Benzimidazole derivatives, based pharmaceutical composition and methods of using them


FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

 

The technical field to which the invention relates.

The present invention relates to a medicinal product, in particular a new condensed bicyclic heteroaryl compound or its pharmacologically priemlemim salt, which has a hypoglycemic effect or treats and/or prevents the violation of the metabolism of carbohydrates, or lipids, or a disease mediated by receptor-activated peroxisome proliferation (PPAR)γ.

The present invention relates also to a therapeutic and/or preventive agent against diabetes (in particular type II diabetes), hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance, insulin resistance, impaired glucose tolerance on an empty stomach, cachexia, psoriasis, diabetic complications, arteriosclerosis, atherosclerosis, hypertension, pancreatitis, polycystic ovary syndrome, fatty liver (fatty liver), non-alcoholic steatohepatitis (NASH), gestational diabetes mellitus, inflammatory diseases, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease, hyperuricemia, metabolic syndrome or like, which has the effect of improving the metabolism of carbohydrates, or lipids, the effect of improving insulinresistant the spine, anti-inflammatory effect, or the effect of inhibiting the growth of cancer cells, therapeutic agent and/or preventive agent containing the new condensed bicyclic heteroaryl compound or its pharmacologically acceptable salt as an active component.

Background of invention

In recent years, the number of patients with metabolic syndrome, such as diabetes type II, hyperinsulinemia, dyslipidemia, obesity, hypertension or atherosclerotic disease, increased worldwide due to such reasons as changes in lifestyle. Patients with metabolic syndrome repeatedly exposed to an increased risk of coronary artery disease, cerebral infarction and intracerebral hemorrhage, and chronic complications, such as nephropathy, neuropathy and retinopathy. The increase in the number of patients with complications was the main reason for the rising cost of medical treatment (non-patent document 1).

Recent studies have shown that ligands acting on PPARγ, useful for the prevention or attenuation of symptoms of the pathology caused by the metabolic syndrome, such as diabetes type II, hyperinsulinemia, dyslipidemia, obesity, hypertension, atherosclerotic disease, or insulin resistance (non-patent document 2). Ligands, is operating on PPARγ, inhibit the production of inflammatory cytokines (non-patent documents 3 and 4) and inducyruya apoptosis, inhibit the growth of cancer cells (non-patent document 5). Thus, the ligands are also useful for the prevention or attenuation of symptoms of inflammatory diseases or cancer. Specific examples of ligands acting on PPARγ include pioglitazone (non-patent document 6) and rosiglitazone (non-patent document 7), included in class thiazolidinedione drugs already used in medicine for treatment of diabetes type II. These thiazolidinedione medicines have side effects such as fluid retention, weight gain and increased risk of heart disease. Consequently, there was a need to develop safe pharmaceutical products (patent document 1). Many researchers are currently in the research and development of pharmaceutical products to prevent insulin resistance, disease caused by inflammation or the like, or metabolic syndrome or improve their symptoms by identifying ligands, activating or inhibiting PPARα, PPARγ or PPARδ (non-patent document 8).

Non-patent document 1: Annual Reports in Medicinal Chemistry, 39, 41-56 (2004).

Non-patent document 2: Annual Reviews of Medicine, 53, 409-435 (2002).

Non-patent document is UNT 3: Nature, 391, 79-82 (1998).

Non-patent document 4: Nature, 391, 82-86 (1998).

Non-patent document 5: Biochemical and Biophysical Research Communications, 270, 400-405nm (2000).

Non-patent document 6: Chem. Pharm. Bull., 39, 1440-1445 (1991).

Non-patent document 7: Bioorganic and Medicinal Chemistry Letter, 4, 1181-1184 (1994).

Patent document 1: WO 2004/014308.

Non-patent document 8: Annual Report in Medicinal Chemistry, 38, 71-80 (2003).

Disclosure of the invention

Problems to be solved by the invention of

The authors of the present invention conducted extensive research to create a therapeutic and/or prophylactic drugs against metabolic disorders of carbohydrate or lipid or diseases mediated by receptor-activated peroxisome proliferation (PPAR) γ. The authors found that condensed bicyclic heteroaryl compounds having a specific chemical structure, have excellent hypoglycemic effect, or have the effect of improving the metabolism of carbohydrates, or lipids, the effect of attenuation of the symptoms of insulin resistance and the effect of attenuation of the symptoms of the so-called metabolic syndrome, such as arteriosclerosis, hypertension, cardiovascular disorders or complications, or pathology caused by different infections. The authors found that these compounds are ligands acting on PPRγ, and so have the effect of inhibiting the growth of cancer cells. These research results have led to the creation of the present invention.

In particular, in accordance with the present invention offers a new condensed bicyclic heteroaryl compounds or their pharmacologically acceptable salts, are useful as therapeutic or prophylactic agents against metabolic syndrome, in particular diseases such as diabetes (in particular type II diabetes), hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance (IGT), insulin resistance, impaired glucose tolerance on an empty stomach (IFG), hypertension, fatty liver, nonalcoholic steatohepatitis (NASH), diabetic complications (such as retinopathy, nephropathy or neuropathy), arteriosclerosis, gestational diabetes diabetes (GDM) or polycystic ovary syndrome (PCOS), inflammatory diseases (such as osteoarthritis, pain or inflammatory enteritis), acne, solar erythema, psoriasis, eczema, allergic diseases, asthma, peptic ulcers, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic maculopathy, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular the violation, peripheral circulatory disorders, autoimmune diseases (such as systemic lupus erythematosus, chronic rheumatoid arthritis, Sjogren syndrome, systemic sclerosis, mixed soedinitelnotkannaja disease, Hashimoto's disease, Crohn's disease, ulcerative colitis, idiopathically Addison disease, male infertility syndrome?, rapidly progressive glomerulonephritis, severe psevdomatematicheskoe myasthenia gravis, polymyositis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Behcet's disease or CREST syndrome), pancreatitis, cachexia, cancer (such as stomach cancer, lung cancer, breast cancer, colon cancer, prostate cancer, cancer pancreas or liver cancer), leukemia, sarcoma (such as liposarcoma), osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease, hyperuricemia, dry eye, or the like.

Means for solving the problem

The present invention relates to

(1) to the Compound of General formula (I):

[Formula 1]

[where R1represents a C1-C6alkyl group, a C6-C10aryl group which may be substituted by 1-5 groups independently selected from the group of substituents (a), a heterocyclic group, the which may be substituted by 1-3 groups independently selected from the group of substituents (a), or C3-C6cycloalkyl group,

R2represents a C1-C6alkyl group,

R3represents a C6-C10aryl group which may be substituted by 1-5 groups independently selected from the group of substituents (a), or a heterocyclic group which may be substituted with 1-3 groups independently selected from the group of substituents (a),

Q represents a group represented by the formula =CH-or a nitrogen atom, and

the group of substituents (a) represents the group consisting of a halogen atom, a C1-C6alkyl group, a C1-C6hydroxyalkyl group, a C1-C6halogenated alkyl group, carboxyl group, carbamoyl group, C2-C7alkylcarboxylic group, C2-C7alkoxycarbonyl group, a hydroxy-group, C1-C6alkoxygroup, C1-C6halogenated alkoxygroup, C2-C7alkylcarboxylic, C2-C7alkoxycarbonylmethyl, amino, C2-C7alkylcarboxylic, C2-C7alkoxycarbonylmethyl, C1-C6alkylsulfonamides, 4-morpholinyl group and di(C1-C6alkyl)amino group],

or its pharmacologically priemlemoj salt.

Preferred embodiments of the present invention include the following compounds:

(2) the compound or its pharmacologically acceptable salt according to item (1), where R1is a 1-ethylpropyl group, phenyl group which may be substituted by 1-3 groups independently chosen from a halogen atom, a C1-C6alkyl group, a C1-C6alkoxygroup, C1-C6halogenated alkoxygroup and amino group, or 2,3-dihydro-1-benzofuran-6-ilen group;

(3) the compound or its pharmacologically acceptable salt according to item (1), where R1is a 1-ethylpropyl group, 2-florfenicol group, 3-florfenicol group, 3-chloraniline group, 2,5-differenly group, 4-chloro-3-florfenicol group, 3-chloro-4-florfenicol group, 4-methylphenyl group, 3-ethylphenyl group, 3,4-dimethylphenyl group, 3-triphtalocyaninine group, 3-metoksifenilny group, 3-methoxy-4-methylphenyl group, 4-amino-3,5-dimethylphenyl group or a 2,3-dihydro-1-benzofuran-6-ilen group;

(4) the compound or its pharmacologically acceptable salt according to item (1), where R1is a 2-florfenicol group, 3-florfenicol group, 3-chloraniline group, 2,5-differenly group, 4-chloro-3-florfenicol group, 3-chloro-4-florfenicol group, 4-methylp niloy group or a 2,3-dihydro-1-benzofuran-6-ilen group;

(5) the compound or its pharmacologically acceptable salt according to any one of items (1)to(4), where R2represents a methyl group and Q represents a group represented by the formula =CH-;

(6) the compound or its pharmacologically acceptable salt according to any one of items (1)to(5), where R3represents a phenyl group substituted by 1-3 fluorine atoms and/or carboxyl group(s);

(7) the compound or its pharmacologically acceptable salt according to any one of items (1)to(5), where R3is a 3-carboxyphenyl group or 3-carboxyl-5-florfenicol group;

(8) the compound or its pharmacologically acceptable salt according to item (1), where R1is a 1-ethylpropyl group, phenyl group which may be substituted by 1-3 groups independently chosen from a halogen atom, a C1-C6alkyl group, a C1-C6alkoxygroup, C1-C6halogenated alkoxygroup and amino group, or 2,3-dihydro-1-benzofuran-6-ilen group, R2represents a methyl group, R3represents a phenyl group substituted by 1-3 fluorine atoms and/or carboxyl group(s), and Q represents a group represented by the formula =CH-or a nitrogen atom;

(9) the compound or its pharmacologically acceptable salt according to item (1), where R1is the Wallpaper 1-ethylpropyl group, 2-florfenicol group, 3-florfenicol group, 3-chloraniline group, 2,5-differenly group, 4-chloro-3-florfenicol group, 3-chloro-4-florfenicol group, 4-methylphenyl group, 3-ethylphenyl group, 3,4-dimethylphenyl group, 3-triphtalocyaninine group, 3-metoksifenilny group, 3-methoxy-4-methylphenyl group, 4-amino-3,5-dimethylphenyl group or a 2,3-dihydro-1-benzofuran-6-ilen group, R2represents a methyl group, R3is a 3-carboxyphenyl group or 3-carboxyl-5-florfenicol group and Q represents a group represented by the formula =CH-or a nitrogen atom;

(10) the compound or its pharmacologically acceptable salt according to item (1), where R1is a 2-florfenicol group, 3-florfenicol group, 3-chloraniline group, 2,5-differenly group, 4-chloro-3-florfenicol group, 3-chloro-4-florfenicol group, 4-methylphenyl group or a 2,3-dihydro-1-benzofuran-6-ilen group, R2represents a methyl group, R3is a 3-carboxyphenyl group or 3-carboxyl-5-florfenicol group and Q represents a group represented by the formula =CH-;

(11) the compound or its pharmacologically acceptable salt according to item (1), where the compound having General formula (I), is

3-{[6-(3-pertenece)-1-methyl-1H-benzoni the azole-2-yl]methoxy}benzoic acid,

3-[6-(3-chlorophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzoic acid,

3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(3-chloro-4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(1-ethylpropoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(2-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[1-methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(3-ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(3-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-({1-methyl-6-[3-(triptoreline)phenoxy]-1H-benzimidazole-2-yl}methoxy)benzoic acid,

3-{[6-(2,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(3,4-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(3-methoxy-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(2,3-dihydro-1-benzofuran-6-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[3-methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid,

3-fluoro-5-{[3-methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid sludge is

3-{[5-(3,4-dimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid;

(12) the compound or its pharmacologically acceptable salt according to item (1), where the compound having General formula (I), is

3-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-[6-(3-chlorophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzoic acid,

3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(3-chloro-4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(2-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[1-methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(2,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid, or

3-{[6-(2,3-dihydro-1-benzofuran-6-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid;

(13) the compound according to item (1), where the compound having General formula (I), is

3-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-[6-(3-chlorophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzoic acid,

3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(3-chloro-4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(2-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzo is ina acid,

3-{[1-methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid,

3-{[6-(2,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid, or

3-{[6-(2,3-dihydro-1-benzofuran-6-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid;

(14) a pharmaceutical composition comprising a compound according to any one of items (1)to(13) or its pharmacologically acceptable salt as an active ingredient;

(15) the pharmaceutical composition according to item (14) to reduce blood glucose containing compound according to any one of items (1)to(13) or its pharmacologically acceptable salt as an active ingredient;

(16) the pharmaceutical composition according to item (14) for the treatment and/or prevention of diabetes containing the compound according to any one of items (1)to(13) or its pharmacologically acceptable salt as an active ingredient;

(17) the pharmaceutical composition according to item (14) for the treatment and/or prevention of diabetes type II containing the compound according to any one of items (1)to(13) or its pharmacologically acceptable salt as an active ingredient;

(18) the pharmaceutical composition according to item (14) to activate PPARγ containing compound according to any one of items (1)to(13) or its pharmacologically acceptable salt as an active ingredient;

(19) the pharmaceutical composition according to item (14) to improve the met is bolism carbohydrates or lipids, to mitigate the symptoms of insulin resistance, inhibition of inflammation, or to inhibit the growth of cancer cells containing the compound according to any one of items (1)to(13) or its pharmacologically acceptable salt as an active ingredient;

(20) the pharmaceutical composition according to item (14) for the treatment and/or prevention of diseases caused by metabolic syndrome containing the compound according to any one of items (1)to(13) or its pharmacologically acceptable salt as an active ingredient;

(21) the pharmaceutical composition according to item (14) for the treatment and/or prevention of hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance, insulin resistance, impaired glucose tolerance on an empty stomach, hypertension, fatty liver, non-alcoholic steatohepatitis, diabetic complications, arteriosclerosis, atherosclerosis, gestational diabetes or polycystic ovarian syndrome, containing a compound according to any one of items (1)to(13) or its pharmacologically acceptable salt as an active ingredient;

(22) the pharmaceutical composition according to item (14) for the treatment and/or prevention of inflammatory diseases, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease, or hyperuricemia, containing the link is on any of the items (1)to(13) or its pharmacologically acceptable salt as an active ingredient;

(23) the pharmaceutical composition according to item (14) for the treatment and/or prevention of acne, solar erythema, psoriasis, eczema, allergic diseases, asthma, peptic ulcers, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic maculopathy, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorders, peripheral circulatory disorders, autoimmune disease, pancreatitis, cachexia, leukemia, sarcoma, or dry eye, containing the compound according to any one of items (1)to(13) or its pharmacologically acceptable salt as an active ingredient;

(24) activator/modulator of PPARγ containing compound according to any one of items (1)to(13) or its pharmacologically acceptable salt as an active ingredient;

(25) the use of compounds according to any one of items (1)to(13) or its pharmacologically acceptable salts for the manufacture of pharmaceutical compositions;

(26) the application under paragraph (25), where the pharmaceutical composition is intended to reduce blood glucose;

(27) the application under paragraph (25), where the pharmaceutical composition is intended for the treatment and/or prevention of diabetes;

(28) the application under paragraph (25), where the pharmaceutical composition is intended for the treatment or prevention of type II diabetes;

(29) the application under paragraph (25), where the pharmaceutical composition is intended to activate PPARγ;

(30) the application under paragraph (25), where the pharmaceutical composition is intended to improve the metabolism of carbohydrates, or lipids, to ease the symptoms of insulin resistance, inhibition of inflammation, or to inhibit the growth of cancer cells;

(31) the application under paragraph (25), where the pharmaceutical composition is intended for treating and/or preventing diseases caused by metabolic syndrome;

(32) the application under paragraph (25), where the pharmaceutical composition is intended for the treatment and/or prevention of hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance, insulin resistance, impaired glucose tolerance on an empty stomach, hypertension, fatty liver, non-alcoholic steatohepatitis, diabetic complications, arteriosclerosis, atherosclerosis, gestational diabetes or polycystic ovary syndrome;

(33) the application under paragraph (25), where the pharmaceutical composition is intended for treating and/or preventing inflammatory diseases, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease, or hyperuricemia;

(34) the application under paragraph (25), where the pharmaceutical composition is destined is ACANA for the treatment and/or prevention of acne, solar erythema, psoriasis, eczema, allergic diseases, asthma, peptic ulcers, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic maculopathy, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorders, peripheral circulatory disorders, autoimmune disease, pancreatitis, cachexia, leukemia, sarcoma or dry eyes;

(35) the application under paragraph (25), where the pharmaceutical composition is an activator/modulator of PPARγ;

(36) a method of reducing blood glucose, including the introduction of a pharmacologically effective amount of a compound according to any one of items (1)to(13) or its pharmacologically acceptable salt warm-blooded animal;

(37) a method of activating PPARγ, containing the introduction of a pharmacologically effective amount of a compound according to any one of items (1)to(13) or its pharmacologically acceptable salt warm-blooded animal;

(38) a method for improving metabolism of carbohydrates, or lipids, easing symptoms of insulin resistance, inhibition of inflammation or inhibit the growth of cancer cells, including the introduction of a pharmacologically effective amount of a compound according to any one of items (1)to(13) or its pharmacologically acceptable salt replacr who ate animal;

(39) the method of treatment and/or prevention of diseases, containing the introduction of a pharmacologically effective amount of a compound according to any one of items (1)to(13) or its pharmacologically acceptable salt warm-blooded animal;

(40) the method according to item (39), where the specified disease is diabetes;

(41) the method according to item (39), where the specified disease is type II diabetes;

(42) the method according to item (39), where the specified disease is a disease caused by metabolic syndrome;

(43) the method according to item (39), where the specified condition is hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance, insulin resistance, impaired glucose tolerance on an empty stomach, hypertension, fatty liver, nonalcoholic steatohepatitis, diabetic complications, arteriosclerosis, atherosclerosis, gestational diabetes or polycystic ovary syndrome;

(44) the method according to item (39), where the specified disease is an inflammatory disease, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease, or hyperuricemia;

(45) the method according to item (39), where the specified condition is acne, solar erythema, psoriasis, eczema, allergic disease, asthma, peptic ulcer, ulcerative colitis, Crohn's disease, a disease coronary artery is, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic maculopathy, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorder, impaired peripheral circulation, autoimmune disease, pancreatitis, cachexia, leukemia, sarcoma, or dry eyes; and

(46) the method according to any one of items (36)-(45), where the specified warm-blooded animal is a human.

"C1-C6alkyl group" in the present invention is unbranched or branched alkyl group having 1-6 carbon atoms. Examples of such groups include methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, pentelow group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexoloy group, isohexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group and 3,3-dimethylbutyl group. The group represents preferably 1-ethylpropyl group for R1and preferably unbranched or branched alkyl group having 1-4 carbon atoms (C1-C4alkyl group), more preferably a methyl group or E. the ilen group (C 1-C2alkyl group and more preferably a methyl group to the other deputies.

"C3-C6cycloalkyl group" in the present invention is cyclopropyl group, cyclobutyl group, cyclopentyl group or tsiklogeksilnogo group, preferably cyclopentyloxy group.

"Halogen atom" in the present invention is a fluorine atom, chlorine atom, bromine atom or iodine atom. Preferably the halogen atom is a fluorine atom or a chlorine atom.

"C1-C6hydroxyalkyl group" in the present invention represents a group in which the hydroxy-group is attached to the above "C1-C6alkyl group". This group represents, for example, hydroxymethylene group, hydroxyethylene group or hydroxypropyl group and is preferably a group in which the hydroxy-group is attached to an unbranched or branched alkyl group having 1-4 carbon atoms (C1-C4alkyl group substituted by a hydroxy-group), more preferably hydroxymethylene group or 2-hydroxyethylene group and even more preferably hydroxymethylene group.

"C1-C6halogenated alkyl group" in the present invention represents g is the SCP, in which the same or different 1-5 above "halogen atoms" attached to the above "C1-C6alkyl group". Examples of such groups include triptorelin group, trichlorethylene group, deformational group, dichloromethylene group, dibromomethyl group, formeterol group, 2,2,2-triptorelin group, 2,2,2-trichlorethylene group, 2-bromatology group, 2-chloraniline group and 2-foretelling group. This group represents preferably a group in which the same or different 1-5 above "halogen atoms" attached to the above "C1-C4alkyl group, (C1-C4halogenated alkyl group), more preferably a group in which the same or different 1-5 above "halogen atoms" attached to the above "C1-C2alkyl group, (C1-C2halogenated alkyl group), and even more preferably triptorelin group.

"C2-C7acylcarnitine group" in the present invention represents a group in which the above "C1-C6alkyl group attached to a carbonyl group. Examples of such groups include acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, pentanoyl group, pivaloyloxy GRU is PU, valerino group and isovaleryl group. This group represents preferably a group in which the above "C1-C4alkyl group attached to a carbonyl group (C2-C5alkylcarboxylic group), more preferably acetyl group or propionyl group (C2-C3alkylcarboxylic group), and even more preferably acetyl group.

"C1-C6alkoxygroup" in the present invention represents a group in which the above "C1-C6alkyl group attached to the oxygen atom and is unbranched or branched alkoxygroup containing 1-6 carbon atoms. Examples of such groups include a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, phenoxypropan and 2-methylbutoxy. This group represents preferably an unbranched or branched alkoxygroup containing 1-4 carbon atoms (C1-C4alkoxygroup), and more respectfully a methoxy group or isopropoxy.

"C2-C7alkoxycarbonyl group" in the present invention represents a group in which the above "C1-C6alkoxygroup" attached to the carbonyl is the RUPE. Examples of such groups include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxyethanol group, sec-butoxycarbonyl group, tert-butoxycarbonyl group and phenoxycarbonyl group. This group represents preferably a group in which the above "C1-C4alkoxygroup" attached to a carbonyl group (C2-C5alkoxycarbonyl group), more preferably methoxycarbonyl group or ethoxycarbonyl group (C2-C3alkoxycarbonyl group), and even more preferably methoxycarbonyl group.

"C1-C6the halogenated alkoxygroup" in the present invention represents a group in which the same or different 1-5 above "halogen atoms" attached to the above "C1-C6alkoxygroup". Examples of such groups include cryptometer, trichlormethiazide, dipterocarp, formatexpr, 2,2,2-triptracker, 2,2,2-trichlorethene, 2-pomatocalpa, 2-choreograph and 2-floridacheap. This group represents preferably a group in which the same or different 1-5 above "halogen atoms" attached to the decree which authorized above, "C 1-C4alkoxygroup" (C1-C4the halogenated alkoxygroup), more preferably a group in which the same or different 1-5 above "halogen atoms" attached to the above "C1-C2alkoxygroup" (C1-C2the halogenated alkoxygroup), and even more preferably cryptometer.

"C2-C7alkylcarboxylic" in the present invention represents a group in which the above "C2-C7acylcarnitine group attached to the oxygen atom. Examples of such groups include acetoxy, propionyloxy, butyryloxy and isobutyryloxy. This group represents preferably a group in which the above "C2-C5acylcarnitine group attached to the oxygen atom (C2-C5alkylcarboxylic), more preferably acetoxy or propionyloxy (C2-C3alkylcarboxylic) and even more preferably acetoxy.

"C2-C7alkoxycarbonylmethyl" in the present invention represents a group in which the above "C2-C7alkoxycarbonyl group attached to the oxygen atom. Examples of such groups include methoxycarbonylamino, ethoxycarbonylethyl the PU, propoxycarbonyl, isopropoxycarbonyloxymethyl, butoxycarbonylamino and isobutoxyethene.svg. This group represents preferably a group in which the above "C2-C5alkoxycarbonyl group attached to the oxygen atom (C2-C5alkoxycarbonylmethyl), more preferably methoxycarbonylamino or ethoxycarbonylmethoxy (C2-C3alkoxycarbonylmethyl) and even more preferably methoxycarbonylamino.

"C2-C7alkylcarboxylic" in the present invention represents a group in which one carbonyl group attached to it above "C1-C6alkyl group attached to the amino group. Examples of such groups include acetaminoph, ethylcarbodiimide, propylnitrosamine, isopropylcarbodiimide and BUTYLCARBAMATE. This group represents preferably a group in which one carbonyl group attached to it above "C1-C4alkyl group attached to the amino group (C2-C5alkylcarboxylic), and more preferably acetaminoph or ethylcarbodiimide (C2-C3alkylcarboxylic).

"C2-C7alcox carbonylation" in the present invention is a group, in which one carbonyl group attached to it above "C1-C6alkoxygroup" attached to the amino group. Examples of such groups include methoxycarbonylamino, ethoxycarbonylmethoxy, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonylamino, isobutoxyethanol and second-butoxycarbonylamino. This group represents preferably a group in which a carbonyl group attached to it above "C1-C4alkoxygroup" attached to the amino group (C2-C5alkoxycarbonylmethyl), more preferably methoxycarbonylamino or ethoxycarbonylmethoxy (C2-C3alkoxycarbonylmethyl) and even more preferably methoxycarbonylamino.

"C1-C6alkylsulfonamides" in the present invention represents a group in which one sulfonylurea group attached to it above "C1-C6alkyl group attached to the amino group. Examples of such groups include methylsulfonylamino, ethylsulfonylimidazo, propylsulfonyl, isopropylbenzylamine and butylmethylamine. This group represents preferably a group in which one su is Honiley group attached to it above "C 1-C4alkyl group attached to the amino group (mono-C1-C4alkylsulfonamides), more preferably methylsulfonylamino or ethylsulfonylimidazo (mono-C1-C2alkylsulfonamides) and even more preferably methylsulfonylamino.

"Di(C1-C6alkyl)amino group" in the present invention represents a group in which the same or different two above "C1-C6alkyl groups attached to the amino group. Examples of such groups include dimethylaminopropyl, diethylaminopropyl, dipropylamino, diisopropylamino, dibutylamino, diisobutylamine, dimetilaminovogo, diisobutylamine, dineopentyl, Vexillology, N-ethyl-N-methylaminopropyl, N-methyl-N-propylamino, N-isopropyl-N-methylaminopropyl, N-butyl-N-methylaminopropyl, N-isobutyl-N-methylaminopropyl, N-methyl-N-pentylamine, N-isopentyl-N-methylaminopropyl, N-ethyl-N-propylamino, N-ethyl-N-isopropylamino, N-butyl N-ethylamino and N-ethyl-N-isopentylamine. This group represents preferably a group in which the same or different two above "C1-C4alkyl groups attached to the amino group (di(C1-C4alkyl)amino group), more than before occhialino dimethylaminopropyl, diethylaminopropyl or N-ethyl-N-methylaminopropyl (di(C1-C2alkyl)amino group), and even more preferably dimethylaminopropyl.

"C6-C10aryl group" in the present invention represents an aromatic hydrocarbon group containing 6-10 carbon atoms. This group represents preferably a phenyl group or naftalina group and more preferably a phenyl group.

"Heterocyclic group" in the present invention is a four-semicolony heterocyclic group that contains 1-3 sulfur atom, oxygen atom and/or nitrogen atom and may optionally contain 1 or 2 nitrogen atom and in which two atoms of oxygen can be attached to the sulfur atom. Examples of such groups include the "aromatic heterocyclic group", such as furilla group, thienyl group, pyrrolidine group, aspenlea group, pyrazolidine group, imidazolidinyl group, oxazoline group, isoxazolyl group, thiazolidine group, isothiazolinone group, 1,2,3-oxadiazolyl group, thiazolidine group, tetrataenia group, thiadiazolyl group, Pernilla group, Peregrina group, pyridazinyl group, pyrimidinyl group and piratininga group and partially or completely restored the rich heterotic the practical group", such as tetrahydropyranyl group, tetrahydroquinoline group, morpholinyl group, thiomorpholine group, pyrrolidinyl group, pyrrolidinone group, imidazolidinyl group, pyrazolidinone group, piperidinyl group, piperazinilnom group, oxazolidinyl group, isoxazolidinone group, diazolidinylurea group, pyrazolidinone group, DIOXOLANYL group and dioxinlika group. The above heterocyclic group may be fused with another cyclic group such as benzene ring ("condensed bicyclic heteroaryl group"). Examples of such groups include benzothiazoline group, benzothiazolyl group, benzoxazolyl group, isobenzofuranyl group, 1,3-dihydroisobenzofuran group, pinolillo group, 1,3-benzodioxolyl group, 1,4-benzodioxolyl group, indolenine group, isoindolyl group and indolinyl group. This group represents preferably six-membered heterocyclic group or condensed bicyclic heteroaryl group that contains 1-3 sulfur atom, oxygen atom and/or nitrogen atom, more preferably pyridyloxy group, morpholinyl group, tetrahydro-2H-pyranyloxy group, 2,3-dihydro-1-benzofuranyl group, or 1,3-benzodioxole the group, even more preferably 3-pyridyloxy group, 4-morpholinyl group, tetrahydro-2H-Piran-4-ilen group, 2,3-dihydro-1-benzofuran-6-ilen group, or 1,3-benzodioxol-5-ilen group, and particularly preferably 2,3-dihydro-1-benzofuran-6-ilen group.

"C6-C10aryl group which may be substituted by 1-5 groups independently selected from the group of substituents (a), in the present invention is the above "C6-C10aryl group which may be substituted by 1-5 groups independently selected from the group of substituents (a). This group is for R1represents preferably a phenyl group which may be substituted by 1-3 groups independently chosen from a halogen atom, a C1-C6alkyl group, a C1-C6alkoxygroup, C1-C6halogenated alkoxygroup and amino groups, more preferably 2-florfenicol group, 3-florfenicol group, 3-chloraniline group, 2,5-differenly group, 4-chloro-3-florfenicol group, 3-chloro-4-florfenicol group, 4-methylphenyl group, 3-ethylphenyl group, 3,4-dimethylphenyl group, 3-triphtalocyaninine group, 3-metoksifenilny group, 3-methoxy-4-methylphenyl group or 4-amino-3,5-dimethylphenyl group, and even more preferably 2-florfenicol group, 3-fluoro-Christ.enelow group, 3-chloraniline group, 2,5-differenly group, 4-chloro-3-florfenicol group, 3-chloro-4-florfenicol group or 4-methylphenylene group. This group is for R3represents preferably a phenyl group substituted by 1-3 fluorine atoms and/or carboxyl group(s), and more preferably 3-carboxyphenyl group or 3-carboxyl-5-florfenicol group.

"Heterocyclic group which may be substituted with 1-3 groups independently selected from the group of substituents (a), in the present invention is the above-mentioned "heterocyclic group"which may be substituted with 1-3 groups independently selected from the group of substituents (a). This group represents preferably pyridyloxy group substituted by 1-3 groups independently chosen from a halogen atom and C1-C6alkoxygroup, pyridyloxy group, tetrahydro-2H-Piran-4-ilen group, tetrahydrofuran-3-ilen group, 2,3-dihydro-1-benzofuran-6-ilen group, or 1,3-benzodioxol-5-ilen group, and more preferably 2,3-dihydro-1-benzofuran-6-ilen group.

In the present invention R1represents preferably 1-ethylpropyl group, phenyl group which may be substituted by 1-3 groups independently chosen from a halogen atom, a C1-C6alkyl group, a C1 -C6alkoxygroup, C1-C6halogenated alkoxygroup and amino group, or 2,3-dihydro-1-benzofuran-6-ilen group. R1is more preferably 1-ethylpropyl group, 2-florfenicol group, 3-florfenicol group, 3-chloraniline group, 2,5-differenly group, 4-chloro-3-florfenicol group, 3-chloro-4-florfenicol group, 4-methylphenyl group, 3-ethylphenyl group, 3,4-dimethylphenyl group, 3-triphtalocyaninine group, 3-metoksifenilny group, 3-methoxy-4-methylphenyl group, 4-amino-3,5-dimethylphenyl group or a 2,3-dihydro-1-benzofuran-6-ilen group. R1represents even more preferably 2-florfenicol group, 3-florfenicol group, 3-chloraniline group, 2,5-differenly group, 4-chloro-3-florfenicol group, 3-chloro-4-florfenicol group, 4-methylphenyl group or a 2,3-dihydro-1-benzofuran-6-ilen group.

In the present invention R2represents preferably a methyl group.

In the present invention R3represents preferably a phenyl group substituted by 1-3 fluorine atoms and/or carboxyl group(s). R3is more preferably 3-carboxyphenyl group or 3-carboxyl-5-florfenicol group.

In the present invention Q is a preference for the equipment group, represented by the formula =CH-.

Condensed bicyclic heteroaryl compound or its pharmacologically acceptable salt of General formula (I) in accordance with the present invention includes all isomers such as catenary isomer, diastereoisomer, optical isomer, rotamer etc).

Condensed bicyclic heteroaryl compound or its pharmacologically acceptable salt of General formula (I) in accordance with the present invention has various isomers, because in the molecule exists(ut) asymmetric(s) atom(s) of carbon. These isomers and mixtures of these isomers according to the present invention are all represented by a single formula, in particular the General formula (I). Thus, the present invention includes all of these isomers and mixtures thereof in an arbitrary ratio.

The aforementioned stereoisomers, if necessary, may be obtained by synthesis of the compounds of the present invention with an optically active starting compound or asymmetric synthesis or by the technology of asymmetric induction or selection of the synthesized compounds according to the present invention the conventional method of optical separation or separation.

"Pharmacologically acceptable salt" is a salt, which can be obtained by conducting the outdoor is consistent bicyclic heteroaryl compounds of General formula (I) in accordance with the present invention, containing ó group such as amino group, with an acid or a realization of interaction of the compounds containing an acid group such as carboxyl group with a base.

Preferred examples of the salt ó group include hydrogenogenic, such as hydrohloride, hydrochloride, hydrobromide and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates and phosphates; alkyl sulphonates such as methanesulfonate and econsultancy; halogenated.sulphonated, such as triftoratsetata; arylsulfonate, such as benzosulfimide and p-toluensulfonate, and organic acid salts such as acetates, malaty, fumarate, succinate, citrates, ascorbates, tartratami, oxalates and maleate.

On the other hand, preferred examples of the salt of the acidic group include salts of alkali metals such as sodium salts, potassium salts and lithium salts; salts of alkaline earth metals such as calcium salts and magnesium salts, and metal salts such as aluminum salt and iron salt.

Condensed bicyclic heteroaryl compound or its pharmacologically acceptable salt of General formula (I) in accordance with the present invention can absorb water or adsorbed water with the formation of hydrate while leaving in the air or on the stud and cleaning or receive and salt of the present invention also includes such a hydrate.

Condensed bicyclic heteroaryl compound or its pharmacologically acceptable salt of General formula (I) in accordance with the present invention can absorb some other specific solvents with the formation of MES and salt of the present invention also includes such MES.

Specific examples of the compounds of General formula (I) in accordance with the present invention include compounds shown in table 1, but these groups do not limit the present invention.

Reduction in the given below table 1 mean the following. In particular:

Me means methyl group,

Et means ethyl group,

1-Et-Pr means 1-ethylpropyl group,

Cycpent means cyclopentyloxy group,

Ph means phenyl group,

3-CO2H-Ph means 3-carboxyphenyl group,

4-Mor means 4-morpholinyl group,

5-CO2H-3-Py means 5-carboxy-3-pyridyloxy group,

Het (A) means tetrahydro-2H-Piran-4-ilen group,

Het (B) means tetrahydrofuran-3-ilen group,

Het (C) means 2,3-dihydro-1-benzofuran-6-ilen group and

Het (D) means 1,3-benzodioxol-5-ilen group.

Table 1
[Forms of the La 2]
Connection # R1QR3
1-1Et=CH-2-CO2H-Ph
1-2Et=CH-2-CO2Et-Ph
1-3Et=CH-3-CO2H-Ph
1-4Et=CH-3-CO2Me-Ph
1-5Et=CH-4-CO2H-Ph

td align="justify"> 1-48
1-6Et=CH-4-CO2Et-Ph
1-7Et=CH-5-CO2H-3-Py
1-8Et=CH-5-CO2Me-3-Py
1-9EtN2-CO2H-Ph
1-10EtN2-CO2Et-Ph
1-11EtN3-CO2H-Ph
1-12EtN3-CO2Me-Ph
1-13EtN4-CO2H-Ph
1-14EtN4-CO2Et-Ph
1-15EtN5-CO2H-3-Py
1-16EtN5-CO2Me-3-Py
1-17Ph=CH-2-CO2H-Ph
1-18Ph=CH- 2-CO2Et-Ph
1-19Ph=CH-3-CO2H-Ph
1-20Ph=CH-3-CO2Me-Ph
1-21Ph=CH-4-CO2H-Ph
1-22Ph=CH-4-CO2Et-Ph
1-23Ph=CH-5-CO2H-3-Py
1-24Ph=CH-5-CO2Me-3-Py
1-25PhN2-CO2H-Ph
1-26PhN2-CO2Et-Ph
1-27PhN3-CO2H-Ph
1-28Ph3-CO2Me-Ph
1-29PhN4-CO2H-Ph
1-30PhN4-CO2Et-Ph
1-31PhN5-CO2H-3-Py
1-32PhN5-CO2Me-3-Py
1-333-F-Ph=CH-2-CO2H-Ph
1-343-F-Ph=CH-2-CO2Et-Ph
1-353-F-Ph=CH-3-CO2H-Ph
1-363-F-Ph=CH-3-CO2Me-Ph
1-373-F-Ph=CH-4-CO2H-Ph
1-38 3-F-Ph=CH-4-CO2Et-Ph
1-393-F-Ph=CH-5-CO2H-3-Py
1-403-F-Ph=CH-5-CO2Me-3-Py
1-413-F-PhN2-CO2H-Ph
1-423-F-PhN2-CO2Et-Ph
1-433-F-PhN3-CO2H-Ph
1-443-F-PhN3-CO2Me-Ph
1-453-F-PhN4-CO2H-Ph
1-463-F-PhN4-CO2Et-Ph
1-473-F-PhN5-CO2H-3-Py
3-F-PhN5-CO2Me-3-Py
1-493-Cl-Ph=CH-2-CO2H-Ph
1-503-Cl-Ph=CH-2-CO2Et-Ph
1-513-Cl-Ph=CH-3-CO2H-Ph
1-523-Cl-Ph=CH-3-CO2Me-Ph
1-533-Cl-Ph=CH-4-CO2H-Ph
1-543-Cl-Ph=CH-4-CO2Et-Ph
1-553-Cl-Ph=CH-5-CO2H-3-Py
1-563-Cl-Ph=CH-5-CO2Me-3-Py

1-57 3-Cl-PhN2-CO2H-Ph
1-583-Cl-PhN2-CO2Et-Ph
1-593-Cl-PhN3-CO2H-Ph
1-603-Cl-PhN3-CO2Me-Ph
1-613-Cl-PhN4-CO2H-Ph
1-623-Cl-PhN4-CO2Et-Ph
1-633-Cl-PhN5-CO2H-3-Py
1-643-Cl-PhN5-CO2Me-3-Py
1-653-(4-Mor)-Ph=CH-2-CO2H-Ph
1-663-(4-Mor)-Ph=CH-2-CO2Et-Ph
1-673-(4-Mor)-Ph=CH-3-CO2H-Ph
1-683-(4-Mor)-Ph=CH-3-CO2Me-Ph
1-693-(4-Mor)-Ph=CH-4-CO2H-Ph
1-703-(4-Mor)-Ph=CH-4-CO2Et-Ph
1-713-(4-Mor)-Ph=CH-5-CO2H-3-Py
1-723-(4-Mor)-Ph=CH-5-CO2Me-3-Py
1-733-(4-Mor)-PhN2-CO2H-Ph
1-743-(4-Mor)-PhN2-CO2Et-Ph
1-753-(4-Mor)-PhN3-CO2H-Ph
1-76 3-(4-Mor)-PhN3-CO2Me-Ph
1-773-(4-Mor)-PhN4-CO2H-Ph
1-783-(4-Mor)-PhN4-CO2Et-Ph
1-793-(4-Mor)-PhN5-CO2H-3-Py
1-803-(4-Mor)-PhN5-CO2Me-3-Py
1-812,4-Cl2-Ph=CH-2-CO2H-Ph
1-822,4-Cl2-Ph=CH-2-CO2Et-Ph
1-832,4-Cl2-Ph=CH-3-CO2H-Ph
1-842,4-Cl2-Ph=CH-3-CO2Me-Ph
1-852,4-Cl2-Ph =CH-4-CO2H-Ph
1-862,4-Cl2-Ph=CH-4-CO2Et-Ph
1-872,4-Cl2-Ph=CH-5-CO2H-3-Py
1-882,4-Cl2-Ph=CH-5-CO2Me-3-Py
1-892,4-Cl2-PhN2-CO2H-Ph
1-902,4-Cl2-PhN2-CO2Et-Ph
1-912,4-Cl2-PhN3-CO2H-Ph
1-922,4-Cl2-PhN3-CO2Me-Ph
1-932,4-Cl2-PhN4-CO2H-Ph
1-942,4-Cl2-Ph N4-CO2Et-Ph
1-952,4-Cl2-PhN5-CO2H-3-Py
1-962,4-Cl2-PhN5-CO2Me-3-Py
1-974-Cl-3-F-Ph=CH-2-CO2H-Ph
1-984-Cl-3-F-Ph=CH-2-CO2Et-Ph
1-994-Cl-3-F-Ph=CH-3-CO2H-Ph
1-1004-Cl-3-F-Ph=CH-3-CO2Me-Ph
1-1014-Cl-3-F-Ph=CH-4-CO2H-Ph
1-1024-Cl-3-F-Ph=CH-4-CO2Et-Ph
1-1034-Cl-3-F-Ph=CH-5-CO2 H-3-Py
1-1044-Cl-3-F-Ph=CH-5-CO2Me-3-Py
1-1054-Cl-3-F-PhN2-CO2H-Ph
1-1064-Cl-3-F-PhN2-CO2Et-Ph
1-1074-Cl-3-F-PhN3-CO2H-Ph

1-1084-Cl-3-F-PhN3-CO2Me-Ph
1-1094-Cl-3-F-PhN4-CO2H-Ph
1-1104-Cl-3-F-PhN4-CO2Et-Ph
1-1114-Cl-3-F-PhN5-CO2H-3-Py
1-1124-Cl-3-F-PhN5-CO2Me-3-Py/td>
1-1133-Cl-4-F-Ph=CH-2-CO2H-Ph
1-1143-Cl-4-F-Ph=CH-2-CO2Et-Ph
1-1153-Cl-4-F-Ph=CH-3-CO2H-Ph
1-1163-Cl-4-F-Ph=CH-3-CO2Me-Ph
1-1173-Cl-4-F-Ph=CH-4-CO2H-Ph
1-1183-Cl-4-F-Ph=CH-4-CO2Et-Ph
1-1193-Cl-4-F-Ph=CH-5-CO2H-3-Py
1-1203-Cl-4-F-Ph=CH-5-CO2Me-3-Py
1-1213-Cl-4-F-PhN2-CO2H-Ph
1-122 3-Cl-4-F-PhN2-CO2Et-Ph
1-1233-Cl-4-F-PhN3-CO2H-Ph
1-1243-Cl-4-F-PhN3-CO2Me-Ph
1-1253-Cl-4-F-PhN4-CO2H-Ph
1-1263-Cl-4-F-PhN4-CO2Et-Ph
1-1273-Cl-4-F-PhN5-CO2H-3-Py
1-1283-Cl-4-F-PhN5-CO2Me-3-Py
1-1294-NH2for 3,5-Me2-Ph=CH-2-CO2H-Ph
1-1304-NH2for 3,5-Me2-Ph=CH-2-CO2Et-Ph
1-1314-NH2for 3,5-Me2 =CH-3-CO2H-Ph
1-1324-NH2for 3,5-Me2-Ph=CH-3-CO2Me-Ph
1-1334-NH2for 3,5-Me2-Ph=CH-4-CO2H-Ph
1-1344-NH2for 3,5-Me2-Ph=CH-4-CO2Et-Ph
1-1354-NH2for 3,5-Me2-Ph=CH-5-CO2H-3-Py
1-1364-NH2for 3,5-Me2-Ph=CH-5-CO2Me-3-Py
1-1374-NH2for 3,5-Me2-PhN2-CO2H-Ph
1-1384-NH2for 3,5-Me2-PhN2-CO2Et-Ph
1-1394-NH2for 3,5-Me2-PhN 3-CO2H-Ph
1-1404-NH2for 3,5-Me2-PhN3-CO2Me-Ph
1-1414-NH2for 3,5-Me2-PhN4-CO2H-Ph
1-1424-NH2for 3,5-Me2-PhN4-CO2Et-Ph
1-1434-NH2for 3,5-Me2-PhN5-CO2H-3-Py
1-1444-NH2for 3,5-Me2-PhN5-CO2Me-3-Py
1-1453-Py=CH-2-CO2H-Ph
1-1463-Py=CH-2-CO2Et-Ph
1-1473-Py=CH-3-CO2H-Ph
1-1483-Py=CH- 3-CO2Me-Ph
1-1493-Py=CH-4-CO2H-Ph
1-1503-Py=CH-4-CO2Et-Ph
1-1513-Py=CH-5-CO2H-3-Py
1-1523-Py=CH-5-CO2Me-3-Py
1-1533-PyN2-CO2H-Ph
1-1543-PyN2-CO2Et-Ph
1-1553-PyN3-CO2H-Ph
1-1563-PyN3-CO2Me-Ph
1-1573-PyN4-CO2H-Ph
1-1583-Py N4-CO2Et-Ph

1-1593-PyN5-CO2H-3-Py
1-1603-PyN5-CO2Me-3-Py
1-1611-Et-Pr=CH-3-CO2H-Ph
1-162Cycpent=CH-3-CO2H-Ph
1-163Cychex=CH-3-CO2H-Ph
1-1642-F-Ph=CH-3-CO2H-Ph
1-1654-F-Ph=CH-3-CO2H-Ph
1-1662-Me-Ph=CH-3-CO2H-Ph
1-1673-Me-Ph=CH- 3-CO2H-Ph
1-1684-Me-Ph=CH-3-CO2H-Ph
1-1692-Et-Ph=CH-3-CO2H-Ph
1-1703-Et-Ph=CH-3-CO2H-Ph
1-1714-Et-Ph=CH-3-CO2H-Ph
1-1722-OMe-Ph=CH-3-CO2H-Ph
1-1733-OMe-Ph=CH-3-CO2H-Ph
1-1744-OMe-Ph=CH-3-CO2H-Ph
1-1753-CF3-Ph=CH-3-CO2H-Ph
1-1763-OCF3-Ph=CH-3-CO2H-Ph
1-177 3-NMe2-Ph=CH-3-CO2H-Ph
1-1782,4-F2-Ph=CH-3-CO2H-Ph
1-1792,5-F2-Ph=CH-3-CO2H-Ph
1-1803,4-F2-Ph=CH-3-CO2H-Ph
1-181the 3.5-F2-Ph=CH-3-CO2H-Ph
1-1822-F-4-Me-Ph=CH-3-CO2H-Ph
1-1834-F-2-Me-Ph=CH-3-CO2H-Ph
1-1842-F-5-Me-Ph=CH-3-CO2H-Ph
1-1855-F-2-Me-Ph=CH-3-CO2H-Ph
1-186 3-F-4-Me-Ph=CH-3-CO2H-Ph
1-1874-F-3-Me-Ph=CH-3-CO2H-Ph
1-1883-F-5-Me-Ph=CH-3-CO2H-Ph
1-1892-F-4-OMe-Ph=CH-3-CO2H-Ph
1-1904-F-2-OMe-Ph=CH-3-CO2H-Ph
1-1912-F-5-OMe-Ph=CH-3-CO2H-Ph
1-1925-F-2-OMe-Ph=CH-3-CO2H-Ph
1-1933-F-4-OMe-Ph=CH-3-CO2H-Ph
1-1944-F-3-OMe-Ph=CH-3-CO2H-Ph
1-1953-F-5-OMe-Ph=CH- 3-CO2H-Ph
1-1962,4-Me2-Ph=CH-3-CO2H-Ph
1-1972,5-Me2-Ph=CH-3-CO2H-Ph
1-1983,4-Me2-Ph=CH-3-CO2H-Ph
1-1993,5-Me2-Ph=CH-3-CO2H-Ph
1-2002-OMe-4-Me-Ph=CH-3-CO2H-Ph
1-2014-OMe-2-Me-Ph=CH-3-CO2H-Ph
1-2022-OMe-5-Me-Ph=CH-3-CO2H-Ph
1-2035-OMe-2-Me-Ph=CH-3-CO2H-Ph
1-2043-OMe-4-Me-Ph=CH-3-CO2H-Ph
1-2054-OMe-3-Me-Ph=CH-3-CO2H-Ph
1-2063-OMe-5-Me-Ph=CH-3-CO2H-Ph
1-2073-Cl-5-F-Ph=CH-3-CO2H-Ph
1-208Het(A)=CH-3-CO2H-Ph
1-209Het(B)=CH-3-CO2H-Ph

1-210Het(C)=CH-3-CO2H-Ph
1-211Het(D)=CH-3-CO2H-Ph
1-2123-F-Ph=CH-3-CO2H-5-F-Ph
1-2134-F-Ph=CH-3-CO2H-5-F-Ph
1-2143-Cl-Ph=CH-3-CO2H-5-F-Ph
1-2154-Cl-Ph=CH-3-CO2H-5-F-Ph
1-2163-Me-Ph=CH-3-CO2H-5-F-Ph
1-2174-Me-Ph=CH-3-CO2H-5-F-Ph
1-2183-OMe-Ph=CH-3-CO2H-5-F-Ph
1-2194-OMe-Ph=CH-3-CO2H-5-F-Ph
1-2204-Cl-3-F-Ph=CH-3-CO2H-5-F-Ph
1-2214-Me-PhN3-CO2H-Ph
1-2224-Me-PhN3-CO2H-5-F-Ph
1-2233,4-Me2-Ph N3-CO2H-Ph
1-2243,4-Me2-PhN3-CO2H-5-F-Ph
1-2253,5-Me2-PhN3-CO2H-Ph
1-2263,5-Me2-PhN3-CO2H-5-F-Ph
1-2273-F-4-Me-PhN3-CO2H-Ph
1-2283-F-4-Me-PhN3-CO2H-5-F-Ph

In table 1, the preferred compounds are compounds No. 1-19, 1-27, 1-35, 1-43, 1-50, 1-59, 1-99, 1-107, 1-115, 1-123, 1-131, 1-139, 1-161, 1-164, 1-168, 1-170, 1-173, 1-175, 1-176, 1-179, 1-188, 1-198, 1-204, 1-210, 1-217, 1-220, 1-221, 1-222, 1-223, 1-224 and 1-227.

