2h-chromen compound and derivative thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P₁ agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

The technical field to which the invention relates.

The invention relates to the compound 2H-chromene and its derivative, which is useful as an active ingredient for a pharmaceutical composition, in particular pharmaceutical compositions for prevention or treatment of diseases caused by undesirable infiltration of lymphocytes, or diseases caused by abnormal proliferation or accumulation of cells.

Prior art

Sphingosine-1-phosphate is a metabolite of sphingolipid, which is a physiologically active substance, Sekretareva from activated platelets (Annual Review Biochemistry, 2004, Vol. 73, pp. 321-354). The receptor for sphingosine-1-phosphate is a binding to G-protein-type receptor and belongs to the Edg-family, which is a gene differentiation of endothelial cells. Still were discovered five receptors S1P₁(Edg1), S1P₂(Edg5), S1P₃(Edg3), S1P₄(Edg6) and S1P₅(Edg8). All these receptors are widely distributed in cells and tissues throughout the body, but S1P₁, S1P₃and S1P₄predominantly expressed in lymphocytes and endothelial cells, S1P₂predominantly expressed in cells of smooth muscles of vessels, S1P₅predominantly expressed in brain and spleen, and it is minocyclinee sequence preserved in humans and rodents (Annual Review Biochemistry 2004, Vol. 73, pp. 321-354).

Many receptors are linked to G-proteins in the stimulation of sphingosine-1-phosphate. S1P₁associated with G_i/0, S1P₂and S1P₃contact G_i/0, G_q, G_12/13and G_s, S1P₄associated with G_i/0, G_12/13and G_s, S1P₅associated with G_i/0and G_12/13and induced cell proliferation induced MAPK activation, changes in cytoskeletal system and cellular infiltration caused by activation of Rac or Rho), and the production of cytokines and mediators induced activation of PLC and the influx of calcium into the cell, and the like (Annual Review Biochemistry, 2004, Vol. 73, pp. 321-354).

It is known that through the stimulation action of S1P₁sphingosine-1-phosphate induced migration of lymphocytes, inhibition of apoptosis, cytokine production and sequestration of lymphocytes in the thymus and other secondary lymphoid tissues, and it helps angioplasty in the endothelial cells of blood vessels (Nature Review Immunology, 2005, Vol. 5, pp. 560-570). On the other hand, the expression of S1P₃also found in cardiomyocytes, and experience a temporary decrease in heart rate (a rare heart rate or blood pressure through stimulation of sphingosine-1-phosphate (Japanese Journal of Pharmacology, 2000, Vol. 82, pp. 338-342). Rare pulse is not observed during stimulation of sphingosine-1-phosphate in mice with “knockout”where there is a genetic deficiency S1Psub> 3(Journal of Pharmacology and Experimental Therapeutics, 2004, Vol. 309, pp. 758-768).

It is known that FTY720 and FTY720 phosphate, which is its main active member, have an excellent action agonist S1P₁and, thus, induce sequestration of lymphocytes, and reported about their effects on skin graft or multiple sclerosis, which are autoimmune diseases (Cellular & Molecular Immunology, 2005, Vol. 2, No. 6, pp. 439-448; and The New England Journal of Medicine, 2006, Vol. 355, pp. 1124-40). However, there have also been reports of side effects, such as a rare heart rate, decreased pulmonary function (Transplantation, 2006, 82, pp. 1689-1967). It was reported that FTY720 phosphate has a non-selective agonistic effect on S1P₃, S1P₄and S1P₅(Science, 2002, Vol. 296, pp. 346-349), and reported on the results of clinical trials revealed as an unwanted side-effect of the very frequent cases of rare pulse induced stimulating effect through S1P₃(Journal of American Society of Nephrology, 2002, Vol. 13, pp. 1073-1083).

As compounds with the action of the agonist S1P₁Patent document 1 discloses a compound of General formula (A):

[where n is 1 or 2; A represents-C(O)OR₉or the like; R₉represents hydrogen or alkyl; X represents a bond, C_1-4alkylene, -X₁OX₂or the like, where X₁The X ₂independently selected from communication and C_1-3alkylene; Y represents a condensed 5,6 - or 6,6-heterobicyclic ring system containing at least one aromatic ring, where a condensed bicyclic ring system Y can be substituted, if so desired; R₁selected from C_6-10aryl and C_2-9heteroaryl, where any aryl or heteroaryl substituted C_6-10aryl C_0-4the alkyl, C_2-9heteroaryl, C_0-4the alkyl, C_1-6the alkyl or the like, if desired, R₂, R_3,R₅, R₆, R₇and R₈independently represent hydrogen, C_1-6alkyl, halogen or the like; R₄represents hydrogen or C_1-6alkyl; or R₇and any of R₂, R₄or R₅combined with the atom to which they relate, with the formation of a 4-7-membered ring; where a 4-7-membered ring is saturated or partially unsaturated] and its pharmaceutically acceptable salt, hydrate, MES, isomer and the prodrug (see Patent document 1), and as a specific compound, such as described above benzothiazepine compound disclosed as Example 1.

In addition, Patent document 2 discloses that the compound of General formula (B):

[in the General formula, Ring A represents cyclica the forge group; Ring B represents a cyclic group which may contain a Deputy; X represents a spacer containing from one to eight atoms in the main chain, or the like; Y represents a spacer containing from one to ten atoms in the main chain, or the like; n is 0 or 1; when n is 0, m is 1 or more, R¹represents a hydrogen atom or Deputy; when n is 1, m is 0 or an integer from 1 to 7, and further, R¹is a Deputy (when m has a value of 2 or more, multiple groups of R¹may be the same or different from each other)], its salt, its MES or its prodrug (see Patent document 2) have the ability of binding to S1P receptor, and as such specific compounds, for example, disclosed tetrahydronaphthalene derived as an Example 31-06.

In addition, Patent document 3 discloses that the compound of General formula (C):

[where the Ring A represents a cyclic group, Ring B represents a cyclic group which may optionally contain a Deputy, X represents a connecting shoulder or spacer containing from one to eight atoms in the main chain, where one atom of the spacer can b the th United with Deputy Ring B to form a ring, which can include Deputy, Y represents a linking shoulder or spacer containing from one to ten atoms in the main chain, where one atom of the spacer can be combined with Deputy Ring B to form a ring which may contain a Deputy, Z represents an acidic group which may be protected, and n is 0 or 1, provided that when n is 0, m is 1 and further, R¹represents a hydrogen atom or Deputy, in the case when n is 1, m is 0 or an integer from 1 to 7, and further, R¹is a Deputy (when m has a value of 2 or more, multiple groups R1 may be the same or different from each other)], its salt, N-oxide, its MES or its prodrug possess the ability to bind to the receptor S1P. As such specific compounds disclosed, for example, tetrahydronaphthalene derivative represented by the Example 37-6.

However, until now, remained a need for a new and highly stable S1P₁the agonist with strong action of S1P₁agonist of the sphingosine-1-phosphate and, accordingly, has an excellent effect of sequestration of lymphocytes and, in addition, do not have unwanted effects, such as a rare pulse, the attenuation function is tion of the lungs and the like, reported in connection with the usual S1P₁agonists.

The documents of the prior art,

Patent documents

[Patent document 1] Pamphlet of international publication WO 2005/000833

[Patent document 2] Pamphlet of international publication WO 2005/020882

[Patent document 3] Pamphlet of international publication WO 2006/064757

Disclosure of inventions

The problems solved by the present invention

Presents the connection, which is useful as an active ingredient of pharmaceutical compositions, particularly pharmaceutical compositions for prevention or treatment of diseases caused by undesirable infiltration of lymphocytes, or diseases caused by abnormal proliferation or accumulation of cells on the basis of agonistic actions against S1P₁.

Means of solving problems

The authors of the present invention have conducted extensive studies of compounds with the action of the agonist S1P₁and , as a result, it was found that the combination of 2N-chromene represented by the following formula (I)or its derivative has an excellent action of agonist S1P₁and is useful as an active ingredient in pharmaceutical compositions for preventing or treating diseases caused by undesirable infiltration of lymphocytes, elizababy, caused by abnormal proliferation or accumulation of cells, completing thus the present invention.

Thus, the present invention relates to the compound 2H-chromene, represented by the following formula (1):

(where

A represents lower alkyl, cycloalkyl, aryl or heteroaryl,

where aryl and heteroaryl can be, respectively, substituted with one to five substituents R¹that are the same or different from each other,

R¹represents a halogen, -CN, -NO₂, lower alkyl, lower alkenyl, lower quinil, halogen-lower alkyl, aryl, heteroaryl, cycloalkyl, -OH, -O-(lower alkyl), -O-(halogen-lower alkyl), -O-(aryl), -O-(cycloalkyl), -O-(heteroaryl), -NH₂, -NH(lower alkyl), -NH(halogen-lower alkyl), -N(lower alkyl)₂or cyclic amino,

where aryl, heteroaryl, cycloalkyl and the cyclic amino may be, respectively, substituted with one to five substituents, which are the same or different from each other and selected from the group comprising halogen, -CN, lower alkyl and halogen-lower alkyl,

L is a lower alkylene, lower albaniles, lower akinyan, -(lower alkylene)-O-, -O-(lower alkylene)- or -(lower alkylene)-O-(lower alkylene)-,

Q represents S or-C(R^2B)=C(R^2C)-,

R^2A, R^B and R^2Care the same or different from each other and represent H, halogen, lower alkyl, halogen-lower alkyl, -O-(lower alkyl) or-O-(halogen-lower alkyl),

Y represents O, S or-CH₂-, provided that when Y represents-CH₂-, Q represents S,

m is 0 or 1,

R³represents-H, halogen, lower alkyl or aryl,

R^4Arepresents-H or lower alkyl,

R^4Brepresents lower alkyl substituted by a group selected from Group G, or cycloalkyl substituted by a group selected from Group G,

or R^4Aand R^4Bcombined with the N atom to which they relate, with the formation of cyclic amino, substituted by a group selected from Group G, where the cyclic amino may optionally contain from one to four substituents, which are the same or different from each other and selected from the group comprising halogen, lower alkyl and halogen-lower alkyl, and

The group G represents-C(=O)OH, tetrazolyl, -C(=O)NHS(=O)₂(lower alkyl), -(lower alkylene)-C(=O)OH, or

or its derivative, or its salt.

In this regard, in the case when the characters in any of the chemical formulas in the present description are also used in other chemical formulae, the same symbols have the same the s values, unless specifically described otherwise.

In addition, the present invention relates to a pharmaceutical composition which contains a compound 2H-chromene formula (I) or its derivative or its salt and a pharmaceutically acceptable excipient, in particular, to (1) S1P₁the agonist, (2) pharmaceutical compositions for prevention or treatment of diseases caused by undesirable infiltration of lymphocytes associated with S1P₁, (3) pharmaceutical composition for the prevention or treatment of rejection reactions or graft versus host for the transplantation of organs, bone marrow, or tissues, autoimmune diseases or inflammatory diseases in humans or animals, (4) a pharmaceutical composition for the prevention or treatment of rejection reactions or graft versus host for the transplantation of organs, bone marrow, or tissues from humans or animals, (5) the pharmaceutical composition for prevention or treatment of multiple sclerosis, (6) a pharmaceutical composition for the prevention or treatment of diseases caused by abnormal proliferation or accumulation of cells associated with S1P₁and (7) the pharmaceutical composition for prevention or treatment of cancer or leukemia.

