Compound with successive aricyclic structure, possessing activity of inhibiting acycloenzyme a diacylglycerolacyltransferase (dgat1)

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

[0001]

The present invention relates to a connection with a serial articlecache structure or its pharmaceutically acceptable salt having the activity of inhibiting allgovernment A: diacylglycerides (DGAT) 1.

BACKGROUND of INVENTION

[0002]

Obesity is a condition in which excessive fat accumulates in the body (non-Patent literature 1), hyperlipidemia, hypertriglyceridemia (TG), and causes disease associated with lifestyle, such as lipid metabolism, fatty liver, diabetes, hypertension, atherosclerosis, and so on; cerebrovascular disease, ischemic heart disease, shortness of breath, lumbago, osteoarthritis of the knee joint and so on, and among the diseases associated with obesity, diseases mentioned above or which may cause such diseases in the future, defined as obesity and considered as one disease.

[0003]

DGAT is an enzyme that catalyzes the reaction from diacylglycerol to TG, which is the final stage of synthesis of TG, and it is known that in DGAT there are two subtypes of DGAT1 and DGAT2. Of them DGAT1 known to exist in the liver, skeletal muscle, adipocytes, etc., and participates in the synthesis of TG in the respective tissues (Repatent the th literature 2).

[0004]

In addition, upon absorption of TG in the small intestine, TG degraded to fatty acids and monoacylglycerol under the action of pancreatic lipase in the cavity of the small intestine, then is captured by the epithelial cells of the small intestine and absorbed after resynthesis to TG in the epithelial cells. It is also known that DGAT1 is involved in the resynthesis of TG at the final stage in the epithelial cells of the small intestine (non-Patent literature 3).

[0005]

Thus, a drug that inhibits the action of DGAT1 may inhibit the final stage of TG synthesis, thus it can not only inhibit the synthesis of TG in adipocytes, liver, and so on, but also to inhibit the resynthesis of TG in the small intestine, so you can expect that it will inhibit the absorption of TG in the small intestine, and can alleviate the severity of painful conditions associated with obesity (non-Patent literature 4).

[0006]

In addition, the widespread thesis that the accumulation of TG in the liver, skeletal muscle, etc. (ectopic obesity causes insulin resistance in diabetes mellitus type 2, accompanied by obesity, thus, indicated that the drug, which inhibits the effect of DGAT1, will improve insulin sensitivity and to have a therapeutic effect on diabetes dia is no type 2 by reducing ectopic obesity (non-Patent literature 4). In addition, it was reported that the improvement in insulin sensitivity may be recognized as a mouse, which DGAT1 suppressed by genetic manipulation of the mouse with “knocked out” the gene DGAT1) compared with mouse wild-type (non-Patent literature 5). Recently it was also reported that the compound that inhibits the effect of DGAT1, stimulates action of like peptide-1 (GLP-1) and protein, which causes loss of appetite (anorexia) (non-Patent literature 6).

[0007]

As compounds having serial articlecheck structure have been known. For example, Patent literature 1 discloses (2S)-2-[4'-(1-benzyl-1H-benzimidazole-2-yl)-biphenyl-4-yloxy]-3-phenyl-propionic acid (Example 70), etc. as a compound that inhibits patientinitiated (PTPases), and which is useful for the treatment of obesity, impaired glucose tolerance, diabetes, hypertension and tolerance to insulin, followed by coronary artery disease.

[0008]

Patent literature 2, as compounds with activity inhibition patientinitiated-1B (PTP-1B), useful for the treatment of type 2 diabetes, discloses 2-benzyl-4-[4'-(2-benzyl benzofuran-3-yl)-biphenyl-4-yl]-4-oxo-butyric acid (Example 1), ({4'-(3-benzylamino)imidazo[1,2-a]pyridine-2-yl)biphenyl-4-yl}oxy)(phenyl)acetic acid, {[4'-(5-methyl-1H-ind the l-1-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid (Example 3), and so on

[0009]

Patent literature 3, Patent literature 4 and Patent literature 5 discloses compounds having structures in which the biphenyl having inhibitory activity against factor VIIa, factor IXa, factor Xa and factor Xia, and nitrogen-containing condensed heterokonta linked. However, their chemical structure is limited to structures in which the nitrogen-containing condensed heterokonta linked to 3-position of the biphenyl.

[0010]

Patent literature 6 discloses 2-[[2'-(5-phenyl-1H-imidazol-2-yl)[1,1'-biphenyl]-3-yl]oxy]acetic acid (Example 46), etc. as compounds that have a therapeutic effect on obesity and diabetes by inhibiting protein, fatty acid binding adipocytes type (aP2).

[0011]

Non-patent literature 7 discloses 2-[[2'-(1-ethyl-4,5-diphenyl-1H-imidazol-2-yl)[1,1'-biphenyl]-3-yl]oxy]acetic acid, 2-[[2'-(4,5-diphenyl-1H-imidazol-2-yl)[1,1'-biphenyl]-3-yl]oxy]acetic acid, etc. as a connection that communicates with adipocytes type protein, to bind to the fatty acid (aFABP).

The LITERATURE of the PRIOR art,

[Patent literature]

[0012]

[Patent literature 1] WO99/58518A

[Patent literature 2] WO2004/99168A

[Patent literature 3] WO2003/6670A

[Patent literature 4] WO2003/6011A

[Patent literature 5] US 2003/0114457A

[Patent literature 6] WO00/5506A

[Non-patent literature]

[0013]

[Non-patent literature 1] Nanzando Co., Ltd., Medical Dictionary (19th Edition) p.2113, 2006

[Non-patent literature 2] Proc. Natl. Acad. Sci. USA vol. 95, p.13018, 1998

[Non-patent literature 3] J. Biol. Chem. Vol.278, p.18532, 2003

[Non-patent literature 4] Arterioscler. Thromb. Vasc. Biol. Vol.25, p.482, 2005

[Non-patent literature 5] The Journal of Clinical Investigation, 109(8) 1049-1055, 2002

[Non-patent literature 6] American Chemical Society National Meeting Abst. MEDI 315, 2010

[Non-patent literature 7] Bioorganic & Medicinal Chemistry Letters 17(12) 3511-3515, 2007

DISCLOSURE of INVENTIONS

The problems SOLVED by the PRESENT INVENTION

[0014]

The present invention is to provide a connection with a serial articlecache structure or its pharmaceutically acceptable salt having the activity of inhibition of DGAT1, and DGAT1 inhibitor, useful for the prevention and/or treatment of obesity or hyperlipidemia caused by obesity, hypertriglyceridemia, lipid metabolism, fatty liver, hypertension, arteriosclerosis, diabetes, etc. in Addition, another objective is the provision of a DGAT1 inhibitor, including a connection with the serial articlecache structure or its pharmaceutically acceptable salt as an effective ingredient.

The METHODS of problem SOLVING

[0015]

The authors of the present invention conducted intensive studies DL is solving the above problems, and in the result it was found that the connection with the serial articlecache structure or its pharmaceutically acceptable salt according to the present invention has excellent activity inhibition of DGAT1, the result of which was created the present invention. Thus, the present invention is as follows.

[0016]

1. Connection to a serial articlecache structure represented by the formula:

[Formula 1]

{where Alk represents a linear C1-6alkylenes group, a branched C1-6alkylenes group or a C1-6alkylenes group having a ring structure (part of carbon atoms constituting the ring structure optionally may be substituted by an oxygen atom, a nitrogen atom or a sulfur atom.),

in the ring X,

X1represents N or CRX1,

X2represents N or CRX2,

X3represents N or CRX3,

X4represents N or CRX4,

RX1, RX2, RX3and RX4each independently represent a hydrogen atom; a linear or branched C1-6alkyl group which may be substituted atom(atoms) halogen; C3-7alkyl group having a ring structure, which may be substituted atom(atoms) is alogena; linear or branched C1-6alkoxygroup; halogen atom or a cyano,

in the ring Y,

Y1represents N or CRY1,

Y2represents N or CRY2,

Y3represents N or CRY3,

Y4represents N or CRY4,

RY1, RY2, RY3and RY4each independently represents a hydrogen atom; a linear or branched C1-6alkyl group which may be substituted atom(atoms) halogen; C3-7alkyl group having a ring structure, which may be substituted atom(atoms) halogen; linear or branched C1-6alkoxygroup; halogen atom or a cyano,

in the ring Z,

RZrepresents a linear or branched C1-6alkyl group which may be substituted atom(atoms) halogen, or C3-7alkyl group having a ring structure, which may be substituted atom(atoms) halogen.}

or its pharmaceutically acceptable salt.

[0017]

2. Connection to a serial articlecache structure or its pharmaceutically acceptable salt described above in paragraph 1, where the ring X has a structure represented by any of the following formulas:

[Formula 2]

where RX1-RX4matter, the op is edelenyi above,

Ring Y has a structure represented by any of the following formulas:

[Formula 3]

where RY1-RY4have the meanings given above.

[0018]

3. Connection to a serial articlecache structure or its pharmaceutically acceptable salt described above in paragraph 2, where the Ring X has a structure represented by any of the following formulas:

[Formula 4]

where RX1-RX4have the meanings given above,

Ring Y has a structure represented by any of the following formulas:

[Formula 5]

where RY1-RY4have the meanings given above.

[0019]

Preferably, the ring X had the structure represented by any of the following formulas:

[Formula 6]

where RX1-RX4have the meanings given above,

Ring Y has a structure represented by any of the following formulas:

[Formula 7]

where RY1-RY4have the meanings given above.

[0020]

Preferably, the ring X and the ring Y had a structure represented by any of the following formulas:

[Formula 8]

where RX1-RX4and RY1-RY4have the meanings given to enter the.

[0021]

4. Connection to a serial articlecache structure or its pharmaceutically acceptable salt described above in paragraph 3, where RZrepresents a linear or branched C1-6alkyl group which is substituted by an atom(atoms) halogen, or C3-7alkyl group having a ring structure, which may be substituted atom(atoms) halogen.

[0022]

5. Connection to a serial articlecache structure or its pharmaceutically acceptable salt described above in paragraph 4, where Alk is a branched C2-4alkylenes group.

[0023]

6. Connection to a serial articlecache structure that represents any of the following connections:

2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoic acid;

2,2-dimethyl-3-(4-{5-[5-(2,2,2-Cryptor-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoic acid;

2,2-dimethyl-3-(4-{4-methyl-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoic acid;

2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridine-2-yl)phenoxy)propanoic acid;

2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoic acid;

1-[(3-methyl-4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)methyl]cyclobutanecarbonyl acid;

<> 3-(4-{5-[5-(3,3-diversilobum)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)-2,2-dimethylpropanoate acid;

2,2-dimethyl-3-({4-methyl-6'-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)propanoic acid;

2,2-dimethyl-3-({4'-methyl-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2,3'-bipyridine-6'-yl}oxy)propanoic acid;

2,2-dimethyl-3-[(4-methyl-5-{4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]propanoic acid;

2,2-dimethyl-3-[(6-methyl-5-{4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]propanoic acid;

3-[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]-2,2-dimethylpropanoate acid;

2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyrazin-2-yl)oxy]propanoic acid;

2,2-dimethyl-3-[(4-methyl-5-{3-methyl-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]propanoic acid;

3-[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid;

2,2-dimethyl-3-[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoic acid;

3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid;

3-{[5-(3-fluoro-4-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}phenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate acid;

2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridine-2-yl)oxy]about the anew acid;

3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-forfinal}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid;

1-[({4-methyl-6'-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]cyclobutanecarbonyl acid;

1-{[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarbonyl acid;

1-[({5'-chloro-4-methyl-6'-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]cyclobutanecarbonyl acid;

1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxamide acid;

1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarbonyl acid

or its pharmaceutically acceptable salt.

[0024]

7. Inhibitor of acyl coenzyme a: diacylglycerides (DGAT) 1, including a connection with the serial articlecache structure or its pharmaceutically acceptable salt described in any of the above PP 1-6, as an effective ingredient.

[0025]

8. The DGAT1 inhibitor, described above in paragraph 7, which is an agent for the prevention or treatment of obesity.

[0026]

9. The DGAT1 inhibitor, described above in paragraph 8, which is an agent for the prophylaxis or treatment of hyperlipidemia, hypertriglyceridemia, lipid metabolism or fat is howling dystrophy of the liver.

[0027]

10. The DGAT1 inhibitor, described above in paragraph 7, which is an agent for the prevention or treatment of type 2 diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macrovascular disease), arteriosclerosis, hypertension, cerebrovascular disease, ischemic heart disease, shortness of breath, back pain or osteoarthritis of the knee.

[0028]

11. The DGAT1 inhibitor, described above in paragraph 10, which is an agent for the prevention or treatment of type 2 diabetes or diabetic complications.

[0029]

12. The application connect to the serial articlecache structure or its pharmaceutically acceptable salt described in any of the PP 1-6, above, for the prevention or treatment of hyperlipidemia, hypertriglyceridemia, lipid metabolism, fatty liver, type 2 diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macrovascular disease), arteriosclerosis, hypertension, cerebrovascular disease, ischemic heart disease, shortness of breath, back pain or osteoarthritis of the knee.

[0030]

13. A method of preventing or treating hyperlipidemia, Gobert is glyceridae, disorders of lipid metabolism, fatty liver, type 2 diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macrovascular disease), arteriosclerosis, hypertension, cerebrovascular disease, ischemic heart disease, shortness of breath, back pain or osteoarthritis of the knee joint, which includes an introduction to the patient a therapeutically effective amount of compounds with serial articlecache structure or its pharmaceutically acceptable salt described in any of the PP 1-6, above.

[0031]

The above-described linear or branched C1-6Allenova group includes linear C1-6alkylenes group and branched C2-6alkylenes group and specifically the following alkylenes group.

1) -CH2-;

2) -CH2CH2-, -CH(CH3)-;

3) -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2-, -CH(C2H5)-;

4) -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(C2H5)CH2-, -CH2CH(C2H5)-, -CH(n-C3H7)-, -CH(ISO-C3H7)-;

5) -CH2CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2-, -CH2CH(CH3)CH2CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(CH3)CH(CH3)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH(CH3)-, -CH(C2H5)CH2CH2-, -CH2CH(C2H5)CH2-, -CH2CH2CH(C2H5)-, -C(CH3)2CH(CH3)-, -CH(CH3)C(CH3)2-, -CH(C2H5)CH(CH3)-, -CH(CH3)CH(C2H5)-, -CH(n-C3H7)CH2-, -CH(ISO-C3H7)CH2-, -CH2CH(h-C3H7)-, -CH2CH(ISO-C3H7)-, -CH(n-C4H9)-, -CH(ISO-C4H9)-, -CH(Deut-C4H9)- or-CH(tert-C4H9)-;

6) -CH2CH2CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2CH2-, -CH2CH(CH3)CH2CH2CH2-, -CH2CH2CH(CH3)CH2CH2-, -CH2CH2CH2CH(CH3)CH2-, -CH2CH2CH2CH2CH(CH3)-, -C(CH3)2CH2CH2CH2-, -CH2C(CH3)2CH2CH2-, -CH2CH2C(CH3 )2CH2-, -CH2CH2CH2C(CH3)2-, -CH(CH3)CH(CH3)CH2CH2-, -CH(CH3)CH2CH(CH3)CH2-, -CH(CH3)CH2CH2CH(CH3)-, -CH2CH(CH3)CH(CH3)CH2-, -CH2CH(CH3)CH2CH(CH3)-, -CH2CH2CH(CH3)CH(CH3)-, -CH(C2H5)CH2CH2CH2-, -CH2CH(C2H5)CH2CH2-, -CH2CH2CH(C2H5)CH2-, -CH2CH2CH2CH(C2H5)-, -CH(CH3)CH(CH3)CH(CH3)-, -CH(C2H5)CH(CH3)CH2-, -CH(C2H5)CH2CH(CH3)-, -CH(CH3)CH(C2H5)CH2-, -CH2CH(C2H5)CH(CH3)-, -CH(CH3)CH2CH(C2H5)-, -CH2CH(CH3)CH(C2H5)-.

Of these alkilinity groups is preferred branched C2-6Allenova group, more preferred is a branched C2-4Allenova group, and particularly preferred is a group-C(CH3)2-.

[0032]

In the above description, “C1-6Allenova group having a ring structure includes a structure represented by the following formula:

[Formula 9]

(where D represents CH2, NH, O or S, p is an integer, the number is about 1 to 2, and q is an integer from 0 to 2.)

more specifically, included the following structure.

[Formula 10]

[0033]

Linear and branched C1-6alkyl group and a linear or branched C1-6alkoxygroup can be specified as alkyl groups and alkoxygroup corresponding to the above linear and branched alkilinity groups. The alkyl group preferably is a linear C1-6alkyl group, more preferably a linear C1-4alkyl group, particularly preferably methyl group and ethyl group. Also, alkoxygroup preferably represents a linear C1-6alkoxygroup, more preferably linear C1-4alkoxygroup, particularly preferably a methoxy group and ethoxypropan.

C3-7an alkyl group having a ring structure that includes a group containing only cycloalkyl ring, and groups containing cycloalkyl ring and a linear alkyl group in combination, and specifically mentioned the following:

3)

[Formula 11]

4)

[Formula 12]

5)

[Formula 13]

6)

[Formula 14]

7)

[Formula 15]

From C3-6alkyl groups having a ring structure RX1, RX2, RX3, RX4, RY1, RY2, RY3and RY4more preferred is C3-5an alkyl group having a ring structure, and particularly preferred is the following cyclopropylmethyl group.

[Formula 16]

[0034]

From C3-6alkyl groups having a ring structure RZpreferred is C3-5an alkyl group having a ring structure, and particularly preferred are the following:

[Formula 17]

[0035]

As the halogen atom, which may be a Deputy in a linear or branched C1-6alkyl group or a C3-7alkyl group having a ring structure, you can specify a fluorine atom, chlorine atom, bromine atom or iodine atom, and preferred is a fluorine atom.

[0036]

Linear or branched C1-6alkyl group or a C3-7an alkyl group having a ring structure may be substituted by 1-5 halogen atoms, and more preferably may be substituted by 2 or 3 halogen atoms.

[0037]

Connection to a serial articlecache structure (I) according to the present invention has a structure in which ring X ring and Y both represent clannie aromatic ring, and they are linked in the 1,4-positions, thus, it has a linear structure of the molecule as a whole and has a new structure in which it contains a carboxylic acid group at one end of the molecule and contains the bulk of the imidazole ring at the other end.

[0038]

In connection with the serial articlecache structure (I) of the present invention, tautomerism shown using the following formula, caused by the migration of hydrogen ions in the ring Z, and even when the connection with the serial articlecache structure (I) of the present invention shown with one of these chemical structures, it includes any of these tautomers and their mixture.

[0039]

[Formula 18]

[0040]

Connection to a serial articlecache structure (I) according to the present invention contains a basic group and an acidic group in the molecule, and its pharmaceutically acceptable salt may be a specified acid additive salt (for example, salt of an inorganic acid such as hydrochloride, sulfate, phosphate, hydrobromide, etc., salt of organic acid such as acetate, fumarate, maleate, oxalate, citrate, methanesulfonate, bansilalpet, toluensulfonate and so on) and salt with a base (for example, salt of an alkali metal such as sodium salt, potassium salt, etc., with the ü alkaline-earth metal, such as calcium salt, etc., salt with organic base, such as salt of triethylamine, etc., salt, amino acids such as lysine salt and so on).

The EFFECTS of the INVENTION

[0041]

Connection to a serial articlecache structure (I) or its pharmaceutically acceptable salt according to the present invention has excellent activity inhibition of DGAT1 and useful as a drug for prevention and/or treatment of the following specified diseases of warm-blooded animals (preferably mammals, including humans).

[0042]

(1) Diseases associated with the accumulation of fat (obesity): hyperlipidemia, hypertriglyceridemia, lipid metabolism, fatty liver, and so on

(2) Diseases considered to be caused by the accumulation of fat (obesity): type 2 diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macrovascular disease), arteriosclerosis, hypertension, cerebrovascular disease, ischemic heart disease; dyspnea, lumbago, osteoarthritis of the knee joint and so on

[0043]

In addition, the connection with the serial articlecache structure (I) or its pharmaceutically acceptable salt according to the present invention has a reinforcing sec is Ezio GLP-1 action based on activity of DGAT1 inhibition, thus, it can be expected that it stimulates insulin secretion effect and protective effect on the pancreas.

The BEST WAY of carrying out the INVENTION

[0044]

Connection to a serial articlecache structure (I) according to the present invention can be obtained in accordance with the methods described below.

[0045]

(Method A)

[Formula 19]

[0046]

(in the above formulae, HAL1HAL2and HAL3each represents a halogen atom, PROT1represents a protective group for a polar functional group, PROT2represents a protective group for hydroxyl group, PROT3represents a protective group for carboxyl group, and other symbols have the meanings given above.)

[0047]

(Method B)

[Formula 20]

[0048]

(in the above formulas, reactions, HAL4and HAL5each represents a halogen atom, and other symbols have the meanings given above.)

[0049]

(Method C)

[Formula 21]

[005]

(in the above formulas, reactions symbols have the meanings given above.)

(Method D)

[Formula 22]

[0051]

(in the above formulas, reactions, HAL6represents a halogen atom, PROT4represents a protective group for carboxyl group, and other symbols have the meanings given above.)

[0052]

(Method A)

Stage 1A

As the Compound (II) and Compound (III) can be used such compounds, in which HAL1HAL2and HAL3represent a chlorine atom, a bromine atom or an iodine atom.

