Heterocompound

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

 

The technical field to which the invention relates

The present invention relates to a new heteroskedasticy and medicinal product containing it as active ingredient, namely as a tool for the treatment of immunological diseases.

The prior art inventions

Sphingosine-1-phosphate is a metabolite of sphingolipid, which is the physiologically active substance is released from activated platelet (non-Patent document 1). The receptor for sphingosine-1-phosphate is G proteinsathome type and belongs to the Edg-family, which is a gene of endothelial differentiation. At present, it was found five receptors S1P1(Edg1), S1P2(Edg5), S1P3(Edg3), S1P4(Edg6) and S1P5(Edg8). All these receptors are widely represented in cells and tissues throughout the body, however, S1P1, S1P3and S1P4mainly expressed in lymphocyte and endothelial cell S1P2mainly expressed in vascular smooth muscle cell and S1P5mainly expressed in brain and spleen, and their amino acid sequence is well conserved in humans and rodents (non-Patent document 1). Many receptors linked to G proteins by stimulation of sphingosine-1-phosphate. S1P1associated with Gi/0, S1P2and S1P3associated with G i/0, Gq, G12/13and Gs, S1P4associated with Gi/0, G12/13and Gs, S1P5is a combination of Gi/0and G12/13and cause growth of cells? due to the activation of absence, a change in the cytoskeletal system and infiltration of cells due to activation of Rac or Rho), and the generation of cytokine and mediator, due to activation of PLC and the influx of calcium into the cell, and the like (non-Patent document 1). It was known that when the stimulating action of S1P1sphingosine-1-phosphate is called migration of lymphocytes, inhibition of apoptosis, generation of cytokine, the sequestration of lymphocytes in the thymus and other secondary lymphoid tissues and angioplasty in vascular endothelial cells (non-Patent document 2). On the other hand, S1P3also found in the cardiomyocyte and found a random decrease in heart rate (bradenville) and blood pressure during stimulation of sphingosine-1-phosphate (non-Patent document 3), while predispose not detected during stimulation of sphingosine-1-phosphate in knockout mouse, in which S1P3genetically deleted (non-Patent document 4). It was reported that the phosphate ester FTY720, which is an active substance FTY720, is currently undergoing clinical trials is non-selective agonistic activity against S1P1, S1P3, S1P4and S1 5(Non-patent document 5), and, in particular, predispose due to the effect of stimulation of S1P3often expressed as an unwanted side effect in clinical trials (non-Patent document 6). Thus, it is believed that lymphocyte sequestration through receptor for sphingosine-1-phosphate necessary stimulation of S1P1(Non-patent document 7), while stimulation of S1P3not needed, and it is rather considered as a cause unwanted side-effect. Therefore, to develop IMMUNOSUPRESSIVE funds with fewer side effects, it is desirable to develop an agonist with weak effect on S1P3and selectively affect S1P1.

For example, as compounds with activity as agonist S1P1, it was known carboxylic acid derivative represented by the following formula (Patent document 1):

[Him]

[about the symbol in the formula, refer to publication]

As compounds having activity as an agonist S1P1known derivative indana represented by the following formula (Patent document 2):

[Him]

[about the symbol in the formula, refer to publication]

As compounds with activity as as the honest S1P 1known derived oxadiazole represented by the following formula (subsequent figures, Patent documents 3, 4, 5, and 6):

[Him]

[about the symbol in the formula, refer to publication]

As compounds having activity as an agonist S1P1known derivative represented by the following formula (the following figure, Patent document 7):

[Him]

[about the symbol in the formula, refer to publication]

However, the connection of the present invention was not described in any document.

Non-patent document 1: Annulan Review Biochemistry, 204, 73, 321-354

Non-patent document 2: Nature Review Immunology, 2005, 5, 560-570

Non-patent document 3: Japanese Journal of Pharmacology, 2000, 82, 328-342

Non-patent document 4: Journal of Pharmacology and Experimental Therapeutics, 2004, 309, 758-768

Non-patent document 5: Science, 2002, 296, 346-349

Non-patent document 6: Journal of the American Society of Nephrology, 2002, 13, 1073-1083

Non-patent document 7: Nature, 2004, 427, 355 to 360 above

Patent document 1: international patent application WO 2005/058848 brochure

Patent document 2: international patent application WO 2004/058149 brochure

Patent document 3: international patent application WO 2003/105771 brochure

Patent document 4: international patent application WO 2004/103279 brochure

Patent document is t 5: international patent application WO 2005/032465 brochure

Patent document 6: international patent application WO 2006/047195 brochure

Patent document 7: the international patent application WO 2006/001463 brochure

Description of the invention

The problem which the invention aims to solve

The authors of the present invention conducted a study to detect substances that are applicable for the prevention and/or treatment of rejection in transplantation of an organ/bone marrow/tissue or autoimmune diseases, based on agonistic activity towards S1P1and, further, to provide a pharmaceutical preparation containing this substance.

Means of solving the problem

The developers of this invention have conducted extensive studies with respect to the substance with S1P1agnostic activity, and as a result, they found that the new geterosoedineniya can be used as agonist S1P1after completing thus the present invention. In other words, according to this invention, it is possible to provide a new geterosoedineniya represented by the following formula (I)or its pharmaceutically acceptable salt.

The compound represented by formula (I):

[Chem. 5]

or its pharmaceutically acceptable salt

[In the formula, the symbols mean as follows.]

Ring before the hat is:

[Chem. 6]

X represents a simple bond, -CH2-, -NR3-, -O-, -S-, -S(=O)- or-S(=O2)-,

R1represents H, halogen, aryl, heteroaryl, (C3-C8)cycloalkyl,3-C8)cycloalkenyl, (C3-C8)heteroseksualci; or (C1-C6)alkyl or (C2-C6)alkenyl, each of which may contain halogen, -CONH2, aryl, or (C3-C8)cycloalkyl, as a substitute,

R2represents-CN, -O-(C1-C6)alkyl, -C(=O)H, halogen or (C1-C6)alkyl which may be substituted with halogen or-HE,

R3represents-H, where R3can form morpholino, 1-pyrrolidinyl or 3,4-dihydropyrimidin-1-yl, together with R1and nitrogen,

where X represents a simple bond, R1and R2may in combination form a 5-membered ring and, in addition, contain (C1-C6)alkyl, as Deputy.

R4represents the following ring:

where any one of the links from the ring associated with oxadiazoline ring,

[Him]

R5represents-H; and (C1-C6)alkyl which may be substituted by at least one group selected from the series consisting of: -CN, -C(=O)NRXRY-The otherX-SR X, -S(=O)2RXand-ORX(this is defined as R0-(C1-C6)alkyl); R0-(C1-C6)alkyl-O-; R0-(C1-C6)alkyl-C(=O)-; R0-(C1-C6)alkyl-S(=O)2-, R0-O-(C1-C6)alkyl; R0-C(=O)(C1-C6)alkyl; R0-S(=O)2-(C1-C6)alkyl-; (C2-C6)alkenyl-; -C(=O)H; -ORX; -S(=O)2RX; halogen; =O; NRXRY; -C(=O)NRXRY;

RXand RYmay be the same or different with each other and represent H; or (C1-C6)alkyl which may be substituted " HE, NH2that can be protected by a protective group, or heteroaryl, in which RXcan form (C3-C8)heteroseksualci with RYand nitrogen.

As for the X-, he's in the formula (I) preferably represents a simple bond or-O -, and more preferably represents-O-. As for R1, it preferably represents a (C1-C4)alkyl or (C2-C4)alkenyl, each of which may be substituted with halogen or (C3-C8)cycloalkyl and, in addition, more preferably represents a (C1-C4)alkyl which may be substituted with F. as for the ring And it preferably represents:

[X is p]

As for R2he preferably represents halogen, -CN, (C1-C4)alkyl which may be substituted with halogen, and more preferably, it represents Cl, CF3. As for R4he preferably represents:

[Him]

and more preferably it represents:

[Him]

As for R5he preferably represents-H, (C1-C6)alkyl which may be substituted with-C(=O)NRXRY. As for RXhe preferably represents-H, (C1-C6)alkyl which may be substituted with-IT. As for RYhe preferably represents-N; and (C1-C6)alkyl which may be substituted with-IT.

The compound of the present invention, represented by formula (I), characterized by a chemical structure from the point of view of what bicyclic nitrogen-containing unsaturated heterocycle or a bicyclic nitrogen-containing partially unsaturated heterocycle linked to 3-position of oxazole and has pharmacological characteristics from the point of view that the connection has S1P1agonistic activity.

The effects of the invention

Because Obedinenie according to the invention has S1P 1agonistic activity, it can be used as an active ingredient means for treatment or prophylaxis of diseases caused by adverse lymphocytic infiltration, such as transplant rejection in organ transplantation, bone marrow or tissue or graft versus host disease, autoimmune diseases or inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, bulbospinal paralysis, pancreatitis, hepatitis, nephritis, diabetes, lung disorders, asthma, atopic dermatitis, inflammatory intestinal diseases, atherosclerosis or ischemic-reperfusion injury, and, in addition, diseases caused by an abnormal growth or accumulation of cells, such as cancer or leukemia.

The best option of carrying out the invention

Further in this document present invention will be described in more detail.

In the description of the "alkyl" means a linear or branched monovalent group. "C1-C6alkyl" means1-C6linear or branched group, and specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-propyl and n-hexyl, preferably With1-sub> 4alkyl and especially preferred methyl, ethyl, n-propyl and isopropyl.

In the description of "halogen" means F, Cl, Br and I, and preferred examples include F and CL.

In the description "2-C6alkenyl" means2-C6linear or branched group, which has the double bond in this place, and their specific examples include: ethinyl (vinyl), 1-propenyl, 2-propenyl, 1-mutilation-1-yl, 1-butene-1-yl, 2-butene-1-yl, 3-butene-1-yl, 1-methyl-1-propen-1-yl, 2-methyl-1-propen-1-yl, 1-methyl-2-propen-1-yl and 2-methyl-2-propen-1-yl, and preferably, 1-methyl-2-propen-1-yl or 1-pentenyl.

In the description "3-C8cycloalkyl" means a monovalent group of non-aromatic carbon cycle, with the degree of recovery 3-8, which may have partially unsaturated communication. Thus, specific examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the description "3-C8heteroseksualci" means a monovalent non-aromatic group having a degree of recovery from 4 to 9, containing one or more heteroatoms, the same or different with each other chosen from the series consisting of nitrogen, oxygen and, optionally oxidized sulfur, which may be partially unsaturated. Their specific examples include aziridinyl, azetidin, pyrrolidinyl, piperidinyl, homopiperazine, orfali, thiomorpholine, tetrahydropyranyl and tetrahydrothiopyran.

In the description of "aryl" means an aromatic hydrocarbon group, but preferred are aryl groups having 6-14 carbon atoms. Their specific examples include phenyl, naphthyl and anthranol, and more preferred is phenyl.

In the description of "heteroaryl" means 5 - or 6-membered cycle aromatic heterocycle containing one or more heteroatoms that are different or are different from each other, selected from the group consisting of nitrogen, oxygen and sulfur. Their specific examples include pyridyl, Persil, pyrimidinyl, paradisial, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, furyl, oxadiazolyl and thiadiazolyl. Preferred is a 6-membered heteroaryl and, in particular, preferred is pyridyl.

The compound of the present invention in some cases may exist as geometric isomers or tautomers, depending on the type of substituent. Moreover, this connection may have asymmetric carbon. The present invention includes isolated forms of these isomers and their mixture. In addition, labeled compounds, i.e. compounds in which at least one element in the compound of the present invention substituted radioactive or non-radioactive isotopes, that is also included in the present invention.

Moreover, pharmaceutically applicable, so-called prodrugs containing compound of the present invention, also included in the present invention. Pharmaceutically acceptable prodrug is a compound having a group which can be converted into the amino group, hydroxyl group, carboxyl group, or the likeness of compounds of the present invention, by means of solvolysis or as a result of physiological conditions. Examples of the group capable of forming prodrugs include groups described in Prog. Med., vol. 5, 2157-2161 (1985) and "Iyakuhin no Kaihatsu (Development of Medicines) (Hirokawa Shoten, 1990), vol. 7, Bunshi Sekkei (Molecular Design)", 163-198.

The compound represented by formula (I)can form salts with acids or bases. It can be any pharmaceutically acceptable salts, and their specific examples include salts of accession acid inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acids is, aspartic acid and glutamic acid; and salts with inorganic bases, such as sodium, potassium, magnesium, calcium and aluminum, and organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine and ammonium salt.

Additionally, the present invention also includes various hydrates and solvate and polymorph connection connection represented by the formula (I)and their salts.

The description used the following abbreviations.

Pr: a method of obtaining, Asón: acetic acid, n-BuLi: normal utility, t-BuOH: tertiary butanol, n-BuOH: normal butanol, Enrichment: methyl cyanide, CDI 1,1'-carbonylbis-1H-imidazole, DBU: diazobicyclo[5.4.0]undeca-7-ene, DMAP: 4 - (N,N-dimethylamino)pyridine, DIC: N,N'-diisopropylcarbodiimide, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, DPPA: diphenylphosphinite, Et: ethyl, EDCI/HCl: N - [3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride, EtOH: ethanol, Et3N: triethylamine, EtOAc: ethyl acetate; HOBt: 1-hydroxy-1H-benzotriazole, HPLC: high performance liquid chromatography, IPE: diisopropyl ether, i-D: 2-propanol, K2CO3: potassium carbonate, N: potassium cyanide, KHCO3: potassium bicarbonate, KOtBu: tertiary piperonyl potassium, LC-MS: liquid chromatography-mass spectroscopy, LiH: lithium hydride, MeOH: methanol, NaH: sodium hydride, NaOH: sodium hydroxide, NaBH4: sodium borohydride, NaCN: cyan is d sodium, NaHCO3: sodium bicarbonate, Na2CO3: sodium carbonate, NaOMe: sodium methoxide, NaOEt: ethoxide sodium, NCS: N-chlorosuccinimide, NH4Cl: ammonium chloride, NMP: N-an organic, POCl3: oxochloride phosphorus, P2About5: phosphorous pentoxide, THF: tetrahydrofuran, TLC: thin layer chromatography, TMEDA: N,N,N',N'-tetramethylethylenediamine, Zn(CN)2: cyanide zinc.

(Method Get)

The compound (I) of the present invention and its pharmaceutically acceptable salt can be obtained by applying various known synthetic methods, using the advantages given them the main frame or type of substituents. Here, depending on the type of functional groups, in some cases, from the point of view of preparation technique, effectively protect the functional group suitable protective group, or to replace it with a group that can be easily converted into the functional group, during the stages from the original substances to intermediate compounds. Examples of such functional groups include amino group, hydroxyl group, carboxyl group, and examples of protective groups for them include the protective groups described in "Protective Groups in Organic Synthesis" edited by T.W. Green and P.G.M. Wuts, (USA) (3rdedition, 1999), which can be selected at will, and their use is determined by the reaction conditions When using such methods, the desired compound can be obtained by introducing protective groups for the purpose of carrying out the reaction, and then, if necessary, removing the protective group or transformation into the desired group.

Additionally, procarta compounds (I) according to the present invention can be prepared by introducing a specific group during the stages from the original substances to intermediate compounds similar to the above-described protective groups, or by carrying out the reaction using the obtained compound (I) of the present invention. The reaction can be carried out with conventional methods etherification, amination, degidrirovaniya or method, well known to the person skilled in the technical field.

<the First method of obtaining the intermediate substances>

[Him]

[where R or R' represents lower alkyl which may be substituted by at least one Deputy, selected from a number containing-CN, -C(=O)OH, -C(=O)ORX, -C(=O)NRXRY, -C(=O)NHSO2RX, -C(=O)-(C1-C8heteroseksualci), -otherX, -OH, - SRX, -S(=O2RX, halogen and-ORX(which is defined as RZlower alkyl); R0-(C1-C6)alkyl-O-, R0-(C1-C6)alkyl-C(=O)-; R0-(C1-C6)alkyl-S(=O)2-; R0-O-(C1-C6)alkyl; R0-C(=O)-(C1-C6)alkyl; R0-S(=O)2-(C1-C6)alkyl-; and (C2-C6)alkenyl-C(=O)H, -ORX; -S(=O2RX; halogen; =O; -NRXRYor-C(=O)NRXRY;

RXand RYthe same or different from each other and each means-N; and (C1-C6)alkyl which may be substituted with-HE or pyridyl. Also RXcan be associated with RYand the nitrogen atom, form a (C3-C8)heteroseksualci.