In addition, the present invention relates to a method for prevention or treatment of diseases caused by N. the desired infiltration of lymphocytes, associated with S1P₁in particular, reactions of rejection or graft versus host for the transplantation of organs, bone marrow or tissue, or multiple sclerosis in humans or animals which comprises the administration to the patient an effective amount of compound 2H-chromene formula (I) or its derivative or its salt. In addition, the present invention includes the use of compounds 2N-chromene formula (I) or its derivative or its salts for the prevention or treatment of diseases caused by undesirable infiltration of lymphocytes associated with S1P₁in particular, reactions of rejection or graft versus host for the transplantation of organs, bone marrow or tissue, or multiple sclerosis in humans or animals, and the connection 2N-chromene formula (I) or its derivative or its salt for use for the prevention or treatment of diseases caused by undesirable infiltration of lymphocytes associated with S1P₁in particular, reactions of rejection or graft versus host for the transplantation of organs, bone marrow or tissue, or multiple sclerosis in humans or animals.

The effects of the present invention

The compound of formula (I) or its salt of the present invention has the effect of agonist S1P₁and can be used for prevention or treatment of diseases is s, caused by unwanted infiltration of lymphocytes, for example, autoimmune diseases or inflammatory diseases such as rejection or graft versus host for the transplantation of organs, bone marrow or tissue, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, meningoencephalitis, severe myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, pulmonary disease, bronchial asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemic reperfusion disorder, and diseases caused by abnormal proliferation or accumulation of cells, for example, cancer, leukemia and the like.

The best option is the implementation of the present invention

Following is a detailed explanation of the present invention.

In the description of “halogen” means F, Cl, Br or I. Preferably, its examples include F and Cl.

In the present description “lower alkyl” represents a linear or branched alkyl containing from one to six carbon atoms (hereinafter referred to simply as C_1-6), and its examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like, in another variant embodiment, C_1-4alkyl, and the following variant embodiment, methyl, ethyl and isopropyl is.

“Lower alkenyl” represents a linear or branched C_2-6alkenyl, and its examples include vinyl, propenyl, butenyl, pentenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl and the like, and in another variant embodiment, C_2-4alkenyl.

“Lower alkylene” represents a linear or branched C_1-6alkylen, and its examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, METROTILE, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene and the like, in another variant embodiment, C_1-4alkylen, and in the following variant embodiment, the methylene and ethylene.

“Lower albaniles” represents a linear or branched C_2-6albaniles, and its examples include vinile, ethylidene, propylen, butylen, penttinen, hexarelin, 1,3-butadienyl, 1,3-pentadiene and the like, in another variant embodiment, C_2-4albaniles, and in the following variant embodiment, vinile and ethylidene.

“Lower akinyan” represents a linear or branched C_2-6akinyan, and its examples include ethynylene, propylen, Butyrin, pentikinen, geksanalem, 1,3-butadienyl, 1,3-pentadiene and the like, in another variant embodiment, C_2-4akinyan, and in the following variant embodiment, ethynylene, propylen, Butyrin and PE is Tinian.

“Halogen-lower alkyl” represents a C_1-6alkyl, substituted by one or more halogen atoms, in another variant embodiment, lower alkyl, substituted by one to five halogen atoms, the following variant embodiment, C_1-3lower alkyl, substituted by one to five halogen atoms, and in another variant of embodiment of his examples include-CF₃, -CH₂CF₃, -CH(CH₃CF₃and-CH(CH₂F)₂.

“Cycloalkyl” represents a C_3-10saturated hydrocarbon ring group which may contain a bridge. His examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, substituted and the like, in another variant embodiment, C_3-8cycloalkyl, in the next version of the incarnation, C_3-6cycloalkyl, and in another variant embodiment, cyclopropyl, cyclopentyl and cyclohexyl.

“Aryl” represents a C_6-14monocyclic-tricyclic aromatic hydrocarbon ring group, and examples include phenyl and naphthyl, and in another variant embodiment, the phenyl.

“Heteroaryl” is a 5-6-membered monocyclic heteroaryl containing from one to four heteroatoms selected from N, S and O, and bicyclic heteroaryl formed by condensation with a benzene ring or a 5-6-membered monocyclic is Kim heteroaryl, and may be partially saturated. In another variant embodiment, its examples include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolin, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, benzothiazolyl and indolyl, in another variant embodiment, heteroaryl consisting of 5-membered ring which may be condensed with a benzene ring, and in another variant embodiment, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzothiazolyl and indolyl.

“Nitrogen-containing monocyclic heteroaryl” means monocyclic heteroaryl, in which one of the components of the ring atoms necessarily represent N, and may contain one or two heteroatoms selected from N, S and O, as constituents of the ring atoms, and in another variant embodiment, its examples include 5-6-membered ring, in the following variant embodiment, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolin, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl and such, in one embodiment, the embodiment 5-membered ring, and in another variant embodiment, pyrrolyl and imidazolyl.

“Cyclic amino” means a monocyclic-tricyclic heteroseksualci where Odie the components of the ring atoms necessarily represent N, may contain one or two heteroatoms selected from N, S and O, as constituents of the ring atoms, and may contain partially unsaturated bond. In another variant embodiment, it is a ring, with the degree of recovery from 4 to 9, the next version of the incarnation, his examples include azetidine, pyrrolidine, piperidinyl, morpholinyl, homopiperazine, 3-azabicyclo[3,1,0]hexanal, tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl, hinokitiol and the like, in another variant embodiment, its examples include cyclic amino, consisting of 6-membered rings, in another variant embodiment, its examples include piperidinyl, piperazinil, morpholinyl and tetrahydropyranyl, and in another variant embodiment, it examples include azetidine, pyrrolidine, piperidinyl and tetrahydropyranyl.

In the present description, the expression "which may be substituted by one to five substituents R¹that are the same or different from each other” means unsubstituted or contains one to five groups, R¹as deputies. In addition, when there is more than one of the substituents R¹the substituents R¹can be identical or different from each other.

Variants of the embodiment of the present invention will be described below.

(1) Connection of 2N-chromene Il is its salt, where Y represents O, Q represents-C(R^2B)=C(R^2C)-, and m has a value of 0.

(2) Connection of 2N-chromene or its salt, where R^4Aand R^4Bcombined with the N atom to which they relate, with the formation of cyclic amino selected from azetidine, pyrrolidine, piperidine and tetrahydropyridine, which is substituted by a group(or groups)selected from the Group G, and may be substituted by lower alkyl or halogen.

(3) Connection of 2N-chromene or its salt, where the group represented by Group G represents-C(=O)OH or-C(=O) NHS(=O)₂CH₃.

(4) Connection of 2N-chromene or its salt, where A represents phenyl, pyridyl or thienyl, which can be substituted one to three substituents R¹which may be identical or different from each other.

(5) Connection of 2N-chromene or its salt, where L represents -(lower alkylene)-O-, lower albaniles or lower akinyan.

(6) Connection of 2N-chromene or its salt, where R^2Arepresents-H or lower alkyl, R^2Brepresents-H, R^2Crepresents-H or halogen, R³represents-H or halogen, R¹represents halogen, lower alkyl, halogen-lower alkyl, phenyl, pyrrolyl, cycloalkyl, -O-(lower alkyl) or-O-(halogen-lower alkyl), and further, L represents a-CH₂-O-, -CH=CH - or 3-Buti is strong.

(7) the Compound 2H-chromene or its salt, where R^4Aand R^4Bcombined with the N atom to which they relate, with the formation of piperidinyl or tetrahydropyranyl, which is replaced by the group-C(=O)OH, L represents a-CH₂-O-, R^2Arepresents-H, R^2Brepresents-H, R^2Crepresents-H or halogen, R³represents-H, and A represents phenyl or pyridyl, which is substituted by two substituents R¹that are the same or different from each other, where R¹represents halogen, halogen-lower alkyl, -O-(lower alkyl) or-O-(halogen-lower alkyl).

(8) Connection of 2N-chromene or its salt, where R^4Aand R^4Bcombined with the N atom to which they relate, with the formation of piperidinyl, which is replaced by the group-C(=O)OH, and A represents phenyl, which is substituted by two substituents R¹that are the same or different from each other.

(9) Connection of 2N-chromene or its salt, where R^4Aand R^4Bcombined with the N atom to which they relate, with the formation of tetrahydropyridine, which is replaced by the group-C(=O)OH, A represents pyridyl, which is substituted by two substituents R¹that are the same or different from each other.

Examples of specific compounds included in the present invention include SL is blowing compounds or their salts:

1-{[7-({3-chloro-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]benzyl}oxy)-2H-chromen-3-yl]methyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,

1-({7-[(3-chloro-4-isopropylbenzyl)oxy]-2H-chromen-3-yl}methyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid,

1-[(7-{[4-isopropoxy-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid,

1-{[7-({3-chloro-4-[2-fluoro-1-(permitil)ethoxy]benzyl}oxy)-2H-chromen-3-yl]methyl}-1,2,3,6-tetrahydropyridine-4-carboxylic acid,

1-{[7-({5-chloro-6-[(1S)-2,2,2-Cryptor-1 methylethoxy]pyridine-3-yl}methoxy)-2H-chromen-3-yl]methyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,

(3R)-1-{[7-({4-[(1,3-ditropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,

1-[(7-{[4-cyclopentyl-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid,

(3R)-1-{[7-({3-chloro-4-[(1,3-ditropan-2-yl)oxy]benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,

(3S)-1-{[7-({4-[(1,3-ditropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,

(3R)-1-[(7-{[4-(2,2,2-triptoreline)-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,

(3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-tryptophan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,

(3S)-1-[(7-{[4-(2,2,2-trifter the toxi)-3-(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,

(3R)-1-{[7-({4-[(1,3-ditropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}-N-(methylsulphonyl)piperidine-3-carboxamide or

1-[(7-{[4-(2,2,2-triptoreline)-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-4-carboxylic acid.

The compound of formula (I) may exist as tautomers or geometrical isomers, depending on the type of substituents. In the present description, the compound of formula (I) will be described in only one form isomer, although the present invention includes other isomers, isolated forms of the isomers, or a mixture thereof.

In addition, the compound of formula (I) may contain asymmetric carbon atoms or axial chirality, in some cases, and, accordingly, it may be in the form of optical isomers. The present invention includes as a separate form of optical isomers of compounds of formula (I), and mixtures thereof.

In addition, the present invention also includes pharmaceutically acceptable prodrug of the compound represented by formula (I). Pharmaceutically acceptable prodrug is a compound containing a group which can be converted into the amino group, hydroxyl group, carboxyl group or the like as a result of solvolysis or under physiological conditions. Examples of the group forming a prodrug include groups described the data in Prog. Med., 5, 2157-2161 (1985) and Pharmaceutical Research and Development, Drug Design, Hirokawa Publishing Company (1990), Vol. 7, 163-198.

