Condensed heterocyclic compounds

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

 

The scope of the invention

The present invention relates to new nitrogen-containing condensed heterocyclic compounds having antagonistic activity against CRF (releasing factor corticotropin), and to pharmaceutical compositions containing such compounds.

Background of invention

Releasing factor corticotropin (hereinafter abbreviated listed as “CRF”) is a neuropeptide consisting of 41 amino acids, and he was isolated and purified as a peptide that helps to release adrenocorticotropic hormone (ACTH) from the pituitary. Was first determined its structure from the hypothalamus of the sheep, and then his presence was also confirmed in rat and man, and was determined its structure [Science, 213, 1394(1981); Proc. Natl. Acad. Sci USA, 80, 4851(1983); EMBO J. 5, 775(1983)]. Amino acid sequence in humans and rats are the same, but in sheep 7 different amino acids. CRF is synthesized as carboxy-end of the pre-produced CRF, cut and secrete. CRF peptide and its mRNA in the greatest amounts are present in the hypothalamus and the pituitary gland and is widely distributed in the brain, such as cerebral cortex, cerebellum, hippocampus and corpus amygdaloideum. In addition, in peripheral tissues, their presence was confirmed in the placenta, adrenal glands, lungs, liver, pagelog who offered gland, the skin and the digestive tract [J. Clin. Endocrinol. Metab., 65, 176(1987); J. Clin. Endocrinol. Metab., 67, 768(1988); Regul. Pept., 18, 173(1987), Peptides, 5 (Suppl. 1), 71(1984)]. The CRF receptor is a 7-transmembrane associated with G protein receptor, and there are two subtypes CRF1 and CRF2. It was reported that CRF1 mainly present in the cerebral cortex, cerebellum, olfactory bulb, pituitary and amygdala. On the other hand, the CRF2 receptor has two subtypes CRF2α and CRF2β. It was found that the CRF2α receptor is widely distributed in the hypothalamus, septal area and choroids plexus, and the receptor CRF2β mainly present in peripheral tissues such as skeletal muscle, and circulated in the blood vessels of the brain [J. Neurosci. 15, 6340(1995); Endocrinology, 137, 72(1996); Biochim. Biophys. Acta, 1352, 129(1997)]. Because each of these receptors has different areas of distribution in the body, was the assumption that their role is also different [Trends. Pharmacol. Sci. 23, 71(2002)].

With regard to the physiological action of CRF, we know its action on the endocrine system, where CRF is produced and secreted in response to stress in the hypothalamus and acts on the pituitary gland, promotora the release of ACTH [Recent Prog. Horm. Res., 39, 245(1983)]. In addition to the action on the endocrine system, CRF acts as a neurotransmitter or neuroregulatory factor in the brain and integrates electrophysiology, Autonomous nerve and stress behavior [Brain Re. Rev., 15, 71(1990); Pharmacol. Rev., 43, 425(1991)]. When CRF injected into the ventricle of the brain of experimental animals such as the rat, see the alarm condition, and in mice with overexpression of CRF observed significantly higher anxiety compared to normal animals [Brain Res., 574, 70(1992); J. Neurosci., 10, 176(1992); J. Neurosci., 14, 2579(1994)]. In addition, α-helical CRF(9-41) of the peptide of the CRF receptor antagonist takes action against anxiety in an animal model [Brain Res., 509, 80(1990); J. Neurosci., 14, 2579(1994)]. Blood pressure, heart rate and body temperature in rats raised under the action of stress or administration of CRF, but α-helical CRF(9-41) peptide CRF antagonist inhibits increase of blood pressure, heart rate and body temperature, caused by stress [J. Physiol., 460, 221(1993)]. α-Helical CRF(9-41) peptide CRF antagonist inhibits abnormal behavior caused by the withdrawal of funds, causing physical and psychological dependence, such as alcohol and cocaine [Psychopharmacology, 103, 227(1991); Pharmacol. Rev.53, 209(2001)]. In addition, there were reports that in rats improves memory and memory with the introduction of CRF [Nature, 375, 284(1995); Neuroendocrinology, 57, 1071(1993); Eur. J. Pharmacol., 405, 225(2000)].

Because CRF is associated with the stress response in the body, there are clinical information about stress-related States of depression or anxiety. Con is entrace CRF in the cerebrospinal fluid of patients with depression is higher in comparison with healthy subjects [Am. J. Psychiatry, 144, 873(1987)], and the level of CRF mRNA in the hypothalamus of patients with depression have increased in comparison with healthy subjects [Am. J. Psychiatry, 152, 1372(1995)]. The binding site of CRF in the cerebral cortex of patients who committed suicide in depression, reduced [Arch. Gen. Psychiatry, 45, 577(1988)]. Increasing the concentration of ACTH in the plasma resulting from the introduction of CRF in patients with minor depression [N. Engl. J. Med., 314, 1329(1986)]. In patients with panic disorder increasing the concentration of ACTH in the plasma resulting from the introduction of CRF small [Am. J. Psychiatry, 143, 896(1986)]. The concentration of CRF in the cerebrospinal fluid of patients with anxiety caused by stress, such as obsessive-compulsive neurosis, stress disorder after trauma, Tourette syndrome, etc., higher compared with healthy subjects [Arch. Gen. Psychiatry, 51, 794(1994); Am. J. Psychiatry, 154, 624(1997); Biol. Psychiatry, 39, 776(1996)]. The concentration of CRF in the cerebrospinal fluid of patients with schizophrenia are higher in comparison with healthy subjects [Brain Res., 437, 355(1987); Neurology, 37, 905(1987)]. Thus, it was reported that there are variations in the system response of the body through the CRF in stress-related mental illness.

About the action of CRF on the endocrine system can be assumed on the basis of the characteristics of animals with the introduced gene CRF and on the effects on experimental animals. In mice, the cat is where the overexpression of CRF, there is excessive secretion of ACTH and adrenal cortical steroids, as well as anomalies, similar to Cushing's syndrome, such as muscle atrophy, alopecia, infertility, etc. [Endorcrinology, 130, 3378(1992)]. CRF inhibits the ability of ingesting food in experimental animals such as rats [Life Sci., 31, 363 (1982); Neurophamacology, 22, 337(1983)]. In addition, α-helical CRF(9-41) peptide CRF antagonist inhibited the reduction in the ability of ingestion, caused by stress load in experimental models [Brain Res. Bull., 17, 285(1986)]. CRF inhibited weight gain in animals with hereditary obesity [Physiol. Behav., 45, 565(1989)]. Geodinamica patients suffering from nervous orexia, increasing the concentration in plasma ACTH in the introduction of CRF minor [J. Clin. Endocrinol. Metab., 62, 319(1986)]. There are suggestions that low CRF is associated with a syndrome of obesity [Endocrinology, 130, 1931(1992)]. It is assumed the possibility that inhibition of the ability to swallow food and action aimed at weight loss, the agent inhibiting re-uptake of serotonin via CRF [Pharmacol. Rev., 43, 425(1991)].

CRF Central or perifericheskie associated with the movement of the digestive tract with stress or inflammation [Am. J. Physiol. Gastrointest. Liver Physiol. 280, G315(2001)]. CRF acts of the Central or perifericheskie, weakens the ability to reduce the stomach and reduces the gastric secretion [Regulatory Peptides, 1, 173(1988); Am. J. Physiol., 253, G241(1987)]. In addition, α-helical CRF(9-41) peptide CRF antagonist has a restorative effect on the reduced function of the stomach as a result of operations in the abdominal cavity [Am. J. Physiol., 258, G152(1990)]. CRF inhibits the secretion of bicarbonate ions in the stomach, reduces the secretion of gastric acid and inhibits the formation of ulcers in the cold stress [Am. J. Physiol., 258, G152(1990)]. Moreover, α-helical CRF(9-41) peptide CRF antagonist exhibits an inhibitory effect on the reduction of the secretion of gastric acid, reducing gastric excretion, slow transport in the area of the small intestine and acceleration of vehicles in the region of the large intestine in the limiting stress [Gastroenterology, 95, 1510(1988)]. In healthy patients, mental stress increases flatulence and pain in the abdominal region resulting anxiety and dilatation of the bowel, and CRF reduces the threshold of discomfort [Gastroenterology, 109, 1772(1995); Neurogastroenterol. Mot., 8, 9[1996]. In patients with irritable bowel syndrome motion in the area of the large intestine excessively increases with the introduction of CRF compared with healthy subjects [Gut, 42, 845(1998)].

There is information confirmed by animal experiments and clinical studies that CRF induced inflammation and is involved in inflammatory reactions. At the site of inflammation in experimental the different animals and in synovial fluid from patients with rheumatoid arthritis products CRF locally increased [Science, 254, 421(1991); J. Clin. Invest., 90, 2555(1992); J. Immunol., 151, 1587(1993)]. CRF induces mast cell degranulation and increases the permeability of blood vessels [Endocrinology, 139, 403(1998); J.Pharmacol. Exp. Ther., 288, 1349(1999)]. CRF can also be identified in the thyroid gland in patients with autoimmune thyroiditis [Am. J. Pathol. 145, 1159(1994)]. When CRF injected rats with autoimmune cerebrospinal meningitis, the development of symptoms, such as paralysis, significantly inhibited [J. Immunil., 158, 5751(1997)]. In rats, the activity of the immune response, such as proliferation of T-lymphocytes and the activity of natural killer cells is reduced with the introduction of CRF or stress load [Endocrinology, 128, 1329(1991)].

On the basis of the above messages, it is expected that the compound is an antagonist of CRF receptor will have excellent therapeutic or prophylactic effect against various diseases involving CRF.

As for antagonists of CRF, for example, there are reports of the peptide CRF receptor antagonists, in which a part of amino acid sequence of CRF or a corresponding peptide of a human or other mammal changed or demeterova, and reported that they exhibit pharmacological action, such as inhibition of release of ACTH, aimed at the relief of anxiety [Science, 224, 889(1984); J. Pharmacol. Exp. Ther., 269, 564(1994); Brain Res. Rev., 15, 71(1990)]. However, from the point the rhenium pharmacokinetics, for example, chemical stability, and namely, by oral administration in the body, bioavailability and the ability to transfer intracerebral, peptide derivatives have a low utility value as medicines.

Disclosure of invention

In accordance with the present invention is provided with:

(1)the Compound represented by formula (I):

where R1represents an optionally substituted hydrocarbon, optionally substituted C-linked heterocyclic group, optionally substituted N-linked heteroaryl group, or acyl, provided that methyl and trifluoromethyl are eliminated;

R2represents an optionally substituted cyclic hydrocarbon or optionally substituted heterocyclic group, provided that 2-[2-(1,1-dimethylethyl)phenyloxy]-3-pyridinyl excluded;

X represents oxygen, sulfur or-NR3- (where R3represents hydrogen, optionally substituted hydrocarbon or acyl);

Y1, Y2and Y3each represents an optionally substituted carbon or nitrogen, provided that one or less of the Y1, Y2and Y3represents nitrogen; and

Z represents a bond, -CO-, oxygen, sulfur, -SO-, -SO2-, -NR4-, -NR4-alk-, -CONR 4- or-NR4CO- (where alk is an optionally substituted C1-4alkylene, and R4represents hydrogen, optionally substituted hydrocarbon or acyl);

provided that (i) compound, where X represents-NH - and R2represents an optionally substituted thiophene ring,

(ii) compound, where R1represents cyano, Y3represents carbon which is substituted by stands, substituted with three substituents, one of which is acyl and the other two may form a ring,

(iii) (a) 6-amino-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carbonitrile,

b) 6-amino-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carboxamide and

c) 6-{[(allylamino)carbonothioyl]amino}-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carboxamide,

(iv) 4-({2-[(4-chlorophenyl)amino]-1,7-dimethyl-1H-benzimidazole-5-yl}oxy)-N-methylpyridin-2-carboxamid,

(v) compound, where R3represents a substituted heteroaromatic, R2is a 4-piperidinyl containing a substituent in the 1-position,

(vi) compound, where R2represents a substituted 8-oxo-5-thia-1-Aza-bicyclo[4.2.0]Oct-2-EN-7-yl, and

(vii) 7-ethyl-1-methyl-N-[4-(triptoreline)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-amine and 7-ethynyl-1-methyl-N-[4-(triptoreline)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-a is in

excluded;

or its salt;

(2) a Prodrug of the compound according to the above item (1);

(3) the Compound according to the above item (1), where R1represents an optionally substituted acyclic branched C3-11hydrocarbon;

(4) the Compound according to the above item (1), where R1represents an optionally substituted C6-10aryl;

(5) the Compound according to the above item (1), where R1represents an optionally substituted C-linked 5 to 14-membered heterocyclic group or a N-linked 5-to 10-membered heteroaryl group;

(6) the Compound according to the above item (1), where X represents a-NR3- (where R3defined above in paragraph (1));

(7) the Compound according to the above item (6), where R3represents methyl, ethyl or hydroxyethyl;

(8) the Compound according to the above item (1), where Y1represents CR3a, Y2represents CR3band Y3represents CR3c(where R3a, R3band R3cindependently represent hydrogen, halogen, nitro, cyano, optionally substituted C1-4hydrocarbon, optionally substituted C1-4hydrocarbonate, optionally substituted C1-4hydrocarbide, optionally substituted amino or acyl containing up to 4 carbon atoms;

(9) Connect the imposition of the above item (8), where R3arepresents hydrogen, halogen, cyano, optionally substituted C1-3alkyl or optionally substituted C1-3alkoxy, R3brepresents hydrogen, and R3crepresents hydrogen;

(10) the Compound according to the above item (9), where R3arepresents chlorine, bromine, methoxy or methyl;

(11) the Compound according to the above item (1), where one of the Y1, Y2and Y3represents nitrogen;

(12) the Compound according to the above item (1), where R2represents an optionally substituted C6-10aryl or optionally substituted 5-8-membered heterocyclic group;

(13) the Compound according to the above item (1), where R2represents phenyl, which is 2,4,6-triple-substituted, 2,4,5-triple-substituted or 2,4-disubstituted;

(14) the Compound according to the above item (1), where Z represents a-NR4- (where R4defined above in paragraph (1)), or oxygen;

(15) the Compound according to the above item (14), where R4represents hydrogen;

(16) the Compound according to the above item (1), which is a

N-(4-chloro-2-methoxy-6-were)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazole-2-amine,

N-(4-bromo-2-methoxy-6-were)-7-(3,5-diethyl-1H-pyrazole-1-yl)-1-methyl-1H-benzimidazole-2-amine,

N-(4-bromo-2-methoxy-6-were)-4-chloro-7-(1-ACELP the filing)-1-methyl-1H-benzimidazole-2-amine,

4-chloro-2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole,

N-(4-chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazole-2-amine, or

2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole, or its salt;

(17) the Method of obtaining the compounds according to the above item (1), which includes the interaction of the compounds represented by the formula:

where L represents a removable group selected from a halogen atom, sulfonyloxy and alloctype, and other symbols are defined above in paragraph (1), with the compound represented by the formula:

where each symbol is defined above in paragraph (1);

(18) a Pharmaceutical composition which contains a compound according to the above item (1);

(19) the CRF receptor Antagonist which is a compound represented by the formula (I'):

where R1represents an optionally substituted hydrocarbon, optionally substituted C-linked heterocyclic group, optionally substituted N-linked heteroaryl group, cyano or acyl;

R2represents an optionally substituted cyclic hydrocarbon or optionally substituted heterocyclic group;

X represents to slort, sulfur or-NR3- (where R3represents hydrogen, optionally substituted hydrocarbon or acyl);

Y1, Y2and Y3each represents an optionally substituted carbon or nitrogen, provided that one or less of the Y1, Y2and Y3represents nitrogen;

Z represents a bond, -CO-, oxygen, sulfur, -SO-, -SO2-, -NR4-, -NR4-alk-, -CONR4- or-NR4CO- (where alk is an optionally substituted C1-4alkylene and R4represents hydrogen, optionally substituted hydrocarbon or acyl); or its salt;

(20) a Method for the treatment or prevention of disease involving the CRF receptor, which includes an introduction to the subject in need, an effective amount of a CRF receptor antagonist according to the above item (19);

(21) the Method according to the above item (20), where the disease to be treated or prophylaxis is selected from affective disorder, depression or anxiety;

(22) Application of the CRF receptor antagonist according to the above item (19) to obtain drugs for prevention or treatment of diseases involving the CRF receptor;

(23) the Use according to the above item (22), where the disease to be treated or prophylaxis is selected from affective disorder, depression or Tr is wage;

(24) the Pharmaceutical composition for prevention or treatment of diseases involving the CRF receptor, which includes the CRF receptor antagonist according to the above item (19);

(25) the Pharmaceutical composition according to the above item (24), where the disease to be treated or prophylaxis is selected from affective disorder, depression or anxiety; and so on

The best way of carrying out the invention

In the present description, the term "hydrocarbon" means a monovalent group containing only carbon and hydrogen.

In the formula (I) and (I') X represents oxygen, sulfur or-NR3- (where R3represents hydrogen, optionally substituted hydrocarbon or acyl). Thus, examples of 5-membered ring in the formula (I) and (I') include oxazole ring, thiazole ring and imidazole ring.

Examples of "hydrocarbide" of the "optionally substituted hydrocarbide"represented by R3in the formula-NR3-include optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, optionally substituted alicyclic-aliphatic hydrocarbon group, an optionally substituted alicyclic-alicyclic hydrocarbon group, optionally substituted aromatic hydrocarbon group, neo is Astelin substituted aromatic-aliphatic hydrocarbon group (aracelio group), etc.

Examples specified aliphatic hydrocarbon group include a saturated aliphatic hydrocarbon group containing 1-8 carbon atoms (e.g., alkyl group)such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl etc.; and unsaturated aliphatic hydrocarbon group containing 2-8 carbon atoms (for example, alkenylphenol group, alkylamino group, akadeemiline group, akadeemiline group, and so on), such as vinyl, allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-heptenyl, 1-octenyl, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-heptenyl, 1-octenyl etc.

The examples mentioned alicyclic hydrocarbon groups include saturated alicyclic hydrocarbon group containing 3-7 carbon atoms (for example, cycloalkyl group, and so on), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; unsaturated alicyclic hydrocarbon group containing 3-atomov carbon (for example, cycloalkenyl group, cycloalkenyl group, and so on), such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadiene etc.; partially saturated and condensed bicyclic hydrocarbon group [preferably, C9-10partially saturated and condensed bicyclic hydrocarbon group, etc. (including those of the group where the benzene ring is combined with a 5 - or 6-membered non-aromatic cyclic hydrocarbon group)], such as 1-indanyl, 2-indanyl, 1 indanyl, 2-indanyl, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl, 1,4-dihydro-2-naphthyl, 3,4-dihydro-1-naphthyl, 3,4-dihydro-2-naphthyl etc; etc. Mentioned alicyclic hydrocarbon group can be cross-linked.

The examples mentioned alicyclic-aliphatic hydrocarbon groups include such groups where the above alicyclic hydrocarbon group and the above aliphatic hydrocarbon group, for example group containing 4-14 carbon atoms, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylmethyl, 3-cyclopentylmethyl, cyclopentylmethyl, cyclohexylmethyl is l, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylmethyl, 2-(3,4-dihydro-2-naphthyl)ethyl, 2-(1,2,3,4-tetrahydro-2-naphthyl)ethyl, 2-(3,4-dihydro-2-naphthyl)ethynyl etc. (for example, C3-7cycloalkyl-C1-4alkyl group, a C3-7cycloalkenyl-C1-4alkyl group, a C3-7cycloalkyl-C2-4Alchemilla group, C3-7cycloalkenyl-C2-4Alchemilla group, C9-10partially saturated and condensed bicyclic hydrocarbon-C1-4alkyl group, a C9-10partially saturated and condensed bicyclic hydrocarbon-C2-4alkeneamine group and so on).

The examples mentioned alicyclic-alicyclic hydrocarbon group include1-4alkyl group, a substituted two C3-7cycloalkyl selected from the above alicyclic hydrocarbon group such as a group represented by the formula:

Examples of the specified aromatic hydrocarbon groups include aryl group containing 6-10 carbon atoms (including the group, where 5-6-membered non-aromatic hydrocarbon ring condensed with the phenyl group)such as phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl,5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl, etc.; etc.

Examples of the specified aromatic-aliphatic hydrocarbon groups include aracelio group containing 7 to 14 carbon atoms (C6-10aryl-C1-4alkyl group)such as phenyl-C1-4alkyl group, for example benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl etc.; naphthyl-C1-4alkyl group such as α-naphthylmethyl, α-naphtalate, β-naphthylmethyl, β-naphtalate etc.; C6-10aryl-C2-4Alchemilla group, such as phenyl-C2-4Alchemilla group, such as styryl, cinnamyl etc; etc.

The above "gidrolabilna" group may contain a substituent in position, which may be substituted. Examples of such substituent include halogen, nitro, cyano, oxo, (1) optionally substituted heterocyclic group, (2) optionally substituted sulfinyl group, (3) optionally substituted sulfonyloxy group, (4) optionally substituted hydroxyl group, (5) optionally substituted Tilney group, (6) optionally substituted by an amino group, (7) acyl group, (8) optionally esterified or amidinophenoxy carboxyl group, (9) optionally substituted phosphoryl group, or the like

Examples of the substituent of the above (2) optionally substituted sulfanilic group, (3) optional alsenoy sulfonyloxy group, (4) optionally substituted hydroxyl group, (5) optionally substituted Tilney group, and (6) optionally substituted amino groups include optionally substituted hydrocarbon. Examples of "hydrocarbide" from a specified group optionally substituted hydrocarbide include groups represented in the example above. This hydrocarbon may be substituted by one or more substituents in position, which may be substituted. Examples of groups of deputies, which is used as the substituents in the optionally substituted hydrocarbide include halogen, nitro, cyano, hydroxyl, thiol, amino and carboxyl.

As optionally substituted sulfanilic group specified above (2)may, in particular, to specify as an example, C1-6alkylsulfonyl (for example, methylsulfinyl, ethylsulfinyl, propylsulfonyl, butylsulfonyl etc.) and C6-10arylsulfonyl (for example, phenylsulfinyl, naphthylmethyl etc).

As optionally substituted sulfonyloxy group specified above (3)may, in particular, to specify as an example, C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl etc.) and C6-10arylsulfonyl (for example, phenylsulfonyl, naphthylmethyl etc).

As the optionally substituted hydroxyl group is s, the above (4), it is possible, in particular, to specify as an example, hydroxyl, C1-6alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, neopentylene etc.) and C6-10aryloxy (for example, phenoxy, naphthoxy etc).

As optionally substituted Tilney group specified above (5), it is possible, in particular, to specify as an example, thiol, C1-6alkylthio (for example, methylthio, ethylthio, propylthio etc.) and C6-10aaltio (for example, phenylthio, naphthylthio etc).

As the optionally substituted amino group, the above (6), it is possible, in particular, to specify as an example, amino, mono-C1-6alkylamino (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino and so on), di-C1-6alkylamino (for example, dimethylamino, diethylamino, ethylmethylamino, dipropylamino, diisopropylamino, dibutylamino etc), etc.

Examples of the acyl group of the above (7) include the same group as the acyl for R3.

Examples of the ester group or amide group in the optionally esterified or amidinophenoxy carboxyl group specified above in (8)include ester group such as optionally substituted hydrocarbon as Deputy optionally substituted hydroxyl group specified above in (4), or amide group optionally substituted amino group, as indicated above in (6).

As the optionally esterified carboxyl group can, in particular, to specify as an example carboxyl, C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.), C6-10aryloxyalkyl (for example, phenoxycarbonyl etc.), C7-16Uralelectromed (for example, benzyloxycarbonyl, pentyloxybenzoyl etc), etc.

As optional amidinophenoxy carboxyl group can, in particular, to specify as an example, carbarnoyl, mono-C1-6allylcarbamate (for example, methylcarbamoyl, ethylcarbitol and so on), di-C1-6allylcarbamate (for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylamino etc.), C6-10arylcarbamoyl (for example, phenylcarbamoyl, 1-afterburner, 2-afterburner etc), 5-6-membered heterocyclic carbarnoyl (for example, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, 2-taylornol, 3-taylornol etc), etc.

Examples of the "acyl"represented by R3in the formula-NR3-include formyl and the group, where the carbonyl group is combined with1-10alkyl group, a C2-10alkenylphenol group2-10alkenylphenol group3-7cycloalkyl group5-7clearchannel group or an aromatic group (for example, phenyl group, peredelnoj group etc) (for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cyclohexylcarbonyl, crotonyl, 2-cyclohexanecarbonyl, benzoyl, etc. and so on

R3preferably represents hydrogen, C1-10alkyl, C2-10alkenyl, C2-10quinil, and more preferably hydrogen, C1-10alkyl.

In particular, as R3preferred are methyl, ethyl, hydroxyethyl, etc.

R1in the formula (I) and (I') is an optionally substituted hydrocarbon, optionally substituted C-linked heterocyclic group, optionally substituted N-linked heteroaryl group, cyano or acyl. In this description, the term "C-linked" in the above optional replaced With-linked heterocyclic group" means that R1is linked via a carbon atom of the heterocyclic group, R1with a condensed bicyclic ring represented by the formula (I). Also, the term "N-linked" in the "optionally substituted N-linked heteroaryl group" means that R1is linked via a nitrogen atom heteroaryl group, R1with a condensed bicyclic ring represented by f is rmulas (I).

Examples of "optionally substituted hydrocarbide for R1include the same groups that are represented as for example optionally substituted hydrocarbide R3.

Examples of the "optionally substituted heterocyclic group" in "optionally substituted C-linked heterocyclic group" for R1include the same groups, which are presented as an example below for optionally substituted heterocyclic group, R2.

Examples of "heteroaryl group" in "optionally substituted N-linked heteroaryl group" for R1include 5-10-membered aromatic heterocyclic group, optionally containing 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to one nitrogen atom (for example, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazane, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, benzimidazolyl, indazolin etc). Specified heteroaryl group may be substituted by 1-3 substituents selected from the group comprising halogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6alkyl, Csub> 5-7cycloalkyl, C6-10aryl (the aryl may contain 1 or 2 substituent selected from halogen, C1-6of alkyl, halogeno C1-6the alkyl and C1-6alkoxy), C7-14aralkyl (specified aralkyl may contain 1 or 2 substituent selected from halogen, C1-6of alkyl, halogeno C1-6the alkyl and C1-6alkoxy), hydroxy, hydroxy-C1-6alkyl, C6-10aryloxy (specified aryloxy may contain 1 or 2 substituent selected from halogen, C1-6of alkyl, halogeno C1-6the alkyl and C1-6alkoxy), C7-14aralkylated, C6-10arylcarbamoyl, carboxyl, C1-6alkoxycarbonyl, carbarnoyl, C6-10arylcarbamoyl, amino, C6-10arylcarboxamide, C1-6alkylcarboxylic, C1-6alkoxycarbonyl, C6-10aaltio, C6-10arylsulfonyl, cyano, 5-7-membered heterocyclic group and oxo.

Examples of the "acyl" for R1include the same groups, as groups, are presented as examples of the acyl for R3.

From these values, R1in the formula (I) and (I') preferably represents an optionally substituted acyclic branched C3-14hydrocarbon (preferably acyclic branched C3-7hydrocarbon, such as 2-propyl, 3-hexyl, 3-pentyl, 4-heptyl, etc.), optionally substituted C6-10aryl, neobyazatel the substituted C-linked 5 to 14-membered heterocyclic group or a N-linked 5-to 10-membered heteroaryl group.

R2in the formula (I) and (I') is an optionally substituted cyclic hydrocarbon or optionally substituted heterocyclic group.

Examples of "cyclic hydrocarbide" group "optionally substituted cyclic hydrocarbon for R2include3-7cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.)3-7cycloalkenyl group (for example, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl etc), aryl group containing 6-10 carbon atoms (including groups, where 5-6-membered non-aromatic hydrocarbon ring is condensed with the phenyl group)such as phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl, etc.; etc.

Examples of "heterocyclic group" of the "optionally substituted heterocyclic group" for R2include (i) a 5-7 membered heterocyclic group containing one sulfur atom, one nitrogen atom or one oxygen atom, (ii) a 5-6-membered heterocyclic group containing 2-4 nitrogen atom, (iii) a 5-6-membered heterocyclic group, containing the Yu 1-2 nitrogen atom and one sulfur atom or oxygen, (iv) 8-12-membered condensed bicyclic or tricyclic heterocyclic group containing 1-4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, etc. in Addition, each of the heterocyclic groups mentioned in (i)to(iv)may be saturated or unsaturated heterocyclic group, and an unsaturated heterocyclic group may be either aromatic or non-aromatic.

Examples of the heterocyclic group optionally substituted heterocyclic group, R2include monocyclic aromatic heterocyclic group and non-aromatic heterocyclic group.

Specific examples of the heterocyclic group optionally substituted heterocyclic group include (i) aromatic monocyclic heterocyclic group (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazane, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl etc), (ii) non-aromatic heterocyclic group (for example, oxiranyl, azetidine, oxetanyl, titanyl, pyrrolidinyl, tetrahydrofuryl, tylenol, piperidyl, tetrahydropyranyl, morpholinyl, Timor oliner, piperazinil etc.) and (iii) condensed heterocyclic group, such as 8-12-membered bicyclic or tricyclic heterocyclic group (for example, benzofuranyl, isobenzofuranyl, benzothiazyl, indolyl, isoindolyl, 1H-indazole, begindetail, benzoxazolyl, 1,2-benzisoxazole, benzothiazole, benzopyranyl, 1,2-benzothiazolyl, 1H-benzotriazolyl, hinely, ethanolic, cinnoline, hintline, honokalani, phthalazine, naphthyridine, purinol, pteridinyl, carbazolyl, α-carbonyl, β-carbolines, γ-carbolines, acridines, phenoxazines, phenothiazines, phenazines, femoxetine, thianthrene, phenanthridines, phenanthrolines, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]chinoline etc).

The above "cycloalkyl", "cycloalkenyl", "aryl" and "heterocyclic group" in R2can contain the same substituents as groups, as for example optionally substituted hydrocarbones group for R3and, in addition, as the substituent may include the same group as an optionally substituted gidrolabilna group specified for R3.

In addition, two of the deputies "cilice is anyone hydrocarbide" in the "optionally substituted cyclic hydrocarbide" or "heterocyclic group" in "optionally substituted heterocyclic group" for R 2can be combined with each other to form condensed rings with circular hydrocarbon or heterocyclic group. Examples of the condensed ring include, for example, an aromatic condensed heterocyclic group, such as 8-12-membered aromatic condensed heterocyclic group (preferably a heterocyclic group including the above-mentioned 5 - or 6-membered aromatic monocyclic heterocyclic group fused with a benzene ring, or heterocyclic group comprising the above-mentioned 5 - or 6-membered aromatic monocyclic heterocyclic group fused with the same above mentioned 5 - or 6-membered aromatic monocyclic heterocyclic group or a group other than her) and so (for example benzofuranyl, isobenzofuranyl, benzothiazyl, indolyl, isoindolyl, 1H-indazole, begindetail, benzoxazolyl, 1,2-benzisoxazole, benzothiazole, benzopyranyl, 1,2-benzothiazolyl, 1H-benzotriazolyl, hinely, ethanolic, cinnoline, hintline, honokalani, phthalazine, naphthyridine, purinol, pteridinyl, carbazolyl, α-carbonyl, β-carbolines, γ-carbolines, acridines, phenoxazines, phenothiazines, phenazines, femoxetine, thianthrene, phenanthridines, phenanthrolines, indolizinyl, pyrrolo[1,2-b]peridas the Nile, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl etc); and so on

In addition, the Deputy "cyclic hydrocarbide" in the "optionally substituted cyclic hydrocarbide" or "heterocyclic group" in "optionally substituted heterocyclic group" for R2can be combined together with the Deputy: R4in the groups-NR4-, -NR4-alk-, -CONR4- or-NR4CO-defined for Z in formula (I) or (I'), with the formation of the nitrogen-containing condensed ring with circular hydrocarbon or heterocyclic group, R2. Examples of the condensed ring include, for example, 8-12 membered bicyclic heterocyclic group formed by condensation of benzene ring with a saturated monocyclic heterocyclic group containing one nitrogen atom, such as 1,2,3,4-tetrahydroquinolin, 2,3,4,5-tetrahydro-1H-1-benazepril etc.

Above the "condensed ring" and "nitrogen-containing condensed ring may also contain one to three substituent selected from acyl (e.g. acetyl, propionyl etc), amide (e.g., dimethylaminoborane, methylaminomethyl etc), amine (for example, dimethylamino, methylamino, amino, etc.), halogen (for example the EP, fluorine, chlorine, bromine, etc.), lower alkyl (e.g. methyl, ethyl, trifloromethyl etc) and lower alkoxy (e.g. methoxy, ethoxy, triptoreline and so on), each of which may be substituted.

From these values, R2preferably represents optionally substituted C6-10aryl (more preferably phenyl) or optionally substituted 5-8-membered (more preferably 5 to 6 membered) heterocyclic group (preferably pyridyl). R2more preferably represents phenyl, which is a 2,4-disubstituted, 2,4,6-triple-substituted or 2,4,5-triple-substituted two or three substituents, or pyridyl, which is disubstituted or tizamidine two or three substituents. The substituents for phenyl and pyridyl may be the same or different from each other, and examples of such substituents include acyl (e.g. acetyl, propionyl etc), amide (e.g., dimethylaminoethyl, methylaminomethyl etc), amine (e.g., dimethylamino, methylamino, amino, etc.), halogen (e.g. fluorine, chlorine, bromine, etc.), lower alkyl (e.g. methyl, ethyl, trifluoromethyl, etc.) and lower alkoxy (e.g. methoxy, ethoxy, triptoreline and so on), each of which can be replaced.