[0053]

The cyclization reaction of Compound (II) or its salt and the Compound (III) or its salts and ammonia can be accomplished, for example, in accordance with the description of J. J. Baldwin et al., Journal of Medicinal Chemistry, 29(6), 1065-1080, 1986, and so on, in a suitable solvent, in the presence of a base. As a solvent, you can use water and an alcohol solvent such as methanol, ethanol and so on, separately or in mixture. The base can be an optionally used organic base, such as alkali metal acetate (e.g. sodium acetate), and so on, the Reaction can be performed by heating the first Compound (III) or its salt at 90-100°C in the presence of a base and, after cooling, adding the Compound (II) or with the ü and ammonia to the mixture under ice cooling to 50°C, preferably at a temperature from room temperature to 40°C.

[0054]

Stage 2A

As compounds (V) can indicate that PROT1represents, for example, the protective group for the polar functional groups, which are commonly used in the chemistry of organic synthesis, as described in “Protective Groups in Organic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons 1991, and as such a protective group can be specified, for example, 2-(trimethylsilyl)ethoxymethyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, benzyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichlorocarbanilide group and so on

[0055]

The reaction of the Compound (IV) formed in Stage 1A, with the Compound (V) can be realized, depending on the type of protective group, in accordance with the usual way of introducing a protective group into a polar functional group. For example, when PROT1represents a 2-(trimethylsilyl)ethoxymethyl group or benzyl group, it can be done in the presence of a strong base in an aprotic polar solvent. Aprotic polar solvent may constitute, for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-organic and so on, and a strong base can represent, for example, alkali metal hydride (sodium hydride, lithium hydride or carbon is tons of alkali metal (potassium carbonate). The reaction can be performed at a temperature of 20 to 50°C, preferably in the conditions of a cooling with ice to room temperature.

[0056]

Stage 3A

As the compound (VII) can indicate that PROT2represents, for example, a protective group for hydroxyl group, which are commonly used in the chemistry of organic synthesis, as described in “Protective Groups in Organic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons 1991, and as such a protective group can be specified, for example, benzyl group, trimethylsilyl group, tert-butyldimethylsilyloxy group and so on

[0057]

The reaction mix of the Compound (VI) or its salt formed in Stage 2A, and the Compound (VII) or its salt can be realized, for example, in accordance with the method described in Advanced Organic Chemistry Part B (F. A. Carey &R. J. Sundberg, Springer), and so on, in the presence of a palladium catalyst and a base in a suitable solvent. Part-B(OH)2Compounds (VII) can be protected, if necessary, and, for example, part-B(OH)2can form 4,4,5,5-tetramethyl-1,3-dioxaborolan-2-ilen group with a protective group. The solvent may be a water, an amide solvent such as N,N-dimethylformamide, etc., ether solvent such as tetrahydrofuran, 1,4-dioxane, dimethoxyethane and so on, and toluene and so on, separately or in combination as a mixture thereof. As PA is ladiesare catalyst can be used palladium chloride, the palladium acetate, tetrakis(triphenylphosphine)palladium, and so on, and as a basis you can use the connection of an alkali metal such as sodium carbonate, potassium carbonate, potassium phosphate, sodium hydroxide, and so on, and cesium carbonate, etc. If necessary, you can use a ligand such as 1,1'-bis(diphenylphosphino)ferrocene and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and so on, the Reaction can be performed in conditions from room temperature to 150°C, preferably at 60 to 120°C.

[0058]

Stage 4A

The reaction of removing the protective group (PROT2) from Compound (VIII) formed in Stage 3A, it is possible to carry out removal method of protection used for the removal of the hydroxyl protecting groups which are commonly used in the chemistry of organic synthesis, as described in “Protective Groups in Organic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons 1991, and the best method can be chosen arbitrarily depending on the type of the protective group. For example, when PROT2represents a benzyl group, removing the protective group can be performed in the presence of a palladium catalyst such as palladium hydroxide, palladium on carbon, and so on, in an alcohol solvent such as methanol, ethanol, etc. or ethereal solvent such as tetrahydrofuran, 1,4-dioxane, and so on, in an atmosphere of hydrogen.

[0059]

Stage 5A

As the compound (Xa) and (Xb), you can specify such compounds in which PROT3represents, for example, the protective group for the carboxyl group, which are commonly used in the chemistry of organic synthesis, as described in “Protective Groups in Organic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons 1991, and as such a protective group can be specified, for example, alkyl group such as methyl group, ethyl group and so forth, benzyl group, tert-boutelou group, allyl group, and so on

[0060]

The dehydration reaction of the Compound (IX) or its salt formed at the Stage 4A, and the Compound (Xa) or its salt can be realized, for example, in accordance with the method described in Advanced Organic Chemistry Part B (F. A. Carey &R. J. Sundberg, Springer), Okuda, M.; Tomioka, K.; Tetrahedron Lett [TELEAY] 1994, 35 (26), 4585-4586 and so on, in the presence of a dehydrating agent in a suitable solvent. As a solvent, you can use ethereal solvent such as tetrahydrofuran, 1,4-dioxane, and so on, halogenated aliphatic hydrocarbon solvent such as methylene chloride, etc. and toluene, alone or in combination as a mixture thereof. As the dehydrating agent can be used azodicarboxylic acid derivative such as tetramethyldisiloxane, diethylazodicarboxylate and so on, trialkylphosphine, such as tri-n-butylphosphine and so on; and triarylphosphine, such as triphenylphosphine, and so on, the Reaction can be performed pritemperature from 0 to 80°C. The reaction may also be carried out using the corresponding para-toluensulfonate (Xb) obtained from the Compound (Xa), subjecting the interaction with the Compound (IX) in the reaction conditions are similar to those described in Stage 2A.

[0061]

Stage 6A

The reaction of removing the protective group (PROT1) from Compound (XI), educated at the Stage 5A, can be realized, for example, a method of removing protection, which is usually used in the chemistry of organic synthesis, as described in “Protective Groups in Organic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons 1991, and the best method can be chosen arbitrarily depending on the type of the protective group. For example, when PROT1represents a 2-(trimethylsilyl)ethoxymethyl group, the reaction can be accomplished by treatment with acid, such as hydrochloric acid, triperoxonane acid, methanesulfonate acid, etc. in the water, a water-soluble ether solvent such as 1,4-dioxane, tetrahydrofuran, etc. or an alcohol solvent such as methanol, ethanol, etc. or in the absence of solvent. The reaction may suitably be carried out at room temperature. In addition, when PROT1represents a benzyl group, the reaction can be performed by treatment with palladium catalyst such as palladium hydroxide on coal and so on, in an atmosphere of hydrogen in vocarstvo the Imam of the ether solvent, such as tetrahydrofuran, etc. or an alcohol solvent such as methanol, ethanol, etc.

[0062]

Stage 7A

The reaction of removing the protective group (PROT3) from Compound (XII) is formed on the Stage 6A, can be realized, for example, by the method of removal of the carboxyl protecting groups which are commonly used in the chemistry of organic synthesis, as described in “Protective Groups in Organic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons 1991, and the best method can be chosen arbitrarily depending on the type of the protective group. For example, when PROT3represents an alkyl group such as methyl group, ethyl group and so forth, the reaction can be carried out in accordance with a conventional method using ester hydrolysis, and, for example, it can be accomplished by treatment with alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, etc. in the water, an alcohol solvent such as methanol, ethanol, etc. or ethereal solvent such as tetrahydrofuran, 1,4-dioxane, etc. in Addition, when PROT3represents a benzyl group, removing the protective group can be performed in the presence of a palladium catalyst such as palladium hydroxide, palladium on carbon, and so on, in an atmosphere of hydrogen in an alcohol solvent such as methanol, ethanol, etc. or ethereal solvent such as tet is hydrofuran, 1,4-dioxane, etc. in Addition, when PROT3represents a tert-boutelou group, the reaction can be accomplished by treatment with acid, such as hydrochloric acid, triperoxonane acid, methanesulfonate acid, etc. in the water, the water-soluble solvent such as 1,4-dioxane, tetrahydrofuran, etc. or an alcohol solvent such as methanol, ethanol, etc. or in the absence of solvent. The reaction in a suitable manner can be performed at room temperature.

[0063]

(Method B)

Stage 1B

You can use the compound (XIII), in which HAL4represents a chlorine atom, a bromine atom or an iodine atom, and preferred is a compound in which HAL4represents a bromine atom. The dehydration reaction of the Compound (X) or its salt and the Compound (XIII) or its salt can be performed in a manner analogous to the method of performing the reaction of dehydration of the aforesaid Stage 5A.

[0064]

Stage 2B

The reaction of the Compound (XIV) or its salt formed at the Stage 1B, and bis(pinacolato)Debora can be done in the presence of a palladium catalyst and a base in a suitable solvent. The solvent can be used amide solvent such as N,N-dimethylformamide, etc., ether solvent, such as dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, d is methoxyethane and so on, and toluene and so on, separately or in mixture. As the palladium catalyst can be used palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, etc. and, if necessary, you can use a ligand such as 1,1'-bis(diphenylphosphino)ferrocene, etc. as a basis you can use the connection of an alkali metal such as sodium carbonate, potassium carbonate, potassium acetate, potassium phosphate, sodium hydroxide, etc. and cesium carbonate etc., the Reaction can be performed in conditions from room temperature to 150°C, preferably at 80-120°C.

[0065]

Stage 3B

You can use the Compound (XVI) in which HAL5represents a chlorine atom, a bromine atom or an iodine atom. The reaction mix of the Compound (XV) or its salt formed in Stage 2B, and Compound (XVI) or its salt can be performed in a manner analogous to that described for the reaction in Stage 3A above.

[0066]

Stage 4B

The reaction of the Compound (XVII) or its salt formed at Stage 3B, and hydroxylamine can be done, for example, in accordance with the usual way of communicating ceanography and hydroxylamine as described in U.S. patent No. 5576447 and so on, in a suitable solvent. As a solvent it is possible to use water, an alcohol solvent such as methanol, ethanol, etc. and ethereal solvent, such as tetrahed furan, 1,4-dioxane and so on, separately or in mixture. The reaction can be performed in conditions from room temperature to 100°C, preferably at 50 to 80°C.

[0067]

The product is treated with acetic acid-acetic anhydride in accordance with the usual way, then stirred in a solvent such as an alcohol solvent including methanol, ethanol, etc. or an ethereal solvent such as tetrahydrofuran, etc. in the presence of palladium catalyst such as palladium on carbon, and so on, in an atmosphere of hydrogen, to obtain the Compound (XVIII). The reaction can be performed in conditions from cooling with ice up to 50°C, preferably at room temperature.

[0068]

Stage 5B

The conversion from the Compound (XIXa) in the Compound (XX) can be achieved by interaction of oxalicacid with Compound (XIXa) or its salt in a suitable solvent, the solvent is distilled from the reaction mixture, (trimethylsilyl)diazomethane subjected to interaction with the product in a suitable solvent and the product is treated with Hydrobromic acid.

[0069]

As the solvent for use in the reaction of the Compound (XIXa) and oxalicacid you can specify methylene chloride and tetrahydrofuran, etc. and the reaction can be performed by adding a catalytic amount of N,N-dimethylformamide at a temperature of 20°to 40 ° C, preferably andforming from cooling with ice to room temperature.

[0070]

As the solvent for use in subsequent reactions with trimethylsilyldiazomethane, you can specify acetonitrile, tetrahydrofuran, methylene chloride, etc. Reaction can be performed at a temperature of 20°to 40 ° C, preferably in the conditions of a cooling with ice to room temperature.

[0071]

Processing Hydrobromic acid can be performed, gradually adding Hydrobromic acid to the product of the previous reaction. The reaction can be performed at a temperature of 20°to 40 ° C, preferably in the conditions of a cooling with ice to room temperature.

[0072]

Also, the conversion from the Compound (XIXb) in the Compound (XX) can be performed by reacting Compound (XIXb), or its salts with brainwashin reagent, such as dioxane dibromide, and so on, in a suitable solvent, such as methanol, etc.

[0073]

Stage 6B

The reaction of the Compound (XVIII), educated at Stage 4B, and Compound (XX) or its salt formed at the Stage 5B, can be realized, for example, in accordance with the method described in I. M. Mallick et al., Journal of the American Chemical Society, 106(23), 7252-7254, 1984, etc. in the presence of a base in a suitable solvent. As a solvent it is possible to use water, an alcohol solvent such as methanol, ethanol, etc., aprotic polar solvent such as N,N-dimethylformamide, N-methylpyrrole is n and so on, halogenated hydrocarbon solvent such as methylene chloride, etc. and tetrahydrofuran, acetonitrile and so on, separately or in a mixture, and as a basis you can use the connection of an alkali metal such as potassium bicarbonate, potassium carbonate, sodium ethylate, and so on, the Reaction can be performed in conditions from room temperature to 100°C, preferably at 50 to 80°C.

[0074]

The next stage 7B is similar to reaction (stage 7A) corresponding to the above-mentioned Method A, and it can be done in the same way as described above.

[0075]

Stage 8B

The reaction mix of the Compound (XIV) or its salt formed at the Stage 1B, and Compound (XXVI) or its salt can be performed in the same way as described for the reaction of a combination of Stage 3A above.

[0076]

(Method C)

Stage 1C stage 2C stage stage 3C and 4C each similar Stage 1A, Stage 2A, Stage 1B and Stage 2B, respectively, and can be carried out in the same manner as described above.

[0077]

Stage 5C

The reaction of the Compound (VI) or its salt formed at the Stage 2C, and the Compound (XV) or its salt formed at the Stage 4C, can be done in the same way as described for the reaction of a combination of Stage 3A above.

[0078]

Stage 6C

The reaction of removing the protective group (PROT3) from Compound (XI), educated at the Stage 5C can about what westwith in the same way, as described for the reaction of removing the protective group at the Stage 7A above.

[0079]

Stage 7C

The reaction of removing the protective group (PROT1) from Compound (XXI), educated at the Stage 6C, can be done in the same way as described for the reaction of removing the protective group at the Stage 6A above.

[0080]

Stage 8C

The reaction of formation of Compound (XXVII) from Compound (VI) formed in Stage 2C, a similar reaction in Stage 2B, and can be carried out in the same way.

[0081]

Stage 9C

The reaction of the Compound (XIV) or its salt formed in Stage 3C, and Compound (XXVII) or its salt formed at the Stage 8C, can be done in the same way as described for the reaction of a combination of Stage 3A above.

[0082]

(Method D)

Stage 1D

You can specify the Compound (XXII), in which HAL6represents a chlorine atom, a bromine atom or an iodine atom, PROT4you can remove, for example, by the method of removal of the carboxyl protecting groups which are commonly used in the chemistry of organic synthesis, as described in “Protective Groups in Organic Synthesis” T. W. Greene, P. M. G. Wuts, John Wiley and Sons 1991, and as such a protective group can be specified, for example, ester residue, for example, alkyl group such as methyl group, ethyl group and so forth, benzyl group, and so on

[0083]

The reduction of Compound (XXII) can be done in according to the accordance with the usual method of recovery of ester of carboxylic acid to alcohol, by treatment with a reducing agent in a suitable solvent. As a solvent, you can use ethereal solvent such as tetrahydrofuran, ether and so on, and as a reducing agent can be used Isobutyraldehyde, alumoweld lithium, lithium borohydride, and so on, the Reaction can be performed at temperatures from -30°C to room temperature.

[0084]

Stage 2D stage 3D

Reaction Stage 2D Stage and 3D are similar to the reactions described above at the Stage of Stage 3C and 4C, and can be done in the same way as above.

[0085]

Stage 4D

Reaction Stage 4D can be done in the same way as a reaction to the above-described Stage 3B.

[0086]

Stage 5D

Oxidation of Compound (XXIV) or its salt formed at the Stage 4D can be carried out in accordance with the usual method of oxidation of the alcohol, and, for example, this can be accomplished by oxidation according to the method Swarna. The reaction may be carried out using an oxidant, such as dimethyl sulfoxide, in a suitable solvent. As a solvent it is possible to use halogenated hydrocarbon solvent such as methylene chloride, etc. and as the activating agent preferably you can use oxalicacid and so on, the Reaction can be performed at a temperature from -78°C to room temperature.

[0087]

Stage 6D

EDINENIE (XXV), educated at the Stage 5D, subjected to the same interaction as described above Stage 1A, to obtain the Compound (XII).

[0088]

Stage 7D

The reaction of the Compound (XII) is formed on the Stage 6D, and the Compound (V) can be performed in the same manner as described above Stage 2A.

[0089]

Stage 8D

The reaction of removing the protective group (PROT3) from Compound (XI), educated at the Stage 7D, can be performed in the same manner as the reaction of removing the protective group at the above Stage 7A.

[0090]

Stage 9D

The reaction of removing the protective group (PROT1) from Compound (XXI), educated at the Stage 8D, can be performed in the same manner as the reaction of removing the protective group at the above Stage 7C.

[0091]

In the above-described (Method A) (Method B), (Method C) and (Method D) carry out the isolation and/or purification of the product, this can be accomplished by conventional means of separation and/or purification such as extraction, fractional crystallization, various types of chromatography and so on

[0092]

Thus obtained Compound (I) can be converted to a pharmaceutically acceptable salt, depending on the need, by treatment with acid or base, the corresponding pharmaceutically acceptable salts, in a suitable solvent. Also, the compound or its pharmaceutically acceptable the AI Sol of the present invention include as their MES, and hydrate etc., for Example, the alkali metal salt of Compound (I) can be obtained by treating the Compound (I) an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc. or carbonate of an alkali metal such as sodium carbonate, potassium carbonate, etc. in the water, a water-soluble ether solvent such as tetrahydrofuran, 1,4-dioxane, etc., a nitrile solvent such as acetonitrile and so on, an alcohol solvent such as methanol, ethanol, etc. or including their mixed solvent, obtaining the appropriate metal salt. Moreover, hydrate or MES compounds can be obtained by treatment with water, water-containing solvent or gidratirovannym solvent or other solvents, in accordance with a customary method.

[0093]

When the Compound (I) or its pharmaceutically acceptable salt according to the present invention is a racemic mixture, or contains optical isomers, each optical isomer can be isolated in accordance with conventional optical separation. For example, by optical separation it is possible to obtain the desired optical isomer method fractionated crystallization with the use of a salt with an optically active acid or base, or by passing through a column Packed with an optically asset is a diversified media. Or another way in which optically active isomer of the compounds of formula (I) or its pharmaceutically acceptable salt can be synthesized using optically pure source substances or compounds whose configuration is already known.

[0094]

Thus obtained compound with serial articlecache structure (I) or its pharmaceutically acceptable salt according to the present invention can be formulated in the form of a medical composition containing a pharmaceutically effective amount of the compounds and a pharmaceutically acceptable carrier. As a pharmaceutically acceptable carrier, you can specify a binder (for example, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol), excipient (for example, lactose, sucrose, mannitol, sorbitol, corn starch, potato starch, crystalline cellulose, calcium carbonate), grease (for example, magnesium stearate, calcium stearate, talc), baking powder (for example, hydroxypropylcellulose with a low degree of substitution, cross-linked carboxymethylcellulose) and a humidifier (for example, sodium lauryl sulphate), and so on

[0095]

Connection to a serial articlecache structure (I) or its pharmaceutically acceptable salt according to the present invention can be administered orally or couples who nterline and can be used as a suitable drug. As a suitable drug for oral administration, you can specify, for example, solid preparations such as tablets, granules, capsules, powders, etc. or drugs in the form of a solution, suspension or emulsion, etc. as a suitable drug for parenteral administration, you can specify suppositories, preparations for injection by using distilled water for injection, physiological saline or an aqueous solution of glucose, and so on, or drugs for infusion or inhalation, and so on

[0096]

Dose for introducing connections with serial articlecache structure (I) or its pharmaceutically acceptable salt according to the present invention may vary depending on the method of administration, age, weight and condition of the patient, and in the case of oral administration, usually injected from 0.001 to 100 mg/kg/day, preferably from 0.1 to 30 mg/kg/day, more preferably from 0.1 to 10 mg/kg/day, once a day or dividing into 2-4 receptions. In the case of parenteral administration, preferably introduced from 0.0001 to 10 mg/kg/day, once a day or dividing into several introductions. In addition, when transmucosal introduction introduce preferably from 0.001 to 100 mg/kg/day, once a day or dividing into several introductions.

[0097]

Further, the present invention will be described on the discovering with reference to Examples and Experimental examples, but the present invention is not limited to this. Also, in the chemical formulas in the Examples of the atom of hydrogen on a saturated ring, the hydrogen atom on the alkyl chain and the hydrogen atom on the nitrogen atom in some cases not shown.

EXAMPLES

[0098]

Example 1

[0099]

[Formula 23]

[0100]

1) After adding dropwise a 40% solution of diethylazodicarboxylate in toluene (313,1 ál) to tertrahydrofuran ring solution (3 ml) containing 4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}phenol (150 mg), methylhydroxylamine (65,9 μl) and triphenylphosphine (180,7 mg) under ice cooling, the mixture was stirred at room temperature for one hour and at 70°C during the night. To the mixture was further added methylhydroxypropyl (22 μl), triphenylphosphine (63 mg) and 40% solution of diethylazodicarboxylate in toluene (109 μl) and the mixture was stirred at 70°C for one hour. After cooling the temperature of the reaction mixture was brought to room temperature, the mixture was concentrated under reduced pressure and the obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 88:12 to 76:24) to obtain methyl 2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoate (144,2 mg).

