reaction with a reagent based on broowaha of ester, such as pinacolborane, in the presence of a base such as potassium acetate, palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and in a solvent such as dioxane, N,N-dimethylformamide, toluene or mixtures thereof, at elevated temperature.

It should be clear that the scheme of the synthesis and the specific examples shown in the section "Examples of synthesis are illustrative and do not limit the scope of this invention defined by the claims. All alternatives, modifications and equivalents of the methods of synthesis and the specific examples included in the scope of the claims.

Optimal reaction conditions and reaction time for each stage can vary depending on the particular applicable reagents and substituents present in the reagents. Unless otherwise noted, solvents, temperatures and other reaction conditions can be easily selected by a person skilled in the art. Specific methods are presented in the section "Examples of synthesis". The reaction mixture can be processed by conventional methods, for example, removing the solvent from the residue, followed by purification using methods generally known in the art, such as, but not limited to them, crystallization, distillation, extraction, rubbing and chromatography. If not what is shown otherwise, starting materials and reagents are either commercially available or can be obtained by the specialist in the art from commercially available materials using methods described in the chemical literature.

Conventional experimentation, including the appropriate modification of reaction conditions, reagents and sequence synthesis, protection, any functional group which may not be compatible with the reaction conditions, and the removal of protection in a suitable time sequence of reactions included in the scope of this invention. Suitable protective groups and methods to protect and unprotect, different substituents, which are suitable protective groups are well known to experts in the art; examples can be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rded.), John Wiley & Sons, NY (1999), which is fully incorporated into the present description by reference. The synthesis of compounds in accordance with this invention can be carried out by methods similar to those described in the presented schemes of synthesis and in the specific examples.

Source materials if they are not commercially available, can be obtained by techniques selected from standard techniques of organic chemistry, techniques which are analogous to the synthesis of known compounds with similar structure, is whether techniques which is similar to that described above schemes or methodologies presented in the section "Examples of synthesis".

If you want optically active form of compounds in accordance with this invention, it can be obtained using the techniques described in the present description, with the use of optically active starting material (for example, asymmetric induction of a suitable reaction stage) or by separation of a mixture of stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic separation).

Also, if you want a pure geometric isomer of the compounds in accordance with this invention, it can be obtained using the procedures described above from a pure geometric isomer of the source material, or the separation of a mixture of geometrical isomers using conventional techniques, such as chromatographic separation.

Biological data

Inhibition DGAT-1

Identification of compounds in accordance with this invention as inhibitors DGAT-1 can be easily carried out using high-throughput screening FlashPlate. In this assay, recombinant human DGAT-1, containing N-terminal His6-epitope tag, get in the system ekspressirovali baculovirus. Tile and insects (for example, Sƒ9 or High Five) infect within 24-72 hours and harvested by centrifugation. Debris re-suspended in homogenization buffer [250 mm sucrose, 10 mm Tris-HCl (pH of 7.4), 1 mm etc] and are lysed with application of the device for homogenizing, such as fluidization Micro (single pass, 4°C). Debris is removed by centrifugation at 10000×g for 30 min and microsomal membranes collected by centrifugation at 100000×g for 30 minutes

Activity DGAT-1 is determined as follows: analytical buffer [20 mm HEPES (pH 7.5), 2 mm MgCl2, 0,04% BSA]containing 50 μm of enzyme substrate (decanoylamino) and 7.5 μm radiochango acyl-CoA substrate. [1-14C]decanoyl-CoA) is added to each well phospholipid FlashPlate (PerkinElmer Life Sciences). A small aliquot of membranes (1 μg/well) is added to start the reaction, which takes place within 60 minutes the Reaction is stopped by adding an equal volume (100 ál) of isopropanol. Tablets, sealed, incubated overnight and read the next morning on a TopCount Scintillation Plate Reader (PerkinElmer Life Science). DGAT-1 catalyzes the transfer radiochannel technoloy group in position sn-3 decanoylamino. Received radiolucency tridecanoate (triapin) mainly associated with the hydrophobic membrane phospholipid FlashPlate. Proximity radiochango product to solid scintil is ataru, introduced in the lower part of the FlashPlate, induces the release of fluorescent agent of scintillant measured in a TopCount Plate Reader. Different concentrations (for example, of 0.0001 μm to 0.001 μm to 0.01 μm to 0.1 μm, and 1.0 μm, and 10.0 μm) of the model compounds in accordance with this invention added to individual wells prior to the addition of membranes. The power of inhibition DGAT-1 for compounds in accordance with this invention is determined by calculating the values of the IC50defined as the concentration of the inhibitor of the sigmoidal curve dose-effect, in which the enzyme activity is inhibited by 50%. Compounds in accordance with this invention are effective for inhibiting the activity DGAT-1 and, therefore, are useful as therapeutic agents for treatment of compounds and diseases that are associated with the activity DGAT-1.

Table 1
DGAT-1 inhibition by the compounds in accordance with this invention (IC50nm)
334455
777 888
8911151619
243846495275
93105106113133279
294311429440492494
5015686086778531030
112011601170127013401790
18302160331035104060160
420055303,58,5

Evaluation of the effectiveness of the connection by reducing the mobility chylomicron DIO mice or CD1

The purpose of this Protocol is to define the actions abrupt introduction of compounds on the motility of chylomicrons caused by bolus with corn oil or in lean mice (mouse CD1, Jackson Laboratories) or in mice backward from an arbitrary absorption ad libitum diet with high fat content (Buhman, K.K. et al., J. Biol. Chem. 2002, 277, 25474-25479). Obesity is caused by diet (DIO) in rodents mimics key aspects of human obesity and metabolic syndrome. It was shown that mouse DIO used in this analysis, have resistance to hyperinsulinemia and insulin, have resistance to hyperleptinemia and leptin and markedly obese internal organs (review in the study of DIO mice, see Collins et al., Physiol. Behav. 81: 243-248, 2004).

Typical compounds in accordance with this invention is usually given at a dose of 0.03 mg/kg, 0.3 mg/kg, 3 mg/kg or 10 mg/kg P.O. in the form of a composition in 1% Tween 80 in water for an hour before bolus injection with corn oil. One hour after bolus injection take plasma samples and analyzed for triglycerides. Compounds are considered active if the medication gives > 30% reduction of triglycerides in plasma from patients drug animals (measured one hour after bolus injection with corn oil) in relation to the processed media control group. In this model, the standard connections give a significant reduction in relation to the processed media control animals.

Compounds in accordance with this invention and pharmaceutically acceptable salts are used as therapeutic agents. Therefore, one variant of the present invention includes a method of treatment of various conditions in a patient in need of such (including mammals), which includes the introduction of patient number of the compounds of formula (I), (II) or (III), or its pharmaceutically acceptable salts, prodrugs or salts of prodrugs, which is effective for the treatment of the target state, or containing pharmaceutical compositions.

In another aspect of the present invention presents a method of treating, slowing or prevention of various conditions in a patient (such as a mammal, preferably human), which mediaready DGAT-1, which includes the introduction of the patient, the compounds of formula (I), (II) or (III), or its pharmaceutically acceptable salts, prodrugs, salts of prodrugs, which is effective for the treatment of the target state, or includes farmacevticheskoi composition.

Another aspect of the present invention include methods of preventing, slowing or treatment of obesity and promote weight loss in a patient, which includes the introduction of a patient compounds in accordance with this invention or its pharmaceutically acceptable salts, prodrugs or salts of prodrugs, which is effective for the treatment of the target state, or containing pharmaceutical compositions. In another aspect, the invention provides a method of preventing weight gain in a patient by introduction of at least one compound in accordance with this invention, its pharmaceutically acceptable salts, prodrugs or salts of prodrugs, or combinations thereof, in a quantity sufficient to prevent weight gain.

This invention also relates to the use of compounds in accordance with this invention for treatment-induced obesity diseases, including concomitant dyslipidemia, and other complications associated with obesity or excessive weight, such as, for example, cholesterol gallstones, gallbladder disease, gout, cancer (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder and bile ducts), menstrual abnormalities, infertility, polycystic ovaries, osteoarthritis and the Noe in a dream, and many other similar pharmaceutical applications, such as the regulation of appetite and food intake, dyslipidemia, hypertriglyceridemia, metabolic syndrome or syndrome X, diabetes mellitus type 2 (not insulin-dependent diabetes), atherosclerotic diseases such as heart failure, hyperlipidemia, hypercholesterolemia, low HDL, hypertension, cardiovascular disease (including atherosclerosis, coronary heart disease, coronary artery disease and hypertension), cerebrovascular disease such as stroke, and peripheral vascular disease. Compounds in accordance with this invention can also be used for treating physiological disorders related to, for example, regulation of insulin sensitivity, inflammatory reaction, fatty degeneration of the liver, an increased level triacylglycerides in the liver, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, triglycerides in plasma levels of HDL, LDL and cholesterol, and the like. Metabolic syndrome is a group of metabolic risk factors in one person. Such factors include, but are not limited to, abdominal obesity, atherogenic dyslipidemia (disorders of blood fat, such as high triglycerides, low HDL cholesterol and high LDL cholesterin is), high blood pressure, insulin resistance or glucose intolerance), prothrombotic state (for example, high levels of inhibitor-1 activator, fibrinogen or plasminogen in the blood), and proinflammatory state (e.g., elevated C-reactive protein in the blood). In one embodiment, the present invention presents methods of treatment of the above diseases, where the methods include the stage of introduction to a patient in need of such, one or more compounds in accordance with this invention, or its pharmaceutically acceptable salts, or pharmaceutical compositions comprising it. Compounds in accordance with this invention or their pharmaceutically acceptable salts, or including them, pharmaceutical compositions are also used to reduce the levels of triglycerides in the plasma. Thus, the present invention presents a method for lowering plasma triglycerides in a patient (including a mammal)in need of such, where the method includes a step of introducing to a patient in need of such, one or more compounds in accordance with this invention or their pharmaceutically acceptable salts or including their pharmaceutical compositions.

The term "treatment" or "treat" includes any process, action, application, therapy, or similar, where patients who NTU, including humans, provided medical assistance with the application object, which improves the patient's condition, directly or indirectly, or slowing down the development of the condition or disorder in a patient.

Compounds in accordance with this invention or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, can be administered separately or in combination (i.e. co-administration with one or more additional pharmaceutical agents. Combination therapy includes the introduction of a single dosage form containing one or more compounds in accordance with this invention or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs, and one or more additional pharmaceutical agents, as well as the introduction of compounds in accordance with this invention or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs and each additional pharmaceutical agent in a separate dosage forms. For example, the compound of formula (I), (II) or (III), or its pharmaceutically acceptable salts, prodrugs, salts of prodrugs, and one or more additional pharmaceutical agents can be administered to the patient together in a single oral dosage form having a fixed ratio of each active ingredient, such as tablets is whether the capsule; or each agent may be administered in separate oral dosage forms.

If you use a separate dosage forms, the compounds in accordance with this invention or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs) and one or more additional pharmaceutical agents can be entered almost at the same time (e.g., simultaneously) or at different times (e.g., sequentially).

For example, the compounds in accordance with this invention (their pharmaceutically acceptable salts, prodrugs, salts of prodrugs may be used in combination with one or more of the following pharmaceutical agents, including, but not limited to, drugs against obesity, including agonists β-3, such as CL-316,243; antagonists of CB-1 and/or inverse agonists (e.g., rimonabant); inhibitors of neuropeptide Y5; agents that suppress the appetite, such as, for example, sibutramine (By); MCHr1 antagonists and inhibitors, lipase, such as, for example, orlistat (Xenical), and drug compound that modulates digestion and/or metabolism, such as drugs that modulate thermogenesis, lipolysis, the mobility of the intestine, the absorption of fats and satiety.

In addition, the compounds in accordance with this invention or their pharmaceutically acceptable salt, n is Lekarstva, salts of the prodrugs) may be introduced in combination with one or more of the following pharmaceutical products, including ligands RAPP (agonists, antagonists), tools that increase insulin secretion (e.g., based medications sulfonylureas and not sulfonylurea stimulators of secretion), inhibitors of α-glucosidase, activators of insulin, compounds decreasing the production of glucose in the liver, and insulin and derivatives of insulin. Such funds can be entered before, concurrently or after administration of the compounds in accordance with this invention. Insulin and derivatives of insulin include forms of long and short steps and compositions of insulin. The PPAR ligands may include agonists and/or antagonists of any PPAR, or combinations thereof. 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. Medicines on the basis of sulfonylureas include, for example, gliburid, glimepiride, hlorpropamid, tolbutamide and glipizide, inhibitors of α-glucosidase include acarbose, miglit and voglibose. Activators of insulin include agonists of PPAR-γ, such as glitazone (for example, troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone and the like) and other thiazolidinedione and nationalidentity connected to the I; biguanides, such as Metformin and phenformin; inhibitors patientinitiated-1B (PP-1B); inhibitors of dipeptidylpeptidase IV (DPP-IV) (e.g., sitagliptin), and inhibitors beta-HSD. Connections, decreasing the production of glucose in the liver include antagonists of glucagon and Metformin, such as Glucophage and Glucophage XR. Stimulants of insulin secretion include sulfonylurea and not sulfonylurea drugs: GLP-1, GIP, PACAP, secretin and their derivatives; nateglinide, meglitinide, Repaglinide, glibenclamide, glimepiride, hlorpropamid, glipizide. GLP-1 include derivatives of GLP-1 with a longer half-life than natural GLP-1, such as, for example, derived from fatty acids of GLP-1 and the basis.

Compounds in accordance with this invention or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs) may also be used in methods in accordance with this invention in combination with one or more pharmaceutical means, including, but not limited by them, inhibitors of HMG-CoA reductase inhibitors, nicotinic acid (for example, Niaspan), compounds lowering fatty acid (for example, acipimox); medicines, lowering lipids (for example, esters of stanol, sterolglucoside, such as tiqueside, and azetidinone, such as ezetimibe), ACAT inhibitors (such as avasimibe), airing GLCN the th acid, inhibitors of re-absorption of bile acids, inhibitors of microsomal transport triacylglycerides and derivatives fibre 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 fibre acid include, for example, clofibrate, fenofibrate, bezafibrat, ciprofibrate, clofibrate, etofibrate and gemfibrozil. Airing include, for example, cholestyramine, colestipol and derivatives dialkylaminoalkyl cross-linked dextran.

Compounds in accordance with this invention or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs) may also be used in combination with antihypertensive drugs, such as, for example, β-blockers and ACE inhibitors. Examples of additional antihypertensive agents for use in combination with compounds in accordance with this 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, trichlormethiazide, polythiazide, benzthiazide, ticrynafen etakrinova acid, chlorthalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g. captopril, zofenopril, fosinopril, enalapril, ceronapril, cilazapril, delapril, pentopril, quinapril, ramipril, lisinopril), antagonists of the receptor AT-1 (e.g., losartan, irbesartan, valsartan), antagonists of ET receptor (e.g., sitaxentan, atrasentan, inhibitors of neutral endopeptidase (NEP)inhibitors vasopeptidase (dual inhibitors of NEP-ACE) (for example, omapatrilat and gemopatrilat), and nitrates.

Compounds in accordance with this invention can also be administered together with mimic incretin, such as, but not limited by them, ecstatic.

Compounds in accordance with this invention or their pharmaceutically acceptable salts, prodrugs, salts of prodrugs can be applied to achieve the desired pharmacological effect by introducing a patient in need of such, properly prepared pharmaceutical composition. The patient, for example, may be a mammal, including man, in need of treatment of a particular condition or disease. Therefore, this invention includes pharmaceutical compositions that contain a therapeutically effective amount of the compound (or pharmaceutically acceptable salts, prodrugs, salts of prodrugs), a specific item is zestawienie in the present description methods in combination with a pharmaceutically acceptable carrier. Compounds identified by the methods in accordance with this invention, can be administered with pharmaceutically acceptable carrier in the form of any effective standard dosage forms, for example, in the form of the drug with immediate or delayed allocation, orally, parenterally, topically, or other similar ways.

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

The term "pharmaceutically acceptable carrier" in this description means a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or additive compositions of any type. Examples of therapeutically suitable fillers include sugar, cellulose and its derivatives; oil; glycols; solutions; buffer, coloring, highlighting, cover, sweetening and perfume agents; and the like. Such therapeutic compositions can be administered parenterally, intracisternally, orally, rectally, intravenously or intraperitoneally.

Liquid dosage forms for oral administration in accordance with this invention include compositions in the form of emulsions, microemulsions, solutions, suspensions, syrups and elixirs. the addition to the compounds, the liquid dosage forms may contain diluents and/or solubilizing or emulsifying agents. Besides inert diluents, the oral compositions can include moisturizing, emulsifying, sweetening, flavoring and perfume agents.

Injectable preparations of the compounds in accordance with this invention include sterile, injectable, aqueous and oily solutions, suspensions or emulsions, any of which can be optionally connected with a suitable parenteral diluents, dispersing, wetting or suspendresume agents. Such injections can be sterilized by filtration through a retaining bacteria filter or connected with sterilizing agents that dissolve or disperse in the environment for injection.

Inhibition DGAT-1 compounds in accordance with this invention can be slowed by using a liquid suspension of crystalline or amorphous material having 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 achieved by dissolving or suspendirovanie compounds in the oil. Depot injectable compounds can also be obtained by microencapsulation compounds in biodegradable polymers. Depending on the ratio of connections to the alimera and the nature of the polymer, the release rate can be controlled. Composition depot injection also get the capture compounds in liposomes or microemulsions that are compatible with body tissues.

Solid dosage forms for oral administration of the compounds in accordance with this invention include capsules, tablets, pills, powders and granules. In such forms, the compound is mixed with at least one inert, therapeutically appropriate filler, such as a carrier, filler, additive, disintegrating agent, inhibitor solution, a wetting agent, absorbent or lubricating agent. Capsules, tablets and pills, the filler may also include buffering agents. Suppositories for rectal injection can be obtained by mixing the compounds with a suitable not irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature.

Compounds in accordance with this invention can be microencapsulated using one or more of the excipients described above. Solid dosage forms such as tablets, pills, capsules, pills and granules can have a shell, such as intersolubility and slowing down the selection. These compounds may be mixed with at least one inert diluent, and may not necessarily include tabletiruemye lubricating agents and add the I. Capsules may also contain fogging agents which inhibit the secretion of compounds in the desired part of the intestine.

Transdermal patches have the added advantage of controlled delivery of compounds in accordance with this invention in the body. Such dosage forms obtained by dissolving or dispersing the compounds in a suitable medium. The absorption improvers can also be used to enhance the flow of compounds through the skin, and the speed of absorption can be controlled by using a membrane that controls the speed, or by dispersing the compound in a polymer matrix or gel.

Compounds in accordance with this invention can be applied in the form of pharmaceutically acceptable salts, esters or amides derived from inorganic or organic acids. The term "pharmaceutically acceptable salts, esters and amides" in this description includes salt, zwitter ions, esters and amides of the compounds described above, which, according to medical opinion, are suitable for use in contact with the tissues of humans and lower animals without causing toxicity, irritation, allergic response and the like, commensurate with a reasonable ratio of benefit/risk and effective for its intended use.