More preferred compounds are

3-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-35),

3-[6-(3-chlorophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzoic acid (compound No. 1-51),

3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-99),

3-{[6-(3-chloro-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-115),

3-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-131),

3-{[6-(1-ethylpropoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-161),

3-{[6-(2-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-164),

3-{[1-methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-168),

3-{[6-(3-ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-170),

3-{[6-(3-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-173),

3-({1-methyl-6-[3-(triptoreline)phenoxy]-1H-benzimidazole-2-yl}methoxy)benzoic acid (compound No. 1-176),

3-{[6-(2,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-179),

3-{[6-(3,4-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-198),

3-{[6-(3-methoxy-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-204),

3-{[6-(2,3-dihydro-1-benzofuran-6-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-210),

3-{[3-methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid (compound No. 1-221),

3-fluoro-5-{[3-methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid (compound No. 1-222) and

3-[5-(3,4-dimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid (compound No. 1-223).

Even more preferred compounds are:

3-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-35),

3-[6-(3-chlorophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzoic acid (compound No. 1-51),

3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-99),

3-{[6-(3-chloro-4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-115),

3-{[6-(2-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-164),

3-{[1-methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-168),

3-{[6-(2,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-179) and

3-{[6-(2,3-dihydro-1-benzofuran-6-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-210).

Advantages of the invention

As was found, condensed bicyclic heteroaryl compounds or their pharmacologically acceptable salts, having the General formula (I), in accordance with the present invention have excellent hypoglycemic effect, the effect of improving the metabolism of carbohydrates, or lipids, the effect of easing the symptoms of insulin resistance and the effect of easing the symptoms of the so-called metabolic syndr the mA such as arteriosclerosis, hypertension, cardiovascular disorders or related complications or pathology caused by different infections. It was also discovered that these compounds are ligands acting on PPARγ, and therefore have the effect of inhibiting the growth of cancer cells. The compounds are useful as therapeutic or prophylactic agent against metabolic syndrome, in particular diseases, such as diabetes, hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance (IGT), insulin resistance, impaired glucose tolerance on an empty stomach (IFG), hypertension, fatty liver, nonalcoholic steatohepatitis (NASH), diabetic complications (such as retinopathy, nephropathy or neuropathy), arteriosclerosis, gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS), inflammatory diseases (such as osteoarthritis, pain or inflammatory enteritis), acne, sun erythema, psoriasis, eczema, allergic diseases, asthma, peptic ulcers, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic maculopathy, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorders, disorders of perifericos the th circulation, autoimmune diseases (such as systemic lupus erythematosus, chronic rheumatoid arthritis, Sjogren syndrome, systemic sclerosis, mixed soedinitelnotkannaja disease, Hashimoto's disease, Crohn's disease, ulcerative colitis, idiopathic Addison disease, male infertility syndrome?, rapidly progressive glomerulonephritis, severe psevdomatematicheskoe myasthenia gravis, polymyositis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Behcet's disease or CREST syndrome), pancreatitis, cachexia, cancer (such as stomach cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer or cancer liver, leukemia, sarcoma (such as liposarcoma), osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease, hyperuricemia, or dry eyes. These compounds may be also used as a medicine for the treatment and/or prevention of the above diseases.

Brief description of drawings

Figure 1 presents a schematic representation of PPARγ expression plasmid, referred to in example 1 trials;

figure 2 presents a schematic representation of PPRE reporter plasmid, referred to in example 1 tests; and

figure 3 presents the concept is property of the image dose-dependent curve, mentioned in example 1 tests.

Figure 3 luciferase activity of the positive control group was defined as 100%, and luciferase activity of the control group is defined as 0%. Maximum luciferase activity showed only the test connection is defined as Emax (%) and maximum inhibition of luciferase activity shown by the test compound in the presence of compound A, is defined as Imax (%). The concentration of the partial agonist as medicines, presents Emax/2, defined as EC50and the partial concentration of the antagonist as a medicine, presents (100-Imax)/2, is defined as IC50. ---- mean concentration in the presence of compound A and········· mean concentration in the absence of compound A.

The best way of carrying out the invention

The compound having General formula (I), in accordance with the present invention can be obtained by methods A-C, described below.

The solvent used in the reaction at each stage of the following methods A to C are not particularly limited, but he would not slow down the reaction and to some extent dissolve the starting material. The solvent chosen, for example, from the following group of solvents. The group of solvents consisting of hydrocarbons, such as pentane, hexane, octane, Petrola the initial ether, naphtha and cyclohexane; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl-2-pyrrolidinone and hexamethylphosphoric triamide; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, 2-methyl-1-propanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; sulfoxidov, such as dimethyl sulfoxide; sulfones, such as sulfolane; NITRILES, such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ketones, such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; carboxylic acids, such as acetic acid, formic acid, propionic acid, butyric acid and triperoxonane acid; water; and mixed solvents of the above solvent is.

Examples of the base used in the reaction at each stage of the following methods A-C, include inorganic bases such as carbonates of alkali metals such as sodium carbonate, potassium carbonate, lithium carbonate and cesium carbonate; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and lithium bicarbonate; hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride; hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide, and alkali metal fluorides such as sodium fluoride and potassium fluoride; alkoxides of alkali metals such as sodium methoxide, ethoxide sodium tert-piperonyl sodium, potassium methoxide, ethoxide potassium tert-piperonyl potassium and lithium methoxide; trialkylsilanes alkali metals, such as trimethylsilanol sodium, trimethylsilanol potassium and trimethylsilanol lithium; mercaptans alkali metals, such as methylmercaptan sodium and ethyl mercaptan sodium; organic osnovaniya, such as N-methylmorpholine, triethylamine, Tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinedione, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]non-5-ene (DBN), 1,4-diazabicyclo[,2,2]octane (DABCO) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU); and ORGANOMETALLIC bases, such as utility, diisopropylamide lithium bis(trimethylsilyl)amide and lithium.

In the reaction at each stage of the following methods A to C, the reaction temperature is changed in accordance with the solvent, starting material, reagent and the like, and the reaction time is changed in accordance with the solvent, starting material, reagent, reaction temperature and the like.

In the reaction at each stage of the following methods A-C, each desired compound is collected from the reaction mixture in accordance with conventional methods after the reaction. Connection required to receive, for example, as follows. The reaction mixture is appropriately neutralized and removed by filtration of the insoluble material, if any. Then add water and immiscible organic solvent, such as ethyl acetate, and the organic layer containing the desired compound is separated. The organic layer is washed with water or the like and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and filtered. Then the solvent is evaporated. Obtained the desired compound can be isolated and purified, if necessary, appropriately combined with conventional methods, for example methods used by the La separation and purification of organic compounds, such as recrystallization and pereosazhdeniya, and chromatography with elution with a suitable eluent. The desired compound is insoluble in the solvent can be purified by washing the obtained solid product with a solvent. Connection required at each stage can also be used as such for the next reaction without purification.

The following describes the reaction at each stage of the methods A-C.

Method a is a method of obtaining compounds having General formula (I).

[Formula 3]

In the present invention R1, R2, R3and Q are such as defined above, and R1aand R3athe same group, as defined above, R1and R3except that the amino group, the hydroxy-group and/or carboxyl group, present(s) as substituent(s) in groups of R1and R3is an amino group, a hydroxy-group and/or carboxyl group which may be protected.

Stage A1

This stage is the stage of obtaining compounds having General formula (IV).

This stage is performed by engagement of the compounds having General formula (II), which is a known compound or is easily produced from a known compound as a starting material in a manner similar to known with the person, with a compound having General formula (III), which is a known compound or is easily produced from a known compound as a starting material in a manner similar to a known method, in a solvent in the presence of a base.

The solvent used at this stage is preferably amide, and more preferably N,N-dimethylformamide or N-methyl-2-pyrrolidone.

The basis used at this stage is preferably a carbonate of an alkali metal or hydride of an alkali metal, preferably cesium carbonate or sodium hydride.

The reaction temperature at this stage is usually 50°C-150°C, preferably 80°C to 120°C.

The reaction time at this stage is usually 0.5 to 48 hours, and preferably 1-30 hours.

Stage A2

This stage is the stage of obtaining compounds having General formula (V).

This stage is performed by engagement of the compounds having General formula (IV)with iron in a solvent in the presence of ammonium chloride or recovering compounds having General formula (IV)in a solvent in the presence of palladium catalyst in a hydrogen atmosphere.

The solvent used at this stage is preferably a simple ether, alcohol or water, more preferably tetrahydrofuran, methane is, ethanol or water, and even more preferably ethanol or a mixed solvent of ethanol and water.

Palladium catalyst used at this stage is, for example, the catalyst on the basis of divalent palladium, or a catalyst based on zero-valent palladium, preferably palladium on charcoal, palladium(II)acetate, triptorelin palladium(II), palladium black, palladium bromide(II), palladium chloride(II)iodide, palladium(II)cyanide, palladium(II)nitrate, palladium(II)oxide, palladium(II)sulfate, palladium(II), dichlorobis(acetonitrile)palladium(II), dichlorobis(benzonitrile)palladium(II), dichloro(1, 5cyclooctadiene)palladium(II), acetylacetonate(II), sulfide, palladium(II), Tris(dibenzylideneacetone)dipalladium(0), tetrafluoroborate tetrakis(acetonitrile)palladium(II) or areshared-dimer palladium, and more preferably palladium-on-charcoal.

The reaction temperature at this stage is usually -20°C-120°C, preferably 0°C-100°C.

The reaction time at this stage is usually 1-48 hours, preferably 2-24 hours.

Stage A3

This stage is the stage of obtaining compounds having General formula (VI).

This stage is performed by engagement of the compounds having General formula (V), and glycolic acid in a solvent in the presence of hydrochloric to the slots (preferably 4 N. hydrochloric acid).

The solvent used at this stage is preferably a simple air or water, more preferably dioxane or water, and even more preferably a mixed solvent of dioxane and water.

The reaction temperature at this stage is usually 50°C-150°C, preferably 80°C to 120°C.

The reaction time at this stage is usually 0.5 to 48 hours, preferably 1-24 hours.

Stage A4

This stage is the stage of obtaining compounds having General formula (I).

This stage is performed by engagement of the compounds having General formula (VI)with a compound having the General formula (VII), which is a known compound or is easily produced from a known compound as a starting material in a manner similar to a known method, in a solvent in the presence of a condensing agent, and then remove when required, a protective group or groups for amino groups, hydroxyl groups and/or carboxyl group in R1aand/or R3a.

The solvent used at this stage is preferably an aromatic hydrocarbon, more preferably toluene.

Examples of the condensing agent used at this stage include a combination of azodicarboxylate and tertiary phosphine, combination is of azodicarboxylic amide and tertiary phosphine and (trialkylphosphine)acetonitrile. The condensing agent is preferably a combination of azodicarboxylic amide and tertiary phosphine, and more preferably a combination of tributylphosphine and 1,1'-(azodicarbon)dipiperidino.

The reaction temperature at this stage is usually -78°C-120°C, preferably 0°C-50°C.

The reaction time at this stage is usually 0.5 to 24 hours, preferably 1-12 hours.

Method B is another method of obtaining compounds having General formula (I).

[Formula 4]

In the present invention R1, R2, R3, Q, R1aand R3asuch as defined above.

Stage B1

This stage is the stage of obtaining compounds having General formula (IX).

This stage is performed by engagement of the compounds having General formula (V)with a compound having General formula (VIII), which is a known compound or is easily produced from a known compound as a starting material in a manner similar to a known method, in a solvent in the presence of a condensing agent and base.

The solvent used at this stage is preferably amide or halogenated hydrocarbon, and more preferably N,N-dimethylformamide or dichloromethane.

Examples of the condensing agent COI is lisemore at this stage include hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (HATU), cyclic anhydride 1-papapostolou acid (T3P), dicyclohexylcarbodiimide (into), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), isobutylparaben (IBCF), 1,1'-carbonylbis-1H-imidazole (CDI), diethylthiophosphate (DEPC), diphenylphosphoryl (DPPA), N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide and dipyridamole. The condensing agent can be used, when required, in the presence of 1-hydroxybenzotriazole or hydrate of 1-hydroxybenzotriazole. The condensing agent is preferably EDCI.

The basis used at this stage is preferably triethylamine, N-methylmorpholine or 4-(N,N-dimethylamino)pyridine.

The reaction temperature at this stage is usually -50°C-100°C, preferably -20°C-60°C.

The reaction time at this stage is usually 0.1-24 hours, and preferably 0.5 to 10 hours.

Stage B2

This stage is the stage of obtaining compounds having General formula (I).

This stage is performed by engagement of the compounds having General formula (IX), with hydrochloric acid and then remove when required, a protective group or groups for amino groups, hydroxy-group and/or carboxyl group in R1aand/or R3a.

The reaction temperature at this stage with what is usually -20°C to 150°C, and preferably 0°C-100°C.

The reaction time at this stage is usually 0.5 to 150 hours, and preferably 1-72 hours.

Method C is another way of obtaining compounds having General formula (I).

[Formula 5]

In the present invention R1, R2, R3, Q, R1aand R3asuch as defined above.

Stage C1

This stage is the stage of obtaining compounds having General formula (XI).

This stage is performed by engagement of the compounds having General formula (X), which is a known compound or is easily produced from a known compound as a starting material in a manner similar to a known method, with the compound having General formula (III)in a solvent in the presence of a base.

The solvent used at this stage is preferably amide, and more preferably N,N-dimethylformamide or N-methyl-2-pyrrolidone.

The basis used at this stage is preferably an alkali metal hydride, preferably sodium hydride.

The reaction temperature at this stage is usually -78°C to 150°C, preferably 0°C-100°C.

The reaction time at this stage is usually 0.5 to 48 hours, preferably 1-24 hours.

Stage C2

This stage is one the camping stage receiving the connection having the General formula (XII).

This phase of the exercise in the same way as stage A2 of the above method A, the engagement of the compounds having General formula (XI), with iron in a solvent in the presence of ammonium chloride or recovering compounds having General formula (XI)in a solvent in the presence of palladium catalyst in a hydrogen atmosphere.

Stage C3

This stage is the stage of obtaining compounds having the General formula (XIII).

This phase of the exercise in the same way as stage B1 of the above method B, the engagement of the compounds having General formula (XII)with a compound having General formula (VIII)in a solvent in the presence of a condensing agent and base.

Stage C4

This stage is the stage of obtaining compounds having General formula (I).

This stage is performed by engagement of the compounds having General formula (XIII), with acetic acid in the same way as in stage B2 of the above method B, and then remove when required, a protective group or groups for amino groups, hydroxy-group and/or carboxyl group in R1aand/or R3a.

The original compound having General formula (II), (III), (VII), (VIII) or (X), a known compound or is easily obtained from known is soedineniya as source material in a known manner or way, such a known method.

The protective group for amino group which may be protected", "hydroxy-group, which may be protected" and "carboxyl group which may be protected", as defined above for R1aand R3arefers to a protective group which can be removed by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and is a protective group commonly used in the chemistry of organic synthesis (see, for example, T. W. Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

"Protective group for the hydroxy-group, which may be protected", as defined above for R1aand R3anot particularly limited, if only she was protecting group for a hydroxy-group, used in chemistry for organic synthesis; specified protective group is, for example, "conventional protecting group for a hydroxy-group, representing ester". Preferred examples of the protective group include a formyl group; "alkylcarboxylic groups, such as the above, "C2-C7alkylcarboxylic groups, halogenated alkylcarboxylic groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and TRIFLUOROACETYL, alkoxycarbonyl groups, such as methoxyacetyl, and unsaturated alkylcarboxylic groups, such as acryloyl about iloil, methacryloyl, crotonoyl, isocrotonic and (E)-2-methyl-2-butanol; "arylcarbamoyl groups, such as arylcarbamoyl groups such as the benzoyl, α-naphtol and β-naphtol, halogenated arylcarboxylic groups such as 2-bromobenzoyl and 4-chlorobenzoyl, C1-C6alkylated arylcarbamoyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl, C1-C6alkoxysilane arylcarbamoyl groups such as 4-anisoyl, nitride arylcarbamoyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl, C2-C7alkoxycarbonylmethyl arylcarbamoyl groups such as 2-(methoxycarbonyl)benzoyl, and allrounda arylcarbamoyl groups such as 4-phenylbenzyl; "alkoxycarbonyl groups, such as the aforementioned "C2-C7alkoxycarbonyl group" and C2-C7alkoxycarbonyl group substituted with halogen or tri-(C1-C6alkyl)silyl group such as 2,2,2-trichlorocyanuric and 2-trimethylsilylethynyl; "tetrahydropyranyl or tetrahydropyranyl groups, such as tetrahydropyran-2-yl, 3-bromotetradecane-2-yl, 4-methoxyacridine-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytryptamine-4-yl; "tetrahydrofuranyl or tetrahydrofuranyl group"such as tetrahydrofuran-2-yl and tetrahydrofuran-2-yl; "Seeley is performance communications group", such as three-(C1-C6alkyl)silyl groups such as trimethylsilyl, triethylsilyl, isopropylimidazole, tert-butyldimethylsilyl, methyldiisopropanolamine, methyldi-tert-Boticelli and triisopropylsilyl, and (C1-C6alkyl)derisorily or di-(C1-C6alkyl)Arielle groups, such as diphenylmethylene, diphenylbutyric, diphenylethylene and phenyldimethylsilane; "alkoxymethyl groups, such as (C1-C6alkoxy)methyl group, such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl and tert-butoxymethyl, (C1-C6alkoxy)-(C1-C6alkoxy)methyl group, such as 2-methoxyethoxymethyl, and (C1-C6halogenated alkoxy)methyl group, such as 2,2,2-trichloroacetyl and bis(2-chloroethoxy)methyl; "substituted ethyl group such as a (C1-C6alkoxy)ethyl groups such as 1-ethoxyethyl and 1-(isopropoxy)ethyl and halogenated ethyl group such as 2,2,2-trichloroethyl; "kalkilya groups, such as C1-C6alkyl groups, substituted 1-3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthylmethyl and 9-antimetal, and C1-C6alkyl groups, substituted 1-3 aryl gr is pami, aryl cycle, substituted C1-C6the alkyl, C1-C6alkoxy, nitro, halogen or cyano, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylalanine, 2-nitrobenzyl, 4-nitrobenzyl, 4-Chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl; "altneratively groups, such as vinyloxycarbonyl and allyloxycarbonyl; and "aracelikarsaalyna groups, aryl cycle, which may be substituted by 1 or 2 C1-C6alkoxy or nitro groups, such as benzyloxycarbonyl, 4-methoxybenzenesulfonyl, 3,4-dimethoxyphenylacetone, 2-nitrobenzeneboronic and 4-nitrobenzenesulfonyl. Acylcarnitine group, silyl group or kalkilya group are more preferred.

"Protective group for a carboxyl group which may be protected", as defined above for R1aand R3anot particularly limited, if only she was protecting group for carboxyl group used in the field of chemistry for organic synthesis; specified protective group is, for example, "conventional protecting group for carboxyl group, representing ester". Preferred examples of the protective group include the above "C1-C6alkyl groups"; "C2-C6alkeneamine GRU is p' such as ethynyl, 1-propenyl and 2-propenyl; "C2-C6alkyline groups, such as ethinyl, 1-PROPYNYL and 2-PROPYNYL; above "C1-C6halogenated alkyl groups"; the above "C1-C6hydroxyalkyl groups; (C2-C7alkylsulphonyl)-(C1-C6alkyl group), such as acetylenyl; above "kalkilya group" and the above "silyl group". C1-C6alkyl group or kalkilya group are more preferred.

"Protective group" for the "amino group which may be protected", as defined above for R1aand R3anot particularly limited, if only she was protecting group for the amino group used in the field of chemistry for organic synthesis; specified protective group is, for example, the same "alkylcarboxylic group"; "arylcarbamoyl group"; "alkoxycarbonyl group"; "silyl group"; "Uralkaliy group"; "altneratively group" or "aracelikarsaalyna group"as "conventional protective group for a hydroxy-group, representing ester"or "substituted methylene group, forming a Schiff base such as N,N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylic, diphenylmethylene or (5-chloro-2-hydroc iphenyl)phenylmethylene, and preferably is alkylcarboxylic group, arylcarbamoyl group or alkoxycarbonyl group, and more preferably alkoxycarbonyl group.

Stage, which consists in protecting and Unprotecting carried out in accordance with known methods (such as the method described in "Protective Groups in Organic Synthesis" (Theodora W. Greene, Peter G. M. Wuts, 1999, published by A Wiley-Interscience Publication)).

Condensed bicyclic heteroaryl compound or its pharmacologically acceptable salt of General formula (I) in accordance with the present invention when applied as a drug can be introduced(a), for example, orally in the form of tablets, capsules, granules, powders or syrups, or parenterally in the form of dosage forms for injection or suppository alone or in a mixture with a suitable pharmacologically acceptable excipient, diluent or the like.

These drugs get get by known methods using additives such as excipients (examples of which include organic excipients such as sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, α-starch and dextrin; cellulose derivatives such as crystalline cellulose; Arabian gum; decstr the h & pullulan; and inorganic fillers, such as derivatives of silicate, such as light silicic anhydride, synthetic aluminum silicate, calcium silicate and alumosilicate magnesium; phosphates such as calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate), lubricants (examples of which include stearic acid, and metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as veegum and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium salts of fatty acids; laurilsulfate, such as sodium lauryl sulfate and lauryl sulfate, magnesium; silicic acids such as silicic anhydride and silicic acid hydrate; and the above starch derivatives), binders (examples of which include hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, macrogol, and compounds similar to the above fillers), leavening agents (examples of which include cellulose derivatives, such as nizkozameshhennoj hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose and internally cross-linked sodium carboxymethylcellulose, and chemically modified to omaly, such as carboximetilkrahmal, sodium carboximetilkrahmal, stabilizers (examples of which include the esters of para-hydroxybenzoic acid, such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; along with dehydroacetic acid and sorbic acid), corrigentov (examples of which include commonly used sweeteners, podnikatel and flavourings) and thinners.

The dose varies according to centomani, age and the like of the patient (warm-blooded animal, in particular people). However, the drug is administered preferably orally with a dose of from 0.0015 mg/kg body weight (preferably 0.008 mg/kg of body weight) per day with a lower limit of 70 mg/kg body weight (preferably 7 mg/kg of body weight) per day, with an upper limit or intravenous dose of from 0,00015 mg/kg body weight (preferably 0.0008 mg/kg of body weight) per day at the lower limit to 8.5 mg/kg body weight (preferably 5 mg/kg of body weight) per day, with an upper limit of one adult to six times a day in accordance with cintamani.

EXAMPLES

Further, the present invention is described in more detail by way of examples, examples, test examples and manufacturing, however, the scope of the present invention is not restricted by them.

p> Chromatographic elution in the examples was performed under control using TLC (thin layer chromatography). When the control TLC as the plates used for TLC silica gel 60F254Merck & Co., Inc., as the developing solvent used, the solvent used in column chromatography as an eluting solvent, and as a method of detection used the method with UV-detection. As silica gel for the column used silica gel SK-85 (230-400 mesh mesh) or silica gel SK-34 (70-230 mesh) is also produced by Merck & Co., Inc. or Chromatorex NH (200-350 mesh) manufactured by Fuji Silysia Chemical Ltd. In addition to the usual system for column chromatography appropriately used the system for automatic chromatography production Biotage AB (SP-1). Abbreviations used in the examples have the following meanings:

mg: milligram, g: grams, ml: milliliter, MHz (MHz): MHz.

In the following examples, the chemical shifts in the spectrum of nuclear magnetic resonance (hereinafter1H NMR) is presented in δ values (ppm) using tetramethylsilane as a standard substance. As for the spectrograms of separation, " s " is singlet, d is doublet, t (t) represents the triplet, q (q) represents the Quartet, Quint (quint) represents the quintet and Sep (sep) p is ecstasy septet.

Mass spectrometry (hereinafter MS) was carried out FAB (fast atom bombardment), EI (electron ionization) or ESI (electron spray ionization).

(Example 1) Dihydrochloride methyl 3-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate (dihydrochloride of compound No. 1-132)

(1a) [6-(4-tert-Butoxycarbonylamino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol (13 g, 43,7 mmol) Japanese Patent Laid-Open No. 2004-123711) and (Boc)2O (19 g, 87 mmol) was dissolved in 150 ml of isopropanol followed by stirring overnight. The reaction solution was diluted with ethyl acetate, washed with water and saturated salt solution and dried over sodium sulfate. The solvent is then evaporated. The residue was subjected to chromatography on a column of silica gel (10% methanol-ethyl acetate). The obtained foamy substance was led from a mixture of ethyl acetate and hexane to obtain the desired compound (4.5 g, yield: 26%).

1H-NMR (CDCl3, 400 MHz) δ: 1.26 in (9H, s), of 2.21 (6H, in), 3.75 (3H, s), 4,89 (2H, s), to 6.67 (2H, s), 6,93 (1H, d, J=2 Hz), of 6.96 (1H, DD, J=2, 9 Hz), 7,63 (1H, d, J=9 Hz).

(1b) Dihydrochloride methyl 3-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Tri-n-butylphosphine (0,41 g, 2.0 mmol) and 1,1'-(azodicarbon)piperidine (0.50 g, 2.0 mmol) was added to a solution of {6-[4-(tert-butile is starsonline)for 3,5-dimethylphenoxy]-1-methyl-1H-benzimidazole-2-yl}methanol (0.40 g, 1.0 mmol) and methyl 3-hydroxybenzoate (0,23 g, 1.5 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required is listed in the title compound (0.32 g, yield: 63%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: of 2.25 (6H, s), a 3.87 (3H, s), a 3.87 (3H, s), ceiling of 5.60 (2H, s), 6,74 (2H, s), 7,03 (1H, d, J=8,8 Hz), 7,41 (1H, s), 7,45 (1H, d, J=8,3 Hz), 7,52 (1H, DD, J=7,8, 8,3 Hz), 7,63 (1H, d, J=7.8 Hz), 7,69 (1H, s), 7,72 (1H, d, J=8,8 Hz).

MS (ESI+) m/z: 432 (M+H)+.

Msvr HRMS (ESI+) m/Z: 432,19037 (M+H)+calculated 432,19233 (-1,96 mmu).

(Example 2) of the Dihydrochloride of 3-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (dihydrochloride of compound No. 1-131)

1 N. aqueous sodium hydroxide solution (10 ml, 10 mmol) was added to a solution of dihydrochloride methyl 3-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate produced in example 1 (0,22 g, 0.4 mmol)in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated chlorine is estevadeordal acid (1.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure to obtain the desired specified in the title compound (0.12 g, yield: 61%).

TPL 235-239°C.

1H-NMR (DMSO-d6, 400 MHz) δ: 2,30 (6H, s), 3,91 (3H, s), the 5.65 (2H, s), 6,78 (2H, s), 7,11 (1H, DD, J=2.0 a, 8,8 Hz), the 7.43 (1H, d, J=7.8 Hz), 7,49 (1H, DD, J=7,8, and 7.8 Hz), 7,51 (1H, d, J=2.0 Hz), 7,63 (1H, d, J=7.8 Hz), 7,76 (1H, d, J=8,8 Hz).

MS (ESI+) m/z: 418 (M+H)+, 440 (M+Na)+, 462 (M+2Na-H)+.

Msvr (ESI+) m/Z: 418,18023 (M+H)+calculated 418,17668 (3,55 mmu).

(Example 3) Dihydrochloride ethyl 4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate (dihydrochloride of compound No. 1-134)

Tri-n-butylphosphine (0,41 g, 2.0 mmol) and 1,1'-(azodicarbon)piperidine (0.50 g, 2.0 mmol) was added to a solution of {6-[4-(tert-butyloxycarbonyl)for 3,5-dimethylphenoxy]-1-methyl-1H-benzimidazole-2-yl}methanol (0.40 g, 1.0 mmol) and ethyl 4-hydroxybenzoate (0.25 g, 1.5 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required is specified in the header of the giving (0.35 g, yield: 67%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: is 1.31 (3H, t, J=7.0 Hz), 2,12 (6H, s), 3,90 (3H, s), the 4.29 (2H, square, J=7,0 Hz), to 5.66 (2H, s)of 6.71 (2H, s), 7,10 (1H, d, J=8,8 Hz), 7,29 (2H, d, J=8,8 Hz), 7,51 (1H, s), of 7.75 (1H, d, J=8,8 Hz), 7,98 (2H, d, J=8,8 Hz).

MS (ESI+) m/z: 446 (M+H)+.

Msvr (ESI+) m/Z: 446,20801 (M+H)+calculated 446,20798 (0,03 mmu).

(Example 4) of the Dihydrochloride of 4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (dihydrochloride of compound No. 1-133)

1 N. aqueous sodium hydroxide solution (10 ml, 10 mmol) was added to a solution of dihydrochloride of ethyl 4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate (0.26 g, 0.4 mmol) in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated hydrochloric acid (1.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure to obtain the desired specified in the title compound (0.15 g, yield: 77%).

1H-NMR (DMSO-d6, 400 MHz) δ: 2,30 (6H, s)to 3.89 (3H, s), 5,64 (2H, s), 6,77 (2H, s), was 7.08 (1H, d, J=8,8 Hz), 7,25 (2H, d, J=8,8 Hz), 7,49 (1H, s), of 7.75 (1H, d, J=8,8 Hz), 7,95 (2H, d, J=8,8 Hz).

MS (ESI+) m/z: 418 (M+H)+.

Msvr (ESI+) m/Z: 418,17523 (M+H)+calculated 418,17668 (of-1.45 mmu).

(Example 5) Dihydrochloride ethyl 2-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate (on the hydrochloride of compound No. 1-130)

Tri-n-butylphosphine (0,41 g, 2.0 mmol) and 1,1'-(azodicarbon)piperidine (0.50 g, 2.0 mmol) was added to a solution of {6-[4-(tert-butyloxycarbonyl)for 3,5-dimethylphenoxy]-1-methyl-1H-benzimidazole-2-yl}methanol (0.40 g, 1.0 mmol) and ethyl 2-hydroxybenzoate (0,23 g, 1.5 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required is listed in the title compound (0.34 g, yield: 65%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: of 1.20 (3H, t, J=7.2 Hz), of 2.33 (6H, s), of 3.94 (3H, s)to 4.23 (2H, square, J=7,2 Hz), 5,64 (2H, s), 6,79 (2H, s), 7,11 (1H, d, J=8,8 Hz), 7,13 (1H, DD, J=7,3, 7,8 Hz), was 7.45 (1H, d, J=8,4 Hz), 7,55 (1H, C), 7,60 (1H, DDD, J=1,4, and 7.3, and 8.4 Hz), 7,72 (1H, DD, J=1,4, and 7.8 Hz), to 7.77 (1H, d, J=8,8 Hz).

MS (ESI+) m/z: 446 (M+H)+, 468 (M+Na)+.

Msvr (ESI+) m/Z: 446,21002 (M+H)+calculated 446,20798 (2,04 mmu).

(Example 6) of the Dihydrochloride of 2-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (dihydrochloride of compound No. 1-129)

1 N. aqueous sodium hydroxide solution (10 ml, 10 mmol) was added to a solution of dihydrochlor is Yes ethyl 3-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate (0.26 g, 0.4 mmol) in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated hydrochloric acid (1.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure to obtain the desired specified in the connection header (0,13 g, yield: 66%).

1H-NMR (DMSO-d6, 400 MHz) δ: 2,30 (6H, s)to 3.92 (3H, s), 5,62 (2H, s), 6.87 in (2H, s), 7,10 (1H, m), 7,11 (1H, m), the 7.43 (1H, d, J=8,3 Hz), 7,55 (1H, m), 7,58 (1H, s), of 7.69 (1H, DD, J=1,4, and 7.6 Hz), of 7.75 (1H, d, J=8,8 Hz).

MS (ESI+) m/z: 418 (M+H)+.

Msvr (ESI+) m/Z: 418,17421 (M+H)+calculated 418,17668 (-2,47 mmu).

(Example 7) of the Hydrochloride of methyl 3-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate (hydrochloride of compound No. 1-36)

(7a) tert-Butyl [5-(3-pertenece)-2-nitrophenyl]methylcarbamate

Tert-piperonyl potassium (3,93 g 35,0 mmol) was added to a solution of 3-terfenol (3,53 g of 31.5 mmol) and tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (at 8.60 g, 30.0 mmol) in N,N-dimethylacetamide (15 ml) and tetrahydrofuran (60 ml) under ice cooling and the mixture was stirred at 100°C for 30 hours. The reaction solution was concentrated and added to it in ethyl acetate (200 ml) and water (200 ml) followed by extraction. The organic layer was dried and concentrated to obtain the desired specified in the connection header (of 9.21 g, yield: 81%).

(7b) (6-Fluoro-1-methyl-1H-BAA is imidazol-2-yl)methanol

Iron powder (7,53 g, 135,0 mmol) was added to a solution of tert-butyl [5-(3-pertenece)-2-nitrophenyl]methylcarbamate (of 9.21 g of 25.4 mmol) and ammonium chloride (0,80 g, 15.0 mmol) in water (30 ml) and ethanol (120 ml) and the mixture was stirred at 70°C for nine hours. The reaction solution was concentrated and to the resulting brown solid substance was added 4 N. hydrochloric acid (90 ml). The mixture was stirred at 120°C for 30 minutes to obtain a homogeneous solution. Glycolic acid (6,84 g of 90.0 mmol) was added to the solution and the mixture was stirred at 120°C for four hours. The reaction solution was concentrated and then podslushivaet gradual addition of 2 N. aqueous sodium hydroxide solution to precipitate a solid. The obtained solid was recrystallized from ethanol to obtain the desired specified in the connection header (4,90 g, yield: 71%).

1H-NMR (DMSO-d6, 400 MHz) δ: of 3.80 (3H, s), 4,71 (2H, d, J=5.5 Hz), 5,59 (1H, t, J=5.5 Hz), 6.75 in-PC 6.82 (2H, m), 6.87 in-6,97 (2H, m), 7,33-7,42 (2H, m), a 7.62 (1H, d, J=8.6 Hz).

(7c) of the Hydrochloride of methyl 3-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Tri-n-butylphosphine (and 0.61 g, 3.0 mmol) and 1,1'-(azodicarbon)dipiperidino (0,76 g, 3.0 mmol) was added to a solution of [6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol (0,41 g, 1.5 mmol) and methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol) in toluene and subsequent re what asianam for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required specified in the header of the connection (of 0.43 g, yield: 64%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: a 3.87 (3H, s), 3,90 (3H, s), 5,62 (2H, s), PC 6.82 (1H, DDD, J=0.8, the 2,4, and 8.2 Hz), 6,86 (1H, DDD, J=2,4, 2,4, 8,2 Hz), of 6.96 (1H, dddd, J=0,8, 2,4, 8,4, 8,4 Hz), 7,14 (1H, DD, J=2,2, 8,8 Hz), 7,41 (1H, DDD, J=6,9 and 8.2, and 8.4 Hz), 7,46 (1H, DDD, J=1,1, 2,6, 8,2 Hz), 7,52 (1H, DD, J=7,5, 8,2 Hz), to 7.59 (1H, d, J=2.2 Hz), to 7.64 (1H, DDD, J=1,1, 1.5 and 7.5 Hz), of 7.70 (1H, DD, J=1,5, 2,6 Hz), 7,78 (1H, d, J=8,8 Hz).

MS (ESI+) m/z: 407 (M+H)+, 429 (M+Na)+.

Msvr (ESI+) m/Z: 407,13957 (M+H)+calculated 407,14071 (-1,14 mmu).

(Example 8) of the Hydrochloride of 3-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (hydrochloride of compound No. 1-35)

1 N. aqueous sodium hydroxide solution (15 ml, 15 mmol) was added to a solution of the hydrochloride of methyl 3-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate produced in example 7 (0.33 g, of 0.74 mmol)in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated chloritoid the Oh acid (2.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure to obtain the desired specified in the connection header (0,22 g, yield: 69%).

1H-NMR (DMSO-d6, 400 MHz) δ: 3,95 (3H, s)5,70 (2H, s), 6,85 (1H, DDD, J=0.8, the 2,4, and 8.2 Hz), 6.89 in (1H, DDD, J=2,3, 2,4, 8,2 Hz), 6,99 (1H, dddd, J=0,8, 2,3, and 8.2, and 8.4 Hz), 7,24 (1H, DD, J=2.2, while the 8.9 Hz), 7,42 (1H, DDD, J=6,9, and 8.2 and 8.2 Hz), was 7.45 (1H, DDD, J=1,1, 2,6, 8,2 Hz), 7,51 (1H, DD, J=7,5, 8,2 Hz), to 7.64 (1H, DDD, J=1,1, 1,3, 7.5 Hz), 7,69 (1H, d, J=2,23 Hz), 7,71 (1H, DD, J=1,3, and 2.6 Hz), to 7.84 (1H, d, J=8,9 Hz).

MS (ESI+) m/z: 393 (M+H)+, 415 (M+Na)+, 437 (M+2Na-H)+.

Msvr (ESI+) m/Z: 393,12228 (M+H)+calculated 393,12506 (-2,78 mmu).

(Example 9) of the Hydrochloride of methyl 3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate (hydrochloride of compound No. 1-100)

(9a) tert-Butyl [(4-chloro-3-pertenece)-2-nitrophenyl]methylcarbamate

Sodium hydride (>56% in oil, 1.31 g, 30.0 mmol) was added to a solution of 4-chloro-3-terfenol (4.94 g, 30.0 mmol) and tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (at 8.60 g, 30.0 mmol) in N,N-dimethylformamide (150 ml) under cooling with ice. The mixture was gradually heated to room temperature and then was heated up to 80°C, followed directly by stirring for eight hours. The reaction solution was let to stand still at room temperature overnight and then stirred at 80°C for one hour. Allowing the reaction solution to cool to room is temperature, was added water and a saturated salt solution, followed by extraction with ethyl acetate three times. The organic layers were combined and dried over magnesium sulfate and evaporated under reduced pressure the solvent. The residue was purified by chromatography on silica gel to obtain the desired compound (12,63 g, yield: 100%) as pale yellow needle crystals.