MS (m/z): 550 [M+H]

[0101]

[Formula 24]

[0102]

2) In triperoxonane acid (2.9 ml) and water (0.3 ml) under ice cooling was dissolved methyl 2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoate (144 mg) and the mixture was stirred at room temperature overnight. To the residue obtained by concentrating the reaction mixture under reduced pressure, was added chloroform and saturated aqueous sodium bicarbonate solution. The resulting insoluble matter was dissolved in methanol and combined with the organic layer. The organic layer was washed with water and concentrated under reduced pressure. The obtained residue was ground into a powder chilled ether, collected by filtration and dried to obtain methyl 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoate (85,9 mg).

MS (m/z): 420 [M+H]+

[0103]

[Formula 25]

[0104]

3) In tetrahydrofuran (0,85 ml) and methanol (0,85 ml) was dissolved methyl 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoate (85 mg), to the solution was added 2 N. aqueous sodium hydroxide solution (1013,35 μl) and the mixture was stirred at room temperature overnight. To the reaction mixture was added acetic acid and the mixture is concentrated is under reduced pressure. To the residue was added acetic acid, water and phosphate buffer (pH 6,8), and after stirring the mixture, the organic layer was separated and concentrated under reduced pressure. After purification of the residue using LC-MS it was dissolved in water and ethyl acetate and liquid were separated by the addition of 0.1 Na phosphate buffer (pH 7.0). The organic layer was separated and concentrated under reduced pressure and the obtained residue was ground into powder using a chilled ethyl acetate and collected by filtration to obtain 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoic acid (29.3 mg).

MS (m/z): 406 [M+H]+

[0105]

[Formula 26]

[0106]

4) In tetrahydrofuran (2.5 ml) was dissolved 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoic acid (250 mg), to the solution was added 10M aqueous sodium hydroxide solution (65 ml) several separate portions and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with tetrahydrofuran (1 ml) and dried at 40°C under reduced pressure to obtain sodium 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoate (216 mg).

MS (m/z): 404 [M-Na]-

[0107]

Example 2

[0108]

[Formula 27]

[0109]

1) IU is Langlade (5 ml) was dissolved 3,3,3-Cryptor-2,2-dimethylpropanoyl acid (250 mg) and dropwise to the mixture was added oxalicacid (279 μl). After adding N,N-dimethylformamide (one drop) and the mixture was stirred at room temperature for one hour. After concentrating the reaction mixture under reduced pressure, to the residue was added acetonitrile (2 ml). Dropwise under ice cooling to the mixture was added a solution of 2M (trimethylsilyl)diazomethane-n-hexane (1682 ml) and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was cooled with ice, was added dropwise 48% Hydrobromic acid (272 μl) and the mixture was stirred for 15 minutes. To the reaction mixture was added a simple ether and water and the liquids were separated. The organic layer was separated, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oily substance was dissolved in methylene chloride (5 ml), to the solution was added methyl 3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate (558 mg), potassium carbonate (885 mg) and saturated saline (5 ml) and the mixture was stirred at 45°C during the night. To the reaction mixture were added ethyl acetate and water and the liquids were separated. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and the residue obtained by concentrating the reaction mixture under reduced pressure, was purified at the same time column chromatography on silica gel (chloroform:methanol = 100:0 to 95:5) to obtain methyl 2,2-dimethyl-3-(4-{5-[5-(2,2,2-Cryptor-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoate (178 mg).

MS (m/z): 462 [M+H]+

[0110]

[Formula 28]

[0111]

2) In methanol (2 ml) and tetrahydrofuran (2 ml) was dissolved methyl 2,2-dimethyl-3-(4-{5-[5-(2,2,2-Cryptor-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoate (176 mg), to the solution was added 2 N. aqueous sodium hydroxide solution (900 μl) and the mixture was stirred at room temperature overnight.

[0112]

Acetic acid (3 ml) was added to the mixture and the resulting mixture was concentrated under reduced pressure. To the residue was added water and the resulting solid was collected by filtration and dried to obtain 2,2-dimethyl-3-(4-{5-[5-(2,2,2-Cryptor-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoic acid (167 mg).

MS (m/z): 448 [M+H]+

[0113]

[Formula 29]

[0114]

3) In acetonitrile (4 ml) was added 2,2-dimethyl-3-(4-{5-[5-(2,2,2-Cryptor-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoic acid (175 mg) and to the suspension was added dropwise 2 N. aqueous sodium hydroxide solution (391 μl). After adding acetonitrile (1 ml), the reaction mixture was stirred at room temperature overnight. Added methanol to until the reaction mixture became a homogeneous solution, and resinous undissolved substance was separated by filtration. The filtrate was concentrated at eigendom pressure and the resulting solid residue was ground into powder using a simple ester, collected by filtration, washed with simple ether and dried at room temperature in vacuum to obtain sodium 2,2-dimethyl-3-(4-{5-[5-(2,2,2-Cryptor-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoate (174 mg).

MS (m/z): 446 [M-Na]-

[0115]

Example 3

[0116]

[Formula 30]

[0117]

1) using 2-(4-bromophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (400 mg) and methyl 2,2-dimethyl-3-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}of propanoate (537 mg), the procedure was carried out in the same manner as described in Reference example 1-3), to obtain methyl 2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]propanoate (490 mg).

MS (m/z): 550 [M+H]+

[0118]

[Formula 31]

[0119]

2) In ethanol (10 ml) was dissolved methyl 2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]propanoate (490 mg), to the solution was added 2 N. aqueous sodium hydroxide solution (2.2 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was cooled with ice and neutralized with 2 n hydrochloric acid (2.2 ml), and then to the mixture was added ethyl acetate and a saturated saline solution and liquid were separated. the content of inorganic fillers layer was separated, was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (chloroform:methanol = 100:0 to 97:3) to obtain 2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]propanoic acid (287 mg).

MS (m/z): 536 [M+H]+

[0120]

[Formula 32]

[0121]

3) In triperoxonane acid (10 ml) and water (1 ml) was dissolved 2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]propanoic acid (287 mg) and the mixture was stirred at room temperature overnight. The residue obtained by concentrating the reaction mixture under reduced pressure, was dissolved in acetic acid and the mixture was concentrated under reduced pressure. The obtained solid residue was ground into powder by adding a simple ether, collected by filtration, washed with simple ether and dried to obtain 2,2-dimethyl-3-[(5-{4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-pyridine-2-yl)oxy]propanoic acid (175 mg).

MS (m/z): 406 [M+H]+

[0122]

Example 4

[0123]

[Formula 33]

[0124]

1) using methyl 3-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2,2-dimethylpropanoate (375 mg) and a-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (300 mg), the procedure was carried out in the same way, as described in Reference example 1-3), with methyl 3-(2-fluoro-4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)-2,2-dimethylpropanoate.

MS (m/z): 568 [M+H]+

[0125]

[Formula 34]

[0126]

2) In methanol (6 ml) and tetrahydrofuran (3 ml) was dissolved methyl 3-(2-fluoro-4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)-2,2-dimethylpropanoate obtained in the above stage 1), to the solution was added 10 N. aqueous sodium hydroxide solution (0.3 ml) and the mixture was stirred at room temperature overnight and then boiled under reflux for 4 hours. The residue obtained by concentrating the reaction mixture under reduced pressure, was dissolved in triperoxonane acid (10 ml) and water (1 ml) and the mixture was stirred at room temperature overnight. The residue obtained by concentrating the reaction mixture under reduced pressure, was dissolved in acetic acid (2 ml) and the solution was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (0.5 ml) and water (10 ml) and the mixture was stirred at room temperature for 2 hours. Powdered solid substance was collected by filtration, washed with water, dried, washed with simple ether and dried to p is by receiving 3-(2-fluoro-4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)-2,2-dimethylpropanoate acid (281 mg).

MS (m/z): 424 [M+H]+

[0127]

Example 5

[0128]

[Formula 35]

[0129]

1) In tetrahydrofuran (5.0 ml) was mixed with 2-chloro-4-methyl-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (400 mg), methyl 2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propanoate (409,4 mg), palladium acetate (22.9 mg), potassium phosphate (433,3 mg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (83,8 mg) and the mixture was stirred at 70°C in nitrogen atmosphere overnight. To the mixture was added saturated aqueous sodium bicarbonate solution and after stirring mixture was added ethyl acetate, and the liquids were separated. The organic layer was separated, washed with saturated salt solution and the residue obtained by concentrating the organic layer under reduced pressure, was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 90:10 to 65:35) to obtain methyl 2,2-dimethyl-3-(4-{4-methyl-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoate (152 mg).

MS (m/z): 564 [M+H]+

[0130]

[Formula 36]

[0131]

2) using methyl 2,2-dimethyl-3-(4-{4-methyl-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoate (150 mg), the procedure was carried out in the same manner as in Example 3-2),with 2,2-dimethyl-3-(4-{4-methyl-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}-phenoxy)propanoic acid (141 mg).

MS (m/z): 550 [M+H]+

[0132]

[Formula 37]

[0133]

3) using 2,2-dimethyl-3-(4-{4-methyl-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoic acid (140 mg), the procedure was carried out in the same manner as in Example 3-3), with 2,2-dimethyl-3-(4-{4-methyl-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-pyridine-2-yl}phenoxy)propanoic acid (35,9 mg).

MS (m/z): 420 [M+H]+

[0134]

Example 6

[0135]

[Formula 38]

[0136]

1) using 1-(trifluoromethyl)-1-cyclopropanecarboxylic acid (300 mg) and methyl 3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate (453 mg), the procedure was carried out in the same manner as in Example 2-1), to obtain methyl 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridine-2-yl)phenoxy)propanoate (439 mg).

MS (m/z): 460 [M+H]+

[0137]

[Formula 39]

[0138]

2) using methyl 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridine-2-yl)-phenoxy)propanoate (369 mg), the procedure was carried out in the same manner as in Example 2-2), with 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridine-2-yl)phenoxy)propanoic acid (320 mg).

MS (m/z):446[M+H]+

[0139]

[Formula 40]

[0140]

3) using 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridine-2-yl)-phenoxy)propanoic acid (320 mg), the procedure was carried out in the same manner as in Example 2-3), with sodium 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridine-2-yl)phenoxy)propanoate (313 mg).

MS (m/z):444 [M-Na]-

[0141]

Example 7

[0142]

[Formula 41]

[0143]

1) In tetrahydrofuran (75 ml) was dissolved methyl 5-chloropyrazine-2-carboxylate (2,589 g) to the solution at 0°C was added dropwise 1M solution of diisobutylaluminium in tetrahydrofuran (30 ml) and the mixture was stirred at the same temperature for 15 minutes. To the mixture was added water and 1 n hydrochloric acid, then was added a saturated aqueous solution of sodium bicarbonate to bring the pH to 7. The mixture was filtered through celite and then extracted with chloroform 3 times. The organic layer was separated, dried over anhydrous sodium sulfate and the residue obtained by concentration under reduced pressure, was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 90:10 to 65:35 to 50:50), with (5-chloropyrazine-2-yl)methanol (465 mg).

MS (m/z): 147/145 [M+H]+

[0144]

[Formula 42]

[0145]

2) In N,N-dimethylacetamide (6.4 ml) and 2M water is th solution of sodium carbonate (6.4 ml) suspended (5-chloropyrazine-2-yl)methanol (460 mg) and methyl 2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propanoate (1,600 g), to the suspension was added to the complex of palladium chloride (dppf) with methylene chloride (261 mg) and the mixture was stirred at 80°C during the night. To the reaction mixture were added ethyl acetate and water and the mixture was filtered through celite. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with water, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 70:30 to 40:60 to 0:100) to obtain methyl 3-{4-[5-(hydroxymethyl)pyrazin-2-yl]phenoxy}-2,2-dimethylpropanoate (660 mg).

MS (m/z): 317 [M+H]+

[0146]

[Formula 43]

[0147]

3) To a solution of oxalicacid (355 ml) in methylene chloride (11 ml) was added dropwise a solution of dimethylsulfoxide (450 μl) in methylene chloride (2 ml) at -78°C and the mixture was stirred for 15 minutes. To the mixture was added dropwise a solution of methyl 3-{4-[5-(hydroxymethyl)pyrazin-2-yl]phenoxy}-2,2-dimethylpropanoate (655 mg) in methylene chloride (6 ml) at -78°C and the mixture was stirred for 10 minutes and the mixture was stirred for 1 hour and 30 minutes. To the mixture was added triethylamine (2,05 ml), the temperature of the mixture was raised to 0°C and the mixture was stirred for 30 minutes. To the reaction mixture were added acadeny aqueous solution of ammonium chloride and ethyl acetate and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 95:5 to 75:25), to obtain methyl 3-{4-[5-formylpyridine-2-yl]phenoxy}-2,2-dimethylpropanoate (585 mg).

MS (m/z): 315 [M+H]+

[0148]

[Formula 44]

[0149]

4) using methyl 3-{4-[5-formylpyridine-2-yl]phenoxy}-2,2-dimethylpropanoate (580 mg), the procedure was carried out in the same manner as described in Reference example 1-1), to obtain methyl 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoate (640 mg).

MS (m/z): 421 [M+H]+

[0150]

[Formula 45]

[0151]

5) using methyl 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoate (640 mg), the procedure was carried out in the same manner as described in Reference example 1-2), to obtain methyl 2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoate (759 mg).

MS (m/z): 551 [M+H]+

[0152]

[Formula 46]

[0153]

6) using methyl 2,2-dimethyl-3-(-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoate (755 mg), the procedure was carried out in the same way, as in Example 3-2), with 2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoic acid (545 mg).

MS (m/z): 537 [M+H]+

[0154]

[Formula 47]

[0155]

7) using 2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoic acid (540 mg), the procedure was carried out in the same manner as in Example 3-3), with 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoic acid (335 mg).

MS (m/z): 407 [M+H]+

[0156]

Example 8

[0157]

[Formula 48]

[0158]

1) using 2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenol (224 mg) and tert-butyl 3-hydroxy-2,2-dimethylpropanoate (284 mg), the procedure was carried out in the same manner as in Example 1-1), with tert-butyl 2,2-dimethyl-3-[2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenoxy]propanoate (104 mg).

MS (m/z): 606 [M+H]+

[0159]

[Formula 49]

[0160]

2) In triperoxonane acid (5 ml) and water (0.5 ml) was dissolved tert-butyl 2,2-dimethyl-3-[2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenoxy]propanoate (103 mg) and the mixture is stirred at room temperature overnight. The residue obtained by concentrating the reaction mixture under reduced pressure, was dissolved in tetrahydrofuran, and to the mixture was added 1 N. aqueous sodium hydroxide solution to bring the pH to 7. To the mixture was added 0.1 G. of phosphate buffer, acetate and water and the liquids were separated. The organic layer was separated, dried over anhydrous sodium sulfate and the residue obtained by concentrating the solution under reduced pressure, was added a simple ether for grinding into powder precipitated substances to obtain 2,2-dimethyl-3-[2-methyl-4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoic acid (59,1 mg).

MS (m/z): 420 [M+H]+

[0161]

When using the appropriate starting compounds, the following specified compounds synthesized in the same manner as in Example 8.

[0162]

[0163]

Example 13

[0164]

[Formula 50]

[0165]

1) using 5-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridine]pyridine-2-ol (200 mg), the procedure was carried out in the same manner as in Example 1-1), to obtain methyl 2,2-dimethyl-3-[[5-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]-2-pyridyl]oxy]propanoate (156 mg).

MS (m/z): 551 [M+H]+

[0166]

[Formula 51]

[0167]

p> 2) using methyl 2,2-dimethyl-3-[[5-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]-2-pyridyl]oxy]propanoate (148 mg), the procedure was carried out in the same manner as in Example 3-2), with 2,2-dimethyl-3-[[5-[5-[4-(trifluoromethyl)-1-(2-trimethylsilyloxy-methyl)imidazol-2-yl]-2-pyridyl]-2-pyridyl]oxy]propanoic acid (135 mg).

MS (m/z): 537 [M+H]+

[0168]

[Formula 52]

[0169]

3) using 2,2-dimethyl-3-[[5-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]-2-pyridyl]oxy]propanoic acid (135 mg), the procedure was carried out in the same manner as in Example 3-3), with 2,2-dimethyl-3-[[5-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]-2-pyridyl]oxy]propanoic acid.

MS (m/z): 407 [M+H]+

[0170]

When using the appropriate starting compounds, the following specified compounds synthesized in the same manner as in Example 13.

[0171]

[0172]

Example 18

[0173]

[Formula 53]

[0174]

1) using 4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}-phenol (400 mg) and benzyl 4-hydroxy-2,2-dimethylbutanoate (306 mg), the procedure was carried out in the same manner as in Example 1-1) and 1-2), with benzyl 2,2-dimethyl-4-[4-[5-[5-(cryptomite is)-1H-imidazol-2-yl]-2-pyridine]phenoxy]butanoate (366 mg).

MS (m/z): 510 [M+H]+

[0175]

[Formula 54]

[0176]

2) In tetrahydrofuran (20 ml) was dissolved benzyl 2,2-dimethyl-4-[4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridine]phenoxy]-butanoate (365 mg), to the solution was added 10% palladium on coal (400 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 6 hours. Palladium on coal was filtered and washed with tetrahydrofuran and chloroform. The filtrate was concentrated under reduced pressure, the obtained solid residue was added isopropanol and isopropyl simple ether for suspension and a solid substance was collected by filtration to obtain 2,2-dimethyl-4-[4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridine]phenoxy]butane acid (200 mg).

MS (m/z): 420 [M+H]+

[0177]

Example 19

[0178]

[Formula 55]

[0179]

1) In N,N-dimethylformamide (1.4 ml) was dissolved 4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}phenol (305 mg), to the solution was added 60% sodium hydride (34 mg) at room temperature and the mixture was stirred for one hour. To the reaction mixture under ice cooling was added a solution of N,N-dimethylformamide (1 ml) containing methyl 2-ethyl-2-(para-tolylsulfochloride)butanoate (264 mg). The reaction mixture was stirred at 100°C during the night. To implement the operating mixture under ice cooling was added 60% sodium hydride (9 mg) and the mixture was stirred at 100°C during the night. To the reaction mixture were added saturated aqueous solution of ammonium chloride and ethyl acetate, and the liquids were separated. The aqueous layer was separated and was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline in that order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 95:5 to 50:50) to obtain methyl 2-ethyl-2-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenoxy]methyl]butanoate (248 mg).

MS (m/z): 578 [M+H]+

[0180]

[Formula 56]

[0181]

2) using methyl 2-ethyl-2-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenoxy]-methyl]butanoate (474 mg), the procedure was carried out in the same manner as in Example 3-2), with 2-ethyl-2-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenoxy]methyl]butane acid (414 mg).

MS (m/z):564 [M+H]+

[0182]

[Formula 57]

[0183]

3) using 2-ethyl-2-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenoxy]-methyl]butane acid (465 mg), the procedure was carried out in the same manner as in Example 3-3), with 2-these�-2-[[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]methyl]-butane acid (249 mg).

MS (m/z): 434 [M+H]+

[0184]

When using the appropriate starting compounds, the following specified compounds synthesized in the same manner as in Example 19.

[0185]

[0186]

When using the appropriate carboxylic acid, the following compounds were synthesized in the same manner as in Example 2.

[0187]

[0188]

Example 35

[0189]

[Formula 58]

[0190]

1) To methylene chloride (10 ml) was added 3,3,3-Cryptor-2,2-dimethylpropanoyl acid (1000 mg) and dropwise to the mixture was added oxalicacid (1132 µl). To the mixture was added N,N-dimethylformamide (5 drops) and the resulting mixture was stirred at room temperature for one hour. After concentrating the reaction mixture under reduced pressure, to the residue was added acetonitrile (7 ml). Dropwise to the mixture was added a solution of 2M trimethylsilyldiazomethane-n-hexane (6814 μl) at 0°C and the mixture was stirred at room temperature for 1.5 hours. After cooling the mixture to 0°C. to the mixture was added dropwise 48% Hydrobromic acid (1.1 ml) and the mixture was stirred for 30 minutes. To the reaction mixture were added ethyl acetate and saturated aqueous sodium bicarbonate solution and the liquid was separated. The organic layer was separated, about ivali saturated salt solution, was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-bromo-1-[1-(trifluoromethyl)cyclopropyl]ethanone (1413 mg).

NMR (400 MHz, CDCl3) σ: 1,47-of 1.75 (m, 4H), to 4.38 (s, 3H)

[0191]

[Formula 59]

[0192]

2) To methylene chloride (10 ml) and saturated salt solution (10 ml) was added methyl 3-[4-(5-carbamimidoyl-4-methylpyridin-2-yl)phenoxy]-2,2-dimethylpropanoate (500 mg) and potassium carbonate (430,3 mg), and then to the mixture was added 2-bromo-1-[1-(trifluoromethyl)cyclopropyl]alanon (431,6 mg) and the resulting mixture was stirred at 50°C during the night. The organic layer was separated and the residue obtained by concentration under reduced pressure, was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 75:25 to 25:75), to obtain methyl 2,2-dimethyl-3-[4-(4-methyl-5-{5-[1-(trifluoromethyl)-cyclopropyl]-1H-imidazol-2-yl}pyridine-2-yl)phenoxy]propanoate (423 mg).

MS (m/z): 474 [M+H]+

[0193]

[Formula 60]

[0194]

3) using methyl 2,2-dimethyl-3-[4-(4-methyl-5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridine-2-yl)-phenoxy]propanoate (422 mg), the procedure was carried out in the same manner as in Example 2-2), with 2,2-dimethyl-3-[4-(4-methyl-5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridine-2-yl)phenoxy]propanoic acid (378 mg).

MS (m/z): 460 [M+H]+

[0195]

Using appropriate starting compounds, the following compounds were synthesized in the same manner as in Example 35.

