Sulfonamide peri-substituted bicycles for treatment of occlusive affection of arteries

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel acylsulfonamide peri-substituted condensed bicyclic compounds of general formula (I), values of radicals are given in invention formula. Also described is pharmaceutical composition based on formula (I) compound.

EFFECT: compounds can be used for inhibition of prostaglandin E2 binding with receptor EP3.

30 cl, 371 ex, 4 tbl

 

Description

The present invention relates to the chemical class of peri-substituted bicyclic arylsulfonamides, which are useful for the treatment and prevention of occlusive artery disease and related prostaglandin-mediated disorders.

Atherosclerosis is a pathology, which lies at the basis of a number of diseases characterized by high mortality, such as myocardial infarction and peripheral occlusive lesion artery disease (PAOD). PAOD is a atherosclerosis of large and medium arteries of the extremities, particularly the lower limbs, and also affects the aorta and iliac arteries. This disease often occurs simultaneously with coronary artery and cerebrovascular disorder. Patients with PAOD 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]. Clinically significant damage can gradually narrowed peripheral arteries, causing pain when walking, usually falling at rest (claudication), ischemic ulcers, gangrene and even amputation. Therapeutic treatment is usually ineffective, but the operation of the bypass or replace damaged or artificial venous the grafts distal improve blood flow, at least up until arteries are narrowed [Haustein, K.O., Int. J. Clin. Pharmacol. Ther., 35:266 (1997)]. Recently in the process of genetic analysis of groups of coupling person was found that changes in DNA PTGER3 gene, which encodes prostaglandin E2receptor subtype 3 (known as EP3), increase the risk of developing the individual PAOD (see publication of the patent application U.S. 2003/0157599). Thus, antagonists of prostaglandin E2(PGE2)that communicates with the EP3 receptor, can provide effective treatment or prevention of PAOD.

In response to various extracellular stimuli prostaglandins easily produced from free arachidonic acid by the sequential action of cyclooxygenase and synthases. Prostaglandins appear to act in the immediate vicinity of the site, where they are synthesized. Up to the present time has been cloned and characterized eight prostanoid receptors. These receptors are members of a growing class of G-protein-linked receptors. PGE2communicates preferably with receptors EP1, EP2, EP3 and EP4; PGD2- with receptors DP and FP receptors; PGF2a- with receptors FP and EP3 receptors; PGI2- with the IP receptor, and TXA2- with the TP receptor. It was found that PGE2that communicates with the EP3 receptor, plays a key is Yu role in the regulation of ion transport, the contraction of smooth muscles LCD tract, secretion of acid, the reduction of the uterus in the process of fertilization and implantation, when the fever (fever generation) and hyperalgesia. The EP3 receptor has been found in many organs such as the kidneys, gastrointestinal tract, uterus and brain. In the cardiovascular system EP3 downregulation of vascular endothelial and smooth muscle, and at least four isoforms of the EP3 expressed on human platelets [Paul, B.Z., B. Ashby. 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 specific membrane receptors belonging to the superfamily of G-protein-binding receptors (GPCR), play a significant role in vascular homeostasis, including the regulatory function of platelets. Among prostanoids the thromboxane A2 (tha2) is a potent stimulator of platelet aggregation, whereas prostaglandin (PG)I2inhibits their activation. On the other hand, it was reported that prostaglandin E2(PGE2) has a biphasic effect on the response of platelets, potentsiruya their aggregation at low concentrations and inhibiting it at higher concentrations. It was shown that the stimulatory effects of PGE2on platelet aggregation is carried out mainly through ER receptor, one of the n of the four subtypes of receptors, activated PGE2.

Localized synthesis of prostaglandins in the wall of the blood vessel can play an important role in the development of atherosclerosis. Although in the wall of the healthy vessel is present only MOR-1 in the atherosclerotic plaque are present as MOR-1 and MOR-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 in combination with increased expression of properdin-E-synthase may explain the increased production of PGE2noted above. In the body of the genetically modified mice that lack the receptor low density lipoprotein (LDL-R) the formation of atherosclerotic plaques can be reduced by treatment with rofecoxib, selective inhibitor SOH-2 through a reduction in the production of PGE2and other prostaglandins [Burleigh M.E., Babaev V.R., J.A. Oates, Harris R.C., Gautam S., Riendeau D., Mamett L.J., Morrow J.D., Fazio s, Linton M.F. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation. 2002 Apr 16; 105(15):1816-23].

It was shown that in atherosclerotic plaques of smooth muscle cells Express ER receptor, and PGE2stimulates their proliferation and migration, which is an indicator of the formation of atherosclerotic the Oh plaques [R. Blindt, A.K. Bosserhoff, vom Dahl j, Hanrath P., Schror K, Hohlfeld, T., Meyer-Kirchrath J. Activation of IP and EP(3) receptors alters cAMP-dependent cell migration. Eur. J. Pharmacol. 2002 May 24; 444 (1-2): 31-7]. Therefore, we can safely assume that chronically inflamed blood vessels produce PGE2in a quantity sufficient to activate EP3receptors on cells of the vascular smooth muscle (contributing to the formation of atherosclerotic damage) and platelets (contributing to thrombosis). Locally produced PGE2(directly from the platelet component of the vessel wall and inflammatory cells) enhances platelet aggregation with suboptimal amounts of prothrombotic tissue factors, which by themselves may not cause their aggregation in the process of sensitization of protein kinase C. Intracellular events initiated by the activation EP3receptor may increase platelet aggregation, counteracting the effect of PGI2and increasing the effects of agents that cause primary aggregation, such as collagen. Thus, activation of EP3receptor may contribute to the development of atherosclerosis and risk of thrombosis observed in pathological conditions, such as vasculitis and PAOD.

The currently used methods of treatment OD aimed at reducing the risk of painful manifestations of cardiovascular disorders, such as infer the t infarction and stroke, or provide symptomatic relief of claudication. All of these treatments act on functions trombotsitov. Treatments that reduce the risk of painful manifestations of cardiovascular disorders include the introduction of aspirin in low doses (sufficient to reduce platelet aggregation, but allowing the vessel wall to produce PGE2and the introduction of inhibitors adenosintriphosphate receptor of platelets (clopidogrel). The binding of adenosine with trombotsitnoy adenosintriphosphate receptor causes a decrease trombotsitnoy of camp and subsequent activation and aggregation of platelets. The treatments provide symptomatic relief of claudication include inhibitors trombotsitnoy phosphodiesterase type 3, such as Cilostazol, which causes an increase in intracellular levels of camp. Inhibitors trombotsitnoy adenosintriphosphate receptor or trombotsitnoy phosphodiesterase type 3 directly or indirectly cause increased levels of camp in platelets, inhibiting thus, the activation and subsequent platelet aggregation with formation of blood clots. PGE2linking ER reduces camp, so it is expected that the antagonist PGE2binding OR receptor, counteracting PGE2-dependent reduction of camp required for the induction of platelet activation and subsequent the th aggregation, or counteracting PGE2-dependent decrease in cellular camp vascular smooth muscle needed to encourage migration, may provide useful therapeutic effect with PAOD. Such an antagonist may also modify the disease inhibition or reduction in the formation of plaques.

Thus, prostaglandins are involved in a wide range of painful conditions, including pain, fever or inflammation associated with rheumatic attack, flu, or other viral infections, common cold, lumbar pain and pain in the neck, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, dental pain, pain associated with sprains and strains of ligaments, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative arthritis (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation (radiation and corrosive chemical injuries and sunburns, pain following surgical and dental procedures, immune and autoimmune diseases; regeneration of normal cells into tumor cells or metastatic tumor growth; diabetic retinopathy, tumor angiogenesis; prostanoid-induced smooth muscle contraction associated with dysmenorrhea, premature birth, asthma or disorders associated with eosino the ilen granulocytes; Alzheimer's disease; glaucoma; bone loss; osteoporosis; Paget's disease; peptic ulcers, gastritis, regional enteritis (Crohn's disease), ulcerative colitis, diverticulitis or other gastrointestinal disorders; gastrointestinal bleeding; disorders in coagulation disorder selected from gipoprotrombinemii, hemophilia and other disorders associated with bleeding; and kidney disease.

Although the levels of circulating prostaglandins in healthy organisms are extremely low [FitzGerald G.A., A.R. Brash, Falardeau, P. & OatesJ A. JCI 1981 68:12472-1275], the local concentration of PGE2may be increased in areas of inflammation. For example, it was shown that local production of PGE2in vitroincreased more than 30 times with occlusive lesions of the aorta ['reilly J., Miralles, M., Wester, W. & Sicard G. Surgery, 1999, 126:624-628]. Therefore, we can safely assume that chronically inflamed blood vessels produce a sufficient amount of PGE2to activate EP3receptors on the platelets. In this environment, the intracellular events triggered by the activation of the EP3receptor may increase platelet aggregation counter-effect PGI2and the increasing effects of the primary enzymes that cause aggregation, such as ADP. Thus, activation of ER3the recipe is RA may contribute to thrombosis, observed under pathological conditions, such as vasculitis and atherosclerosis. Peripheral occlusive lesion of the artery (PAOD) is an atherosclerotic disease that occurs primarily in the elderly due to occlusion of the lumen of the peripheral arteries, mainly the femoral artery, and is associated with an increased risk of vascular events such as myocardial infarction and stroke [Waters, R.E., R.L. Terjung, K.G. Peters & B.H. Annex J. Appl. Physiol. 2004; OurielK. Lancet, 2001, 258:1257-64; Kroger K. Angiology, 2004, 55:135-138]. The results of some clinical studies have shown that treatment with prostaglandins improves symptoms of PAOD [Reiter M, Bucek R, Stumpflen A & Minar E. Cochrane Database Syst. Rev. 2004, 1:CD000986; Bandiera G., Forletta M., Di Paola F.M., 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], confirming the link between PAOD and function prostanoid receptor.

Ortho-substituted phenylalaline and their use for the treatment of prostaglandin-mediated disorders described in U.S. patent No. 6242493 and two publications: Juteauet al.BioOrg. Med. Chem. 9, 1977-1984 (2001); Gallantet al.BioOrg. Med. Chem. Let. 12, 2583-2586 (2002), the contents of which are introduced in this description by reference.

In accordance with one aspect, the invention relates to compounds of the formula

where a and b represent two condensed 5-, 6 - or 7-membered ring. To generowania a/b ring system may contain from 0 to four heteroatoms, selected from nitrogen atoms, oxygen and sulfur and may be optionally substituted by from 0 to four 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, di-lower alkylamino, di-lower acylaminoalkyl, carboxy, carbalkoxy, acyl, arylalkyl, carboxamido, lower alkylsulfonate, acylamino, phenyl, benzyl,Spirothiazolidine, phenoxy and benzyloxy. Branching, designated as "a" and "b"represent the attachment point of the residues Y and W, respectively, and that the point "a" and "b" on the condensed a/b ring system in relation to each other are located in the peri-position. Branching, designated as "d" and "e"represent the condensation point of ring a and ring B in condensed a/b ring system. Each of the branches a, b, d, and e may represent a carbon atom or nitrogen.

W and Y are links containing from zero to 8 atoms in the chain.

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

In one subgroup of compounds (Ia) Q select the n of N(SO 2R1)-, -N(COR1)-, -N[PO(O-alkyl)2]-, -NHNR10(SO2Rland, when W represents-CF2- or-CH2CF2-, Q may additionally represent-NH-; R1selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl,3-C20the alkyl and foralkyl; and R10selected from alkyl, aryl and heteroaryl. In another subgroup (Ib), Q represents-O-, and the compounds are carboxylic acids. The claims presented below, refers to compounds of the subgroup (Ia). Claims related application entitled "Bicyclic peri-substituted carboxylic acid for the treatment of occlusive arterial filed for registration after filing of the present application, refers to a subgroup of compounds Ib.

Other related compounds, useful for the treatment of occlusive lesions of the arteries and related prostaglandin-mediated disorders, include compounds of formula Ic:

where U is selected from-O - and-NH-; and

R20-R25independently selected from hydrogen, halogen and methyl.

In accordance with the second aspect, the invention relates to pharmaceutical preparations containing pharmaceutically acceptable carrier and a compound as described above, or its ester, pharmaceutically when mleay salt or hydrate.

In accordance with a third aspect, the invention relates to methods for treating or preventing a prostaglandin mediated disease or condition. The methods include the administration to the mammal therapeutically effective amounts of compounds described in this invention.

The disease or condition may represent, for example, pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, common cold, lumbar pain and pain in the neck, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, dental pain, pain associated with sprains and strains of ligaments, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative arthritis (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation (radiation and corrosive chemical injuries, as well as solar burns, pain after surgery and dental procedures, immune and autoimmune diseases. Compounds according to the present invention are antagonists OR penetrating into the Central nervous system and especially suitable for the treatment of pain.

Compounds according to the present invention, which inhibit platelet aggregation and increase regional blood flow, useful for the treatment of primary thromboembolism, thrombosis and occlusion the ion lesions of blood vessels. Compounds can preferably be used in combination with other platelet aggregation inhibitors and inhibitors of the biosynthesis or uptake of cholesterol. Connections can also be successfully used in combination with inhibitors of cyclooxygenase-2 for the treatment of an inflammatory condition.

Other diseases or conditions that can be treated are, for example, the degeneration of the cells with the formation of a tumor or metastatic tumor growth; diabetic retinopathy, tumor angiogenesis; prostanoid-induced smooth muscle contraction associated with dysmenorrhea, premature birth, asthma or disorders associated with eosinophilic granulocytes; Alzheimer's disease; glaucoma; bone loss; osteoporosis or Paget's disease; peptic ulcers, gastritis, regional enteritis (Crohn's disease), diverticulitis or other gastrointestinal disorders; gastrointestinal bleeding; coagulation disorders selected from gipoprotrombinemii, hemophilia and other disorders associated with bleeding; and kidney disease. The aspect of the invention, associated with the method also includes methods of acceleration of bone formation, cytoprotective and reduce plaque in the treatment of multiple sclerosis.

In accordance with the fourth aspect, the present invention relative to the tsya to methods of screening for selective prostanoid receptors in particular ER ligands. The method of screening may be a screening in vitro.

Compounds of the class represented by the above formulas Ia and Ic, are antagonists OR receptor. They are useful for the treatment and prevention of prostaglandin-mediated conditions, which are described above, particularly conditions such as occlusive vascular lesions.

Compositions according to the present invention contain an effective dosage or therapeutically effective amount of the compounds described above, and may optionally contain 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. Additional non-limiting list of examples of the antihyperlipidemic tools that can be used in combination with the compounds according to the present invention, can be found in columns 5-6 of U.S. patent No. 6498156, the content of which is introduced in the present description by reference. Preferred inhibitors of cyclooxygenase-2 inhibitors that are selective towards Cox-2 relative to recloak is igenity-1. Preferred inhibitors of cyclooxygenase-2 include rofecoksib, meloxicam, celecoxib, etoricoxib, lumiracoxib, valdecoxib, parecoxib, cimicoxib, diclofenac, sulindac, etodolac, Ketorolac, Ketoprofen, piroxicam and LAS-34475, although the invention is not limited to these or other known inhibitors of cyclooxygenase-2.

The methods according to the invention apply equally to compositions and preparations. The methods include administration to a patient in need of treatment a therapeutically effective amount of peri-substituted condensed And/In cyclic compounds according to the invention. The present invention relates also to methods of screeningin vitroselective agonists and antagonists prostanoid receptors. Prostanoid receptors include ER, EP2, EP3, EP4, IP connection and F receptors. Selective ER ligands are of great interest for a method that includes contacting the labeled compound according to the present invention with cloned ER receptor of a man and a quantitative measure of the replacement test connection.

The class of compounds according to the present invention includes compounds of formula Ia:

where Q is selected from-N(SO2R1)-, -N(COR1)- and-N[PO(O-alkyl)2]when W represents CF2-, Q fill the nutrient can represent-NH-. The substituents on Q is selected to make the hydrogen is attached to Q, the acid properties. In one subclass of compounds Q represents-N[PO(O-alkyl)2]. In another subclass of Q represents-N(COR1)-. In the third subclass Q represents-N(SO2Rl). R1selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl and CF3. In one embodiment of the invention R1selected from phenyl, substituted phenyl, 5-membered heteroaryl, substituted 5-membered ring heteroaryl and CF3.

Each of a and b independently represents a 5-, 6 - or 7-membered ring. Condensed a/b ring system contains from zero to four heteroatoms selected from nitrogen atoms, oxygen and sulfur, and the ring optionally substituted by from 0 to four substituents. Suitable substituents include 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, di-lower alkylamino, di-lower acylaminoalkyl, carboxy, carbalkoxy, complex orthoepy, acyl, carboxamido, lower alkylsulfonyl, acylamino, phenyl, benzyl, spiritualizing, phenoxy and benzyloxy. As condensed a/b ring system which may include a nitrogen atom, or sulfur, the substituents can include oxides, such as N→O and S→O.

In one subclass of the a/b ring system is a pair of condensed 5-membered rings:

Examples of such 5/5 ring systems are

In another subfamily a/b ring system is a pair of condensed 6-membered rings:

Examples of such 6/6 ring systems are:

In another subfamily a/b ring system is a condensed pair of 5 - and 6-membered rings

Examples of such 5/6 ring systems are indoles, indoline, Indology, satiny, benzimidazole, benzoxazolinone, benzofuranyl and indazole:

As indicated above, the ring system can be substituted, for example:

W and Y represent a bridge of communication, containing from 0 to 8 atoms in the chain. Preferably, they represent a1-C8alkyl, in which one and the both-CH 2- may be replaced by-O-, -S(=O)-, -CH=CH-, -CF2-, -S-, -SO-, -SO2-, -NH - or-N(alkyl)-. More preferably, W and Y represent diatomic chain, i.e. With1or2alkyl, in which one or both-CH2- can be substituted by the groups mentioned above. In one embodiment of the invention W is selected from-CH2-CH2-, -Och2-, -C(=O)-, -CH2O-, -OCF2-, -OC(CH3)2-, -Och(CH3)-, -CH=CH-, -NHC(=O) -, and-NHCH2-; and Y is selected from-CH2-, -O-, -OCH2-,=N-, -S-, -SO - and-SO2-. The left link shows the point of connection to the ring a or C.

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

In one embodiment of the invention a/b ring system is an indole. In another additional embodiment of the invention, Q represents-N(SO2R1)and R1selected from phenyl, substituted phenyl, 5-membered heteroaryl, substituted 5-membered heteroaryl and CF3. In another variationbetween invention, M is selected from substituted phenyl, naphthyl and bicyclic nitrogen-containing heteroaryl. In yet another embodiment of the invention Y is-CH2- and W represents-CH=CH-.

Subclass, which includes all the above elements, is a subclass of disubstituted indoles of the formula:

The preferred compound in this subfamily represents a connection, where M represents a 2,4-dichlorophenyl and R1is dichlorotin-2-yl (example R).

where U is selected from-O - and-NH-; and

R20-R25selected from hydrogen, halogen and methyl.

In some embodiments of the invention U represents O. In other embodiments, U represents O, and R22, R23, R24and R25are halogen-free. In specific embodiments of the invention R22, R23, R24and R25all are chlorine.

In other embodiments of the invention U represents-NH-. In some embodiments, the implementation of U represents-NH - and R22and R23represent halogen.

Compounds according to the present invention are acidic, which gives the opportunity to present them in the form of salts. The term "pharmaceutically acceptable salt" refers to salts, the counterion of which is derived from pharmaceutically acceptable non-toxic acids and bases. Suitable pharmaceutically acceptable basic additive salts of the compounds of the present invention include, but without limitation, metal salts derived from salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts derived from lysine, N,N-dialkylaminoalkyl derivatives (for example, N,N-dimethylglycine, piperidine-1-acetic acid and morpholine-4-acetic acid), N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine. When the compounds contain a basic residue, suitable pharmaceutically acceptable basic additive salts of the compounds according to the present invention include inorganic acids and organic acids. Examples of such salts include the 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.

Definition

Used hereinafter in the present description the terms and substituents have the following definitions.

As used herein, the term "alkyl" includes linear, branched and cyclic hydrocarbon, structurai combinations thereof. The term "lower alkyl" refers to alkyl groups containing from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec - and tert-butyl and the like, the Preferred alkyl and alkionovymi groups are groups from C20and below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups containing 3 to 8 carbon atoms. Examples cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, substituted etc.

The term "C1-C20the hydrocarbon includes alkyl, cycloalkyl, alkenyl, quinil, aryl, and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, Campari and naphtalate.

The terms "alkoxy" or "alkoxyl" refers to groups containing from 1 to 8 carbon atoms in the straight, branched, ring configuration, and their combinations that are attached to the main structure through oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropylamine, cyclohexyloxy, etc. the Term "lower alkoxy" refers to groups containing one to four carbon atoms.

The term "oxaalkyl" refers to alkyl residues in which one or more carbon atoms (and their associated hydrogen atoms) are replaced by oxygen. Examples of such groups include methoxypropane, 3,69-trioxadecyl etc. It is implied that the meaning of the term well-known in this area [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 196, but without limitation l27(a)], i.e. refers to compounds where the oxygen is connected to the adjacent atom through a single bond (forming ether linkages). Similarly, the terms "thioalkyl and isoalkyl" refers to alkyl radicals in which one or more carbon atoms are replaced by sulfur atom and nitrogen, respectively. Examples of such radicals include acylaminoacyl and metaltipped. It is implied that the term "oxo" refers to the Deputy, which is attached via a double bond and a represents oxygen (carbonyl). Thus, for example, 2-oxoindole according to the invention should have a structure:

The term "acyl" refers to a group containing from 1 to 8 carbon atoms in the straight, branched, ring configuration, saturated, unsaturated and aromatic and their various combinations, which are attached to the main structure via a carbonyl functional group. One or more of the carbon atoms in the acyl residue may be replaced by nitrogen atoms, oxygen or sulfur, provided that the point of connection to the main structure remains with the carbonyl. Examples of such groups include formyl, acetyl, propio the sludge, isobutyryl, tert-butoxycarbonyl, benzoyl, benzyloxycarbonyl, etc. the Term "lower acyl" refers to a group containing from one to four carbon atoms. The term "arylalkyl" refers to the residue, in which the acyl group is connected with the alkyl group, which is in turn connected with the main part of the molecule. An example of such a group can serve as a CH3C(=O)CH2-. These residues can be characterized as "oxoalkyl balances.

The terms "aryl" and "heteroaryl" means 5 - or 6-membered aromatic and heteroaromatic ring containing 0-3 heteroatoms selected from the atoms O, N or S; a bicyclic 9 - or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from the atoms O, N or S; or a tricyclic and 13 - or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from 0 atoms, N, or S. the Aromatic 6 to 14-membered carbocyclic rings include, for example, benzene, naphthalene, indan, tetralin and fluoran, and 5-10-membered aromatic heterocyclic rings include, for example, imidazole, pyridine, indole, thiophene, benzopyrane, thiazole, furan, benzimidazole, quinoline, isoquinoline, cinoxacin, pyrimidine, pyrazin, tetrazole and pyrazole.

The term "arylalkyl" means an alkyl residue attached to relname ring. Examples of such groups are benzyl, phenethyl, etc.

The terms "substituted alkyl", "substituted aryl", "substituted cycloalkyl", "substituted heterocyclyl"refer to alkyl, aryl, cycloalkyl or heterocyclyl, respectively, in which up to three atoms of N substituted by halogen, lower alkyl, halogenation, hydroxy-group, the lower alkoxygroup, 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 claims, methylendioxy, Ethylenedioxy specified as substituents. Although methylenedioxy attached to adjacent carbon atoms of the ring, Ethylenedioxy can be attached either to the adjacent carbon atoms of the ring or to the same carbon atom, forming sporadical (ketal), similar to spiritualizing. Different variants of this accession is shown in connection 114, 144 and 160.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "prodrug" refers to a connection that is more active in vivo. Activation in vivo can be performed by chemical action ilipi the action of the enzyme. Microflora in the LCD tract may also contribute to the activation of prodrugsin vivo.

When the characteristic variables indicated that a and b represent a pair of condensed 5-, 6 - or 7-membered rings, and that condensed a/b ring system may contain from 0 up to four heteroatoms selected from nitrogen atoms, oxygen and sulfur. It is implied that these rings can be presented in varying degrees of unsaturation from fully saturated to aromatic. Aromatic and partially unsaturated ring is preferable.

When the characteristic variables indicated that the ring can be optionally substituted by from 0 to four substituents, independently selected from the list of different definitions. The structure below illustrates the method of attachment. In this example, a condensed ring substituted with three substituents: CH3, -OH and oxo.

It should be understood that the compounds according to the invention can exist in radiolabelled forms, i.e. the compounds may contain one or more atoms from the atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine and chlorine include2H,3H,13C,14C,15N35 S18F and36Cl, respectively. Compounds that contain data radioisotopes and/or other isotopes of other atoms are included in the scope of this invention. Tritium, i.e3N, and carbon-14, i.e14With a radioisotope, especially preferred because of their easy access and discovery. Labeled with radioactive isotopes of the compounds of formula I and formula Ic according to the invention and their prodrugs can typically be easily obtained using methods well-known to specialists in this field. Such labeled with radioisotopes connection conveniently be obtained using the methods presented in the examples and schemes, replacing the usual reagents available labeled radioisotopes reagents.

The person skilled in the art it is clear that the term "connection"as used in this description, includes salt, solvate, co-crystals and inclusion complexes of this connection.

The term "MES" refers to the compound of formula I in the solid state, where the lattice entered molecules of a suitable solvent. A suitable solvent for therapeutic injection is the solvent, which entered doses is physiologically tolerant. Examples of suitable solvents for therapeutic injection are ethanol and water. When water is the solvent, solutizers hydrate. Typically, the solvate can be obtained by dissolving the compound in a suitable solvent and the release of MES cooling or using antibacterial. MES is usually dried or subjected to azeotropic distillation under standard conditions. Co-crystals are a combination of two or more different types of molecules, arranged in such a way that they form a unique crystalline form, physical properties, which differ from the physical properties of these substances in a pure state. Pharmaceutical co-crystals have been of interest from the point of view of the improved stability, the method of obtaining the drug and bioavailability of such drugs as Itraconazole [see Remenaret al.J. Am. Chem. Soc. 125. 8456-8457 (2003)] and fluoxetine. The inclusion complexes described in the publication: Remington: The Science and Practice of Pharmacy 19thEd. (1995) volume 1, page 176-177]. The most common complexes are complexes with cyclodextrins, and all such cyclodextrine complexes, natural and synthetic, with the addition of various additives and polymers, as described in U.S. patent 5324718 and 5472954 included in the scope of the present invention. These publication Remingtona and U.S. patents are also introduced in this described by reference.

The term "treatment and prevention" means the improvement of the status the status, the prevention or relief of symptoms and/or effects associated with lipid disorders. The term "prevention" in this description refers to the administration of a medicinal product for the prevention of pain sensitivity. Specialist in this field (for which the proposed method is intended) understands that the term "prevention" is not an absolute term. In the medical field are recognized to prescribe prophylactic administration of a medicinal product to reduce the likelihood of disease occurrence or reduce the severity of the condition, and this meaning is implied in the claims. As used herein, the term "treating" a patient includes prevention. In this description of the various references made on this term. Descriptions of these publications is hereby incorporated into this description by reference in its entirety.

The term "mammal" is used in the conventional sense. People included in the group of mammals, and people should be preferred by patients treatment methods.

Stereoisomers

Compounds described herein may contain asymmetric centers and may thus give the enantiomers, the diastereomers and the other isomeric form. Each chiral center may be defined as (S)- or (R)- in accordance with the terms of the erased is kimii. The present invention includes all such possible isomers, as well as their racemic and optically active forms. Optically active (R)- and (S)- or (D)and (L)-isomers may be obtained using chiral methods or reagents or with use of standard methods of dissolution. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is assumed that the compounds according to the invention include both E and Z geometric isomers. Thus, all tautomeric forms are also included.

A graphical representation of racemic, ambisyllabicity and selamicesme or enantiomerically pure compounds used in the present description, taken from the publication Maehr. J. Chem. Ed. 62. 114-120 (1985), black and bright wedges are used to show the absolute configuration of chiral element, wavy lines and one thin line show a waiver of any stereochemical problems, which may give, and the black outlines and bright outlines not only represent the relative geometrical configuration, but also determine the racemic compounds; and wedges, circled in black, and hollow or dashed lines denote enantiomerically pure intermediate products absolute to the hence, adaptation. Thus, it is understood that the formula II includes all the pure enantiomers as well as racemic mixtures, and any intermediate products of mixtures of enantiomers.

while the formula III includes any pure enantiomers of this structure:

and formula IV is clean, the only specific (S)-enantiomer:

The configuration of any carbon-carbon double bond shown in the present description, selected for convenience only and, unless expressly indicated otherwise, is not intended to highlight a particular configuration. So carbon-carbon double bond depicted arbitrarily above as E, can be represented as Z, E or a mixture of both in any proportion.

In this description uses terminology associated with "protecting" the "unprotect" and "secure connections". This terminology is well known to the person skilled in the art and is used in complex ways, which include sequential processing of a series of reagents. In this complex, the term "protective group" refers to a group that is used for masking functional groups at this stage of the synthesis, which is otherwise exposed to an undesirable interaction. Protective group prevents the reaction to this from the adiya's, but can later be removed for open source functional groups. Deleting or removing the protection is carried out after completion of the reaction or reactions in which the functional group may be subjected to adverse reactions. Thus, when the sequence of reagents is specific, as in the method of the present invention, the person skilled in the art will easily determine the groups that are suitable as a "protective groups". Suitable group for this purpose is described in the standard reference, known in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W.Greene [John Wiley & Sons, New York, 1991], which is included in this description by reference. Special attention is paid to the heads of the "Protection for the Hydroxyl Group, Including 1,2 - and 1,3-Diols" (pages 10-86).

The abbreviations Me, Et, Ph, Tf, Ts and Mf denote methyl, ethyl, phenyl, cryptomelane, toluensulfonyl and methanesulfonyl, respectively. A complete list of abbreviations used by chemists organically (i.e. a specialist in this area) is published in the first issue of each volume of the Journal of Organic Chemistry. This list, which is usually presented in a table entitled "Standard List of Abbreviations included in this description by reference.

Pharmaceuticals

Although the compounds of formula I or formula Ic can be entered directly, predpochtitelney be provided in the form of pharmaceutical compositions. According to an additional aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt or MES and one or more pharmaceutical carriers and, optionally, one or more other therapeutic ingredients. According to another additional aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (Ic) or its pharmaceutically acceptable salt or MES and one or more pharmaceutically acceptable carriers and, optionally, one or more other therapeutic ingredients. The carrier(s) need(s) to be acceptable from the viewpoint of compatibility with other ingredients of the drug and not to have a harmful effect on them.

Drugs include compositions suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and local (including dermal, buccal, sublingual and eye) injection. The most suitable route of administration may be chosen depending on condition and disease of the recipient. Drugs can conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the field of pharmaco is Ogii. All methods include the stage of contacting the compounds of formula I or formula Ic or its pharmaceutically acceptable salt or MES ("active ingredient") with the carrier which constitutes one or more accessory ingredients. Usually medications get uniform and thorough mixing of the active ingredient with liquid carriers or finely powdered solid carrier, or both such carriers, and then, if necessary, shaping the product into the desired product.

The preparations according to the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets and tablets, each containing a predetermined amount of the active ingredient; as a powder (including micronized and finely ground powder or as granules; as solutions or suspensions in aqueous liquids or non-aqueous liquid; or as an emulsion of the type oil-in-water" or type "water in oil". The active ingredient may also be presented as a bolus, elixir or paste.

A tablet may be made by extrusion or melt, optionally with one or more accessory ingredients. Peresuvannya tablets can be obtained by compressing in a suitable machine the active ingredient in free-flowing form is, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface-active agent or dispersant. Fused tablets can be obtained in a suitable machine by melting a mixture of the powdered compound moistened with a suitable liquid inert diluent. Tablets may not necessarily be coated or have a notch or can be made so to provide supported, slow or controlled release of her active ingredient.

Pharmaceutical compositions can include pharmaceutically acceptable inert carrier, and understood that this term includes one or more of inert excipients, which include starches, polyols, granulating substance, microcrystalline cellulose, diluents, lubricants, binders, dezintegriruetsja agents, etc. If necessary, the dosage of the tablets described compositions can be coated standard aqueous or nonaqueous techniques. The term "pharmaceutically acceptable carrier" also includes a controlled release of the active substance.

Compositions according to the invention can also optionally contain other therapeutic ingredients, additives, prevent the possibility sintering, preservatives, sweeteners, colorants, flavorings, moist collectors, plasticizers, dyes, etc. of Any such optional ingredient must, undoubtedly, be compatible with the connection according to the invention in order to guarantee the stability of the drug.

The range of doses for adults is usually from 0.1 μg to 10 g per day orally. Pills and other forms presented in discrete units may conveniently contain an amount of compound according to the present invention, which is effective at such dosage or in several doses, for example in unit doses containing from 0.5 to 500 mg, usually from about 5 mg to 200 mg of the Exact number of connections, enter the patient will be determined by the attending physician. However, the dose administered will depend on a number of factors, including the age and gender of the patient, an accurate diagnosis of the disorder to be treated, and its severity. The frequency of introduction will depend on the pharmacodynamics of individual compounds and drug in dosage form, which can be optimized by methods well known in this field (e.g., controlled or prolonged release of the active substance, intersolubility coating and so on).

Combination therapy can be achieved by the introduction of two or more drugs, each the of which is prepared and injected to the patient separately, or the introduction of two or more drugs in the same drug. Other combinations are also included in the concept of combination therapy. For example, two drugs can be combined in one product and put the patient together with the third medicine that is presented in a separate drug. Although such two or more drugs in combination therapy may be administered simultaneously, they should not be together.

Was synthesized approximately three hundred compounds. Their structures are presented in tables 1-2 below. In the tables a dash indicates a direct relationship. Thus, for example, the connection R159, where x2 and X6 show the relationships, is imidazolate (i.e. is a pair of condensed five-membered rings). Saturation and desaturation shows hydrogen bond; thus, the connection R is hexahedronal-2-he:

CH
Table 1

Compounds in table 1 contain "d", meaning [C], and U, meaning-NHSO2-except in connection R159, where "d" stands for N and U means-NHSO2and the connection R, where "d" means [X] and U represents NH2.
.NoX1X2X4X5X6X8Y-W(C=O)-MabeV
P001CH-CHCHCHCHCH2CH=CHC(=O)2-NaphthasNC2-Thiophene
P002CH-CHCHCHCHCH2CH=CHC(=O)PhNCC2-Thiophene
P003CH2-CH2CHCHCHCH2CH=CHC(=O)2-NaphthasNCC2-Thiophene
P004C(=O)CHCHCHCHCHCH2OCH2C(=O)2-NaphthasNCC2-Thiophene
P005CH-CHCHCHCHC(=O)CH=CHC(=O)2-NaphthasNCC2-Thiophene
P006CH-CHCHCHCHCH2CH=CHC(=O)(2-CF3)PhNCC2-Thiophene
P007CH-CHCHCHCHCH2CH=CHC(=O)(3-CF3)PhNCC2-Thiophene
P008CH-CHCHCHCHCH2CH=CHC(=O)[2,5-(CH3)2]PhNCC2-Thiophene
P009 CH-CHCHCHCHCH2CH=CHC(=O)[3,4-(CH3)2]PhNCC2-Thiophene
P010CH-CHCHCHCHCH2CH=CHC(=O)[2,6-Cl2]PhNCC2-Thiophene
P011CH-CHCHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC2-Thiophene
P012CHCHCHCHC(=O)OCH2CH2C(=O)2-NaphthasCNC2-Thiophene
P015CHCHCHCH2CH2CH2OCH2CH2C(=O)2-NaphthasCNC2-Thiophene
P016CH-CHCHCHCHCH2CH=CHC(=O)2-NaphthasNCCCF3
P017CH -CHCHCHCHCH2CH=CHC(=O)(4-OCH3)PhNCC2-Thiophene
P018C(=O)CH2OCHCHCHCH2OCH2C(=O)2-NaphthasNCC2-Thiophene
P019C(=O)CH2OCHCHCHCH2NC(=O)C(=O)2-NaphthasNCC2-Thiophene
P020C(=O)CH OCHCHCHCH2OCH2C(=O)[3,4-(CH3)2]PhNCC2-Thiophene
P021C(=O)CH2OCHCHCHCH2OCH2C(=O)[2,5-(CH3)2]PhNCC2-Thiophene
P022C(=O)CH2OCHCHCHCH2OCH2C(=O)PhNCC2-Thiophene

P023

C(=O)CH2OCHCHCHCH2OCH2C(=O)[4-CH3]PhNCC2-Thiophene
P024C(=O)CH2OCHCHCHCH2OCH2C(=O)[4-F]PhNCC2-Thiophene
P025C(=O)CH2OCHCHCHCH2OCH2C(=O)[4-Cl]PhNCC2-Thiophene
P026C(=O)CH2OCHCHCHCH2OCH2C(=O)[4-OCF2]PhNCC2-Thiophene
P027C(=O)CH2OCHCHCHCH2OCH2C(=O)[4-OCF3]PhNCC2-Thiophene
P028C(=O)CH2OCHCHCHCH2OCH2C(=O)[3-OCF3]PhNC2-Thiophene
P029C(=O)CH2OCHCHCHCH2.OCH2C(=O)[3-CF3]PhNC2-Thiophene
P030C(=O)CH2OCHCHCHCH2OCH2C(=O)[3-OCH3]PhNC2-Thiophene
P031C(=O)CH2OCHCHCHCH2OCH2C(=O)[2-CF3]PhNC 2-Thiophene
P034CH-CHN-CHCH2CH=CHC(=O)2-NaphthasNCN2-Thiophene
P035CH-CHCHCHCHCH2CH=CHC(=O)[3,4-OCH2O]PhNC2-Thiophene
P036CH-CHCHCHCHCH2CH=CHC(=O)[(3,5-OCH3)2]PhNCC2-Thiophene
P037C(CH3)-NCHCHCHCH2OCH2C(=O)2-NaphthasNCC2-Thiophene
P038CH-CHCHCHCHCH2CH2-OC(=O)2-NaphthasNCC[4-Me]Ph
P039C(=O)CH2OCHCHCHCH2OCH2C(=O)[3,4-Cl2]PhNC2-Thiophene
P040C(=O)CH2OCHCHCHCH2OCH2C(=O)[2,4-Cl2]PhNCC2-Thiophene
P041C(=O)CH2OCHCHCHCH2OCH2C(=O)[3,5-(OCH3)2]PhNCC2-Thiophene
P042C(=O)CH2OCHCHCHCH2OCH2C(=O)[3,4-(=N-O-N=]PhNCC 2-Thiophene
P043CH-CHCHCHCHCH2CH=CHC(=O)(2-Ph)PhNCC2-Thiophene
P045CH2-CH2CHCHCHSO2CH=CHC(=O)2-NaphthasNC2-Thiophene
P046C(=O)-OCHCHCHCH2OCH2C(=O)2-NaphthasNCC 2-Thiophene
P047C(=O)-OCHCHCHCH2OCH2C(=O)2-NaphthasNC[2-MeO-5-Br]Ph
P048C(=O)-OCHCHCHCH2OCH2C(=O)2-NaphthasNCCF3
P049C(=O)CH2OCHCHCHCH2NHCH2C(=O)2-NaphthasNC2-Thiophene
P050C(=O)-OCHCHCHCH2OCH2C(=O)[3,4-OCH2O-]PhNC2-Thiophene
P051C(=O)-OCHCHCHCH2OCH2C(=O)[3,4-Cl2]PhNC2-Thiophene
P052C(=O)-OCHCHCHCH2OCH2C(=O)[2,4-Cl2]PhNC2-T is open
P053C(=O)-OCHCHCHCH2OCH2C(=O)[2,5-Me2]PhNC2-Thiophene
P054CH-CHCHCHCHCH2CH=CHC(=O)3-PyridylNC2-Thiophene
P055CHCHCHCHCHCH2CH=CHC(=O)2-[3,5-Me2-4-OMe]pyridylNC2-Thiophene
P056CH-C(CH3)CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNC2-Thiophene
P057CH-C(CH3)CHCHCHCH2CH=CHC(=O)2-NaphthasN2-Thiophene
P058C(=O)-CH(CH3)CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhN 2-Thiophene
P059C(=O)-CH(CH3)CHCHCHCH2CH=CHC(=O)2-NaphthasNCC2-Thiophene
P060CH-CHCHCFCHCH2CH=CHC(=O)2-NaphthasNCC2-Thiophene
P061CH-CHCHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC 2-Thiophene
P062CH-C(CH2OH)CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNC2-Thiophene
P063CH-C(CH3)CHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC2-Thiophene
P064CH-C(CH3)CHCFCHCH2CH=CHC(=O)2-NaphthasNC 2-Thiophene
P065C(=O)-CH(CH3)CHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC2-Thiophene
P066C(=O)-CH(CH3)CHCFCHCH2CH=CHC(O)2-NaphthasNC2-Thiophene
P067CH-C(CH3)CHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC 4,5-Dichloro-2-thiophene
P068CH-C(CH3)CHCFCHCH2CH=CHC(=O)2-NaphthasNCC4,5-Dichloro-2-thiophene
P069CH-C(CH=O)CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNC2-Thiophene
P070CH-C(CH2OCH3)CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC/td> 2-Thiophene
P071CH-NHCHCHCHC(=O)OCH2C(=O)2-NaphthasCCC2-Thiophene
P072CH-C(CH3)CHCHCHCH2CH2CH2C(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P073CH-C(CH3)CHCHCHCH2CH2CH2C(=O)2-NaphthasN C4,5-Dichloro-2-thiophene
P074CH-CHCHCHCHCH2CH2CH2C(=O)2-NaphthasNCC2-Thiophene
P075CH-NHCHCHCHCH2OCH2C(=O)2-NaphthasCC4,5-Dichloro-2-thiophene
P077CH-C(CH3)CHCFCHCH2CH2CH2C(=O)2-NaphthasNC 2-Thiophene
P079CH-C(CH3)CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNC4,5-Dichloro-2-thiophene
P083C(=O)-C(OCH2CH2O)CHCHCHCH2CH=CHC(=O)2-NaphthasNC2-Thiophene
P084CH-C(CH3)CHCHCHCH2CH=CHC(=O)PhenylN CC2-Thiophene

P085CH-C[C(CH3)=O]CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC2-Thiophene
P086CH-C(CH3)CHCHCHCH2CH=CHC(=O)[2-Cl]PhNCC2-Thiophene
P087CH-C(CH3)CHCHCHCH2CH=CHC(=O)[3,4-Cl2 ]PhNC2-Thiophene
P088CH-C(CH3)CHCHCHCH2CH=CHC(=O)[3,5-F2]PhNC2-Thiophene
P089CH-C(CH3)CHCHCHCH2CH=CHC(=O)[2-Cl-4,5-OCH2O-]PhNC2-Thiophene
P090CH-C(CH3)CHCHCHCH2CH=CHC(=O) [2,4-Cl2]PhNCCPhenyl
P091CH-C[CH(CH3)2]CHCHCHCH2CH2CH2C(=O)[2,4-Cl2]PhNCC2-Thiophene
P092CH-C[CH(CH3)2]CHCHCHCH2CH2CH2C(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P093C(=O)-CH[CH(CH3)2]CHCHCH CH2CH2CH2C(=O)[2,4-Cl2]PhNCC2-Thiophene
P094CH-NHCHCHCHCH2CH=CHC(=O)2-NaphthasCC4,5-Dichloro-2-thiophene
P095CH-NHCHCHCHCH2CH2CH2C(=O)2-NaphthasCCC4,5-Dichloro-2-thiophene
P096C(=O)-C(=O)CHCHCH CH2CH=CHC(=O)2-NaphthasNCC2-Thiophene
P097C(=O)-C(OCH2CH2O)CHCHCHCH2CH2CH2C(=O)2-NaphthasNCC2-Thiophene
P098CHN(CH3)CHCHCHCH2CH2CH2C(=O)2-NaphthasCCC4,5-Dichloro-2-thiophene
P099CH-C(CH3)CHCH CHCH2CH=CHC(=O)2-GenoliniNCC2-Thiophene
P100CH-C(CH3)CHCHCHCH2CH=CHC(=O)2-PyridinylNCC2-Thiophene
P101CH-C(CH3)CHCHCHCH2CH=CHC(=O)[3,4-OCH2O-]PhNCC2-Thiophene
P102CH-C(CH3)CHCH CHCH2CH=CHC(=O)[(2,3-OCH2OCH2)-5F]PhNCC2-Thiophene
P103CH-C(CH3)CHCHCHCH2CH=CHC(=O)[3,4-F2]PhNCC2-Thiophene
P104C(=O)-C(OH)CF3CHCHCHCH2CH=CHC(=O)2-NaphthasNC2-Thiophene
P105C(=O)-NHCHCH CHCH2CH2CH2C(=O)2-NaphthasCHCC4,5-Dichloro-2-thiophene

/tr>
P106C(=O)-N(CH3)CHCHCHCH2CH2CH2C(=O)2-NaphthasCHC4,5-Dichloro-2-thiophene
P107C(=O)-CH(CH3)CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNC4,5-Dichloro-2-thiophene
P108C(=O)- C(OCH2CH2O)CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNC4,5-Dichloro-2-thiophene
P109CH-C(CH3)CHCHCHCH2CH=CHC(=O)3-PyridinylN2-Thiophene
P110C(=O)-C(Br)CH3CHCHCHCH2CH=CHC(=O)2-NaphthasN2-Thiophene
P111C(=O)C(OH)CH3CHCHCHCH2CH=CHC(=O)2-NaphthasN2-Thiophene
P112C(=O)-CHCH3CHCHCHCH2CH=CHC(=O)2-NaphthasN4,5-Dichloro-2-thiophene
P113C(=O)-C(=O)CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhN4,5-Dichloro-2-thiophene
P114C(=O) -C(OCH2CH2O)CHCHCHCH2CH=CHC(=O)2-NaphthasN4,5-Dichloro-2-thiophene
P115C(=O)-C(=O)CHCHCHCH2CH=CHC(=O)2-NaphthasN4,5-Dichloro-2-thiophene
P116N-NHC(=O)-N(CH3)CH2CH=CHC(=O)[2,4-Cl2]PhC4,5-Dichloro-2-thiophene
P117 N-NHC(=O)-N(CH3)CH2CH2CH2C(=O)[2,4-Cl2]PhC4,5-Dichloro-2-thiophene
P118CH-C(CH3)CHCHCHCH2CH=CHC(=O)[3,4-Cl2]PhN4,5-Dichloro-2-thiophene
P119CH-C(CH3)CHCHCHCH2CH=CHC(=O)[3-CF3]PhN4,5-Dichloro-2-thiophene
P120CH-C(CH3)CHCHCHCH2CH=CHC(=O)[4-F]PhNCC4,5-Dichloro-2-thiophene
P121CH-C(CH3)CHCHCHCH2CH=CHC(=O){2-[5,6-(OCH3)2]-Pyridinyl}NCC4,5-Dichloro-2-thiophene
P122CH-C(CH3)CHCHCHCH2CH=CHC(=O)PhenylNC 4,5-Dichloro-2-thiophene
P123CH-C(CH3)CHCHCHCH2CH=CHC(=O)[2-Cl]PhNC4,5-Dichloro-2-thiophene

CH=CHC(=O)
P124CH-C(CH3)CHCHCHCH2CH=CHC(=O)[2,6-Cl2]PhNCC4,5-Dichloro-2-thiophene
P125 businessCH-C(CH3)CHCHCHCH2CH=CHC(=O)[2-Ph]PhN C4,5-Dichloro-2-thiophene
P126C(=O)-C(NHCH2CH2S)CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P127C(=O)-CH2CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P128C(=O)-C(OH)CH2C(=O)CH3CHCHCHCH2CH=CHC(=O)[2,4-Cl2/sub> ]PhNCC4,5-Dichloro-2-thiophene
P129CH-CHCHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNC4,5-Dichloro-2-thiophene
P130C(=O)-CH(OH)CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P131C(=O)-C(CH3)2CHCHCHCH2CH=CHC(=O) [2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P132C(=O)-CF2CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P133C(=O)-C(OH)CH3CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhNC4,5-Dichloro-2-thiophene
P134C(=O)-C(OH)CH2NO2CHCHCHCH2[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P135CH-C(CH3)CHCHCHCH2CH=CHC(=O)[3,4-F2]PhNCC4,5-Dichloro-2-thiophene
P136CH-C(CH3)CHCHCHCH2CH=CHC(=O)[3,5-F2]PhNCC4,5-Dichloro-2-thiophene
P137CH-C(CH3)CHCHCH CH2CH=CHC(=O)[4-Cl]PhNCC4,5-Dichloro-2-thiophene
P138CH-C(CH3)CHCHCHCH2CH=CHC(=O)[2,5-Me2]PhNCC4,5-Dichloro-2-thiophene
P139CH-C(CH3)CHCHCHCH2CH=CHC(=O)[3,4-OCH2O]PhNCC4,5-Dichloro-2-thiophene

P140CH-C(CH3)C CHCHCH2CH=CHC(=O)[3-OCF3]PhNCC4,5-Dichloro-2-thiophene
P141CH-C(CH3)CHCHCHCH2CH=CHC(=O)[3,5-(OCH3)2]PhNCC4,5-Dichloro-2-thiophene
P142CH-C(CH3)CHCHCHCH2CH=CHC(=O)[3-OCH3]PhNCC4,5-Dichloro-2-thiophene
P143CH- C(CH3)CHCHCHCH2CH=CHC(=O)[4-OCF3]PhNCC4,5-Dichloro-2-thiophene
P144CH-C(CH3)CHCHCHCH2CH=CHC(=O)4-TetrahydropyranylNCC4,5-Dichloro-2-thiophene
P145CH-C(CH3)CHCHCHCH2CH=CHC(=O)[4-OCHF2]PhNCC4,5-Dichloro-2-thiophene
P146CH -C(CH3)CHCHCHCH2CH=CHC(=O)2-GenoliniNCC4,5-Dichloro-2-thiophene
P147CH-N(CH3)CHCHCHCH2CH=CHC(=O)2-NaphthasCCC4,5-Dichloro-2-thiophene
P148C(=O)-N(CH3)CHCHCHCH2CH=CHC(=O)2-NaphthasC(CH3)CC4,5-Dichloro-2-thiophene
P149 CH-NCHCHCHCH2OCH2C(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P150CH-NHCHCHCHSO2OCH2C(=O)2-NaphthasCCC4,5-Dichloro-2-thiophene
P151CH-NHCHCHCHSOCH2C(=O)2-NaphthasCC4,5-Dichloro-2-thiophene
P152 CH-NCHCHCHCH2OCH2C(=O)2-NaphthasNC4,5-Dichloro-2-thiophene
P154C(=O)-N(CH3)CHCHCHCH2CH=CHC(=O)2-NaphthasCHC4,5-Dichloro-2-thiophene
P155C(=O)-NHCHCHCHCH2CH=CHC(=O)2-NaphthasCHC4,5-Dichloro-2-thiophene
P156 C(=O)-N(CH3)CHCHCHCH2CH2CH2C(=O)2-NaphthasC(CH3)C4,5-Dichloro-2-thiophene

P157C(=O)-NHCHCHCHCH2OCH2C(=O)2-NaphthasCFCC4,5-Dichloro-2-thiophene
P158C(=O)-NHCHCHCHCH2OCH2C(=O)2-NaphthasCHC 4,5-Dichloro-2-thiophene
P159CH-NS-CHCH=CHCH2CH2C(=O)2-NaphthasCCC4,5-Dichloro-2-thiophene
P160C(=O)-CF(CH3)CHCHCHCH2CH=CHC(=O)2-NaphthasNC2-Thiophene
P161C(=O)-CF(CH3)CHCHCHCH2CH=CHC(=O)2-NaphthasN 4,5-Dichloro-2-thiophene
P162CH-NHCHCHCHCH2OCH(CH3)C(=O)2-NaphthasC4,5-Dichloro-2-thiophene
P163CH-NHCHCHCHCH2OCH2C(=O)2-NaphthasC2-Thiophene
P164CH-NHCHCHCHSOCH2C(=O)2-GenoliniC 4,5-Dichloro-2-thiophene
P165CH-NHCHCHCHSOCH2C(=O)[2,4-(CH3)2]PhC4,5-Dichloro-2-thiophene
P166CH-NHCHCHCHSOCH2C(=O)2-NaphthasC2-Thiophene
P167CH-NHCHCHCHSOCH2C(=O)[3,4-(OCH3)2]PhC 4,5-Dichloro-2-thiophene
P168CH-NHCHCHCHSOCH2C(=O)[2-Cl-4-F]Ph4,5-Dichloro-2-thiophene
P169CH-NHCHCHCHSO2OCH2C(=O)2-Genolini4,5-Dichloro-2-thiophene
P170CH-NHCHCHCHSO2OCH2C(=O)[3,4-(OCH3)2]Ph4,5-Dichloro-2-thiophene
P171CH-NHCHCHCHCH2OC(CH3)2C(=O)2-Naphthas4,5-Dindar-2-thiophene
P172CH-NHCHCHCHSO2OCH2C(=O)[2,4-(CH3)2]Ph4,5-Dichloro-2-thiophene
P173CH-NHCHCHCHSOCH2C(=O)[4-Cl]Ph 4,5-Dichloro-2-thiophene
P174CH-NHCHCHCHSOCH2C(=O)2-Naphthas5-Chloro-2-thiophene

P175CH-NHCHCHCHSOCH2C(=O)2-NaphthasPhenyl
P176CH-NHCHCHCHSOCH2C(=O)2-Naphthas [(2,5-OCH3)2]Ph
P177CH-NHCHCHCHSOCH2C(=O)2-Naphthas[3,5-Cl2]Ph
P178CH-NHCHCHCHSOCH2C(=O)[3,4-Cl2]Ph4,5-Dichloro-2-thiophene
P179C(=O)-CH2CHCHCHCH2CH=CHC(=O)2-Naphthas N4,5-Dichloro-2-thiophene
P180C(=O)-CF2CHCHCHCH2CH=CHC(=O)2-NaphthasN4,5-Dichloro-2-thiophene
P181CH-NHCHCHCHSOCH2C(=O)2-BenzoxazolCCC4,5-Dichloro-2-thiophene
P182CH-NHCHCHCHSOCH2C(=O)2-Benzothiazole CCC4,5-Dichloro-2-thiophene
P183CH-NHCHCHCHSOCH2C(=O)2-NaphthasCCC[2-Cl]Ph
P184CH-NHCHCHCHSOCH2C(=O)2-NaphthasCC[3-Cl]Ph
P185CH-NHCHCHCHSOCH2C(=O)2-NaphthasC C[4-OCH3]Ph
P186CH-NHCHCHCHSO2OCH2C(=O)2-NaphthasCCC[3,5-Cl2]Ph
P187CH-NHCHCHCHSO2OCH2C(=O)2-NaphthasCC5-Chloro-2-thiophene
P188CH-NHCHCHCHSO2OCH2C(=O)2-NaphthasCC/td> Phenyl
P190CH-NHCHCHCHSO2OCH2C(=O)[4-Cl]PhCC4,5-Dichloro-2-thiophene
P191CH-NHCHCHCHSO2OCH2C(=O)2-NaphthasCC[2-Cl]Ph
P192CH-NHCHCHCHSO2OCH2C(=O)2-NaphthasCC [3-Cl]Ph
P193CH-NHCHCHCHSO2OCH2C(=O)2-NaphthasCC[4-OCH3]Ph
P194CH-NHCHCHCHSOCH2C(=O)[2,5-(OCH3)2]PhCC4,5-Dichloro-2-thiophene
P195CH-NHCHCHCHSOCH2C(=O)2-(1-Methylbenzimidazole)CC 4,5-Dichloro-2-thiophene
P196CH-NHCHCHCHSO2OCH2C(=O)2-BenzothiazoleC4,5-Dichloro-2-thiophene

P197CH-NHCHCHCHSOCH2C(=O)[2,4-F2]PhC4,5-Dichloro-2-thiophene
P198CH-NHCHCHCHSOCH2C(=O)PhenylC 4,5-Dichloro-2-thiophene
P199CH-NHCHCHCHSOCH2C(=O)2-NaphthasC4-[3,5-(CH3)2]isoxazol
P200CH-NHCHCHCHSOCH2C(=O)[4-OCH3]PhCCC4,5-Dichloro-2-thiophene
P201CH-NHCHCHCHSOCH2C(=O)2-PyridinylCC4,5-Dichloro-2-thiophene
P202CH-NHCHCHCHSO2OCH2C(=O)[2,5-(OCH3)2]PhCC4,5-Dichloro-2-thiophene
P203CH-NHCHCHCHSO2OCH2C(=O)2-NaphthasCCC4-[3,5-(CH3)2]isoxazol
P204CH-NHCHCHCHSO2OCH2C(=O)[3,4-Cl2]Ph CCC4,5-Dichloro-2-thiophene
P205CH-NHCHCHCHSOCH2C(=O)[2,4-Cl2]PhCCC4,5-Dichloro-2-thiophene
P206CH-NHCHCHCHSO2OCH2C(=O)[2,4-F2]PhCCC4,5-Dichloro-2-thiophene
P207CH-NHCHCHCHSO2OCH2C(=O)Phenyl CCC4,5-Dichloro-2-thiophene
P208CH-NHCHCHCHSO2OCH2C(=O)[3-OMe]PhC4,5-Dichloro-2-thiophene
P209CH-NHCHCHCHSOCH2C(=O)[3,4-F2]PhC4,5-Dichloro-2-thiophene
P210CH-NHCHCHCHSO2OCH2C(=O)[4-OMe]Ph C4,5-Dichloro-2-thiophene
P211CH-NHCHCHCHSOCH2C(=O)2-PyrimidinylC4,5-Dichloro-2-thiophene
P212CH-NHCHCHCHSOCH2C(=O)[2-OMe]PhC4,5-Dichloro-2-thiophene
P213CH-NHCHCHCHSOCH2C(=O)[2-Cl]PhC4,5-Dichloro-2-thiophene

P214CH-NHCHCHCHSOCH2C(=O)2-NaphthasC[3,5-F2]Ph
P215CH-NHCHCHCHSOCH2C(=O)2-NaphthasC[3,4-F2]Ph
P216C(=O)-CF2CHCHCHCH2CH=CHC(=O)[2,4-Cl2]Ph N2-Thiophene
P217C(=O)-CH2CHCHCHCH2CH=CHC(=O)2-NaphthasNCC2-Thiophene
P218C(=O)-CF2CHCHCHCH2CH=CHC(=O)2-NaphthasNCC2-Thiophene
P219C(=O)-CH2CHCHCHCH2CH=CHC(=O)[2,4-Cl2]PhN CC2-Thiophene
P220CH-NHCHCHCHSOCH2C(=O)2-imidazolylCCC4,5-Dichloro-2-thiophene
P221CH-NHCHCHCHSO2OCH2C(=O)2-PyridinylCCC4,5-Dichloro-2-thiophene
P222CH-NHCHCHCHSO2OCH2C(=O)[2-OMe]Ph CC4,5-Dichloro-2-thiophene
P223CH-NHCHCHCHSO2OCH2C(=O)2-NaphthasCCC[3,5-F2]Ph
P224CH-NHCHCHCHSO2OCH2C(=O)2-NaphthasCCC[3,4-F2]Ph
P225CH-NHCHCHCHSOCH2C(=O)2-NaphthasC CC[4-F]Ph
P226CH-NHCHCHCHSOCH2C(=O)2-NaphthasCCC[2,4,5-F3]Ph
P227CH-NHCHCHCHSOCH2C(=O)5-[1-Methyltetrazolyl]CCC4,5-Dichloro-2-thiophene
P228CH-NHCHCHCHSOCH2C(=O)3-[1,2,4-Triazolyl]CC C4,5-Dichloro-2-thiophene
P229C(=O)-N(CH3)CHCHCHSOCH2C(=O)2-NaphthasCHCC4,5-Dichloro-2-thiophene
P230CH-NHCHCHCHSOCH2C(=O)2-[5-Methyl-1,3,4-thiadiazolyl]CCC4,5-Dichloro-2-thiophene
P231CH-NHCHCHCHSO2OCH2C(=O)2-[5-Methyl-1,3,4-thiadiazolyl]C CC4,5-Dichloro-2-thiophene
P232CH-NHCHCHCHSO2OCH2C(=O)[2-Cl]PhCCC4,5-Dichloro-2-thiophene
P233CH-NHCHCHCHSOCH2C(=O)[4-NHC(=O)CH3]PhCCC4,5-Dichloro-2-thiophene
P234CH-NHCHCHCHSO2OCH2C(=O)[2-Cl-4-F]PhC CC4,5-Dichloro-2-thiophene

C CH
P235CH-NHCHCHCHSO2OCH2C(=O)[4-NHC(=O)CH3]PhCCC4,5-Dichloro-2-thiophene
P236CH-NHCHCHCHSO2OCH2C(=O)2-NaphthasCCC[4-F]Ph
P237CH-NHCHCHCHSO2OCH2C(=O)2-N is ft CCC[2,4,5-F3]Ph
P238CH-NHCHCHCHSO2OCH2C(=O)[2,4-Cl2]PhCCC4,5-Dichloro-2-thiophene
P239CH-NHCHCHCHSO2OCH2C(=O)5-[1-Methyltetrazolyl]CCC4,5-Dichloro-2-thiophene
P240CH-NHCHCHCHSO2OCH2C(=O) 3-[1,2,4-Triazolyl]CCC4,5-Dichloro-2-thiophene
P241C(=O)-NHCHCHCHNHCH=CHC(=O)2-NaphthasCHCC4,5-Dichloro-2-thiophene
P242C(=O)-N(CH3)CHCHCHNHCH=CHC(=O)2-NaphthasCHCC4,5-Dichloro-2-thiophene
P243CH-NHCHCHCHSOCH2C(=O)2-On the t CCCCF3
P244C(=O)-NHCHCHCHNCH=CHC(=O)2-NaphthasCCC4,5-Dichloro-2-thiophene
P245C(=O)-N(CH3)CHCHCHNCH=CHC(=O)2-NaphthasCCC4,5-Dichloro-2-thiophene
P246CH-OCHCHCHSOCH2C(=O)2-NaphthasC CC4,5-Dichloro-2-thiophene
P247C(=O)-N(CH3)CHCHCHNHC(=O)CH=CHC(=O)2-NaphthasCHCC4,5-Dichloro-2-thiophene
P248C(=O)-N(CH3)CHCHCHSO2OCH2C(=O)2-NaphthasCHCC4,5-Dichloro-2-thiophene
P249C(=O)-N(CH3)CHCHCHNSO2CH=CHC(=O)2-NaphthasCC4,5-Dichloro-2-thiophene
P250C(=O)-N(CH3)CHCHCHNCH=CHC(O)[2,4-Cl2]PhCCC4,5-Dichloro-2-thiophene
P251C(=O)-N(CH3)CHCHCHNHSO2CH=CHC(=O)2-NaphthasCHCC4,5-Dichloro-2-thiophene
P252C(=O)-N(CH3)CHCHCHNHCH=CHC(=O)[2,4-Cl2]PhCC4,5-Dichloro-2-thiophene

P253C(=O)-CH2CH2CH2CH2CH2CH=CHC(=O)2-NaphthasNCC(CH3)4,5-Dichloro-2-thiophene
P254CH-OCHCHCHSO2OCH2C(=O)2-NaphthasCCC4,5-Dichloro-2-thiophene
P255C(=O)-N(CH3)CHCHCHNC(=O) OCH2C(=O)2-NaphthasCHCC4,5-Dichloro-2-thiophene
P256CH-OCHCHCHSOOCH2C(=O)2-NaphthasCCC4,5-Dichloro-2-thiophene
P257N-N(CH3)CHCHCHNHC(=O)CH=CHC(=O)2-NaphthasCCC4,5-Dichloro-2-thiophene
P258C(=O)-N(CH3)CHCHCHNH/td> OCH2C(=O)[3,4-Cl2]PhCHCC4,5-Dichloro-2-thiophene
P259CH-OCHCHCHSOCH2C(=O)2-[1-Ethylbenzamide]CCC4,5-Dichloro-2-thiophene
P260C(=O)-CH2CH2CH2CH2CH2CH=CHC(=O)[3-OMe]PhNCC(CH3)4,5-Dichloro-2-thiophene
P262C(=O)-CH2CH2 CH2CH2CH2CH=CHC(=O)[3-F]PhNCC(CH3)4,5-Dichloro-2-thiophene
P263C(=O)-CH2CH2CH2CH2CH2CH=CHC(=O)[4-F]PhNCC(CH3)4,5-Dichloro-2-thiophene
P264C(=O)-CH2CH2CH2CH2CH2CH=CHC(=O)[3,4-F2]PhNCC(CH3)4,5-Dichloro-2-thiophene
P265C(=O) -N(CH3)CHCHCHOCH=CHC(=O)2-NaphthasCHCC4,5-Dichloro-2-thiophene
P266C(=O)-CH2CH2CH2CH2CH2CH=CHC(=O)[3,4-F2]PhNCC(CH3)[3,5-Cl2]Ph
P267C(=O)-CH2CH2CH2CH2CH2CH=CHC(=O)[3,4-F2]PhNCC(CH3)[2,4,5-F3]Ph
P268C(=O)-NHCHCHCHNHCH=CHC(=O)[3,4-Cl2]PhCHCC4,5-Dichloro-2-thiophene
P269C=O-CH2CH2CH2CH2CH2CH=CHC(=O)2-NaphthylNCC(CH3)[4-OCF3]Ph
P270C=O-N(CH3)CHCHCHNHCH=CHC(=O)[2,4-F2]PhCHCCP271C=O-N(CH3)CHCHCHNHCH=CHC(=O)[3,4-Cl2]PhCHCC4,5-Dichloro-2-thiophene

tr>
P272C=O-N(CH3)CHCHCHNHCH=CHC(=O)[3,4-F2]PhCHCC4,5-Dichloro-2-thiophene
P273CH2CH2CH2CHCHCHC=OOCH2C(=O)OC(CH3)3 NCC2-Thiophene
P274C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,4-Cl2]PhNCC(CH3)[4-F]Ph
P275C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,4-Cl2]PhNCC(CH3)[2,4,5-F3]Ph
P276C=O-CH2CH2CH2CH2CH2/td> CH=CHC(=O)[2,4-Cl2]PhNCC(CH3)2-Thiophene
P277CH-N(CH3)CHCHCHOCH=CHC(=O)2-NaphthylCCC4,5-Dichloro-2-thiophene
P278C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,4-Cl2]PhNCC(CH3)4,5-Dichloro-2-thiophene
P279C=O-CH2CH2CH 2CH2CH2CH=CHC(=O)[2,4-Cl2]PhNCC(CH3)5-Chloro-2-thiophene
P280C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,4-Cl2]PhNCC(CH3)[3,5-Cl2]Ph
P281C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,4-Cl2]PhNCC(CH3)[3-Cl]Ph
P282C=O -CH2CH2CH2CH2CH2CH=CHC(=O)[2,4-Cl2]PhNCC(CH3)[3,5-F2]Ph
P283C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,4-Cl2]PhNCC(CH3)[3,4-F2]Ph
P284CHCHCH2N(CH3)NO2-NaphthylCCC4,5-Dichloro-2-thiophene
P285C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[3-Cl]PhNCC(CH3)4,5-Dichloro-2-thiophene
P286C=O-NHCHCHCHNHCH=CHC(=O)[3,5-Cl2]PhCHCC4,5-Dichloro-2-thiophene
P287C=O-NHCHCHCHNHCH=CHC(=O)[2,4-Cl2]PhCHCC 4,5-Dichloro-2-thiophene
P288C=O-NHCHCHCHNHCH=CHC(=O)[3,4-F2]PhCHCC4,5-Dichloro-2-thiophene
P290CHCHCHN(CH3)-CHOCH=CHC(=O)[3,4-Cl2]PhCCC4,5-dichloro-2-thiophene
291CHCHCHN(CH3)-CHOCH=CHC(=O)[2,3-Cl2]PhCCCP292CHCHCHN(CH3)-CHOCH=CHC(=O)[3,4-Cl2]PhCCC[2,4,5-F3]Ph