This method of obtaining is a method for obtaining compounds of benzimidazole represented by the formula (1-C), with the introduction of the aldehyde compound in the reaction with the compound 1,2-diaminobenzene represented by the formula (1-b), which can be obtained by reduction of compound represented by formula (1-a).

Stage shows Stage 1-1, is a stage of recovery of the nitro group of compounds represented by formula (1-a), the amino group, which can be carried out at normal pressure or at elevated pressure in a solvent inert to the reaction.

At the stage depicted Stage 1-2, where R' represents H, you can create an imidazole ring, for example, when joining ortogonalnogo ether, such as utilitarian, in the reaction with the compound represented by the formula (1-b), in the presence of an acidic catalyst.

In addition, at the stage depicted Stage 1-2, where R' is H, for example, a method in which the amino group with the organisations, represented by the formula (1-a), pre-braziliana using carboxylic acid, acid chloride of carboxylic acid, carboxylic acid anhydride or the like and cyklinowanie when heated or in the presence of acid, a method in which tetraalkylammonium, SDI and Enrichment used instead ortogonalnogo ether, or other methods can be cited as an example.

In addition, along with other methods, we can cite as an example and the method in which the amine connection part nitrobenzene (1-a) is subjected to carbonyliron, leading to acylamino the compound (1-e), subject to recovery of its nitro group and cyclization when heated (stage 1-3 stage 1-4).

All these reactions can be carried out in a solvent inert to the reaction or without solvent, at room temperature to under heating or under heating to boiling.

<a Second method of obtaining the intermediate connection>

[Him]

[where R has the same significance as defined above]

This method of obtaining is a method of obtaining imidazo[1,2-a]pyridine, substituted nitrile group represented by the formula (2-b), when using connection 2-aminopyridine, depicted by formula (2-a), as the source of the connection.

Stage depicted Stud who she 2-1, represents a reaction Assembly ring imidazo[1,2-a]pyridine in accession to the reaction chloroacetaldehyde or α-chloroethane with the compound represented by formula (2-a).

It is preferably carried out in the presence of a base, and specific examples of bases include carbonates of alkali metals such as Na2CO3and K2CO3; bicarbonates of alkali metals, such as NaHCO3and KHCO3; alkoxides such as NaOMe, NaOEt and KOtBu; tertiary amines, such as Et3N and DIPEA; and organic amines such as DBU, pyridine and lutidine.

All these reactions can be carried out in a solvent inert to the reaction or without solvent at room temperature to under heating or under heating to boiling.

<a Third method of obtaining the intermediate connection>

[Chem. 13]

[where R has the same significance as defined above]

This method of obtaining is a method for obtaining compounds of imidazole represented by the formula (3-C), if the reaction of hydrazine hydrate is added to the nitrile group of the compound of cyanobenzoyl represented by formula (3-b)obtained by substitution of a halogen compound represented by the formula (3-a).

Stage shows Stage 3-1, is a reaction of halogen, associated aromaticheskogo with a nitrile group. An example of this can serve as the reaction Zn(CN)2in the presence of tetrakisphosphate palladium (0), the reaction of TMEDA and Pd catalyst in the presence of Na2CO3in DMA, and reactions in which KCN, NaCN or similar react instead of Zn(CN)2. Typically, the compound represented by formula (3-b), can be obtained by reaction of the compound represented by formula (3-a), with Tris(dibenzylideneacetone)dipalladium (0),

1'-bis(diphenylphosphino)ferrocene and Zn(CN)2.

Here, examples of the leaving group include halogen, such as Br and CL; methansulfonate, econsultancy, benzosulfimide, p-toluensulfonate, tripterocalyx.

Stage shows Stage 3-2, is a reaction to the creation of imidazole series of compounds cyanobenzaldehyde represented by formula (3-b). Typically, this reaction using hydrazinehydrate, this reaction can be carried out without solvent or in a solvent inert to the reaction, such as the Meon and toluene, at room temperature to under heating, or by heating at boiling. Additionally, as an example, a method using copper cyanide and can be added base, such as pyridine. Also this reaction is preferably carried out in an atmosphere of nitrogen.

<a Fourth method of obtaining intermediate>

[Him]

[where R has the same meanings as defined above. Z represents-CH= or-N=].

This method of obtaining is a method for obtaining compounds of benzotriazole or benzimidazole represented by formula (4-C), by dehydration of the amide compounds represented by the formula (4-b), obtained using as a starting compound carboxylic acid represented by the formula (4-a).

Stage shows stage 4-1, is a condensation reaction of carboxylic acid represented by the formula (4-a), with ammonia and creating a functional group carboxylic acid amide represented by the formula (4-b). The compound represented by formula (4-a), can be used in the form of the free acid, but can also be used its reactive derivative. Examples of such reactive derivatives, based on the compound represented by formula (4-b)include halides of carboxylic acids, such as acid chloride acid and brokenheartedly; ordinary esters, such as methyl ether, ethyl ether and benzyl ether; carboxylic acid azides; activated esters, such as Bt, p-nitrophenyloctyl and N-hydroxysuccinimidyl; symmetric anhydrides of carboxylic acids; mixed anhydrides of carboxylic acids alilovic esters of Galaga the carboxylic acids, such as the acid chloride alkylphenol acid, pivaloyloxy and the acid chloride p-toluensulfonate acid; mixed anhydrides of carboxylic acids, such as mixed anhydrides of phosphoric acid, such as those obtained by the reaction of diphenylpropylamine with N-methylmorpholine.

In the case where the compound represented by formula (4-a), is reacted in the form of the free acid, or without isolation of the activated ester, or the like, preferably use a condensing agent such as DCC, CDI, DPPA, diethylphosphoramidite and EDCI/HCl.

The solvent for the reaction varies depending on the reactivity of the derivative or condensing agent which is used, but the reaction is carried out in an organic solvent inert to the reaction, such as halogenated derivatives of hydrocarbons, aromatic hydrocarbons, ethers, esters such as EtOAc, acetonitrile, DMF and DMSO, or their mixtures. The reaction is carried out under cooling, under cooling to at room temperature or at room temperature to under heating.

In addition, in the reaction, to the reaction proceeded well, it is desirable to conduct the reaction with an excess amount of ammonia or in the presence of a base, such as N-methylmorpholine, trimethylamine, Et3N, DIPEA, N,N-dimethylaniline, pyridine, DMAP, picoline and loot the Dean. Pyridine can be used in combination with the solvent.

Stage shows Stage 4-2, is a dehydration, for which the Foundation may or may not be used and can be used such dehydrating agents as triperoxonane anhydride, POCl3and R2About5.

In addition, in the case of the synthesis of condensed, intermediate heterocyclic compounds other than those described in the above-described methods to obtain intermediates, it is possible to apply the methods described in Reference Examples or the Examples herein, or equivalent methods, or in addition, to obtain, use well-known methods or methods that are obvious to a person skilled in this technical field.

<a First receiving method>

[Him]

[where A, X, R1and R4as explained above. Lv denotes a leaving group. Carboxylic acid represented by the formula (5-C), (5-d) and (5-g), can be purchased as a commercially available product, or cooked in the same way as a commercially available product].

This method of obtaining is a method for obtaining compounds of the present invention, represented by formula (I), by reaction of hydroxyamide represented by the formula (5-b), obtained by joining the reaction of the hydroxyl is mine with aromatic nitrile, represented by the formula (5-a)with a carboxylic acid represented by the formula (5-C).

At the stage depicted Stage 5-1, hydroxyamide represented by the formula (5-b), can be obtained by joining the reaction of free hydroxylamine or hydroxylamine hydrochloride in the presence of a base.

This reaction should be carried out in a solvent inert to the reaction. Specific examples of solvents include alcohols, such as Meon, EtOH and i-D; aromatic hydrocarbons such as toluene and xylene; ethers, such as THF, dioxane and diethoxyethane; kalogeropoulou, such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; acetonitrile; aprotic polar solvents such as DMF, 1,3-dimethyl-2-imidazolidinone and DMSO; water, or a mixture of such solvents. As a rule, in the reaction using alcohols. As described above, when using hydroxylamine hydrochloride, the reaction is carried out preferably in the presence of a base, and specific examples of bases include carbonates of alkali metals such as Na2CO3and K2CO3; bicarbonates of alkali metals, such as NaHCO3and knso3; alkoxides such as NaOMe, NaOEt and KOtBu; tertiary amines, such as Et3N and DIPEA; organic amines such as DBU, pyridine and lutidine. The reaction temperature varies over the threaded depending on the type of the original substances, the reaction conditions and the like, but the reaction should be carried out, generally at room temperature to about the boiling point of the solvent. As a rule, in the presence of evidence, such as Na2CO3the reaction should be carried out in an organic solvent inert to the reaction, such as Meon, from at room temperature to under heating.

Stage shows Stage 5-2, consists of two stages, i.e. from the stage of acylation of hydroxyamides and stage reaction tickitaly in the appropriate order. Phase acylation can hold as follows. Compounds represented by formula (5-C), can be used in the reaction in the form of the free acid, but its reactive derivative can also be used in the reaction. Examples of such reactive derivatives include acid chloride acid and bromohydrin acid, ethers such as methyl ether, ethyl ether and benzyl ether; acid azides; activated esters, such as HOBt, n-nitrophenyloctyl, N-hydroxysuccinimidyl; symmetric acid anhydride; a mixed acid anhydride with alkylamine esters halogencarbonic acids, such as Elgiloy ether halogenosilanes acid, mixed mixed anhydride of phosphoric acid, such as obtained by the reaction of diphenylphosphinylchloride with N-methylmorpholine.

In case the, when the compound represented by the formula (5-C), reacts in the form of the free acid, or without isolating the activated ester or the like, preferably use a condensing agent such as DCC, CDI, DPPA, diethylphosphoramidite and EDCI/HCl.

The solvent for the reaction varies depending on the reactivity of the derivative and of the condensing agent used, but the reaction is carried out in an organic solvent inert to the reaction, such as kalogeropoulou, aromatic hydrocarbons, ethers, esters, such as EtOAC, acetonitrile, DMF and DMSO, or a mixture of these solvents, under cooling, under cooling to at room temperature or at room temperature to under heating.

In order to have a good reaction, in some cases it is preferable to carry it out in the presence of such bases, as N-methylmorpholine, trimethylamine, Et3N, DIPEA, N,N-dimethylaniline, pyridine, DMAP, picoline and lutidine. The pyridine may be used in combination with the solvent. Acylated product as an intermediate connection can be cleared by selecting and heated in an organic solvent inert to the reaction, such as EtOH, dioxane, toluene, and water. Typically, this two-stage reaction should be carried out in one stage, by heating or microwave exposed the AI product in the form in which he is, or in the form of the reaction mixture after acylation.

Specific examples of the solvents off aromatic, such as toluene, xylene and pyridine; ethers such as diethyl ether, THF, dioxane and diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; acetonitrile; aprotic polar solvents such as DMF, DMA, 1,3-dimethyl-2-imidazolidinone, NMP and DMSO; water, or a mixture of these solvents. The reaction temperature varies depending on the type of starting compounds, the reaction conditions or the like, but the reaction should be carried out usually at room temperature to under heating.

When X represents-O - or-NH-, synthesis can be carried out following the method of preparation.

Stage shows Stage 5-3 and Stage 5-5, can be carried out in the same manner as stage shows Stage 5-2.

Stage shows Stage 5-4 and Stage 5-6 represent the stage of the preparation of the compounds of the present invention, represented by formula (I), carried out at the introduction into the reaction of phenol, aniline, alcohol or amine, represented by formula (5) or formula (5-i), with the compound having a leaving group represented by formula (5-f), or formula (5-h). Here, examples of leaving groups include the with halogen, such as chlorine or bromine; and sulfonyloxy, such as methansulfonate, econsultancy, benzosulfimide, p-toluensulfonate, p-nitrobenzenesulfonate, tripurasundari.

The reaction is carried out at normal pressure or at elevated pressure, without solvent or in a suitable solvent.

Specific examples of solvents include aromatic hydrocarbons, such as toluene or xylene; ketones such as acetone and methyl ethyl ketone; ethers such as ether, THF, dioxane and diethoxyethane; alcohols, such as Meon, EtOH, i-D and n-BuOH; halogenated hydrocarbons such as dichloromethane, 1,2-dihloretan, chloroform and carbon tetrachloride; acetonitrile; aprotic polar solvents such as DMF, 1,3-dimethyl-2-imidazolidinone, NMP and DMSO; water, or a mixture of such solvents. In this reaction it is preferable to use the base, and specific examples of bases include NaH; carbonates of alkali metals such as Na2CO3and K2CO3the bicarbonates of alkali metals, such as Panso3and knso3, alkoxides such as NaOMe, NaOEt and KOtBu, tertiary amines, such as Et3N, tributylamine and DIPEA; organic amines such as DBU, pyridine and lutidine, but excessive amounts can be combined with the amine represented by the formula (5) or (5-i). The temperature of the reactions which varies depending on the type of the original substances, the reaction conditions or the like, but, as a rule, the reaction should be carried out from room temperature to about the boiling point of the solvent. Typically, the reaction should be carried out in the presence of a base, such as NaH and Na2CO3, in an organic solvent inert to the reaction, such as DMF and DMA, at -10°C. to under heating. Also amine represented by the formula (5) or formula (5-i), can be represented in the form of its salt. Additionally, it can be microwave radiation when heated during cooking.

In addition, some compounds represented by formula (I)can be prepared by combining the well-known processes, which can usually be used by qualified specialists in the field of technology, such as the well-known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, removing the protective group and halogenoalkane, based on the compounds of the present invention, as prepared by the method described above.

For example, alkylation, alkylation reaction, which is typically used by qualified specialists in the field of technology can be applied, which must be carried out in an organic solvent inert to the reaction, such as ethers; aromatic uglevodorov is s; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; DMF; acetonitrile; and polar aprotic solvents, under cooling, under cooling to room temperature, or from room temperature to under heating, in the presence of a base, such as NaH; carbonates of alkali metals; carbonates of alkali metals; alkoxides; tertiary amines and organic bases.

In addition, for example acylation, reaction of acylation, which, as a rule, use qualified specialists in the field of technology can be used, in particular, one that can be carried out in the presence of HOBt, in a solvent, varying depending on the condensing agent such as EDCI/HCl or CDI and diphenylphosphorylacetamide, in a solvent, varying the reaction conditions, but usually in an organic inert solvent, such as ethers; aromatic hydrocarbons; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; esters, such as EtOAc; acetonitrile; and aprotic solvents, under cooling, under cooling to at room temperature or at room temperature to under heating.

Thus prepared compound is purified by isolating, as if it or its salt after coloradoescortgi using the appropriate method. Purification using allocation is performed with the use of well-known chemical operations such as extraction, concentration, removal by distillation, crystallization, filtration, recrystallization and various chromatography methods.

Different types of isomers can be separated using appropriate methods, using the difference in physicochemical properties between the isomers. For example, the racemic mixture can be converted into optically pure isomers, for example, using a standard method of splitting of racemic products, such as the method of splitting the optical isomers in the form of diastereoisomeric salts with well-known optically active acids such as tartaric acid. Also diastereomers the mixture can be separated, for example, by fractional crystallization or chromatography methods. In addition, optically active compounds can also be prepared using the appropriate optically active educt.

The effect of the compounds of this invention have confirmed by the following pharmacological tests.

Experimental Example 1: Test for confirmation of agonistic S1P1activity

1) Evaluation of agonist activity of the receptor by analysis of the binding of GTP[γ-35S]using the membrane of human cells expressing S1P 1.