[0196]

[0197]

Example 54

[0198]

[Formula 61]

[0199]

1) N,N-dimethylformamide (30 ml) was added to 4-bromo-2-perbenzoate (2000 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}-propanoate (4191 mg) and the complex of palladium chloride (dppf) with methylene chloride (408 mg) and after adding to the mixture 2 N. of an aqueous solution of sodium carbonate (15 ml) the atmosphere was replaced with nitrogen and the resulting mixture was stirred at 60°C for 7 hours. To the reaction mixture were added ethyl acetate and water and the liquids were separated. The organic layer was separated, washed with saturated salt solution and the residue obtained by concentrating the mixture under reduced pressure, was purified using column chromatography on silica gel (n-hexane: ethyl acetate = 90:10 to 80:20) to obtain methyl 3-{[5-(4-cyano-3-forfinal)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate (3587 mg).

MS (m/z): 343 [M+H]+

[0200]

[Formula 62]

2) the Mixture obtained by adding methanol (20 ml) and tetrahydrofuran (20 ml) of methyl 3-{[5-(4-cyano-3-forfinal)4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate (3.55 g) and hydroxylamine (50% aqueous solution, of 13.7 g) was stirred at 80°C for 5 hours. After concentrating the mixture under reduced pressure, to the residue were added chloroform and water and the liquids were separated. The organic layer was separated, washed with saturated brine, concentrated under reduced pressure and dried to obtain methyl 3-({5-[3-fluoro-4-(N-hydroxycarbamoyl)phenyl]-4-methylpyridin-2-yl}oxy)-2,2-dimethylpropanoate (3,66 g).

MS (m/z): 376 [M+H]+

[0201]

[Formula 63]

[0202]

3) Acetic anhydride (1,62 ml) was added to a solution of acetic acid (10 ml) containing methyl 3-({5-[3-fluoro-4-(N-hydroxycarbamoyl)phenyl]-4-methylpyridin-2-yl}oxy)-2,2-dimethylpropanoate (3,65 g) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 ml), the resulting solution was added 10% palladium on carbon (50%, 365 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 13 hours. The catalyst was filtered through the filter membrane and the filtrate was concentrated under reduced pressure. To the obtained residue was added a simple ether and the precipitated solid substance was collected by filtration, washed with simple ether and dried to obtain methyl 3-{[5-(4-carbamimidoyl-3-forfinal)-4-methylpyridin-2-yl]oxy}-2,2-is emailprotect, salts of acetic acid (2,45 g).

MS (m/z): 360 [M+H]+

[0203]

[Formula 64]

[0204]

4) the Mixture obtained by adding methylene chloride (8 ml) and saturated brine (8 ml) of methyl 3-{[5-(4-carbamimidoyl-3-forfinal)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate in the form of a salt of acetic acid (400 mg), 2-bromo-1-[1-(trifluoromethyl)cyclopropyl]ethanone (289 mg) and potassium carbonate (404 mg), was stirred at 50°C for 8 hours. The organic layer was separated and concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (2.0 ml) and methanol (2.0 ml) and after adding to this solution 2 N. aqueous sodium hydroxide solution (3.0 ml) the resulting mixture was stirred at 50°C for 3 hours. The mixture was diluted with ethyl acetate and then neutralized by adding 1 n hydrochloric acid. The organic layer was separated, the residue obtained by concentrating the mixture under reduced pressure, was added a simple ether and the resulting mixture was stirred. The precipitated solid was collected by filtration and dried to obtain 3-{[5-(3-fluoro-4-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}phenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate acid (339 mg).

MS (m/z): 478 [M+H]+

[0205]

Example 55

[0206]

[Formula 65]

[0207]

1) In methanol (30 ml) was dissolved 1-cyclobutylamine (1,05 g), to the solution was added deoxyribose (2,68 g) and the mixture was stirred at room temperature for 1 hour and 40 minutes. To the reaction mixture were added saturated aqueous sodium bicarbonate solution, then added water and the mixture was extracted with simple ether. The organic layer was separated, washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by concentrating the mixture under reduced pressure, dissolved in methylene chloride (20 ml), then to the solution was added methyl 3-(4-{5-[amino(imino)methyl]pyridin-2-yl}-phenoxy)-2,2-dimethylpropanoate acetate (700 mg), potassium carbonate (1.25 g) and saturated saline (20 ml) and the resulting mixture was stirred at 50°C during the night. The reaction mixture was separated and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate. The residue obtained by concentrating the reaction mixture under reduced pressure, was purified column chromatography on NH-silica gel (n-hexane:ethyl acetate = 65:35 to 15:85) and then using column chromatography on silica gel (n-hexane:ethyl acetate = 65:35 to 20:80) to obtain methyl 3-[4-[5-(5-cyclobutyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoate (266 mg).

MS (m/z): 406 [M+H]+

[0208]

[The form is and the 66]

[0209]

2) using methyl 3-[4-[5-(5-cyclobutyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoate (260 mg), the procedure was carried out in the same manner as in Example 2-2), with 3-[4-[5-(5-cyclobutyl-1H-imidazol-2-yl)-2-pyridyl]-phenoxy]-2,2-dimethylpropanoate acid (230 mg).

MS (m/z): 392 [M+H]+

[0210]

Using the corresponding ketone was synthesized following compounds in the same manner as in Example 55.

[0211]

[0212]

Example 58

[0213]

[Formula 67]

[0214]

1) using the acetate salt of methyl 3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate (400 mg) and 1-rambutan-2-she (234 mg), the procedure was carried out in the same manner as in Example 28, to obtain methyl 3-[4-[5-(5-ethyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoate (397 mg).

MS (m/z): 380 [M+H]+

[0215]

[Formula 68]

[0216]

2) using methyl 3-[4-[5-(5-ethyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoate (270 mg), the procedure was carried out in the same manner as in Example 2-2), with 3-[4-[5-(5-ethyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoate acid (218 mg).

MS (m/z): 366 [M+H]+

[0217]

Using appropriate starting compounds of sleduyusheye synthesized in the same way, as in Example 58.

[0218]

[0219]

Example 60

[0220]

[Formula 69]

[0221]

1) To dimethoxyethane (12 ml) was added 2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (489 mg), methyl 1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropanecarboxylate (500 mg), tetrakis(triphenylphosphine)palladium (134 mg) and 2M aqueous sodium carbonate solution (2,32 ml) and the mixture was stirred at 80°C under nitrogen atmosphere over night. The reaction mixture was passed through a short column with NH-silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on NH-silica gel (n-hexane:ethyl acetate = 88:12 to 71:29) to obtain methyl 1-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenoxy]-methyl]cyclopropanecarboxylate (491 mg).

MS (m/z): 548 [M+H]+

[0222]

[Formula 70]

[0223]

2) using methyl 1-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenoxy]-methyl]cyclopropanecarboxylate (484 mg), the procedure was carried out in the same manner as in Example 3-2), with 1-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenoxy]methyl]cyclopropane the OIC acid (439 mg).

MS (m/z): 534 [M+H]+

[0224]

[Formula 71]

[0225]

3) using 1-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenoxy]-methyl]cyclopropanecarboxylic acid (431 mg), the procedure was carried out in the same manner as in Example 3-3), with 1-[[4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]methyl]cyclopropanecarbonyl acid (KZT 235.7 mg).

MS (m/z): 404 [M+H]+

[0226]

Example 61

[Formula 72]

[0227]

1) a Mixture obtained by adding tetrahydrofuran (6 ml) for 5-bromo-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]pyridine (542 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine-2-yl]oxy}propanoate (372 mg), the potassium phosphate (302 mg), palladium acetate (8 mg) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (29 mg), was stirred in nitrogen atmosphere at 50°C for 6 hours. After cooling the mixture to room temperature, to the mixture was added saturated aqueous sodium bicarbonate solution, water and ethyl acetate and the resulting mixture was stirred. The organic layer was separated, washed with saturated salt solution and the residue obtained by concentration under reduced pressure, was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 90:10 to 60:40) in order obtain methyl 2,2-dimethyl-3-({4-methyl-6'-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)propanoate (100 mg).

MS (m/z): 565 [M+H]+

[0228]

[Formula 73]

[0229]

2) Methanol (0.7 ml) and tetrahydrofuran (0.7 ml) was added to methyl 2,2-dimethyl-3-({4-methyl-6'-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)propanoate (99 mg) and after adding to the mixture 2 N. aqueous sodium hydroxide solution (0.7 ml) the resulting mixture was stirred at 50°C for 2 hours. To the reaction mixture were added ethyl acetate and the mixture was neutralized with 2 n hydrochloric acid. The organic layer was separated, washed with saturated salt solution and the residue obtained by concentrating the mixture under reduced pressure, was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 76:24 to 0:100) to obtain 2,2-dimethyl-3-({4-methyl-6'-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)propanoic acid (81 mg).

MS (m/z): 551 [M+H]+

[0230]

[Formula 74]

[0231]

3) In triperoxonane acid (2.0 ml) and water (0.1 ml) was dissolved 2,2-dimethyl-3-({4-methyl-6'-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)propanoic acid (80 mg) and the solution was stirred at room temperature for 7 hours. To the solution was added 2 N. aqueous sodium hydroxide solution is La bring the pH to 2-3, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated saline, the organic layer was separated and concentrated under reduced pressure. To the obtained residue was added isopropyl ether and the precipitated solid substance was collected by filtration and dried under reduced pressure to obtain 2,2-dimethyl-3-({4-methyl-6'-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)propanoic acid (30 mg).

MS (m/z): 421 [M+H]+

[0232]

Example 62

[0233]

[Formula 75]

[0234]

1) N,N-dimethylformamide (4 ml) was added to 2-(4-bromo-2-forfinal)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (500 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}propanoate (477 mg) and the complex of palladium chloride (dppf) with methylene chloride (46 mg) and after adding to the mixture 2 N. of an aqueous solution of sodium carbonate (1,71 ml), the atmosphere was replaced with nitrogen and the resulting mixture was stirred at 60°C for 5 hours. To the reaction mixture were added ethyl acetate and water and the liquids were separated. The organic layer was separated, washed with saturated salt solution and the residue obtained by concentrating the mixture under reduced pressure, was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 95:5 to 82:18) to obtain methyl 3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]m is Tyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (677 mg).

MS (m/z): 582 [M+H]+

[0235]

[Formula 76]

[0236]

2) Methanol (3.0 ml) and tetrahydrofuran (3.0 ml) was added to methyl 3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (660 mg) and after adding to the mixture 2 N. aqueous sodium hydroxide solution (4.0 ml) the resulting mixture was stirred at 50°C for 2 hours. To the reaction mixture were added ethyl acetate and the mixture was neutralized with 2 n hydrochloric acid. The organic layer was separated, washed with saturated saline and concentrated under reduced pressure to obtain 3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid (721 mg).

MS (m/z): 568 [M+H]+

[0237]

[Formula 77]

[0238]

3) In triperoxonane acid (2.0 ml) and water (0.1 ml) was dissolved 3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoyl acid (640 mg) and the solution was stirred at room temperature for 10 hours. The solution was neutralized by adding 2 N. aqueous sodium hydroxide solution and the resulting mixture was extracted with ethyl acetate. The extract was washed nassen the m salt solution, the organic layer was separated and concentrated under reduced pressure. To the obtained residue was added a simple ether and the precipitated solid substance was collected by filtration and dried under reduced pressure to obtain 3-[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)-oxy]-2,2-dimethylpropanoate acid (432 mg).

MS (m/z): 438 [M+H]+

[0239]

Example 63

[0240]

[Formula 78]

[0241]

1) N,N-dimethylformamide (2 ml) was added to 2-(4-bromo-2-chlorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (297 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}propanoate (228 mg) and the complex of palladium chloride (dppf) with methylene chloride (27 mg) and after adding to the mixture 2 N. of an aqueous solution of sodium carbonate (0,98 ml), the atmosphere was replaced with nitrogen and the resulting mixture was stirred at 60°C for 5 hours. To the reaction mixture were added ethyl acetate and water and the liquids were separated. The organic layer was separated, washed with saturated salt solution and the residue obtained by concentrating the mixture under reduced pressure, was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 94:6 to 82:18) to obtain methyl 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)ox is]-2,2-dimethylpropanoate (278 mg).

MS (m/z): 598/600 [M+H]+

[0242]

[Formula 79]

[0243]

2) Methanol (1.5 ml) and tetrahydrofuran (1.5 ml) was added to methyl 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (274 mg) and after adding to the mixture 2 N. aqueous sodium hydroxide solution (1.5 ml) the resulting mixture was stirred at 50°C for 2 hours. To the reaction mixture were added ethyl acetate and the resulting mixture was neutralized 1 N. a solution of hydrochloric acid. The organic layer was separated, washed with saturated saline and concentrated under reduced pressure to obtain 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid (279 mg).

MS (m/z): 584/586 [M+H]+

[0244]

[Formula 80]

[0245]

3) In triperoxonane acid (1.0 ml) and water (0.05 ml) was dissolved 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoyl acid (268 mg) and the solution was stirred at room temperature for 10 hours. The solution was neutralized by adding 2 N. aqueous sodium hydroxide solution and was extracted with ethyl acetate. The extract was washed the feast upon the major salt solution and the organic layer was separated and concentrated under reduced pressure. To the obtained residue was added a simple ether and the precipitated solid substance was collected by filtration and dried under reduced pressure to obtain 3-[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid (133 mg).

MS (m/z): 454/456 [M+H]+

Using appropriate starting compounds, the following compounds were synthesized in the same manner as in Example 60.

[0246]

[0247]

Example 85

[0248]

[Formula 81]

[0249]

1) using 4-chloro-3-ethylphenol (2000 mg) and methyl hydroxypivalic (2025 mg), the procedure was carried out in the same manner as in Example 1-1), with methyl 3-(4-chloro-3-ethylenoxy)-2,2-dimethylpropanoate (2951 mg).

MS (m/z): 288/290 [M+NH4]+

[0250]

[Formula 82]

[0251]

2) using methyl 3-(4-chloro-3-ethylenoxy)-2,2-dimethylpropanoate (2000 mg) procedure was carried out in the same manner as described in Reference example 6-2), with methyl 3-[3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2,2-diethylpropane (2311 mg).

MS (m/z): 380 [M+NH4]+

[0252]

[Formula 83]

[0253]

3) using methyl 3-[3-ethyl-4-(4,4,55-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2,2-diethylpropane (200 mg) and 2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (233,2 mg), the procedure was carried out in the same way, as described in Reference example 1-3), with methyl 3-(3-ethyl-4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}-phenoxy)-2,2-dimethylpropanoate (94 mg).

MS (m/z): 578 [M+H]+

[0254]

[Formula 84]

[0255]

4) using methyl 3-(3-ethyl-4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)-2,2-dimethylpropanoate (80 mg), the procedure was carried out in the same manner as in Example 4-1) and (4-2), 3-(3-ethyl-4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}-phenoxy)-2,2-dimethylpropanoate acid (434 mg).

MS (m/z): 434 [M+H]+

[0256]

Example 86

[0257]

[Formula 85]

[0258]

1) using benzyl 3-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2,2-dimethylpropanoate (1,03 g) and 2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (494 mg), the procedure was carried out in the same manner as described in Reference example 1-3), to obtain benzyl 3-[3-methoxy-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl]-2-pyridyl]phenoxy]-2,2-dimethylpropanoate (639 mg).

MS (m/z): 656 [M+H]+

[0259]

[Formula 86]

[0260]

2) using benzyl 3-[3-methoxy-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)imidazol-2-yl-2-pyridyl]phenoxy]-2,2-dimethylpropanoate (638 mg), the procedure was carried out in the same way, as in Example 1-2), to obtain benzyl 3-[3-methoxy-4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]-2,2-dimethylpropanoate.

MS (m/z): 526 [M+H]+

[0261]

[Formula 87]

[0262]

3) using benzyl 3-[3-methoxy-4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]-2,2-dimethylpropanoate obtained as described above in 2), the procedure was carried out in the same manner as in Example 18-2), to obtain 3-[3-methoxy-4-[5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]-2,2-dimethylpropanoate acid (246 mg).

MS (m/z): 436 [M+H]+

[0263]

Example 87

[0264]

[Formula 88]

[0265]

1) In tetrahydrofuran (100 ml) was dissolved methyl 6-chloropyridazine-3-carboxylate (cash consideration of USD 1,726 g), the solution was cooled to 0°C, the solution was added dropwise a solution of 1M of diisobutylaluminium in tetrahydrofuran (20 ml) and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was sequentially added water (10 ml) and 1 n hydrochloric acid (20 ml) at 0°C. After adding to the mixture of saturated aqueous sodium bicarbonate solution at room temperature, the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the residue obtained by concentrating the extract under reduced pressure, was purified by using column is a chromatography on silica gel (n-hexane:ethyl acetate = 90:10 to 25:75) to give (6-chloropyridin-3-yl)methanol (177 mg).

MS (m/z): 147/145 [M+H]+

[0266]

[Formula 89]

[0267]

2) using (6-chloropyridin-3-yl)methanol (170 mg) and methyl 3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2,2-dimethylpropanoate (606 mg), the procedure was carried out in the same manner as described in Reference example 1-3), to obtain methyl 3-{4-[6-(hydroxymethyl)pyridin-3-yl]phenoxy}-2,2'-dimethylpropanoate (188 mg).

MS (m/z): 317 [M+H]+

[0268]

[Formula 90]

[0269]

3) To methylenchloride solution (8 ml) containing oxacillin (278 μl), was added dropwise methylenechloride solution (2 ml) containing dimethyl sulfoxide (350 μl) at -78°C and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added dropwise a methylene chloride (5 ml) containing methyl 3-{4-[6-(hydroxymethyl)pyridin-3-yl]phenoxy}-2,2'-dimethylpropanoate (519 mg) for 10 minutes and the mixture was stirred at the same temperature for 1 hour. To the mixture at 0°C was added drop wise addition of triethylamine (1.6 ml) and the mixture was stirred for 30 minutes. To the reaction mixture were added saturated aqueous solution of ammonium chloride and ethyl acetate, and the liquids were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water (twice) and saturated saline solution, dried the hell anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 90:10 to 50:50) to obtain methyl 3-[4-(6-formylpyridine-3-yl)phenoxy]-2,2'-dimethylpropanoate (443 mg).

MS (m/z): 315 [M+H]+

[0270]

[Formula 91]

4) using methyl 3-[4-(6-formylpyridine-3-yl)phenoxy]-2,2'-dimethylpropanoate (443 mg), the procedure was carried out in the same manner as described in Reference example 1-1), to obtain methyl 2,2-dimethyl-3-(4-{6-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridazin-3-yl}phenoxy)propanoate (360 mg).

MS (m/z): 421 [M+H]+

[0271]

[Formula 92]

[0272]

5) using methyl 2,2-dimethyl-3-(4-{6-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridazin-3-yl}phenoxy)propanoate (359 mg), the procedure was carried out in the same manner as described in Reference example 1-2), to obtain methyl 2,2-dimethyl-3-(4-{6-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridazin-3-yl}phenoxy)propanoate (309 mg).

MS (m/z): 551 [M+H]+

[0273]

[Formula 93]

[0274]

6) using methyl 2,2-dimethyl-3-(4-{6-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridazin-3-yl}phenoxy)propanoate (309 mg), the procedure was carried out in the same manner as in Example 3-2), with 2,2-dimethyl-3-(4-{6-[4-(trifluoromethyl)-1-{[2-(three is lilcely)-ethoxy]methyl}-1H-imidazol-2-yl]pyridazin-3-yl}phenoxy)propanoic acid (259 mg).

MS (m/z): 537 [M+H]+

[0275]

[Formula 94]

[0276]

7) using 2,2-dimethyl-3-(4-{6-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridazin-3-yl}phenoxy)propanoic acid (257 mg), the procedure was carried out in the same manner as in Example 3-3), with 2,2-dimethyl-3-(4-{6-[4-(trifluoromethyl)-1H-imidazol-2-yl]pyridazin-3-yl}-phenoxy)propanoic acid (194 mg).

MS (m/z): 407 [M+H]+

[0277]

Example 88

[0278]

[Formula 95]

[0279]

1) using 1-(trifluoromethyl)-1-CYCLOBUTANE carboxylic acid (300 mg) and methyl 3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate acetate (415 mg), the procedure was carried out in the same manner as in Example 2-1), to obtain methyl 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}pyridine-2-yl)phenoxy)propanoate (369 mg).

MS (m/z): 474 [M+H]+

[0280]

[Formula 96]

[0281]

2) using methyl 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}pyridine-2-yl)-phenoxy)propanoate (367 mg), the procedure was carried out in the same manner as in Example 2-2), with 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}pyridine-2-yl)-phenoxy)propanoic acid (350 mg).

MS (m/z): 460 [M+H]+

[0282]

[Formula 97]

[0283]

3) using 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}pyridine-2-yl)-phenoxy)propanoic acid (350 mg), the procedure was carried out in the same manner as in Example 2-3), with sodium 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}pyridine-2-yl)phenoxy)propanoate (296 mg).

MS (m/z): 458 [M-Na]-

[0284]

Example 89

[0285]

[Formula 98]

[0286]

1) Dimethoxyethane (10 ml) and 2M aqueous sodium carbonate solution (1290 ml) was added to tert-butyl 3-[(5-chloropyrazine-2-yl)oxy]-2,2-dimethylpropanoate (185 mg), tetranitropentaerythritol (75 mg) and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (363 mg) and the mixture was stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature and filtered through Celite. To the filtrate was added ethyl acetate and water and the liquids were separated. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 99:1 to 90:10) to give tert-butyl 2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]phenyl}pyrazin-2-yl)oxy]propane is a (256,2 mg).