C
P293CHCHCHN(CH3)-CHOCH=CHC(=O)[3,4-Cl2]PhCCC[3,4-F2]Ph
P294C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[4-F]PhNC(CH3)[3,4-F2]Ph
P295C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[4-F]PhNCC(CH3)[3,5-F2]Ph
P296C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,3-Cl2]PhNCC(CH3)[2,4,5-F3]Ph
P297C=O-CH2CH2CH2CH2CH2 CH=CHC(=O)[2,3-Cl2]PhNCC(CH3)[3,4-F2]Ph
P298C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,3-Cl2]PhNCC(CH3)[3,5-F2]Ph
P299C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,3-Cl2]PhNCC(CH3)4,5-Dichloro-2-thiophene
P300C=O-CH2CH2 CH2CH2CH2CH=CHC(=O)[4-F]PhNCC(CH3)[2,4,5-F3]Ph
P301CHCHCHN(CH3)-CHOCH=CHC(=O)[2,4-Cl2]PhCCC[2,4,5-F3]Ph
P302CHCHCHN(CH3)-CHOCH=CHC(=O)[2,4-Cl2]PhCCC[3,4-F2]Ph
P303CHCHCHN(CH3 )-CHOCH=CHC(=O)[2,4-Cl2]PhCCC4,5-Dichloro-2-thiophene
P304C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[3,4-F2]PhNCC(CH3)[3,4-F2]Ph
P305C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[3,4-F2]PhNCC(CH3)[3,5-F2]Ph
P306C=O -CH2CH2CH2CH2CH2CH=CHC(=O)[3-MeO]PhNCC(CH3)[2,4,5-F3]Ph
P307C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[3-MeO]PhNCC(CH3)[3,5-F2]Ph
P308C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[3-MeO]PhNCC(CH3)[3,4-F 2]Ph
P309CHCHCHN(CH3)-CHOCH=CHC(=O)[4-Cl]PhCCC[2,4,5-F3]Ph
P310CHCHCHN(CH3)-CHOCH=CHC(=O)[4-Cl]PhCCC[3,4-F2]Ph
P311CHCHCHN(CH3)-CHOCH=CHC(=O)[4-Cl]PhCCC4,5-Dichloro-2-thiophene
P312CH-C(CH3)CHCFCHCH2CH=CHC(=O)[4-F]PhNCC[2,4,5-F3]Ph
P313CH-C(CH3)CHCFCHCH2CH=CHC(=O)[3,4-F2]PhNCC[2,4,5-F3]Ph
P314CH-C(CH3)CHCFCHCH2CH=CHC(=O)[4-F]PhNCC[3,4-F2]Ph
P315CH-C(CH3)CHCFCHCH2CH=CHC(=O)[3,4-F2]PhNCC[3,4-F2]Ph
P316CH-C(CH3)CHCFCHCH2CH=CHC(=O)[4-F]PhNCC[3,5-F2]Ph
P317CH-C(CH3)CHCFCHCH2CH=CHC(=O)[3,4-F2]PhNCC[3,5-F2]Ph
P318CHCHCHN(CH3)-CHOCH=CHC(=O)[3,4-F2]PhCCC[2,4,5-F3]Ph
P319CHCHCHN(CH3)-CHOCH=CHC(=O)[3,4-F2]PhCCC[3,4-F2]Ph
P320CHCHCHN(CH3)-CHOCH=CHC(=O)[3,4-F2]PhCCC4,5-Dichloro-2-thiophene

/tr>
P321CH-C(CH3)CHCFCHCH2CH=CHC(=O)[3,4-F2]PhNCC4,5-Dichloro-2-thiophene
P322CH-C(CH3)CHCFCHCH2CH=CHC(=O)[4-F]PhNCC4,5-Dichloro-2-thiophene
P323CHC(CH3)CHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC [2,4,5-F3]Ph
P324CHCHCHN(CH3)-CHOCH=CHC(=O)[2,4-F2]PhCCC[2,4,5-F3]Ph
P325CHCHCHN(CH3)-CHOCH=CHC(=O)[2,4-F2]PhCCC[3,4-F2]Ph
P326CHCHCHN(CH3)-CHOCH=CHC(=O)[2,4-F2]PhCCC 4,5-Dichloro-2-thiophene
P327CH-C(CH3)CHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P328CHCHCHN(CH3)-CHOCH=CHC(=O)[3-Cl-4-F]PhCCC[2,4,5-F3]Ph
P329CHCHCHN(CH3)-CHOCH=CHC(O)[3-Cl-4-F]PhCCC [3,4-F2]Ph
P330CHCHCHN(CH3)-CHOCH=CHC(=O)[3-Cl-4-F]PhCCC4,5-Dichloro-2-thiophene
P331CHCHCHN(CH3)-CHOCH=CHC(=O)[4-Cl-3-F]PhCCC[2,4,5-F3]Ph
P332CHCHCHN(CH3)-CHOCH=CHC(=O)[4-Cl-3-F]PhCCC[3,4-F2Ph
P333CHCHCHN(CH3)-CHOCH=CHC(=O)[4-Cl-3-F]PhCCC4,5-Dichloro-2-thiophene
P334CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[3,4-F2]Ph
P335CH-C(CH3)CHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC[3,4-F2]h
P336CH-C(CH3)CHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC[3,5-F2]Ph
P337CHCHCHN(CH3)-CHOCH=CHC(=O)[4-Cl-2-F]PhCCC[2,4,5-F3]Ph
P338CHCHCHN(CH3)-CHOCH=CHC(=O)[4-Cl-2-F]PhCCC[3,4-F2]Ph
P339CHCHCHN(CH3)-CHOCH=CHC(=O)[4-Cl-2-F]PhCCC4,5-Dichloro-2-thiophene
P340CHCHCHN(CH3)-CHOCH=CHC(=O)[2-Cl-4-F]PhCCC[2,4,5-F3]Ph
P341CHCHCHN(CH3)-CHOCH=CHC(=O)[2-Cl-4-F]PhCCC[3,4-F2]Ph
P342CHCHCHN(CH3)-CHOCH=CHC(=O)[2-Cl-4-F]PhCCC4,5-Dichloro-2-thiophene
P343CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[2,4,5-F3]Ph
P344C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,4-Cl2]PhNCC(CO2Et)[2,4,5-F3 ]Ph

C
P345C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,4-Cl2]PhNCC(CO2Et)4,5-Dichloro-2-thiophene
P346C=O-CH2CH2CH2CH2CH2CH=CHC(=O)[2,4-Cl2]PhNCC(CO2Et)[3,4-F2]Ph
P347CHCHCHN(CH3)-CHOCH=CHC(=O) [3,4-Cl2]PhCCC4,5-Dichloro-2-thiophene
P348CH-C(CH3)CHNCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P349CH-C(CH3)CHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P350CH-C(CH3)CHCFCHCH2 C(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P351CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[4-F]Ph
P352CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[2-Cl]Ph
P353CHCHCHN(CH3)-CHOCH=CHC(=O) 2-NaphthylCCC[3-Cl]Ph
P354CH-C(CH3)CHCFCHCH2C(=O)-C(=O)[2,4-Cl2]PhNCC[2,4,5-F3]Ph
P355CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[3,4-Cl2]Ph
P356CHCHCHN(CH3)-CHOCH=CHC(=O)2-Naphthas the l CCC[2,4-Cl2]Ph
P357CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[3,5-Cl2]Ph
P358CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[2,4-F2]Ph
P359CHCHCHN(CH3)-CHOCH=CHC(=O)2-Naphthyl CCC[2,5-F2]Ph
P360CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[2,6-F2]Ph
P361CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[3,5-F2]Ph
P362CHCHCHN(CH3)-CHOCH2CH2C(=O)2-NaphthylCC[3,4-F2]Ph
P363CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[3-F]Ph
P364CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[2-F]Ph
P365CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCC[4-Cl]Ph
P366CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[4-OCH3]Ph
P367CH-C(CH3)CHCFCHCH2CH=CHC(=O)[3-OCH3]PhNCC[2,4,5-F3]Ph
P368CH-C(CH3)CHCFCHCH2CH=CHC(=O)[3-OCH3]PhNC C[3,4-F2]Ph
P369CH-C(CH3)CHCFCHCH2CH=CHC(=O)4-[3,5-(CH3)2]isoxazolNCC[3,4-F2]Ph

P370CH-C(CH3)CHCFCHCH2CH=CHC(=O)4-[3,5-(CH3)2]isoxazolNCC[2,4,5-F3]Ph
P371CHCHCHN(CH3)-CHOCH=CHC(=O) [3-OCH3]PhCCC[3,4-F2]Ph
P372CHCHCHN(CH3)-CHOCH=CHC(=O)[3-OCH3]PhCCC[2,4,5-F3]Ph
P373CHCHCHN(CH3)-CHOCH=CHC(=O)2-NaphthylCCC[2,3,4,5,6-F5]Ph
P374CH-C(CH3)CHCFCHCH2CH=CHC(=O) [3,5-(OCH3)2]PhNC[3,4-F2]Ph
P375CH-C(CH3)CHCFCHCH2CH=CHC(=O)[3,5-(OCH3)2]PhNCC[2,4,5-F3]Ph
P376CHCHCHN(CH3)-CHOCH=CHC(=O)6-genoliniCCC[3,4-F2]Ph
P377CHCHCHN(CH3)-CHOCH=CHC(O) 6-genoliniCCC[2,4,5-F3]Ph
P378CHCFCHC(CH3)-CHOCH2CH2C(=O)2-NaphthylCNC[2,4,5-F3]Ph
P379CHCFCHC(CH3)-CHOCH2CH2C(=O)2-NaphthylCNC[3,4-F2]Ph
P380CHCFCHC(CH3)-CHO CH2CH2C(=O)2-NaphthylCNC4,5-Dichloro-2-thiophene
P381CHCFCHC(CH3)-CHOCH2CH2C(=O)2-NaphthylCNC[3-Cl]Ph
P382CHCFCHC(CH3)-CHOCH2CH2C(=O)[2,4-Cl2]PhCNC[2,4,5-F3]Ph
P383CHCFCHC(CH3)-CH OCH2CH2C(=O)[2,4-Cl2]PhCNC[3,4-F2]Ph
P384CHCFCHC(CH3)-CHOCH2CH2C(=O)[2,4-Cl2]PhCNC4,5-Dichloro-2-thiophene
P385CHCFCHC(CH3)-CHOCH2CH2C(=O)[2,4-Cl2]PhCNC[3-Cl]Ph
P386CHCFCHC(CH3)- CHOCH2CH2C(=O)[3,4-Cl2]PhCNC[2,4,5-F3]Ph
P387CHCFCHC(CH3)-CHOCH2CH2C(=O)[3,4-Cl2]PhCNC[3,4-F2]Ph
P388CHCFCHC(CH3)-CHOCH2CH2C(=O)[3,4-Cl2]PhCNC4,5-Dichloro-2-thiophene
P389CH-C(CH3)CH CFCHCH2CH=CHC(=O)[2-CN]PhNCC4,5-Dichloro-2-thiophene
P390CH-C(CH3)CHCFCHCH2CH=CHC(=O)[3-CN]PhNCC4,5-Dichloro-2-thiophene
P391CH-C(CH3)CHCFCHCH2CH=CHC(=O)[4-CN) PhNCC4,5-Dichloro-2-thiophene
P393CHCHCHN(CH3) -CHOCH=CHC(=O)2-HonokalaniCCC[3,4-F2]Ph
P394CHCHCHN(CH3)-CHOCH=CHC(=O)2-HonokalaniCCC[2,4,5-F3]Ph

td align="center"> N
P395CH-C(CH3)CHCFCHCH2CH=CHC(=O)2 imidazo[1,2a]pyridinylNCC4,5-Dichloro-2-thiophene
P396CH- C(CHO)CHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P397CH-C(CH2OH)CHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P398CH-C(CO2H)CHCFCHCH2CH=CHC(=O)[2,4-Cl2]PhNCC4,5-Dichloro-2-thiophene
P399CH -C(CH3)CHCFCHCH2CH=CHC(O)2 imidazo[1,2a]
pyridinyl
NCC[3,4-F2]Ph
P400CH-C(CH3)CHCFCHCH2CH=CHC(=O)2 imidazo[1,2a]
pyridinyl
NCC[3-Cl]Ph
P401CH-C(CH3)CHCFCHCH2CH=CHC(=O)2 imidazo[1,2a]
pyridinyl
NCC[3-F]Ph
P402 CH-C(CH3)CHCFCHCH2CH=CHC(=O)2 imidazo[1,2a]
pyridinyl
NCC[2,4,5-F3]Ph
P403CH-C(CH3)CHCFCHCH2CH=CHC(=O)2 imidazo[1,2a]
pyridinyl
NCC[4-F]Ph
P404CH-.C(CH3)CHCFCHCH2CH=CHC(=O)2 imidazo[1,2a]
pyridinyl
NCC[3,5-F2]Ph
P405CH-C(CH3)CHCFCHCH2CH=CHC(=O)2 imidazo[1,2a]
pyridinyl
NCC[4-Cl]Ph
P406CH-C(CH3)CHCFCHCH2CH=CHC(=O)2 imidazo[1,2a]
pyridinyl
NCC[3,4-Cl2]Ph
P407CH-C(CH3)CHCFCHCH2CH=CHC(=O)2 imidazo[1,2a]
pyridinyl
NC C[2,5-F2]Ph
P408CH-C(CH3)CHCFCHCH2CH=CHC(=O)2 imidazo[1,2a]
pyridinyl
NCC[3,5-Cl2]Ph
P409CH-C(CH3)CHCFCHCH2CH=CHC(=O)2 imidazo[1,2a]
pyridinyl
NCC[2-F]Ph
P410C=O-CH2CH2CH2CH2CH2CH2CH2C(=O)[3,4-F2]PhCHC(CH3)[2,4,5-F3]Ph
P411C=O-CH2CH2CH2CH2CH2CH2CH2C(=O)[3,4-F2]PhNCC(CH3)[2,4,5-F3]Ph
P412CHCHCHN(CH3)-CHOCH2CH2C(=O)2-NaphthylCCC[2,4,5-F3]Ph

P413CH-C(CH3)CHCF CHCH2CH=CHC(=O)2 imidazo[1,2a]
pyridinyl
NCC[2,4-F2]Ph
P414C=O-CH2CH2CH2CH2CH2CH2CH2C(=O)[3-OCH3]PhNCC(CH3)[2,4,5-F3]Ph
P415C=O-CH2CH2CH2CH2CH2CH2CH2C(=O)[3,4-F2]PhNCHC(CH3)4,5-Dichloro-2-thiophene
P416C=O -CH2CHCHCHCH2CH=CHC(=O)2-NaphthylNCC[2,4,5-F3]Ph
P417CH-C(CH3)CHCFCHCH2C(=O)[2,4-Cl2]PhNCC[3,4-F2]Ph

Table 2

Where 'a' means [N], and 'b'='c'='d' means [C]
Conn. No.. P(x)X1X2X4X5X6X8Y-W(C=O)- MUV
P76CH-C(CH3)CHCFCHCH2CH=CHC(=O)2-NaphthasN(CH3)SO24,5-Dichloro-2-thiophene
P44CH-CHCHCHCHCH2CH2-OC(=O)2-NaphthasNH(P=O)(OEt)2-

Compounds according to the invention were tested for their binding c prostanoids ER receptors in accordance with the method Abramovitzet al.[Bioch. Biophys. Acta, 1473, 286-293 (2000)]. In chart 1 in column 2 presents the activity of the compounds. Connection with IC50<1 μm is presented as a +++++; connection with IC501-10 microns represented as +++; connection with IC50>10 μm presented as ++. All examples of the compounds shown in tables 1 and 2, were SYN is azarowny, characterized and tested for binding OR receptor.

Compounds according to the present invention were tested for their activity against platelet aggregationin vitro. In experiments on human platelets whole blood was collected from human donors, hungry during the night. Each experiment was performed with blood from one individual. In experiments with rodent platelets whole blood was collected from the heart of female mice or male rats under isoflurane anesthesia (Abbott). In each experiment with the blood of rats or mice blood was pooled from two or ten individuals, 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×g for 15 minutes at 25°C for human blood, at 150×g for rat blood or at 80×g for 10 minutes for the blood of mice. The plasma with a low platelet was obtained by centrifugation of the remaining blood at 2400×g for 10 minutes at 25°C. After counting on autoceste (Model 920 EO, Swelab) platelets were diluted when it was necessary, until the desired initial concentrations (200000-300000 platelets/µl) using a 0.9% isotonic NaCl (Braun).

Platelet aggregation was determined by light absorption using trombotsitnoy of aggregometry with the permanent magnetic stirrer (Model 490, Chronolog Cop., Havertown, Pennsylvania, USA) and a volume of 500 ál in a cell. During execution of the experiments, the solution of platelets continuously stirred with moderate horizontal shaking. Collagen (Sigma) and PGE2or sulprostone (Cayman Chemicals) was used as accelerators of platelet aggregation. The compounds used in this analysis, was dissolved and stored in 100% DMSO solution. After dilution the final concentration of DMSO in the assay was below 0.1%.about. It was found that this concentration of DMSO did not inhibit platelet aggregation in this analysis. Accelerators and ER compound was dissolved in isotonic saline solution to the desired concentration. To calculate the concentration of the test compound necessary for inhibiting platelet aggregation by 50%, used a sigmoidal non-linear regression. The values of the IC50the tested compounds were calculated using the software Graph.Pad. Prism to 3.02 for Windows (GraogPad Software, San Diego California USA). The obtained data are presented in table 3.

Table 3
IC50(nm) for the tested compounds
View AgonistSerum,%P67R75R
PeopleSulprostone50of 9.2114,115,88
PGE2505,15
RatSulprostone2087,8578,54
PGE220304,35

Compounds were tested against PGE2(940 nm), or in respect of sulprostone (100 nm), or collagen (0.125 mg ml) for a person who has produced 90% aggregation.

Compounds were tested against PGE2(940 nm), or sulprostone (100 nm), or collagen (2.0 µg ml) for rats that were produced 60% aggregation.

Compounds according to the present invention were also evaluated for their effect on the aggregation of thrombocy the s in vivo. In the testin vivoactivation of platelets is an introduction pulmonary embolism by arachidonic acid, the precursor to the formation of prostaglandins. Inhibitors of prostaglandin synthesis, such as MOR-1 inhibitor, such as aspirin, have a protective effect in this analysis. For analysis of pulmonary embolism females mouse C57BL/6 oral injected compound and 30 minutes later was introduced the venous injection of anhedonia acid into the tail vein at a dose of 30 mg per kg of body weight. The number of surviving individuals were counted in one hour after administration of arachidonic acid, because mice that survived during this period of time, usually fully survived. The injection of arachidonic acid was performed via the lateral tail vein of a mouse, which in a short time were warmed under a heat lamp (an extension of the caudal vein using thermal stimulation, contributing to the injection). For the dosage used a syringe for injection of insulin volume of 0.5 ml (Becon Dickinson). This volume dose of the test compounds and arachidonic acid lead in accordance with the weight of the mouse (the oral dose for the tested compounds and intravenous solution arachidonic acid was 10 μl and 5 μl per gram of body weight, the fit is underway. The percentage of surviving mice treated with arachidonic acid, amounted to only 1 individual 10 tested or 10%. The share of the surviving mice treated with test compounds (100 mg/kg, orally) and then anhedonia acid, are presented in table 4 below.

Table 4
Connection # The number of surviving mice/total number of tested miceThe proportion of surviving animals
P6715/2268%
R4/1428%
R7520/4346%
P1504/850%

Usually the compounds according to the present invention can be obtained by methods illustrated in the General reaction schemes as, for example, described below, or by modifications using readily available starting compounds, reagents and standard methods of synthesis. In the above reactions can also apply their options, which is known as the e, but not specified in this description. The initial substance in the case of appropriately substituted compounds with condensed And/rings either commercially available or can be obtained by methods well known to the specialist in this field.

Chart 1

Chemical synthesis

Usually the compounds of formula I can be obtained from an appropriately functionalized substituted bicyclic cores, as shown in the diagrams 1-17. In particular, when the node "a" represents a nitrogen atom, the introduction of any functional groups at the carbon atom, the node "b", bicyclic kernel G1 (where scheme 1 shows a halogen atom), it is possible to spend by means of combination reaction with a palladium catalyst Hake with obtaining a carbon-linked complex ether (G2) or amide (G4). Another way of carbon sequestration node "b" may be true heteroatom (connection G6), as shown in scheme 2. Intermediate products G2 and G6 can then be functionalized at node "a" (the nitrogen atom of the bicyclic nucleus) receive polozhenii esters G3 and G7, as shown in schemes 1 and 2, respectively. The introduction of the nitrogen substituents can be accomplished either before (with the organisations G3 or G7), or after functionalization of the carboxylic acid (compound G4 or G8) to produce acylamide/arylsulfonamides G5 and G9, which are covered by formula I.

Scheme 1

Scheme 2

When the node "b" represents a carbon atom bearing a complex of essential or nitrile functional group, recovery leads to the corresponding alcohol or amine G10 as shown in schemes 3 and 4. The alcohol or amine can be alkylated, allyawan or subjected to interaction with the isocyanate with the receipt of peri-substituted bicyclic intermediate product G11, which, in turn, can be converted into compounds of formula I, where sulfonamidnuyu fragment, etc. contain various substituents, as shown in connection G12. Alternatively, amine G10 may be subjected to interaction with the cyclic (saturated, or aryl/heteroaryl) isocyanates bearing group of ester carboxylic acids with more rigid circular relationships, separating the bicyclic core, and arylsulfonamides functional groups, as shown in connection G14 (scheme 4). Similarly, derivatives, where the carbon bicyclic core G1, directly the public is nitrogen atom (i.e. nitro/Amin, G15/G16), gives the corresponding amides or urea as spatial Deputy for arylsulfonamides G18, as shown in figure 5.

Scheme 3

Scheme 4

Scheme 5

Bicyclic core, in which the node "a"and "b" represent the carbon atoms can be obtained from such source materials as the connection G19. Functionalization of the carbon atom bearing the halogen, via palladium-mediated formation of a simple ester or amine in accordance with the chemistry Buchwald, followed by the introduction of acetyl or formyl group by electrophilic reaction leads to the production of key peri-functionalized intermediate product G20. The latter reaction is particularly suitable when the ring (b) bicyclic core is rich in electrons. Reaction of a ketone or aldehyde by using a Wittig reagent results in the desired reinsulating of ester, which can be recovered by retrieving the corresponding saturated connection, if necessary. Alternatively, the ketones or aldehydes can be subjected to interaction with the corresponding enolate (or even Homo-enolate) with additional functional groups (e.g., Y4=OH, etc.) in the linker part of obtaining connection G22. Functional group Y4 may be further modified or deleted obtain olefinic bridge. In addition, benzyl alcohol G21 can be converted to a halide (for example, Br), and benzylamine, thus, can be converted by means of the Heck reaction or, alternatively, interaction with ICH2CH2COOR [K. Higuchi et al. Org. Letters 2003, 3704] product G24. Aldehyde/ketone G20 as a result of reaction with homoeopaths gives ester G22. The subsequent conversion of compounds G22 and G24 results in products G23 and G24, respectively.

Scheme 6

Additional examples of highly reactive/electrophilic bicyclic nuclei, in which the introduction of functional groups are linked by a heteroatom, provides both carbon-related peri-functional groups shown in schemes 7 and 8. Such methods of synthesis provided by the introduction of the acyl part of the fragment containing different linkers. This chemistry provides an introduction aryl and heteroaryl groups linked through sulfur, and gives the possibility to adjust the oxidation state of sulfur, and to receive, thus, analogs, represented by the compounds G31 and G36. Alternatively, using ketones G37 is possible to obtain compounds related compounds G31/G36, which provide such a kernel, to the to benzofuran and benzothiophene, connection G40.

Scheme 7

Scheme 8

Scheme 9

Vysokosulfidnye thiols give the opportunity to use a kernel that is similar to the connection G27, as shown when converting compounds G33 in connection G34 in scheme 8. To obtain the corresponding Aza-(oxa)-linked aryl/heteroaryl/alkyl groups (R1), it is possible to use intermediate products, related to isatin, as shown in the example connection G43, which is obtained from the connection G41, figure 10. As shown in scheme 10, the intermediate product G43 provides various Aza-related compounds, which are formed in the carbon-linked accession to the bicyclic core. Another on the basis of the isatin derivative (shown in scheme 11) results in peri-substituted bicyclic compounds; this method provides a functional group that is linked via carbon atoms and nitrogen nucleus bicyclic system. In addition, the provision of a key intermediate product G56, which contains a reactive carbonyl, vaguely reminiscent of the end groups peri-substituents R1 and R2, gives the possibility to apply a wide range of chemical methods presented in figure 11. Such chemical transformations, for example the er getting ketals, in addition to carbonyl and reaction with DAST provide analogues of various functional groups, as shown in the examples of the compounds G56-G60. Counterparts in schemes 10 and 11 also provide the bicyclic nucleus containing one or two rings that are not aromatic.

Scheme 10

Scheme 11

In all the above synthesis methods essentially use the bicyclic core, which is suitable modification, to obtain compounds of the above formula I. the following chemical transformations shows how the introduction of at least peri-fragments, as part of the construction of the bicyclic core. The sequence of chemical transformations presented in figure 12, includes a three-component condensation reaction, whereby a complex of α,γ-diketonates (G62) in the reaction with the aldehyde and the primary amine yields a monocyclic product G63. Product G63 in the reaction, for example, with hydrazine (or monosubstituted hydrazine) gives peri-substituted bicyclic core (in this case, 5-5 ring system, as shown by the connection G64), which then results in similar G65.

Scheme 12

Other examples of chemical PR the spins which include the formation of bicyclic nuclei are presented on figures 13 and 14, which represent a synthesis of benzimidazole nuclei. To obtain peri-substituted systems group R1 is injected regiospecific on stage compounds G67-G68, which after the closure of the ring provides the desired peri-substituted derivative G69. In figure 14 the desired regiospecific introduction group R1 conduct through the migration O to N acyl, followed by reduction of amide to a secondary amide. In this case, the closure ring also results in the target peri-substituents, such as in connection G77.

Scheme 13

Scheme 14

Another example of chemical reactions, including the formation of bicyclic cores with the desired peri-functional groups presented in figure 15. Here thermal cyclization of amine with a cyclic spatial oriented γ-ketokislot G82 results in the desired bicyclic intermediate product G83. Bromination followed, for example, by reaction Hake results in the target peri-bicyclic derivative G85, which as a result of subsequent transformations results in connection G87. This sequence of chemical reactions allows to synthesize on), the Wu nonaromatic ring system, and also allows you to create a bicyclic ring system, which ring (a) is 5-membered. Ring (a) is formed by the reaction of cyclization, while the size of the ring (b) is controlled by the use of cyclic ketone in the initial stage of synthesis and, thus, gives the possibility to obtain 5-N-bicyclic system. In addition to being able to influence the size, the Deputy and the presence of heteroatoms in the cyclic ketone also gives you the opportunity to give greater flexibility. The nature of the tertiary group may also vary, and can be entered on the cyclization stage ketone, which allows a significant degree of control regioniniu. The provisions of the X5/X6 can also contain heteroatoms and/or additional deputies.

Scheme 15

An example, which gives the opportunity to introduce acyl fragment (carrying R2) via electrophilic reactions presented in scheme 16. This sequence leads to the production of analogues of compounds G90 and G91. Benzyl carbonyl group present in the compound G90 and G91, can be subjected to further transformations, such as the recovery of alcohol or CH2the formation of the oxime, imine or hydrazine, ketals, etc. in the Last stage of recovery also gives the possibility of the ability to enter a radioactive carbon atom ( 14C) or tritium (3N) to create analogues used in the variousin vivoandin vitroresearch.

Scheme 16

Compounds of General structure G92 (below) are either commercially available or can be easily obtained from commercially available materials using the techniques described in the literature. Replacing Y (halogen/triplet) in connection G92 can be done with simple arolovich esters, sulfides or anilides, respectively (G93). In connection G93, when W represents NH, N-derived compounds G94 can be formed either through N-alkylation, or by reacting joining Michael on the acrylate (or propionate). Ester G94 sequentially synthesized as shown in schemes above for compounds of G95. However, when the connection G93 represents the bicyclic heterocycle, where W stands for CH, the introduction of a side chain bearing a functional group of ester, results in connection G97. Deriving from compounds G93 can be performed via formirovanie (G96, X=CHO) with subsequent Wittig reaction or by other chemical transformations to obtain the corresponding esters G97. Alternatively, the connection G93 can be galogenirovannami getting connection G96 (X=Galaga is). Replacement of this halogen heteroatomic nucleophiles (hydroxyl, mercapto - or complex-amino esters) leads to a simple air, tiefer or amino derivatives product G97 (where Z7=O, N or S). The compounds obtained are then subjected to rigorous chemical treatment to obtain the desired arylsulfonamides or related products, G98, as described above. Connection G98 can be subjected to further transformations with obtaining connection G99. In addition, derivatives of carboxylic acids of compounds G94 and/or G97 can be subjected to reaction combination with H2N-Z3where Z3mean NH2-Z2-R2 (when Z2means NHSO2, NHCO or NHPO) obtaining acylhydrazides (RC(=O)NHNHC(=O)R), arylsulphatase (RC(=O)NHNHS(=O)2R) or acylphosphatase (RC(=O)NHNHP(=O)R1R2), respectively. In fact, these transformations can be carried out with carboxylic acids, which are obtained as a result of chemical transformations presented in schemes 1-16 above.

Scheme 17

Finally, some appropriately functionalityand bicyclic cores are commercially available or their synthesis is described in the literature or may be obvious to a person skilled in this field. Examples of some of them are briefly described in the experimental part.

For bicyclic systems where a node represents a nitrogen atom, indole derivatives are easily accessible and usable by the kernel. 4-Bromo - and 4-hydroxyindole are commercially available. 7-Substituted indoles, such as 7-CO2R, 7-alkoxy, 7-benzyloxy etc. can be obtained in accordance with the chemistry of Batco-Leimgruber (Batcho-Leimgruber) from appropriately substituted 2-nitrotoluene (Org. Synthesis Co., Vol. 7). This path also provides 7-IU-, 7-SNO-, 7 -, CN -, and 7-on-indoles by the manipulation of functional groups. Alternative 7-galagonidae available from 2-halogenosilanes in accordance with the chemistry Bartoli (by Bartoli, G. et al. Tett. Letters, 1989, 30, 2129-2132). Various 7-substituted indoles can also be obtained through selective functionalization of indole via directed ortho-metallation in accordance with the methodology Snakes [V. Snieckus et al. Org. Letters 2003, 1899-1902]. These different approaches also provide other substituted derivatives of indole. 8-Hydroxymitragynine [6:6]nucleus can be obtained from commercially available 8-hydroxyquinoline solution recovery. 8-HE-1H-Quinoline-2-he, 8 HE-3,4-dihydro-1H-quinoline-2-it, 2,6-dehydroalanine and related heterocycles can be converted to 5-hydroxy-4H-benzo[1,4]oxazin-3-one, 5-hydroxy-4H-benzo[1,4]oxazin-2,3-dione, 4-hydroxy-3H-benzooxazol-2-it, bicyclic derivatives. About Islena 1,7-disubstituted derivative of indole or 3,4-disubstituted bicyclic analogue of indole results relevant oxindol-derivatives. Various anilines can be converted into analogues of isatin using the techniques described in the literature, and examples of such transformations are described below. Synthesis of some derivatives [5:5]-bicyclic cores (for example, imidazothiazole and pyrrolopyrazole) described in the specific examples. Another group [6:5]-bicyclic nuclei can be obtained by methods similar to those described in the literature for the synthesis of such nuclei as imidazopyridine and imidazopyrimidines [Katritzky A.R., et al. JOC 2003, 68, 4935-37], pyrrolopyrimidine [Norman M. et al. JMC 2000, 43, 4288-4312]. These various bicyclic cores can then be converted to obtaining analogues of compounds of formula I.

In General, the range of chemical transformations described above, provides the ability to get powerful prostanoid antagonists/agonists. Chemistry gives you the ability to manipulate the structure of the nucleus and enter the optimal functional groups to achieve the desired balance of hydrophobicity-hydrophilicity; it gives the opportunity to introduce the hydrogen bond donor and acceptors with the desired typology; it gives the possibility to adjust the desired physical characteristics suitable for the desired pharmaceutical properties and properties of absorption, distribution, metabolism, excretion (e.g., membrane permeability, low plasma protein binding, the desired profile meta is Alisma etc). The ability to regulate the physico-chemical characteristics makes it possible to produce a suitable preparation for oral bioavailability, which, in turn, gives the possibility to control the size and frequency of the dose, introduced mammals to achieve the desired pharmacological response. The ability to regulate metabolic profile allows to minimize possible interactions between medicines. Thus, the scope of the present invention provides not only a strong prostanoid antagonists with isozyme selectivity as useful research tools, but also the connection of value in therapy.

Examples

The following examples do not limit the scope of the present invention are only illustrative examples.

Example 1. Getting connection P001

Indole-7-carboxaldehyde (I-1). Ethylindole-7m-carboxylate receive in accordance with the methodology described in the literature [Batcho B. and Leimgruber, K., Org. Syn. Vol I-IV, page 34-40]. To a solution of methyl-7-indocarbocyanine (13 g, to 74.2 mmol) in 250 ml of anhydrous THF add LiA1H4(10,9 g, in 0.288 mol) in several portions and the reaction mixture is refluxed for 2 hours. After cooling to room temperature, the excess hydride quenched by addition of water (12 ml), 15% NaOH (12 ml) and water(26 ml). The solid precipitate is removed by filtration through a layer of celite and the filtrate evaporated in vacuum, obtaining (1H-indol-7-yl)methanol (10.7 g, 98%).1H-NMR (CDCl3). To a solution of alcohol (1H-indol-7-yl)methanol (8.0 g, to 54.3 mmol) in 400 ml of methylene chloride added activated manganese oxide (IV) (85%, 41,0 g, 0.40 mol) and the mixture was stirred at ambient temperature for 72 hours. The reaction mixture was added 200 ml of methylene chloride and 400 ml of methanol and the mixture is filtered through a layer of silica gel to remove solids. The filtrate is concentrated, obtaining the crude product, which was purified column chromatography on silica gel, receiving 1H-indole-7-carbaldehyde, I-1 (6,55 g, 83%).1H-NMR (CDCl3).

Ethyl ester of 3-(1H-indol-7-yl)acrylic acid(I-2). In a round bottom flask (100 ml), which contains a suspension of NaH (60% in mineral oil, 320 mg, 8 mmol) in THF (20ml) add triethylphosphate (1.5 g, 6.6 mmol) at 0°C. the mixture allow to warm to room temperature and the mixture is stirred for 2 hours, then cooled to 0°C. To the resulting solution was added indole-7-carboxaldehyde I-1 (450 mg, 3 mmol) at 0°C. the Obtained reaction mixture was allow to warm to room temperature and stirred for 2 hours, then heated to 78°C and stirred at 78°C for 14 hours. The reaction mixture is cooled on the 5°C and quenched by adding aqueous NH 4Cl (saturated, 15 ml) followed by extraction with EtOAc (3×30ml). The combined organic layers washed with saturated salt solution (2×20ml), dried (Na2SO4) and the solvent is removed under reduced pressure. The residue is purified flash chromatography (silica gel, EtOAc/hexane=1:20-1:8) receiving the target ethyl ester 3-(1H-indol-7-yl)acrylic acid I-2 (450 mg, 68%) as a white solid. MS(ESI) m/z (216,3,100%). 1H-NMR (CDCl3), 13C NMR(CDCl3).

3-(1H-indol-7-yl)acrylic acid (I-3). In a round bottom flask (500 ml), which contains a solution of NaOH (1.2 g, 30 mmol) in EtOH (100 ml) and H2O (30 ml), add ethyl ester 3-(1H-indol-7-yl)acrylic acid 2 (3.2 g, 15 mmol) at 5°C. the mixture allow to warm to room temperature and the mixture is stirred for 10 minutes, then heated to 78°C and stirred for 4 hours. The reaction mixture is cooled to 5°C and acidified by addition of aqueous HCl (10%) to pH 1, then extracted with CH2Cl2/MeOH (95/5, 3×150 ml). The combined organic layers washed with saturated salt solution (2×20 ml), dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product which is purified by recrystallization from a mixture of acetone/EtOAc/hexane, receiving targeted 3-(1H-indol-7-yl)acrylic acid I-3 (2.4 g, 86%) as a white solid. MS(APCI-) m/z(186,2, 100%). IHMS(APCI-> 95%.

((E)-3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4). In a round bottom flask (500 ml), which contains the solution thiophenesulfonyl (1,05 g, 6 mmol), 4-dimethylaminopyridine (DMAP, 1.56 g, 13 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCl, 2.4 g, 13 mmol) in CH2Cl2(150 ml) is added 3-(1H-indol-7-ID)acrylic acid I-3 (1.2 g, 6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 72 hours, then cooled to 5°C and acidified to pH=1 by addition of aqueous HCl (10%) followed by extraction of CH2Cl2/MeOH (9/1, 3×100 ml). The combined organic layers dried over anhydrous Na2SO4and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2; CH2Cl2/EtOAc/hexane=1:10:20-1:20:10), receiving target (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4 (1.2 g, 56%) as a white solid. MS(ESI) m/z (331,1, 100%). IHMS(ESI-)>95%.

The General procedure of N-alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (A-1). To a suspension of NaH (60% in mineral oil, 5 mg, 0.11 mmol) in DMF (5 ml) is added (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4 (20 mg, of 0.066 mmol) at 0°C. [except in the case when the Ar/R-CH2Br(CL) is used in salt form, nab the emer HCl salt, use additional amount NaH]. The mixture allow to warm to room temperature, stirred for 2 hours and then cooled to 0°C. To the resulting solution was added ArCH2Br(or Cl) (0,072 mmol, 1.1 EQ.) at 0°C, the obtained reaction mixture was allow to warm to room temperature and stirring is continued for 16-48 hours. The reaction mixture is cooled to 5°C and acidified by addition of aqueous HCl (10%) to pH=1 with subsequent extraction of CH2Cl2/MeOH (9/1, 3×10ml). The combined organic layers dried over anhydrous Na2SO4and the solvent is removed under reduced pressure, obtaining the crude product which is purified flash chromatography (silica gel, CH2Cl2; EtOAc/hexane=1:8-1:2); by recrystallization or by rubbing in the air, getting the target N-alkylated (3[CH2R]-1H-indole-7-ylacrylic)amides thiophene-2-sulfonic acid.

Example 2. Getting connection P002.

A General method (A-1) used for alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4) benzylbromide, receiving the connection P002, MS(ESI) m/z UAH 421,2, (100%). IHMS(ESI-)>80%.

Example molchanie connection P006

A General method (A-1) used for alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4) 2-cryptomethodoverrides, receiving connection is out P006 MS(ESI -)m/z=489,4, (100%), GHMC(ESI-)>85%.

Example 4. Getting connection P007

A General method (A-1) used for alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4) 3-cryptomethodoverrides, receiving the connection P007.

1H NMR (500 MHZ, acetone-d6); of 5.75 (2H, s), 6,47 (d, J=15 Hz, 1H), 6,65 (d, J=3.0 Hz, 1H), was 7.08 (t, J=7.5 Hz, 1H), 7.24 to 7,34 (m, 4H), 7,45 (t, J=8.0 Hz, 1H), 7,52-EUR 7.57 (m, 2H), of 7.70 (d, J=8.0 Hz, 1H), 7,92 (m, 1H), 8,00 (m, 1H), 8,23 (d, J=15 Hz, 1H). LC/MS (86%) ESI-Calculated: 490,5; m/z found: 489,4 m/z (M-1).

Example 5. Getting connection P008

A General method (A-1) used for alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4) 2,5-dimethylbenzylamine, receiving the connection P008. MS(ESI) m/z 449,3 (100%), GHMC(ESI-)>70%.

Example 6. Getting connection P009

A General method (A-1) used for alkylation (3-1H-indol-7-acryloyl)amide thiophene-2-sulfonic acid (I-4) 3,4-dimethylbenzylamine, receiving the connection P009. MS(ESI-) m/z=449,4(100%), GHMC(ESI-) >91%.

Example 7. Getting connection P010

A General method (A-1) used for alkylation of 3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4) 2,6-dichlorobenzamide, receiving the connection P010. MS(ESI-) m/z=489,3, (100%), GHMC (ESI-) >70%.

Example 8. Getting connection P011.

A General method (A-1) used for alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-Sul is about acid (I-4) (100 mg, 0.3 mmol) of 3,4-dichlorobenzamide (50 mg, 0.33 mmol)to give the crude product (75 mg, 51%), which is then purified by recrystallization from ether to obtain 53 mg (>90%) of compound P011 as a pale yellow solid. MS(ESI-) m/z=489,4, (100%). IHMS(ESI-) >90%.1H NMR (CDCl3).

Example 9. Getting connection P017.

A General method (A-1) used for alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4) using 4-methoxybenzylamine, receiving the connection P017.

1H NMR (500 MHz, methanol-d4); 6,62 (d, J=16 Hz, 1H), 7,01 (d, J=3.5 Hz, 1H), 7,12 (t, J=7.5 Hz, 1H), 7,19 (t, J=7.5 Hz, 1H), 7,37 (DD, J=8,5, 2.0 Hz, 1H), 7,60 (t, J=7.5 Hz, 1H), 7,65-to 7.68 (m, 2H), 7,73 (m, 1H), 7,80 (1H, ush.), 7,86-7,89 (m, 2H), to 7.93 (d, J=8.5 Hz, 1H), of 8.06 (s, 1H), 8,19 (d, J=8.0 Hz, 1H). LC/MS (65%) ESI-Calculated: 524,6; m/z found: 523,5 m/z (M-1).

Example 10. Getting connection P035

A General method (A-1) used for alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4) 5-bromeilles[1,3]dioxolan, receiving the connection P035. MS(ESI-) m/z=465,3, (100%), GHMC(ESI-)>81%.

Example 11. Getting connection P036

A General method (A-1) used for alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4) 3,5-dimethoxybenzamide, receiving the connection P36. MS(ESI-)m/z=481,2, (100%), GHMC(ESI-)>77%.

Example 12. Getting connection P043.

A General method (A-1) used is a comfort for alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4) (2-phenyl)benzylbromide, receiving a connection P043. MS(ESI-) m/z=497,6 (100%), GHMC(ESI) >85%.

Example 13. Getting connection P054.

A General method (A-1) used for alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4) hydrobromide 3-pyridylmethylamine, receiving the connection P054. MS(ESI-)m/z=422,3, (100%), GHMC(ESI-)>95%.

Example 14. Getting connection P055.

A General method (A-1) used for alkylation (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4) of the hydrobromide of 2-(3,5-dimethyl-4-methoxy)pyridylmethylamine, receiving the connection P055. MS(ESI-) m/z=480,3, (100%), GHMC(ESI-) >80%.

Example 15. Getting connection P056.

Obtain 7-bromo-3-methyl-1H-indole (I-5). 2-Pantropical subjected to interaction with allylanisole in accordance with the methods described in the literature (A. Dobbs J.Org Chem. 2001, 66, 638-641)to give 7-bromo-3-methyl-1H-indole.

Obtaining methyl ester (E)-3-(3-methyl-1H-indol-7-yl)acrylic acid (I-6). To a mixture of compound I-5 (300 mg, of 1.42 mmol) and methyl acrylate (183 mg, 2,13 mmol) in triethylamine (1 ml) is added palladium acetate (H)(31 mg, 0.14 mmol) and tri-o-tolylphosphino (129 mg, 0.42 mmol) in an argon atmosphere at room temperature. The reaction mixture was stirred at 100oC for 4 hours in a sealed tube under pressure and then cooled to room temperature. The mixture is diluted with methylene chloride (50 m is), washed with water (3×30 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using EtOAc/hexane as eluent, receiving 250 mg of compound I-6 as a yellow solid.1H-NMR (500 MHz, CDCl3) MS(ESI-) 214,5 (M-1).

Obtaining (E)-3-(3-methyl-1H-indol-7-yl)acrylic acid (I-7). To a solution of methyl ester (E)-3-(3-methyl-1H-indol-7-yl)acrylic acid (2,180 mg, 0.84 mmol) in THF (5 ml) and methanol (4 ml) is added at room temperature, aqueous NaOH (4 ml). The reaction mixture was stirred at room temperature overnight and then water 2H. HCl pH was adjusted to acidic. The reaction mixture was extracted with EtOAc (2×30 ml). The combined organic phases are washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent to obtain 170 mg of compound I-7.1H-NMR (500 MHz, DMSO-d6). Getting [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8). The mixture of acid I-7 (170 mg, 0.84 mmol), 2-thiophenesulfonyl (163 mg, 1 mmol), 4-dimethylaminopyridine (207 mg, 1.7 mmol) and EDCl (325 mg, 1.7 mmol) in dichloromethane (20 ml) and DMSO (0.5 ml) is stirred over night. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. Dissolve the al is removed and the residue purified column chromatography on silica gel, using as eluent a mixture of methanol/CH2Cl2and getting 170 mg of compound I-8.1H-NMR (500 MHz, DMSO-d6).

General procedure (A-2) N-alkylation of I-8. To a solution of arylsulfonamides (I-8) in DMF at room temperature add 2,8 water NaH (60% suspension in mineral oil) [except in those cases where the Ar/R-CH2Br(Cl) is used in the form of a salt, such as HCl salt, use an additional amount of water-NaH]. Add the corresponding aryl halides and the mixture is stirred at room temperature overnight. The mixture is diluted with EtOAc and acidified with 10% HCl. The organic phase was washed with water (3×), saturated salt solution and dried over anhydrous Na2SO4. The solution is filtered, concentrated in vacuo and the residue purified flash chromatography on SiO2using dichloromethane as eluent, or recrystallized, getting listed at the beginning of the connection.

Example 16. Getting connection P057

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) 2-(bromoethyl)naphthalene, receiving the connection P057.1H-NMR (500 MHz, DMSO-d6). MS (ESI-): 485,5 (M-1), LC-MS: purity 97%.

Example 17. Getting connection P084

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-Sul the background of the acid (I-8) benzylbromide, receiving a connection P084. ESI-MS (M-1): 435,4 with 91%1H-NMR (500 MHz, CDCl3).

Example 18. Getting connection P086

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) 2-chlorophenylalanine, receiving the connection P086.

Example 19. Getting connection P087

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) 3,4-dichlorobenzamide, receiving the connection P087. ESI-MS gives (M-1): 503,3, JHMC=84%;1H-NMR (500 MHz, CDCl3).

Example 20. Getting connection P088.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) 3,5-diferenciada, receiving the connection P088. ESI-MS gives (M-1): 471,4 IHMS 84%.1H-NMR (500 MHz, CDCl3).

Example 21. Getting connection P089

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) 5-chloro-6-chlorodibenzo[1,3]dioxolan, receiving the connection P089. ESI-MS gives (M-1): 513,6, JHMC=80%.1H-NMR (500 MHz, CDCl3).

Example 22. Getting connection P099.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) 2-chloromethylene, receiving the connection P099. ESI -MS (M-1): 486,5, JHMC=92%.

Example 23. The connection is P100.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) of the hydrobromide of 2-pyridylmethylamine, receiving the connection P100. ESI MS (M-1)=436,4, JHMC=86%.

Example 24. Getting connection P101

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) 5-bromeilles[1,3]dioxolan, receiving the connection P101. ESI-MS (M-1): 479,3, JHMC=87%.1H-NMR (500 MHz, CDCl3).

Example 25. Getting connection P102

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) 5-methyl bromide-7-fluoro-2,3-dihydrobenzo[1,4]dioxin, receiving the connection P102.1H-NMR (500 MHz, CDCl3) to 2.35 (s, 3H), is 4.93 (s, 2H), of 5.34 (s, 2H), of 5.40 (s, 2H), 5,98 (DD, J=8,5, 2.5 Hz, 1H), x 6.15 (d, J=to 15.0 Hz, 1H), to 6.57 (DD, J=8,5, 2.5 Hz, 1H), 6,91 (s, 1H), 7,12 (m, 2H), 7.23 percent (d, J=7.5 Hz, 1H), 7,66 (d, J=7.5 Hz, 1H), of 7.70 (DD, J=5.0 and 1.5 Hz, 1H), of 7.90 (DD, J=4,0,1,5 Hz, 1H), of 7.96 (d, J=to 15.0 Hz, 1H), 7,97 (ush. s, 1H). LC/MS=85% purity; MS (ESI-) Calculated (M-H) 511,6; found: 511,5.

Example 26. Getting connection P103

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) 3,4-diferenciada, receiving the connection P103. ESI-MS (M-1)=471,4, JHMC=84%.1H-NMR (500 MHz, CDl3).

Example 27. Getting connection P109

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) 3-pyridylmethylamine, receiving the connection P109. ESI MS (M-1)=436,4, JHMC=88%;1H-NMR (500 MHz, CDCl3).

Getting [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9). To (E)-3-(3-methyl-1H-indol-7-yl)acrylic acid (I-7) (1 mmol), 4-dimethylaminopyridine (DMAP, 2 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 2 mmol) in CH2Cl2(30 ml) is added amide 4,5-dichlorothiophene-2-sulfonic acid (1.1 mmol). The reaction mixture was stirred at room temperature for 24-40 hours. The reaction mixture is diluted with 30 ml dichloromethane and then acidified with 10% aqueous HCl solution to pH~1-2. The organic phase is washed with saturated salt solution, dried over anhydrous Na2SO4and concentrate under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2CI2; CH2Cl2/EtOAc/hexane=1:10:20-1:20:10), obtaining the target product, I-9.1H-NMR (500 MHz, CDCl3)ESI-MS (M-1): 436,4, 88%.

Example 28. Getting connection P118

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 3,4-dichlorobenz what bromidum, receiving a connection P118. ESI-MS (M-1)=573,1, JHMC=97%.1H-NMR (DMSO-d6) confirms the structure.

Example 29. Getting connection P119

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 3-cryptomethodoverrides, receiving the connection P119. ESI MS (M-1)=573,0 IHMS=96%. 1H-NMR (500 MHz, CDCl3).

Example 30. Getting connection P120

A General method (A-2) used for alkylation [(E)-3-(1,3-dimethyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 4-farbensymposium, receiving the connection P120. ESI MS (M-1)=523,1; JHMC=88%.1H-NMR (500 MHz, CDCl3).

Example 31. Getting connection P121

A General method (A-2) used for alkylation [(E)-3-(1,3-dimethyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 3,4-dimethoxy-2-pyridylmethylamine, receiving the connection P121. ESI-MS (M-1)=568,3; JHMC=96%.1H-NMR (500 MHz, CDCl3).

Example 32. Getting connection P122

A General method (A-2) used for alkylation [(E)-3-(1,3-dimethyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) benzylbromide, receiving the connection P122. ESI-MS (M-1)=505,0, JHMC=91%.1H-NMR (DMSO-d6) confirms the structure.

Example 33. Getting connection P123

A General method (A-2) used for alkylation [(E)-3-(1,3-dimethyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 2-chlorobenzylamino, receiving a connection P123. ESI MS (M-1)=TO 539.3, JHMC=94%.1H-NMR (DMSO-d6) confirmed the structure.

Example 34. Getting connection P124

A General method (A-2) used for alkylation of 4,5-dichlorothiophene-2-sulfonic acid [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide (I-9) 2,6-dichlorobenzamide, receiving the connection P124. ESI-MS (M-1)=573,2, JHMC=99%.1H-NMR(DMSO-d6) confirmed the structure.

Example 35. Getting connection P125 business

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 2-bromomethylbiphenyl, receiving the connection P125 business. ESI MS (M-1)=579,5, JHMC=88%.1H-NMR(DMSO-d6) confirmed the structure.

Example 36. Getting connection P135.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 3,4-diferenciada, receiving the connection P135. ESI-MS (M-1)=541,2, JHMC=96%.1H-NMR (500 MHz, CDCl3).

Example 37. Getting connection P136.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 3,5-diferenciada, receiving the connection P136. ESI MS (M-1)=541,2, JHMC=96%.1H-NMR (500 MHz, CDCl3).

Example 38. Getting connection P137.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 4-chlorobenzylamino, receiving a connection P137. ESI MS (M-1): 539,2, 99%.

1H-NMR(DMSO-d6) confirmed the structure.

Example 39. Getting connection P138.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 2,5-dimethylbenzylamine, receiving the connection P138. ESI MS (M-1)=531,3, JHMC=99%.1H-NMR(DMSO-d6) confirmed the structure.

Example 40. Getting connection P139.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 5-bromeilles[1,3]dioxolan, receiving the connection P139.1H-NMR (500 MHz, DMSO-d6), and 2.27 (s, 3H), of 5.40 (s, 2H), to 5.93 (s, 2H), 6,33 (d, J=to 15.0 Hz, 1H), 6.42 per (d, J=7.5 Hz, 1H), 6,47 (s, 1H), of 6.68 (d, J=8.0 Hz, 1H), was 7.08 (DD, J=8,0, 7.5 Hz, 1H), 7,24 (d, J=7.5 Hz, 1H), 7,29 s, 1H), to 7.61 (d, J=7.5 Hz, 1H), of 7.90 (s, 1H), 8,17 (d, J=to 15.0 Hz, 1H), 12,6 (ush. s, 1H). LC/MS=95% purity; MS (ESI-) Calculated (M-H+2)549; Found: 549.

Example 41. Getting connection P140.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 3-cryptomethodoverrides, receiving the connection P140. ESI-MS (M-1)=587,3, JHMC=98%.1H-NMR(DMSO-d6) confirmed the structure.

Example 42. Getting connection P141

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 3,5-dimethoxybenzamide, receiving a connection P141. ESI-MS (M-1)=563,3, JHMC=93%.1H-NMR(DMSO-d6) confirmed the structure.

Example 43. Getting connection P142.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 3-methoxybenzylamine, receiving the connection P142. ESI-MS (M-1)=535,2, JHMC=86%.1H-NMR(DMSO-d6) confirmed the structure.

Example 44. Getting connection P143.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 4-cryptomethodoverrides, receiving the connection P143. ESI-MS (M-1)=587,5, JHMC=99%.1H-NMR(DMSO-d6) confirmed the structure.

Example 45. Getting connection P144.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 4-bromoethylamine, receiving the connection P144.1H-NMR(DMSO-d6) of 1.02 (m, 2H), 1.39 in (m, 2H), 1,89 (m, 1H), of 2.21 (s, 3H), 3,10 (m, 2H), of 3.77 (m, 2H), 4,10 (d, J=5.6 Hz, 2H), to 6.39 (d, J=12,4 Hz, 1H), 7,05 (DD, J=6,4, 6.0 Hz, 1H), 7,10 (s, 1H), 7,28 (d, J=5.6 Hz, 1H), 7,55 (d, J=6,4 Hz, 1H), 7,76 (s, 1H), 8,27(d, J=12 Hz, 1H). LC/MS (96%) ESI-Calculated 513,5 m/z; found: 511,5 m/z.

Example 46. Getting connection P145.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 4-ditto what methoxybenzylamine, receiving a connection P145.1H-NMR (500 MHz, DMSO-d6) of 2.28 (s, 3H), 5,51 (s, 2H), 6,28 (d, J=to 15.0 Hz, 1H), 6,99 (m, 4H), was 7.08 (t, J=7.5 Hz, 1H), 7,19 (t, J=74 Hz, 1H), 7,22 (d, J=7.5 Hz, 1H), 7,33 (s, 1H), 7.62mm (d, J=7.5 Hz, 1H, to $ 7.91 (s, 1H), 8,12 (d, J=15,0 Hz). LC/MS=95% purity; MS (ESI-) Is calculated: (M-H) 569; found: 569.

Example 47. Getting connection P146.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid (I-9) 2-bromoethylene, receiving the connection P146 ESI-MS (M-1)=556,0, JHMC=96%.1H-NMR(DMSO-d6) confirmed the structure.

Example 48. Getting connection P072.

Methyl ester 3-(3-methyl-1H-indol-7-yl)propionic acid (I-10). A mixture of methyl ester (E)-3-(3-methyl-1H-indol-7-yl)acrylic acid (I-6a) (190 mg, 0.88 mmol) and Pd/C (5%, 100 mg) in methanol (15 ml) and EtOAc (5 ml) hydronaut hydrogen at a pressure of 40 pounds per square inch at room temperature over night. The reaction mixture was filtered through a layer of celite and a layer of celite washed with EtOAc and methanol. The filtrate is concentrated, receiving 170 mg of the product of I-10 (methyl ester 3-(3-methyl-1H-indol-7-yl)propionic acid)1H-NMR (500 MHz, CDCl3).

3-(3-Methyl-1H-indol-7-yl)propionic acid (I-11). To a solution of ester I-10 (170 mg, 0.78 mmol) in THF (8 ml) and methanol (8 ml) is added 2n. aqueous NaOH (3 ml) at room temperature. The reaction mixture was stirred at room temperature in those who tell the night and then the pH is acidified by addition of aqueous 2n. HCl. The reaction mixture was extracted with EtOAc (2×40 ml). The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After filtration and removal of solvent the residue is washed with a mixture of ether/hexane, receiving 75 mg of 3-(3-methyl-1H-indol-7-yl)propionic acid (I-11).1H-NMR (500 MHz, DMSO-d6).

[3-(3-Methyl-1H-indol-7-yl)propionyl]amide 4,5-dichlorothiophene-2-sulfonic acid, I-12: the Mixture of acid I-11 (75 mg, and 0.37 mmol), 4,5-dichloro-2-thiophenesulfonyl (103 mg, 0.44 mmol), 4-dimethylaminopyridine (90 mg, of 0.74 mmol) and EDCI (141 mg, of 0.74 mmol) in dichloromethane (10 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water and dried over sodium sulfate. After filtration and removal of solvent the residue is washed with ether, receiving 60 mg of arylsulfonamides I-12.1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P072. To a solution of sulfonamida I-12 (35 mg, 0,084 mmol) in DMF (3 ml) is added NaH (60% in oil, 15 mg, and 0.37 mmol) at 0oC. After stirring at room temperature for 20 minutes, add 2,4-DICHLOROSILANE (47 mg, 0.24 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with methylene chloride (12 ml). The reaction mixture is washed with dilute aqueous HCl (2×8 ml), water (4×8 ml), saturated salt solution and with the shat over sodium sulfate. After filtration and removal of solvent the residue is washed with a mixture of ether/hexane, receiving 33 mg connection P072. MS (ESI-)=575,2 (M-1), JHMS: 86%.1H-NMR (500 MHz, DMSO-d6).

Example 49. Getting connection P073

To a solution of sulfonamida I-12 (35 mg, 0,084 mmol) in DMF (3 ml) is added NaH (60% in oil, 15 mg, and 0.37 mmol) at 0°C. After stirring at room temperature for 20 minutes, add 2-(methyl bromide)naphthalene (53 mg, 0.24 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with methylene chloride (12 ml). The reaction mixture is washed with dilute aqueous HCl (2×8 ml), water (4×8 ml), saturated salt solution and dried over sodium sulfate. After filtration and removal of solvent the residue is washed with a mixture of ether/hexane, receiving 35 mg connection P073. MS(ESI-)=557,0 (M-1), JHMS: 70%.1H-NMR (500 MHz, DMSO-d6).

Example 50. Getting connection P078 and P079

Synthesis of methyl ester (E)-3-[1-(2,4-dichlorobenzyl)-3-methyl-1H-indol-7-yl]acrylic acid (I-13). To a solution of methyl ester (I-6a) (730 mg, 3.4 mmol) in DMF (15 ml), added NaH (60% in oil, 272 mg, 6.8 mmol) at 0°C. After stirring at room temperature for 30 minutes, add 2,4-DICHLOROSILANE (1326 mg, 6.8 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with methylene chloride (150 ml). The reaction is second mixture is washed with dilute aqueous HCl (2×50 ml), water (4×100 ml), saturated salt solution and dried over sodium sulfate. After filtration and removal of solvent the residue is purified column chromatography on silica gel, using hexane and EtOAc/hexane as eluent and receiving 60 mg methyl ester I-13 and 470 mg of ester I-14 (2,4-dichlorobenzoyl ester of 3-[1-(2,4-dichlorobenzyl)-3-methyl-1H-indol-7-yl]acrylic acid).1H-NMR (500 MHz, DMSO-d6).

Synthesis of (E)-3-[1-(2,4-dichlorobenzyl)-3-methyl-1H-indol-7-yl]acrylic acid, I-15. To a solution of ester I-13 (300 mg, 0.8 mmol) in THF (6 ml) and methanol (6 ml) at room temperature, add aqueous 2n. NaOH (3 ml). The reaction mixture was stirred at room temperature overnight and then the pH is acidified by addition of aqueous 2n. HCl. The reaction mixture was extracted with EtOAc (2×40 ml). The combined organic phases are washed with water, saturated salt solution and dried over sodium sulfate. After filtration and removal of solvent the residue is washed with ether, receiving 280 mg of the acid I-15.1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P079. The mixture of acid I-15 (54 mg, 0.15 mmol), 4,5-dichloro-2-thiophenesulfonyl (42 mg, 0.18 mmol), 4-dimethylaminopyridine (37 mg, 0.3 mmol) and EDCI (57 mg, 0.3 mmol) in dichloromethane (5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl (2×10 ml), water (4×10 ml) and Ishenim salt solution and dried over sodium sulfate. After filtration and removal of solvent the residue is purified column chromatography on silica gel using dichloromethane and a mixture of methanol/dichloromethane as eluents and receiving 45 mg connection P079. MS(ESI-)=573,1 (M-1), JHMS: 93%.1H-NMR (500 MHz, DMSO-d6).

Example 51. Getting connection P090

The mixture of acid I-15 (54 mg, 0.15 mmol), benzosulfimide (28 mg, 0.18 mmol), 4-dimethylaminopyridine (37 mg, 0.3 mmol) and EDCI (57 mg, 0.3 mmol) in dichloromethane (5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl (2×10 ml), water (4×10 ml), saturated salt solution and dried over sodium sulfate. After filtration and removal of solvent the residue is purified column chromatography on silica gel using dichloromethane and methanol/dichloromethane as eluents and receiving 40 mg connection P090. MS (ESI-)=499,3 (M-1), JHMS: 92%.1H-NMR (500 MHz, DMSO-d6).

Example 52. Getting connection P074

In a round bottom flask (50 ml) was placed a solution P001 (40 mg, 0.8 mmol) in EtOH (5 ml), added Pd/C (60 mg) at room temperature. In the create a vacuum flask and fill with H2(3×) and the resulting reaction mixture was stirred at room temperature in an atmosphere of H2within 72 hours. The catalyst is filtered off and washed with EtOH (3×10 ml). The solvent is removed in vacuum, receiving about who headed the remainder of that which is purified by recrystallization from a mixture of acetone/EtOAc/hexane, receiving targeted P074 (25 mg, 60% yield) as a solid, not quite white matter. MS (ESI-)=473,4 (M-1), GHMC (ESI-)>90%.1H-NMR (500 MHz).

Example 53. Getting connection P005

To a suspension of NaH (60% in mineral oil, 5 mg, 0,122 mmol) in anhydrous DMF (1 ml) at 0°C, add a solution of (3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-8 (20 mg, 0.061 mmol) in DMF (1 ml). The resulting mixture was stirred at room temperature for 0.5 hours, cooled to 0°C and add 2-aftercare (13 mg, 0,067 mmol). The reaction mixture was stirred at room temperature for 18 hours. Then add saturated aqueous solution of NH4Cl (1 ml) and the mixture is extracted with a mixture of ether/EtOAc 8:2 (2×15 ml). The combined organic layers dried over MgSO4the mixture is filtered, the solvent removed and the crude product is purified column chromatography using methylene chloride, 2% MeOH/methylene chloride, receiving 4.5 mg connection P005.

Example 54. Getting connection P016.

Synthesis of trifter-N-(3-1H-indol-7-ylpropionic)methanesulfonamide, I-17. To a suspension of NaH (60% in mineral oil, 360 mg, 9.0 mmol) in DMF (30 ml) is added 3-(1H-indol-7-yl)acrylic acid, I-7 (560 mg, 3.0 mmol) at 0°C. the mixture allow to warm to room temperature, stirred for 2 hours and is then cooled to 0°C. To the resulting solution was added 2-bromethalin (680 mg, 3.1 mmol) at 0°C, the mixture allow to warm to room temperature and stirred for 16 hours, then the reaction mixture is cooled to 5°C and acidified by adding aqueous 10% HCl to reach pH 1. The resulting mixture was extracted with CH2Cl2/MeOH(9/1,3×50 ml). The combined organic extracts dried (Na2SO4), filtered and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2/EtOAc/hexane=1:8-1:2), receiving targeted of acrylic acid, I-17 (400 mg, 41%) as a white solid. MS(ESI-) m/z 326, 100%), GHMC (ESI-)>95%.1H-NMR (CDCl3), 13C-NMR (CDCl3).

The synthesis of compounds P016. To a solution of triftormetilfullerenov (17 mg, 0.11 mmol), 4-dimethylaminopyridine (DMAP, 20 mg, 0.18 mmol) and hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 32 mg, 0.18 mmol) in CH2Cl2(5 ml) under stirring at room temperature add intermediate I-17 (33 mg, 0.1 mmol). The resulting reaction mixture was stirred at room temperature for 72 hours, then cooled to 5°C, acidified with aqueous HCl (10%) until pH=1 and extracted with CH2Cl2/MeOH (9/1, 3×10 ml). The combined organic layers are dried (Na2SO4), the solvent is dilaut under reduced pressure, receiving the crude product, which was purified flash chromatography (silica gel, CH2Cl2;EtOAc/hexane=1:4-2:1)to give compound P016 (26 mg, 56%) as a bright yellow solid.1H NMR (500 MHz, CDCl3); 6,62 (d, J=16.0 Hz, 1H), 7,01 (d, J=3.5 Hz, 1H), 7,12 (t, J=7.5 Hz, 1H), 7,19 (t, J=8.0 Hz, 1H), 7,25-7,30 (m, 3H), 7,43-of 7.48 (m, 2H), of 7.70 (m, 1H), 7,78-7,81 (m, 3H), to 8.45 (d, J=15 Hz, 1H). LC/MS (99%) ESI-Calculated: 458,5 m/z, found: 457,4 m/z (M-1).

Example 55. Getting connection P003

To a suspension of (E)-3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-8 (20 mg, holding 0.062 mmol) in glacial acetic acid (1 ml) in small portions at 0°C add cyanoborohydride sodium (95%, 8 mg, 0,124 mmol). The mixture allow to warm to room temperature and stirred for 4 hours. The reaction mixture was concentrated and then quenched with water (1 ml). The pH value of the mixture was adjusted to 5 by addition of an aqueous 5% NaHCO3and the mixture is extracted with methylene chloride (2×5 ml). The combined organic layers washed with water and dried (MgSO4). The solution is filtered and the solvent is removed under reduced pressure, receiving the product, I-18. The resulting product is then used without further purification. To a suspension of potassium carbonate (17 mg, 0,123 mmol) in anhydrous DMF (1 ml) add indolin I-18 (20 mg, 0.061 mmol), 2-bromethalin (13.5 mg, 0.061 mmol) and potassium iodide (10 mg, 0.061 mmol). The reaction mixture was stirred at anatoy temperature for 2 days. Add water (6 ml) and the mixture extracted with ether (2×10 ml). The combined organic layers washed with water (2 ml), saturated salt solution (2 ml), dried over MgSO4and concentrated in vacuo. The crude product is purified by preparative chromatography, receiving product P003.

Example 56. Getting connection P045

To a suspension of (E)-3-1H-indol-7-ylacrylic)amide thiophene-2-sulfonic acid (I-4 (120 mg, 0,39 mmol) in acetic acid (ice, 10 ml) in small portions at room temperature add cyanoborohydride sodium (95%, 150 mg, 2.5 mmol). The resulting mixture is heated and stirred at 70°C for 4 hours. The reaction mixture was cooled to 0 °C and the reaction quenched with water (10 ml) at 0°C. the Mixture is acidified with aqueous HCl (10%) to pH 1, then extracted with CH2Cl2/MeOH (20:1,3×30 ml). The combined organic layers are dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, EtOAc/hexane=1:5-1:1) to obtain the target indoline I-18 (80 mg, 65%) as a white solid. MS(ESI-)m/z=335,2. To the solution obtained indoline I-18 (37 mg, 0.11 mmol) in CH2Cl2(7 ml) with stirring, add triethylamine (21 mg, 0.22 mmol) and then 2-naphthalenesulfonate (25 mg, 0.11 mmol) at 0°C. the mixture allow to warm to room temperature and stirred at room temperature for 24 hours. The reaction mixture was cooled to 0°C, then acidified with aqueous HCl (10%) to pH 1, then extracted with CH2Cl2/MeOH (10:1, 3×20 ml). The combined organic layers are dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, EtOAc/hexane=1:5-1:1), obtaining the target product P045 (12 mg, 21%) as a pale yellow solid. MS(ESI-) m/z=523,5, 100%, IHMS(ESI)>70%.1H NMR (500 MHz, CD3OD) 2,11 (t, J=8.0 Hz, 2H), 4,08 (t, J=8.0 Hz, 2H), 6,62 (d, J=16.0 Hz, 1H), 7,01 (DD, J=7,5, 1.0 Hz, 1H) 7,11 (DD, J=5.0 and 4.0 Hz, 1H), 7,19 (DD, J=7,5, 7.5 Hz, 1H), was 7.36 (DD, J=8,5, 2.0 Hz, 1H), 7,60 (m, 1H), to 7.67 (m, 2H), 7,73 (DD, J=5,5, 1.5 Hz, 1H), 7,79 (DD, J=3,5, 0.5 Hz, 1H), 7,87 (m, 2H), to 7.93 (d, J=8.5 Hz, 1H), of 8.06 (s, 1H), 8,19 (d, J=16.0 Hz, 1H).

Example 57. Getting connection P085.

Methyl ester (E)-3-(3-acetyl-1H-indol-7-yl)acrylic acid, I-19. In a pre-dried round bottom flask (100 ml) load methyl ester I-2a (645 mg, 3 mmol) in DMF (5 ml) and added dropwise POCl3(330 ml) at 0-5°C. the resulting reaction mixture, allow to warm to room temperature, the mixture is stirred at room temperature for 20 minutes, then heated to 40°C and stirred at 40°C for 1 hour. The reaction mixture was cooled to 0°C and poured into ice water suspension (50 ml), then add aqueous NaOH (0.5 g in 10 ml water). The mixture is extracted with EtOAc (3×50 ml), joint the United organic layers washed with water (3×50 ml), dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the target I-19 (450 mg, 58% yield) as a yellow solid. MS (ESI-)=256,3 (M-1).1H-NMR (500 MHz, CDCl3).