In vitro S1P1agonistic activity of the compounds of this invention was evaluated by means of increasing functional binding activity by G-protein GTP[γ-35S]using the membrane of human S1P1expressed cells. The cDNA encoding human S1P1cloned from a library of human colorectal cDNA was introduced into the expression vector pcDNA3.1 to create S1P1-pcDNA3.1. Then using Lipofectamine 2000 (GIBCO) S1P1-pcDNA3.1 was transfectional in the cell line Cho and cultured in Ham''s F-12 culture medium containing 10% fetal bovine serum, 100 U/ml penicillin, 100 μg/ml streptomycin and 1 mg/ml of G418 disulfate getting G418-resistant strain. Cultured human S1P1accessimagine cells were isolated in pure form in 1 mmol EDTA/2Na-containing FSB and destroyed under ice cooling in the homogenizer, made of glass, 1 mmol Tris-Hcl (pH 7.4) buffer solution containing 0.1 mmol of EDTA and the inhibitor protein. It centrifugally at 1400×10 min and the supernatant further centrifugally at 4°C for 60 min at Hg and suspended in 10 mmol per 1 mmol of Tris-Hcl (pH 7.4) buffer solution containing 1 mmol of EDTA. The obtained membrane (0.13 mg/ml) and 50 pmol GTP[γ-35S] (NEN; inactive 1250 CI/mmol) was introduced into the reaction in 20 mmol HEPES (pH 7.0) buffer solution (total the number 150 μl), containing 100 mmol NaCl, 10 mmol MgCl2, 0.1% of free fatty acid bovine serum albumin and 5 mmol of citydistance for 1 hour together with the compound of the present invention (10-12up to 10-15Mol) and then the membrane was separated in GF-tablet halestorm cells (Packard FilterMate). FilterMate was dried at 50°C for 60 min and in addition added Microscinti-o (Packard) for calculations using the scintillation detector of lipids for microplate (Packard TOP count). For the evaluation of agonistic activity towards human S1P1compounds of the present invention and comparative compounds, the percentage value of the maximum response, making GTP[γ-35S] due saturated in the presence of the compound was taken as 100% and the value of the reaction GTP[γ-35S] relations in the absence of the compounds was taken as 0%, created a non-linear regression curve, and the concentration that causes the occurrence of agonistic activity at 50% of maximum response, defined as the value of the EU50(nmol).

Table 1
Etc.
No.
S1P1
EC50
Etc.
No.
S1P1
EC50/sub>
Etc.
No.
S1P1
EC50
213602,115111
55,564the 5.71527,6
61,2654,01581,8
8of 5.4673,71631,9
12the 4.7815,91642,8
152,1873,71734,3
236,81068,7 181the 4.7
26the 4.71106,21824,2
37of 5.41194.31936,8
486,51204,61942,0
5113121121965,3
542,3143of 5.41973,3
59the 3.81473,2

The result was confirmed that the compounds of the present invention possess S1P1agonistic activity.

2) Assess lymphocytopenia peripheral blood in rats

Lymphocytoma the human peripheral blood in rats was determined 24 hours after oral administration in the following way. Male Lewis rats aged six to ten weeks (Japan Charles river laboratory) were randomly divided into groups (n=3) and the compound of the present invention suspended in containing 0.5% methylcellulose distilled water and orally was administered using a probe. 24 hours after injection under ether anesthesia were selected by 0.2 ml of blood from the ocular fundus. The blood sample was immediately added EDTA/4K and heparin to prevent clotting and the number of lymphocytes in the blood was calculated using the automated Hematology analyzer (Sysmex Corp.; XT-2000i).

To reduce the number of lymphocytes in the peripheral blood under the action of the compounds according to the present invention, the percentage by number of lymphocytes in the group, which was appointed containing 0.5% methylcellulose distilled water was taken as 100%, as it did last time, and the dose that causes a 50% reduction in the number of lymphocytes in the peripheral blood in the appointment of the compounds of the present invention, defined as the value of the ED50(µg/kg).

For comparative compounds 1 and 2, which are described in the explanatory Memorandum of the International Application No. WO2004/103279, comparative compound 3, which is accurately described in the explanatory note to International Application no WO2005/032465, and the compound of Example 119, compared to the value of the ED5024 hours after destinations is ment to reduce the number of lymphocytes in the peripheral blood of rats.

Table 2
ConnectionStructureThe value of ED50after 24 hours
Approx. 1190,071 m/kg
Comparative compound 11.4 mg/GK
Comparative compound 28,8 mg/GK
Comparative compound 33.7 mg/kg

The result shows that the compound of Example 119 shows the high value of the ED50even after 24 hours, suggesting a preservation effect.

Due to the fact that the compound of the present invention has S1P1agonistic activity, it is applicable as an active ingredient means for treatment or prophylaxis of diseases caused adverse lymphocytic infiltration, such as autoimmune diseases, is such as graft rejection in organ transplantation, bone marrow or tissue or graft versus host disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, malignant myasthenia gravis, pancreatitis, hepatitis, pulmonary diseases, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemic reperfusion injury, or an inflammatory disease, and in addition, diseases caused by abnormal growth or accumulation of cells, such as cancer or leukemia.

In addition, the connection according to the present invention is applicable to treatment and/or prophylaxis of the following diseases, based on agonistically activity against S1P1.

It is applicable for the treatment and/or prevention of inflammatory or hyperplastic skin diseases such as psoriasis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, red flat zoster, vulgar disease, pemphigoid, builtny a bullosa, urticaria, vascular edema, occlusion of vessels, erythema, eosinophilic leukocytosis skin, lupus erythematosus, acne and circular alopecia or symptoms of skin diseases caused by the immune system, autoimmune diseases or allergic diseases of the eye, such as keratoconjunctivitis, vernal conjunctivitis, allerg the ical conjunctivitis, UALITY associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus keratitis, corneal epithelial dystrophy, corneal leukoma, atrophic mucociliary bullous dermatitis, corroding ulcer of the cornea, inflammation of the sclera, the ophthalmopathy of graves ' disease Vogt-Koyanagi-Harada, dry keratoconjuctivitis (dry eyes), bubbles, iridocyclitis, sarcoidosis, and ophthalmic diseases gland; reversible obstructive lung disease (asthma, such as bronchial asthma, allergic asthma, endogenous bronchial asthma, exogenous asthma and asthma on dirt), particularly chronic or severe asthma (e.g. late asthma at the beginning, or respiratory tract infections); mucos or angina (for example, stomach ulcers, ischemic or thrombotic vascular injury, age maculate, diabetic muscularity, ischemic bowel disease, bowel disease, necrotizing enteritis, intestinal damage by thermal burn and diseases caused by neurotransmitter leukotriene B4) inflammation of the intestine or allergic bowel disease, including, for example, proctitis, eosinophilic enteritis, mastocytosis, coeliac disease, Crohn's disease and ulcerative colitis; food related allergic diseases manifesting symptoms on participation is ke, remote from the gastrointestinal tract, including, for example, migraine, rhinitis and eczema; autoimmune diseases or inflammatory diseases, including, for example, primary mucosal edema, autoimmune atrophic gastritis, premature menopause, juvenile diabetes, common bladderwort, pemphigoid, sympathetic destruction of the eyeball, phacoanaphylaxis endophthalmitis, proximally leukopenia, chronic active hepatitis, preceisely cirrhosis, discoid lupus erythematosus, Sjogren syndrome, an autoimmune inflammation of the testicles, arthritis (e.g., modified arthritis) and polyandria; renal diseases, such as membranous nephropathy, membranosa-proliferative nephritis, focal global glomerulosclerosis, sickle nephritis, glomerular nephritis, primary IgA nephropathy-type, tubulopathy interstitial nephritis and diabetic nephropathy. In addition, the compound of the present invention is also applicable to treatment and/or prevention of liver diseases (such as immunogenic diseases (for example, autoimmune liver disease, chronic autoimmune liver diseases such as biliary cirrhosis, sclerosing cholangitis), partial delamination of the liver, acute necrotic hepatitis (e.g., necrosis, obuslovlen the St toxin, viral hepatitis, shock, anoxia or similar), hepatitis b, non-type a hepatitis, cirrhosis, liver failure (e.g., fulminant hepatitis, hepatitis with late-onset hepatic failure (acute liver failure or chronic liver disease)) and the like.

Additionally, the connection of the present invention may be administered as agonist S1P1yourself go in combination with at least one tool, in the same Doge or different doses, by the same or different route of administration. Examples of tools that can be combined include, but are not limited to, cyclosporin a, tourkolias, sirolimus, everolimus, mycophenolate, azathioprin, brequinar, Leflunomide, fingolimod, and antibodies anti-IL-2 receptor (e.g., daclizumab) and anti-CD3 antibodies (e.g., OCT), and atni-T cell immunoglobulin (for example, AtGam), belatacept, abatacept, cyclophoshamide, β-interferon, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroid (eg, prednisone and dexamethasone).

The preparation containing the compound represented by formula (I), either one, two or more of its salts as active ingredients are manufactured using the media, excipients or other additives commonly used in the manufacture of medicines.

The reception can about usestate in any form, as in the form of tablets, granules, powders and solutions, as well as parenteral injection as intravenous and intramuscular, suppositories, subcutaneous preparations, transnasal preparations, inhalations and the like, the Dose is calculated in each individual case, taking into account symptoms, age, sex and thepatient, but usually it ranges from 0.001 mg/kg to 100 mg/kg / day for an adult in the case of oral administration and can be made in one piece or divided into 2-4 servings. Also, in the case of intravenous administration, in accordance with the symptoms, the drug is taken from the calculation of from 0.0001 mg/kg to 10 mg/kg / day for an adult, one or two or more times a day. Additionally, in the case of inhalation, the admission is based of 0.0001-1 mg/kg for an adult, one or two or more times a day.

As for the solid compositions of the present invention for oral administration, are tablets, powders, granules, etc. In such solid compositions one or more active substance is mixed with at least one inactive excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and aluminum-magnesium silicate. In the standard method, the composition may contain inactive additives such as lubricating substance, such as with earth magnesium, disintegrator such as sodium carboximetilkrahmal or solubilizers component. If necessary, tablets or pills may be coated with sugar or soluble in the stomach, or intersolubility the floor.

Liquid composition for oral administration includes pharmaceutically applicable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert solvents such as purified water and ethanol. In addition to the inert solvent, the composition may contain an auxiliary agent such as solubilizers agent, a moisturizing agent or suspendisse agent, a sweetener, a neutralizing agent, a flavoring and a preservative.

Injections for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions and emulsions. Examples of aqueous solvents include distilled water for injection and physiological saline. Examples of non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (Pharmacopeia). This composition may also contain a means for maintaining muscle tone, antiseptic, moisturizing, emulsifying agent, dispersing agent, stabilizing agent and solubilizers tool. These substances sterile is described, for example, by filtering through the filter traps bacteria, mixing bactericidal drugs or by irradiation. In addition, they can be used in the manufacture of sterile solid compositions and dissolving or suspendirovanie it in sterile water or a sterile solvent for injection immediately before its introduction.

As for transmucosal means, as, for example, inhalation or transnasal means, there is used a solid, liquid or semi-liquid form, which may be made in accordance with a conventional known method. For example, if necessary, may be added fillers, such as lactose or starch, pH-controlling means, antiseptic, surfactant, lubricant, stabilizer, thickener. For their reception, can be used appropriate device for inhalation or injection. For example, the connection may be made through traditional devices or sprinklers, such as a device for the metered inhalation, in pure form or in powder form, made according to the recipe or in the form of a solution or suspension in which it is combined with a pharmaceutically applicable carrier. An inhaler for the inhalation of a dry powder can be both disposable and reusable, with the use of dry powder doubt the capsule, containing the powder. Alternatively can be used aerosol spray with high pressure, which is applied corresponding to the gas propellant is used, for example chlorphenesin, hydrofluroalkane and carbon dioxide.

External means include ointments, plasters, creams, jellies, pastes, sprays, lotions, eye drops, eye ointments, etc. External means may include ointment bases, lasonya bases, aqueous and non-aqueous liquids, suspensions, emulsions, etc. used in such cases. Examples of bases ointments or lotions include polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyethoxyethanol solid castor oil, glycerylmonostearate, stearyl alcohol, cetyl alcohol, laurenmichal and servicesexperience.

Example

Further in this document, the compounds of the present invention will be described in more detail with reference to Examples. The present invention is not limited to the invention as described in the following examples. Methods for the preparation of starting compounds shown in the Examples Received.

[In the following tables Pr means the Sample Receipt no., and Structure means the structural formula. Lightweight characters in the structural formula, Me represents a methyl group and Et represents ethyl group. Perekrashivat the double bond denotes a mixture of CIS/TRANS, and if the Data section describes only the numbers, it shows the MS data. MS refers to mass spectrometry data. In tables RT means retention time in high-performance liquid chromatography (HPLC) and M indicates minutes. Conditions the following HPLC: column: Intertsil ODS of 34.6×150 mm, eluent 0,01M KH2PO4aq./MeCN(3:7), the flow rate of eluent (1.0 ml/min, wavelength of detection: 254 nm. If data1H-NMR described in the tables as the internal standard tetramethylsilane was used, and unless stated otherwise, δ (ppm) (integrated value, the measurement scheme) signals in1H-NMR shown in DMSO-d6as the solvent used for registration. Abbreviated symbols have the same meaning as the following: s: singlet, d: doublet, t: triplet, q: Quartet, dd: doublet of doublets, ddd: doublet of doublet of doublets, dt: doublet of triplets, dm: doublet multiplet, br: extended, brs: broadened singlet, Hz: Hertz, CDCl3: deuterated chloroform, DMSO-d6: dimethylsulfoxide-d6in this description, the NMR indicates1H-NMR: proton nuclear magnetic resonance. Such will be applied here in this document].

Example Obtain 1

Imidazo[1,2-a]pyridine-7-carbonitrile hydrochloride (1.5 g), hydroxylamine hydrochloride (301 mg) and Na2CO3(3.5 g) was stirred at 60°C for 6 hours is in CH 3HE (57 ml). The reaction solution was cooled and concentrated and the completion of the reaction was determined using LC-MS. To the residue was added water, then was extracted with EtOAC. The organic layer was washed with water and saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated, obtaining N'-hydroxyamides[1,2-a]pyridine-7-carboxamide (850 mg) as a solid.

Compounds shown in Pr 1-1 to 1-17 Pr was obtained in the same manner as in the Example of Obtaining 1.

Table 3
PrStructureMSPrStructureData
11771-1191
1-21911-3205
-4 2631-5177
1-61911-7RT:
1,79
M
1-81911-9177
1-101911-11RT:
1,64M
1-12RT:
1,60
M
1-13192
1-142331-15 231
1-163911-17

Example of Getting 2

In the reaction vessel of 50 ml to a solution of 1H-indole-4-carbonitrile (5,00 g) in CH3HE (100 ml) was added hydroxylamine (50% aqueous solution) at room temperature, then boiled for 15 hours (completion of the reaction was confirmed using TLC). The reaction solution was concentrated under reduced pressure and dried by azeotropic distillation with toluene three times. The obtained solid is washed with IPE. Got N'-hydroxy-1H-indol-4-carboxamidine (6,12 g) as a white solid.

Compounds shown in Pr 2-1 to Pr 2-26, was obtained in the same manner as in Example Getting 2.

Table 4
PrStructureMSPrStructureData
2 1762-1191
2-22052-3263
2-41772-5191
2-61912-7221
2-81922-9193
2-101912-11188

Table 5
PrStructureMSPrStructureData
2-122022-13
2-14RT:
1,68
M
2-15177
2-16NMR
below
2-17
2-18RT:
1,62
M
2-19200
RT:
1,69
M
2-21RT:
1,62M current
2-22RT:
1,62M current
2-23177
2-242252-25177
2-26177

Table 6
PrNMR
2-165,71(2H, s), 6,47(1H, d), to 7.50(1H, d), to 7.61(1H, d), to 7.93(1H, d), 9,78(1H, s), 11,70(1H, s)

Example of Getting 3

A suspension of N2-hydroxy-1H-indole-4-carboxamide (of 1.00 g), 4-fluoro-3-(trifluoromethyl)benzoic acid (1.19 g) and EDCI/HCl (1,32 g) in dioxane(30 ml) was stirred at room temperature for 1 hour, and then was heated at boiling for 18 hours. The reaction mixture was concentrated under reduced pressure, was added chloroform and water, and then stirred. Nerastvorim part was separated by filtration. The organic layer the mother liquor, washed with water, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated under reduced pressure. Insolubles were separated by filtration, together with the mother liquid was purified using chromatography on silica gel (n-hexane:EtOAc=80:20). The target substance was added acetone, then dissolved under heating was added n-hexane, precipitated precipitate was separated by filtration, receiving 4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (391 mg) as a white solid.