Pharmaceutically acceptable salts are well known in this allestimenti. Salts can be obtained during the final isolation and purification of the compounds or separately by the interaction of the amino compounds with the appropriate acid. Typical salts include acetate, adipate, alginate, citrate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, comfort, camphorsulfonate, digluconate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, formate, isetionate, fumarate, lactate, malate, maleate, methanesulfonate, naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, pivalate, propionate, succinate, tartrate, trichloracetic, triptorelin, glutamate, para-toluensulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, phosphate and the like. The amino compounds can also be stereoselectivity chlorides, bromides and iodides of alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

The basic additive salts can be obtained during the final isolation and purification of compounds in accordance with this invention by the interaction of the carboxyl group with a suitable base such as the hydroxide, carbonate or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium or aluminum, or an organic primary, secondary or tertiary amine. Quaternary amine salts derived from metiram is on, 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 the like, included in the scope of this invention.

The term "pharmaceutically acceptable ester" in this description refers to esters of the compounds in accordance with this invention, which is hydrolyzed in vivo and include those that easily break down in the human body to release the parent compound or its salts. Examples of pharmaceutically acceptable non-toxic esters in accordance with this invention include C1-6alkalemia esters and C5-7cycloalkyl esters, although C1-4alkalemia esters are preferred. Esters in accordance with this invention can be obtained by conventional methods. Pharmaceutically acceptable esters can be attached to hydroxypropy interaction of the compound that contains the hydroxy-group, acid and alkalicarbonate acid, such as acetic acid, or with acid and arylcarbamoyl acid, such as benzoic acid. For connected the th, the group containing carboxylic acid, pharmaceutically acceptable esters derived from compounds containing the carboxylic acid group by the interaction of the compound with base such as triethylamine, and alkylhalogenide, alkylacrylate, for example methyliodide, benzimidazol, cyclopenthiazide. They can also be obtained by the interaction of the compounds with acid, such as hydrochloric acid, and alkalicarbonate acid, such as acetic acid, or with acid and arylcarbamoyl acid, such as benzoic acid.

The term "pharmaceutically acceptable amide" in this description refers to non-toxic Amida in accordance with this invention derived from ammonia, mainly to C1-6the bonds alkylamines and secondary C1-6dialkylamines. For secondary amines, the amine may be in the form of a 5 - or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-3alkyl primary amides and C1-2dialkyl secondary amides are preferred. Amides of the compounds in accordance with this invention can be obtained by conventional methods. Pharmaceutically acceptable amides can be obtained from compounds containing primary or secondary amine group interaction of a compound that contains an amino group, anhydride alkyl, anhydride aryl-allelochemical or arilgalogenide. For compounds containing groups, carboxylic acids, pharmaceutically acceptable esters derived from compounds containing the carboxylic acid group, the interaction 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 the interaction of the compounds with acid, such as sulfuric acid, and alkalicarbonate acid, such as acetic acid, or arylcarbamoyl acid, such as benzoic acid, under conditions of dehydration using molecular sieves. The composition may contain the compound in accordance with this invention in the form of pharmaceutically acceptable prodrugs.

The term "pharmaceutically acceptable prodrug" or "prodrug" in this description is such prodrugs of the compounds in accordance with this invention, which, from a medical point of view, suitable for use in contact with the tissues of humans and lower animals without causing toxicity, irritation, allergic response and the like, commensurate with a reasonable ratio of benefit/risk and effective for its intended use. Prodrugs in accordance with this invention can be quickly Ave is vrasene in vivo in the original connection in accordance with this invention, for example, by hydrolysis in blood. A detailed discussion is provided in T. Higuchi and V. Stella, Prodrugs 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).

Disorders can be treated or prevented in a patient by administration to the patient a therapeutically effective amount of the compound (or pharmaceutically acceptable salts, prodrugs or salts of prodrugs in accordance with this invention in such amount and within such period of time that is required to achieve the desired result. The term "therapeutically effective amount" refers to sufficient amounts of the compounds in accordance with this invention for effective relief of disorders through inhibition DGAT-1 with a smart combination of risk/benefit, applicable to any medical treatment. The specific therapeutically effective dose for each particular patient depends on many factors, including treat the disorder and the severity of the disorder; activity of the applied compounds; specific applied 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 joint therapy.

Amounts of the RNA daily dose of the compounds in accordance with this invention, required for inhibition of action DGAT-1, one or more doses can be, for example, from about 0.01 to 50 mg/kg of body weight. In a more preferred embodiment, compounds in accordance with this invention inhibit the action DGAT-1 in single or multiple dose of from about 0.05 to 25 mg/kg of body weight. Compositions with a single dose may contain such whole number of doses of the compounds in accordance with this invention, which provide a daily dose. In General, treatment regimens include administration to a patient in need of such, from about 1 mg to about 1000 mg of the compounds per day in single or multiple doses.

Compounds identified by the methods in accordance with this invention, can be administered in a single pharmaceutical agents or in combination with one or more other pharmaceutical means, if the combination does not cause unacceptable side effects. For example, the compounds in accordance with this invention can be combined with anti-obesity, or with known antidiabetic or other means according to the testimony, and the like. Thus, this invention also includes pharmaceutical compositions that include a therapeutically effective amount of a compound identified by the methods described in the present description, or its pharmaceutically acceptable salt, pharmaceutically acceptable carrier, and one or more pharmaceutical agents described above.

Compounds and methods in accordance with this invention will be more clear from the following examples which are given for illustration only and do not limit the scope of the present invention. All quotes included in this description as a reference.

Examples

Example 1

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}urea

Example 1A

1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

To have an ambient temperature solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 9,13 mmol) in tetrahydrofuran (30 ml) is added 2-fluoro-5-triftormetilfullerenov (1,32 ml, 9,13 mmol). After 1 h the mixture was concentrated under reduced pressure to obtain specified in the title compounds as white solids. MS (ESI, IER) m/z 425 [M+H]+.

Example 1B

4-(5-iodiesel-2-yl)tetrahydro-2H-Piran-4-ol

To a cold (-78°C) solution of thiazole (2.0 ml, of 28.2 mmol) in tetrahydrofuran (140 ml) is added n-utility (11,4 ml of 28.2 mmol, 2,48 M in hexane) dropwise. After 15 minutes add dihydro-2H-Piran-4(3H)-he (2,59 ml of 28.2 mmol) in one portion. After 30 minutes, dropwise on billaut n-utility (11,4 ml, of 28.2 mmol, 2,48 M in hexane). The reaction mixture is stirred for another 20 minutes, then add a solution of iodine (7,24 g of 28.2 mmol) in tetrahydrofuran (15 ml) dropwise. Then the reaction quenched by addition of saturated aqueous Na2S2O3and ethyl acetate (100 ml) and heated to ambient temperature. The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×100 ml). The combined organic phases are dried with anhydrous Na2SO4, filtered and concentrated to obtain a dark solid. Rubbing the residue with dichloromethane gives specified in the title compound as a beige solid. MS (EEC) m/z 312 [M+H]+.

Example 1C

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}urea

A solution of example 1B (183 mg, 0.59 mmol), example 1A (250 mg, 0.59 mmol), CsF (269 mg, 1.77 mmol) and tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.06 mmol) in a mixture of solvents dimethoxyethane (1 ml) and methanol (1 ml) heated to 90°C for 16 hours, the Reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (2 ml) and H2O (1 ml). The layers are separated and the organic layer is dried with anhydrous Na2SO4, filtered and concentrated to obtain a solid substance. The residue is purified OF ghvd (preparative liquid chromatography vysokopostavlennye with reversed phase) using column Bond SB-C18 7M of 21.2×250 mm, UV definition analyzed at 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 obtain the specified title compound as a white solid.1H NMR (300 MHz, DMSO-d6) δ h/1,69 million (userd, J=12,2 Hz, 2H), 2,07-2,17 (m, 2H), 3,70 is 3.76 (m, 4H), 6,16 (s, 1H), 7,37-7,42 (m, 1H), 7,51-rate of 7.54 (m, 3H), to 7.59 (m, 2H), 8,00 (s, 1H), 8,61 (m, 1H), to 8.94 (m, 1H), 9,35 (s, 1H); MS (IER) m/z 482 [M+H]+.

Example 2

N-{4-[2-(1-ethyl-4-hydroxypiperidine-4-yl)-1,3-thiazol-5-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Example 2A

1-ethyl-4-(5-iodiesel-2-yl)piperidine-4-ol

Example 2A receive the procedure described for example 1A, substituting dihydro-2H-Piran-4(3H)-1-ethylpiperidine-4-one. MS (EEC) m/z 338 [M+H]+.

Example 2B

N-{4-[2-(1-ethyl-4-hydroxypiperidine-4-yl)-1,3-thiazol-5-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Salt triperoxonane acid specified in the connection header receive the procedure described for example 1C, substituting example 1B in example 2A.1H NMR (300 MHz, DMSO-d6) δ h/million of 1.06 (t, J=7,1 Hz, 3H), 1,78 (userd, J=11.5 Hz, 2H), 2,12 (ushort, J=10,9 Hz, 2H), 2,69-2,87 (m, 2H), 3,30-3,44 (m, 4H), 6,00 (s, 1H), 7,38-the 7.43 (m, 1H), of 7.48-rate of 7.54 (m, 3H), 7,58 (m, 2H), to 7.99 (s, 1H), 8,61 (m, 1H), 8,93 (m, 1H), to 9.32 (s, 1H); MS (EEC) m/z 509 [M+H]+.

Example 3

4-(5-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]-3-forfinal}-1,3-thiazol-2-yl)tetrahydro-2H-feast of the-4-ol

Example 3A

N-(4-bromo-2-forfinal)-5,7-dimethylbenzo[d]oxazol-2-amine

With an ambient temperature solution of 2-amino-4,6-dimethylphenol of 0.85 g, 6.2 mmol) and 2-fluoro-4-bromonicotinate (1.44 g, of 6.20 mmol) in tetrahydrofuran (20 ml) is stirred for 16 hours, the Reaction mixture was cooled (0°C) and add LiOH*H2O (0,521 g, 12,41 mmol), followed by adding dropwise 30% H2O2(3,41 ml, was 31.0 mmol) for 15 minutes. The reaction mixture is heated to room temperature and stirred for 16 h Then the reaction mixture was quenched by adding 20% aqueous solution of sodium sulfite (50 ml) and ethyl acetate (75 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×75 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira 25% ethyl acetate in hexane, to obtain specified in the connection header. MS (EEC) m/z 335 [M+H]+.

Example 3B

N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,7-dimethylbenzo[d]oxazol-2-amine

A mixture of example 3A (2,34 g, mmol 6,98), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2,13 g scored 8.38 mmol), potassium acetate (2.06 to g, 21,0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2(0,171 g, 0,209 mmol) in dioxane (30 ml) is heated to 95°C for 24 hours The reaction mixture is cooled to room temperature and diluted with saturated salt solution (100 ml) and ethyl acetate (100 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×75 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira 25% ethyl acetate in hexane, to obtain specified in the connection header. MS (EEC) m/z 383 [M+H]+.

Example 3C

4-(5-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]-3-forfinal}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol

A solution of example 3B (0,062 g, 0,161 mmol), example 1B (0,050 g, 0,161 mmol), CsF (0,073 g, 0,482 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,019 g, 0,0161 mmol) in a mixture solvent dimethoxyethane/methanol (1/1, 1 ml) heated to 90°C for 16 hours, the Reaction mixture was cooled to room temperature and divided between the H2O (2 ml) and ethyl acetate (2 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×2 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 220 and 254 nm (ven is exploring method: water with 0.1% triperoxonane acid and CH 3CN with 0.1% triperoxonane acid, gradient 5-95% CH3CN for 30 minutes at 15 ml/min) to obtain the specified title compound as a white solid.1H NMR (300 MHz, DMSO-d6) δ h/1,69 million (d, J=12,6 Hz, 2H), 2,08-of 2.20 (m, 2H), 2,34 (s, 3H), 2,39 (s, 3H), 3,64-a 3.87 (m, 4H), of 6.20 (s, 1H), 6,80 (s, 1H), was 7.08 (s, 1H), 7,51 (m, 1H), 7,65 (m, 1H), 8,10 (s, 1H), 8.34 per (m, 1H), 10,50 (s, 1H); MS (EEC) m/z 440 [M+H]+.

Example 4

4-(5-{4-[(7-methyl-1,3-benzoxazol-2-yl)amino]phenyl}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol

Example 4A

N-(4-bromophenyl)-7-methylbenzo[d]oxazol-2-amine

With an ambient temperature solution of 2-amino-6-METHYLPHENOL (0.74 g, 6.0 mmol) and 4-bromonicotinate (1.28 g, 6.0 mmol) in tetrahydrofuran (20 ml) is stirred for 16 hours, the Reaction mixture was cooled (0°C) and add LiOH*H2O (0,521 g, 12,41 mmol), followed by adding dropwise 30% H2O2(3,41 ml, was 31.0 mmol) for 15 minutes. The reaction mixture is heated to room temperature and stirred for 16 h Then the reaction mixture was quenched by adding 20% aqueous solution of sodium sulfite (50 ml) and ethyl acetate (75 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×75 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira 25% of etelaat the om in hexane, obtaining specified in the connection header. MS (EEC) m/z 303 [M+H]+.

Example 4B

7-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-2-amine

Example 4B receive the procedure described for example 3B, substituting example 3A example 4A. MS (EEC) m/z 351 [M+H]+.

Example 4C

4-(5-{4-[(7-methyl-1,3-benzoxazol-2-yl)amino]phenyl}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol

Example 4C receive according to the method described for example 3C, substituting example 3B example 4C.1H NMR (300 MHz, DMSO-d6) δ h/1,69 million (d, J=12,2 Hz, 2H), 2,04-of 2.20 (m, 2H), 2,44 (s, 3H), 3,66-3,81 (m, 4H), 6,14 (s, 1H), 6,98 (m, 1H), 7,13 (m, 1H), 7,30 (m, 1H), 7,60-7,71 (m, 2H), 7,76-7,87 (m, 2H), to 7.99 (s, 1H), 10,83 (s, 1H); MS (EEC) m/z 408 [M+H]+.

Example 5

4-(5-{2-chloro-4-[(7-chloro-1,3-benzoxazol-2-yl)amino]phenyl}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol

Example 5A

N-(4-bromo-3-chlorophenyl)-7-chlorobenzo[d]oxazol-2-amine

With an ambient temperature solution of 2-amino-6-chlorophenol (0,86 g, 6.0 mmol) and 3-chloro-4-bromonicotinate (1,49 g, 6.0 mmol) in tetrahydrofuran (20 ml) is stirred for 16 hours, the Reaction mixture was cooled (0°C) and add LiOH*H2O (0,521 g, 12,41 mmol), followed by adding dropwise 30% H2O2(3,41 ml, was 31.0 mmol) for 15 minutes. The reaction mixture is heated to room temperature and stirred for 16 h Then the reaction mixture was quenched by adding 20% aqueous solution of sulfi the sodium (50 ml) and ethyl acetate (75 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×75 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira 25% ethyl acetate in hexane, to obtain specified in the connection header. MS (EEC) m/z 359 [M+H]+.

Example 5B

7-chloro-N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazol-2-amine

Example 5B receive the procedure described for example 3B, substituting example 3A for example 5A. MS (EEC) m/z 405 [M+H]+.

Example 5C

4-(5-{2-chloro-4-[(7-chloro-1,3-benzoxazol-2-yl)amino]phenyl}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol

Example 5C get the procedure described for example 3C, substituting example 3B for example 5V.1H NMR (300 MHz, DMSO-d6) δ h/million of 1.70 (d, J=12,2 Hz, 2H), 2,04-of 2.21 (m, 2H), 3,65-a-3.84 (m, 4H), 6,23 (s, 1H), 7.24 to 7,29 (m, 2H), 7,51 (m, 1H), to 7.67-7,72 (m, 2H), 7,95 (s, 1H), of 8.09 (s, 1H), 11,36 (s, 1H); MS (EEC) m/z 462 [M+H]+.

Example 6

4-(5-{4-[(7-chloro-1,3-benzoxazol-2-yl)amino]-2-were}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol

Example 6A

N-(4-bromo-3-were)-7-chlorobenzo[d]oxazol-2-amine

Example 6A receive according to the method described for example 5A, substituting 3-chloro-4-bromonicotinate 3-methyl-4-bromonicotinic. MS (EEC) m/z 339 [M+H]+.

Example 6B

7-chloro-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxano the olan-2-yl)phenyl)benzo[d]oxazol-2-amine

Example 6B receive according to the method described for example 3B, substituting example 3A example 6A. MS (EEC) m/z 385 [M+H]+.

Example 6C

4-(5-{4-[(7-chloro-1,3-benzoxazol-2-yl)amino]-2-were}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol

Example 6C receive according to the method described for example 3C, substituting example 3B example 6B.1H NMR (300 MHz, DMSO-d6) δ h/1,71 million (d, J=12,2 Hz, 2H), 2.06 to 2,22 (m, 2H), 2.40 a (s, 3H), 3,65-a-3.84 (m, 4H), 6,17 (s, 1H), 7,16-7,33 (m, 2H), 7,37-7,53 (m, 2H), 7,62-7,76 (m, 3H), 11,09 (s, 1H); MS (EEC) m/z 519 [M+H]+.

Example 7

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{6-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]pyridine-3-yl}urea

Example 7A

4-(5-(5-nitropyridine-2-yl)thiazol-2-yl)tetrahydro-2H-Piran-4-ol

To a cold (-78°C) solution of thiazole (0,382 ml, 5.41 mmol) in tetrahydrofuran (30 ml) is added n-utility (3,38 ml, 5.41 mmol, of 1.6 M in hexane) dropwise. After 15 minutes add dihydro-2H-Piran-4(3H)-he (0,49 ml, 5.41 mmol) in one portion. After 30 minutes, add n-utility (3,38 ml, 5.41 mmol, of 1.6 M in hexane) dropwise. The reaction mixture is stirred for another 20 minutes, then add ZnCl2(10,8 ml, about 10.8 mmol, 1 M in diethyl ether). The cooling bath removed and the reaction mixture is heated to room temperature. Add 2-bromo-5-nitropyridine (1.10 g, 5.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,623 g, 0.54 mmol) and the reaction mixture is heated to 55°C for 16 h Re is clonney the mixture is cooled to ambient temperature and quenched by addition of saturated NH 4Cl (30 ml) and ethyl acetate (30 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×30 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2, elwira gradient 10% ethyl acetate in hexane to 35% ethyl acetate in hexane, to obtain specified in the connection header. MS (EEC) m/z 308 [M+H]+.

Example 7B

4-(5-(5-aminopyridine-2-yl)thiazol-2-yl)tetrahydro-2H-Piran-4-ol

To a solution of example 7A (0,106 g, 0,344 mmol) in a mixture solvent of methanol (2 ml) and acetic acid (2 ml) was added Zn powder (0,067 g of 1.03 mmol). The reaction mixture is heated to 50°C for 5 h and then cooled to room temperature. The reaction mixture was quenched by addition of saturated aqueous NaHCO3(5 ml) and ethyl acetate (5 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×5 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure to obtain specified in the title compound, which was used without further purification. MS (EEC) m/z 278 [M+H]+.