Methyl ester (E)-3-[3-acetyl-1-(2,4-dichlorobenzyl)-1H-indol-7-yl]acrylic acid, I-20. In a round bottom flask (250 ml) upload a suspension of compound I-19 (400 mg, 1.6 mmol), KI (300 mg) and CsCO3(600 mg) in DMF (40 ml) at room temperature, with stirring, add 2,4-DICHLOROSILANE (350 mg, 1.8 mmol). The resulting reaction mixture was stirred at room temperature for 72 hours. The mixture is cooled to 0°C, add water NH4Cl (saturated, 10 ml), then extracted with EtOAc (2×100 ml), the combined organic layers washed with water (3×100 ml), dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2; EtOAc/hexane=1:8-1:2)to give compound I-20 (480 mg, 74% yield) as a yellow solid. MS (ESI+)=416,7 (M). 1H-NMR (500 MHz, CDCl3).

(E)-3-[3-Acetyl-1-(2,4-dichlorobenzyl)-1H-indol-7-yl]acrylic acid, I-21. In a round bottom flask (50 ml) download NaOH solution (300 mg, 7.5 mmol) in EtOH (20 ml) and H2O (10 ml), add connection I-20 (300 mg, 0.7 mmol) at 5°C. the resulting reaction mixture is heated to 50°C and stirred at 50°C for 5 h the owls. The reaction mixture was cooled to 0°C and acidified with aqueous HCl (10%) until pH=1, then add water (100 ml) and extracted with a mixture of dichloromethane-MeOH (10:1, 3×20 ml). The combined organic layers dried over Na2SO4and the solvent is removed in vacuum, obtaining the crude product which is purified by recrystallization from a mixture of acetone/EtOAc/Hex, receiving acid (I-21 (260 mg, 90% yield) as a yellow solid. MS (ESI-)=386,4 (M-2). IHMS(ESI-)>90%.1H-NMR (500 MHz).

The synthesis of compounds P085. In a round bottom flask (25 ml)to which was added a solution of 2-thiophenesulfonyl (28 mg, 0,17 mmol), 4-dimethylaminopyridine (DMAP, 23 mg, 0.3 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 40 mg, 0.4 mmol) in (5 ml) at room temperature add the acrylic acid I-21 (60 mg, 0.16 mmol). The resulting mixture was stirred at room temperature for 72 hours, then cooled to 0°C. After addition of MeOH (1 ml) and water (5 ml) the reaction mixture is acidified with aqueous HCl (10%) to pH 1, then extracted with CH2Cl2/MeOH (9/1, 3×5 ml). The combined organic layers are dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2/EtOAc/hexane=1:1:4, EtOAc)to give the target product P085 (35 mg, 40% yield) as a bright yellow solid.1H is the Mr (500 MHz, CDCl3); 2,53 (c, 3H), of 5.53 (c, 2H), of 6.20 (d, J=to 15.0 Hz, 1H), 6.42 per (d, J=8.5 Hz, 1H), 7,07 (DD, J=8.0 a, 3.0 Hz, 1H), 7,16 (t, J=4.5 Hz, 1H), 7,26-7,30 (m, 2H), 7,41 (d, J=2.0 Hz, 1H), 7,69 (s, 1H), 7,74 (DD, J=of 5.5, 1.5 Hz, 1H), to $ 7.91-7,94 (m, 2H), to 8.57 (DD, J=7,0, 2.0 Hz, 1H). LC/MS (78%) ESI-: calculated: 533,5 m/z, found: 535,1 m/z (M).

Example 58. Getting connection P091

Methyl ester (E)-3-[1-(2,4-dichlorobenzyl)-3-Isopropenyl-1H-indol-7-yl] acrylic acid, I-22. In a pre-dried round bottom flask (250 ml) load the solution Ph3PCH3Br (1300 mg, 0.6 mmol) in THF (55 ml), under stirring at 0°C is added BuLi (2.0 ml, 1.6 m in ether). The obtained reaction mixture was allow to warm to room temperature, then the mixture is heated to 40°C and stirred at 40°C for 2 hours. The mixture is cooled to 0°C and added to the mixture of the compound I-20 (460 mg, 1.1 mmol). The mixture is heated to room temperature, then heated to 40°C and stirred at 40°C for 3 hours. After cooling to 0°C the reaction is quenched with aqueous NH4Cl (saturated, 5 ml), then extracted with EtOAc (2×100 ml), the combined organic layers washed with water (3×100 ml), dried (Na2SO4), the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, EtOAc/hexane=1:8-1:4), receiving the target I-22 (380 mg, 85% yield)as a bright yellow solid. MS (ESI+): 414,8 (M).1H-NMR (500 MHz, CDCl3).

Meth is lovy ester of 3-[1-(2,4-dichlorobenzyl)-3-isopropyl-1H-indole-7-ml]propionic acid, I-23. In a round bottom flask (50 ml) download solution of compound I-22 (260 mg, 0.6 mmol) in EtOH (55 ml) and add water Pd/C (30 mg) at room temperature. Then create a vacuum flask and download H23 times, the resulting reaction mixture was stirred at room temperature for 16 hours. The catalyst is filtered off and washed with EtOAc (3×50 ml), the filtrate washed with water (3×50 ml), dried over Na2SO4and the solvent is removed in vacuum, obtaining the compound I-23 (240 mg, 95% yield) as a solid, not quite white matter.1H-NMR (500 MHz).

3-[1-(2,4-dichlorobenzyl)-3-isopropyl-1H-indol-7-yl]propionic acid, I-24. In a round bottom flask (50 ml) download NaOH solution (200 mg, 5 mmol) in EtOH (30 ml) and H2O (20 ml) at 5°C, add the compound I-23 (180 mg, 0.4 mmol). The resulting reaction mixture is heated to 50°C and stirred at 50°C for 5 hours. The reaction mixture was cooled to 0°C and acidified with aqueous HCl (10%) until pH=1, then add water (100 ml) and extracted with a mixture of dichloromethane-MeOH (10:1, 3×20 ml). The combined organic layers dried over Na2SO4and the solvent is removed in vacuum, obtaining the crude product which is purified by recrystallization from a mixture of acetone/EtOAc/Hex, receiving the target I-24 (150 mg, 90% yield) as a yellow solid. MS (ESI-)=388,3 (M-1). IHMS(ESI-)>85%.1H-NMR (500 MHz).

The synthesis of compounds P091. In to padonou flask (25 ml), which is the solution of 2-thiophenesulfonyl (28 mg, 0.16 mmol), 4-dimethylaminopyridine (DMAP, 30 mg, 0.3 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 40 mg, 0.4 mmol) in CH2Cl2(12 ml) was added propionic acid I-24 (60 mg, 0.15 mmol) at room temperature. The resulting mixture was stirred at room temperature for 48 hours, then cooled to 0 °C. After addition of MeOH (1 ml) and water (5 ml) the reaction mixture is acidified with aqueous HCl (10%) to pH 1, then extracted with CH2C12(3×5 ml). The combined organic layers are dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2, EtOAc/hexane=1:1, EtOAc)to give the target P091 (40 mg, 40% yield) as a solid, not quite white matter. MS(ESI-) m/z=535,2, (M+); IHMS(ESI-) >95%.1H-NMR (500 MHz).

Example 59. Getting connection P092.

In a round bottom flask (25 ml) load the solution of 4,5-dichlorodiphenylmethane (21 mg, 0.09 mmol), 4-dimethylaminopyridine (DMAP, 15 mg, 0.2 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI (20 mg, 0.2 mmol) in CH2Cl2(7 ml) at room temperature add the acrylic acid I-24 (30 mg, 0.08 mmol). The resulting mixture was stirred at room temperature for 48 hours, then cooled is about 0°C. After addition of MeOH (1 ml) and water (5 ml) the reaction mixture is acidified with aqueous HCl (10%) to pH 1, then extracted with CH2Cl2(3×5 ml). The combined organic layers are dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2, EtOAc/hexane=1:1, EtOAc) to give the target P092 (15 mg, 32% yield) as a solid not quite white matter. MS(ESI-)m/z=603,2, (M-1); IHMS(ESI-)> 95%.1H-NMR (500 MHz).

Example 60. Getting connection P093

In capacity (10 ml) under stirring download solution P091 (3 mg, 0.05 mmol) in DMSO-d6 (1 ml)slowly at 0°C. add HCl (concentrated, 3 ml). The mixture allow to warm to room temperature and the mixture is stirred at room temperature for 4 hours, then cooled to 0°C and add water (10 ml). The resulting solid product is filtered off, washed with water and dried in air and then in vacuum, obtaining oxindol-derived P093 (1.5 mg, 48% yield) as a solid, not quite white matter.1H NMR (500 MHz, acetone-d6); and 0.98 (d, J=7,0 Hz, 3H), of 1.06 (d, J=7,0 Hz, 3H), 2,48-2,52 (m, 2H), 2,68-a 2.71 (m, 2H), 5,15 (m, 2H), 6,94 (d, J=8.0 Hz, 1H), 6,97 (d, J=8.0 Hz, 1H), 7,03 (d, J=7.5 Hz, 1H), 7,18 (t, J=3.5 Hz, 1H), 7.23 percent (d, J=7.5 Hz, 1H), 7,28 (DD, J=8.0 a, 3.0 Hz, 1H), 7,45 (d, J=2.5 Hz, 1H), of 7.75 (d, J=3.0 Hz, 1H), of 7.90 (d, J=5.0 Hz, 1H). LC/MS (97%) ESI-. Calculated: 551,5 m/z,found: 551,2 m/z (M).

Example 61. Getting connection P069

Ethyl ester of (E)-3-(3-formyl-1-methyl-1H-indol-7-yl)acrylic acid, I-23. In a pre-dried round bottom flask (100 ml) load the solution of compound I-2 (2.6 g, 13 mmol) in DMF (5.2 ml) and added dropwise POCl3(1250 ml) at 0-5°C. the resulting reaction mixture, allow to warm to room temperature, stirred at room temperature for 20 minutes and then heated to 40°C and stirred at 40°C for 1 hour. The reaction mixture was cooled to 0°C and poured into a slurry of ice water (50 ml), then add aqueous NaOH (1.5 g in 20 ml water). The mixture is extracted with EtOAc (3×100 ml), the combined organic layers washed with water (3×100 ml), dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the target I-23 (2.0 g, 75%) as a yellow solid. MS (ESI-): 242,2 (M-1).1H-NMR (500 MHz, CDCl3).

Ethyl ester of (E)-3-[1-(2,4-dichlorobenzyl)-3-formyl-1H-indol-7-yl]acrylic acid, I-24. In a round bottom flask (250 ml) upload a suspension of compound I-23 (480 mg, 2 mmol), KI (500 mg) and CsCO3(1 g) in DMF (40 ml) with stirring, add 2,4-DICHLOROSILANE (440 mg, 24 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 72 hours. The mixture is cooled to 0°C and add water NH4Cl (us. 10 ml), ZAT is extracted with EtOAc (2×100 ml), the combined organic layers washed with water (3×100 ml), dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2; EtOAc/hexane=1:4-1:2), receiving the target I-24 (400 mg, 50%) as a yellow solid. MS (ESI+): 402,3 (M+1). 1H-NMR (500 MHz, CDCl3).

(E)-3-[1-(2,4-Dichlorobenzyl)-3-formyl-1H-indol-7-yl]acrylic acid, I-25: In a round bottom flask (50 ml) download NaOH solution (80 mg, 2 mmol) in EtOH (5 ml) and H2About (3 ml), added compound I-24 (80 mg, 0.2 mmol) at 5°C. the resulting reaction mixture is heated to 50°C and stirred at 50°C for 4 hours. The reaction mixture was cooled to 0°C and acidified with aqueous HCl (10%) until pH=1, then add water (20 ml) and extracted with a mixture of dichloromethane-MeOH (10:1, 3×20 ml). The combined organic layers dried over Na2SO4and the solvent is removed in vacuum, obtaining the crude product which is purified by recrystallization from a mixture of acetone/EtOAc/Hex, receiving compound I-25 (60 mg, 80% yield) as a yellow solid. MS (ESI-): 372,1 (M-2).1H-NMR (500 MHz).

The synthesis of compounds P069. In a round bottom flask (25 ml) download solution of 2-thiophenesulfonyl (9 mg, 0.05 mmol), 4-dimethylaminopyridine (DMAP, 20 mg, 0.2 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 25 mg, 0.3 mmol) in (5 ml) and on the th temperature add the acrylic acid I-25 (9 mg, 0.03 mmol). The resulting mixture was stirred at room temperature for 72 hours, then cooled to 0°C. After addition of MeOH (1 ml) and water (5 ml) the reaction mixture is acidified with aqueous HCl (10%) to pH 1, then extracted with CH2Cl2/MeOH (9/1, 3×5 ml). The combined organic layers are dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2/EtOAc/hexane=1:1:4, EtOAc)to give the target P069 (6.3 mg, 45% yield) as a bright yellow solid.1H NMR (500 MHz, methanol-d4); 5,70 (s, 2H), 6,13 (d, J=to 15.0 Hz, 1H), 6,36 (d, J=8.5 Hz, 1H), 7,09-7,11 (m, 2H), 7.23 percent (m, 1H), 7,29-7,35 (m, 2H), 7,60 (m, 1H), of 7.70 (m, 1H), 7,89-7,94 (m, 2H), 8.34 per (DD, J=9,0, 1.5 Hz, 1H), 9,95 (s, 1H). LC/MS (71%) ESI-Calculated: 519,4 m/z, found: 517,4 m/z (M-2).

Example 62. Getting connection P062

Ethyl ester of (E)-3-[1-(2,4-dichlorobenzyl)-3-hydroxymethyl-1H-indol-7-yl]acrylic acid, I-26: In a round bottom flask (100 ml) load the suspension of compound I-24 (100 mg, 0.25 mmol) in EtOH (5 ml) and stirring NaBH4(100 mg, excess) at 0°C. the Obtained reaction mixture was allow to warm to room temperature and the mixture is stirred at room temperature for 4 hours. The mixture is cooled to 0°C, add water NH4Cl (saturated, 5 ml), then extracted with CH2Cl2(2×30 ml), the combined organic is Lois washed with water (3×30 ml), dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2; EtOAc/hexane (elution with a gradient from 1:4 to 1:1)to give alcohol I-26 (85 mg, 84% yield) as a solid not quite white matter. MS (APCI+): 406,2 (M+2).1H-NMR (500 MHz, CDCl3).

(E)-3-[1-(2,4-dichlorobenzyl)-3-hydroxymethyl-1H-indol-7-yl]acrylic acid, I-27. In a round bottom flask (50 ml) download solution of compound I-26 (80 mg, 0.2 mmol) in MeOH (15 ml) at room temperature, add aqueous NaOH (2n., 0.5 ml). The resulting reaction mixture is heated to 80°C and stirred at 80°C for 48 hours. The reaction mixture was cooled to 0°C and acidified with aqueous HCl (10%) to achieve pH=1, then add water (20 ml) and extracted with a mixture of dichloromethane-MeOH (10:1, 3×20 ml). The combined organic layers dried over Na2SO4and the solvent is removed in vacuum, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2; EtOAc/hexane=1:4-1:1, EtOAc)to give the acid I-27 (65 mg, 80% yield) as a solid not quite white matter. MS (ESI)=374,3 (M-2). IHMS(ESI-)>90%. 1H-NMR(500 MHz).

The synthesis of compounds P062. In a round bottom flask (25 ml) upload solution2-thiophenesulfonyl (35 mg, 0.15 mmol), 4-dimethylaminopyridine (DMAP, 45 mg, 0.5 mmol) and the hydrochloride of 1-[3-(dimethylamino)is ropyl]-3-ethylcarbodiimide (EDCI, 60 mg, 0.6 mmol) in CH2Cl2(5 ml) and add the acrylic acid I-27 (25 mg, 0.07 mmol) at room temperature. The resulting mixture was stirred at room temperature for 48 hours, then cooled to 0°C. After addition of MeOH (1 ml) and water (5 ml) the reaction mixture is acidified with aqueous HCl (10%) to achieve pH=1, then extracted with CH2Cl2(3×5 ml). The combined organic layers dried over anhydrous Na2SO4and the solvent is removed under reduced pressure, obtaining the crude product which was purified flash chromatography (silica gel, CH2Cl2, EtOAc/hexane=1:1, EtOAc)to give compound P062 (16 mg, 35% yield) as a solid not quite white matter. MS (ESI-) m/z=519,3, (M-2); IHMS(ESI) >85%. 1H-NMR (500 MHz).

Example 63. Getting connection P070

Ethyl ester of (E)-3-[1-(2,4-dichlorobenzyl)-3-methoxymethyl-1H-indol-7-yl]acrylic acid, I-28. In a round bottom flask (25 ml) upload a suspension of NaH (15 mg, 0.25 mmol) in DMF (5 ml), under stirring at 0°C. add compound I-26 (30 mg, 0.08 mmol). The mixture allow to warm to room temperature and stirred at room temperature for 90 minutes, then cooled to 0°C and add Me (1 ml). The obtained reaction mixture was allow to warm to room temperature and stirred at room temperature for 72 hours, cooled the to 0°C and add water NH 4Cl (saturated, 1 ml), then extracted with EtOAc (2×5 ml), the combined organic layers washed with water (2×5 ml), dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, EtOAc/hexane=1:8)to give compound I-28 (17 mg, 50% yield) as a solid not quite white matter.1H-NMR (500 MHz, CDCl3).

(E)-3-[1-(2,4-Dichlorobenzyl)-3-methoxymethyl-1H-indol-7-yl]acrylic acid, I-29. In a round bottom flask (50 ml) download NaOH solution (50 mg, 1.2 mmol) in MeOH (1 ml) in water (2 ml) and add ester I-28(17 mg, 0.04 mmol) at room temperature. The resulting reaction mixture is heated to 50°C and stirred at 50°C for 4 hours, then cooled to 5°C, acidified with aqueous HCl (10%) until pH=1. After dilution with water (10 ml), the mixture is extracted with a mixture of dichloromethane-MeOH (10:1,3×5 ml). The combined organic layers dried over Na2SO4and the solvent is removed in vacuum, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2; EtOAc/hexane=1:4-1:1, EtOAc) to give the acid I-29 (15 mg, 90% yield) as a solid not quite white matter. MS (ESI-)=388,3 (M-2).1H-NMR (500 MHz).

The synthesis of compounds P070. In a round bottom flask (25 ml) download solution of 2-thiophenesulfonyl (15 mg, 0.09 mmol), 4-dimethylaminopyridine (DMAP, 20 mg, 0.2 mmol) of the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 25 mg, 0.25 mmol) in CH2Cl2(5 ml)at room temperature add the acrylic acid I-29 (10 mg, of 0.025 mmol). The resulting mixture was stirred at room temperature for 48 hours, then cooled to 0°C. After addition of MeOH (1 ml) and water (5 ml) the reaction mixture is acidified by addition of aqueous HCl (10%) to achieve pH=1 and extracted with CH2Cl2(3×5 ml). The combined organic layers dried over anhydrous Na2SO4and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2, EtOAc/hexane=1:1)to give compound P070 (1.5 mg, 10% yield) as a solid not quite white matter.1H NMR (500 MHz, methanol-d4); 3,39 (s, 3H), of 4.67 (s, 2H), 5,70 (s, 2H), 6,16 (d, J=15,5 Hz, 1H), 6,36 (d, J=9.5 Hz, 1H), 7,05 (DD, J=8.0 a, 3.0 Hz, 1H), 7,12 (t, J=8.0 Hz, 1H), 7,20 (m, 1H), 7,25 (m, 1H), 7,31 (m, 1H), 7,74 (d, J=7.5 Hz, 1H), 7,84 - 7,87 (m, 2H), to $ 7.91 (d, J=to 15.0 Hz, 1H). LC/MS (78%) ESI-Calculated: 535,5 m/z, found: 535,0 m/z (M-1).

Example 64. Getting connection P060

Synthesis of methyl ester (E)-3-(5-fluoro-1H-indol-7-yl)acrylic acid methyl, I-30. To a mixture of 7-bromo-5-fluoro-1H-indole [which is produced in accordance with the known method (Dobbs, A., J. Org. Chem., 66,638-641 (2001)] (400 mg, of 1.87 mmol) and methyl acrylate (241 mg, 2.8 mmol) in triethylamine (1.5 ml) in an argon atmosphere add palladium(II) acetate (43 mg, 0,19 mmol) and tri-o-tolylphosphino (170 mg, 0,56 mmol), d is clonney the mixture is stirred at 100°C for 4 hours in a sealed reactor and then cooled to room temperature, diluted with CH2Cl2(50 ml), washed with water (3×30 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using EtOAc/hexane as eluent, the result is 300 mg of compound I-30 in the form of a yellow solid.1H-NMR (500 MHz, CDCl3).

Synthesis of (E)-3-(5-fluoro-1H-indol-7-yl)acrylic acid, I-31. To a solution of compound I-30 (219 mg, 1 mmol) in THF (5 ml) and methanol (4 ml) is added aqueous NaOH (4 ml) at room temperature. The reaction mixture was stirred at room temperature overnight and then the pH was adjusted to acidic by addition of 2n. HCl water. The reaction mixture was extracted with EtOAc (2×30 ml). The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent to obtain 180 mg of the acid I-31. 1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 204,2 (M-1).

Synthesis of thiophene-2-sulfonic acid [(E)-3-(5-fluoro-1H-indol-7-yl)acryloyl]amide, I-32. The mixture of acid I-31 (180 mg, 0.88 mmol), 2-thiophenesulfonyl (172 mg, 1.2 mmol), 4-dimethylaminopyridine (215 mg, 1.77 mmol) and EDCI (336 mg, 1.77 mmol) in dichloromethane (20 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and with the shat over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using a mixture of methanol/CH2Cl2as eluent and receiving 150 mg sulfonamida I-32.1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P060. To a solution of compound I-32 (45 mg, 0.13 mmol) in DMF (2 ml) is added NaH (60% in oil, 16 mg, 0.4 mmol) at 0°C, the resulting mixture was stirred at room temperature for 1 hour and then add 2-(methyl bromide)naphthalene (57 mg, 0.26 mmol). The resulting mixture was stirred at room temperature overnight and diluted with CH2Cl2(10 ml). The reaction mixture is washed with dilute aqueous HCl (2×8 ml), water (4×8 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using a mixture of methanol/CH2Cl2as eluent and receiving 30 mg of compound P060.1H-NMR (500 MHz, DMSO-d6) MS (ESI-): 489,4 (M-1), LC-MS: 80%.

Example 65. Getting connection P061.

To a solution of compound I-32 (45 mg, 0.13 mmol) in DMF (2 ml) is added NaH (60% in oil, 16 mg, 0.4 mmol) at 0°C, the mixture is stirred at room temperature for 1 hour and then add 2,4-DICHLOROSILANE (51 mg, 0.26 mmol). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2(10 ml). The reaction is mesh washed with dilute aqueous HCl (2×8 ml), water (4×8 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using methanol/CH2Cl2as eluent and receiving 55 mg of compound P061.1H-NMR (500 MHz, DMSO-d6) MS (ESI-): 509,3 (M-1), LC-MS: 93%.

Example 66. Getting connection P063.

Synthesis of methyl ester (E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acrylic acid, I-33. To a mixture of 7-bromo-5-fluoro-3-methyl-1H-indole [which is obtained similarly to the compound of I-30 in accordance with the methodology described Dobbs, A., J. Org. Chem., 66, 638-641 (2001)], (870 mg, 3.8 mmol) and methyl acrylate (819 mg, 9.5 mmol) in triethylamine (4 ml) was added palladium(II) acetate (112 mg, 0.5 mmol) and tri-o-tolylphosphino (428 mg, of 1.42 mmol) in an argon atmosphere at room temperature. The reaction mixture was stirred at 100oC for 3 hours in a sealed reactor under pressure and then cooled to room temperature. The reaction mixture was diluted with CH2Cl2(70 ml), washed with water (3×40 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using a mixture of methanol/dichloromethane as eluent and getting 690 mg of compound I-33 in the form of solids. 1H-NMR (500 MHz, CDCl3).

Synthesis of (E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acrylic acid is, I-34. To a solution of compound I-33 (233 mg, 1 mmol) in THF (5 ml) and methanol (5 ml) is added aqueous NaOH (3 ml) at room temperature. The reaction mixture was stirred at room temperature overnight and then the pH was adjusted to acidic by addition of aqueous 2n. HCl. The reaction mixture was extracted with EtOAc (2×40 ml). The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent to obtain 210 mg of the acid I-34.1H-NMR (500 MHz, DMSO-d6).

Synthesis of [(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid, I-35. The mixture of acid I-34 (100 mg, 0.46 mmol), 2-thiophenesulfonyl (90 mg, 0.55 mmol), 4-dimethylaminopyridine (112 mg, of 0.92 mmol) and EDCI (176 mg, of 0.92 mmol) in dichloromethane (10 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl and water. The formed solid is filtered off and washed with water, dichloromethane, receiving 55 mg of compound 4. The remaining dichloromethane uterine fluid purified column chromatography on silica gel using a mixture of methanol/CH2Cl2as eluent and receiving 45 mg arylsulfonamides I-35. Receive 100 mg of compound I-35.1H-NMR (500 MHz, DMSO-d6).

Getting connection P063.

To a solution of compound I-35 (45 mg, 0.12 mmol) in DMF (3 ml) DOB is given NaH (60% in oil, 15 mg, 037 mmol) at 0oC. the resulting mixture was stirred at room temperature for 1 hour and then add 2,4-DICHLOROSILANE (47 mg, 0.24 mmol). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2(12 ml). The reaction mixture is washed with dilute aqueous HCl (2×8 ml), water (4×8 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with ether, receiving 55 mg of compound P063.1H NMR (DMSO-d6) of 2.25 (s, 3H), 5,52 (s, 2H), 6,14 (d, J=8.0 Hz, 1H), and 6.25 (d, J=to 15.0 Hz, 1H), 7,02 (DD, J=10,0, 2.0 Hz, 1H), 7,22 (m, 2H), 7,33 (s, 1H), 7,43 (DD, J=10,2,0 Hz, 1H), 7,51 (m, 1H), 7,66 (d, J=15,0 Hz, 1H), 7,76 (m, 1H), 8,01 (d, J=5.0 Hz, 1H), 12,4 (ush., 1H). LC/MS (94%) ESI-Calculated: 521,4 m/z;found: 521,6 m/z.

Example 67. Getting connection P065

To a solution of compound P063 (10 mg, 0.02 mmol) in DMSO (1 ml) was added dropwise concentrated hydrochloric acid (3 ml). The reaction mixture was stirred at room temperature for 5 hours, then diluted with CH2Cl2, washed with water (4×10 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using EtOAc/hexane as eluent and receiving 4 mg of compound P065. 1H-NMR (500 MHz, CDCl3), MS (ESI-): 537,3 (M-1), LC-MS: 77%.

Example 68. Getting connection P064.

It is astory compounds I-35 (45 mg, 0.12 mmol) in DMF (3 ml) is added NaH (60% in oil, 15 mg, 037 mmol) at 0°C, the reaction mixture is stirred at room temperature for 1 hour and then add 2-(methyl bromide)naphthalene (53 mg, 0.24 mmol). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2(12 ml). The reaction mixture is washed with dilute aqueous HCl (2×8 ml), water (4×8 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with a mixture of ether/hexane, receiving 55 mg of compound P064.1H-NMR (500 MHz, DMSO-d6) MS (ESI-): 503,4 (M-1), LC-MS: 95%.

Example 69. Getting connection P066.

To a solution of compound P064 (10 mg, 0.02 mmol) in DMSO (1 ml) was added dropwise concentrated hydrochloric acid (3 ml). The reaction mixture was stirred at room temperature for 5 hours, diluted with CH2Cl2and washed with water (4×10 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using EtOAc/hexane as eluent and receiving 4 mg of compound P066.1H-NMR(CDCl3) to 1.61 (d, J=7.5 Hz, 3H), 3,62 (sq, J=7.5 Hz, 1H), 5,26 (s, 2H), 6,01 (d, J=to 15.0 Hz, 1H), 6,83 (DD, J=10,2,0 Hz, 1H),? 7.04 baby mortality (m, 1H), 7,13 (m, 1H), 7,29 (DD, J=8, 2.0 Hz, 1H), 7,43 (m, 2H), 7,69 (m, 3H), 7,76 (m, 2H), to $ 7.91 (m, 1H), 8,01 (d, J=to 15.0 Hz, 1H). LC/MS (80%) ESI-Vechicle is about: 519,6 m/z; found: 519,4 m/z.

Example 70. Getting connection P067.

Synthesis of [(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid, I-36. The mixture of acid I-34 (100 mg, 0.46 mmol), 4,5-dichloro-2-thiophenesulfonyl (128 mg, 0.55 mmol), 4-dimethylaminopyridine (112 mg, of 0.92 mmol) and EDCI (176 mg, of 0.92 mmol) in dichloromethane (10 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous Hcl and water. The resulting solid product is filtered off and washed with water, dichloromethane, receiving 140 mg of compound I-36. 1H-NMR (500 MHz, DMSO-d6) MS (ESI-): 433,1 (M-1)LC-MS: 97.

The synthesis of compounds P067. To a solution of sulfonamida I-36 (52 mg, 0.12 mmol) in DMF (3 ml) at 0°C is added NaH (60% in oil, 15 mg, 037 mmol), the mixture is stirred at room temperature for 1 hour and then add 2,4-dichlorobenzyl (47 mg, 0.24 mmol). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2(12 ml). The reaction mixture is washed with diluted aqueous HCl (2×8 ml), water (4×8 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel, elwira a mixture of methanol/dichloromethane and receiving 35 mg connection P067.1H NMR (DMSO-d6) of 2.25 (s,3H), 5,54 (s,2H), 6,13 (d, J=8.0 Hz, 1H), 6,21 (d, J=to 15.0 Hz, 1H),? 7.04 baby mortality (DD, J=10, 2.0 Hz, 1H, of 7.23 (m, 1H), 7,38 (m, 2H), 7,45 (m, 1H), 7,74 (d, J=to 15.0 Hz, 1H), of 7.90 (s, 1H), 12.5cm (ush. s, 1H). LC/MS (98%) ESI-Calculated: 591,3 m/z; found: to $ 591.1 m/z.

Example 71. Getting connection P068

To a solution of compound I-36 (52 mg, 0.12 mmol) in DMF (3 ml) is added NaH (60% in oil, 15 mg, and 0.37 mmol) is added at 0°C. the Mixture was stirred at 0 °C for 1 hour and then at room temperature for 1 hour, then add 2-(methyl bromide)naphthalene (53 mg, 0.24 mmol). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2(12 ml). The reaction mixture is washed with dilute aqueous HCl(2×8 ml), water (4×8 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel, elwira a mixture of methanol/dichloromethane and receiving 44 mg of compound P068.1H-NMR (500 MHz, DMSO-d6) MS (ESI-): 571,3 (M-1) LC-MS: 97%.

Example 72. Getting connection P077.

The mixture of compounds P064 (25 mg, 0.05 mmol) and Pd/C (5%, 50 mg) in methanol (5 ml) and THF (5 ml) hydronaut hydrogen at a pressure of 40 pounds per square inch over night at room temperature. The mixture is filtered through celite and washed with methanol. After removal of solvent the residue is washed with ether, receiving 16 mg connection P077 in the form of solids. 1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 505,4 (M-1), LC-MS: 86%.

Example 73. Getting connection P07.

To a mixture of compound P068 (10 mg, is 0.017 mmol) and Cs2CO3(17 mg, 0,052 mmol) in DMSO (1 ml) add logmean (2 drops). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc and then washed with dilute aqueous HCl (2×8 ml), water (4×8 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using dichloromethane as eluent and receiving 5 mg of compound P076.1H NMR (DMSO-d6) of 2.33 (s, 3H), 3,18 (s, 3H), to 5.57 (s, 2H), 6.89 in (l, 15,0 Hz, 1H), 7,00 (DD, J=10,0, 2.0 Hz, 1H), 7,05 (s, 1H), 7,13 (m, 1H), 7,31 (m, 1H), 7,41 (m, 2H), 7,50 (m, 2H), to 7.67 (m, 1H), 7,73 (d, J=8.5 Hz, 1H), 7,76 (m, 1H), 8,27 (d, J=to 15.0 Hz, 1H).

Example 74. Getting connection P058.

To a solution of compound P056 (7 mg, 0.014 mmol) in DMSO (1 ml) was added dropwise concentrated hydrochloric acid (3 ml). The reaction mixture was stirred at room temperature for 2 hours, then diluted with dichloromethane (10 ml), washed with water (4×6 ml) and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using a mixture of methanol/CH2Cl2as eluent and receiving 6 mg of compound P058.1H-NMR (500 MHz, CDCl3)MS(ESI-): 519,4 (M-1), LC-MS: 76%.

Example 75. Getting connection P059.

To a solution of compound P057 (33 mg, 0,067 mmol) in DMSO (5 ml) what about the drops is added concentrated hydrochloric acid (2 ml). The reaction mixture was stirred at room temperature for 2 hours, diluted with EtOAc (40 ml), washed with water (3×30 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using a mixture of methanol/CH2Cl2as eluent and receiving 15 mg of compound P059.1H NMR (DMSO-d6) 1,49(d, J=7.5 Hz, 3H), 3,79 (sq, J=7.5 Hz, 1H), 5,22 (m, 2H), 6,18 (d, J=to 15.0 Hz, 1H), 7,07 (t, J=7.5 Hz, 1H), 7,20 (d, J=7.5 Hz, 1H), 7,27 (m, 2H), 7,46 (m, 3H), 7,66 (m, 2H), 7,73 (d, J=8,5 Hz, 1H), a 7.85 (m, 2H), of 7.97 (d, J=to 15.0 Hz, 1H), 8,13 (d, J=5.5 Hz, 1H), 12,3 (USS, 1H). LC/MS (99%). ESI-Calculated: 501,6 m/z; found: 501,4 m/z.

Example 76. Getting connection P107

Synthesis of (E)-3-[1-(2,4-dichlorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-7-yl]acrylic acid (I-37): To a solution of compound I-15 (135 mg, the 0.375 mmol) in DMSO (3 ml) slowly at room temperature, add 40 ml of a mixture of AcOH/concentrated HCl (4:1). The reaction mixture was stirred at room temperature for 5 hours, diluted with EtOAc, washed with water (4×200 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with ether, getting 105 mg of compound I-37. 1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P107. The mixture of acid I-37 (56 mg, 0.15 mmol), 4,5-dichloro-2-thiophenesulfonyl (42 mg, 0.18 mmol), 4-dimethylaminopyridine (37 mg, 0.3 mmol) and EDCI (57 mg, 0.3 mmol) in dichloro is ane (8 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl (2×10 ml), water (4×10 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using dichloromethane and methanol/dichloromethane as eluents and receiving 40 mg connection P107.1H-NMR (500 MHz, DMSO-d6) MS (ESI-): 589,0 (M-1), LC-MS: 87%.

Example 77. Getting connection P112.

Synthesis of compound (E)-3-(3-methyl-1-naphthalene-2-ylmethyl-1H-indol-7-yl)acrylic acid (I-39): the Hydrolysis of I-39. To a solution of acid (I-7 (300 mg, 1.5 mmol) in DMF (15 ml) at 0°C is added dropwise to NaH (60% in oil, 180 mg, 4.5 mmol) and stirred at room temperature for 20 minutes, then at 0°C. is added 2-(methyl bromide)naphthalene (365 mg, of 1.65 mmol). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2(100 ml). The reaction mixture is washed with dilute aqueous HCl (2×100 ml), water (4×100 ml), saturated salt solution and dried over sodium sulfate. After removal of the solvent the solid residue was washed with CH2Cl2getting 165 mg of compound I-39. Yield: 32%.1H-NMR (500 MHz, DMSO-d6).

Synthesis of (E)-3-(3-methyl-1-naphthalene-2-ylmethyl-2-oxo-2,3-dihydro-1H-indol-7-yl)acrylic acid (I-40). To a solution of compound I-39 (102 mg, 0.3 mmol) in DMSO (3 ml) slowly at room temperature until ablaut 40 ml of a mixture of AcOH/concentrated HCl (4:1). The reaction mixture was stirred at room temperature for 4 hours, diluted with EtOAc, washed with water (4×200 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with ether, receiving 80 mg of compound I-40.1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P112. The mixture of acid I-40 (53 mg, 0.15 mmol), 4,5-dichloro-2-thiophenesulfonyl (42 mg, 0.18 mmol), 4-dimethylaminopyridine (37 mg, 0.3 mmol) and EDCI (57 mg, 0.3 mmol) in dichloromethane (8 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl (2×10 ml), water (4×10 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using dichloromethane and methanol/dichloromethane as eluents, receiving 40 mg connection P112.1H-NMR (500 MHz, DMSO-d6) MS (ESI-): 569,4 (M-1), LC-MS: 82%.

Example 78. Getting connection P110.

To a mixture of compound P057 (160 mg, 0.33 mmol) in THF (15 ml) and 95% tert-BuOH/H2O (30 ml) at room temperature add NBS (125 mg, 0.7 mmol) in 95% tert-BuOH/H2O (4 ml) and THF (2 ml). The reaction mixture was stirred at room temperature for 4 hours, add NBS (125 mg, 0.7 mmol) and the resulting mixture was stirred at room temperature overnight. After the removal process is Italia the residue is dissolved in EtOAc and washed with water (3×50 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with ether, receiving the 135 mg of compound P 110. MS (ESI-): 581,1 (M-1), LC-MS: 82%,1H-NMR (500 MHz, DMSO-d6).

Example 79. Getting connection P111.

To a solution of compound P057 (58 mg, 0.1 mmol) in THF (6 ml) and water (3 ml) at room temperature, add aqueous NaOH (2n., 0.15 ml). The reaction mixture was stirred at room temperature overnight and then acidified to acidic pH by the addition of 2n. HCl (aq.). The reaction mixture was extracted with EtOAc. The organic phase is washed with water, saturated salt solution and dried over sodium sulfate. After removal of solvent, the residue is purified column chromatography on silica gel using dichloromethane and methanol/dichloromethane as eluents and receiving 6 mg of compound P111. 1H NMR (CDCl3) of 1.73 (s, 3H), 3,01 (s, 1H), total of 5.21 (s, 2H), 6,02 (d, J=to 15.0 Hz, 1H), 6,99 (t, J=8.0 Hz, 1H), 7,13 (m, 2H), 7,27 (m, 1H), 7,43 (m, 3H), 7,71 (m, 5H), to $ 7.91 (m, 1H), 8,00 (d, J=to 15.0 Hz, 1H), 8,39 (, 1H). LC/MS (81%) ESI+ Calculated: 517,6 m/z; found: 517,4 m/z.

Example 80. Getting connection P161

Synthesis of (E)-3-(3-fluoro-3-methyl-1-naphthalene-2-ylmethyl-2-oxo-2,3-dihydro-1H-indol-7-yl)acrylic acid (I-41). To a mixture of compound I-39 (160 mg, 0.47 mmol) in acetonitrile (8 ml) and water (3 ml) was added Selectfluor (500 mg, of 1.41 mmol) and the resulting mixture was stirred at room temperature overnight, the solution was diluted with EtOAc and the ATEM washed with dilute aqueous HCl, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using dichloromethane and methanol/dichloromethane as eluents and receiving 65 mg of compound I-41.1H-NMR (500 MHz, CDCl3),19F-NMR (400 MHz, CDCl3).

The synthesis of compounds P161. The mixture of acid I-41 (32 mg, of 0.085 mmol), 4,5-dichloro-2-thiophenesulfonyl (23 mg, 0.1 mmol), 4-dimethylaminopyridine (21 mg, 0,17 mmol) and EDCI (33 mg, 0,17 mmol) in dichloromethane (5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl (2×10 ml), water (4×10 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using dichloromethane and methanol/dichloromethane as eluents and receiving 12 mg connection P161. MS (ESI-): 589,0 (M-1), LC-MS: 91%.1H-NMR (500 MHz, Acetone-d6).

Example 81. Getting connection P160.

The mixture of acid I-41 (32 mg, of 0.085 mmol), 2-thiophenesulfonyl (16 mg, 0.1 mmol), 4-dimethylaminopyridine (21 mg, 0,17 mmol) and EDCI (33 mg, 0,17 mmol) in dichloromethane (5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl (2×10 ml), water (4×10 ml), saturated salt solution and dried over sodium sulfate. the donkey removal of the solvent the residue is purified column chromatography on silica gel, using dichloromethane and methanol/dichloromethane as eluents and receiving 20 mg of compound P160.1H-NMR (CDCl3) 1,90 (d, J=22 Hz, 3H), 5,20 (d, J=16 Hz, 1H), 5,33 (d, J=16 Hz, 1H), 6,02 (d, J=to 15.0 Hz, 1H), to 7.09 (t, J=8.0 Hz, 1H), 7,15 (m, 1H), 7.23 percent (d, J=8.0 Hz, 1H), 7,26 (s, 1H), 7,30 (d, J=8.0 Hz, 1H), 7,44 (m, 2H), 7,0 (d, J=7 Hz, 1H), of 7.70 (m, 2H), to 7.75 (m, 2H), 7,87 (s, 1H), 7,92 (m, 1H), 8,00 (d, J=to 15.0 Hz, 1H). LC/MS (93%) ESI-Calculated: 519,6 m/z; found: 519,3 m/z.

Example 82. Getting connection P044.

Synthesis of methyl ester 1-naphthalene-2-ylmethyl-1H-indole-7-carboxylic acid (I-41). Methyl ester 1H-indole-7-carboxylic acid, obtained in accordance with methods described in the literature [Batcho B., Leimgruber, K., Org. Syn. Vol. IIV, page 34-40], (1 g, 5.7 mmol) in DMF (10 ml), add NaH (60% in oil, 275 mg, 6,9 mmol) at 0°C, the resulting mixture was stirred at room temperature for 1 hour and then add 2-(methyl bromide)naphthalene (1.26 g, 5.7 mmol). The reaction mixture was stirred at room temperature overnight. DMF is removed and the residue diluted with EtOAc (25 ml). The reaction mixture was washed with water (2×15 ml), dried over sodium sulfate, filtered and the solvent is removed. The result of 1.59 g of compound I-41.1H-NMR (500 MHz, DMSO-d6).

Synthesis of (1-naphthalene-2-ylmethyl-1H-indol-7-yl)methanol (I-42). It chilled in an ice bath) suspension LiAl4 (216 mg, 5.7 mmol) in 15 ml of anhydrous THF in an atmosphere of N2drop by drop add a solution of ester I-41 940 mg, to 2.85 mmol) in 8 ml anhydrous THF. The reaction mixture was stirred at 0°C for 1 hour, then allow it to warm to room temperature. TLC (25% EtOAc/hexane) shows the absence of starting material. The mixture is quenched at 0°C by slow addition of 1 ml water, 1 ml of 1N NaOH, 1.5 ml of water. The mixture is stirred for 10 minutes at room temperature. The suspension is filtered and the solid residue is washed several times THF and EtOAc. The combined organic layers washed with saturated salt solution, dried over MgSO4and concentrate, receiving 800 mg of the crude product. Purification of column chromatography using 5%-15% mixture of EtOAc/hexane leads to obtain 450 mg of the alcohol I-42.1H-NMR (500 MHz, CDCl3).

The synthesis of compounds P044. To a solution of alcohol I-42 (57,8 mg, 0.2 mmol) in 1 ml of anhydrous methylene chloride added at 0°C diethoxymethylsilane (34 mg, 0,191 mmol). The reaction mixture was stirred at 0°C for 2 hours, then at room temperature for 3 hours. The mixture is treated with an aqueous solution, and then purified column chromatography, using as eluent CH2Cl2up to 2% MeOH/CH2Cl2deliver 79 mg of compound P044.1H NMR (400 MHz, CDCl3) 1,21-of 1.24 (t, J=7.2 Hz, 6H), 4,01-4,10 (m, 4H), 5,23 (s, 2H), 5,73 (s, 2H), to 6.67 (d, J=3.6 Hz, 1H), 7,10 (t, J=7.2 Hz, 1H), 7,17 (m, 2H), 7,2 (d, J=3.6 Hz, 1H), 7,24 (USS, 1H), 7,42 was 7.45 (m, 3H), 7,65 (m, 1H), 7,72 (DD, J=8,0, 1,2 Hz, 1H), and 7.8 (d, J=8.0 Hz, 2H) LC-MS (93%): ESI-Calculated: 466 m/z; Found: 465.

Example 83. Getting connection P108

Synthesis of 7-bromo-1H-indole-2,3-dione, the I-45. In a round bottom flask (500 ml) under stirring download solution chloralhydrate (12 g, 66 mmol) in water (150 ml), add Na2SO4(14 g, 100 mmol) and a suspension of 2-bromoaniline (9 g, 50 mmol) in 2n. aqueous HCl (60 ml) at room temperature. The reaction mixture is refluxed for 30 minutes, then cooled to room temperature. The resulting solid precipitate is filtered off, washed with water (3×100 ml) and dried in vacuum at 50°C, obtaining the crude N-(2-bromophenyl)-2-hydroxykynurenine, (I-44) (9 g), which are immediately used in the next stage without additional purification. In a round bottom flask (500 ml) was placed in a preheated (50°C) solution of concentrated H2SO4(80 ml) and with stirring in one portion add intermediate product I-44 at 50°C. the resulting reaction mixture is heated to 80°C and stirred at 80°C for 30 minutes, then cooled to room temperature, poured with stirring into 600 ml of a mixture of ice water. The formed solid is filtered off, washed with water (3×100 ml) and dried in vacuum at 50°C, receiving the target I-45 (5,2 g, 44% for two steps) MS (ESI+): 227 (M+1).sup> 1H-NMR: (500 MHz, CDCl3).

Synthesis of compound I-46. In a round bottom flask (500 ml) download solution of 7-bromoindole-2,3-dione (I-45 (5 g, 22 mmol) and the monohydrate p-toluensulfonate acid (500 mg, 10 mol.%) in dry benzene (200 ml) and added ethylene glycol (5 g, 82 mmol, 3.8 EQ.). The reaction mixture is refluxed for 23 hours with azeotropic distillation of the water trap Dean-stark). The reaction mixture is cooled to room temperature, washed with 10% aqueous NaHCO3(100 ml) and then water (100 ml). After removal of the solvent to obtain 6 g of the crude product, which was purified by recrystallization from a mixture of CH2Cl2/EtOAc/hexane, receiving targeted acetal, I-46 (5.4 g, 90% yield) as a solid not quite white matter. MS (ESI+): 270 (M+1).1H-NMR (500 MHz, CDCl3).

Synthesis of compound I-47. In a test tube at room temperature upload a solution of compound I-46 (5.4 g, 20 mmol), tri-o-tolylphosphino (2,2, 7 mmol, 0.3 EQ.) and palladium acetate (500 mg, 2 mmol, 0.1 EQ.) in triethylamine (20 ml) and added methyl acrylate (5 g, 70 mmol, 3.5 EQ.). The test tube is sealed, the reaction mixture is heated and stirred at 100°C for 6 hours, then cooled to room temperature, poured with stirring into 600 ml of a mixture of ice water, extracted with CH2Cl2(3×100 ml). The organic layers washed with water (2×100 ml), n is sasenum salt solution (100 ml) and dried (Na 2SO4). After removal of the solvent to obtain 6 g of the crude product, which was purified by recrystallization from a mixture of CH2Cl2/EtOAc/hexane and flash chromatography (silica gel, CH2Cl2; CH2Cl2/EtOAc/hexane, vol./about./about.=1:10:20-1:20:10; EtOAc)to give the desired product I-47 (4.5 g, 81%) as a solid not quite white matter. MS (APCI-): 274 (M-1).1H-NMR (500 MHz, CDCl3).

Synthesis of compound I-48. In a round bottom flask (250 ml) upload a suspension of compound I-47 (3 g, 11 mmol) and K2CO3(10 g, 55 mmol, 5 EQ.) in DMF (40 ml), add 2,4-DICHLOROSILANE (2.4 g, 12 mmol, of 1.05 EQ.). The resulting reaction mixture is heated to 50°C, stirred at 50°C for 3 hours and stirred at room temperature overnight. The mixture was poured with stirring into 600 ml of a mixture of ice water. The formed solid is filtered off, washed with water (3×100 ml) and dried in vacuum at 50°C, receiving the target I-48 (2.8 g) in the form of a solid not quite white matter. An additional 1 g of compound I-48 is obtained from the residue after extraction with EtOAc (2×100 ml) and then after purification with flash chromatography (silica gel, CH2Cl2;CH2Cl2/EtOAc/hexane, vol./about./about.=1:10:20-1:20:10; EtOAc). Just obtain 3.8 g of compound I-48 (80%). MS (APCI+): 434,3 (M), 436,3 (M+2).1H-NMR (500 MHz, CDCl3).

Synthesis of (E)-3-[1-(2,4-dichlorobenzyl)-2,3-dio is co-2,3-dihydro-1H-indol-7-yl]acrylic acid I-49. In a round bottom flask (200 ml) download NaOH solution (500 mg, 12 mmol) in MeOH (40 ml) and H2O (40 ml) and at 5°C add compound I-48 (450 mg, or 10.3 mmol). The obtained reaction mixture was allow to warm to room temperature and stirred for 10 minutes, heated to 50°C., stirred at 50°C for 2 hours and then at 75°C for 2 hours. The reaction mixture was cooled to 0°C and acidified with aqueous HCl (2n.) to pH=1, then add water (150 ml). The resulting solid product is filtered off, washed with water (3×60 ml) and dried in vacuum at 50°C, receiving the target I-49 (430 mg, 95%) as a solid not quite white matter. MS (APCI-): 418,2 (M-2).1H-NMR (500 MHz, CDCl3).

The synthesis of compounds P108. In a round bottom flask (200 ml) load the solution of 4,5-dichlorothiophene-2-sulfonamida (243 mg, 1.1 mmol), 4-dimethylaminopyridine (DMAP, 350 mg, 3 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 450 mg, 3 mmol) in CH2Cl2(50 ml) was added acrylic acid I-49 (420 mg, 1.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 days, then cooled to 0°C and acidified with aqueous HCl (10%) to pH 1, then extracted with CH2Cl2/MeOH (9/1, 3×100 ml). The combined organic layers are dried (Na2SO4), the solvent is removed under reduced pressure, obtaining the crude product, which is first purified flash chromatography (silica gel, CH2Cl2; EtOAc/hexane=1:2-1:0) to obtain the target P108 (350 mg, 55%) as a white solid.1H NMR (500 MHz, acetone-d6); 4,36-to 4.38 (m, 2H), 4,48-4,51 (m, 2H), of 5.05 (s, 2H), 6,17 (d, J=15,5 Hz, 1H), 6,97 (d, J=8.0 Hz, 1H), 7,11 (t, J=8.0 Hz, 1H), 7,25 (DD, J=8,0, 2.0 Hz, 1H), 7,35-7,45 (m, 2H), 7,45 (DD, J=to 7.5, 1.0 Hz, 1H), 7,53 (d, J=15,5 Hz, 1H), 7,63 (s, 1H). LC/MS (99,5%) ESI-Calculated: 634,3 m/z, found: 633,2 m/z (M-1).

Example 84. Getting connection P113.

Synthesis of methyl ester (E)-3-[1-(2,4-dichlorobenzyl)-2,3-dioxo-2,3-dihydro-1H-indol-7-yl]acrylic acid, I-50. To a suspension of I-48 (2.1 g, 5 mmol) in MeOH (50 ml) at room temperature with stirring, add concentrated HCl (50 ml). The resulting reaction mixture is heated to 90°C, stirred at 90°C for 3 hours, cooled to room temperature and poured with stirring into 200 ml of a mixture of ice water. The resulting solid product is filtered off, washed with water (3×100 ml) and dried in vacuum at 50°C, receiving 1.7 g (83%) target isatin-derived, I-50, in the form of an orange solid. MS (APCI+): 390,3 (M), 392,2 (M+2).1H-NMR (500 MHz, CDCl3).

Synthesis of (E)-3-[1-(2,4-dichlorobenzyl)-2,3-dioxo-2,3-dihydro-1H-indol-7-yl]acrylic acid, I-51. In a round bottom flask (500 ml) download NaOH solution (1 g, 25 mmol) in MeOH (50 ml) and H2O (50 ml) and added compound I-50 (1.6 g, 15 mmol) at 5°C. the Obtained reaction mixture was allow to warm to room so the temperature, the mixture is stirred at room temperature for 10 minutes, then heated to 50°C and stirred at 50°C for 4 hours. The reaction mixture is cooled to 5°C and acidified by addition of aqueous HCl (10%) until pH=1, then add water (250 ml). The formed solid is filtered off, washed with water (3×100 ml) and dried in vacuum at 50°C, receiving the target acid I-51 (1,34 g, 85%) as an orange solid. MS (APCI-): 374,1(M-2), 376,2 (M).1H-NMR (500 MHz, CDCl3).

The synthesis of compounds P113.

In a round bottom flask (250 ml) load the solution of 4,5-dichlorothiophene-2-sulfonamida (1.28 g, 5.5 mmol), 4-dimethylaminopyridine (DMAP, 1.5 g, 15 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 1.8 g, 15 mmol) in CH2Cl2(150 ml) and add the acrylic acid I-51 (1.9 g, 5 mmol) at room temperature. The resulting mixture was stirred at room temperature for 72 hours, then cooled to 0°C and acidified with aqueous HCl (10%) until pH=1. Add 150 ml of a mixture of ice water, the mixture is vigorously stirred for 30 minutes. The formed solid is filtered off, washed with water (3×150 ml) and dried in vacuum at 50°C, receiving the target P113 (2.3 g, 77%) as an orange solid.1H NMR (500 MHz, DMSO-d6); 4,96 (s, 2H), 6,16 (d, J=15,5 Hz, 1H), 7,22 (t, J=7.5 Hz, 1H), 7,30-7,33 (m, 3H), 7,55 (d, J=8.5 Hz, 1H), 7,58 (d, J=8.0 Hz, 1H), of 7.70 (d, J=7.5 Hz, 1H), of 7.90 (s, 1H). LC/MS (99) ESI -Calculated: 590,3 m/z, found: 589,1 m/z (M-1).

Example 85. Getting connection P128.

In a round bottom flask (25 ml) upload solution P113 (50 mg, 0.09 mmol) in acetone (5 ml), add Et2NH (0.5 ml) at 0°C. the mixture allow to warm to room temperature and the mixture is stirred at room temperature for 72 hours, then cooled to 0°C and acidified with aqueous HCl (2n.) to pH=1. To the mixture is added a mixture of ice water and 200 ml, the resulting solid product is filtered off, washed with water (3×20 ml) and dried in vacuum at 50°C, receiving the target P128 (30 mg, 55%) as a solid bright yellow substance. MS (ESI-) m/z 647, M-1). IHMS (ESI-)>95%.1H-NMR.

Example 86. Getting connection P134.

In a round bottom flask (25 ml) upload solution P113 (50 mg, 0.09 mmol) in CH3NO2(5 ml) and at 0°C add Et2NH (0.5 ml). The resulting mixture was stirred at room temperature for 72 hours, then cooled to 0°C and acidified with aqueous HCl (2n.) to pH=1. Add 200 ml of a mixture of ice water. The formed solid is filtered off, washed with water (3×20 ml) and dried in vacuum at 50°C, obtaining the target product P134 (30 mg, 55%) as a bright yellow solid.1H NMR (500 MHz, acetone-d6); 5,08-5,20 (m, 2H), 5.25-in, 5,32, (m, 2H), 6,33 (d, J=to 15.0 Hz, 1H), 7,17-7,21 (m, 2H), 7,28 (DD, J=8,5, 2.0 Hz, 1H), 7,39 (d, J=2.0 Hz, 1H), 7,42 (d, J=8.0 Hz, 1H), 7,56 (d, J=to 15.0 Hz, 1H), of 7.70 (d, J=7.5 Hz, 1H), 778 (d, J=2.0 Hz, 1H). LC/MS (99%) ESI-Calculated: 651,3 m/z, found: 650,2 m/z (M-1).

Example 87. Getting connection P129.

In a round bottom flask (25 ml) upload solution P113 (50 mg, 0.09 mmol) in EtOH (10 ml) and at 0°C is added NaBH4(50 mg). The mixture allow to warm to room temperature and stirred at room temperature for 2 hours, then cooled to 0°C, quenched by adding 20 ml of a mixture of ice water and acidified with aqueous HCl (2n.) to pH=1. The mixture is extracted with dichloromethane (3×30 ml). The combined organic layers dried over Na2SO4and the solvent is removed in vacuum, obtaining a mixture, which will cut flash chromatography (silica gel, CH2Cl2; CH2Cl2/EtOAc/hexane, vol./about./about.=1:10:20-1:20:10; EtOAc)to give 6 mg of the compound P129 (10%) as a white solid. MS(ESI-) m/z 559, M-1). IHMS(ESI-a 95%.1H-NMR.

Example 88. Getting connection P130.

In a round bottom flask (25 ml) upload solution P113 (50 mg, 0.09 mmol) in EtOH (10 ml) and at -78°C is added NaBH4(50 mg). The resulting mixture was stirred at -78 °C for 6 hours, then quenched by addition of aqueous HCl (2n.) to pH=1. The mixture is diluted with 100 ml, the mixture is extracted with EtOAc(3×30 ml). The combined organic layers washed with water (2×30 ml), dried over Na2SO4and the solvent is removed in vacuum, obtaining a mixture which is purified flash chromatography (forces the Kagel, CH2Cl2;CH2Cl2/EtOAc/hexane, vol./about./about.=1:10:20-1:20:10; EtOAc) to give 20 mg of the compound P130 (70%) as a white solid.1H-NMR (500 MHz, acetone-d6); 5,02-5,14 (m, 2H), 5,23 (s, 1H), 6,33 (d, J=15,5 Hz, 1H), 7,07 (d, J=8.5 Hz, 1H), 7,14 (t, J=8.0 Hz, 1H), 7,24 (DD, J=8,5, 2.0 Hz, 1H), 7,34 (d, J=7.5 Hz, 1H), 7,39 (d, J=2.0 Hz, 1H), 7,54 (d, J=7,0 Hz, 1H), 7,58 (d, J=15,5 Hz, 1H), 7,79 (s, 1H). LC/MS (96%) ESI-Calculated: 592,3 m/z, found: 591,0 m/z (M-1).

Example 89. Getting connection P133.

In a round bottom flask (50 ml) load suspension P113 (50 mg, 0.09 mmol) in THF (10 ml) and added dropwise MeMgBr (3h. in ether, 0.5 ml) at -78°C. the mixture allow to warm to room temperature and stirred at room temperature for 30 minutes and then cooled to 0°C, quenched by addition of aqueous HCl (2n.) to achieve pH=1, then diluted with 100 ml water and the mixture extracted with dichloromethane (3×30 ml). The combined organic layers dried over Na2SO4and the solvent is removed in vacuum, obtaining a mixture, which will cut flash chromatography (silica gel, CH2Cl2; CH2Cl2/EtOAc/hexane, vol./about./about.=1:10:20-1:20:10; EtOAc)to give compound P133 (20 mg, 40%) as a white solid.1H-NMR (500 MHz, DMSO-d6); is 1.51 (s, 3H), 4,99 (d, J=5.0 Hz, 2H), 6,13 (d, J=to 15.0 Hz, 1H), 6,98 (d, J=8.5 Hz, 1H), 7,16 (t, J=8.0 Hz, 1H), 7,27 (d, J=8.0 Hz, 1H), 7,32 (DD, J=8,0, 2.0 Hz, 1H), 7,35 (d, J=2,0 Hz, 1H), 7,44 (d, J=15,5 Hz, 1H), 7,51 (d, J=6.0 Hz, 1H), 7,87 (s, 1H). LC/MS (95%) ESI-is chileno: 606,3 m/z, found: 605,3 m/z (M-1).

Example 90. Getting connection P132

Synthesis of methyl ester (E)-3-[1-(2,4-dichlorobenzyl)-3,3-debtor-2-oxo-2,3-dihydro-1H-indol-7-yl]acrylic acid, I-52. In a round bottom flask (25 ml) download solution of compound I-50 (200 mg, 0.5 mmol) in CH2Cl2(8 ml) and at 5°C add TRIFLUORIDE diethylaminoethyl (DAST, 0.5 ml, excess). The obtained reaction mixture was allow to warm to room temperature and stirred at room temperature for 3 days, then cooled to 5°C. the Reaction is quenched by adding MeOH (1 ml) at 0°C and stirred at 0°C for 20 minutes, then at room temperature for 10 minutes. A reaction chamber is cooled to 5°C, add water (10 ml) and enable the mixture to warm to room temperature and stirred at room temperature for 30 minutes, then extracted with dichloromethane (2×30 ml). The combined organic layers washed with water (2×20 ml), dried over Na2SO4and the solvent is removed in vacuum, obtaining the crude product I-52 (200 mg, 95%) as a bright yellow solid, which is used in the next stage without additional purification. MS (APCI-): (410,3, M-2).1H-NMR (400 MHz, CDCl3).

Synthesis of (E)-3-[1-(2,4-dichlorobenzyl)-3,3-debtor-2-oxo-2,3-dihydro-1H-indol-7-yl]acrylic acid, I-53. In a round bottom flask (50 ml) download NaOH solution (120 is g, 3 mmol) in MeOH (7.5 ml) and H2O (7.5 ml), the mixture is cooled to 5°C and add the compound I-52 (120 mg, 0.3 mmol). The obtained reaction mixture was allow to warm to room temperature and stirred at room temperature for 2 hours, then heated to 50°C and stirred at 50°C for 2 hours. The reaction mixture was cooled to 0°C and acidified with aqueous HCl (10%) until pH=1, then add water (50 ml) and extracted with a mixture of dichloromethane-MeOH (10:1, 5×30 ml). The combined organic layers dried over Na2SO4and the solvent is removed in vacuum, obtaining the crude product which is purified by recrystallization from a mixture of acetone/EtOAc/hexane, obtaining the target acid (I-53 (90 mg, 75% yield) as a solid not quite white matter. MS (ESI-):(396,1, M-2; 398,0, M). IHMS(ESI-a 95%.1H-NMR (500 MHz, DMSO-d6)).

The synthesis of compounds P132. In a round bottom flask (100 ml) load a solution of 4,5-dichlorothiophene-2-sulfonamida (60 mg, 0.26 mmol), 4-dimethylaminopyridine (DMAP, 60 mg, 0.6 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 70 mg, 0.6 mmol) in CH2Cl2(20 ml) and added acrylic acid (I-53 (80 mg, 0.21 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 days, then cooled to 0°C. After addition of MeOH (5 ml) and water (20 ml), the reaction mixture was acidified with the addition of the aqueous HCl (10%) to pH 1 and stirred at room temperature for 30 minutes. The resulting solid product is filtered off, washed with water (3×20 ml) and dried in vacuum at 50°C, obtaining the crude product 19 (80 mg), which was purified flash chromatography (silica gel, CH2Cl2; EtOAc/hexane=1:4-1:2)to give the target product P132 (55 mg, 45%) as a white solid.1H-NMR (500 MHz, DMSO-d6); of 5.05 (s, 2H), 6,13 (d, J=15,5 Hz, 1H), 7,03 (d, J=8.0 Hz, 1H), 1,29-135 (m, 3H), 7,41 (d, J=to 15.0 Hz, 1H), 7,87 (d, J=7.5 Hz, 1H), 7,89 (s, 1H). LC/MS (99%) ESI-Calculated: 612,3 m/z, found: 611,0 m/z (M-1).

Example 92. Getting connection P216

In a round bottom flask (25 ml) load the solution of thiophene-2-sulfonamida (17 mg, 0.11 mmol), 4-dimethylaminopyridine (DMAP, 20 mg, 0.2 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 23 mg, 0.3 mmol) in CH2Cl2(2 ml) and at room temperature add the acrylic acid I-53 (40 mg, 0.1 mmol). The resulting mixture was stirred at room temperature for 2 days, then cooled to 0°C. After addition of MeOH (2 ml) and water (10 ml) the reaction mixture is acidified by addition of aqueous HCl (10%) until pH=1 and extracted with a mixture of CH2Cl2/MeOH (9/1, 3×10 ml). The combined organic layers are dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2/EtOAc/hexane=1:1:4, EtOAc) to give the target arylsulfonamides P216 (15 m is, 25%) as a white solid.1H NMR (500 MHz, acetone-d6); 5,04 (s, 2H), x 6.15 (d, J=to 15.0 Hz, 1H), 7,01 (d, J=8.5 Hz, 1H), 7,25-7,27 (m, 2H), 7,33 (t, J=8.6 Hz, 1H), 7,38 (d, J=15,5 Hz, 1H), 7,41 (d, J=2.0 Hz, 1H), 7,53 (d, J=8.0 Hz, 1H), 7,81 (d, J=4.0 Hz, 1H), a 7.85 (d, J=8.0 Hz, 1H), 8,10 (d, J=4.0 Hz, 1H). LC/MS (92%) ESI-Calculated: 543,4 m/z, found: 541,4 m/z (M-2).

Example 93. Getting connection P127.

Synthesis of (E)-3-[1-(2,4-dichlorobenzyl)-2-oxo-2,3-dihydro-1H-indol-7-yl]acrylic acid, I-54. In baratono flask (350 ml) load connection I-51 (430 mg, 1.2 mmol), and at room temperature add NH2NH2H2O (20 ml). The resulting mixture was sealed, heated to 130°C and stirred at 130°C for 1 hour, then cooled to 0°C. To the mixture is added a mixture of ice water (300 ml), the reaction mixture is acidified by addition of aqueous HCl (10%) to pH 1 and stirred at room temperature for 30 minutes. The resulting solid product is filtered off, washed with water (3×50 ml) and dried in vacuum at 50°C, receiving the target oxindol-derived, I-54 (300 mg, 73%) as a white solid. MS(ESI-)m/z=360,1, (M-2);1H-NMR (500 MHz, acetone-d6).

The synthesis of compounds P127. In a round bottom flask (100 ml) load a solution of 4,5-dichlorothiophene-2-sulfonamida (130 mg, 0.55 mmol), 4-dimethylaminopyridine (DMAP, 150 mg, 1.5 mmol) and hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 180 mg, 1.5 mmol) in CH2Cl2 (20 ml) was added acrylic acid P-54 (180 mg, 0.5 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 days, then cooled to 0°C. After addition of MeOH (5 ml) and water (120 ml) the reaction mixture is acidified by addition of aqueous HCl (10%) to pH 1 and stirred at room temperature for 30 minutes. The formed solid substance was separated by filtration, washed with water (3×50 ml) and dried in vacuum at 50°C, obtaining the target product P127 (143 mg, 40%) as a white solid. MS(APCI-) m/z=574,9 (M-1); IHMS(ESI-)>95%. HPLC>95%.1H-NMR (500 MHz, DMSO-d6).

Example 94. Getting connection P219

In a round bottom flask (25 ml) upload solution thiophenesulfonyl (17 mg, 0.11 mmol), 4-dimethylaminopyridine (DMAP, 20 mg, 0.2 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 23 mg, 0.3 mmol) in CH2Cl2(2 ml) and at room temperature add the acrylic acid I-54 (26 mg, 0.1 mmol). The resulting mixture was stirred at room temperature for 2 days, then cooled to 0°C. After addition of MeOH (2 ml) and water (10 ml) the reaction mixture is acidified by addition of aqueous HCl (10%) to pH 1, then extracted with a mixture of CH2Cl2/MeOH (9/1,3×10 ml). The combined organic layers are dried (Na2SO4) and the solvent is removed under reduced pressure, getting neocidin the th product which purified flash chromatography (silica gel, CH2Cl2/EtOAc/hexane=1:1:4, EtOAc) to give the target product P219 (23 mg, 45%) as a white solid. MS(ESI-) m/z (505,2, M-2); IHMS(ESI-)>95%.1H-NMR (500 MHz, DMSO-d6).

Example 95. Getting connection P131.

Synthesis of methyl ester (E)-3-[1-(2,4-dichlorobenzyl)-2-oxo-2,3-dihydro-1H-indol-7-yl]acrylic acid, I-55. In baratono flask (50 ml) upload a suspension of compound I-54 (100 mg, 0.3 mmol) in MeOH (15 ml) at room temperature and with stirring, add concentrated HCl (0.5 ml), the reaction mixture was sealed, heated to 85°C, stirred at 85°C for 5 hours, cooled to 0°C, neutralized mixture by addition of an aqueous NH4Cl (saturated, 2 ml), diluted with water (30 ml) and extracted with EtOAc (3×20 ml). The combined organic layers washed with water (2×20 ml), dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the compound I-55 (103 mg, 99%) as a white solid. MS (ESI-):(374,2, M-2).1H-NMR (500 MHz, CDCl3).

Synthesis of methyl ester (E)-3-[1-(2,4-dichlorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-7-yl]acrylic acid, I-56. In a round bottom flask (20 ml) upload a suspension of compound I-55 (45 mg, 0.12 mmol) and stirring at 0°C type K2CO3(45 mg) in DMF (2 ml) and methyliodide (0.5 ml, of itoc). The obtained reaction mixture was allow to warm to room temperature and stirred at room temperature for 3 days. The mixture is then poured into 30 ml of a mixture of ice water and extracted with EtOAc (3×20 ml). The combined organic layers washed with water (2×20 ml), dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product is 25, which is purified flash chromatography (silica gel, CH2Cl2; EtOAc/hexane=1:5)to give the desired product I-56 (35 mg, 75%) as a white solid. MS (APCI-): (404,2, M).1H-NMR (500 MHz, CDCl3).