Table 7
PrStructureMS
3346

Example 4

N2-{[(5,6-Dichloropyridine-3-yl)carbonyl]oxy}-1H-indol-4-carboxamid (1,91 g) were added to dioxane (40 ml), then was heated at boiling for 5 hours. The reaction mixture was concentrated when the mind is grannom pressure and then purified using column chromatography on silica gel (EtOAc). To the obtained solid substance was added acetone, and then suspended when heated. After the solution was allowed to cool, insoluble particles were removed by filtration, obtaining 4-[5-(5,6-dichloropyridine-3-yl)-1,2,4-oxadiazol-3-yl]-1H-indole (1.44 g) as a pale yellow powder.

Table 8
PrStructureMS
4331,
329

Example of Getting 5

A solution of N2-hydroxy-1H-indole-4-carboxamide (3.42 g) and 4-fluoro-3-(trifluoromethyl)benzoic acid (4,07 g) in THF (70 ml) was cooled to -10°C or lower was added DIC (3,7 ml). After stirring at -15 to -5°C for 3 hours the reaction mixture was concentrated under reduced pressure. The residue is suspended in chloroform and then nerastvorim part was separated by filtration. The resulting powder was purified using chromatography on silica gel (n-hexane:EtOAc=50:50), receiving the N2-{[4-fluoro-3-(trifluoromethyl)benzoyl]oxy}-1H-indol-4-carboxamid (8,40 g) as a white solid.

The connection shown in Pr 5-1 was obtained in the same manner as in Example Polucheniya.

Table 9
PrStructureMSPrStructureMS
5388,
366
5-1-

An example of Obtaining 6

To a solution of 6-amino-2-methylnicotinamide (960 mg) in ethanol (34 ml) was added 40% aqueous solution of chloroacetaldehyde (2,36 ml) at 60°C. the Reaction mixture is boiled for 8 hours. The formed precipitate was separated by filtration, receiving 5-methylimidazo[1,2-a]pyridine-6-carbonitrile hydrochloride (580 mg) as a white solid.

Compounds shown in Pr 6-1 to Pr 6-11, received the same manner as in the Example of a 6.

Table 10
PrStructureMSPrStructure MS
61586-1158
6-21586-3252
6-41446-5172
6-6NMR
below
6-7252
6-81726-9NMR
below
6-10158 6-11158

Table 11
PrNMR
6-62,39(3H, s), 7,14(2H, m), 7,92(1H, s), 8,18(1H, s), to 8.62(1H, d)
6-9of 7.48(1H, DD, J=1,6, 9,3 Hz), 7,74(1H, d, J=9,3 Hz), 7,76(1H, d, J=1,GZ), of 8.06(1H, s), 9,37(1H, s)

Example of Getting 7

To a solution of 3,4-diaminobenzanilide (500 mg) in AcOH (10 ml) was added AU2(372 μl) at room temperature. The reaction mixture is boiled for 15 hours (oil bath at 150°C). The reaction mixture was cooled to room temperature and concentrated until then, until the number of Asón not decreased to half. The reaction mixture was neutralized with an aqueous solution of Na2CO3and was extracted with EtOAc. The organic layer was washed saturated aqueous NaHCO3and saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified column chromatography on silica gel, obtaining 2-methyl-1H-benzimidazole-5-carbonitrile (390 mg) as pale-red substance.

Table 12
PrStructureMS
7158

Example Obtain 8

The reaction mixture of 4,5-diamino-2-methylbenzonitrile (20 mg) and formic acid (6 ml) was boiled for 3 hours. The reaction solution was cooled and concentrated. To the residue was added 1M aqueous NaOH solution and was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4then filtered and the filtrate was concentrated, receiving 5-methyl-1H-benzimidazole-6-carbonitrile as colored powder.

Compounds shown in Pr 8-1, was obtained in the same manner as in Example Receipt 8.

Table 13
PrStructureMSPrStructureMS
81588-1 211,
213

Example of Getting 9

In a solution of 3,4-diaminobenzanilide (400 mg) in utilitiarian (6,48 g) was added Asón (238 mg), then stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature and separated between EtOAc and 1M aqueous solution of NaOH. The organic layer was washed with saturated salt solution, dried over anhydrous Na2SO3and then was separated by filtration and the filtrate was concentrated and purified using column chromatography on silica gel, receiving 2-ethoxy-1H-benzimidazole-6-carbonitrile (164 mg) in the form of colored powder.

Table 14
PrStructureMS
9210

Example 10

To a suspension of 3,4-diaminobenzanilide (400 mg) in CH3HE (4 ml) was added Enrichment (477 mg), then stirred at 20°C for 14 hours. To the reaction mixture was added 1M aqueous NaOH solution (0,117 ml), then concentrated. To the residue was added chloroform:CH3HE=10:1 (10 ml) and the resulting insolubles were removed by filtration. The filtrate was concentrated and p is obtained residue was purified using column chromatography on silica gel, getting 2-amino-1H-benzimidazole-6-carbonitrile (311 mg) as a pale orange powder.

Table 15
PrStructureMS
10159

Example of Getting 11

To a solution of 3,4-diaminobenzanilide (350 mg) in toluene (5.5 ml) was added CDI (554 mg), then stirred at 125°C for 2 hours. To the reaction mixture was added 1M aqueous NaOH solution (0,117 ml) and then was extracted with EtOAc. Organic layer was dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was pereirae in powder/washed IPE/IPA, receiving 2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (423 mg) in the form of colored powder.

Table 16
PrStructureNMR
117,07(1H, d, J=8,2 Hz), 7,31(1H, d, J=1,GZ), 7,39(1H, DD, J=1,6,
8,2 Hz), 11,12(2H, user.)

When is EP 12

To a mixed solution of N-(4-cyano-2-nitrophenyl)Penta-4-enamide (1.0 g) in Asón)/ethanol (1:1,20 ml) was added iron powder (710 mg). The reaction solution was heated at 110°C for 3 hours and then concentrated. To the residue was added chloroform, and then neutralized with a saturated aqueous solution of NaHCO3. The organic layer was dried anhydrous MgSO4and then filtered to remove the drying agent and the solvent was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel, receiving 3-butenyl-1H-benzimidazole-5-carbonitrile (405 mg) in the form of a colored liquid.

Compounds shown in Pr 12-1 to Pr 12-2, was obtained in the same manner as in Example 12.

Table 17
PrStructureMSPrStructureMS
1222012-1266
12-2 218

Example of Getting 13

To a solution of 2-torturefacial (500 mg) and Et3N (572 μl) in EtOH (20 ml) was added hydrazine (monohydrate), then the mixture was allowed to react at 60°C for 16 hours and concentrated. The residue was washed with diethyl ether, obtaining 3-amino-1H-imidazole-6-carbonitrile (488 mg) as a yellow solid.

The connection shown in Pr 13-1, was obtained in the same manner as in the Example of a 13.

Table 18
PrStructureMSPrStructureMS
1315713-1

Example of Getting 14

To a suspension of 3-amino-1H-imidazole-6-carbonitrile (345 mg) in Asón was slowly added an aqueous solution of NaNO2(301 mg) at 0°C. the Reaction mixture was stirred at room temperature for 2.5 days and the rest of acceleratordriven and washed with cold water. To the residue was added 0,1M HCl and DME, then stirred at 80°C for 2 hours. The reaction mixture was neutralized with a saturated aqueous solution of NaHCO3and was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4and concentrated. The residue was purified using column chromatography on silica gel (n-hexane:EtOAc=80:20 to 50:50)to give 1H-indazol-6-carbonitrile (175 mg) as a yellow solid.

Table 19
PrStructureMS
14142

Example Get 15

Methyl(4-cyano-2-nitrophenyl)acetate (128 mg) was dissolved in Asón (3.0 ml), then was added iron powder (129 mg) and the reaction solution was stirred on an oil bath at 100°C for 1.5 hours. The reaction solution was concentrated to remove the Asón, then added EtOAc. The brown solid was separated by filtration and the organic layer washed with 1M HCl and saturated salt solution, dried over anhydrous MgSO4and concentrated. The residue was purified using column chromatography on silica gel (chloroform:CH3HE=99:1 to:5), getting 2-oxoindole-6-carbonitrile (52,0 mg) as a pale yellow solid.

Table 20
PrStructureMS
15157

Example 16

To a solution of 6-bromo-2,2-dimethylindoline-1-she (124 mg) in TFA (4.44 g, 3.0 ml) was added triethylsilane (150 mg, 207 μl) at room temperature. After stirring at room temperature for 2.5 days to the reaction solution were added water to stop the reaction, and then washed with water and a saturated solution of NaHCO3. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography (n-hexane)to give 5-bromo-2,2-dietlinde (114 mg) in the form of a colored oil.

Table 21
RfStructureNMR
16 of 1.09(6H, s), 2.63 in(2H, s), 2,68(2H, s), 7,13(1H, d), 7,27(1H, DM), was 7.36(1H, m)

Example of Getting 17

In THF (30 ml) to a mixture of 6-bromo-1-indanone (300 mg) and diazomethane (504 mg, 221 ml) was added 60% NaH (125 mg) at 0°C. the Mixture was stirred at room temperature for 3.5 hours and washed with saturated solution of NH4Cl. The mixture was extracted with EtOAc and the organic layer was dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified column chromatography on silica gel (n-hexane:EtOAc=100:0 to 80:20)to give 6-bromo-2,2-dimethyl-1-indanone (158 mg) as a pale yellow oil.

Table 22
PrStructureMS
17261,
263

Example of Getting 18

To a solution of 3-amino-4-hydroxybenzonitrile (730 mg) in DMF (10 ml) was added CDI (1.06 g) at 0°C, then stirred at room temperature for 3.5 hours. The reaction solution was diluted with water (10 ml) and was extracted with EtOAc (200 ml). The organic layer was dried over anhydrous MgSO4and then was filtered and the filtrate is the end of what was tarawali under reduced pressure. The residue was purified using column chromatography on silica gel (chloroform:CH3HE=98:2 to 97:3)to give 2-oxo-2,3-dihydro-1,3-benzoxazol-5-carbonitrile (647 mg) as a pale yellow solid.

Join Pr 18-1 received the same manner as Example Get 18.

Table 23
PrStructureMSPrStructureMS
1815918-1183

Example of Getting 19

To a solution of 60% NaH (12,38 g) in DMF (480 ml) was added a solution of 1H-indole-4-carbonitrile (40,0 g) in DMF (80 ml) at 0°C. After stirring at 0°C for 30 min, the solution was stirred at room temperature for 0.5 hours. Subsequently, a solution of 2-bromoacetamide (40,76 g) in DMF (80 ml) was added dropwise at 0°C. the Solution was heated from 0°C to room temperature and was stirred for 12 hours. To the reaction solution were added water (1200 ml) and the precipitated solid is the precipitate was separated by filtration. The solution was washed with hot water (300 ml) and diisopropyl ether (200 ml)to give 2-(4-cyano-1H-indol-1-yl)ndimethylacetamide (a total of 5.21 g) as a white solid.

Table 24
PrStructureMS
19222

Example of Getting 20

To a solution of 3-chloro-4-(2,2,2-Cryptor-1 methylethoxy)benzonitrile (430 mg) in IPA (3 ml) was added 5 M aqueous solution of NaOH (1,37 ml), then stirred at 80°C for 24 hours and further was added 5 M aqueous solution of NaOH (1,37 ml), then stirred at 95°C for 24 hours. The reaction solution was concentrated until until its number is not reduced to half. To the residue was added 12 M HCl and the precipitate was separated by filtration and then dried, obtaining 3-chloro-4-(2,2,2-Cryptor-1 methylethoxy)benzoic acid as a yellow solid.

The connection shown in Pr 20-1 to Pr 20-3, was obtained in the same manner as in the Example of a 20.

Table 25
Pr StructureMSPrStructureMS
2026720-1251
20-224720-3263

Example of Getting 21

To 3-(deformity)-4-(2,2,2-Cryptor-1 methylethoxy)benzonitrile (234 mg) was added water (2 ml) and sulfuric acid (2 ml), then boiled for 24 hours. After cooling to room temperature the reaction solution was podslushivaet with 5M aqueous NaOH solution and was extracted with diethyl ether (30 ml). The aqueous layer was acidified using 1M HCl and was extracted with EtOAc. The organic layer was dried anhydrous MgSO4and then was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography (chloroform:CH3HE=97:3 to 90:10)to give 3-formyl-4-(2,2,2-Cryptor-1 methylethoxy)benzoic acid (151 mg) as a white solid.

Compounds shown in Pr 21-1 to Pr 21-6, was obtained in the same manner as in the Example of Getting 21.

Table 26
PrStructureMSPrStructureMS
2126121-1315
21-224521-3257
21-430121-5261
21-6311,
313

Example of Getting 22

To 5-bromo-2-(2,2,-Cryptor-1 methylethoxy)benzonitrile in a solvent mixture of toluene/THF (4:1) solution was added n-BuLi in n-hexane at -78°C. The solution was stirred for 0.5 hours, passing through him gaseous CO2. To the reaction solution was added 1M aqueous NaOH solution for complete reaction and then was extracted with diethyl ether. The organic layer was acidified by adding 1 m HCl, and was extracted with EtOAc, dried over anhydrous MgSO4and concentrated. The residue was purified using column chromatography on silica gel (chloroform:CH3HE=97:3 to 90:10)to give 3-cyano-4-(2,2,2-Cryptor-1 methylethoxy)benzoic acid as a white solid.

The connection shown in Pr 22-1, was obtained in the same manner as in the Example of Obtaining 22.

Table 27
PrStructureMSPrStructureMS
2225822-1189

An example of retrieving 23

To a stirred solution of methyl 1-isobutyl-2-oxo-1,2-dihydropyridines-4-carboxylate (430 mg) in CH3OH-TF (4 ml 3 ml) was added an aqueous solution of 1M NaOH. The solution was stirred at room temperature for 10 hours and then concentrated under reduced pressure and added water (10 ml) and then was added 1M HCl up until the pH has reached the value 3. The formed solid substance was separated by filtration, washed with water and dried at reduced pressure, obtaining 1-isobutyl-2-oxo-1,2-dihydroxypyridine-4-carboxylic acid (235 mg) as a white powder.

Table 28
PrStructureMS
23194

Example of Getting 24

A solution of 1H-benzimidazole-5-carboxylic acid (75,0 g) in dichloromethane (750 ml) was reacted with oxalyl chloride (76,3 g, 52,4 ml) at room temperature for 1 hour, and then the reaction solution was concentrated. To a solution of the residue in THF (750 ml) was added 28% aqueous solution of NH3(5 ml) under cooling with ice. This reaction mixture was stirred at the same temperature and the reaction solution was concentrated. The purple residue was ground into a powder/washed IPE/IPA and was separated by filtration, receiving 1H-benzimidazole-6-carboxamide (129 g) (including neo the organic salt).

The connection shown in Pr 24-1, was obtained in the same manner as in Example completion of 24.

Table 29
PrStructureMSPrStructureMS
2416224-1184

Example Get 25

Example of Getting 25-1

To a solution of 1H-1,2,3-benzotriazol-5-carboxylic acid (2 g), EDCI/HCl (2,82 g) and HOBt in DMF (70 ml) was added an aqueous solution of NH3(5,1 ml), the mixture is then reacted at room temperature for 2 hours. The mixture was concentrated and the residue was washed with a saturated aqueous solution of NaHCO3was separated by filtration and dried, obtaining 1H-1,2,3-benzotriazol-5-carboxamid (1.98 g) as a black solid.

Example of Getting 25-2

In the reaction vessel of 50 ml to a solution of methyl 4-chloro-2-methyl-1H-benzimidazole-6-carboxylate ether (300 mg) in formamide (2.65 ml) was added a Na3(288 mg) at room temperature is. The solution was stirred at 80°C for 3 hours. Completion of reaction was determined by TLC and LC and then the reaction solution was concentrated and added water to complete the reaction. The reaction mixture was extracted with EtOAc. The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (automatic cleaner, chloroform:CH3IT=100:0 to 90:10)to give 4-chloro-2-methyl-1H-benzimidazole-6-carboxamide (257 mg) as a white solid.

Compounds shown in Pr 25-2, was obtained in the same manner as in the Example of Obtaining 25-1.

Table 30
PrStructureMSPrStructureMS
25-118525-2201
25-3 232,
234

Example of Getting 26

To a solution of 3-formyl-4-(2,2,2-Cryptor-1 metatarsi)benzoic acid (490 mg) and K2CO3(387 mg) in acetone (10 ml) was added logmean (350 μl) at room temperature and then was stirred for 2 hours. The reaction mixture was diluted with water (15 ml) and was extracted with EtOAc (30 ml). The organic layer was dried over anhydrous MgSO4and filtered to remove the drying agent and the solvent was concentrated. The residue was purified using column chromatography on silica gel (n-hexane:EtOAC=95:5 to 80:20)to give methyl 3-formyl-4-(2,2,2-Cryptor-1 methylethoxy)benzoate (122 mg) as a solid.