In the formula (I) and (I'), Y1represents CR3aor nitrogen, Y2represents CR3b or nitrogen, and Y3represents CR3cor nitrogen (where R3a, R3band R3cindependently represent hydrogen, halogen, nitro, cyano, optionally substituted hydrocarbon, optionally substituted, hydrocarbonate, optionally substituted, hydrocarbide, optionally substituted amino or acyl), provided that one or less of the Y1, Y2and Y3represents nitrogen.

6-Membered ring with Y1, Y2and Y3formula (I) and (I') is a ring containing one nitrogen atom or less, such as benzene ring and pyridine ring.

Examples of the halogen include fluorine, chlorine, bromine, iodine and the like, preferably chlorine and bromine.

Examples of "optionally substituted hydrocarbide" in R3a, R3band R3cinclude the same groups, as groups, as for example optionally substituted hydrocarbide R3. Of them optionally substituted C1-3alkyl is preferred, and an unsubstituted C1-3alkyl, C1-3alkyl, substituted hydroxy, and C1-3alkyl, substituted amino (e.g. dimethylamino, methylamino, pyrrolidin etc) are more preferred. Examples hydrocarbide for the above "optionally substituted, hydrocarbonate" and "optionally substituted, hydrocarbide" in R3a, R3band R 3cinclude the same groups, as groups, as for example optionally substituted hydrocarbide in R3. In particular, hydrocarbon containing from 1 to 4 carbon atoms, is preferred.

Of these groups optionally substituted C1-3alkoxy is preferred, and substituted C1-3alkoxy and halogenated substituted C1-3alkoxy are preferred, particularly preferred are methoxy, deformedarse, triptoreline. Examples of the optionally substituted amino" for R3a, R3band R3cinclude amino group, N-monosubstituted the amino group and N,N-disubstituted an amino group. Examples of these substituted amino groups include groups containing one or two substituent selected from optionally substituted hydrocarbones group (for example, C1-8alkyl group, a C3-7cycloalkyl group2-8alkenylphenol group2-8alkenylphenol group3-7cycloalkenyl group6-10aryl group which may contain a1-4alkyl group, etc), optionally substituted heterocyclic group (for example, the same groups as optionally substituted heterocyclic group, R2), or a group of the formula: -COR3d(where R3dis an atom of water is an ode, or optionally substituted hydrocarbonous group, or optionally substituted heterocyclic group. As for the “hidrocarburos group” or “heterocyclic group” in "optionally substituted hydrocarbones group" or "optionally substituted heterocyclic group"defined for R3dthey may contain the same Deputy, as specified for “hidrocarburos group” or “heterocyclic group” in “optionally substituted hydrocarbide for R3or "optionally substituted heterocyclic group” for R2preferably With1-10acyl group (for example, C2-7alkanoyl, benzoyl, nicotinoyl etc). Specific examples of such groups include methylamino, dimethylamino, ethylamino, diethylamino, dipropylamino, dibutylamino, diallylamine, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionamido, benzoylamine, nicotinamine etc.

In addition, two groups in these substituted amino groups may be combined with the formation of nitrogen-containing 5-7-membered ring (for example, piperidine, piperazine derivatives, morpholine, thiomorpholine etc).

Examples of acyl for R3a, R3band R3cinclude the same groups, as groups, are presented as examples of the acyl for R3. In particular, acyl containing from 2 to 4 atoms ug is erode, is preferred.

In the formula (I) and (I'), Y1, Y2and Y3preferably represent CR3a, CR3band CR3crespectively, or one of the Y1, Y2and Y3represents nitrogen. R3a, R3band R3cpreferably represent hydrogen, halogen, cyano, acyl, C1-4alkyl, optionally substituted by hydroxy (e.g., methyl, ethyl, hydroxymethyl, amino and C1-4alkoxy (e.g. methoxy, ethoxy). As R3achlorine, bromine, methoxy and methyl are preferred.

In the formula (I) and (I') Z is a bond, -CO-, oxygen (-O-), sulfur (-S-), -SO-, -SO2-, -NR4-, -NR4-alk-, -CONR4- or-NR4CO.

Specified alk is an optionally substituted C1-4alkylene, such as methylene, ethylene, propylene, butylene, etc.

R4represents hydrogen, optionally substituted hydrocarbon or acyl. "Optionally substituted hydrocarbon" and "acyl" for R4include the same group as the group presents as an example, optionally substituted hydrocarbones group and acyl for R3.

In addition, R4can be combined together with the Deputy cyclic hydrocarbide or heterocyclic group optionally substituted hydrocarbide or optional Samusenko the heterocyclic group, R 2with the formation of rings. Examples of the specified ring include the same ring, as a group, are presented as examples of the rings formed by two substituents R2specified above.

Provided that (i) compound, where X represents-NH - and R2represents an optionally substituted thiophene ring,

(ii) compound, where R1represents cyano, R3crepresents methyl, substituted with three substituents, one of which represents the acyl and the other two may form a ring,

(iii) (a) 6-amino-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carbonitrile,

b) N-{7-cyano-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-6-yl}acetamide", she

c) 6-amino-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carboxamide, and

d) 6-{[(allylamino)carbonothioyl]amino}-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carboxamide,

(iv) 4-({2-[(4-chlorophenyl)amino]-1,7-dimethyl-1H-benzimidazole-5-yl}oxy)-N-methylpyridin-2-carboxamid,

(v) N-[3,5-bis(trifluoromethyl)phenyl]-7-methyl-1H-benzimidazole-2-amine,

(vi) compound, where R3represents a substituted heteroaromatic, R2is a 4-piperidinyl containing a substituent in the 1-position,

(vii) 6-chloro-4-methyl-N-piperidine-4-yl-1H-benzimidazole-2-amine, and

(viii) compound, where R2represents a substituted 8-oxo-thia-1-Aza-bicyclo[4.2.0]Oct-2-EN-7-yl, are excluded from the compounds of formula (I).

As preferred compounds of formula (I) and (I') you can specify the connection, where X represents NR3(where R3preferably represents methyl, ethyl, hydroxyethyl, etc.); Y1represents CR3a(where R3apreferably represents H, Me, halogen (such as F, Cl, Br), cyano, acyl, alkoxy, etc.), Y2represents CR3b(where R3bpreferably represents H, Me, halogen (such as F, Cl, Br) and so on) or nitrogen and Y3represents CR3c(where R3cpreferably represents H, Me, halogen (such as F, Cl, Br), etc. or nitrogen; Z represents NR4(where R4preferably represents H, C1-4alkyl etc) or oxygen; R1represents an optionally substituted acyclic branched C3-7hydrocarbon (in particular, 2-propyl, 3-hexyl, 3-pentyl, 4-heptyl); and R2represents an optionally substituted C6-10aryl (in particular phenyl, more preferably di - or tri-substituted phenyl or optionally substituted pyridyl (in particular, pyridyl, more preferably di - or tri-substituted pyridyl). Of these groups, particularly preferred is the compound where R1is a 3-pentyl, 3-hexyl or 4-heptyl, X PR is dstanley a NR 3, R3represents methyl, ethyl or hydroxyethyl, Y1represents CR3a, Y2represents CR3b, Y3represents CR3c, R3arepresents chlorine, bromine, methoxy or methyl, R3brepresents hydrogen, R3crepresents hydrogen, R2represents phenyl, which is 2,4,6-triple-substituted, 2,4,5-triple-substituted or 2,4-disubstituted groups substituents, or pyridyl, which is tizamidine or disubstituted by groups of deputies. Examples of substituents for phenyl and pyridyl include acyl such as acetyl and propionyl, amide, such as dimethylaminoethyl and methylaminomethyl, amine, such as dimethylamine, methylamino, amino, halogen, such as fluorine, chlorine and bromine, lower alkyl, such as methyl, ethyl and trifluoromethyl, and lower alkoxy, such as methoxy, ethoxy, triptoreline, each of which may be substituted.

The compound (I) or (I') can be in the form of prodrugs of the compound. The prodrug of compound (I) or (I') refers to a compound that is converted into compound (I) or (I') when interacting with an enzyme, gastric acid or the like under physiological conditions of the organism, namely, (i) compound which is converted to compound (I) or (I') by enzymatic oxidation, restoring the population, hydrolysis or the like, and (ii) the compound, which is converted to compound (I) or (I') by hydrolysis in the interaction with gastric acid or the like, Examples of the prodrug of compound (I) or (I') include a compound or its salt, where the hydroxyl group in compound (I) or (I') is acylated, alkilirovanny, phosphorylated, or converted to borate (for example, the compound or its salt, where the hydroxyl group in compound (I) or (I') is transformed into the atomic charges, palmitoleic propenyloxy, pivaloyloxy, succinylate, fumaroles, alanylons, dimethylaminoethylacrylate etc), the compound or its salt, where the carboxyl group in compound (I) or (I') is esterified or amidinophenoxy (for example, the compound or its salt, where the carboxyl group in compound (I) or (I') is subjected to ethyl esterification, phenyl esterification, carboxypolymethylene esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonylmethylene esterification, italicising esterification, (5-methyl-2-oxo-1,3-dioxolane-4-yl)methyl esterification, cyclohexyloxycarbonyloxy esterification or conversion of methylamide etc), or the like, Such prodrugs can be obtained in accordance with the method known per se, or mod the qualifications.

In addition, the prodrug of compound (I) or (I') may be a compound or its salt, which is converted to compound (I) or (I') in physiological conditions, as described in “Development of Drugs”, Volume 7, Molecular Design, Hirokawa Shoten, 1990; pages 163-198.

General method of synthesis

Obtaining the compounds of formula (I) or its salt of the present invention is described below. The examples below are intended to illustrate the invention and should not be construed as in any way limiting the present invention. Specialists in this field may use alternative methods.

The method of obtaining the compound (I) or its salt of the present invention is represented by the following methods.

(Scheme 1)

where R1arepresents an optionally substituted hydrocarbon, optionally substituted C-linked heterocyclic group, optionally substituted N-linked heteroaryl or acyl, Ar represents optionally substituted aryl, L1represents a group to delete (for example, a halogen atom, such as chlorine, bromine and iodine, etc., sulfonyloxy, such as p-toluensulfonate, methysulfonylmethane and triftormetilfullerenov etc., and alloctype, such as acetyloxy and benzoyloxy the PA and so on), and each of the other symbols are defined above.

The compound (III) or its salt can be obtained by halogenation, sulfonylurea or acylation of compound (II) or its salt using a halogenation agent, agent sulfonylurea or agent acylation, respectively.

Examples of the halogenation agent include phosphorus oxychloride, oxybromide phosphorus, trichloride phosphorus, tribromide phosphorus, pentachloride phosphorus, chlorine, bromine and thionyl chloride. The halogenation agent is used in an amount of from 1 mole to excess per 1 mole of compound (II) or as a solvent.

Examples of the solvent that do not have any adverse effect on the reaction include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, dioxane and tetrahydrofuran, esters such as ethyl acetate, NITRILES, such as acetonitrile, halogenated hydrocarbon such as chloroform and dichloromethane, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones, such as acetone and 2-butanone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio.

Although the reaction temperature may vary depending on compound (II) or the th salt, as well as other conditions, it is 0 to 200oC, preferably from 20 to 150oC. the reaction Time is from 10 minutes to 24 hours, preferably from 30 minutes to 12 hours.

Received, therefore, the compound (III) can be isolated and purified by known methods of separation and purification such as concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

When L1represents sulfonyloxy or alloctype in the compound (III) or its salt, the compound (III) or its salt can be obtained by reacting the compound (II) with the agent sulfonylurea or acylation agent after processing the base of the compound (II).

The base can represent, for example, alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide etc, bicarbonate of an alkali metal such as sodium bicarbonate and potassium bicarbonate, etc., a carbonate of an alkali metal such as sodium carbonate and potassium carbonate, etc., cesium salt, such as cesium carbonate, etc., alkali metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, alkoxide, such as sodium methoxide and ethoxide sodium, etc. amines, such as trimethylamine, triethylamine and diisopropylethylamine etc., cyclically the amine, such as pyridine, etc.

Examples of agent sulfonylamine include p-toluensulfonate, methanesulfonate, triftormetilfullerenov etc. Agent sulfonylurea used in an amount of from 1 to 10 mol, preferably 1 to 5 mol per 1 mol of compound (II).

Examples of acylation agent include acetylchloride, benzoyl chloride, etc. the acylation Agent is used in an amount of from 1 to 10 mol, preferably 1 to 5 mol per 1 mol of compound (II).

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio.

Although the reaction temperature may vary depending on compound (II) or its salt, as well as other conditions, it is 0 to 200oC, preferably 0 to 150oC. the reaction Time is from 10 minutes to 24 hours the owls, preferably from 30 minutes to 12 hours.

Received, therefore, the compound (III) can be isolated and purified by known methods of separation and purification such as concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

The compound (Ia) or its salt, which is covered by a compound (I) of the present invention, can be obtained by reacting compound (III) with ArZH.

At this stage use from 1 to 20 mol, preferably from 1 to 10 mol of the compound represented ArZH, or its salt per 1 mol of compound (III) or its salt.

This reaction can be performed in alkaline conditions. The base can represent, for example, alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide etc, bicarbonate of an alkali metal such as sodium bicarbonate and potassium bicarbonate, etc., a carbonate of an alkali metal such as sodium carbonate and potassium carbonate, etc., cesium salt, such as cesium carbonate, etc., alkali metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl sodium tert-piperonyl potassium, etc., amine, such as trimethylamine, triethylamine and diisopropylethylamine etc. cyclic amine, such as pyridine, etc.

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones, such as acetone and 2-butanone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio or not to use.

Although the reaction temperature may vary depending on compound (III) or its salts, as well as other reaction conditions, it is 0 to 200°C, preferably from 20 to 150 °C., or the reaction mixture can be heated using microwave irradiation. The reaction time is from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

Obtained, so that the compound (Ia) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, paracrystal what grouting, dissolution with transfer and chromatography.

(Scheme 2)

where R5represents hydrogen and optionally substituted hydrocarbon, R3and R5can be combined with each other to form a ring, R6and R7represent optionally substituted hydrocarbon, L2and L3represent the atoms of halogen, such as chlorine, bromine and iodine, and each of the other symbols are defined above.

The compound (IIa) or its salt can be obtained by treating compound (IV) 1,1'-carbonyl diimidazol, phosgene, triphosgene, alkylhalogenide, such as ethylchloride, pergalogenated, such as phenylchloropyruvate, or urea, etc. of the Compound (IV) or its salt are generally commercially available or can be obtained from nitro-derivatives, corresponding to the compound (IV).

At this stage use from 1 to 5 mol, preferably 1 to 3 mol of a cyclization agent or its salt per 1 mol of compound (IV) or its salt.

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenide the data hydrocarbons, such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones, such as acetone and 2-butanone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio or not to use.

Although the reaction temperature may vary depending on compound (IV) or its salt, as well as other reaction conditions, it is 0 to 150°C, preferably from 20 to 100°C. the reaction Time is from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

Obtained, so that the compound (IIa) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

The compound (IIb) or its salt can be obtained by the Grignard reaction of the compound (IIa) or its salt with R6MgL2and R7MgL3. When R6has the same meaning as R7in the compound (IIb), at this stage, you can use the R6MgL2. When R6has a value other than R7in the compound (IIb), the Grignard reaction can be performed Paladino using R 6MgL2and R7MgL3on this stage.

At this stage use from 1 to 20 mol, preferably from 1 to 10 mol of the compound represented by R6MgL2and R7MgL3or its salt to 1 mol of compound (IIa) or its salt.

Examples of the solvent that do not have any adverse effect on the reaction include ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform and dichloromethane, ketones, such as acetone and 2-butanone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio or not to use.

Although the reaction temperature may vary depending on compound (IIa) or its salts, as well as other reaction conditions, it is -20 to 150°C, preferably from 0 to 100°C. the reaction Time is from 5 minutes to 24 hours, preferably from 5 minutes to 12 hours.

Obtained, so that the compound (IIb) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

With the unity (IIc) or its salt can be obtained by dehydration of the compound (IIb) or its salts with acids, and olefin then restore using a suitable reducing agent or catalytic hydrogenation.

The acid may represent, for example, inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and thionyl chloride, etc. and organic acid such as formic acid, acetic acid, triperoxonane acid and methanesulfonamide acid, etc. and a Lewis acid.

At the stage of dehydration use from 1 mole to excess amount of acid per 1 mol of compound (IIb) or its salt, or acid can be used as a solvent.

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones, such as acetone and 2-butanone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio or not to use.

Although the rate the temperature of the reaction may vary depending on compound (IIb) or its salt, as well as other reaction conditions, it is 0 to 200°C, preferably from 20 to 150°C. the reaction Time is from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

Obtained, thus, the olefin can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

Recovering a reducing agent, preferably, represents borohydride sodium, borohydride lithium, cyanoborohydride sodium and triacetoxyborohydride sodium. The catalytic hydrogenation can be performed at this stage. Examples of the catalyst include palladium-based catalyst such as palladium black, palladium oxide, sulfate, palladium-barium, palladium on carbon, palladium hydroxide, platinum catalyst, such as platinum black, platinum oxide and platinum on carbon, or Nickel catalyst such as reduced Nickel, oxidized Nickel and Raney Nickel.

At this stage use from 1 to 20 mol, preferably from 1 to 10 moles of reducing agent per 1 mol of the olefin or its salts.

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and e is anal, ethers, such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones, such as acetone and 2-butanone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio.

Although the reaction temperature may vary depending on the olefin or its salts, as well as other reaction conditions, it is 0 to 150°C, preferably from 0 to 100°C. the reaction Time is from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

Obtained, so that the compound (IIc) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

(Scheme 3)

where each symbol is defined above.

Obtaining the compound (Ic) or its salt, which are covered by the compound (I) of the present invention, from compound (Ib) or its salt can be carried out is similar to obtaining the compounds (IIb), as shown in Scheme 2.

Obtaining the compound (Id) or its salt, which are covered by the compound (I) of the present invention, from compound (Ic) or its salt can be carried out like in a compound (IIc)as shown in Scheme 2.

(Scheme 4)

where each symbol is defined above.

Obtaining the compound (IId) or its salts of the compounds (IIa) or its salt can be carried out like in a compound (IIb), as shown in Scheme 2.

(Scheme 5)

where each symbol is defined above.

Obtaining the compound (Ie) or its salt, which are covered by the compound (I) of the present invention, from compound (Ib) or its salt can be carried out like in a compound (IIb), as shown in Scheme 2.

(Scheme 6)

where R1brepresents an optionally substituted hydrocarbon and optionally substituted C-linked heterocyclic group, R1crepresents an optionally substituted hydrocarbon, optionally substituted C-linked heterocyclic group and optionally substituted N-linked heteroaryl, R8and R9independently represent hydrogen, optionally substituted hydrocarbon, hydroxy, and optionally substituted alkoxy, and can be combined in the Rog other to form rings, is heteroaryl, L4represents a halogen atom such as chlorine, bromine and iodine, each of the other symbols are defined above.

The compound (VI) or its salt can be obtained by halogenation of the compound (V) or its salt using a halogenation agent.

Examples of the halogenation agent include chlorine, bromine, iodine, thionyl chloride, chloride of copper(I)chloride copper(II)bromide copper(I)bromide copper(II), sodium chloride, sodium bromide, sodium iodide, potassium iodide, etc. the halogenation Agent is used in an amount of from 0.5 mol to 10 mol, preferably from 0.5 mol to 5 mol per 1 mol of compound (V).

At this stage it is possible to obtain a diazonium compound of the type before the introduction of the halogen atom. Examples of the agent to obtain the diazonium compound type include sodium nitrite, potassium nitrite and tert-butylnitrite etc. Such agent is used in an amount of from 1 mol to 10 mol, preferably from 1 mol to 5 mol per 1 mol of compound (V).

This reaction can be performed in acidic conditions. Examples of the acid include inorganic acid such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid and copper sulfate, etc. and Lewis acid. The acid is used in an amount of from 2 mol to excess per 1 mol of compound (V).

P is emery solvent, not having any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones, such as acetone and 2-butanone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio.

Although the reaction temperature may vary depending on compound (V) or its salt, as well as other conditions, it is -20 to 150oC, preferably from 0 to 100oC. the reaction Time is from 10 minutes to 24 hours, preferably from 30 minutes to 12 hours.

Obtained, so that the compound (VI) can be isolated and purified by known methods of separation and purification such as concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

When R1crepresents an optionally substituted hydrocarbon, optionally substituted With-associated GE is eroticlick group in the compound (IIe) or its salt, the compound (IIe) or its salt can be obtained by reacting compound (VI) with R1bBR8R9or its salt in the presence of a palladium catalyst, preferably tetrakis(triphenylphosphine)palladium(0) and Tris(dibenzylideneacetone)diplegia(0), catalytic amounts of phosphine ligand, preferably 2-(dicyclohexylphosphino)biphenyl, 2-(dicyclohexylphosphino)-2',6'-dimethoxy-1,1'-biphenyl (S-Phos) and 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (X-Phos), and the Foundation in accordance with the procedure binding assays Suzuki (Organic Synthesis via Boranes, vol. 3: Suzuki coupling, A.Suzuki and H.C.Brown, Aldrich, 2002) and modified methods, or trialkylsilyl, such as alltimelow or arilcarboksilova etc., or its salt, and optional additives, in accordance with the procedure of binding the Steele (Angew. Chem. Int. Ed. Engl., 25, 504 (1986)and modified methods.

When R1crepresentsin the compound (IIe), the compound (IIe) or its salt can also be obtained by reacting compound (VI) or its salt withor its salt in the presence of a palladium catalyst, preferably palladium(II) acetate or agent on the basis of copper, preferably copper acetate(II). You can use a catalytic amount of phosphine ligand, preferably 2-(DICYCLOHEXYL Ospina)biphenyl. This reaction can be carried out in accordance with the procedure of Buchwald et al. (J. Am. Chem. Soc. 1998, 120, 9722) and Lam et. al. (Tetrahedron Lett., 1998, 39, 2941) and modified methods.

(Scheme 7)

where each symbol is defined above.

The compound (VII) or its salt can be obtained by reacting compound (VI) or its salt by reacting litvinovna or binding agent on the basis of boron.

When the reaction is performed via litvinovna, examples of agent-based boron include trialkylborane, preferably triisopropylsilyl.

At this stage use from 1 to 10 mol, preferably 1 to 5 mol based agent boron per 1 mol of compound (VI) or its salt.

Agent litvinovna can represent, for example, alkylate, preferably n-utility, second-utility and tert-utility, and it is used in an amount of from 1 to 5 mol, preferably 1 to 3 mol per 1 mol of compound (VI) or its salt.

Examples of the solvent that do not have any adverse effect on the reaction include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, dioxane and tetrahydrofuran, and halogenated hydrocarbons such as chloroform and dichloromethane. These solvents can be used by mixing them in a suitable ratio.

Although those is the temperature of the reaction may vary depending on compound (VI) or its salt, as well as other conditions, it ranges from -100 to 100oC, preferably from -80 to 50oC. the reaction Time is from 10 minutes to 24 hours, preferably from 30 minutes to 12 hours.

When carry out the binding reaction using a metal catalyst, examples of the agent on the basis of boron include 4,4,5,5-tetramethyl-1,3,2-dioxaborolan and bis(pinacolato)DIBORANE.

At this stage use from 1 to 10 mol, preferably 1 to 5 mol based agent boron per 1 mol of compound (VI) or its salt.

Palladium catalyst, preferably palladium diacetate(II)a catalytic amount of phosphine ligand, preferably 2-(dicyclohexylphosphino)biphenyl, and the base can be used in accordance with the procedure described in J. Org. Chem., 62, 6458 (1997) and modified methods.

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones, such as acetone and 2-butanone, the sulfoxidov, such as dimethyl sulfoxide. These solvents can be used by mixing them in a suitable ratio or not to use.

Although the reaction temperature may vary depending on compound (VI) or its salt, as well as other conditions, it is 0 to 200oC, preferably from 20 to 150oC. the reaction Time is from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours.

Obtained, so that the compound (VII) can be isolated and purified by known methods of separation and purification such as concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

Obtaining the compound (IIe) or its salts of the compounds (VII) or its salt can be carried out like in a compound (IIe), as shown in figure 6.

(Scheme 8)

where each symbol is defined above.

Obtaining the compound (VIII) or its salt of the compound (VI) or its salt can be carried out like obtaining compound (III) or its salt according to Scheme 1.

Obtaining the compound (IX) or its salt of the compound (VIII) or its salt can be carried out like in a compound (Ia) or its salt according to Scheme 1.

Obtaining the compound (If) or its salt, which covers the connection is tion (I) of the present invention, from the compound (IX) or its salt can be carried out like in a compound (IIe) or its salt according to Scheme 6.

(Scheme 9)

where R10and R11represent hydrogen and optionally substituted hydrocarbon, and each of the other symbols are defined above.

The compound (X) or its salt can be obtained by reacting compound (V) or its salt with sodium nitrite, and the resulting diazonium salt to restore using a suitable reducing agent.

At this stage use from 1 to 5 mol, preferably 1 to 3 mol of sodium nitrite per 1 mol of compound (V) or its salt.

Examples of reducing agents include borohydride alkali metal, preferably of borohydride sodium, borohydride lithium, cyanoborohydride sodium and triacetoxyborohydride sodium metal, preferably Fe, Zn, Sn and SnCl2and the metal catalyst, palladium catalyst, such as palladium black, palladium oxide, sulfate, palladium-barium, palladium on carbon, palladium hydroxide, platinum catalyst, such as platinum black, platinum oxide and platinum on carbon, or Nickel catalyst such as reduced Nickel, oxidized Nickel and Raney Nickel. The reducing agent is used in quantities of from a catalytic amount to excess per 1 mol the compound (V).

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio or not to use.

Although the reaction temperature may vary depending on compound (V) or its salt, as well as other conditions, it is -20 to 150oC, preferably from 0 to 100oC. the reaction Time is from 10 minutes to 24 hours, preferably from 30 minutes to 12 hours.

Obtained, so that the compound (X) can be isolated and purified by known methods of separation and purification such as concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

The compound (IIf) or its salt can be obtained by reacting compound (X) or its salt with a compound (X) or its salt.

At this stage use from 1 to 5 mol, preferably 1 to 3 mol of compound (XI) or its salt to 1 mol of compound (X) or its salt.

You can use the acid, for example an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, etc. and organic acid such as formic acid, acetic acid, p-toluensulfonate acid, triperoxonane acid and methanesulfonamide acid, etc. and a Lewis acid.

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, acids such as formic acid and acetic acid, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio.

Although the reaction temperature may vary depending on compound (V) or its salt, as well as other conditions, it is 0 to 200oC, PR is doctitle from 20 to 150 oC. the reaction Time is from 10 minutes to 24 hours, preferably from 30 minutes to 12 hours.

Obtained, so that the compound (IIf) can be isolated and purified by known methods of separation and purification such as concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

(Scheme 10)

where each symbol is defined above.

Obtaining compound (IIg) or its salts of the compounds (V) or its salt can be carried out like in a compound (IIf) or its salt according to Scheme 9.

(Scheme 11)

where R12represents an optionally substituted C1-6alkylsulphonyl (for example, formyl, methylcarbamyl and ethylcarboxyl etc), phenylcarbinol,1-6allyloxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl and tert-butoxycarbonyl etc), vinyloxycarbonyl (for example, menthoxycarbonyl), C7-10aralkylamines (for example, benzyloxycarbonyl), C7-10aralkyl (for example, benzyl and 4-methoxybenzyl etc), trityl, phthaloyl etc. Deputy in each of the groups listed above may be a halogen atom (e.g. fluorine, chlorine, bromine and iodine, etc.)1-6alkylsulphonyl (for example, methylcarbamoyl, ethylcarboxyl and butylboron the l etc) and the nitrogroup, and each of the other symbols are defined above.

The compound (IIa) or its salt can also be obtained using the procedures shown in Scheme 11.

The compound (XIV) or its salt can be obtained by nitration of the compound (XIII) or its salt using a nitration agent. The compound (XIII) or its salt are generally commercially available or can be obtained from aniline derivative corresponding to the compound (XIII), in the usual way acetylation.

Examples of the agent include nitration with nitric acid (for example, fuming nitric acid, nitric acid and sulfuric acid, etc.), nitrates (for example, sodium nitrate, potassium nitrate, silver nitrate, ammonium nitrate, benzoylmethyl, nitrate benzyltriphenylphosphonium, subnitrate bismuth etc). The nitration agent is used in an amount of from 0.5 mol to 50 mol, or it can be used as solvent, preferably in an amount of from 0.5 mol to 30 mol per 1 mol of compound (XIII).

This reaction is also carried out in the presence of additives. Examples of additives include anhydrides (e.g. acetic anhydride, triperoxonane anhydride, the anhydride methanesulfonic acid etc), acid anhydrides (for example, thionyl chloride etc), acids (e.g. acetic acid, methanesulfonate acid etc), metals (such as iron and so on).

Supplement use the form in the amount of from 0.5 mol to 50 mol, preferably 0.5 mol to 30 mol per 1 mol of compound (XIII).

Examples of the solvent that do not have any adverse effect on the reaction include water, acetic acid, halogenated hydrocarbons such as chloroform and dichloromethane, 1,2-dichloroethane, etc. Such solvents can be used by mixing them in a suitable ratio or not to use. Although the reaction temperature may vary depending on compound (XIII) or its salts, as well as other reaction conditions, it is -20 to 150°C, preferably from 0 to 100°C. the reaction Time is from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours. Obtained, so that the compound (XIV) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

The compound (XV) or its salt can be obtained by deacetylation of compound (XIV) or its salt with acid or base, and then nitrogroup reduction using a suitable reducing agent or catalytic hydrogenation.

The acid may represent, for example, inorganic acid such as hydrochloric sour is a, sulfuric acid, nitric acid and thionyl chloride, etc. and organic acid such as formic acid, acetic acid, triperoxonane acid and methanesulfonamide acid, etc. and a Lewis acid.

The base can represent, for example, alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide etc, bicarbonate of an alkali metal such as sodium bicarbonate and potassium bicarbonate, etc., a carbonate of an alkali metal such as sodium carbonate and potassium carbonate, etc., cesium salt, such as cesium carbonate, etc., alkali metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl sodium tert-piperonyl potassium, etc.

At the stage of deacetylation use from 1 mole to excess amount of acid or base per 1 mol of compound (XIV) or its salt, or acid can be used as a solvent.

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons, so the e as chloroform and dichloromethane, NITRILES, such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones, such as acetone and 2-butanone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio, or do not use.

Although the reaction temperature may vary depending on compound (XIV) or its salts, as well as other reaction conditions, it is 0 to 200°C, preferably from 20 to 150°C. the reaction Time is from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

Obtained, thus, the nitro compounds can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

Recovering a reducing agent, preferably, represents borohydride sodium, borohydride lithium, cyanoborohydride sodium and triacetoxyborohydride sodium. The catalytic hydrogenation can be performed at this stage. Examples of the catalyst include palladium-based catalyst such as palladium black, palladium oxide, sulfate, palladium-barium, palladium on carbon, palladium hydroxide, platinum was pushing the congestion, such as platinum black, platinum oxide and platinum on carbon, or Nickel catalyst such as reduced Nickel, oxidized Nickel and Raney Nickel.

At this stage use from 1 to 20 mol, preferably from 1 to 10 moles of reducing agent per 1 mol of nitro compounds or their salts.

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones, such as acetone and 2-butanone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio.

Although the reaction temperature may vary depending on compound (XIV) or its salts, as well as other reaction conditions, it is 0 to 150°C, preferably from 0 to 100°C. the reaction Time is from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

Obtained, so that the compound (XV) can be isolated and purified famous pic is the means of separation and purification, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

Obtaining the compound (XVI) or its salt of the compound (XV) or its salt can be carried out like in a compound (IIa)as shown in Scheme 2.

The compound (XVII) or its salt can be obtained by reacting compound (XVI) with R12-L2or anhydride (R12)2O.

At this stage use from 1 to 10 mol, preferably 1 to 5 mol of the compound represented by R12-L2or anhydride (R12)2O, or its salt per 1 mol of compound (XVI) or its salt.

This reaction can be performed in alkaline conditions. The base can represent, for example, alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide etc, bicarbonate of an alkali metal such as sodium bicarbonate and potassium bicarbonate, etc., a carbonate of an alkali metal such as sodium carbonate and potassium carbonate, etc., cesium salt, such as cesium carbonate, etc., alkali metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl sodium tert-piperonyl potassium, etc., amine, such as trimethylamine, three is Tramin and diisopropylethylamine etc., cyclic amine, such as pyridine, 4-dimethylaminopyridine, DBU, etc.

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones, such as acetone and 2-butanone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio or not to use.

Although the reaction temperature may vary depending on compound (XVI) or its salts, as well as other reaction conditions, it is 0 to 200°C, preferably from 20 to 150°C., or the reaction mixture can be heated using microwave irradiation. The reaction time is from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

Obtained, so that the compound (XVII) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction RA is solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

Obtaining the compound (XVIII) or its salt of the compound (XVII) or its salt can be carried out like in a compound (XVII).

The compound (IIa) or its salt can be obtained by removing protection from compound (XVIII) or its salt with acid or base, or catalytic hydrogenation.

The acid may represent, for example, inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and thionyl chloride, etc. and organic acid such as formic acid, acetic acid, triperoxonane acid and methanesulfonamide acid, etc. and a Lewis acid.

The base can represent, for example, alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide etc, bicarbonate of an alkali metal such as sodium bicarbonate and potassium bicarbonate, etc., a carbonate of an alkali metal such as sodium carbonate and potassium carbonate, etc., cesium salt, such as cesium carbonate, etc., alkali metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl sodium tert-piperonyl potassium, etc.