Example 7C

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{6-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]pyridine-3-yl}urea

To a solution of example 7B (0.042 mg, 0,151 mmol) in tetrahydrofuran is (1 ml) is added 2-fluoro-5-triftormetilfullerenov (of 0.022 ml, 0,151 mmol). After 1 h the mixture was concentrated under reduced pressure. The residue is purified OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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 obtain the specified title compound as a white solid.1H NMR (300 MHz, DMSO-d6) δ h/1,68 million (userd, J=12.9 Hz, 2H), 2,07-2,17 (m, 2H), 3,68-of 3.80 (m, 4H), x 6.15 (s, 1H), 7,40 was 7.45 (m, 1H), 7,52 (m, 1H), 7,89 (m, 1H), 8,08 (m, 1H), of 8.25 (s, 1H), 8,55 at 8.60 (m, 2H), 9,10 (s, 1H), 9,40 (s, 1H); MS (EEC) m/z 483 [M+H]+.

Example 8

N-{4-[2-(1-ethyl-4-hydroxypiperidine-4-yl)-1,3-thiazol-5-yl]-2-forfinal}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Example 8A

tert-butyl 4-(2-(1-ethyl-4-hydroxypiperidine-4-yl)thiazol-5-yl)-2-ftorhinolonami

A solution of example 2A (0.33 g, 0.98 mmol), 4-(tert-butoxycarbonylamino)-3-ftorhinolonovy acid (0.25 g, 0.98 mmol), CsF (and 0.46 g, 3.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0,098 mmol) in a mixture of solvents dimethoxyethane (2 ml) and methanol (1 ml) heated to 90°C for 16 hours the Reaction mixture is cooled and diluted with ethyl acetate (5 ml) and H2O (5 ml). The layers are separated and the organic layer washed with 10% aqueous HCl (3×15 ml). It United the output acidic aqueous layers add 2N NaOH to pH=8. The aqueous layer was extracted with ethyl acetate (3×15 ml). The extract is then dried with anhydrous Na2SO4filter and concentrate under reduced pressure to obtain specified in the connection header in the form of solids. MS (EEC) m/z 422 [M+H]+.

Example 8B

4-(5-(4-amino-3-forfinal)thiazol-2-yl)-1-ethylpiperidine-4-ol

To have an ambient temperature solution of example 8A (0.20 g, 0.48 mmol) in dichloromethane (2 ml) is added triperoxonane acid (2 ml). The reaction mixture was stirred for 2 h and then concentrated under reduced pressure. The remainder is divided between saturated aqueous NaHCO3(5 ml) and ethyl acetate (5 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×5 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure to obtain specified in the title compound, which was used without further purification. MS (EEC) m/z 322 [M+H]+.

Example 8C

N-{4-[2-(1-ethyl-4-hydroxypiperidine-4-yl)-1,3-thiazol-5-yl]-2-forfinal}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To have an ambient temperature solution of example 8B (0.02 g, 0,062 mmol) in tetrahydrofuran (1 ml) is added 2-fluoro-5-triftormetilfullerenov (0,010 g 0,065 mmol). After 1 hour, the mixture is concentrated under reduced pressure. The residue is purified OF ghvd preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV definition analyzed at 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). The fractions containing the desired product was diluted with saturated aqueous NaHCO3and extracted with ethyl acetate. The organic layer is dried with anhydrous Na2SO4filter and concentrate under reduced pressure to obtain specified in the title compound as a white solid.1H NMR (300 MHz, DMSO-d6) δ h/million of 1.01 (t, J=7,1 Hz, 3H), 1,73 (userd, J=11,9 Hz, 2H), 2,08 (dt, J=11,9 and 3.7 Hz, 2H), 2,25-is 2.37 (m, 4H), 2,64-by 2.73 (m, 2H), x 6.15 (s, 1H), 7,33-7,52 (m, 3H), to 7.61 (m, 1H), with 8.05 (s, 1H), 8,24 (m, 1H), 8,64 (m, 1H), of 8.90 (s, 1H), 9,34 (s, 1H); MS (EEC) m/z 527 [M+H]+.

Example 9

N-(2,5-differenl)-N'-{4-[2-(1-ethyl-4-hydroxypiperidine-4-yl)-1,3-thiazol-5-yl]-2-forfinal}urea

Specified in the header connection receive according to the method of example 8C substituting 2-fluoro-5-triftormetilfullerenov 2,5-diftorhinolonom.1H NMR (300 MHz, DMSO-d6) δ h/million of 1.03 (t, J=7,1 Hz, 3H), 1,73 (userd, J=11,9 Hz, 2H), 2,08 (dt, J=11,9 and 3.7 Hz, 2H), 2,33 is 2.44 (m, 4H), 2,71 was 2.76 (m, 2H), 6,85 (s, 1H), 7,21-7,29 (m, 1H), was 7.36-7,44 (m, 2H), 7,63-of 7.69 (m, 1H), 8,02-8,07 (m, 1H), 8,10 (s, 1H), they were 8.22 (m, 1H), of 8.90 (s, 1H), of 9.30 (s, 1H); MS (EEC) m/z 477 [M+H]+.

Example 10

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{6-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]pyridine-3-yl}urea

Example 10A

1-(5-Iodiesel-2-yl)Cyclops is stanol

Example 10A receive according to the method of example 1B, substituting dihydro-2H-Piran-4(3H)-he Cyclopentanone. MS (EEC) m/z 296 [M+H]+.

Example 10B

1-(5-(5-nitropyridine-2-yl)thiazol-2-yl)Cyclopentanol

Example 10B receive according to the method of example 7A, substituting dihydro-2H-Piran-4(3H)-he Cyclopentanone. MS (EEC) m/z 292 [M+H]+.

Example 10C

1-(5-(5-aminopyridine-2-yl)thiazol-2-yl)Cyclopentanol

Example 10C receive according to the method of example 7B, substituting example 7A example 10B. MS (EEC) m/z 262 [M+H]+.

Example 10D

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{6-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]pyridine-3-yl}urea

Example 10D get by the method of example 7C, substituting example 7B example 10C.1H NMR (300 MHz, DMSO-d6) δ h/1,74 million-of 1.92 (m, 6H), 2,04-2,12 (m, 2H), 6,50 (s, 1H), 7,40-7,42 (m, 1H), and 7.4 (m, 1H), 7,87 (m, 1H), 8,07 (m, 1H), 8,21 (s, 1H), 8,56-8,58 (m, 2H), 8,93 (s, 1H), 9,44 (s, 1H); MS (EEC) m/z 467 [M+H]+.

Example 11

Phenyl 4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenylcarbamate

Example 11A

4-(5-(4-nitrophenyl)thiazol-2-yl)tetrahydro-2H-Piran-4-ol

A solution of example 1B (1.0 g, 3.2 mmol), 4-nitrophenylarsonic acid (0.75 g, 4.5 mmol), KF (0.56 g, 9.6 mmol) and dichloride bis(triphenylphosphine)palladium(II) (0,22 g, 0.32 mmol) in a mixture of solvents dimethoxyethane (5 ml) and methanol (5 ml) is heated to 90°C for 16 hours, the Reaction mixture was cooled to room temperature and separated between ethyl acetate (10 ml) and H2 O (10 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×10 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira 50% ethyl acetate in hexane, to obtain specified in the connection header. MS (EEC) m/z 307 [M+H]+.

Example 11B

4-(5-(4-AMINOPHENYL)thiazol-2-yl)tetrahydro-2H-Piran-4-ol

Example 11B receive according to the method of example 7B, substituting example 7A example 11A. MS (EEC) m/z 277 [M+H]+.

Example 11C

Phenyl 4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenylcarbamate

To have an ambient temperature solution of example 11B (0,040 g, 0,145 mmol) and triethylamine (0,020 ml, 0,145 mmol) in tetrahydrofuran (1 ml) add phenylcarbamate (0,016 ml, 0,145 mmol). After 16 h, the reaction mixture was concentrated under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira with ethyl acetate, to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/million of 1.57-1.77 in (m, 2H), 2,02-of 2.20 (m, 2H), 3,64-3,81 (m, 4H), 6,12-6,18 (m, 1H), 7,12-7,19 (m, 1H), 7,22-7,28 (m, 2H), 7,40-of 7.48 (m, 2H), 7,54-the 7.65 (m, 4H), of 8.00 (s, 1H); MS (EEC) m/z 397 [M+H]+.

Example 12

N-{4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}piperidine-1-carboxamide

To have the ambient temperature of the solution note the RA 11B (0,040 g, 0,145 mmol) and triethylamine (0,020 ml, 0,145 mmol) in tetrahydrofuran (1 ml) is added piperidine-1-carbonylchloride (0,018 ml, 0,145 mmol). After 16 h, the reaction mixture was concentrated under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira with ethyl acetate, to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/1,43 million-of 1.62 (m, 6H), 1,68 (d, J=12,2 Hz, 2H), 2,02-of 2.21 (m, 2H), 3,39-of 3.46 (m, 4H), 3,64-of 3.80 (m, 4H), 6,12 (s, 1H), 7,45-7,56 (m, 4H), 7,94 (s, 1H), 8,56 (s, 1H); MS (EEC) m/z 388 [M+H]+.

Example 13

tert-Butyl 3-(5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1,3-thiazol-2-yl)-3-hydroxypyrrolidine-1-carboxylate

Example 13A

tert-Butyl 3-hydroxy-3-(5-iodiesel-2-yl)pyrrolidin-1-carboxylate

To a cold (-78°C) solution of thiazole (0,382 ml, 5.41 mmol) in tetrahydrofuran (30 ml) is added n-utility (3,38 ml, 5.41 mmol, of 1.6 M in hexane) dropwise. After 15 minutes, add N-boc-3-pyrrolidinone (0,49 ml, 5.41 mmol) in one portion. After 30 minutes add diisopropylamide lithium (5,41 ml, 5.41 mmol, and 1.0 M in tetrahydrofuran) dropwise. The reaction mixture is stirred for a further 30 minutes, then add a solution of I2(of 1.37 g, 5.4 mmol) in tetrahydrofuran (10 ml) dropwise. After 10 minutes the reaction is quenched by addition of saturated aqueous Na2S2O3(100 ml) and ethyl acetate (100 ml) and heated to ambient temperature. Layers R is sdelat and the aqueous layer was extracted with additional ethyl acetate (2×100 ml). The combined organic layers dried with anhydrous Na2SO4, filtered and concentrated to obtain a dark solid. The residue is purified by chromatography on SiO2the gel elwira 50% ethyl acetate in hexane, to obtain specified in the connection header in the form of solids. MS (EEC) m/z 397 [M+H]+.

Example 13B

tert-Butyl 3-(5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1,3-thiazol-2-yl)-3-hydroxypyrrolidine-1-carboxylate

Example 13B receive according to the method of example 1C, substituting example 1B in example 13A.1H NMR (500 MHz, DMSO-d6) δ h/1,33 million-for 1.49 (m, 9H), 2.05 is-2,17 (m, 1H), 2,28-to 2.42 (m, 1H), 3,40-of 3.53 (m, 1H), 3,52-3,61 (m, 2H), 3,62-3,71 (m, 1H), is 6.54 (s, 1H), 7,34-the 7.65 (m, 6H), of 8.04 (s, 1H), 8,56-8,66 (m, 1H), 8,93 (m, 1H), 9.28 are-9,40 (m, 1H); MS (EEC) m/z : 567 [M+H]+.

Example 14

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(3-hydroxypyrrolidine-3-yl)-1,3-thiazol-5-yl]phenyl}urea

To have an ambient temperature solution of example 13B (0,30 g of 0.53 mmol) in dichloromethane (2 ml) is added triperoxonane acid (2 ml). After 1 h the solution is concentrated under reduced pressure. The remainder is divided between saturated aqueous NaHCO3(5 ml) and ethyl acetate (5 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×5 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure to receive the drug specified in the connection header. 1H NMR (500 MHz, DMSO-d6) δ h/1,97 million-2,11 (m, 1H), 2,23 of-2.32 (m, 1H), 2.91 in-is 3.08 (m, 2H), 3,07-3,19 (m, 2H), 4,06-4,17 (m, 1H), 6,17 (s, 1H), 7,35-of 7.70 (m, 6H), to 7.99 (s, 1H), 8,56-8,67 (m, 1H), of 8.95 (s, 1H), 9,37 (s, 1H); MS (IER) m/z 467 [M+H]+.

Example 15

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(3-hydroxy-1-methylpyrrolidine-3-yl)-1,3-thiazol-5-yl]phenyl}urea

To have an ambient temperature solution of example 14 (0,050 g, 0,107 mmol) in methanol containing 1% vol./about. acetic acid (1 ml) was added formaldehyde (0,012 ml, 0,161 mmol, 37% of the mass. in H2O) and MP-CNBH3(0,054 g, 0,161 mmol, 3.0 mmol/g). The reaction mixture is heated to 50°C. and shaken for 16 hours, the Reaction mixture was filtered and concentrated under reduced pressure. The residue is purified OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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). The fractions containing the desired product was diluted with saturated aqueous NaHCO3and extracted with ethyl acetate. The organic layer is dried with anhydrous Na2SO4filter and concentrate under reduced pressure to obtain specified in the title compound as a white solid.1H NMR (500 MHz, D IS the CO-d 6) δ h/2,01 million and 2.13 (m, 1H), 2,25 is 2.33 (m, 3H), 2,35 is 2.46 (m, 1H), of 2.51-of 2.58 (m, 1H), 2,73-to 2.94 (m, 3H), 6,22 of 6.31 (m, 1H), 7,37-7,44 (m, 1H), 7,47-7,56 (m, 3H), 7,56 to 7.62 (m, 2H), 7,98 (s, 1H), to 8.62 (m, 1H), of 8.92 (m, 1H), to 9.32 (s, 1H); MS (EEC) m/z 481 [M+H]+.

Example 16

N-{4-[2-(1-ethyl-3-hydroxypyrrolidine-3-yl)-1,3-thiazol-5-yl]phenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Specified in the header connection get the procedure described for example 15, replacing formaldehyde with acetaldehyde.1H NMR (300 MHz, DMSO-d6) δ h/million of 1.03 (t, J=7.29 trend Hz, 3H), 2.00 in a 2.12 (m, 1H), 2,34 is 2.43 (m, 1H), 2,53-2,63 (m, 1H), 2,83-2,96 (m, 3H), 4.09 to (m, 2H), 6,24 (s, 1H), 7,33-of 7.70 (m, 6H), 7,98 (s, 1H), 8,61 (m, 1H), 8,92 (m, 1H), to 9.32 (, 1H); MS (EEC) m/z 495 [M+H]+.

Example 17

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}urea

Example 17 receive according to the method of example 1C, substituting example 1B example 10A.1H NMR (500 MHz, DMSO-d6) δ h/1,69 million-of 1.95 (m, 6H), 2,01-of 2.16 (m, 2H), 5,91 (s, 1H), was 7.36-the 7.43 (m, 1H), 7,47-of 7.55 (m, 3H), 7,55-to 7.61 (m, 2H), of 7.96 (s, 1H), to 8.62 (m, 1H), 8,92 (m, 1H), to 9.32 (s, 1H); MS (EEC) m/z 466 [M+H]+.

Example 18

N-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea

Example 18A

1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3-(3-triptoreline)urea

Example 18A receive according to the method of example 1A, substituting 2-fluoro-5-triftormetilfullerenov 3-triftormetilfullerenov. MS (EEC) m/z 407 [M+H]+.

Example 18B

N-{4-[2-(1-hydroxycyclopent the l)-1,3-thiazol-5-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea

Example 18B receive according to the method of example 1C, substituting example 1B example 10A and substituting example 1A example 18A.1H NMR (500 MHz, DMSO-d6) δ h/1,70 million is 1.96 (m, 6H), 2,01-2,17 (m, 2H), 5,80 (s, 1H), 7,32 (m, 1H), 7,46-the 7.65 (m, 6H), 7,95 (s, 1H), 8,02 (s, 1H), 8,96 (s, 1H), 9,05-9,16 (m, 1H); MS (EEC) m/z 448 [M+H]+.

Example 19

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}urea

Example 19A

1-(5-Iodiesel-2-yl)cyclobutanol

Example 19A receive according to the method of example 1B, substituting dihydro-2H-Piran-4(3H)-he cyclobutanones. MS (EEC) m/z 282 [M+H]+.

Example 19B

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}urea

Example 19B receive according to the method of example 1C, substituting example 1B example 19A.1H NMR (500 MHz, DMSO-d6) δ h/1,77 million of 1.99 (m, 2H), 2,25-2,39 (m, 2H), of 2.51 at 2.59 (m, 2H), of 6.49 (s, 1H), was 7.36-7,44 (m, 1H), 7,47-of 7.55 (m, 3H), 7,56 to 7.62 (m, 2H), 8,00 (s, 1H), to 8.62 (m, 1H), 8,92 (m, 1H), to 9.32 (s, 1H); MS (EEC) m/z 452 [M+H]+.

Example 20

N-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea

Example 20 receive according to the method of example 1C, substituting example 1B example 19A and substituting example 1A example 18A.1H NMR (500 MHz, DMSO-d6) δ h/1,78 million-of 1.97 (m, 2H), 2.26 and-2,39 (m, 2H), 2,50-of 2.58 (m, 2H), of 6.49 (s, 1H), 7,32 (m, 1H), 7,45-to 7.64 (m, 6H), 7,95-8,07 (m, 2H), 8,96 (s, 2H), remaining 9.08 (s, 2H); MS (EEC) m/z 434 [M+H]+.

Example 21

(±)-CIS-3-hydroxy-3-{4'-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1,1'-iphenyl-4-yl}cyclopentanecarbonyl acid

Example 21A

(±)-CIS-(1S,3S)-3-(4-bromophenyl)-3-hydroxycyclohexanecarboxylate acid

To a cold (-78°C) solution of 1,4-dibromobenzene with (1.0 g, to 4.23 mmol) is added n-utility (1,69 ml, to 4.23 mmol, 2.5 M in hexane). After 30 minutes add (±)-3-oxocyclopentanecarboxylate acid (0,271 g, 2,12 mmol) in solution in tetrahydrofuran (20 ml). The reaction mixture is stirred for 30 minutes and then quenched with saturated aqueous NH4Cl (50 ml) and ethyl acetate (50 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×50 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira with ethyl acetate, to obtain specified in the connection header. MS (EEC) m/z 287 [M+H]+.

Example 21B

(±)-CIS-3-hydroxy-3-{4'-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1,1'-biphenyl-4-yl}cyclopentanecarbonyl acid

A mixture of example 21A (0,041 g, 0,154 mmol), example 18A (0,050 g, 0,154 mmol), Na2CO3(0,049 g, 0.46 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,017 g, 0.015 mmol) in a mixture solvent of toluene/dimethoxyethane/ethanol/H2O (10:3:2:1.1 ml) was heated to 90°C for 16 hours, the Reaction mixture was cooled to room temperature and divided between 10% HCl (5 ml) and ethyl acetate (5 ml). The layers are separated and the aqueous layer was extragere the t additional ethyl acetate (2×5 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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 obtain the specified title compound as a white solid.1H NMR (500 MHz, DMSO-d6) δ h/million 1,86-2,03 (m, 3H), 2,14-of 2.26 (m, 3H), 2,92 was 3.05 (m, 1H), equal to 4.97 (s, 1H), 7,32 (m, 1H), 7,47-7,66 (m, 10H), 8,03 (s, 1H), 8,89 (s, 1H), 9,07 (s, 1H), 12,0 (s, 1H); MS (EEC) m/z 484 [M+H]+.

