Peri-substituted arylsulphonamide bicyclic compounds for treating artery occlusive diseases

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

 

The scope to which the invention relates

The invention relates to chemical compounds of the type peri-substituted bicyclic arylsulfonamides, which can be used for the treatment and prevention of occlusive disease of the arteries and related mediated by prostaglandin disorders.

Prior art

Atherosclerosis is a pathology that can lead to the development of some of the most dangerous deadly human diseases, such as myocardial infarction and occlusive disease of the peripheral arteries (OSPA). SPA is a atherosclerosis of large and medium arteries of the extremities, particularly the lower extremities, including the aorta and iliac arteries. This disease is often accompanied by ischemic heart disease and cerebrovascular disease. Individuals suffering from OSPA, increased risk of other cardiovascular diseases such as myocardial infarction or stroke [Waters, RE, Terjung RL, Peters KG & Annex BH. J. Appl. Physiol. 2004; Ouriel K. Lancet, 2001, 258:1257-64; Kroger, K. Angiology, 2004, 55:135-138]. Such serious from a clinical point of view, the lesions can lead to a gradual narrowing of the peripheral arteries causing pain when walking (claudication), which usually subsides at rest, ischemic ulcers, gangrene, and sometimes such paragraph the expression can lead to limb amputation. Drug therapy is usually ineffective and surgery bypass surgery or replacement of the affected artificial arteries or venous grafts lead to the improvement of peripheral blood circulation, at least, only as long as these artificial blood vessels will not again be subjected to the stenosis [Haustein, K.O., Int. J. Clin. Pharmacol. Ther., 35:266 (1997)]. Recently, the study of adhesion genes in humans it was found that the variants of DNA PTGER3 gene, which encodes the receptor for prostaglandin E2subtype 3 (known as ER), cause an increase risk of developing individual OSPA (see published application U.S. 2003/0157599). Thus, antagonists of prostaglandin E2(PGE2), to bind to the receptor ER, can provide effective treatment or prevention OSPA.

Prostaglandins, in response to various external stimuli, are generated quickly from free arachidonic acid under continuous action of cyclooxygenase and synthases. Prostaglandins act in the immediate vicinity of the site of their synthesis. Now cloned and characterized eight prostanoid receptors. These receptors are members of a growing class associated with G-protein receptors. The PG2binds preferentially to receptors EPl, EP2, EP3 and EP4; PGD2associated with what ecapture DP and FP; PGFbinds to receptors FP and EP3; PGI2binds to the receptor IP, and TXA2associated with the TP receptor. It was found that the PG2binding to the receptor ER, plays a key role in the regulation of ion transport, reduction of smooth muscles of the gastrointestinal tract, gastric secretion, uterine contractions during fertilization and implantation, increased temperature and in the development of hyperalgesia. Receptor ER was detected in many organs such as the kidneys, gastrointestinal tract, uterus and brain. In the cardiovascular system ER is expressed in vascular endothelium and smooth muscle, and at least four isoforms ER expressed on human platelets [Paul, B.Z., B. Ashby, and S.B. Sheth, Distribution of prostaglandin IP and EP receptor subtypes and isoforms in platelets and human umbilical artery smooth muscle cells. British Journal of Haematology, 1998. 102(5): p. 1204-11].

Prostanoids, acting through membranostaticheskim receptors belonging to the superfamily associated with G protein-coupled receptors (GPCR), play an important role in vascular homeostasis, including the regulation of platelet function. Among prostanoids, a strong stimulator of platelet aggregation is thromboxane A2 (TxA2), and prostaglandin (PGI2) inhibits their activation. On the other hand, it was reported that prostaglandin E2 (PG2has bilateral deystvitelna response of platelets, that is, at low concentrations it promotes their aggregation at higher concentrations inhibits their aggregation. It was shown that the stimulatory effect of PG2on platelet aggregation occurs primarily through receptor ER, i.e. one of the four subtypes of receptors, activated by PG2.

Local synthesis of prostaglandins in the walls of blood vessels may play a significant role in the development of atherosclerosis. In the walls of healthy blood vessels is present only COX-1, and in arteriosclerotic plaques are COX-1 and COX-2 [Schonbeck, U., et al., Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol, 1999. 155(4): p. 1281-91; Cipollone, F., et al., Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of PGE2-dependent plaque instability. Circulation, 2001. 104(8): p. 921-7]. Their increased expression along with increased expression of prostaglandin-E-synthase, can lead to an increase in the production of the above PG2. Genetically modified mice lacking the receptor for low density lipoprotein (LDL-R), the formation of atherosclerotic plaques can be reduced by treatment with rofecoksib, selective COX-2 inhibitor, acting by decreasing production of PG2and other prostaglandins [Burleigh ME, Babaev VR, Oates JA, Harris RC, Gautam S, Riendeau D, Marnett LJ, Morrow JD, Fazio S, Linton MF. yclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation. 2002 Apr 16; 105(15):1816-23].

It has been shown that atherosclerotic plaques, cells vascular smooth muscle Express receptors ER and PG2stimulates their proliferation and migration, which is an indication of the formation of atherosclerotic plaques [Blindt R, Bosserhoff AK, vom Dahl J, Hanrath P, Schror K, Hohlfeld T, Meyer-Kirchrath J. Activation of JP and EP(3) receptors alters cAMP-dependent cell migration.Eur J Pharmacol. 2002 May 24;444(l-2):31-7]. Therefore, it is likely that in chronically inflamed blood vessels responsible for the generation of PG2sufficient for activation of EP3 receptors on cells of the vascular smooth muscle (which promotes the formation of atherosclerotic lesions) and platelets (which contributes to the development of thrombosis). Locally produced, PG2(from the platelet component of cell walls and inflammatory cells) potentiate platelet aggregation, under the action of suboptimal amounts of prothrombin tissue factors, which themselves do not cause platelet aggregation, and act only by stimulation of protein kinase C. Intracellular processes triggered by activation of the receptor EP3may increase platelet aggregation by preventing the action PGI2and enhance the effects of the main factors that enhance aggregation, such as collagen. Therefore, activation of the receptor ER can stimulate the development is therosclerosis and increase the risk of tromsa, observed in such pathological conditions as vasculitis and SPA.

Modern methods of treatment OSPA aimed either at reducing the risk of cardiovascular diseases such as myocardial infarction and stroke, or symptomatic loosening of lameness. All of these methods of treatment aimed at inhibiting the platelet function. Treatment, leading to reduced risk of cardiovascular diseases, involves the introduction of small doses of aspirin (sufficient to reduce platelet aggregation, but not enough to stop the production of PGI2in the walls of blood vessels) and inhibitors of platelet adenosintriphosphate receptor (clopidogrel). The binding of ADP to platelet adenosintriphosphate receptor leads to a decrease in the level of platelet cAMP and subsequent activation and aggregation of platelets. Treatment conducive symptomatic weakening of lameness, includes the introduction of inhibitors of platelet phosphodiesterase type 3, such as Cilostazol, which increases intracellular levels of cAMP. Inhibitors of platelet adenosintriphosphate receptor or platelet phosphodiesterase type 3 have a direct or indirect effect, increase the content of cAMP in platelets, inhibiting, thereby, activation of platelets and subsequent the Yu their aggregation, leading to the formation of blood clots. Linking the PG2with EP3 leads to a decrease of cAMP levels, and therefore, an antagonist of PG2that communicates with the EP3 receptor, by preventing the PG2-dependent decrease of cAMP level required to induce platelet activation and subsequent aggregation, or by preventing the PG2dependent reduction in the level of cAMP in the cells of the vascular smooth muscle needed to stimulate migration of platelets, and therefore, this binding could have a beneficial therapeutic effect in the treatment of SPA. Such an antagonist may also reduce the symptoms of the disease by inhibiting or reducing the formation of atherosclerotic plaques.

In addition, prostaglandins are involved in the pathogenesis of a number of pathological conditions, including pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, runny nose, pain in the neck, back pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprain and strain of joints, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, including burns caused about the teaching and corrosive chemical compounds sunburn, pain after surgery and dental procedures, immune and autoimmune diseases; neoplastic degeneration of cells or metastatic tumor growth; diabetic retinopathy, tumor angiogenesis; induced prostanoids smooth muscle contraction associated with dysmenorrhea, premature birth, asthma or eosinophilic disorders; Alzheimer's disease; glaucoma; razreshenie bones; osteoporosis; disease Tuck; peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal tract bleeding in the gastrointestinal tract; blood clotting disorders selected from gipoprotrombinemii, hemophilia and other disorders associated with increased bleeding; and kidney disease.

Although the levels of prostanoids in blood flow in healthy individuals are extremely low [FitzGerald GA, Brash AR, Falardeau P & Oates JA. JCI 1981 68:12472-1275], however, the local concentration of PG2can dramatically increase in inflammatory diseases. So, for example, was shown to bein vitrothat when occlusive disease of the aorta, ileum local production of PG2there are now more than 30 times ['reilly J, Miralles M, Wester W & Sicard G. Surgery, 1999, 126:624-628]. Therefore, it is likely that in vessels with chronic inflammation of the PG2produc is regulated in quantity, sufficient to activate the receptor EP3on the platelets. In this case, intracellular processes, triggered by activation of the receptor EP3, can lead to increased platelet aggregation by inhibiting the action PGI2and enhance the effects of the main factors that enhance aggregation, such as ADP. Therefore, activation of the receptor EP3can stimulate the development of thrombosis observed in such pathological conditions as vasculitis and atherosclerosis. Occlusive disease of the peripheral arteries (OSPA) is an atherosclerotic disease, which develops mainly in the elderly due to occlusion of the lumen of the peripheral arteries, mainly the femoral arteries, and this disease is associated with an increased risk of developing cardiovascular disorders such as myocardial infarction or stroke [Waters, RE, Terjung RL, Peters KG & Annex BH. J. Appl. Physiol. 2004; Ouriel K. Lancet, 2001, 258:1257-64; Kroger, K. Angiology, 2004, 55:135-138]. Various clinical studies have shown that treatment with the use of prostaglandins helps to reduce the symptoms OSPA [Reiter M, Bucek R, Stumpflen A & Minar E. Cochrane Database Syst. Rev. 2004, 1:CD000986; Bandiera G, Forletta M, Di Paola FM, Cirielli C Int. Angiol. 2003, 22:58-63; Matsui K, Ikeda U, Murakami Y, Yoshioka T, Shimada K. Am. Heart J. 2003, 145:330-333], which confirms the relationship OSPA function prostanoid receptor.

Ortho-substituted phenyl is ralfinamide and their effectiveness in the treatment mediated by prostaglandin disorders described in U.S. patent No. 6242493 and in two articles Juteau et al. [BioOrg. Med. Chem. 9, 1977-1984 (2001)] and Gallant et al. [BioOrg. Med. Chem. Let. 12, 2583-2586 (2002)], which are introduced in the present description by reference.

The invention

In one of its aspects, the present invention relates to compounds of the formula I:

where a and b represent a pair of condensed 5-, 6 - or 7-membered rings. Condensed system of rings A/B can contain from 0 to 4 heteroatoms selected from nitrogen, oxygen and sulfur and may be optionally substituted by 0-4 substituents independently selected from halogen, -HE, lower alkyl, -O-(lower alkyl), lower foralkyl, -O-(lower foralkyl), methylendioxy, Ethylenedioxy, alkoxy(lower alkyl), hydroxy(lower alkyl), oxo, oxide, -CN, nitro, -S-(lower alkyl), amino, lower alkylamino, lower dialkylamino the bottom dialkylaminoalkyl, carboxy, carbalkoxy, acyl, carboxamido, lower alkylsulfonate, acylamino, phenyl, benzyl,Spiro-thiazolidine, phenoxy and benzyloxy. Nodal positions marked a and b represent the position of joining residues Y and D, respectively, and the positions a and b are in the peri-position relative to each other on the condensed ring system And/Century Nodal position marked d and e, represent the condensed position between ring a and ring BB condensed ring system A/C. Each of the key provisions of a, b, d, and e may denote carbon or nitrogen.

D represents aryl or heteroaryl cyclic system, which may be optionally substituted by 0-4 substituents. Such substituents independently selected from halogen, -HE, lower alkyl, -O-(lower alkyl), lower foralkyl, -O-(lower foralkyl), methylendioxy, Ethylenedioxy, alkoxy(lower alkyl), hydroxy(lower alkyl), -CN, nitro, -S-(lower alkyl), amino, lower alkylamino, lower dialkylamino, lower dialkylaminoalkyl, carboxy, carbalkoxy, acyl, carboxamido, lower alkylsulfonate, acylamino, phenyl, benzyl, phenoxy and benzyloxy.

Y is a linker containing from 0 to 8 atoms in the chain.

M is selected from aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,6-C20of alkyl and substituted C6-C20the alkyl.

R1selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl and CF3; and if Y is a saturated linker, R1additionally may be a lower alkyl.

In its second aspect, the present invention relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and the above-described compound or its ester, pharmaceutically acceptable salt or hydrate.

In its third aspect, the present invention relates to a method of treatment or prevention of a disease or condition mediated by prostaglandins. These methods include the administration to the mammal therapeutically effective amounts of compounds described herein. Such diseases or conditions may be, for example, fever or inflammation associated with rheumatic fever, influenza or other viral infections, migraine, common cold, dysmenorrhea, sprain and strain of joints, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, including burns caused by radiation and corrosive chemical compounds, sunburn, immune and autoimmune diseases; and pain (such as pain in the neck, pain in the spine, postpartum pain, headache, toothache, pain after surgery and dental procedures). Connection-antagonists ER according to the invention, which penetrate into the Central nervous system are particularly suitable for the treatment of pain.

Compounds according to the invention, which inhibit platelet aggregation and increase regional blood flow, can be used for the treatment of primary t is abimbola, thrombosis and occlusive vascular diseases. These compounds can be preferably used in combination with other platelet aggregation inhibitors and inhibitors of the biosynthesis or uptake of cholesterol. These compounds can also be advantageously used in combination with an inhibitor of cyclooxygenase-2 for the treatment of inflammatory conditions.

Other diseases or conditions that can be treated are, for example, neoplastic degeneration of cells or metastatic tumor growth; diabetic retinopathy, tumor angiogenesis; induced prostanoids smooth muscle contraction associated with dysmenorrhea, premature birth, asthma or eosinophilic disorders; Alzheimer's disease; glaucoma; razreshenie bones, osteoporosis or disease Tuck; peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal tract bleeding in the gastrointestinal tract; blood clotting disorders selected from gipoprotrombinemii, hemophilia and other circulatory disorders; and renal disease. This aspect of the invention also includes methods of stimulation of osteogenesis, cytoprotective and reducing the amount of plaques in the treatment of atherosclerosis.

In its included four is the aspect the present invention relates to methods of screening for selective prostanoid receptors, and in particular, the ligands HER.

Detailed description of the invention

Compounds of a certain type represented by the above formula 1, are antagonists of the receptor ER. Such compounds can be used for the treatment and prevention mediated by prostaglandin conditions described above, and in particular, conditions such as occlusive vascular disease.

Compositions according to the invention include an effective dose or pharmaceutically effective amount or therapeutically effective amount of the compounds described above, and may also include other therapeutic agents, such as platelet aggregation inhibitors (tirofiban, dipyridamole, clopidogrel, ticlopidine and the like), inhibitors of HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, rosuvastatin, mevastatin, atorvastatin, tseriwastatina, pitavastatin, fluvastatin, etc.) and cyclo-oxygenase inhibitors. Other non-limiting examples of lipid that can be used in combination with the compounds according to the invention can be found in columns 5-6 of U.S. patent 6498156, the description of which is introduced in the present invention by reference. Preferred inhibitors ziklooksig the basics-2 inhibitors, selective towards cyclooxygenase-2, but not cyclooxygenase-1. Preferred inhibitors of cyclooxygenase-2 are rofecoksib, meloxicam, celecoxib, etoricoxib, lumiracoxib, valdecoxib, parecoxib, cimicoxib, diclofenac, sulindac, etodolac, Ketorolac, Ketoprofen and LAS-34475, although the present invention is not limited to these or other known inhibitors of cyclooxygenase-2.

The methods according to the invention include the use of the compositions and preparations. These methods include administration to a patient in need of treatment a therapeutically effective amount of peri-substituted condensed-cyclic compound A/B according to the invention. The present invention also relates to methods of screening for selective agonists or antagonists prostanoid receptors. Prostanoid receptors are receptors EP1, EP2, EP3, EP4, IP and FP. The most interesting are selective ligands for the EP3, the method which comprises contacting the labeled compounds according to the invention with the cloned human receptor EP3 and measuring the displacement of the label test connection.

The compounds according to the invention are the compounds of formula I:

where a and b represent a pair of condensed 5-, 6 - or 7-membered rings, and D an aryl or heteroaryl cyclic system. In the connection of one of the subspecies, D represents phenyl which may be substituted or unsubstituted. In the connection of the other subspecies, D represents a naphthyl which can be substituted or unsubstituted. In the connection of the third subspecies, D represents a monocyclic heteroaryl, which may be substituted or unsubstituted. In connection four subspecies, D represents a bicyclic heteroaryl, which may be substituted or unsubstituted. In one embodiment of the invention, R1selected from phenyl, substituted phenyl, 5-membered cyclic heteroaryl, substituted 5-membered cyclic heteroaryl and CF3.

Each of a and b independently represents a 5-, 6 - or 7-membered ring. Condensed system of rings A/B contains from 0 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and these rings are optionally substituted by 0-4 substituents. Suitable substituents are halogen, -HE, lower alkyl, -O-(lower alkyl), lower foralkyl, -O-(lower foralkyl), methylendioxy, Ethylenedioxy, alkoxy(lower alkyl), hydroxy(lower alkyl), oxo, oxide, -CN, nitro, -S-(lower alkyl), amino, lower alkylamino, lower dialkylamino, lower dialkylaminoalkyl, carboxy, carbalkoxy, orthoepy, acyl, carboxamido, lower alkylsulfonyl, acylamino, phenyl, benzyl,Spiro-tiaso idini, phenoxy and benzyloxy. Because of the condensed system of rings a/b may include nitrogen or sulfur, the substituents can be the oxides, for example, N→O and S→O.

In the compounds of one of the subspecies, the cyclic system A/B is a pair of condensed 5-membered rings:

Examples of such 5/5-cyclic systems are:

and

In the compounds of the other subspecies, the cyclic A/is a pair of 6-membered rings:

Examples of such 6/6-cyclic systems are:

In the compounds of the other subspecies, the cyclic system A/B is a pair of condensed 5 - and 6-membered rings:

or

Examples of such 5/6-cyclic systems are indoles, indoline, Indology, satiny, benzimidazole, benzoxazolinone, benzofuranyl and indazols:

As shown previously, the cyclic systems may be substituted, for example:

Y is a linker containing from 0 to 8 atoms in the chain. Prepact the tion, Y a1-C8alkyl in which one or two CH2- may be replaced by groups-O-, -C(=O)-, -CH=CH-, -CF2-, -S-, -SO-, -SO2-, -NH - or-N(alkyl)-. More preferably, Y represents a diatomic chain, i.e. With1- or2alkyl in which one or both of CH2can be substituted by the groups mentioned above. In one embodiment of the invention, Y is selected from-CH2-, -O-, -OCH2-, -S-, -SO - and-SO2-. Left a link indicates the position of attachment of ring a or C.

M is selected from aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,6-C20of alkyl and substituted C6-C20the alkyl. In one of the preferred variants of the invention, M is selected from aryl, substituted aryl, heterocyclyl and substituted heteroaryl, and more preferably from phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and substituted heteroaryl.

These compounds can be obtained in the form of salts. The term “pharmaceutically acceptable salt” means a salt counterions which come from pharmaceutically acceptable non-toxic acids and bases. Suitable pharmaceutically acceptable basic additive salts of the compounds according to the invention are, but are not limited to, metal salts derived from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts derived from lysine-derived N,N-dialkylaminoalkyl (for example, N,N-dimethylglycine, piperidine-1-acetic acid and morpholine-1-acetic acid), N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine. If these compounds contain a basic residue, suitable pharmaceutically acceptable basic additive salts of the compounds according to the invention are salts of inorganic acids and organic acid salts. Examples include acetate, bansilalpet (besylate), benzoate, bicarbonate, bisulfate, carbonate, camphorsulfonate, citrate, aconsultant, fumarate, gluconate, glutamate, bromide, chloride, isetionate, lactate, maleate, malate, mandelate, methanesulfonate, mukat, nitrate, pamoate, Pantothenate, phosphate, succinate, sulfate, tartrate, n-toluensulfonate etc.

Definitions

In the description of the present application provides definitions for terms used here and deputies.

“Alkyl” means a straight, branched, and, if not otherwise specified, the cyclic hydrocarbon structures and combinations thereof. “Lower alkyl” means alkyl groups having from 1 to 6 carbon atoms. Examples of the lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec - and tert-butyl and the like, Preferably the e alkyl and alkylene groups have 20 carbon atoms or less. Cycloalkyl is a subgroup of Akilov and includes cyclic hydrocarbon groups having 3 to 8 carbon atoms. Examples cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, substituted etc.

With1-C20the hydrocarbons are alkyl, cycloalkyl, alkenyl, quinil, aryl, and combinations thereof. Examples are benzyl, phenethyl, cyclohexylmethyl, Campari and naphtalate.

“Alkoxy” or “alkoxyl” means the group having 1-8 carbon atoms in the straight, branched and cyclic structures and their combinations, attached to the original structure through an oxygen atom. Examples are methoxy, ethoxy, propoxy, isopropoxy, cyclopropylamine, cyclohexyloxy etc. “Lower alkoxy” means a group containing from one to four carbon atoms.

“Oxaalkyl” means alkyl residues in which one or more carbon atoms (and their associated hydrogen atoms) are replaced by the oxygen atom. Examples are methoxypropane, 3,6,9-trioxadecyl, etc. the Term “oxaalkyl” friendly professionals [see underNaming and Indexing of Chemical Substances for Chemical Abstractspublished by the American chemical society, see §196, where 127(a) given without restrictions] and mean compounds in which the oxygen atom is linked with the adjacent atoms by simply the th connection with the formation of ether bonds). Similarly, thioalkyl and isoalkyl mean alkyl residues in which one or more carbon atoms is replaced by a sulfur atom or nitrogen, respectively. Examples are acylaminoacyl and metaltipped. The term “oxo”, referring to the Deputy means the oxygen associated double bonds (carbonyl). So, for example, 2-oxoindole according to the invention has the following formula:

“Acyl” means a group having 1 to 8 carbon atoms in a straight chain, branched chain and cyclic structure, saturated, unsaturated and aromatic structure and in their combinations, and attached to the original structure through the carbonyl functional group. One or more of the carbon atoms in the acyl residue may be replaced by nitrogen, oxygen or sulfur, provided that the position of joining to the original structure is located at the carbonyl. Examples are formyl, acetyl, propionyl, isobutyryl, tert-butoxycarbonyl, benzoyl, benzyloxycarbonyl and other Lower acyl means a group containing from one to four carbon atoms.

“Aryl” and “heteroaryl” means 5 - or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N or S; a bicyclic 9 - or 10-membered aromatic or heteroaromatic qi the symbolic system, containing 0-3 heteroatoms selected from O, N or S; or a tricyclic 13 - or 14-membered aromatic or heteroaromatic cyclic system containing 0-3 heteroatoms selected from O, N, or S. the Aromatic 6 to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indan, tetralin and fluoran, and 5-10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyrane, thiazole, furan, benzimidazole, quinoline, isoquinoline, cinoxacin, pyrimidine, pyrazin, tetrazole and pyrazole.