1H-NMR (CDCl3, 400 MHz) δ: of 1.32 (9H, s), 3,26 (3H, s), 6,85-6,92 (4H, m), the 7.43 (1H, t, J=8.6 Hz), to 7.93 (1H, t, J=8.6 Hz).

(9b) [6-(4-Chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol

tert-Butyl [(4-chloro-3-pertenece)-2-nitrophenyl]methylcarbamate (br12.62 g, 30.0 mmol) was dissolved in ethanol (150 ml) and water (75 ml). Then was added iron powder (8,03 g, 150 mmol) and ammonium chloride (803,2 mg, 15.0 mmol) and the mixture was heated at the boil under reflux for 4.5 hours. The reaction solution was allowed to cool and then diluted with water, saturated salt solution and ethyl acetate and filtered through celite. The filtrate was separated and the organic layer was dried over magnesium sulfate. Then evaporated under reduced pressure, the solvent to obtain tert-butyl [2-amino-5-(4-chloro-3-pertenece)phenyl]methylcarbamate in the form of a white solid (12,01 g, yield: 100%). To the obtained product was added glycolic acid (3.42 g, 45,0 mmol) and 4 n hydrochloric acid in 1,4-dioxane (150 ml) and MES was heated at the boil under reflux for two hours. The reaction solution was slowly poured into a saturated aqueous solution of sodium bicarbonate under ice cooling. Added next diisopropyl ether, followed by stirring. After a few minutes had formed a pale yellow powder. The powder was collected by filtration, successively washed with a mixed solution of ethyl acetate and n-hexane and water and dried to obtain the desired compound (3,85 g, yield: 42%) as a pale yellow powder.

H-NMR (CDCl3, 400 MHz) δ: of 3.78 (3H, s), 4,88 (2H, s), 6,69 (1H, DD, J=3,9, 10.1 Hz), was 6.73 (1H, DD, J=3.2, and a 10.1 Hz), 6,93-to 6.95 (2H, m), 7,28 (1H, t, J=8.7 Hz), 7,05 (1H, d, J=8.7 Hz).

(9c) of the Hydrochloride of methyl 3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Tri-n-butylphosphine (and 0.61 g, 3.0 mmol) and 1,1'-(azodicarbon)dipiperidino (0,76 g, 3.0 mmol) was added to a solution of [6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol (0,46 g, 1.5 mmol) and methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required criminal code is related to the title compound (0,44 g, yield: 61%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: a 3.87 (3H, s)to 3.92 (3H, s), to 5.66 (2H, s), to 6.88 (1H, DDD, J=1,3, 2,8, a 8.9 Hz), to 7.15 (1H, DD, J=2,8, and 10.8 Hz), 7,21 (1H, DD, J=2,2, 8,8 Hz), 7,47 (1H, DDD, J=1,1, 2,6, 8,3 Hz), 7,53 (1H, DD, J=7,5, 8,3 Hz), to 7.59 (1H, DD, J=8,8, an 8.9 Hz), to 7.64 (1H, DDD, J=1,1, 1.5 and 7.5 Hz), the 7.65 (1H, d, J=2.2 Hz), 7,71 (1H, DD, J=1,5, 2,6 Hz), 7,81 (1H, d, J=8,8 Hz).

MS (ESI+) m/z: 441 (M+H)+, 443 (M+H+2)+, 463 (M+Na)+, 465 (M+Na+2)+.

Msvr (ESI+) m/Z: 441,10171 (M+H)+calculated 441,10174 (-0,03 mmu).

(Example 10) of the Hydrochloride of 3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (hydrochloride of compound No. 1-99)

1 N. aqueous sodium hydroxide solution (10 ml, 10 mmol) was added to a solution of the hydrochloride of methyl 3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate produced in example 9 (0.33 g, 0.69 mmol)in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated hydrochloric acid (1.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure to obtain the desired specified in the connection header (0,23 g, yield: 72%).

TPL 197-201°C.

1H-NMR (DMSO-d6, 400 MHz) δ: of 3.94 (3H, s), of 5.68 (2H, s), to 6.88 (1H, DDD, J=1,3, 2,8, a 8.9 Hz), 7,16 (1H, DD, J=2,8, to 10.7 Hz), 7.23 percent (1H, DD, J=2,2, 8,8 Hz), 7,44 (1H, DDD, J=1,1, 2,6, 8,3 Hz)to 7.50 (1H, DD, J=7,6, 8,3 Hz), to 7.59 (1H, DD, J=8,8, 8,9 G IS), 7,63 (1H, DDD, J=1,1, 1,3, a 7.6 Hz), to 7.68 (1H, d, J=2.2 Hz), of 7.70 (1H, DD, J=1,3, and 2.6 Hz), 7,82 (1H, d, J=8,8 Hz).

MS (ESI+) m/z: 427 (M+H)+, 429 (M+H+2)+, 449 (M+Na)+, 451 (M+Na+2)+.

Msvr (ESI+) m/Z: 427,08529 (M+H)+calculated 427,08609 (-0,80 mmu).

(Example 11) of the Hydrochloride of methyl 3-{[6-(3-chloro-4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate (hydrochloride of compound No. 1-116)

(11a) tert-Butyl [(3-chloro-4-pertenece)-2-nitrophenyl]methylcarbamate

The desired compound (15,50 g, yield: 100%) was obtained as pale-yellow needle crystals synthesis of 3-chloro-4-terfenol (5,97 grams of 36.7 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (the 10.40 g of 36.3 mmol), sodium hydride (>56% in oil, 1,58 g of 36.3 mmol) and N,N-dimethylformamide (200 ml) in the same manner as in example 7a.

1H-NMR (CDCl3, 400 MHz) δ: of 1.32 (9H, s), 3,26 (3H, s), 6,79-6,85 (2H, m), 6,95-6,97 (1H, m), 7,15-to 7.18 (2H, m), to $ 7.91-to 7.93 (1H, m).

(11b) tert-Butyl [2-amino-5-(3-chloro-4-pertenece)phenyl]methylcarbamate

The desired compound was obtained as brown crystals (6,98 g, yield: 93%) by synthesis from tert-butyl [(3-chloro-4-pertenece)-2-nitrophenyl]methylcarbamate (7.51 g, to 18.1 mmol), iron powder (4,84 g, 90,5 mmol), ammonium chloride (0,48 g, 9,05 mmol), ethanol (100 ml) and water (50 ml) in the same manner as in example 7b.

1H-NMR (CDCl3, 400 MHz) δ: was 1.58 (9H, s), 3,14 (3H, s), and 3.72 (1H, usher.), 6,74-PC 6.82 (4H, m), 6.90 to-6,99 (1H, m), 7,05 (1H, t, J=8,8 Hz).

(11c) [6-(3-Chloro-4-pertenece)-1-methyl-1H-Benson Gasol-2-yl]methanol

The desired compound was obtained as brown crystals (2,42 g, yield: 48%) synthesis of tert-butyl [2-amino-5-(3-chloro-4-pertenece)phenyl]methylcarbamate (6,89 g of 16.6 mmol), glycolic acid (1.89 g, 24,9 mmol) and 4 n hydrochloric acid in 1,4-dioxane (120 ml) in the same manner as in example 7b.

H-NMR (CDCl3, 400 MHz) δ: of 3.78 (3H, s), 4,89 (2H, s), 6,85-to 7.00 (4H, m), to 7.09 (1H, t, J=8.6 Hz), 7,05 (1H, d, J=8,8 Hz).

(11d) of the Hydrochloride of methyl 3-{[6-(3-chloro-4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Tri-n-butylphosphine (and 0.61 g, 3.0 mmol) and 1,1'-(azodicarbon)dipiperidino (0,76 g, 3.0 mmol) was added to a solution of [6-(3-chloro-4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol (0,46 g, 1.5 mmol) and methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required specified in the header of the connection (of 0.48 g, yield: 67%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: a 3.87 (3H, s)to 3.92 (3H, s), to 5.66 (2H, s), 7,06 (1H, DDD, J=3,0, 3,9, and 9.1 Hz), 7,19 (1H, DD, J=2,2, the 8.9 Hz), 7,28 (1H, DD, J=3,0, 6.3 Hz), 7,46 (1H, DD, J=8,9, and 9.1 Hz), 7,47 (1H, DDD, J=1,1, 2,2, 8,2 Hz), 7,53 (1H, DD, J=7,6, 8,2 Hz), to 7.59 (1H, d, J=2.2 Hz), the 7.65 (1H, DDD, J=1,1, 1,5, with 7.6 Hz), 7,71 (1H, DD, J=1,5, the 2.2 Hz), 7,79 (1H, d, J=8,9 Hz).

MS (ESI+) m/z: 441 (M+H)+, 443 (M+H+2)+, 463 (M+Na)+, 465 (M+Na+2)+.

Msvr (ESI+) m/Z: 441,10182 (M+H)+calculated 441,10174 (0,08 mmu).

(Example 12) of the Hydrochloride of 3-{[6-(3-chloro-4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (hydrochloride of compound No. 1-115)

1 N. aqueous sodium hydroxide solution (10 ml, 10 mmol) was added to a solution of the hydrochloride of methyl 3-{[6-(3-chloro-4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate produced in example 11 (0.34 g, 0.7 mmol)in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated hydrochloric acid (1.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure to obtain the desired specified in the connection header (0,23 g, yield: 70%).

1H-NMR (DMSO-d6, 400 MHz) δ: of 3.94 (3H, s)5,69 (2H, s), 7,07 (1H, DDD, J=3,0, 3,9, and 9.1 Hz), 7,22 (1H, DD, J=2.2, while the 8.9 Hz), 7,29 (1H, DD, J=3,0, 6.2 Hz), 7,44 (1H, DDD, J=1,1, of 2.7 and 8.2 Hz), 7,46 (1H, DD, J=9,1, 9.1 Hz), to 7.50 (1H, DD, J=7,6, 8,2 Hz), 7,63 (1H, d, J=2.2 Hz), to 7.64 (1H, DDD, J=1,1, 1,3, a 7.6 Hz), of 7.70 (1H, DD, J=1,3, 2.7 Hz), 7,82 (1H, d, J=8,9 Hz).

MS (ESI+) m/z: 427 (M+H)+, 429 (M+H+2)+, 449 (M+Na)+, 451 (M+Na+2)+.

Msvr (ESI+) m/Z: 427,08535 (M+) +calculated 427,08609 (-0,74 mmu).

(Example 13) of the Hydrochloride of methyl 3-[(1-methyl-6-phenoxy-1H-benzimidazole-2-yl)methoxy]benzoate (hydrochloride of compound No. 1-20)

(13a) (6 Phenoxy-1-methyl-1H-benzimidazole-2-yl)methanol

tert-Butyl 2-nitro-4-chlorophenyl(methyl)carbamate (22,5 g of 78.6 mmol) and phenol (7.5 g, up 78.6 mmol) was dissolved in tetrahydrofuran (180 ml) and DMF (20 ml). Was added sodium hydride (3.4 g, 78,6 mmol) and the mixture was stirred at 80°C for 10 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated salt solution and dried over sodium sulfate. Then evaporated under reduced pressure the solvent. The residue was dissolved in 250 ml of ethanol was added 10% palladium-on-coal (8 g). The mixture was stirred in hydrogen atmosphere at 60°C for four hours. Was removed through celite, the catalyst and evaporated under reduced pressure the solvent. The residue was dissolved in 1,4-dioxane (80 ml) and the mixture 4 N. hydrochloric acid-dioxane (80 ml). Added glycolic acid (8.7 g, 115 mmol) and the mixture was heated at the boil under reflux for two hours. The reaction solution was cooled and then neutralized with a saturated solution of sodium bicarbonate. The resulting crystals were filtered off and washed with water and ethyl acetate to obtain 14 g of the desired connected to the I (yield: 73%).

1H-NMR (DMSO-d6, 400 MHz) δ: of 3.77 (3H, s), 4,70 (2H, s), 6,85-6,97 (3H, m), 7,05-7,11 (1H, m), 7.23 percent-7,28 (3H, m), 7,58-to 7.61 (1H, m).

(13b) of the Hydrochloride of methyl 3-[(1-methyl-6-phenoxy-1H-benzimidazole-2-yl)methoxy]benzoate

Tri-n-butylphosphine (and 0.61 g, 3.0 mmol) and 1,1'-(azodicarbon)dipiperidino (0,76 g, 3.0 mmol) was added to a solution of (1-methyl-6-phenoxy-1H-benzimidazole-2-yl)methanol (0,38 g, 1.5 mmol) and methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required is specified in the header connection (0,42 g, yield: 66%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: 3,88 (3H, s), 3,93 (3H, s)5,69 (2H, s), 7,02 (2H, d, J=8.7 Hz), 7,12 (1H, DD, J=2,2, 8,8 Hz), to 7.15 (1H, t, J=7.5 Hz), 7,41 (2H, DD, J=7,5, and 8.7 Hz), of 7.48 (1H, DDD, J=1,3, 2,6, 8,2 Hz), 7,54 (1H, DD, J=7,5, 8,2 Hz), to 7.59 (1H, d, J=2.2 Hz), 7,66 (1H, DDD, J=1,3, 1,5, 7.5 Hz), 7,72 (1H, DD, J=1,5, 2,6 Hz), 7,80 (1H, d, J=8,8 Hz).

MS (ESI+) m/z: 389 (M+H)+, 441 (M+Na)+.

Msvr (ESI+) m/Z: 389,15176 (M+H)+calculated 389,15013 (-1,63 mmu).

(Example 14) of the Hydrochloride of 3-[(1-methyl-6-phenoxy-1H-benzimidazole-2-yl)is ethoxy]benzoic acid (hydrochloride of compound No. 1-19)

1 N. aqueous sodium hydroxide solution (10 ml, 10 mmol) was added to a solution of the hydrochloride of methyl 3-[(1-methyl-6-phenoxy-1H-benzimidazole-2-yl)methoxy]benzoate produced in example 13 (0.28 g, 0.7 mmol)in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated hydrochloric acid (1.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure to obtain the desired specified in the connection header (0,19 g, yield: 70%).

1H-NMR (DMSO-d6, 400 MHz) δ: 3,95 (3H, s)5,72 (2H, s),? 7.04 baby mortality (2H, d, J=8,8 Hz), 7,16 (1H, t, J=7.5 Hz), 7,21 (1H, DD, J=2,4, 8,8 Hz), 7,41 (2H, DD, J=7,5, 8,8 Hz), 7,46 (1H, DDD, J=1,1, 2,6, 8,2 Hz), to 7.50 (1H, DD, J=7,5, 8,2 Hz), a 7.62 (1H, d, J=2.2 Hz), to 7.64 (1H, DDD, J=1,1, 1.5 and 7.5 Hz), 7,71 (1H, DD, J=1,5, 2,6 Hz), 7,82 (1H, d, J=8,8 Hz).

MS (ESI+) m/z: 375 (M+H)+, 397 (M+Na)+, 419 (M+2Na-H)+.

Msvr (ESI+) m/Z: 375,13441 (M+H)+calculated 375,13448 (-0,07 mmu).

(Example 15) Dihydrochloride methyl 3-[(3-methyl-5-phenoxy-3H-imidazo[4,5-b]pyridine-2-yl)methoxy]benzoate (dihydrochloride of compound No. 1-28)

(15a) (3-Methyl-5-phenoxy-3H-imidazo[4,5-b]pyridine-2-yl)methanol

Phenol (12,08 g, 128 mmol) was dissolved in THF (200 ml) was added sodium hydride (60%, 5,12 g, 128 mmol). Then was added 6-chloro-N-methyl-3-nitropyridine-2-amine (20 g, 107 mmol) and the mixture was stirred at 80°C for four hours. The reaction solution vovalep water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water, 1 N. potassium hydroxide solution, water and saturated salt solution, dried and then concentrated. The residue was dissolved in a mixture of THF (50 ml)-ethanol (50 ml) was added palladium hydroxide (500 mg). The mixture was stirred in an atmosphere of hydrogen overnight. Was removed through celite, the catalyst and evaporated under reduced pressure the solvent. The residue was dissolved in 1,4-dioxane (150 ml) and the mixture 4 N. hydrochloric acid-dioxane (150 ml). Added glycolic acid (24.4 g, 321 mmol) and the mixture was heated at the boil under reflux for 10 hours. The reaction solution was cooled and then neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated salt solution and dried. Then evaporated under reduced pressure the solvent. The formed crystals are carefully washed with diisopropyl ether to obtain 21.8 g of the desired compound (yield: 80%).

1H-NMR (DMSO-d6, 400 MHz) δ: to 3.67 (3H, s, J=7 Hz), 4,69 (2H, d, J=5 Hz), 5,61 (1H, t, J=5 Hz), at 6.84 (1H, d, J=8 Hz), 7,12-of 7.23 (3H, m), 7,39 was 7.45 (2H, m), of 8.06 (1H, d, J=8 Hz).

(15b) Dihydrochloride methyl 3-[(3-methyl-5-phenoxy-3H-imidazo[4,5-b]pyridine-2-yl)methoxy]benzoate

Tri-n-butylphosphine (and 0.61 g, 3.0 mmol) and 1,1'-(azodicarbon)dipiperidino (0,76 g, 3.0 mmol who) was added to a solution of (3-methyl-5-phenoxy-3H-imidazo[4,5-b]pyridine-2-yl)methanol (0,38 g, 1.5 mmol) and methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required is listed in the title compound (0.40 g, yield: 58%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: and 3.72 (3H, s), 3,86 (3H, s)5,54 (2H, s), of 6.96 (1H, d, J=8.6 Hz), 7,18 (1H, d, J=7.5 Hz), 7,22 (1H, t, J=7,3 Hz), the 7.43 (2H, m), 7,45 (1H, DD, J=7,6, 8,2 Hz), to 7.61 (1H, DD, J=1,5, with 7.6 Hz), 7,66 (1H, DD, J=1.5 and 2.3 Hz), 8,18 (1H, d, J=8.6 Hz).

MS (ESI+) m/z: 390 (M+H)+, 412 (M+Na)+.

Msvr (ESI+) m/Z: 390,14693 (M+H)+calculated 390,14538 (1,55 mmu).

(Example 16) of the Dihydrochloride of 3-[(3-methyl-5-phenoxy-3H-imidazo[4,5-b]pyridine-2-yl)methoxy]benzoic acid (dihydrochloride of compound No. 1-27)

1 N. aqueous sodium hydroxide solution (10 ml, 10 mmol) was added to a solution of dihydrochloride methyl 3-[(3-methyl-5-phenoxy-3H-imidazo[4,5-b]pyridine-2-yl)methoxy]benzoate produced in example 15 (0.25 g, 0.6 mmol)in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated chlorine is estevadeordal acid (1.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure to obtain the desired specified in the title compound (0.16 g, yield: 65%).

1H-NMR (DMSO-d6, 400 MHz) δ: of 3.73 (3H, s), of 5.53 (2H, s), of 6.96 (1H, d, J=8.6 Hz), 7,18 (1H, d, J=8.7 Hz), 7,22 (1H, t, J=7.5 Hz), 7,38 (1H, DDD, J=1,1, 2,6, 8,2 Hz), 7,42 (2H, m), 7,46 (1H, DD, J=7,6, 8,2 Hz), to 7.59 (1H, DDD, J=1,1, 1,3, a 7.6 Hz), to 7.64 (1H, DD, J=1,3, and 2.6 Hz), 8,18 (1H, d, J=8.6 Hz).

MS (ESI+) m/z: 376 (M+H)+, 398 (M+Na)+, 420 (M+2Na-H)+.

Msvr (ESI+) m/Z: 376,12947 (M+H)+calculated 376,12973 (-0,26 mmu).

(Example 17) 5/2 hydrochloride methyl 5-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}nicotinate (5/2 hydrochloride compound No. 1-136)

Tri-n-butylphosphine (and 0.61 g, 3.0 mmol) and 1,1'-(azodicarbon)dipiperidino (0,76 g, 3.0 mmol) was added to a solution of {6-[4-(tert-butyloxycarbonyl)for 3,5-dimethylphenoxy]-1-methyl-1H-benzimidazole-2-yl}methanol (0,60 g, 1.5 mmol) and methyl 5-hydroxynicotinate (0.34 g, 2.3 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required is shown in the header connection (0,48 g, yield: 61%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: of 2.34 (6H, s), 3,91 (3H, s), 3,93 (3H, s)5,80 (2H, s), 6,79 (2H, s), to 7.15 (1H, DD, J=2,0, 8.0 Hz), 7,58 (1H, d, J=2.0 Hz), 7,78 (1H, d, J=8.6 Hz), of 8.09 (1H, DD, J=1,6, 2.7 Hz), the rate of 8.75 (1H, d, J=2.7 Hz), 8,78 (1H, d, J=1.6 Hz).

MS (ESI+) m/z: 433 (M+H)+, 455 (M+Na)+.

Msvr (ESI+) m/Z: 433,18576 (M+H)+calculated 433,18758 (-1,82 mmu).

(Example 18) Dihydrochloride 5-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}nicotinic acid (dihydrochloride of compound No. 1-135)

1 N. aqueous sodium hydroxide solution (10 ml, 10 mmol) was added to a solution 5/2 hydrochloride methyl 5-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}nicotinate (0.35 g, 0.7 mmol) in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated hydrochloric acid (1.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure to obtain the desired specified in the title compound (0.17 g, yield: 52%).

1H-NMR (DMSO-d6, 400 MHz) δ: 2,30 (6H, s)to 3.89 (3H, s), 5,71 (2H, s)6,76 (2H, s), 7,05 (1H, DD, J=2,0, 8.6 Hz), 7,46 (1H, d, J=2.0 Hz), 7,73 (1H, d, J=8.6 Hz), of 8.04 (1H, DD, J=1,6, 3.1 Hz), 8,68 (1H, d, J=3.1 Hz), a total of 8.74 (1H, d, J=1.6 Hz).

MS (ESI+) m/z: 419 (M+H)+, 441 (M+Na)+.

Msvr (ESI+) m/Z: 419,17103 (M+H)+calculated 419,17193 (-0,90 mmu).

(Example 19) Dihydrochloride methyl 3-{[1-ethyl-6-(3-morpholine-4-elfenix)-1H-benzimidazole-2-yl]methoxy}benzoate (dihydrochloride of compound No. 1-68)

(19a) of tert-Butyl methyl[5-(3-morpholine-4-elfenix)-2-nitrophenyl]carbamate

The desired crude compound was obtained from tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (5.0 g, 17 mmol), sodium hydride (761 mg, 17 mmol) and 3-morpholine-4-kilfenora (3.2 g, 17 mmol) in the same manner as in example 7a. The compound obtained was purified by chromatography on a column of silica gel to obtain the desired compound (6.5 g, yield: 86%) as a yellow foamy substance.

1H-NMR (CDCl3, 400 MHz) δ: of 1.32 (9H, s), 3,15-up 3.22 (4H, m)of 3.25 (3H, s), 3,81-3,88 (4H, m), to 6.57 (1H, t, J=7,3 Hz), 6,62 (1H, s), 6,79 (1H, d, J=7.8 Hz), 6,82-6,91 (2H, m), 7.24 to 7,33 (1H, m), 7,92 (1H, d, J=8,8 Hz).

(19b) tert-Butyl [2-amino-5-(3-morpholine-4-elfenix)phenyl]methylcarbamate

tert-Butyl methyl[5-(3-morpholine-4-elfenix)-2-nitrophenyl]carbamate synthesized in example 19a (6.5 g, 15 mmol), and palladium-on-coal (10%, 1.0 g) is suspended in ethyl acetate (100 ml) and the suspension was stirred in an atmosphere of hydrogen for two hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the desired compound (5.8 g, yield: 96%) as a pale orange solid.

1H-NMR (CDCl3, 400 MHz) δ: to 1.38 (9H, s), 3,09-3,16 (7H, m), 3,80-a-3.84 (4H, m), 6,38 (1H, users), 6,51 (1H, s), 6,56 (1H, d, J=7,4 Hz), 6,70-to 6.80 (3H, m), 7,13 (1H, t, J=8.0 Hz).

(19c) [1-Methyl-6-(3-morpholine-4-elfenix)-1H-benzimidazole-2-yl]methanol

tert-Butyl [2-amino-5-(3-morpho is in 4 elfenix)phenyl]methylcarbamate, synthesized in example 19b (5.8 g, 15 mmol)and glycolic acid (1.66 g, 22 mmol) was dissolved in a mixed solvent of 4 N. hydrochloric acid (60 ml) and 1,4-dioxane (60 ml) followed by heating under reflux. The organic solvent is evaporated from the reaction solution under reduced pressure. The remaining aqueous solution was washed with methylene chloride, neutralized with excess amount of sodium bicarbonate, diluted with ethyl acetate and stirred. The resulting solid was filtered to obtain the desired compound (2.8 g, yield: 57%) as a pale brown solid.

1H-NMR (DMSO-d6, 400 MHz) δ: 3,03-is 3.08 (4H, m), 3,67-3,71 (4H, m), 3,76 (3H, s), 4,66-4,69 (2H, m), 6,30 (1H, DD, J=2.0 a, 7,8 Hz), 6,55 (1H, t, J=2,35), of 6.65 (1H, DD, J=2,2, 8.0 Hz), 6,86 (1H, DD, J=2,4, 8.6 Hz), 7,14 (1H, t, J=8,2 Hz), 7,22 (1H, d, J=2.4 Hz), 7,55 (1H, d, J=8.6 Hz).

(19d) Dihydrochloride methyl 3-{[1-methyl-6-(3-morpholine-4-elfenix)-1H-benzimidazole-2-yl]methoxy}benzoate

Tri-n-butylphosphine (and 0.61 g, 3.0 mmol) and 1,1'-(azodicarbon)dipiperidino (0,76 g, 3.0 mmol) was added to a solution of [1-methyl-6-(3-morpholine-4-elfenix)-1H-benzimidazole-2-yl]methanol (0.51 g, 1.5 mmol) and methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: Huck is an/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required is specified in the header connection (0,49 g, yield: 60%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: 3,13 (4H, t, J=4,7 Hz), and 3.72 (4H, t, J=4,7 Hz), a 3.87 (3H, s), of 3.97 (3H, s), USD 5.76 (2H, s), 6.42 per (1H, DD, J=2.0 a, 7,8 Hz), 6,70 (1H, DD, J=2,0, 2,0 Hz), to 6.80 (1H, DD, J=2.0 a, 8,2 Hz), 7.23 percent (1H, DD, J=7,8, and 8.2 Hz), 7.23 percent (1H, DD, J=2,3, 8.6 Hz), to 7.50 (1H, DDD, J=1,2, 2,4, 8,3 Hz), 7,54 (1H, DD, J=7,1, 8,3 Hz), to 7.64 (1H, d, J=2.3 Hz), the 7.65 (1H, DDD, J=1,2, of 1.6 and 7.1 Hz), 7,72 (1H, DD, J=1,6, 2.4 Hz), 7,82 (1H, d, J=8.6 Hz).

MS (ESI+) m/z: 474 (M+H)+, 496 (M+Na)+.

Msvr (ESI+) m/Z: 474,20084 (M+H)+calculated 474,20290 (-2,06 mmu).

(Example 20) 1/2 hydrochloride 3-{[1-methyl-6-(3-morpholine-4-elfenix)-1H-benzimidazole-2-yl]methoxy}benzoic acid (1/2 hydrochloride compound No. 1-67)

1 N. aqueous sodium hydroxide solution (10 ml, 10 mmol) was added to a solution of dihydrochloride methyl 3-{[1-methyl-6-(3-morpholine-4-elfenix)-1H-benzimidazole-2-yl]methoxy}benzoate (0.34 g, 0.7 mmol) in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated hydrochloric acid (1.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure with what rucenim required is specified in the title compound (0.18 g, yield: 59%).

1H-NMR (DMSO-d6, 400 MHz) δ: at 3.69 (4H, t, J=4,7 Hz), 3,80 (4H, t, J=4,7 Hz), the 5.45 (2H, s), 6,32 (1H, DD, J=2.0 a, 8,2 Hz), to 6.57 (1H, DD, J=2.0 a, 2,4 Hz), of 6.66 (1H, DD, J=2,4, and 8.2 Hz), make 6.90 (1H, DD, J=2,4, 8.6 Hz), to 7.15 (1H, DD, J=to 8.2 and 8.2 Hz), 7,28 (1H, d, J=2.4 Hz), was 7.36 (1H, DDD, J=8,2 Hz), the 7.43 (1H, DD, J=7,4, 8,2 Hz), 7,55 (1H, DDD, J=7,4 Hz), to 7.61 (1H, usher.), a 7.62 (1H, d, J=8.6 Hz).

MS (ESI+) m/z: 460 (M+H)+, 482 (M+Na)+.

Msvr (ESI+) m/Z: 460,18678 (M+H)+calculated 460,18725 (-0,47 mmu).

(Example 21) Dihydrochloride ethyl 4-{[1-methyl-6-(3-morpholine-4-elfenix)-1H-benzimidazole-2-yl]methoxy}benzoate (dihydrochloride of compound No. 1-70)

Tri-n-butylphosphine (and 0.61 g, 3.0 mmol) and 1,1'-(azodicarbon)dipiperidino (0,76 g, 3.0 mmol) was added to a solution of [1-methyl-6-(3-morpholine-4-elfenix)-1H-benzimidazole-2-yl]methanol (0.51 g, 1.5 mmol) and ethyl 4-hydroxybenzoate (0,37 g, 2.3 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required is listed in the title compound (0.55 g, yield: 65%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: is 1.31 (3H, t, J=7.0 Hz), 3,11 (4H, t, J=,7 Hz), 3,71 (4H, t, J=4,7 Hz), of 3.94 (3H, s), 4,28 (2H, square, J=? 7.04 baby mortality Hz), 5,73 (2H, s)6,40 (1H, DD, J=2.0 a, 7,8 Hz), of 6.66 (1H, DD, J=2,0, 2,0 Hz), 6,76 (1H, DD, J=2.0 a, 8,2 Hz), 7,18 (1H, DD, J=2,4, and 9.0 Hz), 7,22 (1H, DD, J=7,8, and 8.2 Hz), 7,29 (2H, d, J=9.0 Hz), to 7.59 (1H, d, J=2,4), 7,78 (1H, d, J=9.0 Hz), of 7.97 (2H, d, J=9.0 Hz).

MS (ESI+) m/z: 488 (M+H)+, 510 (M+Na)+.

Msvr (ESI+) m/Z: 488,21667 (M+H)+calculated 488,21855 (-1,87 mmu).

(Example 22) of the Dihydrochloride of 4-{[1-methyl-6-(3-morpholine-4-elfenix)-1H-benzimidazole-2-yl]methoxy}benzoic acid (dihydrochloride of compound No. 1-69)

1 N. aqueous sodium hydroxide solution (10 ml, 10 mmol) was added to a solution of dihydrochloride of ethyl 4-{[1-methyl-6-(3-morpholine-4-elfenix)-1H-benzimidazole-2-yl]methoxy}benzoate (0,43 g, 0.8 mmol) in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated hydrochloric acid (1.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure to obtain the desired specified in the title compound (0.24 g, yield: 59%).

1H-NMR (DMSO-d6, 400 MHz) δ: 3,11 (4H, t, J=4,7 Hz), 3,71 (4H, t, J=4,7 Hz), of 3.94 (3H, s)5,72 (2H, s), to 6.39 (1H, DD, J=2,3, 7,8 Hz), of 6.65 (1H, DD, J=2.0 a, and 2.3 Hz), 6,76 (1H, DD, J=2.0 a, 8,2 Hz), 7,18 (1H, DD, J=2,4, and 9.0 Hz), 7,22 (1H, DD, J=7,8, and 8.2 Hz), 7,26 (2H, d, J=9.0 Hz), 7,58 (1H, d, J=2.3 Hz), 7,78 (1H, d, J=9.0 Hz), 7,94 (2H, d, J=9.0 Hz).

MS (ESI+) m/z: 460 (M+H)+, 482 (M+Na)+.

Msvr (ESI+) m/Z: 460,18703 (M+H)+calculated 460,18725 (-0,22 mmu).

(Example 23) is hydrochloric methyl 3-[(6-ethoxy-1-methyl-1H-benzimidazole-2-yl)methoxy]benzoate (hydrochloride of compound No. 1-4)

(23a) (6 Ethoxy-1-methyl-1H-benzimidazole-2-yl)methanol

tert-Butyl 2-nitro-4-ethoxy(methyl)carbamate (4 g, 13.5 mmol) was dissolved in 100 ml of ethanol was added 10% palladium-on-coal (1 g). The mixture was stirred in hydrogen atmosphere for two hours. Was removed through celite, the catalyst and evaporated under reduced pressure the solvent. The residue was dissolved in 1,4-dioxane (30 ml) and the mixture 4 N. hydrochloric acid-dioxane (30 ml). Added glycolic acid (2,05 g, 27 mmol) and the mixture was heated under reflux for 5.5 hours. The reaction solution was cooled and then neutralized with a saturated solution of sodium bicarbonate. The resulting crystals were filtered off and washed with water and ethyl acetate to obtain 1.51 g of the desired compound (yield: 54%).

1H-NMR (DMSO-d6, 400 MHz) δ: of 1.36 (3H, t, J=7 Hz), of 3.77 (3H, s)4,07 (2H, square, J=7 Hz)and 4.65 (2H, s), 6,77 (1H, DD, J=2 Hz, 8 Hz), 7,05 (1H, d, J=2 Hz), 7,44 (1H, d, J=8 Hz).

(23b) of the Hydrochloride of methyl 3-[(6-ethoxy-1-methyl-1H-benzimidazole-2-yl)methoxy]benzoate

Tri-n-butylphosphine (0,91 g, 4.5 mmol) and 1,1'-(azodicarbon)dipiperidino (1.13 g, 4.5 mmol) was added to a solution of (6-ethoxy)-1-methyl-1H-benzimidazole-2-yl]methanol (0,60 g, 2.0 mmol) and methyl 3-hydroxybenzoate ones (0.46 g, 3.0 mmol) in toluene, followed by stirring for 10 hours. The reaction solution was concentrated and then purified by chromatography on a column of silica gel (e is yuushi solvent: hexane/ethyl acetate = 1/2). Then was added a 4 n solution of chloritoid in 1,4-dioxane (10 ml) followed by stirring for two hours. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate and simple ether. Required is specified in the header connection (0,49 g, yield: 65%) was obtained by drying under reduced pressure.

1H-NMR (DMSO-d6, 400 MHz) δ: of 1.39 (3H, t, J=7,1 Hz), 3,88 (3H, s), 3,98 (3H, s)to 4.16 (2H, square, J=7,1 Hz), 5,71 (2H, s), 7,13 (1H, DD, J=2.2, while the 8.9 Hz), 7,47 (1H, d, J=2.2 Hz), 7,49 (1H, DDD, J=1,3, 2,6, 8,2 Hz), 7,55 (1H, DD, J=to 7.5, and 8.2 Hz), to 7.67 (1H, DD, J=1,3, 7.5 Hz), 7,69 (1H, d, J=8,9 Hz), 7,72 (1H, d, J=2,6 Hz).

MS (ESI+) m/z: 341 (M+H)+, 363 (M+Na)+.

Msvr (ESI+) m/Z: 341,15051 (M+H)+calculated 341,15013 (0,37 mmu).

(Example 24) of the Hydrochloride of 3-[(6-ethoxy-1-methyl-1H-benzimidazole-2-yl)methoxy]benzoic acid (hydrochloride of compound No. 1-3)

1 N. aqueous sodium hydroxide solution (10 ml, 10 mmol) was added to a solution of the hydrochloride of methyl 3-[(6-ethoxy-1-methyl-1H-benzimidazole-2-yl)methoxy]benzoate (to 0.38 g, 1.0 mmol) in 1,4-dioxane and the mixture was stirred at 60°C for two hours. The reaction solution was treated with concentrated hydrochloric acid (1.5 ml) and then concentrated. The obtained solid substance was washed with water and ethyl acetate and dried under reduced pressure to obtain the desired specified in the connection header (0,22 g, yield: 61%).

1H-NMR (DMSO-d6, 400 MHz) δ: of 1.40 (3H, t, J=7,1 Hz), 3,98 (3H, s)to 4.16 (2H, square, J=7,1 Hz), 5,71 (2H, s), 7,13 (1H, DD, J=2.2, while the 8.9 Hz), was 7.45 (1H, DDD, J=1,1, 2,6, 8,2 Hz), 7,52 (1H, DD, J=7,5, 8,2 Hz), the 7.65 (1H, DDD, J=1,1, 1,3, 7.5 Hz), of 7.70 (1H, d, J=8,9 Hz), 7,71 (1H, DD, J=1,3, and 2.6 Hz).

MS (ESI+) m/z: 327 (M+H)+, 349 (M+Na)+, 371 (M+2Na-H)+.

Msvr (ESI+) m/Z: 327,13292 (M+H)+calculated 327,13448 (-1,56 mmu).

(Example 25) Dihydrochloride methyl 3-{[1-methyl-6-(pyridine-3-yloxy)-1H-benzimidazole-2-yl]methoxy}benzoate (dihydrochloride of compound No. 1-148)

(25a) [1-Methyl-6-(pyridine-3-yloxy)-1H-benzimidazole-2-yl]methanol

Glycolic acid (2,75 g, and 36.2 mmol) was added to a mixed solution of tert-butyl 2-amino-5-(pyridine-3-yloxy)phenyl(methyl)carbamate (to 7.61 g, 24,1 mmol) [US 6432993 B1] in 1,4-dioxane (75 ml) and 4 n hydrochloric acid (75 ml). The mixture was stirred at 50°C for 30 minutes and heated under reflux for seven hours. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. Evaporated under reduced pressure, the solvent and the obtained residue was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/methanol = 5/1) to obtain the desired specified in the connection header (or 4.31 g of 16.9 mmol).

1H-NMR (CDCl3, 400 MHz) δ: of 3.78 (3H, s), the 4.90 (2H, s), 96-7,01 (2H, m), 7,25-7,28 (2H, m), 7,65-to 7.68 (1H, m), 8.34 per-8,42 (2H, m).

(25b) Dihydrochloride methyl 3-{[1-methyl-6-(pyridine-3-yloxy)-1H-benzimidazole-2-yl]methoxy}benzoate

[1-Methyl-6-(pyridine-3-yloxy)-1H-benzimidazole-2-yl]methanol synthesized in example 25a (1.0 g, to 3.92 mmol), was dissolved in toluene (17 ml). Was added methyl 3-hydroxybenzoate (895 mg, 5,88 mmol), 1,1'-(azodicarbon)dipiperidino (2,97 g, 9,65 mmol) and n-tributylphosphine (2,90 ml of 11.8 mmol) and the mixture was stirred at room temperature overnight. Evaporated under reduced pressure, the solvent and the obtained residue was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/methanol = 5/1) to obtain methyl 3-{[1-methyl-6-(pyridine-3-yloxy)-1H-benzimidazole-2-yl]methoxy}benzoate (1.5 g, of 3.85 mmol). Methyl 3-{[1-methyl-6-(pyridine-3-yloxy)-1H-benzimidazole-2-yl]methoxy}benzoate (681 mg, about 1.75 mmol) was dissolved in ethyl acetate (15 ml). Added 4 N. hydrochloric acid solution in 1,4-dioxane, 5 ml) and the mixture was stirred at room temperature for 10 minutes. The solid is collected by filtration and recrystallized from ethanol to obtain the desired specified in the title compound (627 mg, of 1.36 mmol).

TPL 195-208°C.

IR (KBr) νmax 1238, 1272, 1489, 1546, 1707.

1H-NMR (DMSO-d6, 400 MHz) δ: 3,88 (3H, s), of 3.97 (3H, s), of 5.75 (2H, s), of 7.36 (1H, DD, J=8,8, 2.2 Hz), 7,50-7,56 (2H, m), 7,65-7,66 (1H, m), 7,73-of 7.82 (3H, m), 7,86-to $ 7.91 (2H, m), to 8.57 (1H, DD, J=5,1, 1,3 is C), 8,63 (1H, d, J=2,4 Hz).

MS (FAB) m/z: 390 (M+H)+.

Analyte. calculated for C22H19N3O4+2HCl: C, 57,15; H, 4,58; Cl, 15,34; N, which is 9.09. Found C, 53,52; H, 4,99; Cl, 14,73; N, 8,48.

(Example 26) 3-{[1-Methyl-6-(pyridine-3-yloxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-147) 1 N. aqueous sodium hydroxide solution (of 2.26 ml, and 2.26 mmol) was added to a solution of intermediate methyl 3-{[1-methyl-6-(pyridine-3-yloxy)-1H-benzimidazole-2-yl]methoxy}benzoate produced in example 25b (800 mg, 2.05 mmol)in 1,4-dioxane (5 ml) and the mixture was stirred at 70°C for one hour. The reaction solution was brought to pH 7 by addition of a solution of 1 N. hydrochloric acid. Precipitated precipitated solid substance was collected by filtration and washed with ethyl acetate to obtain the desired specified in the title compound (332 mg, 0,885 mmol).

TPL 240-245°C.

IR (KBr) νmax 1219, 1290, 1421, 1478, 1586, 1697.

1H-NMR (DMSO-d6, 400 MHz) δ: a 3.83 (3H, s), of 5.48 (2H, s), 7,00 (1H, DD, J=8,6, 2.4 Hz), 7,34-7,47 (5H, m), EUR 7.57-to 7.59 (1H, m), 7,63-of 7.70 (2H, m), 8,32 (1H, DD, J=4,0, 1.5 Hz), scored 8.38 (1H, DD, J=2,8, and 0.9 Hz).

MS (FAB) m/z: 376 (M+H)+.

Analyte. calculated for C21H17N3O4: C, 67,19; H, 4,56; N, 11,19. Found C, 67,14; H, 4,71; N, 11,04.

(Example 27) 3-{[6-(4-Pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-165)

(27a) of tert-Butyl [5-(4-pertenece)-2-nitrophenyl]methylcarbamate

Specified in the header of the prophetic the STV (3.2 g, yield: 88%) was obtained as a yellow solid by synthesis from 4-terfenol (1.1 g, 10 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (2.9 g, 10 mmol), sodium hydride (>56% in oil, of 0.38 g, 10 mmol) and N,N-dimethylformamide (40 ml) in the same way as in example (28a), and crystallization from hexane.

1H-NMR (CDCl3, 400 MHz) δ: of 1.33 (6H, s)of 1.50 (3H, s), 3,26 (3H, s), for 6.81 (1H, DD, J=2.7, and 9.0 Hz), 6,85 (1H, users), 7,07-7,17 (4H, m), 7,93-of 7.97 (1H, m).

(27b) tert-Butyl [2-amino-5-(4-pertenece)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(4-pertenece)-2-nitrophenyl]methylcarbamate obtained in example (27a) (3.2 g, 8,8 mmol), iron powder (2.4 g, 12 mmol), ammonium chloride (0.24 g, 1.2 mmol), ethanol (40 ml) and water (20 ml). The oil obtained directly used for the next reaction.

(27c) [6-(4-Pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol

The synthesis was carried out in the same way as in example (28c)using tert-butyl [2-amino-5-(4-pertenece)phenyl]methylcarbamate obtained in example (27b) (2.9 g, 8,8 mmol), glycolic acid (1.0 g, 13 mmol) and 4 n hydrochloric acid in 1,4-dioxane (40 ml). The obtained dark brown oil directly used for the next reaction.

(27d) of Methyl 3-{[6-(4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and subsequent processing executed by the Yali in accordance with example (28d), using [6-(4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (27c) (0,30 g, 1.1 mmol), methyl 3-hydroxybenzoate (0.25 g, 1.7 mmol), tri-n-butylphosphine (0,55 ml, 2.2 mmol), 1,1'-(azodicarbon)piperidine (0.56 g, 2.2 mmol) and dichloromethane (6.0 ml), to obtain the desired compound (0.36 g, yield: 81%).