(E)-3-[1-(2,4-dichlorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-7-yl]acrylic acid, I-57. In a round bottom flask (50 ml) download NaOH solution (25 mg, 0.6 mmol) in MeOH (5 ml) and H2O (5 ml), then cooled to 5°C and add the compound I-56 (25 mg, 0.05 mmol). The obtained reaction mixture was allow to warm to room temperature and stirred at room temperature for 16 hours. The reaction mixture was cooled to 0°C and acidified by addition of aqueous HCl (10%) until pH=1, add water (10 ml) and then extracted with dichloromethane (3×20 ml). The combined organic layers dried over Na2SO4and the solvent is removed in vacuum, obtaining the crude product I-57 (20 mg, 80% yield) as a solid not quite white matter. MS (ESI-): (388,3, M-2).1NMR (500 MHz, CDCl3).

The synthesis of compounds P131. In a round bottom flask (25 ml) load the solution of 4,5-dichlorothiophene-2-sulfonamida (7 mg, 0.03 mmol), 4-dimethylaminopyridine (DMAP, 9 mg, 0.9 mmol), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCl 12 mg, 0.9 mmol) in CH2Cl2(3 ml) and added to the mixture of the acrylic acid I-57 (10 mg, of 0.025 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 days, then cooled to 0°C. After addition of MeOH (5 ml) and water (20 ml), the reaction mixture is acidified by addition of aqueous HCl (10%) until pH=1, the mixture is extracted with CH2Cl2/MeOH (9/1, 3×10 ml). The combined organic layers are dried (Na2SO4) and the solvent is removed under reduced pressure, obtaining the crude product, which was purified flash chromatography (silica gel, CH2Cl2/EtOAc/hexane=1:1:4, EtOAc)to give compound P131 (6.5 mg, 45%) as a white solid.1H-NMR (500 MHz, DMSO-d6); of 1.40 (s, 6H), to 5.03 (s, 2H), 6,12 (d, J=15,5 Hz, 1H), for 6.81 (d, J=8.5 Hz, 1H), 7,12-7,16 (m, 1H), 7.23 percent (d, J=8.5 Hz, 1H), 7,28 (DD, J=8,5, 2.0 Hz, 1H), 7,37 (d, J=2.0 Hz, 1H), 7,47 (d, J=15,5 Hz, 1H), 7,51 (d, J=7,0 Hz, 1H), 7,86 (s, 1H). LC/MS (85%) ESI-Calculated: 604,4 m/z, found: 603,0 m/z (M-1).

Example 96. Getting connection P019.

Synthesis of 5-nitro-4H-benzo[1,4]oxazin-3-it, I-58. A mixture of 2-amino-3-NITROPHENOL (1.54 g, 10 mmol), ethylbromoacetate (1,67 g, 10 mmol), potassium carbonate (1.54 g, 11 mmol) and DMF (5.0 ml) var who're asked at room temperature for 20 hours. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (100 ml×3). The combined EtOAc layers washed with water (50 ml×2), dried (saturated salt solution, sodium sulfate), concentrated and dried in high vacuum, receiving 5-nitro-4H-benzo[1,4]oxazin-3-one, I-58(1.6 g).

Synthesis of 4-naphthalene-2-ylmethyl-5-nitro-4H-benzo[1,4]oxazin-3-it, I-59. Sodium hydride (94 mg, 3.0 mmol) is added by portions to a solution of 5-nitro-4H-benzo[1,4]oxazin-3-it, I-58 (388 mg, 2 mmol) in DMF. After 30 minutes, add 2-bromethalin (442 mg, 2 mmol) and the mixture is stirred at room temperature for 20 hours. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (100 ml×3). The combined EtOAc layers washed with water (50 ml×2), dried (saturated salt solution, sodium sulfate), concentrated and dried in high vacuum, receiving 4-naphthalene-2-ylmethyl-5-nitro-4H-benzo[1,4]oxazin-3-one, I-59 (653 mg).

Synthesis of 5-amino-4-naphthalene-2-ylmethyl-4H-benzo[1,4]oxazin-3-it, I-60. A solution of 4-naphthalene-2-ylmethyl-5-nitro-4H-benzo[1,4]oxazin-3-it, I-59 (0.65 g) in methanol (30 ml) and dioxane (7.0 ml) hydronaut in the presence of 10% Pd-C with hydrogen at a pressure of 45 psi for 22 hours. The reaction mixture is filtered and the filtrate is concentrated, obtaining 5-amino-4-naphthalene-2-ylmethyl-4H-benzo[1,4]oxazin-3-one, I-60 (620 mg).

Synthesis of methyl ester of N-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)oxalic key is lots I-61. To a solution of 5-amino-4-naphthalene-2-ylmethyl-4H-benzo[1,4]oxazin-3-it, I-60 (120 mg, 04 mmol) and acylglucuronide (52 mg, 0.4 mmol) in THF (3.0 ml) dropwise at room temperature is added triethylamine (0.1 ml, 1.0 mmol) and the resulting mixture stirred for 18 hours. The reaction mixture was concentrated and the residue purified on silica gel using a mixture of chloroform:methanol (97:3) as eluent, obtaining the methyl ester of N-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)oxalic acid, I-61 (102 mg).

Synthesis of N-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)oxalic acid, I-62. To a suspension of methyl ester of N-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)oxalic acid, I-61 (95 mg)in methanol (2.0 ml) is added 1.0m NaOH (0.5 ml) and then THF (2.0 ml)to give a clear solution. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated to remove solvents. The residue is transferred into the water (2.0 ml), acidified by the addition of 1.0m HCl and extracted with EtOAc (5.0 ml×4). The combined extracts washed with water (5.0 ml), dried (saturated solution of salt, Na2SO4) and concentrated, obtaining N-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)oxalic acid, I-62 (69 mg). APCIm/z375 (M-H)+.

Synthesis of N-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)-oxo-2-(thiophene-2-sulfonylamino)ndimethylacetamide, P019: a Mixture of N-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)oxalic acid, I-62 (52 mg, 0.14 mmol), thifensulfuron (28 mg, 0,17 mmol), EDCI (33 mg, 0,17 mmol), DMAP (22 mg, 0,17 mmol) in methylene chloride is stirred at room temperature for 24 hours. The reaction mixture was diluted with chloroform (10 ml) and washed 6.0m HCl (3.0 ml×4), water (3.0 ml). The chloroform layer concentrated and the residue purified on silica gel using a mixture of chloroform:methanol (90:10) as eluent and receiving N-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)-2-oxo-2-(thiophene-2-sulfonylamino)ndimethylacetamide, P019 (7,0 mg).1H-NMR (500 MHz, DMSO-d6) 4,59 (s, 2H), to 5.35 (s, 2H), at 6.84 (DD, J=8,0, 1.5 Hz, 1H), 6.90 to (DD, J=8,0, 8.0 Hz, 1H), 7,02 (m, 2H), 7,06 (DD, J=5.0 and 3.5 Hz, 1H), 7,44 (m, 1H), 7,56 (s, 1H), to 7.61 (DD, J=3,5, 1.5 Hz, 1H), 7,71-the 7.65 (m, 3H), 7,78 (m, 1H), of 10.05 (s, 1H). MS (ESI-) Is calculated: (M+) 521,6; found: 520,7 (M-1).

Example 97. Getting connection P049.

Synthesis of ethyl ether (4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)acetic acid, I-63: a Mixture of 5-amino-4-naphthalene-2-ylmethyl-4H-benzo[1,4]oxazin-3-it, I-60 (152 mg, 0.5 mmol), ethylhexanate (50% in toluene, 370 mg) and anhydrous Na2SO4(520 mg) in toluene (4.0 ml) was heated to 110°C and maintained at this temperature for 4 hours. The reaction mixture is filtered. The filtrate is concentrated and the resulting residue is transferred in methanol (4.0 ml) and at room tempera is ur add borohydride sodium (40 mg). The mixture is stirred for 18 hours, then the methanol is evaporated. To the residue is added water (10 ml) and extracted with chloroform (10.0 ml×2). The combined organic layers dried (saturated solution of salt, Na2SO4), concentrated and dried, obtaining the ethyl ester of (4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)acetic acid, I-63 (105 mg).

Synthesis of (4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)acetic acid, I-64. A mixture of ethyl ether (4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)acetic acid, I-63 (105 mg), methanol (3.0 ml), THF (2.0 ml) and 2.0m NaOH (0.5 ml) was stirred at room temperature for 18 hours. The methanol is evaporated and the residue is transferred into the water (3.0 ml) and acidified to pH 1 by the addition of 2.0m HCl in the falls solid white precipitate. The solid product is extracted with chloroform (10 ml×2), and the combined extracts dried (saturated solution of salt, anhydrous sodium sulfate), concentrated and dried in high vacuum, obtaining (4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)acetic acid, I-64 (102 mg).

The synthesis of compounds P049. [2-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)acetyl]amide thiophene-2-sulfonic acid. A solution of (4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)acetic acid, I-64 (102 mg, 0,281 m is ol), thiophene-2-sulfonamida (46 mg, 0,281 mmol), EDCI (40 mg, 0.33 mmol), DMAP (40 mg, 0.33 mmol) in CH2Cl2stirred at room temperature for 48 hours. The reaction mixture was diluted with CH2Cl2(30,0 ml) and washed with 6N. HCl (5 ml×3), water (5 ml), dried (saturated solution of salt, Na2SO4) concentrated and the resulting residue purified on silica gel, using as eluent a mixture of chlorform:methanol (95:5)to give [2-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)acetyl]amide thiophene-2-sulfonic acid, P049 (16 mg).1H-NMR (500 MHz, DMSO-d6) 3,76 (s, 2H), 4,48 (s, 2H), of 5.39 (s, 2H), 5,52 (ush. s, 1H), 6,11 (DD, J=8,5, 1.0 Hz, 1H), 6,32 (DD, J=8,5, 1.0 Hz, 1H), 6,74 (t, J=8.5 Hz, 1H), 7,12 (m, 2H), 7,44 (m, 2H), 7,60 (s, 1H), 7,73-to 7.67 (m, 2H), 7,79 (m, 1H), of 7.90 (d, J=4.5 Hz, 1H), 12,45 (ush. s, 1H). LC/MS=93,8% purity; MS (ESI-) Is calculated: (M+) 511,6; found: 511,5 (M-1).

Example 98. Getting connection P018.

Synthesis of methyl ester (3-ethoxycarbonylmethoxy-2-nitrophenoxy)acetic acid, I-65. Methylbromide (23 g, 150 mmol) is added under stirring to a mixture of 2-nitrobenzene-1,3-diol (9.3 g, 60 mmol), K2CO3(24.8 g, 180 mmol) in acetone (250 ml) and water (5 ml) at room temperature. The reaction mixture was stirred at room temperature for weeks. The solvent is removed in vacuo and the residue partitioned between EtOAc (200 ml) and water (200 ml). The solid precipitate is filtered off and washed with water is, EtOAc and ether. After drying obtain 9.5 g of compound 2 as a white solid. The aqueous layer was extracted with EtOAc (2×100 ml). The combined organic phases are washed with water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue was washed with EtOAc, receiving 4 g of compound I-65. Just get 13.5 g of compound 2.1H-NMR (500 MHz, DMSO-d6).

Synthesis of methyl ester of 2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)propionic acid, I-66. A mixture of compound I-65 (3,9 g, 13 mmol) and 1.4 g of Pd/C (5%) in THF (300 ml) and methanol (100 ml) hydronaut at room temperature for 2 days. The reaction mixture was filtered through celite and the celite washed with EtOAc and methanol. After removal of the solvent in vacuo the solid product is washed with ether, receiving of 3.07 g of compound I-66 in the form of a white solid.1H-NMR (500 MHz, CDCl3).

Synthesis of methyl ester of 2-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)propionic acid, I-67. A mixture of compound I-66 (350 mg, 1.5 mmol), 2-(methyl bromide)naphthalene (500 mg, 2.25 mmol), KI (374 mg, 2.25 mmol) and K2CO3(310 mg, 2.25 mmol) in DMF (8 ml) and water (10 drops) was stirred at room temperature overnight and then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (3×30 ml). The combined organic phase washed with water (4×30 ml), basenum salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using a mixture of EtOAc/hexane as eluent, and receiving 300 mg of compound I-67.1H-NMR (500 MHz, CDCl3).

Synthesis of 2-(4-naphthalene-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)propionic acid, I-68. To a solution of compound I-67 (300 mg, 0.8 mmol) in EtOH (5 ml) and THF (5 ml) at room temperature with stirring aqueous NaOH (2n., 5 ml). The reaction mixture was stirred at room temperature overnight and then the pH was adjusted to acidic by addition of 2n. aqueous HCl. The reaction mixture was extracted with EtOAc (2×30 ml). The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is dissolved in ether and the solid precipitate filtered off. After removal of ether to obtain 140 mg of compound I-68.1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P018. To a mixture of acid I-68 (140 mg, 0.38 mmol), 2-thiophenesulfonyl (76 mg, 0.45 mmol), 4-dimethylaminopyridine (94 mg, 0.77 mmol) in dichloromethane (8 ml) was added EDCl (147 mg, 0.77 mmol). The reaction mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent p the obtained solid residue is washed with ether, getting 135 mg connection P018. MS (ESI-): are 507, 5 (M-1), LC-MS: 83%,1H-NMR (500 MHz, DMSO-d6).

Example 99. Getting connection P020.

Synthesis of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetic acid, I-69. To a solution of compound I-66: (1.5 g, 6.3 mmol) in EtOH (15 ml) and THF (35 ml) at room temperature, add aqueous NaOH (2n., 10 ml). The reaction mixture was stirred at room temperature for one week and then the pH was adjusted to acidic by addition of 2n. aqueous HCl. The resulting solid product is filtered off and washed with water, EtOAc and ether. After drying obtain 1.3 g of compound I-69 as a white solid.1H-NMR (500 MHz, DMSO-d6).

Synthesis of [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70. To a mixture of acid I-69 (1,11 g, 5 mmol), 2-thiophenesulfonyl (913 mg, 5.5 mmol), 4-dimethylaminopyridine (1.22 g, 10 mmol) in dichloromethane (200 ml) is added EDCI (1,91 g, 10 mmol). The reaction mixture was stirred at room temperature overnight. The solution was diluted with water and the pH adjusted to acidic by addition of aqueous HCl (2n.). The resulting solid precipitate is filtered off and washed with dilute aqueous HCl, CH2Cl2and ether. After drying obtain 1.6 g of compound I-70 in the form of a white solid.1H-NMR (500 MHz, DMSO-d6). MS (ESI-): 367,2 (M-1), LC-IS FROM: 96%.

General procedure (A-3) N-alkylation of compound I-70.

A mixture of compound I-70 (50 mg, 0,136 mmol), substituted benzylbromide (or chloride) (0.27 mmol), KI (45 mg, 0.27 mmol) and K2CO3(38 mg, 0.27 mmol) in DMF (3 ml) and water (3 drops) was stirred at room temperature for 5 days. The solution was diluted with water and the pH adjusted to acidic by addition of aqueous HCl (2n.). The resulting solid precipitate is filtered off and washed with dilute aqueous HCl and water. The solid product was dissolved in CH2Cl2and the insoluble precipitate is filtered off. After removal of solvent the residue is washed with ether to obtain the product.

The synthesis of compounds P020. A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 3,4-dimethylbenzylamine getting connection P020.1H-NMR (500 MHz, DMSO-d6), MS (ESI): 485,4 (M-l) LC-MS: 85%.

Example 100. Getting connection P021.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid (I-70 2,5-dimethylbenzylamine, receiving the connection P021.1H-NMR(500 MHz, DMSO-d6) MS (ESI-): 485,4 (M-1), LC-MS: 95%.

Example 101. Getting connection P022.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]is casin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, benzylbromide, receiving the connection P022.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 457,4 (M-1), LC-MS: 93%.

Example 102. Getting connection P023.

A General method (A-3) is used for the alkylation of thiophene-2-sulfonic acid [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide, I-70, 4-methylbenzylamino, receiving the connection P023. 1H-NMR (500 MHz, DMSO-d6) MS (ESI): 471,4 (M-l), LC-MS: 87%.

Example 103. Getting connection P024.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 4-farbensymposium, receiving the connection P024.1H-NMR (500 MHz, DMSO-d6) MS (ESI-): 475,2 (M-1), LC-MS: 87%.

Example 104. Getting connection P025.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 4-chlorobenzylchloride, receiving the connection P025.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 491,3 (M-1), LC-MS: 90%.

Example 105. Getting connection P026.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 1-methyl bromide-4-deformatsionnom, receiving the connection P026.1H-NMR (DMSO-d6) of 4.57 (s, 2H), 4,59 (s, 2H), to 5.35 (s, 2H), 6,45 (d, J=8.5 Hz, 1H), to 6.67 (d, J=8.5 Hz, 1H), 6,91 (t, J=8.0 Hz, 1H), 6,99 (m, 2H), 7,02 (m,2H), 7,14 (s, 1H), 7,20 (m, 1H), 7,79 (s, 1H), 8,02 (s, 1H), 12.5cm (USS, 1H). LC/MS (91%) ESI-Calculated: 523,5 m/z; Found: about 523.4 m/z.

Example 106. Getting connection P027.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 4-cryptomethodoverrides, receiving the connection P027.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): TO 541.5 (M-1), LC-MS: 90%.

Example 107. Getting connection P028.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 3-cryptomethodoverrides, receiving the connection P028.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 542,9 (M-1), LC-MS: 81%.

Example 108. Getting connection P029.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 3-cryptomethodoverrides, receiving the connection P029.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 526,9 (M-1), LC-MS: 83%.

Example 109. Getting connection P030.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 3-methoxybenzylamine, receiving the connection P030.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 487,4 (M-1), LC-MS: 83%.

Example 110. On the doctrine connection P031.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 2-cryptomethodoverrides, receiving the connection P301.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 525,5 (M-1), LC-MS: 90%.

Example 111. Getting connection P032.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 4-methylsulfonylamino, receiving the connection P032.1H-NMR (DMSO-d6) 3,15 (s,3H), 4.53-in (s,2H)and 4.65 (s, 2H), of 5.40 (s, 2H), 6,46 (d, J=8,5Hz, 1H), of 6.71 (d, J=8.0 Hz, 1H), 6,93 (t, J=8,5Hz, 1H), 7,21 (t, J=4 Hz, 1H), 7,29 (d, J=8.5 Hz, 2H), 7,75 (d, J=8.5 Hz, 2H), 7,79 (m, 1H), 8,04 (m, 1H). LC/MS (98%) ESI-Calculated: 535,6 m/z; found: 535,3 m/z.

Example 112. Getting connection P039.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 3,4-dichlorobenzamide, receiving the connection P039.1H-NMR (500 MHz, DMSO-d6), MS (ESI-):525,5 (M-1), LC-MS: 90%.

Example 113. Getting connection P040.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 2,4-dichlorobenzamide, receiving the connection P040.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 525,4 (M-1), LC-MS: 78%.

Example 114. P is the receiving connection P041.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 3,5-dimethoxybenzamide, receiving the connection P041.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 517,5 (M-1), LC-MS: 94%.

Example 115. Getting connection P042.

A General method (A-3) used for alkylation [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)acetyl]amide thiophene-2-sulfonic acid, I-70, 5-bromeilles[1,2,5]oxadiazole, receiving the connection P042.1H-NMR (DMSO-d6) 4,55 (s, 2H), 4,69 (s, 2H), to 5.35 (s, 2H), 6.48 in (d, J=8.5 Hz, 1H), 6,74 (d, J=8.0 Hz, 1H), 6,94 (t, J=8.0 Hz, 1H), 7,21 (t, J=4.0 Hz, 1H), 7,30 (d, J=9.0 Hz, 1H), 7,60 (s, 1H), to 7.77 (m, 1H), of 7.90 (d, J=9.0 Hz, 1H), 8,07 (d, J=5.0 Hz, 1H), 12.5cm (USS, 1H). LC/MS (92%) ESI-; Calculated: 499,5 m/z; found: 499,8 m/z.

Example 116. Getting connection P004.

Synthesis of methyl ester (2-oxo-1,2-dihydroquinoline-8 yloxy)acetic acid, I-71. Methylbromide (367 mg, 2.4 mmol) is added under stirring to a mixture of 8-hydroxy-1H-quinoline-2-it [which is produced in accordance with the methodology described in the literature (Wang, T.C. et al.,Synthesis,1997, 87-90)], (322 mg, 2 mmol) and K2CO3(414 mg, 3 mmol) in DMF (10 ml) at room temperature. The reaction mixture was stirred at room temperature overnight and then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×50 ml). Obyedinennaya phase washed with water (3×50 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with ether, receiving 250 mg of compound I-71.

Synthesis of methyl ester (1-naphthalene-2-ylmethyl-2-oxo-1,2-dihydroquinoline-8 yloxy)acetic acid, I-72. A mixture of compound I-71 (233 mg, 1 mmol), 2-(methyl bromide)naphthalene (332 mg, 1.5 mmol), KI (250 mg, 1.5 mmol) and K2CO3(207 mg, 1.5 mmol) in DMF (8 ml) and water (2 drops) was stirred at room temperature for one week and then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×50 ml). The combined organic phase washed with water (4×50 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent, the residue is purified column chromatography on silica gel, using as eluent 2% methanol in dichloromethane and receiving 120 mg of compound I-72 and 50 mg of O-alkylated side product: methyl ether (1-naphthalene-2-ylmethyl-2-oxo-1,2-dihydroquinoline-8 yloxy)acetic acid. For compound I-72:1H-NMR (500 MHz, CDCl3),13C-NMR (125 MHz, CDCl3).

Synthesis of (1-naphthalene-2-ylmethyl-2-oxo-1,2-dihydroquinoline-8 yloxy)acetic acid, I-73. To a solution of compound I-72 (120 mg, 0.32 mmol) in EtOH (8 ml) at room temperature, add aqueous NaOH (2n., 5 ml). The reaction mixture was stirred at room temperature over night and is eating the pH was adjusted to acidic by addition of aqueous 2n. HCl. The reaction mixture was extracted with EtOAc (2×10 ml). The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with ether, receiving 100 mg of compound I-73.1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P004. To a mixture of acid I-73 (36 mg, 0.1 mmol), 2-thiophenesulfonyl (20 mg, 0.12 mmol) and 4-dimethylaminopyridine (25 mg, 0.2 mmol) in dichloromethane (5 ml) is added EDCI (38 mg, 0.2 mmol). The reaction mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent the solid residue was washed with ether, receiving 35 mg connection P004.1H-NMR (DMSO-d6) 4,36 (s, 2H), the 6.06 (s, 2H), 6,74 (d, J=9 Hz, 1H), 6,92 (d, J=8.0 Hz, 1H), 7,11 (t, J=7.5 Hz, 1H), 7,16 (m, 2H), 7,34 (d, J=7 Hz, 1H), 7,38-7,42 (m, 3H), 7,63-7,72 (m, 3H), 7,81 (m, 1H), to 7.95 (m, 2H). LC/MS (90%) ESI-Calculated: 503,6 m/z; found: 503,4 m/z

Example 117. Getting connection P012.

Synthesis of 8-(naphthalene-2-ylethoxy)-1H-quinoline-2-it, I-74. 2-(methyl bromide)naphthalene (530 mg, 2.4 mmol) at room temperature is added under stirring to a mixture of 8-(naphthalene-2-admetox)-1H-quinoline-2-she (322 mg, 2 mmol) and K2CO3(414 mg, 3 mmol) in DMF (10 ml). The reaction mixture was stirred at room temperature overnight and then races Radelet between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×50 ml). The combined organic phase washed with water (3×50 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with ether, getting 470 mg of compound I-74.1H-NMR (500 MHz, CDCl3).

Synthesis of methyl ester [8-(naphthalene-2-ylethoxy)-2-oxo-2H-quinoline-1-yl]acetic acid, I-75. A mixture of compound I-74 (210 mg, 0.7 mmol), methylpropanoate (230 mg, 1.5 mmol), KI (250 mg, 1.5 mmol) and K2CO3(207 mg, 1.5 mmol) in DMF (8 ml) and water (2 drops) was stirred at room temperature overnight and then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×50 ml). The combined organic phase washed with water (4×50 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel, using as eluent hexane, hexane/dichloromethane (1:1), dichloromethane, 1% methanol in dichloromethane, receiving 160 mg of compound I-75 and 30 mg O-alkylated by-product methyl ester [8-(naphthalene-2-ylethoxy)quinoline-2-yloxy]acetic acid. To connect with I-75:1H-NMR (500 MHz, CDCl3);13C-NMR (125 MHz, CDCl3).

Synthesis of [8-(naphthalene-2-ylethoxy)-2-oxo-2H-quinoline-1-yl]acetic acid, I-76. To a solution of compound I-75 (30 mg, 0.08 to IMO is ü) in THF (3 ml) and MeOH (3 ml) at room temperature, add aqueous NaOH (2n., 3 ml). The reaction mixture was stirred at room temperature overnight and the pH value was adjusted to acidic by addition of aqueous 2n. HCl. The reaction mixture was extracted with EtOAc (2×15 ml). The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with ether, receiving 25 mg of acid I-76.1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P012. To a mixture of acid I-76 (25 mg, 0.07 mmol), 2-thiophenesulfonyl (14 mg, 0,084 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) is added EDCI (29 mg, 0.15 mmol). The reaction mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent the solid residue was washed with ether, receiving 30 mg of compound P-12.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 503,3 (M-1), LC-MS: 91%.

Example 119. Getting connection P015.

Synthesis of 8-(naphthalene-2-ylethoxy)quinoline, I-81. 2-(methyl bromide)naphthalene (663 mg, 3 mmol) at room temperature with stirring to a mixture of 8-hydroxyquinoline solution (435 mg, 3 mmol) and K2CO3(621 mg, 4.5 mmol) in acetone (20 ml). The reaction mixture was stirred at room temperature for weeks and zatebradine between EtOAc and water. The aqueous layer was extracted with EtOAc (2×100 ml). The combined organic phase washed with water (2×100 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with ether, receiving 650 mg of compound I-81.1H-NMR (500 MHz, CDCl3).

Synthesis of 8-(naphthalene-2-ylethoxy)-1,2,3,4-tetrahydroquinoline, I-82. To a solution of compound I-81 (285 mg, 1 mmol) in AcOH (15 ml) at room temperature add NaCNBH3(252 mg, 4 mmol). The reaction mixture was stirred at room temperature for 1 hour and then at 60°C for 1 hour. The reaction mixture was stirred at room temperature overnight and the solvent is removed in vacuum. The residue is partitioned between dichloromethane and water and the pH was adjusted to 8-8 adding aqueous solution of NH4OH. The aqueous phase is extracted with dichloromethane (3×50 ml). The combined organic phase was washed with saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel, using as eluent dichloromethane and 2% methanol/dichloromethane and receiving 200 mg of compound I-82.1H-NMR (500 MHz, CDCl3).

Synthesis of methyl ester [8-(naphthalene-2-ylethoxy)-3,4-dihydro-2H-quinoline-1-yl]acetic acid, I-83. A mixture of compound I-82 (200 mg, 0.7 mmol), methylpropanoate (153 mg, 1 mmol), KI (233 mg, 1,4 shall mol) and K 2CO3(193 mg, 1.4 mmol) in DMF (10 ml) and water (0.2 ml) was stirred at room temperature overnight and then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×50 ml). The combined organic phase washed with water (4×50 ml), saturated salt solution and dried over sodium sulfate. After removal of the solvent receive 250 mg of the crude compound I-83.1H-NMR (500 MHz, CDCl3).

Synthesis of [8-(naphthalene-2-ylethoxy)-3,4-dihydro-2H-quinoline-1-yl]acetic acid, I-84. To a solution of compound I-83 (250 mg, 0.7 mmol) in THF (3 ml) and EtOH (6 ml) at room temperature, add aqueous NaOH (2n., 4 ml). The reaction mixture was stirred at room temperature overnight, then the pH was adjusted to acidic values by addition of an aqueous 2n. HCl. The reaction mixture was extracted with EtOAc (2×15 ml). The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with ether, receiving 120 mg of compound I-84.1H-NMR (500 MHz, DMSO-d6).

Synthesis of compound P015. To a mixture of acid I-84 (25 mg, 0.07 mmol), 2-thiophenesulfonyl (16 mg, 0.1 mmol), 4-dimethylaminopyridine (24 mg, 0.2 mmol) in dichloromethane (6 ml) and DMSO (0.5 ml) is added EDCI (38 mg, 0.2 mmol). The reaction mixture was stirred at room temperature overnight. The solution was diluted with di is loretana, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using dichloromethane and 2% methanol/dichloromethane as eluent and receiving 7 mg of compound P015. 1H NMR (DMSO-d6) of 1.81 (m, 2H), 2,78 (t, J=6.5 Hz, 2H), 3,03 (m, 2H), 3,62 (s, 2H), 5,12 (s, 2H), 6,66 (d, J=7.5 Hz, 1H), 6,72 (d, J=7,5 Hz, 1H), 6,79 (m, 1H), 6.87 in (m, 1H), 7,19 (m, 1H), 7,35 (m, 1H), the 7.43 (m, 1H), 7,49 (m, 2H), 7.62mm (m, 1H), 7,72 (m, 2H), 7,82 (m, 3H). LC/MS (97%) ESI-Calculated: 491,6 m/z; found: 491,2 m/z.

Example 120. Getting connection P046.

Synthesis of 2-aminobenzoyl-1,3-diol, and I-85. A mixture of 2-nitrobenzene-1,3-diol (3.1 g, 20 mmol) and 1 g of Pd/C (5%) in methanol (100 ml) hydronaut hydrogen at a pressure of 30 pounds per square inch at room temperature for 2 days. The reaction mixture was filtered through celite, the celite washed with ethanol, water and methanol. After removal of solvent in vacuo obtain 2.6 g of compound I-85 in the form of a white solid.1H-NMR (500 MHz, DMSO-d6).

Synthesis of 2-[(naphthalene-2-ylmethyl)amino]benzene-1,3-diol, I-86. A mixture of compound I-85 (250 mg, 2 mmol) and 2-naphthaldehyde (343 mg, 2.2 mmol) in methanol (20 ml) was stirred at room temperature for 2 hours, then cooled to -10°C. the reaction mixture slowly at a temperature in the range from -10°C to 0°C is added NaBH4(304 mg, 8 mmol). The mixture is stirred at 0°C in those which begins 30 minutes and at room temperature for 2 hours, then cooled to 0°C and quenched with water. The pH value of the reaction mixture was adjusted to ~4 and extracted with EtOAc (2×100 ml). To the aqueous layer add the sodium chloride and the resulting mixture extracted with dichloromethane. From a mixture of water/CH2Cl2solid material precipitates. The solid is filtered off and washed with water and CH2Cl2receiving 140 mg of compound I-86.1H-NMR (500 MHz, DMSO-d6).

Synthesis of 4-hydroxy-3-naphthalene-2-ylmethyl-3H-benzoxazol-2-it, I-87. A mixture of compound I-86 (140 mg, 0.46 mmol), triethylamine (46 mg, 0.46 mmol) and 1,1'-carbonyldiimidazole (80 mg, 0.5 mmol) in THF (20 ml) is refluxed overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase was washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent to obtain 140 mg of compound I-87 in the form of a white solid.1H-NMR (500 MHz, DMSO-d6).13C-NMR (125 MHz, DMSO-d6).

Synthesis of tert-butyl methyl ether (3-naphthalene-2-ylmethyl-2-oxo-2,3-dihydroisoxazole-4-yloxy)acetic acid, I-88. A mixture of compound I-87 (140 mg, 0.48 mmol), tert-butylbromide (136 mg, 0.7 mmol) and K2CO3(95 mg, 0.7 mmol) in acetone (10 ml) and DMF (5 ml) was stirred at room temperature overnight and then partitioned between EtOAc and water. In the hydrated layer is extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent receive 160 mg of compound I-88.1H-NMR (500 MHz, CDCl3).

Synthesis of (3-naphthalene-2-ylmethyl-2-oxo-2,3-dihydroisoxazole-4-yloxy)acetic acid, I-89. To a solution of compound I-88 (150 mg, and 0.37 mmol) in dichloromethane (5 ml) at room temperature add TFOC (10 ml). The reaction mixture was stirred at room temperature for 2 hours and the solvent is removed in vacuum. The residue is washed with ether, receiving 130 mg of compound I-89. MS (ESI-): 348,2 (M-1), LC-MS: 99%,1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P046. The mixture of acid I-89 (35 mg, 0.1 mmol), 2-thiophenesulfonyl (20 mg, 0.12 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution is diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent the solid residue was washed with ether, receiving 30 mg of compound P046. MS (ESI-): 493,4 (M-1), LC-MS: 81%,1H-NMR (500 MHz, DMSO-d6).

Example 121. Getting connection P047.

The mixture of acid I-89 (35 mg, 0.1 mmol), 2-methoxy-5-bromophenylacetate (32 mg, 0.12 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel, using as eluent a mixture of methanol/dichloromethane and receiving 24 mg of compound P047. MS (ESI-): 597,2 (M-1), LC-MS:94%,1H-NMR (500 MHz, DMSO-d6).

Example 122. Getting connection P048.

The mixture of acid I-89 (35 mg, 0.1 mmol), triftormetilfullerenov (18 mg, 0.12 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCl (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent receive 30 mg of compound P048 in the form of DMAP salt. MS (ESI-): 479,3 (M-1), LC-MS: 96%,1H-NMR (500 MHz, DMSO-d6).

Example 123. Getting connection P050.

Synthesis of 4-hydroxy-3H-benzoxazol-2-it, I-90. A mixture of 2-aminobenzo-1,3-diol (2,03 g, 16.2 mmol) and 1,1'-carbonyldiimidazole (2,63 g, 16.2 mmol) in THF (200 ml) is refluxed overnight. After removal of THF under vacuum, the residue is dissolved in EtOAc and washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent the solid mod is to washed with ether, getting to 1.9 g of compound I-90.1H-NMR (500 MHz, DMSO-d6).

Synthesis of tert-butyl methyl ether 2-oxo-2,3-dihydroisoxazole-4-silt ether, I-91. To a solution of compound I-90 (1 g, 6.6 mmol) in THF (20 ml) and water (8 ml) at room temperature with stirring aqueous NaOH (2n., 13 ml) and di-tert-BUTYLCARBAMATE (3,16 g, 14.5 mmol) in THF (15 ml). After stirring at room temperature overnight, the reaction mixture was diluted with water and EtOAc and cooled with ice, and then the pH adjusted to 2-3 by addition of aqueous HCl (2n.). The aqueous layer was extracted with EtOAc (2×100 ml). The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent to obtain 2.3 g of compound I-91.1H-NMR (500 MHz, DMSO-d6).

Synthesis of 3-benzo[1,3]dioxol-5-ylmethyl-4-hydroxy-3H-benzoxazol-2-it, I-92. A mixture of compound I-91 (251 mg, 1 mmol), 3,4-methylenedioxyaniline (255 mg, 1.5 mmol), K2CO3(207 mg, 1.5 mmol) and KI (249 mg, 1.5 mmol) in acetone (10 ml) and water (5 drops) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of solvent, the intermediate O-BOC-compound (3-benzo[1,3]dioxol-5-ylmethyl-2-oxo-2,3-dihyd benzoxazol-4-silt ether tert-butyl methyl ether carboxylic acid) dissolved in dichloromethane (6 ml) and at room temperature add TFOC (3 ml). The reaction mixture was stirred at room temperature for 15 minutes and the solvent is removed in vacuum. The residue is washed with ether, receiving 100 mg of compound I-92.1H-NMR (500 MHz, DMSO-d6).

Synthesis of tert-butyl methyl ether (3-benzo[1,3]dioxol-5-ylmethyl-2-oxo-2,3-dihydroisoxazole-4-yloxy)acetic acid, I-93. A mixture of compound I-92 (100 mg, 0.35 mmol), tert-butylbromide (136 mg, 0.7 mmol) and K2CO3(95 mg, 0.7 mmol) in acetone (8 ml) and DMSO (2 ml) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent receive 100 mg of compound I-93.1H-NMR (500 MHz, CDCl3).

Synthesis of (3-benzo[1,3]dioxol-5-ylmethyl-2-oxo-2,3-dihydroisoxazole-4-yloxy)acetic acid, I-94. To a solution of compound I-93 (100 mg, 0.25 mmol) in dichloromethane (4 ml) at room temperature add TFOC (8 ml). The reaction mixture was stirred at room temperature for 3 hours and the solvent is removed in vacuum. The residue is washed with ether, receiving 80 mg of compound I-94.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 342,2 (M-1), LC-MS:>90%.

The synthesis of compounds P050. The mixture of acid I-94 (35 mg, 0.1 mmol), 2-thiophenesulfonyl (20 mg, 0.12 mmol), 4-dimethylamino what iridin (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel, using as eluent a mixture of methanol/dichloromethane and receiving 35 mg connection P050. MS (ESI): 487,4 (M-1), LC-MS: 87%,1H-NMR (500 MHz, DMSO-d6).

Example 124. Getting connection P051.

Synthesis of 3-(3,4-dichlorobenzyl)-4-hydroxy-3H-benzoxazol-2-it, I-95. A mixture of compound I-91 (251 mg, 1 mmol), 3,4-dichlorobenzaldehyde (292 mg, 1.5 mmol), K2CO3(207 mg, 1.5 mmol) and KI (249 mg, 1.5 mmol) in acetone (10 ml) and water (5 drops) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent O-BOC product (tert-butyl ether 3-(3,4-dichlorobenzyl)-2-oxo-2,3-dihydroisoxazole-4-silt ether carboxylic acid) dissolved in dichloromethane (6 ml), then at room temperature add TFOC (3 ml), the reaction mixture was stirred at room temperature for 15 minutes and the solvent is removed in vacuum. The remainder ol myauth ether, receiving 80 mg of compound I-95.1H-NMR (500 MHz, DMSO-d6).

Synthesis of tert-butyl methyl ether [3-(3,4-dichlorobenzyl)-2-oxo-2,3-dihydroisoxazole-4-yloxy]acetic acid, I-96. A mixture of compound I-95 (80 mg, 0.26 mmol), tert-butylbromide (136 mg, 0.7 mmol) and K2CO3(95 mg, 0.7 mmol) in acetone (8 ml) and DMSO (2 ml) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent receive 90 mg of compound I-96.1H-NMR(500 MHz,CDCl3).

Synthesis of [3-(3,4-dichlorobenzyl)-2-oxo-2,3-dihydroisoxazole-4-yloxy]acetic acid, I-97:20. To a solution of compound I-96 (90 mg, 0.21 mmol) in dichloromethane (4 ml) at room temperature add TFOC (8 ml). The reaction mixture was stirred at room temperature for 3 hours and the solvent is removed in vacuum. The residue is washed with ether, receiving 70 mg acid I-97. MS (ESI-): 367,9 (M-1), LC-MS: >90%,1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P051. The mixture of acid I-97 (37 mg, 0.1 mmol), 2-thiophenesulfonyl (20 mg, 0.12 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution was diluted with dichloro is an, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel, using as eluent a mixture of methanol/dichloromethane and receiving 32 mg connection P051. MS (ESI-): 511,4 (M-1), LC-MS:89%,1H-NMR (500 MHz, DMSO-d6).

Example 125. Getting connection P052.

Synthesis of 3-(2,4-dichlorobenzyl)-4-hydroxy-3H-benzoxazol-2-it, I-98. A mixture of compound I-91 (251 mg, 1 mmol), 2,4-dichlorobenzaldehyde (292 mg, 1.5 mmol), K2CO3(207 mg, 1.5 mmol) and KI (249 mg, 1.5 mmol) in acetone (10 ml) and water (5 drops) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent O-BOC-derivative (3-(2,4-dichlorobenzyl)-2-oxo-2,3-dihydroisoxazole-4-silt ether tert-butyl methyl ether carboxylic acid) dissolved in dichloromethane (6 ml)at room temperature add TFOC (3 ml), the mixture was stirred at room temperature for 15 minutes and the solvent is removed in vacuum. The residue is washed with ether, receiving 110 mg of compound I-98.1H-NMR (500 MHz, DMSO-d6).

Synthesis of tert-butyl methyl ether 3-(2,4-dichlorobenzyl)-2-oxo-2,3-dihydro isoxazol-4-yloxy]acetic acid, I-99. A mixture of compound I-98 (80 mg, 0.26 mmol), tert-butylbromide (136 mg, 0.7 mmol) and K2CO3(95 mg, 0.7 mmol) in acetone (8 ml) and DMSO (2 ml) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent to obtain 140 mg of compound I-99.1H-NMR (500 MHz, CDCl3).

Synthesis of tert-butyl methyl ether (3-naphthalene-2-ylmethyl-2-oxo-2,3-dihydroisoxazole-4-yloxy)acetic acid, I-88. A mixture of compound I-87 (140 mg, 0.48 mmol), tert-butylbromide (136 mg, 0.7 mmol) and K2CO3(95 mg, 0.7 mmol) in acetone (10 ml) and DMF (5 ml) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent receive 160 mg of compound I-88. 1H-NMR (500 MHz, CDCl3).

Synthesis of (3-naphthalene-2-ylmethyl-2-oxo-2,3-dihydroisoxazole-4-yloxy)acetic acid, I-89. To a solution of compound I-88 (150 mg, and 0.37 mmol) in dichloromethane (5 ml) at room temperature add TFOC (10 ml). The reaction mixture was stirred at room temperature for 2 hours and the solvent is removed in in the cosmology vacuum. The residue is washed with ether, receiving 130 mg of compound I-89. MS (ESI-): 348,2 (M-1), LC-MS: 99%,1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P046. The mixture of acid I-89 (35 mg, 0.1 mmol), 2-thiophenesulfonyl (20 mg, 0.12 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution is diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent the solid residue was washed with ether, receiving 30 mg of compound P046. MS (ESI-): 493,4 (M-1), LC-MS: 81%,1H-NMR (500 MHz, DMSO-d6).

Example 121. Getting connection P047.

The mixture of acid I-89 (35 mg, 0.1 mmol), 2-methoxy-5-bromophenylacetate (32 mg, 0.12 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel, using as eluent a mixture of methanol/dichloromethane and receiving 24 mg of compound P047. MS (ESI-): 597,2 (M-1), LC-MS:94%,1H-NMR (500 MHz, DMSO-d6).

Example 122. Getting connection P048.

the Mixture of acid I-89 (35 mg, 0.1 mmol), triftormetilfullerenov (18 mg, 0.12 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCl (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent receive 30 mg of compound P048 in the form of DMAP salt. MS (ESI-): 479,3 (M-1), LC-MS: 96%,1H-NMR (500 MHz, DMSO-d6).

Example 123. Getting connection P050.

Synthesis of 4-hydroxy-3H-benzoxazol-2-it, I-90. A mixture of 2-aminobenzo-1,3-diol (2,03 g, 16.2 mmol) and 1,1'-carbonyldiimidazole (2,63 g, 16.2 mmol) in THF (200 ml) is refluxed overnight. After removal of THF under vacuum, the residue is dissolved in EtOAc and washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent the solid residue was washed with ether, receiving of 1.9 g of compound I-90.1H-NMR (500 MHz, DMSO-d6).

Synthesis of tert-butyl methyl ether 2-oxo-2,3-dihydroisoxazole-4-silt ether carboxylic acid, I-91. To a solution of compound I-90 (1 g, 6.6 mmol) in THF (20 ml) and water (8 ml) at room temperature with stirring aqueous NaOH (2n., 13 ml) and di-tert-BUTYLCARBAMATE (3,16 g, 14.5 mmol) in THF (15 ml). After stirring at room temperature for the eyes, the reaction mixture was diluted with water and EtOAc and cooled with ice, then pH was adjusted to 2-3 by addition of aqueous HCl (2n.). The aqueous layer was extracted with EtOAc (2×100 ml). The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent to obtain 2.3 g of compound I-91.1H-NMR (500 MHz, DMSO-d6).

Synthesis of 3-benzo[1,3]dioxol-5-ylmethyl-4-hydroxy-3H-benzoxazol-2-it, I-92. A mixture of compound I-91 (251 mg, 1 mmol), 3,4-methylenedioxyaniline (255 mg, 1.5 mmol), K2CO3(207 mg, 1.5 mmol) and KI (249 mg, 1.5 mmol) in acetone (10 ml) and water (5 drops) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of solvent, the intermediate O-BOC-compound (3-benzo[1,3]dioxol-5-ylmethyl-2-oxo-2,3-dihydroisoxazole-4-silt ether tert-butyl methyl ether carboxylic acid) dissolved in dichloromethane (6 ml) and at room temperature add TFOC (3 ml). The reaction mixture was stirred at room temperature for 15 minutes and the solvent is removed in vacuum. The residue is washed with ether, receiving 100 mg of compound I-92.1H-NMR (500 MHz, DMSO-d6).

Synthesis of tert-butyl methyl ether (3-benzo[1,3]dioxol-5-ylmethyl-2-oxo-2,3-dihydroisoxazole-4-yloxy)acetic KIS is the notes, I-93. A mixture of compound I-92 (100 mg, 0.35 mmol), tert-butylbromide (136 mg, 0.7 mmol) and K2CO3(95 mg, 0.7 mmol) in acetone (8 ml) and DMSO (2 ml) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent receive 100 mg of compound I-93.1H-NMR (500 MHz, CDCl3).

Synthesis of (3-benzo[1,3]dioxol-5-ylmethyl-2-oxo-2,3-dihydroisoxazole-4-yloxy)acetic acid, I-94. To a solution of compound I-93 (100 mg, 0.25 mmol) in dichloromethane (4 ml) at room temperature add TFOC (8 ml). The reaction mixture was stirred at room temperature for 3 hours and the solvent is removed in vacuum. The residue is washed with ether, receiving 80 mg of compound I-94.1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 342,2 (M-1), LC-MS:>90%.

The synthesis of compounds P050. The mixture of acid I-94 (35 mg, 0.1 mmol), 2-thiophenesulfonyl (20 mg, 0.12 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified colonoscopy because it allows the Noah chromatography on silica gel, using as eluent a mixture of methanol/dichloromethane and receiving 35 mg connection P050. MS (ESI): 487,4 (M-1), LC-MS: 87%,1H-NMR (500 MHz, DMSO-d6).

Example 124. Getting connection P051

Synthesis of 3-(3,4-dichlorobenzyl)-4-hydroxy-3H-benzoxazol-2-it, I-95. A mixture of compound I-91 (251 mg, 1 mmol), 3,4-dichlorobenzaldehyde (292 mg, 1.5 mmol), K2CO3(207 mg, 1.5 mmol) and KI (249 mg, 1.5 mmol) in acetoin (10 ml) and water (5 drops) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent O-BOC-product (3-(3,4-dichlorobenzyl)-2-oxo-2,3-dihydroisoxazole-4-silt ether tert-butyl methyl ether carboxylic acid) dissolved in dichloromethane (6 ml), then at room temperature add TFOC (3 ml), the reaction mixture was stirred at room temperature for 15 minutes and the solvent is removed in vacuum. The residue is washed with ether, receiving 80 mg of compound I-95.1H-NMR (500 MHz, DMSO-d6).

Synthesis of tert-butyl methyl ether [3-(3,4-dichlorobenzyl)-2-oxo-2,3-dihydroisoxazole-4-yloxy]acetic acid, I-96. A mixture of compound I-95 (80 mg, 0.26 mmol), tert-butylbromide (136 mg, 0.7 mmol) and K2CO3(95 mg, 0.7 mmol) in acetone (8 ml) and DMSO (2 ml) is stirred PR is room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent receive 90 mg of compound I-96.1H-NMR(500 MHz,CDCl3).

Synthesis of [3-(3,4-dichlorobenzyl)-2-oxo-2,3-dihydroisoxazole-4-yloxy]acetic acid, I-97:20. To a solution of compound I-96 (90 mg, 0.21 mmol) in dichloromethane (4 ml) at room temperature add TFOC (8 ml). The reaction mixture was stirred at room temperature for 3 hours and the solvent is removed in vacuum. The residue is washed with ether, receiving 70 mg acid I-97. MS (ESI-): 367,9 (M-1), LC-MS: >90%,1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P051. The mixture of acid I-97 (37 mg, 0.1 mmol), 2-thiophenesulfonyl (20 mg, 0.12 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel, using as eluent a mixture of methanol/dichloromethane and receiving 32 mg connection P051. MS (ESI-): 511,4 (M-1), LC-MS:89%,1H-NMR (500 MHz, DMSO-d6).

Example 125. Getting connection P052.

Synthesis of 3-(2,4-dichl benzyl)-4-hydroxy-3H-benzoxazol-2-it, I-98. A mixture of compound I-91 (251 mg, 1 mmol), 2,4-dichlorobenzaldehyde (292 mg, 1.5 mmol), K2CO3(207 mg, 1.5 mmol) and KI (249 mg, 1.5 mmol) in acetone (10 ml) and water (5 drops) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent O-BOC-derivative (3-(2,4-dichlorobenzyl)-2-oxo-2,3-dihydroisoxazole-4-silt ether tert-butyl methyl ether carboxylic acid) dissolved in dichloromethane (6 ml)at room temperature add TFOC (3 ml), the mixture was stirred at room temperature for 15 minutes and the solvent is removed in vacuum. The residue is washed with ether, receiving 110 mg of compound I-98.1H-NMR (500 MHz, DMSO-d6).

Synthesis of tert-butyl methyl ether 3-(2,4-dichlorobenzyl)-2-oxo-2,3-dihydroisoxazole-4-yloxy]acetic acid, I-99. A mixture of compound I-98 (80 mg, 0.26 mmol), tert-butylbromide (136 mg, 0.7 mmol) and K2CO3(95 mg, 0.7 mmol) in acetone (8 ml) and DMSO (2 ml) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of solvent which are square-140 mg of compound I-99. 1H-NMR (500 MHz,CDCl3).

Synthesis of 3-(2,4-dichlorobenzyl)-2-oxo-2,3-dihydroisoxazole-4-yloxy]acetic acid, I-100. To a solution of compound I-99 (90 mg, 0.33 mmol) in dichloromethane (4 ml) at room temperature add TFOC (8 ml). The reaction mixture was stirred at room temperature for 3 hours and the solvent is removed in vacuum. The residue is washed with ether, getting 105 mg of compound I-100. MS (ESI-): 366,2 (M-1), LC-MS: >90%,1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P052. The mixture of acid I-100 (37 mg, 0.1 mmol), 2-thiophenesulfonyl (20 mg, 0.12 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of solvent, the residue is purified column chromatography on silica gel, using as eluent a mixture of methanol/dichloromethane and receiving 34 mg of compound P052. MS (ESI-): 511,4 (M-1), LC-MS: 89%,1H-NMR (500 MHz, DMSO-d6).

Example 126. Getting connection P053.

Synthesis of 3-(2,5-dimethylbenzyl)-4-hydroxy-3H-benzoxazol-2-it, I-101. A mixture of compound I-91 (251 mg, 1 mmol), 2,5-dimethylbenzylamine (233 mg, 1.5 mmol), K2CO3(207 mg, 1.5 mmol) and KI (249 mg, 1.5 mmol) in acetone (0 ml) and water (5 drop) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent O-BOC-derivative (3-(2,5-dimethylbenzyl)-2-oxo-2,3-dihydroisoxazole-4-silt ether tert-butyl methyl ether carboxylic acid) dissolved in dichloromethane (6 ml) and then at room temperature add TFOC (3 ml). The reaction mixture was stirred at room temperature for 15 minutes and the solvent is removed in vacuum. The residue is washed with ether, receiving 110 mg of compound I-101.

Synthesis of tert-butyl methyl ether 3-(2,5-dimethylbenzyl)-2-oxo-2,3-dihydroisoxazole-4-yloxy]acetic acid, I-102. A mixture of compound I-101 (110 mg, 0.4 mmol), tert-butylbromide (136 mg, 0.7 mmol) and K2CO3(95 mg, 0.7 mmol) in acetone (8 ml) and DMSO (2 ml) was stirred at room temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent receive 150 mg of compound I-102.1H-NMR (500 MHz,CDCl3).

Synthesis of [3-(2,5-dimethylbenzyl)-2-oxo-2,3-dihydroisoxazole-4-yloxy]acetic acid, I-103. To a solution of compound I-102 (150 mg, 0,39 mmol) in dichloromethane (4 ml) at room temperature add TFOC (8 ml). Reactionary see what camping is stirred at room temperature for 3 hours and the solvent is removed in vacuum. The residue is washed with ether, receiving 120 mg of compound I-103. MS(ESI-): 326,4 (M-1), LC-MS: >90%,1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P053. The mixture of acid I-103 (33 mg, 0.1 mmol), 2-thiophenesulfonyl (20 mg, 0.12 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel, using as eluent a mixture of methanol/dichloromethane and receiving 37 mg connection P053.1H-NMR (DMSO-d6) 2,11 (s, 3H), 2,24 (s, 3H), 4,58 (s, 2H), 5,13 (s, 2H), 6,69 (s, 2H), 6,92 (d, J=8.0 Hz, 1H), 7,01 (d, J=8.0 Hz, 1H),? 7.04 baby mortality (m, 2H), 7,18 (m, 1H), 7,73 (m, 1H), 8,01 (m, 1H), 12.5cm (ush. s, 1H). LC/MS (88%) ESI-Calculated: 471,5 m/z; found: 471,4 m/z.

Example 127. Getting connection P083.

Synthesis of compound I-104. A mixture of compound I-47 (0.7 g, 2.54 mmol, 1 EQ.), 2-bromoethylamine (0,59 g, to 2.67 mmol, of 1.05 equiv.) and K2CO3(1,76 g 12,72 mmol, 5 EQ.) in DMF (10 ml) maintained at 50°C for 1 hour. The suspension is filtered, washed with water, saturated salt solution, dried over MgSO4receiving the product I-104, 0,89 g (84%) as a yellow solid. MS (ESI-): 416 (M+1).1H-NMR (500 MHz, CDCl 3) confirms the structure.

Synthesis of compound I-105. A solution of ester I-104 (600 mg, 1.44 mmol,l equiv.) LiOH H2O (70 mg, 1.6 mmol, 1.15 EQ.) in THF/MeOH/H2O (3:1:1, 22 ml) was stirred at 45°C for 5 hours. The reaction mixture was concentratedin the vacuumand to the residue add us. NH4Cl (10 ml). The precipitate is extracted with CH2Cl2. The resulting solution was washed with saturated NH4Cl, saturated salt solution, dried over MgSO4and concentrated in vacuo.The residue is triturated in ether (8 ml) to obtain the acids I-105 [362 mg (62%)] as a white solid. MS (ESI-): 400 (M-1).1H-NMR (500 MHz, CDCl3) confirms the structure.

The synthesis of compounds P083. To a mixture of acid, I-105 (71 mg, 0,177 mmol, 1 EQ.) in 2 ml of dichloromethane added DMAP (43 mg, 0,354 mmol, 2 equiv.) 2-thiophenesulfonyl (37 mg, 0,225 mmol) and EDCI (82 mg, 0,425 mmol). The mixture is stirred at room temperature for 16 hours and then quenched by the addition of NH4Cl (6 ml). The mixture is extracted with EtOAc (6 ml). The extract is washed with saturated salt solution and then dried over MgSO4. The solvent is removedin a vacuum.The residue is triturated in ether (2 ml) to give 86 mg (86%) sulfonamida P083 in the form of a solid not quite white matter. LC-MS (ESI-): 545 (M-1) (81%).1H-NMR (500 MHz, CDCl3) confirms the structure.

Example 128. Getting connection P097.

The sulfonamide P083 (mg, in 0.104 mmol) dissolved in a mixture of EtOH-THF (24 ml, 5:1) and the solution saturated with hydrogen. The balloon with hydrogen attached to the apparatus and the reaction mixture was stirred at room temperature for 20 hours, then at 60 C for 22 hours. The resulting solution was filtered through a filter from Whatman 0.45 µm. The solvent is removed in vacuum. Rubbing of the residue in ether (2×2 ml) results 44 mg (67%) sulfonamida P097 in the form of a solid not quite white matter. LC-MS (ESI-): 547 (M-1) (95%).1H-NMR (500 MHz, CDCl3) confirms the structure.

Example 129. Getting connection P096.

Synthesis of (E)-3-(1-naphthalene-2-ylmethyl-2,3-dioxo-2,3-dihydro-1H-indol-7-yl)acrylic acid, I-106. A solution of compound I-105 (48 mg, 0.12 mmol) in a mixture of concentrated HCl andiD (1:1, 4 ml) was kept at 100°C for 30 minutes. The reaction mixture is cooled to room temperature, filtered and washed with water, getting isatin-derived I-106, 28 mg (66%) as a bright orange solid, which is insoluble in ether, EtOAc, or CH2Cl2. MS(ESI-) 356 (M-1).

The synthesis of compounds P096. To a mixture of compound I-106 (21 mg, 0,059 mmol, 1 EQ.) in 0.5 ml of dichloromethane added DMAP (19 mg, of) 0.157 mmol, 2.6 equiv.) 2-thiophenesulfonyl (13 mg, 0,078 mmol, 1.3 EQ.) and EDCI (30 mg, of) 0.157 mmol, 2.6 EQ.). The mixture is stirred at room temperature for 16 hours, then quenched with 10% HCl and extracted mixture is Yu EtOAc-CH 2Cl2. The extract is washed with water, saturated salt solution and then dried over MgSO4. The solvent is removed in vacuum.Aboutthe STATCOM is dissolved in CH2Cl2(2 ml) and filtered. Chromatography on SiO2(5 g) using EtOAc/hexane (1:1) leads to obtain 10 mg (33%) sulfonamida P096 in the form of a solid, not quite white matter. LC-MS (ESI-): 501 (M-1) (98%).1H-NMR (500 MHz, CDCl3) confirms the structure.

Example 130. Getting connection P126.

A solution of isatin-derived P113 (64 mg, to 0.108 mmol, 1 EQ.), 2 mercaptoethylamine (8,3 mg, to 0.108 mmol, 1 EQ.) in AcOH (1 ml) is heated to 100°C and kept at this temperature for 20 minutes. Add another part 2-mercaptoethylamine (4.3 mg, 0,056 mmol, 0.5 EQ.) and the heating continued for 10 minutes. The reaction mixture is evaporated, the resulting oil is triturated in a mixture of THF-ether (1:3), the solution is filtered, receiving thiazolidin-derived P126 (28,3 mg, 40%) as a red solid.1H NMR (DMSO-d6) of 3.5-3.7 (m, 3H), 3,99 (DD, J=11, 8.0 Hz, 1H), is 4.93 (d, J=18,0 Hz, 1H), free 5.01 (d, J=18,0 Hz, 1H), 6,03 (d, J=15.2 Hz, 1H), 6,85 (d, J=8,4 Hz, 2H), 7,11 (t, J=4.0 Hz, 1H), 7,19 (d, J=15,0 Hz, 2H), 7,30-7,34 (m, 2H), was 7.36 (s, 1H), was 7.36 (d, J=2.0 Hz, 1H), 7,51 (DD, J=7,2, 1.2 Hz, 1H). LC-MS (99%): ESI-Calculated: 547 m/z; found: 547.

Example 131. Getting connection P037

Synthesis of 2-benzyloxy-6-nitrophenylamino, I-107: a Mixture of 2-amino-3-NITROPHENOL (1.54 g, 0.01 mol), benzilla the IDA (1,71 g, 0.01 mol) and K2CO3(1.54 g, to 0.011 mol) in DMF (5.0 ml) was stirred at room temperature. After 20 hours the reaction mixture was diluted with water (100 ml) and extracted with EtOAc (100 ml×3). The combined organic layers are washed with 2n. NaOH (20 ml×3), water (100 ml), saturated salt solution (100 ml), dried over anhydrous sodium sulfate and concentrated, obtaining 2-benzyloxy-6-nitrovanillin, I-107 (2,01 g).

Synthesis of N-(2-benzyloxy-6-nitrophenyl)acetamide", she I-108. To a solution of 2-benzyloxy-6-nitrophenylamino (I-107, 1.52 g, 0,0062 mol) in acetic anhydride (1.27 g, of 0.0125 mol) add 4 drops of concentrated H2SO4at room temperature and stirred for one minute, then the reaction flask is transferred to an oil bath at 90°C. After 2 minutes, the solidified reaction mixture is transferred into water (20 ml) and the solids filtered off. The solid residue optionally washed with water (20 ml×2) and dried in vacuum, obtaining N-(2-benzyloxy-6-nitrophenyl)acetamide", she I-108 (1,59 g).

Synthesis of N-(2-benzyloxy-6-nitrophenyl)-N-naphthalene-2-immutilated, I-109. To a solution of N-(2-benzyloxy-6-nitrophenyl)ndimethylacetamide (0,576 g, 2.0 mmol) in DMF (2.0 ml) in small portions over 10 minutes at room temperature add NaH as a 60% dispersion in mineral oil (160 mg, 4.0 mmol). The reaction mixture was added 2-(methyl bromide)naphthalene (442 mg, 2.0 mmol) and the mixture peremeshivayte room temperature for 1.5 hours. DMF is removed under vacuum, the residue is transferred in CH2Cl2(60 ml) and washed with water (20 ml), saturated salt solution (20 ml), dried over anhydrous sodium sulfate and concentrated. The obtained dark brown oily syrup is transferred into 40 ml of a mixture of ether/hexane (1:1) and stirred for 1 hour, the precipitate is filtered off and dried, obtaining N-(2-benzyloxy-6-nitrophenyl)-N-naphthalene-2-ylmethylene, I-109 (478 mg).

Synthesis of 7-benzyloxy-2-methyl-1-naphthalene-2-ylmethyl-1H-benzoimidazole, I-110. Fe (470 mg) in portions with stirring to a suspension of N-(2-benzyloxy-6-nitrophenyl)-N-naphthalene-2-immutilated (517 mg) in MeOH (15 ml) and concentrated HCl (1.5 ml). The reaction mixture is refluxed for 17 hours and then filtered to remove solids. The filtrate is concentrated and the resulting residue is transferred into water (5 ml), adjusted pH to 14 by addition of 6N. NaOH and then extracted with methylene chloride (10 ml×3). Combined fractions washed with water (10 ml), saturated salt solution (10 ml), dried over anhydrous sodium sulfate and concentrated. The obtained residue is purified on silica gel, elwira a mixture of chloroform/methanol (97:3.about.) obtaining 7-benzyloxy-2-methyl-1-naphthalene-2-ylmethyl-1H-benzimidazole, I-110 (212 mg).

Synthesis of 2-methyl-3-naphthalene-2-ylmethyl-1H-benzimidazole-4-ol, I-111. 7-Benzyloxy-2-methyl-1-naftol is n-2-ylmethyl-1H-benzimidazole (211 mg) in methanol (12 ml) and acetic acid (1.0 ml) hydronaut in the presence of 10% Pd-C with hydrogen at a pressure of 45 pounds per square inch for 20 hours. The reaction mixture was filtered through a layer of celite. The filtrate is concentrated, obtaining 2-methyl-3-naphthalene-2-ylmethyl-1H-benzimidazole-4-ol, I-111 (211 mg).

Synthesis of 2-methyl-3-naphthalene-2-ylmethyl-1H-benzimidazole-4-yloxy)acetic acid, I-112. A mixture of 2-methyl-3-naphthalene-2-ylmethyl-1H-benzimidazole-4-ol (200 mg), methylpropanoate (162 mg), potassium carbonate (530 mg) and acetone (20 ml) is refluxed for 36 hours. The reaction mixture is filtered. The obtained filtrate is concentrated and the resulting residue is transferred in methanol (1.0 ml), THF (10 ml) and 2n. NaOH (1.0 ml) and stirred at room temperature for 48 hours. The reaction mixture was concentrated and the residue is transferred into the water (5.0 ml) and acidified with 1,0N. HCl to pH 1. The mixture is extracted with ethyl acetate (10 ml×4), the combined organic fractions are dried (saturated salt solution, sodium sulfate), concentrated and dried, obtaining 2-methyl-3-naphthalene-2-ylmethyl-1H-benzimidazol-4-yloxy)acetic acid, I-112 (77 mg).

Synthesis of [2-(2-methyl-3-naphthalene-2-ylmethyl-3H-benzimidazole-4-yloxy)acetyl]amide thiophene-2-sulfonic acid, P037. 2-Methyl-3-naphthalene-2-ylmethyl-1H-benzimidazole-4-yloxy)acetic acid (77 mg, 2.2 mmol), thiophene-2-sulfonamide (36 mg, 2.2 mmol), EDCI (47 mg, 0.25 mmol), DMAP (30 mg, 2.5 mmol) in methylene chloride (2.0 ml) was stirred at room temperature for 48 hours. The reaction mixture was concentrate is their and the residue purified on silica gel, using a mixture of chloroform:methanol (97:3) as eluent, to obtain [2-(2-methyl-3-naphthalene-2-ylmethyl-3H-benzimidazol-4-yloxy)acetyl]amide thiophene-2-sulfonic acid, P037 (5.2 mg).1H-NMR (500 MHz, CD3OD) 2,47 (s, 3H), 4,50 (s, 2H), 5,86 (s, 2H), 6,60 (d, J=8.0 Hz. 1H), 6,1 (DD, J=5.0 and 4.0 Hz, 1H), 7,06 (DD, J=8,5, 8.0 Hz, 1H), 7,26 (m, 2H), 7,32 (s, 1H), was 7.36 (DD, J=5,0,1,0 Hz, 1H), 7,45-7,40 (m, 3H), 7,51 (DD, J=3,5, 1.0 Hz, 1H), 7,68 (m, 1H), 7,72 (d, J=8.5 Hz, 1H), 7,70 (m, 1H). LC/MS=95,7% purity; MS (ESI-) Is calculated: (M+) 491,5; Found: 490,5 (M-l).

Example 132. Getting connection P149

Synthesis of 2-amino-3-nitrophenylthio ester 2,4-dichlorobenzoyl acid, I-113. In a round bottom flask 500 ml one-neck, equipped with a magnetic stirrer and a septum, add 2-amino-3-NITROPHENOL (4,25 g, 27.6 mmol), anhydrous CH2Cl2(140 ml), 4-(dimethylamino)pyridine (3,37 g, 27.6 mmol) and 2,4-dichlorobenzophenone (5,78 g, a 3.87 ml, 27.6 mmol). The reaction mixture was stirred at room temperature overnight. TLC analysis indicates complete consumption of the original substance. The reaction mixture was diluted with CH2Cl2(300 ml) and the mixture was washed with H2O (2×200 ml), dried (Na2SO4and concentrate, receiving 8,91 g (98,7%) of product as a yellow-orange solid.1H-NMR analysis shows that the substance, I-113, sufficiently pure for use in the next stage.1H-NMR (500 MHz, CDCl3).

Synthesis ,4-dichloro-N-(2-hydroxy-6-nitrophenyl)benzamide, I-114. Round bottom odnogolosy flask, 500 ml, containing I-113 (8,91 g of 27.2 mmol), provide a magnetic stir bar and make anhydrous THF (300 ml) and the reaction container is placed in an atmosphere of N2. Cautiously in small portions under stirring for 2 minutes add sodium hydride (1.08 g, with 44.9 mmol, 60% oil dispersion). After an additional 2 minutes to see the release of gaseous H2(pretty quickly), and a small heat release. The mixture is stirred at room temperature for 1 hour. TLC analysis at this time shows that the reaction is fully completed. The mixture is stirred at room temperature overnight. The mixture was carefully quenched by slow addition of water is first added dropwise (50 ml), and then in small portions. The mixture is then poured into EtOAc (1 l) and water (200 ml). The aqueous layer was acidified with 1N. HCl to pH~1 and extracted. The layers are separated and the aqueous layer was extracted with EtOAc (100 ml). The combined organic extracts dried (Na2SO4), filtered and concentrated, receiving compound I-114 (9,36 g) as a yellowish brown solid.1H-NMR (500 MHz, CDC13).

Synthesis of N-(2-amino-6-hydroxyphenyl)-2,4-dichlorobenzamide I-115. In a reactor for the hydrogenation of 250 ml is added to an aqueous suspension of Raney Nickel (700 mg) and carefully diluted with EtOH (60 ml). Compound I-114 (700 mg, 2.14 mmol) is added to VI is e solids. The side walls of the reactor rinse EtOH (10 ml) and the mixture hydronaut on the shaker Pair of gaseous hydrogen at a pressure of 50 psi at room temperature overnight. The reaction mixture was filtered through a layer of celite and a layer of celite washed with EtOH (400 ml). The filtrate is concentrated and receiving with a quantitative yield of a dark-brown solid, I-115.1H-NMR (400 MHz, DMSO-d6).

Synthesis of 3-amino-2-(2,4-dichloraniline)phenol, I-116. In a round bottom flask with a volume of 250 ml one neck, equipped with a magnetic stirrer, reflux condenser and placed in an atmosphere of N2add compound I-115 (635 mg, 2.14 mmol). Add anhydrous THF (31 ml), then added dropwise 1M BH3in THF (8.6 ml, 8.6 mmol). The reaction mixture was refluxed over night. The cooled reaction mixture is carefully quenched with dropwise adding methanol (50 ml). The resulting mixture was concentrated on a rotary evaporator. The residue is again dissolved in methanol (50 ml) and again concentrated. Such dissolution of the residue in methanol and concentration is repeated two more times, getting quantitative yield brown oil, I-116.1H-NMR (500 MHz, DMSO-d6).