Table 31
PrStructureMS
26275

Example of Getting 27

Under ice cooling to a DMF (30 ml) was slowly added dropwise l3(of 6.68 g, 4,06 ml), the mixture is reacted at room temperature for 2 hours and then the solution was added 1N-benzimidazol-6-carboxamide (2.38 g) in DMF (47,6 ml) and the mixture is then stirred at room te is the temperature for 2 hours. To the solution was added 1M aqueous NaOH solution (pH 6-7), then stirred at room temperature for 0.5 hours. The solution was extracted with EtOAc and the organic layers were combined and washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography and triturated to powder/washed IPE, receiving 1H-benzimidazole-6-carbonitrile (0,58 g) as pale red crystals.

Compounds shown in Pr 27-1 to Pr 27-2, was obtained in the same manner as in the Example of a 27.

Table 32
PrStructureMSPrStructureMS
2714427-1192
27-2144

Example of Getting 28

A solution of 1,3-benzothiazol the-6-carboxamide (1,96 g) in POCl 3(10 ml) was boiled for 4 hours. The reaction solution was concentrated and slowly added water at 0°C. the Mixture was extracted with EtOAc and the organic layer was dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography (n-hexane:EtOAc=80:20 to 60:40)to give 1,3-benzothiazol-6-carbonitrile in the form of a light yellow solid.

The following Pr 28-1 received the same manner as in the Example of Obtaining 28

Table 33
PrStructureMSPrStructureMS
2818328-1143

An example of Obtaining 29

To a solution of 6-bromo[1,2,4]triazolo[1,5-a]pyridine (400 mg) in DMF was added Tris(dibenzylideneacetone)dipalladium (0), 1'-bis(diphenylphosphino)ferrocene and Zn(CN)2in nitrogen atmosphere, then stirred at 110°C for 23 hours. The mixture was cooled to room temperature the market and was added saturated NH 4Cl (2 ml), a saturated solution of NH3(6 ml) and N2O (12 ml). The reaction mixture was three times extracted with EtOAc. The organic layer was washed with saturated salt solution and dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using chromatography on silica gel (0-5% CH3HE/chloroform)to give [1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile in the form of a dark red solid.

Example 30

In a reaction vessel of 100 ml to a solution of 6-bromo-7-methyl-1H-benzimidazole (500 mg) in DMF was added Zn(CN)2(834 mg) and Pd(PPh)4(547 mg) at room temperature, then was stirred at 150°C for 5 hours. The reaction solution was poured into a mixture of 1:1 saturated solution of NaHCO3and EtOAc and stirred for 1 hour. The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography (automatic cleaner, chloroform:CH3HE=98:2 to 90:10)to give 7-methyl-1H-benzimidazole-6-carbonitrile (161,8 mg) as a brown solid.

The following Pr 30-1 to Pr 30-7 received the same manner as in Example 30. They also were obtained using the method of Example Obtaining 29.

Table 34
PrStructureDataPrStructureData
29NMR:7,98
(1H, d), 8,04
(1H, d), a total of 8.74
(1H, s), 9,90-
9,87(1H, m)
30MS:158
30-1NMR:to 7.67
(1H,DD), 8,25
(1H, DDD),
a 8.34(1H, DD), 10,17(1H, s)
30-2MS:158
30-3MS:14430-4MS:176
30-5NMR:10,17
(1H, s), 8.34 per
(1H, DD), 8,25
(1H, DDD),
to 7.67(1H, DD)
30-6 NMR:
of 7.95(1H,
DD), 8,19
(1H, DD),
8,23(1H,DD)
30-7MS:157

An example of retrieving 31

To a mixed solution of 4-hydroxy-3-nitrobenzonitrile (1 g) and NH4Cl (163 mg) in ethanol (20 ml), THF (10 ml) and water (10 ml) was added Celite (5 g) and reduced iron (1.7 g) was further heated at boiling at 70°C for 30 minutes the Reaction solution was cooled to room temperature, diluted with EtOAc (200 ml) and then filtered through celite. The solution was washed with saturated salt solution, the organic layer was dried over anhydrous MgSO4and was filtered and the filtrate was evaporated at reduced pressure, obtaining 3-amino-4-hydroxybenzonitrile (740 mg) as a light brown solid.

The following Pr 31-1 to Pr 31-3 were prepared in the same manner as in Example of Preparation 31.

Table 35
PrStructureMSPrStructureMS
31 13331-1157
31-2225,
227
31-3170

Example of Getting 32

To a solution of 4-amino-3-nitrobenzonitrile (8 g) in a solvent mixture of EtOH/THF (40 ml/40 ml) was added Pd-C (50% by weight) (0.8 g), then stirred in an atmosphere of H2within 12 hours. The reaction solution was filtered through celite and concentrated. The residue was ground into a powder/washed with a mixture of solvents and IPA IPE and was separated by filtration, receiving 3,4-diaminobenzoate (6.3 g) as an orange powder.

Table 36
PrStructureMS
32156

An example of Obtaining 33

To a solution of 2-amino-3-nitrobenzonitrile (2 g) in THF (30 ml) was added 4-retinoicacid (2,90 g) and diisopropylethylamine (4,27 g) was further stirred at 80°C in accordance with is their 12 hours. The reaction solution was poured into water and was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (chloroform:CH3OH)to give N-(4-cyano-2-nitrophenyl)Penta-4-UNAMID (174 mg) in the form of a colored liquid.

The following Pr 33-1 to Pr 33-2 received the same manner as in the Example of Obtaining 33.

Table 37
PrStructureMSPrStructureMS
3324433-1290
33-2264

An example of retrieving 34

To a solution of 3-chloro-4-perbenzoate (300 mg) and 1,1,1-Cryptor-2-propanol in THF (15 ml) was added 60% NaH (92,5 mg) at 5°C, then displacement is ivali at room temperature for 2 hours, was added a saturated solution of NH4Cl for completion of the reaction and was extracted with EtOAc. The obtained organic layer was dried over anhydrous MgSO4and concentrated. The residue was purified using column chromatography on silica gel (n-hexane:EtOAc=97:3 to 85:15, getting 3-chloro-4-(2,2,2-Cryptor-1 methylethoxy)benzonitrile (435 mg) in the form of colored oily substance.

The following Pr 34-1 to Pr 34-6 was obtained in the same manner as in the Example of Obtaining 34.

Table 38
PrStructureDataPrStructureData
34NMR below34-1NMR below
34-2MS:
252
34-3MS:
268
34-4NMR below34-5MS:
316,
318
34-6MS:
242

Table 39
PrNMR
34to 1.48(3H, d), of 5.53(1H, m), EUR 7.57(1H, d), 7,87(1H, DD), of 8.09(1H, d)
34-1of 1.47(3H, d), of 5.50(1H, m), to 7.59(1H, t), 7,74(1H, DM), 7,95(1H, DD)
34-4of 1.47(3H, d), of 5.48(1H,m), 7,46(1H, d), of 7.90(1H, DD), 8,08(1H, d)

Example of Getting 35

In the reaction vessel of 50 ml to a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (100 mg) in DMF (1 ml) was added 60% NaH (10,9 mg) at 0°C. Next, tert-butyl(2-iodoxy)dimethylsilane was added to the mixture at 0°C, then stirred at room temperature for 15 hours. Completion of reaction was confirmed using MAM-MS and then to the reaction solution were added water (30 ml). The mixture was extracted with EtOAC (20 ml). The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaner, (n-hexane:EtOAC=100:0 to 90:10)to give 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-{5-[3-(trifluoromethyl)-4-2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (86,4 mg) as a white solid.

Table 40
PrStructureMS
35622

Example of Getting 36

LiH was suspensively in DMF (5 ml) and to the suspension was added dropwise a suspension of methyl-2-oxo-1,2-dihydropyridines-4-carboxylate (500 mg) in DMF (5 ml) at room temperature. The suspension was mixed, and the solution was added 1-iodine-2-methylpropane (506 μl) in DMF (5 ml) dropwise over 10 min, then stirred at 50°C for 15 hours. To the reaction solution was added 1M HCl at 0°C and then was extracted with EtOAc and the organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and filtered and the solvent was evaporated p. and reduced pressure. The residue was purified using column chromatography on silica gel (n-hexane:EtOAc=90:10 to 50:50)to give methyl-1-isobutyl-2-oxo-1,2-dihydropyridines-4-carboxylate (440 mg) as a white powder.

Table 41
PrStructureMS
36210

An example of retrieving 37

To a solution of 4-fluoro-3-nitrobenzonitrile (300 mg) and diethylmalonate (286 mg) in DMF was added 60% NaH at 0°C., then the mixture was reacted at room temperature, forming dimethyl(4-cyano-2-nitrophenyl)malonate (198 mg).

Table 42
PrStructureMS
37301

An example of retrieving 38

To a solution of dimethyl(4-cyano-2-nitrophenyl)malonate (198 mg) in DMSO (5 ml) was added LiCl (60,3 mg) and N2O (12 ml), then stirred at 100°C for 3 hours. The reaction solution was cooled what about room temperature and was poured into EtOAc and a saturated solution of salt portions. The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (n-hexane:EtOAc=90:10 to 75:25)to give methyl(4-cyano-2-nitrophenyl)acetate (128 mg) as a yellow solid.

Table 43
PrStructureMS
38219

An example of retrieving 39

To a solution of 4-chloro-3-(trifluoromethyl)benzonitrile (1 g) and iron(3+)Tris[(2Z)-4-oxopent-2-ene-2-oleate] (86 mg) and 1-methylpyrrolidine-2-she (2.8 ml) in THF (30 ml) was added a 3M solution of bromine(isobutyl)of magnesium in diethyl ether (2,9 ml) under cooling with ice. The solution was stirred at room temperature for 30 minutes and diluted with diethyl ether (30 ml) and then carefully added 1M HCl to complete the reaction. The reaction solution was extracted with EtOAc (100 ml) and the organic layer was dried over anhydrous MgSO4and then was filtered and the filtrate was evaporated under reduced pressure. The residue was purified using column chromatography on silica gel (n-Gex is n:EtOAc=100:5 to 95:5), getting 4-isobutyl-3-(trifluoromethyl)benzonitrile (320 mg) as a pale yellow liquid.

The following Pr 39-1 was obtained in the same manner as in the Example of Obtaining 39.

Table 44
PrStructureData
39NMR:0,89(6H, d), 1,91-2,03(1H, m), 2,70(2H, DM), of 7.70(1H, d), of 8.09(1H, DD), 8,21(1H, d)
39-1MS:262

Example of Getting 40

To a solution of 4-fluoro-3-formylbenzoate (300 mg) in dichloromethane (7 ml) was added 2-metkei-N-(2-methoxyethyl)-N-(trifter-λ4-sulfanyl)ethanamine (757 mg) at room temperature, then was stirred for 6 hours and was added saturated aqueous solution of NaHCO3(15 ml). After extraction with chloroform (30 ml) the organic layer was dried over anhydrous MgSO4, filtered and concentrated. The residue was purified using column chromatography on silica gel (n-hexane:EtOAc=95:5 to 80:20)to give 3-(deformity)-4-perbenzoate (174 mg) in the form of a colored liquid.

The following Pr 40-1 received in the same way, the AK and the Example of a 40.

Table 45
PrStructureDataPrStructureData
40NMR:7,25(1H,
t), 7,66(1H, DD), 8,14-to 8.20(1H,m), by 8.22(1H, DM)
40-1MS:
321

An example of retrieving 41

The following Pr 41-1 to Pr 41-10 received the same manner as in Example 2.

Table 46
PrStructureMSPrStructureMS
41-142741-2393
4-3 37341-4585
41-534941-6437
41-736241-8551
41-940541-10410

An example of retrieving 42

The following Pr 42-1 to Pr 42-3 received the same manner as in Example 5.

Table 47
PrStructureData
42-1 NMR:1,67(6H, s), 7,71(1H, d), to 8.12(1H, DD), compared to 8.26(1H, d)

42-2MS:282
42-3NMR:1,67(6H, s), 7,71(1H, d), to 8.12(1H, DD), compared to 8.26(1H, d)
MS:288

An example of retrieving 43

The following Pr 43 was obtained in the same manner as in Example 6.

Table 48
PrStructureMS
43627

An example of retrieving 44

The following Pr 44-1 to Pr 44-3 was obtained in the same manner as in Example 12.

td align="center">
Table 49
PrStructureMS
44-1536
44-2222

An example of retrieving 45

The following Pr 45 was obtained in the same manner as in the Example of Obtaining 47.

Table 50
PrStructureNMR
45of 1.47(3H, d), 5,49-the ceiling of 5.60(1H, m), to 7.09(1H, t), to 7.50(1H, d),
8,07-8,13(2H, m)

An example of retrieving 46

The following Pr 46-1 to Pr 46-5 was obtained in the same manner as in Example 19.

Table 51
Etc.StructureMS
46-1625
46-2661
46-3657
46-4 751
46-5380

An example of retrieving 47

To a solution of ethyl(7-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxazol-3-yl}imidazo[1,2-a]pyridine-2-yl)acetate (230 mg) in THF (2.0 ml) was added aqueous NaOH solution (1 ml), then stirred at 80°C for 2 hours. After cooling to room temperature was added 1M HCl, then was extracted with chloroform. The organic layer was dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (chloroform:CH3HE=10:1 to 5:1), obtaining the colored powder. To a solution of this colored powder in EtOAc solution was added 4M HCl/EtOAc, then concentrated. The resulting coated powder was ground into powder/washed IPE, receiving (7-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxazol-3-yl}imidazo[1,2-a]pyridine-2-yl)acetic acid hydrochloride (180,4 mg) in the form of colored powder.

The following Pr 47-1 to Pr 46-13 was obtained in the same manner as in the Example of Obtaining 47.

Table 52
PrArt is ucture PrStructure
4747-1

47-247-3
47-447-5
47-647-7
47-847-9
47-1047-11
47-1247-13

Table 53
PrMSPrMSPrMSPrMS
4750147-151547-250147-3499
47-452247-551447-649947-7530
47-850047-946847-1050447-11555
47-1249847-13585

p> Example 1

A solution of 3-(trifluoromethyl)-4-(2,2,2-Cryptor-1-metasomatic)benzoic acid (810 mg), EDCI/HCl (616 mg) and N'-hydroxy-7-methylimidazo[1,2-a]pyridine-6-carboxamide (510 mg) in dioxane was stirred at 115°C for 60 hours. The reaction solution was concentrated and the residue was distributed between water and chloroform. The organic layer was dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified column chromatography on silica gel (CH3HE/chloroform=0%to 5%) and recrystallized from EtOH, receiving 7-methyl-6-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (60 mg) as a white solid.

Example 2

To a solution of 3-(trifluoromethyl)-4-(2,2,2-Cryptor-1-metasomatic)benzoic acid (349 mg) in dichloromethane (6 ml) was added oxalyl chloride (333 mg) and catalytic amount of DMF under ice cooling, then stirred at room temperature for 1 hour. The reaction solution was concentrated and dried by azeotropic distillation with toluene. To a solution of the residue in THF was added N'-hydroxy-2-methyl-1H-benzimidazole-6-carboxamide (200 mg), N-ethyl-N-isopropyl-2-propanamine (543 mg). The reaction mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, then was extracted with EtOAc three times. Organic with the AOI were United, was dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was dissolved in dioxane and then stirred at 100°C for 3 hours. After cooling to room temperature the solution was concentrated under reduced pressure to remove solvent and purified using column chromatography on silica gel, getting colored oily substance. To a solution of this oily substance in EtOAc solution was added 4M HCl/EtOAc, then was stirred for several minutes and concentrated, obtaining 2-methyl-5-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole hydrochloride (239 mg) as colored crystals.