MS (m/z): 593 [M+H]+

[0287]

[Formula 99]

[0288]

2) using tert-butyl 2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}pyrazin-2-yl)oxy]propanoate (256 mg), the procedure was carried out in the same manner as in Example 8-2), with 2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-pyrazin-2-yl)oxy]propanoic acid (the 122.7 mg).

MS (m/z): 407 [M+H]+

[0289]

Using appropriate starting compounds, the following compounds were synthesized in the same manner as in Example 89.

[0290]

[0291]

Example 93

[0292]

[Formula 100]

[0293]

1) using 1-benzyl-2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole (815 mg) and methyl 2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propanoate (1,43 g) the procedure was carried out in the same manner as described in Reference example 1-3), with methyl 3-({4'-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl] - biphenyl-4-yl}oxy)-2,2-dimethylpropanoate (901 mg).

MS (m/z): 509 [M+H]+

[0294]

[Formula 101]

[0295]

2) using methyl 3-({4'-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl] - biphenyl-4-yl}oxy)-2,2-dimethylpropanoate (900 mg), the procedure was carried out in the same manner as in Example 3-2), with whom rucenim 3-({4'-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl] - biphenyl-4-yl}oxy)-2,2-dimethylpropanoate acid (832 mg).

MS (m/z): 495 [M+H]+

[0296]

[Formula 102]

[0297]

3) Mix 3-({4'-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl] - biphenyl-4-yl}oxy)-2,2-dimethylpropanoate acid (830 mg), 20% palladium hydroxide on carbon (850 mg) and tetrahydrofuran (20 ml) was stirred at 60°C in an atmosphere of hydrogen for 6 hours. After the reaction mixture was passed gaseous nitrogen and the mixture was diluted with chloroform. The mixture was filtered through filter membrane and the filtrate was washed with tetrahydrofuran, methanol and chloroform. The filtrates were combined and the residue obtained by concentration under reduced pressure, was added n-hexane and propanol. The precipitated solid was collected by filtration to obtain 3-({4'-[5-(trifluoromethyl)-1H-imidazol-2-yl] - biphenyl-4-yl}oxy)-2,2-dimethylpropanoate acid (635 mg).

MS (m/z): 405 [M+H]+

[0298]

Example 94

[0299]

[Formula 103]

[0300]

1) N,N-dimethylformamide (7,4 ml) was added to 6-bromo-nicotinamide (273 mg), tert-butyl 2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propanoate (552 mg) and 2 N. aqueous solution of sodium carbonate (2.2 ml) and after replacing the atmosphere with nitrogen to the mixture was added to the complex of palladium chloride (dppf) with methylene chloride (60 mg) and the resulting mixture was stirred at 60°C over night. To the reaction mixture add the Yali ethyl acetate and water and the liquids were separated. After filtration through Celite the organic layer was separated, washed with water and then saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 90:10 to 70:30) to give tert-butyl 3-[4-(5-formylpyridine-2-yl)-phenoxy]-2,2-dimethylpropanoate (459 mg).

MS (m/z): 356 [M+H]+

[0301]

[Formula 104]

[0302]

2) using 3,3-dibromo-1,1,1-tryptophan-2-it (2,02 g) and tert-butyl 3-[4-(5-formylpyridine-2-yl)phenoxy]-2,2-dimethylpropanoate (889 mg), the procedure was carried out in the same manner as described in Reference example 1-1), with tert-butyl 2,2-dimethyl-3-{4-[5-(4-trifluoromethyl-1H-imidazol-2-yl)-pyridine-2-yl]phenoxy}propanoate in the form of a pale yellow solid (806 mg).

MS (m/z): 462 [M+H]+

[0303]

[Formula 105]

[0304]

3) using tert-butyl 2,2-dimethyl-3-{4-[5-(4-trifluoromethyl-1H-imidazol-2-yl)-pyridine-2-yl]phenoxy}of propanoate (325 mg), the procedure was carried out in the same manner as in Example 8-2), with 2,2-dimethyl-3-[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoic acid (167 mg).

MS (m/z):420 [M+H]+

[0305]

[Formula 106]

[0306]

4) In tetrahed is furane (10 ml) was added 2,2-dimethyl-3-[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoic acid (1001 mg) and the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise 10M aqueous solution of potassium hydroxide (0.25 ml) and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with tetrahydrofuran and dried under reduced pressure to obtain potassium 2,2-dimethyl-3-[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoate (995 mg).

MS (m/z): 406 [M-K+2H]+

[0307]

Example 95

[0308]

[Formula 107]

[0309]

1) In tetrahydrofuran (66 ml) was dissolved methyl 5-chloropyrazine-2-carboxylate (3.3 g) and to the solution was added dropwise a solution of 1M of diisobutylaluminium/hexane (38,3 ml) in nitrogen atmosphere at -70°C or below for 10 minutes and the resulting mixture then was stirred for 10 minutes. At a temperature of -60°C or below to the mixture was added dropwise a solution of 1M of diisobutylaluminium/hexane (31,3 ml) for 20 minutes and the mixture is again stirred at -70°C or below within 1 hour. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and after stirring at room temperature, filtered through Celite. The filtrate was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromium is ographie on silica gel (n-hexane:ethyl acetate = 100:0 to 80:20) to give 5-chloropyrazine-2-carbaldehyde (970 mg).

MS (m/z): 142/144 [M+H]+

[0310]

[Formula 108]

[0311]

2) N,N-dimethylformamide (10 ml) was added to 5-chloropyrazine-2-carbaldehyde (500 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}propanoate (1410 mg) and 2 N. aqueous solution of sodium carbonate (5,26 ml) and, after replacing the atmosphere with nitrogen, the mixture was added to the complex of palladium chloride (dppf) with methylene chloride (143 mg) and the resulting mixture was stirred at 65°C for 2 hours. To the reaction mixture were added ethyl acetate and water and the liquids were separated. After filtration through Celite the organic layer was separated, washed with water and then saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 100:0 to 70:30) to obtain methyl 3-{[5-(5-formylpyridine-2-yl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate (855 mg).

MS (m/z): 330 [M+H]+

[0312]

[Formula 109]

[0313]

3) the Mixture obtained by adding 3,3-dibromo-1,1,1-tryptophan-2-it (1311 mg) and sodium acetate (797 mg), water (2 ml) was stirred at 90°C for 1 hour and then cooled with ice. After the dissolution of methyl 3-{[5-(5-formylpyridine-2-yl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate (40 mg) and 28% aqueous ammonia solution (8 ml) in methanol (4 ml) and tetrahydrofuran (4 ml) of this solution was added to the above reaction solution and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, to the residue was added ethyl acetate, and the liquids were separated. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 90:10 to 66:34) to obtain methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridine-2-yl)oxy]propanoate (325 mg).

MS (m/z): 436 [M+H]+

[0314]

[Formula 110]

[0315]

4) sodium Hydride (60%, 35 mg) was added to N,N-dimethylformamide (3 ml) solution containing methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-pyrazin-2-yl}pyridine-2-yl)oxy]propanoate (320 mg) at 0°C and the resulting mixture was stirred at the same temperature for 1 hour. To the mixture was added 2-(trimethylsilyl)ethoxymethylene (195 μl), the temperature of the mixture was raised to room temperature and the mixture was stirred for 1 hour. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and then saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography the raffia on silica gel (n-hexane:ethyl acetate = 90:10 to 80:20) to obtain the mixture (324 mg), methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridine-2-yl)oxy]propanoate and methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridine-2-yl)oxy]propanoate.

MS (m/z): 566 [M+H]+

[0316]

[Formula 111]

[0317]

5) In methanol (6.4 ml) was dissolved the compound (320 mg) of methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridine-2-yl)oxy]propanoate and methyl 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridine-2-yl)oxy]propanoate and 1 N. aqueous sodium hydroxide solution and 2.83 ml) and the resulting mixture was boiled under reflux for 1 hour. After concentrating the mixture under reduced pressure, the residue was acidified (pH=4 by adding 1 n hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a mixture of 2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridine-2-yl)oxy]propanoic acid and 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}-pyridine-2-yl)oxy]propanoic acid.

MS (m/z): 552 [M+H]+

[0318]

[Formula 112]

[0319]

6) In triperoxonane acid (3.1 ml) and water (0,31 ml) was dissolved a mixture of 2,2-dimethyl-3-[(4-methyl-5-{5-[4-(trifluoromethyl)-1-{[2-trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridine-2-yl)oxy]propanoic acid and 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyrazin-2-yl}pyridine-2-yl)oxy]propane acid, obtained as described above in 5) and the solution was stirred at room temperature. To the residue obtained by concentrating the solution under reduced pressure, was added acetic acid and the resulting mixture was concentrated under reduced pressure. The solid residue was added a simple isopropyl ether to grind it into powder and powdered substance was dried to obtain 2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridine-2-yl)oxy]propanoic acid (197 mg).

MS (m/z): 422 [M+H]+

[0320]

Example 96

[0321]

[Formula 113]

[0322]

1) a Mixture obtained by adding methylene chloride (10 ml) and saturated brine (10 ml) of methyl 3-{[5-(4-carbamimidoyl-3-forfinal)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate in the form of a salt of acetic acid (300 mg), 1-bromo-3-cyclopropylamino-2-ONU (190 mg) and potassium carbonate (346 mg), was stirred at 40°C for 5 hours. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (chloroform:methanol = 100:0 to 97:3) to give methyl 3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-forfinal}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (248 mg).

MS (m/z): 438 [M+H]+

[033]

[Formula 114]

[0324]

2) In tetrahydrofuran (10 ml) and methanol (10 ml) was dissolved methyl 3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-forfinal}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (247 mg) and after adding to this solution 2 N. aqueous sodium hydroxide solution (2.8 ml) the resulting mixture was stirred at 50°C for 7 hours. To the residue obtained by concentrating the reaction mixture under reduced pressure, adding water and acetic acid. The precipitated solid was collected by filtration, washed with water and dried to obtain 3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-forfinal}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid (339 mg).

MS (m/z): 424 [M+H]+

[0325]

Example 97

[0326]

[Formula 115]

[0327]

1) In tetrahydrofuran (11 ml) was dissolved 5-bromo-4-methylpyridin-2-ol (639 mg), ethyl 1-(hydroxymethyl)cyclobutanecarboxylic (538 mg) and triphenylphosphine (1.07 g), to the solution was added dropwise a 40% solution of diethyl azodicarboxylate in toluene (1,86 ml) at room temperature and then the mixture was stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the precipitated solid was removed by filtration. The filtrate was concentrated PR is the reduced pressure and the obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 100:0 to 90:10) to give ethyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}of cyclobutanecarboxylic (638 mg).

MS (m/z): 328/330 [M+H]+

[0328]

[Formula 116]

[0329]

2) 1,4-Dioxane (32 ml) was added to ethyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic (1.6 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (1.24 g), and the complex of palladium chloride (dppf) with methylene chloride (170 mg) and potassium acetate (1.44 g) and the mixture was stirred in nitrogen atmosphere at 100°C for 4 hours. To the reaction mixture were added ethyl acetate and water for the extraction of the target compounds. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 100:0 to 80:20) to obtain ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}methyl)cyclobutanecarboxylic (1.30 grams).

MS (m/z): 376 [M+H]+

[0330]

[Formula 117]

[0331]

3) N,N-dimethylformamide (3 ml) was added to 5-bromo-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (338 mg), ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}methyl)-cyclobutanecarboxylic (300 mg) and the complex of palladium chloride (dppf) with methylene chloride (33 mg) and after adding to the mixture 2 N. of an aqueous solution of carbonate of soda is I (1.2 ml) in the atmosphere was replaced with nitrogen and the mixture was stirred at 65°C for 2 hours. The reaction mixture was filtered through Celite and was added to the filtrate ethyl acetate and water for the extraction of the target compounds. The organic layer was separated, washed with saturated saline and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 100:0 to 90:10) to obtain ethyl 1-[({4-methyl-6'-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]-cyclobutanecarboxylic (344 mg).

MS (m/z): 591 [M+H]+

[0332]

[Formula 118]

[0333]

4) Methanol (7 ml) was added to ethyl 1-[({4-methyl-6'-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]cyclobutanecarboxylic (343 mg), and then to the mixture was added 1 N. aqueous sodium hydroxide solution (2.9 ml) and the resulting mixture was boiled under reflux for 1 hour. Methanol drove under reduced pressure and the residue was neutralized 1 N. a solution of hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1-[({4-methyl-6'-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-meth is l}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]-cyclobutanecarboxylic acid.

MS (m/z): 563[M+H]+

[0334]

[Formula 119]

[0335]

5) In triperoxonane acid (3.3 ml) and water (0.33 ml) was dissolved 1-[({4-methyl-6'-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]cyclobutanecarbonyl acid (327 mg) and the solution was stirred at room temperature for 60 hours. The reaction mixture was concentrated under reduced pressure, subjected to azeotropic distillation with acetic acid and to the obtained residue was added a simple isopropyl ether. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-[({4-methyl-6'-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)-methyl]cyclobutanecarboxylic acid (217 mg).

MS (m/z): 433 [M+H]+

[0336]

Example 98

[0337]

[Formula 120]

[0338]

1) N,N-dimethylformamide (5 ml) was added to 2-(4-bromo-2-forfinal)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (293 mg), ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}methyl)-cyclobutanecarboxylic (250 mg) and the complex of palladium chloride (dppf) with methylene chloride (28 mg) and after adding to the mixture 2 N. of an aqueous solution of sodium carbonate (1 ml), the atmosphere was replaced with nitrogen and the mixture was stirred at 65°C for 3 hours. To the reaction sm is si was added ethyl acetate and water for the extraction of the target compounds. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 100:0 to 80:20) to give ethyl 1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}of cyclobutanecarboxylic (316 mg).

MS (m/z): 608 [M+H]+

[0339]

[Formula 121]

[0340]

2) Methanol (6.3 ml) and 1 N. aqueous sodium hydroxide solution (2.6 ml) was added to ethyl 1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic (315 mg) and the mixture is boiled under reflux for 1 hour. Methanol drove under reduced pressure and the residue was neutralized 1 N. a solution of hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified using column chromatography on silica gel (chloroform:methanol = 100:0 to 95:5) to obtain 1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]phenyl}-4-metier the DIN-2-yl)oxy]methyl}-cyclobutanecarboxylic acid (308 mg).

MS (m/z): 580 [M+H]+

[0341]

[Formula 122]

[0342]

3) In triperoxonane acid (3.0 ml) and water (0.3 ml) was dissolved 1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarbonyl acid (299 mg) and the solution was stirred at 50°C for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was brought to pH=4 with a saturated aqueous solution of sodium bicarbonate and 1 N. hydrochloric acid, was extracted with ethyl acetate and the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the obtained residue was added a simple isopropyl ether. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-{[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)-oxy]methyl}cyclobutanecarboxylic acid (200 mg).

MS (m/z): 450 [M+H]+

[0343]

Example 99

[0344]

[Formula 123]

[0345]

1) In N,N-dimethylformamide (24 ml) was dissolved 5-bromo-3-chloropyridin-2-carboxylic acid (2,36 g), 1-hydroxybenzotriazole (2.2 g) and the hydrochloride of 3-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2,87 g), the solution is obavljale hydrochloride of N,O-dimethylhydroxylamine (1.27 g) and triethylamine (1,95 ml) and the resulting mixture was stirred at room temperature for 20 hours. To the obtained residue was added ice water, extracted with ethyl acetate and the organic layer was washed with water and then saturated saline solution. After drying the mixture over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain 5-bromo-3-chloro-N-methoxy-N-methylpyridine-2-carboxamide (2.67 g).

MS (m/z): 279/281/283 [M+H]+

[0346]

[Formula 124]

[0347]

2) In tetrahydrofuran (27 ml) was dissolved 5-bromo-3-chloro-N-methoxy-N-methylpyridin-2-carboxamide (2.66 g), the mixture was cooled in nitrogen atmosphere at -70°C or below and to the mixture was added dropwise a suspension of lithium aluminum hydride (180 mg) in tetrahydrofuran (5 ml). The mixture was stirred at -70°C or below within 2 hours, then to the mixture was added dropwise water (10 ml) and saturated saline (10 ml). The temperature of the mixture was raised to room temperature, the mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 100:0 to 90:10) to obtain a mixture of aldehyde compounds and aldehyde equivalent (2.1 g). In water (36 ml) was added 3,3-dibromo-1,1,1-tryptophan-2-he (6,61 g) and sodium acetate(as 4.02 g) and the mixture was stirred at 95°C for 30 minutes. An aqueous solution obtained by cooling the mixture with ice, was added to the mixture containing the previously obtained mixture of aldehyde/aldehyde equivalent (1.8 g), 28% aqueous ammonia solution (18 ml) and methanol (36 ml) at room temperature and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, the residue was extracted with ethyl acetate and the organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 80:20) and the obtained solid substance was collected by filtration, washed simple isopropyl ether and dried to obtain 5-bromo-3-chloro-2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (935 mg).

MS (m/z): 326/328/330 [M+H]+

[0348]

[Formula 125]

[349]

3) In N,N-dimethylformamide (13 ml) was dissolved 5-bromo-3-chloro-2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (1.27 g), to the solution was added with ice cooling 60% sodium hydride (187 mg) and after raising the temperature of the mixture to room temperature, the mixture was stirred for 1 hour. The reaction mixture was cooled with ice, to the mixture was added 2-(trimethylsilyl)ethoxymethylene (1,03 ml) and after raising the temperature of the mixture up to matnog temperature and the mixture was stirred for 1 hour. To the reaction mixture was added water, the mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 100:0 to 95:5) to give 5-bromo-3-chloro-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (1.56 g).

MS (m/z): 458/460/462 [M+H]+

[0350]

[Formula 126]

[0351]

4) N,N-dimethylformamide (3 ml) was added to 5-bromo-3-chloro-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (365 mg), ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}methyl)-cyclobutanecarboxylic (300 mg) and the complex of palladium chloride (dppf) with methylene chloride (33 mg) and after adding to the mixture 2 N. aqueous sodium carbonate solution (1.2 ml), the atmosphere was replaced with nitrogen and the mixture was stirred at 65°C for 2 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, concentrated under reduced pressure and the obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 100:0 to 90:10) to obtain ethyl 1-[({5'-chloro-4-methyl-6'-[-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]cyclobutanecarboxylic (318 mg).

MS (m/z): 625/627 [M+H]+

[0352]

[Formula 127]

[0353]

5) Methanol (7 ml) and 1 N. aqueous sodium hydroxide solution (2.6 ml) was added to ethyl 1-[({5'-chloro-4-methyl-6'-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]cyclobutanecarboxylic (327 mg) and the mixture is boiled under reflux for 1 hour. Methanol drove under reduced pressure and the residue was neutralized 1 N. a solution of hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure to obtain 1-[({5'-chloro-4-methyl-6'-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]cyclobutanecarboxylic acid.

MS (m/z): 597/599 [M+H]+

[0354]

[Formula 128]

[0355]

6) In triperoxonane acid (3.1 ml) and water (0.3 ml) was dissolved 1-[({5'-chloro-4-methyl-6'-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]cyclobutanecarbonyl acid (312 mg) and the mixture was allowed to stand at room temperature for 60 hours. The reaction mixture was concentrated under reduced pressure, subjected to azeotropic distillation with acetic acid, to receive the resultant residue was added a simple isopropyl ether and the precipitated solid substance was collected by filtration and dried under reduced pressure to obtain 1-[({5'-chloro-4-methyl-6'-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)-methyl]cyclobutanecarbonyl acid (151 mg).

MS (m/z): 467/469 [M+H]+

[0356]

Example 100

[0357]

[Formula 129]

[0358]

1) In tetrahydrofuran (26 ml) was dissolved 5-bromo-4-methylpyridin-2-ol (1.3 g), methyl 1-(hydroxymethyl)-cyclopropanecarboxylate (1.08 g) and to the solution was added dropwise triphenylphosphine (2,72 g) and 40% solution of diethylazodicarboxylate in toluene (4,72 ml) at 0°C. the Mixture was stirred at 70°C for 4 hours. The reaction mixture was cooled to room temperature, to the mixture were added water and ethyl acetate and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 99:1 to 99:5) to give methyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}-cyclopropanecarboxylate (2,08 g).

MS (m/z): 300/302 [M+H]+

[0359]

[Formula 130]

[0360]

2) 1,4-Dioxane (20 ml) was added to methyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylate (1.01 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (1,03 g), the complex of palladium chloride (dppf) with methylene chloride (71 mg) and potassium acetate (994 mg) and the mixture was stirred in nitrogen atmosphere at 100°C for 3 hours. To the reaction mixture were added ethyl acetate and water for extra the investments of the target compounds. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 95:5 to 80:20) to give methyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}methyl)cyclopropanecarboxylate (1.08 g).

MS (m/z): 348 [M+H]+

[0361]

[Formula 131]

[0362]

3) N,N-dimethylformamide (11 ml) was added to 2-(4-bromo-2-chlorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (220 mg), methyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}methyl)-cyclopropanecarboxylate (201 mg) and the complex of palladium chloride (dppf) with methylene chloride (39 mg) and after adding to the mixture 2 N. of an aqueous solution of sodium carbonate (to 0.72 ml), the atmosphere was replaced with nitrogen and the mixture was stirred at 65°C for 2 hours. To the reaction mixture were added ethyl acetate and water for the extraction of the target compounds and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 95:5 to 80:20) to obtain methyl 1-{[(5-{3-chloro-4-[4-(trif ormetal)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}of cyclopropanecarboxylate (237 mg).