Example 22

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(1-methoxycyclohexyl)-1,3-thiazol-5-yl]phenyl}urea

Example 22A

5-Iodine-2-(1-methoxycyclohexyl)thiazole

To a suspension of NaH (0,176 g, to 4.41 mmol, 60% of the mass. in mineral oil) in N,N-dimethylformamide (10 ml) add example 10A (1.0 g, 3,39 mmol). After 0.5 h add logmean (MX 0.317 ml, 5,09 mmol)and the reaction mixture is stirred for 16 hours the Reaction mixture is divided between the H2O (10 ml) and ethyl acetate (10 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×10 ml). The combined organic layers dried with anhydrous Na2SO4filter and will centerour under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira 5% ethyl acetate in hexane, to obtain specified in the connection header. MS (EEC) m/z 310 [M+H]+.

Example 22B

N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(1-methoxycyclohexyl)-1,3-thiazol-5-yl]phenyl}urea

Example 22B receive according to the method of example 1C, substituting example 1B example 22A.1H NMR (300 MHz, DMSO-d6) δ h/1,68 million-is 1.81 (m, 4H), 2,03-of 2.16 (m, 4H), 3,11-3,15 (m, 3H), 7,35-7,44 (m, 1H), 7,46-to 7.64 (m, 5H), of 8.00 (s, 1H), 8,61 (m, 1H), 8,93 (m, 1H), 9,36 (s, 1H); MS (EEC) m/z 553 [M+H]+.

Example 23

{[1-(5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 23A

Ethyl ester [1-(5-iodiesel-2-yl)cyclopentyloxy]acetic acid

Example 23A receive according to the method of example 22A, replacing itmean Bromeliaceae. MS (EEC) m/z 382 [M+H]+.

Example 23B

{[1-(5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

A solution of example 23A (0.187 g, 0,491 mmol), example 1A (0,208 g ml, 0,491 mmol), CsF (0,223 g of 1.47 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,057 g 0,049 mmol) in a mixture of solvents dimethoxyethane (1 ml) and methanol (1 ml) heated to 90°C for 16 hours, the Reaction mixture was cooled to room temperature and diluted with H2O (5 ml). The solid is filtered, washed with diethyl ether and dried n the air with obtaining the intermediate of ester. Ester is dissolved in methanol (15 ml) and 2N NaOH (2 ml) and stirred for 16 hours, the Methanol is removed under reduced pressure and the aqueous layer washed with diethyl ether (20 ml). The aqueous layer was acidified to pH 1 by adding 10% HCl. The solid is filtered, washed with CH3CN and dried in air to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/of 1.66 million is 1.91 (m, 4H), 2,07-2,17 (m, 4H), 3,91 (s, 2H), 7,34-7,66 (m, 6H), 8,02 (s, 1H), 8,61 (m, 1H), 9,02 (m, 1H), 9,54 (s, 1H), 10,45 (s, 1H); MS (EEC) m/z 524 [M+H]+.

Example 24

{[1-(5-{4-[(bicyclo[4.2.0]OCTA-1,3,5-triene-7-ylcarbonyl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutyl]oxy}acetic acid

Example 24A

Ethyl 2-(1-(5-iodiesel-2-yl)CYCLOBUTANE)acetate

To have the ambient temperature suspension of NaH (0,390 g of 9.75 mmol) in N,N-dimethylformamide (40 ml) add example 19A (2,74 g of 9.75 mmol) as a solution in N,N-dimethylformamide (10 ml). After 1 h, ethyl 2-bromoacetate (1.08 ml of 9.75 mmol) added in one portion. After 16 h, the reaction mixture was quenched by addition of H2O (50 ml) and ethyl acetate (50 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×50 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira gradient from hexane to 5% ethyl acetate in hexane, to obtain the specified in the connection header. MS (EEC) m/z 368 [M+H]+.

Example 24B

Methyl 2-(1-(5-(4-AMINOPHENYL)thiazol-2-yl)CYCLOBUTANE)acetate

A solution of example 24A (0,750 g 2/04 mmol), CsF (0.930 g, 6.12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0,447 g, 2.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,231 g, 0,200 mmol) in a mixture of solvents dimethoxyethane (5 ml) and methanol (5 ml) is heated to 90°C for 16 hours, the Reaction mixture was cooled to room temperature and divided between the H2O (10 ml) and ethyl acetate (10 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×10 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira gradient from 10% ethyl acetate in hexane to 50% ethyl acetate in hexane, to obtain specified in the connection header. MS (EEC) m/z 319 [M+H]+.

Example 24C

{[1-(5-{4-[(bicyclo[4.2.0]OCTA-1,3,5-triene-7-ylcarbonyl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutyl]oxy}acetic acid

To a solution of example 24B (0,150 g, 0,470 mmol), 1,2-dihydrocyclopenta-1-carboxylic acid (0,070 g, 0,470 mmol), N-methylmorpholine (0,103 ml, 0,940 mmol) and hydrate of 1-hydroxybenzotriazole (0,080 g, 0,940 mmol) in N,N-dimethylformamide (2 ml) was added the hydrochloride of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (0,115 g, 0,589 mmol). The solution is heated to 50 the C for 3 h, cooled to room temperature and divided between the H2O (2 ml) and ethyl acetate (2 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×2 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is dissolved in methanol (5 ml) and added 2N NaOH (0,50 ml). After 5 h, the methanol is removed under reduced pressure. The aqueous layer was acidified with 10% HCl to pH 1. The solid is filtered and air-dried. Purification of the residue OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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) gives specified in the title compound as a white solid.1H NMR (300 MHz, DMSO-d6) δ h/1,67 million-was 1.94 (m, 2H), 2,39-2,47 (m, 4H), 3,31 is 3.40 (m, 2H), 3,93 (s, 2H), of 4.44 (DD, J=4.9 and 2.9 Hz, 1H), 7,09-7,31 (m, 4H), 7,56-to 7.68 (m, 2H), to 7.67 for 7.78 (m, 2H), 8,07 (s, 1H), 10,37 (s, 1H); MS (EEC) m/z 435 [M+H]+.

Example 25

({1-[5-(4-{[(2-forfinal)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid

Example 25 receive according to the method of example 24C, substituting 1,2-dihydrocyclopenta-1-carboxylic acid 2-(2-forfinal)acetic acid.1 H NMR (300 MHz, DMSO-d6) δ h/1,67 million is 1.96 (m, 2H), 2,39-2,47 (m, 4H), of 3.75 (s, 2H), 3,92 (s, 2H), 7,10-7,25 (m, 2H), 7,26 was 7.45 (m, 2H), 7,53 to 7.75 (m, 4H), of 8.06 (s, 1H), 10,37 (s, 1H), 12,64 (s, 1H); MS (EEC) m/z 441 [M+H]+.

Example 26

{[1-(5-{4-[(anilinoacrolein)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 26A

1-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

Example 26A receive according to the method of example 1A, substituting 2-fluoro-5-triftormetilfullerenov phenylisocyanate. MS (EEC) m/z 339 [M+H]+.

Example 26B

{[1-(5-{4-[(anilinoacrolein)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 26B receive according to the method of example 23B, substituting example 1A example 26A.1H NMR (300 MHz, DMSO-d6) δ h/1,62 million-of 1.95 (m, 4H), 2,01-of 2.20 (m, 4H), 3,90 (s, 2H), 6,98 (m, 1H), 7,21 and 7.36 (m, 2H), 7,40-7,63 (m, 6H), of 8.00 (s, 1H), 8,73 (s, 1H), 8,88 (s, 1H), 12,59 (s, 1H); MS (EEC) m/z 438 [M+H]+.

Example 27

{[1-(5-{4-[(anilinoacrolein)amino]phenyl}-1,3-thiazol-2-yl)cyclobutyl]oxy}acetic acid

A solution of example 24A (0,304 g, 0,953 mmol), example 26A (0,209 g, 0,953 mmol), CsF (0,434 g of 2.86 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,110 g 0,095 mmol) in a mixture of solvents dimethoxyethane (5 ml) and methanol (5 ml) is heated to 90°C for 16 hours, the Reaction mixture was cooled to room temperature and diluted with H2O (10 ml). The solid is filtered, washed with diethyl ether and dried in air to obtain between the exact complex ester. Ester is dissolved in methanol (50 ml) and 2N NaOH (2 ml) and stirred for 16 hours, the Methanol is removed under reduced pressure and the aqueous layer washed with diethyl ether (15 ml). The aqueous layer was acidified to pH 1 by adding 10% HCl. The solid is filtered, washed with CH3CN and dried in air to obtain specified in the connection header.1H NMR (500 MHz, DMSO-d6) δ h/1,67 million-of 1.97 (m, 2H), 2,35-2,52 (m, 4H), 3,93 (s, 2H), 6,91-7,01 (m, 1H), 7.23 percent-7,33 (m, 2H), 7,41-to 7.50 (m, 2H), 7,51-to 7.59 (m, 4H), of 8.04 (s, 1H), 8,73 (s, 1H), 8,82 (s, 1H), 8,97 (s, 1H); MS (EEC) m/z 424 [M+H]+.

Example 28

{[1-(5-{6-[(anilinoacrolein)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 28A

1-phenyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)urea

To have an ambient temperature solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine (0,350 g of 1.59 mmol) in tetrahydrofuran (4 ml) add phenylisocyanate (0,174 ml of 1.59 mmol). The solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. The solid is washed with diethyl ether (2 ml) and dried in air to obtain specified in the connection header. MS (EEC) m/z 221 [M+H]+.

Example 28B

{[1-(5-{6-[(anilinoacrolein)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 28B receive according to the method of example 23B, replacing the use of the example 1A 28A. 1H NMR (300 MHz, DMSO-d6) δ h/million 1,60 is 1.96 (m, 4H), 2,13 (t, J=5,26 Hz, 4H), to 3.92 (s, 2H), 7,03 (t, J=7,3 Hz, 1H), 7,26-7,37 (m, 2H), 7,47-7,58 (m, 2H), 7,66 (m, 1H), 7,99-to 8.14 (m, 2H), at 8.60 (m, 1H), to 9.57 (s, 1H), 10,14 (s, 1H), 12,60 (s, 1H); MS (EEC) m/z 439 [M+H]+.

Example 29

{[1-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 29A

1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)-3-(3-(trifluoromethyl)phenyl)urea

Example 29A receive according to the method of example 28A, substituting phenylisocyanate 3-triftormetilfullerenov. MS (EEC) m/z 408 [M+H]+.

Example 29B

{[1-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 29B receive according to the method of example 23B, substituting example 1A example 29A.1H NMR (300 MHz, DMSO-d6) δ h/1,63 million-of 1.95 (m, 4H), 2,13 (t, J=5.1 Hz, 4H), to 3.92 (s, 2H), 7,38 (d, J=7.8 Hz, 1H), 7,56 (t, J=7.9 Hz, 1H), to 7.61 to 7.75 (m, 2H), 7,95-of 8.15 (m, 3H), 8,63 (m, 1H), to 9.70 (s, 1H), 10,52 (s, 1H), 12,61 (s, 1H); MS (EEC) m/z 507 [M+H]+.

Example 30

{[1-(4-{6-[(anilinoacrolein)amino]pyridine-3-yl}phenyl)cyclopentyl]oxy}acetic acid

Example 30A

1-(4-Bromophenyl)Cyclopentanol

To a cold (-78°C) solution of 1,4-dibromobenzene with (33 g, 139,8 mmol) in tetrahydrofuran (200 ml) is added n-utility (59,0 ml, 146,8 mmol, 2,49 M in hexane) dropwise. A viscous solution was stirred at -78°C for 45 min, and then add cyclopen the anon (to 13.6 ml, 153,8 mmol) dropwise within 30 minutes the resulting solution was stirred at -78°C for 1 h and then quenched by the addition of 0,5M HCl (200 ml) and ethyl acetate (200 ml). The layers are separated and the organic layers washed with water (1×100 ml), saturated salt solution (1×100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira 5% ethyl acetate in hexane to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/1,71 million to 1.76 (m, 2H), 1,78-of 1.88 (m, 6H), is 4.85 (s, 1H), 7,39-the 7.43 (m, 2H), 7,44-7,49 (m, 2H).

Example 30B

2-(1-(4-Bromophenyl)cyclopentyloxy)acetic acid

To have the ambient temperature suspension of NaH (332 mg, 8,30 mmol, 60% of the mass. in mineral oil) in N,N-dimethylformamide (2 ml) is added dropwise a solution of example 30A (1.0 g, 4,15 mmol) in N,N-dimethylformamide (1 ml). After 30 minutes add bromoxynil acid (577 mg, 4,15 mmol) in N,N-dimethylformamide (13 ml) dropwise. The solution was stirred at room temperature for 16 h and then heated to 50°C for 3 hours, the Reaction mixture was cooled to room temperature and quenched by addition of water (10 ml). The solution is alkalinized to pH 10 by addition of 2.5 M NaOH. The aqueous layer was extracted with ethyl acetate (2×10 ml)and the organic layers discarded. The aqueous layer was acidified to pH 1 by addition of 6 M HCl, and then extracted etelaat is ω (3×10 ml). The combined organic layers washed with water (3×10 ml), saturated salt solution (1×10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/of 1.66 million-1,72 (m, 2H), 1,74-of 1.85 (m, 4H), 2,02-of 2.15 (m, 2H), 3,56-of 3.60 (m, 2H), 7,33-7,39 (m, 2H), 7,49-7,56 (m, 2H), 12,37 (s, 1H).

Example 30C

Methyl 2-(1-(4-bromophenyl)cyclopentyloxy)acetate

To have an ambient temperature solution of example 30B (200 mg, 0,668 mmol) in N,N-dimethylformamide (4 ml) add logmean (0,208 ml, to 3.34 mmol) and potassium carbonate (184 mg, of 1.34 mmol). The mixture is stirred at room temperature for 40 h and then diluted with water (10 ml) and ethyl acetate (20 ml). The layers are separated and the organic layer washed with water (3×10 ml), saturated salt solution (1×10 ml), dried over sodium sulfate and concentrated under reduced pressure to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/1,67 million-1,72 (m, 2H), 1,74-of 1.84 (m, 4H), 2,10 (m, 2H), to 3.58 (s, 3H), 3,67-3,70 (m, 2H), 7,34-7,40 (m, 2H), 7,51-EUR 7.57 (m, 2H).

Example 30D

{[1-(4-{6-[(anilinoacrolein)amino]pyridine-3-yl}phenyl)cyclopentyl]oxy}acetic acid

A solution of example 30C (0,040 g, 0,122 mmol), example 28A level (0.041 g, 0,122 mmol), CsF (0,056 g, 0,366 mmol) and tetrakis(triphenylphosphine)palladium(0) (of 0.014 g, 0.012 mmol) in dimethoxyethane (0.5 ml) and methanol (0.5 ml) is heated to 90°C during the course the e 16 PM The reaction mixture was diluted with H2O (5 ml) and diethyl ether (5 ml) and the solid filtered. To solid substance dissolved in a mixture of tetrahydrofuran (2 ml) and methanol (1 ml) is added 2 N NaOH (0.8 ml). After stirring at room temperature for 16 h, the organic matter is removed under reduced pressure. The aqueous layer was extracted with diethyl ether (1×5 ml) and the organic matter drop. The aqueous layer was acidified to pH 1 by adding 10% HCl and the solid is filtered. Purification of the solid residue OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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) gives specified in the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) δ h/million 1,60-of 1.78 (m, 2H), 1.77 in is 1.91 (m, 4H), 2,02-2,19 (m, 2H), 3,53 (s, 2H), 7,02 (t, J=7,3 Hz, 1H), 7,31 (t, J=7.9 Hz, 2H), of 7.48-to 7.59 (m, 4H), to 7.61-7,72 (m, 3H), 8,07 (m, 1H), 8,61 (m, 1H), 9,67 (s, 1H); MS (EEC) m/z 432 [M+H]+.

Example 31

(±)-CIS-3-(4'-{[(2-forfinal)acetyl]amino}-1,1'-biphenyl-4-yl)-3-hydroxycyclohexanecarboxylate acid

Example 31A

(±)-CIS-methyl 3-(4-bromophenyl)-3-hydroxycyclohexanecarboxylate

To the temperature of the environment and the surrounding environment to a solution of example 21A (1,69 g, to 5.93 mmol) in methanol (15 ml) add trimethylsilyldiazomethane (5.0 ml, 10.0 mmol, 2.0 M in tetrahydrofuran). The reaction is quenched by addition of acetic acid (2 ml) and concentrate under reduced pressure. Purification of the residue by chromatography on SiO2the gel elwira 25% ethyl acetate in hexane, gives specified in the title compound in the form of oil. MS (EEC) m/z 299 [M+H]+.

Example 31B

(±)-CIS-methyl 3-(4'-aminobiphenyl-4-yl)-3-hydroxycyclohexanecarboxylate

A solution of example 31A (0,500 g, 1,67 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0,366 g, 1,67 mmol), CsF (0,761 g, 5,01 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,192 g, 0,167 mmol) in dimethoxyethane (4.0 ml) and methanol (4.0 ml) was heated to 90°C for 16 hours, the Reaction mixture was cooled to room temperature and divided between the H2O (10 ml) and ethyl acetate (10 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (10 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The crude residue is purified by chromatography on SiO2the gel elwira with ethyl acetate, to obtain specified in the connection header. MS (EEC) m/z 312 [M+H]+.

Example 31C

(±)-CIS-3-(4'-{[(2-forfinal)acetyl]amino}-1,1'-biphenyl-4-yl)-3-hydroxycyclohexanecarboxylate acid

To a solution of example 31B (0,100 g, 0,321 mmol), 2-(2'-perfe who yl)acetic acid (0,0490 g, 0,321 mmol), hydrate of 1-hydroxybenzotriazole (0,0540 g, 0,402 mmol) and N-methylmorpholine (0,070 ml, 0,064 mmol) in N,N-dimethylformamide add the hydrochloride of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (0,0770 g, 0,402 mmol). The reaction mixture is heated to 50°C for 3 h, cooled to room temperature and divided between the H2O (5 ml) and ethyl acetate (5 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×5 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The crude residue is dissolved in methanol (10 ml) and add 2 N NaOH (1 ml). The reaction mixture was stirred at room temperature for 16 hours, the Methanol is removed under reduced pressure and the aqueous layer was acidified to pH 1 by adding 10% HCl. The solid is filtered, air-dried and cleaned OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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 obtain the specified title compound as a white solid.1H NMR (300 MHz, DMSO-d6) δ h/million 1,86-2,03 (m, 3H), 2,14-of 2.26 (m, 3H), 2,92 was 3.05 (m, 1H), 4,06 (s,2H), 6,27 (s, 1H), 7,16-7,20 (m, 2H), 7,31-7,35 (m, 1H), 7,39-7,42 (m, 1H), 7,52-7,56 (m, 2H), 7,62-7,71 (m, 6H), 10,32 (s, 1H), 12,0 (s, 1H); MS (EEC) m/z 434 [M+H]+.