Example 3

To a solution of 4-(2,2,2-Cryptor-1,1-dimethylmethoxy)-3-(trifluoromethyl)benzoic acid (118 mg) and 2-{4-[amino(hydroxyimino)methyl]-1H-indol-1-yl}ndimethylacetamide (104 mg) in dioxane (5 ml) was added DIC (69 μl) was further stirred at room temperature for 3 hours and then was heated at boiling for 20 hours. The reaction solution was concentrated and then the residue was added water (15 ml), then was extracted with chloroform (15 ml). The organic layer was washed saturated aqueous NaHCO3and saturated salt solution, dried over anhydrous MgSO4was filtered and the filtrate was concentrated under reduced pressure. The residue was purified is ri using preparative VIH (column: CAPCEL PAK, C18, MG, S-5, 30×50 mm; solvent: 50 to 90% acetonitrile/10 mmol ammonium carbonate-ammonia (pH 9,2); 40 ml/min) and recrystallized from diisopropyl ether, obtaining 2-(4{5-[4-(2,2,2-Cryptor-1,1-Dimethicone)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)ndimethylacetamide (40 mg) as a white solid.

Example 4

To a suspension of 60% NaH (68,0 mg) in DMF was added cyclopropylmethanol (99 mg) at 0°C, then stirred at the same temperature and then was added 5-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (120 mg). The reaction mixture was stirred at room temperature for 2 hours and then added water. The mixture was extracted with EtOAc and the organic layer was concentrated. The residue was purified using column chromatography on silica gel (CH3HE/chloroform=0%to 5%) to give oily substance. In the solution of the oily substance in chloroform-CH3HE added a solution of 4M HCl/dioxane (0.5 ml) and concentrated receiving 5-{5-[4-(cyclopropylmethoxy)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole hydrochloride (20 mg) as a white substance.

HPLC analysis Conditions (TSK-GEL (TOSOH) ODS-80TM of 4.6×150 mm, MeCN: 0,01M KH2PO4(7:3), 1.0 ml/min, 254 nm)[RT: of 7.90 min]

Example 5

To a solution of 2-(4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)ndimethylacetamide (100 mg) and 2-propanol (35 ml) in DMF (3 ml) was added 60% NaH (12 mg) PR is 0°C. then stirred at room temperature for 9 hours. To the reaction solution was added water (5 ml) to complete the reaction and extracted with a mixture of solvents chloroform:CH3HE (8:2). The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (chloroform:CH3HE=98:2 to 93:7) and was led from diethyl ether, obtaining 2-(4-{5-[4-isopropoxy-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)ndimethylacetamide (25 mg) as a pale yellow solid.

Example 6

To a solution of 1,3-deferrable (62 mg) in DMF (2.4 ml) was added 60% NaH (19 mg) at -10°C, then stirred at -10°C. for 0.5 hours. To this reaction mixture was added 2-{4-[5-(3-chloro-4-forfinal)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}ndimethylacetamide (120 mg) at -10°C and further stirred at -10°C for 3 hours. After adding water to the reaction solution, the reaction mixture was extracted with EtOAc, the organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (chloroform:CH3IT=100:0 to 95:5)to give 2-[4-(5-{3-chloro-4-[2-fluoro-1-(permitil)ethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]ACET the MFA (76,9 mg) as a white substance.

Example 7

To a solution of 2-{4-[5-(4-fluoro-3-were)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}ndimethylacetamide (100 mg) and (2R)-1,1,1-tryptophan-2-ol (109 mg) in DMF (3 ml) was added 60% NaH (17 mg) at 0°C. then stirred at 80°C for 4 hours. In the reaction solution were added water (15 ml) for completion of the reaction, was filtered and then dried. The resulting powder was purified using column chromatography (chloroform:CH3IT=100:0 to 95:5) and was led from diisopropyl ether, obtaining 2-[4-(5-{3-methyl-4-[(1R)-2,2,2-Cryptor-1 methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]ndimethylacetamide (70 mg) as a pale yellow solid.

Example 8

To a suspension of 60% NaH (43 mg) in DMF (4 ml) was added 2-propanol (65 mg) at 0°C, then stirred at room temperature for 20 min. After cooling to 0°C was added 2-{4-[5-(3-chloro-4-forfinal)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl-ndimethylacetamide (200 mg). The reaction mixture was irradiated with microwave radiation at 60°C for 50 minutes, the Reaction mixture was added to aqueous solution of NH4Cl, then mixed, and then the solvent was evaporated. After addition of the solvent mixture (4:1) chloroform-CH3HE and suspension of solid particles were separated, was added silica gel and the solvent was evaporated. The residue was purified using column chromatography (chloroform:CH3IT=100:0 to 98:2; n-hexane:EtOAc=0:100)to give 2-{4-[5-(-chloro-4-isopropylphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}ndimethylacetamide (17.5 mg) as a white solid.

Example 9

To a solution of 4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (300 mg) in THF (1.5 ml) was added propan-2-amine (0.75 ml) and after plugging in the receiver solution was stirred at 50°-55°C for 40 hours. The solution was concentrated under reduced pressure and then purified using column chromatography (n-hexane:EtOAc). The obtained solid substance was dissolved in acetone under heating was added n-hexane and the precipitate was filtered, obtaining 4-[3-(1H-indol-4-yl)-1,2,4-oxadiazol-5-yl]-N-isopropyl-2-(trifluoromethyl)aniline (295 mg).

Example 10

To a mixed solution of 2-{4-[5-(5,6-dichloropyridine-3-yl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}ndimethylacetamide (100 mg) in dioxane (2 ml) and NMP (2 ml) was added Isopropylamine (220 ml), then stirred at 150°C for 1 hour in a microwave reaction vessel. The reaction mixture was concentrated under reduced pressure and then the residue was purified using column chromatography on silica gel (n-gascan:EtOAc=40:60 to 0:100), and the resulting residue is suspended in diisopropyl ether by heating and was separated by filtration, obtaining 2-(4-{5-[5-chloro-6-(isopropylamino)pyridine-3-yl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)ndimethylacetamide (62 mg) as a white powder.

Example 11 (11-1 and 11-2)

To a solution of 5-{5-[3-(trifloromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (105 mg) in DMF (3.15 ml) d is balali 60% NaH (31 mg) under ice cooling, next was stirred at the same temperature for 15 min and added methyliodide (0,22 ml), then stirred at room temperature for 5 hours. To the reaction mixture was added water, then was extracted with EtOAc, the organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography (automatic processor, chloroform:CH3HE=10:1). The target compound was dissolved in EtOAc (5 ml), was added a solution of 4M HCl/EtOAc (5 ml) and concentrated, gaining approximately 1:1 two regioisomer. The mixture was led from acetonitrile, getting 1-methyl-5-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole hydrochloride (12.1 mg). The mother liquid was concentrated, obtaining 1-methyl-5-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole hydrochloride and 1-methyl-6-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole hydrochloride (70,2 mg) in the form of colored powder.

Example 12

To a solution of 4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]phenyl}-1,2,4-oxazol-3-yl)-1H-indole (150 mg) in DMF (1.5 ml) was added 60% NaH (16 mg) at 0°C and further stirred at room temperature for 0.5 hours. Then to the reaction mixture to relax the 2-bromoacetamide (70 mg) also at 0°C, next was stirred at room temperature for 3 hours. To the reaction mixture was added water, then was extracted with EtOAc, the organic layer was separated, washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography (chloroform:CH3IT=100:0 to 90:10)to give 2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1 methylphenoxy]phenyl}-oxadiazol-3-yl)-1H-indol-1-yl]ndimethylacetamide (145 mg) as a white solid.

Example 13

To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy]phenyl]-1,2,4-oxadiazol-3-yl)indoline (100 mg) in acetonitrile (2.5 ml) was added To a2CO3(46 mg) and 3-jetpropelled (124 mg) at room temperature, then was stirred at 80°C for 15 hours. To the reaction solution was added saturated aqueous solution of NaHCO3, then was extracted with EtOAc. The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography (chloroform:CH3IT=100:0 to 90:10)to give 3-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-indol-1-yl)propanamide (23,6 mg) as a white solid.

When is EP 14

To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole-3-carbaldehyde (150,0 mg) in CH3HE (1.5 ml) was added a 40% solution of CH3HE in CH3NH2(74,5 mg) at 0°C. After warming to room temperature, the solution was stirred at room temperature for 4 hours. After confirming the formation of iminium salts in organic solvent was evaporated under reduced pressure. The residue was dissolved in EtOH (1.5 ml). To this solution was added NaBH4(12,09 mg). After heating to room temperature, the solution was stirred at room temperature for 15 hours. To the reaction solution were added water (30 ml), then was extracted with EtOAc three times (20 ml). The organic layer was combined, washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (automatic cleaner, chloroform:CH3IT=100:0 to 90:10)to give N-methyl-1-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)methanamine (87,4 mg) as a white substance.

Example 15

To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}endline (100 mg) in DMF (1.0 ml) was added 69% NaH (10,9 mg) at 0°C, then stirred at room themes is the temperature value for 0.5 hours. Alkylchloride (24,1 μl) was added at 0°C, then stirred at room temperature for 3 hours. To the reaction solution were added water (30 ml), then was extracted with EtOAc three times (20 ml). The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (automatic cleaner, n-Hasan: EtOAc=90:10 to 60:40)to give 1-acetyl-4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}indoline (56,8 mg) as white crystals.

Example 16

To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (80 mg) in DMF (0,80 ml) was added 60% NaH (8,7 mg) at 0°C, then stirred at room temperature for 0.5 hours. Added methanesulfonamide (21,1 μl) at 0°C, then stirred at room temperature for 3 hours. To the reaction solution were added water (30 ml), then was extracted with EtOAc three times (20 ml). The organic layer was combined, washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The filtrate was purified using column chromatography on silica gel (automatic cleaner, chloroform:CH3IT=100:0 to 98:2)to give 1-(methylsulphonyl)-4-{5-[3-(trifluoromethyl)-4(2,2,2-Cryptor-1 metatarsi)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (15.6 mg) as a white solid.

Example 17

4-{5-[3-(Trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (100 mg) was dissolved in DMF (1.0 ml), then was added 60% NaH (10,9 mg) at 0°C and stirred at room temperature for 0.5 hours. Methyl chloride carbonate (26,3 μl) was added at 0°C, then stirred at room temperature for 3 hours. To the reaction solution were added water (30 ml), then was extracted with EtOAc three times (20 ml), the organic layer was combined, washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (automatic cleaner, chloroform:CH3IT=100:0 to 98:2)to give methyl 4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole-1-carboxylate (98,6 mg) as a white solid.

Example 18

To a solution of 3-(5-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole-2-yl)propanoic acid (23,5 mg) in dichloromethane was added oxalyl chloride (0.01 ml) and few drops of DMF, then stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove solvent and reagent. To a solution of the residue in THF was added NH4HE was further stirred for 1 hour. To the reaction solution after the Lyali saturated aqueous solution of NH 4Cl, then was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (chloroform:CH3HE=10:1), obtaining the colored powder. To a solution of colored powder in EtOAc solution was added 4N-HCl in EtOAc. The reaction mixture was concentrated and the residue was ground into a powder and washed with IPE, getting 3-(5-{5-[3-(tryptomer)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole-2-yl)propanamide hydrochloride as a pale yellow powder.

Example 19

To a solution of (4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetic acid (150 mg) and HOBt (65 mg) in DMF (1.5 ml) was added EDCI/HCl(69 mg) at 0°C, then stirred at room temperature for 1 hour. After cooling to 0°C was added 1-pyridine-2-ylmethanone (39 mg) and then stirred at room temperature for 15 hours. To the reaction solution was added saturated aqueous solution of NaHCO3to complete the reaction. The reaction solution was extracted with EtOAc, the organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (chloroform:CH3IT=100:0 to 95:5), olucha N-(pyridine-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)ndimethylacetamide (157,8 mg) as a white solid. To a solution of N-(pyridine-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)ndimethylacetamide (120 mg) in methylene chloride (2.2 ml) was added dropwise to 10 equivalents 4M NS/dioxane, further stirring for 1 hour. The reaction mixture was concentrated under reduced pressure and triturated to powder/washed in IPE. The obtained solid substance was separated by filtration and dried, obtaining N-(pyridine-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)ndimethylacetamide hydrochloride (126 mg) as a white solid.

Example 20

To a solution of [4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1 metatarsi]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetic acid (100 mg) in DMF (1 ml) was added CDI (39 mg) and after 30 minutes was added methanesulfonamide (23 mg) and 2,3,4,6,7,8,9,10-octadecenamide[1,2-a]azepin (37 mg), then stirred at room temperature for 15 hours. To the reaction mixture were added water to complete the reaction. The reaction solution was extracted with EtOAc, the resulting organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (chloroform:CH3IT=100:0 to 90:10)to give N-(methylsulphonyl)-2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1-mutilator and]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]ndimethylacetamide (of 56.4 mg) as a white solid.

Example 21

Cl3(of 158.4 ml) was added dropwise to a solution of DMF (4 ml) at 0°C. After warming to room temperature, the solution was stirred for 0.5 hours. Then a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (500.0 mg) in DMF (1 ml) was added at 0°C, then stirred at room temperature for 15 hours. After cooling to 0°C. to the reaction solution was added 1M aqueous solution of NaOH to bring the pH to 9-10. This solution was stirred at 100°C for 1 hour. Then left for cooling, to the reaction solution were added water (30 ml), then was extracted with EtOAc three times (20 ml). The organic layer was combined, washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (automatic cleaner, n-hexane: EtOAc =90:10 to 70:30)to give 4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole-3-carbaldehyde (456,7 mg) as a white solid.

Example 22

To a mixture solution of 5-[3-(1H-benzimidazole-6-yl)-1,2,4-oxadiazol-5-yl]-2-(2,2,2-Cryptor-1 methylethoxy)benzaldehyde (83 mg), potassium dihydrophosphate (421 mg) and 2-methyl-2-butene (0.5 ml) in tBuOH (2 ml) and water (0.5 ml) was added sodium chloride (187 mg) at room temperature. Mixed the reaction solution was stirred at room temperature for 3 hours, then was diluted with water (10 ml) and was extracted with EtOAc (20 ml). The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. To a solution of the residue in dioxane was added 4 N. HCl-dioxane solution, then concentrated. The resulting residue was recrystallized from IPA (10 ml)to give 5-[3-(1H-benzimidazole-5-yl)-1,2,4-oxadiazol-5-yl]-2-(2,2,2-Cryptor-1 methylethoxy)benzoic acid hydrochloride (80 mg) as a white powder.

Example 23

To a solution of 2-[2-(methylthio)ethyl]-5-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (400 mg) in dichloromethane (8.0 ml) was added (CBA) (534 mg), then stirred at room temperature for 3 hours. To the reaction mixture were added an aqueous solution of Na2S2O4, then was stirred for 1 hour. The reaction solution was extracted with EtOAc three times and the organic layer was combined, dried over anhydrous MgSO4was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (chloroform:CH3HE=10:1)to give yellow oily substance. This substance was dissolved in EtOAc was added 4M-HCl/EtOAc and then concentrated. The residue was washed IPE, receiving 2-[2-(methylsulfanyl)ethyl]-5-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-yl}-1H-benzimidazole hydrochloride (146 mg) as a pale yellow powder.

Example 24

To the reaction mixture 2-but-3-EN-1-yl-5-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (200 mg) in acetone and water (1 ml) was added tetraoxane (51 mg) and 4-methylmorpholine-4-oxide (94 mg), then stirred overnight. The reaction mixture was filtered and to the filtrate was added an aqueous sodium thiosulfate solution, and then was stirred for 1 hour. The solution was extracted with chloroform and the organic layers were concentrated. The residue was purified using column chromatography on silica gel (chloroform-CH3HE and concentrated and the resulting coated powder was added to a solution of HCl in ethanol and was dissolved therein, and then concentrated. The residue was ground into a powder/washed with diisopropyl ether, receiving 4-(5-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole-2-yl)butane-1,2-diol hydrochloride (to 102.3 mg).

Example 25

To a solution of 3-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-indol-1-yl)propanamide (100 mg) in chloroform (1 ml) was added manganese dioxide (67,7 mg) and then boiled for 15 hours. The reaction solution was left to cool to room temperature and filtered through Celite to remove manganese dioxide. The filtrate was concentrated under reduced pressure. OST the current was purified using column chromatography on silica gel (chloroform:CH 3IT=100:0 to 90:10)to give 3-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)propanamide (46,3 mg).

Example 26

To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (100 mg) in Asón (3 ml) was added in portions cyanobac sodium (29 mg). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, podslushivaet 1M aqueous solution Paon and was extracted with EtOAc.