“Arylalkyl” means an alkyl residue associated with the aryl ring. Examples are benzyl, phenethyl, etc.

“Substituted alkyl, aryl, cycloalkyl, heterocyclyl”, etc. mean alkyl, aryl, cycloalkyl or heterocyclyl, where 1-3 atoms N in each residue are replaced with halogen, lower alkyl, halogenation, hydroxy, lower alkoxy, carboxy, carbalkoxy (also called alkoxycarbonyl), carboxamido (also called alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfonal, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy or heteroaromatic. In the following description of the present application, methylendioxy, Ethylenedioxy mentioned as substituents. Methylendioxy with azan with the adjacent carbon atoms on the ring, and Ethylenedioxy can be associated either with the adjacent carbon atoms on the ring, or with the same carbon atom, forming, thereby, sporadical (ketal), similar to spiritualizing. Different variants of such compounds are compounds 114, 144 and 160.

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “prodrug” means a compound thatin vivoforms a more active connection. Activationin vivomay occur under the action of a chemical reaction or by the enzyme. Activationin vivomay also participate microflora of the gastrointestinal tract.

When defining symbols indicated that A and B are a pair of condensed 5-, 6 - or 7-membered rings, and that the condensed system of rings A/B can contain from zero to four heteroatoms selected from nitrogen atoms, oxygen and sulfur. This implies that these rings may have different degree of saturation, i.e. they can be fully saturated or aromatic. Moreover, preferred are aromatic and partially unsaturated ring.

When defining different substituents provided that the said condensed ring may be optionally substituted by 0-4 substituents independently selected from the list of defined substituents. C is a mix of this type is reflected in the structure illustrated below. In this example, the condensed ring is substituted by three substituents: -CH3-HE and oxo:

It should be noted that the compounds according to the invention can be present in the radioactively labelled form, i.e. these compounds can contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the usual elements found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine and chlorine are2H,3H,13C,14C,15N35S18F and36Cl, respectively. Compounds containing these radioisotopes and/or other isotopes of other atoms are included in the scope of the present invention. To facilitate the receipt and detection of compounds particularly preferred are such radioisotopes as tritium, i.e3H, and carbon-14, that is,14C. Radioactively labeled compounds of formula Ia according to the invention and their prodrugs are usually obtained by methods well known in the art. Usually, such radioactively labeled compounds produced by the methods described in the section “Examples” and “Schemes”, by replacement of radioisotope-labeled reagent is easily accessible radioactively labeled reagent.

Used here and understandable to specialists, the term “joint which includes salt, the solvate and complexes of the compounds containing the crystals and on.

The term “MES" means a compound of formula I in the solid state, where the molecules of a suitable solvent are incorporated in the crystal lattice. The solvent suitable for therapeutic administration, a well-tolerated in the input doses. Examples of suitable solvents for therapeutic injection are ethanol and water. If water is the solvent, then the MES is called a hydrate. In General, the solvate is obtained by dissolving the compound in an appropriate solvent and the allocation of the received MES by cooling or by using antibacterial. Received MES usually dried or subjected to azeotropic distillation in the environment. Co-crystals are a combination of two or more different molecules, arranged so that they form a unique crystal form, and physical properties differ from the properties of its pure components. Recently, pharmaceutical co-crystals are of more interest from the viewpoint of increasing the solubility, ease of preparation and improvement of bioavailability of drugs such as Itraconazole [see Remenar et al. SoC. 125, 8456-8457 (2003)] and fluoxetine. Complexes fluctuation manual Remington: The Science and Practice of Pharmacy 19 thEd. (1995) volume 1, page 176-177. The most commonly used inclusion complexes are complexes with cyclodextrins, and all of these natural and synthetic cyclodextrine complexes, whether or not containing additives and polymers and are described in U.S. patent No. 5324718 and 5472954, are included in the scope of claims of the present invention. Manual Remington and patents '718 and '954 introduced into the present description by reference.

The term “treatment or prevention” mean intensity reduction, prevention or mitigation of symptoms and/or effects, diseases associated with lipid metabolism. Used herein, the term “prevention” means the preliminary administration of a medicinal product for preventing or reducing acute attack of the disease. The average specialist-physician (who designed the method, as claimed in the present invention, it is known that the term “warning” is not an absolute term. In medicine, this term means the prophylactic administration of a medicinal product in order to significantly reduce the likelihood or severity of this condition, and in this application the term is used in this sense. Used herein, the term “treating” a patient also includes prevention. E is th link, in the description of this application, there are references to various publications. Descriptions of these publications in their entirety are introduced in the present invention by reference, if there are indications.

The term “mammal” is used here in its ordinary sense, which is defined in dictionaries. Person included into the group of mammals and is the preferred mammal for the treatment of which can be applied to the described methods.

These compounds may contain asymmetric centers and thus can form an enantiomeric, diastereomeric and other stereoisomeric forms. From the point of view of the absolute stereochemical configuration of each chiral center may be defined as (R)- or (S)-. The present invention includes all such possible isomers, as well as their racemic and optically pure forms. Optical active (R)- and (S)- or (D)and (L)-isomers may be obtained using chiral synthons or chiral reagents, or these reagents can be separated by standard methods. If the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified particularly, it is envisaged that these connections include geometric E - and Z-isomers. Similarly, in the present invention takewhat all tautomeric forms.

The graphical representation used here racemic, ambisyllabic and solemny or enantiomerically pure compounds were taken from the work Maehr J. Chem. Ed. 62, 114-120 (1985): shaded and not shaded wedge-shaped lines are used to denote the absolute configuration of a chiral element; a wavy line and a single thin line indicates that the bond that can be formed, does not have any particular stereochemistry; solid and dashed thick lines are geometric descriptors indicating the relative configuration illustrating and indicating racemic; and wedge-shaped, dotted or broken lines denote enantiomerically pure compounds are not specifically defined absolute configuration.

Presented here is the configuration of any carbon-carbon double bond selected only for illustration, if it is not specifically mentioned, do not imply any particular configuration. For example, the above carbon-carbon double bond, arbitrarily chosen asEmay beZ,Eor a mixture of these two isomers in any proportion.

Throughout the description of this application uses the terms relating to “protection of functional groups to “unprotect” with functional groups and to “protected” function is a diversified groups. These terms are well known to the average person skilled in the art and are used for description of methods, which include sequential processing of multiple reagents. In this context, the protective group means a group that is used to mask a functional group during the stages of this process, in which the group is exposed to one or another reaction, but this reaction is undesirable. Protective group prevents reaction at this stage, but it can then be removed to the original functional group was again available for the reaction. The removal of the protective group or “removing protection” carried out after completion of the reaction or reactions in which part of this functional group is undesirable. For example, if the methods according to the invention the known exact sequence of reactions involving reagents, the average specialist in this field can easily identify groups that may be suitable as a “protective groups”. Groups suitable for use in these purposes are discussed in known chemical handbooks such as the Handbook Protective Groups in Organic Synthesis by T.W.Greene [John Wiley & Sons, New York, 1991], which is incorporated into the present description by reference. Special attention should be given to the chapters: "Proection for the Hydroxyl Group, Including 1,2 - and 1,3-Diols" (page 10-86).

The abbreviations Me, Et, Ph, Tf, Ts and Ms denote methyl, ethyl, phenyl, trifloromethyl, toluensulfonyl and methanesulfonyl, respectively. A comprehensive list of abbreviations and acronyms used by chemists organically (i.e. average specialists in this field), is given in the first edition of each volume of the Journal of Organic Chemistry. The list, which is usually given in the table entitled “Standard abbreviations” (“Stndard List of Abbreviations"), is entered into the present description by reference.

Although the compounds of formula I can be introduced as source of chemical compounds, however, it is preferable that these compounds were introduced in the form of pharmaceutical compositions. In accordance with another of its aspects, the present invention relates to pharmaceutical compositions containing a compound of formula I or its pharmaceutically acceptable salt or MES in combination with one or more pharmaceutical carriers, and, optionally, with one or more other therapeutic ingredients. Such media must be “acceptable” in terms of their compatibility with the other ingredients specified composition and should not have a negative impact on the recipient.

These drugs are preparations suitable for oral and parenteral call is to be placed (including subcutaneous, percutaneous, intramuscular, intravenous and intraarticular introduction), rectal and local administration (including skin, transbukkalno, sublingual and intraocular introduction). The most suitable route of administration may depend on the condition and disorder of the recipient. Usually, these drugs can be obtained in the form of a uniform dosage form and may be prepared by any method well known to pharmacists. All of these methods include the stage of mixing the compounds of formula I or its pharmaceutically acceptable salt or MES (“active ingredient”) with the carrier which comprises one or more accessory ingredients. In General, these drugs are obtained by a thorough and uniform mixing of the active ingredient with liquid carriers or finely dispersed solid carriers or both and then, if necessary, shaping the product to obtain the desired product.

The preparations according to the invention suitable for oral administration may be prepared in the form of a discrete dosage units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; powders (including powders, consisting of microparticles and nanoparticles) or granules; solutions or with whom spencie in aqueous or anhydrous liquid; or a liquid emulsion of the type oil-in-water” or “water in oil”. The active ingredient can be prepared in the form of a bolus, medicinal porridge or paste.

A tablet may be prepared by compressing or molding, optionally with one or more accessory ingredients. Compressed tablets can be obtained by pressing the active ingredient in granular form, such as powder or granules optionally mixed with a binder agent, lubricant, inert diluent, surface-active agent or dispersing agent, in a suitable apparatus. Molded tablets may be made by molding a mixture of the powdered compound moistened inert liquid diluent, in a suitable apparatus. Such tablets may, but not necessarily, have a coating or notches and can be obtained in the form of dosage forms with delayed, extended or controlled release described here of the active ingredient.

The pharmaceutical compositions can contain pharmaceutically acceptable inert carrier”, and this term includes one or more inert fillers, which are starches, polyols, granulating agents, microcrystalline cellulose, diluents, oil, binder, disintegrator and so on If necessary, described here dosage of the composition type of the tablets can be coated with aqueous or anhydrous coating by standard methods. The term “pharmaceutically acceptable carrier” also includes a tool with adjustable release.

Compositions according to the invention may also, but need not, include other therapeutic ingredients, namely, substances that prevent sintering, preservatives, sweeteners, coloring tools, fragrances, executory, plasticizers, dyes, etc. it is obvious that in order to guarantee the stability of this drug, any such optional ingredient must be compatible with the connection according to the invention.

The interval of the dose for an adult is usually from 0.1 μg to 10 g/day for oral administration. Tablets or other forms obtained in the form of a discrete dosage units can generally contain the compound according to the invention in a quantity effective at such dosage or if these drugs are intended for repeated administration, they may contain, for example, from 0.1 mg to 500 mg, and typically from approximately 5 mg to 200 mg of this compound. The exact number of connections, enter the patient should be prescribed by the attending physician. However, the dose administered will depend on a number of factors, including who the AST and sex of the patient, the particular disorder being treated and its severity. The frequency of introduction will depend on the pharmacodynamic properties of individual compounds and the preparation of this dosage form and can be optimized by methods well known in the art (for example, through the introduction of tablets controlled or slow-release tablets with intersolubility coating and so on).

Combination therapy can be carried out by introducing two or more tools, each of which receive and injected separately, either by introducing two or more funds that are present in the same preparation. Combination therapy may also include other combinations. For example, two drugs can be cooked together and put in combination with a separate preparation containing the third drug. In combination therapy, two or more means may be, but not necessarily, introduced at the same time.

Was synthesized approximately 300 representative compounds according to the General concept. Their structure is presented in two jointly consider the applications having the same filing date, and entitled "SULFONAMIDE PERI-SUBSTITUTED BICYCLICS FOR OCCLUSIVE ARTERY DISEASE" and "CARBOXYLIC ACID PERI-SUBSTITUTED BICYCLICS FOR OCCLUSIVE ARTERY DISEASE". Both of these applications are introduced in the description of the present invention through the links. Examples of the subspecies of the compounds claimed in the present invention, are compounds W, V, W and B13.

Compounds according to the invention can be analyzed for their binding prostanoid receptors OR the method described Abramovitz et al. [Bioch. Biophys. Acta, 1473, 285-293 (2000)]. All examples of the compounds shown in the tables below, were synthesized, characterized and tested for binding with the receptor ER.

Compounds according to the invention can also be analyzed for their effect on platelet aggregationin vitro. In experiments conducted with human platelets from donors who did not eat food during the night, took whole blood. Each experiment was performed using blood samples taken from one particular individual. In experiments with rodent platelets, whole blood was taken from the heart of female mice or male rats shot with isoflurane (Abbott). In each experiment, conducted in rats and mice, blood was taken two or ten separate rodents, respectively. In all cases, blood was collected in tubes with 3.8% sodium citrate (Greiner Bio-one). Platelet-rich plasma (PRP) was obtained by centrifugation at 100 x g for 15 min at 25°C for a person at 150·g for rats or 80·g within 10 mi of the Sabbath. - for mice. Depleted platelet plasma was obtained by centrifugation of the rest of the blood at 2400·g for 10 min at 25°C. After counting the number of platelets on the counter Autocounter (Model 920 EO, Swelab), these platelets were diluted, if necessary, to the desired concentration (200000-300000 platelets/µl) using a 0.9% isotonic NaCl (Braun).

Platelet aggregation was determined by measuring optical density using aggregometry platelets, equipped with a magnetic stirrer continuous action (Model 490, Chronolog Cop., Havertown, Pennsylvania, USA) in a volume of 500 ál in a cell. During the experiment, a solution of platelets was constantly stirring his by lightly shaking with horizontal shift. As accelerators of platelet aggregation used collagen (Sigma) and PGE2or sulprostone (Cayman Chemicals). The compounds used in this analysis, was dissolved and stored in 100% DMSO solution. After dilution, the final concentration of DMSO in this analysis was less than 0.1%.about. In this analysis it was determined that this concentration of DMSO did not inhibit platelet aggregation. Agents that accelerate the aggregation of platelets and compounds tested for binding to EP3diluted in isotonic saline solution to the desired concentration. To calculate the concentration of test compound required for 0%inhibition of platelet aggregation (IC 50), used the method of sigmoidal non-linear regression. The value of the IC50for test compounds were calculated using the computer program GraphPad Prism version 3.02 for Windows (GraphPad Software, San Diego California USA).

Analysis for pulmonary embolism: nearestterminal female mice 57BL/6 oral introduced these test connection, and after 30 min in these animals induced embolism by injection of arachidonic acid into the tail vein. Survival was evaluated one hour after administration of arachidonic acid, because the mice that survived for a specified period of time, usually observed full recovery. The injection of arachidonic acid was made in the lateral tail vein of mice, whose body is rapidly heated under the heating lamp (to extend the tail vein, to facilitate the introduction of injection). To administer the dose used insulin syringe 0.5 ml (Becton Dickinson). The amount of doses of the test compounds and arachidonic acid was adjusted in accordance with the weight of the mouse (the amount of oral input (p.o.) doses of the test compounds and intravenous (i.v.) doses of a solution of arachidonic acid was 10 μl and 5 μl per gram of body weight, respectively). Then evaluated the degree of survival of mice with a model of thromboembolic disease who were treated with test compounds (100 mg/kg, orally).

In General erth, compounds according to the invention can be obtained by the methods illustrated in the General schemes of reactions, for example, described below, or their various modifications, using available starting materials, reagents and conventional synthesis techniques. In these reactions can be used in ways that are, in themselves, are known but not mentioned in the description of this application. As for the original substances, such substances, if appropriate substituted condensed cyclic compounds And/In, may be commercially available or can be obtained by methods well known to specialists in this field.

In General, the compounds of formula I can be obtained from bicyclic systems, appropriately substituted functional groups, as shown in schemes 1-16. In particular, if the node position “a" is a nitrogen atom, then after attaching a functional group in this position followed by the mediated palladium reaction combinations Suzuki receive arylamino derived G3, which is then subjected to derivatization with getting associated with aryl amide, sulfonamida or phosphoramide G5 (scheme 1). Alternatively, the N-functionalized intermediate connection, through mediated by palladium the reactions the combination Suzuki, turn in a derived kilowog ether G6, from which, after hydrolysis and reaction interactions with Ph2P(O)N3with a production ofin situutilised, there is a reaction product of the rearrangement of kurzius - arylamine G8. Utilised can also be obtained from the complex ester G6 using hydrazine followed by reaction of interaction with solidities and with the formation of intermediate acylated. Then Amin G8 make in connection G8, as shown in scheme 2. Acid G7 may also be subjected to a reaction between, for example, sulfonamide, obtaining arylsulfonamides G9. In negativeone schemes, R1represents the balance that the claims represented as M, and R2represents the balance that the claims represented as R1.

Scheme 1

Scheme 2

If carbon hub in position “b” is present ester or nitrile functional group, after reaction with the anion generatedin situfrom acetonitrile, there is formed the corresponding β-hydroxymandelonitrile G11 (scheme 3) or β-aminoacetonitrile G15 (scheme 4), respectively. Then these intermediate compounds may be subjected to a cyclization reaction with getting attadia is a 5 - or 6-membered heterocyclic amines (G12), which in turn derivatizing the amine product G13 (schemes 3 and 4). Alternatively, via the Heck reaction of aromatic halide bicyclic system can be obtained from α,β-unsaturated nitrile, from which, by reaction of interaction with hydrazine or amidino receive dihydroguaiaretic that after the reaction of oxidative aromatization into heterocyclic amines G12, as shown in figure 5.

Scheme 3

Scheme 4

Scheme 5

After the reaction between β-hydroxy - or β-aminoacetonitrile derivatives (G11 and G15, respectively) with hydroxylamine get aminoisoquinoline derived G18, which then receive the product G19 with regiospecifically shown in scheme 6.

Scheme 6

After hydrolysis, of the bicyclic ester systems receive the corresponding carboxylic acid. Due to the diversity of these intermediates of them can be obtained a wide range of 5-membered azole derivatives as shown in scheme 7. This acid by conducting the reaction in a single vessel, can be turned into aminothiadiazole (G22, where Z4=S). The corresponding aminoimidazole (G22, where Z4=O) can be obtained from the corresponding hydrazide (G23) after treatment with bromine cyan. Alternatively, the acid G20 may be subjected to the reaction of interaction with semicarbazide with obtaining the intermediate G21, which can be converted into a 5 - or 6-membered heterocyclic amine, which can then be functionalized with receipt of the products represented by formula I.

Scheme 7

In the above examples, if the node position “a” is N, it means that you've entered one of the peri-substituted linker groups. If both of the substituent in the bicyclic system are linked through a carbon atom, as in the previous examples, there may be associated with an aryl amine and amine functionalized part. In the case of bicyclic systems, which are electrophilic in nature, can be entered With the second-associated peri-substituents, which leads to the formation of the substituents a wide range, in which the joining node to the carbon atom through the heteroatom. Connection in which the connection to the carbon atom through a sulfur atom, presented in figure 8. Due to the high nucleophilicity thiols using such systems, as G24, allows you to enter the second peri-substituents. The formation of a thioester linker provides a retroactive sulfoxide or self the new products, i.e. getting bearily analogues bearing sulfide, sulfoxide or sulfones as linkers. Figure 9 presents the cases in which the analogues of the chemical compounds described in schemes 3 and 4, give input reagents and intermediate compounds flexibility and, thereby, provide a large variety of products.

An example of a reaction that allows you to enter the acyl fragment (carrying the group R2) via electrophilic reactions presented in scheme 16. This reaction leads to the formation of analogues presented G90 and G91. Benzylcarbamoyl group present in G90 and G91, can then be derivatisation, for example, by restoring to alcohol or CH2by the formation of oxime etc.

Scheme 8

Scheme 9

To obtain the corresponding Aza or oxa-linked aryl/heteroaryl/alkyl groups (R1) can be used reactive intermediate compounds, related to isatin, as shown in the G37, and originating from G34 (scheme 10). As shown in scheme 10, the intermediate 37 get different Aza-related compounds, each of which is formed by the joining associated with the carbon group to the bicyclic system. Other variants produced is walking from isatin intermediate compounds is presented in scheme 11. This way you can receive peri-substituted aryl bicyclic compounds which have a functional group linked through carbon atoms and nitrogen with the main bicyclic system. In addition, the availability of key intermediate compounds G48 containing reactive carbonyl located at a considerable distance from the peri-substituents, ending with a group R1 and R2, allows the specialist in this area to conduct a series of chemical reactions with the receipt of the products indicated in scheme 11. Such a chemical reaction, for example, education Catala, in addition to carbonyl and the reaction of interaction with DAST allow to obtain analogues containing various functional groups, as shown in G47-G52. Of the analogues presented in schemes 10 and 11, can also be obtained bicyclic system containing one or two rings that are not aromatic.

Scheme 10

The way of synthesis described above mainly involve the use of a bicyclic system, which accordingly derivateservlet with obtaining the compounds represented by formula I. the Following chemical reaction allow you to enter at least one of the peri-fragments in the process of formation of the bicyclic system. Himicheskaya in figure 12 include three-component condensation reaction, whereby α,γ-diketonates (G54), after reaction of interaction with the aldehyde and the primary amine forms a monocyclic product G63. This product G63, after the interaction, for example, with hydrazine (or monosubstituted hydrazine), forms a peri-substituted bicyclic system (in this case, 5,5-cyclic system, as shown in G64), then get similar G56. α,β-unsaturated ester can be converted into the corresponding α,β-unsaturated nitrile, from which, through chemical reactions illustrated in scheme 5, get 5 - or 6-membered heterocyclic system connected with 5:5-bicyclic system, and thereby, receive a connection represented in G58, as shown in formula I.

Scheme 12

Other examples of chemical reactions that lead to the formation of bicyclic systems shown in schemes 13 and 14. These examples illustrate the synthesis benzimidazolone structures. To obtain peri-substituted systems, the group Rl regiospecificity introduced at the stage of obtaining compounds G61-G62. In figure 14, the desired regiospecifically introduction group Rl is through migration of the acyl O→N with the subsequent recovery of the amide to the secondary amine. In this case, the reaction ring closure also leads to the introduction of the desired Perry-for whom estately, as shown in the G70. The intermediate G62 and G70, after carrying out the successive stages of the reactions described in scheme 11 can be derivatization with getting the right products G64 and G71, respectively.

Scheme 13

Other examples of chemical reactions leading to the formation of bicyclic systems with desired functional groups in the peri-position, illustrated in scheme 15. In this case, terminliste amine with a cyclic γ-ketokislot G74 leads to the formation of the desired bicyclic intermediate G75. The reaction of the synthesized enables you to obtain the key intermediate compound, which, by carrying out various reactions can be transformed into various desired options, connections. Product G77 can be obtained by the reaction of Suzuki. Alternatively, vinylboronic can be converted into the corresponding tizamidine unsaturated ester or nitrile, which can then be derivatization after carrying out chemical reactions illustrated in scheme 3/4 [Jasbir: what should this scheme?] 6 and 7, with the receipt of the products G80, G79 and G81, respectively. These chemical reactions allow for the synthesis of essentially non-aromatic cyclic systems, as well as to lead to the formation of bicyclic systems where Ko is ICO (a) is 5-membered. Ring (a) is formed in the reaction of cyclization and ring size (b) adjusted using a cyclic ketone in the initial stage of the synthesis, which leads to the formation of a bicyclic system “5-N. In addition to the size, the flexibility of the structure specified cyclic ketone attached as a Deputy and heteroatoms. The nature of the tertiary group may also vary, such group may be introduced during the formation of cyclic ketone, which can largely be adjusted his regiochemistry structure. In terms X5/X8 may also contain heteroatoms and/or other substituents.