Example 32

[(1-{5-[4-({2-[(4-chlorophenyl)amino]-3,4-dioxocyclohex-1-EN-1-yl}amino)phenyl]-1,3-thiazol-2-yl}cyclobutyl)oxy]acetic acid

Example 32A

3-(4-chlorpheniramine)-4-amoxicillinum-3-ene-1,2-dione

To boiling under reflux a solution of 3,4-detoxicant-3-ene-1,2-dione (1,05 g, 6,14 mmol) in ethanol (25 ml) add a solution in ethanol (10 ml) of 4-Chloroaniline (0,784 g, 6,14 mmol) reciprocating pump within 2 hours of the Heating bath is removed and the reaction mixture was stirred at room temperature for 16 hours, the Reaction mixture was concentrated under reduced pressure and purified by chromatography on SiO2the gel elwira 50% ethyl acetate in hexane to obtain specified in the connection header. MS (EEC) m/z 252 [M+H]+.

Example 32B

[(1-{5-[4-({2-[(4-chlorophenyl)amino]-3,4-dioxocyclohex-1-EN-1-yl}amino)phenyl]-1,3-thiazol-2-yl}cyclobutyl)oxy]acetic acid

A solution of example 32A (0,063 g, 0,198 mmol) and example 24B (0,050 g, 0,198 mmol) is heated to 90°C for 16 hours, the Reaction mixture was cooled to room temperature and add 2 N NaOH (0.5 ml). After 16 h, the ethanol is removed under reduced pressure and the aqueous layer was acidified to pH 1 by adding 10% HCl. The solid is filtered, air-dried and cleaned OF ghvd (preparative liquid chromate what graphy high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV definition analyzed at 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 obtain the specified title compound as a white solid.1H NMR (500 MHz, DMSO-d6) δ h/1,72 million-of 1.95 (m, 2H), 2.40 a-2,49 (m, 4H), 3,93 (s, 2H) 7,40-7,47 (m, 2H), of 7.48-7,53 (m, 2H), 7,55 (m, 2H), 7,68 (m, 2H), 8,11 (s, 1H), 10,12 (m, 2H), 12,0 (s, 1H); MS (EEC) m/z 510 [M+H]+.

Example 33

{[1-(5-{4-[(anilinoacrolein)amino]phenyl}-4-methyl-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 33A

1-(5-iodine-4-methylthiazole-2-yl)Cyclopentanol

To a cold (-78°C) solution of 4-methylthiazole (2.0 ml, at 20.2 mmol) in tetrahydrofuran (130 ml) is added n-utility (8,10 ml, at 20.2 mmol, 2,48 M in hexane) dropwise. After 15 minutes add Cyclopentanone (1,79 ml, at 20.2 mmol) in one portion. After 30 minutes, add n-utility (8,10 ml, at 20.2 mmol, 2,48 M in hexane) dropwise. The reaction mixture is stirred for another 20 minutes, then add a solution of iodine (5,13 g, a 20.2 mmol) in tetrahydrofuran (15 ml) dropwise. Then the reaction mixture was quenched by addition of saturated aqueous Na2S2O3and ethyl acetate (100 ml) and heated to ambient temperature. The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×100 ml). The combined organic layers dried with anhydrous Na2 SO4, filtered and concentrated to obtain a dark solid. Rubbing the residue with hexane gives specified in the title compound as a beige solid. MS (EEC) m/z 310 [M+H]+.

Example 33B

Ethyl 2-(1-(5-iodine-4-methylthiazole-2-yl)cyclopentyloxy)acetate

To a suspension of NaH (0,808 g, a 20.2 mmol, 60% of the mass. in mineral oil) in N,N-dimethylformamide (40 ml) add example 33A (6,24 g, a 20.2 mmol). After 0.5 h add ethylbromoacetate (2,23 ml, at 20.2 mmol) and the reaction mixture is stirred for 16 hours the Reaction mixture is divided between the H2O (50 ml) and ethyl acetate (50 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×50 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira 5% ethyl acetate in hexane, to obtain specified in the connection header. MS (EEC) m/z 396 [M+H]+.

Example 33C

{[1-(5-{4-[(anilinoacrolein)amino]phenyl}-4-methyl-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

A solution of example 33B (0,090 g, 0,228 mmol), example 26A (0,077 g, 0,228 mmol), CsF (0.104 g g 0,684 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,027 g, is 0.023 mmol) in a mixture of solvents dimethoxyethane (1 ml) and methanol (1 ml) heated to 90°C for 16 hours, the Reaction mixture is cooled to a warm temperature the tours and diluted with H 2O (2 ml). The solid is filtered, washed with diethyl ether and air-dried to obtain an intermediate of ester. Ester dissolved in a mixture of methanol (8 ml) and 2N NaOH (1 ml) and stirred for 16 hours, the Methanol is removed under reduced pressure and the aqueous layer washed with diethyl ether (5 ml). The aqueous layer was acidified to pH 1 by adding 10% HCl. The obtained solid is filtered, washed with CH3CN, air-dried and cleaned OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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 obtain the specified title compound as a white solid.1H NMR (500 MHz, DMSO-d6) δ h/of 1.66 million-1,90 (m, 4H), 2,03-of 2.16 (m, 4H), 2.40 a (s, 3H), 3,92 (s, 2H), 6,98 (t, J=of 7.48 Hz, 1H), 7.24 to 7,32 (m, 2H), 7,40 (m, 2H), 7,46 (m, 2H), 7,55 (m, 2H), 8,71 (s, 1H), cent to 8.85 (s, 1H), 12,38-12,80 (s, 1H); MS (EEC) m/z 452 [M+H]+.

Example 34

{[1-(4-methyl-5-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 34 receive according to the method of example 33C, substituting example 26A example 18A.1H NMR (500 MHz, DMSO-d6) δ h/1,69 million-a 1.88 (m, 4H), 2,03 with 2.14 (m, 4H), 2,36 is 2.43 (m, 3H), 3,92 (who, 2H), 7,29-7,35 (m, 1H), 7,39-7,44 (m, 2H), 7,50-of 7.55 (m, 2H), 7,55 to 7.62 (m, 2H), 8,02 (s, 1H), 8,99 (s, 1H), 9,11 (s, 1H); MS (EEC) m/z 521 [M+H]+.

Example 35

{[1-(5-{6-[(anilinoacrolein)amino]pyridine-3-yl}-4-methyl-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 35 receive according to the method of example 33C, substituting example 26A example 28A.1H NMR (500 MHz, DMSO-d6) δ h/1,64 million-of 1.92 (m, 4H), 2,11 (t, J=5,34 Hz, 4H), to 2.41 (s, 3H), of 3.94 (s, 2H), 6,91-7,11 (m, 1H), 7.24 to 7,37 (m, 2H), 7,46-EUR 7.57 (m, 2H), 7,60-7,73 (m, 1H), 7,81-to 7.93 (m, 1H), 8,32-8,46 (m, 1H), of 9.56 (s, 1H), of 10.21 (s, 1H) ; MS (EEC) m/z 453 [M+H]+.

Example 36

{[1-(4-methyl-5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 36 receive according to the method of example 33C, substituting example 26A example 29A.1H NMR (500 MHz, DMSO-d6) δ h/1,67 million is 1.91 (m, 4H), 2,02-2,17 (m, 4H), 2,33 is 2.46 (m, 3H), 3,91-of 3.97 (m, 2H), was 7.36-7,40 (m, 1H), 7,49 to 7.62 (m, 1H), to 7.61 to 7.75 (m, 2H), of 7.90-a 7.92 (m, 1H), of 8.09 (s, 1H), 8,44 (s, 1H), to 9.70 (s, 1H), or 10.60 (s, 1H); MS (EEC) m/z 521 [M+H]+.

Example 37

{[1-(5-{6-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 37A

1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)urea

Example 37A receive according to the method of example 28A, substituting phenylisocyanate 2-fluoro-5-triftormetilfullerenov. MS (EEC) m/z 426 [M+H]+.

Example 37B

{[1-(5-{6-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}ka is bonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

Example 37B receive according to the method of example 33C, substituting example 26A example 37A and substituting example 33B example 23A.1H NMR (300 MHz, DMSO-d6) δ h/1,65 million is 1.91 (m, 4H), 2.06 to 2,19 (m, 4H), to 3.92 (s, 2H), 7,43-7,49 (m, 1H), 7,51-to 7.59 (m, 1H), to 7.59-to 7.68 (m, 1H), 8,08 (m, 1H), 8,15 (s, 1H), 8,56-8,63 (m, 1H), 8,63-to 8.70 (m, 1H), to 10.09 (s, 1H), 10,75 (s, 1H); MS (EEC) m/z 584 [M+H]+.

Example 38

2-{[l-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}propanoic acid

Example 38A

Ethyl 2-(1-(5-iodiesel-2-yl)cyclopentyloxy)propanoate

Example 38A receive according to the method of example 22A, replacing itmean 2-bromopropane. MS (EEC) m/z 396 [M+H]+.

Example 38B

2-{[1-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}propanoic acid

A solution of example 38A (0,040 g, 0,101 mmol), example 29A (0,041 g, 0,101 mmol), CsF (0,046 g, 0,304 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,0120 g 0,010 mmol) in a mixture of solvents dimethoxyethane (0.5 ml) and methanol (0.5 ml) is heated to 90°C for 16 hours, the Reaction mixture was cooled to room temperature and diluted with H2O (2 ml). The solid is filtered, washed with diethyl ether and air-dried to obtain an intermediate of ester. Ester is dissolved in methanol (2 ml) and 2N NaOH (0.3 ml) and stirred for 16 hours, the Methanol is removed under reduced pressure and the aqueous layer was washed with IER the silt ether (2 ml). The aqueous layer was acidified to pH 1 by adding 10% HCl. The solid is filtered, washed with CH3CN, air-dried and cleaned OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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 obtain the specified title compound as a white solid.1H NMR (300 MHz, DMSO-d6) δ h/million of 1.25 (d, J=is 6.78 Hz, 3H), 1,64-of 1.78 (m, 2H), 1,80-of 1.92 (m, 2H), 1,96-to 2.18 (m, 3H), 2,21 of-2.32 (m, 1H), 3,84-4,00 (m, 1H), 7,32-7,42 (m, 1H), 7,50-of 7.60 (m, 2H), of 7.64-7,72 (m, 2H), 8,03-to 8.12 (m, 2H), 8,12 (s, 1H), 8,51-to 8.70 (m, 1H), to 9.70 (s, 1H), 10,51 (s, 1H); MS (EEC) m/z 521 [M+H]+.

Example 39

2-{[1-(5-{6-[(anilinoacrolein)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}propanoic acid

Example 39 receive according to the method of example 38B, replacing the example 29A example 28A.1H NMR (300 MHz, DMSO-d6) δ h/million of 1.25 (d, J=is 6.78 Hz, 3H), 1,63-of 1.78 (m, 2H), 1,80-of 1.92 (m, 2H), 1.93 and-2,04 (m, 2H), 2,04-to 2.18 (m, 2H), 2,20-of 2.33 (m, 1H), 3,90-3,95 (m, 1H), 7,35-7,41 (m, 1H), 7,54-7,58 (m, 2H), 7,63-7,72 (m, 2H), 8,05-8,11 (m, 2H), 8,12 (s, 1H), 8,59-8,66 (m, 1H), to 9.70 (s, 1H); MS (EEC) m/z 521 [M+H]+.

Example 40

{[1-(5-{4-[(7-methyl-1,3-benzoxazol-2-yl)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid

A solution of example 4B (0.20 g, or 0.57 mmol), example 23A (to 0.19 g, 0.5 mmol), CsF (0.26 g, 1,71 mmol) and tetrakis(triphenylphosphine)palladium(0) (of 0.066 g, 0,057 mmol) in a mixture of solvents dimethoxyethane (1 ml) and methanol (1 ml) heated to 90°C for 16 hours, the Reaction mixture was cooled to room temperature and diluted with H2O (5 ml). the solid is filtered, air-dried. The solid is dissolved in tetrahydrofuran (10 ml) and methanol (10 ml) and add 2 N NaOH (2 ml). After 16 h, the organic layers are removed under reduced pressure and the aqueous layer was acidified to pH 1 by adding 10% HCl. The solid is filtered, air-dried and cleaned OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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 obtain the specified title compound as a white solid.1H NMR (500 MHz, DMSO-d6) δ h/million of 1.65-1.77 in (m, 2H), 1,76-1,89 (m, 2H), 2,08-of 2.20 (m, 4H), of 2.44 (s, 3H), 3,91 (s, 2H), 6,85-7,02 (m, 1H), 7,10-7,19 (m, 1H), 7,22 and 7.36 (m, 1H), to 7.59-7,70 to 7.75 (m, 2H), to 7.77-7,88 (m, 2H), 7,94-with 8.05 (m, 1H), 10,87 (s, 1H); MS (EEC) m/z 482 [M+H]+.

Example 41

N-(4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}-2-[3-(trifluoromethyl)phenyl]ndimethylacetamide

A solution of example 11B (0.025 g, 0,091 mmol), 2-(3-(trifluoromethyl)phenyl)who kusnoy acid is 0.019 g, 0,091 mmol), hydrochloride of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide is 0.019 g, 0.10 mmol), hydrate of 1-hydroxybenzotriazole (0,013 g, 0.10 mmol) and N-methylmorpholine (0,050 ml, 0.46 mmol) in N,N-dimethylformamide (1 ml) is heated to 55°C for 16 hours, the Reaction mixture was cooled to room temperature and diluted with ethyl acetate (2 ml) and H2O (2×1 ml). The layers are separated and the organic layer was washed with saturated salt solution (1×1 ml), dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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 obtain the specified title compound as a white solid.1H NMR (300 MHz, DMSO-d6) δ h/of 1.66 million-1,72 (m, 2H), is 2.09 and 2.13 (m, 2H), 3,67-of 3.78 (m, 5H), 3,80 (s, 2H), EUR 7.57-7,71 (m, 8H), to 7.99 (s, 1H), 10,36 (s, 1H); MS (EEC) m/z 463 [M+H]+.

Example 42

2-(2,4-differenl)-N-{4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}ndimethylacetamide

Example 42 receive according to the method of example 41, substituting 2-(3-(trifluoromethyl)phenyl)acetic acid 2-(2,4-differenl)acetic acid.1H NMR (300 MHz, DMSO-d6 ) δ h/of 1.66 million is 1.70 (m, 2H), is 2.09 and 2.13 (m, 2H), 3.72 points is 3.76 (m, 7H), 7,02-was 7.08 (m, 1H), 7,20-7,24 (m, 1H), 7,40-of 7.48 (m, 1H), 7,54-to 7.67 (m, 4H), of 8.00 (s, 1H), 10,34 (s, 1H); MS (EEC) m/z 431 [M+H]+.

Example 43

2-(2,5-differenl)-N-{4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}ndimethylacetamide

Example 43 receive according to the method of example 41, substituting 2-(3-(trifluoromethyl)phenyl)acetic acid 2-(2,5-differenl)acetic acid.1H NMR (300 MHz, DMSO-d6) δ h/of 1.66 million is 1.70 (m, 2H), 2.06 to of 2.16 (m, 2H), 3,74-of 3.78 (m, 7H), 7,15-7,30 (m, 3H), EUR 7.57-to 7.67 (m, 4H), of 8.00 (s, 1H), 10,36 (s, 1H); MS (EEC) m/z 431 [M+H]+.

Example 44

[(1-{5-[4-(benzoylamine)phenyl]-1,3-thiazol-2-yl}cyclobutyl)oxy]acetic acid

A solution of N,N-dimethylformamide (1 ml) of example 24B (0.025 g, 0,079 mmol), benzoic acid (0,011 g, 0,087 mmol), hydrochloride of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (0.015 g, 0,079 mmol), hydrate of 1-hydroxybenzotriazole (0,011 g 0,079 mmol) and N-methylmorpholine (0,345 ml, 0,314 mmol) is heated to 55°C for 16 hours the Solution is cooled to room temperature and diluted with ethyl acetate (2 ml) and H2O (2 ml). The layers are separated and the organic layer was washed with saturated salt solution (1×1 ml), dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is dissolved in methanol (2 ml) and add 2,5M NaOH (0.95 ml, 0,237 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated under reduced pressure and, and clear OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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 obtain the specified title compound as a white solid.1H NMR (300 MHz, methanol-d4) δ h/1,83 million-of 1.93 (m, 1H), 1,95-2,05 (m, 1H), 2,53-to 2.67 (m, 5H), to 3.99 (s, 2H), 7,49-of 7.60 (m, 4H), 7,63-to 7.67 (m, 2H), 7,81 (m, 2H), 7,92-7,94 (m, 2H), of 7.97 (s, 1H); MS (EEC) m/z 409 [M+H]+.

Example 45

({1-[5-(4-{[(3-forfinal)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid

Example 45 receive according to the method of example 44, substituting benzoic acid 2-(3-forfinal)acetic acid.1H NMR (300 MHz, methanol-d4) δ h/million 1,81-of 1.92 (m, 1H), 1.93 and-2,05 (m, 1H), 2,50-to 2.65 (m, 5H), 3,71 (s, 2H), 3,94-3,98 (m, 2H), 7,00 (m, 1H), 7,09-7,19 (m, 2H), 7,34 (m, 1H), 7,56-to 7.67 (m, 5H), to 7.93 (s, 1H); MS (EEC) m/z 441 [M+H]+.

Example 46

({1-[5-(4-{[4-(trifluoromethyl)benzoyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid

Example 46 receive according to the method of example 44, substituting benzoic acid 4-(trifluoromethyl)benzoic acid.1H NMR (300 MHz, methanol-d4) δ h/million of 1.88 (m, 1H), 1,95-2,05 (m, 1H), of 2.51-of 2.66 (m, 5H), 3,98 (s, 2H), 7,66 (m, 2H), 7,80-7,86 (m, 5H), 7,98 (s, 1H), 8,11 (m, 2H); MS (EEC) m/z 477 [M+H]+.

Note the p 47

[(1-{5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]acetyl}amino)phenyl]-1,3-thiazol-2-yl}cyclobutyl)oxy]acetic acid

Example 47 receive according to the method of example 44, substituting benzoic acid 2-(2-fluoro-5-(trifluoromethyl)phenyl)acetic acid.1H NMR (300 MHz, methanol-d4) δ h/million to 1.87 (m, 1H), 1.93 and-2,05 (m, 1H), 2,49-of 2.64 (m, 5H), a 3.87 (s, 2H), of 3.97 (s, 2H), 7,31 (m, 1H), EUR 7.57-to 7.68 (m, 6H), to 7.75 (m, 1H), 7,94 (s, 1H); MS (EEC) m/z 509 [M+H]+.

Example 48

{[1-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-oxazol-2-yl)cyclopentyl]oxy}acetic acid

Example 48A

1-(oxazol-2-yl)Cyclopentanol

With the ambient temperature of the solution oxazole (1,00 g, 14.5 mmol) and borane complex·tetrahydrofuran (of 14.5 ml, 14.5 mmol, 1 M in tetrahydrofuran) and stirred for 30 minutes, the Reaction mixture was cooled to -78°C. and add n-utility in 9.5 ml of 15.2 mmol, of 1.6 M in hexane) dropwise. After 30 minutes add Cyclopentanone (1,42 ml, 16.0 mmol) dropwise. After 30 minutes, a cold (-78°C.) mixture is quenched by addition of 5% acetic acid in ethanol (70 ml) and warmed to room temperature. The solution was diluted with diethyl ether (100 ml) and saturated NaHCO3(50 ml). The layers are separated and the organic layer was washed with saturated salt solution (1×50 ml), dried over Na2SO4concentrate under reduced pressure and purified by chromatography on SiO2the gel elwira 50% ethyl acetate in g is the Ksan, obtaining specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/1,59 million-1,71 (m, 2H), 1,72-of 1.84 (m, 2H), 1,84 is 1.96 (m, 2H), 1,98-of 2.09 (m, 2H), of 5.40 (s, 1H), 7,11 (s, 1H), 8,02 (s, 1H).