In addition, the salt of the compounds of formula (I) is a pharmaceutically acceptable salt of the compounds of formula (I) can form acid additive salt or a salt with a base depending on the type of substituents. Specific examples include acid additive salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid, phosphoric acid and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, Detelina acid, citric acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, para-toluensulfonate acid, aspartic acid, glutamic acid and the like, and salts with inorganic bases, such as sodium, potassium, magnesium, calcium, aluminum and the like, or with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like, salts with various amino acids or amino acid production is DNAME, such as acetylleucine and the like, ammonium salts, etc.

In addition, the present invention also includes various hydrates or solvate and polymorph crystalline substances the compounds of formula (I) and salts thereof. In addition, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

In the present description, in some cases, there may be used the following abbreviations.

ADDP=1,1'-(azodicarbon)dipiperidino, AIBN=2,2'-azobisisobutyronitrile, AcOH=acetic acid, CDI=1,1'-carbonylbis-1H-imidazole, DAST=(diethylamino)sulfur TRIFLUORIDE, DBU=1,8-diazabicyclo[5,4,0]undec-7-ene, DCC=dicyclohexylcarbodiimide, DCE=dichloroethane, DHM=dichloromethane, DIBAL=diisobutylaluminum, DIBOC=di-tert-BUTYLCARBAMATE, DIC=N,N'-diisopropylcarbodiimide, DIPEA=diisopropylethylamine, DMA=N,N'-dimethylacetamide, DMAP=4-(N,N'-dimethylamino)pyridine, DME=dimethoxyethane, DMF=N,N'-dimethylformamide (DMF), DMSO=dimethyl sulfoxide (DMSO), DPPA=diphenylphosphinite, DPPP=1,3-bis(diphenylphosphino)propane, EDCI·HCl=N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide, Et=ethyl, Et₂O=diethyl ether, TEA=triethylamine, EtOAc=ethyl acetate; EtOH=ethanol, HOBt=1-hydroxy-1H-benzotriazole, IPE=diisopropyl ether, t-BuOK=tert-piperonyl potassium, LAH= socialogical, MS4 Angstrom=molecular sieves 4 Angstrom, MeCN=acetonitrile, MeOH=methanol, MgSO₄=anhydrous sulfate mage is Oia, NBS=N-bromosuccinimide, NCS=N-chlorosuccinimide, NMP=N-organic, NT = not tested, Na₂SO₄= anhydrous sodium sulfate, NaBH(OAc)₃=triacetoxyborohydride sodium, NaBH₄= sodium borohydride, NaOEt=ethoxide sodium NaOH=sodium hydroxide, NaOMe=sodium methoxide, TBP=three normal butylphosphine, PDC=pyridinediamine, POCl₃=oxychloride phosphorus, PPh₃=triphenylphosphine, Pd(OAc)₂=palladium (II)acetate, Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium (0), TEA=triethylamine, TFA=triperoxonane acid, THF=tetrahydrofuran, TMEDA=N,N,N, N'-tetramethylethylenediamine, Tf=CF₃S(=O)₂-saturated salt solution=saturated saline solution, i-D=2-propanol, n-BuLi=normal utility, n-BuOH=normal butyl alcohol, t-BuOH=tertiary butyl alcohol and tert= tertiary.

(Methods of obtaining)

The compound of formula (I) and its salt can be obtained using the characteristics based on the basic structure or the type of substituents, and by applying various known synthesis methods. In the retrieval process, replacement of the corresponding functional group suitable protecting group (a group that can be easily converted into the functional group) at the stage from the original substance to the intermediate connection in some cases it may be effective, depending on the type of functional group used in the act is both receipt. The protective group for such a functional group may include, for example, protective groups described in “Greene's Protective Groups in Organic Synthesis (4^thEd., 2006)” the authors P. G. M. Wuts and T. W. Greene, and you can choose one of these groups and use, as necessary, depending on the reaction conditions. In this way, the desired compound can be obtained by introducing a protective group, by carrying out the reaction by removal of the protective groups as necessary.

In addition, the prodrug of the compounds of formula (I) can be obtained by introducing a specific group or by performing the reaction using the obtained compound of formula (I) at the stage from the original substance to the intermediate connections, as in the case of the above-mentioned protective group. The reaction may be carried out using methods known to experts in this field, such as an ordinary esterification, amidation, dehydration and the like.

Described below are representative methods for obtaining the compounds of formula (I). Each of the methods of obtaining it is also possible to carry out with reference to the Reference documents referred to in the present description. In addition, methods of obtaining of the present invention is not limited by the examples presented below.

<a Method of obtaining 1>

The compound (I) nastasemarian can be obtained, subjecting the compound (A) and the compound (B) rehabilitation aminating.

The way in stage 1 is a reductive amination. The compound (A) and the compound (B) used in equivalent amounts, or any of them use in an excessive amount, and the mixture is stirred under any conditions, including temperatures from -45°C to the boiling temperature under reflux, in particular from 0°C to room temperature, usually in a period of time from 0.1 hour to 5 days, in a solvent which is inert to the reaction, in the presence of a reducing agent. Examples of the solvent include alcohols such as MeOH, EtOH and the like; ethers, such as Et₂O, THF, dioxane, DME and the like; halogenated hydrocarbons, such as DHL, DCE, chloroform and the like; and which consists of them mixed solvent. Examples of reducing agents include NaBH₃CN, NaBH(OAc)₃, NaBH₄and similar. It may be preferable in some cases to carry out the reaction in the presence of a dehydration agent such as molecular sieves and the like, or acid, such as acetic acid, hydrochloric acid, a complex of isopropoxide titanium (IV) and the like. Imin, which is an intermediate compound in the reaction, it is possible to allocate in the form of stable intermediate compounds and by restoring iminovogo Prohm is the filling compound can be obtained compound (I). Furthermore, the reaction can be carried out in a solvent such as MeOH, EtOH, EtOAc and the like, in the presence or in the absence of acid, such as acetic acid, hydrochloric acid and the like, using a catalyst recovery (for example, palladium on carbon, Raney Nickel and the like), instead of reducing agent. In this case, the reaction is carried out in a hydrogen atmosphere at a pressure of from normal to 50 atmospheres, a temperature condition from cooling to heating.

[Reference documents] (1) “Comprehensive Organic Functional Group Transformations II” written by A. R. Katritzky and R. J. K. Taylor, Vol. 2, Elsevier Pergamon, 2005, (2) “Jikken Called Koza (Courses in Experimental Chemistry) (5^thEdition)” edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

<a Method of obtaining 2>

(where Hal represents a halogen).

The compound (I) of the present invention can be obtained by alkylation of the compound (C) compound (B).

The way in stage 2 represents the alkylation. The compound (B) and the compound (C) used in equivalent amounts, or any of them use in an excessive amount, and the mixture is stirred in the temperature condition from cooling to heating and boiling under reflux, preferably from 0°C to 80°C, usually in a period of time from 0.1 hour to 5 days, in a solvent which is inert to the reaction or without solvent. Examples of the solvent include aromatic hydrocarbons; ethers; halogenated hydrocarbons, DMF, DMSO, EtOAc, and MeCN; and composed of them, a mixed solvent. May be advantageous in some cases for the smooth progress of the reaction to carry out the reaction in the presence of an organic base such as TEA, DIPEA or N-methylmorpholine and the like, or inorganic bases, such as K₂CO₃, Na₂CO₃or KOH and the like. May be advantageous in some cases for the smooth progress of the reaction to add an inorganic salt, such as NaI and the like, in the reaction system.

[Reference document] “Jikken Called Koza (Courses in Experimental Chemistry) (5^thEdition)” edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

<Intermediate process of obtaining 1>

(where Tf represents CF₃S(=O)₂-, and L¹represents the lowest alkylene or lower albaniles).

The compound (A-1) can be obtained using the reaction Sonogashira, based on the compound (D).

Stage 3-1 represents the stage of receipt of the triflate. The compound (E) can be obtained by subjecting the compound (D) interaction with triftormetilfullerenov anhydride. As a solvent, which usually does not interfere with the reaction, use of a solvent selected from halogenated hydrocarbons, reaction assests the Ute in the presence of organic bases, such as pyridine, TEA, DIPEA and the like, at temperatures from -10°C to cooling with ice. In addition, the organic base can be used in combination with the solvent.

Stage 3-2 is a so-called reaction Sonogashira. The compound (A-1) can be obtained by adding a catalytic amount of Pd(0) catalyst and a base to the compound (E), giving the opportunity to react terminal acetylene. May be advantageous in some cases for the smooth progress of the reaction to add the copper iodide in the reaction system. Examples of the solvent include ethers; aromatic hydrocarbons, such as toluene, xylene and the like; DMF, DMSO, EtOAc; and composed of them, a mixed solvent. For example, a base such as TEA, pyrrolidine and the like, can be used in combination with the solvent. As for the reaction temperature, the reaction can be performed at temperatures from room temperature to the boiling temperature under reflux.

[Reference document] K. Sonogashira, hedron Letters, 1975, 50, pp. 4467.

<Intermediate process of obtaining 2>

the compound (A-2) can be obtained by reconnection (G) and its dehydration and formirovaniya of the obtained compound (J).

Stage 4-1 represents the reduction of the ketone. Link is (G) is treated with an equivalent amount or excess amount of reducing agent in the temperature condition from cooling to heating, preferably from -20°C to 80°C, usually in a period of time from 0.1 hours to 3 days, in a solvent which is inert to the reaction. Examples of the solvent include ethers; alcohols; aromatic hydrocarbons, DMF, DMSO, EtOAc, and composed of them, a mixed solvent. As reducing agent, suitable for use are hydride reducing agents such as NaBH₄That DIBAL and the like, a metal reducing agents such as sodium, zinc, iron and the like, and reducing agents in the following Reference documents.

[Reference documents] (1) “Reductions in Organic Chemistry, 2^nded. (ACS Monograph: 188)” written by M. Hudlicky, ACS, 1996, (2) “Comprehensive Organic Transformations” written by R. C. Larock, 2^nded., VCH Publishers, Inc., 1999, (3) “Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)” written by T. J. Donohoe, Oxford Science Publications, 2000, (4) “Jikken Called Koza (Courses in Experimental Chemistry) (5^thEdition)” edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

Stage 4-2 is a dehydration reaction. Usually the original substance is stirred in concentrated sulfuric acid under conditions of heat and then continue the distillation until the complete disappearance of the eluent.