1H-NMR (CDCl3, 500 MHz) δ: 3,82 (3H, s)to 3.92 (3H, s), of 5.39 (2H, s), 6,94-7,05 (5H, m), 7,29 (1H, users), 7,38 (1H, t, J=7.8 Hz), 7,69 (1H, d, J=7.8 Hz), 7,71-7,74 (2H, m).

MS (FAB) m/z: 407 (M+H)+.

(27e) 3-{[6-(4-Pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (27d) (0.34 g, 0.84 mmol), 1 N. aqueous sodium hydroxide solution (1.3 ml, 1.3 mmol) and 1,4-dioxane, to obtain the desired compound (0.10 g, yield: 37%) as a white solid.

1H-NMR (DMSO-d6, 500 MHz) δ: 3,81 (3H, s), 5,46 (2H, s), 6,93 (1H, DD, J=2,4, 8,8 Hz), 7,01? 7.04 baby mortality (2H, m), 7,19 (2H, t, J=8,8 Hz), 7,30 (1H, d, J=2.4 Hz), 7,37-7,39 (1H, m), 7,45 (1H, t, J=7.8 Hz), EUR 7.57 (2H, d, J=7.8 Hz), 7,66 (1H, d, J=8,8 Hz), 7,63 (1H, s), 13,03 (1H, users).

MS (FAB) m/z: 393 (M+H)+.

Analyte. calculated for C22H17FN2O4+0,14H2O: C, 66,91; H, TO 4.41; N, 7,09; F, 4,81. Found C, 66,85; H, To 4.46; N, 7,21; F, 4,81.

(Example 28) 3-{[6-(2-Pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-164

(28a) of tert-Butyl [5-(2-pertenece)-2-nitrophenyl]methylcarbamate

2-Terfenol (0.16 ml, 1.7 mmol) was dissolved in N,N-dimethylformamide (10 ml) under nitrogen atmosphere. Added tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (500 mg, 1.7 mmol) and sodium hydride (>56% in oil, 0.84 g, 1.9 mmol) and the mixture was stirred at 80°C for seven hours. The reaction solution was concentrated and added an aqueous solution of sodium bicarbonate, followed by extraction with diethyl ether twice. Then the organic layers were washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. Evaporated under reduced pressure, the solvent and the resulting yellow oil was directly used for the next reaction.

(28b) of tert-Butyl [2-amino-5-(2-pertenece)phenyl]methylcarbamate

Iron powder (0,47 g, 8,8 mmol) and ammonium chloride (0,047 g, 0.88 mmol) was added to a mixture of tert-butyl [5-(2-pertenece)-2-nitrophenyl]methylcarbamate obtained in example (28a) (0.74 g, 1.7 mmol), ethanol (8.0 ml) and water (4.0 ml) and the resulting mixture was heated under reflux for two hours. Insoluble material was filtered through celite. To the concentrated filtrate was added water, followed by extraction with ethyl acetate twice. Then the organic layers were washed with saturated salt solution and dried over anhydrous magnesium sulfate. Viparis is whether under reduced pressure, the solvent and the oil obtained directly used for the next reaction.

(28c) [6-(2-Pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol

tert-Butyl [2-amino-5-(2-pertenece)phenyl]methylcarbamate obtained in example (28b) (0,58 g 1,749 mmol), was dissolved in 4 BC solution of hydrochloric acid in 1,4-dioxane (10 ml). Added glycolic acid (0.20 g, 2.6 mmol) and the mixture was heated under reflux for 1.5 hours. The reaction solution was concentrated and added an aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate twice. Then the organic layers were washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. Evaporated under reduced pressure, the solvent and the obtained residue was subjected to a simple purification by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 5/1 → only the ethyl acetate → methanol/dichloromethane = 1/5). Evaporated under reduced pressure, the solvent and the resulting dark brown oil was directly used for the next reaction.

(28d) of Methyl 3-{[6-(2-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Tri-n-butylphosphine (0,36 ml, 1.4 mmol) and 1,1'-(azodicarbon)piperidine (0.36 g, 1.4 mmol) was added to a solution of [6-(2-pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (28c) (0.20 g, 0.7 mmol), and methyl 3-hydroxybenzoate (0.16 g, 1.1 mmol) in dichloromethane and subsequent AC is sevanam within 12 hours. The reaction solution was concentrated and then suspended in a mixed solvent of hexane/ethyl acetate (= 3/2). After ultrasonic treatment of precipitated precipitated solid substance was separated by filtration. The filtrate was concentrated and then purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 5/1→1/1). The desired compound (0.16 g, yield: 58%) was obtained by drying under reduced pressure.

1H-NMR (CDCl3, 400 MHz) δ: 3,81 (3H, s)to 3.92 (3H, s), of 5.39 (2H, s), of 6.96 (1H, s), 7,00-7,05 (2H, m), 7,07-7,13 (2H, m), 7,20 (1H, t, J=9.5 Hz), 7,29 (1H, d, J=7,3 Hz), 7,37 (1H, t, J=7,3 Hz), 7,69 (1H, d, J=7.8 Hz), 7,70-7,74 (2H, m).

MS (FAB) m/z: 407 (M+H)+.

(28e) 3-{[6-(2-Pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

1 N. aqueous solution of sodium hydroxide (0.54 ml, 0.54 mmol) was added to a solution of methyl 3-{[6-(2-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (28d) (0.16 g, 0.36 mmol)in 1,4-dioxane and the mixture was stirred at 70°C for 1.5 hours. The reaction solution was concentrated and added water to it. The mixture was neutralized by adding dropwise 1 n hydrochloric acid. Precipitated precipitated solid substance was collected by filtration to obtain the desired compound (0,096 g, yield: 68%) as a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: 3,81 (3H, s), vs. 5.47 (2H, s)6,94 (1H, DD, J=2.5 a, 8,8 Hz),? 7.04 baby mortality-to 7.09 (1H, m), 7,18(2H, DDD, J=3.1 and 3.3, which is 6.1 Hz), 7,30 (1H, d, J=2.4 Hz), 7,35-7,42 (2H, m), 7,45 (1H, t, J=7.8 Hz), 7,58 (1H, d, J=7,4 Hz), 7,66 (1H, d, J=8.6 Hz), 7,63 (1H, s), 13,03 (1H, users).

MS (FAB) m/z: 393 (M+H)+.

Analyte. calculated for C22H17FN2O4+0,14H2O: C, 66,91; H, TO 4.41; N, 7,09; F, 4,81. Found C, 66,86; H, 4,48; N, 7,08; F, 4,80.

(Example 29) 3-{[6-(3-Methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-173)

(29a) of tert-Butyl [5-(3-methoxyphenoxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 3-methoxyphenol (to 0.19 ml, 1.7 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (0.50 g, 1.7 mmol), sodium hydride (>56% in oil, 0.84 g, 1.9 mmol) and N,N-dimethylformamide (10 ml). The obtained yellow oil was directly used for the next reaction.

(29b) of tert-Butyl [2-amino-5-(3-methoxyphenoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(3-methoxyphenoxy)-2-nitrophenyl]methylcarbamate obtained in example (29a) (0.65 g, 1.7 mmol), iron powder (0,47 g, 8,7 mmol), ammonium chloride (0,047 g, 0.87 mmol), ethanol (8.0 ml) and water (4.0 ml). The oil obtained directly used for the next reaction.

(29c) [6-(3-Methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

The synthesis was carried out in the same way as in example (28c)using tert-butyl [2-amino-5-(3-methoxyphenoxy)phenyl]IU is ylcarbamate, obtained in example (29b) (0,60 g, 1.7 mmol), glycolic acid (0.20 g, 2.6 mmol) and 4 n hydrochloric acid in 1,4-dioxane (10 ml). The obtained dark brown oil directly used for the next reaction.

(29d) Methyl 3-{[6-(3-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(3-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (29c) (0.24 g, 0.85 mmol), methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butylphosphine (of 0.43 ml, 1.7 mmol), 1,1'-(azodicarbon)dipiperidino (of 0.43 g, 1.7 mmol) and dichloromethane (6.0 ml), to obtain the desired connection (0,23 g, yield: 65%).

1H-NMR (CDCl3, 400 MHz) δ: of 3.77 (3H, s)to 3.89 (3H, s), to 5.57 (2H, s), 6,55 return of 6.58 (2H, m), 6,61-6,69 (1H, m), 7,00-7,07 (2H, m), 7,19-of 7.25 (2H, m), 7,38 (1H, t, J=7.8 Hz), to 7.84 (1H, d, J=8.6 Hz), 7,78 (1H, d, J=7,4 Hz), 8,03 (1H, s).

(29e) 3-{[6-(3-Methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(3-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (29d) (0,23 g of 0.56 mmol), 1 N. aqueous sodium hydroxide solution (or 0.83 ml, 0.83 mmol) and 1,4-dioxane, to obtain the desired compound (0.20 g, yield: 89%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: of 3.77 (3H, s), 89 (3H, C)to 5.57 (2H, s), 6,55 return of 6.58 (2H, m), 6,61-6,69 (1H, m), 7,00-7,07 (2H, m), 7,19-of 7.25 (2H, m), 7,38 (1H, t, J=7.8 Hz), to 7.84 (1H, d, J=8.6 Hz), 7,78 (1H, d, J=7,4 Hz), 8,03 (1H, s).

MS (FAB) m/z: 405 (M+H)+.

Analyte. calculated for C23H20N2O5+0,33H2O: C, 67,31; H, TO 5.08; N, 6,83. Found C, 67,47; H, 4,94; N, 6,92.

(Example 30) 3-{[6-(4-Methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-174)

(30a) of tert-Butyl [5-(4-methoxyphenoxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 3-methoxyphenol (0.20 g, 1.7 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (0.50 g, 1.7 mmol), sodium hydride (>56% in oil, 0.84 g, 1.9 mmol) and N,N-dimethylformamide (10 ml). The obtained yellow oil was directly used for the next reaction.

(30b) of tert-Butyl [2-amino-5-(4-methoxyphenoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(4-methoxyphenoxy)-2-nitrophenyl]methylcarbamate obtained in example (30a) (0.65 g, 1.7 mmol), iron powder (0,47 g, 8,7 mmol), ammonium chloride (0,047 g, 0.87 mmol), ethanol (8.0 ml) and water (4.0 ml). The oil obtained directly used for the next reaction.

(30c) [6-(4-Methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

The synthesis was carried out in the same way as in example (28c)using tert-butyl [2-amino-5-(4-methoxyphenoxy)phenyl]methylcarbamate, who must register in example (30b) (0,60 g, 1.7 mmol), glycolic acid (0.40 g, 5.2 mmol) and 4 n hydrochloric acid in 1,4-dioxane (20 ml). The obtained dark brown oil directly used for the next reaction.

(30d) Methyl 3-{[6-(4-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(4-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (30c) (0,23 g of 0.79 mmol), methyl 3-hydroxybenzoate (0.18 g, 1.2 mmol), tri-n-butylphosphine (and 0.40 ml, 2.0 mmol), 1,1'-(azodicarbon)dipiperidino (0.39 g, 2.0 mmol) and dichloromethane (4.0 ml), to obtain the desired compound (0.25 g, yield: 75%) as a pale brown oil.

1H-NMR (CDCl3, 400 MHz) δ: with 3.79 (3H, s), 3,81 (3H, s)to 3.92 (3H, s)5,38 (2H, s), 6,88-6,91 (3H, m), 6,97-7,01 (3H, m), 7,27-7,31 (1H, m), 7,37 (1H, t, J=7.8 Hz), 7,66-7,73 (3H, m).

(30e) 3-{[6-(4-Methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(4-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (30d) (0.25 g, 0.59 mmol), 1 N. aqueous sodium hydroxide solution (0,89 ml, 0.89 mmol) and 1,4-dioxane, to obtain the desired compound (0.21 g, yield: 86%) as a white solid.

1H-NMR (CDCl3, 500 MHz) δ: with 3.79 (3H, s), 3,81 (3H, s), are 5.36 (2H, users), 6,87-6,93 (H, m) 6,98 (3H, d, J=8,3 Hz), 7,20-7,29 (1H, m), of 7.36 (1H, s), 7,65-7,76 (3H, m).

MS (FAB) m/z: 405 (M+H)+.

Analyte. calculated for C23H20N2O5+1,5H2O: C, 64,03; H, LOWER THAN THE 5.37; N, OF 6.49. Found C, 63,96; H, And 5.30; N, 6,52.

(Example 31) of the Hydrochloride of 3-[6-(3-chlorophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzoic acid (hydrochloride of compound No. 1-51)

(31a) of tert-Butyl [5-(3-pertenece)-2-nitrophenyl]methylcarbamate

Sodium hydride (56%, of 0.38 g, 10 mmol) was added to a solution of 3-chlorophenol (1.29 g, 10 mmol) and tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (2,87 g, 10 mmol) in N,N-dimethylformamide (20 ml) under cooling with ice. The reaction mixture was stirred at 80°C for six hours. Allowing the reaction solution to cool, was added to the reaction mixture water (100 ml) followed by extraction with ethyl acetate (100 ml). Then the organic layer was washed with water (100 ml) twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure the residue was purified by chromatography on silica gel (hexane:ethyl acetate, 6:1) to obtain specified in the connection header (3,79 g, yield: 99%) as a yellow oil.

1H-NMR (CDCl3, 400 MHz) δ: of 1.33 (6H, s)of 1.50 (3H, s), with 3.27 (3H, s), 6.87 in (1H, DD, J=2.7, and 8.6 Hz), 6.89 in (1H, users), 7,01 (1H, d, J=8.1 Hz), 7,12 (1H, t, J=2.0 Hz), 7.24 to 7,26 (1H, m), 7,38 (1H, t, J=8,2 Hz), of 7.96 (1H, d, J=9,0 Hz).

(31b) of tert-Butyl [2-amino-5-(3-chlorophenoxy)phenyl]methylcarbamate

A solution of tert-butyl [5-(3-what lovenox)-2-nitrophenyl]methylcarbamate, obtained in example (31a) (3,79 g, 10 mmol), ammonium chloride (0.27 g, 5.0 mmol) and iron powder (2,79 g, 50 mmol) in ethanol (50 ml) and water (25 ml) was stirred at reflux for one hour. Allowing the reaction solution to cool, the reaction mixture was filtered through celite. The filtrate was concentrated and then added water (100 ml) followed by extraction with ethyl acetate (100 ml). Then the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by chromatography on silica gel (hexane:ethyl acetate, 5:1) to obtain specified in the connection header (3,49 g, yield: 99%) as a yellow oil.

1H-NMR (CDCl3, 400 MHz) δ: of 1.41 (9H, s), and 3.16 (3H, s), 3,70 (2H, users), 6,77 (1H, d, J=8.6 Hz), 6,82-of 6.90 (4H, m), 6,99-7,01 (1H, m), 7,20 (1H, t, J=8,2 Hz).

(31c) [6-(3-Chlorophenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

A solution of tert-butyl [2-amino-5-(3-chlorophenoxy)phenyl]methylcarbamate (3,49 g, 10 mmol)obtained in example (31b), and glycolic acid (1.52 g, 20 mmol) in a mixture of 4 M hydrochloric acid-dioxane (10 ml) was stirred at reflux for nine hours. Allowing the reaction solution to cool, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (100 ml) followed by extraction with ethyl acetate (100 ml). Then the organic leisurely over anhydrous sodium sulfate. After concentration under reduced pressure the residue was purified by chromatography on silica gel (methylene chloride:methanol, 95:5) to obtain the specified title compound (0.66 g, yield: 23%) as a pale brown powder.

1H-NMR (CDCl3, 400 MHz) δ: with 3.79 (3H, s), 4,91 (2H, s), to 6.88 (1H, d, J=8.6 Hz), to 6.95 (1H, s), 6,98-7,01 (2H, m), 7,05 (1H, d, J=8,2 Hz), 7,24 (1H, d, J=8,2 Hz), 7,69 (1H, d, J=9.4 Hz).

(31d) of Methyl 3-{[6-(3-chlorophenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

A solution of [6-(3-chlorophenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (31c) (660 mg, 2.3 mmol), methyl 3-hydroxybenzoate (522 mg, 3.4 mmol), tri-n-butylphosphine (925 mg, 4.6 mmol) and 1,1'-(azodicarbon)dipiperidino (1,15 g, 4.6 mmol) in methylene chloride (5 ml) was stirred for three hours. The reaction mixture was concentrated and then purified by chromatography on a column of silica gel (hexane:ethyl acetate, 2:1) to obtain specified in the connection header (935 mg, yield: 97%) as a white amorphous solid.

1H-NMR (CDCl3, 400 MHz) δ: of 3.85 (3H, s), 3,93 (3H, s)5,41 (2H, s), 6.89 in (1H, DDD, J=0,8, 3,1, 8,2 Hz), 6,97 (1H, t, J=2.0 Hz), 7,01-7,07 (3H, m), 7,24 (1H, d, J=8,2 Hz), 7,29-to 7.32 (1H, m), 7,39 (1H, t, J=7.8 Hz), of 7.70 (1H, dt, J=1,1, 7,4 Hz), 7,73-7,74 (1H, m), to 7.77 (1H, d, J=9.4 Hz).

(31e) of the Hydrochloride of 3-[6-(3-chlorophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzoic acid

A solution of methyl 3-{[6-(3-chlorophenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate, obtained the sample (31d) (933 mg, 2.21 mmol), 2 M aqueous sodium hydroxide solution (5 ml) and dioxane (10 ml) was stirred at reflux for two hours. Allowing the reaction solution to cool, was added to the reaction mixture 5 M hydrochloric acid (20 ml). Precipitated precipitated solid substance was collected by filtration to obtain specified in the connection header (829 mg, yield: 84%) as a white powder.

1H-NMR (DMSO-d6, 400 MHz) δ: 3,91 (3H, s), 5,62 (2H, s), 6,98 (1H, DD, J=3.1 and 9.0 Hz),? 7.04 baby mortality (1H, t, J=2.0 Hz), 7,17 (1H, DD, J=2,4, and 9.0 Hz), 7.18 in-7,20 (1H, m), 7,40 (1H, d, J=8,2 Hz), 7,42-7,44 (1H, m), 7,49 (1H, t, J=7,8 Hz), to 7.61 (1H, s), a 7.62 (1H, d, J=7,4 Hz), 7,69 (1H, s), 7,79 (1H, d, J=9.0 Hz).

MS (FAB+) m/z: 409 (M+H)+.

TPL: 218-222°C.

(Example 32) 3-{[1-Methyl-6-(3-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-167)

(32a) of tert-Butyl methyl[5-(3-methylphenoxy)-2-nitrophenyl]carbamate

The synthesis was carried out in the same way as in example (28a)using m-cresol (0,36 ml, 3.5 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (1.0 g, 3.5 mmol), sodium hydride (>56% in oil, 0.17 g, 3.8 mmol) and N,N-dimethylformamide (20 ml). The obtained yellow oil was directly used for the next reaction.

(32b) of tert-Butyl [2-amino-5-(3-methylphenoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl methyl[5-(3-methylphenoxy)-2-nitrophenyl]carbamate, the floor is built in (32a) (1.2 g, 3.5 mmol), iron powder (0,93 g, 17 mmol), ammonium chloride (0,093 g, 1.7 mmol), ethanol (16 ml) and water (8.0 ml). The oil obtained directly used for the next reaction.

(32c) [1-Methyl-6-(3-methylphenoxy)-1H-benzimidazole-2-yl]methanol

tert-Butyl [2-amino-5-(3-methylphenoxy)phenyl]methylcarbamate obtained in example (32b) (1.1 g, 3.5 mmol), was dissolved in 4 BC solution of hydrochloric acid in 1,4-dioxane (20 ml). Added glycolic acid (0,80 g, 10 mmol) and the mixture was heated under reflux overnight. Evaporated under reduced pressure, the solvent and then added an aqueous solution of sodium bicarbonate (100 ml) followed by extraction with ethyl acetate (100 ml × 2). The obtained organic layer was washed with saturated salt solution (80 ml) and then dried over anhydrous magnesium sulfate. Evaporated under reduced pressure the solvent. The obtained solid is washed with diisopropyl ether to obtain the desired compound (0,59 g, yield: 63%).

1H-NMR (CDCl3, 400 MHz) δ: 2,32 (3H, in), 3.75 (3H, s), the 4.90 (2H, s), to 6.80 (2H, s), make 6.90 (1H, d, J=7,4 Hz), 6,94-7,02 (2H, m), 7,21 (1H, t, J=7.8 Hz), the 7.65 (1H, d, J=8.6 Hz).

(32d) of Methyl 3-{[1-methyl-6-(3-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [1-methyl-6-(3-methylphenoxy)-1H-benzimidazole-2-yl]methanol obtained in PR is as (32c) (0.24 g, 0.89 mmol), methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butylphosphine (0.45 ml, 1.8 mmol), 1,1'-(azodicarbon)piperidine (0.45 g, 1.8 mmol) and dichloromethane (6.0 ml), to obtain the desired compound (0.31 g, yield: 85%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: 3,81 (3H, users), to 3.92 (3H, s), of 5.39 (2H, s), 6,78-6,83 (2H, m)6,91 (1H, d, J=7.8 Hz), 6,97? 7.04 baby mortality (2H, m), 7,21 (1H, t, J=8.0 Hz), 7,27-to 7.32 (1H, m), 7,38 (1H, t, J=7.8 Hz), 7,69 (1H, TD, J=1,2, the 1.4 and 7.6 Hz), 7,71 to 7.75 (2H, m).

MS (FAB) m/z: 403 (M+H)+.

(32e) 3-{[1-Methyl-6-(3-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[1-methyl-6-(3-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (32d) (0.29 grams, to 0.72 mmol), 1 N. aqueous sodium hydroxide solution (1.1 ml, 1.1 mmol) and 1,4-dioxane (1.0 ml), to obtain the desired compound (0.17 g, yield: 60%) as a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: of 2.27 (3H, s), 3,81 (3H, s), vs. 5.47 (2H, s), 6,74-6,83 (2H, m), 6.87 in-6,97 (2H, m), 7,32 (1H, d, J=2.4 Hz), of 7.36-7,41 (1H, m), 7,45 (1H, t, J=8.0 Hz), 7,58 (1H, dt, J=1,2, 1,4, 7,6 Hz), 7,62-to 7.68 (2H, m).

MS (FAB) m/z: 389 (M+H)+.

Analyte. calculated for C23H20N2O4+0,33H2O: C, 70,04; H, 5,28; N, 7,10. Found C, 69,99; H, 5,16; N, 7,15.

(Example 33) 3-({1-Methyl-6-[3-(triptoreline)phenoxy]-1H-benzimidazole-2-yl}methoxy]benzoic acid (compound No. 1-176)

(33a) of tert-Butyl methyl{2-nitro-[3-(triptoreline)phenoxy]phenyl}carbamate

Required is specified in the header connection (4,28 g, yield: 99%) was obtained as a yellow oil according to the method described in example (31a), using 3-cryptomaterial (1.78 g, 10 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (2,87 g, 10 mmol) and sodium hydride (56%, of 0.38 g, 10 mmol).

1H-NMR (CDCl3, 400 MHz) δ: of 1.33 (6H, s)of 1.50 (3H, s), with 3.27 (3H, s), 6.89 in-6,91 (2H, m), of 6.99 (1H, s), 7,05 (1H, d, J=8.6 Hz), 7,13 (1H, d, J=7.8 Hz), 7,47 (1H, t, J=8,2 Hz), of 7.97 (1H, d, J=8.6 Hz).

(33b) tert-Butyl {2-amino-5-[3-(triptoreline)phenoxy]phenyl}methylcarbamate

Required is listed in the title compound (3.98 g, yield: 99%) was obtained as a yellow oil according to the method described in example (31b), using tert-butyl methyl{2-nitro-5-[3-(triptoreline)phenoxy]phenyl}carbamate obtained in example (33a) (2,87 g, 10 mmol)and iron powder (2,79 g, 50 mmol).

1H-NMR (CDCl3, 400 MHz) δ: of 1.41 (9H, users)and 3.15 (3H, s), and 3.72 (2H, users), 6,76-6,89 (5H, m), 7,26-7,30 (2H, m).

(33c) {1-Methyl-6-[3-(triptoreline)phenoxy]-1H-benzimidazole-2-yl}methanol

Required is specified in the header connection is 3.08 g, yield: 91%) was obtained as pale-brown powder in accordance with the method described in example (31c), using tert-butyl {2-amino-5-[3-(triptoreline)phenoxy]phenyl}methylcarbamate obtained in example (33b) (3.98 g, 10 mmol)and glycolic acid (1.52 g, 20 mmol).

1H-NMR (CDCl3, 400 MHz) δ: with 3.79 (3H, s), 491 (2H, C), 6,85 (1H, s), 6.89 in (1H, DD, J=2,4, 8.6 Hz), 6,92-to 6.95 (1H, m), 6,98-7,01 (2H, m), 7,32 (1H, t, J=8,2 Hz), to 7.67 (1H, d, J=9.0 Hz).

(33d) Methyl 3-({1-methyl-6-[3-(triptoreline)phenoxy]-1H-benzimidazole-2-yl}methoxy)benzoate

Required is specified in the header connection (3,52 g, yield: 91%) was obtained as a white powder in accordance with the method described in example (31d), using {1-methyl-6-[3-(triptoreline)phenoxy]-1H-benzimidazole-2-yl}methanol obtained in example (33c) (is 3.08 g, 9.1 mmol), methyl 3-hydroxybenzoate (2,08 g, 13.7 mmol), tri-n-butylphosphine (3,68 g, 18.2 mmol) and 1,1'-(azodicarbon)dipiperidino (4.59 g, 18.2 mmol).

1H-NMR (CDCl3, 400 MHz) δ: of 3.85 (3H, s), 3,93 (3H, s), 5,42 (2H, s)6,86 (1H, s)6,91 (1H, DD, J=2,4, 7,4 Hz), 6,93-of 6.96 (1H, m), 7,02-7,06 (2H, m), 7,29-7,34 (2H, m), 7,39 (1H, t, J=7.4 Hz), 7,69-7,74 (2H, m), to 7.77 (1H, d, J=8,2 Hz).

(33e) 3-({1-Methyl-6-[3-(triptoreline)phenoxy]-1H-benzimidazole-2-yl}methoxy]benzoic acid

A solution of methyl 3-({1-methyl-6-[3-(triptoreline)phenoxy]-1H-benzimidazole-2-yl}methoxy)benzoate obtained in example (33d) (3,52 g, 7,45 mmol), 2 M aqueous sodium hydroxide solution (20 ml) and dioxane (40 ml) was stirred at reflux for two hours. Allowing the reaction solution to cool, was added to the reaction mixture of 1 M hydrochloric acid (50 ml) and precipitated precipitated solid substance was collected by filtration. The solid was dissolved in 1 M aqueous sodium hydroxide solution (50 ml) is added 1 M hydrochloric acid (50 ml). Precipitated precipitated solid substance was collected by filtration to obtain specified in the connection header (2,75 g, yield: 81%) as a white powder.

1H-NMR (DMSO-d6, 400 MHz) δ: a 3.83 (3H, s), of 5.48 (2H, s), 6,95-6,97 (2H, m), 7,00 (1H, DD, J=2,4, 8.6 Hz), 7,07-to 7.09 (1H, m), of 7.36-7,39 (1H, m), 7,43-7,49 (3H, m), 7,58 (1H, dt, J=1,2, 7,8 Hz), to 7.64 (1H, DD, J=1,2, 2,4 Hz), 7,71 (1H, d, J=8,2 Hz), 13,08 (1H, users).

MS (FAB+) m/z: 459 (M+H)+.

TPL: 221-227°C.

(Example 34) 3-{[6-(4-Fluoro-3-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-187)

(34a) of tert-Butyl [5-(4-fluoro-3-methylphenoxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 4-fluoro-3-METHYLPHENOL (0,78 ml, 7.0 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (2.0 g, 7.0 mmol), sodium hydride (>56% in oil, 0.28 g, 7.0 mmol) and N,N-dimethylformamide (20 ml). The obtained yellow oil was directly used for the next reaction.

(34b) of tert-Butyl [2-amino-5-(4-fluoro-3-methylphenoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(4-fluoro-3-methylphenoxy)-2-nitrophenyl]methylcarbamate obtained in example (34a) (2.6 g, 7.0 mmol), iron powder (1.9 g, 35 mmol), ammonium chloride (0,19 g, 3.5 mmol), ethanol (20 ml) and water (10 ml). The oil obtained directly used for the next reaction.

(34c) [6-(4-Fluoro-3-methylphenoxy)-1-methyl-1H-benzimida the evils-2-yl]methanol

tert-Butyl [2-amino-5-(4-fluoro-3-methylphenoxy)phenyl]methylcarbamate obtained in example (34b) (2.4 g, 7.0 mmol), was dissolved in a solution of 5 N. hydrochloric acid (20 ml) and 1,4-dioxane (20 ml). Added glycolic acid (0,80 g, 10 mmol) and the mixture was heated under reflux overnight. The reaction solution was cooled to room temperature and was added an aqueous solution of sodium bicarbonate (100 ml) followed by extraction with ethyl acetate (100 ml × 2). The obtained organic layer was washed with saturated salt solution (80 ml) and then dried over anhydrous magnesium sulfate. Evaporated under reduced pressure the solvent. The obtained solid is washed with diisopropyl ether to obtain the desired compound (1.5 g, yield: 77%) as pale red-brown solid.

1H-NMR (CDCl3, 400 MHz) δ: 2,25 (3H, d, J=2.0 Hz), of 3.78 (3H, s), of 4.05 (1H, users), 4,91 (2H, s), 6.75 in-for 6.81 (1H, m), 6,83 (2H, DD, J=2,9, 6,1 Hz), 6.87 in (1H, d, J=2.0 Hz), of 6.96 (2H, d, J=8.6 Hz), 7,60 (1H, d, J=8.6 Hz).

(34d) Methyl 3-{[6-(4-fluoro-3-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(4-fluoro-3-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (34c) (0.25 g, 0.88 mmol), methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butylphosphine (of 0.44 ml, 1.8 mmol), 1,1'-(azodicarbon)depypere is in (0,44 g, 1.8 mmol) and dichloromethane (4 ml), to obtain the desired compound (0,30 g, yield: 80%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: 2,25 (3H, d, J=2.0 Hz), 3,81 (3H, s)to 3.92 (3H, s), of 5.39 (2H, s), 6,76-6,86 (2H, m), 6,92-to 7.00 (3H, m), 7,27-7,31 (1H, m), 7,38 (1H, t, J=8.0 Hz), 7,71 (3H, d, J=8.6 Hz).

(34e) 3-{[6-(4-Fluoro-3-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(4-fluoro-3-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (34d) (0.31 g, to 0.72 mmol), 1 N. aqueous sodium hydroxide solution (1.2 ml, 1.2 mmol) and 1,4-dioxane (1.0 ml), to obtain the desired compound (0.24 g, yield: 81%) as a white solid matter.

1H-NMR (DMSO-d6, 500 MHz) δ: 2,20 (3H, s), 3,81 (3H, s), 5,46 (2H, s), 6,80-6,87 (1H, m), 6.89 in-6,95 (2H, m), 7,12 (1H, t, J=9.0 Hz), 7,28 (1H, d, J=2.0 Hz), of 7.36-7,41 (1H, m), 7,45 (1H, t, J=7.8 Hz), EUR 7.57 (1H, d, J=7,8 Hz), a 7.62 to 7.67 (2H, m), 13,03 (1H, users).

MS (FAB) m/z: 407 (M+H)+.

Analyte. calculated for C23H19FN2O4+0,10 HCl: C, 67,37; H, 4,69; F, 4,63; N, 6,83; Cl, 0,86. Found C, 67,24; H, 4,70; F, 4,56; N, 7,00; Cl, 0,64.

(Example 35) 3-{[6-(3,4-Divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-180)

(35a) of tert-Butyl [5-(3,4-divergence)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 3,4-diferena (0.95 g, 7.0 mmol), tert-bout the l (5-chloro-2-nitrophenyl)methylcarbamate (2.0 g, 7,0 mmol), sodium hydride (>56% in oil, 0.28 g, 7.0 mmol) and N,N-dimethylformamide (20 ml). The obtained yellow solid was directly used for the next reaction.

(35b) of tert-Butyl [2-amino-5-(3,4-divergence)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(3,4-divergence)-2-nitrophenyl]methylcarbamate obtained in example (35a) (2.7 g, 7.0 mmol), iron powder (1.9 g, 35 mmol), ammonium chloride (0,19 g, 3.5 mmol), ethanol (20 ml) and water (10 ml). The oil obtained directly used for the next reaction.

(35c) [6-(3,4-Divergence)-1-methyl-1H-benzimidazole-2-yl]methanol

The reaction and post treatment were carried out according to example (34c)using tert-butyl [2-amino-5-(3,4-divergence)phenyl]methylcarbamate obtained in example (35b) (2.4 g, 7.0 mmol), glycolic acid (0,80 g, 10 mmol), 5 n hydrochloric acid (20 ml) and 1,4-dioxane (20 ml), to obtain the desired compound (1.5 g, yield: 76%) as a pale brown solid.

1H-NMR (CDCl3, 400 MHz) δ: of 3.78 (3H, s), the 4.90 (2H, s), 6,67-6,74 (1H, m), 6,77-6,85 (1H, m), 6,97 (2H, s), 7,11 (1H, square, J=9,3 Hz), to 7.67 (1H, d, J=8,2 Hz).

(35d) of Methyl 3-{[6-(3,4-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(3,4-divergence)-1-methyln-benzimidazole-2-yl]methanol obtained in example (35c) (0.25 g, 0.88 mmol), methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butylphosphine (of 0.44 ml, 1.8 mmol), 1,1'-(azodicarbon)dipiperidino (of 0.44 g, 1.8 mmol) and dichloromethane (4.0 ml), to obtain the desired compound (0,30 g, yield: 80%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: a-3.84 (3H, s), of 3.94 (3H, s), of 5.40 (2H, s)5,41 (10H, users), 6,69 to 6.75 (1H, m), 6,79-6,85 (1H, m), 6,97-7,02 (2H, m), 7,07-to 7.15 (1H, m), 7,28-to 7.32 (1H, m), 7,38 (1H, t, J=8.1 Hz), to 7.67-7,71 (1H, m), 7,74 (2H, s).

MS (FAB) m/z: 425 (M+H)+.

(35e) 3-{[6-(3,4-Divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(3,4-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (35d) (0.31 g, to 0.72 mmol), 1 N. aqueous sodium hydroxide solution (1.2 ml, 1.2 mmol) and 1,4-dioxane (1.0 ml), to obtain the desired compound (0.25 g, yield: 82%) as a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: 3,82 (3H, s), vs. 5.47 (2H, s), 6,77-6,84 (1H, m), 6,97 (1H, DD, J=2,4, 8.6 Hz), 7,10-to 7.18 (1H, m), 7,35-of 7.48 (4H, m), 7,55-of 7.70 (3H, m).

MS (FAB) m/z: 411 (M+H)+.

Analyte. calculated for C22H16F2N2O4+0,10HCl: C, 67,37; H, 4,69; F, 4,63; N, 6,83; Cl, 0,86. Found C, 67,24; H, 4,70; F, 4,56; N, 7,00; Cl, 0,64.

(Example 36) 3-({1-Methyl-6-[3-(trifluoromethyl)phenoxy]-1H-benzimidazole-2-yl}methoxy)benzoic acid (compound No. 1-175)

(36a) of tert-Butyl methyl{2-NIT is about-5-[3-(trifluoromethyl)phenoxy]phenyl}carbamate

The synthesis was carried out in the same way as in example (28a)using 3-(trifluoromethyl)phenol (of 0.87 ml, 7.0 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (2.00 g, 7.0 mmol), sodium hydride (>56% in oil, 0.28 g, 7.0 mmol) and N,N-dimethylformamide (20 ml). The obtained yellow solid was directly used for the next reaction.

(36b) tert-Butyl {2-amino-5-[3-(trifluoromethyl)phenoxy]phenyl}methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl methyl{2-nitro-5-[3-(trifluoromethyl)phenoxy]phenyl}carbamate obtained in example (36a) (2.9 g, 7.0 mmol), iron powder (1.9 g, 35 mmol), ammonium chloride (0,19 g, 3.5 mmol), ethanol (20 ml) and water (10 ml). The oil obtained directly used for the next reaction.

(36c) {1-Methyl-6-[3-(trifluoromethyl)phenoxy]-1H-benzimidazole-2-yl}methanol

The reaction and post treatment were carried out according to example (34c)using tert-butyl {2-amino-5-[3-(trifluoromethyl)phenoxy]phenyl}methylcarbamate obtained in example (36b) (2.4 g, 7.0 mmol), glycolic acid (0,80 g, 10 mmol), 5 n hydrochloric acid (20 ml) and 1,4-dioxane (20 ml), to obtain the desired compound (1.3 g, yield: 57%) as a pale brown solid.

1H-NMR (CDCl3, 400 MHz) δ: of 3.78 (3H, s), is 4.93 (2H, s), 6,97? 7.04 baby mortality (2H, m), 7,09-to 7.18 (1H, m), 7,21 (1H, s), 7,33 (1H, d, J=8.6 Hz), the 7.43 (1H, t, J=7.8 Hz), 7,71 (1H, d, J=8,2 Hz.

(36d) Methyl 3-({1-methyl-6-[3-(trifluoromethyl)phenoxy]-1H-benzimidazole-2-yl}methoxy)benzoate

The reaction and post treatment were carried out according to example (28d)using {1-methyl-6-[3-(trifluoromethyl)phenoxy]-1H-benzimidazole-2-yl}methanol obtained in example (36c) (0.25 g, 0.88 mmol), methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butylphosphine (of 0.44 ml, 1.8 mmol), 1,1'-(azodicarbon)dipiperidino (of 0.44 g, 1.8 mmol) and dichloromethane (4.0 ml), to obtain the desired compound (0.33 g, yield: 81%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: of 3.85 (3H, s), 3,93 (3H, s)5,41 (8H, s)5,41 (2H, s), 7,00-7,06 (2H, m), to 7.15 (1H, DD, J=2,4, and 8.2 Hz), 7.23 percent (1H, s), 7,28-7,46 (4H, m), 7.68 per-7,79 (3H, m).

MS (FAB) m/z: 457 (M+H)+.

(36e) 3-({1-Methyl-6-[3-(trifluoromethyl)phenoxy]-1H-benzimidazole-2-yl}methoxy]benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-({1-methyl-6-[3-(trifluoromethyl)phenoxy]-1H-benzimidazole-2-yl}methoxy)benzoate obtained in example (36d) (0.33 g, to 0.72 mmol), 1 N. aqueous sodium hydroxide solution (1.1 ml, 1.1 mmol) and 1,4-dioxane (1.0 ml), to obtain the desired compound (0.28 g, yield: 89%) as a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: a-3.84 (3H, s), of 5.48 (2H, s), 7,01 (1H, DD, J=2,2, 8,8 Hz), 7,22-7,28 (2H, m), 7,32 is 7.50 (4H, m), 7,60 (3H, s), 7,72 (1H, d, J=8.6 Hz).

MS (FAB) m/z: 443 (M+H)+.

Analyte. calculated for C23H17F3N2Osub> 4+0,10 HCl: C, 61,93; H, 3,86; F, 12,78; N, 6,28; Cl, 0,79. Found C, 61,78; H, 3,85; F, 12,55; N, 6,37; Cl, 0,83.

(Example 37) 3-{[6-(3-Fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-186)

(37a) of tert-Butyl [5-(3-fluoro-4-methylphenoxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 3-fluoro-4-METHYLPHENOL (0,93 g, 7.4 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (2.0 g, 7.0 mmol), sodium hydride (>56% in oil, 0,29 g, 7.4 mmol) and N,N-dimethylformamide (20 ml). The obtained yellow oil was directly used for the next reaction.

(37b) tert-Butyl [2-amino-5-(3-fluoro-4-methylphenoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(3-fluoro-4-methylphenoxy)-2-nitrophenyl]methylcarbamate obtained in example (37a) (2.6 g, 7.0 mmol), iron powder (1.9 g, 35 mmol), ammonium chloride (0,19 g, 3.5 mmol), ethanol (20 ml) and water (10 ml). The oil obtained directly used for the next reaction.

(37c) [6-(3-Fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

The reaction and post treatment were carried out according to example (34c)using tert-butyl [2-amino-5-(3-fluoro-4-methylphenoxy)phenyl]methylcarbamate obtained in example (37b) (2.4 g, 7.0 mmol), glycolic acid (0,80 g, 10 mmol), 5 n hydrochloric acid (20 ml) and 1,4-dioxane (20) - Rev. l), to obtain the desired compound (1.6 g, yield: 81%) as a pale brown solid.

1H-NMR (CDCl3, 400 MHz) δ: 2,24 (3H, d, J=2.0 Hz), 3,76 (3H, s), the 4.90 (2H, s), 6,63-6,72 (2H, m), 6,92-7,01 (2H, m), 7,11 (1H, t, J=9.0 Hz), the 7.65 (1H, d, J=8.6 Hz).

(37d) Methyl 3-{[6-(3-fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(3-fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (37 ° C) (0.25 g, 0.88 mmol), methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butylphosphine (of 0.44 ml, 1.8 mmol), 1,1'-(azodicarbon)dipiperidino (of 0.44 g, 1.8 mmol) and dichloromethane (4 ml)with obtaining the desired compound (0,30 g, yield: 82%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: 2,24 (3H, d, J=1.6 Hz), 3,82 (3H, s)to 3.92 (3H, s), of 5.40 (2H, s), 6,66-of 6.71 (2H, m), 6,98? 7.04 baby mortality (2H, m), 7,11 (1H, t, J=9.0 Hz), 7,27-to 7.32 (1H, m), 7,38 (1H, t, J=8.0 Hz), to 7.67-of 7.70 (1H, m), 7,71 to 7.75 (2H, m).

MS (FAB) m/z: 421 (M+H)+.

(37e) 3-{[6-(3-Fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(3-fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (37d) (0,30 g to 0.72 mmol), 1 N. aqueous sodium hydroxide solution (1.1 ml, 1.1 mmol) and 1,4-dioxane (1.0 ml), to obtain the desired compound (0.27 g, yield: 94%) in VI is e white solids.

1H-NMR (DMSO-d6, 400 MHz) δ: 2,18 (3H, s), 3,82 (3H, s), vs. 5.47 (2H, s), 6,72 (6H, DD, J=2,4, 8.6 Hz), to 6.80 (6H, DD, J=2,5 and 11.1 Hz), 6,95 (6H, DD, J=2,4, 8.6 Hz), 7,25 (6H, t, J=8.6 Hz), 7,35-7,40 (2H, m), of 7.36 (1H, d, J=2,4 Hz), was 7.45 (1H, t, J=7.8 Hz), 7,58 (1H, d, J=7.8 Hz), to 7.67 (1H, d, J=8.6 Hz), 7,63-of 7.69 (1H, m), 13,08 (1H, users).

MS (FAB) m/z: 407 (M+H)+.

Analyte. calculated for C23H19FN2O4: C, 67,97; H, 4,71, F, OF 4.67; N, 6.89 IN. Found C, 67,58; H, 4,63, F, Of 4.67; N, 6,91.

(Example 38) 3-{[6-(3-Chloro-5-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-207)

(38a) of tert-Butyl [5-(3-chloro-5-pertenece)-2-nitrophenyl]methylcarbamate

Required is specified in the header connection (7,94 g, yield: 99%) was obtained as a yellow powder in accordance with the method described in example (31a), using 3-chloro-5-terfenol (2,93 g, 20 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (5.73 g, 20 mmol) and sodium hydride (56%, from 0.76 g, 20 mmol).

1H-NMR (CDCl3, 400 MHz) δ: of 1.33 (6H, s)and 1.51 (3H, s), or 3.28 (3H, s), 6,74 (1H, dt, J=2,4, and 9.0 Hz), 6.90 to-6,93 (3H, m), 7,00 (1H, d, J=7.8 Hz), 7,98 (1H, d, J=8.6 Hz).