The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated and the residue was purified using column chromatography on silica gel (n-Hasan: EtOAc =90:10 to 75:25) and washed with n-hexane, obtaining 4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}indoline (90 mg) as a pale yellow solid.

Example 27

To a solution of 5-[3-(1H-benzimidazole-6-yl)-1,2,4-oxadiazol-5-yl]-2-(2,2,2-Cryptor-1 methylethoxy)benzaldehyde (80 mg) in ethanol (3 ml) was added NaBH4(9 mg) at 0°C. After stirring at room temperature for 0.5 hours was added a saturated solution of NH4Cl (10 ml), then was extracted with EtOAc (20 ml). The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate concentrate which has demonstrated. To a solution of the residue in dioxane was added 4M HCl/dioxane and then concentrated. The resulting powder was recrystallized from IPA (10 ml)to give [5-[3-(1H-benzimidazole-5-yl)-1,2,4-oxadiazol-5-yl]-2-(2,2,2-Cryptor-1 methylethoxy)phenyl]methanol hydrochloride (70 mg) as a white powder.

Example 28

A solution of 5-methyl-6-{5-[3-Cryptor)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (120 mg) and NCS in THF/EtOH (1/1) was stirred at 80°C during the night. The solution was concentrated and the resulting residue was purified using column chromatography on silica gel (CH3HE/chloroform 0-5%)to give 3-chloro-5-methyl-6-{5-[3-(Cryptor)-4-(2,2,2-Cryptor-1-methoxyethyl)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (45 mg) as a pale yellow solid.

Example 29

To a solution of 5-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (150 mg) in ethanol was added NCS (67 mg) at room temperature, and then stirred at 80°C for 15 hours. To the reaction solution was added water, then was extracted with EtOAc. The organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (n-Hasan: EtOAc=90:10 to 75:25)to give 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-t is iftar-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (110,4 mg) as a white solid. To a solution of 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (100 mg) in methylene chloride (2 ml) was added dropwise to 10 equivalents of 4M HCl/dioxane at room temperature. After stirring at room temperature in the form in which it exists, within 1 hour the mixture was concentrated under reduced pressure. The residue was ground into a powder/washed with diisopropyl ether and then separated by filtration, getting 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine hydrochloride (102,6 mg) as a white solid.

Example 30

1-(2-{[Tert-butyldimethylsilyl]oxy}ethyl)-4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (60 mg) was dissolved in THF (1.2 ml), and TBAF (150 μl) were added at 0°C, then stirred at room temperature for a period of 3.0 hours. To the reaction mixture were added water (30 ml), then three times was extracted with EtOAc (20 ml). The organic layer was combined, washed with saturated salt solution, dried over anhydrous MgSO4and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (chloroform:CH3IT=100:0 to 90:10)to give 2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl-1H-indol-1-yl)et is Nol (to 36.5 mg) as a white solid.

Example 31

To a solution of tert-butyl 4-{[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetyl}piperazine-1-carboxylate (70,7 mg) in methylene chloride (1 ml) was added dropwise to 10 equivalents of 4M HCl/dioxane and then stirred at room temperature for 3 hours. After 5 hours the reaction solution was concentrated. Adding diisopropyl ether precipitated white solid. White solid washed with IPE, getting 1-(2-oxo-2-piperazine-1-retil)-4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole hydrochloride (of 58.9 mg) as a pale red solid.

The following tables shows the structural formulas of the compounds of Examples. Ex: Example No.

Table 54
Etc.
No.
StructureEtc.
No.
Structure
12
34

56
78
910
11/111/2
1213
1415

Table 55
Etc.
No.
The structure is and Ave., No.Structure
1617

tr>
1819
2021
2223
2425
2627
Table 56
Etc.
No.
StructureEtc.
No.
Structure
2829
3031

td align="center" namest="c3" nameend="c4"> 39
3233
3435
3637
38
4041
Table 57
Etc.
No.
StructureEtc.
No.
Structure
4243
4445
4647

484
5051
5253
5455
Table 58
Etc.
No.
StructureEtc.
No.
Structure
5657
5859
6061
6263

6465
6667
6869
7071
Table 59
Etc.
No.
StructureEtc.
No.
Structure
7273
7475
7677
7879

8081
82img src="https://img.russianpatents.com/1085/10858515-s.jpg" height="20" width="52" /> 83
8485
8687
Table 60
Etc.
No.
StructureEtc.
No.
Structure
8889
9091
92
9495

9697
9899
100101
102103
Table 61
Etc.
No.
StructureEtc.
No.
Structure
104 105
106107
108109
110111

112113
114115
116117
Table 62
Etc.
No.
Etc.
No.
Structure
118119
120121
122123
124125

126127
128129
130131
132133
Table 63
Etc.
No.
StructureEtc.
No.
Structure
134135
136137
138139
140141

142
144145
146147
Table 64
Etc.
No.
StructureEtc.
No.
Structure
148149
150151
152153
154155

156157
158159
160161
Table 65
Etc.
No.
StructureEtc.
No.
Structure
162163
164165
166167
168169

170171
172173
174175
Table 66
Etc.
No.
StructureAve., No.Structure
176177
178179
180181
182183

184185
186187
188189
Table 67
Etc.
No.
StructureEtc.
No.
Structure
190191
192193
194195

196197
198

The following tables shows the NMR data of the compounds of Examples. As an internal standard tetramethylsilane was used and, unless stated otherwise, δ (ppm) signal1H-NMR is shown as measured in DMSO-d6used as a solvent. Ref-Ex represents Example number, which should be attributed to the receipt.

Application in industrial environments

The connection according to the present invention is applicable as a medicinal product and, in particular, for the prevention and/or treatment of rejection following organ transplantation, bone marrow, or tissues, autoimmune diseases, etc. as it has S1P1agonistic activity.

1. The compound of formula (I)
[Chem. 16]

or its pharmaceutically acceptable salt,
where the symbols have the following meanings:
the ring And is a
[Chem. 17]
or
X is a simple with the IDE, -CH2-, -NR3-, -O-, -S-,
R1represents halogen, phenyl, pyridyl, (C3-C8) cycloalkyl, or (C1-C6) alkyl, or (C2-C6) alkenyl, each of which may contain halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as Deputy,
R2represents-CN, -O-(C1-C6)alkyl, -C(=O)H, halogen, or (C1-C6)alkyl which may be substituted with halogen or-HE,
R3can form morpholino or 1-pyrrolidinyl with R1and nitrogen, and, when X represents a simple bond, R1and R2may in combination form a 5-membered ring and optionally contain (C1-C6)alkyl as a substituent,
R4represents the following ring:
[Chem. 18]
,,,
,,,,
,,or
where any one of the links from the ring associated with oxazoline ring
R5represents-H, (C1-C6)alkyl which may be substituted by at least one group selected from the row containing the his-C(=O)NR XRY-The otherXand-ORX- (C2-C6)alkenyl-, -C(=O)H, -C(=O)NRXRY,
RXand RYcan be the same or different from each other and represent H or (C1-C6) alkyl.

2. The compound according to claim 1, which is represented by the formula (II):
[Chem. 19]

or its pharmaceutically acceptable salt.

3. The compound according to claim 2 or its pharmaceutically acceptable salt, in which R1is a (C1-C6) alkyl, which may contain halogen as a substituent.

4. The compound according to claim 2 or its pharmaceutically acceptable salt, in which R2represents-CN, halogen or (C1-C6)alkyl which may be substituted with halogen or-HE.

5. The compound according to claim 2 or its pharmaceutically acceptable salt, in which R5represents H; or (C1-C6)alkyl which may be substituted by at least one-C(=O)NRXRY.

6. The compound according to claim 2 or its pharmaceutically acceptable salt, in which X represents a simple bond, -CH2- or-O-.

7. The compound according to claim 2 or its pharmaceutically acceptable salt, in which R4represents the following ring:
[Him]
or
where any one of the links from the number of the CA R 4associated with oxadiazoline ring.

8. The compound of formula (I)
[Chem. 16]

or its pharmaceutically acceptable salt, where the symbols have the following meanings:
the ring And is a

X represents-O-,
R1is a (C1-C4) alkyl, optionally substituted by F,
R2represents a halogen, -CN, or (C1-C6)alkyl, optionally substituted with halogen,
R4represents the following ring:
[Chem. 18]

where any one of the links from the ring associated with oxazoline ring,
R5represents-N; (C1-C6) alkyl, optionally substituted-C(=O)NRXRY,
RXrepresents-H; and (C1-C6)alkyl,
RYrepresents-N.

9. A compound selected from the following:
5-(5-[3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-benzimidazole hydrochloride;
5-(5-[3-(trifluoromethyl)-4-[(1R)-2,2,2-Cryptor-1 methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-benzimidazole hydrochloride;
6-{5-[3-bromo-4-(2,2,2-Cryptor-1 methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl}-1H-benzimidazole hydrochloride;
5-(5-[4-phenoxy-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-benzimidazole hydrochloride;
2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1-mutilator and)phenyl)-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)ndimethylacetamide;
4-{5-[3-(trifluoromethyl)-4-(2,2,2-Cryptor-1 methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride;
6-{5-[3-(deformity)-4-(2,2,2-Cryptor-1 methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-benzimidazole hydrochloride;
2-(4-{5-[3-chloro-4-(2,2,2-Cryptor-1 methylethoxy)phenyl)-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)ndimethylacetamide;
2-(4-{5-[4-cyclopentyl-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)ndimethylacetamide;
2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)ndimethylacetamide;
2-[4-(5-{4-[2-fluoro-1-(permitil)ethoxy]-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)ndimethylacetamide;
2-(4-{5-[3-cyano-4-(2,2,2-Cryptor-1 methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)ndimethylacetamide;
N-(2-hydroxyethyl)-2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)ndimethylacetamide;
2-[4-(5-{5-chloro-6-[(1S)-2,2,2-Cryptor-1 methylethoxy]pyridine-3-yl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)ndimethylacetamide;
2-[4-(5-{5-chloro-6-[2-fluoro-1-(permitil)ethoxy]pyridine-3-yl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)ndimethylacetamide;
2-[4-(5-{3-chloro-4-[2-fluoro-1-(permitil)ethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)ndimethylacetamide;
2-[4-(5-{3-methyl-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)ndimethylacetamide;
2-(4-{5-[4-isopropyl-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)ndimethylacetamide;
2-{4-[5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl)aceta the ID;
N-(2-hydroxyethyl)-2-[4-(5-{3-methyl-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)ndimethylacetamide;
N-(2-hydroxyethyl)-2-(4-{5-[4-isopropoxy-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)ndimethylacetamide; and
2-[4-(5-{3-chloro-4-[2-fluoro-1-(permitil)ethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]-N-(2-hydroxyethyl)ndimethylacetamide.

10. Pharmaceutical composition having activity of agonist S1P1containing an effective amount of a compound according to any one of claims 1 to 9, or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

11. The compound according to any one of claims 1 to 9, or its pharmaceutically acceptable salt, used for the treatment and/or prevention of rejection in organ transplantation/tissue in the human or animal, autoimmune disease or multiple sclerosis.

12. The agent with the activity of the agonist S1P1containing the compound according to any one of claims 1 to 9, or its pharmaceutically acceptable salt, as an active ingredient and a pharmaceutically acceptable carrier or excipient.

13. The method of treatment and/or prevention of rejection in transplantation of an organ/bone marrow/tissue in the human or animal, graft-versus-host or multiple sclerosis, and this method includes the introduction of the connection, and the and its pharmaceutically acceptable salt according to any one of claims 1 to 9 to a patient, suffering from the above disease.

14. The use of compounds according to any one of claims 1 to 9, or its pharmaceutically acceptable salt to obtain funds for the treatment and/or prevention of rejection in transplantation of an organ/bone marrow/tissue in the human or animal, graft-versus-host or multiple sclerosis.

15. The use of compounds according to any one of claims 1 to 9, or its pharmaceutically acceptable salts for the treatment and/or prevention of rejection in transplantation of an organ/bone marrow/tissue in the human or animal, graft-versus-host or multiple sclerosis.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or its pharmaceutically acceptable salt, for use for the treatment and/or prevention of rejection in transplantation of an organ/bone marrow/tissue in the human or animal, graft-versus-host or multiple sclerosis.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 2,8-dimethyl-5-[2-(6-methyl-pyridyl-3)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole salts of general formula (1) exhibiting antidepressive and antihypoxic activity where n=1, 2 Y = (CH2COOH)2, HOOCCH(OH)CH2COOH, (HOOCCH2)2C(OH)COOH. Besides, the invention concerns a pharmaceutical agent.

EFFECT: ensured production of new biologically active compounds exhibiting antidepressive and antihypoxic activity.

6 cl, 5 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I ; or to its pharmaceutically acceptable salts where n represents 0, 1 or 2; Y1 represents a bond or a group C(O); Y2, represents a bond, the groups C(O) or S(O)2; R1 represents hydrogen, halogen, cyano, C1-2alkyl; R2 represents hydrogen, halogen, cyano, C1-4alkyl, C1-3alkoxy, halogen-substituted-C1-3alkyl, halogen-substituted-C1-3alkoxyl, C6aryl-C0alkyl, tetrazolyl, C3-6cycloalkyl-C0alkyl, C6-7heterocycloalkyl-C0-4alkyl where 1 or 2 carbon atoms in the ring are substituted by the groups selected from -O-, -NH-, -S(O) and -SO2-; and phenoxy groups; where said aryl and heterocycloalkyl groups R2 can be substituted by 1 or 2 radicals independently selected from C1-6alkyl; R3 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group and a group -NR6aR6b where R6a and R6b are independently selected from hydrogen and C1-4alkyl; R4 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group; R5 represents hydrogen or C1-3alkyl group; L represents a bivalent radical selected from ; ; ; ; ; ; ; ; ; ; ; ; and ; where asterisks the junctions of Y2 and R2; where any bivalent radical L can be substituted by 1 or 2 radicals independently selected from halogen, hydroxy, cyano, C1-4alkyl, C1-4alkyl carbonylamino, C1-4alkoxy, C1-4alkoxycarbonyl, halogen-substituted - C1-4alkyl, C1-3alkylsulfonyl, C1-3alkylsulfonyl-amino, cyano-substituted - C1-4alkyl and halogen-substituted -C1-4alkoxy radicals. Also, the invention refers to a method of Hedgehog path inhibition in a cell and to a method of undesired cell proliferation inhibition which involves the interaction of the compound of formula I and the cell.

EFFECT: new substituted imidazole derivatives which can be effective in treatment of some types of cancer are prepared.

13 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a condensed cyclic aromatic compound having the formula [2] given below: , where each R1 R2, R3, R5-R8, R10-R13, R15-R18, R20 denotes a hydrogen atom, R4, R9, R14, R19 denote phenyl, optionally substituted with two substitutes selected from tertbutyl. The invention also relates to use of said compound as an organic light-emitting layer in an organic light-emitting device.

EFFECT: obtaining a substance which can be used to make a light-emitting device which is durable and has high radiation efficiency.

2 cl, 6 ex, 2 tbl, 6 dwg

FIELD: medicine.

SUBSTANCE: invention refers to new amino acid derivatives of formula (I), , in which R-groups have the following value: -R1 is -H;-R2 is -C(O)R15 or -SO2R15; -R3 is -H;-R4 is -H or -(1-4C)alkyl; -R6 is -H; -R7 is -H; -R8 is -H, cyanogroup, halogen, nitrogroup; -(1-6C)alkyl optionally substituted by amino group, hydroxyl or halogen; -heteroaryl representing a 5 or 6-members aromatic ring containing one or more heteroatoms N optionally substituted by -(1-4C) alkyl; -C(R16)NOR16, -C(O)N(R17)2, -C(O)R18 or -C(O)OR19; -R9 is -H; -R10 is -H or -(1-4C)alkyl; -R11 is -H; -R12 is -H; -R13 is -H; -R14 is -H; -R15 is -H; -(1-6C)alkyl, -(2-6C)alkynyl, -O(2-6C)alkyl) all optionally substituted by one or more, halogen, cyanogroup or 5-members heteroaryl where 5-members heteroaryl represents an aromatic ring containing one or more heteroatoms selected from a group including N, O or S; -(hetero)aryl representing 5 or 6-members aromatic ring system containing one or more heteroatoms selected from group including N, O or S, optionally substituted by -(1-4C)alkyl, halogen or NH2; -NH2, -(di)(1-4C)alkylamihogroup, -(1-4C)alkylamihogroup or -NR16OR16; R16 is -H or -(1-4C)alkyl; -R17 is -H or -(1-6C)alkyl optionally substituted by halogen, or 5 or 6-members heteroaryl or aryl optionally substituted by halogen, -(1-4C)alkyl or -(1-4C)alkoxygroup where heteroaryl represents an aromatic ring containing one or more heteroatoms selected from the group including N, O or S; -R18 is -H or -(1-4C)alkyl; -R19 is -H or -(1-6C)alkyl.