Scheme 15

Scheme 16 illustrates an alternative substitution reaction involving carbon bicyclic peri-substituents in comparison with the reaction described above in schemes 8 and 9. Conducting the reaction of a bicyclic system indelaware type with a cyclic ketone bearing an appropriately substituted ester or protected amine, allows you to enter the substituents in position C3. Can be made functionalization or derivatization of the specified complex ester or amine with getting nearely peri-substituents (compounds G87 or compounds derived from G86 as arylsulfonamides), or may be conducted by reaction aromates the tion, and then derivatization of amine/acid Deputy obtaining peri-substituted bicyclic arylsulfonamides, amides, phosphoramides, etc. represented by formula I.

Scheme 16

From the connection G10, where R=alkyl (e.g., IU), after the reaction of interaction with gianina 2-bromoxynil acid, and then the reaction decarboxylation receive α-Bratton G89 (X=Br). After the reaction between compounds G89 with thiourea get 2-aminothiazole G90. Aminothiazol G90 can then be derivatization getting connection G91 methods similar to the methods described above. These series of reactions (reactions interaction with gianina bromoxynil acid and thiourea) can also be conducted with other esters derived from bellsystem, such as G78 (scheme 15), the result can be obtained the corresponding 2-aminothiazole, which is subjected to subsequent processing.

Scheme 17

Connection G10, where R=H (carboxylic acid)can be converted into the corresponding acid chloride, which, after the reaction of interaction with diazomethane, get diazoketone G89 (X=N2). Such an intermediate connection G89 can then be subjected to the reaction of interaction with cyanamide, and then with hydroxylamine is m, the result can be obtained 3-amino-1,2,4-oxadiazole G92. After that the amino compounds G92 derivateservlet (for example, sulphonylchloride) and get a connection G93 (sulfonamide).

Functional α-Bratton can also be put in the position C-3 antolovich systems, such as G83, using bromoacetanilide. After the reaction between the obtained α-brometea with thiourea is formed 4-(2-aminothiazol)[similar G91], attached at position C-3 indelaware rings. Functional amino group of the compounds obtained can then be derivatization, as described above. The methods described in scheme 17, serve as additional examples of the preparation of various aminoheterocycles as a key derived from which can be derived compounds related to the type of compounds according to the invention.

Finally, a suitably functionalized bicyclic systems are either commercially available, or their synthesis is described in the literature either assumes that they can be obtained by the person skilled in the art. Some of these systems are described with specific examples. Some of these systems systematized below.

Examples of bicyclic systems where one of the key provisions is nitrogen, can serve as an easily accessible and Shir is used to indole derivatives. 4-bromo - and 4-hydroxyindole are commercially available. 7-substituted indoles, for example, 7-CO2R-, 7-alkoxy-, 7-benzyloxy -, etc. can be obtained through the chemical reaction Bacho-Leimgruber from an appropriately substituted 2-nitrotoluene (Org. Synthesis Co., Vol. 7). This method also allows to obtain 7-Me-, 7-CHO-, 7 -, CN -, and 7-OH-indoles by modifications with the use of functional groups. Alternative 7-galagonidae can be obtained from 2-halogenosilanes through chemical reactions Bartoli (by Bartoli, G. et.al. Tett.Letters, 1989, 30, 2129-2132). Various 7-substituted indoles can also be obtained by selective functionalization of indole by direct ortho-metallation in accordance with the procedure of Cnicus [Snieckus V. et.al. Org Letters 2003, 1899-1902]. These different methods also allow you to get other substituted indologie derivatives. 8-hydroxymitragynine, [6:6]system, can be obtained from commercially available 8-hydroxyquinoline solution by reaction of recovery. 8-OH-1H-quinoline-2-it, 8-OH-3,4-dihydro-1H-quinoline-2-it, 2,6-dihydroquinoline or related heterocycles can be transformed into bicyclic derivatives, 5-hydroxy-4H-benzo[l,4]oxazin-3-one, 5-hydroxy-4H-benzo[1,4]oxazin-2,3-dione, 4-hydroxy-3H-benzooxazol-2-it. As a result of oxidation antolovich 1,7-disubstituted or 3,4-disubstituted bicyclo-analogues education is described corresponding oxindole derivatives. Various anilines can be converted into analogues of isatin in accordance with the procedures described in the literature, and their examples are described below in the “Examples”section. The synthesis of a number [5:5]-bicyclo-systems (e.g., imidazothiazole and pyrrolopyrazole) described in the specific examples. Another group [6:5]-bicyclo-systems can also be obtained by methods similar to those described in the literature methods for the synthesis of such systems, as imidazopyridine and imidazopyrimidines [Katritzky A.R., et al. JOC 2003, 68, 4935-37], and pyrrolopyrimidine [Norman M. et al. JMC 2000, 43, 4288-4312]. Then these different bicyclo structure can be derivationally obtaining analogues of formula I.

In General, various chemical reactions, described above, provide effective antagonists/agonists of prostanoids. These chemical reactions allow to modify these patterns, and to impose optimal functional groups to achieve the hydrophobic-hydrophilic balance; to enter donor and acceptor hydrogen bond with the desired topology; to regulate the desired physical characteristics suitable for the desired pharmaceutical properties and ADME properties (e.g., membrane permeability, binding of low molecular weight plasma protein, the desired metabolic profile and so on). The ability to adjust the physical properties allows recip shall be suitable preparations, convenient for oral administration, which, in turn, allows you to adjust the size and frequency of doses, introduced mammals to achieve the desired pharmacological response. The ability to regulate metabolic profile allows you to minimize the possible interaction of drugs with each other. Thus, the scope of the present invention includes not only obtaining effective antagonists prostanoids with relevant isozyme selectivity, which are a valuable tool for research, and obtaining compounds which are valuable therapeutic tools.

The present invention is illustrated in the following specific non-limiting examples provided in table 1. In table 1, “Xl”=CH, except B47, where X1 represents C(=O); X2 is absent, except B43, B44, B45, where x2 represents CH; g=C; “h”=C except B02, where h is a N; “b” and “d” represent a =C.

Example 1

Getting B0l

Synthesis of (4-bromo-1H-indol-3-yl)naphthalene-2-yl-methanone, I-1. To a solution of 4-bromoindole (5 g, 25.5 mmol) in anhydrous methylene chloride (100 ml) calendarall MeMgBr (3M solution in ether, of 8.95 ml, or 26.7 mmol) at 20°C. there was observed a weak exothermic reaction (the maximum temperature was 28°C). Received the orange solution was stirred at room temperature for 10 min, and then to this solution via an addition funnel was added ZnCl2(1M solution in ether, 76.5 ml, with a 76.5 mmol). The reaction mixture was stirred for 30 minutes Then the solution was added nafolklore (5,1 g, to 26.7 mmol) in methylene chloride (25 ml), and while adding the color of the solution changed from light orange to dark red. The resulting mixture was stirred at room temperature overnight. TLC (EtOAc/hexane, 1:2) indicated completion of the reaction, after which the reaction was suppressed saturated NH4Cl (100 ml). The resulting suspension was stirred for 15 min. and the Obtained solid was filtered and repeatedly washed with methylene chloride. The filtrate was washed with saturated NH4Cl, water and a saturated saline solution and then dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product (7 g). The obtained solid substance was dissolved in 10% aqueous HCl and was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution and then dried over MgSO4, filtered and concentrated to obtain 500 mg of the crude product. United neojidanni the product (7.5 g) washed with MTBE (15 ml), the solvent decantation, and the solid matter suspended in a mixture of MTBE/hexane (1:1) (10 ml)and then filtered, resulting in a received 4.61 in, net specified in the connection header. The filtrate was concentrated, and the residue was purified column chromatography (SiO2), elwira gradient mixture of ethyl acetate/hexane(1:3→1:1), as a result, we received 2 g of pure indicated in the title compounds I-1, all of 6.61 g (yield 74%).1H-NMR (400 MHz, CDC13) confirmed the above structure.

Synthesis of (4-bromo-1-methyl-1H-indol-3-yl)naphthalene-2-yl-methanone, I-2. Logmean (4,55 g, 32 mmol, 2 EQ.) was added to a stirred solution of compound I-1 (5,55 g, 15.9 mmol, 1 EQ.) and K2CO3(5,48 g, to 39.6 mmol, 2.5 EQ.) in acetone (110 ml). The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated, diluted with water (100 ml) and was extracted with ethyl acetate (3·100 ml). The combined organic layers were washed with water (50 ml), saturated salt solution (50 ml), dried over MgSO4was filtered and concentrated, resulting in received of 5.45 g (94%) indicated in the title compound I-2 as a brown oil.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 4-bromo-1-methyl-3-naphthalene-2-ylmethyl-1H-indole, I-3. 1 M solution BH3·THF (of 16.3 ml, 16.3 mmol, 3.3 EQ.) in THF was added during the course the e 15 min to a stirred solution of I-2 (1.8 g, 4.9 mmol, 1 EQ.) in THF (48 ml) at 0°C and slowly warmed up to room temperature. Then the reaction mixture was stirred at room temperature overnight. Then, dropwise over 5 min was added MeOH (3 ml)and then was added MeOH (50 ml). The solvent is evaporated in vacuo, and then was added MeOH (50 ml)and the mixture was evaporated in vacuum. This procedure was repeated twice and received 2 g of yellow oil. The oil obtained was dissolved in a mixture of CH2Cl2/hexane, 1:4 (8 ml) at 40°C, and then cooled to room temperature and was purified by chromatography on SIO, SIS2(27 g), elwira gradient mixture of CH2Cl2/hexane(1:4→1:1), resulting received compound I-3 (1.04 g, 60%).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-carbonitrile, I-4. A solution of compound I-3 (200 mg, 0,571 mmol, 1 EQ.) and copper cyanide(I) (153 mg, 1,713 mmol, 3 EQ.) in anhydrous dimethylacetamide (0,83 ml) was degirolami with argon for 15 min at room temperature, and then heated at 210°C in a closed vessel for 2 hours and Then twice was added water and ethyl acetate (4 ml each), and the resulting suspension was filtered through celite. The residue is twice washed with ethyl acetate (2 ml) and filtered. The organic layer was separated, washed with water (4·4 ml) and saturated salt solution (4 ml), was dried in the MgSO 4, filtered and concentrated in vacuo, resulting in the received compound I-4 (167 mg, 99%) as a brown oil, which crystallized on standing. Rfof 0.42 (EtOAc/hexane, 1:3). MS (ESI-): 296 (M-1).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 3-amino-3-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)Acrylonitrile, I-5. A solution of n-BuLi (1,6 M, 1.7 ml, 2.7 mmol, 10 EQ.) in hexane was added dropwise to a solution of compound I-4 (80 mg, 0.27 mmol, 1 EQ.) in anhydrous acetonitrile (111 mg, 2.7 mmol, 10 EQ.) and THF (2 ml) at -78°C. the Reaction mixture was left to warm to room temperature and was stirred for 1.5 hours Then the reaction was suppressed saturated NH4Cl, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and evaporated to obtain the crude I-5 (186 mg) as dark brown oil. Rf=0,52 (EtOAc/hexane, 1:1). MS (AP+): 338 (M+l).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 3-hydroxy-3-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)Acrylonitrile, I-6. A solution of the crude compound I-5 (186 mg) in Cl3(2 ml) was stirred in 10% aqueous HCl (2 ml) at room temperature over night. The organic layer was separated, filtered through celite and washed with CHCl3(2 ml). After concentration of the filtrate was obtained crude soybean is inania I-6 (106 mg, quantitative yield) as a dark brown oil. Rf=0,73 (EtOAc/hexane, 1:1). MS (AP+): 338 (M+l).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 5-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)-1H-pyrazole-3-ylamine, I-7. A solution of compound I-6 (46 mg, 0,136 mmol, 1 EQ.) and hydrazine hydrate (68 mg, of 1.36 mmol, 10 EQ.) in ethanol (0.3 ml) was heated at 100°C overnight, and then at 120°C for 2 h the Reaction was suppressed saturated NH4Cl, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated salt solution, and then evaporated in vacuum to obtain 46 mg of the crude product. The residue was chromatographically on SIO, SIS2(1 g), elwira gradient mixture of ethyl acetate/hexane(1:4, 1:3, 1:1), and then pure ethyl acetate, resulting in the received compound I-7 (10 mg, 46%) as a yellow oil. Rf=0,19 (EtOAc). MS (AP+): 353 (M+l).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of [5-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)-1H-pyrazole-3-yl]amide 4,5-dichloro-thiophene-2-sulfonic acid, B0l, and l-(4,5-dichloro-thiophene-2-sulfonyl)-5-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)-1H-pyrazole-3-ylamine, B02. A solution of compound I-7 (12 mg, 0,034 mmol, 1 EQ.), 2,3-dichlorothiophene-5-sulphonylchloride (8.6 mg, 0,034 mmol, 1 EQ.) and DMAP (0.2 mg, 0,0017 mmol, of 0.05 EQ.) in pyridine (0.2 ml) was stirred at room temperature during the 1 o'clock Then the reaction was suppressed 10% aqueous HCl, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and saturated saline solution and then dried over MgSO4. The solution was concentrated in vacuum, and received the crude mixture of the sulfonamide (23 mg) as a red solid. This crude product was combined with the crude product obtained in the previous reaction (9 mg, obtained in the reaction with 7 mg, 0.02 mmol I-7). The combined crude mixture was chromatographically on SIO, SIS2(2 g), elwira gradient mixture of ethyl acetate/hexane(1:4→1:1), resulting in the less polar compound B02 (6,7 mg, 22%) as orange solids; Rf= 0,26 (EtOAc/hexane, 1:3); LC-MS (80%): ESI+calculated: 567 (M), found: 568,9 (M+l).1H-NMR (CDCl3) and 3.72 (s, 3H), of 4.05 (s, 2H), 4,70 (Shir. s, 2H), from 5.29 (s, 1H), 6,65 (Shir. s, 1H),? 7.04 baby mortality (DD, J=8,8, 0.8 Hz, 1H), 7,15 (DD, J=8,8, 2.0 Hz, 1H), 7,21 (DD, J=8,0, 7.2 Hz, 1H), 7,34 (DD, J=8,4, 1.2 Hz), 7,35-7,42 (m, 3H), to 7.61 (s, 1H), 7,66 (d, J=8,4 Hz, 1H), 7,70-7,73 (m, 1H), 7,75-7,78 (m, 1H), BOl (8 mg, 26%) as a red solid; Rf=0,41 (EtOAc/hexane, 1:1); LC-MS (92%): ESI+calculated: 566 (M), found: 567,3 (M+l).1H-NMR (CDCl3): and 3.72 (s, 3H), 3,86 (s, 2H), 6,47 (s, 1H), 6,65 (Shir. s, 1H), 7,05 (DD, J=7,2, 0.8 Hz, 1H), 7,10 (DD, J=8,8, 2.0 Hz, 1H), 7,22 (s, 1H), 7,25 (d, J=8.0 Hz, 1H), 7,27 (d, J=8,8 Hz, 1H), 7,34 (Shir. s, 1H), was 7.36-7,41 (m, 3H), 7,62-7,66 (m, 2H), 7,73 (DD, J=6,8, 2.8 Hz, 1H).

Example 2

Getting B03/u>

Synthesis of 3-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)-phenylamine, I-8. A mixture of compound I-3 (175 mg, 0.5 mmol, 1 EQ.), hydrate 3-aminobenzeneboronic acid (103 mg, 0.75 mmol, 1.5 equiv.) of barium hydroxide (103 mg, 0.75 mmol, 1.5 equiv.) and tetranitroaniline (58 mg, 0.05 mmol, 0.1 EQ.) in DME-H2O (1:1, 7.2 ml) was heated at 110°C for 4 h in a closed vessel. Then added tetranitropentaerithrite (25 mg, of 0.022 mmol, 0.4 EQ.) and cesium carbonate (160 mg, 0.5 mmol, 1 EQ.), and the reaction mixture was again heated at 110°C for 3 hours Then added tetranitropentaerithrite (58 mg, 0.05 mmol, 0.1 equiv.) the reaction mixture was heated at 120°C for 3 hours the Reaction mixture was distributed between water and EtOAc (1:1), and the aqueous phase was extracted with EtOAc. The organic layer was filtered through a small column with SiO2-celita and obtained 0.32 g of the crude product in the form of oil. The crude product was purified by chromatography on SIO, SIS2(5 g), elwira gradient mixture of CH2Cl2/hexane(1:3→2:3), as a result, we received 113 mg (in the form of a yellow solid substance) of the crude product containing two spots, as it was shown by TLC (EtOAc/hexane, 1:3). This crude product was dissolved in MTBE (3 ml), and then the mixture was besieged by adding hexane (~6 ml). The mixture was cooled at -20°C, and the mixture was filtered. The mother liquor was concentrated, andreceived compound I-8 (64 mg, 35%) as yellow crystals. Rf=0,17 (EtOAc/hexane, 1:3); LC-MS (ESI+): 364 (M+l) (95%).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of [3-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)phenyl]amide 4,5-dichloro-thiophene-2-sulfonic acid, B03: a Solution of compound I-8 (20 mg, by 0.055 mmol, 1 EQ.), 2,3-dichlorothiophene-5-sulphonylchloride (14 mg, by 0.055 mmol, 1 EQ.) and DMAP (0.3 mg, 0,0028 mmol, of 0.05 EQ.) in pyridine (0.2 ml) was stirred at room temperature for 2 hours the Reaction was suppressed 10% aqueous HCl, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution and then dried over MgSO4. The solution was filtered and concentrated in vacuo to obtain the crude product (35 mg) as a red oily solid. The crude product was chromatographically on SIO, SIS2(1 g), elwira gradient mixture of ethyl acetate/hexane(3:17→1:1), resulting in the received connection B03 (13 mg, 41%) as a white foam. Rf=0,30 (EtOAc/hexane, 1:3). LC-MS (92%): ESI-calculated: 576 (M), found: 577,3 (M-1).1H-NMR (400 MHz, CDCl3) 3,74 (s, 2H), of 3.78 (s, 3H), 6,03 (Shir. s, 1H), 6,76 (s, 1H), 6,78 (m, 1H), 6,83 (DD, J=6,4, 1.2 Hz, 1H), 7,01 (DD, J=8,4, and 1.6 Hz, 1H), 7,07 (s, 1H), 7,15 (m, 1H), 7,18 (m, 1H), 7,20 (m, 1H), 7,25 (m, 1H), 7,34 (DD, J=6,4, 0.8 Hz, 1H), 7,41-7,44 (m, 2H), 7,63 (m, 1H), 7,65 (d, J=7,6, 1H), 7,79 (m, 1H).

Example 3

Getting B04

Synthesis of 4-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)phenyl) - Rev. ina, I-9. A mixture of compound I-3 (175 mg, 0.5 mmol, 1 EQ.), 4-(4,4,5,5-tetramethyl)-l,3,2-dioxaborolan-2-yl)aniline (164 mg, 0.75 mmol, 1.5 equiv.) tetranitroaniline (58 mg, 0.05 mmol, 0.1 EQ.) and cesium carbonate (244 mg, 0.75 mmol, 1.5 equiv.) in the DMA (3.8 ml) was heated at 120°C for 3 h in a closed vessel. The cooled reaction mixture was diluted with ethyl acetate and filtered through a small column with SiO2-telicom, which was obtained 0.34 g of the crude product in the form of oil. This crude product was purified by chromatography on SiO2(2 g), elwira gradient mixture of CH2Cl2/hexane (1:3→1:1) and received compound I-9 (88 mg, 49%) as a white foamy solid. Rf=0,22 (EtOAc/hexane, 1:3); LC-MS (ESI+): 364 (M+l) (96%).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of [4-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)phenyl]amide 4,5-dichloro-thiophene-2-sulfonic acid, B04. A solution of compound I-9 (20 mg, by 0.055 mmol, 1 EQ.), 2,3-dichlorothiophene-5-sulphonylchloride (14 mg, by 0.055 mmol, 1 EQ.) and DMAP (0.3 mg, 0,0028 mmol, of 0.05 EQ.) in pyridine (0.2 ml) was stirred at room temperature for 2 hours the Reaction was suppressed 10% aqueous HCl, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution and then dried over MgSO4. The solution was filtered and concentrated in vacuum to obtain crude n is oduct (39 mg) as a pink oil. The crude product was purified by chromatography on SIO, SIS2(1 g), elwira a mixture of ethyl acetate/hexane (1:8), resulting in the received connection B04 (8 mg, 25%) as not quite white foamy solid. Rf=0,30 (EtOAc/hexane, 1:3).1H-NMR (400 MHz, CDCl3) and 3.72 (s, 2H, in), 3.75 (s, 3H), 6,54 (Shir. s, 1H), 6,66 (s, 1H), 6,91 (DD, J=7,2, 1.2 Hz, 1H), 7,00-7,05 (m, 2H), 7,05 (s, 1H), 7.23 percent (s, 1H), 7.24 to 7,28 (m, 3H), 7,29 (m, 1H), 7,33 (DD, J=7,2, 1.2 Hz, 1H), 7,40 (m, 2H), 7,60 (d, J=8,4 Hz, 1H), to 7.61-7,7,64 (m, 1H), 7,74-7,76 (m, 1H). LC-MS (89%): ESI-calculated: 576 (M), found: 577,3 (M-1).

Example 4

Getting B17

Synthesis of N-[4-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)-phenyl]acetamide", she B17. To a solution of arylamine I-9 (0.06 mmol) in THF (0.2 ml) was added triethylamine (2 EQ.), and then 2 EQ. of acetic anhydride at 0°C. the Reaction mixture was stirred at room temperature for 4 h Then the reaction mixture was concentrated in vacuum, diluted with ethyl acetate and washed with 10% aqueous HCl. The organic layer was separated, washed with water and saturated salt solution, and then dried and obtained as crude product. This product was purified column chromatography and obtained N-acetyloxy product B17 exit 73%.1H-NMR (CDCl3): 2,2 (s, 3H), of 3.73 (s, 3H), of 3.78 (s, 2H), 6,62 (s, 1H), 6,91 (DD, J=6,8, 1.2 Hz, 1H), 7,06 (DD, J=8,4, and 1.6 Hz, 1H), 7,13 (Shir. s, 1H), 7,21-7,31 (m, 4H), 7,29 (s, 1H), 7,37-7,41 (m, 4H), to 7.61 (d, J=8,4, 1H), of 7.64-the 7.65 (m, 1H), 7,73 to 7.75 (m, 1H). LC-MS (APCI+): 405 (Ml), 94%.