The catalytic hydrogenation can be made is TLAT at this stage. Examples of the catalyst include palladium-based catalyst such as palladium black, palladium oxide, sulfate, palladium-barium, palladium on carbon, palladium hydroxide, platinum catalyst, such as platinum black, platinum oxide and platinum on carbon, or Nickel catalyst such as reduced Nickel, oxidized Nickel and Raney Nickel.

At this stage use from 1 mole to excess amount of acid or base per 1 mol of compound (XVIII) or its salt, or acid can be used as a solvent.

Examples of the solvent that do not have any adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, NITRILES such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones, such as acetone and 2-butanone, and sulfoxidov, such as dimethylsulfoxide. These solvents can be used by mixing them in a suitable ratio or not to use.

Although the reaction temperature may vary depending on compound (XVIII) is whether its salts, as well as other reaction conditions, it is 0 to 200°C, preferably from 20 to 150°C. the reaction Time is from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

Obtained, thus, the compounds can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, dissolution with transfer and chromatography.

The original connection for the compound (I) in accordance with the present invention can be in the form of a salt, including salt with inorganic acid (e.g. hydrochloric acid, phosphoric acid, Hydrobromic acid and sulfuric acid, etc. and salts with organic acid (e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid and benzosulfimide acid and so on). When any of these compounds contains an acid group such as-COOH, etc. may be formed salt with an inorganic base (e.g. alkali metal or alkaline-earth metal such as sodium, potassium, calcium and magnesium, ammonia and d) or with an organic base (for example, three-C1-3alkylamines, such as triethylamine, etc.).

In each reaction described above, when the original compound contains as a substituent of the amino group, amide group, gadringer, a urea group, carboxyl group or hydroxyl group, then that group may be derivatization using protective groups commonly used in the chemistry of peptides, which otscheplaut after the reaction, if desired, to give the desired compound.

The protective group for amino groups, amide groups and groups of urea may represent, for example, optionally substituted C1-6alkylsulphonyl (for example, formyl, methylcarbamyl and ethylcarboxyl etc), phenylcarbinol,1-6allyloxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl and tert-butoxycarbonyl etc), vinyloxycarbonyl (for example, menthoxycarbonyl), C7-10aralkylamines (for example, benzyloxycarbonyl), C7-10aralkyl (for example, benzyl and 4-methoxybenzyl etc), trityl, phthaloyl etc. Deputy in each of the groups listed above may be a halogen atom (e.g. fluorine, chlorine, bromine and iodine, etc.)1-6alkylsulphonyl (for example, methylcarbamoyl, ethylcarboxyl and butylcarbamoyl etc) and the nitro-group, and these substituents may be from 1 to about 3.

The protective group for carboxyl what the group can represent, for example, optionally substituted C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl, etc.), phenyl, trityl and silyl etc. Deputy in each of the groups listed above may be a halogen atom (e.g. fluorine, chlorine, bromine and iodine, etc.)1-6alkylsulphonyl (for example, formyl, methylcarbamyl, ethylcarboxyl and butylcarbamoyl etc) and the nitro-group, and these substituents may be from 1 to about 3.

The protective group for hydroxyl group may represent, for example, optionally substituted C1-6alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl, etc.), phenyl, C7-10aralkyl (for example, benzyl, etc.)1-6alkylsulphonyl (for example, formyl, methylcarbamyl and ethylcarboxyl etc), vinyloxycarbonyl (for example, menthoxycarbonyl etc.), C7-10aralkylamines (for example, benzyloxycarbonyl etc), pyranyl, furanyl, silyl etc. Deputy in each of the groups listed above may be a halogen atom (e.g. fluorine, chlorine, bromine and iodine, etc.)1-6alkyl, phenyl, C7-10aralkyl, nitro, etc. and such substituents may be from 1 to about 4.

The method of removal of the protective group is a method known per se or a similar method, such as processing, for example, an acid, a base, a reducing agent, UV light is m, hydrazine, phenylhydrazine, N-methyldithiocarbamate sodium, tetrabutylammonium, palladium acetate, etc.

Pharmaceutical composition containing compound (I) or (I') according to the present invention are expected to be useful for the treatment and prevention of diseases involving CRF such as depression, major depression, bipolar depression, dysthymia, seasonal affective disorder, recurrent depression, postpartum depression, symptom of depression, manic symptom, anxiety, generalized anxiety, symptoms of anxiety, panic disorder, obsessive fear, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder induced by stress, insomnia, stress disorder after trauma, cider Tourette's, autism, emotsionalnye disorders, adaptation disorders, disorder dysthymia, a sleep disorder, insomnia, bipolar disorder, circulatory disease, neurosis, schizophrenia, ulcers of the digestive tract, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, induced by the stress, disorders of the gastrointestinal tract, nervous vomiting, peptic ulcer, diarrhea, constipation, postoperative ileus Kish is cnica, dysfunction of the gastrointestinal tract and nervous vomiting associated with stress, Alzheimer's disease, senile dementia Alzheimera type, nerve degenerative disease such as Parkinson's disease and Huntington's disease, multi-infarct dementia, senile dementia, neurotic anorexia, the eating disorder, anorexia nervosa, hyperphagia and other swallowing disorders, obesity, diabetes, dependence on alcohol, pharmacophilia, the syndrome medicines, migraine, stress headache caused by tension headache, ischemic nervous breakdown, nervous disorder, cerebral palsy, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis, muscle spasms, chronic fatigue syndrome, glaucoma, Meniere's syndrome, a disorder of the autonomic regulation, alopecia, hypertension, cardiovascular disorder, tachycardia, congestive heart attack, hyperpnoea, bronchial asthma, apnea syndrome sudden death of seemingly healthy child, inflammatory disorder, pain, allergic disorder, impotence, postmenopausal disorder, disorder fertilization, infertility, cancer, impaired immune function in HIV infection, impaired immune function under stress, cerebrospinal meningitis, acromegalia, incontinence or osteoporosis.

The compound (I) or (I') according to the present invention can be formulated with a pharmaceutically acceptable carrier, and can be oral or parenteral introduce in the form of solid preparations such as tablets, capsules, granules, powders or the like; or liquid preparations such as syrups, injections, etc. is Also possible to obtain a composition for percutaneous administration, such as lotions, poultices, ointments (including creams), plasters, bandages, lotions, liquids, and solutions, suspensions, emulsions, sprays, etc.

With regard pharmaceutically acceptable carrier, use various organic or inorganic carrier substances that are traditionally used as substances for the formulation and in the form of a flowability agent, lubricant, binder, and disintegrant compounding in the solid composition; media suspendisse substance solubilizing agent, isotonicity agent, a buffering agent and an analgesic in the liquid composition. If necessary, you can use excipients for the formulation of compositions, such as preservative, antioxidant, stabilizer, colorant, sweetener, etc.

Preferred examples of the flowability agent include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic KIS the GTC, etc. Preferred examples of the lubricant include magnesium stearate, potassium stearate, talc, colloidal silicon dioxide and the like, Preferred examples of the binder include crystalline cellulose, α-starch, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone and the like, Preferred examples of disintegrants include starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboximetilkrahmal, nitrosamino hydroxypropylcellulose etc. Preferred examples of the carrier include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, etc.

If this is necessary for taste masking, deposition Intercollege coating or slow-release oral composition can be obtained by coating method known per se. Examples of the coating agent include hypromellose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethyleneglycol, Tween 80, Pluronic F68 [polyoxyethylene (160) polyoxypropylene (30) glycol], acetated cellulose phthalate of hydroxypropylmethylcellulose, acetated of hydroxymethylcellulose, Eudragit (manufactured by Rohm Company, a copolymer of methacrylic acid-acrylic acid), etc.

Preferably the e examples solubilizing substances include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, trilaminate, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like, Preferred examples of the suspending substances include surfactants, such as steartrimonium, sodium lauryl sulfate, lauramidopropyl acid, lecithin, benzylaniline, benzenehexachloride, glycerylmonostearate and the like; hydrophilic high molecular substances such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; etc. Preferred examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like, Preferred examples of buffering agents include buffer solutions of phosphate, acetate, carbonate, citrate, or the like, Preferred examples of analgesics include benzyl alcohol and the like, Preferred examples of the preservative include esters of para-oksibenzoynoy acid, chlorbutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid, sorbic acid and the like, Preferred examples of the antioxidant include sulfites, ascorbic acid, etc.

The following examples and experiments describe the path and method of production and application of the present invention and are illustrative and, and not limiting. You must understand that there may be other variants of embodiments that do not depart from the essence and scope of the present invention, as defined by the claims appended below.

The following examples preparative HPLC was performed under the following conditions.

Equipment: high-performance cleaning system Gilson

Column: YMC CombiPrep ODS-A S-5 m, 50×20 mm

Solvent: A; 0.1% aqueous solution triperoxonane acid, B; 0.1% of triperoxonane acid in acetonitrile

Cycle gradient: 0,00 min (A/B=95/5), 1.00 and min (A/B=95/5), 5,20 min (A/B=5/95), 6,40 min (A/B=5/95), 6,50 min (A/B=95/5), 6,60 min (A/B=95/5)

Flow rate: 20 ml/min

Detection: UV 220 nm

Example 1

The hydrochloride of N-(4-Bromo-2-methoxy-6-were)-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

Methyl 2-chloro-3-nitrobenzoate

A suspension of 20 g (99 mmol) of 2-chloro-3-nitrobenzoic acid in 800 ml of dichloromethane was cooled in an ice bath. To the reaction mixture were added dimethylformamide (0,40 ml) followed by adding dropwise 13,85 g (109 mmol) of oxalicacid. The reaction mixture was allowed to warm to room temperature and was stirred for 6 hours. Was added dropwise methanol (200 ml) and the reaction mixture was stirred over night. The reaction mixture was concentrated to obtain the residue was dissolved in dichloro ethane and was passed through a layer of silica gel, elwira a mixture of 50% ethyl acetate/hexane. The filtrate was concentrated in vacuum to obtain a 21.5 g (100%) specified in the connection header.

1H NMR (CDCl3) δ 3,98 (s, 3H), of 7.48 (t, J=7.8 Hz, 1H), to 7.84 (d, J=8,2 Hz, 1H), 7,95 (d, J=7.8 Hz, 1H).

Methyl 2-Methylamino-3-nitrobenzoic

A solution of 21.5 g (of 99.5 mmol) of methyl 2-chloro-3-nitrobenzoate in 300 ml of tetrahydrofuran (THF) was treated by adding dropwise 300 ml (597 mmol) of methylamine (2M solution in THF) and stirred over night at room temperature. The reaction mixture was concentrated to dryness, dissolved in dichloromethane and washed with aqueous sodium bicarbonate solution and water. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuum with the receipt of 20.8 g (100%) specified in the connection header.

1H NMR (CDCl3) δ 2,82 (d, J=5.5 Hz, 3H), at 3.9 (s, 3H), of 6.65 (t, J=7.8 Hz, 1H), of 7.97 (d, J=8,2 Hz, 1H), 8,04 (J=7.8 Hz, 1H), to 8.57 (s, 1H).

MS Calculated: 210; Found: 211(M+H).

Methyl 3-amino-2-methylaminophenol

A solution of 20.7 g (98 mmol) of methyl 2-methylamino-3-nitrobenzoate in 1200 ml of methanol was made inert by means of nitrogen. To this solution was added 5 g (2.3 mmol) 10% palladium on carbon (50% moisture). The reaction mixture was purged with hydrogen and stirred under pressure balloon of hydrogen for 7 hours. The catalyst was removed by filtration, and the filtrate was concentrated in vacuum to obtain 17.5 g (99%) specified in the agolove connection.

MS Calculated: 180; Found: 181(M+H).

Methyl 1-methyl-2-oxo-1,3-dihydro-1H-benzimidazole-7-carboxylate

To a solution of 17.5 g (97 mmol) of methyl 3-amino-2-methylaminopropane in 550 ml of tetrahydrofuran was added 20.5 g (146 mmol) of 1,1'-carbonyldiimidazole and the reaction mixture was stirred over night at room temperature. The reaction mixture was heated at 50°C for 2 hours and allowed to cool to room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in 1 l of ethyl acetate and washed with 400 ml of water. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to obtain a residue. The residue was purified flash chromatography, elwira solution of 50% ethyl acetate/dichloromethane, to obtain the 7,22 g (78%) specified in the connection header.

1H NMR (CDCl3) δ 3,59 (s, 3H), of 3.95 (s, 3H), was 7.08 (t, J=7.8 Hz, 1H), 7,27 (d, J=7.8 Hz, 1H), 7,52 (d, J=8,2 Hz, 1H).

MS Calculated: 206; Found: 207(M+H).

1-Methyl-7-(1-propinball)-1,3-dihydro-2H-benzimidazole-2-he

A solution of 8.5 ml (17 mmol) of the chloride propylene (2M solution in diethyl ether) was diluted with 10 ml of diethyl ether and cooled in an ice bath. To this solution was slowly added 1.0 g (4,85 mmol) of methyl 1-methyl-2-oxo-1,3-dihydro-1H-benzimidazole-7-carboxylate and the reaction mixture was stirred overnight at 35°C. the Reaction was suppressed by adding 50 ml of methanol, 100 m of the water and 10 ml of 1N aqueous solution of hydrochloric acid. The aqueous mixture was extracted with 50 ml diethyl ether and twice with 50 ml dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo to obtain a residue. This residue was dissolved in 50 ml of ethanol was added 10 ml of 6N aqueous solution of hydrochloric acid. The mixture was heated at 75°C for 2 h and then concentrated in vacuum. The obtained residue was dissolved in dichloromethane and washed with an aqueous solution of sodium bicarbonate. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuum with the receipt of 1.05 g of the crude 1-methyl-7-(1-propilot-1-enyl)-1,3-dihydro-2H-benzimidazole-2-it, which was used without further purification in the next stage. MS Calculated: 244; Found: 245(M+H). The crude substance was dissolved in 50 ml of methanol and made inert by means of nitrogen. This solution was treated with 300 mg (of 2.16 mmol) 10% palladium on carbon (50% moisture)was purged with hydrogen and stirred under pressure balloon of hydrogen for 36 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuum. Received, therefore, the crude residue was purified flash chromatography, elwira mixture of 5% methanol/dichloromethane. The crude mixture was ground into powder with diethyl ether and filtered. The filtrate, containing specified in the header is the connection together with a small amount of an unidentified impurity, concentrated in vacuum. Obtained, thus, the remainder (710 mg) was used in the next reaction without further purification.

MS Calculated: 246; Found: 247(M+H).

2-Chloro-1-methyl-7-(1-propinball)-1H-benzimidazole

The crude 1-methyl-7-(1-propinball)-1,3-dehydrobenzperidol-2-he (710 mg, is 2.88 mmol) was dissolved in 10 ml of phosphorus oxychloride and heated at 100°C during the night. The reaction mixture was allowed to cool to room temperature and concentrated in vacuum. Obtained, thus, the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuum to obtain 655 mg (86%) indicated in the title compound, which was used in the next stage without further purification.

MS Calculated: 264; Found: 265(M+H).

The hydrochloride of N-(4-bromo-2-methoxy-6-were)-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

Not containing a solvent mixture of 100 mg (0.38 mmol) of 2-chloro-1-methyl-7-(1-propinball)-1H-benzimidazole and 163 mg (from 0.76 mmol) 4-bromo-2-methoxy-6-methylphenylimino was heated at 100°C during the night. The reaction mixture was cooled to room temperature, and the residue was dissolved in 10 ml of dichloromethane, washed with water, dried over sodium sulfate, filtered and concentrated in vacuum. This is obtained residue was purified preparative HPLC with the floor is the group specified in the connection header in the form of a salt triperoxonane acid. This salt was dissolved in methanol and was treated with hydrochloric acid (1N solution in diethyl ether). The solution was concentrated in vacuum to obtain 40 mg (23%) indicated in the title compound in the form of cleaners containing hydrochloride salt.

1H NMR (CDCl3) δ of 0.87 (t, J=7.4 Hz, 6H), 1.26 in (m, 4H), 1,71 (m, 4H), 2,12 (s, 3H), 3,40 (m, 1H), 3,82 (s, 3H), with 3.89 (s, 3H), 6,93 (s, 1H), 6,97-6,99 (m, 1H), 7,03 (s, 1H), to 7.09 (t, J=7.2 Hz, 1H), 7,34 (users, 1H).

MS Calculated: 443; Found: 444 (M+H).

The compounds described below were obtained in the same way.

N-(4-chloro-2-methoxy-6-were)-7-[1-(4-methoxyphenyl) propyl]-1-methyl-1H-benzimidazole-2-amine
Table 1
ExampleStructureNamePhysical data
2Hydrochloride of 1-methyl-7-(1-propinball)-N-(2,4,6-trimethoxyphenyl)-1H-benzimidazole-2-amineMS Calculated: 411; Found: 412 (M+N)
3N-mesityl-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine1H NMR (CDCl3) δ of 0.87 (t, 6N, J=7.0 Hz); 1.26 in (users, 6N); 1,67 is 1.70 (m, 4H); 2,19 (s, 4H); of 2.28 (s, 3H); 3,35 (users, 1H); to 3.73 (s, 3H); 5,56 (users, 1H); 6,92 with, 3H); 7,07 (users, 1H); 7,30 (users, 1H).
MS Calculated: 363; Found: 364 (M+N)
4The hydrochloride of N-(4-bromo-2-methoxy-6-were)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine1H NMR (CDCl3) δ 0,86 (t, J=7,4 Hz, 6N); 1,70 of-1.83 (m, 4H); 2,12 (s, 3H); 3,21-of 3.27 (m, 1H), 3,82 (s, 3H), with 3.89 (s, 3H), 6,93 (s, 1H), of 6.96 (d, J=7,6 Hz, 1H), 7,03 (s, 1H), 7,07-7,11 (m, 1H), 7,35 (s, 1H).
MS Calculated: 415; Found: 416 (M+N)
5N-(4-Bromo-2-methoxy-6-were)-7-isopropyl-1-methyl-1H-benzimidazole-2-amine1H NMR (CDCl3) δ of 1.39 (d, J=6,9 Hz, 6N), 2,12 (s, 3H), 3,82 (s, 3H), 3,86 (s, 1H), 3,93 (s, 3H), by 5.87 (m, 1H), 6,92 (s, 1H), 7,00-7,10 (m, 3H), of 7.36 (m, 1H).
MS Calculated: 387; Found: 388 (M+N)
67-[bis(4-methoxyphenyl) methyl]-N-(4-chloro-2-methoxy-6-were)-1-methyl-1H-benzimidazole-2-amine1H NMR (CDCl3) δ a 2.12 (s, 3H), 3,66 (s, 3H), of 3.77 (s, 3H), 3,80 (C, 6N), 6,12 (m, 1H), 6,50 (d, J=8,1 Hz, 1H), 6.75 in-to 6.88 (m, 6N), 6,95-7,00 (m, 5H), 7,41 (m, 1H).
MS Calculated: 529; Found: 530 (M+N)
71H NMR (CDCl3) δ 0,99 (t, J=7.2 Hz, 3H), 2,00-2,25 (m, 2H), 2,12 (s, 3H), 3,74 (s, 1H), 3,75 (s, 3H), of 3.77 (s, 3H), 4,47 (t, J=7.2 Hz, 1H), 6,76 (d, J=2.4 Hz, 1H), PC 6.82 (d, J=8.7 Hz, 1H), 6,86 (d, J=2.4 Hz, 1H), 7,05-7,20 (m, 4H), 7,37 (m, 1H).
MS Calculated: 449; Found: 450 (M+N)

Example 8

{2-[(4-Bromo-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}(4-methoxyphenyl)metano

7-(4-Methoxybenzoyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-he

A solution of 12 ml (6,00 mmol) of 4-methoxyphenamine (0,5M solution in THF) was diluted in 15 ml of THF and cooled in an ice bath. To this solution was slowly added 309 mg (1.50 mmol) of the methyl ester of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-7-carboncarbon acid and the reaction mixture was stirred for 24 hours at 60°C. the Reaction was suppressed by the addition of water. The aqueous mixture was extracted with ethyl acetate. The extract was washed with 1N aqueous hydrochloric acid solution and saturated saline solution, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography, elwira mixture of 20-70% ethyl acetate/n-hexane, obtaining specified in the title compound (148 mg, 35%).

1H NMR (DMSO-d6) δ of 3.00 (s, 3H), a 3.87 (s, 3H), 6,98 (d, J=8,1 Hz, 1H), 7,00-to 7.15 (m, 3H), 7,19 (d, J=8,1 Hz, 1H), 7,81 (d, J=7.2 Hz, 2H.

MS Calculated: 282; Found: 283 (M+H).

(2-Chloro-1-methyl-1H-benzimidazole-7-yl)(4-methoxyphenyl)-methanon

A mixture of 145 mg (0,514 mmol) 7-(4-methoxybenzoyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-it was dissolved in 1.5 ml of phosphorus oxychloride and heated at 100°C for 18 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuum. Obtained, thus, the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuum to obtain 124 mg (80%) indicated in the title compound, which was used in the next stage without further purification.

MS Calculated: 300; Found: 301 (M+H).

{2-[(4-bromo-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}(4-methoxyphenyl)metano

A mixture of 120 mg (0,399 mmol) (2-chloro-1-methyl-1H-benzimidazole-7-yl)(4-methoxyphenyl)methanone and 216 mg (is 0.998 mmol) 4-bromo-2-methoxy-6-methylphenylimino in 0.5 ml of 1-methyl-2-pyrrolidone was heated at 100°C for 20 hours. The reaction mixture was cooled to room temperature and the residue was dissolved in dichloromethane, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuum. This is obtained residue was purified preparative HPLC to obtain specified in the connection header in the form of a salt triperoxonane acid. The salt was dissolved in etelaat the same and washed with an aqueous solution of sodium bicarbonate, was dried over magnesium sulfate, filtered and concentrated in vacuum to obtain 30 mg (16%) specified in the connection header.

1H NMR (CDCl3) δ are 2.19 (s, 3H), of 3.56 (s, 3H), 3,82 (s, 3H), 3,91 (s, 3H), 5,94 (m, 1H), 6,94 (d, J=1.8 Hz, 1H), 6,99 (d, J=8.7 Hz, 2H), 7,06 (d, J=1.8 Hz, 1H), 7,10-7,20 (m, 2H), 7,65 (d, J=6,9 Hz, 1H), of 7.96 (d, J=to 8.7 Hz, 2H); MS Calculated: 481; Found: 482 (M+H).

Example 9

N-(4-Bromo-2-methoxy-6-were)-4-(1-ethylbutyl)-3-methyl-3H-imidazo[4,5-c]pyridine-2-amine

4-Bromo-3-methyl-1H-imidazo[4,5-c]pyridine-2(3H)-he

A solution of 20.0 g (103 mmol) of 3-methyl-4-nitro-1H-imidazo[4,5-c]pyridine-2(3H)-she's in 168 ml of a 48% solution of Hydrobromic acid was heated for 6 hours at 135°C. was Added 33 ml of a 48% solution of Hydrobromic acid and the reaction mixture was stirred at 135°C during the night. The reaction mixture was cooled to room temperature and extinguished in 1675 ml of ice water. The resulting suspension was brought to pH 9 by the addition of 125 ml of a saturated aqueous solution of ammonium hydroxide. The precipitate was filtered and washed with 200 ml of water and dried in a vacuum oven at 50°C overnight with getting 17,58 g (75%) indicated in the title product as a pale yellow solid.

1H NMR (DMSO-d6) δ of 3.54 (3H, s), was 7.08 (1H, d, J=4.9 Hz), 7,94 (1H, d, J=4.9 Hz), 11,71 (1H, s).

MS Calculated: 227; Found: 228 (M+H).

(E)-4-(Gex-3-EN-3-yl)-3-methyl-1H-imidazo[4,5-c]pyridine-2(3H)-he

A mixture of 0.68 g (30 mmol) 4-bromo-3-methyl-1H-imidazo[4,5-c]pyridine-2(3H)-she and 0.17 g (0.20 mmol) of the complex PdCl 2dppf-dichloromethane was dissolved in 12 ml of toluene and treated with 3.8 ml (7.7 mmol) of 2n sodium carbonate solution and 0.72 g (3.6 mmol) of (Z)-2-(Gex-3-EN-3-yl)benzo[d][1,3,2]dioxaborolan. The resulting mixture was heated to 90°C for 5 hours, distributed between water and ethyl acetate, filtered to remove the fine precipitated particles were extracted with ethyl acetate. The combined organic layers were washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. Brown oil, which was obtained, was purified flash chromatography, elwira a mixture of 25% methanol/dichloromethane, to obtain 0.40 g (58%) indicated in the title compound in the form of a cream solid color.

1H NMR (CDCl3) δ is 1.01 (3H, t, J=7,6 Hz), 1,10 (3H, t, J=7,6 Hz), 2,29-of 2.36 (2H, m)to 2.66 (2H, q, J=7.4 Hz), of 3.46 (3H, s), 5,46 (1H, t, J=7.2 Hz), 6,98 (1H, d, J=5.3 Hz), of 8.28 (1H, d, J=5,1 Hz), 10,83 (1H, user. C).

MS Calculated: 231; Found: 232 (M+H).

4-(Hexane-3-yl)-3-methyl-1H-imidazo[4,5-c]pyridine-2(3H)-he

To a solution of 0.36 g (1.6 mmol) of (E)-4-(Gex-3-EN-3-yl)-3-methyl-1H-imidazo[4,5-c]pyridine-2(3H)-she's in 30 ml of ethanol was added 0,99 g (10 mol.% Pd) palladium on carbon (50% moisture, Degussa type). The reaction mixture was stirred in an atmosphere of hydrogen via a balloon and stirred at room temperature for 6 hours. The catalyst was removed by filtration, and the filtrate was concentrated in vacuum to obtain 0.33 g (91%) indicated what about the title compound as a gray oil which was aterials when melting.

1H NMR (CDCl3) δ 0,81 (3H, t, J=7.4 Hz), of 0.87 (3H, t, J=7.4 Hz), 1,12-of 1.29 (2H, m), 1,66-to 1.82 (2H, m), 1,88 of 1.99 (2H, m), 3,21 of 3.28 (1H, m)to 3.67 (3H, s)6,94 (1H, d, J=5,2 Hz), 8,31 (1H, d, J=5,2 Hz), of 10.25 (1H, user. C).

MS Calculated: 233; Found: 234 (M+H).

2-Chloro-4-(hexane-3-yl)-3-methyl-3H-imidazo[4,5-c]pyridine

Was obtained from 4-(hexane-3-yl)-3-methyl-1H-imidazo[4,5-c]pyridine-2(3H)-in accordance with the method described above for 2-chloro-1-methyl-7-(1-propinball)-1H-benzimidazole with a yield of 68%.

1H NMR (CDCl3) δ to 0.80 (3H, t, J=7.4 Hz), 0,86 (3H, t, J=7.4 Hz), of 1.06 to 1.31 (2H, m), 1,68-of 1.93 (2H, m), 1,95-2,04 (2H, m), 3,30-3,37 (1H, m), of 4.05 (3H, s), the 7.43 (1H, d, J=5.4 Hz), 8,43 (1H, d, J=5.4 Hz).

MS Calculated: 251; Found: 252 (M+H).

N-(4-bromo-2-methoxy-6-were)-4-(1-ethylbutyl)-3-methyl-3H-imidazo[4,5-c]pyridine-2-amine

Received in accordance with the method described above for 2-chloro-4-(hexane-3-yl)-3-methyl-3H-imidazo[4,5-c]pyridine, with a yield of 47%.

1H NMR (CDCl3) δ is 0.84 (3H, t, J=7,4 Hz)to 0.88 (3H, t, J=7.4 Hz), 1,14-1,32 (2H, m), 1,68-of 1.84 (2H, m), 1.93 and-2,02 (2H, m)to 2.18 (3H, s), 3,24-of 3.31(1H, m), 3,82 (3H, s), 3,90 (3H, s), 5,98 (1H, user. C)6,94 (1H, s), 7,06 (1H, s), 7.23 percent (1H, d, J=4.5 Hz), 8,29 (1H, d, J=5.3 Hz).

MS Calculated: 430; Found: 431 (M+H).

The compounds described below were obtained in the same way.

Name
Table 2
ExampleStructurePhysical data
10N-(4-bromo-2-methoxy-6-were)-4-[(1E)-1-Etherboot-1-enyl]-3-methyl-3H-imidazo[4,5-c]pyridine-2-amine1H NMR (CDCl3) δ was 1.04 (3H, t, J=7.5 Hz), of 1.12 (3H, t, J=7.5 Hz), 2,22 (3H, s)to 2.35 (2H, m), 2,71 (2H, q, J=7.5 Hz), 3,71 (3H, s), of 5.53 (1H, t, J=7.5 Hz), 5,97 (1H, m)6,94 (1H, d, J=1,8 Hz), 7,07 (1H, d, J=1,8 Hz), 7,28 (1H, d, J=5.4 Hz), of 8.25 (1H, d, J=5.4 Hz).
MS Calculated: 428; Found 429 (M+H).
11N-(4-chloro-2-methoxy-6-were)-7-(1-ethylbutyl)-1-methyl-1H-imidazo[4,5-c]pyridine-2-amine1H NMR (CDCl3) δ of 0.90 (3H, t, J=7,3 Hz)to 0.89 (3H, t, J=7.4 Hz), 1,23-of 1.36 (2H, m), 1,73-1,90 (4H, m)to 2.18 (3H, s), 3,21-of 3.31 (1H, m), 3,83 (3H, s), 3,90 (3H, s), to 5.93 (1H, s), for 6.81 (1H, d, J=2.2 Hz), 6,92 (1H, d, J=1.7 Hz), 8,17 (1H, s), to 8.62 (1H, s).
MS Calculated: 386; Found 387 (M+H).

Example 12

4-[2-[(2,4-Dimetilfenil)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-yl]heptane-4-ol

Methyl 2-chloro-3-nitrobenzoate

A suspension of 20 g (99 mmol) of 2-chloro-3-nitrobenzoic acid in 800 ml of dichloromethane was cooled in an ice bath. To the reaction mixture were added dimethylformamide (0,40 ml) followed by adding dropwise 13,85 g (10 mmol) of oxalicacid. The reaction mixture was allowed to warm to room temperature and was stirred for 6 hours. Was added dropwise methanol (200 ml) and the reaction mixture was stirred over night. The solvent is evaporated in vacuum. The residue was ground into powder with n-hexane. The obtained solid substance was collected by filtration, washed with hexane and dried in vacuum to obtain 21,0 g (98%) specified in the connection header.

1H NMR (CDCl3) δ 3,98 (3H, s), 7,49 (1H, t, J=8,4 Hz), to 7.84 (1H, DD, J=1,8, and 8.4 Hz), of 7.96 (1H, DD, J=1,8, 8,4 Hz).

Methyl 2-[(2-hydroxyethyl)amino]-3-nitrobenzoate

To a solution 4,70 g (21.9 mmol) of methyl 2-chloro-3-nitrobenzoate in 300 ml of THF was added dropwise 300 ml of 2-ethanolamine (80 mmol) and the mixture is boiled under reflux during the night. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate and washed with an aqueous solution of sodium bicarbonate and water. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum with the receipt of 5.00 g (20,8 mmol, 95%) specified in the connection header.

1H NMR (CDCl3) δ 1,68 (1H, usher.), of 3.12 (2H, DD, J=4,8, 10,2 Hz), 3,85 (2H, t, J=4,8 Hz), 3,92 (1H, s), 6,69 (1H, t, J=8.1 Hz), of 7.96 (1H, DD, J=1,8, 8.1 Hz), of 8.09 (1H, DD, J=1,8, 8.1 Hz), 8,72 (1H, usher.).

MS Calculated: 240; Found: 241 (M+H).

9-Nitro-2,3-dihydro-4,1-benzoxazepin-5(1H)-he

To a solution of 2.00 g (8,32 mmol) of methyl 2-[(2-hydroxyethyl)amino]-3-nitrobenzoate in 150 ml of THF on balali dropwise 6N HCl (100 ml) at 0 oC and the mixture was stirred for 30 minutes, the Reaction mixture is boiled under reflux for 16 hours. After cooling to room temperature the mixture was diluted with water (150 ml) and concentrated in vacuum. The residue was dissolved in ethyl acetate and washed with an aqueous solution of sodium hydrosulphate and water. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum with the receipt of 1.03 g (5.00 mmol, 60%) specified in the connection header.

1H NMR (CDCl3) δ: 3,91-of 3.95 (2H, m), 4,58-br4.61 (2H, m), 6,79 (1H, t, J=8,4 Hz), 8,19 (1H, DD, J=1,8, and 8.4 Hz), 8,43 (1H, DD, J=1,8, and 8.4 Hz), 8,96 (1H, usher.).

MS Calculated: 208; Found: 209 (M+H).

9-Amino-2,3-dihydro-4,1-benzoxazepin-5(1H)-he

A solution of 500 mg (2,42 mmol) of 9-nitro-2,3-dihydro-4,1-benzoxazepin-5(1H)-she's in 500 ml of methanol was made inert by means of nitrogen. To this solution was added 100 mg of 10% palladium on carbon (50% moisture) and the reaction mixture was purged with hydrogen and stirred under pressure balloon of hydrogen for 6 hours. The catalyst was removed by filtration, and the filtrate was concentrated in vacuum to obtain 430 mg (99%) specified in the connection header.

1H NMR (CD3OD)δ: 3,00-3,03 (2H, m), of 3.77-of 3.80 (2H, m), 5,95 (1H, t, J=8,4 Hz), and 6.25 (1H, DD, J=1,5, and 8.4 Hz), 6,56 (1H, DD, J=1,5, 8,4 Hz).

MS Calculated: 178; Found: 179 (M+H).