(38b) of tert-Butyl [2-amino-5-(3-chloro-5-pertenece)phenyl]methylcarbamate

Required is specified in the header connection (7,34 g, yield: 99%) was obtained as a brown oil in accordance with the method described in example (31b), using tert-butyl [5-(3-chloro-5-pertenece)-2-nitrophenyl]methylcarbamate obtained in example (38a) (7,94 g, 20 mmol)and iron powder (5,59 g, 100 mmol).

sup> 1H-NMR (CDCl3, 400 MHz) δ: of 1.42 (9H, s)and 3.15 (3H, s), 3,74 (2H, users), 6,53 (1H, d, J=9.8 Hz), 6,68-PC 6.82 (4H, m),? 7.04 baby mortality (1H, DD, J=2,0, 8.6 Hz).

(38c) [6-(3-Chloro-5-pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol

Required is specified in the header connection (2,99 g, yield: 49%) was obtained as a white powder in accordance with the method described in example (31c), using tert-butyl [2-amino-5-(3-chloro-5-pertenece)phenyl]methylcarbamate obtained in example (38b) (7,34 g, 20 mmol)and glycolic acid (3.04 from g, 40 mmol).

1H-NMR (CDCl3, 400 MHz) δ: of 3.80 (3H, s), 4,91 (2H, s), to 6.58 (1H, dt, J=2,4, 10,2 Hz), 6,98-7,02 (2H, m), 7.23 percent (1H, DD, J=2.0 a, and 9.4 Hz), 7,32 (1H, d, J=2.0 Hz), of 7.70 (1H, d, J=8.6 Hz).

(38d) Methyl 3-{[6-(3-chloro-5-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Required specified in the header of the connection (of 1.30 g, yield: 32%) was obtained as a white powder in accordance with the method described in example (31d)using [6-(3-chloro-5-pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (38c) (2,99 g of 9.75 mmol), methyl 3-hydroxybenzoate (2,22 g, 14.6 mmol), tri-n-butylphosphine (3.94 g, a 19.5 mmol) and 1,1'(azodicarbon)dipiperidino (4,92 g of 19.5 mmol).

1H-NMR (CDCl3, 400 MHz) δ: a 3.87 (3H, s), 3,93 (3H, s), 5,42 (2H, s), 6,59 (1H, dt, J=2,4, or 9.8 Hz), to 6.75 (1H, s) to 6.80 (1H, dt, J=2,4, and 7.8 Hz), 7,03 (1H, DD, J=2,0, 8.6 Hz), 7,07 (1H, d, J=2.4 Hz), 7,31 (1H, DDD, J=1,2, 2,7, 8,2 Hz), 7,39 (1H, t, J=7.8 Hz), of 7.70 (1H, DD, J=1,2, 7,8 Hz), 7,74 (1H, s), 7,79 (1H, d, J=8.6 Hz).

(38e) 3-[6-(3-Chloro-5-pertenece)-1-methyl-1H-benzoni the azole-2-ylethoxy]benzoic acid

Required is listed in the title compound (1.26 g, yield: 86%) was obtained as a white powder in accordance with the method described in example (33e), using methyl 3-{[6-(3-chloro-5-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example in example (38d) (1.30 grams, 2,95 mmol).

1H-NMR (DMSO-d6, 400 MHz) δ: a-3.84 (3H, s), of 5.48 (2H, s), 6,83-6,86 (2H, m), 7,02 (1H, DD, J=2,4, and 9.0 Hz), to 7.15 (1H, dt, J=2,0, 8.6 Hz), 7,39 (1H, DDD, J=1,2, 2,4, 8,2 Hz), was 7.45 (1H, t, J=7.4 Hz), 7,49 (1H, d, J=2.4 Hz), 7,58 (1H, dt, J=1,2, 7,4 Hz), the 7.65 (1H, DD, J=1,2, 2,4 Hz), 7,72 (1H, d, J=8.6 Hz), 13,04 (1H, s).

MS (FAB+) m/z: 427 (M+H)+.

TPL: 209-213°C.

(Example 39) 3-{[6-(3,5-Divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-181)

(39a) of tert-Butyl [5-(3,5-divergence)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 3,5-diferena (2.9 g, 22 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (6.0 g, 21 mmol), sodium hydride (>56% in oil, 0.88 g, 22 mmol) and N,N-dimethylformamide (30 ml). The obtained yellow solid was directly used for the next reaction.

(39b) tert-Butyl [2-amino-5-(3,5-divergence)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(3,5-divergence)-2-nitrophenyl]methylcarbamate obtained in example (39a) (8,4 g, 22 mmol), iron powder (5.9 g, 110 mmol), ammonium chloride (0,59 is, 11 mmol), ethanol (30 ml) and water (15 ml). The obtained red-brown solid is directly used for the next reaction.

(39c) [6-(3,5-Divergence)-1-methyl-1H-benzimidazole-2-yl]methanol

The reaction and post treatment were carried out according to example (34c)using tert-butyl [2-amino-5-(3,5-divergence)phenyl]methylcarbamate obtained in example (39b) (7.7 g, 22 mmol), glycolic acid (2.5 g, 33 mmol), 5 n hydrochloric acid (40 ml) and 1,4-dioxane (40 ml), to obtain the desired compound (4.5 g, yield: 69%) of a pale gray solid.

1H-NMR (CDCl3, 400 MHz) δ: of 3.80 (3H, s)to 4.92 (2H, s), 6.42 per-6,55 (3H, m), 7,00 (1H, DD, J=2,4, 8.6 Hz),? 7.04 baby mortality (1H, d, J=2.4 Hz), 7,71 (1H, d, J=8.6 Hz).

(39d) Methyl 3-{[6-(3,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(3,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (39c) (0.25 g, 0.88 mmol), methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butylphosphine (of 0.44 ml, 1.8 mmol), 1,1'-(azodicarbon)dipiperidino (of 0.44 g, 1.8 mmol) and dichloromethane (4.0 ml), to obtain the desired compound (0.32 g, yield: 86%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: 3,86 (3H, s)to 3.92 (3H, s), 3,93 (9H, s)5,41 (2H, s), 6,44-6,55 (2H, m), 7,03 (1H, DD, J=2,2, 8,8 Hz), 7,07 (1H, d, J=2.4 Hz), 7,27-7,33 (2H, m), 7,39 (1H, t, J=7.8 Hz), to 7.67-7,71 (1H, is), 7,73 (1H, DD, J=1,4, 2,5 Hz), 7,78 (1H, d, J=8.6 Hz).

(39e) 3-{[6-(3,5-Divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(3,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (39d) (0.32 g, 0.75 mmol), 1 N. aqueous sodium hydroxide solution (1.9 ml, 1.9 mmol) and 1,4-dioxane (1.5 ml), to obtain the desired compound (0,23 g, yield: 76%) as a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: of 3.85 (3H, s), vs. 5.47 (2H, s), 6,69 (2H, DD, J=2,2, 8,8 Hz), to 6.95 (1H, TT, J=2,2, and 9.3 Hz), 7,02 (1H, DD, J=2,4, 8.6 Hz), 7,30 and 7.36 (1H, m), 7,42 (1H, t, J=7.8 Hz), of 7.48 (1H, d, J=2.4 Hz), EUR 7.57 (1H, d, J=7,4 Hz), 7,63 (1H, DD, J=1,6, 2.4 Hz), 7,72 (1H, d, J=8.6 Hz).

MS (FAB) m/z: 411 (M+H)+.

Analyte. calculated for C22H16F2N2O4+1,00H2O: C, 61,68; H, 4,24; F, 8,87; N, 6,54. Found C, 61,58; H, 3,95, F, 9,06; N, 6,51.

(Example 40) 3-{[6-(3-Fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-188)

(40a) 1-Fluoro-3-methoxy-5-methylbenzoyl

A mixed solution of 3-bromo-5-fernicola (2,05 g, 10 mmol), trimethylboroxine (50% solution in THF, of 2.51 g, 20 mmol), PdCl2(dppf) (0,82 g, 1.0 mmol) and cesium carbonate (6,52 g, 20 mmol) in dioxane (100 ml) and water (50 ml) was stirred at reflux for 10 hours. Allowing the reaction solution to cool, was added to the reaction races the thief water (100 ml) followed by extraction with ethyl acetate (200 ml) twice. The organic layers were washed with water (100 ml) twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure the residue was purified by chromatography on silica gel (hexane:ethyl acetate, 6:1) to obtain the specified title compound (1.40 g, yield: 66%) as a yellow oil.

1H-NMR (CDCl3, 400 MHz) δ: 1,78 (3H, s), 6,44 (1H, DD, J=2.0 a, and 11.0 Hz), 6,50 (1H, d, J=11,0 Hz), 6,51 (1H, s).

(40b) 3-Fluoro-5-METHYLPHENOL

A solution of 1-fluoro-3-methoxy-5-methylbenzene obtained in example (40a) (0,92 g, 6,56 mmol), and tribromide boron (1.0 M solution in methylene chloride, 8.53 ml, 8,53 mmol) in methylene chloride (20 ml) was stirred at 0°C for 10 hours. To the reaction solution were added water (100 ml) followed by extraction with methylene chloride (100 ml). Then the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure the residue was purified by chromatography on silica gel (hexane:ethyl acetate, 1:1) to obtain specified in the connection header (0,83 g, yield: 99%) as a yellow oil.

1H-NMR (CDCl3, 400 MHz) δ: to 2.06 (3H, s), equal to 4.97 (1H, s), 6,37 (1H, dt, J=2,4, 10,2 Hz), 6,44 (1H, s), 6.48 in (1H, d, J=8.6 Hz).

(40c) tert-Butyl [5-(3-fluoro-5-methylphenoxy)-2-nitrophenyl]methylcarbamate

Required is specified in the header connection (1,71 g, yield: 69%) was obtained as a yellow oil according to the method described in example (31a), using 4-fluoro-5-ethylphenol, obtained in example (40b) (0,83 g, 6,56 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (1.88 g, 6,56 mmol) and sodium hydride (56%, 0.25 g, 6,56 mmol).

1H-NMR (CDCl3, 400 MHz): δ of 1.33 (6H, s)and 1.51 (3H, s), of 2.38 (3H, s), with 3.27 (3H, s), 6,63 (1H, dt, J=2,4, and 9.4 Hz), of 6.71 (1H, s), to 6.80 (1H, d, J=8.6 Hz), 6,86-to 6.88 (2H, m), 7,95 (1H, d, J=8,2 Hz).

(40d) tert-Butyl [2-amino-5-(3-fluoro-5-methylphenoxy)phenyl]methylcarbamate

Required is specified in the header connection (1,38 g, yield: 88%) was obtained as a yellow oil according to the method described in example (31b), using tert-butyl [5-(3-fluoro-5-methylphenoxy)-2-nitrophenyl]methylcarbamate obtained in example (40c) (1,71 g of 4.54 mmol)and iron powder (1.27 g, 22.7 mmol).

1H-NMR (CDCl3, 400 MHz) δ: of 1.41 (9H, s)to 2.29 (3H, s)and 3.15 (3H, s), 3,70 (2H, users), 6.42 per-6,56 (3H, m), 6.75 in-6,83 (3H, m).

(40e) [6-(3-Fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

Required is specified in the header connection (0,76 g, yield: 67%) was obtained as pale brown oil in accordance with the method described in example (31c), using tert-butyl [2-amino-5-(3-fluoro-5-methylphenoxy)phenyl]methylcarbamate obtained in example (40d) (1,38 g, 3,98 mmol)and glycolic acid (0,61 g of 7.97 mmol).

1H-NMR (CDCl3, 400 MHz) δ: 2,31 (3H, s), of 3.78 (3H, s)to 4.92 (2H, s), of 6.49 (1H, dt, J=2.0 a, 10,2 Hz), to 6.58 (1H, s), is 6.61 (1H, d, J=11,0 Hz), 6,99-7,01 (2H, m), of 7.69 (1H, d, J=9.4 Hz).

(40f) Methyl 3-{[6-(3-fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Required is specified in the header connection (0,82 g, yield: 74%) was obtained as a white powder in accordance with the method described in example (31d)using [6-(3-fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (40e) (0,76 g, to 2.65 mmol), methyl 3-hydroxybenzoate (0,61 g, 3,98 mmol), tri-n-butylphosphine (1.07 g, 5,31 mmol) and 1,1'(azodicarbon)dipiperidino (1,34 g, 5,31 mmol).

1H-NMR (CDCl3, 400 MHz) δ: 2,30 (3H, s), of 3.84 (3H, s), 3,93 (3H, s), of 5.40 (2H, s), of 6.49 (1H, dt, J=2,4, 10,2 Hz), to 6.58 (1H, s), 6,60 (1H, d, J=a 10.6 Hz), 7,00-7,03 (2H, m), 7,28-7,31 (1H, m), 7,38 (1H, t, J=7.8 Hz), 7,68 (1H, dt, J=1,6, 8.6 Hz), 7,72-7,76 (2H, m).

(40g) 3-{[6-(3-Fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required is listed in the title compound (0.55 g, yield: 73%) was obtained as a white powder in accordance with the method described in example (33e), using methyl 3-{[6-(3-fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example in example (40f) (0,82 g of 1.86 mmol).

1H-NMR (DMSO-d6, 400 MHz) δ: of 2.25 (3H, s), 3,83 (3H, s), vs. 5.47 (2H, s), 6,58-6,60 (2H, m), of 6.75 (1H, d, J=a 10.6 Hz), of 6.96 (1H, DD, J=2,4, 8.6 Hz), 7,37-7,39 (2H, m), 7,45 (1H, t, J=7.4 Hz), EUR 7.57 (1H, dt, J=1,2, 7,8 Hz), to 7.64 (1H, DD, J=1,2, 2,4 Hz), to 7.68 (1H, d, J=8.6 Hz), 13,03 (1H, s).

MS (FAB+) m/z: 407 (M+H)+.

TPL: 224-226°C.

(Example 41) 3-{[6-(2,5-Divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-179)

(41a) of tert-Butyl [5-(2,5-divergence)-2-nitrophe the Il]methylcarbamate

The reaction and post treatment were carried out according to example (28a)using 2.5-diferena (5,1 g, 38 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (9,8 g, 34 mmol), sodium hydride (>56% in oil, 1.5 g, 38 mmol) and N,N-dimethylformamide (90 ml), to obtain the desired compound (12 g, yield: 92%) as a yellow solid.

1H-NMR (CDCl3, 400 MHz) δ: 1,32 (6H, s)of 1.50 (3H, users), or 3.28 (3H, s), for 6.81-7,07 (4H, m), 7,17-7,26 (1H, m), of 7.96 (1H, d, J=9.0 Hz).

(41b) of tert-Butyl [2-amino-5-(2,5-divergence)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(2,5-divergence)-2-nitrophenyl]methylcarbamate obtained in example (41a) (12 g, 31 mmol), iron powder (8,4 g, 160 mmol), ammonium chloride (0.84 g, 16 mmol), ethanol (30 ml) and water (15 ml). The obtained red-brown solid is directly used for the next reaction.

(41c) [6-(2,5-Divergence)-1-methyl-1H-benzimidazole-2-yl]methanol

The reaction and post treatment were carried out according to example (34c)using tert-butyl [2-amino-5-(2,5-divergence)phenyl]methylcarbamate obtained in example (41b) (11 g, 31 mmol), glycolic acid (3.6 g, 47 mmol), 5 n hydrochloric acid (40 ml) and 1,4-dioxane (40 ml), to obtain the desired compound (7.6 g, yield: 83%) as a pale brown solid.

1H-NMR (CDC 3, 400 MHz) δ: of 3.77 (3H, s), 4,91 (2H, s), 6,60-of 6.71 (1H, m), of 6.71-PC 6.82 (1H, m), 6,97-7,06 (2H, m), 7,09-7,21 (1H, m), 7,68 (1H, d, J=9.0 Hz).

(41d) of Methyl 3-{[6-(2,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(2,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (41c) (0.25 g, 0.86 mmol), methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butylphosphine (of 0.43 ml, 1.7 mmol), 1,1'-(azodicarbon)dipiperidino (of 0.43 g, 1.7 mmol) and dichloromethane (4.0 ml), to obtain the desired compound (0.28 g, yield: 78%) as a white solid.

1H-NMR (CDCl3, 400 MHz): δ MMD: a-3.84 (3H, s)to 3.92 (3H, s), of 5.40 (2H, s), 6,65-of 6.71 (1H, m), 6.73 x-to 6.80 (1H, m), 7,01-7,05 (2H, m), 7,11-to 7.18 (1H, m), 7,29 (1H, DD, J=2,7, 8,2 Hz), 7,38 (1H, t, J=8.0 Hz), to 7.67-to 7.77 (3H, m).

(41e) 3-{[6-(2,5-Divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(2,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (41d) (0.28 g, 0.67 mmol), 1 N. aqueous sodium hydroxide solution (1.0 ml, 1.0 mmol) and 1,4-dioxane (1.0 ml), to obtain the desired compound (0.25 g, yield: 91%) as a white solid.

1H-NMR (DMSO-d6, 500 MHz) δ: a 3.83 (3H, s), vs. 5.47 (2H, s), 6,88-to 6.95 (1H, m), 6,98-7,05 (2H, m), 7,38 (2H, s), 7,41-of 7.48 (2H, m), 7,58 (1H, d, J=7,3 Hz), 7,63 (1H, s), to 7.68 (1H, d, J=8,8 Hz), 13,03 (1H, ears is .c).

MS (FAB) m/z: 411 (M+H)+.

Analyte. calculated for C22H16F2N2O4+0,25H2O: C, 63,69; H, 4,01; F, 9,16; N, 6.75 IN. Found C, 63,84; H, 4,05; F, Which 9.22; N, 6,83.

(Example 42) 3-{[6-(3-Ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-170)

(42a) of tert-Butyl [5-(3-ethylenoxy)-2-nitrophenyl]methylcarbamate

Required is listed in the title compound (20.5 g, yield: 97%) was obtained as a yellow oil according to the method described in example (31a), using 3-ethylphenol (6,72 g, 55 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (14,19 g, a 49.5 mmol) and sodium hydride (56%, 2.10 g, 55,0 mmol).

1H-NMR (CDCl3, 400 MHz) δ: of 1.27 (3H, t, J=7.4 Hz), of 1.33 (6H, s)of 1.50 (3H, s), 2,69 (2H, square, J=7,4 Hz), 3,26 (3H, s), 6,82-6,94 (4H, m), 7,11 (1H, d, J=7,0 Hz), 7,35 (1H, t, J=7.4 Hz), 7,94 (1H, d, J=8.6 Hz).

(42b) of tert-Butyl [2-amino-5-(3-ethylenoxy)phenyl]methylcarbamate

Required is listed in the title compound (18.2 g, yield: 99%) was obtained as pale brown oil in accordance with the method described in example (31b), using tert-butyl [5-(3-ethylenoxy)-2-nitrophenyl]methylcarbamate obtained in example (42a) (19,8 g, 53.2 mmol) and iron powder (14.9 g, 266 mmol).

1H-NMR (CDCl3, 400 MHz) δ: 1,22 (3H, t, J=7.4 Hz), and 1.56 (9H, s), 2,61 (2H, square, J=7,4 Hz)and 3.15 (3H, s), 3,66 (2H, users), 6.73 x-6,84 (5H, m), to 6.88 (1H, d, J=7,4 Hz), 7,19 (1H, t, J=7,8 Hz).

(42c) [6-(3-Ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

Demand is specified in the title compound (15.0 g, yield: 83%) was obtained as a brown powder in accordance with the method described in example (31c), using tert-butyl [2-amino-5-(3-ethylenoxy)phenyl]methylcarbamate obtained in example (42b) (18.2 g, 53.2 mmol)and glycolic acid (8,09 g, 106 mmol).

1H-NMR (CDCl3, 400 MHz) δ: of 1.23 (3H, t, J=7.8 Hz), 2,63 (2H, square, J=7,4 Hz), of 3.77 (3H, s)4,08 (2H, s), to 6.80 (1H, DD, J=2.0 a, 8,2 Hz), 6,86 (1H, s), 6,94-to 6.95 (2H, m), 6,98 (1H, DD, J=2,4, and 9.0 Hz), 7,24 (1H, t, J=7.8 Hz), a 7.62 (1H, d, J=8.6 Hz).

(42d) of Methyl 3-{[6-[3-ethylenoxy]-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Required is listed in the title compound (18.5 g, yield: 80%) was obtained as a pale yellow oil in accordance with the method described in example (31d)using [6-(3-ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (42c) (12.5 g, 44,3 mmol), methyl 3-hydroxybenzoate (10.1 g, with 66.5 mmol), tri-n-butylphosphine (17.9 g, 88.7 mmol) and 1,1'-(azodicarbon)dipiperidino (22,4 g, 88.7 mmol).

1H-NMR (CDCl3, 400 MHz) δ: of 1.23 (3H, t, J=7.8 Hz), 2,63 (2H, square, J=7,4 Hz), 3,82 (3H, s), 3,93 (3H, s), of 5.40 (2H, s), PC 6.82 (1H, DD, J=2,4, and 8.2 Hz), 6.87 in (1H, s), to 6.95 (1H, d, J=7,0 Hz), 7,01 (1H, d, J=2.4 Hz), 7,03 (1H, DD, J=2,4, 8.6 Hz), 7.23 percent (1H, d, J=7.8 Hz), 7,29-to 7.32 (1H, m), 7,38 (1H, t, J=7.4 Hz), of 7.70 (1H, d, J=7,4 Hz), 7,72-7,74 (2H, m).

(42e) 3-{[6-(3-Ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required is listed in the title compound (14.2 g, yield: 83%) was obtained as a white powder in accordance with the method described in the example is (33e), using methyl 3-{[6-[3-ethylenoxy]-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example in example (42d) (14,7 g, 35,3 mmol).

1H-NMR (DMSO-d6, 400 MHz) δ: 1,15 (3H, t, J=7.4 Hz), to 2.57 (2H, square, J=7,4 Hz), 3,81 (3H, s), vs. 5.47 (2H, s)6,76 (1H, DD, J=2,4, and 8.2 Hz), at 6.84 (1H, s), 6,92-9,95 (2H, m), 7,25 (1H, t, J=7.8 Hz), 7,32 (1H, d, J=2.4 Hz), 7,37-7,40 (1H, m), 7,45 (1H, t, J=7.8 Hz), 7,58 (1H, d, J=7,4 Hz), 7,63-the 7.65 (1H, m), 7,66 (1H, d, J=8.6 Hz), 13,03 (1H, users).

MS (FAB+) m/z: 403 (M+H)+.

TPL: 204-208°C.

(Example 43) 3-{[6-(2,4-Divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-178)

(43a) 5-(2,4-Divergence)-N-methyl-2-nitroaniline

The synthesis was carried out in the same way as in example (28a)using 2,4-diferena (5.2 g, 38 mmol), 5-chloro-N-methylnitramine (6.5 g, 35 mmol), sodium hydride (>56% in oil, 1.8 g, 46 mmol) and N,N-dimethylformamide (80 ml). The obtained yellow solid was directly used for the next reaction.

(43b) 4-(2,4-Divergence)-2-N-methylenedianiline

The synthesis was carried out in the same way as in example (28b)using 5-(2,4-divergence)-N-methyl-2-nitroaniline (9,8 g, 35 mmol)obtained in example (43a), iron powder (9.3 g, 170 mmol), ammonium chloride (0,93 g, 17 mmol), ethanol (30 ml) and water (15 ml). The obtained red-brown oil is directly used for the next reaction.

(43c) [6-(2,4-Divergence)-1-methyl-1H-benzimidazole-2-yl]methanol

The reaction and subsequent the General processing was carried out according to example (34c), using 4-(2,4-divergence)-2-N-methylenedianiline obtained in example (43b) (2.4 g, 7.0 mmol), glycolic acid (3.1 g, 41 mmol), 5 n hydrochloric acid (40 ml) and 1,4-dioxane (40 ml), to obtain the desired compound (7.7 g, yield: 76%) as a reddish-gray solid.

1H-NMR (CDCl3, 400 MHz) δ: 3,74 (3H, s), 4,58 (1H, users), to 4.87 (2H, s), 6,79-of 6.90 (2H, m), 6.90 to-7,07 (3H, m), to 7.61 (1H, d, J=8.6 Hz).

(43d) Methyl 3-{[6-(2,4-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(2,4-divergence)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (43c) (0.25 g, 0.86 mmol), methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butylphosphine (of 0.43 ml, 1.7 mmol), 1,1'-(azodicarbon)dipiperidino (of 0.43 g, 1.7 mmol) and dichloromethane (4.0 ml), to obtain the desired compound (0.31 g, yield: 84%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: 3,81 (3H, s)to 3.92 (3H, s), of 5.39 (2H, s), for 6.81-to 6.88 (1H, m), 6.90 to (1H, d, J=2.4 Hz), 6,94-7,07 (3H, m), 7,29 (1H, d, J=1.6 Hz), 7,37 (1H, t, J=8,2 Hz), 7,66-7,76 (3H, m).

MS (FAB) m/z: 425 (M+H)+.

(43e) 3-{[6-(2,4-Divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(2,4-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (43d) (0.31 g, 0.73 m is ol), 1 N. aqueous sodium hydroxide solution (1.2 ml, 1.2 mmol) and 1,4-dioxane (1.0 ml), to obtain the desired compound (0.14 g, yield: 48%) as a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: of 3.80 (3H, s), the 5.45 (2H, s), 6,93 (1H, DD, J=2.5 a, 8,8 Hz), 7,05 for 7.12 (1H, m), 7,19 (1H, dt, J=5,9, 9,2 Hz), 7,25 (1H, d, J=2.4 Hz), 7,32-7,37 (1H, m), the 7.43 (1H, t, J=of 7.82 Hz), 7,44-7,51 (1H, m), 7,54-to 7.59 (1H, m), a 7.62 (1H, DD, J=1,4, 2,5 Hz), to 7.64 (1H, d, J=8.6 Hz).

MS (FAB) m/z: 411 (M+H)+.

Analyte. calculated for C22H16F2N2O4+0,50H2O: C, 63,01; H, 4.09 TO; F, 9,06; N, 6,68. Found C, 63,13; H, 3,86; F, 9,20; N, 6,70.

(Example 44) 3-{[1-Methyl-6-(2-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-166)

(44a) of tert-Butyl methyl[5-(2-methylphenoxy)-2-nitrophenyl]carbamate

The crude product of the desired specified in the title compound was obtained as brown oil in accordance with the method described in example (28a)using 2-METHYLPHENOL (4,53 g, a 41.9 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (10.0 g, is 34.9 mmol) and sodium hydride (63%, of 1.59 g of 41.9 mmol). The crude product is directly used for the next reaction.

(44b) of tert-Butyl [2-amino-5-(2-methylphenoxy)phenyl]methylcarbamate

The crude product of the desired specified in the title compound was obtained as brown oil in accordance with the method described in example (28b)using tert-butyl methyl[5-(2-methyl is enocsi)-2-nitrophenyl]carbamate, obtained in example (44a) (12.5 g, is 34.9 mmol), iron powder (9,74 g, 174 mmol) and ammonium chloride (0,933 g of 17.4 mmol). The crude product is directly used for the next reaction.

(44c) [1-Methyl-6-(2-methylphenoxy)-1H-benzimidazole-2-yl]methanol

Required specified in the header of the connection (of 6.71 g, yield: 72%) was obtained as a brown powder in accordance with the method described in example (28c)using tert-butyl [2-amino-5-(2-methylphenoxy)phenyl]methylcarbamate obtained in example (44b) (11.5g, is 34.9 mmol)and glycolic acid (3.98 g, 52,3 mmol).

1H NMR (CDCl3, 400 MHz) δ: 2,28 (3H, s), of 3.73 (3H, s), a 4.86 (2H, s), to 6.80 (1H, d, J=2.0 Hz), 6,83-6,87 (1H, m)6,91 (1H, DD, J=2,0, 8.6 Hz), 7.03 is-was 7.08 (1H, m), 7,12-to 7.18 (1H, m), 7.24 to 7,29 (1H, m), to 7.59 (1H, d, J=8.6 Hz).

(44d) Methyl 3-{[1-methyl-6-(2-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoate

Required is specified in the header connection (7,33 g, yield: 81%) was obtained as a white powder in accordance with the method described in example (28d)using [1-methyl-6-(2-methylphenoxy)-1H-benzimidazole-2-yl]methanol obtained in example (44c) (6,00 g of 22.4 mmol), methyl 3-hydroxybenzoate (4,08 g, 26.8 mmol), tri-n-butylphosphine (scored 8.38 ml, of 33.5 mmol) and 1,1'-(azodicarbon)dipiperidino (8,46 g of 33.5 mmol).

1H NMR (CDCl3, 400 MHz) δ: to 2.29 (3H, s), with 3.79 (3H, s)to 3.92 (3H, s)5,38 (2H, s), at 6.84 (1H, d, J=2.3 Hz), to 6.88 (1H, d, J=8,2 Hz), 6,97 (1H, DD, J=2,3, 9.0 Hz),? 7.04 baby mortality-7,10 (1H, m), 7,13-7,19 (1H, m), 7,25-to 7.32 (2H, m), 7,37 (1H, t, J=7.8 Hz), 7,667,73 (3H, m).

(44e) 3-{[1-Methyl-6-(2-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required is specified in the header connection (6,13 g, yield: 98%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-{[1-methyl-6-(2-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoate (6.50 g, 16.2 mmol)obtained in example (44d), and 1 N. aqueous sodium hydroxide solution (and 24.2 ml, and 24.2 mmol).

1H NMR (DMSO-d6, 500 MHz) δ: of 2.25 (3H, s), with 3.79 (3H, s), the 5.45 (2H, s), for 6.81 (1H, d, J=7.8 Hz), 6,86 (1H, DD, J=2,4, 8,8 Hz), 7,06 (1H, t, J=7,3 Hz), 7,14-7,21 (2H, m), 7,32 (1H, d, J=7,3 Hz), of 7.36-7,41 (1H, m), 7,45 (1H, t, J=8.1 Hz), EUR 7.57 (1H, d, J=7,3 Hz), 7,63 (2H, d, J=8,3 Hz), 13,03 (1H, s).

MS (FAB) m/z: 389 (M+H)+.

(Example 45) 3-{[6-(2-Fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-184)

(45a) of tert-Butyl [5-(2-fluoro-5-methylphenoxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 2-fluoro-5-METHYLPHENOL (5,1 g, 40 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (10 g, 36 mmol), sodium hydride (>56% in oil, 1.6 g, 40 mmol) and N,N-dimethylformamide (70 ml). The obtained yellow oil was directly used for the next reaction.

(45b) tert-Butyl [2-amino-5-(2-fluoro-5-methylphenoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(2-fluoro-5-methylphenoxy)-2-nitrophenyl]METI the carbamate, obtained in example (45a) (15 g, 40 mmol), iron powder (11 g, 200 mmol), ammonium chloride (1.1 g, 20 mmol), ethanol (30 ml) and water (15 ml). The oil obtained directly used for the next reaction.

(45c) [6-(2-Fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

The reaction and post treatment were carried out according to example (34c)using tert-butyl [2-amino-5-(2-fluoro-5-methylphenoxy)phenyl]methylcarbamate obtained in example (45b) (15 g, 40 mmol), glycolic acid (4.0 g, 52 mmol), 5 n hydrochloric acid (30 ml) and 1,4-dioxane (30 ml), to obtain the desired compound (8.0 g, yield: 70%) as a pale brown solid.

1H-NMR (CDCl3, 400 MHz) δ: of 2.27 (3H, in), 3.75 (3H, s), 4,89 (2H, s), 6,78-6,84 (1H, m), 6,85-6,91 (1H, m), 6,92 (1H, d, J=2.4 Hz), 6,98 (1H, DD, J=2,2, 8,8 Hz), 7,07 (1H, DD, J=8,6, a 10.6 Hz), to 7.64 (1H, d, J=9.0 Hz).

(45d) Methyl 3-{[6-(2-fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(2-fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (45c) (0.25 g, were 0.94 mmol), methyl 3-hydroxybenzoate (0.16 g, 1.0 mmol), tri-n-butylphosphine (of 0.47 ml, 1.9 mmol), 1,1'-(azodicarbon)dipiperidino (of 0.47 g, 1.9 mmol) and dichloromethane (4 ml)with obtaining the desired compound (0.20 g, yield: 49%) as a white solid.

1H-NMR (CDCl3 , 400 MHz) δ: of 2.27 (3H, s), 3,82 (3H, s)to 3.92 (3H, s), of 5.39 (2H, s), PC 6.82 (1H, s), 6,86-6,92 (1H, m), to 6.95 (1H, d, J=2.4 Hz), 7,01 (1H, DD, J=2,4, and 9.0 Hz), 7,07 (1H, DD, J=8,2, a 10.6 Hz), 7,28-7,31 (1H, m), 7,38 (1H, t, J=7.8 Hz), to 7.67-7,73 (3H, m).

MS (FAB) m/z: 421 (M+H)+.

(45e) 3-{[6-(2-Fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(2-fluoro-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (45d) (0.20 g, 0.46 mmol), 1 N. aqueous sodium hydroxide solution (to 0.70 ml, 0.70 mmol) and 1,4-dioxane (1.0 ml), to obtain the desired compound (0.18 g, yield: 95%) as a white solid matter.

1H-NMR (DMSO-d6, 400 MHz) δ: of 2.23 (3H, s), 3,81 (3H, s), 5,46 (2H, s), 6.87 in (1H, s), 6,93 (1H, DD, J=2,4, and 9.0 Hz), 6,94-6,99 (1H, m), 7,22-7,31 (2H, m), 7,39 (1H, s), 7,45 (1H, t, J=7.8 Hz), 7,58 (1H, d, J=7,4 Hz), a 7.62-7.68 per (2H, m).

MS (FAB) m/z: 407 (M+H)+.

Analyte. calculated for C23H19FN2O4+0,20H2O: C, 67,38; H, 4,77; F, 4,63; N, 6,83. Found C, 67,43; H, 4,71; F, 4,80; N, 6.87 In.

(Example 46) 3-{[6-(4-Fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-183)

(46a) of tert-Butyl [5-(4-fluoro-2-methylphenoxy)-2-nitrophenyl]methylcarbamate

The crude product of the desired specified in the title compound was obtained as brown oil in accordance with the method described in example (28a)using 4-fluoro-2-METHYLPHENOL (5,28 g, 41,9 m is ol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (10.0 g, is 34.9 mmol) and sodium hydride (63%, of 1.59 g of 41.9 mmol). The crude product is directly used for the next reaction.

(46b) tert-Butyl [2-amino-5-(4-fluoro-2-methylphenoxy)phenyl]methylcarbamate

The crude product of the desired specified in the title compound was obtained as brown powder in accordance with the method described in example (28b)using tert-butyl [5-(4-fluoro-2-methylphenoxy)-2-nitrophenyl]methylcarbamate obtained in example (46a) (13,1 g, is 34.9 mmol), iron powder (9,74 g, 174 mmol) and ammonium chloride (0,933 g of 17.4 mmol). The crude product is directly used for the next reaction.

(46c) [6-(4-Fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

Required is specified in the header connection (8,62 g, yield: 86%) was obtained as a brown powder in accordance with the method described in example (28c)using tert-butyl [2-amino-5-(4-fluoro-2-methylphenoxy)phenyl]methylcarbamate obtained in example (46b) (12.1 g, is 34.9 mmol)and glycolic acid (3.98 g, 52,3 mmol).

1H NMR (CDCl3, 400 MHz) δ: of 2.25 (3H, s), of 3.73 (3H, s), a 4.86 (2H, s), of 6.73 (1H, d, J=2.3 Hz), 6,84-of 6.90 (3H, m), of 6.96-7,00 (1H, m), to 7.59 (1H, d, J=8.6 Hz).

(46d) Methyl 3-{[6-(4-fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Required is specified in the header connection (8,49 g, yield: 77%) was obtained in sideblog powder in accordance with the method, described in example (28d)using [6-(4-fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (46c) (7.50 g, to 26.2 mmol), methyl 3-hydroxybenzoate (4,78 g of 31.4 mmol), tri-n-butylphosphine (a 7.85 ml, of 31.4 mmol) and 1,1'-(azodicarbon)dipiperidino (of 7.93 g of 31.4 mmol).

1H NMR (CDCl3, 400 MHz) δ: of 2.25 (3H, s), with 3.79 (3H, s)to 3.92 (3H, s)5,38 (2H, s), 6,77 (1H, d, J=2.3 Hz), 6,84-7,02 (4H, m), 7,25-7,33 (1H, m), 7,37 (1H, t, J=8.0 Hz), 7,66-7,74 (3H, m).

(46e) 3-{[6-(4-Fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required is specified in the header connection (6,48 g, yield: 89%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-{[6-(4-fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (46d) (7.50 g, 17.8 mmol), and 1 N. aqueous sodium hydroxide solution (26,8 ml, 26.8 mmol).

1H NMR (DMSO-d6, 400 MHz) δ: 2,22 (3H, s), of 3.78 (3H, s), the 5.45 (2H, s), 6,82-6,91 (2H, m), 6,98-7,05 (1H, m), 7,12 (1H, d, J=2.3 Hz), 7,20 (1H, DD, J=3.1 and 9.4 Hz), 7,35-7,40 (1H, m), 7,45 (1H, t, J=7.8 Hz), 7,55-to 7.59 (1H, m), 7,60-the 7.65 (2H, m), 13,03 (1H, s).

MS (FAB) m/z: 407 (M+H)+.

(Example 47) 3-{[6-(3-Fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-195)

(47a) of tert-Butyl [5-(3-fluoro-5-methoxyphenoxy)-2-nitrophenyl]methylcarbamate

The reaction and post treatment were carried out according to example (27a), using the known [WO 2005037763] 3-fluoro-5-metoxy the Nol (4.5 g, 32 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (7.7 g, 27 mmol), sodium hydride (>56% in oil, 1.3 g, 32 mmol) and N,N-dimethylformamide (60 ml), to obtain the desired compound (3.7 g, yield: 57%).

1H-NMR (CDCl3, 400 MHz) δ: 1,32 (6H, s)of 1.50 (3H, s), with 3.27 (3H, s), 3,81 (3H, s), 6,37-6,46 (2H, m), of 6.52 (1H, d, J=11,0 Hz), 6,86-of 6.96 (2H, m), to $ 7.91-8,03 (1H, m).

(47b) of tert-Butyl [2-amino-5-(3-fluoro-5-methoxyphenoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(3-fluoro-5-methoxyphenoxy)-2-nitrophenyl]methylcarbamate obtained in example (47a) (3.7 g, 9.5 mmol), iron powder (2.5 g, 47 mmol), ammonium chloride (0.25 g, 4.7 mmol), ethanol (30 ml) and water (15 ml). The obtained pale-brown oil directly used for the next reaction.

(47c) [6-(3-Fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

The reaction and post treatment were carried out according to example (34c)using tert-butyl [2-amino-5-(3-fluoro-5-methoxyphenoxy)phenyl]methylcarbamate obtained in example (47b) (3.1 g, 8,7 mmol), glycolic acid (0,86 g, 11 mmol), 5 n hydrochloric acid (10 ml) and 1,4-dioxane (10 ml), to obtain the desired compound (2.0 g, yield: 75%) as a pale brown solid.

1H-NMR (CDCl3, 400 MHz) δ: and 3.72 (3H, in), 3.75 (3H, s), the 4.90 (2H, d, J=5.5 Hz), is 6.54 (1H, DD, J=2,9, 6,8 Hz), 6,57-6,63 (1H, m), to 6.95 (1H, d, J=2.4 Hz), 7,00 (1H, DD, J=2,2, 8,8 Hz), 10 (1H, DD, J=9,0, to 10.6 Hz), 7,66 (1H, d, J=8.6 Hz).

(47d) Methyl 3-{[6-(3-fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(3-fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (47c) (0.35 g, 1.2 mmol), methyl 3-hydroxybenzoate (0,19 g, 1.3 mmol), tri-n-butylphosphine (of 0.58 ml, 2.3 mmol), 1,1'-(azodicarbon)dipiperidino (of 0.58 g, 2.3 mmol) and dichloromethane (4 ml)with obtaining the desired compound (0.31 g, yield: 60%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: 3,75 (3H, s), of 3.84 (3H, s), 3,93 (3H, s)5,41 (2H, s), 6,27 (1H, DDD, J=2,0, 2,2, 10,0 Hz), 6,32-6,37 (2H, m), 6,98-to 7.09 (2H, m), 7,30 (1H, DD, J=2,7, 8,2 Hz), 7,38 (1H, t, J=7.8 Hz), 7,69 (1H, dt, J=1,3, 7.5 Hz), 7,73 (1H, DD, J=1,4, 2,5 Hz), of 7.75 (1H, DD, J=1,2, 8,2 Hz).

MS (FAB) m/z: 437 (M+H)+.

(47e) 3-{[6-(3-Fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(3-fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (47d) (0.31 g, 0.70 mmol), 1 N. aqueous sodium hydroxide solution (1.1 ml, 1.1 mmol) and 1,4-dioxane (1.0 ml), to obtain the desired compound (0.20 g, yield: 67%) as a white solid matter.

1H-NMR (DMSO-d6, 400 MHz) δ: of 3.73 (3H, s), of 3.84 (3H, s), vs. 5.47 (2H, s)6,38 (1H, s), 6,33 (1H, dt, J=2,3, 10,3 Hz), 6,56 (1H, dt, J=2,4, 11,0 Hz), 6,98 (1H, DD, J=2,4, 8.6 Hz), 7,37-of 7.48 (3H, m), 7,58 (1H, d, J=7,4 Hz), to 7.64 (1H, s), of 7.69 (1H, d, J=8.6 Hz), 13,03 (1H, users).

MS (FAB) m/z: 423 (M+H)+.

Analyte. calculated for C23H19FN2O5+0,20H2O: C, 64,85; H, 4,59; F, TO 4.46; N, 6,58. Found C, 64,77; H, 4,50; F, 4,58; N, 6,65.

(Example 48) 3-{[6-(2-Fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-182)

(48a) of tert-Butyl [5-(2-fluoro-4-methylphenoxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 2-fluoro-4-METHYLPHENOL (5.0 g, 40 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (10 g, 36 mmol), sodium hydride (>56% in oil, 1.6 g, 40 mmol) and N,N-dimethylformamide (50 ml). The obtained yellow oil was directly used for the next reaction.

(48b) tert-Butyl [2-amino-5-(2-fluoro-4-methylphenoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(2-fluoro-4-methylphenoxy)-2-nitrophenyl]methylcarbamate obtained in example (48a) (14 g, 36 mmol), iron powder (10 g, 180 mmol), ammonium chloride (0.96 g, 18 mmol), ethanol (30 ml) and water (15 ml). The obtained brown oil was directly used for the next reaction.

(48c) [6-(2-Fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

The reaction and post treatment were carried out according to example (34c)using tert-butyl [2-amino-5-(2-fluoro-4-IU is elfenix)phenyl]methylcarbamate, obtained in example (48b) (13 g, 36 mmol), glycolic acid (3.0 g, 47 mmol), 5 n hydrochloric acid (30 ml) and 1,4-dioxane (30 ml), to obtain the desired compound (9.0 g, yield: 87%) as a pale brown solid, which was directly used for the next reaction.

(48d) Methyl 3-{[6-(2-fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(2-fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (48c) (0.35 g, 1.2 mmol), methyl 3-hydroxybenzoate (0,19 g, 1.3 mmol), tri-n-butylphosphine (of 0.58 ml, 2.3 mmol), 1,1'-(azodicarbon)dipiperidino (of 0.58 g, 2.3 mmol) and dichloromethane (4 ml)with obtaining the desired compound (0,38 g, yield: 78%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: at 2.36 (3H, s), of 3.80 (3H, s)to 3.92 (3H, s)5,38 (2H, s), 6,88? 7.04 baby mortality (5H, m), 7,29 (1H, s), 7,37 (1H, t, J=8.0 Hz), the 7.65 to 7.75 (3H, m).

MS (FAB) m/z: 421 (M+H)+.

(48e) 3-{[6-(2-Fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(2-fluoro-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (48d) (0,38 g, 0.90 mmol), 1 N. aqueous sodium hydroxide solution (1.4 ml, 1.4 mmol) and 1,4-dioxane (1.5 ml), to obtain the desired is soedineniya (0,41 g, yield: 100%) as a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: 2,31 (3H, s), with 3.79 (3H, s), the 5.45 (2H, s), make 6.90 (1H, DD, J=2,4, and 9.0 Hz), 6,99-7,02 (2H, m), 7,21 (1H, t, J=6,7 Hz), 7,21 (1H, s), 7,35-7,40 (1H, m), 7,45 (1H, t, J=7.8 Hz), 7,55-to 7.59 (1H, m), 7,63 (1H, d, J=8.6 Hz), 7,63 (1H, DD, J=1,6, 2.4 Hz), 13,03 (1H, users).