Example 5

Getting B18

Synthesis of 2,2,2-Cryptor-N-[4-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)phenyl]acetamide", she B18. To a solution of arylamine I-9 (0.06 mmol) in THF (0.2 ml) was added triethylamine (2 EQ.) and 2 EQ. anhydride triperoxonane acid at 0°C. the Reaction mixture was stirred at room temperature for 4 h Then the reaction mixture was concentrated in vacuum, diluted with ethyl acetate and washed with 10% aqueous HCl. The organic layer was separated, washed with water and saturated salt solution, and then dried, filtered and concentrated in vacuo to obtain the crude product. This crude product was purified column chromatography to obtain N-triftoratsetatov product in 51%yield.1H-NMR (CDCl3): 1,25 (s, 3H), of 3.77 (s, 3H), 3,79 (s, 2H), of 6.71 (s, 1H), 6.89 in (DD, J=6,4, 0.8 Hz, 1H), 7 (DD, J=8,4, 1.2 Hz, 1H), 7,2 (Shir. s, 1H), 7.23 percent-7,27 (m, 3H), 7,29 (s, 1H), 7,33-7,39 (m, 4H), EUR 7.57-to 7.6 (m, 2H), 7,73-7,76 (m, 2H). LC-MS (APCI-): 457 (M-1), 100%.

Example 6

Getting B05

Synthesis of N-[4-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)-phenyl]methanesulfonamide, B05. To a solution of compound I-9 (50 mg, was 0.138 mmol) in pyridine (0.25 ml), cooled to 0°C, was added methanesulfonamide (of 31.6 mg, 2 EQ.). The reaction mixture was stirred at room temperature for 3 h Then the reaction mixture was concentrated under vacuum, was added 10% aqueous HCl, and the aqueous layer was extragere the Lee ethyl acetate (2·10 ml). The combined organic layers were washed with water and saturated saline solution and then dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. This crude product was purified column chromatography, elwira a mixture of ethyl acetate/hexane (1:4), resulting in the obtained crude product B05 with the release of 93,7%.1H-NMR (CDCl3): 2,99 (s, 3H), 3,76 (s, 3H), and 3.8 (s, 2H), 6,54 (Shir. s, 1H), 6,7 (s, 1H), 6,9 (DD, J=7,2, 0.8 Hz, 1H), 7,02 (DD, J=8,4, and 1.6 Hz, 1H), was 7.08 (DD, J=8,4, 2 Hz, 2H), 7,21 (Shir. s, 1H), 7,25-7,27 (m, 1H), 7,28 (DD, J=8,4, 2 Hz, 2H), 7,33 (DD, J=8,4, 1.2 Hz, 1H), 7,37 to 7.4 (m, 2H), 7,6 (d, J=8,4 Hz, 1H), 7,62-the 7.65 (m, 1H), 7,73 to 7.75 (m, 1H). LC-MS (APCI-): 439 (M-1), 100%.

Example 7

Getting B08

Synthesis of C,C,C-Cryptor-N-[4-(1-methyl-3-naphthalene-2-ylmethyl-1H-indol-4-yl)-phenyl]methanesulfonamide, B08. To a solution of compound I-9 (50 mg, was 0.138 mmol) and triethylamine (14 mg, 2 EQ.) in methylene chloride (0.25 ml), cooled to -78°C was added dropwise a solution of anhydride triftormetilfullerenov acid (58 mg, 1.5 EQ.) in methylene chloride (0.25 ml). The reaction mixture was slowly heated to room temperature and was stirred for 4 h the Reaction was suppressed 10% aqueous HCl, and the mixture was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with water and saturated saline solution and then dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified column is cromatografia, elwira a mixture of ethyl acetate/hexane (1:9), resulting in received 40 mg of product B08 with access to 58.8%.1H-NMR (CDCl3): 3,76 (s, 2H), of 3.78 (s, 3H), 6,64 (Shir. s, 1H), 6.75 in (s, 1H), to 6.88 (DD, J=6,8, 1.2 Hz, 1H), 6,97 (DD, J=8,4, and 1.6 Hz, 1H), and 7.1 (DD, J=6,4, and 1.6 Hz, 1H), 7,22 (Shir. s, 1H), 7,25-7,27 (m, 3H), 7,34 (DD, J=8,4, 1.2 Hz, 1H), of 7.36 to 7.4 (m, 3H), to 7.59 (d, J=8, 1H), to 7.61-7,63 (m, 1H), 7,73-7,76 (m, 1H). LC-MS (APCT-): 494 (M-1), 100%.

Example 8

Getting B10

Synthesis of 7-bromo-5-fluoro-3-methyl-1H-indole, I-10. This compound was obtained by a known method (Dobbs, A., J. Org. Chem., 66, 638-641 (2001).

Synthesis of 7-bromo-l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indole, I-11. NaH (60% in mineral oil, 526 mg, 13,15 mmol, 1.5 EQ.) was added to a solution of compound I-10 (2 g, 8,77 mmol, 1 EQ.) in DMF (30 ml) at -10°C. the Reaction mixture was left to warm to room temperature and was stirred for 30 minutes a Solution of 2,4-dichlorobenzaldehyde from 2.06 g, 10,52 mmol, 1.2 EQ.) in DMF (10 ml) was added for 2.5 min at -10°C. the Reaction mixture was left to warm to room temperature and was stirred for 1 h This reaction mixture was added to a stirred mixture of 10% aqueous HCl/water/ether (1:1:2, 40 ml). The aqueous layer was extracted with ether (2×10 ml). The combined organic layers were washed with water (3×75 ml) and saturated salt solution (75 ml), then dried over MgSO4, filtered and concentrated in vacuo, resulting in the obtained crude product in the form to ichnevogo solids. To this crude product was added ether (4 ml), the resulting suspension was cooled to -78°C and filtered, resulting in the received compound I-11 (2,49 g, 73%) as not quite white solid. Rf=0,70 (EtOAc/hexane, 1:5).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of ethyl ester of l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indole-7-carboxylic acid, I-12. n-BuLi (of 1.6 M in hexane, to 0.97 ml, 1.55 mmol, 1.5 EQ.) for 7 min in an atmosphere of Ar was added to a solution of compound I-11 (400 mg, of 1.03 mmol, 1 EQ.) in simple ether (7 ml) at -78°C. the Reaction mixture was stirred at -78°C for another 30 minutes Then, to the reaction mixture was slowly added ethylchloride (0.2 ml, 2,07 mmol, 2 equiv.) and the resulting mixture was left to warm to room temperature (water bath) and stirred at room temperature for 30 minutes the Reaction was suppressed by the addition of 10% aqueous HCl (5 ml). The organic layer was washed with water (2×10 ml) and saturated salt solution (10 ml), then dried over MgSO4, filtered and concentrated in vacuo, resulting in the received compound I-12 (386 mg, 98%) as a brown oil. Rf=0,45 (EtOAc/hexane, 1:19). MS (AP+): 380, 382 (M+l).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of hydrazide l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indole-7-carboxylic acid, I-13. A solution of compound I-12 (114 mg, 0.3 for the mol, 1 EQ.) and hydrazine (0.1 ml, 1.5 mmol, 10 EQ.) in ethanol (0.5 ml) was heated at 120°C in a closed vessel during the night. The reaction was suppressed by the addition of 10% aqueous HCl at 0°C, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution and then dried over MgSO4, filtered and concentrated in vacuo to obtain the crude product (100 mg). This crude product is triturated with MTBE and got clean I-13 (72 mg, 66%) as a beige solid. Rf=0,52 (EtOAc/hexane, 1:1). MS (AP+): 366, 368 (M+l).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-ylamine, I-14. The sodium bicarbonate solution (16 mg, 0,188 mmol, 1 EQ.) in water (0.45 ml) was added to a solution of compound I-13 (69 mg, 0.18 mmol, 1 EQ.) in dioxane (0.5 ml) at room temperature and was stirred for 5 min to obtain a suspension. Then at room temperature was added brazian (20 mg, 0,184 mmol, of 1.02 equiv.) and the reaction mixture was stirred at room temperature for 2 hours After this was added hexane (2 ml), and the suspension was filtered, resulting in the received compound I-14 (54 mg, 73%) as a beige solid. Rf=0,45 (EtOAc/hexane, 1:1). LC-MS (ESI+): 391, 393 (M+l) (97%).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

With ntes N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}-2,2,2-trifurcated, B-10. Anhydride triperoxonane acid (13 mg, 0.061 mmol, 1.5 EQ.) was added to a suspension of compound I-14 (15 mg, 0,041 mmol, 1 EQ.) in triethylamine (8 mg, 0,082 mmol, 2 EQ.) and methylene chloride (0.2 ml) at -78°C. the Reaction mixture was left for 10 min to warm to room temperature. Then the reaction was suppressed by the addition of 10% aqueous HCl, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated saline solution and then dried over MgSO4, filtered and concentrated in vacuo, resulting in the received connection B10 (17 mg, 91%) as a yellow solid. Rf=0,17 (EtOAc/hexane, 1:1).1H-NMR (400 MHz, DMSO-d6) 2,24 (s, 3H), ceiling of 5.60 (s, 2H), 6,04 (d, J=8,4 Hz, 1H), 7,20 (DD, J=8,4, 2.4 Hz, 1H), 7,34 (DD, J=8,8, 2.4 Hz, 1H), 7,46 (Shir. s, 1H), of 7.48 (d, J=2.0 Hz, 1H), 7,74 (DD, J=8,8, 2.4 Hz, 1H). LC-MS (90%): ESI-calculated: 486 (M), found: 485,4 (M-1).

Example 9

Getting B1l

Synthesis of N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}methanesulfonamide, B1l. Methanesulfonanilide (13 mg, 9 ml, 0.11 mmol, 2 EQ.) was added to a solution of compound I-14 (22 mg, 0,056 mmol, 1 EQ.) in pyridine (0.2 ml) at room temperature. The reaction mixture was stirred at room temperature overnight, and then heated up to 70°C for 2 h the Reaction was suppressed by the addition of 10% aqueous HCl, and the mixture was extracted with ethyl acetate. The organic layer was washed with water insystem salt solution, and then was dried over MgSO4, filtered and concentrated in vacuum. The resulting oil was subjected to chromatography on SIO, SIS2(0.5 g), elwira gradient mixture of ethyl acetate/hexane(1:3→1:1), and then pure ethyl acetate, resulting in a received B11 (6,8 mg, 26%) as an orange solid. Rf=0,24 (EtOAc).1H-NMR (400 MHz, CDCl3) was 2.05 (s, 3H), 3,11 (s, 3H), ceiling of 5.60 (s, 2H), 6,07 (d, J=8,4 Hz, 1H), 7,00 (DD, J=8,4, 2.4 Hz, 1H), 7,01 (s, 1H), 7,27 (DD, J=8,4, 2.4 Hz, 1H), 7,40 (d, J=2.0 Hz, 1H), 7,50 (DD, J=8,4, 2.4 Hz, 1H). LC-MS (96%): ESI-calculated: 470 (M), found: 469,2 (M-1).

Example 10

Getting B12

Synthesis of N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}-2,4,5-Cryptor-benzosulfimide, B12. A solution of 2,4,5-tripersonality (92 mg, 0.4 mmol, 4 equiv.) in pyridine (0.3 ml) was added to a mixture of compound I-14 (39 mg, 0.1 mmol, 1 EQ.) and DMAP (49 mg, 0.4 mmol, 4 equiv.) at room temperature. The reaction mixture was heated to 90°C for 2 h Then the reaction was suppressed by the addition of 10% aqueous HCl, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution and then dried over MgSO4, filtered and concentrated in vacuum. The resulting oil was subjected to chromatography on SIO, SIS2(0.5 g), elwira CH2Cl2, resulting in the received B12 (10 mg, 17%) as a yellow oil. Rf=0,40 (EtOAc).1H-NMR (400 MHz, CDCl3) 2,3 (d, J=1.2 Hz, 3H), 5,64 (s, 2H), equal to 6.05 (d, J=8,4 Hz, 1H), 6,97 (DD, J=8,4, 2.0 Hz, 1H), 7,03 (s, 1H), was 7.08 (m, 1H), 7,29 (DD, J=a 9.6, 2.4 Hz, 1H), 7,35 (d, J=2.0 Hz, 1H), 7,51 (DD, J=8,4, 2.4 Hz, 1H), 7,86 (m, 1H). LC-MS (95%): ESI-calculated: 586 (M), found: 585,1 (M-1).

Example 11

Getting B13

Synthesis of {5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}amide 4,5-dichloro-thiophene-2-sulfonic acid, B13. A solution of 2,3-dichlorothiophene-5-sulphonylchloride (75 mg, 0.3 mmol, 3 EQ.) in pyridine (0,20 ml) was added to a solution of compound I-14 (39 mg, 0.1 mmol, 1 EQ.) and DMAP (37 mg, 0.3 mmol, 3 EQ.) in pyridine (0.15 ml) at room temperature. The reaction mixture was heated to 70°C for 2 h Then the reaction was suppressed by the addition of 10% aqueous HCl, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution and then dried over MgSO4, filtered and concentrated in vacuum. The resulting oil was subjected to chromatography on SIO, SIS2(1 g), elwira CH2Cl2, resulting in the received B13 (17 mg, 27%) as a white solid. Rf=0,38 (EtOAc).1H-NMR (400 MHz, DMSO-d6) 2,30 (d, J=0.8 Hz, 3H), 5,59 (d, J=0.4 Hz, 2H), of 5.92 (d, J=8,4 Hz, 1H), 7,15 (DD, J=8,4, 2.0 Hz, 1H), 7,24 (DD, J=a 9.6, 2.0 Hz, 1H), 7,27 (m, 1H), 7,45 (Shir. s, 1H), of 7.70 (DD, J=8,4, 2.8 Hz, 1H), 7,71 (s, 1H). LC-MS (96%): ESI-calculated: 606 (M), found: 605,4 (M-1).

Example 12

Getting B06

Synthesis of 7-bromo-1-(3,4-debtor-benzyl)-5-fluoro-3-methyl-1H-indole-15. To a suspension of NaH (60% in mineral oil, 263 mg, 10.5 mmol, 1.5 EQ.) in DMF (20 ml) was added 7-bromo-5-fluoro-3-methyl-1H-indole, I-10 (1 g, of 4.38 mmol, 1 EQ.) at -10°C. the Reaction mixture was left to warm to room temperature and was stirred for 30 minutes 3,4-differenziale (0.95 g, 4.6 mmol, of 1.05 equiv.) was added for 2.5 min at -10°C. the Reaction mixture was left to warm to room temperature and was stirred for 1 h Then the reaction mixture was added to a stirred solution of a mixture of 10% aqueous HCl/water/ether (1:1:2, 40 ml). The layers were separated, and the aqueous layer was extracted with ether (2·20 ml). The combined organic layers were washed with water (3 x 75 ml) and saturated salt solution (25 ml), then dried over MgSO4, filtered and concentrated in vacuo, resulting in the obtained crude product as a brown oil. This crude product was purified column chromatography, elwira a mixture of ethyl acetate/hexane (2.5 percent), which was obtained 1.4 g of compound I-15 with the release of 90%.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 4-[l-(3,4-debtor-benzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-phenylamine, I-16. A mixture of compound I-15 (345 mg, 0,974 mmol), 4-(4,4,5,5-tetramethyl)-l,3,2-dioxaborolan-2-yl)aniline (320 mg, of 1.46 mmol), tetranitroaniline (60 mg, 0,048 mmol) and cesium carbonate (476 mg, of 1.46 mmol) in DMF (4 ml) was heated at 10°C for 3 h in a closed vessel. The reaction mixture was oladele to room temperature and distributed between water and EtOAc. The aqueous layer was extracted with EtOAc (2·20 ml). The combined organic layers were washed with water and saturated saline solution and then dried (MgSO4) and concentrated. The crude product was subjected to chromatography on SIO, SIS2, elwira mixture solvent of 10%-20% EtOAc/hexane, resulting in the received compound I-16 (180 mg, yield 50,6%) as a white foam.1H-NMR (400 MHz, CDCl3), 2,31 (s, 3H), 3,75 (Shir. s, 2H), a 4.86 (s, 2H), to 6.19-6.22 per (m, 1H), 6,27-6,32 (m, 1H), 6,59 (DD, J=8,4, 2 Hz, 2H), of 6.71 (DD, J=8,8, 2.4 Hz, 1H), 6,85 (s, 1H), 6,88-6,91 (m, 1H), 6,94 (DD, J=8,4, 2 Hz, 2H), 7,17 (DD, J=8,8, 2.4 Hz, 1H). LC-MS (ESI+): 367(M+1), 91%.

Synthesis of N-{4-[l-(3,4-diferensial)-5-fluoro-3-methyl-1H-indol-7-yl]phenyl}methanesulfonamide, B06. To a solution of compound I-16 (50 mg, 0,136 mmol) in pyridine (0.25 ml) at 0°C was added methanesulfonamide (31,3 mg, 2 EQ.). The reaction mixture was stirred at room temperature for 3 h Then the reaction mixture was concentrated in vacuo, and added 10% aqueous HCl, after which the aqueous layer was extracted with ethyl acetate (2·10 ml). The combined organic layers were washed with water and saturated saline solution and then dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified column chromatography, elwira a mixture of ethyl acetate/hexane (1:4), resulting in a received 57 mg B0 (yield 50%). 1H-NMR (400 MHz, CDCl3), 2,32 (s, 3H), 3,1 (s, 3H), of 4.83 (s, 2H), 6,1-6,13 (m, 1H), 6,16-6,21 (m, 1H), 6,5 (Shir. s, 1H), 6,69 (DD, J=a 9.6, 2.4 Hz, 1H), 6,84-6,91 (m, 2H), 7,1-7,14 (m, overlapped, 4H), 7.23 percent (DD, J=8,8, 2.4 Hz, 1H). LC-MS (ESI-): 443 (M-1), 97%.

Example 13

Getting B07

Synthesis of N-{4-[l-(3,4-diferensial)-5-fluoro-3-methyl-1H-indol-7-yl]phenyl}-C,C,C-triftoratsetofenona, B07. To a solution of compound I-16 (63 mg, 0,172 mmol) and triethylamine (35 mg, 2 EQ.) in methylene chloride (0.7 ml) at -78°C was added dropwise a solution of anhydride triftormetilfullerenov acid (to 48.5 mg, 1.5 EQ.) in methylene chloride (0.25 ml). The reaction mixture was slowly heated to room temperature and was stirred for 4 h the Reaction was suppressed by the addition of 10% aqueous HCl, and the mixture was extracted with ethyl acetate (2·10 ml). The combined organic layers were washed with water and saturated saline solution and then dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified column chromatography, elwira a mixture of ethyl acetate/hexane (1:9), resulting in received 40 mg of product B07 with the release of 36.5%.1H-NMR (400 MHz, CDCl3), was 2.34 (s, 3H), and 4.8 (s, 2H), 6,05-the 6.06 (m, 1H), 6,1-x 6.15 (m, 1H), 6,69 (DD, J=9,2, 2.4 Hz, 1H), 6,83-6,89 (m, 2H), 6,91 (s, 1H), 7,12 to 7.2 (m, 4H), 7,25 (DD, J=9,2, 2.4 Hz, 1H). LC-MS (APCI-): 497 (M-1), 97%.

Example 14

Getting B14

Synthesis of l-(3,4-diferensial)-5-fluoro-3-methyl-1H-indole-7-carbonitrile, I-17. A solution of compound I-15 (1.1 g,3,106 mmol, 1 EQ.) and copper cyanide(I) (834 mg, to 9.32 mmol, 3 EQ.) in anhydrous dimethylacetamide (3.5 ml) was degirolami with argon for 15 min at room temperature, and then heated at 210°C in a closed vessel for 1.5 hours Then added water and EtOAc (each 30 ml)and the mixture was filtered. The solid residue was washed with ethyl acetate. The organic layer was separated, washed with water (3·50 ml) and saturated salt solution (30 ml), then dried over MgSO4, filtered and concentrated to obtain compound I-17 (903 mg, 97%) as a solid.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of (Z)-3-amino-3-[l-(3,4-debtor-benzyl)-5-fluoro-3-methyl-1H-indol-7-yl]acetonitrile, I-18. n-BuLi (1,6 M, 5.8 ml, 9,324 mmol, 4 equiv.) was added dropwise to a solution of Diisopropylamine (1.3 ml, 9,324 mmol, 4 equiv.) in anhydrous THF (4 ml) at -78°C. Then was added a solution of compound I-17 in anhydrous acetonitrile (0,49 ml) and THF (1.8 ml). The reaction mixture was left for 1.5 h to warm to room temperature and was stirred for 1.5 hours the Reaction was suppressed by the addition of saturated NH4Cl (20 ml)and the mixture was extracted with ethyl acetate (20 ml). The organic layer was washed with saturated salt solution, dried and concentrated in vacuum, resulting in the obtained crude product I-18 (754 mg) as a dark brown oil, which crystallized after settling PR is room temperature. 1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 5-[l-(3,4-diferensial)-5-fluoro-3-methyl-1H-indol-7-yl]-2-methyl-2H-pyrazole-3-ylamine, I-19. To a mixture of compound I-18 (150 mg, 0,438 mmol) in isopropanol (0.2 ml) and acetic acid (0.2 ml) was added methylhydrazine (100 mg, 0,115 ml, 2,19 mmol, 5 EQ.) at room temperature. The reaction mixture was heated at temperatures up to 100°C during the night. Then the reaction mixture was concentrated in vacuum and distributed between water and ethyl acetate. The organic layer was washed with water and saturated saline solution and then dried (MgSO4), filtered and concentrated in vacuo, resulting in received 100 mg of the crude product. After purification column chromatography on silica gel with elution with methylene chloride, received 40 mg I-19 to exit 25%.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of N-{5-[l-(3,4-diferensial)-5-fluoro-3-methyl-1H-indol-7-yl]-2-methyl-2H-pyrazole-3-yl}methanesulfonamide, B14. To a mixture of compound I-19 (18 mg, 0,048 mmol) in pyridine (0.1 ml) was added methanesulfonamide (12 mg, 2 EQ.) at 0°C. the Mixture was stirred at room temperature for 2 h, and then was heated at 60°C for 6 hours the Reaction mixture was concentrated in vacuo and diluted with ethyl acetate (10 ml). The organic layer was washed with 10% aqueous HCl (2 ml), water and saturated salt solution, and the eating was dried (MgSO 4), filtered and concentrated in vacuum to obtain 20 mg of the crude product. This crude product is triturated with a mixture of ether/hexane (2:1) and filtered, resulting in a received 14 mg of compound B14.1H-NMR (CDCl3) 2,32 (s, 3H), 2,99 (s, 3H), 3,92 (s, 3H), from 5.29 (s, 2H), 6,07 (s, 1H), 6,13 (Shir. s, 1H), 6,27-6,32 (m, 1H), 6,32-6,36 (m, 1H), 6,83 (DD, J=a 9.6, 2.4 Hz, 1H), 6,9 (DD, J=8,4, 2 Hz, 1H), 6,95 (s, 1H), 7,25 (DD, J=8,8, 2.8 Hz, 1 H). LC-MS (ESI-): 448 (M-1), 89%.