MS (m/z): 596/598 [M+H]+

[0363]

[Formula 132]

[0364]

4) In methanol (7 ml) and tetrahydrofuran (7 ml) was dissolved methyl 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylate (236 mg), to the solution was added 2 N. aqueous sodium hydroxide solution (1,98 ml) and the resulting mixture was stirred at 50°C for 4 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added acetic acid and ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylic acid (221 mg).

MS (m/z): 582/584 [M+H]+

[0365]

[Formula 133]

[0366]

5) In triperoxonane acid (5.0 ml) and water (0.5 ml) was dissolved 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarbonyl acid (219 mg) and the solution was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, to the residue were added in small amounts, the creation of tetrahydrofuran and the mixture is neutralized 1 N. aqueous solution of sodium hydroxide. To the mixture were added a few drops of acetic acid, the mixture was extracted with ethyl acetate, washed with saturated brine and the organic layer was separated and concentrated under reduced pressure. To the obtained residue was added a simple isopropyl ether and the precipitated solid substance was collected by filtration and dried under reduced pressure to obtain 1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylic acid (95 mg).

MS (m/z): 452/454 [M+H]+

[0367]

Example 101

[0368]

[Formula 134]

[0369]

1) N,N-dimethylformamide (3.3 ml) was added to 2-(4-bromo-2-chlorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (200 mg), ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}methyl)-cyclobutanecarboxylic (164 mg) and the complex of palladium chloride (dppf) with methylene chloride (18 mg) and after adding to the mixture 2 N. of an aqueous solution of sodium carbonate (0,66 ml), the atmosphere was replaced with nitrogen and the mixture was stirred at 65°C for 3 hours. To the reaction mixture were added ethyl acetate and water and the liquids were separated. The organic layer was separated, washed with saturated salt solution and the residue obtained by concentrating the mixture under reduced pressure, was purified by using to lodochnoy chromatography on silica gel (n-hexane:ethyl acetate = 100:0 to 80:20) to give ethyl 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}of cyclobutanecarboxylic (214 mg).

MS (m/z): 624/626 [M+H]+

[0370]

[Formula 135]

[0371]

2) Methanol (4.3 ml) and 1 N. aqueous sodium hydroxide solution (1.7 ml) was added to ethyl 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic (213 mg) and the mixture is boiled under reflux for 1 hour. Methanol drove under reduced pressure and the residue was neutralized 1 N. a solution of hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified using column chromatography on silica gel (chloroform:methanol = 100:0 to 95:5) to obtain 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}-cyclobutanecarboxylic acid (205 mg).

MS (m/z): 596/598 [M+H]+

[0372]

[Formula 136]

[0373]

3) In triperoxonane acid (2.0 ml) and water (0.2 ml) was dissolved 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarbonyl acid (202 mg) and the solution was stirred at 50°C for 3 hours. Reacciona the mixture was concentrated under reduced pressure, the pH of the residue was brought to 4 with a saturated aqueous solution of sodium bicarbonate and 1 N. hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, the organic layer was separated and concentrated under reduced pressure. To the obtained residue was added a simple isopropyl ether and the precipitated solid substance was collected by filtration and dried under reduced pressure to obtain 1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic acid (137 mg).

MS (m/z): 466/468 [M+H]+

Using appropriate starting compounds, the following compounds were synthesized in the same manner as in Examples 1-101.

[0374]

[0375]

Reference example 1

[0376]

[Formula 137]

[0377]

1) To water (15 ml) was added 3,3-dibromo-1,1,1-tryptophan-2-he (of 4.05 g) and sodium acetate (2,46 g) and the mixture was stirred at 95°C for 30 minutes. The solution obtained by cooling with ice, was added to a solution obtained by dissolving 6-bromo-nicotinamide the guide (1.86 g) in 28% aqueous ammonia solution (20 ml) and methanol (60 ml) under ice cooling and the mixture was stirred over night, in this case, the temperature of the mixture was gradually raised to room temperature. The reaction mixture was concentrated under reduced pressure, and then to the mixture were added water and ethyl acetate and liquid were separated and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the resulting solid residue was added a simple ether for grinding residue into a powder and a solid substance was collected by filtration and dried to obtain 2-bromo-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (1.25 g).

MS (m/z): 292/294 [M+H]+

[0378]

[Formula 138]

[0379]

2) 60% sodium Hydride (2,62 g) was added to a solution of 2-bromo-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (13,65 g) dissolved in N,N-dimethylformamide (150 ml), under nitrogen atmosphere and under ice cooling and the mixture was stirred for 30 minutes. To the mixture was added 2-(trimethylsilyl)ethoxymethylene (12,4 ml) under ice cooling and the mixture was stirred overnight while the temperature of the mixture was gradually raised to room temperature. To the reaction mixture were added saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and the aqueous layer at this time was extracted with ethyl acetate. The organic layers were combined and dried, and the residue obtained p is the concentration of the reaction mixture under reduced pressure was purified using column chromatography on silica gel (n-hexane: ethyl acetate), to obtain 2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (9,42 g).

MS (m/z): 422/424 [M+H]+

[0380]

[Formula 139]

[0381]

3) a Complex of palladium chloride (dppf) with methylene chloride (0,193 g) was added to a mixture of 2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (1.0 g), (4-benzyloxyphenyl)Bronevoy acid (1.08 g), 2M aqueous sodium carbonate (4,74 ml) and N,N-dimethylformamide (18,9 ml) in nitrogen atmosphere and the mixture was stirred at 65°C in nitrogen atmosphere overnight. To the mixture were added water and ethyl acetate, and then the insoluble substance was removed by filtration using Celite. The organic layer was separated, washed with saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 88:12 to 80:20) to give 2-[4-(benzyloxy)phenyl]-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]pyridine (1.038 g).

MS (m/z): 526 [M+H]+

[0382]

[Formula 140]

[0383]

4) In methanol (8 ml) and tetrahydrofuran (6 ml) was dissolved 2-[4-(benzyloxy)phenyl]-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]pyridine (0,77 g) and after addition of palladium on carbon (0154 g) in the atmosphere nitrogen atmosphere was replaced with hydrogen and the mixture was stirred at room temperature for 5 hours. The insoluble substance was filtered through the filter membrane and the filtrate was concentrated under reduced pressure. The concentrate was diluted with methanol, was added activated charcoal and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and was led by obtaining 4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}-phenol (0,612 g).

MS (m/z): 436 [M+H]+

[0384]

Reference example 2

[0385]

[Formula 141]

[0386]

1) 40% solution of diethylazodicarboxylate in toluene (9,54 ml) was added to tertrahydrofuran ring (40 ml) solution containing 4-bromophenol (2.0 g), methylhydroxypropyl (2,77 g) and triphenylphosphine (5.49 g) and the mixture was stirred at 70°C for 3 hours. The reaction mixture was concentrated under reduced pressure and purified using column chromatography on silica gel (n-hexane:ethyl acetate = 90:10) to give methyl 3-(4-bromophenoxy)-2,2-dimethylpropanoate (3.2 g).

MS (m/z): 287/289 [M+H]+

[0387]

[Formula 142]

[0388]

2) To 1,4-dioxane (60 ml) was added methyl 3-(4-bromophenoxy)-2,2-dimethylpropanoate (4.68 g), bis(pinacolato)LIBOR (of 5.17 g), a complex of palladium chloride (dppf) with methylene chloride (399 mg) and potassium acetate (4,80 g) and the mixture was stirred at 80°C under nitrogen atmosphere over night. Reactionuses was passed through a short column, filled with silica gel and NH-silica gel, and washed with ethyl acetate. The residue obtained by concentrating the filtrate under reduced pressure, was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 93:7 to 75:25) to obtain methyl 2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]propanoate (4,93 g).

MS (m/z): 335 [M+H]+

[0389]

[Formula 143]

[0390]

3) To N,N-dimethylformamide (140 ml) was added methyl 2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propanoate (8.6 g), 2-chloropyridin-5-cyanide (3.0 g), a complex of palladium chloride (dppf) (788 mg) and 2 N. aqueous sodium carbonate solution (32 ml) and the mixture was stirred at 65°C in nitrogen atmosphere overnight. After cooling the reaction mixture to room temperature, to the mixture were added water and ethyl acetate and the mixture filtered through Celite. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and the residue obtained by concentrating the reaction mixture under reduced pressure, was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 95:5 to 70:30) to obtain methyl 3-[4-(5-cyano-2-yl)phenoxy]-2,2-dimethylpropanoate (6.0 g).

MS (m/z): 311 [M+H]+

[0391]

[Formula 144]

[0392]

4) 50% aqueous solution of hydro is of Salamina (40 g) was added to a solution of methyl 3-[4-(5-cyano-2-yl)phenoxy]-2,2-dimethylpropanoate (6.0 g) in methanol (100 ml) and tetrahydrofuran (100 ml), and the mixture was stirred at 80°C for 4 hours. After cooling the reaction mixture to room temperature the mixture was concentrated under reduced pressure. To the obtained residue were added ethyl acetate and water and the liquids were separated. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. To the solid residue obtained by concentrating the mixture under reduced pressure, was added a simple ether for grinding residue into a powder and a solid substance was collected by filtration and dried to obtain methyl 3-(4-{5-[amino(hydroxyimino)methyl]pyridine-2-yl}phenoxy)-2,2-dimethylpropanoate (5.8 g).

MS (m/z): 344 [M+H]+

[0393]

[Formula 145]

[0394]

5) In acetic acid (60 ml) was dissolved methyl 3-(4-{5-[amino(hydroxyimino)methyl]pyridine-2-yl}phenoxy)-2,2-dimethylpropanoate (5.8 g), to the solution was added acetic anhydride (4 ml) and the mixture was stirred at room temperature for 2 hours. To the residue obtained by concentrating the mixture under reduced pressure, was added methanol (300 ml) and tetrahydrofuran (70 ml) and to the mixture was added in nitrogen atmosphere with 10% palladium on carbon (1.2 g). The atmosphere of the reaction mixture was replaced with an atmosphere of hydrogen and the mixture was stirred at room temperature for 2 hours. After replacing the atmosphere with nitrogen, the mixture was filtered with COI is the whether Celite. The filtrate was concentrated under reduced pressure, the obtained residue was added a simple ether for grinding solids into a powder and a solid substance was collected by filtration and dried to obtain methyl 3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate (6.11 g).

MS (m/z): 328 [M+H]+

[0395]

Reference example 3

[0396]

[Formula 146]

[0397]

1) using 4-bromobenzaldehyde (1.0 g) the procedure was carried out in the same manner as described in Reference example 1-1), obtaining 2-(4-bromophenyl)-5-(trifluoromethyl)-1H-imidazole (1.22 g).

MS (m/z): 291/293 [M+H]+

[0398]

[Formula 147]

[0399]

2) using 2-(4-bromophenyl)-5-(trifluoromethyl)-1H-imidazole (1.22 g) the procedure was carried out in the same manner as described in Reference example 1-2), obtaining 2-(4-bromophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (1.63 g).

MS (m/z): 421/423 [M+H]+

[0400]

Reference example 4

[0401]

[Formula 148]

[0402]

1) using 3-bromo-6-hydroxypyridine (3.57 g) the procedure was carried out in the same manner as described in Reference example 2-1), with methyl 3-[(5-bromopyridin-2-yl)oxy]-2,2-dimethylpropanoate (4.83 g).

MS (m/z): 288/290 [M+H]+

[0403]

[Formula 149]

[0404]

2) using methyl 3-[(5-bromopyridin-2-yl)oxy]-2,2-dimethylpropanoate (4,82 g) the procedure was carried out in the same manner as described in Reference example 2-2), to obtain methyl 2,2-dimethyl-3-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]oxy}of propanoate book (6.16 g).

MS (m/z): 336 [M+H]+

[0405]

Reference example 5

[0406]

[Formula 150]

[0407]

1) using 4-bromo-2-terfenol (2.0 g) the procedure was carried out in the same manner as described in Reference example 2-1), with methyl 3-(4-bromo-2-pertenece)-2,2-dimethylpropanoate (3.11 g).

MS (m/z): 305/307 [M+H]+

[0408]

[Formula 151]

[0409]

2) using methyl 3-(4-bromo-2-pertenece)-2,2-dimethylpropanoate (3.1 g) the procedure was carried out in the same manner as described in Reference example 2-2), with methyl 3-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2,2-dimethylpropanoate (1,912 g).

MS (m/z): 370 [M+H]+

[0410]

Reference example 6

[0411]

[Formula 152]

[0412]

1) In N,N-dimethylformamide (40 ml) was dissolved 4-bromo-2-methyl-phenol (1,87 g), to the solution was added potassium carbonate (4.15 g) and benzylbromide (1.3 ml) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate and the liquid is separated. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 98:2 to 95:5) to give 1-benzyloxy-4-bromo-2-methylbenzo (2,73 g).

NMR (400 MHz, d6-DMSO) σ: 2,19 (s, 3H), 5,11 (s, 2H), 6,97 (d, J=8 Hz, 1H), 7,29-7,46 (m, 7H)

[0413]

[Formula 153]

[0414]

2) To 1,4-dioxane (50 ml) was added 1-benzyloxy-4-bromo-2-methylbenzo (2,73 g), Tris(dibenzylideneacetone)dipalladium (0.18 g), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (0,19 g), potassium acetate (2,90 g) and bis(pinacolato)LIBOR (7,52 g) and the mixture was stirred at 110°C under nitrogen atmosphere over night. After cooling the reaction mixture to room temperature, the insoluble substance was removed by filtration using Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 98:2 to 95:5) to give 2-(4-benzyloxy-3-were)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3,22 g).

MS (m/z): 325 [M+H]+

[0415]

[Formula 154]

[0416]

3) using 2-(4-benzyloxy-3-were)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan is a (1.08 g) and 2-bromo-5-[4-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-2-yl]pyridine (0.7 g) the procedure was carried out in the same way, as described in Reference example 1-3), with 2-[[2-[6-(4-benzyloxy-3-were)-3-pyridyl]-4-(trifluoromethyl)imidazol-1-yl]methoxy]ethyltrimethoxysilane (0,892 g).

MS (m/z): 540 [M+H]+

[0417]

[Formula 155]

[0418]

4) using 2-[[2-[6-(4-benzyloxy-3-were)-3-pyridyl]-4-(trifluoromethyl)imidazol-1-yl]methoxy]-ethyltrimethoxysilane (0,89 g) the procedure was carried out in the same manner as described in Reference example 1-4), with 2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethynyl)-imidazol-2-yl]-2-pyridyl]phenol (0,656 g).

MS (m/z):450 [M+H]+

[0419]

Using appropriate starting compounds synthesized the following compounds in the same manner as described in Reference example 6.

[0420]

[0421]

Reference example 11

[0422]

[Formula 156]

[0423]

1) using 4-bromophenol (1,33 g) and methyl 1-(hydroxymethyl)cyclopropanecarboxylate (663 mg), the procedure was carried out in the same manner as described in Reference example 2-1), with methyl 1-[(4-bromophenoxy)methyl]cyclopropane-of-carboxylate (1,03 g).

MS (m/z): 302/304 [M+H]+

[0424]

[Formula 157]

[0425]

2) using methyl 1-[(4-bromophenoxy)methyl]cyclopropanecarboxylate (1.0 g) the procedure was carried out by the mayor in the same way, as described in Reference example 2-2), with methyl 1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropanecarboxylate (930 mg).

MS (m/z): 350 [M+H]+

[0426]

Using appropriate starting compounds, synthesized the following compounds in the same manner as described in Reference example 11.

[0427]

[0428]

Reference example 20

[0429]

[Formula 158]

[0430]

1) In N,N-dimethylformamide (10 ml) was dissolved 5-bromo-2-chloropyridin (1000 mg) and tert-butyl 3-hydroxy-2,2-dimethylpropanoate (991 mg) and to the solution was added with ice cooling 60% sodium hydride (248 mg). The reaction mixture was stirred at room temperature for 6 hours, at 50°C for 1 hour and 45 minutes and then at room temperature overnight. To the reaction mixture was added water under ice cooling and the mixture was extracted with simple ether. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 100:0 to 95:5) to give tert-butyl 3-(5-bromopyrimidine-2-yl)oxy-2,2-dimethylpropanoate (1,048 g).

MS (m/z): 331/333 [M+H]+

[0431]

Formula 159]

[0432]

2) using tert-butyl 3-(5-bromopyrimidine-2-yl)oxy-2,2-dimethylpropanoate (1,045 g) the procedure was carried out in the same manner as described in Reference example 2-2), with tert-butyl 2,2-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-yl]oxopropanoic (795 mg).

MS (m/z): 379 [M+H]+

[0433]

Reference example 21

[0434]

[Formula 160]

[0435]

1) In tetrahydrofuran (40 ml) was dissolved methyl 3-(4-bromophenoxy)-2,2-dimethylpropanoate (3.2 g), to the solution was added 2 N. aqueous sodium hydroxide solution (10 ml) and the mixture was stirred at room temperature overnight. After adding to the mixture of methanol (10 ml) the resulting mixture was boiled under reflux for 3 hours. To the residue obtained by concentrating the reaction mixture under reduced pressure, was added ethyl acetate and 1 n hydrochloric acid and liquid were separated. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-(4-bromophenoxy)-2,2-dimethylpropanoate acid (2,886 g).

MS (m/z): 273/275 [M+H]+

[0436]

[Formula 161]

[0437]

2) In methylene chloride (10 ml) was dissolved 3-(4-bromophenoxy)-2,2-DIMET propanolol acid (500 mg), to the solution was added dropwise oxalicacid (240 μl) and N,N-dimethylformamide (1 drop) under ice cooling and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure, was dissolved in acetonitrile (5 ml) and to the mixture was added dropwise under ice cooling a solution of n-hexane (1,83 ml) containing 2M (trimethylsilyl)diazomethane. Then the reaction mixture was stirred under ice cooling for 1 hour and at room temperature over night. To the residue obtained by concentrating the reaction mixture under reduced pressure, was added ethyl acetate and saturated aqueous sodium bicarbonate solution and the liquid was separated. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (20 ml), to the solution was added triethylamine (2,04 ml) and silver benzoate (168 mg) and the mixture is boiled under reflux in nitrogen atmosphere for 2 hours. The insoluble substance was filtered using a filter membrane, the filtrate was concentrated under reduced pressure and the residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 95:5 to 90:10) to give ethyl 4-(4-b is emproxy)-3,3-dimethylbutanoate (397 mg).

MS (m/z): 315/317 [M+H]+

[0438]

[Formula 162]

[0439]

3) using ethyl 4-(4-bromophenoxy)-3,3-dimethylbutanoate (396 mg), the procedure was carried out in the same manner as described in Reference example 2-2), with ethyl 3,3-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butanoate (190 mg).

MS (m/z): 363 [M+H]+

[0440]

Using appropriate starting compounds synthesized the following compounds in the same manner as described in Referential example 1.

[0441]

[0442]

Reference example 32

[0443]

[Formula 163]

[0444]

1) To tetrahydrofuran (50 ml) was added methyl 2,2-dimethyl-3-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]-oxy}propanoate (3000 mg), 2-bromopyridin-5-cyanide (1965,4 mg), palladium acetate (100,5 mg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (367 mg) and potassium phosphate (3799,4 mg) and the mixture was stirred at 50°C in nitrogen atmosphere for 2 days. To the reaction mixture were added a saturated saline solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and the residue obtained by concentrating the reaction mixture under reduced pressure, was purified by using column x is matography on silica gel (n-hexane:ethyl acetate = 85:15 to 65:35), to obtain methyl 3-{[5-(5-cyano-2-yl)pyridine-2-yl]oxy}-2,2-dimethylpropanoate (720 mg).

MS (m/z): 312 [M+H]+

[0445]

[Formula 164]

[0446]

2) using methyl 3-{[5-(5-cyano-2-yl)pyridine-2-yl]oxy}-2,2-dimethylpropanoate (718 mg), the procedure was carried out in the same manner as described in Reference example 2-4) and (2-5), with methyl 3-[(5-{5-[amino(imino)methyl]pyridin-2-yl}pyridine-2-yl)oxy]-2,2-dimethylpropanoate (467 mg).

MS (m/z): 329 [M+H]+

[0447]

Using appropriate starting compounds synthesized the following compounds in the same manner as described in Reference example 32.

[0448]

[0449]

Reference example 41

[0450]

[Formula 165]

[0451]

1) using 2,6-dichloro-4-methylpyridin-3-carbonitrile (2000 mg) and methyl 2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propanoate (3573,9 mg), the procedure was carried out in the same manner as described in Reference example 1-3), with methyl 3-[4-(6-chloro-5-cyano-4-methylpyridin-2-yl)phenoxy]-2,2-dimethylpropanoate (2697 mg).

MS (m/z): 359/361 [M+H]+

[0452]

[Formula 166]

[0453]

2) using methyl 3-[4-(6-chloro-5-cyano-4-methylpyridin-2-yl)phenoxy]-2,2-dimethylpropanoate (2660 mg) procedure executed by the Yali in the same way, as described in Reference example 2-4), with methyl 3-{4-[6-chloro-5-(N-hydroxycarbamoyl)-4-methylpyridin-2-yl]phenoxy}-2,2-dimethylpropanoate (2977 mg).

MS (m/z): 392/394 [M+H]+

[0454]

[Formula 167]

[0455]

3) using methyl 3-{4-[6-chloro-5-(N-hydroxycarbamoyl)-4-methylpyridin-2-yl]phenoxy}-2,2-dimethylpropanoate (2900 mg), the procedure was carried out in the same manner as described in Reference example 2-5), with methyl 3-[4-(5-carbamimidoyl-4-methylpyridin-2-yl)phenoxy]-2,2-dimethylpropanoate (2300 mg).