4,5-Dihydro-7H-imidazo[4,5,1-jk][4,1]benzoxazepin-2,7(1H)-dione

To a solution of 200 mg (1.13 mmol) of 9-amino-2,3-d the hydro-4,1-benzoxazepin-5(1H)-she in 20 ml of THF was added 280 mg (2 mmol) of 1,1'-carbonyldiimidazole and the reaction mixture was stirred over night at room temperature. The reaction mixture was heated at 50oC for 4 h and allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in a mixture of ethyl acetate/n-hexane (1:1) and washed with water. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuum to obtain 286 mg (1,40 mmol, 70%) specified in the connection header.

1H NMR (CD3OD) δ: 4,25-4,27 (2H, m), 4.75 V-of 4.77 (2H, m), 7.23 percent (1H, t, J=8,4 Hz), 7,37 (1H, DD, J=1,2, 8,4 Hz), 7,78 (1H, DD, J=1,5, 8,4 Hz).

MS Calculated: 204; Found: 205 (M+H).

2-Chloro-4,5-dihydro-7H-imidazo[4,5,1-jk][4,1]benzoxazepin-7-he

4,5-Dihydro-7H-imidazo[4,5,1-jk][4,1]benzoxazepin-2,7(1H)-dione (1,00 g, 4,89 mmol) was dissolved in 15 ml of phosphorus oxychloride and heated at 110oC for 6 hours. The reaction mixture was allowed to cool to room temperature, poured into ice water and was stirred for 1 hour. The aqueous solution was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum to obtain 1.06 g (98%) indicated in the title compound, which was used in the next reaction without further purification.

MS Calculated: 222; Found: 223 (M+H).

2-[(2,4-Dimetilfenil)amino]-4,5-dihydro-7H-imidazo[4,5,1-jk][4,1]benzoxazepin-7-he

A mixture of 2-chloro-4,5-dihydro-7H-imidazo[4,5,1-jk][4,1]benzoxazepin-7-he is 1.06 g (4.77 mmol) and 2,4-methylaniline 1.73 g (of 14.3 mmol) in 0.1 ml of N-methyl-2-pyrrolidone was heated at 100 oC during the night. The reaction mixture was cooled to room temperature, and the residue was dissolved in dichloromethane, washed with sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was ground into powder with ethyl acetate/n-hexane (1:1) to give 0.96 g (66%) specified in the connection header.

1H NMR (CDCl3)δ and 2.14 (3H, s), 2,22 (3H, s), 4,35-4,37 (2H, m), 4,78-4,80 (2H, m), 5,98 (1H, usher.), 6,59 (1H, d, J=7,2 Hz), at 6.84 (1H, d, J=7,2 Hz), 6.87 in (1H, s), from 7.24 (1H, t, J=7.8 Hz), 7,72 (1H, d, J=7.8 Hz), 7,86 (1H, d, J=7,8 Hz).

MS Calculated: 307; Found: 308 (M+H).

4-[2-[(2,4-Dimetilfenil)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-yl]heptane-4-ol

To the boiling solution of 30 ml of n-propylaniline (27% in tetrahydrofuran) was added 500 mg (1,63 mmol) 2-[(2,4-dimetilfenil)amino]-4,5-dihydro-7H-imidazo[4,5,1-jk][4,1]benzoxazepin-7-she and the mixture is boiled under reflux for 1 hour. The reaction mixture was cooled to room temperature, diluted with 50 ml water and neutralized 1N HCl solution. The aqueous solution was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and concentrated in vacuum. Obtained, thus, the residue was purified preparative HPLC to obtain specified in the connection header in the form of a salt triperoxonane acid. The salt was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate solution, dried the over magnesium sulfate, was filtered and concentrated in vacuum to obtain 161 mg (0.41 mmol, 25%) specified in the connection header.

1H NMR (CDCl3) δ: to 0.92 (6H, t, J=7.5 Hz), 1,23-of 1.41 (4H, m), 1,81 is 1.91 (2H, m), 1,98-of 2.09 (2H, m)to 2.13 (3H, s), 2,22 (3H, s), is 4.21 (2H, t, J=4,8 Hz), of 4.45 (2H, t, J=4,8 Hz), 6,59 (1H, d, J=7,2 Hz), at 6.84 (1H, d, J=7,2 Hz), 6.87 in (1H, s), 6,83 (1H, d, J=8.1 Hz), 7,03 (1H, t, J=8.1 Hz), 7,41 (1H, d, J=8,1 Hz).

MS Calculated: 395; Found: 396 (M+H).

The compounds described below were obtained in the same way.

Table 3
ExampleStructureNamePhysical data
134-[2-[(4-chloro-2-methoxy-6-were)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-yl]heptane-4-ol1H NMR (CDCl3) δ 0,92 (6N, t, J=7.5 Hz), 1,23-of 1.41 (4H, m), 1,81 is 1.91 (2H, m), 1,98-of 2.09 (2H, m), of 2.21 (3H, s), 3,81 (3H, s), is 4.21 (2H, t, J=4,8 Hz), of 4.45 (2H, t, J=4,8 Hz), PC 6.82 (1H, d, J=2.1 Hz), 6,92 (1H, d, J=2.1 and Hz), 6,83 (1H, d, J=8.1 Hz), 7,03 (1H, t, J=8.1 Hz), 7,41 (1H, d, J=8,1 Hz).
MS Calculated: 445; Found 446 (M+H).

Example 14

2-[2-[(2,4-Dimetilfenil)amino]-7-(1-propinball)-1H-benzimidazole-1-yl]ethanol

A solution of 100 mg (0.25 mmol) of 9-nitro-2,3-dig the DRO-4,1-benzoxazepin-5(1H)-it's in 3 ml of ethanol was made inert by means of nitrogen. To this solution was added an ethanolic solution of Raney Nickel and the reaction mixture was purged with hydrogen and stirred under pressure balloon of hydrogen for 6 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuum. Obtained, thus, the residue was purified preparative HPLC to obtain specified in the connection header in the form of a salt triperoxonane acid. The salt was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuum to obtain 27 mg (0.07 mmol, 28%) specified in the connection header.

1H NMR (CDCl3) δ: to 0.92 (6H, t, J=7.5 Hz), 1,22-of 1.41 (4H, m), 1,79-1,89 (2H, m), 1,98-of 2.09 (2H, m), 2,12 (3H, s), 2,22 (3H, s), 2,87 (1H, q, J=7.2 Hz), is 4.21 (2H, t, J=4,8 Hz), of 4.45 (2H, t, J=4,8 Hz), 6,59 (1H, d, J=7,2 Hz), at 6.84 (1H, d, J=7,2 Hz), 6.87 in (1H, s), 6,85 (1H, d, J=8.1 Hz), 7,05 (1H, t, J=8.1 Hz), was 7.45 (1H, d, J=8,1 Hz).

MS Calculated: 379; Found: 380 (M+H).

Example 15

N-(4-Chloro-2-methoxy-6-were)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazole-2-amine

7-Bromo-2-chloro-1-methyl-1H-benzimidazole

7-Bromo-1-methyl-1,3-dihydro-2H-benzimidazole-2-he (2.20 g, RS 9.69 mmol) was dissolved in 30 ml of phosphorus oxychloride and the mixture was heated at 110oC for 2 days. The reaction mixture was allowed to cool to room temperature, poured into ice water and was stirred for 1 hour. The aqueous solution was AKST who was agarawala with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum to obtain 2,32 g specified in the title compound, which was used in the next reaction without further purification.

MS Calculated: 243; Found: 244 (M+H).

7-Bromo-N-(4-chloro-2-methoxy-6-were)-1-methyl-1H-benzimidazole-2-amine

A mixture of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazole-2-it 2,32 g (RS 9.69 mmol) and to 4.98 g of 4-chloro-2-methoxy-6-methylaniline (of 29.1 mmol) in 0.5 ml of N-methyl-2-pyrrolidone was heated at 110oC for 2 days. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The mixture was washed with sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was ground into powder with ethyl acetate/hexane (1:1) to give 3.13 g (8,23 mmol, 85%) specified in the connection header.

1H NMR (CDCl3) δ: 2,17 (3H, s), 3,82 (3H, s), Android 4.04 (3H, s), to 6.80 (1H, d, J=2.4 Hz), 6.89 in (1H, d, J=2.4 Hz), 6,56 (1H, t, J=8.1 Hz), 7,21 (1H, d, J=8.1 Hz), 7,42 (1H, d, J=8,1 Hz).

MS Calculated: 379; Found: 380 (M+H).

N-(4-Chloro-2-methoxy-6-were)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazole-2-amine, salt triperoxonane acid

To a mixture of 25 mg (65,6 mmol) 7-bromo-N-(4-chloro-2-methoxy-6-were)-1-methyl-1H-benzimidazole-2-amine, and 11.8 mg (78,7 mmol) 2-ethylvinylbenzene acid, 12.0 mg (13,1 mmol) of Tris(dibenzylideneacetone)dip lady and 12.5 mg (26,2 mmol) of 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-1,1'-biphenyl in 1 ml of 1,2-dimethoxyethane added 131 ál of 1M aqueous trehosnovnogo solution of potassium phosphate. The reaction mixture was heated using microwave irradiation at 130oC for 10 min and allowed to cool to room temperature. The reaction mixture was diluted with dichloromethane and water were separated using a filter tubes (from the firm Wattmann) and concentrated in vacuum. The residue was purified preparative HPLC to obtain 2.5 mg (9.8 per cent) specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (CDCl3) δ: of 1.05 (3H, t, J=7.5 Hz), 2,17 (3H, s), 2,40-of 2.54 (2H, m), of 3.07 (3H, s), of 3.80 (3H, s), is 6.78 (1H, d, J=2.4 Hz), 6.89 in (1H, d, J=2.4 Hz), 6.89 in (1H, d, J=7.8 Hz), 7,13 (1H, t, J=7.8 Hz), 7.23 percent-7,41 (4H, m), 7,51 (1H, d, J=7,8 Hz).

MS Calculated: 405; Found: 406 (M+H).

Example 16-60

Examples 16-54 in Table 4 was obtained in the form of a salt triperoxonane acid, and examples 55-60 received in the form of a free base by the method similar to that described in Example 15.

Table 4
ExampleStructureNamePhysical data
16N-(4-chloro-2-methoxy-6-were)-1-methyl-7-(2-were)-1H-benzimidazole-2-amineMS Calculated: 391; Found: 392 M+H).
17N-(4-chloro-2-methoxy-6-were)-7-(2,3-dimetilfenil)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 405; Found: 406 (M+H).
18N-(4-chloro-2-methoxy-6-were)-7-(2,4-dimetilfenil)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 405; Found: 406 (M+H).
19N-(4-chloro-2-methoxy-6-were)-7-(3-chloro-2-were)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 425; Found: 426 (M+H).
20N-(4-chloro-2-methoxy-6-were)-7-(3, 5dimethylphenyl)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 405; Found: 406 (M+H).
21N-(4-chloro-2-methoxy-6-were)-7-mesityl-1-methyl-1H-benzimidazole-2-amineMS Calculated: 419; Found: 420 (M+H).
22img src="https://img.russianpatents.com/1068/10686101-s.jpg" height="42" width="51" /> N-(4-chloro-2-methoxy-6-were)-1-methyl-7-[2-(trifluoromethyl)-phenyl]-1H-benzimidazole-2-amineMS Calculated: 445; Found: 446 (M+H).
231-(2-{2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}phenyl)alanonMS Calculated: 419; Found: 420 (M+H).
247-(5-amino-2-were)-N-(4-chloro-2-methoxy-6-were)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 406; Found: 407 (M+H).
25N-(4-chloro-2-methoxy-6-were)-7-(3-methoxyphenyl)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 407; Found: 408 (M+H).
26N-(4-chloro-2-methoxy-6-were)-7-(2-isopropoxyphenyl)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 435; Found: 436 (M+H).
27N-(4-chloro-2-methoxy-were)-7-(2-ethoxyphenyl)-1-methyl-1H-benzimidazole-2-amine MS Calculated: 421; Found: 422 (M+H).
28N-(4-chloro-2-methoxy-6-were)-7-(2-chloro-6-methoxyphenyl)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 441; Found: 442 (M+H).
29N-(4-chloro-2-methoxy-6-were)-7-(2,4-acid)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 437; Found: 438 (M+H).
302-{2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}phenolMS Calculated: 393; Found: 394 (M+H).
317-[3-(benzyloxy)-phenyl]-N-(4-chloro-2-methoxy-6-were)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 483; Found: 484 (M+H).
32N-(4-chloro-2-methoxy-6-were)-7-(2-chlorophenyl)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 411; Found: 412 (M+H).
33N-(4-chloro-2-methoxy-6-were)-7-(2,4-dichlorophenyl)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 445; Found: 446 (M+H).
34N-(4-chloro-2-methoxy-6-were)-7-(4-methoxyphenyl)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 407; Found: 408 (M+H).
35N-(4-chloro-2-methoxy-6-were)-7-(2-ethoxy-5-were)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 435; Found: 436 (M+H).
367-(1,1'-biphenyl-2-yl)-N-(4-chloro-2-methoxy-6-were)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 453; Found: 454 (M+H).
37N-(2-{2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}phenyl)methane-sulfonamideMS Calculated: 470; Found: 471 (M+H).
38 N-(4-chloro-2-methoxy-6-were)-1-methyl-7-(2-nitrophenyl)-1H-benzimidazole-2-amineMS Calculated: 422; Found: 423 (M+H).
397-(3-AMINOPHENYL)-N-(4-chloro-2-methoxy-6-were)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 392; Found: 393 (M+H).
407-(1-benzothieno-2-yl)-N-(4-chloro-2-methoxy-6-were)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 433; Found: 434 (M+H).
417-(1,1'-biphenyl-3-yl)-N-(4-chloro-2-methoxy-6-were)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 453; Found: 454 (M+H).
42N-(4-chloro-2-methoxy-6-were)-1-methyl-7-(1-methyl-1H-pyrazole-4-yl)-1H-benzimidazole-2-amineMS Calculated: 381; Found: 382 (M+H).
433-(3-{2-[(4-the ENT-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}phenyl)propan-1-ol MS Calculated: 435; Found: 436 (M+H).
44N-(4-chloro-2-methoxy-6-were)-7-[(E)-2-cyclohexylethyl]-1-methyl-1H-benzimidazole-2-amineMS Calculated: 409; Found: 410 (M+H).
45N-(4-chloro-2-methoxy-6-were)-1-methyl-7-[(1E)-prop-1-enyl]-1H-benzimidazole-2-amineMS Calculated: 341; Found: 342 (M+H).
461-(5-{2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}Tien-2-yl)alanonMS Calculated: 425; Found: 426 (M+H).
47N-(4-chloro-2-methoxy-6-were)-1-methyl-7-[(E)-2-phenylphenyl]-1H-benzimidazole-2-amineMS Calculated: 403; Found: 404 (M+H).
48N-(4-chloro-2-methoxy-6-were)-1-methyl-7-(1-naphthyl)-1H-benzimidazole-2-amineMS Calculated: 427; Found: 428 (M+H).
49N-(4-chloro-2-methoxy-6-were)-1-methyl-7-phenyl-1H-benzimidazole-2-amineMS Calculated: 377; Found: 378 (M+H).
50N-(4-chloro-2-methoxy-6-were)-7-(4-chloro-2-were)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 425; Found: 426 (M+H).
51N-(4-chloro-2-methoxy-6-were)-7-(4-methoxy-2-were)-1-methyl-1H-benzimidazole-2-amineMS Calculated: 421; Found: 422 (M+H).
52N-(4-chloro-2-methoxy-6-were)-1-methyl-7-(2-naphthyl)-1H-benzimidazole-2-amineMS Calculated: 427; Found: 428 (M+H).
53N-(3-{2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}phenyl)-ndimethylacetamideMS Calculated: 434; Found: 435 (M+H).
54 2-{2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}benzaldehydeMS Calculated: 405; Found: 406 (M+H).
55N-(4-chloro-2-methoxy-6-were)-7-(2-isopropylphenyl)-1-methyl-1H-benzimidazole-2-amine1H NMR (CDCl3) δ: 1,11 (3H, d, J=6,9 Hz)and 1.15 (3H, d, J=6.9 Hz), to 2.18 (3H, s), 2,80-2,95 (1H, m)to 3.09 (3H, s), 3,81 (1H, s), 5,79 (1H, s), is 6.78 (1H, d, J=2.1 Hz), 6.87 in-6,89 (2H, m), 7,12 (1H, t, J=7.5 Hz), 7,20-7,30 (2H, m), 7,42-the 7.43 (2H, m), 7,52 (1H, d, J=7.5 Hz).
MS Calculated: 419; Found: 420 (M+H).
56N-(4-chloro-2-methoxy-6-were)-7-(2-methoxyphenyl)-1-methyl-1H-benzimidazole-2-amine1H NMR (DMSO-d6) δ: 2,09 (3H, s)and 3.15 (3H, s), 3,74 (3H, s), 3,76 (3H, s), of 6.68 (1H, d, J=7.8 Hz), of 6.96-7,14 (6H, m), 7,28 (1H, d, J=7.8 Hz), 7,44 (1H, t, J=7.8 Hz), of 7.90 (1H, s).
MS Calculated: 407; Found: 408 (M+H).
57N-(2',3-dimethoxy-5-methyl-1,1'-biphenyl-4-yl)-7-(2-methoxyphenyl)-1-methyl-1H-benzimidazole-2-amine1H NMR (DMSO-d6) δ a 2.13 (3H, s)and 3.15 (3H, s), 3.75 to (6N, C)3,81 (3H, s), to 6.67 (1H, DD, J=7,5, 1.2 Hz), 6,94-to 7.15 (8H, m), 7,27-7,47 (4H, m), 7,86 (1H, s).
58N-(4-chloro-2-methoxy-6-were)-7-(2-methoxypyridine-3-yl)-1-methyl-1H-benzimidazole-2-amine1H NMR (CDCl3CD3OD) δ are 2.19 (3H, s), with 3.27 (3H, s), 3,81 (3H, s), of 3.94 (3H, s), 6,84-of 6.90 (3H, m), 7,07-7,14 (2H, m), 7,33 (1H, d, J=8,4 Hz), of 7.70 (1H, d, J=7,5, 1.8 Hz), 8,23 (1H, DD, J=5,4, 1.8 Hz).
MS Calculated: 408; Found: 409 (M+H).
59N-(4-chloro-2-methoxy-6-were)-1-methyl-7-(3-methyl-2-thienyl)-1H-benzimidazole-2-amine1H NMR (CDCl3CD3OD) δ 2,07 (3H, s), 2,17 (3H, s), 3,21 (3H, s), 3,81 (3H, s), of 5.81 (1H, s), is 6.78 (1H, d, J=2.1 Hz), 6,88-6,91 (2H, m), 7,05-7,14 (2H, m), 7,22 (1H, d, J=3.0 Hz), 7,51 (1H, d, J=8,1 Hz).
MS Calculated: 397; Found: 398 (M+H).
60N-(4-chloro-2-methoxy-6-were)-7-(2-ethylphenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-2-amine1H NMR (CDCl3) δ of 1.07 (3H, t, J=7,6 Hz) of 2.23 (3H, s), 2.40 a at 2.59 (2H, m), 3,17 (3H, s), 3,82 (3H, s), 5,88 (1H, s), for 6.81 (1H, d, J=1.5 Hz), 6,93 (1H, d, J=1.5 Hz), 7,20-7,51 (4H, m), of 8.09 (1H, s), 8,77 (1H, s).
MS Calculated: 406; Found: 407 (M+H).

Example 61

N-(4-Bromo-2-methoxy-6-were)-7-(2-ethylphenyl)-1-methyl-1H-Benson Gasol-2-amine

7-(2-Ethylphenyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-he

A mixture of 280 mg (1,23 mmol) 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazole-2-it, 222 mg (1.48 mmol) of 2-ethylvinylbenzene acid, 113 mg (0,0123 mmol) of Tris(dibenzylideneacetone)diplodia, 29 mg (0,0615 mmol), X-Phos and 522 mg (2,46 mmol) of potassium phosphate in 9 ml of toluene was stirred at 100oC for 4 hours. After cooling, the reaction mixture was diluted with water and ethyl acetate and passed through celite. The filtrate was extracted with ethyl acetate (×2). The combined organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 25-65% ethyl acetate/n-hexane, to obtain 200 mg (64%) specified in the connection header.

1H NMR (CDCl3)δ was 1.04 (3H, t, J=7,7 Hz), 2,34-2,52 (2H, m), 2,84 (3H, s), 6,86-6,98 (2H, m), 7,05-was 7.08 (2H, m), 7.18 in-7,39 (3H, m), 8,58 (1H, user. C).

MS Calculated: 252; Found: 253 (M+H).

2-Chloro-7-(2-ethylphenyl)-1-methyl-1H-benzimidazole

A mixture of 190 mg (0,753 mmol) 7-(2-ethylphenyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-she and 1.5 ml of phosphorus oxychloride was stirred at 80oC for 5 hours. After cooling, the reaction mixture was poured on ice and neutralized by adding 12 n sodium hydroxide solution. The aqueous suspension was extracted with ethyl acetate (×2). Volume is inanny the organic layer was washed with saturated brine (×1), was dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 3-10% ethyl acetate/n-hexane to obtain 123 mg (60%) specified in the connection header.

1H NMR (CDCl3) δ of 1.02 (3H, t, J=7.5 Hz), 2,30-2,48 (2H, m), 3,19 (3H, s), 7,05-to 7.15 (1H, m), 7,26 was 7.45 (5H, m), 7,60 (1H, m).

MS Calculated: 270, 272; Found: 271, 273 (M+H).

N-(4-Bromo-2-methoxy-6-were)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazole-2-amine

A mixture of 100 mg (0,369 mmol) of 2-chloro-7-(2-ethylphenyl)-1-methyl-1H-benzimidazole and 239 mg (1.11 mmol) of 4-bromo-2-methoxy-6-methylaniline was stirred at 120oC for 15 hours. After cooling, the reaction mixture was neutralized by adding saturated aqueous sodium hydrogen carbonate solution followed by the addition of ethyl acetate. The resulting crystals were collected by filtration and washed with water and ethyl acetate and suspended in hot ethyl acetate. After cooling to room temperature, the crystals were collected by filtration and washed with ethyl acetate and a mixture of 50% dimethyl sulfoxide/methanol to obtain 90 mg (54%) specified in the connection header.

1H NMR (CDCl3) δ of 1.05 (3H, t, J=7,4 Hz)of 2.16 (3H, s), 2.40 a is 2.55 (2H, m)to 3.09 (3H, s), 3,81 (3H, s), 5,79 (1H, user. C)6,88-6,92 (2H, m),? 7.04 baby mortality (1H, d, J=1.5 Hz), 7,12 (1H, t, J=7.8 Hz), 7,26-7,41 (4H, m), 7,52 (1H, d, J=7,8 Hz).

MS Calculated: 449, 451; Found: 450, 452 (M+H).

The compounds described below were obtained in the same way.

Table 5
ExampleStructureNamePhysical data
62N-(4-bromo-2-methoxy-6-were)-1-methyl-7-(3-were)-1H-benzimidazole-2-amine1H NMR (CDCl3) δ of 2.16 (3H, s), 2,43 (3H, s)of 3.25 (3H, s), 3,82 (3H, s)5,80 (1H, users), 6,93-7,53 (9H, m).
MS Calculated: 435, 437; Found: 436, 438 (M+H).
63N-(4-bromo-2-methoxy-6-were)-1-methyl-7-(4-were)-1H-benzimidazole-2-amine1H NMR (CDCl3) δ of 2.16 (3H, s), is 2.44 (3H, s), 3,26 (3H, s), 3,82 (3H, s), of 5.83 (1H, s), 6,92 (1H, d, J=1.0 Hz), 6,94 (1H, d, J=7.5 Hz),? 7.04 baby mortality (1H, t, J=1.0 Hz), 7,13 (1H, t, J=7.5 Hz), 7,25 (2H, d, J=7.8 Hz), 7,35 (2N, d, J=7.8 Hz), to 7.50 (1H, d, J=7.5 Hz).
MS Calculated: 435, 437; Found: 436, 438 (M+H).

Example 64

N-(4-Chloro-2-methoxy-6-were)-1-methyl-7-{2-[(methylamino) methyl]phenyl}-1H-benzimidazole-2-amine

A mixture of 33 mg (0,0813 mmol) 2-[2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl]benzaldehyde, 0,033 ml (0,325 mmol) of 40% metrolog the solution of methylamine and 1 ml of ethanol was boiled under reflux for 4 hours. After cooling, was added to 9.2 mg (0,244 mmol) of sodium borohydride. The mixture was stirred at room temperature for 4 hours and was added 15 mg (0,407 mmol) of sodium borohydride. After stirring at room temperature for 15 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (×2). The combined organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified preparative HPLC and column chromatography on ό silica gel, elwira mixture with a gradient of 50-100% ethyl acetate/n-hexane, obtaining 5 mg (17%) specified in the connection header.

1H NMR (CDCl3) δ to 2.18 (3H, s), and 2.27 (3H, s), is 3.08 (3H, s), of 3.57 (2H, s), 3,81 (3H, s), 6,79 (1H, s), 6.87 in-6,89 (2H, m), 7,10-to 7.15 (1H, m), 7,33-7,53 (5H, m).

Example 65

N-(4-Bromo-2-methoxy-6-were)-1-methyl-7-(3-methyl-1H-pyrazole-1-yl)-1H-benzimidazole-2-amine

1-Methyl-7-(3-methyl-1H-pyrazole-1-yl)-1,3-dihydro-2H-benzimidazole-2-he

A suspension of 50 mg (0,220 mmol) 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazole-2-it, a 0.035 ml (0,440 mmol) of 3-methylpyrazole, 42 mg (0,0220 mmol) of copper iodide(I) and 61 mg (0,440 mmol) of potassium carbonate in 1 ml of 1-methyl-2-pyrrolidinone was stirred under microwave irradiation at 190oC for 2 hours. After cooling, the reaction mixture was diluted with water and was extracted with ethyl what Etat (×2). The combined organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira a mixture of 25% ethyl acetate/n-hexane, to obtain 57 mg of a mixture containing specified in the header of the connection.

1H NMR (CDCl3) δ of 2.34 (3H, s), 2,98 (3H, s), of 6.26 (1H, d, J=2.2 Hz), 6,97-to 7.18 (3H, m), EUR 7.57 (1H, d, J=2.2 Hz), 9,60 (1H, user. C).

MS Calculated: 228; Found: 229 (M+H).

N-(4-Bromo-2-methoxy-6-were)-1-methyl-7-(3-methyl-1H-pyrazole-1-yl)-1H-benzimidazole-2-amine

A mixture of 17 mg (0,0745 mmol) of 1-methyl-7-(3-methyl-1H-pyrazole-1-yl)-1,3-dihydro-2H-benzimidazole-2-it in 0.5 ml of phosphorus oxychloride was stirred at 80oC for 5 days. After cooling, the phosphorus oxychloride is evaporated in vacuum. The residue was neutralized by adding 12 n aqueous solution of sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (×2). The combined organic layer was washed with water (×1) and saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified preparative TLC, elwira a mixture of 30% ethyl acetate/n-hexane, to obtain 2-chloro-1-methyl-7-(3-methyl-1H-pyrazole-1-yl)-1H-benzimidazole. A mixture of 2-chloro-1-methyl-7-(3-methyl-1H-pyrazole-1-yl)-1H-benzimidazole obtained above, 48 mg (0,223 mmol) 4-bromo-2-methoxy-6-methylaniline and 0.15 ml of 1-methyl-2-pyrrolidinone peremeci the Ali @ 120 oC for 3 days. After cooling, the reaction mixture is neutralized by adding a saturated aqueous solution of sodium bicarbonate. The aqueous suspension was extracted with ethyl acetate (×2). The combined organic layer was washed with water (×1) and saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified preparative TLC, elwira a mixture of 75% ethyl acetate/n-hexane, obtaining of 5.7 mg (18%) specified in the connection header.

1H NMR (CDCl3) δ 2,17 (3H, s), is 2.40 (3H, s), 3,23 (3H, s), of 3.80 (3H, s), by 5.87 (1H, user. C)6,28 (1H, d, J=2.1 Hz), 6,92 (1H, d, J=2.4 Hz), 7,00-7,13 (3H, m), 7,53 (1H, d, J=7.8 Hz), 7,63 (1H, d, J=2.1 Hz).

MS Calculated: 425, 427; Found: 426, 428 (M+H).

Example 66

N-(4-Bromo-2-methoxy-6-were)-7-(3,5-diethyl-1H-pyrazole-1-yl)-1-methyl-1H-benzimidazole-2-amine

7 Hydrazino-1-methyl-1,3-dihydro-2H-benzimidazole-2-he

To a suspension of 5.0 g (30,6 mmol) 7-amino-1-methyl-1,3-dihydro-2H-benzimidazole-2-it in 16 ml of concentrated hydrochloric acid was added 8 ml of an aqueous solution of 2.18 g (of 31.6 mmol) of sodium nitrite, the mixture was stirred at 0oC for 30 minutes. Chloride tin(II) (18.0 g, was 94.9 mmol) was dissolved in 10 ml of concentrated hydrochloric acid and the resulting solution was added to the reaction mixture at 0oC. After one hour the mixture was podslushivaet using n solution of the hydroxide is sodium followed by the addition of ethyl acetate to a suspension. After addition of 24.6 ml of di-tert-BUTYLCARBAMATE (107 mmol) and the mixture was stirred at room temperature for 15 hours. The aqueous layer was separated and was extracted with ethyl acetate (×1). The organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The remainder in the form of a solid substance was washed with hexane to obtain 8,53 g Boc-derivative specified in the title compound as yellow crystals. Suspension 8.53 g (17.8 mmol) of Boc-derivative specified in the title compound in 100 ml of 4 n solution of hydrogen chloride in methanol was stirred at room temperature for 12 hours. The resulting crystals were collected by filtration and washed with methanol to obtain 3,17 g (52%) specified in the connection header.

1H NMR (DMSO-d6) δ to 3.52 (3H, s), 6,79-PC 6.82 (2H, m), 6,98 (1H, t, J=8.0 Hz), 8,02 (1H, s), there is a 10.03 (2H, s), 11,00 (1H, s).

7-(2,4-Diethyl-1H-pyrazole-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-he

To a suspension of 211 mg (0,986 mmol) 7-hydrazino-1-methyl-1,3-dihydro-2H-benzimidazole-2-it is in 2 ml of acetic acid was added to 0.13 ml (0,986 mmol) of 3,5-heptanedione, the mixture was stirred at 100oC for 2 hours. After cooling, the reaction mixture is neutralized by adding a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate (×2). The combined organic layer was washed us is placed in brine (×1), was dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 50-80% ethyl acetate/n-hexane, to obtain 221 mg (83%) specified in the connection header.

1H NMR (CDCl3) δ of 1.16 (3H, t, J=7.5 Hz), of 1.29 (3H, t, J=7.8 Hz), 2,35 of $ 2.53 (2H, usher.), 2,69 (2H, q, J=7.8 Hz), 2,85 (3H, s), the 6.06 (1H, s), 7,01 (1H, DD, J=7,8, 1.5 Hz), was 7.08 (1H, t, J=7.8 Hz), 7,14 (1H, DD, J=7,8, 1.5 Hz), 9,49 (1H, user. C).

2-Chloro-7-(3,5-diethyl-1H-pyrazole-1-yl)-1-methyl-1H-benzimidazole

A mixture of 220 mg (0,814 mmol) 7-(2,4-diethyl-1H-pyrazole-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-it is in 2 ml of phosphorus oxychloride was stirred at 85oC for 4 hours. After cooling, the phosphorus oxychloride is evaporated in vacuum. The residue was diluted with ice water and neutralized by addition of an aqueous sodium hydroxide solution. The aqueous suspension was extracted with ethyl acetate (×2). The combined organic layer was washed with water (×1) and saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 25-50% ethyl acetate/n-hexane, obtaining 181 mg (77%) specified in the connection header.

1H NMR (CDCl3) δ of 1.15 (3H, t, J=7.5 Hz), of 1.30 (3H, t, J=7.5 Hz), 2,44 (2H, q, J=7.5 Hz), 2,70 (2H, q, J=7.5 Hz), 3,20 (3H, s), 6,10 (1H, s), 7,21 (1H, DD, J=7,8, 1.2 Hz), 7,30 (1H, t, J=7.8 Hz), 7,76 (1H, DD, J=7,8, 1.2 Hz).

MS RASSC the Eastern Europe and Caucasus: 288, 290; Found: 289, 291 (M+H).

N-(4-Bromo-2-methoxy-6-were)-7-(3,5-diethyl-1H-pyrazole-1-yl)-1-methyl-1H-benzimidazole-2-amine

A mixture of 83 mg (0,287 mmol) of 2-chloro-7-(3,5-diethyl-1H-pyrazole-1-yl)-1-methyl-1H-benzimidazole, 186 mg (0,862 mmol) 4-bromo-2-methoxy-6-methylaniline and 0.15 ml of 1-methyl-2-pyrrolidinone was stirred at 110oC for 20 hours. After cooling, the reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, followed by addition of ethyl acetate. The resulting crystals were collected by filtration and washed with water and ethyl acetate to obtain 112 mg (83%) specified in the connection header.

1H NMR (CDCl3) δ of 1.18 (3H, t, J=7.4 Hz), is 1.31 (3H, t, J=7,6 Hz), 2,17 (3H, s), 2.49 USD (2H, q, J=7.4 Hz), of 2.72 (2H, q, J=7,6 Hz), of 3.07 (3H, s), 3,81 (3H, s), of 5.81 (1H, user. C)6,09 (1H, s), 6,93-7,16 (4H, m), 7,54 (1H, d, J=8,8 Hz).

MS Calculated: 467, 469; Found: 468, 470 (M+H).

The compounds described below were obtained in the same way.