Stage 4-3 represents formirovanie. The compound (A-2) is produced by the interaction of the compound (J) with formamidine derived. In this case, formamidine derived means formamide connection, in which the lower alkali or arily, which are the same or different from each other, are associated with nitrogen atoms of formamide. As for the complex of Vilsmeier obtained by interaction formamide derived from POCl₃, the aromatic ring is subjected to nucleophilic substitution with obtaining ammonium salt. It is possible to hydrolyze under alkaline conditions with obtaining formyl product. In this reaction, the compound (J) and DMF equivalent used in equivalent amounts, or any of them use in an excessive amount, and the mixture is stirred in a solvent which is inert to the reaction or without solvent, in the presence of a halogenation agent. This reaction is carried out at temperatures from room temperature to heating and boiling under reflux, usually during the time from 0.1 hour to 5 days. Examples of the solvent include halogenated hydrocarbons; ethers; or MeCN. The halogenation agent is used in such a way as to convert DMF derived in the complex of Vilsmeier, and usually it is not specifically limited, provided that the reagent used for the halogenation of alcohols, but suitable for use are pentachloride phosphorus, POCl₃or other

[Reference document] (1) “Strategic Applications of Named Reactions in Organic Synthesis” written by L. Kurti and B. Czako, Elevier Inc, 2005, pp. 468-469

<Intermediate process of obtaining 3>

(where Lv is a deleted group).

The compound (A-3) is produced by the interaction of the compound (K) with compound (L).

Stage 5-1 represents the alkylation. Examples of the deleted group Lv include halogen, methanesulfonate, p-toluensulfonate group and the like.

Compound (K) and the compound (L) used in equivalent amounts, or any of them use in an excessive amount, and the mixture is stirred in a solvent which is inert to the reaction or without solvent, in the temperature condition from cooling to heating and boiling under reflux, preferably from 0°C to 80°C, usually in a period of time from 0.1 hour to 5 days. Examples of the solvent include aromatic hydrocarbons; ethers; halogenated hydrocarbons, DMF, DMSO, EtOAc, MeCN; and composed of them, a mixed solvent. May be advantageous in some cases for the smooth progress of the reaction to carry out the reaction in the presence of organic bases such as TEA, DIPEA, N-methylmorpholine and the like, or inorganic bases, such as K₂CO₃, Na₂CO₃, KOH and the like. May be advantageous in some cases for the smooth progress of the reaction to add inorganic salts, is such as NaI and the like, in the reaction system.

[Reference document] “Jikken Called Koza (Courses in Experimental Chemistry) (5^thEdition)” edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

<Intermediate process of obtaining 4>

The compound (C) can be obtained from compounds (A) through connection (M).

Stage 6-1 represents a recovery. Compound (M) can be obtained by mixing the compound (A) with an equivalent amount or excess amount of reducing agent in a solvent which is inert to the reaction, the temperature condition from cooling to heating, preferably from -20°C to 80°C, usually in a period of time from 0.1 hours to 3 days. Examples of the solvent used is not specifically limited, but include ethers, such as diethyl ether, THF, dioxane and dimethoxyethane, alcohols, such as MeOH, EtOH, 2-propanol and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, DMF, DMSO, EtOAc, and composed of them, a mixed solvent. As reducing agent, suitable for use are hydride reducing agents such as NaBH₄That DIBAL and the like, a metal reducing agents such as sodium, zinc, iron and the like, and reducing agents in the following Reference documents.

[Reference documents]

“Reductions in Organic Chemistry, 2^nded. (ACS Monograph: 188)” written by Hudlicky M, ACS, 1996

“Comprehensive Organic Transformations” written by R. C. Larock, 2^nded., VCH Publishers, Inc., 1999

“Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)” written by T. J. Donohoe, Oxford Science Publications, 2000

“Jikken Called Koza (Courses in Experimental Chemistry) (5^thEdition)” edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

Stage 6-2 represents halogenoalkane. The compound (C) can be obtained by subjecting the compound (M) galogenirovannyie. As the halogenation agent using a halogenation agent to convert the hydroxyl group into a halogen. The halogenation agent is not specifically limited, but, for example, use PBr₃, HBr, BBr₃, PCl₃, PCl₅or the like as a solvent ethers are preferred, and for example, using THF, diethyl ether, dimethoxyethane, methyl tert-butyl ether, dioxane, 2-methyltetrahydrofuran or similar

<Intermediate process of obtaining 5>

(where X represents-O - or a bond, R represents a protective group for carboxyl group, R' and R” represent lower alkyl, n and p each represent an integer from 0 to 4, which are the same or different from each other, and further, the sum of n and p is 4 or less. ---- represents a simple bond or double bond).

Connection (T) can be obtained through the progressive implementation of the reaction wit the yoke, recovery, oxidation, and build promenevogo skeleton of the compound (N). Connection (T), in which ---- represents a simple bond, obtained by the implementation of reduction reaction at the stage, which does not interfere with the reaction.

Stage 7-1 represents the response of the education ilide forstora. Compound (O) is produced by the interaction of the compound (N), for example, triethylphosphite or the like, usually in a solvent that does not interfere with the reaction. Examples of the solvent include aromatic hydrocarbons; ethers; halogenated hydrocarbons; ketones, such as acetone, ethylmethylketone and the like; DMF, DMSO, EtOAc, MeCN; and composed of them, a mixed solvent. As for the reaction temperature, the reaction can be performed at temperatures from -20°C to heat.

Stage 7-2 represents the so-called Wittig reaction. Compound (O) can be subjected to interact with the aldehyde compound (P) to obtain the compound (Q). By aldehyde accession replacement phosphoryl group of carbanions, you can get olefins via Wittig-like mechanism. The reaction temperature is any selected from a range from 0°C to heat.

[Reference documents] (1) J. Boutagy CRV, 79, 87, 1974, (2) W. S. Wadsworth Jr'OR, 25, 73, 1977.

Stage 7-3 represents the reaction of recovery. As Voss is novices use LiAlH ₄, LiAlH(OMe)₃or DIBAL, and the reaction can be carried out in a solvent which is inert to the reaction, such as THF, ethers, and the like, usually in the temperature condition from cooling to heating.

Stage 7-4 represents the oxidation reaction. As oxidant using manganese dioxide or PDC. Examples of the solvent usually include halogenated hydrocarbons and the like. As for the reaction temperature, the reaction is carried out at temperatures from 0°C to heat, typically at room temperature. As for other ways, there is a method using a reagent-based DMSO-POCl₃. The method using a reagent such as DCC, anhydrides, acids, chlorine or reagents based on Me₂S-NCS (Corey-Kim oxidation) or using periodinane Dess-Martin, instead of POCl₃you can also use. The reaction is usually carried out at temperatures from room temperature to heating. Examples of the solvent is not specifically limited, but include aromatic hydrocarbons; ethers; halogenated hydrocarbons; MeCN and composed of them, a mixed solvent.

Stage 7-5 represents the response of the education promenevogo rings. Connection (T) can be obtained by adding acrolein derivative to the compound (S) with subsequent displacement is ywaniem temperatures from room temperature to heating in the presence of inorganic bases, such as the K₂CO₃and similar. Examples of the solvent include aromatic hydrocarbons; ethers; halogenated hydrocarbons; MeCN and composed of them, a mixed solvent. Typically use solvents on the basis of simple ether, such as THF, DME, dioxane and the like.

The connection, in which --- in connection (T) represents a simple bond, obtained by recovery of some compounds of the compounds (P) via the connection (S). This so-called reaction recovery of olefins. Usually the connection is stirred in a solvent which is inert to the reaction, in the presence of a metal catalyst, usually in a period of from 1 hour to 5 days, in an atmosphere of hydrogen. This reaction is usually carried out in a temperature condition from cooling to heating, preferably at room temperature. Examples of the solvent is not specifically limited, but include alcohols, such as MeOH, EtOH, i-D and the like; ethers; water, EtOAc, DMF, DMSO; and composed of them, a mixed solvent. As the metal catalyst, suitable for use are palladium catalysts such as palladium on carbon, palladium black, palladium hydroxide and the like, platinum catalysts such as platinum plate, platinum oxide and the like, Nickel catalysts, such canvastown Nickel, of Raney Nickel and the like, rhodium catalysts, catalysts based on iron, such as reduced iron and the like, etc. Instead of gaseous hydrogen can also be used formic acid or ammonium formate in an equivalent amount or excess amount, as the source of hydrogen for the connection.

[Reference documents] (1) “Reductions un Organic Chemistry, 2^nded. (ACS Monograph: 188)” written by M. Hudlicky, ACS, 1996, (2) “Jikken Called Koza (Courses in Experimental Chemistry) (5^thEdition)” edited by The Chemical Society of Japan, Vol. 19 (2005) (Maruzen).

In addition, some compounds represented by formula (I)can also be obtained by combining stages, which usually can be used by the person skilled in the art, such that represent a certain stage of alkylation, acylation, substitution reaction, oxidation, recovery, hydrolysis, delete, protection, halogenation and the like, of the compounds of the present invention, obtained as described above.

For example, alkylation, you can use the alkylation reaction, which is usually used specialists in this area, and the alkylation can be performed in an organic solvent which is inert to the reaction, such as ethers; aromatic hydrocarbons; halogenated hydrocarbons, DMF, MeCN; aprotic polar solvents is similar, in terms of cooling, cooling to room temperature, or from room temperature to heating, in the presence of bases such as NaH; alkaline compounds of carbonic acid; alkaline bicarbonate compounds; alkoxide; tertiary amine; organic bases, etc.

In addition, for example, acylation, you can use the acylation reaction, which is usually used specialists in this area, but the acylation is carried out in an organic solvent which is inert to the reaction, such as ethers; aromatic hydrocarbons; halogenated hydrocarbons; esters such as EtOAc and the like; MeCN; aprotic solvents and the like, using a condensing agent such as EDCI·HCl, CDI, diphenylphosphine and the like, depending on the reaction conditions, but usually in terms of cooling, the temperature condition from cooling to room temperature, or from room temperature to heating, in particular, in the presence of HOBt.

The compounds of formula (I) can be isolated and purified in the form of free compounds, salts, hydrates, solvate or polymorphic crystalline substances. Salts of compounds of formula (I) can be obtained by implementing the traditional reaction of the salt formation.

Isolation and purification carried out using about what cnyh chemical procedures, such as extraction, fractional crystallization, various types of fractional chromatography and the like.

Various isomers can be obtained by choosing a suitable initial connection or separation by using the difference in physicochemical properties between the isomers. For example, optical isomers can be obtained using the General method of the optical separation of the racemic products (e.g., fractionated crystallization for the induction of the diastereomeric salt of optically active bases or acids, chromatography using a chiral column or the like, and others), and, in addition, the isomers can also be obtained from the appropriate optically active starting compound.

The pharmacological activity of the compounds of formula (I) were confirmed by the tests described below.