MS (FAB) m/z: 407 (M+H)+.

Analyte. calculated for C23H19FN2O4+0,20 H2O: C, 67,38; H, 4,77; F, 4,63; N, 6,83. Found C, 67,46; H, 4.72 In, F, Of 4.75; N, 6.89 In.

(Example 49) 3-{[1-Methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-168)

(49a) tert-Butyl methyl[5-(4-methylphenoxy)-2-nitrophenyl]carbamate

The crude product of the desired specified in the title compound was obtained as a yellow powder in accordance with the method described in example (28a)using 4-METHYLPHENOL (4,53 g, a 41.9 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (10.0 g, is 34.9 mmol) and sodium hydride (63%, of 1.59 g of 41.9 mmol). The crude product is directly used for the next reaction.

(49b) tert-Butyl [2-amino-5-(4-methylphenoxy)phenyl]methylcarbamate

The crude product of the desired specified in the title compound was obtained as brown powder in accordance with the method described in example (28b)using tert-butyl methyl[5-(4-methylphenoxy)-2-nitrophenyl]carbamate obtained in example (49a) (12.5 g, is 34.9 mmol), iron powder (9,74 g, 174 mmol) and ammonium chloride(0,933 g, to 17.4 mmol). The crude product is directly used for the next reaction.

(49c) [1-Methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methanol

Required is specified in the header connection (8,31 g, yield: 89%) was obtained as a brown powder in accordance with the method described in example (28c)using tert-butyl [2-amino-5-(4-methylphenoxy)phenyl]methylcarbamate obtained in example (49b) (11.5g, is 34.9 mmol)and glycolic acid (3.98 g, 52,3 mmol).

1H NMR (CDCl3, 400 MHz) δ: of 2.34 (3H, s), 3,74 (3H, s), a 4.86 (2H, s), 6.87 in-6,92 (3H, m), to 6.95 (1H, DD, J=2,3, 8.6 Hz), 7,14 (2H, d, J=7.8 Hz), to 7.59 (1H, d, J=8.6 Hz).

(49d) Methyl 3-{[1-methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoate

Required is specified in the header connection (9,40 g, yield: 83%) was obtained in the form of whitish-brown powder in accordance with the method described in example (28d)using [1-methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methanol obtained in example (49c) (7.50 g, 28,0 mmol), methyl 3-hydroxybenzoate (5.10 g, a 33.5 mmol), tri-n-butylphosphine (scored 8.38 ml, of 33.5 mmol) and 1,1'-(azodicarbon)dipiperidino (8,46 g of 33.5 mmol).

1H NMR (CDCl3, 500 MHz) δ: of 2.34 (3H, s), of 3.80 (3H, s)to 3.92 (3H, s), of 5.39 (2H, s), 6.89 in-6,97 (3H, m), 7,01 (1H, DD, J=2,4, 8,8 Hz), 7,14 (2H, d, J=8,3 Hz), 7,27-7,31 (1H, m), 7,37 (1H, t, J=8.1 Hz), 7,66-7,74 (3H, m).

(49e) 3-{[1-Methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required is specified in the header connection (591, yield: 68%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-{[1-methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoate (9.00 g, of 22.4 mmol)obtained in example (49d), and 1 N. aqueous solution of sodium hydroxide (33.6 ml, 33.6 mmol).

1H NMR (DMSO-d6, 400 MHz): δ of 2.28 (3H, s), of 3.80 (3H, s), 5,46 (2H, s), 6.87 in-6,94 (3H, m), 7,17 (2H, d, J=9.0 Hz), 7,26 (1H, d, J=2.3 Hz), of 7.36-7,41 (1H, m), 7,45 (1H, t, J=8.0 Hz), 7,58 (1H, d, J=7.8 Hz), 7,62-to 7.67 (2H, m,), of 13.05 (1H, s).

MS (FAB) m/z: 389 (M+H)+.

(Example 50) 3-{[6-(5-fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-185)

(50a) of tert-Butyl [5-(5-fluoro-2-methylphenoxy)-2-nitrophenyl]methylcarbamate

The crude product of the desired specified in the title compound was obtained as brown oil in accordance with the method described in example (28a)using 5-fluoro-2-METHYLPHENOL (5,28 g, a 41.9 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (10.0 g, is 34.9 mmol) and sodium hydride (63%, of 1.59 g of 41.9 mmol). The crude product is directly used for the next reaction.

(50b) of tert-Butyl [2-amino-5-(5-fluoro-2-methylphenoxy)phenyl]methylcarbamate

The crude product of the desired specified in the title compound was obtained as brown oil in accordance with the method described in example (28b)using tert-butyl [5-(5-fluoro-2-methylphenoxy)-2-nitrophenyl]metic Ramat, obtained in example (50a) (13,1 g, is 34.9 mmol), iron powder (9,74 g, 174 mmol) and ammonium chloride (0,933 g of 17.4 mmol). The crude product is directly used for the next reaction.

(50c) [6-(5-fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

Required is specified in the header connection (charged 8.52 g, yield: 85%) was obtained as a brown powder in accordance with the method described in example (28c)using tert-butyl [2-amino-5-(5-fluoro-2-methylphenoxy)phenyl]methylcarbamate obtained in example (50b) (12.1 g, is 34.9 mmol)and glycolic acid (3.98 g, 52,3 mmol).

1H NMR (CDCl3, 500 MHz) δ: of 2.26 (3H, s), of 3.77 (3H, s), 4,88 (2H, s), 6,50 (1H, DD, J=2,4, 10,3 Hz), was 6.73 (1H, dt, J=2,4, and 8.3 Hz), 6.87 in (1H, d, J=2.4 Hz), 6,93 (1H, DD, J=2,4, 8,8 Hz), 7,16-7,20 (1H, m), 7,63 (1H, d, J=8,8 Hz).

(50d) Methyl 3-{[6-(5-fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Required is specified in the header connection (7,15 g, yield: 65%) was obtained as a white powder in accordance with the method described in example (28d)using [6-(5-fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (50c) (7.50 g, to 26.2 mmol), methyl 3-hydroxybenzoate (4,78 g of 31.4 mmol), tri-n-butylphosphine (a 7.85 ml, of 31.4 mmol) and 1,1'(azodicarbon)dipiperidino (of 7.93 g of 31.4 mmol).

1H NMR (CDCl3, 400 MHz) δ: of 2.27 (3H, s), 3,82 (3H, s)to 3.92 (3H, s), of 5.40 (2H, s), 6,53 (1H, DD, J=2,7, or 9.8 Hz), 6,74 (1H, dt, J=2,7, 8,2 Hz), 6,91 (1H, d, J=2.0 Hz), 6,98 (1H, DD, J=2,0, 8.6 Hz, 7,17-7,22 (1H, m), 7,27-to 7.32 (1H, m), 7,38 (1H, t, J=8,2 Hz), to 7.67-7,76 (3H, m).

(50e) 3-{[6-(5-fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required specified in the header of the connection (of 6.29 g, yield: 93%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-{[6-(5-fluoro-2-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (50d) (7,00 g, and 16.7 mmol), and 1 N. aqueous sodium hydroxide solution (25,0 ml to 25.0 mmol).

1H NMR (DMSO-d6, 400 MHz) δ: 2,24 (3H, s), 3,82 (3H, s), vs. 5.47 (2H, s), to 6.57 (1H, DD, J=2.5 and 10.4 Hz), 6,85-to 6.95 (2H, m), 7,29 (1H, d, J=2.3 Hz), 7,31-7,41 (2H, m), 7,46 (1H, t, J=7.8 Hz), 7,58 (1H, d, J=7.8 Hz), 7,63-7,66 (1H, m), to 7.67 (1H, d, J=8.6 Hz), 13,04 (1H, s).

MS (FAB) m/z: 407 (M+H)+.

(Example 51) 3-{[6-(2-Fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-191)

(51a) of tert-Butyl [5-(2-fluoro-5-methoxyphenoxy)-2-nitrophenyl]methylcarbamate

The reaction and post treatment were carried out according to example (27a), using the known [Can. J. Chem., 1988, Vol. 66, p. 1479-1482] 2-fluoro-5-methoxyphenol (4.6 g, 32 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (7 g, 36 mmol), sodium hydride (>56% in oil, 1.3 g, 32 mmol) and N,N-dimethylformamide (60 ml), to obtain the desired compound (5.5 g, yield: 57%) as a yellow oil.

1H-NMR (CDCl3, 400 MHz) δ: 1,32 (6H, s)of 1.50 (3H, s), 3,26 (3H, s), of 3.80 (3H, s), 6,67-6,92 (4H, m), to 7.15 (1H, t, J=9.4 Hz), 7,94 (1H, d, J=8.6 Hz).

(51b) of tert-Butyl [2-amino-5-(2-fluoro-5-methoxyphenoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(2-fluoro-5-methoxyphenoxy)-2-nitrophenyl]methylcarbamate obtained in example (51a) (5.5 g, 14 mmol), iron powder (6.5 g, 120 mmol), ammonium chloride (0.65 g, 12 mmol), ethanol (30 ml) and water (15 ml). The oil obtained directly used for the next reaction.

(51c) [6-(2-Fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

The reaction and post treatment were carried out according to example (34c)using tert-butyl [2-amino-5-(2-fluoro-5-methoxyphenoxy)phenyl]methylcarbamate obtained in example (51b) (5.0 g, 14 mmol), glycolic acid (1.4 g, 18 mmol), 5 n hydrochloric acid (30 ml) and 1,4-dioxane (30 ml), to obtain the desired compound (2.3 g, yield: 64%) as a pale brown solid.

1H-NMR (CDCl3, 400 MHz) δ: and 3.72 (3H, in), 3.75 (3H, s), the 4.90 (2H, d, J=5.5 Hz), is 6.54 (1H, DD, J=2,9, 6,8 Hz), 6,57-6,63 (1H, m), to 6.95 (1H, d, J=2.4 Hz), 7,00 (1H, DD, J=2,2, 8,8 Hz), 7,10 (1H, DD, J=9,0, to 10.6 Hz), 7,66 (1H, d, J=8.6 Hz).

(51d) of Methyl 3-{[6-(2-fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(2-fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (51c) (2.7 g, 8,8 mmol), methyl 3-hydroxybenzoate (1.3 g, 8,8 mmol), tri-n-butylphosphine (4,4 ml, 18 mmol), 1,1'-(azodicarbon)piperidine (4.5 g, 18 mmol) and dichloromethane (4 ml), to obtain the desired compound (3.7 g, yield: 95%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: and 3.72 (3H, s), 3,82 (3H, s)to 3.92 (3H, s), of 5.39 (2H, s), 6,55 (1H, DD, J=3,1, 6,7 Hz), is 6.61 (1H, dt, J=3.3, which is 9.0 Hz), 6,97 (1H, d, J=2.4 Hz), 7,03 (1H, DD, J=2,4, 8.6 Hz), 7,10 (1H, DD, J=9,0, 10,2 Hz), 7,29 (1H, DD, J=2.5 a, 9,2 Hz), 7,37 (1H, t, J=8.0 Hz), to 7.67-of 7.70 (1H, m), 7,70-7,74 (2H, m).

MS (FAB) m/z: 437 (M+H)+.

(51e) 3-{[6-(2-Fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(2-fluoro-5-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (51d) (3.7 g, 8.4 mmol), 1 N. aqueous sodium hydroxide solution (13 ml, 13 mmol) and 1,4-dioxane (10 ml), to obtain the desired compound (2.9 g, yield: 81%) as a white solid matter.

1H-NMR (DMSO-d6, 400 MHz) δ: 3,68 (4H, s), 3,81 (3H, s), 5,43 (2H, s), is 6.61 (1H, DD, J=2,9, 6,8 Hz), was 6.73 (1H, dt, J=3.3, which is 9.1 Hz), 6,94 (1H, DD, J=2,5, and 8.8 Hz), 7.24 to 7,40 (4H, m), 7,54 (1H, d, J=7,4 Hz), to 7.61 (1H, users), the 7.65 (1H, d, J=9.0 Hz).

MS (FAB) m/z: 423 (M+H)+.

Analyte. calculated for C23H19FN2O5+0,20H2O: C, 64,85; H, 4,59; F, TO 4.46; N, 6,58. Found C, 64,74; H, To 4.38; F, 4,63; N, 6,51.

(Example 52) 3-({6-[3-(Dimethylamino)phenoxy]-1-methyl-1H-benzimidazole-2-yl}methoxy)benzoic acid (compound No. 1-177

(52a) of Methyl 3-({6-[3-(dimethylamino)phenoxy]-1-methyl-1H-benzimidazole-2-yl}methoxy)benzoate

The reaction and post treatment were carried out according to example (28d)using known [US6432993 B1] {6-[3-(dimethylamino)phenoxy]-1-methyl-1H-benzimidazole-2-yl}methanol (0,30 g, 1.0 mmol), methyl 3-hydroxybenzoate (0.15 g, 1.0 mmol), tri-n-butylphosphine (0,50 ml, 2.0 mmol), 1,1'-(azodicarbon)piperidine (0.51 g, 2.0 mmol) and dichloromethane (3.0 ml), with the desired connection (0,37 g, yield: 84%) as a colourless oil.

1H-NMR (CDCl3, 400 MHz) δ: at 2.93 (6H, s), 3,81 (3H, s)to 3.92 (3H, s), of 5.39 (2H, s), 6,27 to 6.35 (1H, m), to 6.43 (1H, t, J=2.4 Hz), 6,4-6,51 (1H, m), 7,00 (1H, d, J=1.6 Hz),? 7.04 baby mortality (1H, DD, J=2,4, 8.6 Hz), 7,17 (1H, t, J=8,2 Hz), 7,29 (1H, DD, J=3.3, which is 8.8 Hz), 7,37 (1H, t, J=7.8 Hz), 7,66 to 7.75 (3H, m).

MS (FAB) m/z: 432 (M+H)+.

(52b) 3-({6-[3-(Dimethylamino)phenoxy]-1-methyl-1H-benzimidazole-2-yl}methoxy)benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-({6-[3-(dimethylamino)phenoxy]-1-methyl-1H-benzimidazole-2-yl}methoxy)benzoate obtained in example (52a) (0,44 g, 1.0 mmol), 1 N. aqueous sodium hydroxide solution (1.5 ml, 1.5 mmol) and 1,4-dioxane (1.0 ml), to obtain the desired compound (0.33 g, yield: 79%) as a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: 2,87 (6H, s), 3,81 (3H, s), 5,46 (2H, s), 6,18 (1H, DD, J=2,4, 7,4 Hz), 6,36 (1H, t, J=2.4 Hz), 6,46 (1H, DD, J=2,4, and 7.8 Hz), 6,92 (1H, DD, J=2,4, and 9.0 Hz), 7,12 (1H, t, J=8,2 Hz), 7,27 (H, d, J=2.0 Hz), 7,39 (1H, DD, J=1,2, 2.7 Hz), was 7.45 (1H, t, J=8.0 Hz), 7,56-of 7.60 (1H, m), 7,62-the 7.65 (2H, m), 13,03 (1H, users).

MS (FAB) m/z: 418 (M+H)+.

Analyte. calculated for C24H23N3O4+0,20H2O: C, 68,46; H, THE CEILING OF 5.60; N, 9,98. Found C, 68,33; H, 5,52; N, 9,98.

(Example 53) 3-{[6-(3-Methoxy-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-206)

(53a) of tert-Butyl [5-(3-methoxy-5-methylphenoxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 3-methoxy-5-METHYLPHENOL (4.9 g, 35 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (8,1 g, 1.7 mmol), sodium hydride (>56% in oil, 1.7 g, 42 mmol) and N,N-dimethylformamide (50 ml). The obtained yellow oil was directly used for the next reaction.

(53b) of tert-Butyl [2-amino-5-(3-methoxy-5-methylphenoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(3-methoxy-5-methylphenoxy)-2-nitrophenyl]methylcarbamate obtained in example (53a) (11 g, 28 mmol), iron powder (7.6 g, 140 mmol), ammonium chloride (0.75 g, 14 mmol), ethanol (40 ml) and water (10 ml). The oil obtained directly used for the next reaction.

(53c) [6-(3-Methoxy-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

The synthesis was carried out in the same way as in example (34c)using tert-butyl [2-amino-5-(3-methoxy-5-methylphenoxy)phenyl]IU is ylcarbamate, obtained in example (53b) (10 g, 28 mmol), glycolic acid (2.8 g, 37 mmol), 5 n hydrochloric acid (20 ml) and 1,4-dioxane (20 ml). The obtained pale-brown solid was directly used for the next reaction.

(53d) of Methyl 3-{[6-(3-methoxy-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The synthesis was carried out in the same way as in example (28d)using [6-(3-methoxy-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (53c) (5,1 g, 17 mmol), methyl 3-hydroxybenzoate (2.6 g, 17 mmol), tri-n-butylphosphine (8.6 ml, 34 mmol), 1,1'-(azodicarbon)dipiperidino (8.6 g, 34 mmol) and dichloromethane (50 ml). The obtained pale-brown solid was directly used for the next reaction.

(53e) 3-{[6-(3-Methoxy-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(3-methoxy-5-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (53d) (7,4 g, 17 mmol), 1 N. aqueous sodium hydroxide solution (26 ml, 26 mmol) and 1,4-dioxane (25 ml), to obtain the desired compound (5.2 g, yield: 70%) as a white solid matter.

1H-NMR (DMSO-d6, 400 MHz) δ: 2,22 (3H, s), 3,70 (3H, s), 3,82 (3H, s), vs. 5.47 (2H, s), 6,32 (1H, s), 6,36 (1H, t, J=2.4 Hz), 6,50 (1H, s), 6,93 (1H, DD, J=2,4, 8.6 Hz), 7,32 (1H, d, J=2.4 Hz, of 7.36-7,42 (1H, m), 7,45 (1H, t, J=7.8 Hz), 7,55-to 7.61 (1H, m), 7,66 (2H, d, J=9.0 Hz), 13,04 (1H, s).

MS (FAB) m/z: 419 (M+H)+.

Analyte. calculated for C24H22N2O5: C, 68,89; H, AND 5.30; N, 6,69. Found C, 68,64; H, 5,26; N, 6,59.

(Example 54) 3-{[6-(3-Methoxy-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-204)

(54a) of tert-Butyl [5-(3-methoxy-4-methylphenoxy)-2-nitrophenyl]methylcarbamate

The crude product of the desired specified in the title compound was obtained as brown oil in accordance with the method described in example (28a)using 5-fluoro-2-METHYLPHENOL (5,78 g, a 41.9 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (10.0 g, is 34.9 mmol) and sodium hydride (63%, of 1.59 g of 41.9 mmol). The crude product is directly used for the next reaction.

(54b) of tert-Butyl [2-amino-5-(3-methoxy-4-methylphenoxy)phenyl]methylcarbamate

The crude product of the desired specified in the title compound was obtained as brown oil in accordance with the method described in example (28b)using tert-butyl [5-(3-methoxy-4-methylphenoxy)-2-nitrophenyl]methylcarbamate obtained in example (54a) (13,6 g, is 34.9 mmol), iron powder (9,74 g, 174 mmol) and ammonium chloride (0,933 g of 17.4 mmol). The crude product is directly used for the next reaction.

(54c) [6-(3-Methoxy-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-ylmethanol

Required is specified in the header connection (8,93 g, yield: 86%) was obtained as a brown powder in accordance with the method described in example (28c)using tert-butyl [2-amino-5-(3-methoxy-4-methylphenoxy)phenyl]methylcarbamate obtained in example (54b) (12.5 g, is 34.9 mmol)and glycolic acid (3.98 g, 52,3 mmol).

1H NMR (CDCl3, 400 MHz) δ: 2,19 (3H, in), 3.75 (3H, s), of 3.77 (3H, s), to 4.87 (2H, s), 5,10 (1H, s), of 6.45 (1H, DD, J=2,3, 8,2 Hz), to 6.57 (1H, d, J=2.3 Hz), make 6.90 (1H, d, J=2.0 Hz), 6,97 (1H, DD, J=2,0, 8.6 Hz), 7.03 is-7,07 (1H, m,), 7,60 (1H, d, J=8.6 Hz).

(54d) of Methyl 3-{[6-(3-methoxy-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Required is specified in the header connection (compared to 8.26 g, yield: 71%) was obtained as a white powder in accordance with the method described in example (28d)using [6-(3-methoxy-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (54c) (8.00 g, 26.8 mmol), methyl 3-hydroxybenzoate (4,90 g is 32.2 mmol), tri-n-butylphosphine (8,04 ml, to 32.2 mmol) and 1,1'(azodicarbon)dipiperidino (8,12 g is 32.2 mmol).

1H NMR (CDCl3, 500 MHz) δ: 2,19 (3H, s), of 3.77 (3H, s), 3,81 (3H, s)to 3.92 (3H, s), of 5.39 (2H, s), 6,47 (1H, DD, J=2,4, 8,3 Hz), to 6.58 (1H, d, J=2.4 Hz), of 6.96 (1H, d, J=2.4 Hz), 7,02 (1H, DD, J=2.0 a, 8,8 Hz), 7,05 (1H, d, J=8,3 Hz), 7,27-7,31 (1H, m), 7,37 (1H, t, J=7.8 Hz), to 7.67-7,73 (3H, m).

(54e) 3-{[6-(3-Methoxy-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required is specified in the header connection (7,44 g, yield: 96%) was obtained as white on osca in accordance with the method, described in example (28e)using methyl 3-{[6-(3-methoxy-4-methylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (54d) (8.00 g, 18.5 mmol), and 1 N. aqueous sodium hydroxide solution (27.8 ml, 27.8 mmol).

1H NMR (DMSO-d6, 400 MHz) δ: 2,11 (3H, s), 3,74 (3H, s), 3,81 (3H, s), 5,46 (2H, s)6,40 (1H, DD, J=2,3, 7,8 Hz), to 6.67 (1H, d, J=2.3 Hz), 6,94 (1H, DD, J=2,3, 8.6 Hz), was 7.08 (1H, d, J=8,2 Hz), 7,27 (1H, d, J=2.3 Hz), of 7.36-7,42 (1H, m), 7,46 (1H, t, J=8.0 Hz), 7,56-to 7.61 (1H, m), the 7.65 (1H, d, J=8.6 Hz), 7,63-the 7.65 (1H, m).

MS (EI) m/z: 418 M+.

(Example 55) 3-{[6-(3,4-Dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-198)

(55a) tert-Butyl [5-(3,4-dimethylphenoxy)-2-nitrophenyl]methylcarbamate

The crude product of the desired specified in the title compound was obtained as brown powder in accordance with the method described in example (28a)using 3,4-dimethylphenol (5,11 g, a 41.9 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (10.0 g, is 34.9 mmol) and sodium hydride (63%, of 1.59 g of 41.9 mmol). The crude product is directly used for the next reaction.

(55b) tert-Butyl [2-amino-5-(3,4-dimethylphenoxy)phenyl]methylcarbamate

The crude product of the desired specified in the title compound was obtained as brown oil in accordance with the method described in example (28b)using tert-butyl [5-(3,4-dimethylphenoxy)-2-nitrophenyl]methylcarbamate obtained in the example (55a) (13,0 g, to 34.9 mmol), iron powder (9,74 g, 174 mmol) and ammonium chloride (0,933 g of 17.4 mmol). The crude product is directly used for the next reaction.

(55c) [6-(3,4-Dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

Required is listed in the title compound (7.98 g, yield: 81%) was obtained as a brown powder in accordance with the method described in example (28c)using tert-butyl [2-amino-5-(3,4-dimethylphenoxy)phenyl]methylcarbamate obtained in example (55b) (11.9 g, is 34.9 mmol)and glycolic acid (3.98 g, 52,3 mmol).

1H NMR (CDCl3, 400 MHz) δ: of 2.23 (3H, s), 2,24 (3H, s), 3,74 (3H, s), a 4.86 (2H, s), 4,94 (1H, s), 6,74 (1H, DD, J=8,2, 2.3 Hz), for 6.81 (1H, d, J=2.3 Hz), 6.89 in (1H, d, J=2.3 Hz), of 6.96 (1H, DD, J=8,6, and 2.3 Hz), was 7.08 (1H, d, J=8,2 Hz), 7,60 (1H, d, J=8.6 Hz).

(55d) Methyl 3-{[6-(3,4-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Required is specified in the header connection (at 8.36 g, yield: 81%) was obtained as a white powder in accordance with the method described in example (28d)using [6-(3,4-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (55c) (7,00 g of 24.8 mmol), methyl 3-hydroxybenzoate (4,53 g, to 29.8 mmol), tri-n-butylphosphine (7,43 ml, to 29.8 mmol) and 1,1'-(azodicarbon)dipiperidino (7.51 g, to 29.8 mmol).

1H NMR (CDCl3, 500 MHz) δ: of 2.23 (3H, s), 2,24 (3H, s), of 3.80 (3H, s)to 3.92 (3H, s)5,38 (2H, s), of 6.75 (1H, DD, J=2,4, 8,3 Hz), for 6.81 (1H, d, J=2.4 Hz), to 6.95 (1H, d, J=2.4 Hz), 7,00 (1H, DD, J=2,4, 8,8 Hz), was 7.08 (1H, d, J=8,3 Hz), 7,27-7,3 (1H, m), 7,37 (1H, t, J=8,3 Hz), 7,66-7,73 (3H, m).

(55e) 3-{[6-(3,4-Dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required is specified in the header connection (6,21 g, yield: 80%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-{[6-(3,4-dimethylphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (55d) (8.00 g, 19.2 mmol), and 1 N. aqueous sodium hydroxide solution (28.8 ml, 28.8 mmol).

1H NMR (DMSO-d6, 400 MHz) δ: 2,18 (3H, s)to 2.18 (3H, s), of 3.80 (3H, s), 5,46 (2H, s)of 6.71 (1H, DD, J=2,7, and 7.8 Hz), to 6.80 (1H, d, J=2.7 Hz), make 6.90 (1H, DD, J=2,2, 8,8 Hz), 7,11 (1H, d, J=8,2 Hz), 7,25 (1H, d, J=2.3 Hz), of 7.36-7,41 (1H, m), 7,45 (1H, t, J=7.8 Hz), 7,56-of 7.60 (1H, m), to 7.61-the 7.65 (2H, m).

MS (FAB) m/z: 402 M+.

(Example 56) 3-{[6-(4-Ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-171)

(56a) of tert-Butyl [5-(4-ethylenoxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 4-ethylphenol (4.0 g, 33 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (7.5 g, 26 mmol), sodium hydride (>56% in oil, 2.0 g, 51 mmol) and N,N-dimethylformamide (50 ml). The obtained yellow oil was directly used for the next reaction.

(56b) of tert-Butyl [2-amino-5-(4-ethylenoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(4-ethylenoxy)-2-nitrophenyl]metolcarb the Mat, obtained in example (56a) (11 g, 26 mmol), iron powder (7.0 g, 130 mmol), ammonium chloride (0,70 g, 13 mmol), ethanol (30 ml) and water (15 ml). The obtained red oil directly used for the next reaction.

(56c) [6-(4-Ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol

The reaction and post treatment were carried out according to example (34c)using tert-butyl [2-amino-5-(4-ethylenoxy)phenyl]methylcarbamate obtained in example (56b) (9.0 g, 26 mmol), glycolic acid (2.6 g, 34 mmol), 5 n hydrochloric acid (20 ml) and 1,4-dioxane (20 ml), to obtain the desired compound (5.8 g, yield: 78%) as a pale brown solid, which was directly used for the following response.

(56d) Methyl 3-{[6-(4-ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(4-ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (56c) (5,3 g, 19 mmol), methyl 3-hydroxybenzoate (2.8 g, 19 mmol), tri-n-butylphosphine (9.3 ml, 37 mmol), 1,1'-(azodicarbon)dipiperidino (9.4 g, 37 mmol) and dichloromethane (50 ml), to obtain the desired compound (5.6 g, yield: 72%) as a pale red solid.

MS (FAB) m/z: 417 (M+N)+.

(56e) 3-{[6-(4-Ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and will be followed by the second treatment was carried out according to example (28e), using methyl 3-{[6-(4-ethylenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (56d) (5.6 g, 14 mmol), 1 N. aqueous sodium hydroxide solution (20 ml, 20 mmol) and 1,4-dioxane (25 ml), to obtain the desired compound (5.1 g, yield: 94%) as a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: 1,17 (3H, t, J=7,6 Hz), 2,58 (2H, square, J=7,3 Hz), 3,80 (3H, s), 5,46 (2H, s), 6.87 in-6,94 (3H, m), 7,19 (2H, d, J=8,3 Hz), 7,28 (1H, d, J=2.4 Hz), 7,38 (1H, DD, J=2.7, and 8.1 Hz), was 7.45 (1H, t, J=7,8 Hz), 7,58 (1H, d, J=7.8 Hz), 7,62-to 7.67 (2H, m), 13,03 (1H, users).

MS (FAB) m/z: 403 (M+H)+.

Analyte. calculated for C24H22N2O4+0,20H2O: C, 70,99; H, TO 5.56; N, 6.90 TO. Found C, 70,82; H, 5,32; N, 6,88.

(Example 57) 3-{[6-(2,3-Dihydro-1-benzofuran-6-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-210)

(57a) tert-Butyl [5-(2,3-dihydro-1-benzofuran-6-yloxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using known [J. Am. Chem. Soc., 1948, Vol. 70, p. 3619] 2,3-dihydro-1-benzofuran-6-ol (2.2 g, 16 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (4.0 g, 14 mmol), sodium hydride (>56% in oil, 0.66 g, 16 mmol) and N-methylpyrrolidinone (30 ml). The obtained yellow oil was directly used for the next reaction.

(57b) tert-Butyl [2-amino-5-(2,3-dihydro-1-benzofuran-6-yloxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using t the et-butyl [5-(2,3-dihydro-1-benzofuran-6-yloxy)-2-nitrophenyl]methylcarbamate, obtained in example (57a) (5,4 g, 14 mmol), iron powder (3.7 g, 70 mmol), ammonium chloride (0,37 g, 7.0 mmol), ethanol (40 ml) and water (20 ml). The oil obtained directly used for the next reaction.

(57c) Methyl 3-[2-({2-[(tert-butoxycarbonyl)(methyl)amino]-4-(2,3-dihydro-1-benzofuran-6-yloxy)phenyl}amino)-2-oksidoksi]benzoate

tert-Butyl [2-amino-5-(2,3-dihydro-1-benzofuran-6-yloxy)phenyl]methylcarbamate obtained in example (57b) (5.0 g, 14 mmol), and [3-(methoxycarbonyl)phenoxy]acetic acid (2.9 g, 14 mmol) was dissolved in dichloromethane (100 ml). Added the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3.2 g, 17 mmol) and the mixture was stirred at room temperature for 2.2 hours. Was added an aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane twice. Then the organic layers were washed with saturated salt solution and dried over anhydrous magnesium sulfate. Evaporated under reduced pressure, the solvent and the obtained solid is directly used for the next reaction.

(57d) Monohydrochloride methyl 3-{[6-(2,3-dihydro-1-benzofuran-6-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Methyl 3-[2-({2-[(tert-butoxycarbonyl)(methyl)amino]-4-(2,3-dihydro-1-benzofuran-6-yloxy)phenyl}amino)-2-oksidoksi]benzoate obtained in example (57c) (7.7 g, 14 mmol), was dissolved in 5 N. the solution chloritoid the native acid in ethyl acetate (50 ml) and the mixture was heated under reflux for two hours. After cooling to room temperature, precipitated in the sediment of a pale-red solid was collected by filtration to obtain the desired compound (7.9 g, yield: 100%).

1H-NMR (DMSO-d6, 500 MHz) δ: 3.15 in (2H, t, J=8,8 Hz), 3,88 (3H, s), 3,93 (3H, s), of 4.57 (2H, t, J=8,8 Hz), 5,69 (2H, s), 6,47 (2H, s), 7,16 (1H, d, J=8,8 Hz), 7,21 (1H, d, J=7.8 Hz), 7,47-7,56 (3H, m), 7,66 (1H, d, J=8,3 Hz), 7,72 (1H, s), 7,78 (1H, d, J=9,3 Hz).

MS (FAB) m/z: 431 (M+H)+.

(57e) 3-{[6-(2,3-Dihydro-1-benzofuran-6-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using monohydrochloride methyl 3-{[6-(2,3-dihydro-1-benzofuran-6-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (57d) (6.5 g, 14 mmol), 1 N. aqueous sodium hydroxide solution (56 ml, 56 mmol) and 1,4-dioxane (60 ml), to obtain the desired compound (4.3 g, yield: 74%in the form of a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: 3,13 (2H, t, J=8,4 Hz), 3,81 (3H, s)4,55 (2H, t, J=8.6 Hz), 5,46 (2H, s), 6,39-6,44 (2H, m)6,91 (1H, DD, J=2,4, 8.6 Hz), 7,16 (1H, d, J=7.8 Hz), 7,28 (1H, d, J=2.4 Hz), of 7.36-7,40 (1H, m), was 7.45 (1H, t, J=7.8 Hz), 7,58 (1H, dt, J=1,2, 1,4, 7,6 Hz), 7,62-7,66 (2H, m), 13,04 (1H, users).

MS (FAB) m/z: 417 (M+H)+.

Analyte. calculated for C24H20N2O5+0,33H2O: C, 68,24; H, IS 4.93; N, 6,63. Found C, 68,34; H, 4,84; N, 6,79.

(Example 58) 3-{[6-(1,3-Benzodioxol-5-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (soy is inania No. 1-211)

(58a) of tert-Butyl [5-(1,3-benzodioxol-5-yloxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using sesamol (2.9 g, 21 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (5.0 g, 17 mmol), sodium hydride (>56% in oil, of 0.82 g, 21 mmol) and N-methylpyrrolidinone (50 ml). The obtained brown oil was directly used for the next reaction.

(58b) tert-Butyl [2-amino-5-(1,3-benzodioxol-5-yloxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(1,3-benzodioxol-5-yloxy)-2-nitrophenyl]methylcarbamate obtained in example (58a) (6.8 g, 17 mmol), iron powder (4.7 g, 87 mmol), ammonium chloride (0,47 g, 8,7 mmol), ethanol (40 ml) and water (20 ml). The obtained brown oil was directly used for the next reaction.

(58C trainers) Methyl 3-[2-({4-(1,3-benzodioxol-5-yloxy)-2-[(tert-butoxycarbonyl)(methyl)amino]phenyl}amino)-2-oksidoksi]benzoate

The reaction and post treatment were carried out according to example (57c), using tert-butyl [2-amino-5-(1,3-benzodioxol-5-yloxy)phenyl]methylcarbamate obtained in example (58b) (6.7 g, 17 mmol), [3-(methoxycarbonyl)phenoxy]acetic acid (3.7 g, 17 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (4.0 g, 21 mmol) and dichloromethane (70 ml), with solids that directly use the Wali for the next reaction.

(58d) Monohydrochloride methyl 3-{[6-(1,3-benzodioxol-5-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (57d), using methyl 3-[2-({4-(1,3-benzodioxol-5-yloxy)-2-[(tert-butoxycarbonyl)(methyl)amino]phenyl}amino)-2-oksidoksi]benzoate obtained in example (58C trainers) (9.6 g, 17 mmol)and 5 n hydrochloric acid in ethyl acetate (50 ml), to obtain the desired compound (7,3 g, yield: 89%) in the form white solids.

1H-NMR (CDCl3, 400 MHz) δ: 3,11 (3H, users), 3,93 (3H, s), and 4.68 (2H, s), of 5.99 (2H, s), of 6.49 (1H, DD, J=2,4, and 8.2 Hz), to 6.58 (1H, d, J=2.4 Hz), 6,76 (1H, d, J=8,2 Hz), PC 6.82 (1H, users), 6,86-6,93 (1H, m), 7,20 (1H, DD, J=2,2, 8,0 Hz), 7,42 (1H, t, J=8.0 Hz), 7,63 (1H, users), 7,74 (1H, d, J=7,8 Hz).

(58e) 3-{[6-(1,3-Benzodioxol-5-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using monohydrochloride methyl 3-{[6-(1,3-benzodioxol-5-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (58d) (7,3 g, 15 mmol), 2 N. aqueous sodium hydroxide solution (31 ml, 62 mmol) and 1,4-dioxane (60 ml), to obtain the desired compound (6.3 g, yield: 98%) as a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: of 3.80 (3H, s), 5,46 (2H, s), 6,03 (2H, s), of 6.45 (1H, DD, J=2,5, and 8.4 Hz), of 6.71 (1H, d, J=2.4 Hz), 6,86-6,93 (2H, m), 7.23 percent (1H, d, J=2.0 Hz), of 7.36-7,41 (1H, m), 7,45 (1H, t, J=7.8 Hz), 7,56-7,60 (H, m)to 7.61-7,66 (2H, m), 13,07 (1H, users).

MS (FAB) m/z: 419 (M+H)+.

Analyte. calculated for C23H18N2O6+0,25H2O: C, 65,32; H, TO 4.41; N, 6,62. Found C, 65,54; H, 4,71; N, 6,65.

(Example 59) 3-{[6-(4-Chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}-5-Formentera acid (compound No. 1-220)

(59a) Methyl 3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}-5-perbenzoate

Required is listed in the title compound (362 mg, yield: 81%) was obtained as a white powder in accordance with the method described in example (28d)using [6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (9b) (300 mg, 0,978 mmol), methyl 5-fluoro-3-hydroxybenzoate (200 mg, at 1.17 mmol), tri-n-butylphosphine (0,366 ml of 1.47 mmol) and 1,1'-(azodicarbon)dipiperidino (370 mg, about 1.47 mmol).

1H NMR (CDCl3, 400 MHz) δ: a-3.84 (3H, s), 3,93 (3H, s), of 5.40 (2H, s)of 6.71-6,76 (1H, m), is 6.78 (1H, DD, J=2.7, and a 10.2 Hz), 7,00-7,06 (3H, m), 7,31 (1H, DD, J=8,6, 8.6 Hz), of 7.36-7,41 (1H, m), 7,53-7,56 (1H, m), to 7.77 (1H, DD, J=0,6, 8.6 Hz).

(59b) 3-{[6-(4-Chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}-5-Formentera acid

Required is listed in the title compound (292 mg, yield: 85%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}-5-perbenzoate obtained in example in example (59a) (354 mg, 0,772 mmol), and 1 N. aqueous solution g is droxia sodium (1,16 ml, to 1.16 mmol).

1H NMR (DMSO-d6, 400 MHz) δ: a 3.83 (3H, s)5,52 (2H, s), 6,83 (1H, DDD, J=1,2, of 2.7, 9.0 Hz), 7,01 (1H, DD, J=2,3, 8.6 Hz), to 7.09 (1H, DD, J=2.7, and a 10.6 Hz), 7,28-7,33 (1H, m), 7,35 (1H, DDD, J=2,3, 2,3, a 10.6 Hz), was 7.45 (1H, d, J=2.0 Hz), 7,47-7,51 (1H, m), 7,54 (1H, DD, J=8,6, 8.6 Hz), 7,71 (1H, d, J=8.6 Hz).

MS (FAB) m/z: 445 (M+H)+.

(Example 60) 3-Fluoro-5-{[6-(3-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-218)

(60a) of Methyl 3-fluoro-5-{[6-(3-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Required is listed in the title compound (387 mg, yield: 84%) was obtained as a white powder in accordance with the method described in example (28d)using [6-(3-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (29c) (300 mg, 1.06 mmol), methyl 5-fluoro-3-hydroxybenzoate (197 mg, of 1.16 mmol), tri-n-butylphosphine (0,395 ml, was 1.58 mmol) and 1,1'(azodicarbon)dipiperidino (399 mg, was 1.58 mmol).

1H NMR (CDCl3, 400 MHz) δ: of 3.78 (3H, s), 3,81 (3H, s), 3,93 (3H, s), of 5.39 (2H, s), 6,56-6,60 (2H, m), 6,63 is 6.67 (1H, m), 7,00-7,07 (3H, m), 7,19-7,26 (1H, m), of 7.36-7,40 (1H, m), 7,53-7,56 (1H, m), 7,74 (1H, d, J=9.0 Hz).

(60b) 3-Fluoro-5-{[6-(3-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required is listed in the title compound (303 mg, yield: 83%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-fluoro-5-{[6-(3-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate, obtained in PR is as in example (60a) (376 mg, 0,862 mmol), and 1 N. aqueous sodium hydroxide solution (1,29 ml, 1,29 mmol).

1H NMR (DMSO-d6, 500 MHz) δ: and 3.72 (3H, s), 3,82 (3H, s), of 5.50 (2H, s), 6,51 (1H, DD, J=2,2, 8.1 Hz), 6,56 (1H, t, J=2.2 Hz), of 6.68 (1H, DD, J=2,4, 8,3 Hz), to 6.95 (1H, DD, J=2,4, 8,8 Hz), 7,25 (1H, t, J=8,3 Hz), 7,28-7,33 (1H, m,), 7,33-7,38 (2H, m), of 7.48-7,51 (1H, m), to 7.67 (1H, d, J=8,8 Hz).

MS (FAB) m/z: 423 (M+H)+.

(Example 61) 3-Fluoro-5-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-212)

(61a) of Methyl 3-fluoro-5-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Required is listed in the title compound (426 mg, yield: 91%) was obtained as a pink powder in accordance with the method described in example (28d)using [6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (7c) (300 mg, 1.10 mmol), methyl 5-fluoro-3-hydroxybenzoate (206 mg, to 1.21 mmol), tri-n-butylphosphine (0,413 ml of 1.65 mmol) and 1,1'(azodicarbon)dipiperidino (417 mg, of 1.65 mmol).

1H NMR (CDCl3, 400 MHz) δ: a-3.84 (3H, s), 3,93 (3H, s), of 5.40 (2H, s), 6,66-6,72 (1H, m), 6.75 in-for 6.81 (2H, m), 7,01-7,06 (3H, m), 7.23 percent-7,30 (1H, m), of 7.36-7,40 (1H, m), 7,54-7,56 (1H, m), 7,75 for 7.78 (1H, m).

(61b) 3-Fluoro-5-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required is listed in the title compound (304 mg, yield: 80%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-fluoro-5-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example in example (61a) (395 mg, 0,931 mmol), and 1 N. aqueous sodium hydroxide solution (1,40 ml of 1.40 mmol).

1H NMR (DMSO-d6, 500 MHz) δ: a 3.83 (3H, s)5,52 (2H, s), 6,77-6,85 (2H, m), 6.89 in-6,95 (1H, m), of 6.99 (1H, DD, J=2,4, 8,8 Hz), 7,28-7,44 (4H, m), 7,49 (1H, s), of 7.70 (1H, d, J=8,3 Hz), 13,37 (1H, s).

MS (FAB) m/z: 411 (M+H)+.

(Example 62) 3-Fluoro-5-{[6-(4-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-219)

(62a) of Methyl 3-fluoro-5-{[6-(4-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Required is listed in the title compound (432 mg, yield: 94%) was obtained as a yellow oil according to the method described in example (28d)using [6-(4-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (30c) (300 mg, 1.06 mmol), methyl 5-fluoro-3-hydroxybenzoate (197 mg, of 1.16 mmol), tri-n-butylphosphine (0,395 ml, was 1.58 mmol) and 1,1'(azodicarbon)dipiperidino (399 mg, was 1.58 mmol).

1H NMR (CDCl3, 400 MHz) δ: with 3.79 (3H, s), 3,82 (3H, s), 3,93 (3H, s), lower than the 5.37 (2H, s), 6.87 in-6,93 (3H, m), 6,97-7,05 (4H, m), 7,35-7,40 (1H, m), 7,52-of 7.55 (1H, m), of 7.70 (1H, d, J=8.6 Hz).

(62b) 3-Fluoro-5-{[6-(4-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required is listed in the title compound (332 mg, yield: 82%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-fluoro-5-{[6-(4-methoxyphenoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (62a) (420 mg, 0,962 mmol), and 1 N. water is actor sodium hydroxide (1,44 ml, 1.44 mmol).