Example 48B

1-(5-iodixanol-2-yl)Cyclopentanol

To a cold (-78°C) solution of example 48A (500 mg, 3,26 mmol) in tetrahydrofuran (50 ml) is added n-utility (4,08 ml, 6,53 mmol, 1,6M in hexane) dropwise. After stirring for 30 min add iodine solution (0,829 g, 3,26 mmol) in tetrahydrofuran (5 ml) dropwise. After 2 h the reaction mixture was quenched by adding 10% Na2S2O3solution (10 ml) and ethyl acetate (10 ml) and warmed to room temperature. The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×50 ml). The combined organic layers washed with saturated salt solution (1×50 ml), dried over Na2SO4concentrate under reduced pressure and purified by chromatography on SiO2the gel elwira 50% ethyl acetate in hexane, to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/million of 1.65 (s, 2H), 1,79 (s, 2H), 1,89 (s, 2H), 2,02 (s, 2H), 5,50 (s, 1H), 7,22 (s, 1H).

Example 48C

Ethyl 2-(1-(5-iodixanol-2-yl)cyclopentyloxy)acetate

Example 48C receive according to the method of example 24A, replacing the example 19A example 48V.1H NMR (300 MHz, DMSO-d6) δ h/million 1,14-1,17 (m, 3H), 1,59 by 1.68 (m, 2H), 1,71-of 1.81 (m, 2H), 2,03-2,11 (m, 4H), to 3.92 (s, 2H), 3,99-4,06 (m, 2H), 7,28 (s, 1H).

{[1-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-oxazol-2-yl)cyclopentyl]oxy}acetic acid

A solution of example 48C (0,103 g, 0,282 mmol), example 29A (0,115 g, 0,282 mmol), CsF (0,129 g, 0,847 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,033 g 0,028 mmol) in dimethoxyethane (2 ml) and ethanol (1 ml) was heated by microwave irradiation to 150°C for 5 minutes and Then the reaction mixture was concentrated under reduced pressure. The residue is purified OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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 obtain the intermediate of ester. Ester is dissolved in methanol (2 ml) and add 2,5M NaOH (0,340 ml). After 16 h, the organic layers are removed under reduced pressure. The aqueous layer was acidified to pH 1 by adding 10% HCl. The solid is filtered, washed with CH3CN and dried to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/1,67 million (m, 2H), equal to 1.82 (m, 2H), 2,12-2,22 (m, 4H), to 3.92 (s, 2H), 7,38 (m, 1H), 7,52-of 7.60 (m, 1H), to 7.61 (s, 1H), 7,69 (m, 2H), 8,06-8,10 (m, 2H), 8,69 (m, 1H), 9,74 (s, 1H), 10,52 (s, 1H), 12,45 (s, 1H); MS (EEC) m/z 491 [M+H]+.

Example 49

({1-[5-(4-{[(2,5-differenl)acetyl]amino}f the Nile)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid

Example 49 receive according to the method of example 44, substituting benzoic acid 2-(2,5-differenl)acetic acid.1H NMR (300 MHz, DMSO-d6) δ h/1,73 million of-1.83 (m, 1H), 1,83-of 1.94 (m, 1H), 2,43-2,48 (m, 4H), 3.75 to with 3.79 (m, 2H), 3,93 (s, 2H), 7,15-7,31 (m, 3H), to 7.59-of 7.69 (m, 4H), 8,07 (s, 1H), 10,37 (s, 1H), 12,66 (s, 1H); MS (EEC) m/z 459 [M+H]+.

Example 50

({1-[5-(4-{[(3,5-differenl)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid

Example 50 receive according to the method of example 44, substituting benzoic acid 2-(3,5-differenl)acetic acid.1H NMR (300 MHz, DMSO-d6) δ h/1,73 million-of 1.84 (m, 1H), 1,84-of 1.93 (m, 1H), 2,41-2,48 (m, 4H), to 3.73 (s, 2H), 3,93 (s, 2H), 7.03 is-7,17 (m, 3H), to 7.59-of 7.69 (m, 5H), of 8.06 (s, 1H), 10,34 (s, 1H); MS (EEC) m/z 459 [M+H]+.

Example 51

({1-[5-(4-{[(3,4-differenl)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid

Example 51 receive according to the method of example 44, substituting benzoic acid 2-(3,4-differenl)acetic acid.1H NMR (300 MHz, DMSO-d6) δ h/1,73 million of-1.83 (m, 1H), 1,83-of 1.94 (m, 1H), 2,41-2,48 (m, 4H), of 3.69 (s, 2H), 3,93 (s, 2H), 7,17 (m, 1H), 7,34-the 7.43 (m, 2H), to 7.59-of 7.69 (m, 5H), of 8.06 (s, 1H), 10,32 (s, 1H); MS (EEC) m/z 459 [M+H]+.

Example 52

{[1-(4-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}phenyl)cyclopentyl]oxy}acetic acid

Example 52 receive according to the method of example 30D substituting example example 28A 29A.1H NMR (300 MHz, DMSO-d6) δ h/1,71 million (s, 2H), 1,79 is 1.91 (m, 4H), 2,08-to 2.18 (m, 2H), 3,63 (s, 2H), was 7.36-7,40 (m, 1H), 7,50-of 7.55 (m, 2H), 7,55-760 (m, 1H), 7,62-the 7.65 (m, 1H), to 7.67-7,71 (m, 3H), 8.07-a 8,13 (m, 2H), 8,64-8,68 (m, 1H), for 9.64 (s, 1H), of 10.72 (s, 1H), 12,42 (s, 1H); MS (EEC) m/z 500 [M+H]+.

Example 53

2-(1-(2-fluoro-4-(6-(3-(3-(trifluoromethyl)phenyl)ureido)pyridine-3-yl)phenyl)CYCLOBUTANE)acetic acid

Example 53A

Methyl 4-bromo-2-perbenzoate

With the ambient temperature suspension of 4-bromo-2-fermenting acid (15.0 g, 68,5 mmol), iodomethane (21,0 ml, 342,5 mmol) and potassium carbonate (19,0 g, 137 mmol) in N,N-dimethylformamide (200 ml) was stirred at room temperature for 16 h, then diluted with ethyl acetate (200 ml) and water (100 ml). The layers are separated and the organic layers washed with water (3×100 ml) and saturated salt solution (1×100 ml), dried over sodium sulfate and concentrate under reduced pressure. The residue is passed through a layer of SiO2gel, elwira 50% ethyl acetate in hexane, to obtain specified in the connection header in the form of solids. MS (EEC) m/z 233 [M+H]+.

Example 53B

1-(4-bromo-2-forfinal)Cyclopentanol

In 100 ml 3N round-bottomed flask is charged with magnesium (0,700 mg of 23.8 mmol) and tetrahydrofuran (30 ml). The suspension is stirred and cooled to 0°C. Slowly add 1,4-dibromobutane (1.65 ml, 13,94 mmol) and the solution warmed to room temperature. After 30 minutes the solution is cooled to 0°C and add the example 53A (1,00 g, the 4.29 mmol) in tetrahydrofuran (10 ml) dropwise. After 30 min the solution is heated to room the first temperature and stirred for further 1 h The solution is quenched by careful addition of saturated NH4Cl and ethyl acetate (50 ml). The layers are separated and the organic layers washed with water (2×50 ml) and saturated salt solution (1×50 ml), dried over anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira 3% ethyl acetate in hexane, to obtain specified in the connection header. MS (EEC) m/z 259 [M+H]+.

Example 53C

2-(1-(4-bromo-2-forfinal)cyclopentyloxy)acetic acid

Example 53C receive according to the method of example 30B, replacing the example 30A example 53B. MS (EEC) m/z 317 [M+H]+.

Example 53D

2-(1-(2-fluoro-4-(6-(3-(3-(trifluoromethyl)phenyl)ureido)pyridine-3-yl)phenyl)CYCLOBUTANE)acetic acid

A mixture of example 29A (0,37 g, 0.31 mmol), example 53C (0,29 g, 0.31 mmol), potassium phosphate (0,474 g, 2,73 mmol) and dichloride 1,1'-bis(di-tert-butylphosphino)ferienparadies(II) (0.03 g, 0.05 mmol)in a solvent mixture of 2:2:1 N,N-dimethylformamide/ethanol/water (10 ml) heated to 90°C for 1 h, the Reaction mixture was cooled to room temperature and stirred for 16 h the resulting suspension was poured in water (200 ml) and acidified with 1M HCl to pH 1. The solid is filtered, washed with water, dried and cleaned OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV ODA is division, analyzed at 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 obtain the specified title compound as a white solid.1H NMR (300 MHz, DMSO-d6) δ h/1,63 million is 1.75 (m, 2H), 1.77 in-of 1.97 (m, 4H), 2,25-to 2.40 (m, 2H), to 3.67 (s, 2H), 7,32-7,42 (m, 1H), 7,49-7,63 (m, 4H), 7,63-7,72 (m, 2H), 8,02-8,11 (m, 1H), 8,12 were 8.22 (m, 1H), 8,64 is 8.75 (m, 1H), RS 9.69 (s, 1H), for 10.68 (s, 1H); MS (EEC) m/z 518 [M+H]+.

Example 54

1-(5-(4-(4-oxa-1-azabicyclo[3.2.1]Octan-5-yl)phenyl)pyridin-2-yl)-3-prilocaine

Example 54A

Tert-butyl 3-(4-bromophenyl)-3-hydroxypyrrolidine-1-carboxylate

To a cold (-78°C) solution of 1,4-dibromobenzene with (to 3.89 g, 16,49 mmol) in tetrahydrofuran (80 ml) is added n-utility (10.3 ml, 16.5 mmol, of 1.6 M in hexane) dropwise. After 15 minutes, add a solution of tert-butyl 3-oxopyrrolidin-1-carboxylate (3,05 g, 16,49 mmol) in tetrahydrofuran (10 ml) for 5 minutes. The reaction mixture is still stirred at -78°C for 15 minutes and then quenched by addition of saturated NH4Cl (150 ml) and diethyl ether (150 ml). After heating to room temperature, the layers separated and the aqueous layer was extracted with additional diethyl ether (2×100 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue cleaned the Ute IHSD (10% ethyl acetate in hexane to 50% ethyl acetate in hexane) to obtain specified in the connection header. MS (EEC) m/z 342 [M+H]+.

Example 54B

Tert-butyl 3-(4-bromophenyl)-3-(2-ethoxy-2-oksidoksi)pyrrolidin-1-carboxylate

Example 51B receive according to the method of example 33B, replacing the example 33A example 54A. MS (EEC) m/z 428 [M+H]+.

Example 54C

Tert-butyl 3-(4-bromophenyl)-3-(2-hydroxyethoxy)pyrrolidin-1-carboxylate

To have an ambient temperature solution of example 54B (0,530 g of 1.24 mmol) in methanol (5 ml) is added NaBH4(0,188 g, 4,96 mmol). The reaction mixture was stirred for 1 h and then quenched by addition of water (20 ml) and ethyl acetate (20 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×20 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure to obtain specified in the title compound, which was used in the next stage without further purification. MS (EEC) m/z 386 [M+H]+.

Example 54D

Tert-butyl 3-(4-bromophenyl)-3-(2-(tosyloxy)ethoxy)pyrrolidin-1-carboxylate

To have an ambient temperature solution of example 54C (0,450 g at 1.17 mmol), triethylamine (0,178 ml, 1.28 mmol) and 4-dimethylaminopyridine (0.005 g, 0,041 mmol) in dichloromethane (3 ml) is added chloride p-toluensulfonate (0,224 g at 1.17 mmol). The reaction mixture was stirred at room temperature for 8 h and then separated between water (10 ml) and diethyl ether (1 ml). The layers are separated and the aqueous layer was extracted with additional diethyl ether (2×10 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified IHSD (10% ethyl acetate in hexane to 25% ethyl acetate in hexane) to obtain specified in the connection header. MS (EEC) m/z 541 [M+H]+.

Example 54E

5-(4-bromophenyl)-4-oxa-1-azabicyclo[3.2.1]Octan

To have an ambient temperature solution of example 54D (0,100 g, 0,186 mmol) in dichloromethane (1 ml) add triperoxonane acid (0.5 ml). The reaction mixture was stirred for 0.5 h, and the solution is then carefully added to a suspension of K2CO3(3.0 g, and 21.7 mmol) in dichloromethane (10 ml). After completion of gas evolution, the mixture is heated to 40°C for 1 h the Mixture is cooled to room temperature and diluted with water (10 ml). The layers are separated and the aqueous layer was extracted with additional dichloromethane (2×10 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure to obtain specified in the connection header, which is used in the next stage without further purification. MS (EEC) m/z 268 [M+H]+.

Example 54F

1-(5-(4-(4-oxa-1-azabicyclo[3.2.1]Octan-5-yl)phenyl)pyridin-2-yl)-3-prilocaine

A solution of example 54E (0,048 g, 0.18 mmol), example 28A (,063 g, 0.18 mmol), CsF (of 0.085 g, 0,559 mmol) and tetrakis(triphenylphosphine)palladium(0) (0,020 g of 0.017 mmol) in a mixture of solvents dimethoxyethane (0.5 ml) and methanol (0.5 ml) is heated to 90°C for 16 hours, the Reaction mixture was cooled to room temperature and diluted with H2O (2 ml) and ethyl acetate (2 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×2 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV determination, analyzed at 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). The fractions containing the desired product was diluted with saturated aqueous NaHCO3and extracted with ethyl acetate. The organic layer is dried with anhydrous Na2SO4filter and concentrate under reduced pressure to obtain specified in the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) δ h/2,09 million-2,17 (m, 1H), 2,27-of 2.38 (m, 1H), 2,53-2,61 (m, 1H), 2,81-is 2.88 (m, 1H), 2.91 in are 2.98 (m, 2H), 3,02-to 3.09 (m, 1H), 3,10-3,18 (m, 1H), 3,69-with 3.79 (m, 1H), 3,94-a 4.03 (m, 1H), 6,99-7,07 (m, 1H), 7,28-7,38 (m, 2H), of 7.48-EUR 7.57 (m, 4H), 7,60-of 7.69 (m, 3H), 8,02-to 8.12 (m, 1H), 8,53 and 8.6 (m, 1H), 9,45-9,58 (m, 1H), 10,31-10,44 (m, 1H); MS (EEC) m/z 401 [M+H]+.

Example 55

2-(1-(3-fluoro-4-(6-(3-(3-(trifluoromethyl)phenyl)ureido)pyridine-3-yl)phenyl)cyclopentyloxy)acetic acid

Example 55A

1-(4-chloro-3-forfinal)Cyclopentanol

Example 58A receive according to the method of example 30A, substituting 1,4-dibromobenzyl 1-bromo-3-fluoro-4-chlorobenzene. MS (EEC) m/z 215 [M+H]+.

Example 55B

2-(1-(4-chloro-3-forfinal)cyclopentyloxy)acetic acid

Example 55B receive according to the method of example 30B, replacing the example 30A example 55A. MS (EEC) m/z 273 [M+H]+.

Example 55C

2-(1-(3-fluoro-4-(6-(3-(3-(trifluoromethyl)phenyl)ureido)pyridine-3-yl)phenyl)cyclopentyloxy)acetic acid

A mixture of example 55B (0,094 g, 0,346 mmol), example 29A (0,141 g, 0,346 mmol), K3PO4(0,220 g, 1.04 mmol), DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (0,019 g, 0.046 mmol) and Tris(dibenzylideneacetone)diplegia(0) (to 0.011 g, 0.012 mmol) in a solvent mixture of N,N-dimethylformamide/1-butanol/H2O (2/2/1, 1 ml) heated to 90°C for 15 hours the Solution is cooled to room temperature and diluted with 10% HCl (1 ml) and ethyl acetate (1 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×2 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified OF ghvd (preparative liquid chromatography high pressure with bresennol phase) using column Bond SB-C18 7M of 21.2×250 mm, UV definition analyzed at 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 obtain the specified title compound as a white solid.1H NMR (300 MHz, DMSO-d6) δ h/million of 1.66-1.77 in (m, 2H), 1,80 is 1.91 (m, 4H), 2.05 is-to 2.18 (m, 2H), 3,69 (s, 2H), 7,30-7,41 (m, 3H), 7,50-to 7.64 (m, 2H), of 7.64-7,73 (m, 2H), 7,94-8,03 (m, 1H), of 8.09 (s, 1H), of 8.47-8,56 (m, 1H), RS 9.69 (s, 1H), 10,65 (s, 1H); MS (EEC) m/z 518 [M+H]+.

Example 56

2-(1-(3-fluoro-4-(6-(3-(3-(trifluoromethyl)phenyl)ureido)pyridine-3-yl)phenyl)CYCLOBUTANE)acetic acid

Example 56A

1-(4-chloro-3-forfinal)cyclobutanol

To a cold (-78°C) solution of 4-bromo-1-chloro-2-fervently (2,99 g, 14,27 mmol) in tetrahydrofuran (50 ml) is added n-utility (5,71 ml, 14,27 mmol, 2.5 m in hexane) in 5 minutes. The reaction mixture was stirred at -78°C for 15 min and add tibetano (1.0 g, 14,27 mmol) dropwise. After 15 minutes the reaction mixture was quenched by addition of saturated aqueous NH4Cl (50 ml) and diethyl ether (50 ml). The layers are separated and the aqueous layer was extracted with additional diethyl ether (2×50 ml). The combined organic layers dried with anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue is purified OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the application of the m columns of Bond SB-C18 7M of 21.2×250 mm, UV definition analyzed at 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 obtain the specified header connection in the form of solids. MS (EEC) m/z 201 [M+H]+.

Example 56B

2-(1-(4-chloro-3-forfinal)CYCLOBUTANE)acetic acid

To have the ambient temperature suspension of NaH (0,341 g, charged 8.52 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide (7 ml) add a solution of example 56A (0,342 g, 1,71 mmol) in N,N-dimethylformamide (1 ml) dropwise. The reaction mixture was stirred for 0.5 h and add 2-bromoxynil acid (0,474 g to 3.41 mmol) as a solution in N,N-dimethylformamide (2 ml) dropwise. The reaction mixture was stirred at room temperature for 24 h and then quenched by slow addition of H2O (10 ml) and diethyl ether (15 ml). The layers are separated and the organic layer discarded. The aqueous layer was acidified to pH ~4-5 by adding 10% HCl and extracted with diethyl ether (3×15 ml). The combined organic layers are dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a yellow oil which is used without further purification in the next stage. MS (EEC) m/z 259 [M+H]+.