Example test 1: Evaluation of in vitro agonistic activity towards S1P₁receptor in a biological organism

(Method 1) Method of evaluation of agonistic activity on the receptor using GTP[γ-³⁵S] analysis of binding using membranes of cells expressing human S1P₁

In vitro agonistic action of the compounds according to the present invention in relation to S1P₁was evaluated by increasing the functional binding activity of GTP[γ-³⁵S] and G-protein with the use of the cation membranes of cells, expressing human S1P₁. cDNA encoding human S1P₁, cloned from a cDNA library colorectal and human cells were injected in expressing vector pcDNA3.1 to obtain design S1P₁-pcDNA3.1. Then, with the help of Lipofectamine 2000 (GIBCO) S1P₁-pcDNA3.1 was transfusional in CHO cells and cultured in F-12 culture medium ham containing 10% fetal bovine serum, 100 Units/ml penicillin, 100 μg/ml streptomycin and 1 mg/ml of G418 disulfate, with stable G418-resistant strain. Cultured cells expressing human S1P₁isolated in 1 mm EDTA·2Na-containing PBS and tear while cooling with ice using a homogenizer, made of glass, in a buffer solution (1 mm Tris HCl (pH 7,4)containing 0.1 mm EDTA and the inhibitor protein. Was carried out by centrifugation at 1400×10 min and supernatant then centrifuged at 4°C for 60 min at 100000×g and suspended in a buffer solution of 10 mm Tris HCl (pH 7,4)containing 1 mm EDTA to clean the membranes. Cooperated obtained membranes (0.13 mg/ml) and 50 PM GTP[γ-³⁵S] (NEN; inactive 1250 CI/mmol) in a buffer solution of 20 mm HEPES (pH 7.0) (total: 150 μl)containing 100 mm NaCl, 10 mm MgCl₂, 0,1% not containing fatty acid BSA and 5 μm GDP, within 1 hour, together with the compound of the present invention (10^-12-10^-5 M) and then the membrane was manufactured by GF-C filter plate using a cell harvester (Packard FilterMate). The filter plate was dried at 50°C for 60 min and was added Microscinti-o (Packard) for measurement using a liquid scintillation counter for microplate (Packard TOP count). To assess agonistic actions against human S1P₁compounds of the present invention and comparative compounds used percentage set as 100% for the maximum velocity of the reaction, making GTP[γ-³⁵S] due saturated in the presence of the compound, and set as 0% for the rate of formation of GTP[γ-³⁵S] relations in the absence of a connection, built nonlinear regression curve and the concentration that causes agonistic action, which is 50% of maximum response, was defined as the value of EC₅₀(nm).

(Method 2) Method of valuation agonistic action on the receptor using the analysis of the inflow of Ca²⁺using cells expressing human S1P₁

In vitro agonistic action of the compounds according to the present invention in relation to S1P₁was evaluated by increasing the concentration of Ca²⁺in cells expressing human S1P₁. cDNA encoding human S1P₁, cloned from a cDNA library to lorettalynn human cells and was introduced in expressing vector pcDNA3.1 to obtain design S1P ₁-pcDNA3.1. Then, with the help of Lipofectamine 2000 (GIBCO) S1P₁-pcDNA3.1 was transfusional in CHO cells and cultured in F-12 culture medium ham containing 10% fetal bovine serum, 100 Units/ml penicillin, 100 μg/ml streptomycin and 1 mg/ml of G418 disulfate, with stable G418-resistant strain. Cultured cells expressing human S1P₁isolated in 1 mm EDTA·2Na-containing PBS and suspended in F-12 culture medium ham containing 10% fetal bovine serum, 100 Units/ml penicillin, 100 μg/ml streptomycin. This cell suspension was distributed in a 96-well plate at a density of 50,000 cells/well and cultured in CO₂incubator (5% CO₂, 37°C) during the night. The culture medium was replaced with calcium-sensitive fluorescent reagent (FLIPR (registered trademark), a test kit calcium 3, molecular device) loading buffer (balanced salt solution Hank, 20 mm HEPES, 2.5 mm probenecid) and left to stand in CO₂incubator (5% CO₂, 37°C) for 1 hour. The tablet was installed on the system for screening of functional medicines FDSS6000 (Hamamatsu Photonics K. K.) and continuously carried out measurements 124 times every 1,02 s at the wavelength of excitation 480 nm. The test compound (final concentration of 10^-12-10^-5 M) was added simultaneously with the 12th dimension and the change in the Ca ²⁺concentration in the cells was assessed by the change in fluorescence intensity. To assess agonistic actions against human S1P₁compounds of the present invention and comparative compounds used percentage set as 100% for the maximum velocity of the reaction, making the increase of Ca²⁺concentration in the cells after adding saturated compounds, and set as 0% for the rate of increase of Ca²⁺concentrations in cells adding only media, built nonlinear regression curve and the concentration that causes agonistic action, which is 50% of maximum response, was defined as the value of EC₅₀(nm).

The test example 2: Assessment of reduction in the number of lymphocytes in peripheral blood in rats

Effect on peripheral blood lymphocytes was evaluated using rats. 6-10-week-old male Lewis rats (Japan Charles River Laboratories Japan, Inc.) randomly divided into groups (n=3) and the compound of the present invention suspended in containing 0.5% methylcellulose distilled water and orally injected through the probe. At time 4 hours or 24 hours after injection, gathered 0.2 ml of blood from the fundus of the eye under ether anesthesia. The blood sample craze was added EDTA·4K and heparin to prevent clotting and STA is in lymphocytes in the blood was measured using an automatic analyzer of blood corpuscles (Sysmex Corp.; XT-2000i). To determine the reduction in the number of lymphocytes in the peripheral blood of a compound of the present invention used the percentage set as 100% for the number of lymphocytes in groups, which was carried out by an introduction containing 0.5% methylcellulose with distilled water, and the dose which causes a 50% decrease in the number of lymphocytes in the peripheral blood by introducing compounds of the present invention, defined as the value of the ED₅₀(mg/kg).

The results of test Example 1 and test Example 2 for some compounds of formula (I) are presented in Tables 1 and 2. In the tables, column A shows the in vitro effects of agonist S1P₁EC₅₀values (nm)obtained by the method 1 of test Example 1, and the value with * shows EC₅₀values measured by method 2. In addition, column B shows the effect of reduction in the number of lymphocytes in the peripheral blood at the time of 4 hours or 24 hours after administration of the medicinal product of test Example 2, with the values presented ED₅₀4 hour (mg/kg) or ED₅₀24 hour (mg/kg), respectively.

As shown in Table 1 and 2, it was confirmed that the compound of formula (I) according to the present invention has an excellent effect of agonist S1P₁and has a strong effect in reducing the number of lymphocytes in perifericos the th blood, even after 4 hours or 24 hours after administration in pharmacological test using rats.

The test example 3: estimation of the increase of the weight of the lung in rats

Estimated increased mass of the lung in rats, one of the undesirable effects observed for traditional S1P₁agonist. 6-10-week-old male Lewis rats or rats SD (Japan Charles River Laboratories Japan, Inc.) randomly divided into groups (n=3 to 4) and the compound of the present invention suspended in containing 0.5% methylcellulose distilled water and orally injected through the probe. For a single injection, at the time 24 hours after the introduction of the weight of the rats was measured, blood was removed under anesthesia by pentobarbital and lung were removed and measured its mass. For re-introduction, the administration was carried out once a day for 7 days and in the time 24 hours after the final injection was measured body weight and the weight of the lung. For increased mass of the lung, the increase in the average value of the corresponding bulk values of the group, which has introduced a suspension of the compounds according to the present invention containing 0.5% methylcellulose distilled water relative to the mean value of the corresponding mass mn of the values group, which was introduced containing 0.5% methylcellulose distilled water was determined as a percentage, and enter the number that shows 10% or more increase in weight was determined as positive.

It was confirmed that the compounds of the present invention compounds of Examples 31, 43, 44, 45, 56, 62, 66, 69, 74, 81, 85, 89, 109, 116, 137, 143, 149, 151, 152, 160, 171, 178, 181, 183, 212, 216, 223, 230 and 236 provide an increase in the mass of light less than 10%, even at the dose of 1 mg/kg, and have a weak effect on the lungs.

The test example 4: Evaluation of inhibitory effect on rejection in heterotopic rat model of abdominal heart transplant

Heterotopic rat model of abdominal heart transplant can be performed in accordance with the method of Ono and Lindsey (Transplantation, 1969, 517, pp. 225-229). As a donor used 6-8-week-old male ACI rats (CLEA Japan, Inc.) and the heart was exposed under anesthesia by pentobarbital. Right and left Vena cava, other than the aorta, and the pulmonary artery, pulmonary vein and the inferior Vena cava immediately ligated and the aorta and the pulmonary vein is separated and removed as needed. 6-8-week-old male Lewis rats (Japan Charles River Laboratories Japan, Inc.) used as recipients. Under anesthesia pentobarbital, the end of the pulmonary artery graft and abdominal aorta of the recipient connected with anastomosis and end pulmonary artery the graft and Vena cava of the recipient connected by anastomosis with getting models (shared by groups of 6-10 examples per group). Definition of rejection transplanted heart helps abdominal palpation recipient every 29 days after transplantation, and the presence or absence of pulsation of the graft is determined by exclusion. The compound of the present invention suspended in containing 0.5% methylcellulose distilled water and orally was administered once or twice daily for 14 days after transplantation. As a control, oral introduced containing 0.5% methylcellulose distilled water the same number of times during the same period of time. Simultaneously administered by intramuscular 0.02 mg/ml/kg of tacrolimus all animal groups. Using this test determined the effect of the compounds of the present invention for the inhibition of rejection when using tacrolimus in combination.

The test example 5: Evaluation expressed a rare heart rate with the use of awake rats

Male Lewis rats were anestesiologi via inhalation with isoflurane and a polyethylene tube was inserted in the femoral artery and vein. The tube was connected with a device for measuring blood pressure•heart rate via the pressure sensor from the arterial line and measured blood pressure and heart rate. Continually introducing intravenous infusion, including Wear is spruce (10% HCO40/tween80/PEG, 90% saline) and compounds of the present invention, with a speed of 1 ml/kg/min for 10 minutes. The measurements were read (the total time estimate 20 minutes) from a table of values before the introduction, in the time points 1, 2, 5 and 10 minutes after the start of continuous infusion and 1, 2, 5 and 10 minutes after completion of infusion and, thus, with regard to heart rate and blood pressure prior to introduction, the expected speed reduction (%) before and after infusion.

It was confirmed that the compounds of the present invention, for example, the compound of Example 230 does not influence heart rate and blood pressure at a dose injection of 1 mg/kg, according to this assessment and rare pulse is not observed.

As results from the above tests, it was confirmed that the compound of formula (I) according to the present invention has an excellent effect of agonist S1P₁and has the effect of inhibiting the infiltration of lymphocytes. In addition, as shown in the Examples, tests 3 and 4 above, illustrative compounds of some variants of the embodiment of the present invention may have the effect of agonist S1P₁that has little adverse effects, such as observed in traditional S1P₁agonists, such as the increased weight of the lung, a rare pulse and the like, and minor the side effects.

Accordingly, the compound of formula (I) according to the present invention is useful for prevention or treatment of diseases induced unwanted infiltration of lymphocytes, for example, reactions of rejection or graft versus host for the transplantation of organs, bone marrow, or tissues, autoimmune diseases or inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, meningoencephalitis, severe myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, pulmonary disease, bronchial asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemic reperfusion disorder and the like, and diseases, caused by abnormal proliferation or accumulation of cells, such as cancer, leukemia and the like, in particular, for the prevention or treatment of rejection reactions or graft versus host for the transplantation of organs, bone marrow or tissue and multiple sclerosis.