Synthesis of 3-(2,4-dichlorobenzyl)-3H-benzimidazole-4-ol, I-117. In a reactor with a volume of 20 ml, equipped with a magnetic stirrer, add compound I-116 (980 mg, 3.46 mmol) and AB is auty EtOH (8 ml). To the resulting suspension with stirring, add triethylorthoformate (0,634 ml, 3,81 mmol) and monohydrate p-toluensulfonate acid (33 mg, 0,173 mmol). The reactor is closed and kept in an oil bath at 75°C for 1 hour. At this time the cover is removed from the reactor, the temperature of the oil bath is increased to 95-100°C., and the solvent is distilled off. The last traces of solvent are removed under high vacuum. The residue is twice triturated with a mixture of 1:1 hexane/acetone (6 ml each time) and the resulting dark brown solid is filtered off and dried, obtaining the compound I-117, 570 mg (56%).1H-NMR (500 MHz, DMSO-d6).

Synthesis of methyl ester [3-(2,4-dichlorobenzyl)-3H-benzimidazole-4-yloxy]acetic acid, I-118. In the capacity of a volume of 5 ml, equipped with a magnetic stirrer and containing the compound I-117 (60 mg, 0,204 mmol), add anhydrous DMF (0.8 ml), anhydrous potassium carbonate (34 mg, 0,246 mmol) and methylbromide (24 μl, 0,246 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, obtaining a residue which is dissolved in a mixture of 1:1 hexane/acetone (1 ml) and purified column chromatography on flash silica gel (6 g), using as eluent first mixture of 4:1 hexane/acetone, then 7:3 hexane/acetone and receiving compound I-118 (40 mg, 54%) as a semi-solid substance.1H-NMR (500 MHz, CDCl 3).

Synthesis of [3-(2,4-dichlorobenzyl)-3H-benzimidazol-4-yloxy]acetic acid, I-119. In a round bottom flask of 50 ml volume with one throat containing compound I-118 (32 mg, 0,088 mmol), add absolute ethanol (0.5 ml), water (0.5 ml) and 15% aqueous sodium hydroxide (0,025 ml, 0,093 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated, obtaining a solid product. The solid product is dissolved in water (3 ml) and the solution is acidified by adding 1N. HCl (0.25 ml). the pH of the solution is checked litmus test that shows a pH of 2-3. The formed precipitate is filtered off and dried. The aqueous filtrate is extracted with EtOAc (3×1 ml) and the organic extracts concentrated, obtaining a solid product. The solid product combined with previously allocated sediment, receiving 28 mg (91%), I-119, in the form of a solid not quite white matter.1H-NMR (500 MHz, DMSO-d6, LC/MS=96%, ESI/- 349,2.

The synthesis of compounds P149. In a reactor with a volume of 3 ml, equipped with a magnetic stirrer and containing the compound I-119 (21 mg, to 0.060 mmol), add anhydrous CH2Cl2(2 ml) and then DMAP (14,7 mg, 0,120 mmol), the result is a homogeneous solution. To the solution was added 4,5-dichlorothiophene-2-sulfonamide (15,5 mg, 0.66 mmol) and then EDCI (23 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 4 hours and then diluted with CH2Cl2 and water (5 ml each solvent). The aqueous layer was acidified by adding 1N. HCl to achieve pH 2-3 (litmus paper). The layers separated, and the aqueous layer was extracted with CH2Cl2(5 ml). The combined organic layers are concentrated and dried in vacuum. The obtained solid product is triturated with hot CH2Cl2(3 ml) and the cooled solution is filtered and dried, obtaining 26 mg (71%) P149 in the form of a solid, not quite white matter.1H-NMR (500 MHz, DMSO-d6) 4,59 (s, 2H), 5,91 (s, 2H), 6,85 (d, J=8.0 Hz, 1H),? 7.04 baby mortality (d, J=8.5 Hz, 1H), 7,30 (t, J=8.0 Hz, 1H), 7,33 (DD, J=8,5, 2.0 Hz, 1H), was 7.36 (d, J=8.0 Hz, 1H), 7,54 (s, 1H), 7,65 (d, J=2.0 Hz, 1H), 8,98 (s, 1H). LC/MS=of 97.8% purity; MS (ESI+) Calculated: (M+H) 564,4; found: 564,4.

Example 133. Getting connection P152

Synthesis of 2-amino-3-nitrophenylamino ether naphthalene-2-carboxylic acid, I-120. Compound I-119 synthesized from 2-amino-3-NITROPHENOL (99%) by the procedure analogous to the synthesis of compound I-113.1H-NMR (500 MHz, CDCl3).

Synthesis of (2-hydroxy-6-nitrophenyl)amide naphthalene-2-carboxylic acid, I-121. Compound I-121 synthesized from compound I-120 (quantitative yield) analogously to the synthesis of compound I-114 from compound I-113.1H-NMR (500 MHz, CDCl3).

Synthesis of (2-amino-6-hydroxyphenyl)amide naphthalene-2-carboxylic acid, I-122. In a round bottom flask of 50 ml volume with one throat, equipped with a magnetic stirrer, reflux condenser and a device for I/you is Yes N 2add compound I-121 (to 100.7 mg, 0,327 mmol) and absolute ethanol (5 ml). The reaction mixture was placed in an oil bath at 70°C in an atmosphere of N2.Add the tin chloride (II) dihydrate (738 mg, of 3.27 mmol) and then added dropwise 6N. HCl (2,18 ml of 13.1 mmol). After conditioning at 70°C for 1 hour, the reaction mixture was cooled to room temperature, diluted with water and EtOAc (50 ml each) and alkalinized (pH~8) by careful addition of saturated aqueous NaHCO3. The solution is filtered to remove the precipitate of salts of tin and the organic layer is separated, dried (Na2SO4), filtered and concentrated, receiving compound I-122, 81 mg (89%).1H-NMR (500 MHz, DMSO-d6), MS; AP - 277,0.

Synthesis of 3-amino-2-[(naphthalene-2-ylmethyl)amino]phenol, I-123. Compound I-122 synthesized from compound I-121 (quantitative yield) using the procedure similar to the synthesis of compound I-116 from compound I-115.1H-NMR (500 MHz, DMSO-d6).

Synthesis of 3-naphthalene-2-ylmethyl-3H-benzimidazole-4-ol, I-124. Compound I-124 synthesized from compound I-123 (35%) by the procedure analogous to the synthesis of compound I-117 from compound I-116.1H-NMR (500 MHz, DMSO-d6).

Synthesis of methyl ester (3-naphthalene-2-ylmethyl-3H-benzimidazol-4-yloxy)acetic acid, I-125. Compound I-125 synthesized from compound I-124 (55%) by the procedure analogous to the synthesis of compound I-118 connect the s I-117. 1H-NMR (500 MHz, DMSO-d6).

Synthesis of (3-naphthalene-2-ylmethyl-3H-benzimidazol-4-yloxy)acetic acid, I-126. Compound I-126 synthesized from compound I-125 (55%) by the procedure analogous to the synthesis of compound I-119 from compound I-118. LC/MS=95,7%, ESI/-331,1,1H-NMR (500 MHz, DMSO-d6).

The synthesis of compounds P152. Connection P152 synthesized from compound I-126 (52%) by the procedure analogous to the synthesis of compounds P149 from compound I-119.1H-NMR (500 MHz, DMSO-d6) with 4.65 (s, 2H), 6,00 (s, 2H), 6,86 (m, 1H), 7,31 (m, 2H), 7,54-7,44 (m, 3H), 7,60 (DD, J=9,0, 2.0 Hz, 1H), 7,79 (DD, J=9,0, 2.0 Hz, 1H), 7,88-of 7.82 (m, 2H), of 8.09 (s, 1H), 9,36 (ush. s, 1H). LC/MS=96% purity; MS (ESI+) Calculated: (M+H) 546,5; Found: 546,7.

Example 134. Getting connection P253

General methods of synthesis of hexahydro-2-oxindol-derivatives:

Synthesis of 2-methyl-2-allylcyclohexane, I-127: To a solution of sodium hydride (1 EQ.; 60% dispersion in mineral oil) in dimethoxyacetophenone at 5°C in nitrogen atmosphere are added dropwise 2-methylcyclohexanone. Solution allow to warm to room temperature, then heated to 80°C and kept at this temperature for 1.5 hours. Then the solution is cooled to room temperature and then to 5°C. To the mixture are added dropwise allylbromide (1 EQ.), the reaction mixture is heated to 80°C and maintained at this temperature for 1.5 hours. The reaction mixture is cooled to room temperature the s and to the mixture are added dropwise water (~14 EQ.). The aqueous layer was twice extracted with ethyl ether and dried over sodium sulfate. After concentration the crude product is purified by chromatography on silica gel using 2.5 percent ethyl ether in hexano as eluent to obtain compound I-127 35% yield.1H-NMR (CDCl3) confirms the structure.

Synthesis of (1-methyl-2-oxocyclohexyl)acetic acid, I-128: In a two-phase solution of 1-methyl-1-allylcyclohexane, I-127, H2O/AcN/CCl4in nitrogen atmosphere add NaIO4(20 equiv.) then RuCl3-H2O. the Reaction mixture was stirred at room temperature overnight. To the mixture are added dropwise 2-propanol (~88 equiv.) what causes blackening of the reaction mixture. The mixture is diluted with water and ethyl ether, filtered through a layer of celite and washed with ethyl ether. The aqueous layer was extracted with dichloromethane and EtOAc. The combined organic fractions are dried over sodium sulfate and concentrated in vacuo, receiving compound I-128 with a quantitative yield.1H-NMR (CDCl3) confirms the structure.

General procedure (A-4) obtaining hexahedronal-2-ones, I-129x. A solution of (1-methyl-2-oxocyclohexyl)acetic acid, I-128 (1 EQ.) and right arylamine (1 EQ.) in m-xylene is refluxed at 145°C for 3 hours. The reaction mixture was concentrated in vacuo and the residue either use isout crude in the next stage, or purify by chromatography on silica gel using hexane in dichloromethane (10-20%) as eluent to obtain the desired product I-129x. The structure of the obtained product analyze1H-NMR.

General procedure (A-5) synthesized hexahedronal-2-ones, I-129x to obtain vinylboronic I-130x: To a solution of a suitable hexahedronal-2-it, I-129, in dichloromethane at 0°C is added dropwise bromine (1 EQ.). The reaction mixture is stirred until the disappearance of the color of bromine and then for an additional 5 minutes. One portion to the mixture add triethylamine (3 EQ.) and the mixture is stirred at room temperature for 10 minutes. The reaction mixture was washed with water (3×) and dried over magnesium sulfate. The dichloromethane solution was concentrated in vacuo.The remainder either used crude in the next stage, or purify by chromatography on silica gel using dichloromethane as eluent to obtain the appropriate vinylmania, I-130x. The structure of the product is confirmed1H-NMR.

General procedure (A-6) the reaction of a combination of Hake l-130x to obtain complex acrylate ester I-131x: In a round bottom flask, equipped with a reflux condenser and a device for I/o nitrogen, was placed a solution of a suitable 7-bromohexadecane-2-she and triethylamine (10 EQ.) in DMF. To the solution is added in the order listed: methyl acrylate (1 equiv.) the palladium (II) acetate (0.1 EQ.) and three-o-tolylphosphino (0.3 EQ.). The reaction mixture is heated to 100°C, kept at this temperature for 16 hours and then enable the mixture to cool to room temperature. The reaction mixture was filtered through celite and washed with dichloromethane, then diluted with dichloromethane and water and the layers separated. The combined organic phases are washed with water (2×) and saturated salt solution and dried over magnesium sulfate. The organic phase concentratedin a vacuum.The remainder either used raw or purified by chromatography on silica gel using 15% hexane in dichloromethane as eluent to obtain acrylate ester I-131x. The structure of the product is confirmed1H-NMR.

General procedure (A-7) hydrolysis of the methyl esters to obtain acrylic acid, I-132x: To a solution of the appropriate methyl ester, I-131x, in THF/MeOH (2:1) is added aqueous NaOH (3 EQ.) and the reaction mixture was stirred for 24-72 hours at room temperature. The mixture was washed with 2 portions of diethyl ether, diluted with EtOAc and the pH adjusted to 2-3 by addition of 1N. HCl. The organic fraction was washed with saturated salt solution, dried over magnesium sulfate and concentrate to obtain the acid I-132x. The structure of the product is confirmed1H-NMR.

General procedure (A-8) the reaction of a combination of l-132x to obtain arylsulfonyl the Dov: To a solution of a suitable acid, I-132x, add the appropriate sulfonamide (1.2 EQ.) and DMAP (2.4 EQ.) in CH2Cl2and then added EDCI (2 EQ.). The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 1N. HCl (aq.), water and saturated salt solution, dried over magnesium sulfate and concentratein a vacuum.The residue is purified either by chromatography on silica gel using methanol (0-3%) in dichloromethane as eluent or by rubbing with a mixture of dichloromethane/hexane obtaining target arylsulfonamides product. The structure of the product is confirmed1H-NMR, the purity was determined by ESI LC/MS.

The synthesis of compounds P253. Synthesis of 3a-methyl-1-naphthalene-2-ylmethyl-l,3,3a,4,5,6-hexahydrobenzo-2-it, I-129A: IN accordance with the General method A-4, (1-methyl-2-oxocyclohexyl)acetic acid, I-128 is converted into compound I-129A. The structure is confirmed1H-NMR.

Synthesis of 7-bromo-3a-methyl-1-naphthalene-2-ylmethyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-130A IN accordance with the General procedure A-5, 3a-methyl-1-naphthalene-2-ylmethyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-129A, is converted into compound I-130A. The structure is confirmed1H-NMR.

Synthesis of methyl ester (E)-3-(3a-methyl-1-naphthalene-2-ylmethyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl)acrylic acid, I-131A: IN accordance with the General procedure A-6, 7-bromo-3a-methyl-1-naphthalene-2-ylmethyl-l,3,3a,4,5,6-GE is sheronda-2-it, I-130A, is converted into compound I-131A. The structure of the product is confirmed1H-NMR.

Synthesis of (E)-3-(3a-methyl-1-naphthalene-2-ylmethyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl)acrylic acid, I-132A: IN accordance with the General method A-7 methyl ether (E)-3-(3a-methyl-1-naphthalene-2-ylmethyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl)acrylic acid I-131A, is converted into compound I-132A. The structure is confirmed1H-NMR.; GHMC (M-1=362,6).

The synthesis of compounds P253.

In accordance with the General procedure A-8, (E)-3-(3a-methyl-1-naphthalene-2-ylmethyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl)acrylic acid, I-132A transform in connection P253. The structure is confirmed1H-NMR.; LC-MS (M-l=575,2).

Example 135. Getting connection P269.

In a round bottom flask containing I-132A, dissolved in pyridine (1 EQ.) and dichloromethane, under nitrogen atmosphere add lanehead (8 EQ.). The resulting mixture was refluxed for 2 hours. The reaction mixture was washed with chilled (0°C) water and dried over sodium sulfate. The solution is filtered and concentrated in vacuo.The residue is dissolved in dichloromethane, the resulting solution was added 4-dimethylaminopyridine (1.4 EQ.) and 4-triftormetilfullerenov (1.7 equiv.) and the resulting solution was stirred at room temperature overnight. The reaction mixture was washed with 1N. HCl, water and saturated RA is tworoom salt and dried over magnesium sulfate. The solution is filtered and concentrated and the residue purified by chromatography on silica gel using a mixture of methanol/dichloromethane as eluent, to obtain the residue, which is dissolved in acetic acid, precipitated with water and filtered to obtain compound P269. The structure is confirmed1H-NMR; LC-MS (M-1=583,5)

Example 136. Getting connection P262.

Synthesis of 1-(3-terbisil)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-129B: IN accordance with the General method A-4, (1-methyl-2-oxocyclohexyl)acetic acid, I-128, is converted into compound I-129B. The structure of the product is confirmed1H-NMR.

Synthesis of 7-bromo-1-(3-terbisil)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-130B: IN accordance with the General procedure A-5, 1-(3-terbisil)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-129B, is converted into compound I-130B. The structure is confirmed1H-NMR.

Synthesis of methyl ester (E)-3-[1-(3-terbisil)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-131B: IN accordance with the General procedure A-6, 7-bromo-1-(3-terbisil)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-130B, is converted into compound I-131B. The structure is confirmed1H-NMR.

Synthesis of (E)-3-[1-(3-terbisil)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132B: IN accordance with the General method A-7 methyl ether (E)-3-[1-(3-terbisil)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]but iloveu acid, I-131B, is converted into compound I-132B. The structure is confirmed1H-NMR; GHMC (M-1=330,6).

The synthesis of compounds P262. In accordance with the General procedure A-8, (E)-3-[1-(3-terbisil)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132B transform in connection P262. The structure is confirmed1H-NMR; LC-MS (M-1=TO 541.5).

Example 137. Getting connection P263.

Synthesis of 1-(4-terbisil)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-129C: IN accordance with the General method A-4, (1-methyl-2-oxocyclohexyl)acetic acid, I-128, is converted into compound I-129C. The structure is confirmed1H-NMR.

Synthesis of 7-bromo-1-(4-terbisil)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-130C: In accordance with the General procedure A-5, 1-(4-terbisil)-3a-methyl-l,3,3a,4,5,6-hexahydrobenzo-2-it, I-129C, is converted into compound I-130C. The structure is confirmed1H-NMR.

Synthesis of methyl ester (E)-3-[1-(4-terbisil)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-131C: IN accordance with the General procedure A-6, 7-bromo-1-(4-terbisil)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-130C, is converted into compound I-131C. The structure is confirmed1H-NMR.

Synthesis of (E)-3-[1-(4-terbisil)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132C: IN accordance with the General method A-7 methyl ether (E)-3-[1-(4-terbisil)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indole-yl]acrylic acid, I-131C, is converted into compound I-132C. The structure is confirmed1H-NMR; GHMC (M-l=330,5).

The synthesis of compounds P263. In accordance with the General procedure A-8, (E)-3-[1-(4-terbisil)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132C transform in connection P263. The structure is confirmed1H-NMR; LC-MS (M-1=543,3).

Example 138. Getting connection P294.

In accordance with the General procedure A-8, (E)-3-[1-(4-terbisil)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132C transform in connection P294. The structure is confirmed1H-NMR; LC-MS (M-1=503,7).

Example 139. Getting connection P295

In accordance with the General procedure A-8, (E)-3-[1-(4-terbisil)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132C transform in connection P295.1H-NMR (CDC13) of 1.18 (s, 3H), of 1.84 (m, 3H), 2,18 (m, 3H), 2,44 (m, 2H), 4,74 (d, J=16.4 Hz, 1H), 5,26 (d, J=16.0 Hz, 1H), 5,52 (d, J=14,8 Hz, 1H), 6,97 (t, J=8,8 Hz, 2H), 7,11 (m, 1H), 7,18 (DD, J=8,8, 5.6 Hz, 2H), 7.62mm (m, 2H), to 7.77 (d, J=15.2 Hz, 1H). LC/MS (98%) ESI-Calculated: 504,5 m/z; found: 503,7 m/z.

Example 140. The connection is P300.

In accordance with the General procedure A-8, (E)-3-[1-(4-terbisil)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132C transform in connection P300. The structure is confirmed1H-NMR; LC-MS(M-1=521,8).

Example 141. Getting connection P264.

Synthesis of 1-(3,4-diferensial)-3a-methyl-l3,3a,4,5,6-hexahydrobenzo-2-it, I-129D: IN accordance with the General method A-4, (1-methyl-2-oxocyclohexyl)acetic acid, I-128, is converted into compound I-129D. The structure is confirmed1H-NMR.

Synthesis of 7-bromo-1-(3,4-diferensial)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-130D: IN accordance with the General procedure A-5, 1-(3,4-diferensial)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-129D, is converted into compound I-130D. The structure is confirmed1H-NMR.

Synthesis of methyl ester (E)-3-[1-(3,4-diferensial)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-131D: IN accordance with the General procedure A-6, 7-bromo-1-(3,4-diferensial)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-130D, is converted into compound I-131D. The structure is confirmed1H-NMR.

Synthesis of (E)-3-[1-(3,4-diferensial)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132D: IN accordance with the General method A-7 methyl ether (E)-3-[1-(3,4-diferensial)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid I-131D, is converted into compound I-132D. The structure is confirmed1H-NMR; LC-MS (M-1=348,5).

The synthesis of compounds P264. In accordance with the General procedure A-8, (E)-3-[1-(3,4-diferensial)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132D transform in connection P264. The structure is confirmed1H-NMR; LC-MS(M-l=561,3).

Example 142. Getting connection P266.

According the General procedure A-8, (E)-3-[1-(3,4-diferensial)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132D transform in connection P266. The structure is confirmed1H-NMR; LC-MS(M+1=557,0).

Example 143. Getting connection P267.

In accordance with the General procedure A-8, (E)-3-[1-(3,4-diferensial)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132D transform in connection P267. The structure is confirmed1H-NMR; LC-MS(M+1=541,9).

Example 144. Getting connection P304.

In accordance with the General procedure A-8, (E)-3-[1-(3,4-diferensial)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132D transform in connection P304. 1H-NMR (CDCl3) to 1.19 (s, 3H), 1.57 in (m, 1H), 1,87 (m, 3H), 2,19 (d, J=6,8 Hz, 2H), 2.,4 (d, J=1.2 Hz, 2H), and 4.75 (d, J=16.4 Hz, 1H), 5,17 (d, J=16.0 Hz, 1H), of 5.53 (d, J=14,8 Hz, 1H),? 7.04 baby mortality (m, 3H), 7,35 (DDD, J=16,8, of 9.2 and 7.6 Hz, 1H), 7,72 (d, J=14,8 Hz, 1H), 7,88 (m, 2H), to 7.93 (DDD, J=9,2, 7,2, the 2.4 Hz, 1H). LC/MS (95%) ESI-Calculated: 522,5 m/z; found: 521,6 m/z.

Example 145. Getting connection P305.

In accordance with the General procedure A-8, (E)-3-[1-(3,4-diferensial)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132D transform in connection P305. The structure is confirmed1H-NMR.

Example 146. Getting connection P274.

Synthesis of 1-(2,4-dichlorobenzyl)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-129E: IN accordance with the General method A-4, (1-methyl-2-oxocyclohexyl)acetic acid, I-128, is converted into asociat in connection I-129E. The structure is confirmed1H-NMR.

Synthesis of 7-bromo-1-(2,4-dichlorobenzyl)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-130E: IN accordance with the General procedure A-5, 1-(2,4-dichlorobenzyl)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-129E, is converted into compound I-130E. The structure is confirmed1H-NMR.

Synthesis of methyl ester (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-131E: IN accordance with the General procedure A-6, 7-bromo-1-(2,4-dichlorobenzyl)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-130E is converted into compound I-131E. The structure is confirmed1H-NMR.

Synthesis of (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132E: IN accordance with the General method A-7 methyl ether (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid I-131E, is converted into compound I-132E. The structure is confirmed1H-NMR; LC-MS(M-1=380,3).

The synthesis of compounds P274. In accordance with the General procedure A-8, (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132E transform in connection P274. The structure is confirmed1H-NMR; LC-MS (M-1=536,4).

Example 147. Getting connection P275.

In accordance with the General procedure A-8, (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132E, conversion is granted in connection P275. The structure is confirmed1H-NMR; LC-MS (M-1=573,3).

Example 148. Getting connection P276.

In accordance with the General procedure A-8, (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132E transform in connection P276.1H-NMR (DMSO-d6) of 1.20 (s, 3H), of 1.61 (m, 1H), 1,80 (m, 3H), 2,11 (m, 1H), 2,19 (m, 1H), 2,34 (d, J=16.0 Hz, 1H), 2,65 (d, J=16.4 Hz, 1H), and 4.75 (d, J=17.6 Hz, 1H), 4,91 (d, J=17.6 Hz, 1H), 5,73 (d, J=14,8 Hz, 1H), 7,01 (d, J=8 Hz, 1H), 7,19 (d, J=14,8 Hz, 1H), 7,19 (DD, J=4,8, 3.6 Hz, 1H), 7,30 (DD, J=8,0, 2.4 Hz, 1H), to 7.67 (d, J=2.4 Hz, 1H), of 7.70 (DD, J=4,0, 2.4 Hz, 1H), 8,03 (DD, J=4,8, 1.2 Hz, 1H), 12,0 (s, 1H). LC/MS (93%) ESI-Calculated: 525,5 m/z; found: 525,5 m/z.

Example 149. Getting connection P278.

In accordance with the General procedure A-8, (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132E transform in connection P278.

Example 150. Getting connection P279.

In accordance with the General procedure A-8, (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132E transform in connection P279.1H-NMR (CDCl3) of 1.26 (s, 3H), of 1.59 (m, 1H), is 1.81 (m, 2H), 1,89 (DD, J=10,4, 2.4 Hz, 1H), 2,18 (m, 1H), to 2.29 (m, 1H), 2,45 (s, 2H), 4,99 (d, J=4 Hz, 2H), 5,67 (d, J=14,8 Hz, 1H), 6,94 (DD, J 4,0, 0,4 Hz, 1H), 6,97 (d, J=and 8.4 Hz, 1H), 7,16 (DD, J=8,4, 2.4 Hz, 1H), 7,34 (d, J=14,8, 1H), 7,46 (d, J=2.0 Hz, 1H), 7.62mm (d, J=4.0 Hz, 1H). LC/MS (96%) ESI-Calculated: 559,9 m/z; found: 559,3 m/z.

Example 151. Getting connection P280.

In accordance with the General methods which nd A-8, (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132E transform in connection P280. The structure is confirmed1H-NMR; LC-MS(M-1=587,1).

Example 152. Getting connection P281.

In accordance with the General procedure A-8, (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132E transform in connection P281. The structure is confirmed1H-NMR; LC-MS (M-1=553,3).

Example 153. Getting connection P282.

In accordance with the General procedure A-8, (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132E transform in connection P282.

1H-NMR (400 MHz, CDCl3) of 1.26 (s, 3H), of 1.61 (m, 2H), 1,89 (m, 2H), 2,18 (m, 2H), 2,46 (s, 2H), 4.95 points (m, 2H), to 5.58 (d, J=15.2 Hz, 1H), 6,92 (m, 1H), 7,06 (m, 1H), 7,10 (m, 1H), 7,16 (m, 1H), 7,28 (m, 1H), 7,58 (m, 2H). LC/MS=99% purity; MS (ESI-) Is calculated: (M/Z 555; Found: 555.

Example 154. Getting connection P283.

In accordance with the General procedure A-8, (E)-3-[1-(2,4-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132E transform in connection P283. The structure is confirmed1H-NMR; LC-MS (M-1=555,3).

Example 155. Getting connection P285.

Synthesis of 1-(3-Chlorobenzyl)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-129F: In accordance with the General method A-4, (1-methyl-2-oxocyclohexyl)acetic acid, I-128, is converted into compound I-129F. is the structure confirmed 1H-NMR.

Synthesis of 7-bromo-1-(3-Chlorobenzyl)-3A-methyl-1,3,3A,4,5,6-hexahydrobenzo-2-it, I-130F; IN accordance with the General procedure a-5, 1-(3-Chlorobenzyl)-3A-methyl-1,3,3A,4,5,6-hexahydrobenzo-2-it, I-129F, is converted into compound I-130F. The structure is confirmed1H-NMR.

Synthesis of methyl ester (E)-[1-(3-Chlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-131F: IN accordance with the General procedure A-6, 7-bromo-1-(3-Chlorobenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydrobenzo-2-it, I-130F, is converted into compound I-13IF. The structure is confirmed1H-NMR.

Synthesis of (E)-3-[1-(3-Chlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132F: IN accordance with the General method A-7 methyl ether (E)-3-[l-(3-Chlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid I-131F is converted into compound I-132F. The structure is confirmed with 1H-NMR; LC-MS.

The synthesis of compounds of P285. In accordance with the General procedure A-8, (E)-3-[1-(3-Chlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132F transform in connection P285. 1H-NMR (DMSO-d6) 1,24 (s, 1H), 1,7 (s, 5H), and 2.14 (s, 2H), 2,32 (s, 1H), 2,56 (s, 1H), 4,73 (d, J=16,4, 1H), 5,12 (d, J=41,6, 1H), 5,65 (d, J=14,8, 1H), 7,16 (m, 1H), 7,29 (m, 3H). EUR 7.57 (d, J=15,5, 1H), 7,65 (s, 1H). LC/MS (96%) ESI-Calculated: 559,91; Found: 559,3 m/z.

Example 156. Getting connection P296.

Synthesis of 1-(2,3-dichlorobenzyl)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-129G: IN compliance and with the General method A-4, (1-methyl-2-oxocyclohexyl)acetic acid, I-128, is converted into compound I-129G. The structure is confirmed with 1H-NMR.

Synthesis of 7-bromo-1-(2,3-dichlorobenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydrobenzo-2-it, I-130G: IN accordance with the General procedure A-5, l-(2,3-dichlorobenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydrobenzo-2-it, I-129G, is converted into compound I-130G. The structure is confirmed with 1H-NMR.

Synthesis of methyl ester (E)-3-[1-(2,3-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-131G: IN accordance with the General method A-6,7-bromo-1 -(2,3-dichlorobenzyl)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-130G is converted into compound I-131G. The structure is confirmed with 1H-NMR.

Synthesis of (E)-3-[1-(2,3-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132G: IN accordance with the General method A-7 methyl ether (E)-3-[l-(2,3-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid I 13IG is converted into compound I-132G. The structure is confirmed with 1H-NMR; LC-MS.

The synthesis of compounds P296: In accordance with the General procedure A-8, (E)-3-[1-(2,3-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132G transform in connection P296. The structure is confirmed with 1H-NMR.; LC-MS (M-1=573,3).

Example 157. Getting connection P297.

In accordance with the General procedure A-8, (E)-3-[1-(2,3-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-ind the l-7-yl]acrylic acid, I-132G transform in connection P297. The structure is confirmed with 1H-NMR; LC-MS (M-1=553,4).

Example 158. Getting connection P298.

In accordance with the General procedure A-8, (E)-3-[1-(2,3-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132G transform in connection P298. The structure is confirmed with 1H-NMR; LC-MS (M-l=553,4).

Example 159. Getting connection P299.

In accordance with the General procedure A-8, (E)-3-[1-(2,3-dichlorobenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132G transform in connection P299.

The structure is confirmed with 1H-NMR.; LC-MS (M-l=593,3).

Example 160. Getting connection P306.

Synthesis of 1-(3-methoxybenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydrobenzo-2-it, I-129H: IN accordance with the General method A-4, (1-methyl-2-oxocyclohexyl)acetic acid, I-128, is converted into compound I-129H. The structure is confirmed with 1H-NMR.

Synthesis of 7-bromo-1-(3-methoxybenzyl)-3a-methyl-l,3,3a,4,5,6-hexahydrobenzo-2-it, I-130H: In accordance with the General procedure A-5, 1-(3-methoxybenzyl)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-129H, is converted into compound I-130H. The structure is confirmed with 1H-NMR.

Synthesis of methyl ester (E)-3-[1-(3-methoxybenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-131H: IN accordance with the General procedure A-6, 7-bromo-1-(3-methoxybenzyl)-3a-methyl-1,3,3a,4,5,6-hexahydrobenzo-2-it, I-130H, transform into with the Association I-131H. The structure is confirmed with 1H-NMR.

Synthesis of (E)-3-[1-(3-methoxybenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132H. In accordance with the General method A-7 methyl ether (E)-3-[1-(3-methoxybenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-131H, is converted into compound I-132H. The structure is confirmed with 1H-NMR.

The synthesis of compounds P306. In accordance with the General procedure A-8, (E)-3-[1-(3-methoxybenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132H transform in connection P306. The structure is confirmed with 1H-NMR.

Example 161. Getting connection P307

In accordance with the General procedure A-8, (E)-3-[1-(3-methoxybenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132H transform in connection P307. 1H-NMR (400 MHz, CDCl3) of 1.23 (s, 3H), of 1.59 (m, 2H), to 1.87 (m, 2H), 2,16 (m, 2H), 2,45 (s, 2H), of 3.77 (s, 3H), and 4.75 (d, J=16.4 Hz, 1H), 5,24 (d, J=16.4 Hz, 1H), 5,52 (d, J=15.2 Hz, 1H), 6,79 (m, 3H), 7,07 (m, 1H), of 7.23 (m, 1H), 7,58 (m, 2H), 7,71 (d, J=15.2 Hz, 1H). LC/MS=96% purity; MS (ESI-) Calculated (M/Z) 516; found: 515.

Example 162. Getting connection RV in accordance with the General procedure A-8, (E)-3-[1-(3-methoxybenzyl)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid, I-132H transform in connection P308. The structure is confirmed with 1H-NMR.

Example 163. Getting connection P260.

In accordance with the General procedure A-8, (E)-3-[l-(3-methoxybenzyl)-3a-methyl-2-the CSR-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]acrylic acid I-132H transform in connection P260. The structure is confirmed with 1H-NMR; LC-MS (M-l=553,4).

Example 164. Getting connection P151.

Synthesis of methyl ester (1H-indol-4-yloxy)acetic acid, I-138. To a mixture of 4-hydroxyindole (1,33 g, 10 mmol) and K2CO3(2,07 g, 15 mmol) in acetone (50 ml) at room temperature add methylbromide (1.84 g, 12 mmol). The reaction mixture was stirred at room temperature overnight and the solid product removed. After removal of the solvent in vacuo the residue is dissolved in EtOAc and washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent the solid residue is washed with a mixture of ether/hexane, getting 2,02 g of compound I-138. The structure is confirmed with 1H-NMR.

Synthesis of (1H-indol-4-yloxy)acetic acid, I-139. To a solution of compound I-138 (410 mg, 2 mmol) in THF (6 ml) and methanol (6 ml) at room temperature, add aqueous NaOH (2n., 3 ml). The reaction mixture was stirred at room temperature for 4 hours and then the pH was adjusted to acidic by addition of 2n. aqueous HCl. The reaction mixture was extracted with EtOAc (2×30 ml). The combined organic phases are washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent to obtain 370 mg of compound I-139. The structure is confirmed with 1H-NMR.

General method (A) reaction of a combination of I-139 with sulfonamides.

The mixture of acid I-139 (250 mg, 1.3 mmol), the appropriate sulfonamida (1.57 mmol), 4-dimethylaminopyridine (317 mg, 2.6 mmol) and EDCI (497 mg, 2.6 mmol) in dichloromethane (20 ml) and DMSO (8 ml) is stirred over the weekend. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using EtOAc as eluent, and receiving compound I-140x.

General procedure (A-10) the receipt of sulphides.

To a mixture of compound I-140x (0.12 mmol) and the appropriate thiol (0.18 mmol) in ethanol (5 ml) and water (2 ml) is added 0.25 ml of iodine-potassium iodide (1H. in ethanol/H2O, 1:1) and stirred at room temperature over the weekend. The solution was diluted with EtOAc, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal of the solvent the solid residue was washed with CH2Cl2/hexane (1:1), obtaining the target sulphide.

General procedure (A-11) to obtain the sulfone.

To a mixture of sulfide [General methods (A-10)] (0.07 mmol) in methanol (2 ml) and ethanol (2 ml), add the XONE (44 mg, 0.07 mmol in 0.5 ml water) and the mixture is stirred at room temperature for 6 hours. The reaction mixture was diluted with EtOAc, washed with dilute aqueous HCl, water, saturated salt solution and dried over sodium sulfate. After removal the Oia of the solvent the residue is purified column chromatography on silica gel, using dichloromethane, EtOAc/hexane as eluent, and receiving the target sulfonic connection.

Synthesis of 4,5-dichlorothiophene-2-sulfonic acid [2-(1H-indol-4-yloxy)acetyl]amide, I-140A: IN accordance with the General procedure A-9, a compound I-139 subjected to interaction with the amide sulfonamide 4,5-dichlorothiophene-2-sulfonic acid, receiving compound I-140A. The structure is confirmed by 1H-NMR.

The synthesis of compounds P151. In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with naphthalene-2-thiol with obtaining connection P151. The structure is confirmed with 1H-NMR.

Example 165. The connection is P150.

In accordance with the General method A-11, a sulfide P151 subjected to oxidation to sulfone P150. The structure is confirmed with 1H-NMR.

Example 166. Getting connection P164.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with the quinoline-2-thiol with obtaining connection P164. 1H-NMR (500 MHz, DMSO-d6) 4.26 deaths (s, 2H), 6,28 (d, J=8.0 Hz, 1H), 7,03 (m, 3H), 7,10 (d, J=8.0 Hz, 1H), 7,46 (m, 2H), 7,66 (m, 2H), 7,81 (m, 2H), 8,02 (d, J=8.5 Hz, 1H), 11,74 (s, 1H). LC/MS=95% purity; MS (ESI-) Calculated (M/Z 564; found: 562.

Example 167. Getting connection P169

In accordance with the General method A-11, a sulfide P164 subjected to oxidation to sulfone P169. 1H-NMR (500 MHz, DMSO-d6) or 4.31 (s, 2H), 6,34 (s, 2H), 7,07 (m, 2H), 7,49 (s, 1H), 7,71 (m, 1H), 7,80 (m, 1H), of 7.90 (m, 1H), 8,04 (m, 1H), 8,23 (s, 1H), 8,21 (s, 1H), at 8.60 (s, 1H), 12,21 (s, 1H). LC/MS=95%purity, MS (ESI-) Is calculated: (M/Z 596; found: 594.

Example 168. Getting connection P165.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 2,4-dimethylbenzoyl getting connection P165. The structure is confirmed with 1H-NMR.

Example 169. Getting connection P172.

In accordance with the General method A-11, a sulfide P165 subjected to oxidation to sulfone P172. The structure is confirmed with 1H-NMR.

Example 170. Getting connection P167.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 3,4-dimethoxybenzoyl getting connection P167. The structure is confirmed with 1H-NMR.

Example 171. Getting connection P170.

In accordance with the General method A-11, a sulfide P167 subjected to oxidation to sulfone P170. The structure is confirmed with 1H-NMR.

Example 172. Getting connection P168.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 2-chloro-4-fermentation getting connection P168. The structure is confirmed with 1H-NMR.

Example 173. Getting connection P234.

In accordance with the General method A-11, a sulfide P168 is subjected to oxidation to sulfone P234. The structure is confirmed with 1H-NMR.

Example 174. Getting connection P173.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 4-chlorbenzoyl getting connection P13. The structure is confirmed with 1H-NMR.

Example 175. Getting connection P190.

In accordance with the General method A-11, a sulfide P173 subjected to oxidation to sulfone P190. The structure is confirmed with 1H-NMR.

Example 176. Getting connection P178.

In accordance with the General procedure A-10, a sulfonamide, I-140A is subjected to interaction with 3,4-dichlorobenzoyl getting connection P178. The structure is confirmed with 1H-NMR.

Example 177. Getting connection P204.

In accordance with the General method A-11, a sulfide P178 subjected to oxidation to sulfone P204. The structure is confirmed with 1H-NMR.

Example 178. Getting connection P181.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with benzoxazol-2-thiol with obtaining connection P181. The structure is confirmed with 1H-NMR.

Example 179. Getting connection P182.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with benzothiazole-2-thiol with obtaining connection P182. The structure is confirmed with 1H-NMR.

Example 180. Getting connection P196.

In accordance with the General method A-11, a sulfide P182 is subjected to oxidation to sulfone P196. 1H-NMR (DMSO-d6) of 4.54 (s, 2H), 6,51 (d, J=7,0, 1H), 7,14 (m, J=7,5 2H), 7,58 (m, J=6,0, 3H), of 7.96 (m, J=3,5, 1H), 8,35 (d, J=5,0, 1H), 12,58. LC/MS (80%) ESI-Calculated: 602,52; found: 602,0 m/z.

Example 181. Getting connection P194.

In accordance with the General procedure A-10, self named I-140 A is subjected to interaction with 2.5-dimethoxybenzoyl getting connection P194. The structure is confirmed with 1H-NMR.

Example 182. Getting connection P202.

In accordance with the General method A-11, a sulfide P194 subjected to oxidation to sulfone P202. 1H-NMR (500 MHz, DMSO-d6) of 3.60 (s, 3H), of 3.69 (s, 3H), of 4.67 (s, 2H), 6,46 (d, J=7.5 Hz, 1H), 6,98 (d, J=9.0 Hz, 1H), 7,06 (m, 2H), 7,11 (d, J=8.0 Hz, 1H), of 7.48 (d, J=3.0 Hz, 1H), 7,83 (s, 1H), 8,07 (d, J=3.0 Hz, 1H), 12,19 (s, 1H). LC/MS=97% purity; MS (ESI-) Calculated (M+) 605,5; Found: 605,2.

Example 183, Obtaining connection P195.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 1-methyl-1H-benzimidazole-2-thiol with obtaining connection P195. The structure is confirmed with 1H-NMR.

Example 184. Getting connection P197.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 2,4-differentation getting connection P197. The structure is confirmed with 1H-NMR.

Example 185. Getting connection P206.

In accordance with the General method A-11, a sulfide P197 subjected to oxidation to sulfone P206. The structure is confirmed with 1H-NMR.

Example 186. Getting connection P198.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with bentolila getting connection P198. The structure is confirmed with 1H-NMR.

Example 187. Getting connection P207.

In accordance with the General method A-11, a sulfide P198 subjected to oxidation to sulfone P207. The structure is confirmed with 1H-NMR.

Example 18. The connection is P200.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 4-methoxybenzamido getting connection P200. The structure is confirmed with 1H-NMR.

Example 189. Getting connection P210.

In accordance with the General method A-l1, sulfide P200 is subjected to oxidation to sulfone P210. The structure is confirmed with 1H-NMR.

Example 190. Getting connection P201.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with pyridine-2-thiol with obtaining connection P201. The structure is confirmed1H-NMR.

Example 191. Getting connection P221.

In accordance with the General method A-11, a sulfide P201 is subjected to oxidation to sulfone P221. 1H-NMR (500 MHz, DMSO-d6) 4,58 (s, 2H), 6,8 (d, J=7.5 Hz, 1H), to 7.09 (m, 1H), 7,13 (m, 1H), 7,54 (m, 1H), 7,82 (s, 1H), and 8.0 (s, 1H), 8,13 (s, 1H), 8,17 (m, 1H), charged 8.52 (m, 1H), 12,35 (s, 1H). LC/MS=96% purity; MS (ESI-) Calculated (M/Z 546; found: 544.

Example 192. Getting connection P205.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 2,4-dichlorobenzoyl getting connection P205. The structure is confirmed1H-NMR.

Example 193. Getting connection P238

In accordance with the General method A-11, a sulfide P205 is subjected to oxidation to sulfone P238. The structure is confirmed1H-NMR.

Example 194. Getting connection P208.

In accordance with the General methods of the th A-10, the sulfonamide I-140A is subjected to interaction with 3-methoxybenzamido getting connection P208. The structure is confirmed1H-NMR.

Example 195. Getting connection P209

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 3,4-differentation getting connection P209. The structure is confirmed1H-NMR.

Example 196. Getting connection P211

In accordance with the General procedure A-10, a sulfonamide I-140A subjected to interact with the pyrimidine-2-thiol with obtaining connection P211. 1H-NMR (500 MHz, DMSO-d6) of 4.45 (s, 2H), 6,27 (d, J=8.0 Hz, 1H), 6,98 (t, J=8.0 Hz, 2H), was 7.08 (m, 2H), 7,54 (s, 1H), to 7.84 (s, 1H), 8,46 (s, 2H), 11,59 (s, 1H). LC/MS=95% purity; MS (ESI-) Calculated (M/Z) 515; found: 513.

Example 197. Getting connection P212.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 2-methoxybenzamido getting connection P212. The structure is confirmed1H-NMR.

Example 198. Getting connection P222.

In accordance with the General method A-11, a sulfide P212 is subjected to oxidation to sulfone P222. The structure is confirmed1H-NMR.

Example 199. Getting connection P213

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 2-chlorbenzoyl getting connection P213. The structure is confirmed1H-NMR.

Example 200. Getting connection P232.

Rela is availa able scientific C General procedure A-11, sulfide P213 is subjected to oxidation to sulfone P232. The structure is confirmed1H-NMR.

Example 201. Getting connection P233.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with N-(4-mercaptophenyl)ndimethylacetamide getting connection P233. The structure is confirmed1H-NMR.

Example 202. Getting connection P235.

In accordance with the General method A-11, a sulfide P233 subjected to oxidation to sulfone P235. 1H-NMR (500 MHz, DMSO-d6) of 2.05 (s, 3H), 4.72 in (s, 2H), 6,47 (d, J=7.5 Hz, 1H), was 7.08 (d, J=8.0 Hz, 1H), 7,12 (d, J=8.5 Hz, 1H), to 7.67 (d, J=9.0 Hz, 2H), 7,82 (d, J=9.0 Hz, 2H), of 10.25 (s, 1H), 12,24 (s, 1H). LC/MS=90% purity; MS (ESI-) Calculated (M/Z) 602; found 600.

Example 203. Getting connection P220

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 1H-imidazole-2-thiol with obtaining connection P220. The structure is confirmed1H-NMR.

Example 204. Getting connection P227

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 1-methyl-1H-tetrazol-5-thiol with obtaining connection P227. The structure is confirmed1H-NMR.

Example 205. Getting connection P239. In accordance with the General method A-11, a sulfide P227 is subjected to oxidation to sulfone P239. 1H-NMR (DMSO-d6) 4.26 deaths (s, 3H), 4,58 (s, 2H), 6,53 (d, J=7,5, 1H), 7,17 (m, 2H), 7,80 (s, 1H), 8,45 (s, 1H), 12,74 (s, 1H); LC/MS (89%) ESI-Calculated: 551,41; Found: 549,2 m/z.

Example 206. The floor is giving connection P228.

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 4H-[1,2,4]triazole-3-thiol with obtaining connection P228. 1H-NMR (DMSO-d6) with 4.65 (s, 2H), 6,34 (d, J=8,0), 6,97 (t, J=8,0, 1H), 7,05 (d, J=3,0, 1H), 7,58 (d, J=3,0, 1H), 7,81 (s, 1H), of 8.25 (s, 1H) and 11,60 (s, 1H). LC/MS (94%) ESI+Calculated: 504,40; found: 506,1 m/z.

Example 207. Getting connection P240.

In accordance with the General method A-11, a sulfide P228 is subjected to oxidation to sulfone P240. The structure is confirmed1H-NMR.

Example 208. Getting connection P230

In accordance with the General procedure A-10, a sulfonamide I-140A is subjected to interaction with 5-methyl - [l,3,4]thiadiazole-2-thiol with obtaining connection P230. The structure is confirmed1H-NMR.

Example 209. Getting connection P231

In accordance with the General method A-11, a sulfide P230 is subjected to oxidation to sulfone P231. 1H-NMR (500 MHz, DMSO-d6) a 2.71 (s, 3H), of 4.67 (s, 2H), 6,53 (m, 1H), 7,16 (m, 2H), 7,83 (s, 1H), 8,35 (d, J=3.5 Hz, 1H), br12.62 (s, 1H). LC/MS=96% purity; MS (ESI-) Calculated (M/Z) 567; found: 567.

Example 210. Getting connection P166.

Synthesis of thiophene-2-sulfonic acid [2-(1H-indol-4-yloxy)acetyl]amide, I-140B:

In accordance with the General procedure A-9, a compound I-139 is subjected to interaction with Amida thiophene-2-sulfonic acid to obtain compound I-140B. The structure is confirmed1H-NMR.

The synthesis of compounds P166. In accordance with the General procedure A-10, a sulfonamide (I-10B is subjected to interaction with naphthalene-2-thiol with obtaining connection P166. The structure is confirmed1H-NMR.

Example 211. Getting connection P163.

In accordance with the General method A-11, a sulfide P166 is subjected to oxidation to sulfone P163. The structure is confirmed with 1H-NMR.

Example 212. Getting connection P174.

Synthesis of 5-chlorothiophene-2-sulfonol acid [2-(1H-indol-4-yloxy)acetyl]amide, I-140C. In accordance with the General procedure A-9, a compound I-139 is subjected to interaction with Amida 5-chlorothiophene-2-sulfonic acid to obtain compound I-140C. The structure is confirmed1H-NMR.

The synthesis of compounds P174. In accordance with the General procedure A-10, a sulfonamide I-140C is subjected to interaction with naphthalene-2-thiol with obtaining connection P174. The structure is confirmed with 1H-NMR.

Example 213. Getting connection P187.

In accordance with the General method A-1, a sulfide P174 subjected to oxidation to sulfone P187. The structure is confirmed1H-NMR.

Example 214. Getting connection P175.

Synthesis of N-[2-(1H-indol-4-yloxy)acetyl]benzosulfimide, I-140D. In accordance with the General procedure A-9, a compound I-139 is subjected to interaction with benzosulfimide to obtain compound I-140D. The structure is confirmed1H-NMR.

The synthesis of compounds P175. In accordance with the General procedure A-10, a sulfonamide I-140D is subjected to interaction with naphthalene-2-thiol with obtaining connection P175. The structure is confirmed with 1H-NMR.

<> Example 215. Getting connection P188.

In accordance with the General method A-11, a sulfide P175 subjected to oxidation to sulfone P188. The structure is confirmed with 1H-NMR.

Example 216. Getting connection P176.

Synthesis of N-[2-(1H-indol-4-yloxy)acetyl]-2,5-dimethoxy-benzosulfimide, I-140E: IN accordance with the General procedure A-9, a compound I-139 subjected to interaction with 2,5-dimethoxy-benzosulfimide to obtain compound I-140E. The structure is confirmed with 1H-NMR.

The synthesis of compounds P176. In accordance with the General procedure A-10, a sulfonamide I-140E is subjected to interaction with naphthalene-2-thiol with obtaining connection P176. The structure is confirmed1H-NMR.

Example 217. Getting connection P189.

In accordance with the General method A-11, a sulfide P176 subjected to oxidation to sulfone P189. 1H-NMR (DMSO-d6) of 3.75 (s, 3H), of 3.84 (s, 3H), 4,71 (s, 2H), 6,32 (d, J=7.5 Hz, 1H),? 7.04 baby mortality (t, J=8.0 Hz, 1H), 7,10 (d, J=8.0 Hz, 1H), 7,25 (m, 2H), 7,35 (m, 1H), to 7.59 (t, J=7,0 Hz, 1H), 7,66 (t, J=7.5 Hz, 1H), 7,82 (d, J=8.0 Hz, 1H), 7,94 (m, 2H), 8,03 (d, J=8.0 Hz, 1H), 8,17 (d, J=3.0 Hz, 1H), 8,65 (s, 1H), 12,05 (s, 1H), 12,29 (s, 1H). LC/MS (95%) ESI-Calculated: 579,6 m/z; found: 579,5 m/z.

Example 218. Getting connection P177.

Synthesis of 3,5-dichloro-N-[2-(1H-indol-4-yloxy)acetyl]-benzosulfimide, I-140F: IN accordance with the General procedure A-9, a compound I-139 subjected to interaction with 3.5-dichlorobenzenesulfonate to obtain compound I-140F. The structure is confirmed1H-NMR.

Si is TEZ connection P177. In accordance with the General procedure A-10, a sulfonamide I-140F subjected to interaction with naphthalene-2-thiol with obtaining connection P177. The structure is confirmed with 1H-NMR.

Example 219. Getting connection P186.

In accordance with the General method A-11, a sulfide P177 subjected to oxidation to sulfone P186. The structure is confirmed with 1H-NMR.

Example 220. Getting connection P183.

Synthesis of 2-chloro-N-[2-(1H-indol-4-yloxy)acetyl]benzosulfimide, I-140G. In accordance with the General procedure A-9, a compound I-139 is subjected to interaction with sulfonamide 2-chlorobenzenesulfonamide to obtain compound I-140G. The structure is confirmed with 1H-NMR.

The synthesis of compounds P183. In accordance with the General procedure A-10, a sulfonamide I-140 is subjected to interaction with naphthalene-2-thiol with obtaining connection P183. The structure is confirmed1H-NMR.

Example 221. Getting connection P191.

In accordance with the General method A-11, a sulfide P183 is subjected to oxidation to sulfone P191. The structure is confirmed with 1H-NMR.

Example 222. Getting connection P184.

Synthesis of 3-chloro-N-[2-(1H-indol-4-yloxy)acetyl] benzosulfimide, I-140H: IN accordance with the General procedure A-9, a compound I-139 subjected to interaction with 3-chlorobenzenesulfonamide to obtain compound I-140H. The structure is confirmed with 1H-NMR.

The synthesis of compounds P184. In accordance with the General procedure A-10, a sulfonamide I-140H will overhaul interaction with naphthalene-2-thiol with obtaining connection P184. The structure is confirmed1H-NMR.

Example 223. Getting connection P192.

In accordance with the General method A-11, a sulfide P184 subjected to oxidation to sulfone P192. The structure is confirmed1H-NMR.

Example 224. Getting connection P185.

Synthesis of N-[2-(1H-indol-4-yloxy)acetyl]-4-methoxybenzenesulfonamide, I-140I: IN accordance with the General procedure A-9, a compound I-139 subjected to interaction with 4-methoxybenzenesulfonamide to obtain compound I-140I. The structure is confirmed1H-NMR.

The synthesis of compounds of P185. In accordance with the General procedure A-10, a sulfonamide I-140I is subjected to interaction with naphthalene-2-thiol with obtaining connection P185. The structure is confirmed1H-NMR.

Example 225. Getting connection P193

In accordance with the General method A-11, a sulfide P185 subjected to oxidation to sulfone P193. The structure is confirmed1H-NMR.

Example 226 connection P199.

Synthesis of [2-(1H-indol-4-yloxy)acetyl]amide 3,5-dimethylisoxazol-4-sulfonic acid, I-140J: IN accordance with the General procedure A-9, a compound I-139 is subjected to interaction with Amida 3,5-dimethylisoxazol-4-sulfonic acid to obtain compound I-140J. The structure is confirmed1H-NMR.

The synthesis of compounds P199. In accordance with the General procedure A-10, a sulfonamide I-140J is subjected to interaction with naphthalene-2-thiol with obtaining the soybean is inane P199. The structure is confirmed1H-NMR.

Example 227. Getting connection P203.

In accordance with the General method A-11, a sulfide P199 subjected to oxidation to sulfone P203. The structure is confirmed1H-NMR.

Example 228. Getting connection P214.

Synthesis of 3,5-debtor-N-[2-(1H-indol-4-yloxy)acetyl]benzosulfimide, I-140K. In accordance with the General procedure A-9, a compound I-139 is subjected to interaction with sulfonamide 3,5-differentlanguages to obtain compound I-140K. The structure is confirmed with 1H-NMR.

The synthesis of compounds P214. In accordance with the General procedure A-10, a sulfonamide I-140K subjected to interaction with naphthalene-2-thiol with obtaining connection P214. The structure is confirmed1H-NMR.

Example 229. Getting connection P223.

In accordance with the General method A-11, a sulfide P214 is subjected to oxidation to sulfone P223. The structure is confirmed1H-NMR.

Example 230. Getting connection P215.

Synthesis of 3,4-debtor-N-[2-(1H-indol-4-yloxy)acetyl]benzosulfimide, I-140L: IN accordance with the General procedure A-9, a compound I-139 subjected to interaction with 3,4-differentlanguages to obtain compound I-140L. The structure is confirmed1H-NMR.

The synthesis of compounds P215. In accordance with the General procedure A-10, a sulfonamide I-140L is subjected to interaction with naphthalene-2-thiol with obtaining connection P215. The structure of a confirmation is ereaut 1H-NMR.

Example 231. Getting connection P224.

In accordance with the General method A-11, a sulfide P215 subjected to oxidation to sulfone P224. The structure is confirmed1H-NMR.

Example 232. Getting connection P225.

Synthesis of 4-fluoro-N-[2-(1H-indol-4-yloxy)acetyl]benzosulfimide, I-140M: In accordance with the General procedure A-9, a compound I-139 subjected to interaction with 4-fermentalization to obtain compound I-140M. The structure is confirmed1H-NMR.

The synthesis of compounds P225. In accordance with the General procedure A-10, a sulfonamide I-140M is subjected to interaction with naphthalene-2-thiol with obtaining connection P225. The structure is confirmed1H-NMR.

Example 233. Getting connection P236.

In accordance with the General method A-11, a sulfide P225 subjected to oxidation to sulfone P236. The structure is confirmed with 1H-NMR.

Example 234. Getting connection P226

Synthesis of 2,4,5-Cryptor-N-[2-(1H-indol-4-yloxy)acetyl]benzosulfimide, I-140N: IN accordance with the General procedure A-9, a compound I-139 subjected to interaction with 2,4,5-tripersonality to obtain compound I-140N. The structure is confirmed1H-NMR.

The synthesis of compounds P226. In accordance with the General procedure A-10, a sulfonamide I-140N are subjected to interaction with naphthalene-2-thiol with obtaining connection P226. The structure is confirmed with 1H-NMR.

Example 235. Getting connection P237.

1H-NMR.

Example 236. Getting connection P243

Synthesis of methyl ester [3-(naphthalene-2-ylsulphonyl)-1H-indol-4-yloxy]acetic acid, I-141: To a mixture of compound I-138 (102 mg, 0.5 mmol) and naphthalene-2-thiol (160 mg, 1 mmol) in ethanol (10 ml) and water (5 ml) was added 1 ml of iodine-potassium iodide (1H. in ethanol/H2O, 1:1) and the resulting mixture was stirred at room temperature over a weekend. To the reaction mixture are added water (~5 ml) and stirring continued for 30 minutes at room temperature. Solids filtered and washed with water, mixture of water/ethanol (1:1), CH2Cl2/hexane (5 ml/5 ml)to give 50 mg of compound I-141. The structure is confirmed1H-NMR.

Synthesis of [3-(naphthalene-2-ylsulphonyl)-1H-indol-4-yloxy]acetic acid, I-142. To a solution of compound I-141 (50 mg, 13 mmol) in THF (3 ml) and methanol (3 ml) is added aqueous NaOH (2n., 1.5 ml) at room temperature. The reaction mixture was stirred at room temperature overnight and then the pH was adjusted to acidic values by adding 2n. aqueous HCl. The reaction mixture was extracted with EtOAc (2×20 ml). The combined organic phases are washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent to obtain 35 mg of compound I-142. The structure is confirmed1 H-NMR.

The synthesis of compounds P243. The mixture of acid I-142 (35 mg, 0.1 mmol), triftormetilfullerenov (30 mg, 0.2 mmol), 4-dimethylaminopyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (1 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with dilute aqueous HCl, water and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using EtOAc/hexane as eluent and receiving 23 mg of the compound P243. MS (ESI-): 479,2 (M-l), LC-MS: 94% purity,1H-NMR (500 MHz, DMSO-d6) HPLC with reversed phase: 92% purity.

Example 237. Getting connection P277.

Synthesis of 4-bromo-1-methyl-1H-indole, I-133. To a solution of NaH (60% in oil, 600 mg, 15 mmol) in DMF (20 ml) at -10 °C. add 4-bromoindole (a 1.96 g, 10 mmol), the mixture was stirred at room temperature for 10 minutes and then add logmean (6.7 g, 50 mmol). The reaction mixture was stirred at room temperature for 3 hours and diluted with CH2Cl2(200 ml). The reaction mixture was washed with water (3×200 ml), saturated salt solution and dried over sodium sulfate. After removal of the solvent to obtain 3 g of the crude compound I-133, which is used in the next stage without additional purification. The structure is confirmed1H-NMR.

Common methods is (A-12) the reaction of a combination of 4-bromoindole with phenol.

A mixture of compound I-133 (420 mg, 2 mmol), CuI (38 mg, 0.2 mmol, 0.1 EQ.), HCl salt of N,N-dimethylglycine (84 mg, 0.6 mmol, 0.3 equiv.) phenol (3 mmol, 1.5 EQ.) and Cs2CO3(1.3 g, 4 mmol, 2 EQ.) in dioxane (4 ml) is stirred under Ar atmosphere at 105°C for 3 days. The reaction mixture was diluted with EtOAc and washed with water, saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using EtOAc/hexane as eluent and receiving compound I-134.

Synthesis of l-methyl-4-(naphthalene-2-yloxy)-1H-indole, I-134A. In accordance with the General procedure A-12, compound I-133 is subjected to interaction with naphthalene-2-I to obtain compound I-134A. The structure is confirmed with 1H-NMR.

Synthesis of l-methyl-4-(naphthalene-2-yloxy)-1H-indole-3-carbaldehyde, I-135A. General procedure (A-13) the conversion of indole 3-formaldehydyde. To a solution of compound I-134 (1.6 mmol) in DMF (8 ml) dropwise at room temperature add POCl3(1.8 mmol, 1.1 EQ.). The reaction mixture was stirred at 50°C for 1 hour and poured into ice water. The pH of the mixture was adjusted to 8-9 by addition of NaOH (aq.) (2H.) and then the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with EtOAc (2×40 ml). The organic phase is washed with water (3×50 ml), saturated salt solution and dried over with what LifeCam sodium. After removal of the solvent receive I-135 in the form of solids.

In accordance with the General procedure A-13, a connection I-134A is converted into formaldehyde I-135A. The structure is confirmed1H-NMR.

Synthesis of ethyl ester of (E)-3-[l-methyl-4-(naphthalene-2-yloxy)-1H-indol-3-yl]acrylic acid, I-136A. General procedure (A-14) the conversion of 3-formaldehyde in the ethyl ester of 3-intracrinology acid. To a solution of NaH (60% in oil, 100 mg, 2.5 mmol, 2.5 EQ.) in THF (20 ml) at -10°C. add triethylphosphate (493 mg, 2.2 mmol, 2.2 EQ.), the resulting mixture was stirred at room temperature for 10 minutes and then at -10°C type compound I-135 (1 mmol)dissolved in THF (10 ml). The reaction mixture was stirred at 60°C overnight and then diluted with EtOAc and washed with NH4Cl of water, water (2×100 ml), saturated salt solution and dried over sodium sulfate. After removal of the solvent to obtain the crude product I-136, which is used in the next stage without additional purification.

In accordance with the General procedure A-14, compound I-135A is converted into an ethyl ester of acrylic acid I-136A. The structure is confirmed1H-NMR.

Synthesis of (E)-3-[l-methyl-4-(naphthalene-2-yloxy)-1H-indol-3-yl]acrylic acid, I-137A.

General procedure (A-7A). Hydrolysis of ethyl ester of 3 - acrylic acid to 3-acrylic acid. A mixture of the crude compounds the s I-136 (1 mmol) in THF (10 ml), MeOH (10 ml) and NaOH (aq.) (2H., 10 ml) was stirred at 50°C for 3 hours. After removal of THF and MeOH, the reaction mixture was diluted with water (~20 ml), adjusted pH to acidic by addition of aqueous HCl (2n.) and extracted with EtOAc (2×30 ml). The combined organic phases are washed with water (2×30 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is washed with ether, receiving compound I-137.

In accordance with the General method A-7A, compound I-136A hydrolyzing to the acrylic acid I-137A. The structure is confirmed1H-NMR.

General procedure (A-8A) combination acid to arylsulfonamides. The mixture of acid I-137 (0.16 mmol), sulfonamida (0.20 mmol, 1.2 EQ.), 4-dimethylaminopyridine (41 mg, 0.33 mmol, 2 EQ.) and EDCI (63 mg, 0.33 mmol, 2 EQ.) in dichloromethane (10 ml) was stirred at room temperature overnight. The reaction mixture is washed with dilute aqueous HCl, water and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel using a mixture of methanol/dichloromethane as eluent to obtain the product.

The synthesis of compounds P277. In accordance with the General procedure A-8A, the acrylic acid I-137A is subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic acid to obtain compounds P277. The structure is confirmed1H-NMR.

Example 238. Getting a connection is possible P343.

In accordance with the General procedure A-8A, the acrylic acid I-137A is subjected to interaction with 2,4,5-tripersonality getting connection P343.1H-NMR (DMSO-d6) to 3.89 (s, 3H) to 6.43 (d, J=to 15.0 Hz, 1H), 6,70 (d, J=7.5 Hz, 1H), 7.23 percent (t, J=8.0 Hz, 1H), 7,27 (m, 1H), 7,35-of 7.48 (m, 4H), 7,73 (d, J=8.0 Hz, 1H), 7,83-7,98 (m, 5H), of 7.97 (d, J=to 15.0 Hz, 1H), 12,6 (s, 1H). HPLC (97%) ESI MS-Calculated: 535,5 m/z; found 535,7 m/z.

Example 239. Getting connection P334.

In accordance with the General procedure A-8A, the acrylic acid I-137A is subjected to interaction with 3,4-differentlanguages getting connection P334. 1H-NMR (DMSO-d6) to 3.89 (s, 3H), to 6.39 (d, J=to 15.0 Hz, 1H), 6,70 (d, J=7 Hz, 1H), 7.23 percent (t, J=8.0 Hz, 1H), 7,30 (m, 1H), 7,35 (m, 1H), 7,37 (d, J=8.0 Hz, 1H), 7,44 (m, 2H), 7,6-7,8 (m, 3H), 7,89-of 7.97 (m, 4H), of 7.96 (d, J=to 15.0 Hz, 1H), and 12.2 (s, 1H). HPLC (99%) ESI MS-Calculated: 517,5 m/z; found: to 517.7 m/z.

Example 240. Getting connection P290.

Synthesis of 4-(3,4-dichlorophenoxy)-1-methyl-1H-indole, I-134B: IN accordance with the General procedure A-12, compound I-133 is subjected to interaction with 3,4-dichlorophenol to obtain compound I-134B. The structure is confirmed with 1H-NMR.

Synthesis of 4-(3,4-dichlorophenoxy)-1-methyl-1H-indole-3-carbaldehyde, I-135B: IN accordance with the General procedure A-13, a connection I-134B is converted into formaldehyde I-135B. The structure is confirmed with 1H-NMR.

Synthesis of ethyl ester of (E)-3-[4-(3,4-dichlorophenoxy)-1-methyl-1H-indol-3-yl]acrylic acid, I-136B: IN accordance with the General procedure A-14, compound I-35B, converted into an ethyl ester of acrylic acid I-136B. The structure is confirmed with 1H-NMR.

Synthesis of (E)-3-[4-(3,4-dichlorophenoxy)-1-methyl-1H-indol-3-yl]acrylic acid, I-137B. In accordance with the General method A-7A, compound I-136B hydrolyzing to the acrylic acid I-137B. The structure is confirmed with 1H-NMR.

The synthesis of compounds P290. In accordance with the General procedure A-8A, the acrylic acid I-137B is subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic acid to obtain compounds P290. The structure is confirmed1H-NMR.

Example 241. Getting connection P292.

In accordance with the General procedure A-8A, the acrylic acid I-137B is subjected to interaction with 2,4,5-tripersonality getting connection P292. The structure is confirmed1H-NMR.

Example 242. Getting connection P293.

In accordance with the General procedure A-8A, the acrylic acid I-137B is subjected to interaction with 3,4-differentlanguages getting connection P293. The structure is confirmed with 1H-NMR.

Example 243. Getting 291 connection.

Synthesis of 4-(2,3-dichlorophenoxy)-1-methyl-1H-indole, I-134C. In accordance with the General procedure A-12, compound I-133 is subjected to interaction with 2,3-dichlorophenol to obtain compound I-134C. The structure is confirmed1H-NMR.

Synthesis of 4-(2,3-dichlorophenoxy)-1-methyl-1H-indole-3-carbaldehyde, I-135C. In accordance with the General methodical is A-13, compound I-134C is converted into formaldehyde I-135C. The structure is confirmed1H-NMR.

Synthesis of ethyl ester of (E)-3-[4-(2,3-dichlorophenoxy)-1-methyl-1H-indol-3-yl]acrylic acid, I-136C. In accordance with the General procedure A-14, compound I-135C is converted into an ethyl ester of acrylic acid I-136C. The structure is confirmed1H-NMR.

Synthesis of (E)-3-[4-(2,3-dichlorophenoxy)-1-methyl-1H-indol-3-yl]acrylic acid, I-137C. In accordance with the General method A-7A, compound I-136C hydrolyzing to the acrylic acid I-137C. The structure is confirmed with 1H-NMR.

Synthesis of compound 291. In accordance with the General procedure A-8A, the acrylic acid I-137C is subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic acid to obtain compound 291. The structure is confirmed1H-NMR.

Example 244. Getting connection P303.

Synthesis of 4-(2,4-dichlorophenoxy)-1-methyl-1H-indole, I-134D: IN accordance with the General procedure A-12, compound I-133 is subjected to interaction with 2,4-dichlorphenol to obtain compound I-134D. The structure is confirmed1H-NMR.

Synthesis of 4-(2,4-dichlorophenoxy)-1-methyl-1H-indole-3-carbaldehyde, I-135D: IN accordance with the General procedure A-13, a connection I-134D is converted into formaldehyde I-135D. The structure is confirmed with 1H-NMR.

Synthesis of ethyl ester of (E)-3-[4-(2,4-dichlorophenoxy)-1-methyl-1H-indol-3-yl]acrylic acid, I-136D. In accordance with the General method is IR A-14, compound I-135D is converted into an ethyl ester of acrylic acid I-136D. The structure is confirmed1H-NMR.