Example 56C

2-(1-(3-fluoro-4-(6-(3-(3-(trifluoromethyl)phenyl)ureido)pyridine-3-yl)phenyl)CEC is butoxy)acetic acid

Example 56C receive according to the method of example 55C, replacing the example 55V example 56B.1H NMR (300 MHz, DMSO-d6) δ h/1,56 million-of 1.74 (m, 1H), 1,84 is 2.01 (m, 1H), 2,33 at 2.45 (m, 4H), 3,68 (s, 2H), 7,34-7,44 (m, 3H), 7,52-to 7.64 (m, 2H), of 7.64-7,73 (m, 2H), 7.95 is-with 8.05 (m, 1H), of 8.09 (s, 1H), charged 8.52-to 8.57 (m, 1H), 9,67 (s, 1H), at 10.64 (s, 1H); MS (EEC) m/z 504 [M+H]+.

Example 57

[(1-{5-[4-({[(2-forfinal)amino]carbonyl}amino)phenyl]pyridine-2-yl}cyclopentyl)oxy]acetic acid

Example 57A

1-(5-(4-Nitrophenyl)pyridine-2-yl)Cyclopentanol

To a cold (-20°C solution of 5-bromo-2-iopidine (10 g, 35,22 mmol) in tetrahydrofuran (50 ml) is added chloride Isopropylamine (20 ml, 38,74 mmol, 2 M solution in tetrahydrofuran) dropwise over 10 minutes. Heated to 0°C for 1 hour and then cooled to -15°C. a Solution of Cyclopentanone (2.7 ml, 30 mmol) in tetrahydrofuran (25 ml) is added dropwise and the reaction mixture is heated to 15°C for 3 hours. Then the reaction mixture was quenched by adding dropwise a saturated aqueous NH4Cl. The layers are separated and the aqueous layer was extracted with ethyl acetate (3×30 ml). The combined organic layers washed with water, saturated salt solution, dried with anhydrous MgSO4filter and concentrate under reduced pressure to obtain the crude alcohol, which is used in the next stage without further purification.

A mixture of the crude alcohol (1,05 g, 4,34 mmol), pinacolato ether 4-nitrophenylazo the OIC acid (1.4 g, 5,64 mmol), potassium fluoride (0,76 g, 13 mmol) and tetrakis(triphenylphosphine)palladium (0.87 g, 0.43 mmol) in a mixture of solvents (dimethoxyethan:atenol:water:toluene, 10:6:3:1, 50 ml) was heated to 90°C for 10 hours. The reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate (3×50 ml). The combined organic layers washed with water, saturated salt solution, dried with anhydrous MgSO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2(30% ethyl acetate in hexane) to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/1,70 million-to 1.82 (m, 4H), 1,84-of 1.93 (m, 2H), 2,08-to 2.18 (m, 2H), 5,15 (s, 1H), 7,81 (m, 1H), 8,02 (m, 2H), 8,17 (m, 1H), 8,32 (m, 2H), 8,91 (m, 1H).

Example 57B

Methyl 2-(1-(5-(4-nitrophenyl)pyridine-2-yl)cyclopentyloxy)acetate

To have the ambient temperature suspension of sodium hydride (0.2 g, 60% suspension in mineral oil, is 4.85 mmol) in N,N-dimethylformamide (3 ml) add a solution of example 57A (and 0.46 g, 1.6 mmol) in N,N-dimethylformamide (4 ml) at room temperature. After 20 minutes add allylbromide (0,42 ml, is 4.85 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched by addition of saturated aqueous NH4Cl. The layers are separated and the aqueous layer was extracted with ethyl acetate (3×50 ml). The combined organic CL and washed with water, saturated salt solution, dried with anhydrous MgSO4filter and concentrate under reduced pressure to get crude allyl ether, which is used in the next stage without further purification.

The crude product from the previous stage is dissolved in glacial acetic acid (20 ml) and added dropwise to a cold (0°C.) solution of potassium permanganate (1 g, 6,44 mmol) in water (20 ml). The reaction mixture was warmed to room temperature for 20 minutes and then quenched by the addition of benzene (25 ml) and solid sodium sulfite (15 g). A two-phase mixture is acidified to pH 3 by addition of 3N HCl and extracted with ethyl acetate (3×50 ml). The combined organic layers washed with water, saturated salt solution, dried with anhydrous MgSO4filter and concentrate under reduced pressure to obtain the crude acid, which is used in the next stage without further purification.

The crude acid was dissolved in benzene (25 ml) and methanol (15 ml), and add a solution of (trimethylsilyl)diazomethane (1,61 ml, 2M solution in hexano) dropwise at room temperature within 10 minutes. Then the reaction mixture was quenched by adding dropwise acetic acid and the solvents removed under reduced pressure. The residue is treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×30 ml). The combined organic is such layers are washed with water, saturated salt solution, dried with anhydrous MgSO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2(30% ethyl acetate in hexane) to obtain specified in the connection header in the form of butter.1H NMR (400 MHz, DMSO-d6) δ h/1,70 million-to 1.79 (m, 2H), 1,81 is 1.91 (m, 2H), 2,03-of 2.15 (m, 4H), 3,62 (s, 3H), 3,91 (s, 2H), 7,69 (m, 1H), with 8.05 (m, 2H), 8,24 (m, 1H), 8,33 (m, 2H), 8,97 (broad s, 1H); MS (EEC) m/z 357 [M+H]+.

Example 57C

[(1-{5-[4-({[(2-forfinal)amino]carbonyl}amino)phenyl]pyridine-2-yl}cyclopentyl)oxy]acetic acid

A suspension of example 57B (0.15 g, 0.42 mmol), iron powder (0,047 g, 0.84 mmol) and ammonium chloride (0,026 g, 0.46 mmol) in ethanol (10 ml) and water (5 ml) is heated to the boiling temperature under reflux for 1 h, the Reaction mixture was cooled and filtered through a layer of wet celite. The filtrate is diluted with ethyl acetate and the layers separated. The combined organic layers washed with water, saturated salt solution, dried with anhydrous MgSO4filter and concentrate under reduced pressure to get crude complex ester, which is used in the next stage without further purification.

To have the ambient temperature to a solution of the crude complex ester (0.05 g, 0.15 mmol) from the previous step in tetrahydrofuran (5 ml) is added 2-forgenerations (0,034 ml, 0.3 mmol). The reaction mixture is peremeshivayte at room temperature for 15 hours, diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers washed with water, saturated salt solution, dried with anhydrous MgSO4filter and concentrate under reduced pressure to obtain residue, which is used in the next stage without further purification.

The monohydrate of lithium hydroxide (0.02 g) are added to a solution of the crude product in tetrahydrofuran (10 ml) and water (5 ml) and stirred at room temperature for 12 hours. The reaction mixture is acidified (pH 1) by adding 3N HCl and extracted with ethyl acetate (3×25 ml). The combined organic layers washed with water, saturated salt solution, dried with anhydrous MgSO4filter and concentrate under reduced pressure to obtain yellow solid. This solid is recrystallized using methanol/ethyl acetate to obtain specified in the title compounds as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ h/1,68 million-of 1.78 (m, 2H), 1,81-1,90 (m, 2H), 2,01-of 2.15 (m, 4H), of 3.77 (s, 2H), 7,00? 7.04 baby mortality (m, 1H), 7,15 (m, 1H), 7,24 (m, 1H), to 7.59 (d, J=8,55 Hz, 2H), 7.62mm (m, 1H), of 7.70 (m, 2H), 8,07 (m, 1H), 8,16 (m, 1H), at 8.60 (m, 1H), 8,81 (m, 1H), br12.62 (broad s, 1H); MS (EEC) m/z of 450.1 [M+H]+.

Example 58

[1-(4-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}phenyl)cyclopentyl]acetic acid

Example 58A

Ethyl 2-cyano-2-cyclopentylamine is at

To have the ambient temperature of the solution hexamethyldisilazane (17,7 ml of 84.0 mmol) in acetic acid (56 ml) was successively added Cyclopentanone (5.0 ml, 56,3 mmol) and ethyl 2-cyanoacetate (12.0 ml, 113 mmol). The solution is heated to 70°C for 15 hours. The reaction mixture is cooled to room temperature and diluted with water (100 ml) and ethyl acetate (100 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×100 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira 100% hexane to 5% ethyl acetate in hexane, to obtain specified in the title compounds as white solids. MS (EEC) m/z 180 [M+H]+.

Example 58B

2-(1-(4-chlorophenyl)cyclopentyl)-2-tsianuksusnym acid

To have the ambient temperature suspension of magnesium turnings (0,43 g of 17.7 mmol) in tetrahydrofuran (20 ml) is added 4-bromo-1-chlorobenzene (0.4 g, of 2.08 mmol) and a few crystals of iodine. The reaction mixture is gently heated by a heat gun. After dispersion purple color balance 4-bromo-1-chlorobenzene (2.0 g, 15.6 mmol) is added to the reaction mixture dropwise as a solution in tetrahydrofuran (20 ml) at such a rate as to maintain gentle boiling under reflux. Che is ez 1 h, the solution of the Grignard reagent 4-bromo-1-chlorobenzene cooled to ambient temperature and added dropwise to a cold (0°C.) mixture of CuI (0,237 g, to 1.24 mmol) and example 58A (3,18 g of 17.7 mmol) in tetrahydrofuran (20 ml). The reaction mixture was stirred at 0°C for 0.5 hours the Cooling bath removed and the reaction mixture stirred at ambient temperature for 15 hours Then the reaction mixture was quenched by addition of saturated aqueous NH4Cl (100 ml) and ethyl acetate (100 ml). The layers are separated and the aqueous layer was extracted with additional ethyl acetate (2×50 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified by chromatography on SiO2the gel elwira 100% hexane to 10% ethyl acetate in hexane, to obtain specified in the connection header. MS (EEC) m/z 293 [M+H]+.

Example 58C trainers

2-(1-(4-chlorophenyl)cyclopentyl)acetic acid

Example 58B (3.0 g, or 10.3 mmol) was dissolved in 15% vol./about. a solution of KOH in ethylene glycol (50 ml) and heated to 190°C for 4 hours. The reaction mixture is cooled to room temperature, diluted with water (100 ml) and the pH adjusted to about 3 with concentrated HCl. The aqueous layer was extracted with dichloromethane (3×50 ml). The combined organic layers dried with anhydrous Na2SO4filter and concentrate under reduced pressure. The residue is purified OF ghvd (preparative liquid chromatography high-pressure reversed-phase) with the use of speakers Bond SB-C18 7M of 21.2×250 mm, UV op what edelenyi, analyzed at 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 obtain the specified title compound as a beige solid. MS (EEC) m/z 238 [M-H]-.

Example 58D

[1-(4-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}phenyl)cyclopentyl]acetic acid

Example 58D receive according to the method of example 55C, replacing the example 55V example 58C trainers.1H NMR (300 MHz, DMSO-d6) δ h/1,52 million-of 1.84 (m, 4H), 1.85 to and 2.14 (m, 4H), 2,56-to 2.67 (m, 2H), 7,35-7,51 (m, 3H), 7,53-the 7.65 (m, 3H), to 7.67-7,73 (m, 1H), 7,76-a 7.85 (m, 1H), 8,05-8,16 (m, 2H), 8,63 (m, 1H), 9,56-9,68 (m, 1H), 10,66-10,81 (m, 1H), RS 11.80 (s, 1H); MS (EEC) m/z 484 [M+H]+.

Example 59

(1-{4-[6-({[(2-forfinal)amino]carbonyl}amino)pyridine-3-yl]phenyl}cyclopentyl)acetic acid

Example 59A

1-(2-forfinal)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)urea

Example 59A receive according to the method of example 28A, substituting phenylisocyanate 2-perteneciente. MS (EEC) m/z 358 [M+H]+.

Example 59B

(1-{4-[6-({[(2-forfinal)amino]carbonyl}amino)pyridine-3-yl]phenyl}cyclopentyl)acetic acid

Example 59B receive according to the method of example 55C, replacing the example 55V example 58C trainers and substituting example 29A example 59A.1H NMR (300 MHz, DMSO-d6) δ h/1,46 million of-1.83 (m, 4H), 1.85 to 2,11 (m, 4H), 2,54-2,69 (m, 2H), 7,00-7,11 (m, 1H), 7,17 (m, 1H), 7.23 percent-to 7.32 (m, 1H), 7,43 (m, 2H), ,54 (m, 1H), to 7.61 (m, 2H), 8,09 (m, 1H), 8,16-of 8.33 (m, 1H), 8,58 (m, 1H), of 9.89 (s, 1H), of 10.76 (s, 1H), 11,82 (s, 1H); MS (EEC) m/z 434 [M+H]+.

The connection 60

{[1-(2-fluoro-4-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}phenyl)cyclobutyl]oxy}acetic acid

Example 60A

1-(4-bromo-2-forfinal)timborana

a 100 ml 3-necked round-bottom flask is charged with 4-bromo-2-fluoro-1-iadanza (1000 mg, of 3.32 mmol) and diethyl ether (30 ml). The solution is cooled to -78°C. and add n-utility (1,329 ml of 3.32 mmol) dropwise, keeping the temperature below -68°C. After stirring for 15 min add cyclobutanone (0,249 ml of 3.32 mmol) dropwise, keeping the temperature below -68°C. the Solution was stirred at -78°C for 15 minutes Then the reaction mixture was quenched by adding saturated ammonium chloride (25 ml). The layers are separated and the organic layer washed with water (1×10 ml) and saturated salt solution (1×10 ml). The organic layer is dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified flash chromatography (SiO2gel), elwira 3% ethyl acetate/hexane to give the desired product.1H NMR (300 MHz, DMSO-d6) δ h/1,55 million was 1.69 (m, 1H), 1,91, was 2.05 (m, 1H), 2,19-of 2.28 (m, 2H), 2,46 is 2.55 (m, 2H), 5,59 (s, 1H), 7,33-7,40 (m, 2H), 7,44-of 7.48 (m, 2H).

Example 60B

{[1-(4-bromo-2-forfinal)cyclobutyl]oxy}acetic acid

In a 50 ml round-bottom flask is charged with NaH (361 mg, 9,04 mmol) and N,N-dimethylacetamide (5 ml)Raster product from example 60A (443 mg, 1,808 mmol) in N,N-dimethylacetamide (5 ml) is added dropwise and the reaction mixture was stirred at 22°C for 30 minutes a Solution of 2-bromoxynil acid (502 mg, 3.62 mmol) in N,N-dimethylacetamide (5 ml) is added dropwise. The reaction mixture was stirred at 22°C for 16 hours and then quenched by slow addition of water (15 ml). The aqueous layer was extracted with 1:1 diethyl ether/hexane (2×20 ml) and the organic matter drop. The aqueous layer was acidified to pH 1 by addition of 1M HCl and extracted with ethyl acetate (2×75 ml). The combined organic layers washed with water (4×20 ml) and saturated salt solution (1×20 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/1,54 million is 1.70 (m, 1H), 1,91 is 2.10 (m, 1H), 2,34-2,47 (m, 4H), of 3.65 (s, 2H), 7,34-the 7.43 (m, 2H), 7,49-7,53 (m, 1H), 12,45 (s, 1H).

Example 60C

N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]-N'-[3-(trifluoromethyl)phenyl]urea

To have an ambient temperature solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine (0,350 g of 1.59 mmol) in tetrahydrofuran (4 ml) is added 3-triftormetilfullerenov (1,59 mmol). The solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The solid is washed with diethyl ether (2 ml) and Susitna the air with obtaining specified in the connection header. MS (EEC) m/z 408 [M+H]+.

Example 60D

{[1-(2-fluoro-4-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}phenyl)cyclobutyl]oxy}acetic acid

A 25-ml test tube download the product from example 60C (459 mg, 1,128 mmol), the product from example 60B (342 mg, 1,128 mmol), dioskouroi potassium phosphate (590 mg, to 3.38 mmol) and dichloride, 1,1'-bis(di-tert-butylphosphino)ferienparadies(II) (7,38 mg, to 0.011 mmol), N,N-dimethylacetamide (4 ml), ethanol (4,00 ml) and water (2 ml). The suspension is stirred and heated to 90°C, after which the reaction mixture becomes homogeneous. After heating at 90°C for 1 hour, the reaction mixture was cooled to room temperature. The resulting suspension was poured into water (200 ml). The mixture is acidified to pH 1 by addition of 1M HCl. The solid is filtered, washed with water and dried in air to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/1,62 million-1,71 (m, 1H), 1,96-2,07 (m, 1H), 2,39-2,49 (m, 4H), of 3.69 (s, 2H), 7,38 (d, J=7,12 Hz, 1H), 7,47-to 7.61 (m, 4H), 7,65-7,71 (m, 2H), 8,07 (s, 1H), 8,17 (DD, J=2.7 and 8.8 Hz, 1H), 8,71 (d, J=2.7 Hz, 1H), 9,68 (s, 1H), 10,65 (s, 1H), 12.5cm (users, 1H). MS (EEC) m/z 504 [M+H]+.

Example 61

[(1-{2-fluoro-4-[6-({[3-(trifluoromethyl)phenyl]acetyl}amino)pyridine-3-yl]phenyl}cyclobutyl)oxy]acetic acid

Example 61A

6-({[3-(trifluoromethyl)phenyl]acetyl}amino)pyridine-3-Voronova acid

In a 250 ml round-bottom flask is charged with 2-(3-(trifluoromethyl)phenyl)acetic acid (2,39 g, 11,36 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine (2.5 g, 11,36 mmol), hydrochloride of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (at 2,178 g, 11,36 mmol), hydrate of 1-hydroxybenzotriazole (1,740 g, 11,36 mmol), N-methylmorpholin (5,00 ml, to 45.4 mmol) and N,N-dimethylacetamide (50 ml). The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was quenched by adding ethyl acetate (50 ml) and water (50 ml). The layers are separated and the organic layer washed with water (3×50 ml) and saturated salt solution (1×50 ml). The organic layers are dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified jhud with reversed phase using a gradient of 15% water (0.1% of triperoxonane acid) to 95% acetonitrile (0.1% of triperoxonane acid) to obtain Bronevoy acid as a white solid.1H NMR (300 MHz, DMSO-d6) δ h/million 3,88 (s, 2H), 7,54-7,66 (m, 3H), 7,72 (s, 1H), of 7.96 (d, J=8.5 Hz, 1H), 8,12 (DD, J=1.7 and 8.1 Hz, 1H), 8.4V (users, 1H), 10,94 (s, 1H).

Example 61B

[(1-{2-fluoro-4-[6-({[3-(trifluoromethyl)phenyl]acetyl}amino)pyridine-3-yl]phenyl}cyclobutyl)oxy]acetic acid

In 4-ml test tube download the product from example 61A (17,7 mg, by 0.055 mmol) and the product from example 60B (16,56 mg, by 0.055 mmol), dibasic potassium phosphate (28.5 mg, 0,164 mmol), dichloride, 1,1'-bis(di-tert-butylphosphino)ferienparadies(II) (0,357 mg, 0,546 mmol), N,N-dimethylacetamide (1 ml), ethanol (1,000 ml) and water (0,500 ml). When spengiu stirred and heated to 90°C, then the reaction becomes homogeneous. After heating at 90°C for 1 hour, the reaction mixture was cooled to room temperature. Then the reaction mixture was separated between ethyl acetate (2 ml) and water (2 ml). The layers are separated and the organic layer dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified jhud with reversed phase (mobile phase: 10%-100% acetonitrile in 0.1% aqueous solution triperoxonane acid for 60 min, C18 column) to obtain specified in the connection header.1H NMR (300 MHz, DMSO-d6) δ h/1,59 million-1,72 (m, 1H), 1,95-2,07 (m, 1H), 2,38 at 2.45 (m, 4H), of 3.65 (s, 2H), with 3.89 (s, 2H), 7,46-7,52 (m, 1H), 7,55-to 7.67 (m, 5H), 7,73 (s, 1H), 8,11-8,18 (m, 2H), 8,73 (users, 1H), 10,94 (s, 1H). MS (EEC) m/z 503 [M+H]+.