In addition, the compound of the present invention can be entered as S1P₁agonist alone or in combination with at least one tool, in the same or different doses of the same or different by introducing. Examples of agents for use in combination include, but are not limited to those who, cyclosporine A, tacrolimus, sirolimus, everolimus, mycophenolate, azathioprine, brequinar, Leflunomide, fingolimod, the antibody against IL-2 receptor (e.g., daclizumab and the like), anti-CD3 antibody (e.g., OKT3), anti-T-cell immunoglobulin (for example, AtGam, and the like), belatacept, abatacept, cyclophosphamide, β-interferon, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, a steroidal anti-inflammatory agent (for example, prednisolone and dexamethasone) and the like.

Pharmaceutical composition, containing one or two or more types of the compounds of formula (I) or its salt as an active ingredient, can be obtained with the use of excipients that are commonly used in this field, i.e. of excipients for pharmaceuticals, carriers for pharmaceuticals and the like, in accordance with methods that are usually used.

The introduction can be done either by oral administration via tablets, pills, capsules, granules, powders, solutions and the like, or by parenteral administration via injections such as intravascular, intravenous or intramuscular injection and the like, suppositories, ophthalmic solutions, ophthalmic ointments, percutaneous liquid preparations, ointments, transdermal patches, liquid preparations for administration through mucosa, patches to bring the Oia through the mucous membrane, inhalations and the like.

A solid composition for oral use in the form of tablets, powders, granules or the like In such solid compositions one or more active ingredients are mixed with at least one inactive excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, alumosilicate magnesium and/or services In accordance with the conventional method, the composition may contain inactive additives, including lubricants, such as magnesium stearate and the like, disintegrant, such as sodium carboximetilkrahmal, stabilizers and substances that promote solubilization. If necessary, tablets or pills may be sugar coating or film coating of the gastro - or Intercollege substances.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs or the like, and contains a generally used inert diluents, for example, distilled water or ethanol. In addition to the inert diluent, the liquid composition may also contain auxiliary substances, such as a substance that promotes solubilization, wetting agent and suspendisse substance, as well as sweeteners, flavors, fragrances and anti is atiki.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. As the aqueous solvent, for example, included distilled water for injection or physiological saline. Examples of non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and the like, alcohols such as ethanol and the like, Polysorbate 80 (pharmacopeia), etc. such composition may further contain an agent toychest, antiseptics, wetting agent, emulsifier, dispersing agent, stabilizer or substances that promote solubilization. The composition is sterilized, for example by means of filtration through retaining bacteria filter, mixing with bactericides or irradiation. In addition, they can also be used by obtaining sterile solid compositions and dissolving or suspension of such compositions in sterile water or a sterile solvent for injection before use.

Examples of drugs for external use include ointments, plasters, creams, jellies, patches, sprays, lotions, eye drops, eye ointments and the like. The drug contains commonly used bases for ointments, foundations for lotions, aqueous or non-aqueous liquid preparations, suspensions, Amul the FIC or the like Examples of bases for ointments or base for lotions include polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylene-gidrirovannoe castor oil, glycerylmonostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, servicesecurity and similar substances.

As for the means for insertion through the mucous membrane, such as a drug for inhalation, a means for insertion through the nose, etc. use the funds for insertion through the mucous membrane in solid, liquid or semi-solid form, and can be obtained in accordance with the well-known way. For example, you can appropriately add a known excipient, as well as pH control agent, an antiseptic, a surfactant, a lubricating substance, stabilizer, thickener or the like For introducing them, you can use a suitable device for inhalation or insufflation. For example, the connection can be entered separately or as a mixture, formulated into a powder, or in solution or suspension, by combining with pharmaceutically acceptable carrier, using widely known device or atomizer, such as a device for introducing a metered doses by inhalation and the like. Inhaler dry powder or the like may be designed for single or mnogokrat the CSOs introduction, and you can use dry powder or containing powder capsule. Alternatively, it may be in the form of a pressurized aerosol spray, in which the use of a suitable propellant, for example, chlorphenesin, hydroforce, or a suitable gas, such as carbon dioxide and the like.

Usually, in the case of oral administration, is suitable daily dose is from about 0.001 to 100 mg/kg body weight, preferably from 0.1 to 30 mg/kg, and more preferably from 0.1 to 10 mg/kg, and administered as a single dose or divided into 2-4 parts. In the case of intravenous administration, is suitable daily dose is from about 0.0001 to 10 mg/kg of body weight, and it is administered once a day, or two or more times a day. In addition, the means for insertion through the mucous membrane is administered at a dose of from about 0.001 to 100 mg/kg of body weight, and it is administered once a day, or two or more times a day. The dose is appropriately determined taking into account the specific case, taking into account the symptoms, age, gender, and similar factors.

The compound of formula (I) can be used in combination with various methods for treatment or prevention of diseases, where the compound of formula (I)described above is effective. Combined drug can be administered simultaneously or separately, continuously or with the desired intervals. P is aparaty for simultaneous administration can be a mixture or can be obtained separately.

EXAMPLES

In addition, the following abbreviations can be used in some cases in the Examples, the Examples of obtaining and Tables described below.

Prpol. = No. of sample receipt, Etc. = No. Of Example, Sylp = No. Of Reference Example Page. = Structural formula MS = Mass spectrometry data, ESI (EI) = Data analysis ionization elektrorazpredelenie, FAB = Mass spectrometry data in accordance with the method of ionization by fast atom bombardment, Hz = Hertz, CDCl₃= deuterated chloroform, DMSO-d₆= dimethylsulfoxide d₆.

Also, transverse double bonds in the structural formula means a mixture of CIS-form and TRANS-form. Data¹H-NMR, tetramethylsilane was used as internal standard, unless specifically stated otherwise, and δ (ppm) (integrated value, the pattern of splitting signals in¹H-NMR, where DMSO-d₆used as a solvent for measurement. In the present description, the NMR is a¹H-NMR: Proton Nuclear Magnetic Resonance. In addition, the signs + and - MS and ESI (EI), each represents a positive and negative mass values.

Example obtain 1

7-[(5-Bromo-4-phenyl-2-thienyl)methoxy]-2H-chromen-3-carbaldehyde (120 mg) was dissolved in DMF (2.4 ml). To this reaction liquid was added Zn(CN)₂(65 ml) and Pd(PPh₃)_{4 (65 mg) at room temperature. The reaction mixture was stirred at 100°C for 5 hours and then poured into 1:1 mixed solvent consisting of an aqueous solution of NaHCO3and EtOAc, followed by stirring for 1 hour. The organic layer was washed with saturated saline solution, dried over MgSO4and then concentrated under reduced pressure, followed by purification using column chromatography on silica gel (hexane:EtOAc=100:0 to 70:30) to obtain 5-{[(3-formyl-2H-chromen-7-yl)oxy]methyl}-3-phenylthiophene-2-carbonitrile (83 mg) as a pale yellow solid.}

Example of getting 2

To a solution of methyl 5-bromo-4-phenylthiophene-2-carboxylate in dioxane was added 2-Isopropenyl-4,4,5,5-tetramethyl 1,3,2-dioxaborolan and 2 M aqueous solution of Na₂CO₃. To the reaction mixture was added palladium acetate and PPh₃followed by stirring at 100°C for 5 hours. After left to cool, to this mixture was added a saturated aqueous solution of NH₄Cl followed by extraction using EtOAc. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure, followed by purification using column chromatography on silica gel (hexane:EtOAc=95:5 to 80:20) to obtain methyl 5-Isopropenyl-4-phenylthiophene-2-carboxyl is in the form of colorless liquid.

In the same manner as in Example getting 2 got connection Example of getting 2-1 - Example of getting 2-4 shown in the following tables.

Example for the preparation of 3

To a solution of DMF (2 ml) in DHM (3 ml) was added dropwise POCl₃(2 ml) at 0°C, followed by stirring at room temperature for 30 minutes. Then to the reaction liquid was added dropwise 8-(benzyloxy-3,4-dihydro-1-benzoxazepin-5(2H)-he DHM (4 ml), followed by stirring at room temperature for 1 hour and at 50°C for 3 hours. To the reaction liquid was added water, followed by extraction two times with the aid of EtOAc. The organic layer was combined, washed with water and saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning; hexane:EtOAc=97:3 to 90:10) to give 8-(benzyloxy)-5-chloro-2,3-dihydro-1-benzoxazin-4-carbaldehyde (445 mg).

Example 4

To a solution of DMF (2 ml) in DHM (7.5 ml) was added dropwise POCl₃(1.39 ml) at 0°C, followed by stirring at room temperature for 30 minutes. Then to the reaction liquid was added dropwise a solution of 7-{[tert-butyl(diphenyl)silyl]oxy}-2,3-dihydro-4H-chromen-4-it (2.00 g) in DHM (11 ml) with subsequent premesis is observed at room temperature for 1 hour and at 50°C for 3 hours. To the reaction liquid was added water, followed by extraction using EtOAc twice. The organic layer was combined, washed with water and saturated saline and was dried over MgSO₄and the liquid was concentrated. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 80:20) to give 4-chloro-7-hydroxy-2H-chromen-3-carbaldehyde (720 mg).

Example of getting 5

7-(benzyloxy)-2,3-dihydro-4H-chromen-4-one was dissolved in THF, and to this mixture was added dropwise a solution of (0,97 M, 5 ml) methylacrylamide in THF at 0°C, followed by stirring at room temperature for 1 hour and then was added dropwise a solution of (0,97 M, 5 ml) methylacrylamide in THF, followed by stirring at room temperature for 2 hours. To the reaction liquid was added a saturated aqueous solution of NH₄Cl and then 2 M hydrochloric acid solution (20 ml) followed by stirring at room temperature for 2 hours and then was extracted using EtOAc three times. The organic layer was combined, washed with water and saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=95:5 d is 90:10) to give 7-(benzyloxy)-4-methyl-2H-chromene (445 mg) as a colorless transparent liquid.

In the same manner as in Example getting 5 got connection Example of getting 5-1 presented in the following tables.

An example of obtaining 6

To a solution of 2-hydroxy-4-[(2-methoxy-4-propylenoxide)methyl]benzaldehyde (120 mg) in dioxane (2.4 ml) at 25°C was added K₂CO₃(55,2 mg) and acrolein (0,267 ml). The reaction mixture was heated to 100°C, followed by stirring at 100°C for 15 hours. The reaction mixture was left to warm to 25°C and then filtered through celite and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 80:20) to obtain 7-[(2-methoxy-4-propylenoxide)methyl]-2H-chromen-3-carbaldehyde (104,2 mg) as colorless liquid.

In the same way as in the Example of a 6 got connection Example of obtaining 6-1 Sample receiving 6-9 and Example of getting 6-11 shown in the following tables.