Synthesis of (E)-3-[4-(2,4-dichlorophenoxy)-1-methyl-1H-indol-3-yl]acrylic acid, I-137D. In accordance with the General method A-7A, compound I-136D hydrolyzing to the acrylic acid I-137D. The structure is confirmed1H-NMR.

The synthesis of compounds P303. In accordance with the General procedure A-8A, the acrylic acid I-137D is subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic acid to obtain compounds P303. The structure is confirmed1H-NMR.

Example 245. Getting connection P301.

In accordance with the General procedure A-8A, the acrylic acid I-137D is subjected to interaction with 2,4,5-tripersonality getting connection P301. The structure is confirmed1H-NMR.

Example 246. Getting connection P302.

In accordance with the General procedure A-8A, the acrylic acid I-137D is subjected to interaction with 3,4-differentlanguages getting connection P302. The structure is confirmed with 1H-NMR.

Example 247. Getting connection P311.

Synthesis of 4-(4-chlorophenoxy)-1-methyl-1H-indole, I-134E: IN accordance with the General procedure A-12, compound I-133 is subjected to interaction with 4-chlorophenol to obtain compound I-134E. The structure is confirmed1H-NMR.

Synthesis of 4-(4-chlorophenoxy)-1-methyl-1H-indole-3-carbaldehyde, I-135E: according the General procedure A-13, compound I-134E is converted into formaldehyde I-135E. The structure is confirmed with 1H-NMR.

Synthesis of ethyl ester of (E)-3-[4-(4-chlorophenoxy)-1-methyl-1H-indol-3-yl]acrylic acid, I-136E. In accordance with the General procedure A-14, compound I-135E is converted into an ethyl ester of acrylic acid I-136E. The structure is confirmed1H-NMR.

Synthesis of (E)-3-[4-(4-chlorophenoxy)-1-methyl-1H-indol-3-yl]acrylic acid, I-137E. In accordance with the General method A-7A, compound I-136E hydrolyzing to the acrylic acid I-137E. The structure is confirmed1H-NMR.

The synthesis of compounds P311. In accordance with the General procedure A-8A, the acrylic acid I-137 is subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic acid to obtain compounds P311. 1H-NMR (DMSO-d6) a 3.87 (s, 3H), 6,36 (d, J=to 15.0 Hz, 1H), 6,69 (d, J=8.0 Hz, 1H), 6,99 (d, J=7 Hz, 2H), 7.23 percent (d, J=7 Hz, 1H), 7,38 (m, 1H), 7,39 (d, J=7 Hz, 2H), 7,86 (s, 1H), 7,94 (d, J=to 15.0 Hz, 1H), to 7.99 (s, 1H), 12.5cm (ush., 1H). HPLC (97%) ESI MS-Calculated: 41,8 m/z; found: 541,4 m/z.

Example 248. Getting connection P309.

In accordance with the General procedure A-8A, the acrylic acid I-137E is subjected to interaction with 2,4,5-tripersonality getting connection P309. The structure is confirmed1H-NMR.

Example 249. Getting connection P310.

In accordance with the General procedure A-8A, the acrylic acid I-137E is subjected to interaction with 3,4-differentlanguages obtaining compounds the Oia P310. The structure is confirmed1H-NMR.

Example 250. Getting connection P320.

Synthesis of 4-(3,4-divergence)-1-methyl-1H-indole, I-134F: IN accordance with the General procedure A-12, compound I-133 is subjected to interaction with 3,4-differfrom to obtain compound I-134F. The structure is confirmed1H-NMR.

Synthesis of 4-(3,4-divergence)-1-methyl-1H-indole-3-carbaldehyde, I-135F: IN accordance with the General procedure A-13, a connection I-134F is converted into formaldehyde I-135F. The structure is confirmed1H-NMR.

Synthesis of ethyl ester of (E)-3-[4-(3,4-divergence)-1-methyl-1H-indol-3-yl]acrylic acid, I-136F: IN accordance with the General procedure A-14, compound I-135F is converted into an ethyl ester of acrylic acid I-136F. The structure is confirmed1H-NMR.

Synthesis of (E)-3-[4-(3,4-divergence)-1-methyl-1H-indol-3-yl]acrylic acid, I-137F. In accordance with the General method A-7A, compound I-136F hydrolyzing to the acrylic acid I-137F. The structure is confirmed1H-NMR.

The synthesis of compounds P320. In accordance with the General procedure A-8A, the acrylic acid I-137F is subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic acid to obtain compounds P320. The structure is confirmed1H-NMR.

Example 251. Getting connection P318.

In accordance with the General procedure A-8A, the acrylic acid I-137F subjected to interaction with 2,4,5-tripersonality the om connection P318. The structure is confirmed1H-NMR.

Example 252. Getting connection P319.

In accordance with the General procedure A-8A, the acrylic acid I-137F subjected to interaction with 3,4-differentlanguages getting connection P319. The structure is confirmed1H-NMR.

Example 253. Getting connection P326.

Synthesis of 4-(2,4-divergence)-1-methyl-1H-indole, I-134G: IN accordance with the General procedure A-12, compound I-133 is subjected to interaction with 2,4-differfrom to obtain compound I-134G. The structure is confirmed1H-NMR.

Synthesis of 4-(2,4-divergence)-1-methyl-1H-indole-3-carbaldehyde, I-135G. In accordance with the General procedure A-13, a connection I-134G is converted into formaldehyde I-135G. The structure is confirmed with 1H-NMR.

Synthesis of ethyl ester of (E)-3-[4-(2,4-divergence)-1-methyl-1H-indol-3-yl]acrylic acid, I-136G. In accordance with the General procedure A-14, compound I-135G is converted into an ethyl ester of acrylic acid I-136G. The structure is confirmed with 1H-NMR.

Synthesis of (E)-3-[4-(2,4-divergence)-1-methyl-1H-indol-3-yl]acrylic acid, I-137G. In accordance with the General method A-7A, compound I-136G hydrolyzing to the acrylic acid I-137G. The structure is confirmed1H-NMR.

The synthesis of compounds P326. In accordance with the General procedure A-8A, the acrylic acid I-137G subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic acid to obtain the compounds P326. The structure is confirmed1H-NMR.

Example 254. Getting connection P324.

In accordance with the General procedure A-8A, the acrylic acid I-137G subjected to interaction with 2,4,5-tripersonality getting connection P324. The structure is confirmed1H-NMR.

Example 255. Getting connection P325.

In accordance with the General procedure A-8A, the acrylic acid I-137G subjected to interaction with 3,4-differentlanguages getting connection P325.1H-NMR (DMSO-d6) 6,12 (d, J=8.0 Hz, 1H), 6,21 (d, J=15.2 Hz, 1H),? 7.04 baby mortality (DD, J=10,0, 2.4 Hz, 1H), 7.23 percent (DD, J=8,0, 2.4 Hz, 1H), was 7.36 (s, 1H), 7,39 (d, J=2.4 Hz, 1H), 7,45 (DD, J=9,2, 2.4 Hz, 1H), 7,72 (d, J=15.2 Hz, 1H), 7,88 (s, 1H) LC/MS (96%) (ESI-) Calculated: 594,34 m/z; found 593,3 m/z.

Example 256. Getting connection P330.

Synthesis of 4-(3-chloro-4-pertenece)-1-methyl-1H-indole, I-134H: IN accordance with the General procedure a-12, compound I-133 is subjected to interaction with 2,4-differfrom to obtain compound I-134G. The structure is confirmed1H-NMR.

Synthesis of 4-(3-chloro-4-pertenece)-1-methyl-1H-indole-3-carbaldehyde, I-135H. In accordance with the General procedure A-13, a connection I-134H is converted into formaldehyde I-135H. The structure is confirmed1H-NMR.

Synthesis of ethyl ester of (E)-3-[4-(3-chloro-4-pertenece)-1-methyl-1H-indol-3-yl]acrylic acid, I-136H. In accordance with the General procedure A-14, I-135H is converted into an ethyl ester of acrylic acid I-136H. Structure is ru confirm 1H-NMR.

Synthesis of (E)-3-[4-(3-chloro-4-pertenece)-1-methyl-1H-indol-3-yl]acrylic acid, I-137H. In accordance with the General method A-7A, compound I-136H hydrolyzing to the acrylic acid I-137H. The structure is confirmed1H-NMR.

The synthesis of compounds P330. In accordance with the General procedure A-8A, the acrylic acid I-137H subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic acid to obtain compounds P330. The structure is confirmed1H-NMR.

Example 257. Getting connection P328.

In accordance with the General procedure A-8A, the acrylic acid I-137H subjected to interaction with 2,4,5-tripersonality getting connection P328. The structure is confirmed1H-NMR.

Example 258. Getting connection P329.

In accordance with the General procedure A-8A, the acrylic acid I-137H subjected to interaction with 3,4-differentlanguages getting connection P329. The structure is confirmed1H-NMR.

Example 259. Getting connection P333.

Synthesis of 4-(4-chloro-3-pertenece)-1-methyl-1H-indole, I-134I. In accordance with the General procedure A-12, compound I-133 is subjected to interaction with 4-chloro-3-tortenelem to obtain compound I-134L. The structure is confirmed with 1H-NMR.

Synthesis of 4-(4-chloro-3-pertenece)-1-methyl-1H-indole-3-carbaldehyde, I-1351. In accordance with the General procedure A-13, a connection I-134I is converted into formaldehyde I-135I. Art is ucture confirmed 1H-NMR.

Synthesis of ethyl ester of (E)-3-[4-(4-chloro-3-pertenece)-1-methyl-1H-indol-3-yl]acrylic acid, I-1361. In accordance with the General procedure A-14, compound I-135I, is converted into ethyl ester of acrylic acid I-136I. The structure is confirmed with 1H-NMR.

Synthesis of (E)-3-[4-(4-chloro-3-pertenece)-1-methyl-1H-indol-3-yl]acrylic acid, I-137I. In accordance with the General method A-7A, compound I-136I hydrolyzing to the acrylic acid I-1371. The structure is confirmed with 1H-NMR.

The synthesis of compounds P333. In accordance with the General procedure A-8A, the acrylic acid I-137I subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic acid to obtain compounds P333. The structure is confirmed with 1H-NMR.

Example 260. Getting connection P331.

In accordance with the General procedure A-8A, the acrylic acid I-137 is subjected to interaction with 2,4,5-tripersonality getting connection P331. 1H-NMR (DMSO-d6) 3,88 (s, 3H), 6,38 (d, J=to 15.0 Hz, 1H), 6,72 (m, 1H), 6,78 (d, J=7 Hz, 1H), to 7.09 (DD, J=10 and 3 Hz, 1H), 7,26 (t, J=8.0 Hz, 1H), 7,42 (d, J=8.0 Hz, 1H), 7,50 (t, J=9 Hz, 1H), 7,80 (d, J=to 15.0 Hz, 1H), 7,88 (m, 1H), 7,98 (m, 2H), and 12.6 (s, 1H). HPLC (93%) MS ESI - Calculated: 537,9 m/z; found: 537,4 m/z.

Example 261. Getting connection P332.

In accordance with the General procedure A-8A, the acrylic acid I-137I subjected to interaction with 3,4-diftorbenzofenonom getting connection P332, Structure confirmed1H-NMR.

Example 262. Receiving from the organisations P339.

Synthesis of 4-(4-chloro-2-pertenece)-1-methyl-1H-indole, I-134J. In accordance with the General procedure A-12, compound I-133 is subjected to interaction with 4-chloro-2-terfenol to obtain compound I-134J. The structure is confirmed1H-NMR.

Synthesis of 4-(4-chloro-2-pertenece)-1-methyl-1H-indole-3-carbaldehyde, I-135J. In accordance with the General procedure A-13, a connection I-134J is converted into formaldehyde I-135J. The structure is confirmed1H-NMR.

Synthesis of ethyl ester of (E)-3-[4-(4-chloro-2-pertenece)-1-methyl-1H-indol-3-yl]acrylic acid, I-136J. In accordance with the General procedure A-14, compound I-135J is converted into an ethyl ester of acrylic acid I-136J. The structure is confirmed with 1H-NMR.

Synthesis of (E)-3-[4-(4-chloro-2-pertenece)-1-methyl-1H-indol-3-yl]acrylic acid, I-137J. In accordance with the General method A-7A, compound I-136J hydrolyzing to the acrylic acid I-137J. The structure is confirmed1H-NMR.

The synthesis of compounds P339. In accordance with the General procedure A-8A, the acrylic acid I-137J subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic acid to obtain compounds P339. 1H-NMR(DMSO-d6) a 3.87 (s, 3H), 6,40 (d, J=to 15.0 Hz, 1H), of 6.49 (d, J=8.0 Hz, 1H), 7,17 (m, 2H), 7,32 (m, 2H), 7,65 (DD, J=10 and 2 Hz, 1H), 7,86 (s, 1H), 8,02 (s, 1H), 8,04 (d, J=to 15.0 Hz, 1H), 12.5cm (ush., 1H). HPLC (89%) MS ESI - Calculated: 558,8 m/z; found: 559,1 m/z.

Example 263. Getting connection P337.

In accordance with the General procedure A-8A, the acrylic acid is the I-137J subjected to interaction with 2,4,5-tripersonality getting connection P337. The structure is confirmed1H-NMR.

Example 264. Getting connection P338.

In accordance with the General procedure A-8A, the acrylic acid I-137J subjected to interaction with 3,4-differentlanguages getting connection P338. The structure is confirmed1H-NMR.

Example 265. Getting connection P342.

Synthesis of 4-(2-chloro-4-pertenece)-1-methyl-1H-indole, I-134K. In accordance with the General procedure A-12, compound I-133 is subjected to interaction with 2-chloro-4-tortenelem to obtain compound I-134K. The structure is confirmed1H-NMR.

Synthesis of 4-(2-chloro-4-pertenece)-1-methyl-1H-indole-3-carbaldehyde, I-135K. In accordance with the General procedure A-13, a connection I-134K, is converted into formaldehyde I-135K. The structure is confirmed1H-NMR.

Synthesis of ethyl ester of (E)-3-[4-(2-chloro-4-pertenece)-1-methyl-1H-indol-3-yl]acrylic acid, I-136K. In accordance with the General procedure A-14, compound I-135K is converted into an ethyl ester of acrylic acid I-136K. The structure is confirmed with 1H-NMR.

Synthesis of (E)-3-[4-(2-chloro-4-pertenece)-1-methyl-1H-indol-3-yl]acrylic acid, I-137K. In accordance with the General method A-7A, compound I-136K hydrolyzing to the acrylic acid I-137K. The structure is confirmed with 1H-NMR.

The synthesis of compounds P342. In accordance with the General procedure A-8A, the acrylic acid I-137K subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic sour is s getting connection P342. 1H-NMR (DMSO-d6) a 3.87 (s, 3H), of 6.31 (d, J=8.0 Hz, 1H), 6,41 (d, J=to 15.0 Hz, 1H), 7,13 (t, J=8.0 Hz, 1H), 7,25 - 7,30 (m, 3H), of 7.64 (DD, J=8 and 2 Hz, 1H), 7,86 (s, 1H), 8,.01 (s, 1H), 8,11 (d, J=15,0 Hz, 1H), 12.5cm (ush., 1H). HPLC (86%) MS ESI - Calculated: 558,8 m/z; found: 559,1 m/z.

Example 266. Getting connection P340.

In accordance with the General procedure A-8A, the acrylic acid I-137K subjected to interaction with 2,4,5-tripersonality getting connection P340. The structure is confirmed1H-NMR.

Example 267. Getting connection P341.

In accordance with the General procedure A-8A, the acrylic acid I-137K subjected to interaction with 3,4-differentlanguages getting connection P341. The structure is confirmed1H-NMR.

Example 268. Getting connection P034.

Synthesis of ethyl ester of 5-amino-1-(2,2-diatexite)-1H-pyrazole-4-carboxylic acid, I-141. To a solution of hydrazine hydrate is added (17.5 ml, 0,355 moles) in 60 ml of absolute ethanol by boiling under reflux with stirring, added dropwise to bromoacetaldehyde diethylacetal (20 g, 0,101 moles). The mixture is refluxed over night. The cooled reaction mixture was concentrated in vacuo, to the residue add 25 ml of 35% NaOH mixed with 3 g of NaCl, and the resulting mixture extracted with ether (2×100 ml). The combined organic phases are dried over MgSO4and concentrated in vacuo, receiving 12.3 g of oil (I-138). Oil is used in the next stage busdomainalias cleaning. To a solution of compound I-138 (2,2-diatexite)hydrazine (12.3 g, 0,0831 moles) in 25 ml of absolute ethanol is added a solution of athletanimation of cyanoacetate (14 g, 0,0831 mol) in 75 ml of absolute ethanol. The mixture is stirred at room temperature for 3 days. The solvent is removed, obtaining an oily residue ethyl ester (5-amino-1-(2,2-diatexite)-1H-pyrazole-4-carboxylic acid, I-141), which is used in the next stage without additional purification.

Synthesis of ethyl ester 1H-imidazo[1,2-b]pyrazole-7-carboxylic acid, I-142. To a solution of crude compound I-141 (2 g in 10 ml of absolute ethanol) is added aqueous 20% solution of sulfuric acid (12 ml). The mixture is refluxed for 1 hour. The reaction mixture is cooled, the solvent is removed, the mixture was poured on ice and the pH adjusted to 8 by adding sodium hydrogen carbonate solution. The insoluble matter is filtered off and the filtrate is extracted with methylene chloride (2×60 ml). The combined organic fractions dried over MgSO4. Filtration and evaporation of the mixture leads to obtain 1.2 g of residue. The residue is purified column chromatography using CH2Cl2 to 2% MeOH/ CH2Cl2leads to obtain 280 mg of the product of the I-N

Synthesis of 1-naphthalene-2-ylmethyl-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid, I-143. To a suspension of NaH (60% in mineral oil, 65 mg, 1.6 mmol) in 5 the l of DMF at 0°C add connection I-142 (240 mg, of 1.34 mmol). The mixture is stirred at 0°C for 30 minutes, then at room temperature for 2 hours. The reaction mixture was cooled to 0°C and add 2-bromethalin. The mixture is stirred at room temperature overnight. The reaction is quenched by adding a saturated solution of NH4C1 (10 ml) to the mixture and the resulting solution was extracted with CH2Cl2(2×50 ml). The combined organic extracts washed with saturated salt solution and dried over MgSO4. After evaporation of the solvent receive 300 mg of the crude product. Purification of column chromatography using 5%-20% ethyl acetate/hexane leads to obtain 208 mg of compound I-143.

Synthesis of (1-naphthalene-2-emeil-1H-imidazo[1,2-b]pyrazole-7-yl)methanol, I-144. To a solution of compound I-143 (100 mg, 0,313 mmol) in anhydrous methylene chloride (5 ml), cooled to -70°C, are added dropwise DIBAL (1M solution in CH2Cl2, to 0.94 ml, 3 EQ.) The reaction mixture was stirred at the same temperature for 4 hours. The mixture is quenched Meon, then add 50% saturated solution of potassium sodium tartrate and enable the mixture to warm to room temperature. The mixture is extracted with CH2Cl2(2×20 ml), the combined organic layers washed with saturated salt solution and dried over MgSO4. After removal of the solvent receive 70 mg of the crude alcohol, I-144. Product use n the next stage without additional purification.

Synthesis of 1-naphthalene-2-ylmethyl-1H-imidazo[1,2-b]pyrazole-7-carbaldehyde, I-145. Activated MnO2(110 mg, of 1.26 mmol) are added to a suspension of the alcohol (70 mg, 0.25 mmol) in 10 ml of anhydrous methylene chloride. The reaction mixture was stirred at room temperature overnight. TLC shows the presence of a certain amount of neproreagirovavshikh alcohol, so the reaction continue another day. After processing, the mixture is purified column chromatography using 100% CH2Cl2to 5% MeOH/CH2Cl2receiving 70 mg of compound I-145.

Synthesis of ethyl ester of 3-(1-naphthalene-2-ylmethyl-1H-imidazo[l,2-b]pyrazole-7-yl)acrylic acid, I-146. To a suspension of NaH (60% in mineral oil, 21 mg, 0,525 mmol) in anhydrous THF (3 ml) at 0°C add triethylphosphate (92 μl, 0,462 mmol). The reaction mixture is heated to room temperature and maintained at the specified temperature for 1 hour. The mixture is then cooled to 0°C. and add a solution of compound I-145 (60 mg, 0.21 mmol) in 2 ml of anhydrous THF. The mixture allow to warm to room temperature and stirred at room temperature for 1 hour, then the mixture is heated to 70°C and stirred at the same temperature throughout the night. The reaction mixture is cooled to room temperature, the solvent is removed, to the mixture is added 10 ml of CH2Cl2and the mixture is quenched with 1 m is a saturated solution of NH4Cl. The organic layer was washed with saturated salt solution and dried over MgSO4. The solvent is removed, receiving 70 mg of the crude compound I-146, the structure is confirmed by 1H-NMR. The product is used for the subsequent hydrolysis without further purification.

Synthesis of 3-(1-naphthalene-2-ylmethyl-1H-imidazo[1,2-b]pyrazole-7-yl)acrylic acid, I-147. To a solution of compound I-146 (70 mg, 0.2 mmol) in MeOH/THF (2 ml/1 ml) was added 1 ml of 1N. NaOH solution. The reaction mixture was stirred at room temperature for 3 days. The solvent is removed, to the residue was added 1 ml of 10% aqueous HCl and the mixture extracted with EtOAc (3×10 ml). The combined organic layers washed with saturated salt solution and dried over MgSO4. After removal of the solvent receive 50 mg of the crude acid. The product was then purified using a small layer of silica gel (I-147 (25 mg).

Synthesis of 3-(l-naphthalene-2-ylmethyl-1H-imidazo[l,2-b]pyrazole-7-yl)acrylic acid, P034. To a suspension of acid I-147 (18.6 mg, 0,0586 mmol) in anhydrous methylene chloride (1.5 ml) is added DMAP (14.3 mg, 0,117 mmol), 2-thiophenesulfonyl (9.6 mg, 0,0586 mmol) and EDCI (22,5 mg, 0,117 mmol). The reaction mixture was stirred at room temperature for 2 days. The mixture was quenched by adding 10% aqueous HCl (1 ml) and the mixture extracted with EtOAc. The organic layer is dried over MgSO4 and after evaporation of the solvent 10 mg of the crude mod is and purified column chromatography using CH 2Cl2up to 3% MeOH/CH2Cl2receiving 5 mg of compound P034. 1H-NMR (500 MHz, CDCl3) to 5.4 (s, 2H), 5,98 (d, J=14,5 Hz, 1H), 6,78 (s, 1H), 7,05 (t, 1H), 7,30 (DD, J=8.0 a, 1.0 Hz, 1H), 7.5 to 7,53 (m, 3H), 7.62mm (m, 1H), 7,68 (ush., 1H), of 7.70 (m, 1H), 7,76 (d, J=14,5 Hz, 1H), 7,82-a 7.85 (m, 2H), 7,89 (s, 1H). LC-MS (92%): APCI: Calculated 462 m/z; found: 461 (M-1).

Example 269. Getting connection P013.

Synthesis of 1-naphthalene-2-ylmethyl-1H-imidazo[l,2-b]pyrazole-7-carboxylic acid, I-148. To a solution of compound I-145 (24 mg, of 0.075 mmol) in 1,4-dioxane (1 ml) is added 1M aqueous LiOH (0.4 ml). The reaction mixture is heated to 80°C and stirred at the same temperature until the disappearance of the original substance (about 5 hours). The solvent is removed and the residue is transferred in EtOAc (10 ml). Add 10% aqueous HCl to pH=3. The suspension is filtered and the solid residue triturated in ether, receiving 20 mg of the acid, I-148. LC-MS (95%).

The synthesis of compounds P013. To a suspension of acid I-148 (20 mg, 0,068 mmol) in methylene chloride (2 ml), added DMAP (17 mg, 0,137 mmol). The suspension is converted into a homogeneous solution. To the resulting solution was added thiophene-5-sulfanilamide (11 mg, 0,068 mmol) and then EDCI (26 mg, 0,137 mmol). The reaction mixture was stirred at room temperature overnight. The solvent is removed, the residue is dissolved in EtOAc (5 ml) and washed with 10% aqueous HCl solution (1 ml). The organic layer was washed with saturated salt solution and dried over MgSO4. The solvent is evaporated, receiving 20 the g of the crude product. Purification of column chromatography using as eluent from 100% methylene chloride to 3% solution of methanol in methylene chloride yields a 10 mg connection P013.

Example 270. Getting connection P033.

To a solution of p-toluensulfonate (27 mg, is 0.135 mmol) in anhydrous THF (1 ml) at 0°C, add a solution of alcohol I-144 (25 mg, 0.09 mmol) in THF (1 ml). The mixture is stirred at 20°C for 3 hours. The solvent is removed and the residue purified column chromatography using CH2Cl2and 3% MeOHCH2Cl2to obtain 5 mg of the compound P033.1H-NMR (500 MHz, CDC13) of 2.38 (s, 3H), 3.96 points (d, 6.0 Hz, 1H), 4,27 (t, J=6.0 Hz, 1H), to 5.35 (s, 2H), 6,78 (d, J=3.5 Hz, 1H), 7.24 to 7,31 (m, 5H), 7,49-7,51 (m, 2H), 7,66-to 7.68 (m, 3H), 7,80-to 7.84 (m, 3H). LC-MS (95%): APCI-Calculated: 430 m/z; found: 429 (M-l).

Example 271. Getting connection P116.

Methyl ester 5-(2,4-dichlorophenyl)-2,4-dioxopentanoate acid, I-149. Methanol 25% wt. a solution of sodium methoxide (11 ml, 48 mol, 2 EQ.) caution (for 4 minutes) are added to a solution of 2,4-dichlorophenylamino (4,88 g, 24 mmol, 1 EQ.) and dimethyloxalate (4.8 g, 40 mmol, 1.7 EQ.) in methanol (55 ml). The reaction mixture was stirred at room temperature overnight. Add 10% aqueous HCl solution, and the liberated oil was separated, washed with water. The oil is crystallized by adding hexane. The precipitate is filtered off and recrystallized from MTBE (12 ml), Paul is the tea 0,78 g (11%) I-149. MS (AP-): 288 (M-1).1H-NMR (500 MHz, CDCl3) confirms the structure.

Ethyl ester of (E)-3-{3-[2-(2,4-dichlorophenyl)acetyl]-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl}acrylic acid, I-150. 40% aqueous solution of methylamine (28 mg, 0,363 mmol, 1.1 EQ.) add sodium pyruvate (I-149 (96 mg, 0.33 mmol, 1 EQ.) and ethyl ether (E)-4-oxobutanoic acid (45 mg, 0.35 mmol, of 1.05 equiv.) in AcOH-dioxane, 1:1 (0.4 ml). The reaction mixture was stirred at room temperature overnight. To the mixture is added ether and the resulting mixture filtered. Uterine fluid concentratein vacuum,receiving crude pyrrolidin I-150 (117 mg, 87%) as oil. LC-MS (ESI-): 397 (M-1) (87%).1H-NMR (500 MHz, CDC13) confirms the structure.

Ethyl ester of (E)-3-[3-(2,4-dichlorobenzyl)-5-methyl-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-yl]acrylic acid, I-151. Hydrazinehydrate (18 mg, 0.35 mmol, 1.2 EQ.) one portion added to a solution of pyrrolidine I-150 (117 mg, 0,294 mmol, 1 EQ.) in AcOH (1.2 ml), the reaction mixture is heated to 80°C and kept at this temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NaHCO3followed by EtOAc extraction. The organic phase is washed with saturated salt solution, dried over MgSO4, filtered and concentrated to obtain the residue (120 mg). The remainder chromatographic on SiO2(5 g) using ka is este eluent EtOAc, and getting pyrazolopyrimidine I-151 (20 mg, 17%) as a yellow oil. MS(ESI-): 392 (M-l).1H-NMR (500 MHz, CDCl3) confirms the structure.

(E)-3-[3-(2,4-dichlorobenzyl)-5-methyl-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-yl]acrylic acid, I-152. LiOH/H2O (6.2 mg, 0,146 mmol, 1.2 EQ.) add the solution of pyrazolopyrimidine I-151 (48 mg, 0,122 mmol, 1 EQ.) in a mixture of MeOH-water-THF, 1:1:1 (1.2 ml). The reaction mixture was stirred at room temperature overnight. To the mixture is added aqueous saturated solution of NH4Cl (4 ml) and the reaction mixture was extracted with CH2Cl2. The organic phase is washed with saturated salt solution, dried over MgSO4, filtered and concentrated, obtaining the acid I-152 (18.5 mg, 42%) as oil. MS (ESI+): 367 (M+1).

The synthesis of compounds P116. To a mixture of acid I-152 (18.5 mg, 0,0505 mmol, 1 EQ.) in dichloromethane (0.5 ml) is added DMAP (12,4 mg, 0,01010 mmol, 2 equiv.) 4,5-dichloro-2-thiophenesulfonyl (11.7 mg, 0,0505 mmol, 1 EQ.), and EDCI (to 19.4 mg, 0,1010 mmol, 2 EQ.). The mixture is stirred at room temperature for 3 days and then quenched with 10% aqueous HCl. The mixture is then extracted with EtOAc. The extract is washed with saturated salt solution, dried over MgSO4. The solvent is removed in vacuo and the residue chromatographic on SiO2(1 g)using a mixture of MeOH-EtOAc (19:1) as eluent. Receive 2 mg (7%) sulfonamida P116 in the form of oil. LC-MS (ESI-): 579 (M-1) (86%).1 H-NMR (500 MHz, DMSO) confirms the structure.

Example 272. Getting connection P117.

3-{3-[2-(2,4-Dichlorophenyl)acetyl]-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl}propionic acid, I-153. 2.0m THF solution of methylamine (0.2 ml, 0.4 mmol, 1.1 EQ.) add in the pyruvate solution I-149 (100 mg, 0.35 mmol, 1 EQ.) and 15% aqueous solution of tolualdehyde succinic acid (250 mg, 2,42 mmol, 7 EQ.) in AcOH (0.5 ml). The reaction mixture is stirred at a temperature of 80°C for 30 minutes, add another portion of methylamine (0.1 ml, 0.2 mmol, of 0.55 EQ.) and the reaction mixture is stirred at a temperature of 80°C for 30 minutes. The reaction mixture was concentrated, the residue is dissolved in EtOAc, the solution washed with water, saturated salt solution, dried over MgSO4filter and concentrate, getting pyrrolidin I-153 (147 mg, 114%) as a yellow oil. The oil turned into a beige solid (104 mg, 81%) by rubbing in a mixture of MTBE-hexane, 1:1. MS (ESI-): 371 (M-l).1H-NMR (500 MHz, DMSO) confirms the structure.

3-[3-(2,4-Dichlorobenzyl)-5-methyl-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-yl]propionic acid, I-154. To a solution of pyrrolidine I-153 (50 mg, 0,134 mmol, 1 EQ.) in AcOH (0.5 ml) in one portion add hydrazinehydrate (23 mg, 0.46 mmol, 3.4 equiv.) the reaction mixture is heated to 80°C and kept at this temperature for 2.5 hours. The reaction mixture was diluted with water and then extragere the t EtOAc. The organic layer was washed with saturated salt solution, dried over MgSO4, filtered and concentrated, obtaining the crude product (60 mg) as oil. The oil is triturated with ether, receiving pyrazolopyrimidine I-154 (40 mg, 80%) as a yellow solid. MS(AP-): 366 (M-1).1H-NMR (500 MHz, DMSO) confirms the structure.

The synthesis of compounds P117. To a mixture of pyrazolopyrimidine I-154 (30 mg, 0,0815 mmol, 1 EQ.) in dichloromethane (0.8 ml) is added DMAP (20 mg, 0,163 mmol, 2 equiv.) 2-thiophenesulfonyl (19 mg, 0,0815 mmol, 1 EQ.) and EDCI (31 mg, 0,163 mmol, 2 EQ.). The mixture is stirred at room temperature for 3 hours and then quenched with 10% aqueous HCl. The mixture is extracted with EtOAc. The extract is washed with saturated salt solution, then dried over MgSO4filter and concentrate the receiving of 6.5 mg (14%) sulfonamida P117 in the form of a white solid.1H-NMR (DMSO-d6) 1,4-2,0 (m, 4H), 2,77 (s, 3H), 4,08 (s, 2H), 4.26 deaths (s, 1H), 7,37 (s, 2H), 7,49 (s, 1H), 7,81 (s, 1H), 12,4 (ush., 1H), 13.3-inch (ush., 1H). LC-MS (89%): ESI-Calculated 580 m/z; found: 580.

Example 273. Getting connection P344.

Ethyl ester of 1-allyl-2-oxocyclohexanecarboxylic acid, I-155: In a round bottom flask with a volume of 1 l, equipped with a reflux condenser and a magnetic stirrer, under nitrogen atmosphere add ethyl ester 2-oxocyclohexanecarboxylic acid (19,0 g, 112 mmol), allylbromide (14.2 g, 117 mmol), THF (223 ml) and tert-piperonyl potassium (13,2 g, 117 mmol) the Mixture is refluxed on an oil bath (67°C) for 18 hours. The reaction mixture is cooled and the solvent is removed on a rotary evaporator. To the mixture is added 1M aqueous HCl until the mixture becomes paste in a cloudy solution. The mixture is extracted with CH2Cl2(3×250 ml). The combined extracts washed with water (2×250 ml) and saturated salt solution (250 ml), dried (MgSO4) and concentrated under reduced pressure, obtaining 21.8 g (93%) of compound I-155 in the form of a pale yellow oil.1H-NMR analysis shows that the substance is sufficiently pure to be used in the next stage.1H-NMR (400 MHz, CDCl3).

Ethyl ester of l-carboxymethyl-2-oxocyclohexyl carboxylic acid, I-156: In a three-neck flask with a volume of 2 l, equipped with verhneprivodnaya stirrer and two loosely fitting lids, put the connection I-155 (21.8 g, 104 mmol). In the Erlenmeyer flask, equipped with a rod stirrer, add periodate sodium (182 g, 850 mmol), potassium permanganate (3.28 g, of 20.7 mmol), potassium carbonate (10,9 g of 78.8 mmol) and water (430 ml) at room temperature. The oxidation mixture is stirred for 5 minutes and then one portion added to the flask containing the olefin I-155. The mixture is stirred at room temperature for 24 hours. Then the reaction mixture was added an additional portion of potassium permanganate (0,820 g, 5,19 mmol). The flask contents are stirred for an additional 2.5 h the owls. The reaction is quenched by slow addition of water Hydrosulphite solution of sodium up until the mixture will turn from dark brown solution in a clear yellow solution. The aqueous mixture is extracted with CH2Cl2(3×250 ml). The combined extracts washed with water (2×250 ml) and saturated salt solution (250 ml), dried (MgSO4) and concentrated under reduced pressure, obtaining of 18.6 g (79%) I-156 in the form of a pale yellow oil.1H-NMR analysis shows that the product is sufficiently pure for use in the next stage.1H-NMR (400 MHz, CDCl3).

Ethyl ester of 1-(2,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4,5,6-hexahydrobenzo-3a-carboxylic acid, I-157. In a round bottom flask, equipped with reflux condenser and stirrer, load connection I-156 (of 5.00 g, 21.9 mmol), m-xylene (45 ml) and 2,4-dichloraniline (2,95 ml, 21.9 mmol). The mixture is refluxed on an oil bath (138°C) for 6 hours. Then the reaction mixture is cooled to room temperature. The solvent is removed by evaporation, receiving a 7.92 g (98%) of compound I-157 in the form of a reddish-orange oil.1H-NMR analysis shows that the substance is sufficiently pure for use in the next stage.1H-NMR (400 MHz, CDCl3).

Ethyl ester of 7-bromo-1-(2,4-dichlorobenzyl)-2-oxo-1,2,3,4,5,6-hexahydrobenzo-3a-carboxylic acid, I-158: In a container with a volume of 40 ml, supplied the military with a stirrer and lid, put the connection I-157 (600 mg, and 1.63 mmol)dissolved in CH2Cl2(16 ml). The solution is cooled to 0°C in an ice bath and add bromine (416 μl, 8,15 mmol). The mixture is stirred for 2 hours, during which the mixture is slowly warmed to room temperature and then add triethylamine (750 μl, 5,38 mmol). The mixture is stirred for an additional 45 minutes, then the reaction quenched with water (15 ml). After stirring for 30 minutes the organic part is extracted and then dried with MgSO4. The solvent is removed by evaporation, getting a brown oil which is purified by chromatography on silica gel. The system solvent: 20% EtOAc/hexane. After cleaning they receive 431 mg of compound I-158 in the form of a yellowish-brown solid (59%).1H-NMR analysis shows that the substance is sufficiently pure for use in the next stage.1H-NMR (400 MHz, CDCl3).

Ethyl ester of 7-((E)-2-carboxyvinyl)-1-(2,4-dichlorobenzyl)-2-oxo-1,2,3,4,5,6-hexahydrobenzo-3a-carboxylic acid I-159: In a container with a volume of 18 ml, equipped with a stirrer and lid, put the compound I-158 (431 mg, 0,964 mmol), anhydrous DMF (4.8 ml) and triethylamine (of 1.34 ml, for 9.64 mmol). The mixture is stirred for 10 minutes, during which Tegaserod nitrogen. After degassing add tert-butyl acrylate (423 μl, 2.89 mmol), palladium acetate (to 21.6 mg, 0,0964 mmol) and three(o-tolyl)FOSFA is n (88,0 mg, 0,289 mmol). After adding the mixture Tegaserod nitrogen for an additional 3 minutes and then the container tightly closed with the lid. The tank is heated on an oil bath to 100°C and kept at this temperature for 22 hours. Then the reaction mixture is cooled and filtered through celite. The mixture was diluted with CH2C12(75 ml) and then washed with water (2×75 ml) and saturated salt solution (75 ml). The organic portion is dried MgSO4and concentrate under reduced pressure, obtaining tert-butyl ester as a brown oil. The crude product was dissolved in CH2C12(4.4 ml) and cooled to 0°C. To the resulting solution was added triperoxonane acid (440 ml, 5.9 equiv.) and the mixture is stirred at room temperature. After stirring for 4.5 hours impose additional portion triperoxonane acid (440 μl, 5.9 equiv.) and the mixture is stirred for 20 minutes. The solvent is removed by purging with nitrogen and the product is dissolved in ether, washed with saturated aqueous NaHCO3(4×30 ml). During the second washing NaHCO3add a small portion of the 3MNaOH (20 ml) for better separation of the layers. The aqueous layers are combined and acidified with 3M aqueous HCl to pH 1. The aqueous layer was extracted with CH2C12(3×100 ml). The organic fractions combined, dried (MgSO4) and concentrated on a rotary evaporator, the floor is th 182 mg of compound I-159 in the form of a pale yellow solid (43% yield of the reaction I-158 in the compound (I-159). 1H-NMR analysis shows that the purity of the product is sufficient for use in the next stage.1H-NMR (400 MHz, CDCl3) LC/MS purity=81,0%.

The synthesis of compounds P344. In a container with a volume of 8 ml, equipped with a mixer, put the acid I-159 (50.0 mg, 0,114 mmol), CH2Cl2(2.4 ml), 2,4,5-cryptorhynchinae (of 28.9 mg, 0,137 mmol), DMAP (33,5 mg, 0,274 mmol) and EDCI (54,6 mg, 0,285 mmol). The mixture is stirred at room temperature for 18 hours. The mixture was diluted with CH2Cl2(30 ml) and the organic portion washed with 1M aqueous HCl (30 ml), water (3×30 ml) and saturated salt solution (30 ml). The organic portion is dried (MgSO4) and concentrated on a rotary evaporator, receiving the product as a pale yellow solid. After drying receive 40,2 mg connection P344 in the form of a pale yellow solid (56%).1H-NMR (400 MHz, CDCl3) of 1.26 (t, J=7.2 Hz, 3H), 1,53 by 1.68 (m, 2H), 1,92 (m, 1H), 2,20-of 2.26 (m, 2H), 2,54 (m, 1H), 2,78 (AB sq, J=16,8 Hz, 2H), 4,19 (sq, J=7.2 Hz, 2H), 4.95 points (AB sq, J=17,2, and 17.6 Hz, 2H), of 5.68 (d, J=15.2 Hz, 1H), 7.03 is-7,08 (m, 2H), 7,10 (d, J=8.0 Hz, 1H), 7,17 (DD, J=8,4, 2.0 Hz, 1H), 7,22 (s, 1H), 7,94 (m, 1H). LC/MS (95%), MS (ESI-) Calculated: 630,5 m/z; found: 631,3 m/z.

Example 274. Getting connection P345.

The synthesis of compounds P345. In accordance with the method of synthesis P344, based on acid I-159 (50.0 mg, 0,114 mmol), CH2Cl2(2.4 ml), 4,5-dichlorothiophene-2-sulfonamida (31.8 mg, 0,137 mmol), DMAP (33,5 mg, 0,274 mmol) and EDCI (54,6 mg, 0.28 mmol), get 49,0 mg connection P345 in the form of a pale yellow solid (66%).1H-NMR (400 MHz, CDCl3) of 1.27 (t, J=6.8 Hz, 3H), 1,53-of 1.65 (m, 2H), 1,92 (m, 1H), 2,20-to 2.29 (m, 2H), 2,54 (m, 1H), 2,79 (AB sq, J=16,8 Hz, 2H), 4,20 (sq, J=7.2 Hz, 2H), 4,99 (AB sq, J=17,2, and 17.6 Hz, 2H), 5,65 (d, J=15.2 Hz, 1H), 7,12 (d, J=8,4 Hz, 2H), 7,20 (DD, J=8,4, 2.0 Hz, 1H), 7,29 (s, 1H), 7,49 (d, J=2.0 Hz, 1H), 7.62mm (s, 1H). Sulfonamidnuyu part of the spectrum not visible. LC/MS (95%), MS (ESI-) Calculated: 651,4 m/z; found: 651,4 m/z.

Example 275. Getting connection P346.

The synthesis of compounds P346. In accordance with the method of synthesis P344, based on acid I-159 (35,0 mg, 0,0799 mmol), CH2Cl2(1.7 ml), 3,4-diftorhinolonom (18.5 mg, 0,0959 mmol), DMAP (23,5 mg, 0,192 mmol) and EDCI (to 38.3 mg, 0,200 mmol), get 30,8 mg connection P346 in the form of a pale yellow solid (63%).1H-NMR (400 MHz, CDCl3) LC/MS purity=86,5%.

Example 276. Getting connection P075.

1H-Indole-4-silt ether acetic acid, I-160. Acetic anhydride (x 16.75 ml, 169 mmol, 1.5 EQ.) slowly (over 7 minutes) are added to a solution of 4-hydroxyindole (15 g, 113 mmol, 1 EQ.) in pyridine (113 ml) at room temperature (the temperature increases from 25 to 32°C). After stirring for an additional 5 minutes the reaction mixture is cooled with ice water and add 10% aqueous HCl (340 ml), then EtOAc (565 ml). The organic portion was separated and the aqueous layer was extracted with EtOAc (100 ml). The combined organic layers washed with 10% in the ne HCl (2×50 ml), water (2×300 ml), saturated salt solution (300 ml) and dried over MgSO4. Filtration and removal of solvent by evaporation yield 19.3 g (98%) I-160 in the form of a light brown solid.1H-NMR (500 MHz, CDCl3) confirms the structure.1H-NMR (500 MHz, CDCl3) 2,39 ppm (s, 3H), to 6.43 ppm (ush. s, 1H), 6,86 (d, 1H, J=16.0 Hz), 7,14 (m, 2H), 7,24 (m, 1H), 8,20 (ush. s, 1H).

3-(Naphthalene-2-carbonyl)-1H-indol-4-silt ether acetic acid, I-161. Methylanisole (26 ml, 78 mmol, of 1.05 EQ., 3.0m solution in ether) slowly via syringe (within 10 minutes) are added to a solution of acetate I-160 (13 g, 74 mmol, 1 EQ.) in anhydrous CH2Cl2(260 ml) at room temperature. The mixture is stirred for 5 minutes at room temperature, to the mixture via syringe added dropwise within 5 minutes at room temperature zinc chloride (223 ml, 3.0 EQ., 1.0m solution in ether). The mixture is stirred for 10 minutes at room temperature, then at room temperature for 3 minutes, add a solution of 2-nafolklore (14,85 g of 1.05 equiv.) in anhydrous CH2Cl2(87 ml). The reaction mixture is stirred for 3 hours at room temperature and then poured into a saturated aqueous solution of NH4Cl (866 ml) and the mixture was diluted with CH2Cl2(200 ml). The aqueous layer was extracted with CH2Cl2(100 ml). The combined organic layers washed with water (500 m is×2), saturated salt solution (500 ml), dried over MgS4filter and concentrate, receiving 24.4 g (100%) as a brown solid. To the solid product add MTBE (100 ml), the mixture is refluxed, cooled to 30-40°C and filtered, the residue is washed on the filter with MTBE (50 ml, 25 ml, 5 ml×2), then ether (5 ml×2)to give 16.0 g (65%) I-161 in the form of a light brown solid. MS (ESI-): 329.1H-NMR (500 MHz, CDCl3) confirms the structure.1H-NMR (500 MHz, CDCl3) to 2.41 (s, 3H), 6.89 in (d, 1H), 7,03 (DD, 1H, J=16.5 Hz), to 7.09 (m, 2H), 7,52 (t, J=to 15.0 Hz, 1H), 7,56 (t, 1H, J=15,0 Hz), 7,79 (m, 3H), 7,88 (d, 1H, J=16.0 Hz), 8,12 (ush. s, 1H), 9,35 (ush. s, 1H).

3-Naphthalene-2-ylmethyl-1H-indol-4-ol, I-162 BH3THF (1M in THF, 120 ml, 120 mmol, 3.3 EQ.) slowly added to a solution of compound I-161 (12.0 g, of 36.4 mmol, 1 EQ.) at 0°C under nitrogen atmosphere. The reaction mixture allow to warm to room temperature and stirred over night. The reaction mixture was quenched by slow addition of methanol (120 ml), evaporated and subjected to co-evaporation with MeOH (3×120 ml). The residue is purified by chromatography on silica gel (150 g, CH2Cl2)to give compound I-162 (6.2 g, 62%). MS (ESI-): 271(M-1).1H-NMR (500 MHz, CDCl3) confirms the structure.

Methyl ether (3-naphthalene-2-ylmethyl-1H-indol-4-yloxy)acetic acid, I-163. The solution methylpropanoate (3,10 g, 1.9 ml, 20.3 mmol, of 1.05 equiv.) in DM is A (20 ml) is added slowly to a mixture of compound I-162 (5.29 g, to 19.4 mmol, 1 EQ.) and K2CO3(3,21 g, 23.2 mmol, 1.2 EQ.) in DMF (51 ml). The reaction mixture was stirred at room temperature overnight (17 hours). Add the mixture of water:saturated solution of salt (5:1, 180 ml) and the resulting solution extracted with EtOAc (180 ml, 140 ml, 70 ml). The organic layer was washed with saturated salt solution (2×210 ml), dried over MgSO4filter and concentrate the receiving of 7.8 g of a solid substance. The residue is washed with ether (20 ml) and filtered, obtaining 5.0 g (75%) I-163 in the form of a solid not quite white matter. MS (ES+): 346 (M+1).1H-NMR (500 MHz, CDCl3) confirms the structure.

(3-Naphthalene-2-ylmethyl-1H-indol-4-yloxy)acetic acid, I-164. A solution of 2n. NaOH (9.5 ml, 19 mmol, 2 EQ.) added to a solution of compound I-163 (3.3 grams, of 9.55 mmol, 1 EQ.) in a mixture of THF-MeOH, 2:1 (132 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to ~20 ml, add 10% aqueous HCl (10 ml) and then water (50 ml). The mixture is extracted with EtOAc (250 ml) and the organic phase is dried over MgSO4filter and concentrate, receiving compound I-164 (2,95 g, 92%) as a solid, not quite white matter.1H-NMR (500 MHz, DMSO) confirms the structure.

The synthesis of compounds P075. To a solution of compound I-164 (2,87 g, 8,65 mmol, 1 EQ.) in dichloromethane (80 ml) is added DMAP (2,11 g, 17,30 mmol, 2 equiv.) 4,5-dichloro-2-thiophenesulfonyl (2.1 mg, the remaining 9.08 mmol, of 1.05 equiv.) and EDCI (3,22 g, 17,30 mmol, 2 EQ.). The mixture is stirred at room temperature for 16 hours and then quenched with 10% aqueous HCl (5 ml), then EtOAc (100 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The combined organic layers washed with saturated aqueous NH4Cl (100 ml), saturated salt solution (2×100 ml), dried over MgSO4filter and concentrate, getting the balance (of 3.31 g, 63%). The residue is triturated with MeOH (12 ml), refluxed, and then cooled to 0°C and filtered, obtaining of 2.97 g (71%) in the form polunochnogo sulfonamida 4.HPLC: 96,2%.: ESI-Calculated: 544 m/z; found: 544.1H-NMR (DMSO-d6) confirms the structure. 1H-NMR (DMSO-d6) 4,32 (s, 2H), and 4.68 (s, 2H), 6,18 (d, J=7.5 Hz, 1H), 6.87 in (t, J=8.0 Hz, 1H), 6,94 (d, J=8.5 Hz, 1H), 7,01 (d, J=3.5 Hz, 1H), 7,41 (m, 2H), 7,46 (DD, J=8,5, 1.5 Hz, 1H), 7,72 (d, J=8.5 Hz, 2H), 7,79-7,81 (m, 2H), 7,89 (s, 1H), 10,9 (USS, 1H).

Example 277. Getting connection P162.

Methyl ester of 2-(3-naphthalene-2-ylmethyl-1H-indol-4-yloxy)propionic acid, I-165. A solution of indole (I-162 (125 mg, 0.46 mmol, 1 EQ.), methylpropionate (80 mg, 0.48 mmol, of 1.05 equiv.) and K2CO3(76 mg, 0.55 mmol, 1.2 EQ.) in DMF (1.7 ml) was stirred at 50°C for 16 hours. Add a mixture of water and saturated salt solution, 5:1, the suspension is extracted with EtOAc, the organic layer washed with water, saturated salt solution, dried over MgSO4, filtered and concentrated, obtaining the complex is ether I-165 (150 mg, 91%) as a green oil. MS (AP+): 360 (M+1).1H-NMR (500 MHz, CDCl3) confirms the structure.

2-(3-Naphthalene-2-ylmethyl-1H-indol-4-yloxy)propionic acid, I-166. 2n. NaOH solution (of 0.44 ml, 0.88 mmol, 2.1 EQ.) added dropwise to a solution of ester I-165 (150 mg, 0.42 mmol, 1 EQ.) in THF-MeOH (2:1, 6 ml). The reaction mixture is stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo and then the residue is added 10% aqueous HCl (4 ml) and water (6 ml). The residue is extracted with EtOAc (6 ml, 4 ml). The solution was washed with saturated salt solution, dried over MgSO4getting acid I-166 (149 mg) as oil. MS (ESI-): 344 (M-1).1H-NMR (500 MHz, CDCl3) confirms the structure.

The synthesis of compounds P162. The acid I-166 (134 mg, 0,39 mmol, 1 EQ.) in dichloromethane (4 ml) is added DMAP (95 mg, 0.77 mmol, 2 equiv.) 4,5-dichloro-2-thiophenesulfonyl (94 mg, 0.41 mmol, of 1.05 equiv.) and EDCI (148 mg, 0.77 mmol, 2 EQ.). The mixture is stirred at room temperature for 2 hours and quenched with 10% aqueous HCl (1 ml) and then water (4 ml). The aqueous layer was extracted with EtOAc (4 ml). The combined organic layers washed with saturated salt solution and then dried over MgSO4. The resulting residue is purified by chromatography on SiO2(5 g) CH2Cl2receiving a sulfonamide P162 (101 mg, 47%) as a greenish solid. LC-MS (ESI-): 558 (M-1) (99%).1H-NMR (500 MHz, D IS FROM) confirms the structure.

Example 278. Getting connection P171.

Methyl ester of 2-methyl-2-(3-naphthalene-2-ylmethyl-1H-indol-4-yloxy)propionic acid, I-167. A solution of indole (I-162 (300 mg, 1.1 mmol, 1 EQ.), methylpropionate (609 mg, 3,29 mmol, 3 equiv.) K2CO3(607 mg, 4,39 mmol, 4 equiv.) and MgSO4(132 mg, 1.1 EQ.) in DMF (13.3 ml) with stirring, heated to 75°C and maintained at this temperature for 24 hours. The reaction mixture was filtered, concentrated, receiving ~0.4 g of the crude product. Chromatography on SiO2(20 g) using as eluent a mixture of EtOAc/hexane (1:4) leads to the production of compounds I-167 (96 mg, 23%) as oil.Rf=0,31 (EtOAc/hexane, 1:3).1H-NMR (500 MHz, CDCl3) confirms the structure.

2-Methyl-2-(3-naphthalene-2-ylmethyl-1H-indol-4-yloxy)propionic acid, I-168. 2n. NaOH solution (of 0.53 ml, 1.06 mmol, 4.1 EQ.) added dropwise to a solution of ester I-167 (96 mg, 0.26 mmol, 1 EQ.) in a mixture of THF-MeOH (2:1.3 ml). The reaction mixture is stirred at a temperature of 75°C for 1.5 hours. The reaction mixture was concentrated in vacuo and to the residue is added 10% HCl (0.5 ml). The mixture is extracted with EtOAc (6 ml). The solution was washed with saturated salt solution, dried over MgSO4getting acid I-168 (92 mg, 100%) as oil.Rf=0,61 (MeOH/CH2Cl2, 1:7). MS (ESI+): 358 (M+1).1H-NMR (500 MHz, CDCl3) confirms the structure.

Sint is C connection P171. The acid I-168 (88 mg, 0.24 mmol, 1 EQ.) in 4 ml of dichloromethane added DMAP (60 mg, 0.49 mmol, 2 equiv.) 4,5-dichloro-2-thiophenesulfonyl (60 mg, 0.26 mmol, of 1.05 equiv.) and EDCI (94 mg, 0.49 mmol, 2 EQ.). The mixture is stirred at room temperature for 3 days and quenched by adding 10% HCl solution (1 ml) and then water (4 ml). The aqueous layer was extracted with EtOAc (4 ml). The combined organic layers washed with saturated salt solution and dried over MgSO4. The solution is concentrated and the residue is extracted with ether, receiving a sulfonamide P171 (120 mg, 87%) as a yellow solid.Rf=0,56 (MeOH/CH2Cl2, 1:7).1H-NMR (CDCl3) of 1.34 (s, 6H), was 4.42 (s, 2H), of 5.89 (d, J=8.0 Hz, 1H), for 6.81 (t, J=8.0 Hz, 1H), 6,86 (d, J=2.0 Hz, 1H), 7,06 (d, J=8.0 Hz, 1H), 7,33 (DD, J=8.0 a, 3.0 Hz, 1H), 7,39 (s, 1H), 7,40-7,46 (m, 2H), EUR 7.57 (ush., 1H), 7,70-7,83 (m, 2H), 7,79 (d, 8.5 Hz, 1H), 8,09 (ush., 1H), 8,51 (ush., 1H). LC-MS (99%): ESI-Calculated: 572 m/z; found: 572.

Example 279. Getting connection P259.

3-(l-Ethyl-1H-benzimidazole-2-ylsulphonyl)benzofuran-4-ol, I-169. A solution of 2.0m HCl in ether (3.75 ml, 7.5 mmol, 5 EQ.) added to pre-heated (40°C) suspension of 4-hydroxybenzophenone (225 mg, 1.5 mmol, 1 EQ.) and 1-methyl-1H-benzimidazole-2-thiol (Aldrich, 246 mg, 1.5 mmol, 1 EQ.) in ethanol (3.75 ml). The solution was stirred at room temperature overnight, then concentrated to about 0.5 ml To the residue add a mixture of EtOAc/dichloromethane (8 ml, 1:1), washed with a mixture of water (8 ml×2), saturated solution Sol is (6 ml), dried over MgSO4concentrate. Add ether (4 ml), the solid product is filtered off and the mother liquor is concentrated and getting 277 mg of the crude product as a red oil. The oil is triturated with MTBE (c methyl tert-butyl ether and filtered off, getting 260 mg of the product. The oil is purified by chromatography on SiO2(10 g)using a mixture of 3:7 dichloromethane/hexane, 1:1 dichloromethane/hexane and 100% dichloromethane and receiving sulfide I-169 (52 mg, 11%) as a yellow oil.Rf0,28 (dichloromethane). MS (AP-): 309 (M-1).1H-NMR (500 MHz, CDCl3) confirms the structure.

Methyl ester [3-(1-ethyl-1H-benzimidazole-2-ylsulphonyl)benzofuran-4-yloxy]acetic acid, I-170. The solution methylpropanoate (27 mg, 0,173 mmol, 1.2 EQ.) in acetone (0.2 ml) are added to a suspension of the sulfide I-169 (45 mg, 0,1445 mmol, 1 EQ.) and K2CO3(30 mg, 0,217 mmol, 1.5 EQ.) in acetone (0.2 ml). The reaction mixture was sealed in a volume of 4 ml, heated to 50°C and maintained at this temperature for 5 hours. Add water to the mixture and then EtOAc, the emulsion was quenched with 10% HCl to achieve pH=2. The organic layer was separated, washed with water, saturated salt solution, dried over MgSO4receiving 50 mg of product as an orange oil which partially crystallizes in the air. The product is triturated in MTBE, then in a mixture of MTBE/hexane (1:1)to give ester I-170 (36 mg, 65%) in view of the orange solids. Rf0,49 (dichloromethane). MS (ESI-): 381 (M-l),1H-NMR (500 MHz, CDCl3) confirms the structure.

[3-(1-Ethyl-1H-benzimidazole-2-ylsulphonyl)benzofuran-4-yloxy]acetic acid, I-171. 2n. NaOH solution (0.1 ml, 0.21 mmol, 2.5 EQ.) added dropwise to a solution of ester I-170 (32 mg, 0,084 mmol, 1 EQ.) in a mixture of THF-MeOH (1:1, 0.5 ml). The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated invacuum,to the residue water is added, then EtOAc. The suspension is quenched with 10% HCl. The organic layer is washed with water, saturated salt solution, dried over MgSO4getting acid I-171 (27 mg, 88%) as a solid not quite white matter. Rf=0,37 (MeOH/dichloromethane, 1:4). MS (ESI-): 367 (M-1).1H-NMR (500 MHz, CDCl3) confirms the structure.

The synthesis of compounds P259. The acid I-171 (24 mg, 0,065 mmol, 1 EQ.) in 0.5 ml of dichloromethane added DMAP (16 mg, 0,130 mmol, 2 equiv.) 4,5-dichloro-2-thiophenesulfonyl (15 mg, 0,065 mmol, of 1.05 equiv.) and EDCI (25 mg, 0,130 mmol, 2 EQ.). The mixture is stirred at room temperature overnight, then quenched with 10% HCl and water. The aqueous layer was extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried over MgSO4. The solution is concentrated and the solid residue extracted with a mixture of MTBE/hexane (1:1), then ether. The solution is concentrated and receiving of 24.5 mg of product as a yellow oil. the aslo chromatographic on SiO 2(elution: EtOAc/hexane, 1:3, 2:3), receiving a sulfonamide P259 (10 mg, 26%) as a yellow oil.Rf=of 0.28 (EtOAc).1H-NMR (CDCl3) to 1.47 (m, J=7.2 Hz, 3H), 4,29 (sq, J=7.2 Hz, 2H), amounts to 4.76 (s, 2H), of 6.71 (DD, J=6,4, 1.8 Hz, 1H), 6,91 (DD, J=11,6, 0,4 Hz, 1H), 7,16 (DD, J=11,6, 0,4 Hz, 1H), 7,26-to 7.32 (m, 3H), 7,73 (m, 1H), to 8.20 (d, J=4,8 Hz, 2H,). LC-MS (94%): ESI-Calculated: 581 m/z; found: 581.

Example 280. Getting connection P153.

Compound I-162 (0.50 g, 0,0018 mol) is dissolved in DMF (8 ml). To the solution was added potassium carbonate (1,00 g, 0,0072 mol) and the mixture is stirred for 15 minutes. Add ethylbromoacetate (2.5 ml, 0,087 mol) and the resulting mixture was stirred at 70°C. overnight, concentrated and partitioned between CH2Cl2and water. Layer CH2Cl2washed with saturated salt solution, dried over anhydrous Na2SO4filter, concentrate and chromatographic on silica gel (elution with gradient EtOAc/hexane)to give a fraction enriched in ethyl ether debtor(3-naphthalene-2-ylmethyl-1H-indol-4-yloxy)acetic acid (~30%,1H-NMR, LC-MS), which is used in the next stage. Defloration fraction (containing approximately 30 mg) is treated with 7M NH3/MeOH (2 ml) at room temperature overnight in a tightly closed container. Chromatography with reversed phase (C18-silica gel; elution with a gradient of MeCN/water) results in connection P153, 5,8 mg 1H-NMR (400 MHz, DMSO-d6) 4,29 (s, 2H), 6,83 (d, J=8.0 Hz, 1H), 7,03 (d, J=8.0 Hz, 1H), 7,06 (m, 1H), 7,27 (DD, J=8,0, 0.8 Hz, 1H), 7,39-of 7.48 (m, 3H), 7,72 (s, 1H), 7,76-7,86 (m, 3H), 8,24 (ush., 1H), 8,48 (ush., 1H), of 11.15 (ush., 1H). LC/MS (86,3%) ESI-Calculated: M=366,4; found: 365,3 m/z.

Example 281. Getting connection P159.

Synthesis of ethyl ester of 5-bromo-4-oxopentanoic acid, I-171. Bromine (22 g, 7.2 ml, 138,8 mmol) in a stream of N2within half an hour added to a solution of tillemont (20 g, 138,8 mmol) in 250 ml of EtOH at room temperature. After complete addition, the reaction mixture was stirred at room temperature for a further half an hour and then refluxed for 1.5 hours.1H-NMR analysis of the sample shows the presence of three products c ratio SM: monobrom:dibromo=1:2,5:0,5. The reaction mixture is cooled to room temperature and concentrated in vacuo. The residue is transferred in a simple ether, washed with saturated solution of NaHCO3(3×50 ml), water, saturated salt solution, dried over MgSO4and concentrate, receiving of 20.3 g of compound I-171 in the form of a dark brown oil, which was used in the next stage of the synthesis without further purification.1H-NMR confirms the structure.

Synthesis of ethyl-2-amino-4-thiazolyl-3-propionate, I-172. A solution of the crude bromide I-171 (8 g, 35.8 mmol) in 50 ml of ethanol are added to a solution of thiourea (2.85 g, 37,59 mmol) in 20 ml of ethanol. Rea is operating, the mixture is stirred at room temperature for 1 hour and refluxed for 4 hours. The solvent is removed; the residue is transferred into a 100 ml EtOAc, washed with water, saturated solution of NaHCO3saturated salt solution, dried over MgSO4and concentrate, receiving crude oil product. The crude product is purified column chromatography, using as eluent from 100% methylene chloride to 5% MeOH/methylene chloride and receiving 3.75 g of compound I-172.1H-NMR, MS.

Synthesis of ethyl ester of 3-imidazo[2,1-b]thiazole-3-ylpropionic acid, I-173. Diacetyl of bromoacetaldehyde (8 g, 40,31 mmol) in 60 ml of aqueous 3n. HCl is refluxed for 1 hour. The solution is cooled to room temperature and extracted with ether (3×30 ml). The combined organic layers dried over MgSO4and added dropwise to the boiling solution of 3.75 g of ethyl-2-amino-4-thiazolyl-3-propionate, I-172, in 100 ml of EtOH. Athanasius ether is collected. After collection of the ether, the reaction mixture is refluxed for 8 hours. The solvent is removed and the residue is washed with saturated solution of NaHCO3. The mixture is extracted with methylene chloride (3×50 ml). The combined organic layers washed with water, saturated salt solution, dried over MgSO4concentrate with 3 g of the crude product. The crude product is purified column chromatography, using as eluent a mixture of from 20% to 50% EtOAc/hexane and getting 1 is the pure product of the I-173. 1H-NMR.

Ethyl ester of 3-(5-formylamino[2,1-b]thiazole-3-yl)propionic acid, I-174. The reagent of Vilsmeier receive at 0°C-5°C by adding dropwise POCl3(of 0.085 ml, 0,892 mmol) with stirring in a solution of 0.1 ml of DMF. The mixture is stirred at 0°C for ½ hour and then added dropwise to imidazothiazole I-173 (100 mg, 0,446 mmol) in 2 ml of CHCl3. The reaction mixture was stirred at room temperature for 2 hours, then refluxed for 24 hours. The mixture is cooled to room temperature and quenched with water, stirred for ½ hour, then extracted with methylene chloride. The organic layer is dried over MgSO4and concentrate, receiving 30 mg of product, I-174.1H-NMR.

Ethyl ester of 3-[5-((E)-2-naphthalene-2-elwenil)imidazo[2,1-b]thiazole-3-yl]propionic acid, I-175. To a suspension of NaH (60% in mineral oil, 10 mg, 0.25 mmol) in 3 ml of anhydrous THF added bromide (2-naphthyl)methyltriphenylphosphonium (80 mg, 0,158 mmol). The mixture is heated to 60°C and kept at this temperature for 1 hour, then add the aldehyde I-174 (40 mg, 0,158 mmol) in 2 ml of THF. The reaction mixture was stirred at 60°C over night. The mixture is cooled to room temperature, quenched with saturated solution of NH4Cl and extracted with methylene chloride. The organic layer is dried over MgSO4concentrate and received untreated the i.i.d. product is purified column chromatography, using as eluent 20% to 50% EtOAc/hexane and receiving 30 mg of pure product, I-175.1H-NMR.

3-[5-((E)-2-Naphthalene-2-elwenil)imidazo[2,1-b]thiazole-3-yl]propionic acid, I-176. To a solution of ethyl ester I-175 (30 mg, 0.079 in mmol) in a mixture of THF:MeOH (1.5 ml/0.5 ml) is added 0.16 ml LiOH (1N.). The mixture is stirred at 40°C for 2 hours. TLC (5% MeOH/CH2Cl2) shows that the reaction is complete. The reaction mixture was concentrated in vacuo and to the residue is added 10% solution of HCl to achieve pH=5-6. The mixture is extracted with CH2Cl2(2×5 ml). The combined organic layers washed with a saturated solution of salt, dried (MgSO4and concentrate, receiving 20 mg of the crude product, I-176.1H-NMR (500 MHz, CD3OD) confirms the structure, IHMS (ESI-): 348 (M-1), 90%.

The synthesis of compounds P159. To a suspension of acid I-176 (10 mg, 0,028 mmol) in CH2Cl2(0.5 ml) are successively added 2,3-dichlorothiophene-5-sulfonamide (7 mg, 0,028 mmol), DMAP (7 mg, 0,057 mmol) and EDCI (11 mg, 0,057 mmol). The mixture is stirred at room temperature overnight. The solution is acidified with 10% HCl to pH=5-6 and extracted with EtOAc (2×5 ml). The organic layer is washed with water, dried over MgSO4and concentrated in vacuo, receiving 20 mg of the crude product. Purification of column chromatography using CH2Cl2leads to to obtain 7 mg of pure about the ukta, P153.1H-NMR (500 MHz, CDCl3) confirms the structure, IHMS (ESI-): 562 (M-1), 60%.

Example 282. Getting connection P244.

Synthesis of 4-bromo-1H-indole-2,3-dione (I-177) and 6-bromo-1H-indole-2,3-dione (I-178) (2a). To a solution of chloralhydrate (50.0 g, 0,247 mol) in water (237 ml) are successively added Na2SO4(69,0 g, 0,486 mol), 3-bromaniline (40,0 g, 0,233 mol) in a mixture of 37% HCl (25 ml, 0,302 mol) and water (632 ml) with vigorous stirring. After complete addition, the reaction mixture is refluxed for 10 minutes and allow to cool to room temperature. Dropped the precipitate was separated by filtration, washed with water (3×100 ml) and dried in vacuum, obtaining the crude isonicotinamide. This product add one portion with vigorous stirring to concentrated H2SO4(790 ml) at such a rate that the temperature of the reaction mixture was in the range of from 50 to 70°C. the Reaction mixture is heated to 80°C, kept at this temperature for 20 minutes and enable the mixture to cool to room temperature. The cooled mixture was poured into crushed ice (about 3200 g). The mixture is left for 1 hour. Loose orange precipitate was separated by filtration, washed with water and dried, obtaining a mixture of compound I-177 and I-178 (40 g, 83%). MS (ESI+): 227 (M+1).1H-NMR (DMSO-d6).

With ntes of atelectasia I-179. A mixture of compound I-177 and I-178 (25,0 g, 0,111 mol), ethylene glycol (27.5 g, 0,442 mol) and monohydrate p-toluensulfonate acid (2.5 g, 11.3 mmol) in benzene (500 ml) is refluxed with trap Dean-stark removal of the formed water. The reaction mixture allow to cool to room temperature, washed with a 10% aqueous solution of NaHCO3and then water. After concentrating obtain the crude product (25 g)which is purified by recrystallization from a mixture of EtOAc/hexane, receiving 4-bromoisatin-3-atlantal, I-179 (8,2 g, 27%), in the form of a solid, not quite white matter. MS (ESI+): 270 (M+1).1H-NMR (DMSO-d6).