Example 15

Getting B15

Synthesis of {5-[l-(3,4-diferensial)-5-fluoro-3-methyl-1H-indol-7-yl]-2-methyl-2H-pyrazole-3-yl}amide 4,5-dichlorothiophene-2-sulfonic acid, B15. A mixture of compound I-19 (15 mg, 0.04 mmol) and 2,3-dichlorothiophene-5-sulphonylchloride (12,2 mg, 0,048 mmol) in pyridine (0.1 ml) was heated to 60°C over night. TLC analysis indicated that the reaction was only ~50% conversion. Then was added DMAP (9.8 mg, 2 equiv.) and the mixture was heated again was heated at 60°C over night. The reaction mixture was concentrated in vacuum, diluted with ethyl acetate and washed with 10% aqueous HCl. The organic layer was washed with water and saturated saline solution and then dried (MgSO4), filtered and concentrated in vacuo, resulting in a received 20 mg of the crude product. This crude product was purified preparative TLC using 1% MeOH/methylene chloride and was given 10 mg B15.1H-NMR (CDCl3) 2,24 (s, 3H), of 3.65 (s, 3H), 5,31 (s, 2H),5,98 (Shir. s, 1H), 6,29-6,32 (m, 1H), 6,46-6,51 (m, 1H), 6,79 (DD, J=a 9.6, 2.4 Hz, 1H), 7,05-7,14 (m, 2H), 7,29 (DD, J=9,2, 2.4 Hz, 1 H), 7,34 (s, 1H), 7,50 (Shir. s, 1H). LC-MS (ESI-): 585 (M-1), 91%.

Example 16

Getting B16

Synthesis of ethyl ester of 1-(3,4-diferensial)-5-fluoro-3-methyl-1H-indole-7-carboxylic acid I-20. n-BuLi (of 1.6 M in hexane, of 0.64 ml, 1.01 mmol, 1.2 EQ.) was added over 7 min in Ar atmosphere to a solution of 7-bromo-l-(3,4-diferensial)-5-fluoro-3-methyl-1H-indole, I-15 (300 mg, 0,847 mmol, 1 EQ.) in diethyl ether (15 ml) at -78°C. the Reaction mixture was stirred at -78°C for another 30 minutes Then the reaction mixture was added dropwise ethylchloride (and 0.09 ml, 1 mmol, 1.2 equiv.) and the mixture was left to warm to room temperature and was stirred for 30 minutes the Reaction was suppressed by the addition of 10% aqueous HCl (5 ml)and the mixture was diluted simple ether (15 ml). The organic layer was separated, washed with water (2·10 ml) and saturated salt solution (10 ml), then dried over MgSO4, filtered and concentrated in vacuo, resulting in the obtained crude ester as a brown oil. The residue was purified column chromatography, elwira a mixture of ethyl acetate/hexane (1:19), resulting in a received 260 mg I-20.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 3-[l-(3,4-diferensial)-5-fluoro-3-methyl-1H-indol-7-yl]-3-oxo-propionitrile, I-21. Dry acetonitrile (50 μl, 1.1 EQ.) was added to a solution of n-uLi (2.5 M in hexane, the 0.375 ml of 0.93 mmol, 1.25 EQ.) in anhydrous THF (1.5 ml) at -78°C. the resulting mixture was stirred for 30 min and then was added dropwise a solution of compound I-20 in THF (1.5 ml). The reaction mixture was left for 3 hours to warm to room temperature. The reaction is extinguished by water, and then to the mixture was added 10% aqueous HCl. This mixture was stirred for 10 min, and then were extracted with ethyl acetate (3·20 ml). The combined organic layers were washed with water and saturated salt solution, and then dried, filtered and concentrated in vacuo, resulting in a received 280 mg of the crude product I-27.1H-NMR (500 MHz, CDCl3) confirmed the above structure. Product I-21 was used in the next stage without additional purification.

Synthesis of 5-[l-(3,4-diferensial)-5-fluoro-3-methyl-1H-indol-7-yl]-isoxazol-3-ylamine, I-22. To a mixture of compound I-21 (160 mg, 0.46 mmol) and hydroxylamine hydrochloride (86 mg, 1,21 mmol, 2.6 EQ.) in ethanol (2.8 ml) was added a solution of sodium hydroxide (48 mg, 1,21 mmol, 2.6 EQ.) in water (0.6 ml). The resulting mixture was boiled under reflux for 1 h Then the reaction mixture was diluted with water (2 ml) and methylene chloride (5 ml), and the pH was brought to 1 by adding 10% aqueous HCl. The organic layer was separated, and the pH of the aqueous layer was brought to 8 by addition of solid Panso3and the mixture was extracted with ethyl acetate (2·10 ml). United organic the ski layers were washed with water and saturated salt solution, and then was concentrated in vacuo, resulting in a received 80 mg of the crude intermediate compound. This residue was mixed with 2n. aqueous HCl (0.2 ml) and heated to 100°C for 3 hours the Mixture was cooled to room temperature, and the pH was brought to 8 by adding saturated Panso3. The aqueous mixture was extracted several times with methylene chloride, and the combined organic layers were washed with water and saturated salt solution, and then dried, filtered and concentrated in vacuum to obtain 100 mg of the crude mixture of isomers of 3-amino and 5-aminoisoquinoline. The crude product was purified column chromatography on silica gel, elwira with methylene chloride, which was obtained 35 mg of I-22.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of N-{5-[1-(3,4-debtor-benzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-isoxazol-3-yl}methanesulfonamide, B16. To a solution of compound I-22 (30 mg, 0,084 mmol) in pyridine (0.2 ml) was added dropwise methanesulfonanilide (19 mg, has 0.168 mmol, 2 EQ.). The resulting mixture was heated at 60°C for 6 hours Then the mixture was concentrated in vacuum, diluted with ethyl acetate and washed with 10% aqueous HCl. The organic layer was washed with water and saturated salt solution, and then dried, filtered and concentrated in vacuo, resulting in received 30 mg of the crude product. This crude product was purified pre is arational TLC using a mixture of 1% MeOH/methylene chloride, as a result, were given 10 mg B16.1H-NMR (400 MHz, CDCl3), of 2.33 (s, 3H), 3.15 in (s, 3H), by 5.18 (s, 2H), to 6.19 (s, 1H), 6,39 (m, 1H), 6,5 (m, 1H), 6,93-of 6.99 (m, 2H), 7,0 (s, 1H), 7,2 (Shir. s, 1H), 7,39 (DD, J=8,8, 2.4 Hz, 1H). LC-MS (ESI-): 435 (M-1), 88%.

Example 17

Getting B19

Synthesis of (N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[1,3,4]oxadiazol-2-yl}-3,4-differentialgeometry, B19. A solution of 3,4-differentialthreshold (159 mg, 0.75 mmol, 2.5 EQ.) in pyridine (0.5 ml) was added to a solution of I-14 (117 mg, 0.3 mmol, 1 EQ.) and DMAP (92 mg, 0.75 mmol, 2.5 EQ.) in pyridine (0.8 ml) at room temperature. The reaction mixture was stirred and heated at 80°C for 0.5 hours the Reaction was suppressed by the addition of 10% aqueous HCl (4 ml)and the mixture was extracted with EtOAc (4 ml). The organic layer was washed with water (3·4 ml) and saturated salt solution (2 ml), then dried over MgSO4, filtered and concentrated. The obtained oil (154 mg) was washed with hexane (4 ml) and filtered, resulting in a received 145 mg solids. This solid was subjected to chromatography on SIO, SIS2(flash chromatography, 2 g), elwira CH2Cl2(50 ml), a mixture of EtOAc/hexane, 1:3 (30 ml), EtOAc/hexane, 1:1 (30 ml), resulting in the obtained brown oil. This oil is triturated with hexane (2 ml), and got mentioned in the title compound B-19 (33 mg, 19%) as a brown solid. Rf=0,40 (EtOAc),1H-NMR (400 MHz, D IS the CO-d 6) 2,24 (s, 3H), 5,54 (Shir. s, 2H), 5,86 (d, J=8.0 Hz, 1H), was 7.08 (DD, J=8,0, 2.4 Hz, 1H), 7,15 (DD, J=10,4, 2.4 Hz, 1H), 7,18 (d, J=2.0 Hz, 1H), 7,38 (s, 1H), EUR 7.57-to 7.64 (m, 2H), 7,68 (Shir. s, 1H), 7,86 (m, 1H). LC-MS (85%): ESI-calculated: 566 (M), found: 565,3 (M-1).

Example 18

Getting B20

Synthesis of (3,4-dichloro-N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}-benzosulfimide, B20. A solution of freshly prepared LDA (0,525 mmol, 2.1 EQ.) in THF (0.5 ml) was added dropwise over 5 min to a solution of compound I-14 (98 mg, 0.25 mmol, 1 EQ.) and HMPA (87 mg, 0.50 mmol, 2.1 EQ.) in THF (0.5 ml) at -78°C. the Reaction mixture was stirred for 15 min at -78°C. a Solution of 3,4-dichlorobenzenesulfonate (153 mg, 0.625 mg, 2.5 EQ.) in THF (0.5 ml) was added dropwise over 3 min and the reaction mixture slowly over 1 h was heated to 0°C. and then was stirred for 1 h at 0°C and slowly heated for 1 h to room temperature. The reaction mixture was cooled to -78°C, after which the reaction was suppressed by the addition of 10% aqueous HCl (4 ml)and the mixture was extracted with EtOAc (2·4 ml). The combined organic phases were washed with water (2·4 ml) and saturated salt solution (4 ml), then dried over MgSO4was filtered and concentrated, resulting in the obtained crude product (140 mg) as an orange oil. After purification by chromatography on SIO, SIS2(flash chromatography, 2 g) using CH Cl2as eluent was obtained the crude product (10 mg) as a yellow oil. This oil was washed with hexane, and got mentioned in the title compound B20 (10 mg, 7%) as yellowish solid. Rf=0,18 (EtOAc).1H-NMR (400 MHz, DMSO-d6) was 2.34 (s, 3H), to 5.57 (s, 2H), 6,00 (d, J=8,4 Hz, 1H), 6,94 (DD, J=8,4, 2.0 Hz, 1H), 7,01 (s, 1H), 7,22 (DD, J=6,4, 2.0 Hz, 1H), 7,50 (DD, J=8,4, 2.4 Hz, 1H), 7.62mm (d, J=8,8 Hz, 1H), 7,78 (DD, J=8,4, 2.0 Hz, 1H), and 8.50 (d, J=2.0 Hz, 1H). LC-MS (91%): ESI+calculated: 598 (M), found: 599,1 (M+l).

Example 19

Getting B21

Synthesis B21. A solution of the acid chloride diphenylphosphino acid (35 mg, 0.15 mmol, 1.5 equiv.) in pyridine (0.1 ml) was added to a solution of compound I-14 (39 mg, 0.1 mmol, 1 EQ.) and DMAP (1.2 mg, 0.01 mmol, 0.1 EQ.) in pyridine (0.3 ml) at 60°C. the Reaction mixture was stirred and heated at 60°C for 16 hours Then the reaction was suppressed 10% aqueous HCl (2 ml)and the mixture was extracted with EtOAc (2·2 ml). The combined organic layers were washed with water (3·4 ml) and saturated salt solution (4 ml), then dried over MgSO4, filtered and concentrated. The obtained oil (59 mg) was washed with hexane (2 x 1 ml) and ether (1.5 ml)and then filtered to obtain compound B21 (29 mg, 49%) as a white solid. Rf=0,37 (EtOAc/hexane, 1:1).1H-NMR (400 MHz, DMSO-d6) to 2.29 (s, 3H), ceiling of 5.60 (Shir. s, 2H), 5,91 (d, J=8,4 Hz, 1H), 7,00 (Shir. s, 1H), 7,16 (DD, J=8,4, 2.0 Hz, 1H), 7,40 (Shir. s, 1H), 7,43 (s, 1H), 7,46-7,58 (m, 7H), 766 (DD, J=8,8, 2.4 Hz, 1H), 7,75-7,80 (m, 4H). LC-MS (91%): ESI-; calculated: 592 (M), found: 591,2 (M-1).

Example 20

Getting B22

Synthesis of bis-2,4-dichlorophenylamino ether {5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}-phosphoramidites acid, B-22. A solution of bis(2,4-dichlorophenyl)chlorophosphate (73 mg, 0.18 mmol, 1.2 equiv.) in pyridine (0.2 ml) was added to a solution of compound I-14 (59 mg, 0.15 mmol, 1 EQ.) and DMAP (1.8 mg, 0.015 mmol, 0.1 EQ.) in pyridine (0.2 ml) at room temperature. The reaction mixture was stirred and heated at 60°C for 2 h and at 70°C for 1 h, the Reaction mixture was cooled to -78°C., and the reaction was suppressed by the addition of 10% aqueous HCl (4 ml), and then the mixture was extracted with EtOAc (2·2 ml). The combined organic layers were washed with water (3·2 ml) and saturated salt solution (2 ml), then dried over MgSO4, filtered and concentrated. The oil obtained (130 mg) was washed with hexane (2 ml) and MTBE (1 ml)and then filtered and got mentioned in the title compound In 22 (29 mg, 25%) as a white solid. Rf=0,22 (EtOAc/hexane, 1:1).1H-NMR (400 MHz, DMSO-d6) 2,30 (d, J=0.8 Hz, 3H), 5,62 (s, 2H), 5,95 (d, J=8,4 Hz, 1H), 7,16 (DD, J=8,4, 2.0 Hz, 1H), 7,20 (DD, J=9,6, 1,6, 1H), 7,30 (DD, J=8,8, 2,4, 1H), 7,44 (d, J=2.4 Hz, 1H), 7,45 (s, 1H), 7,47 (d, J=2,8 Hz, 1H), 7,51 (d, J=2.4 Hz, 1H), 7,53 (d, J=1.2 Hz, 1H), 7,55 (d, J=0.8 Hz, 1H), 7,69 (DD, J=2,4, 0.8 Hz, 1H), 7,73 (DD, J=8,8, 2.8 Hz, 1H). LC-MS (87%): ESI-calculated: 762 (M), found: 761,1 (M-1.

Example 21

Getting B23

General procedure A-1. The solution of the corresponding acylchlorides (0.30 mmol, 1.2 equiv.) in THF (0.15 ml) for 1 min was added to a solution of compound I-14 (98 mg, 0.25 mmol, 1 EQ.) and the cat. DMAP (1.5 mg, of 0.0125 mmol of 0.05 EQ.) in pyridine (0.6 ml) at room temperature, and the reaction mixture was stirred at room temperature for 3-16 hours the Reaction mixture was cooled to approximately-70°C (bath of dry ice and acetone), was added 10% aqueous HCl (4 ml). The mixture was extracted with EtOAc (2·2 ml). The combined organic phase was washed with water (3·4 ml) and saturated salt solution (4 ml), then dried over MgSO4, filtered and concentrated to obtain the crude product as oil. This oil was led by addition of hexane (2 ml). The obtained solid substance was washed with a mixture of ether/hexane, 1:1 (2 ml), and received specified in the header of the connection.

Synthesis of (N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}-4-fermentated, B23. In accordance with the General procedure a-1 was allocated 70 mg (55%) of compound V in the form of a white solid, Rfof 0.15 (EtOAc/hexane, 1:1).1H-NMR (400 MHz, DMSO-d6) 2,32 (d, J=0.8 Hz, 3H), 5,66 (Shir. s, 2H), 6,00 (d, J=8,4 Hz, 1H), 7,18 (DD, J=6,4, 2.0 Hz, 1H), 7,33 (DD, J=a 9.6, 2.4 Hz, 1H), 7,41 (t, J=8,8 Hz, 2H), 7,45 (d, J=2.0 Hz, 1H), 7,49 (Shir. s, 1H), 7,73 (DD, J=8,8, 2.4 Hz, 1H), 8,06-of 8.09 (m, 2H). LC-MS (92%): ESI-that calc is but: 514 (M), found: was 513.3 (M-1).

Example 22

Getting B24

Synthesis of {5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}amide isoxazol-5-carboxylic acid, B24. In accordance with the General procedure A-1 was identified 41 mg (34%) of compound B24 in the form of a white solid, Rfto 0.17 (EtOAc/hexane, 1:1).1H-NMR (400 MHz, DMSO-d6) 2,32 (d, J = 0.8 Hz, 3H), 5,65 (Shir. s, 2H), 6,01 (d, J=8,4 Hz, 1H), 7,17 (DD, J=8,4, 2.4 Hz, 1H), 7,34 (DD, J=9,6, 2.8 Hz, 1H), was 7.36-7,46 (m, 2H), 7,46 (d, J=2.0 Hz, 1H), 7,49 (s, 1H), 7,74 (DD, J=8,8, 2.4 Hz, 1H), 8,86 (Shir. s, 1H). LC-MS (90%): ESI-calculated: 485 (M), found: 484,3 (M-1).

Example 23

Getting B25

Synthesis of (3,5-dichloro-N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}benzamide, B25. In accordance with the General procedure a-1 was isolated 52 mg (37%) of compound B25 in the form of a white solid, Rf0,31 (EtOAc/hexane, 1:2).1H-NMR (400 MHz, DMSO-d6) 2,32 (d, J=1.2 Hz, 3H), 5,64 (Shir. s, 2H), 6,01 (d, J=8,4 Hz, 1H), 7,18 (DD, J=8,0, 2.0 Hz, 1H), 7,33 (DD, J=a 9.6, 2.0 Hz, 1H), 7,44 (d, J=2.0 Hz, 1H), 7,49 (Shir. s, 1H), 7,74 (DD, J=8,4, 2.4 Hz, 1H), 7,86 (d, J = 2.0 Hz, 1H), 7,95 (Shir. s, 1H), and 8.0 (d, J=1.6 Hz, 2H). LC-MS (78%): ESI-calculated: 564 (M), found: 563,1 (M-1).

Example 24

Getting B26

Synthesis of (N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}-3,4-differentated, B26. In accordance with the General procedure a-1 was isolated 76 mg (57%) of compound B26 in the form of a white solid, Rf0,54 (EtOA/hexane, 1:1).1H-NMR (400 MHz, DMSO-d6) 2,32 (d, J=0.8 Hz, 3H), 5,65 (Shir. s, 2H), 6,01 (d, J=8,4 Hz, 1H), 7,17 (DD, J=8,4, 2.0 Hz, 1H), 7,33 (DD, J=9,2, 2.4 Hz, 1H), 7,45 (d, J=2.0 Hz, 1H), 7,49 (Shir. s, 1H), 7,66 (sq, J=8,4 Hz, 1H), 7.23 percent (DD, J=8,8, 2.4 Hz, 1H), of 7.90 (Shir. s, 1H), 8,02-8,08 (m, 1H), to 12.28 (Shir. s, 1H). LC-MS (92%): ESI-calculated: 532 (M), found: 531,1 (M-1).

Example 25

Getting B27

Synthesis of (N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}-2,4-differentated, B27. In accordance with the General procedure A-1 was allocated 55 mg (41%) of compound B27 in the form of a white solid, Rf0,80 (EtOAc/hexane, 1:1).1H-NMR (400 MHz, DMSO-d6) 2,32 (d, J=0.8 Hz, 3H), 5,67 (s, 2H), 5,98 (d, J=8,4 Hz, 1H), 7,17 (DD, J=8,4, 2.0 Hz, 1H), 7,25 (dt, J=8,4, 2.0 Hz, 1H), 7,31 (DD, J=8,4, 2.4 Hz, 1H), 7,43-7,46 (m, 1H), 7,49 (s, 1H), 7,49 (d, J=2.4 Hz, 1H), 7,73 (DD, J=8,8, 2.4 Hz, 1H), 7,79 (sq, J=7.2 Hz, 1H), of 12.33 (Shir. s, 1H). LC-MS (100%): APCI+calculated: 530 (M), found: 531,0 (M+l).

Example 26

Getting B28

Synthesis of (2,4-dichloro-N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}benzamide, B28. In accordance with the General procedure A-1 was isolated 105 mg (74%) of compound B28 in the form of a white solid, Rfof 0.60 (EtOAc/hexane, 1:1).1H-NMR (400 MHz, DMSO-d6) 2,32 (d, J=0.8 Hz, 3H), 5,67 (s, 2H), 5,94 (d, J=8,4 Hz, 1H), 7,17 (DD, J=8,4, 2.0 Hz, 1H), 7,28 (Shir. d, J=8,4 Hz, 1H), of 7.48 (Shir. s, 1H), 7,52 (d, J=1.6 Hz, 1H), 7,60 (DD, J=8,0, 2.0 Hz, 1H), 7,65 (d, J=8.0 Hz, 1H), 7,73 (DD, J=8,8, 2.4 Hz, 1H), 7,80 (d, J=2.0 Hz, 1H), to 12.52 (Shir. s, 1H). LC-MS (100%): APCI+ calculated: 563 (M), found: 564,0 (M+l).

Example 27

Getting B29

Synthesis of {5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[1,3,4]oxadiazol-2-yl}amide 2,2-debtorrent[1,3]dioxol-5-carboxylic acid, B29. In accordance with the General procedure a-1 was allocated 60 mg (35%) of compound B29 in the form of a yellowish solid, Rfa 0.27 (EtOAc/hexane, 1:2).1H-NMR (400 MHz, DMSO-d6): 2,32 (d, J=0.8 Hz, 3H), 5,65 (Shir. s, 2H), 6,00 (d, J=8,4 Hz, 1H), 7,18 (DD, J=8,0, 2.0 Hz, 1H), was 7.36 (Shir. kV, J=8.0 Hz, 2H), 7,45 (d, J=2.0 Hz, 1H), 7,49 (Shir. s, 1H), to 7.67 (Shir. t, J=8.0 Hz, 2H), 7,74 (DD, J=8,8, 2.4 Hz, 1H), 12,42 (Shir. s, 1H). LC-MS (100%): APCI+calculated: 574 (M), found: 575,2 (M+l).

Example 28

Getting B30

Synthesis of {5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,3,4]oxidiazol-2-yl}amide, furan-2-carboxylic acid, B30. In accordance with the General procedure a-1 was allocated 80 mg (55%) of compound B30 in the form of a yellowish solid, Rfto 0.23 (EtOAc/hexane, 1:1).1H-NMR (400 MHz, DMSO-d6) 2,32 (d, J = 0.8 Hz, 3H), 5,66 (Shir. s, 2H), of 5.99 (d, J =8,4 Hz, 1H), 6.75 in (DD, J = 3,6, 2.0 Hz, 1H), 7,17 (DD, J = 8,4, 2.0 Hz, 1H), 7,33 (DD, J =8,8, 2.8 Hz, 1H), 7,44 (d, J = 2.0 Hz, 1H), of 7.48 (s, 1H), EUR 7.57 (d, J = 3.2 Hz, 1H), 7,72 (DD, J = 8,8, 2,8 Hz, 1H), 8,03 (d, J = 0.8 Hz, 1H), 12,15 (Shir. s, 1H). LC-MS (100%): APCI+Calculated: 484 (M), found: 485,2 (M+l).

Example 29

Getting B31

Synthesis of {5-[l-(3,4-diferensial)-5-fluoro-3-methyl-1H-indol-7-yl]isoxazol-3-yl}amide 4,5-dichloro-thiophene-2-sulfonic acid, B31. It is Uspenie of compound I-22 (42 mg, 0,117 mmol) in pyridine (0.2 ml) was added DMAP (28 mg, 0.23 mmol, 2 EQ.). This mixture was heated at 70°C until the formation of the solution, and then was added 2,3-dichlorothiophene-5-sulphonylchloride (58 mg, 0.23 mmol, 2 EQ.). The reaction mixture was stirred at this temperature for 2 h the Cooled reaction mixture was concentrated to obtain oil, and added 10% aqueous HCl (1 ml). The mixture was extracted with EtOAc (2·5 ml). The combined organic layers washed with 10% aqueous HCl (1 ml), water (2·3 ml) and a saturated solution of salt (C ml), then dried over MgSO4, filtered and concentrated to obtain 55 mg of the crude product. After purification column chromatography using a mixture of 40%→10% hexane/methylene chloride received 12 mg of compound B31 (yield 18%).1H-NMR (400 MHz, CDCl3), 2,32 (s, 3H), 5,09 (s, 2H), of 6.31 (s, 1H), 6,41 (m, 1H), 6,44-of 6.49 (m, 1H), 6,92-6,99 (m, overlapped, 2H), of 6.96 (s, 1H), and 7.4 (DD, J=8,8, 2.4 Hz, 1H), 7,47 (s, 1H), 7,97 (Shir. s, 1H). LC/MS (ESI-): 572 (M-1), 96%.