Example of getting 6-10

K₂CO₃(835 mg) suspended in dioxane (40 ml) and to this mixture was added 2-hydroxy-4-(methoxyethoxy)benzaldehyde (1 g) and 3-methyl-2-butenal (0,787 ml) followed by stirring at 110°C over night. To this mixture was added EtOAc, insoluble substances were removed by filtration through celite and the filtrate was concentrated under reduced pressure. The mod is to purified using column chromatography on silica gel (automatic cleaning device, a mixture of hexane:EtOAc=95:5 to 70:30) to give 7-(methoxyethoxy)-2,2-dimethyl-2H-chromen-3-carbaldehyde (320 mg) as a yellow oil.

Example of getting 7

At 0°C to a stirred solution of concentrated HCl (8 ml) and AcOH (1.6 ml) was added tert-butyl 3-cyano-3-(permitil)azetidin-1-carboxylate (800 mg). The liquid was heated to 25°C, followed by stirring at 25°C for 1 hour and then at 100°C for 5 hours. The reaction liquid was concentrated under reduced pressure, followed by azeotropic distillation with toluene (30 ml) three times. The residue was dissolved in a mixed solvent of acetone (4.8 ml) and water (8.0 ml) and at 0°C. to this mixture was added Na₂CO₃(593,7 mg) and DIBOC (1223 mg). The reaction liquid was heated to 25°C, followed by stirring at 25°C for 15 hours. After fifteen hours, the reaction solution was concentrated and the acetone evaporated. The residue was extracted three times (50 ml ×3) by adding ether (50 ml). The aqueous layer were combined and cooled to 0°C and at 0°C. to this mixture was added 2 M HCl solution (10 ml) to obtain a solution at pH=2-3. The precipitated solid white substance was collected by filtration and washed with hexane (50 ml) to give 1-(tert-butoxycarbonyl)-3-(permitil)azetidin 3-carbonous acid (801,2 mg) as a white solid.

Example obtain 8

tert-Butyl 3-cyano-3-(hydroxymet the l)azetidin-1-carboxylate (5.0 g) was dissolved in DHM (100 ml). To this mixture was added at 0°C. DAST (3,74 ml) followed by stirring at 0°C for 3 hours. After three hours, to the reaction liquid was added an aqueous solution of NaHCO₃(100 ml) followed by extraction using DHM (50 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 50:50) to give tert-butyl 3-cyano-3-(permitil)azetidin-1-carboxylate (1.24 g) as a brown solid.

Example of getting 9

2-Fluoro-4,6-dihydroxybenzaldehyde (12 g) was dissolved in MeCN (250 ml) and to this mixture was added cesium carbonate (25.1 g) and chloromethylation ether (6,95 ml) followed by stirring at room temperature for 1 hour. Insoluble substances were removed by filtration through celite and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 94:6) to give 2-fluoro-6-hydroxy-4-(methoxyethoxy)benzaldehyde (11,89 g) as a white powder.

In the same way as in the Example of a 9 got connection Example of getting 9-1 Sample receiving 9-4 shown in the following tables.

Example 10

₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=90:10 to 80:20) to give 7-{[tert-butyl(diphenyl)silyl]oxy}-2,3-dihydro-4H-chromen-4-it (of 2.08 g) as a colorless transparent syrup.

In the same manner as in Example 10, was received connection Example of obtaining 10-1 presented in the following tables.

Example of getting 11

To a solution of 7-hydroxy-2H-chromen-3-carbaldehyde in DHM at 0°C was added pyridine. To the reaction liquid at 0°C was added dropwise triftormetilfullerenov anhydride. After stirring at room temperature for 1 hour to the mixture at 0°C was added water. The mixture was extracted using EtOAc. The organic layer washed with 1 M HCl solution, water and saturated saline in that order, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc=95:5 to 80:20) to give 3-formyl-2H-chromen-7-yl triftoratsetata in the form of a yellow Mac is anago substances.

In the same manner as in Example receiving 11, received the compound of Example obtaining 11-1 presented in the following tables.

Example 12

To DMF (1 ml) was added dropwise POCl₃(0.25 ml) at 0°C, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added dropwise a solution of 7-(benzyloxy)-4-methyl-2H-chromene (280 mg) in DHM (1 ml) followed by stirring at room temperature for 3 hours. The reaction liquid was poured into a mixture of ice water followed by extraction using EtOAc three times. The organic layer was combined, washed with water and saturated saline in that order, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=85:15 to 70:30) to give 7-(benzyloxy)-4-methyl-2H-chromen-3-carbaldehyde (234 mg) as a pale yellow powder.

In the same manner as in Example 12, the compound of Example obtaining 12-4 was obtained from the compound of Example obtaining 12-1 presented in the following tables.

Example of getting 13

A solution of NaH (105,63 mg) in DMF (5.5 ml) was cooled to 0°C and to this mixture was added methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(diethoxyphosphoryl)methyl]benzoate (550 mg)Reaktsionnuyu the mixture was heated to 25°C, then was stirred for 1 hour and again cooled to 0°C and to this mixture was added 2-methoxy-4-propylbenzamide (235,34 mg). The reaction mixture was heated to 25°C and then stirred for 15 hours. To the reaction liquid was added a saturated aqueous solution of NH₄Cl (50 ml) followed by extraction using EtOAc (50 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 70:30) to obtain methyl 2-hydroxy-4-[(E)-2-(2-methoxy-4-propylphenyl)vinyl]benzoate (304,2 mg) as a white solid.

In the same manner as in Example receiving 13, received the compound of Example obtaining 13-1 presented in the following tables.

Example of getting 14

To DMF (40 ml) under ice cooling was added a 60% solution of NaH (634 mg) and to this mixture was slowly added a solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (2 g) in DMF (20 ml). After stirring at room temperature for 5 hours, the reaction was suppressed with saturated solution of NH₄Cl followed by extraction using EtOAc. The organic layer was washed with saturated saline solution, dried over MgSO₄and then filtered. The filtrate was concentrated with the floor is the group of 4-isopropoxy-3-(trifluoromethyl)benzonitrile (2.4 g) as a pale yellow solid.

In the same way as in the Example of a 14 received connection Example of getting 14-1 Sample receiving 14-16 listed in the following tables.

Example get 15

To a solution of methyl 4-fluoro-2-(trifluoromethyl)benzoate in DMF was added K₂CO₃and piperidine, followed by stirring at 100°C for 3 hours. The reaction mixture was cooled to 0°C and to this mixture was added water, followed by extraction using EtOAc. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc=100:0 to 90:10) to give methyl 4-piperidine-1-yl-2-(trifluoromethyl)benzoate as a colorless oily substance.

In the same way as in the Example of a 15 received connection Example of getting 15-1 Sample receiving 15-4 shown in the following tables.

Example 16

To a solution of methyl 1H-indole-5-carboxylate (1.5 g) in DMF (30 ml) at 0°C was added NaH (410 mg). The reaction mixture was heated to 25°C followed by stirring for 0.5 hours. Then the reaction mixture was again cooled to 0°C and then to this mixture was added methyliodide (1,38 ml). The reaction mixture was heated to 25°C followed by stirring for 3 hours. To the reaction liquid which was added water (50 ml) followed by extraction using EtOAc (50 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic purification, a mixture of CHCl₃:MeOH=100:0 to 98:2) to obtain methyl 1-ethyl-1H-indole-5-carboxylate (1465 mg) as a white solid.

Example of getting 17

To a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid in MeOH at 0°C was added concentrated sulfuric acid. The reaction mixture was heated and boiled under reflux for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was diluted using EtOAc. The organic layer was washed saturated aqueous NaHCO₃, dried over MgSO₄and then concentrated under reduced pressure to obtain methyl 4-fluoro-2-(trifluoromethyl)benzoate as a colorless oily substance.

Example of getting 18

To a suspension of 4-bromo-5-ethylthiophen-2-carboxylic acid (800 mg) in MeOH (4 ml) at 0°C was added dropwise SOCl₂(0,50 ml). The reaction mixture was stirred at 0°C for 1 hour, heated to 60°C and then stirred for 15 hours. The reaction liquid was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning is, a mixture of hexane:EtOAc=98:2 to 70:30) to give methyl 4-bromo-5-ethylthiophen-2-carboxylate (765,0 mg) as colorless liquid.

In the same manner as in Example receiving 18, received a connection Example of getting 18-1 Sample receiving 18-6 shown in the following tables.

Example of getting 19

To a solution of N-isopropylparaben-2-amine (165,5 mg) in THF (1 ml) at -78°C was added dropwise a solution of n-utility in hexane (1,6 M and 0.98 ml) followed by warming to 25°C and followed by stirring for 30 minutes. After re-cooling to -78°C to the mixture was added dropwise a solution of 1-tert-butyl-3-methylpyrrolidine-1,3-in primary forms (300 mg) in THF (1 ml). The reaction mixture was heated to -40°C and then was stirred for 1 hour. The reaction mixture was again cooled to -78°C and to this mixture was added dropwise a solution of N-fluoro-N-(phenylsulfonyl)benzosulfimide (495,1 mg) in THF (1 ml). The reaction mixture was stirred at -78°C for 1 hour, then heated to 25°C and was stirred for 15 hours. Fifteen hours to the reaction liquid was added a saturated aqueous solution of NH₄Cl (30 ml) followed by extraction using EtOAc (30 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using a column of chromatography the on silica gel (automatic cleaning device, a mixture of hexane:EtOAc=100:0 to 80:20) to give 1-tert-butyl 3-methyl-3-ftorpirimidinu-1,3-in primary forms (154,3 mg) as a yellow liquid.

Example of getting 20

To a solution of methyl 4-phenylthiophene-2-carboxylate (1.8 g) in DHM (18 ml) at 0°C portions was added pyridinecarboxamide (13,2 g). The reaction liquid was heated to 25°C and then was stirred for 45 hours. The reaction mixture was cooled to 0°C and slowly was added dropwise a saturated aqueous solution of Na₂S₂O₃(100 ml). The reaction mixture was extracted using DHM (50 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 90:10) to give methyl 5-bromo-4-phenylthiophene-2-carboxylate (of 2.06 g) as a colourless liquid.

Example of getting 21

To a solution of 4-chloro-5,5,5-Cryptor-3-finalment-3-EN-2-it (950 mg) and methylsulfonylamino (446 mg) in MeCN (23,8 ml) at 25°C was added dropwise DBU (0.63 ml), followed by stirring at the same temperature for 15 hours. To the reaction liquid was added a saturated aqueous solution of NH₄Cl (50 ml) followed by extraction with diethyl ether (50 ml) three times. The organic layer was washed with saturated saline solution, sushi is whether over MgSO ₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=98:2 to 90:0) to give methyl 3-methyl-4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylate (1.08 g) as a colourless liquid.

Example of getting 22

To a solution of benzyl 3-cyanopyrrolidine-1-carboxylate (1.0 g) and TEA hydrochloride (2,99 g) in toluene at 25°C was added sodium azide (1,41 g) followed by stirring at 115°C for 5 hours. The reaction liquid was left to cool and to this mixture was added DHM (10 ml). Then 5% aqueous solution of salicylic acid (100 ml) was added dropwise to the reaction liquid, followed by stirring at 25°C for 1 hour. The reaction liquid was extracted using EtOAc (30 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 80:20) to give benzyl 3-(1H-tetrazol-5-yl)pyrrolidin-1-carboxylate (10.8 g) as a colourless liquid.