Table 6
ExampleStructureNamePhysical data
67N-(4-bromo-2-methoxy-6-were)-7-(3,5-dimethyl-1H-pyrazole-1-yl)-1-methyl-1H-benzimidazole--Amin 1H NMR (CDCl3) δ of 2.16 (3H, s)to 2.18 (3H, s), 2,32 (3H, s), 3,10 (3H, s), of 3.80 (3H, s), 6,04 (1H, s)of 6.29 (1H, users), 6,93-6,97 (2H, m), 7,03 (1H, s), 7,10 (1H, t, J=7.5 Hz), to 7.50 (1H, d, J=7.5 Hz).
MS Calculated: 439, 441;
Found: 440, 442 (M+H).
68N-(4-bromo-2-methoxy-6-were)-7-(5-tert-butyl-3-methyl-1H-pyrazole-1-yl)-1-methyl-1H-benzimidazole-2-amine1H NMR (CDCl3) δ of 1.18 (9H, s), and 2.14 (3H, s), 2,31 (3H, s), to 3.02 (3H, s), of 3.80 (3H, s), 5,79 (1H, s), the 6.06 (1H, s)6,91 (1H, d, J=2.1 Hz), 7,03 (1H, d, J=2.1 Hz), 7,10 (2H, t, J=4.5 Hz), 7,54 (1H, d, J=4.5 Hz).
MS Calculated: 481, 483;
Found: 482, 484 (M+H).

Example 69

N-(4-Bromo-2-methoxy-6-were)-7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-benzimidazole-2-amine

7-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-he

To a suspension of 257 mg (1.57 mmol) of 7-amino-1-methyl-1,3-dihydro-2H-benzimidazole-2-it is in 2 ml of acetic acid was added to 0.18 ml (1.57 mmol) of 2,5-hexandione, the mixture was stirred at 90oC for 1 hour. After cooling, the reaction mixture is neutralized by adding a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate (×2). The combined organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuo the E. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 25-50% ethyl acetate/n-hexane, to obtain 258 mg (68%) specified in the connection header.

1H NMR (CDCl3) δ of 1.97 (6H, s), and 2.79 (3H, s), of 5.92 (2H, s), 6,93 (1H, DD, J=7,5, 1.5 Hz), 7,08-7,16 (2H, m), to 9.45 (1H, s).

2-Chloro-7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-benzimidazole

A mixture of 239 mg (0,991 mmol) 7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-it is in 2 ml of phosphorus oxychloride was stirred at 85oC for 4 hours. After cooling, the phosphorus oxychloride is evaporated in vacuum. The residue was diluted with ice and neutralized by adding an aqueous solution of sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (×2). The combined organic layer was washed with water (×1) and saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 10-20% ethyl acetate/n-hexane, to obtain 185 mg (72%) specified in the connection header.

1H NMR (CDCl3) δ of 1.94 (6H, s)to 3.09 (3H, s), 5,95 (2H, s), to 7.15 (1H, DD, J=7,8, 1.0 Hz), 7,32 (1H, t, J=7.8 Hz), of 7.75 (1H, DD, J=7,8, 1.0 Hz).

MS Calculated: 259; Found: 260 (M+H).

N-(4-Bromo-2-methoxy-6-were)-7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-benzimidazole-2-amine

A mixture of 90 mg (0,347 mmol) of 2-chloro-7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-benzimidazole and 225 mg(1.04 mmol) of 4-bromo-2-methoxy-6-methylaniline was stirred at 110 oC for 15 hours. After cooling, the reaction mixture is neutralized by adding a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate (×2). The combined organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient 60-90% ethyl acetate/n-hexane. The target fractions were collected and evaporated in vacuum, the residue in the form of a solid substance was washed with diethyl ether obtaining at 53.4 mg (35%) specified in the connection header.

1H NMR (CDCl3) δ 1,99 (6H, s), are 2.19 (3H, s), 2,96 (3H, s), 3,81 (3H, s)5,94 (2H, s), 6,92-of 6.96 (2H, m), 7,05 (1H, d, J=1,8 Hz), to 7.15 (1H, t, J=7.5 Hz), 7,54 (1H, d, J=7.5 Hz).

MS Calculated: 438, 440; Found: 439, 441 (M+H).

Example 70-71

Examples 70 and 71 in Table 7 were obtained by the method similar to that described in Example 15.

Table 7
ExampleStructureNamePhysical data
70N-(4-chloro-2-methoxy-6-were)-7-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzoni the azole-2-amine 1H NMR (CDCl3) δ 2,17 (3H, s), are 2.19 (3H, s), of 2.33 (3H, s), 3,37 (3H, s), 3,82 (3H, s), 5,90 (1H, users), 6,80-of 7.60 (5H, m).
MS Calculated: 396; Found: 397 (M+H).
71N-(4-chloro-2-methoxy-6-were)-7-(2,6-acid)-1-methyl-1H-benzimidazole-2-amine, salt triperoxonane acid1H NMR (CDCl3) δ 2,17 (3H, s), of 3.07 (3H, s), of 3.80 (3H, s), 3,82-4,12 (6H, m), is 6.78 (1H, d, J=2.4 Hz), 6.89 in (1H, d, J=2.4 Hz), 6.89 in (1H, d, J=7.8 Hz), 7,13 (1H, t, J=7.8 Hz), 7,22-7,40 (3H, m), 7,51 (1H, d, J=7,8 Hz).
MS Calculated:437; Found: 438 (M+H). TPL 288-289°C

Example 72

N-(4-Bromo-2-methoxy-6-were)-1-methyl-7-(3-methyl-5-phenyl-1H-pyrazole-1-yl)-1H-benzimidazole-2-amine

The specified connection was obtained in a manner analogous to the one described in Example 66.

1H NMR (CDCl3) δ: 2,13 (3H, s), 2,42 (3H, s), 3,19 (3H, s), with 3.79 (3H, s), of 5.81 (1H, user. C)of 6.45 (1H, s), 6,91-of 6.96 (2H, m), 7.03 is-was 7.08 (2H, m), of 7.23 (5H, s), 7,51 (1H, d, J=8,4 Hz). MS Calculated: 501, 503; Found: 502, 504 (M+H).

Example 73

4-[1-(2-Hydroxyethyl)-2-(mesitylene)-1H-benzimidazole-7-yl]heptane-4-ol

The specified connection was obtained in a manner analogous to the one described in Example 12.

TPL 267-270oC

1H NMR (CD3OD) δ: 1,24 (6H, t, J=7.5 Hz), 1.60-to around 1.74 (4H, m), 2,16-to 2.40 (4H, m), 2,52 (6H, s), 2.63 in (3H, s), 4,47 (2H, t,J=4,8 Hz), 5,19 (2H, t, J=4,8 Hz), 7,22 (1H, DD, J=7,8, 1.2 Hz), 7,28 (2H, s), 7,32 (1H, t, J=7.8 Hz), 7,47 (1H, DD, J=7,8, 1.2 Hz). MS Calculated: 409; Found: 410 (M+H).

Example 74

2-[2-(Mesitylene)-7-(1-propinball)-1H-benzimidazole-1-yl]ethanol

The specified connection was obtained in a manner analogous to that described above in Example 14.

1H NMR (CDCl3) δ: to 0.92 (6H, t, J=7.5 Hz), 1,20-1,40 (4H, m), 1.77 in-a 1.88 (2H, m), 1,98-of 2.09 (2H, m), 2,53 (6H, s), 2.63 in (3H, s), 2,87 (1H, m), is 4.21 (2H, t, J=4,8 Hz), of 4.45 (2H, t, J=4,8 Hz), 7,22 (1H, DD, J=7,8, 1.2 Hz), 7,27 (2H, s), 7,32 (1H, t, J=7.8 Hz), 7,46 (1H, DD, J=7,8, 1.2 Hz).

MS Calculated: 393; Found: 394 (M+H).

Example 75

2-[2-[(4-Chloro-2-methoxy-6-were)amino]-7-(1-hydroxy-1-propinball)-1H-benzimidazole-1-yl]acetate

A solution of 4-[2-[(4-chloro-2-methoxy-6-were)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-yl]heptane-4-ol (100 mg, 0.22 mmol) in pyridine (5 ml) was treated with acetic anhydride (1 ml) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, diluted aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was chromatographically on silica gel to obtain 97 mg (0.20 mmol, 89%) specified in the connection header.

1H NMR (CDCl3) δ: to 0.92 (6H, t, J=7.5 Hz), 1,23-of 1.41 (4H, m), 1,81 is 1.91 (2H, m), 1,98-of 2.09 (2H, m),2,12 (3H, C)to 2.15 (3H, s), of 3.80 (3H, s), 4,56 (2H, t, J=4,8 Hz), is 4.85 (2H, t, J=4,8 Hz), to 6.80 (1H, d, J=2.1 Hz), 6,83 (1H, d, J=8.1 Hz), to 6.88 (1H, d, J=2.1 Hz), 7,03 (1H, t, J=8.1 Hz), 7,41 (1H, d, J=8,1 Hz). MS Calculated: 487; Found: 488 (M+H).

Example 76

2-{2-[(4-Chloro-2-methoxy-6-were)amino]-7-[(1E)-1-propilot-1-EN-1-yl]-1H-benzimidazole-1-yl}acetic acid ethyl ester and 2-{2-[(4-Chloro-2-methoxy-6-were)amino]-7-[(1Z)-1-propilot-1-EN-1-yl]-1H-benzimidazole-1-yl}acetate

A solution of 2-[2-[(4-chloro-2-methoxy-6-were)amino]-7-(1-hydroxy-1-propinball)-1H-benzimidazole-1-yl]acetic acid ethyl ester (50 mg, 0.10 mmol) and triethylsilane (1 ml) in diethyl ether (10 ml) was stirred at room temperature for 14 hours. The reaction mixture was diluted aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was chromatographically on silica gel to obtain 11 mg (0,023 mmol, 23%) specified in the header connections.

1H NMR (CDCl3) δ: to 0.92 (6H, t, J=7.5 Hz), 1,28-1,49 (4H, m), 1,78 is 1.91 (2H, m), of 2.08 (3H, s), 2,17 (3H, s), with 3.79 (3H, s), 4,20-to 4.41 (4H, m), 5,57 (0,8H, t, J=7.2 Hz), 5,65 (0,2H, t, J=7.2 Hz), to 6.75 (1H, d, J=7,2 Hz), to 6.80 (1H, d, J=2.1 Hz), 6.89 in (1H, d, J=2.1 Hz),? 7.04 baby mortality (1H, t, J=7.2 Hz), 7,41 (1H, d, J=7,2 Hz). MS Calculated: 469; Found: 470 (M+H).

Example 77

N-(4-Bromo-2-methoxy-6-were)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

7-(1-Ethyl-1-HYDR shall xypropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-he

The solution ethylacetamide (3M solution in diethyl ether; 32 ml, 96 mmol) was added dropwise to a suspension of methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (5,00 g, and 24.2 mmol) in tetrahydrofuran (50 ml) at 0°C. the Mixture was stirred at 40°C during the night. The reaction was suppressed by the addition of water and 1N HCl solution, extracted with ethyl acetate, washed with saturated salt solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was led from ethanol/diethyl ether to obtain specified in the title compound as colorless crystals (3,39 g, 70%). TPL 199-201°C.

1H NMR (CDCl3) δ of 0.90 (t, J=7.5 Hz, 6H), 1,90-of 2.20 (m, 5H), of 3.84 (s, 3H), 6.90 to-7,05 (m, 3H), 9,10-of 9.30 (m, 1H).

MS Calculated: 234; Found: 235 (M+H).

7-(1-Ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-he

A mixture of 7-(1-ethyl-1-hydroxypropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-it (6,00 g, 25.6 mmol) and 6N HCl (20 ml) in ethanol (100 ml) was stirred at 50°C for 3 hours. The mixture was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate, washed with an aqueous solution of potassium carbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum to obtain a pale yellow oil, which was used in the next reaction without further purification. MS Calculated: 216; Found: 217(M+H). Crude is emesto was dissolved in ethanol (150 ml). This solution was treated with 10% palladium on carbon (50% moisture; 1,00 g), purged with hydrogen and stirred under hydrogen pressure of 5 psi for 7 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuum. The residue was led from ethanol/diethyl ether to obtain specified in the title compound as colorless crystals (3,02 g, 54%). TPL 130-132°C.

1H NMR (CDCl3) δ of 0.82 (t, J=6.6 Hz, 6H), 1.60-to of 1.85 (m, 4H), 3.15 and is 3.25 (m, 1H), the 3.65 (s, 3H), 6,85-6,98 (m, 2H), 7,00-7,10 (m, 1H), 10,2-10,5 (m, 1H).

MS Calculated: 218; Found: 219 (M+H).

4-Chloro-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-he

2,2'-Azobisisobutyronitrile (AIBN) (94 mg, or 0.57 mmol) was added to a mixture of 7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-it (2,90 g, 13.3 mmol) and N-chlorosuccinimide (1,95 g, 14.6 mmol) in carbon tetrachloride (250 ml). The mixture was stirred at 70°C for 2 days. The reaction mixture was concentrated in vacuo, extracted with ethyl acetate and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to obtain a residue. The residue was led from ethanol/isopropanol to obtain specified in the title compound as colorless crystals (2.28 g, 68%). TPL 165-166°C.

1H NMR (CDCl3) δ 0,81 (t, J=7.2 Hz, 6H), 1.60-to of 1.85 (m, 4H), of 3.10-3.20 (m, 1H), to 3.64 (s, 3H), 6.87 in (d, J=8.7 Hz, 1H), 7,03 (d, J=8.7 Hz, 1H), 8,55 (s, 1H). M Calculated: 251; Found: 252 (M+H).

2,4-Dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

A mixture of 4-chloro-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-it (1,17 g, 4,63 mmol) in phosphorus oxychloride (28 g) was stirred at 90°C for 3 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was subjected to chromatography on silica gel (n-hexane/ethyl acetate=10:1-1:1) and was led from ethyl acetate-hexane to obtain specified in the title compound as colorless crystals (1,03 g, 82%). TPL 94-95°C.

1H NMR (CDCl3) δ of 0.82 (t, J=7.5 Hz, 6H), 1.60-to 1,90 (m, 4H), 3,20-3,30 (m, 1H), 4,01 (s, 3H), 7,05 (d, J=8,4 Hz, 1H), 7,26 (d, J=8,4 Hz, 1H). MS Calculated: 270; Found: 271 (M+H).

N-(4-Bromo-2-methoxy-6-were)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

A mixture of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole (140 mg, 0.52 mmol), 4-bromo-2-methoxy-6-methylaniline (335 mg, 1.55 mmol) and 1-methyl-2-pyrrolidone (5 drops) was stirred at 130°C for 2 days under nitrogen atmosphere. The mixture was dissolved in ethyl acetate/water, extracted with ethyl acetate and washed with saturated saline solution. The organic layer was dried over magnesium sulfate and concentrate which has demonstrated to obtain brown oil. The oil was subjected to purification by chromatography on silica gel (n-hexane/ethyl acetate=10:1-1:1) and was led from isopropanol to obtain specified in the title compound as colorless crystals (115 mg, 49%). TPL 218-220°C.

1H NMR (CDCl3) δ of 0.83 (t, J=7.2 Hz, 6H), 1.60-to of 1.85 (m, 4H), of 2.15 (s, 3H), 3,10-of 3.25 (m, 1H), 3,76 (s, 3H), 3,79 (s, 3H), between 6.08 (s, 1H), 6,86 (d, J=8,4 Hz, 1H), 6,91 (s, 1H), 7,03 (s, 1H), 7,10-7,20 (m, 1H). MS Calculated: 449; Found: 450 (M+H).

Examples 78-96 got a way similar to that described in Example 77.

Example 78

4-Chloro-N-(4-chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 219-221°C.

1H NMR (CDCl3) δ of 0.83 (t, J=7.2 Hz, 6H), 1.60-to of 1.85 (m, 4H), of 2.16 (s, 3H), of 3.10-3.20 (m, 1H, in), 3.75 (s, 3H), 3,79 (s, 3H), 6,07 (s, 1H), 6,77 (d, J=2.1 Hz, 1H), 6,80-of 6.90 (m, 2H), 7,05-7,20 (m, 1H).

MS Calculated: 405; Found: 406 (M+H).

Example 79

4-Chloro-N-[2,6-dichloro-4-(triptoreline)phenyl]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 147-149°C.

1H NMR (CDCl3) δ of 0.85 (t, J=7.2 Hz, 6H), 1.60-to of 1.85 (m, 4H), of 3.10-3.20 (m, 1H), a 3.87 (s, 3H), 6.75 in-6,90 (m, 1H), 6,98 (d, J=8,4 Hz, 1H), 7,20 was 7.45 (m, 2H), 8,30-to 8.40 (m, 1H).

MS Calculated: 479; Found: 480 (M+H).

Example 80

4-Chloro-N-(2,4-dichlorophenyl)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 130-132°C.

1H NMR (CDCl3) δ is 0.84 (t, J=7.5 Hz, 6H), 1.60-to of 1.85 (m, 4H), 3.15 and is 3.25 (m, 1H), 3,84 (s, 3H), 6,72 (s, 1H) of 6.96 (d, J=8,4 Hz, 1H), 7,21 (d, J=8,4 Hz, 1H), 7,29 (d, J=2.4 Hz, 1H), 7,41 (d, J=2.4 Hz, 1H), of 8.09 (d, J=8,4 Hz, 1H). MS Calculated: 395; Found: 396 (M+H).

Example 81

4-Chloro-N-[4-chloro-2-(triptoreline)phenyl]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 126-128°C.

1H NMR (CDCl3) δ is 0.84 (t, J=7.5 Hz, 6H), 1.60-to of 1.85 (m, 4H), 3,15-3,30 (m, 1H), a 3.87 (s, 3H), for 6.81 (s, 1H), 6,98 (d, J=8,4 Hz, 1H), 7,20-7,40 (m, 3H), 8,30-to 8.40 (m, 1H). MS Calculated: 445; Found: 446 (M+H).

Example 82

N-(4-Bromo-2,6-dimetilfenil)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 247-249°C.

1H NMR (CDCl3) δ of 0.82 (t, J=7.5 Hz, 6H), 1.55V and 1.80 (m, 4H), 2,17 (s, 6H), 3,00-3,20 (m, 1H), 3,40-the 3.65 (m, 3H), 5,90-6,00 (m, 1H), 6,70-of 6.90 (m, 2H), 7,00-7,20 (m, 1H), 7,20-7,30 (m, 1H). MS Calculated: 434; Found: 435 (M+H).

Example 83

4-Chloro-N-(4-chloro-2,6-dimetilfenil)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 247-249°C.

1H NMR (CDCl3) δ of 0.82 (t, J=7.5 Hz, 6H), 1.55V and 1.80 (m, 4H), to 2.18 (s, 6H), 3,00-3,20 (m, 1H), 3,40-the 3.65 (m, 3H), 5,90-6,00 (m, 1H), 6,70-of 6.90 (m, 2H), 7,05-7,20 (m, 2H). MS Calculated: 389; Found: 390 (M+H).

Example 84

N-(2-Bromo-4-chlorophenyl)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 136-138°C.

1H NMR (CDCl3) δ is 0.84 (t, J=7.5 Hz, 6H), 1.60-to of 1.85 (m, 4H), 3.15 and is 3.25 (m, 1H), 3,84 (s, 3H), for 6.81 (s, 1H), of 6.96 (d, J=8,4 Hz, 1H), 7,21 (d, J=8,4 Hz, 1H), 7,32 (DD, J=8,4, 2.4 Hz, 1H), 7,56 (d, J=2.4 Hz, 1H), of 8.06 (d, J=8,4 Hz, 1H). MS Calculated is: 440; Found: 441 (M+H).

Example 85

N-(4-Bromo-2-chlorophenyl)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 127-129°C.

1H NMR (CDCl3) δ is 0.84 (t, J=7.5 Hz, 6H), 1.60-to of 1.85 (m, 4H), 3.15 and is 3.25 (m, 1H), 3,85 (s, 3H), 6,80 (s, 1H), of 6.96 (d, J=8,4 Hz, 1H), 7,22 (d, J=8,4 Hz, 1H), 7,42 (DD, J=8,8, 2.4 Hz, 1H), 7,55 (d, J=2.4 Hz, 1H), 8,03 (d, J=8,8 Hz, 1H). MS Calculated: 440; Found: 441 (M+H).

Example 86

N-(2-Bromo-4-were)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 174-176°C.

1H NMR (CDCl3) δ is 0.84 (t, J=7.5 Hz, 6H), 1.60-to of 1.85 (m, 4H), of 2.30 (s, 3H), 3.15 and is 3.25 (m, 1H), 3,80 (s, 3H), 6,74 (s, 1H), 6,94 (d, J=8,4 Hz, 1H), 7,10-to 7.15 (m, 1H), 7,20 (d, J=8,4 Hz, 1H), 7,38 (d, J=1.2 Hz, 1H), to 7.77 (d, J=8,4 Hz, 1H). MS Calculated: 420; Found: 421 (M+H).

Example 87

4-Chloro-N-[2-chloro-4-(triptoreline)phenyl]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 122-123°C.

1H NMR (CDCl3) δ is 0.84 (t, J=7.5 Hz, 6H), 1.60-to of 1.85 (m, 4H), 3.15 and is 3.25 (m, 1H), a 3.87 (s, 3H), for 6.81 (s, 1H), of 6.96 (d, J=8,4 Hz, 1H), 7,21 (d, J=8,4 Hz, 2H), 7,31 (s, 1H), 8,21 (d, J=8,4 Hz, 1H). MS Calculated: 445; Found: 446 (M+H).

Example 88

N5-[4-Chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-yl]-N2N2,4-trimethylpyridine-2,5-diamine

TPL 224-226°C.

1H NMR (CDCl3) δ of 0.82 (t, J=7.2 Hz, 6H), 1.60-to of 1.85 (m, 4H), and 2.26 (s, 3H), 3,00-3,20 (m, 1H), of 3.07 (s, 6H)and 3.59 (s, 3H), 5,90 (s, 1H), 6,41 (s, 1H), 6.87 in (d, J=8,4 Hz, 1H), 7,15 (d, J=8,4 Hz, 1H), to $ 7.91 (s,1H). MS Calculated: 385; Found: 386 (M+H).

Example 89

N-(4-Bromo-2-methoxy-6-were)-4-chloro-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

TPL 210-211°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 6H), 1,15-1,35 (m, 4H), 1,60-1,80 (m, 4H), of 2.15 (s, 3H), 3.25 to 3.40 in (m, 1H, in), 3.75 (s, 3H), 3,79 (s, 3H), 6,07 (s, 1H), 6,85-to 6.95 (m, 2H), 7,00-7,20 (m, 2H). MS Calculated: 477; Found: 478 (M+H).

Example 90

4-Chloro-N-(4-chloro-2-methoxy-6-were)-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

TPL 204-206°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.2 Hz, 6H), 1,10-1,30 (m, 4H), 1,55-1,75 (m, 4H), of 2.15 (s, 3H), 3.25 to 3.40 in (m, 1H, in), 3.75 (s, 3H), 3,79 (s, 3H), between 6.08 (s, 1H), 6,77 (d, J=2.1 Hz, 1H), 6,80-of 6.90 (m, 2H), 7,10 (d, J=8,4 Hz, 1H). MS Calculated: 433; Found: 434 (M+H).

Example 91

4-Chloro-N-(2,4-dichlorophenyl)-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

TPL 146-148°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.2 Hz, 6H), 1,10-1,30 (m, 4H), 1.55V and 1.80 (m, 4H), 3,30 is-3.45 (m, 1H), 3,84 (s, 3H), 6,79 (s, 1H), 6,97 (d, J=8,1 Hz, 1H), 7,21 (d, J=8,1 Hz, 1H), 7,29 (d, J=2.4 Hz, 1H), 7,41 (d, J=2.4 Hz, 1H), of 8.09 (d, J=8,4 Hz, 1H). MS Calculated: 423; Found: 424 (M+H).

Example 92

N-(2-Bromo-4-chlorophenyl)-4-chloro-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

TPL 145-147°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 6H), 1,10-1,30 (m, 4H), 1.55V and 1.80 (m, 4H), 3,30 is-3.45 (m, 1H), 3,84 (s, 3H), 6,80 (s, 1H), 7,00 (d, J=8,1 Hz, 1H), 7,20 (d, J=8,1 Hz, 1H), 7,31 (DD, J=8,7, 2.4 Hz, 1H), 7,55 (d, J=2,4 Hz, 1H),8,04 (d, J=8.7 Hz, 1H). MS Calculated: 469; Found: 470 (M+H).

Example 93

N-(4-Bromo-2-chlorophenyl)-4-chloro-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

TPL 145-147°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 6H), 1,10-1,30 (m, 4H), 1.55V and 1.80 (m, 4H), 3,30 is-3.45 (m, 1H), 3,84 (s, 3H), 6,79 (s, 1H), 7,00 (d, J=8,1 Hz, 1H), 7,21 (d, J=8,1 Hz, 1H), 7,41 (DD, J=9,0, 2.4 Hz, 1H), 7,54 (d, J=2,4 Hz, 1H), 8,03 (d, J=9.0 Hz, 1H). MS Calculated: 469; Found: 470 (M+H).

Example 94

4-Chloro-N-[4-chloro-2-(triptoreline)phenyl]-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

TPL 130-132°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 6H), 1,10-1,30 (m, 4H), 1.55V and 1.80 (m, 4H), 3,30 is 3.40 (m, 1H), 3,81 (s, 3H), 6,56 (s, 1H), 6,97 (d, J=8,1 Hz, 1H), 7,20 (d, J=8,1 Hz, 1H), 7,25-7,30 (m, 2H), 8,00-to 8.20 (m, 1H). MS Calculated: 473; Found: 474 (M+H).

Example 95

4-Chloro-N-[2-chloro-4-(trifluoromethyl)phenyl]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 128-129°C.

1H NMR (CDCl3) δ 0,84 (6 H, t, J=7.4 Hz), 1,65-1,88 (4 H, m), 3,14 - of 3.27 (1 H, m), 3,88 (3 H, s), 6,94? 7.04 baby mortality (2 H, m), 7,20-7,28 (1 H, m), 7,55 (1 H, DD, J=8,8, 1.9 Hz), 7,66 (1 H, d, J=1.9 Hz), to 8.20 (1 H, d, J=9.9 Hz).

MS Calculated: 429; Found: 430(M+H).

Example 96

4-Bromo-N-(4-chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 198-199°C.

1H NMR (CDCl3) δ of 0.83 (t, J=7.2 Hz, 6H), 1,60-1,80 (m, 4H), 2,17 (s, 3H), 3.15 in (m, 1H), and 3.72 (s, 3H), of 3.78 (s, 3H), 6,11 (user, 1H), 6,77 (s, 1H), 6,8 (d, J=8,4 Hz, 1H), 6.87 in (s, 1H), 7,20-7,30 (m, 1H).

MS Calculated: 449; Found: 450 (M+H).

Example 97

4-Chloro-2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

A solution of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole (5.5 g, a 20.2 mmol), 2,4-dichloro-6-METHYLPHENOL (10 g, of 56.5 mmol) and potassium carbonate (8,4 g of 60.8 mmol) in N,N-dimethylformamide (55 ml) was heated at 100°C for 9 hours. To the mixture was added 2,4-dichloro-6-METHYLPHENOL (5 g, 28.3 mmol) and potassium carbonate (4,2 g, 30.4 mmol) and was heated at 100°C for 16 hours. Added additional amount of 2,4-dichloro-6-METHYLPHENOL (5 g, 28.3 mmol) and potassium carbonate (4,2 g, 30.4 mmol) and was heated at 100°C for 9 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on NH silica gel, elwira mixture of 12.5% ethyl acetate/n-hexane. The obtained solid substance was recrystallized from a mixture of 10% ethyl acetate/n-hexane to obtain 5.3 g (64%) indicated in the title compounds as colorless crystals.

TPL 155-157°C.

1H NMR (CDCl3) δ 0,86 (t, J =7.2 Hz, 6H), 1,64 is 1.86 (m, 4H), 2,31 (s, 3H), 3,17 of 3.28 (m, 1H), 3,99 (s, 3H), 6,93 (d, J=8,4 Hz, 1H), 7,14 (d, J=8,4 Hz, 1H), 7,20 (d, J=2.4 Hz, 1H), 7,31 (d, J=2.4 Hz, 1H).

MS Calculated: 410; Found: 411(M+H).

Examples 98-99 received a manner similar to that described in Example 97.

Example 98

4-Chloro-2-(2,4-dichlorphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

TPL 87-89°C.

1H NMR (CDCl3) δ 0,84 (6 H, t, J=7,3 Hz), 1,63-1,88 (4 H, m), 3,16 of 3.28 (1 H, m), of 3.97 (3 H, s)of 6.96 (1 H, d, J=8,2 Hz), 7,18 (1 H, d, J=8,2 Hz), 7,32 (1 H, DD, J=8,8, 2,5 Hz), 7,47 (1 H, d, J=2.5 Hz), 7,74 (1 H, d, J=8,8 Hz).

MS Calculated: 396; Found: 397(M+H).

Example 99

4-Chloro-7-(1-ethylpropyl)-2-(mesityloxy)-1-methyl-1H-benzimidazole

TPL 137-139°C.

1H NMR (CDCl3) δ of 0.87 (6 H, t, J=7.4 Hz), 1,65-1,87 (4 H, m), 2,17 (6 H, s), is 2.30 (3 H, s), 3,17-3,29 (1 H, m), of 3.97 (3 H, s), 6.87 in-6,95 (3 H, m), 7,12 (1 H, d, J=8,2 Hz).

MS Calculated: 370; Found: 371(M+H).

Example 100

N-(4-Chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole-2-amine

7-(1-Ethylpropyl)-4-methoxy-1-methyl-1,3-dihydro-2H-benzimidazole-2-he

A solution of 4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-she (250 mg, 0,841 mmol), anhydrous copper iodide (192 mg, 1.01 mmol) and 28% sodium methoxide in methanol (5.2 ml) in N,N-dimethylformamide (5 ml) was heated at 100oC for 1 hour. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum to obtain specified in the title the information of the compound (190 mg, 0,765 mmol, 91%).

1H NMR(CDCl3) δ 0,81 (6H, t, J=7.5 Hz), of 1.65 and 1.80(4H, m), 3,05 is 3.15 (1H, m), 3,63 (3H, s), 3,90 (3H, s), 6,63 (1H, d, J=8,4 Hz), 6,85 (1H, d, J=8,4 Hz), 8,39 (1H, usher.).

MS Calculated: 248; Found: 249(M+H).

2-Chloro-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole

A mixture of 7-(1-ethylpropyl)-4-methoxy-1-methyl-1,3-dihydro-2H-benzimidazole-2-she (190 mg, 0,765 mmol) in phosphorus oxychloride (2,14 ml) was stirred at 110°C for 6 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuum. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel (n-hexane/ethyl acetate=10:1-1:1) and was led from ethyl acetate/n-hexane to obtain specified in the title compound as colorless crystals (123 mg, 60%).

MS Calculated: 266; Found: 267 (M+H).

N-(4-Chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole-2-amine

A mixture of 2-chloro-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole (120 mg, 0,450 mmol), 4-chloro-2-methoxy-6-methylaniline (231 mg, 1.35 mmol) and 1-methyl-2-pyrrolidone (0.5 ml) was stirred at 130°C for 2 days under nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate and washed with saturated saline R is the target. The organic layer was dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (n-hexane/ethyl acetate=10:1-1:1) and was led from isopropanol to obtain specified in the title compound as colorless crystals (100 mg, 55%).

TPL 188-189°C.

1H NMR (CDCl3) δ of 0.85 (t, J=7.2 Hz, 6H), 1,60-1,80 (m, 4H), of 2.08 (s, 3H), of 3.10-3.20 (m, 1H), 3,79 (s, 3H), 3,82 (s, 3H), 3,90 (s, 3H), of 5.89 (m, 1H), is 6.61 (d, J=8.7 Hz, 1H), 6.75 in (d, J=1.8 Hz, 1H), 6,83 (d, J=1.8 Hz, 1H), 6,86 (d, J=8.7 Hz, 1H). MS Calculated: 401; Found: 402 (M+H).

Example 101

N-(4-Chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazole-2-amine

7-(1-Ethylpropyl)-1,4-dimethyl-1,3-dihydro-2H-benzimidazole-2-he

A solution of 4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-she (250 mg, 0.84 mmol), tetrakis(triphenylphosphine)palladium (194 mg, has 0.168 mmol), tetramethylurea (1,16 ml, 8.4 mmol) in triamide hexamethylphosphoric acid (5 ml) was boiled under reflux for 18 hours. After cooling, the mixture was diluted with water and was extracted with dichloromethane. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel (n-hexane/ethyl acetate=90:10-50:50) to obtain the specified title compound (111 mg, 0.48 mmol, 57%).

1H NMR(CDCl3) δ of 0.82 (6H, t, J=7.5 Hz),1.55V and 1.80(4H, m)of 2.38 (3H, s), of 3.10-3.20 (1H, m), the 3.65 (3H, s), at 6.84 (1H, d, J=8,4 Hz), 6.87 in (1H, d, J=8,4 Hz), 10,15 (1H, usher.).

MS Calculated: 232; Found: 233(M+H).

2-Chloro-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazole

A mixture of 7-(1-ethylpropyl)-1,4-dimethyl-1,3-dihydro-2H-benzimidazole-2-she (105 mg, 0,452 mmol) in phosphorus oxychloride (1.23 ml) was stirred at 110°C for 3 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel (n-hexane/ethyl acetate=10:1-1:1) and was led from ethyl acetate/n-hexane to obtain specified in the title compound as colorless crystals (100 mg, 88%).

MS Calculated: 250; Found: 251 (M+H).