MS (m/z): 342 [M+H]+

[0456]

Reference example 42

[0457]

[Formula 168]

[0458]

Using 2-(4-bromophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (869 mg), the procedure was carried out in the same manner as described in Reference example 2-2), to obtain 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (724,9 mg).

MS (m/z): 469 [M+H]+

[0459]

Using appropriate starting compounds synthesized the following compounds in the same manner as described in Reference example 42.

[0460]

[0461]

Reference example 45

[0462]

[Formula 169]

[0463]

Using 5-chloropyrazine-2-ol is (700 mg) and tert-butyl hydroxypivalic (1402 mg), the procedure was carried out in the same way, as in Example 1-1), with tert-butyl 3-[(5-chloropyrazine-2-yl)oxy]-2,2-dimethylpropanoate (1294,5 mg).

MS (m/z): 287/289 [M+H]+

[0464]

Reference example 46

[0465]

[Formula 170]

[0466]

1) a Mixture of 2-(4-bromophenyl)-5-(trifluoromethyl)-1H-imidazole (3 g), benzylbromide (3,52 g), potassium carbonate (2.85 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature overnight. To the reaction mixture were added water and a simple air and liquid were separated. The organic layer was separated, washed with water and then saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in toluene and purified using column chromatography on silica gel (n-hexane:ethyl acetate = 100:0 to 70:30) to give 1-benzyl-2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole (3,40 g).

MS (m/z): 381/383 [M+H]+

[0467]

Reference example 47

[0468]

[Formula 171]

[0469]

Using 5-bromo-3-herperidin-2-ol (0.96 g) the procedure was carried out in the same manner as in Example 1-1), with methyl 3-[(5-bromo-3-herperidin-2-yl)oxy]-2,2-dimethylpropanoate (1.35 g).

MS (m/z): 306/308 [M+H]+

[0470]

Reference example 48

[0471]

[Formula 172]

[0472]

1) In ethanol (10 ml) was dissolved 2-brough the-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (500 mg), to the solution was added 2 N. aqueous sodium hydroxide solution and the mixture was stirred at 70°C during the night. The reaction mixture was concentrated under reduced pressure and to the mixture was added 1 N. aqueous solution of citric acid. The precipitated solid was collected by filtration, washed with water and then with a simple ether and dried to obtain 2-(6-bromopyridin-3-yl)-1H-imidazole-5-carboxylic acid (722 mg).

MS (m/z): 268/270 [M+H]+

[0473]

[Formula 173]

[0474]

2) To a solution of N,N-dimethylacetamide containing 2-(6-bromopyridin-3-yl)-1H-imidazole-5-carboxylic acid (4,99 g) and diisopropylethylamine (4,21 ml), was added benzylbromide (3,81 g) under ice cooling, after stirring the mixture for 5 minutes, the temperature of the mixture was raised to room temperature and the mixture was stirred over night. To the reaction mixture was added water under ice cooling, and the precipitated solid substance was collected by filtration, washed with water and n-hexane and dried to obtain benzyl 2-(6-bromopyridin-3-yl)-1H-imidazole-5-carboxylate (6,01 g).

MS (m/z): 358/360 [M+H]+

[0475]

[Formula 174]

[0476]

3) using benzyl 2-(6-bromopyridin-3-yl)-1H-imidazole-5-carboxylate (5.5 g) the procedure was carried out in the same manner as described in Reference example 1-2), to obtain benzyl 2-(6-bromo is iridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]-1H-imidazole-4-carboxylate (2,97 g).

MS (m/z): 488/490 [M+H]+

[0477]

[Formula 175]

[0478]

4) using benzyl 2-(6-bromopyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]-1H-imidazole-4-carboxylate (6,69 g) and 2-{4-[(4-methoxybenzyl)oxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6,04 g) the procedure was carried out in the same manner as described in Reference example 1-3), with benzyl 2-(6-{4-[(4-methoxybenzyl)hydroxy]phenyl}pyridine-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-carboxylate (6,54 g).

MS (m/z): 622 [M+H]+

[0479]

[Formula 176]

[0480]

5) To a suspension of lithium aluminum hydride (0.24 g) in tetrahydrofuran (40 ml) was added dropwise a solution of benzyl 2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-carboxylate (2 g) in tetrahydrofuran (30 ml) under cooling with ice. After stirring for 30 minutes, to the mixture was added sodium sulfate (720 mg) and water (0,48 ml). The mixture was stirred at room temperature for 1 hour and filtered. The filtrate was concentrated under reduced pressure, the obtained residue was ground into powder by adding a simple ether and collected by filtration to obtain[2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine-3-yl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-4-yl]methanol.

MS (m/z): 518 [M+H]+

[0481]

[Formula 177]

<>

[0482]

6) In methylene chloride (100 ml) was dissolved[2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine-3-yl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-4-yl]methanol obtained as described above in 5), to the solution was added manganese dioxide (5,59 g) and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and then purified using column chromatography on silica gel (chloroform to chloroform:methanol = 97:3) to obtain 2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine-3-yl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazole-4-carbaldehyde (1,25 d).

MS (m/z): 516 [M+H]+

[0483]

[Formula 178]

[0484]

7) To a solution of tetrahydrofuran (70 ml) containing dibromodifluoromethane (5,09 g) was added dropwise triamide hexamethylphosphoric acid (8,81 ml) at -78°C. the Temperature of the mixture was raised to room temperature and the mixture was stirred for 30 minutes. The mixture was cooled to -78°C was added dropwise a solution of 2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine-3-yl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazole-4-carbaldehyde (1.25 g) in tetrahydrofuran (20 ml). The temperature of the mixture was raised to room temperature and the mixture was stirred for 3 hours. To the mixture was added ethyl acetate, water and saturated aqueous sodium bicarbonate solution and the liquid was separated. About the organic layer was separated, was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (n-hexane:ethyl acetate = 85:15 to 55:45) to give 5-[4-(2,2-deperately)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-2-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine (0.84 g).

MS (m/z): 550 [M+H]+

[0485]

[Formula 179]

[0486]

8) In ethanol (50 ml) and tetrahydrofuran (20 ml) was dissolved 5-[4-(2,2-deperately)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-2-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine (0.84 g), to the solution was added 10% palladium on coal (water content 50%, 395 mg) and the mixture was stirred in an atmosphere of hydrogen for 24 hours. The reaction mixture was filtered through filter membrane, the filtrate was concentrated under reduced pressure and the residue was purified using column chromatography on silica gel with obtaining 4-{5-[4-(2,2-dottorati)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine-2-yl}-phenol (373 mg).

MS (m/z): 432 [M+H]+

[0487]

Experimental example 1 (activity inhibition of DGAT1)

<Experimental method>

(1) Cloning of human DGAT1 gene and preparation of recombinant baculovirus

Human DGAT1 gene was obtained using the library is celoveceskoj cDNA as template and amplification of sequences (245-1711 the access number in Genbank NM_012079), which DGAT1 encodes, using a PCR reaction.

[0488]

Received human DGAT1 gene was subjected to legirovanie with plasmid pVL1392 (BD Biosciences) to obtain expressing plasmid pVL1392-DGAT1. Then, using the expression vector baculovirus BD BaculoGold (BD Biosciences) received recombinant baculovirus.

[0489]

(2) Obtaining microsome assay of insect cells with high expression of human DGAT1 enzyme

Obtaining human DGAT1 enzyme was carried out by infection with recombinant baculovirus obtained as described in the previous section, cells insect expresSF+(R)(available from NOSAN Corporation). Recombinant baculovirus was added to expresSF+(R)the cells were cultured for 72 hours, then cells were isolated by centrifugation and stored in freezing conditions at a temperature of -80°C. Cells, which were stored frozen, thawed on ice, and then suspended in buffer (200 mm sucrose, 1 mm EDTA, 100 mm Tris-HCl (pH 7,4)), to which was added a Complete Protease Inhibitor (Roche) and subjected to sonication. Then received the fraction microsomes in accordance with the usual way and kept as microsomes with high expression of DGAT1 in freezing conditions at a temperature of -80°C.

[0490]

(3) Measurement of activity of inhibition of DGAT1

As a buffer for use in EN zymes is exploring reactions DGAT1, used 100 mm Tris-HCl (pH of 7.4), 200 mm sucrose, 20 mm MgCl2, 0,125% bovine serum albumin (BSA). The buffer was added to the test compound in a predetermined concentration, and 15 μm of dioleoylglycerol, 5 μm [14C]-Palmitoyl-CoA, 100 μg protein/ml of microsomes SF+(R)high expression of DGAT1, 0,75% acetone and 1% DMSO, and reaction was carried out for the synthesis of triglycerides (TG) at 30°C for 20 minutes in a volume of 100 μl. 90 μl of the reaction solution was added to 810 ál of methanol to stop the reaction. The reaction solution was added to Oasis(R)μElution tablet (available from Waters Corporation) and was suirable using 150 μl of a mixed solution of acetonitrile:isopropanol (=2:3). For elution was added 150 μl MicroScintiTM-40 (available from PerkinElmer Inc.) and after thorough mixing the mixture, the amount of [14C]-TG formed in the reaction was calculated by measuring using a TopCountTM-NXT (available from PerkinElmer Inc.).

[0491]

The percentage inhibition was calculated using the following equation.

The percentage of inhibition (%)=(1-(number of TG at the time of adding the test compound - amount of TG in the pure solution)÷( the number of TG in control - the amount of TG in the pure solution))×100

[0492]

Here, the number of [14C]-TG in solution, which carried out the reaction without doba is the control and test compounds identified as “the amount of TG in control” and the number of [14C]-TG in solution, which were not added any experience connection no SF+(R)microsome assay with high expression of DGAT1, specified as the number of TG in pure solution”. In addition, the concentration of test compound necessary for inhibiting 50% of [14C]-TG synthesis (the value of the IC50), was calculated using Prism 5.01 (available from GrafPad Software Co.).

[0493]

<experiment Results>

The results of the experiment are presented in the following Table 16.

[0494]

[Table 16]

Table 16
Test connectionIC50(nm)Test connectionIC50(nm)
The product of Example 1-3)4,2The product of Example 2-2)23
The product of Example 3-3)2,9The product of Example 4-2)2,0
The product of Example 5-3)24The product of Example 6-3)8,9
The product of Example 77) 25The product of Example 8-2)21
The product of Example 95,2The product of Example 109,1
The product of Example 1143The product of Example 1214
The product of Example 13-3)2,3The product of Example 1411
The product of Example 1512The product of Example 1628
The product of Example 173,3The product of Example 18-2)6,7
The product of Example 19-3)4The product of Example 208,3
The product of Example 218,6The product of Example 223,1
The product of Example 230,76The product of Example 24 11
The product of Example 2521The product of Example 2611
The product of Example 2720The product of Example 2819
The product of Example 2920The product of Example 3015
The product of Example 3116The product of Example 3211
The product of Example 3314The product of Example 3416
The product of Example 35-3)79,7The product of Example 36of 5.4
The product of Example 374,4The product of Example 3836
The product of Example 390,63The product of Example 403,7
The product of Example 412,6 The product of Example 42the 5.7
The product of Example 4348The product of Example 4426
The product of Example 452,4The product of Example 4611
The product of Example 4711The product of Example 4814
The product of Example 4931The product of Example 5047
The product of Example 5147The product of Example 521,8
The product of Example 5313The product of Example 54-4)1,5
The product of Example 55-2)the 3.8The product of Example 5611
The product of Example 5716The product of Example 58-2)17
Prod the CT Example 59 2,4The product of Example 60-3)11
The product of Example 61-3)4,2The product of Example 62-3)0,96
The product of Example 63-3)1,2The product of Example 642,7
The product of Example 652The product of Example 66the 3.8
The product of Example 6711The product of Example 6826
The product of Example 692,7The product of Example 708,1
The product of Example 7113The product of Example 723,1
The product of Example 732,1The product of Example 7421
The product of Example 752,2The product of Example 76 1,5
The product of Example 770,78The product of Example 78the 3.8
The product of Example 795,8The product of Example 803,1
The product of Example 8112The product of Example 823,0
The product of Example 834,6The product of Example 842,0
The product of Example 85-4)30The product of Example 86-3)21
The product of Example 87-7)32The product of Example 88-3)5,8
The product of Example 89-2)5,3The product of Example 900,87
The product of Example 9110The product of Example 9223
The product of Example 93-3) 11The product of Example 94-3)1,4
The product of Example 95-6)1,7The product of Example 96-2)3,1
The product of Example 97-5)the 4.7The product of Example 98-3)0,75
The product of Example 99-6)1,6The product of Example 100-5)2,9
The product of Example 101-3)0,82The product of Example 10274
The product of Example 1034,8The product of Example 1043,6
The product of Example 10519The product of Example 10675
The product of Example 1071,4The product of Example 1081,2
The product of Example 1092,2The product of Example 110 19
The product of Example 1115,5The product of Example 1121,3
The product of Example 1132,3The product of Example 1140,7
The product of Example 1154,5The product of Example 1163,5
The product of Example 117the 3.8The product of Example 1188,9
The product of Example 1194,5The product of Example 1201,8
The product of Example 121of 5.4The product of Example 1223,4
The product of Example 1233,5The product of Example 1242,1
The product of Example 1252,2The product of Example 1261,7
The product of Example 127 2,6The product of Example 12864
The product of Example 12911The product of Example 13083
The product of Example 13139The product of Example 132a 3.9
The product of Example 1331,6The product of Example 1341,5
The product of Example 1351The product of Example 1361,9
The product of Example 1372The product of Example 1381,7
The product of Example 1393,5The product of Example 1402,1
The product of Example 1413,1The product of Example 1427,6
The product of Example 14311The product of Example 14411
The product of Example 14548The product of Example 1468,3
The product of Example 1473,5The product of Example 1481,7

[0495]

Experimental example 2 (triglycerides (TG) in plasma resulting from the introduction of lipid)

<Experimental method>

Male ICR mice aged 6-9 weeks went hungry during the night, and oral was administered the test compound, suspended in 0.2% solution of carboxymethylcellulose. After 30 minutes of oral injected lipid (Intralipos 20%, OTSUKA PHARMACEUTICAL CO., LTD., 10 ml/kg). Blood was collected from the tail vein immediately before the introduction of lipid and 2 hours after injection to obtain blood plasma. Measurement of TG in plasma was carried out using analysis determination of triglyceride E-Test Wako (Wako Pure Chemical Industries, Ltd.) and expected elevated levels of TG in plasma with the introduction of lipid. Elevated levels of TG in the blood plasma in the control group, which was injected solvent, used as control, and calculated the percentage inhibition increased level of TG in plasma under injection of the test compounds.

[0496]

<experiment Results>

According the above results, compounds of the Examples showed the effect of inhibiting the increase of the level of TG in plasma, when injected dose of 5 mg/kg, as shown in the following Table 17.

[0497]

[Table 17]

65%
Table 17
Test connectionThe percentage inhibition increased level of TG in plasma (5 mg/kg)Test connectionThe percentage inhibition increased level of TG in plasma (5 mg/kg)
The product of Example 1-3)77%The product of Example 2-2)76%
The product of Example 3-3)78%The product of Example 4-2)60%
The product of Example 5-3)71%The product of Example 6-3)78%
The product of Example 7-7)71%The product of Example 8-2)46%
The product of Example 975%The product of Example 10 62%
The product of Example 1131%The product of Example 1251%
The product of Example 13-3)51%The product of Example 1469%
The product of Example 1532%The product of Example 1674%
The product of Example 1769%The product of Example 18-2)69%
The product of Example 19-3)89%The product of Example 2074%
The product of Example 2120%The product of Example 2276%
The product of Example 2385%The product of Example 2433%
The product of Example 2554%The product of Example 2667%
The product of Example 2769% The product of Example 2859%
The product of Example 2952%The product of Example 3060%
The product of Example 3186%The product of Example 3271%
The product of Example 3354%The product of Example 3419%
The product of Example 35-3)54%The product of Example 3669%
The product of Example 3954%The product of Example 4571%
The product of Example 4613%The product of Example 4772%
The product of Example 4823%The product of Example 4948%
The product of Example 5021%The product of Example 5226%
The product of Example 53 36%The product of Example 54-4)74%
The product of Example 55-2)60%The product of Example 5661%
The product of Example 5743%The product of Example 58-2)64%
The product of Example 5974%(Net)(Net)
The product of Example 60-3)48%The product of Example 61-3)68%
The product of Example 62-3)85%The product of Example 63-3)60%
The product of Example 6460%The product of Example 6575%
The product of Example 6683%The product of Example 6770%
The product of Example 6864%The product of Example 6985%
The product of Example 7067%The product of Example 7150%
The product of Example 7285%The product of Example 7388%
The product of Example 7450%The product of Example 755%
The product of Example 7678%The product of Example 7775%
The product of Example 7861%The product of Example 7962%
The product of Example 8041%The product of Example 8247%
The product of Example 8360%The product of Example 8475%
The product of Example 85-4)69%The product of Example 86-3)68%
The product of Example 87-7)57%The product of Example 88-3)
The product of Example 89-2)52%The product of Example 9083%
The product of Example 9151%The product of Example 9274%
The product of Example 93-3)67%The product of Example 94-3)72%
The product of Example 95-6)70%The product of Example 96-2)48%
The product of Example 97-5)102%The product of Example 98-3)105%
The product of Example 99-6)95%The product of Example 100-5)60%
The product of Example 101-3)71%The product of Example 1038%
The product of Example 10467%The product of Example 10557%
The product of Example 10762%/td> The product of Example 10852%
The product of Example 10950%The product of Example 11141%
The product of Example 11267%The product of Example 11464%
The product of Example 11550%The product of Example 11682%
The product of Example 11757%The product of Example 11864%
The product of Example 11967%The product of Example 12153%
The product of Example 12498%The product of Example 12744%
The product of Example 12916%The product of Example 13157%
The product of Example 13265%The product of Example 13375%
The product of Example 13484%The product of Example 13664%
The product of Example 13781%The product of Example 13952%
The product of Example 14068%The product of Example 14182%
The product of Example 14355%The product of Example 1447%
The product of Example 14543%(Net)(Net)

[0498]

Experimental example 3 (activity aimed at reducing appetite)

<Experimental method>

Male mice C57BL/6J age 7-10 weeks went hungry during the night, and oral was administered the test compound, suspended in 0.2% solution of carboxymethylcellulose. Immediately after the introduction gave them food with high fat content (Oriental Yeast Co., Ltd, soderzhanie fat 60%), to which they had free access. The amount of food eaten for 4 hours, was measured and used to calculate the percentage reduction (percent reduction in food intake) amount of food consumed is in the group the introduction of the test compound, compared with the control group, which was introduced by the solvent, which was used as a control.

[0499]

<experiment Results>

In accordance with the above results, the compounds of the Examples showed a percentage decrease in food intake, shown in the following Table 18, the dose of injection of 5 mg/kg

[0500]

[Table 18]

Table 18
Test connectionThe percentage reduction in food intake (5 mg/kg)Test connectionThe percentage reduction in food intake (5 mg/kg)
The product of Example 1-3)77%The product of Example 2-2)64%
The product of Example 3-3)76%The product of Example 4-2)82%
The product of Example 5-3)37%The product of Example 6-3)71%
The product of Example 7-7)75%The product of Example 8-2) 57%
The product of Example 976%The product of Example 1062%
The product of Example 1240%The product of Example 13-3)60%
The product of Example 1466%The product of Example 1675%
The product of Example 1782%The product of Example 18-2)83%
The product of Example 19-3)78%The product of Example 2070%
The product of Example 2269%The product of Example 2363%
The product of Example 2581%The product of Example 2679%
The product of Example 2766%The product of Example 2854%
The product of Example 2928% The product of Example 3068%
The product of Example 3165%The product of Example 3242%
The product of Example 3344%The product of Example 35-3)56%
The product of Example 3663%The product of Example 3976%
The product of Example 4572%The product of Example 4744%
The product of Example 4958%(Net)(Net)
The product of Example 54-4)46%The product of Example 55-2)39%
The product of Example 5676%The product of Example 58-2)65%
The product of Example 5950%The product of Example 60-3)59%
The product of Example 613) 80%The product of Example 62-3)63%
The product of Example 63-3)83%The product of Example 6478%
The product of Example 6579%The product of Example 6676%
The product of Example 6758%The product of Example 6863%
The product of Example 6987%The product of Example 7059%
The product of Example 7129%The product of Example 7265%
The product of Example 7382%The product of Example 7460%
The product of Example 7661%The product of Example 7765%
The product of Example 7862%The product of Example 794%
The product of Example 8242%The product of Example 8349%
The product of Example 8464%The product of Example 85-4)70%
The product of Example 86-3)21%The product of Example 87-7)59%
The product of Example 88-3)55%The product of Example 89-2)75%
The product of Example 9075%The product of Example 9151%
The product of Example 9266%The product of Example 93-3)68%
The product of Example 94-3)66%The product of Example 95-6)83%
The product of Example 96-2)58%The product of Example 97-5)92%
The product of Example 98-3)89% The product of Example 99-6)85%
The product of Example 101-3)57%The product of Example 10462%
The product of Example 10558%The product of Example 10757%
The product of Example 10862%The product of Example 10941%
The product of Example 11252%The product of Example 11459%
The product of Example 11562%The product of Example 11676%
The product of Example 11755%The product of Example 11861%
The product of Example 11951%The product of Example 12157%
The product of Example 12475%The product of Example 13247%
The product P is the iMER 133 83%The product of Example 13474%
The product of Example 13662%The product of Example 13783%
The product of Example 14078%The product of Example 14155%
The product of Example 1434%(Net)(Net)

[0501]

Experimental example 4 (action, inhibiting weight gain, hypoglycemic effect, the effect of reduction of insulin in the blood plasma of KK-Ay mice)

<Experimental method>

The male mice (KK-Ay age 8 weeks were given food with high fat content (Oriental Yeast Co., Ltd, the fat content of 60%), and oral was administered the test compound, suspended in 0.2% solution of carboxymethylcellulose, once a day. Oral administration was continued for 2 weeks and the percentage of inhibition of weight gain with the introduction of the test compounds was calculated using the weight gain in the control group, which was introduced by the solvent during the test period, which was taken as 100%. After the last injection the mice who were given food during the night and then collecting blood from the tail vein. Measurement of blood sugar level was carried out using samples for glucose Cα Test Wako (Wako Pure Chemical Industries, Ltd.), and measurement of insulin in plasma was performed using the kit for measurement of insulin in mice (Morinaga Institute of Biological Science, Inc.).