EFFECT: compounds of this invention are high-specific to glucocorticoid receptor and can be used for treating inflammatory diseases.

6 cl, 58 ex

FIELD: medicine.

SUBSTANCE: invention refers to aryl-izoxazole-4-yl-imidazo[1,5-a]pyridine derivatives of formula I and to their pharmaceutically acceptable acid addition salts. In formula I , R1 represents hydrogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom, cyano or -(CO)-Ra; Ra represents lower alkoxy or NR'R" where each of R' and R" independently represents hydrogen atom, 6-members heterocycloalkyl with the 1st heteroatom selected from O, or lower alkyl substituted by C3-C7-cycloalkyl. The invention also refers to a drug exhibiting affinity and selectivity to GABA(A) α5-receptor binding sites, containing one or more compounds of formula I and to an application of the compound of the invention in producing the drug exhibiting affinity and selectivity to GABA(A) α5-receptor binding sites.

EFFECT: improved efficacy of the drug.

7 cl, 2 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I): in which the radicals R1, R2, R3 and R4 independently represent hydrogen atom, halogen atom, hydroxy group, amino group, nitro group, an alkyl, alkenyl, cycloalkyl or aralkyl radical. And all these radicals can to be optionally substituted by haloalkyl or hydroxyalkyl, or radicals R2 and R3 in combination can represent a part of an aryl rings; R5 represents hydrogen atom, halogen atom, hydroxy group or thiol group, an alkyl, alkenyl, alkinyl, aryl, cycloalkyl, aralkyl radical or a 5-merous heteroaromatic ring containing 1, 2 heteroatoms selected from nitrogen and oxygen; the radicals R6 and R7 independently represent hydrogen atom, an alkyl or aryl radical; and X represents a group of formula where represents a bond or CH2, V represents O, W represents NH, a Y represents OH, or to its pharmaceutically acceptable salts, and besides to pharmaceutical composition based on said compound showing an inhibitory action on peptide deformylase (PDF).

EFFECT: new compounds which attract a great interest as new antibiotics are produced and described.

11 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of structural formula IIIm: or pharmaceutically acceptable salt thereof, where: R81 is selected from a group comprising hydrogen, halogen, possibly substituted C1-6alkyl, possibly substituted C2-6alkenyl, possibly substituted C2-6alkynyl, possibly substituted cycloalkyl, possibly substituted heterocycloalkyl, possibly substituted aryl, possibly substituted heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR68, -SR68, -NR69R68, -C(O)R68, -C(S)R68, -C(O)OR68, -C(O)NR69R68, -C(S)NR69R68, -S(O)2NR69R68; -NR69C(O)R68, -NR69C(S)R68, -NR69S(O)2R68, -NR69C(O)NH2, -NR69C(O)NR69R68, -NR69C(S)NH2, -NR69C(S)NR69R68, -NR69S(O)2NH2, -NR69S(O)2NR69R68, -S(O)R68 and -S(O)2R68, R83 is selected from a group comprising hydrogen, fluro and chloro; R112 is selected from a group comprising possibly substituted C2-6alkyl, possibly substituted aryl, possibly substituted heteroaryl and -NR79 R80; R68 is selected from a group comprising possibly substituted C1-6alkyl, possibly substituted C2-6alkenyl, but provided that when R68 is possibly substituted C2-6alkenyl, then one of its alkene carbons is not bonded with N, S, O, S(O), S(O)2, C(O) or C(S) from -OR68, -SR68, -NR69R68, -C(O)R68, -C(S)R68, -C(O)OR68, -C(O)NR69R68, -C(S)NR69R68, -S(O)2NR69R68, -NR69C(O)R68, -NR69C(S)R68, -NR69S(O)2R68, -NR69C(O)NH2, -NR69C(O)NR69R68, -NR69C(S)NH2, -NR69C(S)NR69R68, -NR69S(O)2NH2, -NR69S(O)2NR69R68, -S(O)R68 or -S(O)2R68, possibly substituted C2-6alkynyl, but provided that when R68 is possibly substituted C2-6alkynyl, then one of its alkyne carbons is not bonded with N, S, O, S(O), S(O)2, C(O) or C(S) from -OR68, -SR68, -NR69R68, -C(O)R68, -C(S)R68, -C(O)OR68, -C(O)NR69R68, -C(S)NR69R68, -S(O)2NR69R68, -NR69C(O)R68, -NR69C(S)R68, -NR69S(O)2R68, -NR69C(O)NH2, -NR69C(O)NR69R68, -NR69C(S)NH2, -NR69C(S)NR69R68, -NR69S(O)2NH2, -NR69S(O)2NR69R68, -S(O)R68 or -S(O)2R68, possibly substituted cycloalkyl, possibly substituted heterocycloalkyl, possibly substituted aryl and possibly substituted heteroaryl; R69 is selected from a group comprising hydrogen and possibly substituted C1-6alkyl; and R79 and R80 independently denote hydrogen or possibly substituted C1-6alkyl or R79 and R80 together with the nitrogen atom to which they are bonded form a possibly substituted 5-7-member heterocycloalkyl. Described also is a composition and a set for modulating protein kinase based on said compounds and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds which are active towards protein kinase are obtained and described.

71 cl, 59 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic derivatives of general formula (I) where R1 denotes hydrogen, halogen, cyano, lower alkoxy or lower alkyl; R2 denotes aryl or a 5- or 6-member heteroaryl; R3 denotes hydrogen, aryl, a 5- or 6-member heteroaryl, where aryl, cycloalkyl, heterocycloalkyl or 5- or 6-member heteroaryl groups for R2 and R3 may be unsubstituted or substituted with halogen, cyano, lower alkyl, possibly substituted with one or more halogens, lower alkoxy, S(O)2-alkyl, -C(O)R', where R' is a lower alkyl, lower alkoxy; as well as pharmaceutically acceptable salts thereof. The invention also relates to a medicine based on said compounds for treating and preventing diseases mediated by the mGIuR5 receptor and use of compounds of formula (I) in preparing medicines.

EFFECT: novel compounds which are metabotropic glutamate receptor antagonists are obtained and described.

17 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of compounds, characterised by formulae (I) and (IB), or pharmaceutically acceptable salts thereof, isomers or hydrates to prepare a medicinal agent for treating or preventing diseases or conditions mediated by the sigma-receptor, selected from psychosis, neuropathic pain or inflammatory pain and movement disorder, such as dystonia or tardive dyskinesia, motor defects, including allodynia/or hyperalgesia. Radicals and symbols in compounds of formulae (I) and (IB) are described in claims 1 and 2. The invention also relates to novel compounds of formulae (I') and (IB'), in which radicals and symbols are described in claims 4 and 5, having pharmacological activity on the sigma-receptor, methods of producing such compounds, a pharmaceutical composition containing said compounds and use of said compounds in preparing a medicinal agent for treating and/or preventing diseases or conditions whose development involves the sigma-receptor. (I), (IB) (I') and (IB').

EFFECT: high effectiveness of the inhibitors.

22 cl, 1 tbl, 3 dwg, 64 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel AMPA receptor antagonists - 1H-quinazoline-2,4-dione derivatives, selected from the group: N-(6-imidazol-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,4]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrolidin-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-azetidin-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,3]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; (2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)amide ethanesulphonic acid; N-(6-imidazol-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-thiomorpholin-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(6-[1,4]oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide and N-(6-azetidin-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide and physiologically acceptable salts thereof.

EFFECT: compounds can be used in treating such diseases as epilepsy and schizophrenia.

9 cl, 106 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention.

EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths.

20 cl, 5 dwg, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula I and to their pharmaceutically acceptable salts. In formula I p is integer, equal to 0-1; L2 is selected from group including -XOX-, -XSX- and -XSXO-; where X is independently selected from group, including bond and C1-C4alkylene; R13 is selected from group, including halogen, C1-C6alkyl, C1-C6alkoxygroup, -C(O) C1-C6alkyl; R14 is selected from group, including -XOXC(O)OR17 and -C1-C4alkylene-C(O)OR17; where X represents bond or C1-C4alkylene; and R17 is selected from group, including hydrogen and C1-C6alkyl; R15 and R16 are independently selected from group, including -R18 and -YR18; where Y represents C2-C6alkenylene, and R18 is selected from group, including C6-C10aryl, benzo[1,3]dioxolyl, pyridinyl, pyrimidinyl, quinolyl, phenoxatiinyl, benzofuranyl, dibenzofuranyl, benzoxasolyl, 2,3-dihydrobenzofuranyl, 2-oxo-2,3-dihydrobenzooxasolyl, indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl, 2,3-dihydrobenzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, where any C6-C10aryl, pyridinyl, benzoxasolyl, indolyl in R18 is optionally substituted by 1-2 radicals, independently selected from group, including halogen, nitrogroup, cyanogroup, C1-C6alkyl, C1-C6alkoxygroup, C1-C6alkylthiogroup, hydroxy-C1-C6alkyl, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxygroup, piperidinyl, morpholinyl, pyrrolidinyl, phenyl, XS(O)0-2R17, -XNR17R17, -XNR17S(O)2R17, -XNR17C(O)R17, -XC(O)NR17R17, -XC(O)NR17R19, -XC(O)R17, -XC(O)R19 and -XOXR19, where X represents bond; R17 is selected from group, including hydrogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, and R19 is selected from group, including C3-C12cycloalkyl, phenyl, piperidinyl, morpholinyl.

EFFECT: ensuring application of invention compounds for production of medication, modulating activity of activated receptors of peroxisome proliferators δ (ARPPδ), to pharmaceutical composition, possessing properties of ARPPδ activity modulator, including therapeutically efficient quantity of invention compound and to application of pharmaceutical composition for medication manufacturing.

8 cl, 1 tbl, 301 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of cis-2,4,5-triarylimidazoline of general formula I and pharmaceutically acceptable salts thereof, where X1 is selected from a group comprising lower alkoxy; X2 and X3 are independently selected from a group comprising hydrogen, halogen, cyano, lower alkyl, lower alkoxy, piperidinyl, -NX4X5, -SO2NX4X5, -C(O)NX4X5, -C(O)X6, -SOX6, -SO2X6, -NC(O)-lower alkoxy, -C≡C-X7, provided that both X2 and X3 do not denote hydrogen, lower alkyl or lower alkoxy, provided that when X2 or X3 denote hydrogen, the other does not denote lower alkyl, lower alkoxy or halogen, provided that when X2 denotes -HX4X5, X3 does not denote hydrogen, X2 and X3 together can form a ring selected from 5-7-member unsaturated rings which can contain three heteroatoms selected from S, N and O, X4 and X5 are independently selected from a group comprising hydrogen, lower alkyl, lower alkoxy, lower alkyl, substituted by a lower alkoxy, -SO2-lower alkyl, -C(O)piperazinyl-3-one; X6 is selected from a group comprising lower alkyl, morpholine, piperidine, pyrrolidine; X7 is selected from a group comprising hydrogen, lower alkyl, trifluoromethyl; Y1 and Y2 are independently selected from a group comprising halogen; R is selected from a group comprising lower alkoxy, piperidinyl substituted with a five-member heterocyclic ring which contains one nitrogen heteroatom, piperidinyl substituted with a hydroxy, -CH2OH or -C(O)NH2, piperazinyl substituted with one or two R1 [1,4]diazepanyl, substituted R1, R1 can denote one or two substitutes selected from a group comprising oxo, lower alkyl substituted with one R2, -C(O)R3, -SO2-lower alkyl, -SO2-five-memer heterocyclyl, which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl; R2 is selected from a group comprising -SO2-lower alkyl, hydroxy, lower alkoxy, -NH-SO2-lower alkyl, -cyano, -C(O)R4; R3 is selected from a group comprising a five-member heterocyclyl which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl, lower alkyl, lower alkenyl, lower alkyl substituted with a six-member heterocyclyl selected from piperidinyl, piperazinyl, 3-oxopiperazinyl, morpholinyl, C3-cycloalkyl; R4 is selected from a group comprising hydroxy, morpholine, piperidine, 4-acetylpiperazinyl, -NR5R6; R5 and R6 are independently selected from a group comprising hydrogen, lower alkyl, lower alkyl substituted with lower alkoxy or cyano, lower alkoxy and C3-cycloalkyl. The invention also relates to a pharmaceutical composition based on the formula I compound, use of the formula I compound in preparing a medicinal agent and a method for synthesis of the formula I compound.

EFFECT: novel derivatives of cis-2,4,5-triarylimidazoline of general formula I are obtained, which can be used to treat diseases, based on reaction of the MDM2 protein with p53-like protein, particularly as anticancer agent.

54 cl, 412 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazole derivatives of general formula I

and pharmaceutically acceptable salts thereof, where n equals 1 or 2, m equals 0, 1 or 2, A contains in the ring a group selected from -CR1=, -CR2=, -CR3=, -CR4= and -CR5=, where 0 or 1 in these groups is replaced with N, R1, R2, R3, R4 and R5 are independently selected from a group comprising hydrogen, hydroxy, halogen, cyano, cyano(C1-C6)alkyl, C4-C6 heterocycloalkyl-C0-alkyl, where the said heterocycloalkyl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, C5heteroaryl-(C0-C4)alkyl, where the said heteroaryl contains 1-4 heteroatoms selected from nitrogen atoms, -XSO2R11, -XSO2NR11R12, -XSO2NR11C(O)R12, -XC(NR11)NR11OR12, -XCR11=NOR12, -XC(O)R11, -XC(O)OR11, -XNR11R12, -XC(O)NR11R12, -XOC(O)NR11R12, -XNR11C(O)NR11R12, -XNR11XOR12; -XN(XOR12)2, -XNR11XC(O)OR12 -XNR11XNR11C(O)R12 -XNR11XNR11R12, -XNR11C(O)R12, where each X is independently selected from a group comprising a chemical bond and C1-C4alkylene, each R11 is selected from a group comprising hydrogen and C1-C6alkyl, and R12 is selected from a group comprising hydrogen, C1-C6alkyl and phenyl, or R11 and R12 together with a nitrogen atom to which R11 and R12 are bonded form C6heterocycloalkyl. Said heteroaryl or heterocycloalkyl in R1, R2, R3, R4 or R5 optionally contains one substitute selected from a group comprising hydroxyl, cyano, C1-C6alkyl, hydroxyl(C1-C6)alkyl and carboxy, R6 and R7 independently denote hydrogen, R8 is selected from a group comprising C1-C6alkyl, halogen(C1-C3)alkyl, -CH2OR8a and -COOR8a or two R8 groups bonded to different carbon atoms, together form a (C1-C2)alkyl bridge, or two R8a groups bonded to one carbon atom form a (C3-C8)cycloalkyl group, where R8a is selected from a group comprising hydrogen and C1-C6alkyl, R9 is selected from a group comprising phenyl and C6heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen atoms, and C9heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, where the said phenyl or heteroaryl in R9 is optionally substituted with 1-2 substitutes independently selected from a group comprising halogen, cyano, hydroxy, C1-C3alkyl, halogen(C1-C3)alkyl, hydroxy(C1-C3)alkyl, -C(O)R13, -C(O)NR13R14, where each of R13 and R14 is independently selected from a group comprising hydrogen and C1-C6alkyl, R10 denotes hydrogen, Y and Z are independently selected from a group comprising CR20 and N, where R20 denotes hydrogen, provided that compounds of formula I do not include compounds of formula II, which are described in claim 1, and provided that compounds of formula I do not include compounds which are: 1-(4-fluorophenyl)-4-((3-phenyl-1H-pyrazol-4-yl)methyl)piperazine, 1- ((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(4-(trifluoromethyl)-(pyridin-2- yl)piperazine, 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-(trifluoromethyl)-(pyridin-2-yl)piperazine and 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-fluoropyridin-2-yl)piperazine. The invention also relates to specific compounds obtained.

EFFECT: novel pyrazole derivatives which can be used in treating diseases or disorders which are mediated by disrupted activation of the said compound are obtained.

8 cl, 1 tbl, 4 ex

Up!