N-(4-Chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazole-2-amine

A mixture of 2-chloro-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazole (100 mg, 0,399 mmol), 4-chloro-2-methoxy-6-methylaniline (205 mg, 1.20 mmol) and 1-methyl-2-pyrrolidone (0.2 ml) was stirred at 120°C for 2 days under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate, washed with saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated in vacuum. OST the current was purified column chromatography on silica gel (n-hexane:ethyl acetate=10:1-1:1) and was led from isopropanol to obtain specified in the title compound as colorless crystals (53 mg, 34%).

TPL 201-202°C.

1H NMR (CDCl3) δ of 0.85 (t, J=7.2 Hz, 6H), 1,60-1,80 (m, 4H), 2,11 (s, 3H), of 2.45 (s, 3H), of 3.10-3.20 (m, 1H), of 3.78 (s, 3H), 3,81 (s, 3H), 6,00 (m, 1H), 6,78 (d, J=2.1 Hz, 1H), 6,80-to 6.95 (m, 3H). MS Calculated: 385; Found: 386 (M+H).

Example 102

Isopropyl [4-chloro-2-[(4-chloro-2-methoxy-6-were)amino]-7-(1-ethylpropyl)-1H-benzimidazole-1-yl]acetate

Methyl 2,3-diaminobenzoate

To a suspension of methyl 2-amino-3-nitrobenzoate (15 g, a 76.5 mmol) in methanol (800 ml) was added 10% palladium on carbon (50% moisture; 6.5 g)and the mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated in vacuum. The remainder in the form of a solid substance was led from diisopropyl ether-hexane to obtain 11,57 g (69,6 mmol, 91,0%) specified in the title compound as dark yellow needle-shaped crystals.

1H NMR (CDCl3) δ: of 3.33 (2H, user. C)of 3.07 (3H, s)to 5.56 (2H, user. C)6,60 (1H, DD, J=8,1, 7.5 Hz), 6,85 (1H, DD, J=7,5, 1.5 Hz), 7,47 (1H, DD, J=8,1, 1.5 Hz).

MS Calculated: 166; Found: 167 (M+H).

Methyl 2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate

To a solution of methyl 2,3-diaminobenzoate (10.5 g, 63.2 mmol) in tetrahydrofuran (100 ml) was added N,N'-carbonyldiimidazole (10.2 g, 63.2 mmol) and the mixture was stirred at room temperature for 60 hours. The obtained solid substance was collected by filtration and washed the Lee ethyl acetate to obtain 10.2 g (53,1 mmol, 84,0%) specified in the title compounds as colorless crystals.

1H NMR (DMSO-d6) δ: a 3.87 (3H, s), 7,03 (1H, DD, J=8,1, 7.5 Hz), 6,85 (1H, DD, J=7,5, 1.2 Hz), of 7.48 (1H, DD, J=8,1, 1.2 Hz), 10,82 (2H, user. C).

MS Calculated: 192; Found: 193 (M+H).

4-(1-Ethyl-1-hydroxypropyl)-1,3-dihydro-2H-benzimidazole-2-he

To a suspension of methyl 2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (513 mg, to 2.67 mmol) in tetrahydrofuran (5 ml) was added a 3M solution of ethylmagnesium in diethyl ether (3.6 ml, about 10.7 mmol) and the mixture was stirred at room temperature for 1 hour and boiled under reflux for 20 hours. After adding 3M solution ethylacetamide in diethyl ether (5.3 ml, 16.0 mmol) and the mixture was boiled under reflux for 30 hours. The reaction mixture was acidified using 6N hydrochloric acid and was extracted with ethyl acetate (×2). The combined organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The obtained solid is washed with diisopropyl ether to obtain 440 mg (2.00 mmol, 74.8 percent) specified in the connection header.

1H NMR (CDCl3) δ: or 0.83 (6H, t, J=7.5 Hz), 1,76-to 1.98 (4H, m), 2,19 (1H, user. C)6,72 (1H, d, J=7.8 Hz), 6,92-7,02 (2H, m), 9,16 (1H, user. C)9,44 (1H, user. C).

MS Calculated: 220; Found: 203 (M-H2O+H).

4-[(1E)-1-Aterproof-1-EN-1-yl]-1,3-dihydro-2H-benzamid the evils-2-he 4-[(1Z)-1-Aterproof-1-EN-1-yl]-1,3-dihydro-2H-benzimidazole-2-he

To a solution of 4-(1-ethyl-1-hydroxypropyl)-1,3-dihydro-2H-benzimidazole-2-she (410 mg, of 1.86 mmol) in ethanol (6 ml) was added 6N hydrochloric acid solution (1.2 ml)and the mixture was stirred at 75oC for 2 hours. After cooling, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate (×2). The combined organic layer was washed with water (×1) and saturated brine (×1), dried over sodium sulfate, passed through silica gel and concentrated in vacuum to obtain 364 mg (1,80 mmol, 96.8 per cent) indicated in the title compounds as a pale yellow solid.

1H NMR (CDCl3) δ: of 0.95 (3H, t, J=7.5 Hz), 1,49 (0,75H, d, J=6.9 Hz), 1,84 (2,25H, d, J=6.9 Hz), 2,36 (0,5H, kV, J=7.5 Hz), 2,50 (1,5H, kV, J=7.5 Hz), 5,62-of 5.75 (1H, m), 6,82-was 7.08 (3H, m), 8,29 (0,25H, (C), 8,42 (0,75H, (C), of 9.30 (1H, s).

MS Calculated: 202; Found: 203 (M+H).

4-(1-Ethylpropyl)-1,3-dihydro-2H-benzimidazole-2-he

To a suspension of a mixture of 4-[(1E)-1-aterproof-1-EN-1-yl]-1,3-dihydro-2H-benzimidazole-2-it 4-[(1Z)-1-aterproof-1-EN-1-yl]-1,3-dihydro-2H-benzimidazole-2-she (329 mg, and 1.63 mmol) and ammonium formate (820 mg, 13,0 mmol) in ethanol (3 ml) was added 10% palladium on carbon (50% moisture; 120 mg) and the mixture was stirred at room temperature for 15 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuum. The residue was diluted with water and extracted with ethyl acetate (is 1). The organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuum to obtain 354 mg (>99%) specified in the title compound as a colourless solid.

1H NMR (CDCl3) δ: 0,80 (6H, t, J=7.2 Hz), 1,57-to 1.82 (4H, m), 2,50-2,62 (1H, m), to 6.88 (1H, d, J=7.8 Hz), 6,92 (1H, d, J=7.8 Hz), 7,03 (1H, t, J=7.8 Hz), 9,44 (1H, s), 9,54 (1H, s).

MS Calculated: 204; Found: 205 (M+H).

tert-Butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate

To a suspension of 4-(1-ethylpropyl)-1,3-dihydro-2H-benzimidazole-2-it (7,25 g, 35.5 mmol) in 1,2-dichloroethane (5 ml) was added N,N-dimethylaminopyridine (4,34 g, 35.5 mmol) and di-tert-BUTYLCARBAMATE (8,16 ml, 35.5 mmol) at 0oC and the mixture was stirred at 0oC for 30 minutes. The reaction mixture was diluted with water and was extracted with dichloromethane (×2). The combined organic layer was washed with saturated brine (×2), dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 5-40% ethyl acetate/hexane, obtaining 7,87 g (25,9 mmol, 72.8 per cent) indicated in the title compound as a colourless solid.

1H NMR (CDCl3) δ: 0,79 (6H, t, J=7.4 Hz), 1,55 of-1.83 (4H, m), by 1.68 (9H, s), 2,40-2,60 (1H, m), 6,97 (1H, d, J=8.0 Hz), to 7.09 (1H, t, J=8.0 Hz), the 7.65 (1H, d, J=8.0 Hz), 8,93 (1H, s).

tert-Butyl 4-(1-ethylpropyl)-3-(2-isopropoxy-2-oxoid the l)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate

To a suspension of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (of 7.70 g, to 25.3 mmol) in N,N-dimethylformamide (50 ml) was added potassium carbonate (3,84 g, 27.8 mmol) and isopropylbenzene (of 3.60 ml, 27.8 mmol) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×2). The combined organic layer was washed in an aqueous solution of sodium chloride (×2) and saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 5-20% ethyl acetate/hexane, obtaining of 8.95 g (22,1 mmol, 87.5%of the) specified in the title compounds as colorless oils.

1H NMR (CDCl3) δ: of 0.82 (6H, t, J=7.5 Hz), of 1.26 (6H, d, J=6.3 Hz), 1,53 to 1.76 (4H, m)to 1.67 (9H, s), 2.57 m) of 2.68 (1H, m), 4,80 (2H, s), 5,02-5,14 (1H, m), 7,03 (1H, DD, J=8,1, 1.5 Hz), 7,11 (1H, t, J=8.1 Hz), 7,79 (1H, DD, J=8,1, 1.5 Hz).

Isopropyl [7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl]acetate

To a solution of tert-butyl 4-(1-ethylpropyl)-3-(2-isopropoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (of 8.95 g, 22,1 mmol) in ethyl acetate (10 ml) was added a 4n solution of hydrogen chloride in ethyl acetate (20 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous sodium bicarbonate, and ek is was tragically with ethyl acetate (×2). The combined organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 5-20% ethyl acetate/hexane. The remainder in the form of a solid substance was washed with hexane to obtain 5,76 g (of 18.9 mmol, 85,6%) specified in the title compound as a colourless solid.

1H NMR (CDCl3) δ: 0,81 (6H, t, J=7.5 Hz), of 1.26 (6H, d, J=6.3 Hz), 1,55-to 1.79 (4H, m), 2,62-by 2.73 (1H, m), 4,82 (2H, s), of 5.05-of 5.15 (1H, m), 6.90 to-6,94 (2H, m),? 7.04 baby mortality (1H, d, J=7.8 Hz), 9,12 (1H, s).

MS Calculated: 304; Found: 305 (M+H).

Isopropyl [4-chloro-7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl]acetate

To a solution of isopropyl [7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl]acetate (5.29 g, to 17.4 mmol) in carbon tetrachloride (350 ml) was added N-chlorosuccinimide (2.55 g, 19,1 mmol) and 2,2'-azobisisobutyronitrile (86 mg, 0,522 mmol) and the mixture was stirred at 70oC for 3 days. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and was extracted with dichloromethane (×2). The combined organic layer was washed with water (×1) and saturated saline solution (B1), dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 10-50% ethyl acetate/hexane, obtaining a 3.83 g (11,mmol, 65,0%) specified in the title compound as a colourless solid.

1H NMR (CDCl3) δ: or 0.83 (6H, t, J=7.5 Hz), of 1.27 (6H, d, J=6.3 Hz), 1,57-of 1.78 (4H, m), 2,59 of 2.68 (1H, m), 4,80 (2H, s), 5,02-5,14(1H, m)6,86 (1H, d, J=8.7 Hz),? 7.04 baby mortality (1H, d, J=8.7 Hz), 8,67 (1H, s).

MS Calculated: 338; Found: 339 (M+H).

Isopropyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazole-1-yl]acetate

A mixture of isopropyl [4-chloro-7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl]acetate (of 3.73 g, 11.0 mmol) and phosphorus oxychloride (20 ml) was stirred at 100oC for 48 hours. After cooling, the phosphorus oxychloride is evaporated in vacuum. The residue was neutralized with a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate (×2). The combined organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 5-15% ethyl acetate/hexane, obtaining 3,82 g (10,7 mmol, 97,2%) specified in the connection header in the form of oil.

1H NMR (CDCl3) δ: 0,81 (6H, t, J=7.5 Hz), of 1.28 (6H, d, J=6.3 Hz), 1,62 of-1.83 (4H, m), 2,72-2,82 (1H, m), 5,06-to 5.21 (1H, m), to 5.08 (2H, s), 7,05 (1H, d, J=8.0 Hz), 7,28 (1H, d, J=8.0 Hz)

MS Calculated: 356, 358; Found: 357, 359 (M+H).

Isopropyl [4-chloro-2-[(4-chloro-2-methoxy-6-were)amino]-7-(1-ethylpropyl)-1H-benzimidazole-1-yl]acetate

A mixture of isopropyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimida the ol-1-yl]acetate (1.60 g, 4,48 mmol), (4-chloro-2-methoxy-6-methyl)aniline (3,18 g of 18.6 mmol) and N-methyl-2-pyrrolidinone (1 ml) was stirred at 110oC for 4.5 days. After cooling, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate (×1). The organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 5-20% ethyl acetate/hexane. The remainder in the form of a solid substance was washed with ethyl acetate/diisopropyl ether and n-hexane to obtain 1.18 g (2,40 mmol, 53.5 per cent) indicated in the title compound as a colourless solid. The filtrate was purified preparative HPLC to obtain 204 mg (0,414 mmol, 9.2 per cent) indicated in the title compounds as solids. TPL 205-207°C.

1H NMR (CDCl3) δ: of 0.82 (6H, t, J=7.4 Hz), of 1.30 (6H, d, J=6.3 Hz), 1,58-of 1.81 (4H, m), 2,11 (3H, s), 2,80 of 2.92 (1H, m), 3,83 (3H, s), 4,89 (2H, s), 5,09-5,20 (1H, m), 6,56 (1H, s), is 6.78 (1H, s), 6.87 in (1H, d, J=7,6 Hz), 6,87 (1H, s), 7,14 (1H, d, J=7,6 Hz).

MS Calculated: 491, 493; Found: 492, 494 (M+H).

Example 103

2-[4-Chloro-2-[(4-chloro-2-methoxy-6-were)amino]-7-(1-ethylpropyl)-1H-benzimidazole-1-yl]ethanol

To a solution of isopropyl [4-chloro-2-[(4-chloro-2-methoxy-6-were)amino]-7-(1-ethylpropyl)-1H-benzimidazole-1-yl]acetate (453 mg, 0,920 IMO the ü) in tetrahydrofuran (5 ml) was added tetrahydroborate lithium (60 mg, was 2.76 mmol) and the mixture is boiled under reflux for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×2). The combined organic layer was washed with saturated brine (×1), dried over sodium sulfate and concentrated in vacuum. The remainder in the form of a solid substance was recrystallized from ethyl acetate-n-hexane to obtain 250 mg (0,573 mmol, 62,3%) specified in the title compounds as colorless crystals. The filtrate was concentrated in vacuo, and the residue in the form of a solid substance was recrystallized from ethyl acetate-hexane to obtain 91 mg (0,209 mmol, 22.7 per cent) indicated in the title compounds as colorless crystals.

1H NMR (CDCl3) δ: of 0.85 (6H, t, J=7.2 Hz), 1,65 of-1.83 (4H, m)of 2.16 (3H, s), 2,45-2,60 (1H, usher.), 2,79-2,87 (1H, m), 3,76 (3H, s), 4,14 (2H, t, J=4.5 Hz), 4,43 (2H, t, J=4.5 Hz), 6,76 (1H, d, J=1,8 Hz), 6,83 (1H, d, J=7.8 Hz), 6.87 in (1H, d, J=1,8 Hz), of 6.99 (1H, d, J=7.8 Hz), 7,50-of 7.70 (1H, usher.).

MS Calculated: 435, 437; Found: 436, 438 (M+H).

Example 104

[4-Chloro-2-[(4-chloro-2-methoxy-6-were)amino]-7-(1-ethylpropyl)-1H-benzimidazole-1-yl]acetic acid

To a solution of 2-[4-chloro-2-[(4-chloro-2-methoxy-6-were)amino]-7-(1-ethylpropyl)-1H-benzimidazole-1-yl]ethanol (861 mg, about 1.75 mmol) in methanol (5 ml) was added 8h aqueous solution of sodium hydroxide (1.5 ml)and the mixture was stirred at room temperature is within 15 hours. To the reaction mixture was added water, followed by neutralization using 6N hydrochloric acid. The mixture was concentrated in vacuo and the residue was dissolved in methanol. The precipitate was removed by filtration and the filtrate was concentrated in vacuum to obtain 781 mg (1,73 mmol, 99.1 per cent) indicated in the title compound as an amorphous substance.

1H NMR (CDCl3) δ: 0,76 (6H, t, J=7.2 Hz), 1,52-of 1.73 (4H, m)2,07 (3H, s), 3,06 is 3.15 (1H, m), 3,76 (3H, s), of 4.77 (2H, s), 6,77 (1H, d, J=8,4 Hz), 6,93-of 6.99 (3H, m)8,64 (1H, s).

MS Calculated: 449, 451; Found: 450, 452 (M+H).

Example 105

1-{4-Chloro-2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}-2,2-DIMETHYLPROPANE-1-he

Methyl 7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate

A solution of methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (500 mg, 2,42 mmol), N-chlorosuccinimide (355 mg, of 2.66 mmol) and 2,2'-azobis(isobutyronitrile) (20 mg, 0.12 mmol) in carbon tetrachloride (40 ml) was boiled under reflux for 2 days. After cooling, the reaction mixture was concentrated in vacuum. The resulting material was extracted with ethyl acetate and water. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was chromatographically on silica gel to obtain 167 mg (0.07 mmol, 29%) specified in the connection header.

1H NMR (CDC 3) δ of 3.57(3H, s), of 3.95(3H, s), 7,07(1H, d, J=8,4 Hz)to 7.50(1H, d, J=8,4 Hz), 8,03(1H, usher.).

MS Calculated: 240; Found: 241 (M+H).

Methyl 2,4-dichloro-1-methyl-1H-benzimidazole-7-carboxylate

Methyl 7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (150 mg, was 0.63 mmol) was dissolved in 3 ml of phosphorus oxychloride and heated at 110oC during the night. The reaction mixture was allowed to cool to room temperature, then poured into crushed ice and stirred for 1 hour. The resulting material was diluted in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuum. The obtained compound (147 mg, 90%) was used in the next reaction without further purification.

MS Calculated: 257; Found: 258 (M+H).

Methyl 4-chloro-2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-carboxylate

A mixture of methyl 2,4-dichloro-1-methyl-1H-benzimidazole-7-carboxylate (100 mg, 0,39 mmol) and 4-chloro-2-methoxy-6-methylaniline (200 mg, 1,17 mmol) was stirred at 130oC during the night. After cooling, the reaction mixture is neutralized by adding an aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was chromatographically on a column of silica gel to obtain 68 mg (0,17 mmol, 44%) specified in C is the coupling head.

1H NMR (CDCl3) δ are 2.19 (3H, s), 3,74 (3H, s), of 3.80 (3H, s), of 3.95(3H, s), 6,17 (1H, usher.), 6,76 (1H, d, J=1,8 Hz), to 6.88 (1H, d, J=1,8 Hz), 7,14 (1H, d, J=8.1 Hz), 7,53 (1H, d, J=8,1 Hz).

MS Calculated: 393; Found: 394 (M+H).

1-{4-Chloro-2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}-2,2-DIMETHYLPROPANE-1-he

A solution of tert-utility (1,46 M, 0.5 ml) in n-pentane was added to a solution of methyl 4-chloro-2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-carboxylate (100 mg, 0.23 mmol) in diethyl ether (5 ml) at -78oC and was stirred for 1 hour. The reaction mixture was diluted with water (5 ml)was stirred at room temperature for 0.5 hour and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified preparative HPLC. The resulting substance was neutralized with an aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum to obtain 31 mg (0,073 mmol, 32%) specified in the connection header.

TPL 249-250oC

1H NMR (CDCl3) δ of 1.37 (9H, s), measuring 2.20 (3H, s), 3,37 (3H, s), of 3.80 (3H, s), 6,10 (1H, usher.), is 6.78 (1H, d, J=1,8 Hz), 6.89 in (1H, d, J=1,8 Hz), was 7.08 (1H, d, J=8.1 Hz), 7,10 (1H, d, J=8,1 Hz).

MS Calculated: 419; Found: 420 (M+H).

Example 106

3-{4-Chloro-2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}-2,,4,4-tetramethylpentane-3-ol

A solution of tert-utility (1,46 M, 0.5 ml) in n-pentane was added to a solution of methyl 4-chloro-2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-carboxylate (100 mg, 0.23 mmol) in diethyl ether (5 ml) at -78oC and was stirred for 1 hour. The reaction mixture was diluted with water (5 ml)was stirred at room temperature for 0.5 hour and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified preparative HPLC. The resulting substance was neutralized with an aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to obtain 5 mg (0,010 mmol, 5%) specified in the connection header.

TPL 246-248°C.

1H NMR (CDCl3) δ 1.12 in (18H, s), measuring 2.20 (3H, s)to 3.67 (3H, in), 3.75 (3H, s)6,76 (1H, s), 6.87 in (1H, s), to 7.09 (1H, d, J=9.0 Hz), 7,21 (1H, d, J=9.0 Hz).

MS Calculated: 477; Found: 478 (M+H).

Example 107

3-{4-Chloro-2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}-2,4-dimethylpentan-3-ol

To a solution of methyl 4-chloro-2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-carboxylate (200 mg, 0.50 mmol) in diethyl ether (3 ml) was added dropwise a solution of isopropylate (0,7 M solution, 5 ml) in pentane n and -78 oC and was stirred at 0oC for 1 hour. The reaction mixture was extinguished 6N solution of hydrochloric acid and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified preparative HPLC, elwira mixture with a gradient of 5-95% acetonitrile/water to obtain specified in the title compound (153 mg, 68%).

TPL 218-219oC.

1H NMR (CDCl3) δ of 0.87 (d, J=6.9 Hz, 6H), of 0.93 (d, J=6.9 Hz, 6H), are 2.19 (s,3H), 2,31 is 2.43 (m, 2H), of 3.77 (s,3H), a 3.87 (s,3H), 6,76 (d, J=2.1 Hz, 1H), 6,79 (d, J=8,4 Hz, 1H), to 6.88 (d, J=2.1 Hz, 1H), was 7.08 (d, J=8,4 Hz, 1H).

MS Calculated: 449; Found: 450 (M+H).

Example 108

4-Chloro-N-(4-chloro-2-methoxy-6-were)-7-(1-isopropyl-2-methylprop-1-EN-1-yl)-1-methyl-1H-benzimidazole-2-amine

A solution of 3-{4-chloro-2-[(4-chloro-2-methoxy-6-were)amino]-1-methyl-1H-benzimidazole-7-yl}-2,4-dimethylpentan-3-ol (75 mg, 0,17 mmol) in triperoxonane acid (3 ml) was heated at 70oC for 1 hour. After cooling, the reaction mixture was concentrated in vacuo, neutralized with a saturated solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified preparative HPLC, elwira mixture with a gradient of 5-95% acetonitrile/water to obtain specified in the header Conn is in (58 mg, 80%).

TPL 166-168oC.

1H NMR (CDCl3) δ of 0.65 (d, J=6.6 Hz, 3H), of 1.06 (d, J=6.6 Hz, 3H), of 1.40 (s, 3H), equal to 1.82 (s,3H), is 2.37 (s,3H), 3,02-is 3.08 (m, 1H), 3,19 (s,3H), to 3.67 (s,3H), 6,70 (d, J=8.7 Hz, 1H), 6,76 (d, J=2.1 Hz, 1H), make 6.90 (d, J=and 2.1 Hz, 1H), 7,22 (d, J=8.7 Hz, 1H).

MS Calculated: 431; Found: 432 (M+H).

Example 109

4-Chloro-N-(4-chloro-2-methoxy-6-were)-7-[(1Z)-1-aterproof-1-EN-1-yl]-1-methyl-1H-benzimidazole-2-amine

Example 109 was obtained in a manner analogous to the one described in Example 108.

TPL 166-168oC.

1H NMR (CDCl3) δ of 0.96 (t, J=7.5 Hz, 3H), 1,82 (d, J=6.6 Hz, 3H), 2,19 (s, 3H), 2,32-to 2.57 (m, 2H), to 3.58 (s, 3H), of 3.80 (s, 3H), 5,52 (kV, J=6,6 Hz, 1H), 6,04 (s, 1H), 6,70 (d, J=8,1 Hz, 1H), 6,77 (d, J=2.1 Hz, 1H), 6,88 (d, J=2.1 Hz, 1H), 7,05 (d, J=8,1 Hz, 1H).

MS Calculated: 403; Found: 404 (M+H).

Examples 110-124 got a way similar to that described in Example 77.

Example 110

4-Chloro-N-(2,4-dichloro-6-were)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

TPL 237-238°C.

1H NMR (CDCl3) δ of 0.85 (t, J=7.2 Hz, 6H), 1.60-to of 1.85 (m, 4H), to 2.18 (s, 3H), 3.15 and is 3.25 (m, 1H), 3,71 (s, 3H), 6,00-6,05 (m, 1H), 6.87 in (d, J=8,4 Hz, 1H), 7,05 (m, 1H), 7,16 (d, J=2.4 Hz, 1H), 7,31 (d, J=2.4 Hz, 1H).

MS Calculated: 409; Found: 410 (M+H), 412.

Example 111

4-Chloro-N-(2,4-dimethoxy-6-methylpyridin-3-yl)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

1H NMR (CDCl3) δ 0,81 (t, J=7.5 Hz, 6H), 1,60-1,80 (m, 4H), 2,43 (s, 3H), 3.15 in (m, 1H), 3,66 (s, 3H), of 3.78 (s, 3H), 3,88 (s, 3H, of 6.45 (s, 1H), 6,85 (d, J=8,1 Hz, 1H), 7,11 (d, J=8,1 Hz, 1H), 7,25 (m, 1H).

MS Calculated: 402; Found: 403 (M+H), 405.

Example 112

4-Chloro-N-[2-methoxy-5-(trifluoromethyl)phenyl]-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

TPL 178-180°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 6H), 1,10-1,30 (m, 4H), 1.55V and 1.80 (m, 4H), 3,30 is-3.45 (m, 1H, in), 3.75 (s, 3H), 3,99 (s, 3H), 6.90 to-7,00 (m, 3H), 7,20-7,30 (m. 2H), 8,24 (s, 1H).

MS Calculated: 453; Found: 454 (M+H).

Example 113

4-Chloro-N-[2,4-dichloro-5-(trifluoromethyl)phenyl]-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

TPL 206-208°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 6H), 1,10-1,30 (m, 4H), 1.55V and 1.80 (m, 4H), 3,30 is-3.45 (m, 1H), 3,86 (s, 3H), 6.89 in (s, 1H), 7,00 (d, J=8,4 Hz, 1H), 7.23 percent (d, J=8,4 Hz, 1H), 7,56 (s, 1H), 8,25-8,65 (user., 1H).

MS Calculated: 493; Found: 494 (M+H).

Example 114

4-Chloro-N-(4-chloro-2,6-dimetilfenil)-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

TPL 230-232°C.

1H NMR (CDCl3) δ of 0.85 (t, J=7.5 Hz, 6H), 1,10-1,30 (m, 4H), 1.55V and 1.80 (m, 4H), 2,10-of 2.20 (m, 6H), 3,20-3,90 (m, 4H), 6,00 (s, 1H), 6,85 (d, J=8,4 Hz, 1H), 7,00-7,20 (m, 3H).

MS Calculated: 417; Found: 418 (M+H).

Example 115

N-(4-Bromo-2,6-dimetilfenil)-4-chloro-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

TPL 234-236°C.

1H NMR (CDCl3) δ of 0.85 (t, J=7.5 Hz, 6H), 1,10-1,30 (m, 4H), 1.55V and 1.80 (m, 4H), 2,10-of 2.20 (m, 6H), 3,15-of 3.80 (m, 4H), 5,90-6,20 (user., 1H), 6,85 (d, J=8,4 Hz, 1H), 7,00-7,20 (m, 1H), 720-7,25 (m, 2H).

MS Calculated: 463; Found: 464 (M+H).

Example 116

5-{[4-Chloro-1-methyl-7-(1-propinball)-1H-benzimidazole-2-yl]amino}-4-methylpyridin-2(1H)-he

TPL 237-239°C.

1H NMR (CDCl3) δ to 0.80-0.95 (m, 6H), 1,00-1,80 (m, 8H), 2,10-of 2.30 (m, 3H), 3,20-4,85 (m, 4H), of 5.55 (s, 1H), 6.30-in-of 7.70 (m, 4H), 8,35 at 8.60 (user., 1H).

MS Calculated: 386; Found: 387 (M+H).

Example 117

4-Chloro-1-methyl-7-(1-propinball)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-1H-benzimidazole-2-amine

TPL 236-238°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 6H), 1,10-1,30 (m, 4H), 1.60-to of 1.95 (m, 8H), to 2.66 (t, J=6.3 Hz, 2H), of 2.81 (t, J=6.3 Hz, 2H), 3,20-3,40 (m, 1H), 3,60 (s, 3H), 6,11 (s, 1H), 6,69 (d, J=7.8 Hz, 1H), for 6.81 (d, J=7.8 Hz, 1H), of 6.96 (d, J=8,4 Hz, 1H), 7,03 (t, J=7.8 Hz, 1H), 7,20 (d, J=8,4 Hz, 1H).

MS Calculated: 409; Found: 410 (M+H).

Example 118

4-Chloro-2-(5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-methyl-7-(1-propinball)-1H-benzimidazole

1H NMR (CDCl3) δ of 0.89 (t, J=7.5 Hz, 6H), 1,15-1,30 (m, 4H), 1,60-1,80 (m, 4H), 3,17 (t, J=8,1 Hz, 2H), 3,30-to 3.50 (m, 1H), 3,76 (s, 6H), 4,20 (t, J=8,1 Hz, 2H), 6,45-7,30 (m, 5H).

MS Calculated: 411; Found: 412 (M+H).

Example 119

1-[4-Chloro-1-methyl-7-(1-propinball)-1H-benzimidazole-2-yl]-6-methoxy-1,2,3,4-tetrahydroquinolin

1H NMR (CDCl3) δ 0,86 (t, J=7.2 Hz, 6H), 1,15-1,30 (m, 4H), 1,55-1,75 (m, 4H), 2.05 is-of 2.20 (m, 2H), 2,88 (t, J=6.6 Hz, 2H), 3,30 is 3.40 (m, 1H), to 3.58 (s, 3H), of 3.75 (s, 3H), 3,88 (t, J=6.6 Hz, 2H), 6,34 (d, J=8.5 Hz, 1H), to 6.57 (DD, J=8,5, 3,0 Hz,1H), 6,69 (d, J=3.0 Hz, 1H), 6,97 (d, J=8,1 Hz, 1H), 7,19 (d, J=8,1 Hz, 1H).

MS Calculated: 425; Found: 426 (M+H).

Example 120

1-[4-Chloro-1-methyl-7-(1-propinball)-1H-benzimidazole-2-yl]-7-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin

1H NMR (CDCl3) δ 0,80 (t, J=7.2 Hz, 6H), 1,05-1,20 (m, 4H), 1,50-1,90 (m, 8H), 2,80-3,00 (m, 2H), 3,10-of 3.25 (m, 1H), 3,19 (s, 3H), 3,79 (s, 3H), 3,80-4,30 (user., 2H), 6,95 (m, 2H), 6,79 (d, J=2.4 Hz, 1H), 6.87 in (d, J=8,4 Hz, 1H), 7,14 (d, J=8,4 Hz, 1H).

MS Calculated: 439; Found: 440 (M+H).

Example 121

5-Bromo-N-(4-chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine

MP.. 276-278oC.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 3H), 1,66-of 1.84 (m, 4H), for 2.01 (s, 3H), and 2.14 (s, 3H), 3,13-is 3.21 (m, 1H), 3,82 (s, 3H), 3,83 (s, 3H), 5,80-6,20 (user., 1H), 6,80 (d, J=2.4 Hz, 1H), 6.89 in (d, J=2.4 Hz, 1H), 7,05 (s, 1H), 7,47 (s, 1H). MS Calculated: 493; Found: 494 (M+H).

Example 122

5-Chloro-4-{[4-chloro-1-methyl-7-(1-propinball)-1H-benzimidazole-2-yl]amino}-2-(trifluoromethyl)phenol

TPL 197-199°C.

1H NMR (CDCl3) δ of 0.87 (t, J=7.2 Hz, 6H), 1,15-1,35 (m, 4H), 1,60-1,80 (m, 5H), 3,30 is 3.40 (m, 1H), 3,88 (s, 3H), 6,97 (d, J=8,4 Hz, 1H), 7,13 (s, 1H), 7,19 (d, J=8,4 Hz, 1H), 7,20-7,30 (m, 2H).

MS Calculated: 473; Found: 474 (M+H).

Example 123

4-Chloro-N-[2,4-dimethoxy-5-(trifluoromethyl)phenyl]-1-methyl-7-(1-propinball)-1H-benzimidazole-2-amine

TPL 196-198°C.

1H NMR (CDCl3) δ of 0.85 (t, J=7.2 Hz, 6H), 1,15-130 (m, 4H), 1,60-1,80 (m, 4H), 3,30 is 3.40 (m, 1H), of 3.78 (s, 3H), 3,88 (s, 3H), 3,99 (s, 3H), to 6.57 (s, 1H), 6,66 (s, 1H), 6,92 (d, J=8,4 Hz, 1H), 7,17 (d, J=8,4 Hz, 1H), they were 8.22 (s, 1H).

MS Calculated: 483; Found: 484 (M+H).

Examples 124-144 got a way similar to that described in Example 97.

Example 124

4-Chloro-2-(mesityloxy)-1-methyl-7-(1-propinball)-1H-benzimidazole

TPL 165-167°C.

1H NMR (CDCl3) δ to 0.88 (t, J=7.2 Hz, 6H), 1,20-1,40 (m, 4H), 1,60-1,80 (m, 4H), 2,17 (s, 6H), is 2.30 (s, 3H), 3,30 is-3.45 (m, 1H), 3.96 points (s, 3H), 6,85-to 6.95 (m, 3H), 7,10 (d, J=8,1 Hz, 1H).

MS Calculated: 398; Found: 399 (M+H).

Example 125

4-Chloro-2-(4-chloro-2,6-dimethylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

TPL 168-169°C.