[0502]

<experiment Results>

In accordance with the above results, the compounds of the Examples showed hypoglycemic effect, the effect of reduction of insulin in the blood plasma and the effect of inhibiting the growth of mass, as shown in the following table dose injection of 30 mg/kg/day.

[0503]

[Table 19]

Table 19
Test connectionHypoglycemic effect
(30 mg/kg/day)
Action to reduce insulin in the blood plasma
(30 mg/kg/day)
Action, inhibiting weight gain (30 mg/kg/day)
The product of Example 1-3)43%58%67%
The product of Example 2-3)64%62%53%
The product of Example 3-3)41% 51%52%
The product of Example 4-2)50%52%49%
The product of Example 5-3)55%56%48%
The product of Example 6-3)63%72%72%
The product of Example 7-7)62%58%66%
The product of Example 1423%27%17%
The product of Example 2240%47%30%
The product of Example 23-13%14%39%
The product of Example 2640%27%44%
The product of Example 3342%41%39%
Product Use is as 36 23%19%59%
The product of Example 3944%50%38%
The product of Example 4559%56%42%
The product of Example 54-4)74%93%113%
The product of Example 61-3)60%77%90%
The product of Example 62-3)80%95%161%
The product of Example 63-3)77%90%115%
The product of Example 6610%38%46%
The product of Example 6961%#37%#43%#
The product of Example 7052% 27%45%
The product of Example 7238%28%43%
The product of Example 7340%69%62%
The product of Example 7456%51%47%
The product of Example 7665%81%69%
The product of Example 7760%65%60%
The product of Example 7844%49%54%
The product of Example 8344%33%42%
The product of Example 8465%76%48%
The product of Example 87-7)35%19%22%
The product of Example 892) 68%88%63%
The product of Example 9263%58%60%
The product of Example 94-3)42%*29%*35%*
The product of Example 95-6)66%58%75%
The product of Example 96-2)66%71%75%
The product of Example 10757%58%48%
The product of Example 11249%61%47%
The product of Example 11448%60%45%
The product of Example 11736%35%31%
The product of Example 11940%28% 36%
#: At the dose of 10 mg/kg/day
*: Dose injection of 1 mg/kg/day

INDUSTRIAL APPLICABILITY

[0504]

Connection to a serial articlecache structure (I) or its pharmaceutically acceptable salt according to the present invention has excellent activity inhibition of DGAT1 and can be used as a means for the treatment or prevention of diabetes.

1. Connection to a serial articlecache structure represented by the formula:
[Formula 180]

where Alk represents a linear C1-6alkylenes group, a branched C1-6alkylenes group or a C1-6alkylenes group having a ring structure, where part of the carbon atoms constituting the ring structure optionally may be substituted by oxygen atom,
in the ring X,
X1represents N or CRX1,
X2represents N or CRX2,
X3represents CRX3,
X4represents N or CRX4,
where RX1, RX2, RX3and RX4each independently represents a hydrogen atom; a linear or branched C1-6alkyl group; a linear or branched C1-6alkoxygroup; or halogen atom,
in the ring Y,
Y1before the hat is CR Y1,
Y2represents N or CRY2,
Y3represents N or CRY3,
Y4represents N or CRY4,
RY1, RY2, RY3and RY4each independently represents a hydrogen atom; a linear or branched C1-6alkyl group which may be substituted atom (atoms) halogen; C3-7alkyl group having a ring structure; a linear or branched C1-6alkoxygroup; halogen atom or a cyano,
in the ring Z,
RZrepresents a linear or branched C1-6alkyl group which may be substituted atom (atoms) halogen, or C3-7alkyl group having a ring structure, which may be substituted atom (atoms) halogen,
or its pharmaceutically acceptable salt.

2. Connection to a serial articlecache structure or its pharmaceutically acceptable salt p. 1, where the ring X has a structure represented by any of the following formulas:
[Formula 181]

where RX1-RX4have the meanings given above,
and the ring Y has a structure represented by any of the following formulas:
[Formula 182]

where RY1-RY4have the meanings given above.

3. The connection with the serial and acyclically structure or its pharmaceutically acceptable salt according to p. 2, where the ring X has a structure represented by any of the following formulas:
[Formula 183]

where RX1-RX4have the meanings given above,
and the ring Y has a structure represented by any of the following formulas:
[Formula 184]

where RY1-RY4have the meanings given above.

4. Connection to a serial articlecache structure or its pharmaceutically acceptable salt according to p. 3, where RZrepresents a linear or branched C1-6alkyl group which is substituted by an atom (atoms) halogen, or C3-7alkyl group having a ring structure, which may be substituted atom (atoms) halogen.

5. Connection to a serial articlecache structure or its pharmaceutically acceptable salt according to p. 3, where RZrepresents a methylene replaced with an atom or halogen atoms.

6. Connection to a serial articlecache structure or its pharmaceutically acceptable salt according to p. 4, where Alk is a branched C2-4alkylenes group.

7. Connection to a serial articlecache structure or its pharmaceutically acceptable salt according to p. 4, where Alk represents a-C(CH3)2-.

8. Connection to a serial articlecache structure to the / establishment, which represents any one of the following connections:
2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoic acid;
2,2-dimethyl-3-(4-{5-[5-(2,2,2-Cryptor-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoic acid;
2,2-dimethyl-3-(4-{4-methyl-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)propanoic acid;
2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}pyridine-2-yl)phenoxy)propanoic acid;
2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}phenoxy)propanoic acid;
1-[(3-methyl-4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)methyl]cyclobutanecarbonyl acid;
3-(4-{5-[5-(3,3-diversilobum)-1H-imidazol-2-yl]pyridine-2-yl}phenoxy)-2,2-dimethylpropanoate acid;
2,2-dimethyl-3-({4-methyl-6'-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)propanoic acid;
2,2-dimethyl-3-({4'-methyl-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-2,3'-bipyridine-6'-yl}oxy)propanoic acid;
2,2-dimethyl-3-[(4-methyl-5-{4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]propanoic acid;
2,2-dimethyl-3-[(6-methyl-5-{4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]propanoic acid;
3-[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]-2,2-dimethylpropanoate acid;
2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyrazin-2-yl)oxy]propanoic acid;
2,2-dimethyl-3-[(4-methyl-5-{3-methyl-4-[5-(three is tormentil)-1H-imidazol-2-yl]phenyl}pyridine-2-yl)oxy]propanoic acid;
3-[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid;
2,2-dimethyl-3-[4-[5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-2-pyridyl]phenoxy]propanoic acid;
3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid;
3-{[5-(3-fluoro-4-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}phenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate acid;
2,2-dimethyl-3-[(4-methyl-5-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyrazin-2-yl}pyridine-2-yl)oxy]propanoic acid;
3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-forfinal}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid;
1-[({4-methyl-6'-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]cyclobutanecarbonyl acid;
1-{[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarbonyl acid;
1-[({5'-chloro-4-methyl-6'-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3'-bipyridine-6-yl}oxy)methyl]cyclobutanecarbonyl acid;
1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxamide acid;
1-{[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarbonyl acid,
or pharmaceutically acceptable salt of such compounds.

9. 2,2-Dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl] what iridin-2-yl}phenoxy)propanoic acid or its pharmaceutically acceptable salt.

10. 3-{[5-(3-Fluorine-4-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl}phenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate acid or its pharmaceutically acceptable salt.

11. 3-[(5-{3-Fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid or its pharmaceutically acceptable salt.

12. 3-[(5-{3-Chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate acid or its pharmaceutically acceptable salt.

13. Inhibitor allgovernment: diacylglycerides (DGAT) 1, including a connection with the serial articlecache structure or its pharmaceutically acceptable salt according to any one of paragraphs.1-12 as an effective ingredient.

14. The DGAT1 inhibitor under item 13, which is an agent for the prevention or treatment of obesity.

15. The DGAT1 inhibitor under item 14, which is an agent for the prophylaxis or treatment of hyperlipidemia, hypertriglyceridemia, lipid metabolism or fatty liver.

16. The DGAT1 inhibitor under item 13, which is an agent for the prevention or treatment of type 2 diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macrovascular disease), arteriosclerosis, GI is mertensii, cerebrovascular disease, ischemic heart disease, shortness of breath, back pain or osteoarthritis of the knee.

17. The DGAT1 inhibitor under item 16, which is an agent for the prevention or treatment of type 2 diabetes or diabetic complications.

18. The application connect to the serial articlecache structure or its pharmaceutically acceptable salt according to any one of paragraphs.1-6 for the prophylaxis or treatment of hyperlipidemia, hypertriglyceridemia, lipid metabolism, fatty liver, type 2 diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macrovascular disease), arteriosclerosis, hypertension, cerebrovascular disease, ischemic heart disease, shortness of breath, back pain or osteoarthritis of the knee.

19. A method of prophylaxis or treatment of hyperlipidemia, hypertriglyceridemia, lipid metabolism, fatty liver, type 2 diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic macrovascular disease), arteriosclerosis, hypertension, cerebrovascular disease, ischemic heart disease, shortness of breath, lumbago or osteo is rcrit knee joint, which includes an introduction to the patient a therapeutically effective amount of compounds with serial articlecache structure or its pharmaceutically acceptable salt according to any one of paragraphs.1-12.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new phenylpyrimidone derivatives of formula I possessing the properties of a phosphodiesterase type 5 (PDE5) inhibitor. The compounds of formula I can be used for treating various vascular disorders, such as erectile dysfunction, pulmonary arterial hypertension, etc. In formula each R1 and R2 independently means H; C1-C10alkyl; halogen; CF3; CN; OR5; NR6R7; NHCOR8; aryl; or C1-C4alkyl optionally substituted by OR5; Z means OR3; R3 means C1-C6alkyl or C1-C3alkyl, substituted by C1-C3alkoxy group; R4 means SO2NR6R7; NR9R10, providing NR9R10 is other than NH2; COR11; OR12; or R4 means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH and C1-C6 alkyl; or R4 means 5- or 6-merous cyclic monosaccharide group; R5 means C1-C6alkyl; C1-C4alkyl optionally substituted by C1-C4alkoxy group; each R6 and R7 independently means H, OH, C1-C6alkyl, C1-C6alkoxy group, C3-C6alkenyl, C3-C6cycloalkyl, adamantyl, C3-C8lactamyl, aryl, Het or (CH2CH2O)jH, wherein j is 1-3; or each R6 and R7 independently means C1-C6alkyl, optionally substituted by OH, C1-C4alkoxy group, SO3H, SO2NR13R14, SO2R16, NR13R14, aryl, Het or 5-6-merous heterocyclyl; or each R6 and R7 independently means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of C1-C6 alkyl and C1-C6alkyl substituted by hydroxyl; or R6 and R7 together with a nitrogen atom attached whereto form 5-7-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH, COOR8, (CH2CH2O)jH, wherein j is 1-3, C1-C4alkoxy group, Het and C1-C6alkyl substituted by aryl; or R6 and R7 together with a nitrogen atom attached whereto form a glucosyl amino group, an amino acid residue, a residue of an amino acid ester or an amino amide residue. The other radical values are specified in the patent claim.

EFFECT: invention refers to pharmaceutical compositions based on the above compounds, using them, methods for preparing the compounds, and intermediate products.

18 cl, 2 tbl, 224 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing a salt of tetrazole methanesulphonic acid of formula (I) , which involves acylating a compound (II) with a compound (III) and then adding methanesulphonic acid. The invention also relates to an intermediate compound of formula (II) and a method for production thereof.

EFFECT: method according to the present invention can cut reaction time, improve safety and enables to obtain salts of tetrazole methanesulphonic acid of high purity with high output without using a column chromatography technique.

22 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole compounds of formula I or pharmaceutically acceptable salts thereof: I, where: Ar denotes phenyl, thiophenyl; R1 denotes imidazolyl, imidazolyl substituted with C1-C6alkyl, chlorine, bromine, fluorine, hydroxy group, methoxy group; R2 denotes H, CH3, Cl, F, OH, OCH3, OC2H5, propoxy group, carbamoyl, dimethylamino group, NH2, formamide group, CF3; X denotes CO and SO2. The compounds inhibit S-nitrosoglutathione reductase (GSNOR).

EFFECT: using the compound to produce a pharmaceutical composition and for treating asthma.

17 cl, 1 tbl, 14 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I): . Therein the values A, R1, R2, R6, r, Rc are presented in cl.1 of the patent claim, as well as to pharmaceutically acceptable salts or tautomers of the above compound being poly(ADP-ribose)polymerase (PARP) inhibitors.

EFFECT: preparing the pharmaceutically acceptable salts or tautomers of the above compound being poly(ADP-ribose)polymerase (PARP) inhibitors.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: chemistry.

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

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

16 cl, 9 dwg, 1 tbl, 127 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel aryl pyrrolidines of formula I:

, where X, which can be identical or different, denote halogen, halogen-C1-6alkyl, NO2, C1-6alkyl, C1-6alkoxy, CN, halogen-C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl, halogen- C1-6alkylthio, halogen- C1-6alkylthionyl, halogen- C1-6alkylsulphonyl, OH, mercapto groups, NH2, C1-6alkylcarbonyl amino groups, halogen- C1-6alkylcarbonyl-amino, C1-6alkoxycarbonyl amino groups, halogen-C1-6alkoxycarbonylamino; Y, which can be identical or different, denote halogen, halogen- C1-6alkyl, NO2, C1-6alkyl, C1-6alkoxy, CN, halogen- C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl, halogen- C1-6alkylthio, halogen- C1-6alkylthionyl, halogen- C1-6alkylsulphonyl, hydroxyl groups, mercapto groups, NH2, C1-6alkylcarbonyl amino groups, halogen- C1-6alkylcarbonyl amino, C1-6alkoxycarbonyl amino groups, halogen- C1-6alkoxycarbonyl amino; R denotes halogen- C1-6alkyl; m equals 0, 1, 2, 3, 4, 5; n equals 1, 2, 3, 4; G denotes a group: , where R1 and R2 each independently denotes H, unsubstituted C1-6alkyl, halogen- C1-6alkyl, -CH2R7;R3, R4 each independently denotes H; I equals 1, 2, 3; R5 denotes H; R6 denotes C1-6alkylcarbonyl, a group: G6 - G8:

b where k3 equals 0; k4 equals 0; R7 denotes an unsubstituted 6-member heteroaryl with one N; A denotes C, N.

EFFECT: compounds exhibit insecticidal activity, which enables use thereof in insect and/or tick control method.

7 cl, 13 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula

,

where values A, R1-R6 are given in i.1 of the invention formula. Methods of obtaining the formula (I) compound are described.

EFFECT: compounds demonstrate an inhibiting activity of the cathepsin enzyme, which makes it possible to use them for the preparation of a pharmaceutical composition and for the preparation of a medication.

38 cl, 12 dwg, 495 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, possessing a modulating action with respect to the CC chemokine receptor 3 (CCR3), a based on them pharmaceutical composition, versions of treatment methods and a method of controlling the CCR3 activity. In the general formula I R1 and R2 represent halogen or C1-6alkyl; R3 represents cyano or nitro; R4 represents or ; R5 represents oxo; C1-6alkyl, optionally substituted with halogen atoms; or C(O)OR1a; X represents O or S; Y represents -O-, -S-, -N(R1a)-, -C(R1a)(R1d)- or -C(R1a)(NR1bR1c)-; m represents an integer number from 0 to 2; n represents 1; p represents an integer number from 0 to 2; r represents 1 or 2; and each R1a, R1b, R1c and R1d represents (a) hydrogen; (b) C3-7cycloalkyl; or (c) C1-6alkyl, optionally substituted with hydroxyl, or each pair R1b and R1c together with a N atom, which they are bound to, form imidazoimidazolyl, substituted with oxo, butyl or chlorine, or heterocycle, containing 5 or 6 atoms in a cycle.

EFFECT: improvement of the composition properties.

41 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to benzoimidazole derivatives of formula (I), as well as to their enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts, where n equals from 2 to 4, each of R1 substituents is independently selected from H, halogen, -C1-4alkyl, -C1-4pergaloalkyl, trifluoro-C1-4alkoxy, -NO2, -CN, CO2H, -OC1-4alkyl, -SC1-4alkyl, -S(C1-4alkyl)-Rc, -S(O)2(C1-4alkyl)-Rc, -S(O)-C1-4alkyl, -SO2-C1-4alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2-NH-Rc, -O-Rc, -CH2-O-Rc, -C(O)NH-Rc, -NRaRb, benzyloxy, phenyl, optionally substituted with one-two Rd, cyanobiphenyl-4-ylmethylsulpfanyl, cyanobiphenyl-4-ylmethanesulphonyl, or -S-(CH2)2-morpholine and two adjacent groups R1 can bind with formation of an aromatic 5-6-membered ring, optionally substituted with one methyl group or two atoms of halogen, optionally containing one or two S or N; Ra and Rb each independently represents C1-4alkyl, -C(O)C1-4alkyl, -C(O)-Rc, -C(O)CH2-Re, C1-4alkyl-Re, -SO2-Rc, -SO2-C1-4alkyl, phenyl, benzyl; or Ra and Rb together with a nitrogen atom, which they are bound with, form a monocyclic 5-6- membered heterocycloalkyl ring, optionally containing one heteroatom, selected from O; Rc represents -C3-8cycloalkyl, phenyl, optionally substituted with one-two Rd, benzyl, optionally substituted with one-three Rd; morpholine; Rd independently represents halogen, -OH, -C1-4alkyl or -C1-4perhalogenalkyl, trifluorine C1-4alcoxy, -OC1-4alkyl, or -O-benzyl optionally substituted with halogen, Re represents -C6heterocycloalkyl, optionally containing one or two of O or N atoms, optionally substituted with a methyl group; R2 and R3 both represent H, -CF3 or C1-3alkyl; each of Z represents a C or N atom, on condition that simultaneously not more than two Z represent N. The invention also relates to particular compounds, a pharmaceutical composition, based on formula (I) compound or a particular said compound, a method of treating diseases, mediated by propyl hydroxylase activity.

EFFECT: novel derivatives of benzimidazole, possessing an inhibiting activity with respect to PHD are obtained.

11 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinazolinone compounds of formula (I) and its pharmaceutically acceptable salts, wherein n is equal to 0 to 3, and R1 is defined as stated in the patent claim. The above compounds are prolyl hydroxylase inhibitors and can be used in pharmaceutical compositions and methods of treating pathological conditions, disorders and conditions mediated by prolyl hydroxylase activity.

EFFECT: compounds can be administered into the patient for treating, eg anaemia, vascular diseases, metabolic disorders, as well as for wound healing.

22 cl, 2 tbl, 211 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new dihydroindenamide specified in compounds described by general formula II, or their pharmaceutically acceptable salts. In general formula II, R1 represents piperazinyl which can be optionally substituted by one R1a; R1a represents H, CH3, C(O)Rd or C(O)ORa; Y represents pyrimidyl; Z represents pyridyl or pyrimidyl; Ra represents tert-butyl and Rd represents CH3. The above compounds represent tert-butyl-4-{5-[({(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl}amino)carbonyl)-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylate; N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-1-piperazin-1-yl-2,3-dihydro-1H-indene-5-carboxamide; 1-[4-acetylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide; (1R)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide; (1S)-N-[3-(4,5′-bipyrimidin-2-ylamino)-4-methylphenyl]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide; (1R)-N-[3-(4,5′-bipyrimidin-2-ylamino)-4-methylphenyl]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide; (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-4-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide and (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide sulphate.

EFFECT: compounds inhibit activity of protein kinases specified in Abl, c-Kit and PDGFR, and can find application for treating diseases related to disturbed activity of the above protein kinases, eg leukaemia and other cancers.

4 cl, 4 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazole derivatives of general formula or its pharmaceutically acceptable salt, wherein R1 means halogen, C1-6-alkyl or C1-6-alkoxy; R2 means C1-6-alkyl; R3 means hydrogen, C1-6-alkyl; Q means -N= or -CH=; R4 represents a group of formula or , wherein X, Y and Z independently represent -CH= or -N=, and only one of X or Y can be a nitrogen atom; R5 and R6 independently represent a hydrogen atom, C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-alkoxyalkyl, -(CH2)m-(CO)O-C1-6-alkyl, -(CH2)m-S(O)2-C1-6-alkyl, -(CH2)m-C(O)-NR'R" and wherein m=1 and R' and R" independently represent hydrogen or C1-6-alkyl. Also, the invention refers to a therapeutic agent based on the compound of formula (I) and using the compound of formula (I).

EFFECT: there are prepared new imidazole derivatives effective for treating and preventing mGluR5 receptor mediated disorders.

26 cl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

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