It should be clear that the above detailed description and accompanying examples are merely illustrative and do not limit the scope of the present invention. Various variations and modifications, including, but not limited to, relating to the chemical structures, substituents, derivatives, intermediates compounds, synthesis, compositions and/or methods of application of the present invention can be carried out without leaving the gist of the present invention and its scope.

1. The compound of formula (I)

or its pharmaceutically acceptable salt, where
G1is phenylamine pyridium, each of which is optionally additionally substituted by one Deputy, presents T;
G2is phenyl, 1,3-thiazolyl or 1,3-oxazolium, where G2associated with G1in the para-position relative to the junction G1with the NH group in formula (I),
where, when G2means phenyl, G3associated with G2in the para-position G2regarding G1and
where, when G2represents a 1,3-thiazolyl or 1,3-oxazolyl, G2associated with G1in position 5 G2and G3associated with G2in position 2 G2;
T in each case independently selected from the group including1-6alkyl and halogen;
G3represented by formula (a) or formula (b)

W1is-C(R3)(R4)-C(R3)(R4)-, and W2represents N; or
W3represents About;
W4is-C(R3)(R4) -;
R3and R4each is hydrogen;
R5and R6each is hydrogen;
Rcand Rdtogether with the carbon atom to which they are attached are 4-to 5-membered cycloalkyl or a monocyclic heterocycle of formula (C);

where one hydrogen atom attached to the carbon atom of the ring cycloalkyl and monocyclic heterocycle, optionally replacements who are radical, selected from the group of-C(O)O(R8);
W5is-CH2- or-CH3-CH2-;
W6is O or N(Rx), where Rxis hydrogen, C1-6the alkyl or-C(O)O(Rz);
Rzin each case, independently is C1-6by alkyl;
R8is hydrogen;
L1is Oh; and X is hydrogen, C1-6the alkyl, or - (CRgRh)u- C(O)O(R10); or
L1is-CH2- and X is-C(O)HE;
R10is hydrogen; or
Q is G4or Y1-Y3; or Q has the formula (d)

where Z is phenyl;
G4is a benzothiazole or benzoxazole, optionally additionally substituted with 1 or 2 substituents selected from the group consisting of C1-6of alkyl, halogen and-OR1;
Y1in each case, independently is-C(O)-, -C(O)O - or-S(O)N(Rw)-where the right side is-C(O)O - and-C(O)N(Rw)groups attached to the Y3or (CRjRk)v,
Y3in each case independently is phenyl, benzyl, piperidinyl or bicyclo[4.2.0]OCTA-1,3,5-triens, where phenyl and benzyl residues optionally additionally substituted with 1 or 2 substituents selected from the group consisting of halogen and Gialos1-6of alkyl;
Rgand Rhin each case, independently researched the mo are hydrogen, or1-6by alkyl;
R1in each case independently is halogen1-6by alkyl;
Rwis hydrogen; and
u means 1.

2. The compound according to claim 1, having the formula (II),

or its pharmaceutically acceptable salt.

3. The compound according to claim 1, having the formula (III),

or its pharmaceutically acceptable salt.

4. The compound according to claim 3 or its pharmaceutically acceptable salt, where L1is O and X is hydrogen or C1-6by alkyl;
or where L1means-CH2- and X is-C(O)HE.

5. The compound according to claim 3 or its pharmaceutically acceptable salt, where L1is O and X is - (CRgRh)u-C(O)O(R10).

6. A compound selected from the group consisting of:
N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}urea;
4-(5-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]-3-forfinal}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol;
4-(5-{4-[(7-methyl-1,3-benzoxazol-2-yl)amino]phenyl}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol;
4-(5-{2-chloro-4-[(7-chloro-1,3-benzoxazol-2-yl)amino]phenyl}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol;
4-(5-{4-[(7-chloro-1,3-benzoxazol-2-yl)amino]-2-were}-1,3-thiazol-2-yl)tetrahydro-2H-Piran-4-ol;
N-[2-fluoro-5-(trifluoromethyl)phenyl)-N'-{6-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]Piri is INF-3-yl}urea;
N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{6-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]pyridine-3-yl}urea;
phenyl 4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenylcarbamate;
N-{4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}piperidine-1-carboxamide;
tert-butyl 3-(5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1,3-thiazol-2-yl)-3-hydroxypyrrolidine-1-carboxylate;
N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(3-hydroxypyrrolidine-3-yl)-1,3-thiazol-5-yl]phenyl} urea;
N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}urea;
N-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea;
N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}urea;
N-{4-[2-(1-hydroxycyclopent)-1,3-thiazol-5-yl]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea;
(±)-CIS-3-hydroxy-3-{4'-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1,1'-biphenyl-4-yl}cyclopentanecarbonyl acid;
N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-{4-[2-(1-methoxycyclohexyl)-1,3-thiazol-5-yl]phenyl}urea;
{[1-(5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;
{[1-(5-{4-[(bicyclo[4.2.0]OCTA-1,3,5-triene-7-ylcarbonyl)amino]phenyl}-1,3-thiazol-2-yl)cyclobutyl]oxy}acetic acid;
({1-[5-(4-{[(2-forfinal)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}OK and)acetic acid;
{[1-(5-{4-[(anilinoacrolein)amino]phenyl)-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;
{[1-(5-{4-[(anilinoacrolein)amino]phenyl}-1,3-thiazol-2-yl)cyclobutyl]oxy} acetic acid;
{[1-(5-{6-[(anilinoacrolein)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid:
{[1-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy} acetic acid;
{[1-(4-{6-[(anilinoacrolein)amino]pyridine-3-yl}phenyl)cyclopentyl]oxy}acetic acid;
(±)-CIS-3-(4'-{[(2-forfinal)acetyl]amino}-1,1'-biphenyl-4-yl)-3-hydroxycyclohexanecarboxylate acid;
[(1-{5-[4-({2-[(4-chlorophenyl)amino]-3,4-dioxocyclohex-1-EN-1-yl}amino)phenyl]-1,3-thiazol-2-yl}cyclobutyl)oxy]acetic acid;
{[1-(5-{6-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;
2-{[1-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}propanoic acid;
2-{[1-(5-{6-[(anilinoacrolein)amino[pyridine-3-yl}-1,3-thiazol-2-yl)cyclopentyl]oxy}propanoic acid;
{[1-(5-{4-[(7-methyl-1,3-benzoxazol-2-yl)amino]phenyl}-1,3-thiazol-2-yl)cyclopentyl]oxy}acetic acid;
N-{4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}-2-[3-(trifluoromethyl)phenyl]ndimethylacetamide;
2-(2,4-differenl)-N-{4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}ndimethylacetamide;
2-(2,5-differenl)N-{4-[2-(4-hydroxycitrate-2H-Piran-4-yl)-1,3-thiazol-5-yl]phenyl}ndimethylacetamide;
[(1-{5-[4-(benzoylamine)phenyl]-1,3-thiazol-2-yl}cyclobutyl)oxy]acetic acid;
({1-[5-(4-{[(3-forfinal)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid;
({1-[5-(4-{[4-(trifluoromethyl)benzoyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid:
[(1-{5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]acetyl}amino)phenyl]-1,3-thiazol-2-yl}cyclobutyl)oxy]acetic acid;
{[1-(5-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}-1,3-oxazol-2-yl)cyclopentyl]oxy}acetic acid;
({1-[5-(4-{[(2,5-diphosphonic)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid;
({1-[5-(4-{[(3,5-differenl)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid;
({1-[5-(4-{[(3,4-differenl)acetyl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}oxy)acetic acid;
{[1-(4-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}phenyl)cyclopentyl]oxy}acetic acid;
1-(5-(4-(4-oxa-1-azabicyclo[3.2.1]Octan-5-yl)phenyl)pyridin-2-yl)-3-phenylacetone;
[1-(4-{6-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridine-3-yl}phenyl)cyclopentyl]acetic acid;
(1-{4-[6-({[(2-forfinal)amino]carbonyl}amino)pyridine-3-yl]phenyl}cyclopentyl)acetic acid;
or its pharmaceutically acceptable salt.

7. The compound according to claim 1 or 6, or its pharmaceutically acceptable salt, intended for the treatment of disorders selected from the group, including the ment of type 2 diabetes, obesity, elevated levels of triglycerides in plasma, metabolic syndrome, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease.



 

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where: R1 or R2, independently represents a group consisting of R1, R2, N and/or O selected from the groups:

,

Z1 represents hydrogen or hydroxyl; Z2 represents hydrogen or hydroxyl; Z3 represents C6-C10aryl; Z4 represents C1-C6alkoxy. The invention also refers to a method for producing the compounds according to any of claims 1-4, as well as to application of the compounds.

EFFECT: preparation of new biologically active compounds which exhibit anticancer activity.

12 cl, 10 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to synthetic cytoskeleton-active compounds which are from the family of natural latrunculin A or latrunculin B and have structural formulae

and described in the formula of invention. Present invention also relates to a pharmaceutical composition containing said compounds and a pharmaceutically acceptable carrier. The invention also pertains to a method of preventing or treating diseases and conditions associated with actin polymerisation. In one embodiment of the invention, high intraocular pressure, such as during primary open angle glaucoma, is treated using the method. The method involves administering a therapeutically effective amount of the cytoskeleton-active compound of formula I or II to a subject, where the said amount is sufficient for acting on a cytoskeleton, for example through actin polymerisation inhibition.

EFFECT: compounds are highly effective.

16 cl, 75 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of bicyclo[3.1.0]hexane derivatives, used as mGIuR agonists having formulae ,

, where R1 and R2 represent hydrogen, X is a halogen, R3 is -O-Ra , Ra is C1-10alkyl, and R4 is (1) hydrogen or (2) Si-(R9)(R10)(R11), where each of R9, R10 and R11 is C1-10alkyl, as well as intermediate compounds obtained when realising the said methods.

EFFECT: design of an efficient method for synthesis of bicyclo[3,1,0]hexane derivatives.

26 cl, 17 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzodiazepine compounds of general formula , wherein each R1, R2, R3 and R4 independently represent hydrogen or alkyl, or R2 and R3 together represent lower alkylene; A1 is lower alkylene optionally substituted by hydroxy; and R5 is a fragment of formula , wherein each R6 and R7 independently represents hydrogen, lower alkyl, cycloalkyl, phenyl, furyl, thienyl, pyrazolyl, etc.; each XA and XB independently represents a bond, lower alkylene, -CO-, -SO2- etc., a pharmaceutical composition containing them, and using the above compound as the pharmaceutical composition or for preparing the same.

EFFECT: new compounds may be used for preventing and treating cardiac arrhythmia.

8 cl, 1047 ex, 78 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds being aspartyl protease inhibitors applicable for treating cardiovascular, neurodegenerative disorders and fungal infection of formula , wherein W represents -C(=O)-; X represents -NH-; U represents -C(R6)(R7)-; R1 represents methyl, R2, R3 and R6 represent H, R4 and R7 represent optionally substituted phenyl, as well as tautomers and pharmaceutically acceptable salts thereof.

EFFECT: there are presented new effective aspartyl protease inhibitors specified in rennin, cathepsin D, BACE-1, for treating cardiovascular diseases, cognitive and neurodegenerative diseases, as well as fungal infections.

67 cl, 1 tbl, 4393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to indolyl-substituted derivatives of thiadiazinones prepared from oxamic acid thiohydrazide of general formula: , wherein R represents H; R1 represents pyridinyl; phenyl substituted by alkyl C1-C5, Hal, CF3; R2 represents H; alkyl C1-C5; -CH2COOR4; benzyl substituted by Hal, OR4; benzoyl substituted by Hal, OR4, while R4 represents unsubstituted alkyl C1-C4.

EFFECT: there are prepared new compound which can find application in medicine for developing the therapeutic agent possessing pathogenic bacteria inhibitory activity.

2 cl, 2 dwg, 2 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic nitrogen- and oxygen-containing compounds having insecticidal activity. In formulae (A) (B) (C) (D) R1 is a 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/ or sulphur atom, a halogen-substituted 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/or sulphur atom, a substituted or unsubstituted phenyl, where the substitutes are one or more groups selected from a group consisting of halogen atoms, C1-4 halogen alkyl or C1-4 chloroalkoxyl; R5, R6, R7, R8 and R9 are H, saturated or unsaturated C1-4 alkyl, halogen atom, saturated or unsaturated C1-4 alkoxyl, saturated C1-4 halogenalkoxyl, C1-4 alkylcarbonyl, C1-8 alkyl ester, C1-4 alkylsulphonyl, phenyl, benzyl or trifluoromethane sulphonyl ether group; Y is nitro, cyano, trifluoromethyl, trifluoroacetyl or trifluoromethylsuphonyl. Values of radicals R, R2-R4 are given in the claim.

EFFECT: invention also relates to an agrochemical composition containing said compounds, use of the agrochemical composition in pest control and a method of producing said compounds.

12 cl, 7 tbl, 36 ex

Azole compounds // 2493154

FIELD: chemistry.

SUBSTANCE: invention relates to compounds which are pyridin-3-yl 4-(3-phenyl-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[3-(4-fluoromethyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[5-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate, 2,6-dimethylpyridin-3-yl 4-[5-(3,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[3-(2-fluorophenyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[5-(3-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate and 6-methylpyridin-3-yl 4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate or to a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having inhibiting effect on fatty acid amide hydrolase (FAAH).

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for treating neuropathic pain.

13 cl, 38 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound, which is N3-1H-indol-5-yl-5-pyridin-4-ylpyrazine-2,3-diamine, or a pharmaceutically acceptable salt thereof, which can act as inhibitors of protein kinase, especially FLT3 tyrosine kinase. The invention also relates to a pharmaceutical composition which contains said compound in combination with another molecularly directed (target) agent, which is a traditional cytotoxic agent or a compound used after chemotherapy, supporting therapy targeted on stem cells and in case of MLL rearrangement acute lymphoblastic leukaemia in children.

EFFECT: obtaining a novel compound which can be used in medicine for preventing or treating haematological malignant growths such as AML, MLL, T-ALL, B-ALL and CMML, myeloproliferative diseases, autoimmune diseases and skin diseases, such as psoriasis and atopic dermatitis.

16 cl, 2 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to antibacterial compounds of formula (I) , where one or two of U, V, W and X represent N, the remaining ones represent CH or, in case X, can also represent CRa, where Ra represents fluorine; R1 represents alcoxygroup, halogen or cyanogroup; R2 represents H, CH2OH, CH2N3, CH2NH2, alkylcarbonylaminomethyl or triazol-1-ylmethyl; R3 represents H or, when n=1, R3 can also represent OH, NH2, NHCOR6 or triazol-1-yl; A represents CR4; K represents O, NH, OCH2, NHCO, NHCH2; CH2NH5 CH2CH2, CH=CH, CHOHCHOH or CHR5; R3 represents H or together with R5 forms bond, or R4 can also represent OH, when K is not O, NH, OCH2 or NHCO; R5 represents OH or together with R4 forms bond; R6 represents alkyl; m=0 or 1 and n=0 or 1; and G is specified in i.1 of the formula; and to salt of such compound.

EFFECT: obtaining antibacterial compounds.

19 cl, 1 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyridine derivatives pyridine1-A-pyridine2 of formula (1), where pyridine1 represents

, , or , ,

where asterisks stand for bond, which contains pyridine1 ring with A; R1 represents C1-5alkyl, C1-4alkoxygroup, C3-6-cycloalkyl, hydroxymethyl or NR1aR1b, R1a represents C1-4alkyl; R1b represents hydrogen or C1-3alkyl; or R1a and R1b, together with nitrogen atom, which is bound to pyridine, form pyrrolidine ring; R2 represents hydrogen or C1-4alkyl, or in case, when R1 represents C1-5alkyl or C3-6-cycloalkyl, R2 can additionally represent methoxygroup; R3 represents C1-4alkyl, C1-4alkoxygroup, C3-6-cycloalkyl or NR3aR3b; R3a represents C1-4alkyl; R3b represents hydrogen or C1-3alkyl; R4 represents C1-4alkyl or hydrogen; R5 represents C1-5alkyl, methoxygroup or NR5aR5b; and R6 represents C1-2alkyl; R5a represents C1-4alkyl; R5 represents hydrogen or C1-3alkyl; or R5 represents C1-2alkyl or methoxygroup; and R6 represents C1-5alkyl or NR6aR6b; R6a represents C1-4alkyl; R6b represents hydrogen or C1-3alkyl; R7 represents C1-5alkyl; R8 represents C1-2alkyl or methoxygroup; R9 represents C1-5alkyl; R10 represents C1-2alkyl; A represents

, , or ,

where asterisks stand for bond, binding pyridine1 ring with A; pyridine2 represents

, , or , ,

where asterisks stand for bond, which binds pyridine ring with A; R11 represents C1-4alkyl; C1-3alkyloxy group, hydroxymethyl or NR11aR11b; R,1a represents C1-3alkyl; R11b represents hydrogen or C1-2alkyl; R12 represents hydrogen or C1-4alkyl; R13 represents C1-4alkyl or NR13aR13b; R13a represents C1-4alkyl; R13b represents hydrogen or C1-2alkyl; R14 represents C1-2alkyl; R15 represents C1-4alkyl or NR15aR15b; and R16 represents C1-2alkyl; R15a represents C1-3alkyl; R15b represents hydrogen or C1-3alkyl; or R15 represents C1-2alkyl; and R16 represents C1-4alkyl or NR16aR16b; R16a represents C1-3alkyl; R16b represents hydrogen or C1-2alkyl; R17 represents C1-4alkyl; R18 represents C1-2alkyl or methoxygroup; R19 represents C1-4alkyl; and R20 represents C1-2alkyl; with exception of 3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole; or pharmaceutically acceptable salt of such compound.

EFFECT: obtaining pyridine derivatives, which possess agonistic activity with respect to S1P1/EDG1.

15 cl, 2 tbl, 131 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to organic chemistry, more specifically to a method for preparing N-(1,5,3-dithiazocynan-3-yl)amides of formula , wherein R=p-C5H4N (a), (CH3)3CO (b), o-CH3OC6H4 (c), which can find application as biologically active compounds, selective sorbents and precious metal extractants. Substance of the method consists in the reaction of N1,N1,N7,N7 - tetramethyl-2,5-dithiaheptane-1,7-diamine with hydrazides RC(O)NHNH2 in the presence of the catalyst samaric nitrate crystallohydrate Sm(NO3)3·6H2O at temperature 65-75°C for 20-26 h.

EFFECT: what is developed is a method for preparing new high-selectivity N-(1,5,3-dithiazocynan-3-yl)amides.

1 cl, 1 tbl, 1 ex

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