Synthesis of ethylenically I-180 (N-H-derived). A mixture of compound I-179 (5.4 g, 20 mmol), tri-o-tolylphosphino (2.2 g, 7 mmol) and palladium acetate (0.5 g, 2 mmol) in triethylamine (20 ml) and methyl acrylate (5 g, 70 mmol) in a sealed tube was heated to 100°C and stirred at a temperature of 100°C for 6 hours, then cooled. The reaction mixture was poured with stirring into 600 ml of a mixture of ice water, extracted with CH2Cl2. The combined organic layers washed with water, saturated salt solution (100 ml) and dried over Na2SO4. After removal of solvent the crude product is purified by chromatography on silica gel, receiving compound I-180 (4.5 g, 81%) as a solid, not quite white ve is esta. 1H-NMR (DMSO-d6).

Synthesis of ethylenically I-181 (N-CH3-derivative): a Mixture of ketala I-180 (3 g, 11 mmol), methyliodide (g, mmol) and K2CO3(10 g, 55 mmol) in DMF (40 ml) was stirred at room temperature overnight. The mixture is then poured into 600 ml of a mixture of ice water with stirring. Product highlight extraction with ethyl acetate and the crude product is purified by chromatography on silica gel, receiving N-methyl-derivative of the I-181 in the form of a solid not quite white matter (2.8 g, 80%).1H-NMR(DMSO-d6).

Hydrolysis to I-182 (N-H-derived). To a solution of ester I-180 (2.0 g, to 5.58 mmol) in MeOH (20 ml) add a solution of NaOH (0.45 g, and 11.2 mmol) in water and the resulting mixture was stirred at room temperature for 16 hours. After removal of the methanol aqueous residue cooled to -5°C and acidified with 10% HCl to pH~2. The precipitate was separated by filtration, washed with water and dried, obtaining the compound I-182 (1.8 g, 86%).1H-NMR (DMSO-d6).

Hydrolysis to I-183 (N-CH3-derived). Compound I-183 is obtained from the I-181 similarly, to obtain compound I-182 (95% yield).1H-NMR (DMSO-d6).

(E)-3-(2,3-Dioxo-2,3-dihydro-1H-indol-4-yl)acrylic acid, I-184. To a suspension of I-182 (2.1 g, 5 mmol) in MeOH (50 ml) under stirring at room temperature, add concentrated HCl (50 ml). The resulting reaction mixture is heated to 50°C and incubated for p and this temperature for 3 hours, cooled to room temperature and poured with stirring into 200 ml of a mixture of ice water. The formed precipitate was separated by filtration, washed with water and dried, obtaining a mixture of compound I-184 in the form of an orange solid (1.6 g, 90%).1H-NMR (DMSO-d6).

(E)-3-(1-Methyl-2,3-dioxo-2,3-dihydro-1H-indol-4-yl)acrylic acid, I-185. Compound I-185 get with 90% yield from I-183 similarly, to obtain compound I-184.1H-NMR (DMSO-d6).

[(E)-3-(2,3-Dioxo-2,3-dihydro-1H-indol-4-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid, I-186. To the acid solution I-184 (1.4 g, the 6.06 mmol) in CH2Cl2(28 ml) successively at room temperature is added 4-dimethylaminopyridine (1.48 g, 12,11 mmol), 3,4-dichlorodiphenylmethane (1.56 g, to 6.67 mmol) and the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (2,32 g, 12,11 mmol) and the resulting mixture is stirred for 20 hours. After removal of solvent the residue is dissolved in acetic acid (l g/1 ml) and diluted with water (10 ml). The formed precipitate was separated by filtration, washed with water and dried in vacuum, obtaining the compound (I-186 (2.1 g, 78%).1H-NMR (DMSO-d6).

[(E)-3-(1-Methyl-2,3-dioxo-2,3-dihydro-1H-indol-4-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid, I-187. Compound I-187 derived from I-185 similarly, to obtain compound I-186, c 79% yield.1H-NMR (DM what About the-d 6).

A General method of obtaining analogues "3-aminoxide".

General method A-15. A mixture of compound I-187 (1 EQ.), aniline (1.2 EQ.) and monohydrate p-TsA (of 0.05 EQ.) in MeOH was heated to 65°C, maintained at this temperature for 6 hours and then enable the mixture to cool to room temperature. After concentration in vacuo the residue is purified by chromatography on silica gel, getting Imin. To a solution of imine (1 EQ.) in glacial acetic acid add cyanoborohydride sodium (3 EQ.) at room temperature and stirring is continued for 2 hours. The reaction mixture is quenched with water. The mixture is stirred for 30 minutes at room temperature. The precipitate was separated by filtration, washed with water and dried, obtaining 3-amino-2-oxindol-derived.

General method A-16. A mixture of compound I-187 (1 EQ.), aniline (1.2 EQ.) and monohydrate p-TsA (of 0.05 EQ.) in toluene is refluxed for 16 hours, then enable the mixture to cool to room temperature. The reaction mixture is diluted with methylene chloride. To the resulting mixture in several portions add Na(CN)BH3. After stirring at room temperature for 2 hours the reaction is quenched with water. The formed precipitate was separated by filtration, washed with water and dried, obtaining 3-amino-2-oxindol-derived.

The synthesis of the is placed P244. In accordance with method A-15, compound I-186 subjected to interaction with 2-naphthylamine getting connection P244 with 76% yield.1H-NMR (DMSO-d6) is 6.78 (d, J=16.0 Hz, 1H), 6,94 (d, J=8.0 Hz, 1H), 7,22 (DD, J=9,0, 2.5 Hz, 1H), 7,37 (d, J=29.0 Hz, 1H), and 7.4-7.5 (m, 4H), 7,80-of 7.90 (m, 5H), 8,66 (d, J=16.0 Hz, 1H), 11,00 (s, 1H) LC/MS (78%) (ESI-) Calculated: 556,46 m/z; found 556,0 m/z.

Example 283. Getting connection P241.

In accordance with method A-16, a connection I-186 subjected to interaction with 2-naphthylamine getting connection P241 with 82% yield.1H-NMR (DMSO-d6) of 5.40 (s, 1H), is 6.54 (d, J=16 Hz, 1H), of 6.96 (DD, J=20,5, 8.0 Hz, 2H), 7,12 (t, J=7.5 Hz, 1H), 7,21-7,37 (m, 5H), to 7.61 (DD, J=26,5, 8.5 Hz, 2H), a 7.85 (s, 1H), 7,94 (d, J=16.5 Hz, 1H), a 10.74 (s, 1H) LC/MS (82%) (ESI-) Calculated: 558,46 m/z; found 558,0 m/z.

Example 284. Getting connection P245.

In accordance with method A-15, compound I-186 subjected to interaction with 2-naphthylamine, receiving the connection P245 c 71% yield; LC/MS 94%.1H-NMR (DMSO - d6) 3,17 (s, 3H), 6,77 (d, J=16 Hz, 1H), 6,93 (d, J=8 Hz, 1H), 7,24 (DD, J=9,0, 2.5 Hz, 1H), 7,40 (d, J=29.0 Hz, 1H), 7,40-to 7.50 (m, 4H), 7,80-of 7.90 (m, 5H), 8,68 (d, J=16.0 Hz, 1H), 11,03 (s, 1H) LC/MS (71%) (ESI-) Calculated: 570,48 m/z; found 568,5 m/z.

Example 285. Getting connection P242.

In accordance with method A-16, a connection I-187 subjected to interaction with 2-naphthylamine, receiving the connection P242 c 94% yield.1H-NMR (DMSO-d6).

Example 286. Getting connection P252.

In accordance with the methods of the th A-16, compound I-187 subjected to interaction with 2,4-dichloroaniline, receiving the connection P252 with 99% yield.1H-NMR (DMSO-d6) 3,18 (s, 3H), 5,52 (d, J=8,4 Hz, 1H), 6,18 (s, 1H), 6,51 (d, J=15.6 Hz, 2H), 7,01 (DD, J=8,8, 2.8 Hz, 1H), 7,24 (d, J=8,4 Hz, 1H), 7,29 (d, J=2.4 Hz, 2H), 7,42 (t, J=8 Hz, 1H), to 7.84 (d, J=16 Hz, 1H), 7,88 (s, 1H) LC/MS (99%) (APCI-) Calculated: 589 m/z; found 588 m/z.

Example 287. Getting connection P268.

In accordance with method A-16, a connection I-186 subjected to interaction with 2,4-dichloroaniline, receiving the connection P268 with 99% yield.1H-NMR (DMSO-d6).

Example 288. Getting connection P270.

In accordance with method A-16, a connection I-186 subjected to interaction with 3,4-diftorhinolonom, receiving the connection P270 with 99% yield.1H-NMR (DMSO-d6) a 3.15 (s, 3H), of 5.48 (d, J=8.0 Hz, 1H), 6,24 (ush. d, J=8,8 Hz, 1H), 6.48 in (m, 1H), to 6.57 (d, J=16 Hz, 1H), of 6.71 (ush. d, J=9.6 Hz, 1H), 7,07 (sq, J=9,2 Hz, 1H), 7,14 (d, J=8.0 Hz, 1H), 7,30 (d, J=8.0 Hz, 1H), 7,45 (t, J=8.0 Hz, 1H), 7,83 (d, J=16 Hz, 1H), 7,87 (s, 1H). LC/MS (95%) (ESI-). Calculated: 558,41 m/z; found 557 m/z.

Example 289. Getting connection P247.

[(E)-3-(3-Amino-1-methyl-2-oxo-2,3-dihydro-1H-indol-4-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid, I-188. To a solution of isatin-derived I-187 (350 mg, 0.8 mmol) in MeOH (8 ml) at ~5°C add NH4OH (1 ml). The reaction mixture was stirred at room temperature for 16 hours and then diluted with 50 ml of water. The formed precipitate was separated by filtration, dried in in the sbhe and suspended in glacial acetic acid (8 ml). To the resulting mixture add cyanoborohydride sodium (150 mg) at room temperature and stirring is continued for 2 hours. The reaction mixture is quenched with water. The mixture is stirred for 30 minutes at room temperature. The precipitate was separated by filtration, washed with water and dried, obtaining the amino-derivative of the I-188 (300 mg, 85%).1H-NMR; MS.

The synthesis of compounds P247. To a solution of amine I-188 (45 mg, 0.1 mmol) and DMAP (45 mg) in CH2Cl2(5 ml) was added naphthalene-2-carbonylchloride (21 mg, 0.12 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 24 hours. After removal of solvent the residue is dissolved in acetic acid (3 ml) and the solution was diluted with ice water (50 ml). The formed precipitate was separated by filtration, washed with water and dried, obtaining the crude product (60 mg)which is purified by chromatography on silica gel, receiving the connection P247 (25 mg, 40%) as a solid, not quite white matter.1H-NMR (500 MHz, DMSO-d6); 3,20 (s, 3H), 6,40 (s, 1H), 6,46 (d, J=16.0 Hz, 1H),? 7.04 baby mortality (d, J=7.5 Hz, 1H), 7,31-7,39 (m, 2H), 7,52 (d, J=16.0 Hz, 1H), to 7.59 (t, J=7,0 Hz, 1H), to 7.67 (t, J=7,0 Hz, 1H), 7,92 (d, J=7.5 Hz, 1H), 7,99 (d, J=9.0 Hz, 1H), 8,14 (d, J=8.0 Hz, 1H), 8,63 (s, 1H). LC/MS (97%) ESI-Calculated: 600,5 m/z; found: 599,3 m/z (M-1).

Example 290. Getting connection P265.

[(E)-3-(3-amino-1-methyl-2-oxo-2,3-dihydro-1H-indol-4-yl)acryloyl]amide 4,5-dichlorothiophene-2-sulfonic acid, I-188(0,110 g, 0.25 mmol) dissolved in chloroform (3 ml). To the solution was added glacial acetic acid (0,043 ml, 0.75 mmol), then isoamylase (0,34 ml, 0,2525 mmol). The mixture is stirred at 60°C for 30 minutes, then enable the mixture to cool to room temperature, incubated at room temperature for 1 hour, then concentrated under nitrogen atmosphere, washed (3×) with water by decantation (without waste) and dried in nitrogen atmosphere, getting salt page. The obtained salt is used in the next stage without additional purification. IR (pure) shows a significant absorption at 2100 cm-1.

2-Naphthol (0,0540 g, the 0.375 mmol) dissolved in 3 ml of dry toluene. To the solution add leads to compounds, which derode (II) (0,0055 g of 0.0125 mmol) and the mixture is heated in an atmosphere of nitrogen to 65°C, at this time, to the mixture add a solution of 4-[(E)-3-(4,5-dichlorothiophene-2-sulfonylamino)-3-oxopropyl]-1-methyl-2-oxo-2,3-dihydro-1H-indol-3-page (0,250 mmol) in 1 ml anhydrous toluene. The resulting mixture was stirred for 30 minutes at a temperature of more than 65°C, then the mixture is cooled to room temperature and incubated at room temperature for 1 hour, concentrated and chromatographic on silica gel (elution with gradient, MeOH/CH2Cl2). Faction 81 contains 6.5 mg {(E)-3-[1-methyl-3-(naphthalene-2-yloxy)-2-oxo-2,3-dihydro-1H-indol-4-yl]acryloyl}amide 4,5-dilanti the Hairdryer-2-sulfonic acid, P265.1H-NMR (500 MHz, DMSO-d6) 3,30 (s, 3H), of 5.75 (s, 1H), 6,23 (d, J=16.0 Hz, 1H), to 6.57 (d, J=8,4 Hz, 1H), 6,69 (d, J=16.0 Hz, 1H), 6,9-to 7.8 (m, 9H), with 8.05 (d, J=16.0 Hz, 1H), 10,44 (s, 1H), LC/MS(8.3%) of ESI-Calculated: M=573,5; found: 573,3 m/z.

Example 291. Getting connection P284.

Synthesis of 2-fluoro-6-(naphthalene-2-yloxy)benzonitrile, I-189. In a container with a volume of 20 ml, equipped with a magnetic stirrer, add sodium hydride (103,7 mg, 4,32 mmol, 60% in mineral oil), then anhydrous DMF (2 ml), which leads to the emission of the gas. To the obtained mixture under stirring in small portions over 5 minutes add 2-naphthol (623 mg, 4,32 mmol) as a solid. The mixture is stirred at room temperature for 3 minutes and then one portion add 2,6-diferential (601 mg, 4,32 mmol) in anhydrous DMF. The reaction mixture is heated on an oil bath to 100°C and kept at this temperature for 2 hours, then enable the mixture to cool to room temperature. The reaction mixture was diluted with water (15 ml) and extracted with EtOAc (2×20 ml). The combined organic extracts washed with water (3×20 ml), dried (Na2SO4), filtered and concentrated, receiving compound I-189 in the form of a brown solid (1,216 g), which is sufficiently pure for use in the next stage (contains 2-naphthol).1H-NMR.

Synthesis of 1-methyl-4-(naphthalene-2-yloxy)-1H-indazol-3-yl is mine, I-190. In a container with a volume of 20 ml, equipped with a magnetic stirrer, download 2-fluoro-6-(naphthalene-2-yloxy)benzonitrile (966 mg, to 3.67 mmol) and anhydrous N,N-dimethylacetamide and the mixture is stirred to obtain a solution. To the mixture add methylhydrazine (390 μl, 7,34 mmol), the container is closed, the reaction mixture was placed in an oil bath, heated to 120°C and stirred at this temperature overnight. The reaction mixture is heated to 130°C and maintained at this temperature for an additional 3 hours. The cooled reaction mixture is diluted with water (20 ml) and extracted with EtOAc (2×30 ml). The combined organic fractions washed with water (3×15 ml), dried (Na2SO4), filtered and concentrated, obtaining of 1.03 g of the product as a yellowish brown solid. The residue is purified flash chromatography on silica gel (120 g)using first CH2Cl2and then the mixture is CH2Cl2/EtAc (9:1) as eluent and getting 770 mg of compound I-190 in the form of not-quite-white solid. The resulting product is of sufficient purity for use in subsequent reactions.1H-NMR, MS.

Synthesis of [1-methyl-4-(naphthalene-2-yloxy)-1H-indazol-3-yl]amide 4,5-dichlorothiophene-2-sulfonic acid, P284. In the capacity of a volume of 5 ml, equipped with a magnetic stirrer, add the connection to the I-190 (37 mg, 0.13 mmol), anhydrous CH2Cl2(1 is l), N,N-dimethylaminopyridine (17,2 mg, 0,141 mmol) and 4,5-dichlorothiophene-2-sulphonylchloride. The reaction mixture was stirred at room temperature for 36 hours, the resulting solid precipitate is filtered and washed with CH2Cl2getting after drying of 18.5 mg connection P284 in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) of 4.16 (s, 3H), 6,46 (d, J=7,6 Hz, 1H), was 7.08 (DD, J=8,8, 2.4 Hz, 1H), 7,41-7,35 (m, 2H), 7,47 (d, J=8.0 Hz, 1H), 7,53 (m, 2H), 7,87 (ush. d, J=8,4 Hz, 1H), 8,01-to 7.95 (m, 3H). MS (ESI+) Is calculated: (M+H) 504,4; found: 504,4.

Example 292. Getting connection P056.

A General method (A-2) used for alkylation [(E)-3-(3-methyl-1H-indol-7-yl)acryloyl]amide thiophene-2-sulfonic acid (I-8) using 2,4-dichlorobenzamide getting connection P056.1H-NMR (500 MHz, DMSO-d6). MS (ESI-): 505,1 (M-1), LC-MS: 96% purity

Example 293, Obtaining connection P347.

In accordance with the General procedure A-8, the acrylic acid I-137B is subjected to interaction with 4.5-dichlorothiophene-2-sulfonamide getting connection P347. The structure is confirmed1H-NMR.

Example 294. The connection is P350.

Synthesis of 7-bromo-1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indole, I-191. NaH (60% in oil, 526 mg, 13,15 mmol, 1.5 EQ.) added to a solution of 7-bromo-5-fluoro-3-methyl-1H-indole, [obtained similarly to the compound of I-30 in accordance with the method of publication Dobbs, A., J. Org. Chem., 66, 638-641 (2001)], (2 g, 8,77 mmol, 1 EQ.)in DMF (30 ml) at -10°C. The reaction mixture is heated to room temperature and stirred at room temperature for 30 minutes. A solution of 2,4-dichlorobenzaldehyde from 2.06 g, 10,52 mmol, 1.2 EQ.) in DMF (10 ml) was carefully added dropwise within 2.5 minutes at -10°C. the Reaction mixture was allow to warm to room temperature and the mixture is stirred for 1 hour. The reaction mixture with stirring, poured into 10% HCl/water/ether (1:1:2, 40 ml) mixture and the aqueous layer was extracted with ether (2×10 ml). The combined organic layers washed with water (3×75 ml), saturated salt solution (75 ml), dried over MgS4filter and concentrate to obtain the crude product as a brown solid. To the crude product add ether (4 ml), the mixture is cooled to -78°C and filtered, receiving compound I-191 (2,49 g, 73%) as a solid, not quite white matter.1H-NMR (500 MHz, CDCl3) confirms the structure.

Synthesis of ethyl ester of 1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indole-7-carboxylic acid, I-192. To a solution of compound I-191 (400 mg, of 1.03 mmol, 1 EQ.) in ether (7 ml) at -78°C in an atmosphere of Ar slowly over 7 minutes added BuLi (1.6 m in hexano, of 0.97 ml, 1.55 mmol, 1.5 EQ). The reaction mixture was stirred at -78°C for an additional 30 minutes. To the reaction mixture slowly add ethylchloride (0.2 ml, 2,07 mmol, 2 equiv.) the reaction mixture is allowed the possibility of the ability to warm to room temperature and the mixture is stirred at room temperature for 30 minutes. The reaction mixture was quenched by adding 10% aqueous HCl (5 ml). The organic layer was washed with water (2×10 ml), saturated salt solution (10 ml), dried over MgSO4, filtered and concentrated to obtain compound I-192 mg (98%) as a brown oil. MS (AP+): 380,382 (M+1).1H-NMR (500 MHz, CDCl3) confirms the structure.

Synthesis of 1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indole-7-carboxylic acid, I-193. 2n. an aqueous solution of NaOH (2.5 ml, 5 mmol, 5 EQ.) added to a solution of ester I-192 (381 mg, 1 mmol, 1 EQ.) in a mixture of MeOH/THF (1:1,4 ml). The reaction mixture is heated to 75°C and stirred at this temperature for 1 hour. The reaction mixture is concentrated, cooled to -70°C, quenched by adding 10% aqueous HCl solution (6 ml) and extracted with EtOAc (4 ml). The organic layer was washed with water (2×4 ml), saturated salt solution (4 ml), dried over MgSO4filter and concentrate. The resulting residue is triturated in hexane (2×2 ml) and dried, obtaining the compound I-193 (262 mg, 74%) as a solid, not quite white matter. The structure is confirmed1H-NMR (500 MHz, CDCl3).

The synthesis of compounds P350. 4,5-Dichloro-2-thiophenesulfonyl (23,2 mg, 0.1 mmol, 1 EQ.) added at room temperature to a solution of compound I-193 (35 mg, 0.1 mmol, 1 EQ.) DMAP (24.5 mg, 0.2 mmol, 2 EQ.) and anhydrous CH2Cl2(0.5 ml) and then added EDCI (38 mg, 0.2 mmol, 2 EQ.). The reaction mixture is PE is amerivault at room temperature for 1 hour and then left at 0°C for 2 days. The reaction mixture is heated to room temperature, quenched by adding 10% HCl (aq.) (1 ml) and extracted with EtOAc (1 ml). The organic layer is washed with a mixture of water and saturated salt solution (1:1, 3×1 ml), dried over MgS4filter and concentrate to obtain the crude product (51 mg) as a light brown solid. The crude product is triturated in hexane (2×1 ml), and then in a mixture of hexane-MeOH (30:1, 1 ml), and receiving the connection P350 (45 mg, 79%) as a solid not quite white matter. LC-MS (95%): ESI-Calculated: 564 m/z; found: 564.1H-NMR (DMSO-d6) 2,24 (d, J=0.8 Hz, 3H), of 5.39 (s, 2H), 6,01 (d, J=8,4 Hz, 1H), 7,15 (DD, J=8,4, 2.4 Hz, 1H), 7,28 (DD, J=8,4, 2.4 Hz, 1H), 7,29 (s, 1H), 7,25 (d, J=2.4 Hz, 1H), 7,60-to 7.64 (m, 1H), to 7.64 (s, 1H), 7,95 (ush. s, 1H).

Example 295. Getting connection P417.

3,4-Diftorbenzofenonom (19.3 mg, 0.1 mmol, 1 EQ.) at room temperature are added to a solution of compound I-193 (35 mg, 0.1 mmol, 1 EQ.) and DMAP (24.5 mg, 0.2 mmol, 2 EQ.) in anhydrous CH2Cl2(Aldrich, 0.5 ml), then added EDCI (38 mg, 0.2 mmol, 2 EQ.) similarly to the method described for connection P350, obtaining connection P417 (42 mg, 79%) as a beige solid. LC-MS (98%): ESI-Calculated: 526 m/z; found: 526.lH-NMR (DMSO-d6) 2,22 (d, J=1.2 Hz, 3H), with 5.22 (s, 2H), 5,96 (d, J=8,4 Hz, 1H), 7,14 (DD, J=8,2, 1.8 Hz, 1H), 7,24 (s, 1H), 7,29 (DD, J=a 9.6, 2.4 Hz, 1H), was 7.36 (d, J=2.4 Hz, 1H), 7,54 (ush. s, 1H), to 7.61-7,66 (m, 2H), to 7.67-of 7.70 (m, 1H), 7,76-7,81 (m, 1H).

P the emer 296. Getting connection P354.

Synthesis of ethyl ester [1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]octoxynol acid, I-194. A solution of n-BuLi (2.5m in hexano, 0,31 ml, 0.78 mmol, 1.5 EQ.) added slowly at room temperature to a solution of bromide I-191 (200 mg, 0,517 mmol, 1 EQ.) in anhydrous Et2O (4 ml) at -78°C in argon atmosphere. The reaction mixture was stirred at -78°C for 20 minutes. To the mixture slowly for 2 minutes add ethylacetat (0,146 ml, to 1.034 mmol, 2.0 EQ.) at -78°C, then the reaction mixture is heated to 0°C in a bath with a mixture of water with ice. The reaction mixture is heated to room temperature, quenched by adding 10% HCl (aq.) (3 ml) and extracted with ether (3 ml). The organic layer was washed with water (2×6 ml), saturated salt solution (6 ml), dried over MgSO4, filtered and concentrated to obtain compound I-194 (215 mg, 100%) as an orange oil.1H-NMR (500 MHz, CDCl3) confirms the structure.

Synthesis of [1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]octoxynol acid, I-195. An aqueous solution of 2n. NaOH (0,29 ml of 0.58 mmol, 1.1 EQ.) added slowly over 2 minutes to a solution of compound I-194 (215 mg, of 0.53 mmol, 1 EQ.) in a mixture of THF-MeOH (1:1, 4 ml) at 0°C. the Reaction mixture was stirred at 0°C for 30 minutes and then warmed to room temperature. To a mixture of one portion add 2n. aqueous NaOH (to 0.24 ml, 0.48 mmol, 0.9 EQ.) and reaction the second mixture is stirred for 15 minutes. The reaction mixture was concentrated, to the residue add 10% HCl (aqueous, 1 ml), then the resulting mixture was extracted with ether (2 ml). The organic layer was washed with water (3×2 ml), saturated salt solution (2 ml), dried over MgSO4, filtered and concentrated to obtain compound I-195 (141 mg, 95%) as a yellow solid. LC-MS (98%): ESI-Calculated: 380,2 m/z; found: 380,2.1H-NMR (500 MHz, CDCl3) confirms the structure.

The synthesis of compounds P354. To a solution of compound I-195 (40 mg, 0.11 mmol, 1 EQ.) and DMAP (26 mg, 0.2 mmol, 2 EQ.) in anhydrous CH2Cl2(0.6 ml) at room temperature add 2,4,5-tripersonality (22 mg, 0.11 mmol, 1 EQ.), then EDCI (40 mg, 0.2 mmol, 2 EQ.) according to the method similar to that described for compound P350, receiving the crude product as a yellow solid. The crude product is triturated with MTBE (2 ml), boiled for one minute, the solution is filtered and washed with MTBE (2×0.5 ml), hexane (2 ml) at room temperature, receiving the connection P354 (28 mg, 46%) as a yellow solid. LC-MS (100%): AP-Calculated: 572 m/z; found: 572.1H-NMR (DMSO-d6), and 2.27 (d, J=0.8 Hz, 3H), to 5.57 (s, 2H), 6,14 (d, J=8,4 Hz, 1H), 7,15-7,19 (m, 2H), 7,35 (s, 1H), 7,54 (d, J=2.0 Hz, 1H), 7,73 (DD, J=8,6, and 2.6 Hz, 1H), 7,76-of 7.82 (m, 2H).

Example 297. Getting connection P351.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 4-f is albenzaalbenza getting connection P351. The structure is confirmed1H NMR.

Example 298. Getting connection P352.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 2-chlorobenzenesulfonamide getting connection P352. The structure is confirmed1H-NMR.

Example 299. Getting connection P353.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 3-chlorobenzenesulfonamide getting connection P353. The structure is confirmed1H-NMR.

Example 300. Getting connection P355.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 3,4-dichlorobenzenesulfonate getting connection P355. The structure is confirmed1H-NMR.

Example 301. Getting connection P356.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 2,4-dichlorobenzenesulfonic getting connection P356. The structure is confirmed1H-NMR.

Example 302. Getting connection P357.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 3.5-dichlorobenzenesulfonate getting connection P357. The structure is confirmed1H-NMR.

Example 303. Getting connection P358.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 2,4-differentlal what polamidon getting connection P358. The structure is confirmed1H-NMR.

Example 304. Getting connection P359.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 2.5-differentlanguages getting connection P359. The structure is confirmed1H-NMR.

Example 305. Getting connection P360.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 2,6-differentlanguages getting connection P360. The structure is confirmed1H-NMR.

Example 306. Getting connection P361.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 3.5-differentlanguages getting connection P361. The structure is confirmed1H-NMR.

Example 307. Getting connection P363.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 3-fermentalization getting connection P363. The structure is confirmed1H-NMR.

Example 308. Getting connection P364.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 2-fermentalization getting connection P364. The structure is confirmed1H-NMR.

Example 309. Getting connection P365.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 4-chlorobenzylthio what amidon getting connection P365. The structure is confirmed1H-NMR.

Example 310. Getting connection P366.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 4-methoxybenzenesulfonamide getting connection P366. The structure is confirmed1H-NMR.

Example 311. Getting connection P373.

In accordance with the General procedure A-8, the acrylic acid I-137A is subjected to interaction with 2,3,4,5,6-pentafluorobenzaldehyde getting connection P373. The structure is confirmed1H-NMR.

Example 312. Getting connection P367.

Synthesis of 2,4,5-Cryptor-N-[(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]benzosulfimide, I-196. In a container with a volume of 8 ml equipped with a stirrer, at room temperature upload acid I-34 (300 mg, 1.37 mmol), anhydrous CH2Cl2(4 ml), 2,4,5-tripersonality (346 mg, of 1.64 mmol), DMAP (200 mg, of 1.64 mmol) and EDCI (314 mg, of 1.64 mmol). The container tightly closed with the cap and the reaction is carried out for 17 hours at room temperature. The contents of the tank is transferred into a separating funnel and diluted with CH2Cl2(20 ml). Then in the funnel to add water (20 ml) and 1M HCl (20 ml) and the organic portion is removed. The aqueous layer was extracted with EtOAc (2×20 ml). The organic part of the combine, dried (MgSO4and concentrate, getting a brown oil. The crude product is triturated with ice CH2Cl (2 ml), receiving insoluble solid. The solid product is separated by filtering with suction and washed with ice CH2Cl2(4 ml)to give 135 mg of compound I-196 in the form of a yellow solid (24%).1H-NMR (400 MHz, DMSO-d6); LC/MS (87%).

General procedure (A-17) alkylation of arylsulfonamides.

To a solution of arylsulfonamides in THF at room temperature, add 3 EQ. tert-butoxide potassium. To the mixture add the corresponding aryl halides and the mixture is stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and acidified with 10% HCl. The organic fraction washed with water (3×), saturated salt solution and dried over Na2SO4. The solution is filtered, concentrated and the residue purified by rubbing with dichloromethane at 40°C or by chromatography on silica gel using a mixture of methanol/dichloromethane as eluent.

The synthesis of compounds P367. in accordance with the General method (A-17), arylsulfonate I-196 alkylate 3-methoxybenzylamine getting connection P367 (30%). LC/MS (95%) ESI-Calculated: 532,5 m/z; found: 531,5 m/z.1H-NMR(DMSO-d6).

Example 313. Getting connection P368.

Synthesis of 3,4-debtor-N-[(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]benzosulfimide, I-197. In accordance with the procedure described for the synthesis of compound I-196, compound I-34 is subjected to the EOI is modestia with 3,4-differentlanguages, receiving compound I-197. After filtration allocate 223 mg of compound I-197 in the form of a yellow solid (41%).1H-NMR (400 MHz, DMSO-d6); LC/MS (99%).

In accordance with the General method (A-17), arylsulfonate I-197 alkylate 3-methoxybenzylamine getting connection P368 (19%). LC/MS (97%) ESI - Calculated: 514,5 m/z; found: 513,7 m/z.1H-NMR(DMSO-d6).

Example 314. Getting connection P369.

In accordance with the General method (A-17), arylsulfonate I-197 alkylate 4-(chloromethyl)for 3,5-dimethylisoxazole getting connection P369 (31%). LC/MS (92%) ESI-Calculated: 503,5 m/z; found: 502,4 m/z.1H-NMR(DMSO-d6).

Example 315. Getting connection P370.

In accordance with the General method (A-17), arylsulfonate I-196 alkylate 4-(chloromethyl)for 3,5-dimethylisoxazole getting connection P370 (18%). LC/MS (96%) ESI-Calculated: 521,5 m/z; found: 520,6 m/z.1H-NMR (DMSO-d6) 1,68 (s, 3H), of 1.75 (s, 3H), of 2.21 (s, 3H), from 5.29 (s, 2H), 6,40 (d, J=15.6 Hz, 2H), to 7.09 (DD, J=10,4, 2.4 Hz, 1H), 7,21 (s, 1H), 7,44 (DD, J=8,8, 2.4 Hz, 1H), to 7.93 (DDD, J=10,0, 10,0, 6.0 Hz, 1H), 8,02 (d, J=14,8 Hz, 1H), 8,03 (DD, J=18,0, 6.4 Hz, 1H), 12,8 (s, 1H).

Example 316. Getting connection P374.

In accordance with the General method (A-17), arylsulfonate I-197 alkylate 3,5-dimethoxybenzamide getting connection P374 (20%). LC/MS (97%) ESI-Calculated: 544,6 m/z; found: 543,6 m/z.1H-NMR(DMSO-d6)

Example 317. Getting connection P375.

According the General method (A-17), arylsulfonate I-196 alkylate 3,5-dimethoxybenzamide getting connection P375 (37%). LC/MS (98%) ESI-Calculated: 562,5 m/z; found: 561,5 m/z.1H-NMR(DMSO-d6).

Example 318. Getting connection P378.

Synthesis of (5-fluoro-3-methyl-7-(naphthalene-2-yloxy)-1H-indole (I-198A). General method A-18: the capacity of a volume of 40 ml, equipped with a rod stirrer, at room temperature load 7-bromo-5-fluoro-3-methyl-1H-indole [obtained similarly to the compound of I-30 in accordance with the methodology described in the publication Dobbs, A., J. Org. Chem., 66, 638-641 (2001)] (1.10 g, 4,78 mmol), anhydrous dioxane (9.5 ml), 2-naphthol (1,03 g, 7,17 mmol), CuI (91,0 mg, 0,478 mmol), hydrochloride of N,N-dimethylglycine (200 mg, of 1.43 mmol) and Cs2CO3(3.12 g, of 9.56 mmol). The mixture Tegaserod with argon for 15 minutes, tightly covered with a lid, placed in an oil bath, heated to 100°C and kept at this temperature for 65 hours. The reaction is quenched with water (50 ml) and extracted with EtOAc (3×50 ml). The organic fractions combined, washed with water (2×50 ml), saturated salt solution (50 ml), dried (MgSO4and concentrate, getting a dark brown oil. The oil is purified column chromatography on silica gel using a solvent system of 5% EtOAc/hexane as eluent and getting 791 mg of compound I-198A in the form of a yellow solid (57%).1H-NMR (400 MHz, CDCl3).

Synthesis of 3-[5-fluoro-3-METI is-7-(naphthalene-2-yloxy)indol-1-yl]propionic acid (I-200A): the General procedure A-19. In a container with a volume of 18 ml, equipped with a rod stirrer, at room temperature load connection Ib-1 (500 mg, 1,72 mmol), methyl acrylate (3,10 ml, to 34.4 mmol) and DBU (257 μl, 1,72 mmol). Capacity Tegaserod N2within 1 minute, tightly close the lid and the reaction is carried out for 18 hours at room temperature. The reaction is quenched with 1M aqueous HCl solution (8 ml) and the resulting mixture is stirred for 10 minutes. After transferring the mixture into a separating funnel to the mixture an additional quantity of 1M aqueous HCl (50 ml) and the mixture extracted with CH2Cl2(2×100 ml). The organic fractions combined, washed with water (60 ml) and saturated salt solution (60 ml), dried (MgS4and concentrate, getting 749 mg of compound I-199A in the form of a yellow oil. In a container with a volume of 40 ml, equipped with a rod stirrer, at room temperature upload the crude compound 1b-2 (600 mg, of 1.59 mmol), THF (7,40 ml), MeOH (3,70 ml) and 50% aqueous NaOH solution (3,34 ml, a rate of 1.67 mmol). After 10 minutes the reaction is quenched with saturated solution of NaHCO3(75 ml) and extracted with Et2O (100 ml). Layer Et2About washed with a saturated solution NaHC3(2×75 ml). The aqueous fractions are combined acidified with 3M HCl to pH=1 and extracted with CH2Cl2(3×80 ml). The organic fractions combined, washed with water (100 ml), saturated salt solution (100 ml), dried (MgS4and Kon is intronaut, getting 338 mg of compound I-200A as an orange oil (54% yield from compound I-198A to I-200A).1H-NMR (400 MHz, CDCl3).

The synthesis of compounds P378. 2,4,5-Cryptor-N-{3-[5-fluoro-3-methyl-7-(naphthalene-2-yloxy)indol-1-yl]propionyl}benzosulfimide. General method A-20. In a container with a volume of 8 ml, equipped with a rod stirrer, load connection I-200A (65,0 mg, 0,179 mmol), CH2Cl2(1.2 ml), 2,4,5-cryptorhynchinae (45,4 mg, 0,215 mmol), DMAP (52,5 mg, 0,430 mmol) and EDCI (85,9 mg, 0,448 mmol). The mixture is stirred at room temperature for 18 hours. The reaction is quenched with a 1M aqueous solution of HCl (3 ml) and the resulting mixture is stirred for 10 minutes. The mixture is transferred into a separating funnel, add 1M aqueous HCl solution (30 ml), then extracted with CH2Cl2(2×30 ml). Organic part of unite, washed with water (35 ml), saturated salt solution (35 ml), dried (MgS4and focus, getting to 78.3 mg connection P378 in the form of a white solid (79%).1H-NMR(400 MHz, CDCl3). LC/MS purity: 92%.

Example 319. Getting connection P380.

Compound I-200A (65,0 mg, 0,179 mmol) is subjected to interaction with 4.5-dichlorothiophene-2-sulfonamide (to 49.9 mg, 0,215 mmol), DMAP (52,5 mg, 0,430 mmol) and EDCI (85,9 mg, 0,448 mmol) in anhydrous CH2Cl2(1.2 ml) by the procedure similar to that described for compound P378. The crude product is purified column chromatography on si is imagele, using a solvent system of 20% EtOAc/hexane, 1% AcOH. After concentration and azeotropic distillation with toluene (3×75 ml) was isolated and 64.5 mg connection P380 in the form of a white solid (63%).1H-NMR (400 MHz, DMSO-d6) of 2.16 (s, 3H), 2,78 (t, J=6,8 Hz, 2H), 4,36 (t, J=6,8 Hz, 2H), is 6.54 (DD, J=10,4, 2.4 Hz, 1H), 7,00 (s, 1H), 7,10 (DD, J=9,2, 2.4 Hz, 1H), 7,32 (DD, J=8,8, 2.4 Hz, 1H), 7,38 (d, J=2.4 Hz, 1H), 7,44-7,52 (m, 2H), 7,80 (ush. s, 1H), 7,81 (d, J=9.6 Hz, 1H), to 7.93 (d, J=8.0 Hz, 1H), of 7.96 (d, J=8,8 Hz, 1H). HPLC purity: 99%, MS (ESI-) Calculated: 576,5 m/z; found: 577,1 m/z.

Example 320. Getting connection P379.

Compound I-200A (65,0 mg, 0,179 mmol) is subjected to interaction with 3,4-diftorhinolonom (to 49.9 mg, 0,215 mmol), DMAP (52,5 mg, 0,430 mmol) and EDCI (85,9 mg, 0,448 mmol) in anhydrous CH2Cl2(1.2 ml) is similar to the method described for obtaining P378. The crude product is purified column chromatography on silica gel using a solvent system of 30% EtOAc/hexane, 1% AcOH. The mixture is concentrated and distilled azeotrope with toluene (3×75 ml), getting to 48.3 mg connection P379 in the form of a white solid (50%).1H-NMR (400 MHz, DMSO-d6), HPLC purity: 97%.

Example 321. Getting connection P381.

Compound I-200A (65,0 mg, 0,179 mmol) is subjected to interaction with 3-chlorophenylsulfonyl (to 49.9 mg, 0,215 mmol), DMAP (52,5 mg, 0,430 mmol) and EDCI (85,9 mg, 0,448 mmol) in anhydrous CH2Cl2(1.2 ml) by the procedure similar to that described for compound P378. The crude p is oduct purified column chromatography on silica gel, using the solvent system: 30% EtOAc/hexane, 1% AcOH. After concentration and azeotropic distillation with toluene (3×75 ml) receive 86,7 mg connection P381 in the form of a white solid (90%).1H-NMR (400 MHz, DMSO-d6), HPLC purity: 95%. MS: Calculated 537,0; found 535,3.

Example 322. Getting connection P382.

Synthesis of 7-(2,4-dichlorophenoxy)-5-fluoro-3-methyl-1H-indole, I-198B. In accordance with the General method A-18, 7-bromo-5-fluoro-3-methyl-1H-indole (1.60 g, 7,02 mmol) is subjected to interaction with 2,4-dichlorphenol (1,72 g, 10.5 mmol), CuI (134 mg, 0,702 mmol), the hydrochloride of N,N-of dimethylglycine (293 mg, 2.10 mmol) and Cs2CO3(of 4.57 g, 14.0 mmol) in anhydrous dioxane (14 ml). The crude product is purified column chromatography on silica gel using a solvent system of 5% EtOAc/hexane and getting 746 mg of compound I-198B as a yellow oil (34%).1H-NMR (400 MHz, CDCl3).

Synthesis of 3-[7-(2,4-dichlorophenoxy)-5-fluoro-3-methylindol-1-yl]propionic acid (I-200B): In accordance with the General method A-19, compound I-198B (690 mg, 2.22 mmol) is subjected to interaction with methyl acrylate (4,00 ml, 44.4 mmol) and DBU (348 μl,of 2.33 mmol). After concentrating receive 882 mg of compound I-199B in the form of an orange oil. The crude I-199B (880 mg, 2.22 mmol) omelet using THF (10.3 ml), MeOH (5,17 ml) and 50% aqueous NaOH solution (4,66 ml of 2.33 mmol). The first treatment leads to 320 mg of the compounds is of I-200B in the form of a white solid. The ether layer is concentrated and washed with 1M aqueous solution of HCl (35 ml) and extracted with CH2Cl2(2×60 ml). Organic part of unite, washed with water (40 ml), saturated salt solution (40 ml) and dried (MgS4). After concentrating receive 279 mg of compound I-200B in the form of an orange solid. The two parts of the compound I-200B identify1H-NMR and unite, getting 599 mg of compound I-200B (70% based on the I-198B to I-200B).1H-NMR (400 MHz, CDCl3).

The synthesis of compounds P382. Compound I-200B (70.0 mg, 0,183 mmol) is subjected to interaction with 2,4,5-trichorhinophalangeal (46,5 mg, 0,220 mmol), DMAP (53,6 mg, 0,439 mmol), and EDCI (of 87.8 mg, 0,458 mmol) in anhydrous CH2Cl2(1.2 ml) by the procedure similar to that described for compound P378. The crude product is purified column chromatography on silica gel using a solvent system of 30% EtOAc/hexane, 1% AcOH. After concentration and azeotropic distillation with toluene (3×75 ml) receive 73,0 mg connection P382 in the form of a yellow oil (70%).1H-NMR (400 MHz, DMSO-d6). Purity after HPLC: 85%.

Example 323. Getting connection P384.

Compound I-200B (70.0 mg, 0,183 mmol) is subjected to interaction with 4.5-dichlorothiophene-2-sulfonamide (51,1 mg, 0,220 mmol), DMAP (53,6 mg, 0,439 mmol) and EDCI (of 87.8 mg, 0,458 mmol) in anhydrous CH2Cl2(1.2 ml) is similar to the method of obtaining P378. The crude product is purified of colonos the second chromatography on silica gel, using a solvent system of 30% EtOAc/hexane, 1% AcOH. After concentration and azeotropic distillation with toluene (3×75 ml) receive 84,8 mg connection P384 in the form of a yellowish-brown solid (78%).1H-NMR (400 MHz, DMSO-d6). HPLC purity: 94%.

Example 324. Getting connection P383.

Compound I-200B (70.0 mg, 0,183 mmol) is subjected to interaction with 3,4-diftorhinolonom (42,5 mg, 0,220 mmol), DMAP (53,6 mg, 0,439 mmol) and EDCI (of 87.8 mg, 0,458 mmol) in anhydrous CH2Cl2(1.2 ml) by the procedure similar to that described for compound P378. The crude product is purified column chromatography on silica gel using a solvent system of 30% EtOAc/hexane, 1% AcOH. After concentration and azeotropic distillation with toluene (3×75 ml) allocate up to 66.5 mg connection P383 in the form of a white solid (65%).1H-NMR (400 MHz, DMSO-d6) to 2.13 (s, 3H), 2,74 (t, J=6,8 Hz, 2H), 4,32 (t, J=6,8 Hz, 2H), 6,38 (DD, J=10,4, 2.4 Hz, 1H), 6,97 (s, 1H), 7,07 (DD, J=9,2, 2.4 Hz, 1H), 7,11 (d, J=8,8 Hz, 1H), 7,44 (DD, J=9,2, 2.8 Hz, 1H), to 7.67 for 7.78 (m, 3H), 7,87 (m, 1H), 12,25 (ush. s, 1H). HPLC purity: 88%. MS (ESI-) Calculated: 556,4 m/z; found: 555,1 m/z.

Example 325. Getting connection P385.

Compound I-200B (70.0 mg, 0,183 mmol) is subjected to interaction with 3-chlorophenylsulfonyl (42.2 mg, 0,220 mmol), DMAP (53,6 mg, 0,439 mmol) and EDCI (of 87.8 mg, 0,458 mmol) in anhydrous CH2Cl2(1.2 ml) by the procedure similar to that described for compound P378. The crude etc the product is purified column chromatography on silica gel, using a solvent system of 30% EtOAc/hexane, 1% AcOH. After concentration and azeotropic distillation with toluene (3×75 ml) allocate to 72.2 mg connection P385 in the form of a white solid (71%).1H-NMR (400 MHz, DMSO-d6). HPLC purity: 90%.

Example 326. Getting connection P386.

Synthesis of 7-(3,4-dichlorophenoxy)-5-fluoro-3-methyl-1H-indole (I-198C): IN accordance with the General method A-18,7-bromo-5-fluoro-3-methyl-1H-indole (727 mg, 3,19 mmol) is subjected to interaction with 3,4-dichlorophenol (779 mg, 4,78 mmol), CuI (of 60.8 mg, 0,319 mmol), the hydrochloride of N,N-of dimethylglycine (134 mg, 0,957 mmol) and Cs2CO3(2,07 g, 6.38 mmol) in anhydrous dioxane (6,4 ml). The crude product is purified column chromatography on silica gel using a solvent system of 5% EtOAc/hexane and getting 506 mg of compound I-198C in the form of a yellow oil (34%).1H-NMR (400 MHz, CDCl3).

Synthesis of 3-[7-(3,4-dichlorophenoxy)-5-fluoro-3-methylindol-1-yl]propionic acid (I-200C): In accordance with the General method A-19, compound I-198C (450 mg, 1,45 mmol) is subjected to interaction with methyl acrylate (2,61 ml, 29,0 mmol) and DBU (227 μl, of 1.52 mmol). After concentration allocate 584 mg of compound I-199C in the form of an orange oil. The crude I-199C (580 mg, of 1.46 mmol) omelet using THF (6,80 ml), MeOH (3,40 ml) and 50% aqueous NaOH solution (of 3.07 ml, 1.53 mmol). The ether layer is evaporated, washed with 1M aqueous solution of HCl (35 ml) and extragere the CH 2Cl2(2×60 ml). Organic part of unite, washed with water (40 ml), saturated salt solution (40 ml) and dried (MgS4). After concentration emit 240 mg of compound I-200C in the form of a yellow oil (43% yield, based on the I-198C to I-200C).1H-NMR (400 MHz, CDCl3).

The synthesis of compounds P386. Compound I-200C (65,0 mg, 0,170 mmol) is subjected to interaction with 2,4,5-trichorhinophalangeal (to 43.1 mg, 0,204 mmol), DMAP (49,8 mg, 0,408 mmol) and EDCI (81,5 mg, 0,425 mmol) in anhydrous CH2Cl2(1.2 ml) by the procedure similar to that described for compound P378. The crude product is purified column chromatography on silica gel using a solvent system of 30% EtOAc/hexane, 1% AcOH. After concentration and azeotropic distillation with toluene (3×75 ml) allocate 80,6 mg connection P386 in the form of a green solid (82%).1H-NMR(400 MHz, DMSO-d6), HPLC purity: 93%.

Example 327. Getting connection P388.

Compound I-200C (75,0 mg, 0,196 mmol) is subjected to interaction with 4.5-dichlorothiophene-2-sulfonamide (54,5 mg, 0,235 mmol), DMAP (57.4 mg, 0,470 mmol) and EDCI (93,9 mg, 0,490 mmol) in anhydrous CH2Cl2(1.2 ml) by the procedure similar to that described for compound P378. The crude product is purified column chromatography on silica gel using a solvent system of 20% EtOAc/hexane, 1% AcOH. After concentration and azeotropic distillation with toluene (3×75 ml) the separation shall have 93,0 mg compound P388 in the form of a green solid (79%). 1H-NMR (400 MHz, DMSO-d6). HPLC purity: 93%.

Example 328. Getting connection P387.

Compound I-200C (65,0 mg, 0,170 mmol) is subjected to interaction with 3,4-diftorhinolonom (39,4 mg, 0,204 mmol), DMAP (49,8 mg, 0,408 mmol) and EDCI (81,5 mg, 0,425 mmol) in anhydrous CH2Cl2(1.2 ml) by the procedure similar to that described for compound P378. The crude product is purified column chromatography on silica gel using the solvent system: 30% EtOAc/hexane, 1% AcOH. After concentration and azeotropic distillation with toluene (3×75 ml) allocate 62,7 mg connection P387 in the form of a green solid (66%).1H-NMR (400 MHz, DMSO-d6) of 2.13 (s, 3H), 2,69 (t, J=6,8 Hz, 2H), 4,27 (t, J=6,8 Hz, 2H), return of 6.58 (DD, J=10,4, 2.4 Hz, 1H), 6,95 (ush. s, 1H), 7,00 (DD, J=8,8, 2.8 Hz, 1H), 7,10 (DD, J=9,2, 2.4 Hz, 1H), 7,31 (d, J=2,8 Hz, 1H), 7,63 (d, J=8,8 Hz, 1H), 7,65-7,76 (m, 2H), 7,86 (m, 1H), 12,24 (ush. s, 1H). HPLC purity: 95%, MS (ESI-) Calculated: 556,4 m/z; found: 556,9 m/z.

Example 329. Getting connection P389.

In a container with a volume of 8 ml, equipped with a rod stirrer, at room temperature loads compound I-36 (250 mg, 0,576 mmol) and anhydrous THF (2.8 ml). The obtained yellow solution is cooled to 0°C in an ice bath, then slowly, in small portions add NaH (60%) (69,2 mg of 1.73 mmol). The solution turns from yellow to bright red. The mixture allow to warm to room temperature, then cooled to 0°C, and add 2(methyl bromide)benzonitrile (192 mg, 0,981 mmol). The contents of the tank leave for interaction within 18 hours. The reaction is carefully quenched with water (1 ml) and 1M aqueous solution of HCl (3 ml) and the resulting mixture is stirred for 10 minutes. The mixture is transferred into a separating funnel, washed with water (15 ml) and 1M aqueous HCl solution (15 ml), then extracted with EtOAc (3×40 ml). Organic part of unite, washed with water (40 ml) and saturated salt solution (40 ml), dried (MgSO4and concentrate, receiving a yellow solid product. The crude product is triturated with ice CH2Cl2(30 ml) and separated by filtration with suction, then washed with additional ice CH2Cl2(2×30 ml). After filtration allocate 193 mg connection P389 in the form of a pale yellow solid (61%).1H-NMR (400 MHz, d6-DMSO). HPLC purity: 95%.

Example 330. Getting connection P390.

{(E)-3-[1-(3-cyanobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]acryloyl}amide 4,5-dichlorothiophene-2-sulfonic acid. Compound I-36 (250 mg, 0,576 mmol) alkylate using NaH (60%) (69,2 mg of 1.73 mmol) and 3-(methyl bromide)benzonitrile (192 mg, 0,981 mmol) in anhydrous THF (2.8 ml), according to the method similar to that described for compound P389. After filtration allocate 186 mg connection P390 in the form of a light green solid (59%).1H-NMR (400 MHz, DMSO-d6) of 2.26 (s, 3H), 5,59 (s, 2H), 6,32 (d, J=15.6 Hz, 1H), 7,05 (DD, J=10,0, 2.4 G is, 1H), 7,22 (d, J=7,6 Hz, 1H), 7,37 (ush. s, 1H), 7,40-7,47 (m, 3H), of 7.69 (d, J=7,6 Hz, 1H), of 7.90 (s, 1H), 7,94 (d, J=15.6 Hz, 1H). HPLC purity: 87%. MS (ESI-) Calculated: 547,5 m/z; found: 546,2 m/z.

Example 331. Getting connection P391.

Compound I-36 (250 mg, 0,576 mmol) alkylate using NaH (60%) (69,2 mg of 1.73 mmol) and 4-(methyl bromide)benzonitrile (192 mg, 0,981 mmol) in anhydrous THF (2.8 ml) by the procedure similar to that described for compound P389. After filtration allocate 90,8 mg connection P391 in the form of a light green solid (29%).1H-NMR (400 MHz, d6-DMSO). HPLC purity: 95%.

Example 332. Getting connection P396.

To a solution of P067 (4.0 g, of 6.75 mmol) in THF (32 ml) is added water (1.6 ml). To the resulting mixture in one portion added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.6 g, 20.3 mmol) and the resulting solution is stirred over night at room temperature. The mixture of concentratein the vacuumremoval of organic solvents and add ethanol (60 ml). The resulting mixture was refluxed for 1 hour, then allow to cool to room temperature overnight. The resulting suspension is filtered and washed with ethanol until such time as the washing liquid becomes colorless. The obtained solid product is boiled with acetonitrile to remove residual P067 and then enable the mixture to cool to room temperature overnight. Obtained the solid product is treated with boiling ethanol, cooled to room temperature, filtered and dried at 55°C in vacuum during the night, getting 1,72 g P396 (42%). MS (ESI-) Calculated: 606,3 m/z; found: 605,1 m/z.1H-NMR (DMSO-d6)

Example 333. Getting connection P397.

To a solution P396 (1.3 g, of 2.16 mmol) in THF (66 ml) is added water (0,52 ml) and the solution cooled to 0-5°C. in Several portions over 5 minutes add borohydride sodium (409 mg, up 10.8 mmol) and the resulting mixture is stirred for 30 minutes. The reaction mixture was diluted with EtOAc (75 ml) and washed polysystem solution of ammonium chloride in water (2×80 ml), water (2×40 ml) and saturated salt solution (50 ml). Solution concentratein the vacuumand the resulting solid residue triturated in EtOAc, filtered and dried toin a vacuum.The resulting solid product is triturated twice with diethyl ether and dried in vacuum, obtaining 1.07 g (82%) P397.1H-NMR(DMSO-d6).

Example 334. Getting connection P398

To a solution P396 (300 mg, 0,495 mmol) and 2-methyl-2-butene (495 μl, 0,99 mmol) in THF (15 ml) for 5 minutes, add a solution of sodium chloride (246 mg, of 2.72 mmol) and nonoonono phosphate (416 mg, 3.46 mmol) in water (3.6 ml). The mixture is stirred at room temperature for 2 hours, add a further quantity of sodium chloride (246 mg, of 2.72 mmol) and nonoonono phosphate (416 mg, 3.46 mmol) in water (3.6 ml) and the resulting reaction mixture per mesilat at room temperature for additional 2 hours. The layers are separated and the organic fraction was washed with 1N. aqueous solution of hydrochloric acid (15 ml), water (2×15 ml) and saturated salt solution (15 ml). The resulting solution was concentratedinthe vacuum and the resulting solid residue is treated with dichloromethane at 40°C for 2 hours, the mixture is allowed the opportunity to cool spontaneously to room temperature over night. The resulting suspension is filtered, the solid product is washed with dichloromethane and dried at 35°C in a vacuum of,getting 151 mg connection P398 (50%).1H-NMR(DMSO-d6); LC/MS (93%) ESI-Calculated: 622,3 m/z; found: 621,3 m/z.

Example 335. Getting connection P402

The synthesis of compounds P402. In a container with a volume of 8 ml, equipped with a rod stirrer, at room temperature load connection I-196 (100 mg, 0,243 mmol) and anhydrous DMF (500 μl). The obtained yellow solution is cooled to 0°C in an ice bath and then added NaH (60%) (29,2 mg, advanced 0.729 mmol). Received the red mixture is heated to room temperature and then cooled to 0°C, and add 2 chloromethylketone[1,2-a]pyridine (of 48.7 mg, 0,292 mmol). The mixture allow to warm to room temperature and interact within 17 hours. The reaction is quenched with water (2 ml) and 1M HCl (4 ml). The formed solid substance was separated by filtration with suction, washed with cooled in an ice bath CH Cl2(4 ml) and dried in a furnace with high vacuum at 70°C for 5 hours. After drying allocate 14.3 mg connection P402 in the form of a yellowish-brown solid (11%).1H-NMR (400 MHz, DMSO-d6). LC/MS: 74%.

Example 336. Getting connection P395.

Compound I-36 (250 mg, 0,576 mmol) is subjected to interaction with 2-chloromethylketone[1,2-a]pyridine (115 mg, 0,692 mmol) and NaH (60%) (138 mg, 3.46 mmol) in anhydrous DMF (2.8 ml) by the procedure similar to that described for compound P402. After drying allocate 233 mg connection P395 in the form of a yellowish-brown solid (72%).1H-NMR (400 MHz, DMSO-d6) 2,22 (s, 3H), 5,49 (s, 2H), 6,24 (d, J=15.6 Hz, 1H), 6.87 in (m, 1H),? 7.04 baby mortality (DD, J=10,8, 2.8 Hz, 1H), 7,19-7,26 (m, 2H), was 7.36 (ush. s, 1H), 7,47 (s, 1H), of 7.48 (d, J=8,4 Hz, 1H), they were 8.22 (d, J=15.2 Hz, 1H), of 8.27 (s, 1H), 8,43 (d, J=6,8 Hz, 1H). HPLC purity: 89%; MS (ESI-) Calculated: 562,5 m/z, found: 563,1 m/z.

Example 337. Getting connection P399.

Compound I-197 (100 mg, 0,254 mmol) is subjected to interaction with 2-chloromethylketone[1,2-a]pyridine (50,8 mg, 0,305 mmol) and NaH (60%) (30,5 mg, 0,762 mmol) in anhydrous DMF (500 μl) according to the method similar to that described for compound P402. After drying, the highlight of 16.2 mg connection P399 in the form of a yellowish-brown solid (12%).1H-NMR (400 MHz, DMSO-d6), LC/MS: 94%.

Example 338. The connection is P400.

Synthesis of 3-chloro-N-[(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]benzosulfimide, I-201. Compound I-201 synthesize p is the method similar to that described for compound I-196 using compound I-34 (300 mg, 1.37 mmol), anhydrous CH2Cl2(4 ml), 3-chlorobenzenesulfonamide (314 mg, of 1.64 mmol), DMAP (200 mg, of 1.64 mmol) and EDCI (314 mg, of 1.64 mmol). After filtration allocate 286 mg of compound I-201 in the form of a yellow solid (53%).1H-NMR (400 MHz, DMSO-d6). LC/MS: 98%.

The synthesis of compounds P400. Compound I-201 (100 mg, 0,255 mmol) is subjected to interaction with 2-chloromethylketone[1,2-a]pyridine (51,0 mg, 0,306 mmol) and NaH (60%) (30,7 mg, 0,765 mmol) in anhydrous DMF (500 μl) according to the method similar to that described for compound P402. After drying allocate 83,0 mg connection P400 in the form of a yellow solid (62%).1H-NMR (400 MHz, DMSO-d6) 2,24 (s, 3H), 5,73 (s, 2H), 6,40 (d, J=15.2 Hz, 1H), was 7.08 (DD, J=2,4, 10,0 Hz, 1H), 7,26-7,32 (m, 1H), 7,38 (s, 1H), 7,46 (DD, J=2,4, and 9.2 Hz, 1H), 7.68 per-7,74 (m, 3H), 7,80 (s, 1H), 7,82 is 7.85 (m, 1H), 7,89-7,94 (m, 2H), 8,10 (d, J=15.2 Hz, 1H), at 8.60 (d, J=6,8 Hz, 1H). LC/MS: 95%. MS (ESI-) Calculated: 522,0 m/z; found: 521,5 m/z.

Example 339. Getting connection P401.

Synthesis of 3-fluoro-N-[(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]benzosulfimide, I-202. Compound I-202 synthesized according to the method similar to that described for compound I-196 using compound I-34 (300 mg, 1.37 mmol), anhydrous CH2Cl2(4 ml), 3-forbindelsesfaneblad (287 mg, of 1.64 mmol), DMAP (200 mg, of 1.64 mmol) and EDCI (314 mg, of 1.64 mmol). After filtration allocate 212 mg of compound I-202 in the form of a yellow solid (41%). H-NMR (400 MHz, DMSO-d6). LC/MS: 97%.

The synthesis of compounds P401. Compound I-202 (100 mg, 0,266 mmol) is subjected to interaction with 2-chloromethylketone[1,2-a]pyridine (53,1 mg, 0,319 mmol) and NaH (60%) (32,0 mg, 0,798 mmol) in anhydrous DMF (500 μl) according to the method similar to that described for compound P402. After drying, the highlight of 74.9 mg connection P401 in the form of a yellowish-brown solid (55%).1H-NMR (400 MHz, DMSO-d6). LC/MS: 97%.

Example 340. Getting connection P413.

Synthesis of 2,4-debtor-N-[(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)-acryloyl]benzosulfimide, I-203. Compound I-203 synthesized according to the method similar to that described for compound I-196 using compound I-34 (300 mg, 1.37 mmol), anhydrous CH2Cl2(4 ml), 2,4-diftorbenzofenonom (317 mg, of 1.64 mmol), DMAP (200 mg, of 1.64 mmol) and EDCI (314 mg, of 1.64 mmol). After filtration allocate 297 mg of compound I-203 in the form of a yellow solid (55%).1H-NMR (400 MHz, DMSO-d6). LC/MS: 97%.

The synthesis of compounds P413. Compound I-203 (100 mg, 0,254 mmol) is subjected to interaction with 2-chloromethylketone[1,2-a]pyridine (50,8 mg, 0,305 mmol) and NaH (60%) (30,5 mg, 0,762 mmol) in anhydrous DMF (500 μl) according to the method similar to that described for compound P402. After drying allocate 103 mg connection P413 in the form of a yellowish-brown solid (77%).1H-NMR (400 MHz, DMSO-d6); LC/MS: 99%.

Example 341. Getting connection P403.

Synthesis of 4-fluoro-N-[(E)-3-(5-photo the-3-methyl-1H-indol-7-yl)acryloyl]benzosulfimide, I-204. Compound I-204 synthesized according to the method similar to that described for compound I-196 using compound I-34 (300 mg, 1.37 mmol), anhydrous CH2Cl2(4 ml), 4-forbindelsesfaneblad (287 mg, of 1.64 mmol), DMAP (200 mg, of 1.64 mmol) and EDCI (314 mg, of 1.64 mmol). After filtration allocate 273 mg of compound I-204 in the form of a yellow solid (53%).1H-NMR (400 MHz, DMSO-d6). LC/MS (96%).

The synthesis of compounds P403. Compound I-204 (100 mg, 0,266 mmol) is subjected to interaction with 2-chloromethylketone[1,2-a]pyridine (53,1 mg, 0,319 mmol) and NaH (60%) (32,0 mg, 0,798 mmol) in anhydrous DMF (500 μl) according to the method similar to that described for compound P402. After drying allocate 90,9 mg connection P403 in the form of a yellowish-brown solid (67%).1H-NMR (400 MHz, DMSO-d6). LC/MS: 95%.

Example 342. Getting connection P404.

Synthesis of 3,5-debtor-N-[(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]benzosulfimide, I-205. Compound I-205 synthesized according to the method similar to that described for compound I-196 using compound I-34 (300 mg, 1.37 mmol), anhydrous CH2Cl2(4 ml), 3,5-diftorbenzofenonom (317 mg, of 1.64 mmol), DMAP (200 mg, of 1.64 mmol) and DCI (314 mg, of 1.64 mmol). After filtration allocate 278 mg of compound I-205 in the form of a yellow solid (51%).1H-NMR (400 MHz, DMSO-d6); LC/MS: 98%.

The synthesis of compounds P404. Compound I-205 (100 mg, 0.54 mmol) is subjected to interaction with 2-chloromethylketone[,2-a]pyridine (50,8 mg, 0,305 mmol) and NaH (60%) (30,5 mg, 0,762 mmol) in anhydrous DMF (500 μl) according to the method similar to that described for compound P402. After drying allocate 90,2 mg connection P404 in the form of a yellowish-brown solid (68%).1H-NMR (400 MHz, DMSO-d6) 2,24 (s, 3H), 5,77 (s, 2H), 6,44 (d, J=15.2 Hz, 1H), to 7.09 (DD, J=2,8, 10.4 Hz, 1H), 7,34-7,37 (m, 1H), 7,40 (s, 1H), 7,47 (DD, J=2,4, 8,8 Hz, 1H), 7,62-the 7.65 (m, 2H), 7,72-7,80 (m, 3H), 7,86 (s, 1H), 8,07 (d, J=14,8 Hz, 1H), 8,66 (d, J=6,8 Hz, 1H). LC/MS: 95%, MS (ESI-) Calculated: 523,5 m/z, found: 523,6 m/z.

Example 343. Getting connection P405.

Synthesis of 4-chloro-N-[(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]benzosulfimide, I-206. Compound I-206 synthesized according to the method similar to that described for compound I-196 using compound I-34 (300 mg, 1.37 mmol), anhydrous CH2Cl2(4 ml), 4-chlorobenzenesulfonamide (314 mg, of 1.64 mmol), DMAP (200 mg, of 1.64 mmol) and EDCI (314 mg, of 1.64 mmol). After filtration allocate 213 mg of compound I-206 in the form of a yellow solid (40%).1H-NMR (400 MHz, DMSO-d6); LC/MS (98%).

The synthesis of compounds P405. Compound I-206 (100 mg, 0,255 mmol) is subjected to interaction with 2-chloromethyl-imidazo[1,2-a]pyridine (51,0 mg, 0,306 mmol) and NaH (60%) (30,7 mg, 0,765 mmol) in anhydrous DMF (500 μl) according to the method similar to that described for compound P402. After drying allocate 110 mg of the compound P405 in the form of a yellowish-brown solid (83%).1H-NMR (400 MHz, DMSO-d6); LC/MS: 96%.

Example 344. Getting connection P406.

3,4-is ALOR-N-[(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]benzosulfimide, I-207. Compound I-207 synthesized according to the method similar to that described for compound I-196 using compound I-34 (300 mg, 1.37 mmol), anhydrous CH2Cl2 (4 ml), 3,4-dichlorobenzenesulfonate (371 mg, of 1.64 mmol), DMAP (200 mg, of 1.64 mmol) and EDCI (314 mg, of 1.64 mmol). After filtration allocate 321 mg of compound I-207 in the form of a yellow solid (55%).1H-NMR (400 MHz, DMSO-d6); LC/MS: 99%.

The synthesis of compounds P406. Compound I-207 (100 mg, 0,234 mmol) is subjected to interaction with 2-chloromethylketone[1,2-a]pyridine (46.8 mg, 0,281 mmol) and NaH (60%) (28,0 mg, 0,702 mmol) in anhydrous DMF (500 μl) according to the method similar to that described for compound P402. After drying allocate 95,1 mg connection P406 in the form of a yellow solid (73%).1H-NMR (400 MHz, DMSO-d6); LC/MS: 95%.

Example 345. Getting connection P407.

Synthesis of 2,5-debtor-N-[(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]benzosulfimide, I-208. Compound I-208 synthesized according to the method similar to that described for compound I-196 using compound I-34 (300 mg, 1.37 mmol), anhydrous CH2Cl2(4 ml), 2,5-diftorbenzofenonom (317 mg, of 1.64 mmol), DMAP (200 mg, of 1.64 mmol) and EDCI (314 mg, of 1.64 mmol). After filtration allocate 284 mg of compound I-208 in the form of a yellow solid (53%).1H-NMR (400 MHz, DMSO-d6); LC/MS: 99%.

The synthesis of compounds of P407. Compound I-208 (100 mg, 0,254 mmol) is subjected to interaction with 2-chloromethylketone[1,2-a]pyridine (50,8 mg, 0,305 IMO the b) and NaH (60%) (30,5 mg, 0,762 mmol) in anhydrous DMF (500 μl) according to the method similar to that described for compound P402. After drying allocate 106 mg connection P407 in the form of a yellow solid (80%).1H-NMR (400 MHz, DMSO-d6); LC/MS: 97%.

Example 346. Getting connection P408.

Synthesis of 3,5-dichloro-N-[(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]benzosulfimide, I-209. Compound I-209 synthesized according to the method similar to that described for compound I-196 using compound I-34 (300 mg, 1.37 mmol), anhydrous CH2Cl2(4 ml), 3,5-dichlorobenzenesulfonate (371 mg, of 1.64 mmol), DMAP (200 mg, of 1.64 mmol) and EDCI (314 mg, of 1.64 mmol). After filtration allocate 215 mg of compound I-209 in the form of a yellow solid (37%).1H-NMR (400 MHz, DMSO-d6); LC/MS: 98%.