1H NMR (CDCl3) δ of 0.87 (t, J=7.5 Hz, 6H), 1.60-to of 1.85 (m, 4H), of 2.81 (s, 6H), 3,20-3,30 (m, 1H), 3,98 (s, 3H), 6,92 (d, J=8,1 Hz, 1H), 7,10 (s, 2H), 7,13 (d, J=8,1 Hz, 1H).

MS Calculated: 390; Found: 391 (M+H), 393.

Example 126

4-Chloro-2-(2,6-dimethoxy-4-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

TPL 161-162°C.

1H NMR (CDCl3) δ is 0.84 (t, J=7.5 Hz, 6H), 1.60-to of 1.85 (m, 4H), of 2.36 (s, 3H), 3,20-3,30 (m, 1H), of 3.77 (s, 6H), of 3.95 (s, 3H), 6,47 (s, 2H), 6.89 in (d, J=8,4 Hz, 1H), 7,10 (d, J=8,4 Hz, 1H).

MS Calculated: 402; Found: 403 (M+H), 405.

Example 127

4-Chloro-2-(2,4-dichlorophenoxy)-1-methyl-7-(1-propinball)-1H-benzimidazole

TPL 87-88°C.

1H NMR (CDCl3) δ of 0.87 (t, J=7.2 Hz, 6H), 1,10-1,40 (m, 4H), 1.60-to 1,90 (m,4H), 3,30 is-3.45 (m, 1H), of 3.97 (s, 3H), 6,98 (d, J=8,4 Hz, 1H), 7,17 (d, J=8,4 Hz, 1H), 7,32 (DD, J=8,8, 2.4 Hz, 1H), 7,47 (d, J=2.4 Hz, 1H), 7,74 (d, J=8,8 Hz, 1H).

MS Calculated: 424; Found: 425 (M+H).

Example 128

2-(4-Bromo-2-chlorophenoxy)-4-chloro-1-methyl-7-(1-propinball)-1H-benzimidazole

TPL 97-99°C.

1H NMR (CDCl3) δ of 0.87 (t, J=7.2 Hz, 6H), 1,10-1,40 (m, 4H), 1.60-to 1,90 (m, 4H), 3,30 is-3.45 (m, 1H), of 3.97 (s, 3H), 6,98 (d, J=8,4 Hz, 1H), 7,18 (d, J=8,4 Hz, 1H), 7,47 (DD, J=8,8, 2.4 Hz, 1H), 7,63 (d, J=2.4 Hz, 1H), 7,70 (d, J=8,8 Hz, 1H).

MS Calculated: 470; Found: 471 (M+H).

Example 129

4-Chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(1-propinball)-1H-benzimidazole

TPL 148-150°C.

1H NMR (CDCl3) δ to 0.88 (t, J=7.2 Hz, 6H), 1,10-1,40 (m, 4H), 1,60-1,80 (m, 4H), 2,31 (s, 3H), 3,30 is-3.45 (m, 1H), 3,98 (s, 3H), 6,95 (d, J=8,4 Hz, 1H), 7,14 (d, J=8,4 Hz, 1H), 7,20 (d, J=2.4 Hz, 1H), 7,31 (d, J=2.4 Hz, 1H).

MS Calculated: 438; Found: 439 (M+H).

Example 130

4-Chloro-2-(4-chloro-2,6-dimethylphenoxy)-1-methyl-7-(1-propinball)-1H-benzimidazole

TPL 160-162°C.

1H NMR (CDCl3) δ to 0.88 (t, J=7.2 Hz, 6H), 1,15-of 1.40 (m, 4H), 1,60-1,80 (m, 4H), are 2.19 (s, 6H), 3,30 is-3.45 (m, 1H), of 3.97 (s, 3H), 6,94 (d, J=8,4 Hz, 1H), 7,10-7,20 (m, 3H).

MS Calculated: 418; Found: 419 (M+H).

Example 131

2-(4-Bromo-2,6-dimethylphenoxy)-4-chloro-1-methyl-7-(1-propinball)-1H-benzimidazole

TPL 155-157°C.

1H NMR (CDCl3) δ to 0.88 (t, J=7.2 Hz, 6H), 1,20-1,40 (m, 4H), 1,60-1,80 (m, 4H), are 2.19 (s, 6H), from 3.0 to 3.45 (m, 1H), of 3.97 (s, 3H), 6,94 (d, J=8,4 Hz, 1H), 7,13 (d, J=8,4 Hz, 1H), 7,20-7,30 (m, 2H).

MS Calculated: 464; Found: 465 (M+H).

Example 132

4-Chloro-1-methyl-7-(1-propinball)-2-(2,4,6-trichlorophenoxy)-1H-benzimidazole

TPL 148-150°C.

1H NMR (CDCl3) δ to 0.88 (t, J=7.2 Hz, 6H), 1,20-1,40 (m, 4H), 1,60-1,80 (m, 4H), 3,30 is-3.45 (m, 1H), 3,99 (s, 3H), 6,97 (d, J=8,4 Hz, 1H), 7,15 (d, J=8,4 Hz, 1H), 7,26 (s, 1H), 7,43 (s, 1H).

MS Calculated: 458; Found: 459 (M+H).

Example 133

4-Chloro-2-(2,6-dimethoxy-4-methylphenoxy)-1-methyl-7-(1-propinball)-1H-benzimidazole

TPL 203-205°C.

1H NMR (CDCl3) δ of 0.87 (t, J=7.2 Hz, 6H), 1,15-of 1.40 (m, 4H), 1,60-1,80 (m, 4H), of 2.36 (s, 3H), 3,30 is-3.45 (m, 1H), of 3.77 (s, 6H), of 3.95 (s, 3H), 6,47 (s, 2H), make 6.90 (d, J=8,4 Hz, 1H), 7,10 (d, J=8,4 Hz, 1H).

MS Calculated: 430; Found: 431 (M+H).

Example 134

9-{[4-Chloro-1-methyl-7-(1-propinball)-1H-benzimidazole-2-yl]oxy}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

TPL 150-152°C.

1H NMR (CDCl3) δ to 0.88 (t, J=7.2 Hz, 6H), 1,15-of 1.40 (m, 4H), 1,60-1,80 (m, 4H), 2,70 (t, J=7.8 Hz, 2H), 2,98 (t, J=7.8 Hz, 2H), 3,17 (t, J=8.7 Hz, 2H), 3,30 is-3.45 (m, 1H), 3,92 (s, 3H), 4,10 (t, J=8.7 Hz, 2H), 6.90 to-7,05 (m, 3H), 7,17 (d, J=8,1 Hz, 1H).

MS Calculated: 451; Found: 452 (M+H).

Example 135

2-(2-Bromo-4-chlorophenoxy)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

TPL 114-115°C.

1H NMR (CDCl3) δ of 0.85 (t, J=7.2 Hz, 6H), 1.60-to of 1.85 (m, 4H), 3,15-3,30 (m, 1H), 3,98 (s, 3H), of 6.96 (d, J=8,4 Hz, 1H), and 18 (d, J=8,4 Hz, 1H), 7,37 (DD, J=2,4, and 8.7 Hz, 1H), 7,63 (d, J=2.4 Hz, 1H), 7,76 (d, J=7.8 Hz, 1H)

MS Calculated: 440; Found: 441 (M+H), 443, 445.

Example 136

5-Bromo-2-(4-chloro-2,6-dimethylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

TPL 214-216oC.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 6H), 1,65 of-1.83 (m, 4H), to 2.18 (s, 6H), 3,18-3,26 (m, 1H), 3,95 (s, 3H), 7,08-7,10 (m, 3H), 7,46 (d, J=2.1 Hz, 1H).

MS Calculated: 433; Found: 434 (M+H).

Example 137

2-(4-Bromo-2,6-dimethylphenoxy)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

TPL 197-198°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.2 Hz, 6H), 1,75-to 1.82 (m, 4H), to 2.18 (s, 6H), 3,19-of 3.25 (m, 1H), of 3.97 (s, 3H), 6,91 (d, J=8,1 Hz, 1H), 7,12 (d, J=8,1 Hz, 1H), 7,24 (s, 2H).

MS Calculated: 434; Found: 435 (M+H).

Example 138

4-Chloro-7-(1-ethylpropyl)-1-methyl-2-(2,4,6-trichlorophenoxy)-1H-benzimidazole

TPL 155-157°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.2 Hz, 6H), of 1.65-1.77 in (m, 4H), 3,18-of 3.25 (m, 1H), 3,99 (s, 3H), 6,93 (d, J=8,4 Hz, 1H), 7,15 (d, J=8,4 Hz, 1H), 7,42 (s, 2H).

MS Calculated: 430; Found: 431 (M+H).

Example 139

4-Chloro-7-(1-ethylpropyl)-2-[(4-methoxy-2,6-dimethylpyridin-3-yl)oxy]-1-methyl-1H-benzimidazole

TPL 183-184°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.2 Hz, 6H), 1,68-to 1.82 (m, 4H), of 2.45 (s, 3H), 2,52 (s, 3H), 3,20-3,26 (m, 1H), 3,76 (s, 3H), of 3.96 (s, 3H), of 6.66 (s, 1H), 6,91 (d, J=8,4 Hz, 1H), 7,12 (d, J=8,4 Hz, 1H).

MS Calculated: 387; Found: 388 (M+H).

Example 140

4-Chloro-2-[2,6-dichloro-4-(triptoreline)phenoxy]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

TPL 145-147°C.

1H NMR (CDCl3) δ of 0.85 (t, J=7.2 Hz, 6H), 1,68-to 1.82 (m, 4H), 3,20-3,24 (m, 1H), 4.00 points (s, 3H), 6,95 (d, J=8,4 Hz, 1H), 7,16 (d, J=8,4 Hz, 1H), 7,32 (s, 2H).

MS Calculated: 480; Found: 481 (M+H).

Example 141

3-{[4-Chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-yl]oxy}-N,N,2,6-tetramethylpiperidine-4-amine

TPL 175-177°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.2 Hz, 6H), 1.70 to to 1.82 (m, 4H), and 2.27 (s, 3H), of 2.46 (s, 3H), of 2.92 (s, 6H), 3,20-3,24 (m, 1H), of 3.97 (s, 3H), of 6.49 (s, 1H), 6,91 (d, J=8,1 Hz, 1H), 7,12 (d, J=8,1 Hz, 1H).

MS Calculated: 400; Found: 401 (M+H).

Example 142

3,5-Dichloro-4-{[4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-yl]oxy}-N,N-dimethylaniline

TPL 200-202°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.2 Hz, 6H), 1,68-of 1.81 (m, 4H), of 2.97 (s, 6H), 3,20-3,26 (m, 1H), 3,98 (s, 3H), 6,62 (s, 2H), 6,91 (d, J=8,4 Hz, 1H), 7,12 (d, J=8,4 Hz, 1H).

MS Calculated: 439; Found: 440 (M+H).

Example 143

3,5-Dichloro-2-{[4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-yl]oxy}-N,N-dimethylbenzamide

TPL 141-143°C.

1H NMR (CDCl3) δ is 0.84 (t, J=7.2 Hz, 6H), 1,67-of 1.81 (m, 4H), 2.63 in (s, 3H), is 3.08 (s, 3H), 3,20 is 3.23 (m, 1H), 3,95 (s, 3H), 6,95 (d, J=8,4 Hz, 1H), 7,14 (d, J=8,4 Hz, 1H), 7,18 (d, J=2.4 Hz, 1H), 7,51 (d, J=2.4 Hz, 1H).

MS Calculated: 467; Found: 468 (M+H).

Example 144

4-Chloro-2-(4-chloro-2-methoxy-6-metil is noxy)-7-(1-ethyl-propyl)-1-methyl-1H-benzimidazole

TPL 165-167°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.2 Hz, 6H), 1,75-to 1.82 (m, 4H), and 2.27 (s, 3H), 3,20-3,24 (m, 1H), 3,71 (s, 3H), of 3.95 (s, 3H), for 6.81 (d, J=2.4 Hz, 1H), 6,86 (d, J=2.4 Hz, 1H), make 6.90 (d, J=8,1 Hz, 1H), 7,11 (d, J=8,1 Hz, 1H).

MS Calculated: 406; Found: 407 (M+H).

Example 145

2-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole

A mixture of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole (200 mg, 0,750 mmol), 2,4-dichloro-6-METHYLPHENOL (398 mg, 2.25 mmol), potassium carbonate (311 mg, 2.25 mmol) and 1-methyl-2-pyrrolidone (0.5 ml) was stirred at 120°C for 12 hours under nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate and washed with saturated saline solution. The organic layer was dried over magnesium sulfate and concentrated in vacuum. The residue was purified by chromatography on silica gel using a mixture with a gradient 2-30% ethyl acetate/n-hexane and was led from methanol to obtain specified in the title compound as colorless crystals (109 mg, 36%).

TPL 130-131°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 6H), 1.60-to of 1.85 (m, 4H), of 2.30 (s, 3H), 3.15 and is 3.25 (m, 1H), with 3.89 (s, 3H), of 3.97 (s, 3H), only 6.64 (d, J=8,4 Hz, 1H), 6,92 (d, J=8,4 Hz, 1H), 7,15 (d, J=1.8 Hz, 1H), 7,25 (d, J=1.8 Hz, 1H).

MS Calculated: 406; Found: 407 (M+H), 409.

Example 146

2-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole

Example 146 was obtained by a method similar to that described in Example 145.

TPL 106-107°C.

1H NMR (CDCl3) δ of 0.85 (t, J=7.2 Hz, 6H), 1,50-of 1.85 (m, 4H), 3,10-of 3.25 (m, 1H), 3,92 (s, 3H), of 3.97 (s, 3H), of 6.66 (d, J=8.7 Hz, 1H), 6,95 (d, J=8.7 Hz, 1H), 7,32 (DD, J=2,4, and 7.8 Hz, 1H), to 7.59 (d, J=2.4 Hz, 1H), 7,66 (d, J=7.8 Hz, 1H)

MS Calculated: 436; Found: 437 (M+H), 439, 441.

Example 147

2-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-ol

To a solution of 2-(2-bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole (80 mg, 0.18 mmol) in dichloromethane (2 ml) was added dropwise a solution (1M, 2 ml) tribromide boron in dichloromethane at 0oC and was stirred at room temperature for 1 hour. The reaction mixture was cooled at 0oC, extinguished with water and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was washed with isopropyl ether and hexane (1:1) to obtain the specified title compound (67 mg, 86%).

TPL 175-177oC.

1H NMR (CDCl3) δ of 0.85 (t, J=7.5 Hz, 6H), 1,66-to 1.82 (m, 4H), is 3.08-3,18 (m, 1H), 3.96 points (s, 3H), 6,00-6,40 (user. 1H), of 6.71 (d, J=8,1 Hz, 1H), 6,92 (d, J=8,1 Hz, 1H), 7,35 (DD, J=2,4, and 8.7 Hz, 1H), 7,54 (d, J=8.7 Hz, 1H), 7,65 (d, J=2.4 Hz, 1H).

MS Calculated: 422; Found: 423 (M+H).

Example 148

2-(2-Bromo-4-chlorophenoxy)-4-(deformedarse)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

the aqueous solution of potassium hydroxide (50% solution) was added dropwise a solution of 2-(2-bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-ol in dichloromethane (2 ml) at 0 oC. After stirring for 20 min the reaction mixture was barbotirovany Chlorodifluoromethane at 0oC for 30 minutes, the Reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified preparative HPLC, elwira mixture with a gradient of 5-95% acetonitrile/water to obtain specified in the title compound as an oil (24 mg, 43%).

1H NMR (CDCl3) δ of 0.85 (t, J=7.2 Hz, 6H), 1,64-to 1.87 (m, 4H), 3,17-of 3.27 (m, 1H), 3,99 (s, 3H), 6,94-7,00 (m, 2H), to 7.09 (t, J=76 Hz, 1H), 7,38 (DD, J=2,4, and 8.7 Hz, 1H), 7,65 (d, J=2.4 Hz, 1H), 7,68 (d, J=8.7 Hz, 1H).

MS Calculated: 472; Found: 473 (M+H).

Example 149

2-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1H-benzimidazole

7-(1-Ethylpropyl)-4-(2-furyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-he

To a mixture of 4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-she (150 mg, worn : 0.505 mmol) and 2-(tributylstannyl)furan (361 mg, 1.01 mmol) in toluene (2 ml) was added tetrakis(triphenylphosphine)palladium(0) (117 mg, 0,101 mmol) and the mixture is boiled under reflux for 3 hours. After cooling, the solvent is evaporated in vacuum and the residue was diluted with ethyl acetate. An ethyl acetate solution was washed with saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over magnesium sulfate, filter and and concentrated in vacuum. The residue was purified preparative HPLC, elwira mixture with a gradient of 5-95% acetonitrile/water to obtain 81 mg (0,285 mmol, 56%) specified in the connection header.

1H NMR (CDCl3) δ of 0.83 (t, J=7.5 Hz, 6H), 1,60-1,80 (m, 4H), 3,10-of 3.25 (m, 1H), 3,66 (s, 3H), of 6.52 (DD, J=2,1, 3.3 Hz, 1H), of 6.68 (d, J=3.3 Hz, 1H), 6,95 (d, J=8,1 Hz, 1H), 7,25 (d, J=8,4 Hz, 1H), 7,51 (d, J=2.1 Hz, 1H), a total of 8.74 (s, 1H).

MS Calculated: 284; Found: 285 (M+H).

2-Chloro-7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1H-benzimidazole

A mixture of 7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-she (79 mg, 0,278 mmol) in phosphorus oxychloride (0,78 ml of 8.33 mmol) was stirred at 120°C for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuum. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated saline solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified by chromatography on silica gel using a mixture with a gradient 1-30% ethyl acetate/n-hexane to obtain 44 mg (0,145 mmol, 52%) specified in the connection header.

1H NMR (CDCl3) δ of 0.82 (t, J=7.5 Hz, 6H), 1,65-of 1.85 (m, 4H), 3,20-to 3.35 (m, 1H), 4,01 (s, 3H), is 6.54 (DD, J=1,8, 3.3 Hz, 1H), 7,15 (d, J=7.8 Hz, 1H), 7,40-to 7.50 (m, 2H), to 7.67 (d, J=7.8 Hz, 1H).

MS Calculated: 302; Found: 303 (M+H), 305.

2-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1H-benzimidazole

A mixture of 2-chloro-7-1-ethylpropyl)-4-(2-furyl)-1-methyl-1H-benzimidazole (42 mg, 0,139 mmol), 2-bromo-4-chlorophenol (87 mg, 0,417 mmol) and potassium carbonate (58 mg, 0,417 mmol) was heated at 120°C for 18 h in an argon atmosphere. The mixture was diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture with a gradient of 1-20% ethyl acetate/n-hexane to obtain 45 mg (0,0950 mmol, 68%) indicated in the title compounds as colorless crystals.

TPL 159-162°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 6H), 1.70 to of 1.85 (m, 4H), 3,20-to 3.35 (m, 1H), 4,01 (s, 3H), 6,47 (DD, J=1.5 and 3.3 Hz, 1H), to 7.09 (d, J=8,1 Hz, 1H), 7,20 (d, J=3,3 Hz, 1H), 7,35-7,45 (m, 2H), to 7.64 (d, J=8,1 Hz, 1H), 7,66 (s, 1H), a 7.85 (d, J=9.0 Hz, 1H).

MS Calculated: 472; Found: 473 (M+H), 475.

Example 150

2-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile

7-(1-Ethylpropyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carbonitrile

A mixture of 4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-she (300 mg, 1.01 mmol) and copper cyanide (116 mg, of 1.30 mmol) in 1-methyl-2-pyrrolidone (3 ml) was subjected to microwave irradiation (200W) at 150°C for 1 hour. After cooling, the reaction mixture was diluted with saturated sodium bicarbonate solution and was extracted with ethyl acetate. The extract was dried over su is hatom magnesium, was filtered and concentrated in vacuum. The residue was washed with a mixture of 50% isopropyl ether/n-hexane to obtain specified in the title compound (209 mg, 86%).

1H NMR (CDCl3) δ 0,81 (t, J=7.8 Hz, 6H), 1,57 of-1.83 (m, 4H), 3,18-of 3.27 (m, 1H), to 3.67 (s, 3H), 6,98 (d, J=8,4 Hz, 1H), 7,27 (d, J=8,4 Hz, 1H), 9,51 (s, 1H).

MS Calculated: 243; Found: 244 (M+H).

2-Chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile

A mixture of 7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-it (3.80 g, 15.6 mmol) and phosphorus oxychloride (50 ml) was heated at 120°C for 6 hours. After cooling, the reaction mixture was poured into crushed ice and stirred for 30 min, neutralized with sodium bicarbonate and was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum. The residue is washed with diisopropyl ether to obtain specified in the connection header (3,76 g, 92%).

1H NMR (CDCl3) δ of 0.83 (t, J=7.5 Hz, 6H), 1,65 is 1.91 (m, 4H), 3.27 to to 3.36 (m, 1H), of 4.05 (s, 3H), 7,18 (d, J=8,4 Hz, 1H), 7,58 (d, J=8,4 Hz, 1H).

MS Calculated: 261; Found: 262 (M+H).

2-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile

A mixture of 2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile (250 mg, 0,957 mmol), 2-bromo-4-chlorophenol (595 mg, 2,87 mmol), potassium carbonate (397 mg, 2,87 mmol) and 1-methyl-2-pyrrolidone (0.5 ml) was stirred at 120°C for 12 h in an atmosphere of AZ is the same. The mixture was diluted with water, extracted with ethyl acetate and washed with saturated saline solution. The organic layer was dried over magnesium sulfate and concentrated in vacuum. The residue was purified by chromatography on silica gel using a mixture with a gradient 2-30% ethyl acetate/n-hexane and was led from methanol to obtain specified in the title compound as colorless crystals (134 mg, 32%).

TPL 136-137°C.

1H NMR (CDCl3) δ of 0.85 (t, J=7.5 Hz, 6H), 1,65-1,90 (m, 4H), of 3.25 to 3.35 (m, 1H), was 4.02 (s, 3H), 7,07 (d, J=8,1 Hz, 1H), 7,39 (DD, J=2,4, and 8.7 Hz, 1H), 7,47 (d, J=8,1 Hz, 1H), 7,65 (d, J=2.4 Hz, 1H), 7,81 (d, J=7.8 Hz, 1H)

MS Calculated: 431; Found: 432 (M+H), 434.

Example 151

2-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile

Example 151 was obtained by a method similar to that described in Example 150.

TPL 192-192°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.2 Hz, 6H), 1,65-1,90 (m, 4H), 2,31 (s, 3H), 3,20-to 3.35 (m, 1H), 4,01 (s, 3H),? 7.04 baby mortality (d, J=8,4 Hz, 1H), 7,22 (d, J=2.4 Hz, 1H), 7,32 (d, J=2.4 Hz, 1H), 7,43 (d, J=8,4 Hz, 1H).

MS Calculated: 401; Found: 402 (M+H), 404.

Example 152

2-[(4-Chloro-2-methoxy-6-were)amino]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile

A mixture of 2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile (1,00 g is 3.82 mmol), 4-chloro-2-methoxy-6-methylaniline (1.97 g, 11,50 mmol) and 1-methyl-2-pyrrolidone (0.5 ml) was heated the ri 130°C for 48 hours. After cooling, the reaction mixture was diluted with saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel with obtaining specified in the title compound as a white powder (670 mg, 44%).

1H NMR (CDCl3) δ of 0.83 (t, J=7.5 Hz, 6H), 1,64-of 1.85 (m, 4H), of 2.20 (s, 3H), 3,17-of 3.27 (m, 1H), 3,79 (s, 6H), 6,13 (s, 1H), 6,78 (d, J=2.1 Hz, 1H), 6.89 in (d, J=2.1 Hz, 1H), 6,94 (d, J=8,1 Hz, 1H), 7,37 (d, J=8,1 Hz, 1H). MS Calculated: 396; Found: 397 (M+H). TPL 223-225°C.

Example 153

Methyl 2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate

Methyl 7-(1-ethylpropyl)-1-methyl-2-oxo-2,3-dihydro-

1H-benzimidazole-4-carboxylate

A mixture of 7-(1-ethylpropyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carbonitrile (1.50 g, 6,17 mmol), potassium hydroxide (20,0 g, 356 mmol), water (30 ml) and ethanol (30 ml) was heated at the boiling point under reflux for 48 hours. The reaction mixture was concentrated in vacuum. The residue was diluted with ethyl acetate, was added 2n hydrochloric acid solution and was extracted. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to obtain the crude carboncarbon acid. To the residue was added triethylorthoformate (10 ml) and toluene (10ml) was heated at 100°C for 6 hours. The reaction mixture was concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 35% ethyl acetate/n-hexane to obtain 1.31 g (4,74 mmol, 77%) indicated in the title compound as a white powder.

1H NMR (CDCl3) δ 0,81 (t, J=7,44 Hz, 6H), 1.57 in-a 1.88 (m, 4H), 3,15-of 3.31 (m, 1H), the 3.65 (s, 3H), of 3.95 (s, 3H), of 6.96 (d, J=8,48 Hz, 1H), 7.62mm (d, J=8,67 Hz, 1H), of 9.21 (s, 1H).

MS: Calculated: 276; Found: 277 (M+H).

Methyl 2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate

A mixture of methyl 7-(1-ethylpropyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (1.30 grams, 4,70 mmol) and phosphorylchloride (10 ml) was heated at 100°C for 3 hours. The mixture was diluted with toluene and concentrated in vacuo to remove excess reagent. The residue was diluted with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel using a mixture of 10% ethyl acetate/n-hexane to obtain 1.18 g (4.00 mmol, 85%) indicated in the title compounds as colorless oils.

1H NMR (CDCl3) δ of 0.82 (t, J=7,35 Hz, 6H), 1,64 is 1.91 (m, 4H), 3.27 to is 3.40 (m, 1H), 4,01 (s, 3H), of 4.05 (s, 3H), 7,19 (d, J=8,10 Hz, 1H), 7,92 (d, J=8,29 Hz, 1H).

Methyl 2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate

A mixture of methyl 2 the ers-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate (1,15 g, 3.90 mmol), 4,6-dichloro-o-cresol (2,07 g, 11,70 mmol), potassium carbonate (2.16 g, 15,60 mmol) and N,N-dimethylformamide (15 ml) was heated at 110OC for 5 hours. The residue was diluted with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on alumina using a mixture of 15% ethyl acetate/n-hexane to obtain 1,41 g (3,24 mmol, 83%) indicated in the title compound as a white powder.

TPL 177-178°C.

1H NMR (CDCl3) δ 0,86 (t, J=7,44 Hz, 6H), 1,65-of 1.92 (m, 4H), of 2.36 (s, 3H), 3.25 to 3,39 (m, 1H), 3,84 (s, 3H), a 4.03 (s, 3H) 7,06 (d, J=8,29 Hz, 1H), 7,21 (d, J=a 1.88 Hz, 1H), 7,30 (d, J=2,64 Hz, 1H), 7,79 (d, J=8,29 Hz, 1H).

MS: Calculated: 435; Found: 436 (M+H).

Example 154

[2-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-yl]methanol

A mixture of methyl 2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate (1,00 g, 2,30 mmol), lithium borohydride (100 mg, 4,60 mmol) and tetrahydrofuran (20 ml) was heated at 55oC for 1 hour. The reaction mixture was concentrated in vacuum. The residue was diluted with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The remainder of the PTS is looking in column chromatography on silica gel using a mixture of 30% ethyl acetate/n-hexane to obtain 920 mg (of 2.26 mmol, 98%) indicated in the title compound as a white powder.

TPL 141-143°C

1H NMR (CDCl3) δ of 0.87 (t, J=7,35 Hz, 6H), 1,66-of 1.88 (m, 4H), to 2.29 (s, 3H), 3,16-3,30 (m, 1H), 3,90 (d, J=of 6.31 Hz, 1H), 3,99 (s, 3H), around 4.85 (d, J=6.22 per Hz, 2H), 6,98 (s, 2H), 7,20 (d, J=1.70 Hz, 1H), 7,32 (d, J =2,45 Hz, 1H).

MS: Calculated: 407; Found: 408 (M+H).

Example 155

2-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbaldehyde

A mixture of [2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-yl]methanol (100 mg, 0.25 mmol), manganese oxide(IV) (428 mg, to 4.92 mmol) and tetrahydrofuran (5 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuum. The residue was purified column chromatography on alumina using a mixture of 50% ethyl acetate/n-hexane to obtain 93 mg (0.23 mmol, 93%) indicated in the title compound as a white powder.

TPL 148-149°C

1H NMR (CDCl3) δ of 0.87 (t, J=7,44 Hz, 6H), 1.70 to of 1.93 (m, 4H), 2,32 (s, 3H), 3.25 to 3,39 (m, 1H), Android 4.04 (s, 3H), 7,11 (d, J=8,29 Hz, 1H), 7,24 (d, J=a 1.88 Hz, 1H), 7,35 (d, J=2,45 Hz, 1H), 7,72 (d,J=8,10 Hz, 1H), 10,55 (s, 1H).

Example 156

2-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-4-(pyrrolidin-1-ylmethyl)-1H-benzimidazole

To a mixture of 2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbaldehyde (93 mg, 0.23 mmol), pyrrolidine (33 mg, 0.46 mmol), acetic acid is the acid (0.5 ml) and ethyl acetate (1.5 ml) was added triacetoxyborohydride sodium (244 mg, 1.15 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The residue was diluted with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on alumina using a mixture of 5% ethyl acetate/n-hexane to obtain 100 mg (0.22 mmol, 94%) indicated in the title compound as a white powder.

TPL 107-108°C

1H NMR (CDCl3) δ of 0.87 (t, J=7,35 Hz, 6H), 1,65 is 1.86 (m, 8H), is 2.30 (s, 3H), 2,47 at 2.59 (m, 4H), 3,20-3,26 (m, 1H), 3,83 (s, 2H), of 3.97 (s, 3H), 6,98 (d, J=to $ 7.91 Hz, 1H), 7,17 (d, J=to $ 7.91 Hz, 1H), 7,21 (d, J=a 1.88 Hz, 1H), 7,32 (d, J=2,45 Hz, 1H).

MS: Calculated: 460; Found: 461 (M+H).

Example 157

N-{[2-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-yl]methyl}-N-methylethanamine

To a mixture of 2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbaldehyde (120 mg, 0,296 mmol), methylamine (2M solution in tetrahydrofuran, to 1.48 ml, 2,96 mmol), acetic acid (0.5 ml) and ethyl acetate (2.0 ml) was added triacetoxyborohydride sodium (314 mg, 1.48 mmol) and the reaction mixture was stirred at room temperature for 48 hours. The residue was diluted with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The extracts were washed with water, dried over what Ulfat magnesium and concentrated in vacuum. The residue was purified by chromatography on alumina using a mixture of 5% ethyl acetate/n-hexane to obtain 93 mg (0.21 mmol, 70%) indicated in the title compound as a white powder.

1H NMR (CDCl3) δ of 0.87 (t, J=7,35 Hz, 6H), was 1.04 (t, J=7,16 Hz, 3H), 1,65-to 1.87 (m, 4H), to 2.18 (s, 3H), to 2.29 (s, 3H), 2,42 (kV, J=7,16 Hz, 2H), 3,16-of 3.31 (m, 1H), and 3.72 (s, 2H), of 3.97 (s, 3H), 6,98 (d, J=to $ 7.91 Hz, 1H), 7,14 (d, J=to $ 7.91 Hz, 1H), 7.18 in-of 7.23 (m, 1H), 7,31 (d, J=a 1.88 Hz, 1H).

MS: Calculated: 448; Found: 449 (M+H).

Example 158

N-(4-Chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole-2-amine

Methyl 2-nitro-4-(trifluoromethyl)benzoate

A mixture of 2-nitro-4-triftorperasin acid (23,5 g, 0.10 mol), triethylorthoformate (60.1 g, 0.50 mol) and toluene (60 ml) was heated at 80°C for 16 hours. The reaction mixture was concentrated in vacuum. Added toluene and concentrated again to remove excess reagent. The residue was purified column chromatography on silica gel using a mixture with a gradient of 1-10% ethyl acetate/n-hexane to obtain 24,9 g (0.50 mol 100%) specified in the title compounds as colorless oils.

1H NMR (CDCl3) δ:of 3.97 (s, 3H), 7,87-of 7.90 (m, 1H), 7.95 is-of 7.97 (m, 1H), they were 8.22 (s, 1H).

Methyl 2-amino-4-(trifluoromethyl)benzoate

A mixture of methyl 2-nitro-4-(trifluoromethyl)benzoate (2,49 g 0.01 mol), sodium bisulfite (8,71 g, 0.05 mol), ethanol (20 ml) and water (20 ml), the heating is whether at 50°C for 3 hours. Was added water and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 5% ethyl acetate/n-hexane to obtain 1,46 g in (6.67 mmol 67%) indicated in the title compound as a white powder.

1H NMR (CDCl3) δ are 3.90 (s, 3H), 5,50-6,20 (user. s, 2H), 6,85 (d, J=8,48 Hz, 1H), 6.90 to (s, 1H), 7,95 (d, J=8,48 Hz, 1H).

MS Calculated: 219; Found: 220 (M+H).

Methyl 2-(acetylamino)-4-(trifluoromethyl)benzoate

A mixture of methyl 2-amino-4-(trifluoromethyl)benzoate (8.00 g, being 0.036 mol), acetic anhydride (11,18 g, 0,109 mol), pyridine (8,62 g, 0,109 mol) and chloroform (20 ml) was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuum. The residue was diluted with water and extracted with ethyl acetate. The extracts are washed with 1N-hydrochloric acid and water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 50% ethyl acetate/n-hexane to obtain 8,10 g (0,031 mol, 86%) indicated in the title compound as a white powder.