Example 30

Getting B32

General procedure (A-2) sulfonation of 3-aminoisoquinoline. A 5-ml vessel was added the corresponding 3-aminoethoxy (1 EQ.), pyridine (1 ml/0.80 mmol) and DMAP (2 EQ.). The reaction mixture was heated to 75°C., and after 2-3 min added net sulphonylchloride (2-3,5 EQ.). Immediately after it was formed suspension, and the reaction mixture was stirred and heated at 75°C in techenie PM The reaction mixture was cooled to room temperature, and was added 10% aqueous HCl (10 ml/0.80 mmol). The mixture was extracted with EtOAc (10 ml). The organic phase is washed with water (2·10 ml), saturated salt solution (10 ml), dried over MgSO4, filtered and concentrated to obtain the crude product as oil. This product was purified flash chromatography on SIO, SIS2(1 g 0.05 mmol original 3-aminoisoquinoline using CH2Cl2as eluent) to obtain specified in the header of the product as a solid.

Synthesis of (N-{5-[l-(3,4-debtor-benzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-isoxazol-3-yl}-3,4-differentialgeometry, B32. In accordance with the General procedure a-2, of the compound I-22 (143 mg, 0.40 mmol) and 3,4-differentialthreshold (212 mg, 1.00 mmol) received 93 mg (44%) indicated in the title compound as a yellow solid (hexane). Rf0,18 (CH2Cl2-Meon, 19:1).1H-NMR (400 MHz, CDCl3) 2,32 (d, J=1.2 Hz, 3H), 5,10 (s, 2H), and 6.25 (s, 1H), 6,34-to 6.39 (m, 1H), 6,40-of 6.45 (m, 1H), 6,86-to 6.95 (m, 2H), 6,97 (s, 1H), 7,33 (m, 1H), 7,39 (DD, J=8,4, 2.4 Hz, 1H), to 7.67-7,72 (m, 1H), 7,74 for 7.78 (m, 1H), 8,10 (Shir. s, 1H). LC-MS (96%): ESI-calculated: 532,9 (M-1), found: 532,6.

Example 31

Getting B33

Synthesis of (N-{5-[1-(3,4-diferensial)-5-fluoro-3-methyl-1H-indol-7-yl]-isoxazol-3-yl}-2,4,5-tripersonality, B33. In accordance with the General procedure a-2, of the compound I-22 (13 mg, 0.40 mmol) and 2,4,5-tripersonality (323 mg, of 1.40 mmol) received 35 mg (16%) indicated in the title compound as a yellow solid (hexane). Rf0,13 (CH2Cl2-Meon, 19:1).1H-NMR (400 MHz, CDCl3) 2,32 (d, J=0.8 Hz, 3H), 5,10 (s, 2H), 6,23 (s, 1H), 6,33-6,41 (m, 1H), 6,41-6,46 (m, 1H), 6.87 in-6,94 (m, 2H), 6,97 (s, 1H), 7,12 (m, 1H), 7,38 (DD, J=8,8, and 1.6 Hz, 1H), 7,80 (m, 1H), 8,25 (Shir. s, 1H). LC-MS (97%): ESI-calculated: 550,5 found: 550,7.

Example 32

Getting B34

Synthesis of 3-[1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-3-oxopropanenitrile, I-23. To a mixture of n-BuLi (2.5 M in hexane, to 13.7 ml of 2.25 EQ.) in 90 ml of anhydrous THF at -78°C for 5 min was added acetonitrile (1.6 ml, 30,26 mmol, 2 EQ.). The suspension was stirred at this temperature for 0.5 h, and then for 20 min was added to a solution of compound I-12 (5.75 g, 15,13 mmol) in anhydrous THF (40 ml). The mixture was left to warm to 10°C., and the reaction was suppressed by slow addition of 10% aqueous HCl. The mixture was extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with water (2·50 ml) and saturated salt solution (50 ml), then dried over Na2SO4, filtered and concentrated in vacuum to obtain 5.9 g of the product I-23 in the form of oil. This product is used in the next stage without purification.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indole-7-isoxazol-3-ylamine, I-24. To a solution of the crude I-23 (1 g, of 2.66 mmol) in a mixture of EtOH/water (1:1, 54 ml) was added NaOH (124 mg, a 3.06 mmol) and hydroxylamine sulfate (486 mg, at 2.93 mmol). This mixture was heated at 80°C for 22 hours, the Reaction mixture was cooled to room temperature, concentrated to half its original volume and extracted with ethyl acetate (2·50 ml). The combined organic layers were washed with water (2·20 ml), saturated salt solution (20 ml), dried over MgSO4), filtered and concentrated to obtain 900 mg of brown oil. After purification of the residue column chromatography using 20-30% mixture of EtOAc/hexane received 290 mg of the product of I-24 (exit 29%).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of {5-[1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]isoxazol-3-yl}amide 4,5-dichloro-thiophene-2-sulfonic acid, B34. To a suspension of compound I-24 (180 mg, 0,447 mmol) in pyridine (0.5 ml) was added DMAP (81 mg, 0.67 mmol, 1.5 EQ.). This mixture was heated at 70°C until the formation of the solution, and was added 2,3-dichlorothiophene-5-sulphonylchloride (140 mg, 0,536 mmol, 1.2 EQ.). The reaction mixture was stirred at this temperature for 3 h the Cooled reaction mixture was concentrated with the formation of oil and diluted with EtOAc (15 ml). The organic layer was washed with 10% aqueous HCl (2·3 ml), water (2·3 ml) and a saturated solution of salt (2·3 ml), then dried over MgO 4, filtered and concentrated to obtain 280 mg of the crude residue. After purification of the residue column chromatography using 20-50% EtOAc/hexane received 100 mg of the product V (yield 35%).1H-NMR (400 MHz, CDCl3), 2,32 (s, 3H), of 5.05 (s, 2H), 6,24 (d, J=8 Hz, 1H), 6,34 (s, 1H), 6,9 (s, 1H), 6,97 (DD, J=8,8, 2.8 Hz, 1H), 7,03 (DD, J=8,8, 2 Hz, 1H), and 7.3 (d, J=2, 1H), 7,41 (DD, J=8,8, 2.8 Hz, 1H), 7,45 (s, 1H), 7,55 (Shir. s, 1H). LC/MS (ESI-) 604, 97%.

Example 33

Getting B35

Synthesis of N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]isoxazol-3-yl}-3,4-differentialgeometry, B35. To a suspension of compound I-24 (94 mg, 0.24 mmol) in pyridine (0.3 ml) was added DMAP (44 mg, 0.36 mmol, 1.5 EQ.). This mixture was heated at 70°C to obtain a solution, and was added 3,4-differentialalgebraic (64.4 mg, 0,028 mmol, 1.2 EQ.). The reaction mixture was stirred at this temperature for 3 h the Cooled reaction mixture was concentrated to obtain oil, and added 10% aqueous HCl (2 ml). The mixture was extracted with EtOAc (3·10 ml). The combined organic layers were washed with water (2·5 ml) and saturated salt solution (5 ml)and then dried over MgSO4, filtered and concentrated to obtain 100 mg of the residue. After purification of the residue column chromatography using 20-50% EtOAc/hexane received 20 mg of product B35 (yield 15%).1H-NMR (400 MHz, CDCl3), 2,32 (s, 3H), of 5.05 (s, 2H), 6,18 (d, J=8,4 Hz, 1H), 6,29 (C, H), 6,89 (s, 1H), 6,93 (DD, J=9,2, 2.4 Hz, 1H), 7,01 (DD, J=8,4, 2 Hz, 1H), 7,27-7,31 (m, overlapped, 1H), 7,28 (d, J=2 Hz, 1H), and 7.4 (DD, J=8,8, 2.4 Hz, 1H), 7,47 (Shir. s, 1H), of 7.64-7,66 (m,1H), 7,7-7,74 (m, 1H). LC/MS (APCI-) 565, 91%.

Example 34

Getting B36

Synthesis of (N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]isoxazol-3-yl}-2,4,5-tripersonality, B36. In accordance with the General procedure a-2, of the compound I-24 (156 mg, 0.40 mmol) and 2,4,5-tripersonality (185 mg, 0.80 mmol) was obtained 64 mg (27%) indicated in the title compound as a yellow solid (hexane). Rf0,15 (CH2Cl2-MeOH, 19:1).1H-NMR (400 MHz, CDCl3): 2,31 (d, J=1.2 Hz, 3H), of 5.03 (s, 2H), 6,17 (d, J=8,4 Hz, 1H), of 6.26 (s, 1H), 6.89 in (s, 1H), 6,92 (DD, J=8,8, 2.8 Hz, 1H), 7,02 (DD, J=8,4, 2.4 Hz, 1H), 7,11 (m, 1H), 7,28 (d, J=2.4 Hz, 1H), 7,39 (DD, J=an 8.4, 2.8 Hz, 1H), to 7.75 (m, 1H), 8,00 (Shir. s, 1H). LC-MS (96%): ESI-calculated: 585 (M), found: 584,1 (M-1).

Example 35

Getting B37

Synthesis of (3,4-dichloro-N-{5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]isoxazol-3-yl}benzosulfimide, B37. In accordance with the General procedure A-2, of the compound I-24 (156 mg, 0.40 mmol) and 3,4-dichlorobenzenesulfonate (196 mg, 0.80 mmol) received 103 mg (43%) indicated in the title compound as a yellow solid (hexane). Rf=0,18 (CH2Cl2-MeOH, 19:1).1H-NMR (400 MHz, CDCl3) 2,32 (d, J=0.8 Hz, 3H), 5,02 (s, 2H), to 6.19 (d, J=8,4 Hz, 1H), of 6.31 (s, 1H), 6.90 to (s, 1H), 6,94 (DD, J=9,2, 2.4 Hz, 1H), 7,02(DD, J=8,0, 2.0 Hz, 1H), 7,27 (d, J=2.0 Hz, 1H), 7,40 (DD, J=8,8, and 1.6 Hz, 1H), EUR 7.57 (d, J=8,4 Hz, 1H), to 7.67 (DD, J=8,4, 2.0 Hz, 1H), 7,92 (Shir. s, 1H), of 7.97 (d, J=2.0 Hz, 1H). LC-MS (98%): ESI-calculated: 599 (M), found: 598,3 (M-1).

Example 36

Getting B38

Synthesis of 7-bromo-5-fluoro-3-methyl-(l-naphthalene-2-ylmethyl)-1H-indole, I-25. From compound I-10 (4.8 g, 21,04 mmol), NaH (1.26 g, 31,57 mmol), 2-(methyl bromide)naphthalene (5,58 g, 25,25 mmol) and DMF (90 ml), in accordance with the procedure similar to the transformation of compound I-10 in compound I-11 was received 7,00 g (90%) of compound I-25 in the form of a light brown solid (hexane). Rf=0,33 (hexane/acetone, 9:1).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of ethyl ester of 5-fluoro-3-methyl-l-naphthalene-2-ylmethyl-1H-indole-7-carboxylic acid, I-26. From compound I-25 (7,00 g, 19.01 in mmol), 2,5h. BuLi (11,4 ml, 28,50 ml), ethylchloride (3,63 ml, 38,02 mmol) and anhydrous ether (120 ml), in accordance with the procedure similar to that for obtaining the compound I-12 I-11, got to 7.09 g (quantitative yield) of compound I-26 in the form of a brown oil. Rf=0,36 (hexane/acetone, 9:1).1H-NMR (400 MHz, CDCl3) confirmed the above structure.

Synthesis of 3-(5-fluoro-3-methyl-l-naphthalene-2-ylmethyl-1H-indol-7-yl)-3-oxo-propionitrile, I-27. Compound I-27 was obtained from compound I-26 (7,06 g, 19,53 mmol) according to the procedure similar to that described procedure transformation with the unity I-12 I-23. The crude oil (7,16 g, Quant.) triturated with hexane (15 ml) and received solid, which was filtered and washed with hexane (2·5 ml) to obtain compound I-27 (5,56 g, 80%) as a light brown solid. Rf0,06 (hexane/acetone, 9:1).1H-NMR (400 MHz, CDCl3) confirmed the above structure.

Synthesis of 5-(5-fluoro-3-methyl-l-naphthalene-2-ylmethyl-1H-indol-7-yl)isoxazol-3-ylamine, I-28. From compound I-27 (4,43 g, 12,43 mmol), following a procedure similar to the procedure described for the conversion of compound I-23 I-24, received compound I-28 (1,69 g, 37%) as an orange solid. Rf=0,33 (CH2Cl2).1H-NMR (400 MHz, CDC13): 2,32 (d, J=0.8 Hz, 3H), 5,32 (s, 2H), of 5.45 (s, 1H), 6.89 in (DD, J=a 9.6, 2.4 Hz, 1H), 6,91 (DD, J=8,8, and 1.6 Hz, 1H), 7,01 (s, 1H), 7,21 (Shir. s, 1H), 7,34 (DD, J=8,8, 2.4 Hz, 1H), 7,39-7,44 (m, 2H), 7,65 (d, J=8.0 Hz, 1H), 7,65-of 7.69 (m, 1H), 7,73-to 7.77 (m, 1H).

Synthesis of (3,4-debtor-N-[5-(5-fluoro-3-methyl-l-naphthalene-2-ylmethyl-1H-indol-7-yl)isoxazol-3-yl]benzosulfimide, B38. In accordance with the General procedure a-2, of the compound I-28 (297 mg, 0.80 mmol) and 3,4-differentialthreshold (340 mg, 1,60 mmol) were specified in the title compound B38 (106 mg, 24%) as an orange solid. Rf=0,14 (CH2Cl2).1H-NMR (400 MHz, CDC13) 2,31 (d, J=0.8 Hz, 3H), with 5.22 (s, 2H), to 6.19 (s, 1H), at 6.84 (DD, J=8,4, and 1.6 Hz, 1H), 6,91 (DD, J=9,2, 2.8 Hz, 1H), 6,99 (s, 1H), 7,07 (DQC., J=8.0 a, and 1.6 Hz, 1H), 7,14 (s, 1H), 7,41 DD, J=5,6, and 2.4 Hz, 1H), 7,42 was 7.45 (m, 2H), 7,51-of 7.55 (m, 1H), 7,62-of 7.70 (m, 3H), 7,74-7,76 (m, 1H), 7,92 (Shir. s, 1H). LC-MS (98%): ESI-calculated: 547,56 found: 546,4 (M-1).

Example 37

Getting B39

Synthesis of (2,4,5-Cryptor-N-[5-(5-fluoro-3-methyl-l-naphthalene-2-ylmethyl-1H-indol-7-yl)isoxazol-3-yl]benzosulfimide, B39. In accordance with the General procedure a-2, of the compound I-28 (149 mg, 0.40 mmol) and 2,4,5-tripersonality (185 mg, 0.80 mmol) were specified in the title compound B39 (42 mg, 19%) as not quite white solid. Rf0,26 (CH2Cl2-MeOH, 19:1).1H-NMR (400 MHz, CDC13): 2,31 (d, J=0.8 Hz, 3H), with 5.22 (s, 2H), 6,18 (s, 1H), 6,85 (DD, J=8,8, 2.0 Hz, 1H), 6.89 in (DD, J=9,2, 2.4 Hz, 1H), 6,95 (DD, J=9,2, 4.8 Hz, 1H), 6,99 (s, 1H), 7,14 (s, 1H), 7,38 (DD, J=8,8, 2.4 Hz, 1H), 7,43-7,46 (m, 2H), 7,63-to 7.77 (m, 4H), 8,09 (Shir. s, 1H). LC-MS (94%): ESI-calculated: 565,55 found: 564,6 (M-1).

Example 38

Getting B40

Synthesis of (3,4-dichloro-N-[5-(5-fluoro-3-methyl-l-naphthalene-2-ylmethyl-1H-indol-7-yl)isoxazol-3-yl]benzosulfimide, B40. In accordance with the General procedure a-2, of the compound I-28 (149 mg, 0.40 mmol) and 3,4-dichlorobenzenesulfonate (196 mg, 0.80 mmol) were specified in the header connection B40 (76 mg, 33%) as not quite white solid. Rf=0,31 (CH2Cl2-MeOH, 19:1).1H-NMR (400 MHz, CDC13): 2,31 (d, J=0.8 Hz, 3H), with 5.22 (s, 2H), of 6.20 (s, 1H), at 6.84 (DD, J=8,4, and 1.6 Hz, 1H), 6,91 (DD, J=8,4, and 1.6 Hz, 1H), 6,99 (s, 1H), 7,14 (s, 1H), 7,35 (d, J=8,8 Hz, 1H), 7,40 (DD, J=,4, the 2.4 Hz, 1H), 7,42 was 7.45 (m, 2H), 7,56 (DD, J=8,4, 2.0 Hz, 1H), 7,63 (d, J=7,6 Hz, 2H), 7,74-7,76 (m, 1H), 7,95 (d, J=2.4 Hz, 1H), 8,00 (Shir. d, J=4.5 Hz, 1H). LC-MS (93%): ESI-calculated: 581 (M), found: 580,3 (M-1).

Example 39

Getting B41

Synthesis of 5-(5-fluoro-3-methyl-l-naphthalene-2-ylmethyl-1H-indol-7-yl)isoxazol-3-yl]amide 4,5-dichlorothiophene-2-sulfonic acid, B41. In accordance with the General procedure a-2, of the compound I-28 (149 mg, 0.40 mmol) and 2,3-dichlorothiophene-5-sulphonylchloride (201 mg, 0.80 mmol) were specified in the header connection B41 (132 mg, 33%) as not quite white solid. Rf=0,10 (CH2Cl2-MeOH, 19:1).1H-NMR (400 MHz, CDCl3): 2,32 (d, J=0.8 Hz, 3H), of 5.26 (s, 2H), 6,23 (s, 1H), 6,86 (DD, J=8,4, 2.0 Hz, 1H), 6,95 (DD, J=9,2, 2.8 Hz, 1H), 7,00 (s, 1H), 7,19 (Shir. s, 1H), 7,39-the 7.43 (m, 3H), 7,63-7,66 (m, 2H), 7,74-7,76 (m, 1H), 7,98 (s, 1H). LC-MS (99%): ESI-calculated: 587 (M), found: 586,2 (M-1).

Example 40

Getting B42

Synthesis of l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indole-7-carboxylic acid, I-29. A solution of compound I-11 (1.08 g, 2,84 mmol, 1 EQ.) in 2H. aqueous NaOH (7,1 ml, 14,20 mmol, 5 equiv.) methanol (3 ml) and THF (3 ml) was stirred and heated in a closed vessel at 85°C for 1.5 h, the Reaction mixture was cooled to -70°C., and the reaction was suppressed by the addition of 10% aqueous HCl (20 ml). The mixture was extracted with EtOAc (50 ml), the organic layer was washed with water (3·50 ml) and saturated salt solution (50 ml), then dried over MgSO4was filtered and conc is listed. The obtained solid was filtered and washed with hexane to obtain compound I-29 (694 mg, 69%) as not quite white solid. Rf=0,22 (EtOAc/hexane, 1:3).1H-NMR (400 MHz, CDCl3) confirmed the above structure.

Synthesis of iminomethylene l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indole-7-carboxylic acid, I-30. Oxalicacid (0,99 ml of 1.98 mmol, 1.2 EQ.) was added to a solution of compound I-29 (580 mg, of 1.65 mmol) in THF (7 ml) at room temperature in an atmosphere of Ar. The reaction mixture was stirred at room temperature for 30 min, and then concentrated to obtain yellow crystals. To a solution of cyanamide (138 mg, 3,294 mmol, 2 EQ.) in THF (7 ml) was added a solution of 2n. aqueous NaOH (1.65 ml, 3,29 mmol, 2 equiv.) was stirred at room temperature for 20 min, and then the resulting solution was added over 2 min to a suspension obtained from compound I-29 and oxalicacid in THF (2 ml). The reaction mixture was stirred at room temperature for 30 minutes the reaction mixture was concentrated and added water (4 ml)and then added 10% aqueous HCl (2 ml) and the aqueous phase was extracted with EtOAc (8 ml). The organic phase is washed with water (2 x 6 ml), dried over MgSO4, filtered and concentrated in vacuo to obtain an orange oil (400 mg). The resulting oil was washed with hexane (4 ml, 2 ml) to obtain ukazannoj is in the title compound I-30 (325 mg, 52%) as a yellowish powder. Rf=0,30 (EtOAc). MS: ESI-calculated: 375 (M), found: 374,3 (M-1).1H-NMR (400 MHz, CDCl3) confirmed the above structure.

Synthesis of (5-[1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,2,4]oxidiazol-3-ylamine, I-31. Pyridine (0.5 ml) was added to a mixture of compound I-30 (113 mg, 0.3 mmol, 1 EQ.) and hydroxylamine (21 mg, 1 EQ.), and the reaction mixture was stirred and heated at 45°C for 16 h and at 60°C for 1 h, the Reaction mixture was cooled to room temperature and poured into a mixture of 10% aqueous HCl (4 ml) and EtOAc (4 ml). The organic phase is washed with water (3·6 ml) and saturated salt solution (4 ml), then dried over MgSO4, filtered and concentrated to obtain the crude product (136 mg) as an orange oil. After purification by chromatography on SIO, SIS2(flash chromatography, 2 g) using a mixture of CH2Cl2/hexane, 1:1 (20 ml), CH2Cl2(20 ml)was obtained the crude product (45 mg) as oil. The resulting oil triturated with hexane, and got mentioned in the title compound I-31 (30 mg, 26%) as a white powder. Rf=0,78 (EtOAc/hexane, 1:1).1H-NMR (400 MHz, DMSO-d6): 2,31 (d, J=0.8 Hz, 3H), 5,70 (s, 2H), of 5.89 (d, J=8,4 Hz, 1H), 6.35mm (s, 2H), 7,16 (DD, J=8,8, 2.0 Hz, 1H), 7,32 (DD, J=a 9.6, 2.4 Hz, 1H), 7,47 (s, 1H), 7,54 (d, J=2.4 Hz, 1H), 7,71 (DD, J=8,8, 2.4 Hz, 1H). LC-MS (99%): (ESI+calculated: 390 (M), found: 391,2 (M+l).