1H NMR (DMSO-d6, 400 MHz) δ: 3,74 (3H, s), with 3.79 (3H, s)5,49 (2H, s), 6.89 in (1H, DD, J=2,3, 8.6 Hz), 6,92-7,01 (4H, m), 7,20 (1H, d, J=2.3 Hz), 7,27-7,37 (2H, m), 7,47-7,50 (1H, m), 7,63 (1H, d, J=8.6 Hz), 13,37 (1H, s).

MS (FAB) m/z: 423 (M+H)+.

(Example 63) 3-Fluoro-5-{[6-(4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-213)

(63a) of Methyl 3-fluoro-5-{[6-(4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Required is listed in the title compound (263 mg, yield: 56%) was obtained as a yellow powder in accordance with the method described in example (28d)using [6-(4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (27c) (300 mg, 1.10 mmol), methyl 5-fluoro-3-hydroxybenzoate (206 mg, to 1.21 mmol), tri-n-butylphosphine (0,413 ml of 1.65 mmol) and 1,1'(azodicarbon)dipiperidino (417 mg, of 1.65 mmol).

1H NMR (CDCl3, 400 MHz) δ: 3,81 (3H, s), 3,93 (3H, s)5,38 (2H, s), 6,92-to 7.09 (7H, m), 7,35-7,41 (1H, m), 7,52-7,56 (1H, m), 7,73 (1H, d, J=9.0 Hz).

(63b) 3-Fluoro-5-{[6-(4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

Required is listed in the title compound (197 mg, yield: 80%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-fluoro-5-{[6-(4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example in example (63a) (255 mg, 0,601 mmol), and 1 N. aqueous sodium hydroxide solution (to 0.900 ml, to 0.900 mmol).

1H NMR (DM what About the-d 6, 400 MHz) δ: 3,81 (3H, s), of 5.50 (2H, s)6,94 (1H, DD, J=2,3, 8.6 Hz), 7,00-7,06 (2H, m), 7,16-7,24 (2H, m), 7,28-to 7.32 (2H, m), 7,35 (1H, DD, J=2,3, a 10.6 Hz), 7,47-7,50 (1H, m), to 7.67 (1H, d, J=9.0 Hz), 13,37 (1H, C).

MS (FAB) m/z: 411 (M+H)+.

(Example 64) 3-{[1-Methyl-(6-tetrahydro-2H-Piran-4-yloxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-208)

(64a) of tert-Butyl [5-(tetrahydro-2H-Piran-4-yloxy)-2-nitrophenyl]methylcarbamate

Specified in the header of the substance (1,59 g, yield: 60%) was obtained as a yellow oil by synthesis in the same way as in example (28a)using tetrahydro-4-pyranol (780 mg, 7.5 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (2.15 g, 7.5 mmol), sodium hydride (>56% in oil, 290 mg, 7.5 mmol) and N,N-dimethylformamide (30 ml), and purified using an automatic cleaning system (Isco, 15% ethyl acetate-hexane).

1H-NMR (CDCl3, 400 MHz) δ: of 1.33 (6H, s)of 1.50 (3H, s), 3,26 (3H, s), for 6.81 (1H, DD, J=2.7, and 9.0 Hz), 6,85 (1H, users), 7,07-7,17 (4H, m), 7,93-of 7.97 (1H, m).

(64b) tert-Butyl [2-amino-5-(6-tetrahydro-2H-Piran-4-yloxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(6-tetrahydro-2H-Piran-4-yloxy)-2-nitrophenyl]methylcarbamate obtained in example (64a) (3.2 g, 8,8 mmol), iron powder (2.4 g, 12 mmol), ammonium chloride (0.24 g, 1.2 mmol), ethanol (40 ml) and water (20 ml). The oil obtained directly used for the next reaction.

(64c) [6-(6-Tetrahydro-2H-Piran-4-yloxy)-1-ethyl-1H-benzimidazole-2-yl]methanol

The synthesis was carried out in the same way as in example (28c)using tert-butyl [2-amino-5-(6-tetrahydro-2H-Piran-4-yloxy)phenyl]methylcarbamate obtained in example (64b) (2.9 g, 8,8 mmol), glycolic acid (1.0 g, 13 mmol) and 4 n hydrochloric acid in 1,4-dioxane (40 ml). The obtained dark brown oil directly used for the next reaction.

(64d) Methyl 3-{[1-methyl-(6-tetrahydro-2H-Piran-4-yloxy)-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(6-tetrahydro-2H-Piran-4-yloxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (64c) (0,30 g, 1.1 mmol), methyl 3-hydroxybenzoate (0.25 g, 1.7 mmol), tri-n-butylphosphine (0,55 ml, 2.2 mmol), 1,1'-(azodicarbon)piperidine (0.56 g, 2.2 mmol) and dichloromethane (6,0 ml), to obtain the desired compound (0.36 g, yield: 81%).

1H-NMR (CDCl3, 500 MHz) δ: 3,82 (3H, s)to 3.92 (3H, s), of 5.39 (2H, s), 6,94-7,05 (5H, m), 7,29 (1H, users), 7,38 (1H, t, J=of 7.82 Hz), 7,69 (1H, d, J=of 7.82 Hz), 7,71-7,74 (2H, m).

MS (FAB) m/z: 407 (M+H)+.

(64x) 3-{[1-Methyl-(6-tetrahydro-2H-Piran-4-yloxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[1-methyl-(6-tetrahydro-2H-Piran-4-yloxy)-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (64d) (0.34 g, 0.84 mmol), 1 N. aqueous solution is hydroxide sodium (1.3 ml, 1.3 mmol) and 1,4-dioxane, to obtain the desired compound (0.10 g, yield: 37%) as a white solid.

1H-NMR (DMSO-d6, 500 MHz) δ: 3,81 (3H, s), 5,46 (2H, s), 6,93 (1H, DD, J=2,44, 8,79 Hz), 7,01? 7.04 baby mortality (2H, m), 7,19 (2H, t, J=8,79 Hz), 7,30 (1H, d, J=2,44 Hz), 7,37-7,39 (1H, m), 7,45 (1H, t, J=7,81 Hz), EUR 7.57 (2H, d, J=7,81 Hz), 7,66 (1H, d, J=8,79 Hz), 7,63 (1H, s), 13,03 (1H, users).

MS (FAB) m/z: 393 (M+H)+.

Analyte. calculated for C24H22N2O5+0,14H2O: C, 66,91; H, TO 4.41; N, 7,09; F, 4,81. Found C, 66,85; H, To 4.46; N, 7,21; F, 4,81.

(Example 65) 3-[(6-Cyclopentyloxy-1-methyl-1H-benzimidazole-2-yl)methoxy]benzoic acid (compound No. 1-162)

(65a) of tert-Butyl (5-cyclopentyloxy-2-nitrophenyl)methylcarbamate

The synthesis was carried out in the same way as in example (28a)using Cyclopentanol (861 mg, 10 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (2,87 g, 10 mmol), sodium hydride (>56% in oil, 380 mg, 10 mmol) and N,N-dimethylformamide (40 ml). The obtained oil (3.28 g) was directly used for the next reaction.

(65b) of tert-Butyl [2-amino-5-(cyclopentyloxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl (5-cyclopentyloxy-2-nitrophenyl)methylcarbamate obtained in example (65a) (3,27 g, 9.7 mmol), iron powder (2.6 g, 49 mmol), ammonium chloride (0.26 g, 4.9 mmol), ethanol (50 ml) and water (25 ml). The oil obtained (2,98 g) was directly used for the next is eacli.

(65c) [6-(Cyclopentyloxy)-1-methyl-1H-benzimidazole-2-yl]methanol

tert-Butyl [2-amino-5-(cyclopentyloxy)phenyl]methylcarbamate obtained in example (65b) (2,98 g, 9.7 mmol), glycolic acid (1.1 g, 14.6 mmol), 5 n hydrochloric acid (25 ml) and dioxane (25 ml) was heated under reflux for 19 hours. The reaction solution was cooled to room temperature and then was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate and filtered. Next, the filtrate was evaporated under reduced pressure. The crude product washed with diisopropyl ether to obtain the desired compound (0.75 g, yield three stages: 31%).

1H-NMR (CDCl3, 400 MHz) δ: 1,76-of 1.92 (8H, m), of 3.73 (3H, s), 4,76-to 4.81 (1H, m), a 4.83 (2H, s), 6,69-6,72 (1H, m), for 6.81-6,85 (1H, m), 7,51-rate of 7.54 (1H, m).

(65d) of Methyl 3-[(6-cyclopentyloxy-1-methyl-1H-benzimidazole-2-yl)methoxy]benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(cyclopentyloxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (65c) (0.75 g, 3.1 mmol), methyl 3-hydroxybenzoate (0,70 g, 6.1 mmol), tri-n-butylphosphine (1.5 ml, 6.1 mmol), 1,1'-(azodicarbon)dipiperidino (1.54 g, 2.2 mmol) and dichloromethane (30 ml), to obtain the desired with the unity (0,70 g, yield: 60%) as a yellow solid.

1H-NMR (CDCl3, 400 MHz) δ: 1,63-1,71 (2H, m), 1,81 is 2.00 (6H, m), 3,85 (3H, s), of 3.95 (3H, s), 4,84-to 4.87 (1H, m), of 5.40 (2H, s), 6,80-6,83 (1H, m), 6.90 to-6,94 (1H, m), 7,30-7,34 (1H, m), 7,37-7,41 (1H, m), 7,65-to 7.68 (1H, m), 7,69-7,72 (1H, m), 7,73 to 7.75 (1H, m).

MS (ESI) m/z: 381 (M+H)+.

(65e) 3-[(6-Cyclopentyloxy-1-methyl-1H-benzimidazole-2-yl)methoxy]benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-[(6-cyclopentyloxy-1-methyl-1H-benzimidazole-2-yl)methoxy]benzoate obtained in example (65d) (0,69 g and 1.83 mmol), 1 N. aqueous sodium hydroxide solution (2,75 ml to 2.75 mmol) and 1,4-dioxane (2,75 ml), to obtain the desired compound (0.21 g, yield: 31%) as a colourless solid.

1H-NMR (DMSO-D6, 400 MHz) δ: 1,50-to 1.61 (2H, m), of 1.62 and 1.75 (4H, m), 1,84-of 1.95 (2H, m), of 3.77 (3H, s), 4,82-4,88 (1H, m), 5,38 (2H, s), 6.73 x-6,77 (1H, m), 7.03 is-7,05 (1H, m), 7,31-to 7.35 (1H, m), 7,38-the 7.43 (1H, m), 7,44-7,47 (1H, m), 7,51-rate of 7.54 (1H, m), EUR 7.57-to 7.59 (1H, m), 13,00 (1H, users).

MS (FAB) m/z: 389 (M+Na)+.

Analyte. calculated for C21H22N2O4+0,2H2O: C, 68,17; H, 6,10; N, EUR 7.57. Found C, 68,34; H, 6,10; N, 7,54.

(Example 66) 3-{[1-Methyl-(6-tetrahydrofuran-3-yloxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-209)

(66a) of tert-Butyl [5-(tetrahydrofuran-3-yloxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 3-hydroxymitragynine (881 mg, 10 mmol who), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (2,87 g, 10 mmol), sodium hydride (>56% in oil, 380 mg, 10 mmol) and N,N-dimethylformamide (40 ml). The oil obtained (with 2.93 g) was directly used for the next reaction.

(66b) tert-Butyl [2-amino-5-(tetrahydrofuran-3-yloxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(tetrahydrofuran-3-yloxy)-2-nitrophenyl]methylcarbamate obtained in example (66a) (2,93 g, 8,7 mmol), iron powder (2.3 g, 43 mmol), ammonium chloride (0,23 g, 4.3 mmol), ethanol (40 ml) and water (20 ml). The obtained oil (2.67 g) was directly used for the next reaction.

(66c) [6-(Tetrahydrofuran-3-yloxy)-1-methyl-1H-benzimidazole-2-yl]methanol

The synthesis was carried out in the same way as in example (28c)using tert-butyl [2-amino-5-(tetrahydrofuran-3-yloxy)phenyl]methylcarbamate obtained in example (66b) (2.67 g, 8,7 mmol), glycolic acid (1.0 g, 13,0 mmol), 5 n hydrochloric acid (25 ml) and dioxane (25 ml). The obtained oil (1.39 g, yield: 65%) was directly used for the next reaction.

(66d) Methyl 3-{[6-(tetrahydrofuran-3-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

The reaction and post treatment were carried out according to example (28d)using [6-(tetrahydrofuran-3-yloxy)-1-methyl-1H-benzimidazole-2-yl]methanol obtained in example (66c) (,39 g, 5,6 mmol), methyl 3-hydroxybenzoate (2.83 g, and 11.2 mmol), tri-n-butylphosphine (2.8 ml, and 11.2 mmol), 1,1'-(azodicarbon)dipiperidino (2.83 g, and 11.2 mmol) and dichloromethane (56 ml), to obtain the desired compound (1.28 g, yield: 60%) as a colourless solid.

1H-NMR (CDCl3, 400 MHz) δ: 2,23-of 2.27 (2H, m), 3,86 (3H, s), 3,94-3,98 (1H, m), of 3.95 (3H, s), a 4.03-4,08 (3H, m), 5,01-of 5.05 (1H, m), 5,41 (2H, s), 6,80-PC 6.82 (1H, m), 6,91-6,94 (1H, m), 7,30-7,34 (3H, m), 7,38-7,42 (1H, m), 7.68 per-7,72 (2H, m), 7,73 to 7.75 (1H, m).

MS (EI) m/z: 383 (M+H)+.

(66e) 3-{[6-(Tetrahydrofuran-3-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(tetrahydrofuran-3-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate obtained in example (66d) (1.28 g, 3.35 mmol), 1 N. aqueous sodium hydroxide solution (5.0 ml, 5.0 mmol) and 1,4-dioxane (5.0 ml), to obtain the desired compound (0.55 g, yield: 45%) as a colourless solid.

1H-NMR (DMSO-D6, 400 MHz) δ: 1,92 is 2.01 (1H, m), 2,16 was 2.25 (1H, m), 3,71-3,91 (4H, m), of 3.78 (3H, s), 5,03-5,08 (1H, m), 5,38 (2H, s), 6,76-for 6.81 (1H, m), 7,07-7,10 (1H, m), 7,31 and 7.36 (1H, m), 7,38-the 7.43 (1H, m), 7,47-7,53 (2H, m), EUR 7.57-of 7.60 (1H, m), 13,00 (1H, users).

MS (FAB) m/z: 391 (M+Na)+.

Analyte. calculated for C20H20N2O5+0,2H2O: C, 64,58; H, OF 5.53; N, 7,53. Found C, 64,55; H, 5,43; N, 7,43.

(Example 67) 3-{[6-(1-Ethylpropoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid (compound No. 1-161)

(67a) tert-Butyl [5-(1-ethylpropoxy)-2-nitrophenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28a)using 3-pentanol (to 4.23 g, 48 mmol), tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (11,47 g, 40 mmol), sodium hydride (>56% in oil and 1.83 g, 48 mmol) and N,N-dimethylformamide (200 ml). The oil obtained directly used for the next reaction.

(67b) tert-Butyl [2-amino-5-(1-ethylpropoxy)phenyl]methylcarbamate

The synthesis was carried out in the same way as in example (28b)using tert-butyl [5-(1-ethylpropoxy)-2-nitrophenyl]methylcarbamate obtained in example (67a) (13,54 g, 40 mmol), iron powder (10,71 g, 200 mmol), ammonium chloride (1.07 g, 20 mmol), ethanol (100 ml) and water (100 ml). The oil obtained directly used for the next reaction.

(67c) of Methyl 3-[2-({1-ethylpropoxy)-2-[(tert-butoxycarbonyl)(methyl)amino]phenyl}amino)-2-oksidoksi]benzoate

The reaction and post treatment were carried out according to example (68d), using tert-butyl [2-amino-5-(1-ethoxypropane)phenyl]methylcarbamate obtained in example (67b) (12,34 g, 40 mmol), [3-(methoxycarbonyl)phenoxy]acetic acid (to 8.41 g, 40 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (8,43 g, 44 mmol), 1-hydroxybenzotriazole (5,95 g, 44 mmol) and dichloromethane (100 ml), to obtain solid, which was directly used for the next R the shares.

(67d) Methyl 3-{[6-(1-ethylpropoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoate

Methyl 3-[2-({1-ethylpropoxy)-2-[(tert-butoxycarbonyl)(methyl)amino]phenyl}amino)-2-oksidoksi]benzoate obtained in example (67c), was dissolved in 4 BC solution of hydrochloric acid in dioxane and the mixture was heated under reflux for 10 minutes. After cooling to room temperature the reaction solution was evaporated under reduced pressure and the obtained residue was added dichloromethane. The mixture was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. Then, the filtrate was evaporated under reduced pressure. The obtained residue was purified by automated purification system production Isco (30% ethyl acetate-hexane) and washed with a mixture of diisopropyl ether-hexane to obtain specified in the title compound (7.7 g, yield over four steps: 61%) as a colourless solid.

1H-NMR (CDCl3, 400 MHz) δ: 0,95 (5H, t, J=7.4 Hz), 1,63-1,72 (4H, m), with 3.79 (3H, s), 3,88 (3H, s), 4,08-4,16 (1H, m), 5,33 (2H, s), 6,77-to 6.80 (1H, m), 6,86-6,91 (1H, m), 7,22-7,26 (2H, m), 7,31-to 7.35 (1H, m), EUR 7.57-of 7.70 (3H, m).

MS (EI) m/z: 369 (M+H)+.

(67e) 3-{[6-(1-Ethylpropoxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[6-(1-ethylpropoxy)-1-methyl-1H-benzimidazo the-2-yl]methoxy}benzoate, obtained in example (67d) (of 7.69 g, 20,11 mmol), 1 N. aqueous sodium hydroxide solution (30,16 ml, 30,16 mmol) and tetrahydrofuran (100 ml), to obtain the desired compound (6.8 g, yield: 92%) as a colourless solid.

1H-NMR (DMSO-D6, 400 MHz) δ: to 0.89 (6H, t, J=7.4 Hz), 1,53-of 1.65 (4H, m), of 3.77 (3H, s), 4.26 deaths (1H, s)5,38 (2H, s), 6,77-for 6.81 (1H, m), 7,07-7,10 (1H, m), 7,31 and 7.36 (1H, m), 7,38-7,44 (1H, m), 7,44-of 7.48 (1H, m), 7,51-of 7.55 (1H, m,), EUR 7.57-to 7.61 (1H, m), 12,99 (1H, s).

MS (FAB) m/z: 391 (M+Na)+.

Analyte. calculated for C21H24N2O4: C 68,46; H, TO 6.57; N, 7,60. Found C, 68,20; H, Of 6.52; N, 7,58.

(Example 68) 3-{[5-(3-Fluoro-4-methylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid (compound No. 1-227)

(68a) 6-(3-Fluoro-4-methylphenoxy)-N-methyl-3-nitropyridine-2-amine

Required is specified in the header connection (1,94 g, yield: 70%) was obtained as a yellow powder in accordance with the method described in example (31a), using 6-chloro-N-methyl-3-nitropyridine-2-amine (J. Med. Chem., 43, 3052, 2000, 1.88 g, 10 mmol), 3-fluoro-4-METHYLPHENOL (1.51 g, 12 mmol) and sodium hydride (56%, and 0.46 g of 12.0 mmol).

1H-NMR (DMSO-d6, 400 MHz) δ: of 2.25 (3H, s), was 2.76 (3H, d, J=4,7 Hz), 6,30 (1H, d, J=9.0 Hz), 7,02 (1H, DD, J=2,4, 8.6 Hz), 7,18 (1H, DD, J=2,0, a 10.6 Hz), 7,35 (1H, t, J=8.6 Hz), 8,44 (1H, d, J=9.0 Hz), the rate of 8.75 (1H, users).

(68b) 6-(3-Fluoro-4-methylphenoxy)-N2-methylpyridine-2,3-diamine

Required is listed in the title compound (1.73 g, yield: 99%) was obtained as a brown oil in accordance with the by procedure, described in example (31b), using 6-(3-fluoro-4-methylphenoxy)-N-methyl-3-nitropyridine-2-amine, obtained in example (68a) (1,94 g, 7.0 mmol)and iron powder (1,95 g 35,0 mmol).

1H-NMR (CDCl3, 400 MHz) δ: 2,24 (3H, s), 2,96 (3H, d, J=4,7 Hz)to 4.41 (1H, users), 5,95 (1H, d, J=7.8 Hz), to 6.80 (1H, s), PC 6.82 (1H, s), to 6.88 (1H, d, J=7.8 Hz), 7,11 (1H, t, J=8,2 Hz).

(68) [3-(Methoxycarbonyl)phenoxy]acetic acid

A solution of tert-butylbromide (506 g, 2.6 mol), methyl 3-hydroxybenzoate (395 g, 2,60 mol) and potassium carbonate (789 g, 5,71 mol) in DMF (2 l) was stirred at room temperature for four hours. The reaction mixture was concentrated under reduced pressure and added ethyl acetate (2 liters). The mixture was washed with water (1 l) twice, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude tert-butyl [3-(methoxycarbonyl)phenoxy]acetate. The anisole (100 ml) and triperoxonane acid (680 ml) was added to a solution of ester obtained in methylene chloride (1 l) and the mixture was stirred at room temperature for three days. The reaction mixture was concentrated under reduced pressure. The residue was led from diisopropyl ether to obtain specified in the connection header (476 g, 87%) as a white solid.

1H-NMR (CDCl3, 400 MHz) δ: 3,93 (3H, s), was 4.76 (2H, s), 7,18 (1H, DD, J=2,7, 8,2 Hz), 7,40 (1H, t, J=8,2 Hz), 7,58 (1H, DD, J=1,6, 2.7 Hz), 773 (1H, d, J=7,4 Hz).

(68d) Methyl 3-(2-{[6-(3-fluoro-4-methylphenoxy)-2-(methylamino)pyridine-3-yl]amino}-2-oksidoksi)benzoate

A solution of 6-(3-fluoro-4-methylphenoxy)-N2-methylpyridine-2,3-diamine obtained in example (68b) (1,11 g of 4.49 mmol), [3-(methoxycarbonyl)phenoxy]acetic acid obtained in example (68) (0,94 g of 4.49 mmol), WSC·HCl (0,86 g of 4.49 mmol) and HOBt (0,61 g of 4.49 mmol) in methylene chloride (100 ml) was stirred at room temperature for days. The reaction mixture was concentrated under reduced pressure. Then the residue was purified by chromatography on silica gel (hexane:ethyl acetate, 1:1) to obtain the specified title compound (1.97 g, yield: 79%) as a brown oil.

1H-NMR (CDCl3, 400 MHz) δ: of 2.27 (3H, d, J=2.0 Hz), of 2.86 (3H, s), of 3.95 (3H, s), a 4.53 (1H, users), to 4.73 (2H, s), equal to 6.05 (1H, d, J=8,2 Hz), 6,85-of 6.90 (2H, m), to 7.15 (1H, t, J=9.0 Hz), 7,21 (1H, DDD, J=0,8, of 2.7 and 8.2 Hz), was 7.36 (1H, d, J=7.8 Hz), 7,46 (1H, t, J=7.8 Hz), to 7.67 (1H, DD, J=1,1, 2.4 Hz), 7,74 (1H, s), 7,78 (1H, dt, J=1,1, 7,8 Hz).

(68e) Methyl 3-{[5-(3-fluoro-4-methylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoate

Methyl 3-(2-{[6-(3-fluoro-4-methylphenoxy)-2-(methylamino)pyridine-3-yl]amino}-2-oksidoksi)benzoate obtained in example in example (68d) (1.56 g, 3,55 mmol), and acetic acid (20 ml) was stirred at 80°C during the day. Allowing the reaction solution to cool, was added to the reaction mixture water (100 ml) followed by extraction with ethyl acetate (100 ml). Then the organic SL the St was washed with saturated sodium bicarbonate solution (100 ml) twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure the residue was purified by chromatography on silica gel (hexane:ethyl acetate, 1:1) to obtain the specified title compound (1.13 g, yield: 76%) as a white solid.

1H-NMR (CDCl3, 400 MHz): δ to 2.29 (3H, d, J=1.6 Hz), of 3.84 (3H, s), 3,93 (3H, s)5,38 (2H, s), 6,83 (1H, d, J=8.6 Hz), 6,86-6,91 (2H, m), 7,18 (1H, t, J=8.6 Hz), 7,26-7,29 (1H, m), 7,38 (1H, t, J=7.8 Hz), 7,69-7,72 (2H, m,), 8,03 (1H, d, J=8.6 Hz).

(68f) 3-{[5-(3-Fluoro-4-methylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid

Required is specified in the header connection (0,79 g, yield: 72%) was obtained as a white powder in accordance with the method described in example (33e), using methyl 3-{[5-(3-fluoro-4-methylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoate obtained in example (68e) (1.13 g, 2.68 mmol).

1H-NMR (DMSO-d6, 400 MHz) δ: of 2.23 (3H, s), 3,70 (3H, s)5,41 (2H, s)6,91 (1H, d, J=8,2 Hz), 6,91-6,94 (1H, m), 7,05 (1H, DD, J=2,4, and 11.0 Hz), to 7.15 (1H, d, J=9.0 Hz), 7,28 (1H, d, J=7.8 Hz), 7,32 (1H, d, J=8,2 Hz), 7,51 (1H, d, J=7,4 Hz), EUR 7.57 (1H, DD, J=1,2, 2,4 Hz)to 8.14 (1H, d, J=8.6 Hz).

MS (FAB+) m/z: 408 (M+H)+.

TPL: 205-207°C.

(Example 69) 3-{[3-Methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid (compound No. 1-221)

(69a) N-Methyl-6-(4-methylphenoxy)-3-nitropyridine-2-amine

The synthesis was carried out in the same way as in example (28a)using 4-METHYLPHENOL (5.0 g, 46 mmol), 6-chloro-N-methyl-3-nitropyridine-2-amine (7,4 g, 39 mmol), the hydride is the atrium (> 56% in oil, 2.0 g, 51 mmol) and N,N-dimethylformamide (50 ml). The obtained dark brown solid is directly used for the next reaction.

(69b) 3-Amino-2-N-methylamino-6-(4-methylphenoxy)pyridine

The synthesis was carried out in the same way as in example (28b)using N-methyl-6-(4-methylphenoxy)-3-nitropyridine-2-amine, obtained in example (69a) (10 g, 39 mmol), iron powder (11 g, 200 mmol), ammonium chloride (1.1 g, 20 mmol), ethanol (30 ml) and water (15 ml). The resulting oil was purified by chromatography on a column of silica gel (eluting solvent: hexane/ethyl acetate = 6/1 → 3/2). The desired compound (2.2 g, yield: 25%) was obtained as a dark brown oil by drying under reduced pressure.

1H-NMR (CDCl3, 400 MHz) δ: of 2.33 (3H, s), 2.91 in (2H, users), of 2.97 (3H, d, J=5,1 Hz)to 4.41 (1H, users), of 5.84 (1H, d, J=7.8 Hz), 6,85 (1H, d, J=7.8 Hz), 7,01 (2H, d, J=8.6 Hz), 7,13 (2H, d, J=8,2 Hz).

(69c) Methyl 3-(2-{[2-(methylamino)-6-(4-methylphenoxy)pyridine-3-yl]amino}-2-oksidoksi)benzoate

The synthesis was carried out in the same way as in example (28c)using 3-amino-2-N-methylamino-6-(4-methylphenoxy)pyridine (2.2 g, 9.7 mmol)obtained in example 69b), [3-(methoxycarbonyl)phenoxy]acetic acid (2.0 g, 9.7 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.2 g, 12 mmol), monohydrate, 1-hydroxybenzotriazole (1.8 g, 12 mmol) and dichloromethane (40 ml). The crude product was purified of chromatographie is on a column of silica gel (eluting solvent: hexane/ethyl acetate = 3/1→6/5). The desired compound (3.7 g, yield: 90%) was obtained as a dark green oil by drying under reduced pressure.

1H-NMR (CDCl3, 400 MHz) δ: 2,35 (3H, s), is 2.88 (3H, s), of 3.94 (3H, s), 4.72 in (2H, s), 5,96 (1H, d, J=8,2 Hz), 7,02-was 7.08 (2H, m), 7,16 (2H, d, J=8,2 Hz), 7,20 (1H, DDD, J=1,2, of 2.7 and 8.2 Hz), 7,32 (1H, d, J=8,2 Hz), was 7.45 (1H, t, J=8.0 Hz), 7,66 (1H, DD, J=1,4, 2,5 Hz), 7,73 (1H, s), to 7.77 (1H, dt, J=1,0, 1,2, and 7.6 Hz).

MS (FAB) m/z: 422 (M+H)+.

(69d) Monohydrochloride methyl 3-{[3-methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoate

Methyl 3-(2-{[2-(methylamino)-6-(4-methylphenoxy)pyridine-3-yl]amino}-2-oksidoksi)benzoate obtained in example (69c) (3.7 g, 8,7 mmol), was dissolved in acetic acid (40 ml) and the solution was heated under reflux for 3.5 hours. After cooling to room temperature, concentrated to the reaction solution was added an aqueous solution of sodium bicarbonate (100 ml) followed by extraction with ethyl acetate (120 ml × 2). The obtained organic layers were washed with water (100 ml) and saturated salt solution (80 ml) and then dried over anhydrous magnesium sulfate. Evaporated under reduced pressure, the solvent and the resulting pale brown oil directly used for the next reaction.

(69e) 3-{[3-methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using the methyl 3-{[3-methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoate, obtained in example (69d) (3.5 g, 8.3 mmol), 1 N. aqueous sodium hydroxide solution (18 ml, 18 mmol) and 1,4-dioxane (20 ml), to obtain the desired compound (2.8 g, yield: 82%) as a white solid.

1H-NMR (DMSO-d6, 400 MHz) δ: 2,32 (3H, s), 3,70 (3H, s), vs. 5.47 (2H, s)6,86 (1H, d, J=8.6 Hz), 7,06 (2H, d, J=8,2 Hz), 7,22 (2H, d, J=7.8 Hz), 7,35-7,39 (1H, m), 7,45 (1H, t, J=7.8 Hz), a 7.62 (1H, DD, J=1,4, 2,5 Hz), 7,58 (1H, dt, J=1,3, 7.5 Hz), to 8.12 (1H, d, J=8.6 Hz), of 13.05 (1H, users).

MS (FAB) m/z: 389 (M+H)+.

Analyte. calculated for C22H19N3O4: C, 67,86; H, TO 4.92; N, 10,79. Found C, 67,69; H, 4,71; N, Of 10.72.

(Example 70) 3-{[5-(3,4-Dimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid (compound No. 1-223)

(70a) 6-(3,4-Dimethylphenoxy)-N-methyl-3-nitropyridine-2-amine

The crude product of the desired specified in the title compound was obtained as a yellow powder in accordance with the method described in example (28a)using 3,4-dimethylphenol (vs. 5.47 g, with 44.8 mmol), 6-chloro-N-methyl-3-nitropyridine-2-amine (7,00 g of 37.3 mmol) and sodium hydride (63%, 1,71 g, with 44.8 mmol). The crude product is directly used for the next reaction.

(70b) 6-(3,4-Dimethylphenoxy)-N2-methylpyridine-2,3-diamine

Required is listed in the title compound (2.83 g, yield: 31%) was obtained as a brown oil in accordance with the method described in example (28b)using 6-(3,4-dimethylphenoxy)-N-methyl-3-nitrophe the one-2-amine, obtained in example (70a) (10.2 g, of 37.3 mmol), iron powder (10.4 g, 187 mmol) and ammonium chloride (1,00 g, to 18.7 mmol).

1H NMR (CDCl3, 400 MHz) δ: 2,05 (3H, s), of 2.23 (3H, s), 2,98 (3H, d, J=5,1 Hz), of 5.82 (1H, d, J=7.8 Hz), at 6.84 (2H, s), make 6.90 (1H, d, J=2.7 Hz), 7,07 (1H, d, J=8,2 Hz).

(70c) Methyl 3-(2-{[6-(3,4-dimethylphenoxy)-2-(methylamino)pyridine-3-yl]amino}-2-oksidoksi)benzoate

Required is specified in the header connection (4,45 g, yield: 88%) was obtained as a brown powder in accordance with the method described in example (28c), using 6-(3,4-dimethylphenoxy)-N2-methylpyridine-2,3-diamine obtained in example (70b) (2.83 g, 11.6 mmol), [3-(methoxycarbonyl)phenoxy]acetic acid (2,44 g, 11.6 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2,23 g, 11.6 mmol) and the monohydrate of 1-hydroxybenzotriazole (1,57 g, 11.6 mmol).

1H NMR (CDCl3, 400 MHz) δ: of 2.25 (3H, in), 2.25 (3H, s), 2,89 (3H, s), of 3.94 (3H, s), 4.72 in (2H, s), to 5.93 (1H, d, J=8,2 Hz), 6.89 in (1H, DD, J=2,7, 8,2 Hz), 6,94 (1H, d, J=2.3 Hz), 7,11 (1H, d, J=7.8 Hz), 7,19 (1H, DD, J=2,7 and 8.2 Hz), 7,31 (1H, d, J=8,2 Hz), 7,44 (1H, t, J=8.0 Hz), of 7.64-to 7.67 (1H, m), 7,73-7,80 (2H, m).

(70d) Methyl 3-{[5-(3,4-dimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoate

Required is specified in the header connection (3,21 g, yield: 75%) was obtained as a white powder in accordance with the method described in example (28d)using methyl 3-(2-{[6-(3,4-dimethylphenoxy)-2-(methylamino)pyridine-3-yl]amino}-2-oksidoksi)benzoate obtained in example(70c) (4,45 g, 10.2 mmol), and acetic acid (51,0 ml).

1H NMR (CDCl3, 400 MHz) δ: of 2.27 (3H, s), and 2.27 (3H, s), 3,85 (3H, s)to 3.92 (3H, s), lower than the 5.37 (2H, s), of 6.75 (1H, d, J=8.6 Hz), 6.90 to (1H, DD, J=2,3, 7,8 Hz), to 6.95 (1H, d, J=2.3 Hz), 7,14 (1H, d, J=8.6 Hz), 7,25-7,29 (2H, m), 7,38 (1H, t, J=7.8 Hz), to 7.67-7,73 (2H, m).

(70e) 3-{[5-(3,4-Dimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid

Required is specified in the header connection (2,90 g, yield: 95%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-{[5-(3,4-dimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoate obtained in example (70d) (3,16 g, EUR 7.57 mmol), and 1 N. aqueous sodium hydroxide solution (11,4 ml of 11.4 mmol).

1H NMR (DMSO-d6, 400 MHz) δ: 2,22 (3H, s), 2,22 (3H, s), 3,71 (3H, s), vs. 5.47 (2H, s), PC 6.82 (1H, d, J=8.6 Hz), to 6.88 (1H, DD, J=2,7, 8,2 Hz), of 6.96 (1H, d, J=2.7 Hz), 7,16 (1H, d, J=7.8 Hz), 7,37 (1H, DDD, J=1,2, of 2.7 and 8.2 Hz), was 7.45 (1H, t, J=7.8 Hz), 7,56-to 7.59 (1H, m), 7,62-to 7.64 (1H, m), 8,10 (1H, d, J=8,2 Hz), 13,03 (1H, s).

MS (FAB) m/z: 404 (M+H)+.

(Example 71) 3-{[5-(3,5-Dimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid (compound No. 1-225)

(71a) 6-(3,5-Dimethylphenoxy)-N-methyl-3-nitropyridine-2-amine

The synthesis was carried out in the same way as in example (28a)using 3,5-dimethylphenol (5.0 g, 45 mmol), 6-chloro-N-methyl-3-nitropyridine-2-amine (7,1 g, 38 mmol), sodium hydride (>56% in oil, 2.0 g, 49 mmol) and N,N-dimethylformamide (50 ml). The obtained yellow solid neposredno is but used for the next reaction.

(71b) 3-Amino-6-(3,5-dimethylphenoxy)-2-N-methylaminopropyl

6-(3,5-Dimethylphenoxy)-N-methyl-3-nitropyridine-2-amine, obtained in example (71a) (10 g, 37 mmol), was dissolved in ethanol (100 ml) under nitrogen atmosphere was added 10% palladium-on-coal (2.0 g). The atmosphere was replaced with hydrogen and the mixture was intensively stirred at room temperature for 1.2 hours. Again substituted atmosphere of nitrogen, after which the catalyst was filtered through celite. The filtrate was dried under reduced pressure to obtain the desired compound in the form of purple-red oil, which was directly used for the next reaction.

(71c) Methyl 3-(2-{[6-(3,5-dimethylphenoxy)-2-(methylamino)pyridine-3-yl]amino}-2-oksidoksi)benzoate

The synthesis was carried out in the same manner as in (57c), using 3-amino-6-(3,5-dimethylphenoxy)-2-N-methylaminopropyl (12 g, 37 mmol)obtained in example (71b), [3-(methoxycarbonyl)phenoxy]acetic acid (7.7 g, 37 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (8,4 g, 44 mmol) and dichloromethane (150 ml). Obtained the desired compound as a gray amorphous compounds directly used for the next reaction.

(71d) of Methyl 3-{[5-(3,5-dimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoate

Methyl 3-(2-{[6-(3,5-dimethylphenoxy)-2-(methylamino)pyridine-3-yl]amino}-2-oksidoksi)benzoate obtained in example (71c) (16 g, 3 mmol), was dissolved in acetic acid (150 ml) and the mixture was heated under reflux for 2.5 hours. The reaction solution was concentrated. Added ethyl acetate (5 ml) and saturated aqueous sodium bicarbonate solution and the mixture was subjected to ultrasonic processing. Phase precipitate a pale-brown solid was collected by filtration to obtain the desired compound (13 g, yield: 86%).

1H-NMR (DMSO-d6, 400 MHz) δ: 2,32 (6H, s), 3,86 (3H, s), 3,93 (3H, s)5,38 (2H, s)of 6.71-for 6.81 (3H, m), at 6.84 (1H, s), 7,29 (1H, DD, J=1,0, 2,5 Hz), 7,38 (1H, t, J=7.8 Hz), to 7.67-7,71 (1H, m), 7,72 (1H, DD, J=1,4, 2,5 Hz), 7,99 (1H, d, J=8.6 Hz).

MS (FAB) m/z: 418 (M+H)+.

(71e) 3-{[5-(3,5-Dimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid

The reaction and post treatment were carried out according to example (28e)using methyl 3-{[5-(3,5-dimethylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoate obtained in example (71d) (13 g, 32 mmol), 1 N. aqueous sodium hydroxide solution (47 ml, 47 mmol) and 1,4-dioxane (50 ml), to obtain the desired compound (11 g, yield: 85%) in the form white solids.

1H-NMR (DMSO-d6, 400 MHz) δ: of 2.27 (6H, s), and 3.72 (3H, s), of 5.48 (2H, s), 6.75 in (2H, s), at 6.84 (2H, s), 7,34-7,41 (1H, m), 7,45 (1H, t, J=7.8 Hz), 7,58 (1H, d, J=7,4 Hz), 7,63 (1H, s)to 8.12 (1H, d, J=8.6 Hz).

MS (FAB) m/z: 404 (M+H)+.

Analyte. calculated for C23H21N3O4+0,33H2O: C, 67,47; H, 5,33; N, 10,26. Found C, 67,69; H, and 5.30; N, 1028.

(Example 72) 3-Fluoro-5-{[3-methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid (compound No. 1-222)

(72a) of Methyl 3-fluoro-5-(2-{[2-(methylamino)-6-(4-methylphenoxy)pyridine-3-yl]amino}-2-oksidoksi)benzoate

Required is listed in the title compound (2.65 g, yield: 73%) was obtained as a brown powder in accordance with the method described in example (68d), using 6-(4-methylphenoxy)-N2-methylpyridine-2,3-diamine obtained in example 69b) (1.88 g, by 8.22 mmol), [3-fluoro-5-(methoxycarbonyl)phenoxy]acetic acid (1.88 g, by 8.22 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1,58 g, by 8.22 mmol) and the monohydrate of 1-hydroxybenzotriazole (1,11 g, by 8.22 mmol).

1H NMR (CDCl3, 400 MHz) δ: at 2.36 (3H, s), 2,90 (3H, s), of 3.94 (3H, s), 4,71 (2H, s), 5,96 (1H, d, J=8,2 Hz), 6,93 (1H, TD, J=2,3, and 9.4 Hz), 7,05 (2H, d, J=8.6 Hz), 7,17 (2H, d, J=8.6 Hz), 7,31 (1H, d, J=8,2 Hz), 7,44-7,49 (2H, m), 7,71 (1H, s).

(72b) of Methyl 3-fluoro-5-{[3-methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoate

Required is listed in the title compound (2.17 g, yield: 85%) was obtained as a white powder in accordance with the method described in example 68e)using methyl 3-fluoro-5-(2-{[2-(methylamino)-6-(4-methylphenoxy)pyridine-3-yl]amino}-2-oksidoksi)benzoate obtained in example (72a) (2.65 g, 6,09 mmol), and acetic acid (30,0 ml).

1H NMR (CDCl3, 500 MHz) δ: is 2.37 (3H, s), 3,82 (3H, s)to 3.92 (3H, s), are 5.36 (2H, s), is 6.78 (1H, d, J=8,8 Hz), 6,98-7,03 (1H, m), 7,06 (2H,d, J=8,3 Hz), 7,19 (2H, d, J=8,8 Hz), of 7.36-7,40 (1H, m), 7,51-rate of 7.54 (1H, m), to 7.99 (1H, d, J=8,3 Hz).

(72c) 3-Fluoro-5-{[3-methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoic acid

Required is listed in the title compound (1.52 g, yield: 72%) was obtained as a white powder in accordance with the method described in example (28e)using methyl 3-fluoro-5-{[3-methyl-5-(4-methylphenoxy)-3H-imidazo[4,5-b]pyridine-2-yl]methoxy}benzoate obtained in example (72b) (2.17 g of 5.15 mmol), and 1 N. aqueous sodium hydroxide solution (7,72 ml, 7,72 mmol).

1H NMR (DMSO-d6, 400 MHz) δ: 2,32 (3H, s), of 3.69 (3H, s), of 5.50 (2H, s)6,86 (1H, d, J=8.6 Hz), 7.03 is-to 7.09 (2H, m), 7,20-of 7.25 (2H, m), 7,28 and 7.36 (2H, m), 7,46-7,49 (1H, m)to 8.12 (1H, d, J=8.6 Hz), 13,38 (1H, s).

MS (FAB) m/z: 408 (M+H)+.

Example 1 tests: Hypoglycemic effect

Six of male mice (KK) were purchased from CLEA Japan, Inc. and then fed until the age of 15-20 weeks to develop diabetes. Mice were fed individually during the adaptation period and test period, and water and food (FR2, Funabashi Farm), mice received free admission.

In the beginning of the experiment after measurement of body weight took the blood from the tail vein of mice in a glass test tube with heparin coating and perform centrifugation, after which the separated plasma. Measured the level of glucose in plasma using Glucoloader GXT (A&T Corp.) and chose individuals with glucose levels in the plasma of about 350 mg/dl or bol is E. Mice were grouped 3-4 mice in each group so that the average body weight and the average level of glucose in plasma were the same. Each compound was administered to a group of compounds with a nutrient mixture containing 0.03% of the connections. A separate group, in which mice were fed only food was the control group.

The experimental period (the period of drug administration) accounted for three days. Day grouping was at 0, the 3rd was measured body weight and took the blood from the tail vein to measure the level of glucose in plasma.

Hypoglycemic factor was determined by the following formula.

Hypoglycemic factor = [(level of blood glucose in the control group, the level of glucose in the blood in the group of mice that were injected connection)/level of blood glucose in the control group] × 100

The results obtained are shown in table 2.

Table 2
ExampleHypoglycemic factor (%)
237
829
1035
1230
1433
1660
2861
2960
3147
3342
4151
4229
4948
5432
5544
5947
6750
6943
7038
7242

As is clear from table 2, the compound of the present invention has a hypoglycemic effect. Therefore, it is assumed that the connection of the present invention should be useful as a therapeutic agent for diabetes (in particular, a therapeutic agent for diabetes type II).

To trace the actual operation examples 2-5 test each operation was carried out in accordance with the method, described in the literature (Sambrook, J., Fritsch, E. F. and Maniatis, T., "Molecular Cloning", Cold Spring Harbor Laboratory Press, 1989), unless otherwise noted. Commercially available reagents and kits used in accordance with the attached instructions.