TPL 86-87oC.

1H NMR (CDCl3) δ and 2.26 (s, 3H), of 3.97 (s, 3H), 7,32 (DD, J=1,41, scored 8.38 Hz,1H), 8,14 (d, J=8,29 Hz, 1H), remaining 9.08 (s, 1H), 11.11 (with, 1H).

MS Calculated: 261; Found: 262 (M+H).

Methyl 2-(acetylamino)-3-nitro-4-(three is tormentil)benzoate

To ice nitric acid (fuming) (20 ml) was added in portions methyl 2-(acetylamino)-4-(trifluoromethyl) benzoate (7.30 g, 0,028 mol) and was stirred for 30 minutes, the Reaction mixture was poured into ice water and was extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 30% ethyl acetate/n-hexane to obtain 3,20 g (0,010 mol, 38%) indicated in the title compound as a yellow powder.

1H NMR (CDCl3) δ of 2.21 (s, 3H), 3,98 (s, 3H), 7,68 (d, J=8,29 Hz, 1H), 8,19 (d, J=8,29 Hz, 1H), 9,10 (s, 1H).

Methyl 2-amino-3-nitro-4-(trifluoromethyl)benzoate

A mixture of methyl 2-(acetylamino)-3-nitro-4-(trifluoromethyl)benzoate (1,00 g of 3.27 mmol) and 10% hydrochloric acid in methanol (10 ml) was heated at 55°C for 16 hours. The reaction mixture was concentrated in vacuum. The residue was diluted with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 30% ethyl acetate/n-hexane to obtain 780 mg (0,030 90 mol%) specified in the title compound as a yellow powder.

1H NMR (CCl 3) δ of 3.95 (s, 3H), 6.90 to-7,15 (user. s, 2H), 6,99 (d, J=8,29 Hz, 1H), 8,16 (d, J=8,29 Hz, 1H).

Methyl 2,3-diamino-4-(trifluoromethyl)benzoate

To a stirred solution of methyl 2-amino-3-nitro-4-(trifluoromethyl)benzoate (5,80 g of 0.022 mol), ammonium formate (30.0 g, 0,476 mol) in ethanol (300 ml) was added 10% palladium on carbon (500 mg) at room temperature and was stirred for 2 hours. Insoluble substances were filtered off and the filtrate was concentrated in vacuum. The residue was diluted with water and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 20% ethyl acetate/n-hexane to obtain 5.10 g (0,022 mol, 99%) specified in the title compound as a yellow powder.

1H NMR (CDCl3) a 3.87 δ (users, 2H), 3,90 (s, 3H), 5,68 (users, 2H), to 6.88 (d, J=8,67 Hz, 1H), 7,47 (d, J=8,67 Hz, 1H).

MS Calculated: 234; Found: 235 (M+H).

Methyl 2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-4-carboxylate

To a stirred solution of methyl 2,3-diamino-4-(trifluoromethyl)benzoate (5.10 g, of 0.022 mol) and diisopropylethylamine (of 6.26 g, 0,048 mol) in toluene (50 ml) was added dropwise a solution of triphosgene (2.58 g, 0,0087 mol) in toluene (20 ml) and stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuum. The residue was diluted with 1N solution of chlorine is estevadeordal acid and was extracted with ethyl acetate and tetrahydrofuran. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. To the residue was added a solution of 50% isopropyl ether/n-hexane and a white precipitate was filtered, washed with the same solvent with the receipt of 5.00 g (0.019 mol, 87%) indicated in the title compound as a white powder

TPL 281-283°C

1H NMR (DMSO - d6) δ to 3.92 (s, 3H) to 7.32 (d, J=8,48 Hz, 1H), to 7.61 (d, J=8,48 Hz, 1H), 11,23 (s, 1H), 11,63 (s, 1H).

MS Calculated: 260; Found: 261 (M+H)

Methyl 3-methyl-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-

the benzimidazole-4-carboxylate

To a stirred mixture of methyl 2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-4-carboxylate (2,34 g, 9,00 mmol), di-tert-BUTYLCARBAMATE (4,32 g, 20.0 mmol) and N,N-dimethylformamide (240 ml) was added in portions of 60% sodium hydride (800 mg, 20.0 mmol) and stirred at 50°C for 2 hours. The reaction mixture was poured into 1N hydrochloric acid solution and was extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuum. To the residue was added a solution of 50% isopropyl ether/n-hexane and a white precipitate (starting material) was filtered. The filtrate was concentrated in vacuum to obtain crude 1-tert-butyl 4-methyl 2-oxo-7-(trifter-methyl)-2,3-dihydro-1H-benzimidazole-1,4-in primary forms in the form of a colorless oil.

To a stirred mixture of the crude in primary forms, under the conditions (2,82 g, 20.0 mmol) and N,N-dimethylformamide (10 ml) was added in portions of 60% sodium hydride (800 mg, 20.0 mmol) and stirred at room temperature for 30 minutes the Reaction mixture was poured into 1N hydrochloric acid solution and was extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuum to obtain crude 1-tert-butyl 4-methyl 3-methyl-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-1,4-in primary forms in the form of a colorless oil.

A mixture of the crude 1,4-in primary forms and triperoxonane acid (5 ml) was stirred at 50°C for 10 min and concentrated in vacuum. The residue was diluted with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 20% ethyl acetate/n-hexane to obtain 1.13 g (4,12 mmol 46%) indicated in the title compound as a white powder.

1H NMR (CDCl3) δ of 3.57 (s, 3H), 3,99 (s, 3H), 7,29 (d, J=8,48 Hz, 1H), 7,54 (DD, J=0,75, 8,48 Hz, 1H), 9,36 (users, 1H).

MS Calculated: 274; Found: 275 (M+H).

7-(1-Aterproof-1-EN-1-yl)-1-methyl-4-(trifter ethyl)-1,3-dihydro-2H-benzimidazole-2-he

It chilled with ice to a solution of methyl 3-methyl-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-4-carboxylate (2,80 g, 10.2 mmol) in tetrahydrofuran (30 ml) was added a 3M solution of ethylmagnesium in diethyl ether (13,6 ml of 40.8 mmol) dropwise under stirring at 45°C for 16 hours. Caution was added methanol and water to decompose excess reagent. Added 2n hydrochloric acid solution and was extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuum. To the residue was added a solution of ethanol (40 ml) and concentrated hydrochloric acid (10 ml) and the resulting mixture was heated at 80°C for 6 hours. The reaction mixture was concentrated in vacuum. To the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by chromatography on silica gel using a mixture of 20% ethyl acetate/n-hexane to obtain 609 mg (2.14 mmol, 21%, CIS/TRANS=3/1) specified in the title compound as a white powder.

1H NMR (CDCl3) δ of 0.97 (t, J=7,50 Hz, 3H×0,75,), of 1.06 (t, J=7,44 Hz, 3H×0,25,), 1,39-of 1.45 (m, 3H×0,25)and 1.83 (d, J=is 6.78 Hz, 3H×0,75), 2,19 of 2.68 (m, 2H), 3,44 (s, 3H), 5,49 (kV, J=is 6.78 Hz, 1H×0,75), 5,74 (kV, J=is 6.78 Hz, 1H×0,25), to 6.80 (d, J=8,10 Hz, 1H×0,25),6,86 (d, J=8,10 Hz, 1H×0,75), 7,19 (d, J=8,29 Hz, 1H×0,75), from 7.24 (d, J=8,28 Hz, 1H×0,25), 9,07 (s, 1H).

MS Calculated: 284; Found: 285 (M+H).

7-(1-Ethylpropyl)-1-methyl-4-(trifluoromethyl)-1,3-dihydro-2H-benzimidazole-2-he

A mixture of 7-(1-aterproof-1-EN-1-yl)-1-methyl-4-(trifluoromethyl)-1,3-dihydro-2H-benzimidazole-2-it (486 mg, 1,71 mmol), 10% palladium on carbon (200 mg) and acetic acid (5 ml) was first made when hydrogen pressure of 5 ATM at 50°C for 2 hours. The catalyst was filtered and the filtrate was concentrated in vacuum. To the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by recrystallization from diisopropyl ether/n-hexane to obtain 350 mg (1,22 mmol, 72%) indicated in the title compound as a white powder.

TPL 205-206°C

1H NMR (CDCl3) δ 82 (t, J=7,44 Hz, 6H), 1,58-of 1.88 (m, 4H), 3,14-to 3.36 (m, 1H), to 3.67 (s, 3H), 7,02 (d, J=8,48 Hz, 1H), 7,21-7,27 (m, 1H), 8,92 (user. s, 1H).

MS Calculated: 286; Found: 287 (M+H).

2-Chloro-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole

A mixture of 7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1,3-dihydro-2H-benzimidazole-2-she (310 mg, of 1.08 mmol) and phosphorylchloride (5 ml) was heated at 110°C for 1 hour and concentrated in vacuum. Added toluene and concentrated again to remove excess reagent. To the residue was added nasy the n aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 20% ethyl acetate/n-hexane to obtain 300 mg (0,99 mmol, 91%) indicated in the title compounds as colorless oils.

1H NMR (CDCl3) δ of 0.83 (t, J=7,50 Hz, 6H), 1,65 is 1.91 (m, 4H), 3,24 is 3.40 (m, 1H), of 4.05 (s, 3H), 7,19 (d, J=to $ 7.91 Hz, 1H), 7,53 (d, J=8,10 Hz, 1H).

MS Calculated: 304; Found: 305 (M+H).

N-(4-Chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole-2-amine

A mixture of 2-chloro-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole (290 mg, 0.95 mmol), 4-chloro-2-methoxy-6-methylaniline (491 mg, of 2.86 mmol) and N-methyl-2-pyrrolidinone (3 drops) was heated at 110°C for 72 hours. To the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by chromatography on silica gel using a mixture of 10% ethyl acetate/n-hexane and recrystallized from diisopropyl ether/n-hexane to obtain 140 mg (0.32 mmol, 34%) indicated in the title compound as a white powder.

TPL 187-188°C

1H NMR (CDCl3) δ of 0.83 (t, J=7,35 Hz, 6H), 1,63-1,89 (m, 4H), to 2.18 (s, 3H), 3,20-3,30 (m, 1H), 3,74 (s, 3H), of 3.78 (s, 3H), 6,18 (s, 1H), 6,78 (s, 1H), to 6.88 (d, J=2,07 Hz, 1H), 6,97 (d, J=8,29 Hz, 1H), was 7.36 (d, J=8,29 Hz, 1H).

MS Calculated: 440; Found: 441 (M+H).

Example 159

N-(2-Bromo-4-chlorophenyl)-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole-2-amine

Example 159 was obtained by a method similar to that described in Example 158.

TPL 151-152°C

1H NMR (CDCl3) δ is 0.84 (t, J=7,44 Hz, 6H), 1,65 is 1.91 (m, 4H), 3,19-to 3.34 (m, 1H), a 3.87 (s, 3H), 6,93 (s, 1H), 7,07 (d, J=8,10 Hz, 1H), 7,34 (DD, J=2,45, cent to 8.85 Hz, 1H), 7,45 (d, J=7,35Hz, 1H), 7,56 (d, J=2,45 Hz, 1H), 8,29 (d, J=8,67 Hz, 1H).

MS Calculated: 474; Found: 475 (M+H).

Example 160

2-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole

A mixture of 2-chloro-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole (304 mg, 1.00 mmol), 4,6-dichloro-o-cresol (531 mg, 3.00 mmol), potassium carbonate (553 mg, 4.0 mmol) and N,N-dimethylformamide (5 ml) was heated at 110°C for 48 hours. To the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 10% ethyl acetate/n-hexane and recrystallized from diisopropyl ether/n-hexane to obtain 290 mg (of 0.65 mmol, 65%) indicated in the title compound as a white powder.

TPL 149-151°C

1H NMR (CDCl3) δ of 0.87 (t, J=7,35 Hz, 6H), 1,66 is 1.91 (m, 4H), 2,31 (who, 3H), 3,24-3,37 (m, 1H), was 4.02 (s, 3H), 7,05 (d, J=8,10 Hz, 1H), 7,21 (d, J=a 1.88 Hz, 1H), 7,31 (d, J=2,45 Hz, 1H), 7,39 (d, J=8,10 Hz, 1H).

MS Calculated: 445; Found: 446 (M+H).

Example 161

2-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole

Example 161 was obtained by a method similar to that described in Example 160.

TPL 119-120°C

1H NMR (CDCl3) δ of 0.85 (t, J=7,44 Hz, 6H), 1,65 is 1.91 (m, 4H), 3,24-3,37 (m, 1H), was 4.02 (s, 3H), 7,10 (d, J=8,10 Hz, 1H), 7,39 (DD, J=2,45, cent to 8.85 Hz, 1H), 7,44 (d, J=8,29 Hz, 1H), to 7.64 (d, J=2,45 Hz, 1H), 7,95 (d, J=9,04 Hz, 1H).

MS Calculated: 475; Found: 476 (M+H).

Example 162

2-(2,4-Dichloro-6-methylphenoxy)-7-(3,5-diethyl-1H-pyrazole-1-yl)-1-methyl-1H-benzimidazole

A suspension of 2-chloro-7-(3,5-diethyl-1H-pyrazole-1-yl)-1-methyl-1H-benzimidazole (92 mg, 0,318 mmol), 2,4-dichloro-6-METHYLPHENOL (114 mg, 0,643 mmol), potassium carbonate (89 mg, 0,643 mmol) in N,N-dimethylformamide (1.5 ml) was stirred at 90oC for 5.5 days (2,4-dichloro-6-METHYLPHENOL and potassium carbonate was added in three equal portions, each for 5.5 days). After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, elwira mixture with a gradient of 10-25% ethyl acetate/n-hexane, to receive the of 107 mg (0,249 mmol, 78,3%) specified in the connection header in the form of oil. The resulting oil was led from hexane to obtain 70 mg (51%) of pale yellow crystals.

TPL: 115-119oC

1H NMR (CDCl3) δ: 1,19 (3H, t, J=7.5 Hz), 1,32 (3H, t, J=7.5 Hz), and 2.26 (3H, s)of 2.50 (2H, q, J=7.5 Hz), of 2.72 (2H, q, J=7.5 Hz), 3,23 (3H, s), 6,10 (1H, s), 7,09-7,19 (3H, m), 7,31 (1H, d, J=2.4 Hz), EUR 7.57 (1H, d, J=6,9 Hz).

MS Calculated: 428; Found: 429 (M+H), 431.

Example 163

3,5-Dichloro-4-{[7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole-2-yl]oxy}-N,N-dimethylaniline

Example 163 was obtained by a method similar to that described in Example 145.

TPL 176-177°C.

1H NMR (CDCl3) δ 0,86 (t, J=7.5 Hz, 6H), 1,65-of 1.85 (m, 4H), to 2.94 (s, 6H), 3.15 and is 3.25 (m, 1H), with 3.89 (s, 3H), of 3.97 (s, 3H), 6,63 (d, J=8,4 Hz, 1H), 6,63 (s, 2H), 6,91 (d, J=8,4 Hz, 1H).

MS Calculated: 435; Found: 436 (M+H), 438.

Experiment 1

The measurement of the rate of inhibition of the binding releasing factor corticotropin (CRF)

The experiment of the receptor binding was performed using expressing CRF receptor human faction CHO cell membranes and Ovine CRF, [125I]-tyr0(125I-CRF). 1000 nm of the test compounds were incubated with 1 µg expressing CRF receptor human faction CHO cell membranes and 50 PM125I-CRF in the buffer for analysis of binding (50 mm Tris-HCl, 5 mm EDTA, 10 mm MgCl2, of 0.05% CHAPS, 0.1% of BSA, 0.5 mm PMSF, 0.1 mg/ml pepstatin, 20 μg/ml lapat is on, pH 7.5). In addition, to measure non-specific binding (NSB) 0.1 ám its human urocortin incubated with 1 µg expressing CRF receptor human faction CHO cell membranes and 50 PM125I-CRF in the buffer for analysis of binding. After the implementation of the binding reaction at room temperature for 1.5 hour, the membrane was filtered hold on a glass filter (UniFilter plate GF-C/Perkin Elmer) using filtration with suction, using a cell harvester (Perkin Elmer) and washed with ice 50 mm Tris-HCl (pH 7.5). After drying, the glass filter was added to scintillation fluid (Microscinti 0, Perkin Elmer) and measured the radioactivity125I-CRF, remaining on a glass filter, by means of a counter Topcount (Perkin Elmer).

(TB-SB)/(TB-NSB)×100 (SB: radioactivity when adding connections, TB: maximum binding radioactivity, NSB: non-specific binding radioactivity) was calculated by obtaining the rate of inhibition of binding in the presence of 1000 nm of each of the test compounds. Values IR50was calculated using the program GraphPad Prism.

The rate of inhibition of binding for the respective compounds, measured as described above, are presented in Table 8.

Table 8
Example No.The rate of inhibition of binding (%)1000 nm
1>80
9>80
64>80
69>80
77>80
84>80
90>80
97>80
101>80
103>80

Values IR50for the respective compounds, measured as described above, a and b are presented in Table 9. [A: less than 10 nm; B: 10-50 nm]

Table 9
Example No.IR50(nm)
15In
66In
77In
97And
101And
145And

Industrial applicability

The compound (I) or (I') according to the present invention have excellent antagonistic activity against CRF and are therefore useful as pharmaceuticals for the treatment or prophylaxis of affective disorders, depression, anxiety, etc.

1. The compound represented by formula (I):

where R1represents a C3-C8alkyl, optionally substituted by hydroxyl; phenyl, optionally substituted by 1-3 substituents selected from halogen, nitro, amino, hydroxyl, C1-C4alkoxy, C1-C4the alkyl, optionally substituted by hydroxyl or C1-C4alkylamino; naphthyl; With associated 5-6-membered heteroaryl with 1-2 heteroatoms selected from S, N and O, optionally substituted C1-C4the alkyl, C1-C4alkoxy or acetyl; N-linked 5-membered heteroaryl with 1-2 heteroatoms, selected from N, optionally substituted with 1-3 substituents selected from C1-C4the alkyl or phenyl;
R2represents phenyl, optionally substituted by 1-3 substituents selected from C1-C41-C4of alkyl, C1-C4alkoxy, Halogens1-C4alkoxy, halogen, hydroxy, di(C1-C4alkyl)amino or di(C1-C4alkyl)aminocarbonyl; or heterocyclic group, which represents pyridyl, optionally substituted by 1-3 substituents selected from C1-C4of alkyl, C1-C4alkoxy or di(C1-C4alkyl)amino;
X represents-NR3-where R3represents a C1-C4alkyl, optionally substituted by hydroxyl, carboxyla or C1-C4alkoxycarbonyl;
Y1represents CR3awhere R3arepresents hydrogen, halogen, cyano, hydroxy, C1-C4alkyl, optionally substituted by hydroxyl or halogen, C1-C4alkoxy, optionally substituted with halogen;
Y2represents CR3bwhere R3brepresents hydrogen or halogen;
Y3represents N or CR3cwhere R3crepresents hydrogen; and
Z represents oxygen or-NR4-where R4represents hydrogen;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1is an acyclic branched C3-C8alkyl, optionally substituted by hydroxyl.

3. Connect the Addendum according to claim 1, where R1represents phenyl, optionally substituted by 1-3 substituents selected from halogen, nitro, amino, hydroxy, C1-C4alkoxy, C1-C4the alkyl, optionally substituted by hydroxyl or C1-C4alkylamino; or naphthyl.

4. The compound according to claim 1, where R1represents a C-linked 5 or 6 membered heteroaryl with 1-2 heteroatoms selected from S, N and O, optionally substituted C1-C4the alkyl, C1-C4alkoxy or acetyl; or a N-linked 5-membered heteroaryl with 1-2 heteroatoms, selected from N, optionally substituted with 1-3 substituents selected from C1-C4the alkyl or phenyl.

5. The compound according to claim 1, where R3represents methyl, ethyl or hydroxyethyl.

6. The compound according to claim 1, where Y3represents CR3cwhere R3crepresents hydrogen.

7. The connection according to claim 6, where R3arepresents hydrogen, halogen, cyano, C1-C4alkyl, optionally substituted by hydroxy or halogen, or C1-4alkoxy, optionally substituted with halogen, and R3brepresents hydrogen.

8. The connection according to claim 7, where R3arepresents chlorine, bromine, methoxy or methyl.

9. The compound according to claim 1, where Y3represents nitrogen.

10. The compound according to claim 1, where R2represents phenyl, unto the which is 2,4,6-triple-substituted, 2,4,5-triple-substituted or 2,4-disubstituted.

11. The compound according to claim 1, which is a
N-(4-chloro-2-methoxy-6-were)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazole-2-amine,
N-(4-bromo-2-methoxy-6-were)-7-(3,5-diethyl-1H-pyrazole-1-yl)-1-methyl-1H-benzimidazole-2-amine,
N-(4-bromo-2-methoxy-6-were)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine,
4-chloro-2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole,
N-(4-chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-1,4-dimethyl-1 H-benzimidazole-2-amine,
2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole, or
4-chloro-N-(2,4-dichloro-6-were)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine,
or its pharmaceutically acceptable salt.

12. N-(4-chloro-2-methoxy-6-were)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazole-2-amine or its pharmaceutically acceptable salt.

13. N-(4-bromo-2-methoxy-6-were)-7-(3,5-diethyl-1H-pyrazole-1-yl)-1-methyl-1H-benzimidazole-2-amine or its pharmaceutically acceptable salt.

14. N-(4-bromo-2-methoxy-6-were)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine or its pharmaceutically acceptable salt.

15. 4-Chloro-2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole or its pharmaceutically acceptable salt.

16. N-(4-chloro-2-methoxy-6-were)-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzo-imidazol-2-amine or pharmaceutically acceptable the salt.

17. 2-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole or its pharmaceutically acceptable salt.

18. 4-Chloro-N-(2,4-dichloro-6-were)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-2-amine or its pharmaceutically acceptable salt.

19. A method of obtaining a compound according to claim 1, which includes the interaction of the compounds represented by the formula:
,
where L represents a removable group selected from a halogen atom, sulfonyloxy and alloctype, and other symbols defined in claim 1, with a compound represented by the formula:
,
where each character defined in claim 1.

20. Pharmaceutical composition having antagonistic activity against CRF receptor, which contains a compound according to claim 1 in an effective amount.

21. The CRF receptor antagonist which is a compound according to claim 1 or its pharmaceutically acceptable salt.

22. Method of inhibiting the binding releasing factor corticotropin (CRF), which includes the introduction of an effective amount of a CRF receptor antagonist on item 21.

23. The method according to item 22, where the inhibition is effective for diseases selected from affective disorder, depression or anxiety.

24. The use of CRF receptor antagonist in item 21 to obtain medicines for PR is the prevention or treatment of disease, where the CRF receptor.

25. The application of paragraph 24, where the disease is selected from affective disorder, depression or anxiety.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel ligands, including novel compounds of general formula 1, a wide range of biological activity which simultaneously includes alpha-adrenoceptors, dopamine receptors, histamine receptors, imidazoline receptors and serotonin receptors, including serotonin 5-HT7 receptors, in form of free bases, geometric isomers, racemic mixtures or separate optical isomers, as well as in form of pharmaceutically acceptable salts and/or hydrates. In formula 1

R1 denotes hydrogen; C1-C4alkyl optionally substituted with C1-C4alkoxycarbonyl, aromatic or saturated optionally annelated or optionally substituted with a five- or six-member heterocycle containing 1-2 N heteroatoms; C1-C3acyl; saturated optionally substituted six-member N-heterocycle; C1-C4alkoxycarbonyl; optionally substituted arylsulphonyl, R2 denotes a substitute of a cyclic system, including hydrogen; halogen; optionally substituted C1-C4alkyl;CF3, CN, C1-C4alkoxy; C1-C4alkoxycarbonyl; carboxyl; unsaturated six-member N-containing heterocyclyl or optionally substituted arylsulphonyl, Ar denotes phenyl, optionally substituted with C1-C4alkyl, dimethylamino group, one or more C1-C4alkoxy groups, one or more halides, CF3 group, nitro group, carboxyl, C1-C4alkoxycarbonyl, C1-C4acylamino group, CN, optionally annelated with a saturated heterocycle; optionally annelated and optionally substituted unsaturated five- or six-member heterocycle containing one or two heteroatoms selected from nitrogen, oxygen or sulphur; W denotes an optionally substituted (CH2)m group, optionally substituted CH=CH group, optionally substituted CH2-CH=CH group, C≡C group, SO2 group; n = 1 or 2; m=1, 2 or 3, the solid line accompanied by a dotted line (---) denotes a single or double bond.

EFFECT: compounds can be used to treat and/or prevent diseases or pathological conditions of the central nervous system, whose pathogenesis is associated with hyper- or hypo-activation of said receptors, for example anxiety or cognitive disorders, neurodegenerative and psychotic diseases.

42 cl, 26 dwg, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of 3,11b-cis-dihydrotetrabenazine or its pharmaceutically acceptable salts to prepare a medicinal agent for preventing or treating schizophrenia. The invention also relates to compounds for use in preventing or treating psychosis, methods of preventing or treating psychosis, as well as methods of preventing or alleviating a psychotic episode.

EFFECT: use of 3,11b-cis-dihydrotetrabenazine to prepare a medicinal agent for preventing or treating schizophrenia.

34 cl, 7 ex, 6 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound under the invention is represented by formula (I) or its pharmaceutically acceptable salt where R1 and R2 represent H or optionally substituted alkyl where substitutes are specified from -N(CH3)2, -OH, -OCH3; B represents N; Z represents N; each of W, X and Y independently represents C-H, C-J; Ar represents an optionally substituted phenyl ring where substitutes are specified from halogen, -NH-CH3; each J independently represents NR1R2; and n is equal to 0; provided the compound is not 4-[2-(5-chloro-2-fluorophenyl)pteridine-4-ylamino]nicotinamide. The compounds of formula (I) can find application in treating HCV related conditions.

EFFECT: preparation of the new compounds for making a drug for treating HCV infection.

15 cl, 2 tbl, 9 ex

Chemical compounds // 2405780

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I): , in which: R1 and R2 are independently specified from hydrogen, C1-6alkyl, C1-6alkoxy and cyclopropyl; X1, X2 and X3 independently represent =N- or =CR10; R3 and R10 are independently specified from hydrogen, halogen, nitro, cyano, amino, carboxy, carbamoyl, C1-6alkyl, N-(C1-6alkyl)amino, N,N(C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkoxycarbonyl; R4 represents hydrogen; R5 and R6 are independently specified from hydrogen, hydroxy and C1-6alkyl where R5 and R6 independently can be optionally substituted in carbon atom with one or more R16 where R16 represents hydroxy; A represents a single link or C1-2alkylene; where specified C1-2alkylene can be optionally substituted with one or more R18; the ring C represents a saturated, partially saturated or unsaturated mono- or bicyclic ring containing 5 or 6 atoms in which at least one atom can be specified from nitrogen, sulphur or oxygen which can be linked with carbon or nitrogen atom where the -CH2- group can be optionally substituted with -C(O)- and ring sulphur atom can be optionally oxidised to produce S-oxide; R7 is specified from halogen and C1-6alkyl where R7 can be optionally substituted in carbon atom with halogen; n is equal to 0.1 or 2; where R7 values can be equal or different; and R18 is independently specified from halogen and hydroxy; or its pharmaceutically acceptable salt. Also the invention refers to their pharmaceutical compositions and methods for preparation and application thereof for cancer treatment.

EFFECT: preparation of new compounds which can find application for cancer treatment.

23 cl, 96 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: medicine.

SUBSTANCE: invention refers to new derivatives of dihydro-pyrroloquinoline of formula I where values of R1, R2, R3a and R3c radicals are specified in cl. 1 of the patent claim. Also the invention refers to a method for making the compound of formula I, to its application, a composite product based on the compound of formula I and a general antimicrobial agent and a pharmaceutical composition based on the compound of formula I.

EFFECT: there are prepared new derivatives of dihydro-pyrroloquinoline exhibiting antibacterial activity.

26 cl, 4 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 8-sulphonyl-2,3,4,5-tetrahydro-1H-γ-carbolines of general formula 1 or pharmaceutically acceptable salts thereof, which are ligands with a wider range of simultaneous activity towards alpha adrenoceptors, dopamine receptors, histamine receptors, imidazoline receptors, sigma receptors, norepiniphrine receptors and serotonin receptors. In compounds of general formula 1 R1 is an amino group substitute selected from hydrogen; C1-C3alkyl optionally substituted with phenyl; C1-C4alkyloxycarbonyl; R2 is a cyclic system substitute selected from hydrogen, C1-C3alkyl optionally substituted with phenyl, pyridin-(3- or 4-yl), (6-methylpyridin-3-yl); C1-C3alkenyl substituted with phenyl; or optionally substituted phenylsulphonyl; R3 is an optionally halogen-substituted phenyl, six member aromatic azaheterocycle, mono- or di-C1-C3alkylamino group, phenylamino group which is optionally substituted with halogen atoms on the phenyl ring, or a substituted six member azaheterocycle containing an additional nitrogen atom, substituted with C1-C3alkyl.

EFFECT: compounds can be used in treating and preventing diseases and pathological conditions of the central nervous system, such as anxiety disorders, cognitive disorders, neurodegenerative diseases and depression.

18 cl, 2 dwg, 6 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula IB , where radicals R1-R5 have values, given in invention formula. In range of claimed invention also described are pharmaceutical compositions, which include compounds of IB formula, and methods of application of such compounds and compositions for treatment of different malfunctions, mainly selected from immune response reactions.

EFFECT: compounds by claimed invention have inhibiting action with respect to proteinkinases and, in particular with respect to JAK-3, ROCK or Aurora kinases.

55 cl, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-cyclopropyl-1 -{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate of formula:

. The invention also relates to salts and solvates of the said compound, a method of producing said compound, a pharmaceutical agent having angiotensin II antagonist activity, based on said compound.

EFFECT: compound can be used in medicine to prevent and treat blood circulatory system diseases.

18 cl, 1 dwg, 8 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-6-member nitrogen-containing heterocyclic compounds, selected form derivatives of pyridine, pyrimidine, imidasoline, oxadiasoline, such as, for instance , which possess inhibiting activity with respect to aspartylprotease, such as "ВАСЕ-1".

EFFECT: obtaining pharmaceutical composition, method of aspartylprotease inhibition aimed at application of compounds for preparation of medication intended for treatment of state, mediated by aspartylprotease, such as "ВАСЕ-1".

4 cl, 1 tbl, 1832 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or its pharmaceutically acceptable salt or its solvate, where ring A is a monocyclic heterocyclic group optionally substituted with 1-2 substitutes selected from the following group A, where the monocyclic heterocyclic group is selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-yl group, piperidine group, 2-oxopiperidin-1-yl group, 1-piperazinyl group, morpholine group, 3-oxomorpholin-4-yl group, thiomorpholine group, 1,1-dioxoisothiazolin-2-yl group, 2-pyridyl group, 2-thiazolyl group and 1,2,4-oxadiazol-3-yl group; group A consists of a halogen atom, C1-4alkyl group, -(CH2)n-ORa1 and -CORa2, where Ra1 and Ra2 are identical or different and each of them is a hydrogen atom or a C1-4alkyl group and n equals 0; R1 is a C1-6alkyl group optionally substituted with 1 substitute selected from the following group B; group B consists of -ORb1, where Rb1 is a C1-4alkyl group; R2 is a hydrogen atom, C1-4alkyl group or -OR11, where R11 is an atom, C1-4alkyl group; R3 and R4 are identical or different and each is a halogen atom; R5 is a halogen atom; m equals 0 or 1; and R6 is a hydrogen atom. The invention also relates to a pharmaceutical composition, anti-HIV agent, HIV integrase inhibitor, anti-HIV compositions which contain an active ingredient in form of a formula I compound; to use of formula I compounds to prepare an anti-HIV agent and HIV integrase inhibitor; to a method of preventing or treating infectious diseases caused by HIV and to a method of inhibiting HIV integrase in mammals, involving administration of formula I compounds.

EFFECT: useful biological properties.

27 cl, 9 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (I): where R1 and R2 each independently represents a hydrogen atom, C1-8 alkyl or a halogen atom; R3 represents C1-8 alkyl, which can be substituted with 1-3 halogen atom(s) or phenyl; R4 represents a hydrogen atom or C1-8 alkyl; R5 and R6 each independently represents a hydrogen atom; X represents a sulphur atom or oxygen atom; ring A is 4-(trifluoromethyl)piperidin-1-yl, 2,2-difluoro-1,3- benzodioxol-5-yl or 3,4-dihydro-1H-isoquinolin-2-yl. The invention also relates to salts or solvates of this derivative, as well as medicinal preparation, pharmaceutical composition, method of preventing and/or treating diseases, caused by PPAR, and use of this derivative.

EFFECT: obtaining new biologically active compounds, which can be used for preventing and/or treating diseases caused by PPARδ.

8 cl, 39 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of hydroperoxides of alkylaromatic hydrocarbons which can serve as a source of oxygen-containing organic compounds (phenol, methylphenols, acetone, cyclohexanone etc) and as an initiator of emulsion polymerisation of unsaturated hydrocarbons. The invention discloses a method for synthesis of hydroperoxides of alkylaromatic hydrocarbons through liquid-phase oxidation of these hydrocarbons with atmospheric oxygen at atmospheric pressure, process temperature of 110-130°C, for 1-3 hours in the presence of a 4-methyl-N-hydroxyphthalimide catalyst in amount of 1.0-2.0 wt %.

EFFECT: catalyst prevents use of an initiator and alkaline additives, which considerably simplifies the process, higher conversion of initial alkylaromatic hydrocarbons while preserving high selectivity of the process.

2 tbl, 2 ex

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