Synthesis of {5-[l-(2,4-dichlo is benzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-[l,2,4]oxidiazol-3-yl}amide 5-dichloro-thiophene-2-sulfonic acid, B42. A solution of freshly prepared LDA (0,537 mmol, 2.1 EQ.) in THF (0.5 ml) dropwise over 2 min was added to a solution of compound I-31 (100 mg, 0,256 mmol, 1 EQ.) and HMPA (96 mg, 0,537 mmol, 2.1 EQ.) in THF (0.5 ml) at -78°C. the Reaction mixture was stirred for 10 min at -78°C. and Then for 2 min was added dropwise a solution of 2,3-dichlorothiophene-5-sulphonylchloride (161 mg, 0,639 mg, 2.5 EQ.) in THF (0.5 ml)and the reaction mixture slowly over 1 h was heated to -18°C, and then was stirred for 1 h at -18°C and slowly heated for 1 h to room temperature. Then the reaction mixture was poured into a mixture of 10% aqueous HCl (4 ml) and EtOAc (4 ml). The organic phase is washed with water (3·4 ml) and saturated salt solution (4 ml), then dried over MgSO4, filtered and concentrated to obtain the crude product (134 mg) as an orange oil. After purification of the resulting oil by chromatography on SIO, SIS2(flash chromatography, 5 g) using a mixture of CH2Cl2/hexane, 1:2 (30 ml), CH2Cl2/hexane, 1:1 (10 ml), CH2Cl2(10 ml), EtOAc (10 ml) was obtained the crude product (40 mg) as a yellow oil. The resulting oil was purified by chromatography on SIO, SIS2(flash chromatography, 2 g) using a mixture of CH2Cl2/hexane, 1:4 (30 ml) and received partially purified product (35 mg) as a yellow oil. The resulting oil precrystallization is a mixture of CH 2Cl2-hexane, 2:1, and got mentioned in the title compound B42 (15 mg, 9%) as a white solid. Rf=0,10 (EtOAc/hexane, 1:1).1H-NMR (400 MHz, DMSO-d6) 2,31 (s, 3H), 5,59 (s, 2H), of 5.89 (d, J=8,8 Hz, 1H), 7,13 (DD, J=8,4, 2.4 Hz, 1H), 7,26 (d, J=1.6 Hz, 1H), 7,37 (DD, J=a 9.6, 2.4 Hz, 1H), 7,46 (s, 1H), 7,68 (s, 1H), 7,74 (DD, J=8,8, 2.4 Hz, 1H). LC-MS (93%): ESI-calculated: 604 (M), found: 603,1 (M-1).

Example 41

Getting B43

Synthesis of 4-bromo-1-methyl-1H-indole, I-32. To a solution of NaH (60% in mineral oil, 600 mg, 15 mmol) in DMF (20 ml) was added 4-bromo-1H-indole (1,96 g, 10 mmol) at -10°C. Stir the mixture was left for 10 min to warm to room temperature, and then cooled to -10°C, then at -10°C was added iodomethane (6.7 g, 50 mmol). The reaction mixture was stirred at room temperature for 3 h and was diluted in CH2Cl2(-200 ml). The reaction mixture was washed with water (3 x 200 ml), saturated salt solution and dried over sodium sulfate. After filtration and removal of solvent received 3 g of the crude product I-32. The compound obtained is directly used in the next stage without additional purification.

1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 1-methyl-4-(naphthalene-2-yloxy)-1H-indole, I-33. A mixture of compound I-32 (2.4 g, 11,42 mmol), CuI (217 mg, 1,142 mmol), HCl salt of N,N-dimethylglycine (480 mg, of 3.42 mmol), 2-naphthol (,47 g, 17,14 mmol) and Cs2CO3(7,42 g, 22.84 to mmol) in dioxane (22 ml) was stirred in an atmosphere of Ar at 105°C for 2 days. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline solution and then dried over sodium sulfate. After removal of solvent the residue was purified column chromatography on silica gel using 2% ethyl acetate/hexane as eluent, resulting in received 2.16 g of 1-methyl-4-(naphthalene-2-yloxy)-1H-indole, I-33 (yield 83%).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 2-bromo-l-[1-methyl-4-(naphthalene-2-yloxy)-1H-indol-3-yl]ethanone, I-34. To a solution of compound I-33 (500 mg, of 1.83 mmol) in anhydrous methylene chloride (10 ml) at -70°C was added chloride diethylamine (1 M solution in hexane, to 2.74 ml, is 2.74 mmol) at a rate necessary to maintain the temperature below -65°C. After addition of chloride diethylaluminum bath with dry ice-acetone was replaced with a bath with a mixture of water and salt-ice, and the solution was heated to a temperature of -10°C. At this temperature was added bromocatechol (0,23 ml, is 2.74 mmol). The reaction mixture was stirred at this temperature for 1 h TLC analysis indicated completion of reaction. Then slowly, with stirring, was added water (9 ml). The aqueous phase was extracted with methylene chloride (3·15 ml). The combined organic extracts were washed with water and nasy the military solution of salt, and then was dried and concentrated, resulting in received 500 mg of the crude product. After trituration with ether received 450 mg of compound I-34 (yield 62%).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 4-[1-methyl-4-(naphthalene-2-yloxy)-1H-indol-3-yl]-thiazole-2-ylamine, I-35. A suspension of compound I-34 (220 mg, 0,558 mmol) and thiourea (51 mg, 0.67 mmol) in ethanol (5 ml) was boiled under reflux for 2 hours After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and podslushivaet saturated water Panso3. The suspension was filtered, washed with water and dried. After trituration with ether received 200 mg of compound I-35 in the form of a white solid with a yield of 96%.1H-NMR (400 MHz, CDCl3), 3,83 (s, 3H), 4,76 (Shir. s, 2H), 6,7 (DD, J=7,2, 1.2 Hz, 1H), 7,01 (s, 1H), 7,12-7,25 (m, 2H), 7,28-to 7.3 (m, 2H), 7,34-the 7.43 (m, 2H), and 7.6 (s, 1H), to 7.64 (d, J=8 Hz, 1H), 7,78-7,81 (m, 2H). LC/MS (ESI+) 372: 98%.

General procedure for the synthesis sulfonamida, (A-3).

To a solution of compound I-35 (0.1 mmol) in anhydrous THF (0.3 ml) was added NaH (2 EQ., 60% dispersion in oil). The reaction mixture was stirred at room temperature for 15 min, and then added the appropriate sulphonylchloride (2 EQ.). After complete addition, the reaction mixture was acidified, diluted with 10% aqueous HCl and was extracted with EtOAc (2·5 ml). The combined organic layer is washed washed with water and saturated salt solution, and then was dried and concentrated to obtain the crude product. After purification preparative TLC using 5% MeOH/methylene chloride were obtained target product.

Synthesis of {4-[1-methyl-4-(naphthalene-2-yloxy)-1H-indol-3-yl]-thiazol-2-yl}amide 4,5-dichlorothiophene-2-sulfonic acid, B43. Connection B43 synthesized according to General procedure A-3.1H-NMR (400 MHz, CDCl3), the 3.89 (s, 3H), 6,32 (s, 1H), for 6.81 (DD, J=7,6, 1.2 Hz, 1H), of 6.96 (m, 1H), 7,19-7,38 (m, 4H), 7,38 (s, 1H), 7,41 was 7.45 (m, 2H), to 7.61 (d, J=7,6 Hz, 1H), 7,73 (d, J=8,8 Hz, 1H), 7,79-7,81 (m, 1H), 10,6 (Shir. s, 1H). LC/MS (ESI-) 586: 98%.

Example 42

Getting B44

Synthesis of 3,4-debtor-N-{4-[1-methyl-4-(naphthalene-2-yloxy)-1H-indol-3-yl]thiazol-2-yl}benzosulfimide, B44. Connection B43 synthesized according to General procedure A-3.1H-NMR (400 MHz, CDCl3), a 3.87 (s, 3H), 6,28 (s, 1H), 6,79 (DD, J=7,6, 1.2 Hz, 1H), 7,21-7,27 (m, 4H), and 7.3 (d, J=2.4 Hz, 1H), 7,38 (s, 1H), 7,39 was 7.45 (m, 2H), 7,52-7,56 (m,1H), to 7.59-to 7.61 (m, 1H), 7,65-of 7.69 (m, 1H), 7,71 (s, 1H), 7,78 one-7.8 (m, 1H), 10,57 (Shir. s, 1H). LC/MS (AP+) 547: 98%.

Example 43

Getting B45

Synthesis of 3-[1-methyl-4-(naphthalene-2-yloxy)-1H-indol-3-yl]-3-oxo-propionitrile, I-36. The mixture tsianuksusnogo acid (130 mg and 1.51 mmol), acetic anhydride (1.5 g, 1.5 ml, 15.1 mmol) and 1-33 (412 mg and 1.51 mmol) was heated at 50°C for 15 minutes TLC analysis indicated the absence of starting material. The mixture was cooled to room temperature, and the solid wasp is given. Then the mixture was diluted simple ether (5 ml) and was filtered. The solid is triturated with ether (10 ml). After filtration and air drying was received 346 mg (yield 67%) of compound 1-36 in the form of a light yellow substance.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 5-[1-methyl-4-(naphthalene-2-yloxy)-1H-indol-3-yl]isoxazol-3-ylamine, 1-37. A suspension of compound 1-36 (360 mg, 1.05 mmol), hydroxylamine sulphate (104 mg, 1.15 mmol) and sodium hydroxide (50,4 mg of 1.26 mmol) in a mixture of ethanol/water (1:1, 5 ml) was heated at 80°C for 24 h, the Reaction was not completed, and therefore was added 50 mg of sodium hydroxide and 100 mg of hydroxylamine sulphate. The mixture was heated at 100°C for 24 h the Reaction mixture was concentrated to half of its original volume and added 36% HCl (0.25 ml). Then the reaction mixture was heated at 100°C for 3 hours the Mixture was cooled to room temperature, concentrated to obtain oil and was diluted with ethyl acetate (10 ml). The solution was washed with 10% aqueous NaOH. The alkaline aqueous phase was extracted with ethyl acetate (3·10 ml). The combined extracts were washed with water and saturated saline solution and then dried over magnesium sulfate, filtered and concentrated, resulting in the obtained brown solid (400 mg). The crude product was purified column chromatography on silica gel using CME and 30% ethyl acetate/hexane, and received 120 mg of compound 1-37 (yield 32%).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 3,4-debtor-N-{5-[1-methyl-4-(naphthalene-2-yloxy)-1H-indol-3-yl]isoxazol-3-yl}benzosulfimide, B45. To a solution of compound I-37 (90 mg, 0,253 mmol) in anhydrous THF (0.8 ml) was added NaH (21 mg, 0.51 mmol, 60% dispersion in oil). The reaction mixture was stirred at room temperature for 15 min and then was added 3,4-differentialalgebraic (83 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 24 hours After mixing, the mixture was acidified with 10% aqueous HCl and was extracted with EtOAc. The combined organic extracts were washed with water and saturated salt solution, and then dried and concentrated to obtain the crude product. The crude product was purified column chromatography on silica gel using a mixture of 10, 15, 20% ethyl acetate/hexane, and received 39 mg (yield 37%) B45.1H-NMR (400 MHz, CDCl3), the 3.89 (s, 3H), 6,41-6,47 (m, 1H), 6,79 (DD, J=7,6, 0.8 Hz, 1H), 6,99 (s, 1H), 7,02 (m, 1H), 7,18 (d, J=8, 0.8 Hz, 1H), 7,26 (t, J=8,4, 1H), 7,38-of 7.48 (m, 5H), 7,68 (s,1H), 7.7 (d, J=8 Hz, 1H), 7,84 (d, J=8, 1H), of 7.90 (d, J=8,8, 1H), 8,39 (Shir. s, 1H). LC/MS (APCI+) 532: 100%.

Example 44

Getting B46

Synthesis of 5-bromo-2-(2,5-dimethyl-pyrrol-l-yl)pyridine I-38. A mixture of 5-bromopyridin-2-ylamine (3.28 g, 19 mmol), acetonylacetone (2.17 g, 19 mmol) and the monohydrate is p-toluensulfonate acid (0.95 g) in toluene (20 ml) was heated overnight under reflux using traps Dean-stark. The reaction mixture was concentrated in vacuo, diluted with EtOAc (50 ml) and washed with water (2·10 ml), 10% aqueous NaHCO3, water and a saturated saline solution and then dried over MgSO4was filtered and concentrated, resulting in received of 4.2 g of residue. After purification of the residue column chromatography on silica gel using 2-4% EtOAc/hexane received 3 g of the product I-38.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 2-(2,5-dimethyl-pyrrol-1-yl)-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridine I-39. To a solution of compound I-38 (220 mg, 0,876 mmol) in anhydrous THF (10 ml) at -78°C was added n-BuLi (2.5 M in hexane, of 0.43 ml, 1,095 mmol). The reaction mixture was stirred at this temperature for 15 min and then was added dropwise 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (0,36 ml of 1.75 mmol). The reaction mixture was stirred at -78°C for 1 h, and then bath with acetone and dry ice was removed, and the mixture was left to warm to 0°C, after which the reaction was suppressed at this temperature by the addition of saturated aqueous NH4Cl. The mixture was stirred at room temperature for 15 min, and then was extracted with EtOAc (2·10 ml). The combined organic extracts were washed with water and saturated saline solution and then dried over Na2SO4was filtered and concentrated, resulting in a received 300 mg soy is inane I-39. This compound had a sufficient degree of purity, and therefore it was used in the next stage.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 1-(2,4-dichlorobenzyl)-7-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-3-yl]-5-fluoro-3-methyl-1H-indole, I-40. To a solution of compound I-39 (300 mg, 1 mmol) in DME (4 ml) was added compound I-11 (258 mg, 0.66 mmol), and then cesium carbonate (326 mg, 1 mmol). After degassing the suspension by ozonation mixture with argon for 5 min was added the catalyst, Pd(Ph3P)4(46 mg, 0.04 mmol)and the reaction mixture was stirred at 100°C for 3.5 hours and Then the reaction mixture was cooled to room temperature and diluted with water. The resulting mixture was extracted with EtOAc (2·15 ml). The combined organic extracts were washed with water and saturated saline solution and then dried over Na2SO4was filtered and concentrated, resulting in a received 400 mg of residue. After purification of the residue column chromatography on silica gel received 100 mg of compound I-40.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 5-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]pyridine-2-ylamine, I-41. A mixture of compound I-40 (95 mg, 0,198 mmol), triethylamine (110 μl, 0,792 mmol), hydroxylamine hydrochloride (158 mg, 2.28 mmol) in a mixture solvent: EtOH (1.2 ml), water (0.4 ml) and chloroform (0.2 ml) load the Wali at 90°C for 24 h in a closed vessel. TLC analysis indicated that the reaction was not completed. So I added another 130 mg of hydroxylamine hydrochloride, and the mixture was heated at 100°C for 1 day. Then the reaction mixture was cooled to room temperature, concentrated, and added 10% aqueous HCl up until the pH reached 2, after which the mixture was extracted with ether. The aqueous layer was podslushivaet to pH 9 using 6N. aqueous NaOH, and extracted with ethyl acetate (3·10 ml). The combined extracts were washed with water and saturated saline solution and then dried over Na2SO4was filtered and concentrated, resulting in a received 120 mg of residue. After purification of the residue column chromatography on silica gel using 10-50% ethyl acetate/hexane received 50 mg of compound I-40 (the parent compound) and 30 mg of compound I-41.

Synthesis of {5-[1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]pyridine-2-yl}amide 4,5-dichloro-thiophene-2-sulfonic acid, B46. To a mixture of compound I-41 (12 mg, 0.03 mmol) in pyridine (0.15 ml) was added at room temperature, 2,3-dichlorothiophene-5-sulphonylchloride (12 mg, 0.045 mmol). The reaction mixture was stirred at room temperature for 5 hours TLC analysis indicated the absence of product education. Therefore, at this stage, was added DMAP (4 mg), and the mixture was stirred at room temperature for 24 h, the Pyridine was removed in vacuum, is then added 10% aqueous HCl (1 ml), and the mixture was extracted with ethyl acetate (2·4 ml). The combined extracts were washed with saturated salt solution, dried over Na2SO4, filtered and concentrated to obtain 20 mg of the residue. After trituration of the residue with methanol (0.15 ml) and after filtering received 8 mg of compound B46.1H-NMR (400 MHz, CDCl3), was 2.34 (s, 3H), 4,94-to 5.03 (m, 2H), 5,97 (d, J=8,4, 1H), to 6.67 (DD, J=8,8, 2,4, 1H), 6,93 (s, 1H),? 7.04 baby mortality (DD, J=8, 2 Hz, 1H), and 7.1 (d, J=2, 1H), 7.24 to 7,33 (m, 4H), 7,45 (s, 1H), 8,08 (Shir. s, 1H). LC/MS (ESI-) 614: >80%.

Example 45

Getting B47

Synthesis of 2-methyl-2-allylcyclohexane, I-42. To a solution of sodium hydride (1 EQ.; 60% dispersion in mineral oil) in dimethoxyacetophenone at 5°C in an atmosphere of nitrogen was added dropwise 2-methylcyclohexanone (1 EQ.). The solution was left to warm to room temperature, after which it was heated up to 80°C for 1.5 hours the resulting solution was cooled to room temperature and then to 5°C. then was added dropwise allylbromide (1 EQ.), and the reaction mixture was heated up to 80°C for 1.5 hours Then the reaction mixture was cooled to room temperature and was added dropwise water (~14 EQ.). The aqueous layer twice was extracted with ethyl ether and dried over sodium sulfate. After concentration the crude product was purified by chromatography on silica gel using 2.5 percent ethyl ether in hexane, financial p is Tata which received the compound I-42 with the release of 35%. 1H-NMR.

Synthesis of (1-methyl-2-oxo-cyclohexyl)acetic acid, I-43. To a biphasic solution of 1-methyl-1-electroversion, I-42, H2O/CH3CN/Cl4in an atmosphere of nitrogen was added NaIO4(20 equiv.) and then RuCl3·H2O. the Reaction mixture was stirred at room temperature overnight. Then was added dropwise 2-propanol (~88 equiv.) the resulting reaction mixture became black. The resulting mixture was diluted with water and ethyl ether, filtered through a layer of celite, and this layer was washed with ethyl ether. The aqueous layer was extracted with dichloromethane and ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo, resulting in the received compound I-43 with a quantitative yield.1H-NMR confirmed the above structure.

General procedure (A-4) the receipt of hexahydro-indol-2-ones, I-44. A solution of (1-methyl-2-oxo-cyclohexyl)acetic acid, I-43 (1 EQ.), and the corresponding benzylamine (1 EQ.) in m-xylene was heated under reflux for 3 h at 145°C. the Reaction mixture was concentrated in vacuo, and the residue is either used in crude form, or was purified by chromatography on silica gel using hexane in dichloromethane (10-20%) as eluent, resulting in a received desired product I-44. Product structure podtverzhdalis 1H-NMR.

General procedure (A-5) synthesized hexahydro-indol-2-ones, I-45: To a solution of the appropriate hexahydro-indole-2-it, I-44, in dichloromethane, at 0°C was added dropwise bromine (1 EQ.). The reaction mixture was stirred until then, until he disappeared color of bromine, and then another 5 minutes Then one portion was added triethylamine (3 EQ.), and the reaction mixture was stirred at room temperature for 10 minutes the Reaction mixture was washed with water (3×) and dried over magnesium sulfate. The dichloromethane solution was filtered and concentrated in vacuum. The residue was used in the next stage, either in crude form or its purified by chromatography on silica gel using dichloromethane as eluent, resulting in received appropriate vinylboronic, I-45. The product structure was confirmed using1H-NMR.

Synthesis of l-(3-methoxybenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydro-indole-2-it, I-44 In accordance with the General procedure A-4, (1-methyl-2-oxo-cyclohexyl)acetic acid (I-43) was converted to I-44. The structure was confirmed using1H-NMR.

Synthesis of 7-bromo-l-(3-methoxybenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydro-indole-2-it, I-45: In accordance with the General procedure A-5, 1-(3-methoxybenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydro-indole-2-he I-44 was converted into compound I-45. The structure was confirmed using1H-NMR.

Synthesis of 7-(l-ethoxyphenyl)-l-(3-m is oxybenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydro-indole-2-it, I-46. To a solution of bromide I-45 (350 mg, 1 mmol) in dry dioxane (5 ml) was added tributyl(1-ethoxyphenyl)tin (390 mg, 1.05 mmol) and dichlorobis(triphenylphosphine)palladium (36 mg, 0.05 mmol). The reaction mixture was heated in a closed vessel at 100°C for 24 h the Reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with methylene chloride (10 ml) and filtered through a short plug of celite. This tube is repeatedly washed with methylene chloride. The solvent was removed and the crude residue was purified column chromatography on silica gel using hexane and 2% ethyl acetate/hexane, resulting in received 224 mg of compound I-46 (exit 65,7%).1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 7-acetyl-l-(3-methoxybenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydro-indole-2-it, I-47. To a solution of compound I-46 (220 mg, to 0.645 mmol) in THF (5 ml) was added 2n. aqueous HCl (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hours the Reaction mixture was distributed between water and ether (20 ml, 1:1). The mixture was transferred into a separating funnel, and the organic layer was separated. The aqueous layer was extracted with ether (3×15 ml). The combined organic extracts were washed with water and saturated saline solution and then dried over MgSO4, filtered and concentrated to obtain 203 mg is soedineniya I-47. 1H-NMR (500 MHz, CDCl3) confirmed this structure.

Synthesis of 7-(2-bromo-acetyl)-l-(3-methoxybenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydro-indole-2-it, I-48. To a solution of 7-acetyl-1-(3-methoxybenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydro-indole-2-it, I-47 (160 mg, 0,511 mmol)in a mixture of dioxane/chloroform (1:1, 2 ml) every 3 seconds was added one drop of bromine (81,8 mg, 26 μl). The reaction mixture was stirred at room temperature for 2 hours the Mixture was concentrated, diluted with ethyl acetate (10 ml), washed with water and saturated saline solution and then dried over MgSO4was filtered and concentrated, resulting in a received 208 mg of compound I-48. This product was sufficiently pure and was used in the next stage.1H-NMR (500 MHz, CDCl3) confirmed the above structure.

Synthesis of 7-(2-aminothiazol-4-yl)-1-(3-methoxybenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydro-indole-2-it, I-49. A mixture of 7-(2-bromoacetyl)-1-(3-methoxybenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydro-indole-2-it, I-48 (200 mg, 0.51 mmol), thiourea (34 mg, 0.51 mmol) in ethanol (2 ml) was heated at 80°C for 3 hours the Mixture was concentrated, diluted with ethyl acetate (15 ml) and washed with 10% sodium acetate solution (3 ml). The organic layer was separated, washed with water and saturated saline solution and then dried over MgSO4was filtered and concentrated, resulting in a received 150 mg of the crude product. After raster is of the product with ether received 75 mg of compound I-49. 1H-NMR (500 MHz, CDCl3).

Synthesis of 3,4-debtor-N-{4-[l-(3-methoxy-benzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]thiazol-2-yl}-benzosulfimide, B47. To a solution of 7-(2-amino-thiazol-4-yl)-l-(3-methoxy-benzyl)-3a-methyl-l,3,3a,4,5,6-hexahydro-indole-2-it, I-49 (45 mg, 0,122 mmol)in pyridine (0.2 ml) was added DMAP (30 mg, 0.24 mmol). This mixture was heated at 70°C, was added 3,4-differentialalgebraic (52 mg, 0.24 mmol). This solution was turned into a slurry, and after 10 min the reaction was completed. The mixture was cooled to room temperature and concentrated to dryness. The residue was diluted with ethyl acetate (4 ml) and washed with 10% aqueous HCl. The aqueous layer was once again extracted with ethyl acetate. The combined extracts were washed with water and saturated saline solution and then dried over MgSO4was filtered and concentrated, resulting in a received 70 mg of the crude product. After purification of the product by preparative TLC on silica gel using a mixture of ethyl acetate/hexane (1:1) as eluent received 35 mg connection B47 (yield 53%).1H-NMR (400 MHz, CDCl3), to 1.21 (s, 3H), 1,61-to 1.67 (m, 2H), 1,77 of-1.83 (m, 2H), 2,18-of 2.27 (m, 2H), 2,24 (DD, J=16, 4,8 Hz, 2H), of 3.73 (s, 1H), 3,99 (d, J=16 Hz, 1H), to 5.03 (d, J=16 Hz, 1H), 5,95 (s, 1H), 6,36 (d, J=7,6 Hz, 1H), 6,38 (s, 1H), of 6.68 (DD, J=8,4, 2 Hz, 1H), 7 (t, J=8 Hz, 1H), 7.23 percent-7,29 (m, 2H), 7,66-7,76 (m, 2H). LC/MS (ES1+) 546: 93%.