Example 2 tests: evaluation of the activity of PPARγ modulator

(Procedure 1) Chemical synthesis of DNA oligomer as a primer polymerase chain reaction

The primers in polymerase chain reaction ("PCR" (PCR) were designed based on gene sequences of the human PPARγ2 gene (GenBANK accession No. D83233). In areas before and behind the gene coding for the human PPARγ2 protein was injected sequence recognition for restriction enzyme BglII, where the sequence recognition necessary to insert a gene into the restriction site BamHI expressing plasmid pSG5 (Stratagene) for the gene. As PCR primers used two polynucleotide presented as SEQ ID NO:1 and 2 described later in the sequence listing (hereinafter "S1" and "AS1", respectively).

(Procedure 2) Chemical synthesis of DNA oligomer containing sensitive to PPARγ gene sequence

Two polynucleotide presented as SEQ ID NO:3 and 4 described later in the sequence listing (hereinafter "S2" and "AS2"), used to construct reporter plasmids containing sensitive to PPAR sequence, to change the program's ability to transcriptional activity through PPARγ. The inserted DNA fragment was designed based on the gene sequence in the promoter region of acyl-COA oxidase in rats (J. D. Tugwood, EMBO J, 1992, Vol. 11, No. 2, p. 433-439). Sequence recognition for restriction enzymes NheI was introduced in S2 and sequence recognition for the restriction enzyme XhoI was inserted in AS2 for insertion into the reporter plasmid pGV-P2 (Toyo Ink Mfg. Co., Ltd.).

(Procedure 3) Constructing expressing plasmids for human PPARγ

Figure 1 shows a schematic representation of expressing plasmids for PPARγ.

PCR was carried out using a thermostable DNA polymerase Ex-Taq (Takara Shuzo Co., Ltd.) with a cDNA library derived from human adipose tissue (Clontech) as a template and DNA oligomers S1 and AS1 obtained in procedure 1, as primers in PCR. In the amplified DNA fragment of about 1500 base pairs (hereinafter “software” (bp)). Repeating 30 times a cycle consisting of incubation at 94°C for one minute incubation at 55°C for 30 seconds and incubation at 72°C for 30 seconds. The obtained DNA fragment of about 1500 and was partially digested with restriction enzymes BglII and inserted into the restriction site BamHI plasmid pSG5 obtaining expressing plasmids pSG5-hPPARγ for human PPARγ. Method breakage dideoxynucleotides circuit confirmed that the DNA sequence is the basis of the s built-DNA fragment, was the human PPARγ2.

(Procedure 4) Construction of reporter plasmids

Figure 2 shows a schematic representation of PPRE reporter plasmid.

Vydaleny fragment (digest) vector pGV-P2 was obtained by cleavage with restriction enzymes NheI and XhoI and purified by electrophoresis in 1.0% agarose gel. DNA oligomers S2 and AS2 obtained in procedure 2, mixed, incubated in a hot water bath at 94°C for one minute and then incubated at 25°C for one hour to form a double-strand DNA annealed with S2 and AS2. Then the ends of double-strand DNA was fosforilirovanii using DNA polynucleotides (Toyobo Co., Ltd.), and then ligated to the previously obtained visiblename fragment pGV-P2, using the restriction sites NheI and XhoI, obtaining reporter plasmid pGV-P2-PPRE containing sensitive to PPAR sequence.

(Procedure 5) gene Transfer into animal cells

E. coli HB-101 transformed the conventional method using the plasmid obtained in procedures 3 and 4. HB-101 containing the plasmid were cultured in L-medium containing 100 μg/ml ampicillin (containing 10 g of Tryptone (Difco), 5 g yeast extract (Difco) and 5 g of sodium chloride in 1 l of plasmid solution, respectively) at 37°C for 17 hours. Then the corresponding plasmids were purified alkaline-SDS method and used for gene transfer in the animal cells. pSG5-hPPARγ, pGV-P2-PPRE and the LipofectAMINE reagent (Invitrogen Cat. No. 18324-020) were mixed in accordance with the manual attached to the reagent LipofectAMINE. Gene temporarily transferred in osteosarcoma cells line MG63, after which the cells were collected. The collected cells were sown in each well of 96-hole tablet (COSTAR 3917) with the norm 30000-40000 cells/well, using α-MEM medium (GIBCO BRL Cat. No. 12571-048), mixed with 10% fetal serum cows (MOREGATE BATCH: 474030) with 10% (vol./about.) and Penicillin-Streptomycin, Liquid (GIBCO BRL Cat. No. 15140-122) at 1% (vol./about.) (hereinafter abbreviated as 10% α-MEM). Cells were cultured in CO2incubator (NAPCO) under conditions of 37°C, 5% CO2and 95%RH for 24 hours.

(Procedure 6) how to add a reagent for assessing the promoting effect transcriptional activity

Out of the tablet with the culture prepared in procedure 5, was removed Wednesday. The control group was injected with 10% α-MEM with 95 µl/well. The following compound A (compound A is shown as an example and the PPARγ agonist is not limited to them), prepared in the form of a 10 μm solution in DMSO, were diluted 1000-fold using a 10% α-MEM; obtained was inserted in the positive control group with 95 µl/well. Then DMSO, diluted 20-fold with 10% α-MEM, was injected in the control group and positive control group at 5 µl/well. The group entered the test compound was administered to 10% α-MEM with 95 µl/well. Then test the connection, RA is maintained DMSO to various concentrations of diluted 20-fold using a 10% α-MEM; obtained was introduced into the group entered the test compound at 5 µl/well.

(Connection and A method of its production)

Compound a: N-[4-[2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazole-6-yloxy]phenyl]benzamide

of 0.36 ml of triethylamine and 0.10 ml of benzoyl chloride was added dropwise to a solution of 400 mg of the dihydrochloride of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzyl]thiazolidin-2,4-dione in 8 ml of anhydrous N,N-dimethylformamide. The reaction solution was stirred at room temperature for one hour. Then evaporated under reduced pressure, the solvent and to the residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The ethyl acetate evaporated. The residue was purified by chromatography on a column of silica gel (ethyl acetate:n-hexane= 1:1→2:1→3:1→4:1) to obtain 247 mg of the desired compound as a white powder.

Melting point: 200-204°C.

(Procedure 7) how to add a reagent for assessing inhibitory effect transcriptional activity

From tablet c culture, prigotovlennoi in procedure 5, was removed Wednesday. The control group was injected with 10% α-MEM with 95 µl/well. The above compound A prepared in the form of a 10 μm solution VDMA, diluted 1000-fold using a 10% α-MEM; obtained was inserted in the positive control group with 95 µl/well. Then DMSO was diluted 20-fold with 10% α-MEM; obtained was injected in the control group and positive control group at 5 µl/well. The compound A prepared in the form of a 10 μm solution in DMSO, were diluted 1000-fold using a 10% α-MEM; obtained was introduced into the group entered the test compound in 95 µl/well. Then the test compound, diluted with DMSO to various concentrations was diluted 20-fold using a 10% α-MEM; obtained was introduced into the group entered the test compound at 5 µl/well.

(Procedure 8) the Method of measuring luciferase activity

Cells obtained in treatments 6 and 7 were cultured for 24 hours and then deleted the environment. Saline Dulbecco containing phosphate buffer (GIBCO BRL Cat. No. 14040-117 or SIGMA CHEMICAL CO. Cat. No. D8662), was added to equal amount of luciferase luminescent substrate LT 2,0 (Wako Pure Chemical Industries, Ltd., Cat. No. 309-05884); obtained was injected at 50 μl/well. The mixture was allowed to stand at room temperature for about 10 minutes and then stirred by micromixers (TAITEC E-36). We measured luciferase activity instrument Analyst (Molecular Devices) and traced the curve depending on the dose.

(Procedure 9) the Method of calculating the IC50and EC50

IC50, Imax, EC50and Emax tested is imago compounds were determined as follows. Figure 3 shows a conceptual diagram.

When the luciferase activity of the positive control group is equal to 100%, and the luciferase activity of the control group is 0%, maximum luciferase activity showed only the test compound is defined as Emax (%)and the maximum inhibition of luciferase activity of the test compound in the presence of compound A is defined as Imax (%). In this case, the concentration of the test compounds, representing Emax/2, is calculated as EC50. The concentration of the test compounds, representing (100 - Imax)/2, is calculated as IC50. Calculated in the manner described above IC50and EC50used to evaluate the activity of PPARγ modulator.

The measurement results are shown in table 3.

Table 3
ExampleEC50(M)Emax (%)IC50(M)Imax (%)
2of 3.28×10-9705,61×10-8-44
87,72×10-9 397,33×10-8-34
10to 2.06×10-942of 3.32×10-8-50
12of 2.34×10-942Android 4.04×10-8-43
14of 5.17×10-8546,37×10-8-35
16of 2.64×10-846as 4.02×10-7-44

As shown in table 3, the compounds of the present invention have a modulating PPARγ activity and are useful as therapeutic agents or preventive agents against the disease, based on dyslipidemia, arteriosclerosis, hyperlipidemia, diabetes, involutional osteoporosis, obesity, cancer or the like.

Example 3 test: Test for inhibition of adipocyte differentiation

This test was subjected to white adipocytes of rats included in the set for the cultivation purchased from Primary Cell Co. Ltd. Wednesday, which is set for the cultivation of white adipocytes purchased from Primary Cell Co., Ltd., used as a nutrient medium or environment, inducing differentiation. In this test all cells were cultured in an incubator with CO2(37°C, 95% humidity, 5% CO2).

All the transport medium was removed immediately after the arrival of the purchased cells. Was added to the nutrient medium in an amount of 5 ml/flask 25 cm2) and cells were cultured for one day. After that the prepared cell suspension (83000 cells/ml)using a nutrient medium. The cell suspension was distributed in 96-well microplate coated with collagen type I (Becton, Dickinson and Company) 5000-6000 cells/well (60 μl/well). Each tablet was included as a control group hole, which was made only a nutrient medium containing no cells (single hole).

The next day the entire culture medium was removed and introduced the environment, inducing differentiation, 147 μl/well. Then 1) for the group introduced the test connection 100 μm solution of test compound in DMSO was diluted 20-fold environment, inducing differentiation; received were injected with 3 μl/well (final concentration of the test compound: 100 nm, final concentration of DMSO is 0.1% (vol./about.)) in wells in which cells were sown, and added in lanceolatae above compound A at a final concentration of 3.3 nm (in this test the final concentration of DMSO was 0.01%, consequently, there was slight); 2) positive control group, DMSO, diluted 20-fold environment, inducing differentiation, were injected with 3 μl/well (final concentration of DMSO is 0.1% (vol./about.)) in wells in which cells were sown, and added to these wells compound A at a final concentration of 3.3 nm; 3) for the negative control group, DMSO, diluted 20-fold environment, inducing differentiation, were injected with 3 μl/well (final concentration of DMSO is 0.1% (vol./about.)) in wells in which cells were sown.

After culturing for five days of each well was removed the whole environment, inducing differentiation, and was introduced into each well 60 µl of 10% (vol./about.) solution of formaldehyde (fixing solution). Cells were incubated at room temperature for 20 minutes. All the fixing solution was removed and introduced into each well 60 μl of 0.2% (vol./about.) solution of Triton X-100 (Sigma). Cells were incubated at room temperature for five minutes. The whole solution of Triton X-100 was removed. To prepare lipid dye dissolving Oil Red O (Sigma) in 60% (vol./about.) isopropanolate solution at 0.3% (wt./about.) and 60 µl of the lipid dye was introduced into each well. Cells were incubated at room temperature for 10 minutes. All fat dye was removed, after which he entered and removed 60 ál 60% (vol./about.) isopropanolamide solution. That is they way each well was washed two times. Then to each well was injected DMSO at 100 μl per well, followed by stirring at room temperature for five minutes. Measured multiplexity reader (Bio-Tek Instruments Inc.) or the like of the optical density at 550 nm (ABS550) and measured the amount of staining dye Oil Red o was Calculated degree adipocyte differentiation (%) the group entered the test connection, assuming that the measured ABS550 positive control group was 100%and the measured ABS550 negative control group was equal to 0.

The results are shown in table 4. In table detectable (N.D.) means “undetectable” (value).

Table 4
ExampleIC50(M)Imax (%)
2of 1.2×10-8-33
85,3×10-8-29
104,5×10-8-29
12N.D.N.D.
14N.D. N.D.
16N.D.N.D.

As shown in table 4, the compounds of the present invention inhibit differentiation to adipocytes and are useful as anti-obesity.

Example 4 tests: Test for promotion adipocyte differentiation

This test was subjected to white adipocytes of rats included in the set for the cultivation purchased from Primary Cell Co., Ltd. Wednesday, which is set for the cultivation of white adipocytes purchased from Primary Cell Co., Ltd., used as a nutrient medium or environment, inducing differentiation. In this test all cells were cultured in an incubator with CO2(37°C, 95% humidity, 5% CO2).

All the transport medium was removed immediately after the arrival of the purchased cells. Was added to the nutrient medium in an amount of 5 ml/flask 25cm2) and cells were cultured for one day. After that the prepared cell suspension (83000 cells/ml)using a nutrient medium. The cell suspension was distributed in 96-well microplate coated with collagen type I (SUMITOMO BAKELITE Co., Ltd.) 5000 cells/well (60 μl/well). Each tablet was included as a control group hole, which was made only a nutrient medium containing no cells (Holos is th hole).

The next day the entire culture medium was removed and introduced the environment, inducing differentiation, 147 μl/well. Then 1) for the group introduced the test connection 100 μm solution of test compound in DMSO was diluted 20-fold environment, inducing differentiation; received were injected with 3 μl/well (final concentration of the test compound: 100 nm, final concentration of DMSO is 0.1% (vol./about.)) in wells in which cells were sown; 2) positive control group, DMSO, diluted 20-fold environment, inducing differentiation, were injected with 3 μl/well (final concentration of DMSO is 0.1% (vol./about.)) in wells in which cells were sown, and added to these wells compound A at a final concentration of 3.3 nm (in this test the final concentration of DMSO was 0.01% and, therefore, was insignificant); 3) negative control group, DMSO, diluted 20-fold environment, inducing differentiation, were injected with 3 μl/well (final concentration of DMSO is 0.1% (vol./about.)) in wells in which cells were sown.

After culturing for five days of each well was removed the whole environment, inducing differentiation, and was introduced into each well 60 µl of 10% (vol./about.) solution of formaldehyde (fixing solution). Cells were incubated at room temperature for 20 minutes. The whole fixative UD is ranged and introduced into each well 60 μl of 0.2% (vol./about.) solution of Triton X-100 (Sigma). Cells were incubated at room temperature for five minutes. The whole solution of Triton X-100 was removed. To prepare lipid dye dissolving Oil Red O (Sigma) in 60% (vol./about.) isopropanolate solution at 0.3% (wt./about.) and 60 µl of the lipid dye was introduced into each well. Cells were incubated at room temperature for 10 minutes. All fat dye was removed, after which he entered and removed 60 ál 60% (vol./about.) isopropanolamide solution. Thus, each well was washed two times. Then to each well was injected DMSO at 100 μl per well, followed by stirring at room temperature for five minutes. Measured multiplexity reader (Bio-Tek Instruments Inc.) the optical density at 550 nm (ABS550) and measured the amount of staining dye Oil Red o was Calculated degree adipocyte differentiation (%) the group entered the test connection, assuming that the measured ABS550 positive control group was 100%and the measured ABS550 negative control group was equal to 0.

The results are shown in table 5.

73
Table 5
ExampleEC50(M)Emax (%)
2of 4.2×10-9
8of 7.4×10-975
106,6×10-978
12of 5.2×10-982
14of 2.0×10-856
16of 6.4×10-871

As shown in table 5, the compounds of the present invention presumably partly promotirovat differentiation in adipocytes as a result of increased insulin sensitivity and are useful as antidiabetic agents.

Example 5 tests: Measurement of the effect of PPARγ activation and modulation of activity in relation to him

Rosiglitazone used in the examples is commercially available activator of PPARγ and represents a connection that is described in U.S. patent No. 5002953, and can be obtained in accordance with the method described in the above document.

The test was carried out in accordance with the method of reporter analysis, coping with the message Kliewer et al. (Journal of Biological Chemistry, 1995, Vol. 270 (22), p. 12953-12956) as a way of measuring the ability of the Union to activate PPARγ (hereinafter the effect of PPARγ activation and modulation of activity in relation to it). The details are described below.

(1) Obtaining expressing plasmids for chimerical receptor GAL4-PPARγ

The ligand-binding domain of human PPARγ (corresponding to about 300 amino acids at the carboxyl end) was associated with the DNA-binding domain of the yeast transcription factor GAL4 (147 corresponding to amino acids at the amino end), based on the message Kliewer et al., obtaining the gene expressing the receptor GAL4-PPARγ.

The sequence of bases of a gene of the human PPARγ described in gene GenBank database under access number Accession No. X90563.

(1-1) Extraction of total RNA from the cell line HepG2

Cell line HepG2 (American Type Culture Collection HB-8065) were purchased from Dainippon Pharmaceutical Co., Ltd. and were cultured in the flask for culturing tissues, with an area of cultivation 75 cm2(manufactured by BD Biosciences). As the environment used a modified, Dulbecco Wednesday Needle (Gibco D-MEM production Invitrogen Corporation) supplemented with fetal calf serum (manufactured by HyClone) in a volume of about 10% antibiotic solution (Antibiotic Antimycotic Solution, stabilized (100 ×), production Sigma] in volumetric ratio of 1%.

Cells were cultured in an incubator with an atmosphere of carbon dioxide at 37°C in 95% of the carbon dioxide within three days. When the cells were grown to approximately state polyline, the environment of the bulbs is removed by suction. Cells were washed by adding 10 ml) cooled with ice-salt solution with buffer (Gibco Dulbecco''s Phosphate-Buffered Saline production Invitrogen Corporation), after which the salt solution was removed by suction. Then to the cells in the flask was added 7.5 ml of reagent Trizol (Gibco TRIZOL reagent production Invitrogen Corporation) and stirred repeatedly acting pipette. Cells were literally incubation at room temperature for about five minutes.

Cell lysates were subjected to precipitation with isopropyl alcohol in accordance with the instructions for use Trizol. The precipitate RNA was dissolved in pure water and kept in the freezer at about -20°C. In this case, the volume of RNA solution was to 0.22 ml of the Sample obtained 100-fold dilution of a part of the solution RNA clean water, had an optical density equal to 0,562 at 260 nm. To calculate the yield of total RNA: 0,562×100×39,5×0,22=488 ug, assuming that 39,5 µg/ml RNA is available, when the optical density is equal to 1.

(1-2) cDNA Cloning of the ligand-binding domain of PPARγ

The following two deoxyoligonucleotide (primer 3 and primer No. 4), is designed based on the gene sequence of the human PPARγ, chemically synthesized as primers for amplification polymerase chain reaction with reverse transcription (hereinafter RT-PCR) cDNA ligand-binding domain of PPARγ, the use of the UYa Beckman Oligo 1000 (manufactured by Beckman).

PPARγ cDNA amplified using RT-PCR, using beads Ready-To-Go RT-PCR Beads (manufactured by Amersham Pharmacia Biotech, Inc.) with the previously derived HepG2 total RNA as template and the primers # 3 and # 4 as primers. The reaction product was subjected to electrophoresis in 1.5% agarose. Amplified tape length of about 900 base pairs was excised, purified and cloned into plasmid PCRII (produced by Invitrogen Corporation). It was assumed that amplificatory DNA fragment has the nucleotide sequence presented as SEQ ID NO:7 in sequence listing, which includes a sequence encoding a ligand-binding domain, in particular amino acids 175-475, human PPARγ, and is attached to the site of cleavage of the restriction enzyme BamHI and the site of restriction enzyme HindIII at the 5'-end and 3'end, respectively. In confirmation of the specified nucleotide sequence of the selected clone plasmids, containing exactly the sequence represented by SEQ ID NO:7.

(1-3) Obtaining the plasmid pM-PPARγ

Next, the selected plasmid was treated with restriction enzymes BamHI and HindIII to obtain a fragment with 900 base pairs, containing the gene for the ligand-binding domain of PPARγ. The obtained fragment was inserted into BamHI-HindIII site of the plasmid pM with genes DNA-binding domain of the yeast transcription factor GAL4 (manufactured by Clontech Laboratories, Inc.), was klonirovali.

Plasmid pM-PPARγ, obtained as indicated above, includes the nucleotide sequence represented by SEQ ID NO:8 in sequence listing, and encodes the amino acid sequence represented by SEQ ID NO:9 in the sequence listing containing amino acids 1-147 of the yeast transcription factor GAL4 in amine end and amino acids 175-475 human PPARγ and stop-codon at the carboxyl end. This plasmid is a gene that can Express the chimerical receptor GAL4-PPARγ in mammalian cells.

(2) Measurement of the ability to activate PPARγ

Previously obtained plasmid pM-PPARγ and plasmid pFR-Luc, were purchased from Stratagene Cloning Systems, Inc., was dissolved in deionized water at a concentration of 1 mg/ml each.

Derived from monkey kidney cell line COS-7 (American Type Culture Collection CRL-1651) were sown in a 75-cm2the flask cultivation and cultivated using the modified Dulbecco Wednesday Needle containing 10% fetal calf serum (the serum), under conditions of 37°C and 5% gaseous carbon dioxide to achieve the state, approximately 80% confluence.

Cells COS-7 transfectional 4,8-micrograms per flask plasmids pM-PPARγ and 19.2 mcg per flask plasmid pFR-Luc, using transfection reagent Lipofectamine 2000 (manufactured by Invitrogen Corporation), and cells were cultured overnight.

On the trail of the Mering day the cells were collected by treatment with trypsin, suspended in free of phenol red modified Dulbecco environment Needle containing 75 ml of 10% fetal calf serum, were sown in a white 96-well plate (manufactured by Costar), using a medium in a volume of 95 μl per well, and cultured overnight.

The test compound was dissolved in dimethyl sulfoxide at a concentration of 30 mm. The solution was serially diluted 6-fold dimethylsulfoxide to obtain solutions of the compounds with concentrations up to 18 nm. For the control group was used dimethyl sulfoxide. For a positive control group was used to rosiglitazone, dissolved in dimethyl sulfoxide at a concentration of 30 mm. Diluted 150-fold environment and 5 µl of the diluted solution was introduced into the wells, which were seeded cells. The concentration of the test compounds for the treatment of the cells were in the range from 10 μm to 0.006 nm. After this introduction, the cells were cultured overnight.

The next day the medium was removed, was used to Luc Lite (manufactured by PerkinElmer Inc.) in accordance with the enclosed document and contributed at the rate of 50 microliters per well. Tablets with cells in Luc Lite was stirred for about 30 minutes. Measured as luciferase activity value of luminescence in each well using Analyst (Molecular Devices), for 0.5 seconds. Was drew dependent curve is t to the dose.

When the luciferase activity of the positive control group was 100%, and the luciferase activity of the control group was 0%, maximum luciferase activity showed only the test compound was calculated as Emax (%)and concentration of the test compounds represented by Emax/2, was calculated as EC50.

The results obtained are shown in table 6.

Table 6
ExampleEC50(Microm)Emax (%)
20,298773,3
84,742691,0
100,067046,5
120,039760,2
140,844689,6
160,549760,9

As shown in table 6, the compounds of the present invention have an effect of PPARγ activation and modulation of the activity is using against him and are useful as therapeutic agents or preventive agents against diseases based on dyslipidemia, arteriosclerosis, hyperlipidemia, diabetes, involutional osteoporosis, obesity, cancer or the like.

Example 1 fabrication: Capsules

The compound of example 1650 mg
Lactose128 mg
Corn starch70 mg
Magnesium stearate2 mg
Total250 mg

Mix the powder of the above composition and give him pass through a sieve with openings 60 mesh. Then the powder was placed in a 250-mg gelatin capsules No. 3 with obtaining capsules.

Example 2 production: Tablets

The compound of example 1650 mg
Lactose126 mg
Corn starch23 mg
Magnesium stearate1 mg
Total200 mg

Mix the powder decree the frame above composition, put his wet granulation using a doughy mass of corn starch, dried and then tabletirujut using tablet press machine to obtain tablets each having a weight of 200 mg. Tablets can be coated with sugar, when it is needed.

Industrial applicability

Condensed bicyclic heteroaryl compounds or their pharmacologically acceptable salts of General formula (I) in accordance with the present invention have excellent hypoglycemic effects and are useful as therapeutic and/or prophylactic drugs against metabolic syndrome, in particular diseases, such as diabetes, hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance (IGT), insulin resistance, impaired glucose tolerance on an empty stomach (IFG), hypertension, fatty liver, nonalcoholic steatohepatitis (NASH), diabetic complications (such as retinopathy, nephropathy or neuropathy), arteriosclerosis, gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS), inflammatory diseases (such as osteoarthritis, pain or inflammatory enteritis), acne, solar erythema, psoriasis, eczema, allergic diseases, asthma, peptic ulcers, ulcerative colitis, Crohn's disease, coronary artery disease, Arte is esclerose, atherosclerosis, diabetic retinopathy, diabetic maculopathy, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorders, peripheral circulatory disorders, autoimmune diseases (such as systemic lupus erythematosus, chronic rheumatoid arthritis, Sjogren syndrome, systemic sclerosis, mixed soedinitelnotkannaja disease, Hashimoto's disease, Crohn's disease, ulcerative colitis, idiopathically Addison disease, male infertility syndrome?, rapidly progressive glomerulonephritis, severe psevdomatematicheskoe myasthenia gravis, polymyositis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Behcet's disease or CREST syndrome), pancreatitis, cachexia, cancer such as stomach cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, or liver cancer), leukemia, sarcoma (such as liposarcoma), osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease, hyperuricemia, or dry eyes.

Sequence listing

SEQ ID NO:1: PCR primer S1

SEQ ID NO:2: PCR primer AS1

SEQ ID NO:3: PCR primer S2

SEQ ID NO:4: PCR primer AS2

SEQ ID NO:5: PCR sense primer

SEQ ID NO:6: PCR antisense primer

SEQ ID NO:7: nucleotide sequence that is tedna the cDNA sequence synthetic human PPARγ

SEQ ID NO:8: Nucleotide sequence of the gene GAL4 chimerical PPARγ receptor

SEQ ID NO:9: Amino acid sequence of GAL4 chimerical PPARγ receptor

1. The compound of General formula (I)
[Formula 1]

where R1represents a C6-aryl group which may be substituted with 1-3 groups independently selected from the group of substituents (a), or heterocyclic group, which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl, which may be substituted with 1-3 groups independently selected from the group of substituents (a),
R2represents a C1-C6alkyl group,
R3represents a C6-aryl group which may be substituted by 1-2 groups independently selected from the group of substituents (a),
Q represents a group represented by the formula =CH-or a nitrogen atom, and
the group of substituents (a) represents the group consisting of a halogen atom, a C1-C6alkyl group, a C1-C6halogenated alkyl group, a carboxyl group, a C2-C7alkylcarboxylic group2-C7alkoxycarbonyl group, C1-C6alkoxygroup, C1-C6halogenated alkoxygroup, amino, 4-Mohali the ilen group and di(C 1-C6alkyl)amino group,
or its pharmacologically acceptable salt.

2. The compound or its pharmacologically acceptable salt according to claim 1, where R1represents a phenyl group which may be substituted by 1-3 groups independently chosen from a halogen atom, a C1-C6alkyl group, a C1-With6alkoxygroup, C1-C6halogenated alkoxygroup and amino group, or 2,3-dihydro-1-benzofuran-6-ilen group.

3. The compound or its pharmacologically acceptable salt according to claim 1, where R1is a 2-florfenicol group, 3-florfenicol group, 3-chloraniline group, 2,5-differenly group, 4-chloro-3-florfenicol group, 3-chloro-4-florfenicol group, 4-methylphenyl group, 3-ethylphenyl group, 3,4-dimethylphenyl group, 3-triphtalocyaninine group, 3-metoksifenilny group, 3-methoxy-4-methylphenyl group, 4-amino-3,5-dimethylphenyl group or a 2,3-dihydro-1-benzofuran-6-ilen group.

4. The compound or its pharmacologically acceptable salt according to claim 1, where R1is a 2-florfenicol group, 3-florfenicol group, 3-chloraniline group, 2,5-differenly group, 4-chloro-3-florfenicol group, 3-chloro-4-florfenicol group, 4-methylphenyl group or a 2,3-dihydro-1-benzofuran-6-ilen group.

5. Connection or Farmak is logically acceptable salt according to claim 1, where R2represents a methyl group, and Q represents a group represented by the formula =CH-.

6. The compound or its pharmacologically acceptable salt according to claim 1, where R3represents a phenyl group substituted by 1-2 fluorine atoms and/or carboxyl group(s).

7. The compound or its pharmacologically acceptable salt according to claim 1, where R3is a 3-carboxyphenyl group or 3-carboxyl-5-florfenicol group.

8. The compound or its pharmacologically acceptable salt according to claim 1, where the compound of General formula (I) is
3-{[6-(3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,
3-[6-(3-chlorophenoxy)-1-methyl-1H-benzimidazole-2-ylethoxy]benzoic acid,
3-{[6-(4-chloro-3-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,
3-{[6-(3-chloro-4-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,
3-{[6-(2-pertenece)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid,
3-{[1-methyl-6-(4-methylphenoxy)-1H-benzimidazole-2-yl]methoxy}benzoic acid,
3-{[6-(2,5-divergence)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid, or
3-{[6-(2,3-dihydro-1-benzofuran-6-yloxy)-1-methyl-1H-benzimidazole-2-yl]methoxy}benzoic acid.

9. Pharmaceutical composition having modulating activity against PPARγ, containing the connection on l is the Boma one of claims 1 to 8, or its pharmacologically acceptable salt as an active component.

10. The pharmaceutical composition according to claim 9, designed to lower blood glucose.

11. The pharmaceutical composition according to claim 9, intended for the treatment and/or prevention of diabetes.

12. The pharmaceutical composition according to claim 9, intended for the treatment and/or prevention of type II diabetes.

13. The pharmaceutical composition according to claim 9, intended to activate PPARγ.

14. The pharmaceutical composition according to claim 9, intended to improve the metabolism of carbohydrates, or lipids, to ease the symptoms of insulin resistance, inhibition of inflammation, or to inhibit the growth of cancer cells.

15. The pharmaceutical composition according to claim 9, intended for the treatment and/or prevention of diseases caused by metabolic syndrome.

16. The pharmaceutical composition according to claim 9, intended for the treatment and/or prevention of hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance, insulin resistance, impaired glucose tolerance on an empty stomach, hypertension, fatty liver, non-alcoholic steatohepatitis, diabetic complications, arteriosclerosis, atherosclerosis, gestational diabetes or polycystic ovary syndrome.

17. The pharmaceutical composition according to claim 9, intended for the treatment and/or prevention of inflammatory diseases, cancer,osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease, or hyperuricemia.

18. The pharmaceutical composition according to claim 9, intended for the treatment and/or prevention of acne, solar erythema, psoriasis, eczema, allergic diseases, asthma, peptic ulcers, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic maculopathy, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorders, peripheral circulatory disorders, autoimmune disease, pancreatitis, cachexia, leukemia, sarcoma, or dry eyes.

19. Activator/modulator of PPARγ containing compound according to any one of claims 1 to 8, or its pharmacologically acceptable salt as an active component.

20. The use of compounds according to any one of claims 1 to 8, or its pharmacologically acceptable salts for the manufacture of a pharmaceutical composition having modulating activity against PPARγ.

21. The application of claim 20, where the pharmaceutical composition is intended to reduce blood glucose.

22. The application of claim 20, where the pharmaceutical composition is intended for treating and/or preventing diabetes.

23. The application of claim 20, where the pharmaceutical composition is for the treatment of the Oia and/or prevention of type II diabetes.

24. The application of claim 20, where the pharmaceutical composition is intended to activate PPARγ.

25. The application of claim 20, where the pharmaceutical composition is intended to improve the metabolism of carbohydrates, or lipids, to ease the symptoms of insulin resistance, inhibition of inflammation, or to inhibit the growth of cancer cells.

26. The application of claim 20, where the pharmaceutical composition is intended for treating and/or preventing diseases caused by metabolic syndrome.

27. The application of claim 20, where the pharmaceutical composition is intended for the treatment and/or prevention of hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance, insulin resistance, impaired glucose tolerance on an empty stomach, hypertension, fatty liver, non-alcoholic steatohepatitis, diabetic complications, arteriosclerosis, atherosclerosis, gestational diabetes or polycystic ovary syndrome.

28. The application of claim 20, where the pharmaceutical composition is intended for treating and/or preventing inflammatory diseases, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease, or hyperuricemia.

29. The application of claim 20, where the pharmaceutical composition is intended for treating and/or preventing acne,solar erythema, psoriasis, eczema, allergic diseases, asthma, peptic ulcers, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic maculopathy, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorders, peripheral circulatory disorders, autoimmune disease, pancreatitis, cachexia, leukemia, sarcoma, or dry eyes.

30. The application of claim 20, where the pharmaceutical composition is an activator/modulator of PPARγ.

31. A method of reducing blood glucose, including the introduction of a pharmacologically effective amount of a compound according to any one of claims 1 to 8, or its pharmacologically acceptable salt warm-blooded animal.

32. Method of activating PPARγ, including the introduction of a pharmacologically effective amount of a compound according to any one of claims 1 to 8, or its pharmacologically acceptable salt warm-blooded animal.

33. The way to improve metabolism of carbohydrates, or lipids, easing symptoms of insulin resistance, inhibition of inflammation or inhibit the growth of cancer cells, including the introduction of a pharmacologically effective amount of a compound according to any one of claims 1 to 8, or its pharmacologically acceptable salt warm-blooded animal.

34. A method of treating and/or preventing the Erdene disease, mediated by receptor-activated peroxisome proliferation PPARγ, including the introduction of a pharmacologically effective amount of a compound according to any one of claims 1 to 8, or its pharmacologically acceptable salt warm-blooded animal.

35. The method according to clause 34, where the specified disease is diabetes.

36. The method according to clause 34, where the specified disease is type II diabetes.

37. The method according to clause 34, where the specified disease is a disease caused by metabolic syndrome.

38. The method according to clause 34, where the specified condition is hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance, insulin resistance, impaired glucose tolerance on an empty stomach, hypertension, fatty liver, nonalcoholic steatohepatitis, diabetic complications, arteriosclerosis, atherosclerosis, gestational diabetes or polycystic ovary syndrome.

39. The method according to clause 34, where the specified disease is an inflammatory disease, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease, or hyperuricemia.

40. The method according to clause 34, where the specified condition is acne, solar erythema, psoriasis, eczema, allergic disease, asthma, peptic ulcer, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclero is, diabetic retinopathy, diabetic maculopathy, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorder, impaired peripheral circulation, autoimmune disease, pancreatitis, cachexia, leukemia, sarcoma, or dry eyes.

41. The method according to any of p-40, where the specified warm-blooded animal is a human.



 

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New compounds // 2456273

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula: wherein B is specified in a group consisting of pyridine, pyridazine, pyrimidine and oxazole which can be optionally substituted by halogen, C1-7-alkyl or a C1-7-alkoxy group; L1 is specified in a group consisting of -NH-, -C(O)NH- and -NHC(O)-, A means C3-C12-cycloalkyl, C6-C12-aryl, a 4-7-member monocyclic heterocyclic group consisting of 1-3 heteroatoms optionally specified in O N and S, or a bicyclic heterocyclyl specified in a group consisting of benzimidazolyl, benzoxazolyl, benzothiazolyl, wherein cycloalkyl, aryl, mono- or bicyclic heterocyclyl can be optionally substituted by one or more substitutes optionally specified in a group consisting of a cyano group, halogen, an oxo group, C1-7-alkyl, C1-7-halogenalkyl, a C1-7-alkoxy group, C1-7-halogenalkoxy group, an amino group, a di-C1-7-alkylamino group, a C1-7-alkylthio group and C3-8-cycloalkyl, 1-2- means a bivalent residue specified in a group consisting of: - a bivalent alkyl group consisting of 1 to 4 carbon atoms, a bivalent alkenyl group consisting of 2 to 3 carbon atoms, - -C(O)-, - -C(O)-[R4]c-R5- wherein c is equal to 0, and R5 is specified in a group consisting of a bivalent C1-C4-alkyl group optionally substituted by another C1-4-alkyl, a C4-C8-cycloalkyl group, a phenyl group and a 5- or 6-member heterocyclyl group consisting of N heteroatoms, - -C(O)-NH-, - -(CH2)1-3-C(O)-NH-(CH2)1-3-, - -C(O)-NH-R4- wherein R4 is specified in a group consisting of a bivalent C1-C7-alkyl group optionally substituted by another C1-4-alkyl, a cyclohexyl group and a cyclopentyl group, and E is specified in a group consisting of: - COOH, - a ester group of carboxylic acid, or to its pharmaceutically acceptable salts. What is also described is a pharmaceutical composition exhibiting DGAT1 modulatory activity, on the basis of the presented compounds, and also a method of treating pathological conditions or disorders associated with DGAT1 activity.

EFFECT: there are prepared and described new compounds applicable for treating or preventing the pathological conditions or disorders associated with DGAT1 activity.

22 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I),

, where groups and radicals R1, R2 independently denote H, C1-8-alkyl or C3-7-cycloalkyl, where the alkyl or cycloalkyl group can be mono- or poly-substituted with identical or different groups R11; or R2 denotes a -CH2- or -CH2-CH2- bridge which is bonded with a group Y, and R1 is as defined above, or denotes a group selected from C1-4-alkyl-CO-, C1-4-alkyl-O-CO-, (C1-4-alkyl)NH-CO- or (C1-4-alkyl)2N-CO-, where the alkyl groups can be mono- or polyfluorinated; or R1 and R2 form an alkylene bridge such that R1R2N- denotes a group selected from: azetidine, pyrrolidine, piperdine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, in which the free amino group is substituted with R13, piperidin-4-one, morpholine, thiomorpholine, 4-C1-4-alkoxy iminopiperidin-1-yl and 4-hydroxy iminopiperidin-1-yl. Wherein, when R1 and R2 form an alkylene bridge, one or more H atoms in the alkylene bridge can be substituted with identical or different groups R14, and X denotes a C1-3-alkylene bridge which can contain one, two or three identical or different C1-3-alkyl substitutes; and Y denotes a group of subformula selected from: and , where the group can be mono-substituted with a substitute R20; Z denotes -CH2-CH2- or -C(=O)-CH2-; U, V both denote CH, one of groups U, V denotes N, and the other of U, V denotes CH, where CH can be substituted with L; and L independently denotes halogen, cyano or C1-3-alkyl; and k equals 0, 1 or 2; W is selected from a group consisting of -CH2-O- and -O-CH2-; B is selected from a group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thiophenyl and thiazolyl; each of which can be mono- or poly-substituted with identical or different substitutes R20; radicals R11, R13, R14, R20 assume values given in claim 1. The invention also relates to a pharmaceutical composition containing at least one compound of formula I and having action on MCH receptor.

EFFECT: disclosed pharmaceutical compositions are useful in treating metabolic disorders or eating disorders, especially obesity, bulimia, anorexia, hyperphagia and diabetes.

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula 1c

, where A, B, R1, R2 and n have values given in the description, and pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions based on compounds of formula 1c, which are used as modulators of ATP-binding cassette ("ABC") transporters or fragments thereof, including cystic fibrosis transmembrane conductance regulator ("CFTR"). The present invention also relates to a method of modulating ABC-transporter activity and methods of treating ABC-transporter mediated diseases using compounds of formula 1c.

EFFECT: improved method.

32 cl, 3 tbl, 118 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound having the structure of formula (I), or its pharmaceutically acceptable salt, wherein specified radicals are presented in the description, and also concerns a compound representing or its pharmaceutically acceptable salt. The present invention declares a pharmaceutical composition possessing inhibitory activity in the relation to 20S proteasome containing a pharmaceutically acceptable carrier or a diluent and a therapeutically effective amount of the compound, and also the invention refers to methods of treating the immune diseases, such as inflammatory intestinal disease, to treating cancer, to treating infection, to treating proliferative diseases, to treating neurodegenerative disease or asthma.

EFFECT: higher clinical effectiveness.

34 cl, 21 ex, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula

, where X1, X2, Y, R1a, R1b, R2a, R2b, A1, A2, A3 and A4 have the values specified in the description, which are vanilloid receptor subtype 1 (VR1) antagonists.

EFFECT: preparing a pharmaceutical composition on the basis of the compounds of formula 1 and developing methods of managing pain, neurotic pain, allodynia, inflammation or inflammatory disease associated pain, inflammatory hyperalgesia, bladder hyperactivity and urine incontinence.

22 cl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

FIELD: chemistry.

SUBSTANCE: described are novel 7-member heterocyclic compounds of general formula (values of radicals are given in the claim) or salts thereof or solvates thereof having chymase inhibiting activity and suitable for preventing or treating different diseases in which chymase is involved, a method of producing said compounds, intermediate compounds and a pharmaceutical composition for preventing or treating diseases in which chymase is involved, including compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

EFFECT: improved properties of the compound.

23 cl, 12 tbl, 308 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula

wherein R1, R2 and X are those as specified in cl.1 of the patent claim, or its pharmaceutically acceptable salt, as well as using such compound or its pharmaceutically acceptable salt for preparing a drug preparation for prevention and treatment of all types of sleeping, eating or drinking disorders.

EFFECT: preparing the new azetidine compounds showing activity of orexin receptor antagonists.

12 cl, 112 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula I

and/or to all isomer forms of a compound of formula I and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula I, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents aminomethylene, 2) Het-Z, wherein Z represents amino group, and wherein Het is unsubstituted or additionally monosubstituted by group T, R2 represents 1) -(C0)-alkylene-(C6-C14)aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T or 2) -(C0)-alkylene-Het, wherein Het is unsubstituted or monosubstituted by group T, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T, 2) -O-(C6-C14)-alkylene(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 3) -(C0)-alkylene-Het, wherein Het is unsubstituted or mono-, di- or trisubstituted by group T, 4) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryl radicals are unsubstituted, 5) -(C0)-alkylene-(C6-C14)-aryl-Q)-Het, wherein aryl and Het in each case are independently unsubstituted or disubstituted by group T, 6) -(C0)-alkylene-Het-Q-Het, wherein both radicals Het are unsubstituted, Q represents a covalent bond, -(C1-C4)-alkylene, -N((C1-C4)-alkyl)- or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl, wherein alkyl is unsubstituted disubstituted by group -(C1-C3)-fluoralkyl or -N-C(O)-(C1-C4)-alkyl, 3) -(C1-C3)-fluoralkyl, 4) -(C3-C8)-cycloalkyl, 5) -O-(C1-C4)-alkyl, 6) -O-(C1-C3)-fluoralkyl, 7) -N(R10)(R11), wherein R(10) and R(11) independently represent hydrogen atom or -(C1-C6)-alkyl, 8) -C(O)-NH-R10, 9) -SO2-(C1-C4)-alkyl, 10) -SO2-(C1-C3)-fluoralkyl, R4 and R5 are identical and represent hydrogen atom, and R6 represent hydrogen atom with said Het being 5-10-member ring system consisting of 1 or 2 coupled ring systems, and wherein one or two identical or different heteroatoms are selected from oxygen, nitrogen and sulphur. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds exhibiting antithrombotic activity, which particularly inhibit blood coagulation factor lXa.

6 cl, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method of producing benzimidazole derivatives of formula where X is a single bond, involving reaction of nitriles, selected from: 3-phenoxybenzonitrile, 3-phenoxyphenyl acetonitrile, 3-(3-phenoxyphenyl)acrylonitrile, 3-(3-phenoxyphenyl)-2-butenonitrile, 3-(3- phenoxyphenyl)propionitrile, 3-(3-phenoxybenzylamino)propionitrile, 2-methyl-2-(3-phenoxybenzoate)propionitrile, 3-phenoxyphenyl methoxypropionitrile with ortho-phenylene diamine hydrochloride in a sealed glass bulb. The process is carried out with molar ratio of nitrile to ortho-phenylene diamine hydrochloride of 1:1.2 at temperature 190-200°C.

EFFECT: novel method of producing said compound with good output and high degree of purity.

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