The synthesis of compounds P408. Compound I-209 (100 mg, 0,234 mmol) is subjected to interaction with 2-chloromethylketone[1,2-a]pyridine (46.8 mg, 0,281 mmol) and NaH (60%) (28,0 mg, 0,702 mmol) in anhydrous DMF (500 μl) according to the method similar to that described for compound P402. After drying allocate 117 mg connection P408 in the form of a yellowish-brown solid (90%).1H-NMR (400 MHz, DMSO-d6); LC/MS: (96%).

Example 347. Getting connection P409.

Synthesis of 2-fluoro-N-[(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)acryloyl]benzosulfimide, I-210. Compound I-210 synthesized according to the method similar to that described for compound I-196 using compound I-34 (300 mg, 1.37 mmol), anhydrous CH2Cl 2(4 ml), 2-forbindelsesfaneblad (287 mg, of 1.64 mmol), DMAP (200 mg, of 1.64 mmol) and EDCI (314 mg, of 1.64 mmol). After filtration allocate 275 mg of compound I-210 in the form of a yellow solid (53%).1H-NMR (400 MHz, DMSO-d6); LC/MS: 99%.

The synthesis of compounds P409. Compound I-210 (100 mg, 0,266 mmol) is subjected to interaction with 2-chloromethylketone[1,2-a]pyridine (53,1 mg, 0,319 mmol) and NaH (60%) (32,0 mg, 0,798 mmol) in anhydrous DMF (500 μl) according to the method similar to that described for compound P402. After drying allocate 98,1 mg connection P409 in the form of a yellowish-brown solid (73%).1H-NMR (400 MHz, DMSO-d6); LC/MS: 98%.

Example 348. Getting connection P395.

Compound I-36 (250 mg, 0,576 mmol) is subjected to interaction with 2-chloromethylketone[1,2-a]pyridine (115 mg, 0,692 mmol) and NaH (60%) (138 mg, 3.46 mmol) in anhydrous DMF (2.8 ml) by the procedure similar to that described for compound P402. After drying allocate 233 mg connection P395 in the form of a yellowish-brown solid (72%).1H-NMR (400 MHz, DMSO-d6) 2,22 (s, 3H), 5,49 (s, 2H), 6,24 (d, J=15.6 Hz, 1H), 6,85-6,89 (m, 1H),? 7.04 baby mortality (DD, J=2,8, and 10.8 Hz, 1H), 7,19-7,26 (m, 2H), was 7.36 (USS, 1H), 7,47 (s, 1H), of 7.48 (d, J=8,4 Hz, 1H), they were 8.22 (d, J=15.2 Hz, 1H), of 8.27 (s, 1H), 8,43 (d, J=6,8 Hz, 1H). HPLC purity: 89%; MS (ESI-) Calculated: 562,5 m/z; found: 563,1 m/z.

General procedure (A-21) hydrogenation.

To a solution of compound I-131D in ethanol is added 10% Pd/C (0.1 g/g of compound 1). The resulting mixture Tegaserod and atmosphere replaces the hydrogen (3 times). The mixture is stirred in hydrogen atmosphere at atmospheric pressure for 5 days. The reaction mixture was filtered through celite, the filter cake washed with ethanol and the filtrate concentrated. The crude reaction mixture is purified by chromatography on silica gel using dichloromethane as eluent, and then by chromatography on silica gel, using an elution with a gradient mixture of EtOAc/hexane receiving compound I-211 I-212. Compound I-211: methyl ester of 3-[l-(3,4-diferensial)-3a-methyl-2-oxooctanoate-7-yl]propionic acid; MS (ESI+) Calculated: 365,4 m/z; found: 366,0 m/z.1H-NMR(CDCl3). Compound I-212: methyl ester of 3-[1-(3,4-diferensial)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]propionic acid; MS (ESI+) Calculated: 363,4 m/z; found: 364 m/z;1H-NMR(CDCl3).

General procedure (A-22) hydrolysis of the methyl esters

To a solution of the appropriate methyl ester in THF/MeOH (2:1) is added aqueous NaOH solution (3 EQ.) and the resulting reaction mixture is stirred for 24-72 hours at room temperature. The mixture is concentrated to remove organic solvents, diluted with water and washed with 2 portions of dichloromethane. The pH was adjusted to 2-3 (litmus paper) by addition of 1N. HCl and the mixture extracted with EtOAc. The organic fraction was washed with water and saturated salt solution, dried over magnesium sulfate and concentrated to receipt the m target connection.

General procedure (A-23) get arylsulfonamides

To a solution of a suitable source of acid, a suitable sulfonamida (of 1.05 equiv.) and DMAP (2.4 EQ.) in CH2Cl2added EDCI (2.5 EQ.). The reaction mixture was stirred at room temperature for 1-5 days. The reaction mixture was washed with 1N. HCl (aq.), water and saturated salt solution, dried over magnesium sulfate and concentrated in vacuo.The residue is purified either by chromatography on silica gel, using an elution with a gradient (0-5% methanol in dichloromethane), or rubbing in a mixture of dichloromethane/hexane, getting listed at the beginning of the connection.

Example 349. Getting connection P410.

Synthesis of 3-[1-(3,4-diferensial)-3a-methyl-2-oxooctanoate-7-yl]propionic acid I-213.

In accordance with the General method (A-22), compounds I-211 is converted into compound I-213 with a quantitative yield. LC/MS: 100%; APCI - Calculated: 351,4 m/z; found: 350,2 m/z;1H-NMR(CDCl3).

The synthesis of compounds P410. In accordance with the General method A-23, a connection I-213 is subjected to reaction combination with 2,4,5-tripersonality getting connection P410 with 46% yield. LC/MS: 84%; ESI - Calculated: 544,5 m/z; found: 543.5 nm m/z;1H-NMR (DCl3).

Example 350. Getting connection P411.

Synthesis of 3-[1-(3,4-diferensial)-3a-methyl-2-oxo-2,3,3a,4,5,6-hexahydro-1H-indol-7-yl]propionic acid, I-214

The fit is accordance with the General method (A-22), compound I-212 is converted into compound I-214 with the release of 61%. LC/MS (98%) ESI+ Calculated: 349,4 m/z; found: 350,9 m/z;1H-NMR(CDCl3)

The synthesis of compounds P411. In accordance with the General method A-23, a connection I-214 is subjected to reaction combination with 2,4,5-tripersonality getting connection P411 with the release of 81%. LC/MS: 81%; ESI - Calculated: 542,5 m/z; found: USD 542.3 m/z;1H-NMR(CDCl3).

Example 351. Getting connection P415.

In accordance with the General method A-23, a connection I-213 is subjected to reaction combination with 4,5-dichlorothiophene-2-sulfonamide getting connection P415 with the release of 70%. LC/MS: 93%; ESI-Calculated: 563,5 m/z; found: 563,4 m/z 1H-NMR(DCl3).

Example 352. Getting connection P414.

In accordance with the General method A-21, P306 subjected to hydrogenation, receiving the connection P414 with the release of 40%. LC/MS: 98,9%; ESI-Calculated: 537,5 m/z; found: 537,5 m/z;1H-NMR(CDCl3).

Example 353. Getting connection P412.

Synthesis of 3-[1-methyl-4-(naphthalene-2-yloxy)-1H-indol-3-yl]propionic acid, I-215. In accordance with the General method A-21, I-137A is subjected to hydrogenation, receiving compound I-215 exit 40%.1H-NMR(CDCl3).

The synthesis of compounds P412. In accordance with the General method A-23, a connection I-215 is subjected to reaction combination with 2,4,5-tripersonality getting connection P412 with the release of 46%. LC/MS: 90%; ESI - Calculated: 538,4 m/z; ideno: 537,8 m/z. 1H-NMR(CDCl3).

Example 354. Getting connection P362.

In accordance with the General method A-23, a connection I-215 subject of combination reaction with 3,4-differentlanguages getting connection P362 with 54% yield.1H-NMR (400 MHz, DMSO-d6), MS(ESI-): 519,6 (M-1), HPLC c reversed phase: 94%.

Example 355. Getting connection P257.

Synthesis of 4-iodine-1-methyl-1H-indazol-3-ylamine, I-216. In the capacity of 330 ml volume under pressure, equipped with a magnetic stirrer, add 2-fluoro-6-idententical (4.5 g, 18.2 mmol), N,N-dimethylacetamide (45 ml) and methylhydrazine (1.2 ml, with 23.7 mmol). The capacity of the purge gas N2, sealed, heated to 87°C and kept at this temperature during the night, then up to 120°C and kept at this temperature for 5 hours. The reaction mixture is cooled, diluted with EtOAc (300 ml) and washed with water. The aqueous layer was extracted and the combined EtOAc extracts washed with water (3×150 ml), saturated salt solution, dried (Na2SO4), filtered and concentrated, obtaining a brown solid. The solid product is triturated in a mixture of EtOAc/hexane (1:1, 10 ml), filtered, washed with a mixture of EtOAc/hexane (1:1) and dried, obtaining of 4.04 g (81%) I-216 in the form of a beige solid.1H-NMR (400 MHz, DMSO-d6).

Synthesis of (4-iodine-1-methyl-1H-indazol-3-yl)amide naphthalene-2-carboxylic acid, I-217. To compound I-216 (470 mg, 1,71 mmol who), dissolved in anhydrous THF (7 ml), add triethylamine (477 μl, 346 mg of 3.42 mmol) and the resulting mixture with stirring, cooled to 0°C in nitrogen atmosphere. To the solution with stirring in one portion add 2-aftercare (326 mg, 1,71 mmol), allow the reaction mixture to warm to room temperature and stirred over night. The reaction mixture is filtered and the resulting solid precipitate was washed with THF and CH2Cl2. The obtained solid product is mixed with ethanol (15 ml), filtered, the resulting solid residue is washed with ethanol and dried, obtaining 476 mg (65%) I-217 in the form of a white solid.1H-NMR (400 MHz, DMSO-d6).

Synthesis of methyl ester (E)-3-{1-methyl-3-[(naphthalene-2-carbonyl)amino]-1H-indazol-4-yl}acrylic acid, I-218. In high pressure tube, equipped with a magnetic stirrer, load connection I-217 (200 mg, 0,468 mmol), methylamine (10 ml), palladium (II) acetate (10.5 mg, 0,047 mmol) and tri-o-tolylphosphino (43 mg, 0.14 mmol). The solution Tegaserod, barbotine gaseous N2through the solution for 30 minutes. Add methyl acrylate (956 mg, 1 ml, 36 mmol), the solution Tegaserod for an additional 5 minutes and then the tube is sealed, heated to 75°C and maintained at the specified temperature for 30 minutes, then at 100°C for 6 hours. The reaction mixture is cooled to room temperature and the re add anhydrous DMF (20 ml) and an additional portion of the palladium (II) acetate (11 mg, 0,049 mmol). The solution again Tegaserod, sealed, heated at an oil bath to 105°C and maintained at this temperature for 6 hours, then allow to cool to room temperature. The reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc and the combined organic extracts washed with water (3×), saturated salt solution and dried (Na2SO4). The solution is filtered and concentrated, obtaining 210 mg of compound I-218-purity sufficient for use in the next stage of the synthesis.1H-NMR (400 MHz, DMSO-d6).

Synthesis of (E)-3-{1-methyl-3-[(naphthalene-2-carbonyl)amino]-1H-indazol-4-yl}acrylic acid, I-219. In a round bottom flask with a volume of 25 with one throat, equipped with a magnetic stirrer, add a connection I-218 (210 mg, 0,468 mmol), methanol, and THF (5 ml each). To the obtained solution under stirring add 2M aqueous NaOH solution of 0.85 ml, 1.70 mmol). After 2 hours add an additional portion of 2M aqueous NaOH (0.54 ml of 1.08 mmol), the reaction mixture is heated to 40°C and maintained at the specified temperature during the night. The cooled reaction mixture is acidified with 1M aqueous HCl solution and extracted with EtOAc (3×). The combined organic extracts washed with saturated Rast is a PR salt and dried (Na 2SO4). The solution is evaporated, the residue is purified column chromatography using a mixture of 2:2:1 CH2Cl2/THF/hexane and then 6:6:1 CH2Cl2/THF/methanol, receiving 95 mg of compound I-219. 1H-NMR (400 MHz, DMSO-d6).

The synthesis of compounds P257. In accordance with the General procedure A-8, the acrylic acid I-219 is subjected to interaction with Amida 4,5-dichlorothiophene-2-sulfonic acid to obtain compounds P257.1H-NMR (DMSO-d6) 4,06 (s, 3H), of 6.61 (d, J=20,0), 7,47 (m, 2H), 7,56 (s, 1H), 7,66 (m, 2H), 7,72 (m, 1H), 8,01 (m, 3H), 8,16 (m, 1H), 8,67 (s, 1H), a 10.74 (s, 1H). LC/MS (96%) ESI+Calculated: 585,49; found: 585,4 m/z.

Example 356. Getting connection P246.

Synthesis of 1,3-bis-trimethylsilyloxy-2-(l-trimethylsilylethynyl)benzene, I-220.

1M solution of LiHMDS (52 ml, to 51.8 mmol, 3,15 EQ.) in THF carefully added to a solution of 2,6-dihydrotestoterone (2.5 g, 16.4 mmol, 1 EQ.) in THF (100 ml) and the reaction mixture is stirred for 15 minutes at room temperature. To a mixture of one portion add chlorotrimethylsilane (7.3 ml, 57,4 mmol, 3.5 EQ.) (exothermic reaction) and the reaction mixture is stirred for 5 minutes. The reaction mixture is concentrated to about 11, Add anhydrous CH2Cl2(50 ml), the precipitate filtered off, washed with CH2Cl2and uterine fluid concentrate, receiving compound I-220 (6,04 g, 100%) as a brown liquid.1H-NMR (500 MHz, CDCl3) n dtarget structure.

Synthesis of 4-hydroxybenzophenone-3-it, I-221. A solution of N-bromosuccinimide (3.2 g, 18,02 mmol, 1.1 EQ.) in acetonitrile (22 ml) was carefully added to a solution of compound I-220 (6,04 g, 16.4 mmol, 1 EQ.) in acetonitrile (72 ml) and the reaction mixture is stirred for 20 minutes. The crude mixture was concentrated, diluted with CH2Cl2(50 ml). CH2Cl2the solution is washed successively with a saturated aqueous solution NaHC3(30 ml), 1N. aqueous NaOH solution (20 ml×2), water (50 ml), saturated salt solution (50 ml) and concentrated. Add MeOH (34 ml) and water (12 ml). Slowly add concentrated HCl (2 ml), the solution is stirred for 15 minutes, then add water (50 ml) and the mixture was concentrated in vacuo.Add water (50 ml) and the mixture extracted with EtOAc (3×15 ml). The combined organic extracts washed with water, saturated salt solution, dried over MgSO4getting a yellow solid (3,21 g). Add acetone (80 ml), then K2CO3(4.8 g) at room temperature. The suspension is stirred at room temperature for 1 hour, then filtered and concentrated. Add CH2Cl2then 10% HCl. The organic layer is washed with water, saturated salt solution, dried over MgSO4receiving untreated I-221 (2.0 g, 84% crude yield) as an orange solid. Add MTBE (6 ml), suspe is the Zia cooled to 0°C and the solid product is filtered off, getting a pure compound I-221 (1.24 g, 50%) as an orange solid. MS (AP+): 151 (M+1).1H-NMR (500 MHz, CDCl3) confirms the structure.

Synthesis of 3-(naphthalene-2-ylsulphonyl)benzofuran-4-ol, I-222. A solution of HCl (2.0 M in ether, 3.75 ml, 5 EQ.) add to preheated to 40°C solution of compound I-221 (225 mg, 1.5 mmol, 1 EQ.) and 2-naphthalenethiol (240 mg, 1.5 mmol, 1 EQ.) in EtOH (3.75 ml) and stirred at room temperature for 23 hours. The reaction mixture was concentratedin a vacuum.The residue is dissolved in EtOAc, the solution washed with water, saturated salt solution, dried over MgS4getting 470 mg) as a yellow solid. The solid product is triturated in hexane (4 ml) at room temperature, then refluxed with hexane (2 ml) and filtered, receiving compound I-222 (291 mg, 66%) as a yellow solid.

Synthesis of methyl ester [3-(naphthalene-2-ylsulphonyl)benzofuran-4-yloxy]acetic acid, I-123. To a solution of methylpropanoate (156 mg, of 1.02 mmol, 1.2 EQ.) in acetone (1 ml) is added a suspension of compound I-222 (249 mg, 0.85 mmol, 1 EQ.) and K2CO3(176 mg, 1,275 mmol, 1.5 EQ.) in acetone (2 ml). The reaction mixture was sealed in a volume of 20 ml, heated to 70°-80°C and kept at this temperature for 3 hours. Add water (8 ml), then EtOAc (4 ml) and the mixture is acidified with 10% HCl is about pH=5. The organic layer was separated, washed with water, saturated salt solution, dried over MgS4receiving compound I-223 (310 mg, 100%) as a red oil, which crystallizes. MS (ESI+): 366 (M+l). The structure is confirmed1H-NMR (500 MHz, CDCl3).

Synthesis of [3-(naphthalene-2-ylsulphonyl)benzofuran-4-yloxy]acetic acid, I-224. 2n. an aqueous solution of NaOH (1,05 ml of 2.09 mmol, 2.5 EQ.) added dropwise to a solution of compound I-223 (305 mg, 0,834 mmol, 1 EQ.) in a mixture of THF-MeOH (1:1, 5 ml). The reaction mixture was stirred at room temperature for 15 minutes. The mixture of concentratein vacuum,add water, then EtOAc. The mixture is acidified with 10% HCl. The organic layer is washed with water, saturated salt solution, dried over MgSO4receiving compound I-224 (293 mg, 100%) as oil. MS (ESI-): 349 (M-1). The structure is confirmed1H-NMR (500 MHz, CDCl3).

The synthesis of compounds P246. To a solution of compound I-224 (22 mg, 0,063 mmol, 1 EQ.) in 0.5 ml of dichloromethane added DMAP (15 mg, 0,126 mmol, 2 equiv.) 4,5-dichloro-2-thiophenesulfonyl (31 mg, 0,132 mmol, 2.1 EQ.) and EDCI (24 mg, 0,126 mmol, 2 EQ.). The mixture is stirred at room temperature for 3 hours, then quenched with 10% HCl and water. The aqueous layer was extracted with EtOAc. The combined organic extracts washed with water, saturated salt solution and then dried over MgSO4. The solution is concentrated and the residue chromatographic naselesele, elwira a mixture of EtOAc/hexane (3:7, then 1:1)to give compound P246 (13 mg, 37%) as a yellow oil. LC-MS (ESI-): 563 (M-l) (92%).1H-NMR (CDCl3) a 4.53 (s, 2H), 6,55 (m, 1H), 7,33 (ush., 2H), 7,35 (DD, J=11,0, 2.0 Hz, 1H), 7,40-7,47 (m, 3H), 7,60 (d, J=2.0 Hz, 1H), to 7.64 (USD, J=8.5 Hz, 1H), 7,73 for 7.78 (m, 2H), 7,85 (ush. s, 1H), 10,10 (s, 1H). LC-MS (99%): ESI-Calculated: 563 m/z; found: 563,3.

Example 357. Getting connection P256.

The solution oxone (131 mg, 0.21 mmol, 3 EQ.) in water (0.7 ml) carefully added with stirring to a solution P246 (40 mg, 0,071 mmol, 1 EQ.) in a mixture of dioxane/MeOH (1:1, 2 ml) at room temperature. The reaction mixture was stirred over night at room temperature. Add water (5 ml), the precipitate filtered off, washed with water (2×1.5 ml) and ethanol (2 ml) and dried, obtaining the connection P256 (32 mg, 78%) as a white solid. LC-MS (98%): ESI-Calculated: 579 m/z; found: 579.1H-NMR (CDCl3) 4,48 (d, J=14,8 Hz, 1H), to 4.52 (d, J=14,8 Hz, 1H), 6,60 (DD, J=8,0, 0.8 Hz, 1H), 7,25 (DD, J=8,4, 0,4 Hz, 1H), 7,32 (d, J=8,4 Hz, 1H), 7,50 (DD, J=8,8, 2.0 Hz, 1H), to 7.59-7,63 (m, 2H), 7,73 (d, J=4,8 Hz, 1H), 7,88-to 7.93 (m, 4H), 8,32 (d, J=2.0 Hz, 1H), 12,70 (ush. s, 1H).

Example 358. Getting connection P254.

The synthesis of compounds P254. Peracetic acid (0.45 ml, 32%, 2,13 mmol) carefully c by stirring at room temperature are added to a solution P246 (40 mg, 0,071 mmol, 1 EQ.) in CH2Cl2(2 ml). The reaction mixture was stirred at room temperature for 3 days. The quenching reaction is a mixture of water/CH 2Cl2(4 ml each). The organic layer is separated and washed with water, saturated salt solution, dried over MgS4receiving a connection P254 (32 mg, 76%) as oil, which crystallized to obtain white solids. LC-MS (92%): ESI-Calculated: 595 m/z; found: 595.1H-NMR (CDCl3) of 4.67 (s, 2H), 6,94 (DD, J=8.0 a, 0,4 Hz, 1H), 7,28 (DD, J=8,4, 0.8 Hz, 1H), 7,51 (DD, J=8,4, 0.8 Hz, 1H), 7,62-7,71 (m, 2H), 7,72 (s, 1H), 7,88-7,94 (m, 3H), of 7.97 (d, J=9,2 Hz, 1H), 8,08 (s, 1H), to 8.62 (d, J=the 0.8 Hz, 1H), 12,70 (ush. s, 1H).

Example 359. Getting connection P317

Compound I-205 (78 mg, 0.15 mmol) is subjected to interaction with 3,4-diferenciada (37 mg, 0.18 mmol) and NaH (60%) (13 mg, 0.33 mmol) in anhydrous DMF (2 ml) by the procedure similar to that described for compound P402. After drying allocate 57 mg of compound P317 in the form of a yellow solid (73%).1H-NMR (CDCl3) to 2.29 (d, J=1.2 Hz, 3H), of 5.34 (s, 2H), 6,11 (d, J=15.2 Hz, 1H), 6,69 (m, 1H), for 6.81 (m, 1H), 6,95 (s, 1H), 6,97 (DD, J=a 9.6, 2.4 Hz, 1H), 7,03 (m, 1H), 7,12 (m, 1H), 7,29 (DD, J=8,4, 2.4 Hz, 1H), of 7.64-of 7.70 (m, 2H), of 8.09 (DD, J=15,6, 1.2 Hz, 1H), 8,23 (USS, 1H). LC-MS (95%): ESI-Calculated: 520,5 m/z; found: 520,5.

Example 360. Getting connection P321.

Compound I-36 (70 mg, 0.16 mmol) alkylate using NaH (60%) (8.5 mg, 0.36 mmol) and 3,4-differenziale (50 mg, 0.24 mmol) in anhydrous DMF (2.8 ml) by the procedure similar to that described for compound P068. After filtration and allocate column chromatography allocate 50 mg connection P321 in view of the yellow solid (55%). 1H-NMR (DMSO-d6) 5,51 (s, 2H), of 6.26 (d, J=16 Hz, 1H), 6,66 (m, 1H), 6,99 (m, 1H),? 7.04 baby mortality (DD, J=10, 2.4 Hz, 1H), 7,41 (s, 1H), 7.23 percent (m, 1H), 7,43 (DD, J=12, 2.4 Hz, 1H), 7,87 (s, 1H), 7,98 (d, J=11,6 Hz, 1H), LC/MS (92%) (ESI-) Calculated: 558 m/z; found: 557 m/z.

Example 361. Getting connection P258.

Synthesis of 4-methoxy-1-methyl-1H-indole-2,3-dione, the I-225. 4-Methoxyisatin (obtained in accordance with the method of publication Hewaam, P., Meanwell, N. A. Tet. Lett. 1994, 35, 7303-7306, 1.5 grams of 8.47 mmol) dissolved in acetone (30 ml) and add potassium carbonate (2.9 g, of 21.2 mmol) and jodean (1.3 ml, 3.0 g, of 21.2 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was filtered and the solids washed with acetone, obtaining 1.5 g of solid substance. The obtained solid product is heated in ethanol (13 ml) and 33% aqueous solution of KOH (5 ml) to 70°C and maintained at this temperature for 1.5 hours. The mixture is concentrated and then acidified with dilute aqueous HCl solution. Drawn in red precipitate the solid product is filtered off and dried. obtaining 0.8 g of compound I-225.1H-NMR (500 MHz, DMSO-d6).

Synthesis of 4-hydroxy-1-methyl-1H-indole-2,3-dione, I-226. Compound I-225 (0,446 g, 0,0023 mol) is dissolved in anhydrous CH2Cl2(20 ml) and cooled to 0°C in nitrogen atmosphere. To the resulting solution was added dropwise a solution of 1M BBr3in CH2Cl2(of 9.2 ml, 0,0092 mol). The resulting mixture was stirred for 1 hour at the room for the Noah temperature, then concentrated and transferred into a mixture of THF/EtOAc (2:1), washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and concentrated, obtaining the compound (I-226 (0,300 g). MS (ESI-)=176,3 (M-l). LC/MS(ESI-) of 91.3%.1H-NMR (400 MHz, DMSO-d6).

Synthesis of methyl ester (l-methyl-2,3-dioxo-2,3-dihydro-1H-indol-4-yloxy)acetic acid, I-227. Compound I-226 (0,300 g, 0,0017 mol) is dissolved in EtCOMe (10 ml). To the resulting solution was added potassium carbonate (0,2573 g, 0,00186 mol) and methylbromide (of 0.21 ml, 0,0022 mol). The mixture is stirred at room temperature for 3 days and then concentrated. The residue was diluted with EtOAc, washed with saturated salt solution, the organic layer is dried over anhydrous sodium sulfate, filtered and concentrated, obtaining the compound (I-227 (0,300 g). MS (ESI+)=250,2 (M+l). LC/MS (ESI+) 92,8%.

Synthesis of (1-methyl-2,3-dioxo-2,3-dihydro-1H-indol-4-yloxy)acetic acid, I-228.

I-227 (0,300 g, 0,0012 mol) is dissolved in THF (10 ml). To the solution was added aqueous 1M LiOH solution (2.4 ml, 0,0024 mol) and the mixture is stirred for 1 hour at room temperature. The mixture is evaporated, the residue triturated with 2M aqueous HCl solution, water and dried, obtaining the compound (I-228 (0,280 g). MS (ESI+)=236,2 (M+l). LC/MS (ESI+) 86.4 per cent.1H-NMR (400 MHz, DMSO-d6).

Synthesis of [2-(l-methyl-2,3-dioxo-2,3-dihydro-1H-indol-4-yloxy)acetyl]amide 4,5-dichlorothiophene-2-Sultonova the acid, I-229. Compound I-228 (0,280 g, 0,0012 mol) is dissolved in THF (2 ml). To the solution add CH2Cl2(1 ml), EDCI (0,4601 g, 0,0024 mol), DMAP (0,2928 g, 0,0024 mol) and 2,3-dichlorothiophene-5-sulfonamide (0,3062 g, 0,00132 mol), the mixture is stirred for two days at room temperature, concentrated, dissolved in THF/EtOAc (2:1) and distributed in 2M aqueous HCl. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered, concentrated and triturated in a mixture of ether/EtOAc (2:1)to give compound I-229 (0,140 g). MS (ESI-)=447,2 (M-l).1H-NMR (400 MHz, DMSO-d6).

The synthesis of compounds P258. Compound I-229 (0,100 g, 0,223 mmol) dissolved in methanol (2 ml). To the resulting solution was added 3,4-dichloraniline (0,043 g, 0,267 mmol), then the hydrate p-toluensulfonate acid (0.002 g, 0,010 mmol). The resulting mixture is stirred in a closed vessel at 80°C overnight, then cooled to room temperature, concentrated, dissolved again in acetic acid (1 ml) and to the solution add cyanoborohydride sodium (0,100 g, 1,591 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated, washed with water and chromatographic on silica gel (elution with gradient, MeOH/CH2Cl2from 0.5% to 20%), and receiving the connection P258 (9 mg).1H-NMR (500 MHz, DMSO-d6) of 3.07 (s, 3H), 3,50-3,70 (m, 1H), 4,05-and 4.40 (m, 2H), to 4.98 (d, J=7,0 Hz, 1H), of 5.75 (s, 1H), 6,46 (d, J8,5 Hz, 1H), 6,62 (d, J=7.5 Hz, 1H), 6,70 (s, 1H), 6.73 x (m, 1H), 7,18 (DD, J=8,5, 8.0 Hz, 1H), 7.23 percent (s, 1H), 7,34 (s, 1H). LC/MS (90,2%) ESI+Calculated: M=595,3; found: 596,1 m/z.

Example 362. Getting connection P249.

Using method A-15 and substituting 2-afterculture aniline, compound I-186 transform in connection P249 with 70% yield;1H-NMR (DMSO-d6) a 3.15 (s, 3H), for 6.81 (d, J=16 Hz, 1H), 7,15 (d, J=8 Hz, 1H), 7,39 (d, J=8 Hz, 1H), 7,44 (s, 1H), 7,68 (m, 3H), 7,81 (s, 1H), 7,88 (DD, J=8,8, 2.0 Hz, 1H), 8,04 (m, 2H), 8,13 (t, J=9,2 Hz, 2H), by 8.22 (d, J=16.0 Hz, 1H), 8,43 (m, 1H)

Example 363. Getting connection P251.

Using method A-15 and substituting 2-afterculture aniline, compound I-186 transform in connection P242 with 80% yield.1H-NMR (DMSO-d6) to 3.09 (s, 3H), of 6.66 (d, J=16 Hz, 1H), 7,03 (d, J=7,6 Hz, 1H), 7,28 (d, J=8 Hz, 1H), 7,38 (t, J=7,6 Hz, 1H), 7,44 (s, 1H), of 7.64 -7,71 (m, 2H), 7,81 (s, 1H), 7,87 - to 7.93 (m, 2H), 8,02 (d, J=7,6 Hz, 1H), 8,11 (t, J=9,2 Hz, 2H), 8,43 (d, J=1.6 Hz, 1H).

Example 364. Getting connection P323.

Synthesis of methyl ester (E)-3-[1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]acrylic acid, I-230. To a solution of compound I-191 (320 mg, 0,826 mmol) in anhydrous DMF (2 ml) was added palladium (II) acetate (4.6 mg, 0,0206 mmol), tri-o-tolylphosphino of 25.2 mg, 0,0824 mmol) and triethylamine (0,574 ml of 4.12 mmol). The mixture Tegaserod, barbotine through a solution of gaseous N2within 20 minutes. To the mixture add the methyl acrylate (370 μl, 4,12 mmol), the solution Tegaserod for an additional 5 minutes, then the capacity close the offer, placed on an oil bath and heated to 100°C. After keeping at the same temperature for 40 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc and water (4 each solvent) and extracted. The aqueous layer was extracted with ethyl acetate (2×4 ml)and the combined organic extracts washed with water (3×10 ml) and dried (Na2SO4). The solution is filtered and concentrated, obtaining 337 mg of compound I-230 with a degree of purity sufficient for use in the next stage.1H-NMR (400 MHz, CDCl3).

Synthesis of (E)-3-[l-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]acrylic acid, I-231. In a container with a volume of 18 ml, equipped with a rod stirrer, at room temperature load ester I-XXX (337 mg, 0,859 mmol), THF (4 ml), MeOH (2 ml) and 15% aqueous NaOH solution (1,28 ml, to 4.81 mmol). The mixture is stirred at room temperature for 24 hours. The reaction mixture was concentrated, washed with Et2O (3×20 ml), acidified with 1M HCl solution to pH 1 and extracted with CH2Cl2(2×35 ml). The organic part of the combine, dried (MgSO4and concentrate, getting 259 mg acid I-XXX in the form of a light green solid (80%).1H-NMR (400 MHz, CDCl3).

The synthesis of compounds P323. In a container with a volume of 8 ml, equipped with a rod stirrer, at room temperature load connection I-231 (41 mg, to 0.108 mmol), 2,4-tripersonality (23,2 mg, 0,110 mmol), DMAP (of 31.6 mg, 0,259 mmol), anhydrous CH2Cl2(2 ml) and EDCI (51.8% of mg, 0,270 mmol). The container tightly closed with the lid and enable the mixture to interact for 22 hours at room temperature. Content of the vessel was washed with 1M HCl solution (5 ml), water (3×5 ml) and saturated salt solution (5 ml). The organic portion is dried (MgSO4and concentrate, receiving the connection P323 in the form of a light green solid. The crude product is dissolved in boiling Et2O (1 ml), then add hexane (1 ml). Dropped the precipitate was separated by filtration with suction, getting 23.9 mg connection P323 in the form of a light green solid (39%).1H-NMR (400 MHz, CDCl3) to 2.29 (s, 3H), lower than the 5.37 (s, 2H), 6,18 (d, J=15.2 Hz, 1H), of 6.31 (d, J=8,4 Hz, 1H), 6.87 in (s, 1H), PC 6.82 (DD, J=2,8, 10,0 Hz, 1H),? 7.04 baby mortality (DD, J=2.0 a, and 8.4 Hz, 1H), 7,07-7,13 (m, 1H), 7,31 (DD, J=2,8, 8,8 Hz, 1H), 7,41 (d, J=2.4 Hz, 1H), 7,82 (d, J=14,8 Hz, 1H), 7,98-of 8.04 (m, 1H). LC/MS (96%); MS (ESI-) Calculated: 570,4 m/z; found: 569,4 m/z.

Example 365. Getting connection P371.

Synthesis of 4-(3-methoxyphenoxy)-1-methyl-1H-indole, I-134L: IN accordance with the General procedure A-12, compound I-133 is subjected to interaction with 3-methoxyphenol to obtain compound I-134L.1H-NMR confirms the structure.

Synthesis of 4-(3-methoxyphenoxy)-1-methyl-1H-indole-3-carbaldehyde, I-135L: IN accordance with the General procedure A-13, a connection I-134L is converted into formaldehyde I-135L.1H-NMR on the her structure.

Synthesis of ethyl ester of (E)-3-[4-(3-methoxyphenoxy)-1-methyl-1H-indol-3-yl]acrylic acid, I-136L. In accordance with the General procedure A-14, compound I-135L is converted into an ethyl ester of acrylic acid I-136L.1H-NMR confirms the structure.

Synthesis of (E)-3-[4-(3-methoxyphenoxy)-1-methyl-1H-indol-3-yl]acrylic acid, I-137L. In accordance with the General method A-7, compound I-136L hydrolyzing to the acrylic acid I-137L.1H-NMR confirms the structure.

The synthesis of compounds P371. In accordance with the General procedure A-8, the acrylic acid I-137L is subjected to interaction with 2,4,5-tripersonality getting connection P371.1H-NMR confirms the structure.

Example 366. Getting connection P372.

The synthesis of compounds P372. In accordance with the General procedure A-8, the acrylic acid I-137L is subjected to interaction with 2,3,4,5,6-pentafluorobenzaldehyde getting connection P372.1H-NMR confirms the structure.

Example 367. Getting connection P376.

Synthesis of 6-(1-methyl-1H-indol-4-yloxy)quinoline, I-134M: IN accordance with the General procedure A-12, compound I-133 is subjected to interaction with 6-hydroxyquinoline to obtain compound I-134M.1H-NMR confirms the structure.

Synthesis of 1-methyl-4-(quinoline-6-yloxy)-1H-indole-3-carbaldehyde, I-135M: In accordance with the General procedure A-13, a connection I-134M transform in Formaldehyd-135M. 1H-NMR confirms the structure.

Synthesis of ethyl ester of (E)-3-[l-methyl-4-(quinoline-6-yloxy)-1H-indol-3-yl]acrylic acid, I-136M. In accordance with the General procedure A-14, compound I-135M is converted into an ethyl ester of acrylic acid I-136M.1H-NMR confirms the structure.

Synthesis of (E)-3-[1-methyl-4-(quinoline-6-yloxy)-1H-indol-3-yl]acrylic acid, I-137M. In accordance with the General method A-7, compound I-136M hydrolyzing to the acrylic acid I-137M.1H-NMR confirms the structure.

The synthesis of compounds P376. In accordance with the General procedure A-8, the acrylic acid I-137M is subjected to interaction with 3,4-differentlanguages getting connection P376.1H-NMR confirms the structure.

Example 367. Getting connection P377.

The synthesis of compounds P377. In accordance with the General procedure A-8, the acrylic acid I-137M is subjected to interaction with 2,4,5-tripersonality getting connection P377.1H-NMR confirms the structure.

Example 368. Getting connection P393.

Synthesis of 2-(1-methyl-1H-indol-4-yloxy)finokalia I-134N: IN accordance with the General procedure A-12, compound I-133 is subjected to interaction with 6-hydroxyquinoline to obtain compound I-134N.1H-NMR confirms the structure.

Synthesis of 1-methyl-4-(cinoxacin-2-yloxy)-1H-indole-3-carbaldehyde, I-135N: IN accordance with the General procedure A-13, a connection-134N is converted into formaldehyde I-135N. 1H-NMR confirms the structure.

Synthesis of ethyl ester of (E)-3-[l-methyl-4-(cinoxacin-2-yloxy)-1H-indol-3-yl]acrylic acid, I-136N. In accordance with the General procedure A-14, compound I-135N is converted into an ethyl ester of acrylic acid I-136N.1H-NMR confirms the structure.

Synthesis of (E)-3-[l-Methyl-4-(cinoxacin-2-yloxy)-1H-indol-3-yl]acrylic acid, I-137N. In accordance with the General method A-7, compound I-136N hydrolyzing to the acrylic acid I-137N.1H-NMR confirms the structure.

The synthesis of compounds P393. In accordance with the General procedure A-8, the acrylic acid I-137N subjected to interaction with 3,4-diftorbenzofenonom getting connection P393.1H-NMR confirms the structure.

Example 369. Getting connection P394.

The synthesis of compounds P372. In accordance with the General procedure A-8, the acrylic acid I-137N subjected to interaction with 2,4,5-tripersonality getting connection P394.1H-NMR confirms the structure.

Example 371. Getting connection P349.

Synthesis of a,a-di-[2H]-2,4-amyl-metacresol, I-238. To a solution of methyl-2,4-dichlorobenzoate (2.0 g, of 9.75 mmol) in ether (20 ml) is added LiAlD4(0,41 g of 9.75 mmol) at 0°C in an atmosphere of N2. The mixture is stirred at 0°C for 1 hour, the reaction is quenched with water, NaOH (15% aqueous), water (1:1:3). The resulting solid precipitate is filtered off, the filtrate to the center in a vacuum. The crude product is purified column chromatography on silica gel, receiving compound I-238 (1.2 g, 69%).1H-NMR (CDCl3).

Synthesis of a,a-di-[2H]-2,4-dichlorobenzamide, I-239. To a solution of compound I-238 (0.6 g, 3.35 mmol) and triphenylphosphine (0.97 g, of 3.69 mmol) in CH2Cl2(10 ml), cooled to 0°C. in the nitrogen atmosphere add N-bromosuccinimide (0.66 g, of 3.69 mmol). The reaction mixture was stirred at 0°C for 10 minutes and at room temperature for 30 minutes. After removal of solvent the residue is triturated in 10% solution of ether in hexane and filtered through a layer of silica gel, receiving compound I-239 (0,62 g, 77%).1H-NMR(CDCl3).

Synthesis of compound I-240. To a solution of chloralhydrate (11.3 g, to 68.4 mmol) in water (143 ml) with vigorous stirring, Na2SO4(15.7 g, 0,486 mol), 2-bromo-4-ftoranila (10.0 g, for 52.6 mmol) in a mixture of 37% HCl (1.2 ml, to 57.9 mmol) and water (54 ml). After complete addition, the reaction mixture is refluxed for 10 minutes and cooled to room temperature. The formed precipitate was separated by filtration, washed with water (3×100 ml) and dried in vacuum, obtaining the crude isonicotinamide. The product obtained by vigorously stirring in small portions to concentrated H2SO4(178 ml) at such a rate that the temperature of reaction the th mixture was in the range of from 50 to 70°C. The reaction mixture is heated to 80°C and kept at this temperature for 20 minutes, then cooled to room temperature. The cooled mixture was poured into crushed ice (~3200 g). The mixture is left for 1 hour. The formed precipitate a solid substance is filtered off, the aqueous layer was extracted with CH2Cl2, washed with saturated salt solution and dried over Na2SO4. After concentration in vacuo, the residue triturated with a mixture of 20% ether in hexane, receiving compound I-240 (2 g, 17%).1H-NMR(DMSO-d6); MS (APCI-): 243 (M-1).

Synthesis of compound I-241. To Mg (0,44 g/atom) in anhydrous ether (4 ml) at room temperature for 3 hours add CD3I in anhydrous ether (100 ml). After complete addition, the reaction mixture is stirred for an additional 30 minutes.

To a solution of compound I-240 (1.65 g, 6,76 mmol) in anhydrous THF (85 ml) is added CD3MgI obtained as described above, at -78°C for 30 minutes, and stirring is continued for 1 hour. After heating the mixture to -10°C the reaction is quenched with water, extracted with EtOAc, washed with saturated salt solution, dried over Na2SO4and concentrated in vacuo. The residue is purified column chromatography on silica gel, receiving compound I-241 (1.5 g, 84%). 1H-NMR (DMSO-d6); MS (APCI-): 262 (M-l).

Synthesis of compound I-242. To a solution of compounds is s I-241 (1.2 g, 4.61 mmol) in THF (60 ml) add BH3(1M in THF, 11 ml, 11 mmol) at 0°C and the resulting mixture was stirred at room temperature for 5 hours. The reaction is quenched by adding 1N. aqueous HCl, the mixture is extracted with EtOAc, washed with saturated salt solution, dried over Na2SO4and concentrated in vacuo. The residue is purified column chromatography on silica gel, receiving compound I-242 (l g, 95%). 1H-NMR (DMSO-d6).

Synthesis of compound I-243. A mixture of compound I-242 (1.0 g, 4,33 mmol) and methyl acrylate (0.75 g, 8,66 mmol) in triethylamine (6 ml), palladium (II) acetate (97 mg, 0.43 mmol) and tri-o-tolylphosphino (0.26 g, 0,866 mmol) in DMF (20 ml) was stirred at 100°C for 4 hours, then cooled to room temperature. The reaction mixture was diluted with CH2Cl2(70 ml), washed with water (3×40 ml), saturated salt solution and dried over sodium sulfate. After removal of solvent the residue is purified column chromatography on silica gel, receiving compound I-243 (0.9 g, 90%).1H-NMR (CDCl3); MS (APCI-): 235 (M-1).

Synthesis of compound I-244. To a solution of compound I-243 (1.0 g, to 4.23 mmol) in THF (5 ml) and methanol (5 ml) at room temperature add 1H. aqueous NaOH solution (0.51 g, 12.7 mmol). The reaction mixture was stirred at room temperature overnight and then the pH was adjusted to acidic by addition of 2n. aqueous HCl. The reaction is th mixture is extracted with EtOAc (2×40 ml). The combined organic phase washed with water, saturated salt solution and dried over sodium sulfate. After removal of the solvent receive I-244 (0.9 g, 96%).1H-NMR (500 MHz, DMSO-d6)

Synthesis of compound I-245. A mixture of compound I-244 (0.9 g, 4.1 mmol), 3,4-dichloro-2-thiophenesulfonyl (1.0 g, of 4.45 mmol), 4-dimethylaminopyridine (0,99 g, 8.1 mmol) and EDCI (1.55 g, 8.1 mmol) in dichloromethane (20 ml) was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with diluted aqueous HCl solution and water. The crude product is purified column chromatography on silica gel, receiving compound I-245 (1.6 g, 88%).

The synthesis of compounds P349. To a solution of compound I-245 (0.8 g, to 1.83 mmol) in DMF (30 ml) at 0°C is added NaH (60% in mineral oil, 97 mg, a 4.03 mmol). The mixture is stirred at room temperature for 1 hour, then add the connection I-239 (of 0.43 g, 2.2 mmol). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2(12 ml). The reaction mixture is washed with diluted aqueous HCl solution, water, saturated salt solution and dried over sodium sulfate. The solvent is removed, the residue is purified column chromatography on silica gel, receiving the connection P349 (0.34 g, 34%).1H &13C-NMR (DMSO-d6);HPLC: 99% purity. Elemental analysis. Calculated for C23H15C14FN2O32: C 46,64; H To 2.55; N 4,73; Cl 23,94; S 10,83. Found: C 46,31; H 2,63; N 4,70; Cl 23,78; S Of 10.72.

1. The compound of the formula

where a and b represent two condensed 5 - or 6-membered ring, and condensed specified a/b ring system contains from one to three heteroatoms selected from nitrogen atoms, oxygen and sulfur, and these rings are additionally substituted by 0 to three substituents, independently selected from halogen, -HE, lower alkyl, lower foralkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl, oxo, carboxy, Carbo-lower alkoxy and acyl containing 1 to 8 carbon atoms;
"a" and "b" represent the attachment point of the residues Y and W, respectively, and "a" and "b" on the condensed a/b ring system in relation to each other are located in the peri-position;
"d" and "e" represent the point of confluence of the rings and condensed In the specified a/b ring system;
W represents C2-C8alkyl in which one or two CH2each may be substituted by-O-, -S(=O)- or-NH - or two CH2may together be replaced by-CH=CH-;
Y represents a C1-C8alkyl in which one or two CH2each can be replaced by-O-, -S(=O)-, -S-, -SO-, -SO2-, =N - or-NH - or two CH2may together be replaced by-CH=CH - or =NSO2-;
M is selected from phenyl,naphthyl, phenyl, substituted up to three times by halogen, lower alkyl, lower halogenation, lower alkoxygroup, lower halogenlampe, cyano, phenyl, methylenedioxy, acylamino containing from 1 to 8 carbon atoms, heteroaryl, meaning a 5 - or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms selected from O, N or S, bicyclic 9 - or 10-membered heteroaromatic ring system containing 1 to 2 heteroatoms selected from O, N or S, heteroaryl, substituted lower alkyl, lower alkoxygroup, tetrahydropyranyl, imidazopyridine;
Q is selected from-N(SO2R1)- or-N[RO(O-lower alkyl)2]-, Q may additionally represent-NH-;
R1selected from phenyl, phenyl substituted up to five times by halogen, lower alkoxygroup, lower alkyl, thiophene, isoxazol and thiophene, substituted up to 2 times by halogen, lower alkyl, lower foralkyl.

2. The compound according to claim 1, where W represents C1-2alkyl in which one or two
-CH2- may be replaced by-O-, -S(=O) or-NH - or two CH2may together be replaced by-CH=CH-; and
Y represents a C1-C2alkyl in which one or two CH2- may be replaced by-O-, -C(O)-, -S-, -SO-, -SO2-, -NH - or two CH2may together be replaced by
-CH=CH-.

3. The compound according to claim 1, where W is selected from-CH2With the 2-, -Och2-, -C(=O)-, -CH2O-,
-OC(CH3)2-, -Och(CH3)-, -CH=CH-, and-NHCH2-; Y is selected from-CH2-, -O-, -och2-, -N-,
-NH-, -NSO2, -NHSO2, -NHC(=O)-, -S-, -SO - and-SO2-where the left link shows the point of connection to the ring a or the ring Century.

4. The compound according to any one of claims 1 to 3, where Q represents-N[RO(O-lower alkyl)2]-.

5. The compound according to any one of claims 1 to 3, where Q represents-N(SO2R1)-.

6. The compound according to claim 5, where R1selected from phenyl, phenyl substituted up to five times by halogen, lower alkyl, lower alkoxygroup, thiophene, isoxazol and thiophene, substituted up to 2 times by halogen, lower alkyl and CF3.

7. The connection according to claim 6, where R1is forfinal.

8. The compound according to any one of claims 1 to 3, where M is forfinal.

9. The compound according to any one of claims 1 to 3, where a/b ring system is a pair of condensed 5-membered rings:

10. The connection according to claim 9, where a/b ring system is selected from
and

11. The compound according to any one of claims 1 to 3, where a/b ring system is a pair of condensed 6-membered rings:

12. Connection to item 11, where a/b ring system is selected from
and

13. The compound according to any one of claims 1 to 3, where a/b ring system is a condensed pair of 5-membered and 6-membered rings:
or

14. The connection indicated in paragraph 13, where a/b ring system is selected from indole, indolene, peridontology, isatin, benzimidazole, benzoxazolinone, benzofuran and indazole.

15. The compound according to claim 3, where the a/b ring system is an indole or indole.

16. The connection indicated in paragraph 15, where a/b ring system is an indole.

17. Connection P16, where Q represents-N(SO2R1)and R1selected from phenyl, phenyl substituted by from two to three times with halogen, lower alkoxygroup, lower alkyl, thiophene, isoxazol and thiophene, substituted up to 2 times by halogen, lower alkyl, CF3.

18. The connection 17, where M is selected from phenyl, substituted up to three times by halogen, lower alkyl, lower halogenation, lower alkoxygroup, lower halogenlampe, cyano, phenyl, methylendioxyphenyl, naphthyl, hineline and imidazopyridine.

19. Connection p, where at least one of R1and M represents forfinal.

20. Connection p, where Y represents-CH2and W is a
-CH=CH-.

21. Connection claim 20, which depict is to place a

22. Connection item 21, where M represents a 2,4-dichlorophenyl and R1represents a 4,5-dichlorotin-2-yl.

23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 3 or 14-22 for inhibition of the binding of prostaglandin E2with receptor EP3.

24. The compound according to claim 1 of the formula

where a and b represent a 6-membered ring carbocycle fused with 5-membered ring carbocycle containing nitrogen, where a/b ring system is selected from indole, restored indole, 2-oxoindole and restored 2-oxyindole.

25. The connection point 24 where the specified a/b ring system is an indole of the formula

where R3and R4are substituents in one of the two or both rings, independently selected from halogen, -HE, lower alkyl, lower foralkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl, oxo, carboxy, carbalkoxy and acyl containing 1 to 8 carbon atoms.

26. The connection point 24 where the specified a/b ring system is a 2-oxoindole formula

where R3and R4are substituents in one of the two or both rings, independently selected from halogen is, HE, lower alkyl, lower foralkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl, oxo, carboxy, Carbo-lower alkoxy and acyl containing 1 to 8 carbon atoms.

27. The connection point 24 where the specified a/b ring system is a restored 2-oxoindole formula

where R3and R4are substituents in one of the two or both rings, independently selected from halogen, -HE, lower alkyl, lower foralkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl, oxo, carboxy, lower Carbo-lower alkoxy and acyl containing 1 to 8 carbon atoms.

28. The connection point 24, where M is selected from phenyl, naphthyl, phenyl, substituted up to three times by halogen, lower alkyl, lower halogenation, lower alkoxygroup, lower halogenlampe, cyano, phenyl, methylenedioxy, acylamino containing from 1 to 8 carbon atoms, heteroaryl, meaning a 5 - or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms selected from O, N or S, bicyclic 9 - or 10-membered heteroaromatic ring system containing 1 to 2 heteroatoms selected from O, N or S, heteroaryl, substituted lower alkyl, lower alkoxygroup, tetrahydropyranyl, imidazopyridine.

29. Connection p, where W represents ottoway communication, containing two atoms in the chain and Y is a bridging linkage containing one or two atoms in the chain.

30. The connection clause 29, where W is selected-CH2O-, -OCF2-OS, (CH3)2-, -Och(CH3)-,
-CH=CH -, and-NHCH2-;
Y is selected from-CH2-, -O-, -och2-, -S-, -SO - and-SO2-where the left link shows the point of connection to the ring a or the ring C.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat diseases mediated by the nicotinic acetylcholine receptor, such as derangement of memory. In general formulae , and A is an indazolyl, benzothiazolyl or isobenzothiazolyl group which corresponds to structural formulae a) to c) respectively or X is O; R1 is H, F, Cl, Br, I, cycloalkyl containing 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; ; R2 is H; R3 is H; R4 is H, F, Cl, Br, I, cycloalkyl which contains 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; R5 is H; Ar is an aryl group containing 6 carbon atoms which is unsubstituted or substituted once or several times with halogen; and Het is a 5- or 6-member heteroaromatic group containing a heteroatom in the ring which is selected from N, O and S, or a 6-member saturated heterocyclic group which contains a heteroatom in the ring which is selected from N and O; and their pharmaceutically acceptable salts, where, if the said compound has formula I, the indazolyl group of group A is bonded through its 3rd, 4th or 7th position, the benzothiazole group of group A is bonded through the 4th or 7th position, the isobenzothiazole group of group A is bonded through the 3rd, 4th or 7th position.

EFFECT: obtaining compounds with properties of nicotinic acetylcholine receptor (nAChR) ligands, and pharmaceutical compositions based on the said compounds.

53 cl, 95 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: described is a bromohydrate of 4-methoxy-7,7-dimethyl-9-(5'-carboxyamyl)amino-6H-7,8-dihydropyrimido-(4,5-b)-1,4-benzthiazine (hereinafter methiazine) and a method for synthesis of the said compound. Methiazine has anti-tumour and anti-reductase activity, which has cytostatic and cytotoxic effect which inhibits synthesis of nucleic acids and can be used in medicine. Bromohydrate of 4-methoxy-7,7-dimethyl-9-(5'-carboxyamyl)amino-6H-7,8-dihydropyrimido-(4,5-b)-1,4-benzthiazine of formula I , is obtained by reacting dimedone with ω-amino caproic acid in a medium of boiling isopropanol to obtain enamine-ketone which is subjected to bromation with bromosuccinimide with further treatment with 4-methoxy-5-amino-6-mercaptopyrimidine in a medium of boiling isopropanol.

EFFECT: improved method.

2 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: medicine.

SUBSTANCE: invention is related to derivatives of isothiourea of formula I, including their pharmaceutically acceptable salts, which possess properties of antagonist CXCR4. In compounds of formula I , where R1 means remainder of formula (a) , (b) or (c) , R2 means -(CR22R23)1-3-, R3 and R8 each means S, R4 and R5 each independently means C3-C12cycloalkyl, C1-C12alkyl or saturated C8-C12 polycyclic hydrocarbon remainder, such as adamantine, non-substituted phenyl or non-substituted benzyl unnecessarily substituted with group R25, R6 means H or C1-C6alkyl, R7 means CH, R9 means direct connection or -(CR22R23)1-2-, R10-R15 each means H, R16-R23 each independently means H, C1-C6alkyl, or R20 and R21 together with carbon atoms, to which they are connected, create a benzene ring, and R25 has one of values given above for R16-R23.

EFFECT: improved method for production of derivatives of isothiourea.

5 cl, 1 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-acyl-2-aminothiazoles of formula (I) and their pharmaceutically acceptable salts as antagonist of adenosine receptor A2B and to a pharmaceutical composition based on the said compounds. In formula (I) X is -CH2-, -CH2CH2-, -(CH2)3- and O(CH2)-; R is a 5- or 6-member saturated or unsaturated carbocyclic or heterocyclic ring system, which can optionally contain one or more heteroatoms, chosen from N, O and S, where the said ring system is optionally substituted with one or more substitutes, chosen from a group consisting of halogen, hydroxy, lower alkyl, nitrile group, sulfonamide, aminosulfonyl, lower alkoxycarbonyl, lower alkylsufonyl, benzyl, benzoyl, phenylsulfonyl, and the said benzyl, benzoyl or phenylsulfonyl are optionally substituted with a halogen, trihalogeno-lower alkyl group; R1 is chosen from a group consisting of hydrogen, halogen or lower alkoxy group.

EFFECT: obtaining compounds which can be used for treating and preventing diseases caused by adenosine receptors A2B, such as diabetes, diabetic retinopathy, asthma and diarrhea.

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to mono-sodium salt 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]thiazole[4,5-d]pyrimidine-2(3H)-on as a modulator of the activeness of chemokine receptors, method of obtaining it and pharmaceutical composition on its basis, and also its application in production of medicinal agents.

EFFECT: obtaining compounds, which can find application in treatment of diseases mediated by chemokine receptors, such as asthma, allergic rhinitis, COPD (chronic obstructive pulmonary disease), inflammatory bowel disease, osteoarthritis, and rheumatoid arthritis.

10 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazole-pyrimidine derivatives having metabotropic glutamate receptor (mGluR2) antagonist properties and having formula (1): , where A is selected from a group consisting of: Ra is H, halogen or C1-6-alkyl; R1 is II, halogen, C1-6-alkoxy, C1-6-alkyl, C1-6-haloalkyl, C1-6-haloalkoxy; R2 is a halogen, C1-6-haloalkyl; R3 is NRbRc, where Rb and Rc are independently selected from a group consisting of H and C1-6-alkyl which is possibly substituted with one or more substitutes selected from a group consisting of hydroxy and -NRb'Rc', where Rb' and Rc' are independently selected from a group consisting of H and C1-6-alkyl; or Rb and Rc together with the nitrogen atom to which they are bonded form a possibly substituted heterocyclic group containing 5-6 ring atoms, possibly containing an additional N heteroatom, where the substitutes are selected from a group consisting of hydroxy and C1-6-alkyl, R4 is C1-6-haloalkyl or C3-4-cycloalkyl; as well as to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition and use of the compounds in preparing a medicinal agent for treating or preventing diseases and conditions in which mGluR2 activation plays a role.

EFFECT: improved properties of compounds.

10 cl, 2 dwg, 1 tbl, 129 ex

FIELD: chemistry.

SUBSTANCE: invention describes a sodium salt of 2-n-propylthio-6-nitro-1,2,4-triazole[5,1-c]-1,2,4-triazin-7(4H)-one dihydrate and a sodium salt of 2-n-butylthio-6-nitro-1,2,4-triazole[5,1-c]-1,2,4-triazin-7(4H)-one dihydrate having antiviral activity on herpes simplex virus HSV-1.

EFFECT: higher antiviral effect of the compounds.

1 cl, 1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-substituted 3-(2-chloro-1H-indol-3-yl)-4-phenyl-1H-pyrrole-2,5-diones of formula 1: , where R1 denotes H, C1-C6alkyl; R2 denotes compounds which, under the effect of visible light, form fluorescent 2,8-substituted benzo[a]pyrrolo[3,4-c]carbazole-1,3-(2H,8H)diones of formula II: , where R1 and R2 are as described above.

EFFECT: more effective use of the compounds.

10 cl, 2 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication, reducing desire for alcohol, which represents substituted 1H-benzimidazoles of general formula 1 or their pharmaceutically acceptable salts and/or hydrates, pharmaceutical composition, and medication on their basis. Compounds can be applied in treatment of alcohol abuse with application of ethanol-containing products, if necessary, together with antidepressants. In compounds of general formula 1 , where: W represents sulfur atom or group S=O; R1 represents one or more substituents, selected from hydrogen, halogen, C1-C4alkyl, C1-C4alkyloxy, optionally substituted 5-6-member azaheterocyclyl with 1-2 atoms of nitrogen and/or oxygen in cycle; R2 represents atom of hydrogen or optionally substituted C1-C4alkyl; R3 and R4 independently on each other represent optionally similar substituents, selected from hydrogen, optionally substituted C1-C4alkyl, C3-C6cycloalkyl; R5 represents alkyl substituent, selected from hydrogen or optionally substituted C1-C7alkyl, C1-C7alkenyl, C1-C4alkynyl, optionally substituted phenyl, optionally substituted 5-6-member heterocyclyl with 1-3 heteroatoms, selected from nitrogen, oxygen and sulfur, possibly condensed with benzene ring; C1-C4-alkoxycarbonyl, optionally substituted amino carbonyl, or group CR3R4R together stands for group , where Alk stands for C1-C4alkyl.

EFFECT: medication allows to reduce symptoms of alcohol abuse considerably as compared with earlier known compounds and does not produce unfavorable effect on liver function.

12 cl, 3 tbl, 2 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrolotriazines of formula (I) , where R1 is selected from a group which includes phenyl, naphthyl, benzyl and heteroaryl, which denotes a mono- or bicyclic radical containing 5-10 ring atoms and up to 2 heteroatoms selected from a group consisting of nitrogen, oxygen and sulphur, at least one ring of which is aromatic, where, if necessary, phenyl and heteroaryl may be substituted with 0, 1 or 2 substitutes independently selected from a group consisting of -(C1-C4)alkyl, where -(C1-C4)alkyl can be substituted with 0, 1, 2 or 3 halogens, 0 or 1 pyrrolidine, -(C1-C3)alkoxy group, where, if necessary, the (C1-C3)alkoxy group may be substituted with a (C1-C3)alkylamino group, halogen, trifluoromethyl, trifluoromethoxy group, phenyl, if necessary substituted with 1 or 2 halogens, - , where X denotes O, nitro group, - (C1-C3)alkylthio group, trifluoromethylthio group, - (C1-C3)alkylcarbonyl, - (C1-C6)alkoxycarbonyl, and a phenoxy group, and where the benzyl can be substituted with 0, 1, 2 or 3 groups selected from a group which includes halogen; R2 is selected from a group consisting of hydrogen, halogen; R3 is selected from a group consisting of carboxyl, - (C1-C6)alkylcarbonyl, - (C3-C6)cycloalkylcarbonyl, - (C1-C6)alkoxycarbonyl, if necessary substituted with 0, 1, 2 or 3 groups selected from a group which includes amino group and (C1-C6)alkoxycarbonyl; aminocarbonyl, -(C1-C6)alkylaminocarbonyl, where (C1-C6)alkylaminocarbonyl which, if necessary, can be substituted with 0, 1, 2 or 3 substitutes independently selected from a group consisting of (C3-C6)cycloalkyl, halogen, amino group, (C1-C6)alkylamino group, hydroxy group, (C1-C6)alkoxy group, (C1-C6))alkoxycarbonyl, (C1-C6)alkylthio group, (C1-C6)alkoxycarbonylamino group,and where, if necessary, (C1-C6)alkylaminocarbonyl may be substituted with 0 or 1 heterocyclyl, which denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, where, if necessary, the hetecyclyl may be substituted with 0 or 1 (C1-C6)alkyl, heterocyclylcarbonyl, if necessary substituted with 0 or 1 (C1-C6)alkylamino group, cycloalkyl or (C1-C6)alkyl,where, if necessary, (C1-C6)alkyl may be substituted with 0 or 1 (C1-C6)alkylamino group, and where heterocyclyl denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, -(C1-C6)alkyl if necessary substituted with 0, 1 or 2 substitutes independently selected from a group consisting of a) hydroxyl, b) (C1-C6)alkylamino group, where (C1-C6)alkylamino group may be substituted with 0, 1 or 3 substitutes independently selected from a group consisting of halogen, alkylamino group, methoxy group, methylthio group and methylsulphonyl, c) phenylamino group, where the phenylamino group may be substituted with 0, 1 or 2 substitutes independently selected from a group consisting of (C1-C6)alkoxy group and trifluoromethyl, d) heterocyclyl, where heterocyclyl denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, and where the heterocyclyl may be substituted with 0 or 1 (C1-C6)alkyl, where (C1-C6)alkyl may be substituted with 0 or 1 methoxy groups or pyridyls, e) imidazolyl, f) pyridylamino group, g) (C1-C3)alkoxy group, if necessary substituted with fluorine or piperidine,where, if necessary, the piperidine may be substituted with 0 or 1 (C1-C6)alkyl, h) (C1-C3)alkoxy(C2-C3)alkoxy group, and i) (C1-C6)alkoxycarbonyl, j) (C3-C6)cycloalkyl, k) cyano group, - (C3-C6)cycloalkylaminocarbonyl, cyano group, heteroaryl, where heteroaryl denotes a monocyclic radical containing 5-6 ring atoms and up to 3 heteroatoms selected from a group consisting of nitrogen and oxygen, the ring of which is aromatic, where the heteroaryl may be substituted with 0, 1 or 2 groups independently selected from a group consisting of q) (C1-C6)alkyl, where the (C1-C6)alkyl may be substituted with 0 or 1 morpholine or 0 or 1 hydroxy group, r) (C1-C6)alkoxycarbonyl, thiophene carbonyl, and R4 is selected from a group consisting of hydrogen; to a pharmaceutically acceptable salt thereof. The invention also pertains to methods of obtaining said compounds.

EFFECT: obtaining novel compounds which can be used in medicine for preventing or treating hyper-proliferative disorders and diseases associated with angiogenesis.

5 cl, 313 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a crystalline form of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one, which exhibits characteristic peaks on an X-ray powder diffraction pattern expressed in two-theta degrees, selected from approximately 7.1, approximately 12.1 and approximately 16.1; or approximately 7.1, approximately 12.1 and approximately 17.5; or approximately 7.1, approximately 12.1 and approximately 23.5; or approximately 12.1, approximately 16.1 and approximately 17.5; or approximately 12.1, approximately 16.1 and approximately 23.5; or approximately 16.1, approximately 17.5 and approximately 23.5; or approximately 7.1, approximately 17.5 and approximately 23.5; or approximately 7.1, approximately 12.1 and approximately 23.5; or approximately 7.1, approximately 16.1 and approximately 23.5, and to a pharmaceutical composition based on said compound, which can be used in medicine to prepare a medicinal agent which acts on the hepatitis C virus (HCV) in HCV-infected mammals.

EFFECT: improved properties of derivatives.

12 cl, 1 tbl, 3 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted tetracyclic derivatives of tetrahydropyran, pyrrolidine and tetrahydrothiophene of general formula (I), their pharmaceutically acceptable addition salts, their stereochemically isomeric forms, their N-oxide forms, in which all substitutes are defined in claim 1 of the formula of invention. These compounds have binding affinity to serotonin receptors, particularly 5-HT2A and 5-HT2C receptors, and to dopamine receptors particularly D2 dopamine receptors, and have norepiniphrine reuptake inhibition properties. The invention also relates to a pharmaceutical composition containing said compounds, method of preparing said composition and use of said compounds as medicinal agents, particularly for preventing and/or treating several psychiatric and neurological disorders.

EFFECT: new compounds have useful biological properties.

12 cl, 3 tbl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-alkylamino-3-sulfonyl-pyrazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and/or hydrates which have serotonin 5-HT6 receptor antagonist properties and can be used in treating or preventing development of various central nervous system diseases, whose pathogenesis is related to 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases, cognitive and anxiety disorders and obesity. In general formula (I):

R1 and R3 independently denote optionally identical C1-C3alkyl, R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3alkyl; R4 is C1-C3alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3alkyl; i is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3alkyloxycarbonyl, aminocarbonyl CONR6R7 or a NR6R7 amino group; R6 and R7 denote optionally identical hydrogen atom, optionally substituted C1-C3 alkyl, C3-C7cycloalkyl or an optionally substituted 5-7-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl; or R6 and R7 together with the nitrogen atom to which they are bonded form an optionally substituted 5-6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl.

EFFECT: obtaining new biologically active compounds.

26 cl, 12 dwg, 4 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel derivatives of benzo[7,8]azonino[5,4-b]indoles, 7,9-etheno-azecino[5,4-b]indoles and 7,9-ethano-azecino[5,4-b]indoles with general structural formulae: , , , I, IV, VII X=H,Y=CO2Me; II, V, VIII X=H, Y=COMe; III, VI, IX X=Y=CO2Me, which have proved to be cytostatic and cytotoxic compounds. The method involves dissolving 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolysino[8,7-b]indole, ethyl eburnamenine-14-carboxylate or methyl (3-α, 14-β, 16α)-14-hydroxy-14,15-dihydro eburnamenine -14-carboxylate in methanol and then reaction with excess dimethyl acetylenedicarboxylate (ADCX) or methyl propiolate or acetyl acetylene, while stirring at +40-+50°C, with subsequent removal of the solvent and grinding the residue in hexane or a mixture of hexane with ethylacetate (ether) or purified using column chromatography on aluminium oxide.

EFFECT: design of an efficient method of obtaining hazardous compounds.

9 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of general formula: , where R1 - C1-C6alkyl, C1-C6alkoxy, halogen, CN, C(O)NH2 or OCH2CH2OCH3; R2-C1-C6alkyl, possibly substituted with halogen, a halogen, C1-C6alkoxy, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, where n equals 1 or 2; m equals 2 or 3; R6 -R7 -C1C6alkyl, and R8 -OCH2CH2OCH3; or R7 and R8 together with the nitrogen atom to which they are bonded form a 6-member heterocycle which additionally contains one oxygen atom or one nitrogen atom, which in the latter case is substituted with C1-C4alkyl; or R1 and R2 together form a 5-member heterocyclic ring system containing two oxygen atoms as heteroatoms; R3 - hydrogen or C1-C6alkyl; R4 - hydrogen, halogen or C1-C6alkoxy; or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these compounds.

EFFECT: obtaining novel compounds with kinase inhibiting properties, particularly CDK2, or angiogenesis inhibiting properties and can be used in treating malignant growths, particularly in mammary glands, large intestines, lungs and prostate glands.

60 cl, 7 tbl, 101 ex

FIELD: chemistry.

SUBSTANCE: in embodiments of the invention, specific compounds are used to prepare a medicinal agent for treating, relieving and preventing conditions associated with dysfunction of monoamine transmission. The compounds have general formula (1) , where: R1 and R2 are identical or different and denote hydrogen, alkyl, alkenyl, alkynyl, aryl, thio or alkylthio, or R1 and R2 may have extra substitutes which are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkyloxy, morpholin-4-ylalkoxy, piperidin-1-ylalkyloxy, alkylamino, dialkylamino, arylamino.

EFFECT: more efficient use of compounds in preparing medicinal agents.

8 cl, 3 tbl, 4 ex

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