Example 46

Getting B09

Synthesis of 4-(5-fluoro-3-methyl-1H-indol-7-yl)Hairdryer is lamina, I-50. A mixture of compound I-10 (220 mg, 0.96 mmol), 4-(4,4,5,5-tetramethyl)-l,3,2-dioxaborolan-2-yl)aniline (316 mg, 1.44 mmol), tetranitroaniline (56 mg, 0,048 mmol) and cesium carbonate (470 mg, 1.44 mmol) in DMF (4 ml) was heated at 110°C for 2 h in a closed vessel. The reaction mixture was cooled to room temperature and distributed between water and EtOAc. The aqueous layer was extracted with EtOAc (2·20 ml). The combined organic layers were washed with water and saturated saline solution and then dried (MgSO4) and concentrated to obtain 250 mg of the crude product. The crude product was subjected to chromatography on SIO, SIS2using a solvent mixture of 20% EtOAc/hexane, resulting in the received compound I-50 (120 mg, yield 52%) as a white foam.1H-NMR (400 MHz, CDCl3) confirmed the above structure.

Synthesis of N-[4-(5-fluoro-3-methyl-1H-indol-7-yl)-phenyl]methanesulfonamide, I-51. To a solution of 4-(5-fluoro-3-methyl-1H-indol-7-yl)phenylamine, I-50 (120 mg, 0.5 mmol)in pyridine (0.3 ml), cooled to 0°C, was added methanesulfonamide (114,55 mg, 2 EQ.). The reaction mixture was stirred at room temperature for 3 hours the Mixture was concentrated, and then thereto was added 10% aqueous HCl, and the resulting aqueous mixture was extracted with EtOAc (2·10 ml). The combined organic layers were washed with water and saturated saline solution and then dried (MgSO4), filtered and concentrate who has demonstrated obtaining the remainder. The obtained residue was purified column chromatography (SIO, SIS2) using a solvent mixture of 20% EtOAc/hexane, resulting in received 95,5 mg of compound I-51 (yield 60%).1H-NMR (400 MHz, CDCl3) confirmed the above structure.

Synthesis of N-{4-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]phenyl}methanesulfonamide, B09. To a suspension of NaH (60% in mineral oil, 24 mg, 0.59 mmol, 2 EQ.) in DMF (2 ml) was added N-[4-(5-fluoro-3-methyl-1H-indol-7-yl)phenyl]methanesulfonamide, I-51 (95 mg, 0,298 mmol, 1 EQ.) at -10°C. the Reaction mixture was left to warm to room temperature and was stirred for 30 min at room temperature. The reaction mixture was cooled to 0°C and slowly added 2,4-DICHLOROSILANE (71 mg, 0.36 mmol, 1.2 EQ.). The reaction mixture was left to warm to room temperature and was stirred for 4 h the Reaction was suppressed 10% aqueous HCl (10 ml)and the mixture was extracted with ether (3·20 ml). The combined organic extracts were washed with water and saturated saline solution and then dried over MgSO4was filtered and concentrated, resulting in the obtained residue. The obtained residue was purified column chromatography using a mixture of 7% EtOAc/hexane as eluent, resulting in received 38 mg of compound B09 (30%yield).1H-NMR (400 MHz, CDCl3): of 2.34 (s, 3H), of 3.07 (s, 3H), of 4.83 (s, 2H), of 5.99 (d, J=8 Hz, 1H), 6,37 (Sirs, 1H), 6,7 (DD, J=a 9.6, 2.4 Hz, 1H), 6,86 (s, 1H), 6,99 (DD, J=8,4, 2 Hz, 1H), 7,03 (s, 4H), 7,2 (d, J=2 Hz, 1H), 7,26 (DD, J=8,8, 2.4 Hz, 1H). LC-MS (ESI-): 447, 99%.

Compounds according to the invention were analyzed for their binding prostanoid receptors EP3 method described in the publication Abramovitz et al. [Bioch. Biophys. Acta, 1473, 285-293 (2000)]. In Chapter 1, in column 2 specified activity. Connection with IC50<1 μm, +++ marked; connection with IC50=1-10 μm marked ++; compounds with IC50>10 μm marked with +.

Connection No
B(X)
Activity
B01+++
B02++
Who++
B04++
B05++
B06++
B07+
BOS++
B09+
B10++
B11++
+++
B13+++
B14++
B15++
B16+
B17++
B18+++
B19+++
In20+++
B21+
B22+
W++
In 24++
V25+
W+++
27++
B28++
W+++
B30+++
W+++
V32+++
W+++
W+++
W+++
W+++
W+++
W+++
W+++
In40+++
B41 content+++
W+++
W++
B44++
W+++
B46+++
B47+++

1. The compound of the formula

where a and b represent a pair of condensed saturated or unsaturated 5 - or 6-membered ring, where said system condensed rings a/b contains from 0 to 2 nitrogen atoms, and the said ring is optionally substituted by 0-4 substituents independently selected from halogen, Nisse is on the alkyl or oxo;
a and b represent the position of joining residues Y and D, respectively, and these positions a and b are in the peri-position relative to each other at the said condensed ring system And/In;
d and e represent the condensed position between ring a and ring in the specified condensed ring system And/In;
D represents aryl or heteroaryl cyclic system, which means 5 - or 6-membered aromatic ring containing 0-3 heteroatoms selected from O, N or S; which may be optionally substituted by 0-4 substituents independently selected from lower alkyl and amino;
Y is selected from-CH3- and-O-;
M is selected from aryl, aryl substituted with halogen or alkoxy;
R1selected from aryl, aryl substituted with halogen, heteroaryl, heteroaryl substituted with halogen, where heteroaryl means 5 - or 6-membered aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y is-CH2- or-O-, R1additionally represents lower alkyl.

2. The compound according to claim 1, where D represents phenyl, substituted by 0-4 substituents selected from lower alkyl and amino.

3. The compound according to claim 1, where D represents a naphthyl, substituted by 0-4 substituents selected from lower alkyl and amino.

4. The connection p is 1, where D represents a monocyclic heteroaryl, substituted by 0-4 substituents selected from lower alkyl and amino.

5. The compound according to claim 1, where R1selected from phenyl, phenyl substituted by halogen, 5-membered cyclic heteroaryl, 5-membered cyclic heteroaryl, substituted with halogen, CF3.

6. The compound according to claim 1, where M is selected from aryl, aryl substituted by halogen or alkoxy.

7. The connection according to claim 6, where M is selected from phenyl, phenyl substituted by halogen or alkoxy, naphthyl, naphthyl substituted by halogen or alkoxy, heteroaryl and heteroaryl, substituted with halogen or alkoxy.

8. The compound according to claim 1, where said system rings a/b is a pair of condensed 5-membered rings

9. The compound according to claim 1, where said system rings a/b is a pair of condensed 6-membered rings

10. The compound according to claim 1, where said system rings a/b is a pair of condensed 5 - and 6-membered rings
or

11. The connection of claim 10, where said system rings a/b is an indole.

12. The use of compound or complex ester according to claim 1 to obtain a pharmaceutical composition for the treatment or prevention mediated prostage the dynamics of the disease or condition in a mammal.

13. The application indicated in paragraph 12, where the specified condition is occlusive vascular disease.

14. The use of compound or complex ester according to claim 1 to obtain a pharmaceutical composition for reducing the amount of plaques in the treatment of atherosclerosis in a mammal.

15. The use of compound or complex ester according to claim 1 to obtain a pharmaceutical composition for the stimulation of osteogenesis or cytoprotective the mammal.

16. The use of compound or complex ester according to claim 1 to obtain a pharmaceutical composition for the treatment or prevention of pain, inflammation, atherosclerosis, myocardial infarction, stroke, or occlusive vascular disease in a mammal.

17. The pharmaceutical composition intended to inhibit the binding of prostaglandin E2with ER receptor containing a pharmaceutically acceptable carrier and a compound according to claim 1.

18. Method of screening for selective ligands prostanoid receptors, comprising contacting the labeled compound according to claim 1 with prostanoid receptor and measuring the displacement of the label test connection.

19. The method according to p representing a method of screening for selective ligands ER, comprising contacting the specified labeled connection with the cloned human receptor ER and measurement of vitess the deposits label test connection.

20. The compound of the formula

where a and b represent a pair unsaturated condensed 5-or 6-membered ring, and where this condensed system of rings a/b contains 1 heteroatom of nitrogen, and the said ring is optionally substituted by 0-4 substituents independently selected from halogen and lower alkyl;
a and b represent the position of joining residues Y and D, respectively, and these positions a and b are in the peri-position relative to each other at the said condensed ring system And/In;
d and e represent the condensed position between ring a and ring in the specified condensed ring system And/In;
U represents C=O or P=O;
D represents aryl or heteroaryl cyclic system, which means 5 - or 6-membered aromatic ring containing 0-3 heteroatoms selected from O, N or S, which may optionally be substituted by 0-4 substituents independently selected from halogen or lower alkyl;
Y represents-CH2;
M is selected from aryl, aryl substituted with halogen;
R1selected from aryl, aryl substituted with halogen, heteroaryl, which represents a 5 - or 6-membered aromatic ring containing 0-3 heteroatoms selected from O, N or S; CF3and lower alkyl.

21. Connection is about claim 20, where U represents C=O.

22. Connection claim 20, where U is a P=O.

23. The connection to item 21 or 22, where this system of rings a/b is an indole.

24. Connection item 23, where D represents a phenyl or oxadiazolyl.

25. The connection point 24, where R1selected from phenyl, phenyl substituted by halogen, 5-membered cyclic heteroaryl containing 0-3 heteroatoms selected from O, N or S, CH3and CF3.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to uniformly tritium-labelled (R)-(+)-[5-methyl-3-(4-morpholinylmethyl)-2,3-dihydro-[1,4]oxazine[2,3,4-hi]-6-indolyl]-1-naphthalinylmethanone acetate of formula I: .

EFFECT: wide range of labelled analogues of physiologically active compounds.

1 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula: I, where R1 is selected from group, consisting of ethyl, 2-fluorethyl and isopropyl; R2 is selected from group, consisting of hydrogen, C1-7-alkyl, hydroxy, C1-7-alkoxy, C3-7-cycloalkyl, halogen, -C(O)OR6, where R6 represents C1-7-alkyl, amino, phenyl, phenyl, substituted with 1-3 substituents, selected from group, consisting of halogen, halogen-C1-7-alkyl and halogen-C1-7-alkoxy, pyridyl, imidazolyl, triazolyl and pyrrolyl; R3 is selected from group, consisting of hydrogen, C1-7-alkoxy, amino, -O-benzyl and -o-tetrahydropyranyl; or R2 and R3 are bound to each other with formation of cycle together with carbon atoms to which they are bound, and R2 and R3 together represent -CH=CH-NH-; R4 is selected from group, consisting of hydrogen, halogen, pyridyl and pyrimidyl; R5 and R5' independently on each other are selected from hydrogen or methyl; A is selected from group, consisting of isphenyl; phenyl, substituted with 1-3 substituents, selected from group, consisting of C1-7-alkyl, C3-7-cycloalkyl, C1-7-alkylsulfonyl, -O-C1-7-alkylsulfonyl, hydroxy, C1-7-alkoxy, hydroxy-C1-7-alkyl, hydroxy-C2-7-alkoxy, dihydroxy-C3-7-alkoxy, C1-7-alkylamino, di-C1-7-alkylamino, amino-C2-7-alkoxy, amino-C1-7-alkyl, -C(O)NR10R11, -O-C1-7-alkylene-C(O)NR10R11, -C(O)OR10, -C1-7-alkylene-C(O)OR10, -O-C1-7-alkylene-C(O)OR10, halogen, halogen-C1-7-alkoxy, cyano- C1-7-alkoxy, fluorphenyl, pyridyl, tetrazolyl and tetrazolyl- C1-7-alkoxy; 1,3-benzodioxolyl; naphtyl; pyrimidinyl; pyridyl, substituted with one or two substituents, selected from group, consisting of C1-7-alkyl, C1-7-alkoxy, amino, C1-7-alkylamino, di-C1-7-alkylamino, C3-7-cycloalkylamino, halogen, cyano, morpholinyl, imidazolyl and -NH-C(O)-R9, where R9 represents C1-7-alkyl or C3-7-cycloalkyl, and indolyl; R10 and R11 independently on each other represent hydrogen or C1-7-alkyl; and to their pharmaceutically accdeptable salts. Invention also relates to pharmaceutical compositions.

EFFECT: obtaining novel biologically active compounds, which are antagonists of somatostatin receptor subtype 5 (SSTR5).

26 cl, 266 ex

FIELD: chemistry.

SUBSTANCE: in formula (1) A is a nitrogen atom or CH; when A is a nitrogen atom, B is NR9 (where R9 is a C1-10alkyl group), when A is CH, B is a sulphur atom, R1 is a phenyl group (where the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10alkyl group and C1-10alkoxy groups (where C1-10alkyl groups and C1-10alkoxy groups are not substituted of substituted with one or more halogen atoms)); L1 is a bond; X is OH; R2 is a C1-6alkyl group; L2 is a bond; L3 is NH; L4 is a bond or NH; Y is an oxygen atom or sulphur atom; R3 is a thienyl group (where the thienyl group is substituted with CONR29R30 (where R29 is hydrogen or a C1-10alkyl group, and R30 is an amino group (where the amino group is not substituted or substituted with a pyridyl group), mono- or di-C1-10alkylamino group, N-methylpiperzinyl group, piperidine group, morpholine group or C1-10alkyl group (C1-10alkyl group is substituted with one or more substitutes selected from a group consisting of a carboxyl group, carbamoyl groups, pyrroldinyl groups, tetrahydrofuryl groups or morpholine groups) or R29 and R30 together denote -(CH2)m3-G-(CH2)m4- (where G is CR31R32 (where R31 is a hydrogen atom and R32 is a C1-10alkylcarbonylamino group or pyrrolidinyl group) and each of m3 and m4 is independently equal to an integer from 0 to 5 provided that m3+m4 equals 3, 4 or 5), or NR29R30 as a whole denotes a piperidine group or pyrrolidinyl group (where the piperidine group or pyrrolidinyl group is substituted with two substitutes independently selected from a group consisting of: hydroxyl groups and C1-10alkoxy groups) or 2-(4-oxopyrridin-1(4H)-yl)acetyl group), phenyl group (where the phenyl group is substituted with one substitute selected from a group consisting of C1-10alkyl groups, C1-10alkylcarbonyl groups and C1-10alkylaminocarbonyl groups, (where C1-10alkyl group, C1-10alkylcarbonyl group and C1-10alkylaminocarbonyl group are substituted with one or two substitutes selected from a group consisting of hydroxyl groups, carboxyl groups and carbamoyl groups)), phenyl group (where the phenyl group is substituted with one C1-10alkylaminocarbonyl group or one halogen atom), dihydrobenzo[1,4]dioxine group or benzo[1,4]oxazine group. The invention also relates to a medicinal agent containing the disclosed compound as an active ingredient and to a thromopoeitin receptor activator which is a formula (1) compound.

EFFECT: disclosed compounds have thrombopoietin receptor agonist properties.

8 cl, 11 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

EFFECT: novel compounds which can be useful in treating and preventing diabetes and obesity are obtained and described.

29 cl, 227 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK) of formula (I)

, where R0 denotes hydrogen; R1 is a saturated 6-member monocyclic or 10-member bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, which can be substituted with piperidinyl, (C1-C7)alkylpiperidinyl, hydroxy, (C1-C7)alkyl, piperazinyl, (C1-C7)alkylpiperazinyl; R2 and R3 together with the carbon or nitrogen atom to which they are bonded form a 5- or 6-member heterocycle containing one heteroatom selected from a nitrogen atom which is substituted with (C1-C7)alkyl and/or oxo- group, R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; halide, (C1-C7)alkoxy; carbamoyl which is unsubstituted or substituted with (C1-C7)alkyl; (C1-C7)alkoxy(C1-C7)alkoxy; 5- or 6-member heterocycle containing one or two heteroatoms independently selected from nitrogen or oxygen, and is unsubstituted or substituted with a substitute independently selected from hydroxy, (C1-C7)alkyl, mono- or di(C1-C7)alkylamino, 6-member heterocycle containing one or two nitrogen ring atoms which are unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle(C1-C7)alkoxy containing one nitrogen ring atom which is unsubstituted or substituted with (C1-C7)alkyl; R9 is hydrogen; R10 is hydrogen, halide or (C1-C7)alkoxy; or their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and use of formula (I) compounds.

EFFECT: obtaining novel compounds with inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK), having formula (I) .

7 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 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: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound of formula [I]: where A cycle represents a benzene cycle optionally having substitute(s) different from R1, R1 represents a group of formula RaSO2NH-, RaSO2NH-CH2- or (Rb)(Rc)NSO2-, Ra represents C1-C6 alkyl group, C3-C10cycloalkyl group, an amino group, 6-10-member monocyclic or bicyclic aryl group or 5-10-member monocyclic or bicyclic heteroaryl group containing 1-2 heteroatoms, chosen from oxygen, sulphur and nitrogen atoms, Rb and Rc are identical or different, and each represents hydrogen atom, C1-C6alkyl group or C3-C10cycloalkyl group, one of R2 and R3 represents hydrogen atom, halogen atom or C1-C6alkyl group, and the other represents hydrogen atom, C1-C6alkyl group, C1-C6alkoxycarbonyl group or phenyl group, or both are combined with each other together with the neighbouring carbon atom to form C3-C10cycloalkyl group, X represents oxygen atom, sulphur atom, or formula group of -NR4-; Y represents a group of formula -C(=O)-, -C(=S)- or CH(R5)-; Ar represents optionally substituted 6-10-member monocyclic or bicyclic aryl group or 5-10-member monocyclic or bicyclic group; Q represents a simple bond, C1-C6alkylene group or C2-C6alkenylene group, or its pharmaceutically acceptable salts There are described specific compounds of formula [I], and also intermediate compounds.

EFFECT: presented compounds exhibit affinity to mineralocorticoid receptor (MR) and are applicable for prevention or treatment of various diseases or diseased states associated with such receptor.

11 cl, 54 tbl, 410 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where X is C(R8R9), NR10, O, S; R1 is phenyl which is substituted with 1-3 substitutes selected from a group which includes halogen, hydroxy group, lower alkyl, hydroxy-lower alkyl and CN; R2 is hydrogenor lower alkyl; R3 and R4 are hydrogen; R5 and R6 are hydrogen; R7 is oxadiazolyl or triazolyl, where oxadiazolyl or triazolyl is substituted with R11; R8 and R9 denote hydrogen; R10 denotes hydrogen, lower alkyl, lower alkyl-carbonyl or lower alkyl-sulfonyl, R11 denotes aryl or hetearyl, selected from a group comprising pyridinyl, pyrazinyl, pyrimidinyl, pyridinyl-2-one, oxadiazolyl, indazolyl, 1,3-dihydrobenzimidazol-2-one, 1,3-dihydroindol-2-one, benzotriazolyl, imidazopyridinyl, triazolepyridinyl, tetrazolepyridinyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-indol-5-yl, pyrimidin-4-one, furanyl, thiadiazolyl, pyrazolyl, isoxazolyl, pyrimidin-2,4-one, benzoxazin-3-one, 1,4-dihydrobenzoxazin-2-one, indolyl, thiophenyl, oxazolyl, benzooxazin-2-one; 3,4-dihydroquinazolin-2-one, pyridazinyl, quinoxalinyl, benzothiazolyl, benzothiadiazolyl, naphthyridinyl, cinnolinyl, 1,4-dihydroquinoxalin-2,3-dione and 1,2-dihydroindazol-3-one, where the aryl or heteroaryl is optionally substituted with 1-3 substitutes selected from a group which includes lower alkyl, hydroxy group, B(OH)2, carboxy-lower alkoxy group, carbamoyl-lower alkoxy group, cyano group, hydroxy-lower alkyl, fluoro-lower alkyl, lower alkoxy group, halogen, S(O2)R13, C(O)R14, NO2, NR15R16, phenyl-lower alkoxy group, [1,3,4]oxadiazol-2-one, oxadiazolyl, triazolyl and isoxazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrrolyl, where imidazolyl is optionally substituted with lower alkyl, and where isoxazolyl is substituted with lower alkyl; R12 denotes hydrogen or lower alkyl; R13 denotes lower alkyl, NR17R18 or fluoro-lower alkyl; R14 denotes NR19 R20, lower alkoxy group, lower alkenyl-oxy group or lower alkyl; R15 and R16 independently denote hydrogen, lower alkyl, lower alkyl-carbonyl, lower alkyl-SO2, lower alkenyl-oxycarbonyl and lower alkyl-NH-carbonyl; or NR15R16 denotes heterocyclyl selected from a group which includes morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperidin-2-one, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, pyrrolidinyl, 1,1-dioxoisothiazolidinyl, pyrrolidin-2-one, imidazolidine-1,4-dione, 2,4-dihydro[1.2.4]triazol-3-one, pyrrolidine-2,5-dione, azetidin-2-one and 1,3-dihydroimidazol-2-one, where the heterocycle is optionally substituted with hydroxy-lower alkyl or lower alkyl-carbonyl; R17 and R18 independently denote hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl; or NR17 R18 denotes morpholinyl; R19 and R20 independently denote hydrogen, lower alkyl, cycloalkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl or cyano-lower alkyl; or NR19 R20 denotes heterocyclyl selected from a group which includes morpholinyl, pyrrolidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, piperazin-2-one, thiazolidinyl, thiomorpholinyl, 1,3,8-triaza-spiro[4.5]decane-2,4-dione and spiro(1- phthalan)piperidin-4-yl, where the heterocyclyl is optionally substituted with a hydroxy group, lower alkyl-(SO2), lower alkyl, lower alkyl-carbonyl or lower alkoxy group, carboxyl group, carbamoyl, cyano group and phenyl; and to their pharmaceutically acceptable salts. Invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which inhibit hepatic carnitine palmitoyltransferase 1 (L-CPT1).

35 cl, 565 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel salt form of 5-[(2R,5S)-5-methyl-4-propylmorpholin-2-yl]piridine-2-amine (I): , and specifically to 5-[2R,5S)-5-methyl-4-propylmorpholin-2-yl]pyridine-2-amine di-(1S)-camphorsulphonate (di-S-camsylate), to a pharmaceutical composition having effect on dopamine D3 receptor, as well use of the given compound in preparing a medicinal agent for treating sexual dysfunction and neuropsychiatric disorders and a method of obtaining the said compound and an intermediate compound.

EFFECT: novel salt form of a dopamine agonist which has advantages, specifically is not hygroscopic, has a crystalline form and has high melting point is obtained and described.

11 cl, 9 ex, 2 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

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