An example of retrieving 23

To a solution of methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-methylbenzoate (3.4 g) in carbon tetrachloride (68 ml) was added NBS (2.16 g) and to this mixture at anatoy temperature was added AIBN (398 mg), followed by stirring at 80°C for 1 hour. Completion of reaction was confirmed by indicators of TLC and for stopping the reaction to the reaction liquid was added water, followed by extraction using EtOAc. The organic layer was washed with saturated saline solution, dried using MgSO₄, and then concentrated under reduced pressure, followed by purification using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 95:5) to give methyl 4-(methyl bromide)-2-{[tert-butyl(dimethyl)silyl]oxy}benzoate (3,79 g) as a colourless liquid.

Example of getting 23-1

To a solution of (2S)-3-(4-chlorophenyl)-2-methylpropan-1-ol (300 mg) in DHM (20 ml) under ice cooling was added N-bromosuccinimide (347 mg) and triphenylphosphine (511 mg). The reaction liquid was stirred at room temperature for 2 hours and then the reaction liquid was poured into water followed by extraction with chloroform. The organic layer was washed with saturated saline and was dried over MgSO₄and then the solvent is evaporated under reduced pressure. The residue was subjected to purification using column chromatography on silica gel (hexane:EtOAc=100:0 to 90:10) to obtain 1-[(2S)-3-bromo-2-methylpropyl]-4-chlorobenzene (373 mg) as colorless liquid.

Example of getting 24

To a solution of N-isopropylparaben-2-amine (11,54 ml) in THF (50 ml) at -78°Dobavlyali dropwise a solution of n-utility in hexane (1,6 M, 51,45 ml). The reaction mixture was heated to 0°C and then stirred for 30 minutes. The reaction mixture was again cooled to -78°C and then was added dropwise a solution of tert-butyl 3-cyanoacetate-1-carboxylate (5.0 g) in THF (30 ml) followed by stirring at -78°C for 1 hour. To the reaction mixture at -78°C was added dropwise a solution of 1H-benzotriazol-1-yl-methanol (8,19 g) in THF (20 ml) followed by stirring at -78°C for 3 hours. To the reaction mixture were added saturated aqueous solution of NH₄Cl (100 ml) followed by extraction using EtOAc (50 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 50:50) to give tert-butyl 3-cyano-3-(hydroxymethyl)azetidin-1-carboxylate (of 5.68 g) as a white solid.

Example get 25

A solution of methyl 4-amino-(2-trifluoromethyl)benzotrichloride (1.24 g) and 2,5-dimethoxytetrahydrofuran (773 mg) in AcOH (20 ml) was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure and subjected to azeotropic distillation with toluene, and AcOH evaporated. The obtained yellowish-brown oily substance was dissolved in chloroform and the mixture was added saturated aqueous solution of NaHCO ₃. The organic layer was washed saturated aqueous NaHCO₃, water and saturated saline in that order, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (mixture of CHCl₃:MeOH=97:3) to give methyl 4-(1H-pyrrolo-1-yl)-2-(trifluoromethyl)benzoate (to 11.8 g).

In the same way as in the Example of obtaining 25, received a connection Example of getting 25-1 presented in the following tables.

Example of getting 26

To a solution of trimethyl(Pro-1-IDU-1-yl)silane (877 mg) in THF (60 ml) at -78°C was added a solution of n-BuLi in hexane (1,58 M, 4.5 ml). The reaction mixture was stirred at -78°C for 3 hours and then to this mixture was added dropwise a solution of 1-(methyl bromide)-2,4-bis(trifluoromethyl)benzene (2 g) in THF (10 ml) followed by stirring for 1 hour. To the reaction liquid was added an aqueous solution of NH₄Cl followed by extraction with ether. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc=100:0) to give {4-[2,4-bis(trifluoromethyl)phenyl]but-1-in-1-yl}(trimethyl)silane (1.8 g) as a colourless liquid.

Example of getting 27

1-(chloromethyl)-2-methods the C-4-propylbenzoyl (1.1 g) was dissolved in DMF (20 ml) and to this mixture was added 7-hydroxy-2H-chromen-3-carbaldehyde (975 mg) and K ₂CO₃(1,15 g), followed by stirring at 80°C for 1 hour. Next, to this mixture was added sodium iodide (416 mg), followed by stirring at 80°C for 1 hour. After confirming completion of the reaction to the reaction liquid were added water to stop the reaction, followed by extraction using EtOAc three times. The organic layer was combined, washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=95:5 to 80:20) to obtain 7-[(2-methoxy-4-propylbenzyl)oxy]-2H-chromen-3-carbaldehyde (1,21 g) as a yellow powder.

In the same manner as in Example obtaining a 27, the received connection Example of getting 27-1 Sample receiving 27-6 shown in the following tables.

Example of getting 28

7-Hydroxy-2H-chromen-3-carbaldehyde (200 mg) was dissolved in DMF (5 ml) and to this mixture was added K₂CO₃(235 mg) and 1-(methyl bromide)-2,4-bis(trifluoromethyl)benzene (0,234 ml) followed by stirring at 80°C for 30 minutes. The reaction liquid was poured into water and the resulting powder was collected by filtration and dried under reduced pressure to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-2H-chromen-3-carbaldehyde (455 mg) in the form of b is edno-yellow powder.

In the same manner as in Example receiving 28, received a connection Example of getting 28-1 Sample receiving 28-27 shown in the following tables.

An example of obtaining 29

To a solution of 3-formyl-2H-chromen-7-intraformational (520 mg) in DMF (10.4 ml) at room temperature was added 1-ethinyl-4-(trifluoromethyl)benzene (330 μl), dichloride, bis(triphenylphosphine)palladium(II) (355 mg) and copper iodide(I) (161 mg) and TEA (470 μl). The reaction mixture was stirred at 100°C for 5 hours. To the reaction mixture was added water under ice cooling, the undissolved substance was separated by filtration and the filtrate was extracted using EtOAc. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc) to give 7-{[4-(trifluoromethyl)phenyl]ethinyl}-2H-chromen-3-carbaldehyde (189 mg).

In the same manner as in Example receiving 29, received a connection with an Example of obtaining 29-1 to Example getting 29-15 shown in the following tables.

Example 30

To a solution of Pd(PPh₃)₄(542 mg) and TEA (4 ml) in DMF (16 ml) at room temperature was added 1-bromo-4-isobutylbenzene (1 g) and ethinyl(trimethyl)silane (553 mg), followed by stirring at 60°C for 4 hours. To the PE klonoa liquid was added 1 M hydrochloric acid solution, followed by extraction with ether. Undissolved matter was filtered through celite. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane) to give [(4-isobutylphenyl)ethinyl](trimethyl)silane (459 mg) as a yellow liquid.

In the same manner as in Example 30, the received connection Example of getting 30-1 presented in the following tables.

An example of retrieving 31

To a solution of copper chloride (10 mg) and Pd(PPh₃)₄(60 mg) in DMF (2 ml) at room temperature was added [(4-isobutylphenyl)ethinyl](trimethyl)silane (288 mg) and 5-fluoro-3-formyl-2H-chromen-7-intraformational (340 mg), followed by stirring at 80°C for 12 hours. The reaction liquid was concentrated and the residue was purified using column chromatography on silica gel (CHCl₃) to obtain 5-fluoro-7-[(4-isobutylphenyl)ethinyl]-2H-chromen-3-carbaldehyde (83 mg) as a yellow solid.

In the same manner as in Example receiving 31, received the compound of Example obtaining 31-1 presented in the following tables.

Example of getting 32

To a solution of 1-[4-phenyl-5-(trifluoromethyl)-2-thienyl]ethanone (1.0 g) in THF (20 ml) at -78°C was added dropwise DIBAL (0,99 M solution in toluene, 9,34 ml). The reaction mixture is load the Wali to 25°C and was stirred for 3 hours and to this mixture was added a saturated aqueous solution of Rochelle salt (50 ml) followed by extraction using EtOAc (50 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=98:2 to 90:10) to give 1-[4-phenyl-5-(trifluoromethyl)-2-thienyl]ethanol (0,99 g) as a colourless liquid.

An example of obtaining 33

To a solution of 3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]benzoic acid (1,085 g) in THF (43 ml) at 0°C was added dropwise a solution of BH₃·THF in THF (1 M, 14 ml). The reaction mixture was heated to room temperature and then was stirred for 15 hours. To the reaction liquid at 0°C was added 1 M hydrochloric acid solution to stop the reaction, followed by stirring for 30 minutes and extracted using EtOAc. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure to obtain {3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]phenyl}methanol (570 mg) as a white oily substance.

In the same way as in the Example of obtaining 33, received a connection Example of getting 33-1 Sample receiving 33-21 shown in the following tables.

An example of retrieving 34

To a solution of methyl 4-piperidine-1-yl-2-(trifluoromethyl)benzoate (955 mg) in THF (19 ml)under ice cooling was added dropwise a solution of DIBAL in hexane (1 M, 10.0 ml), followed by stirring at the same temperature for 2 hours. To the reaction liquid was added dropwise MeOH and then to this mixture was added a saturated aqueous solution of Rochelle salt, followed by stirring at room temperature for 1 hour. The mixture was extracted using EtOAc and the organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The obtained residue was purified using column chromatography on silica gel (hexane:EtOAc) to give[4-piperidine-1-yl-2-(trifluoromethyl)phenyl]methanol (846 mg).

In the same manner as in Example obtain 34, received a connection Example of getting 34-1 Sample receiving 34-30 shown in the following tables.

Example of getting 35

Methyl 2-hydroxy-4-[(2-methoxy-4-propylenoxide)methyl]benzoate (300 mg) was dissolved in THF (15 ml). To the reaction liquid at 0°C was added LAH (103,4 mg) followed by heating from 0°C to 25°C and stirring for 3 hours. To the reaction liquid was added a saturated aqueous solution of Rochelle salt (30 ml) followed by extraction using EtOAc (30 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using a column of chromatogr is the philosophy on silica gel (automatic cleaning device, a mixture of hexane:EtOAc=100:0 to 80:20) to give 2-(hydroxymethyl)-5-[(2-methoxy-4-propylenoxide)methyl]phenol (245,2 mg) as a white solid.

In the same manner as in Example receiving 35, received a connection Example of getting 35-1 Sample receiving 35-3 shown in the following tables.

Example of getting 36

To a solution of NaBH₄(br93.1 mg) in EtOH (15 ml) was added dropwise a solution of 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-2,3-dihydro-4H-thiochroman-4-it (1.0 g) in EtOH (5 ml) at 0°C. the Reaction mixture was heated to 25°C followed by stirring for 3 hours. The reaction liquid was concentrated under reduced pressure and to the residue at 0°C was added DHM (20 ml) and then saturated aqueous solution of NH₄Cl (30 ml) followed by stirring for 1 hour and extraction using DHM three times (30 ml ×3). The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 60:40) to give 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}thiochroman-4-ol (845 mg) as a white solid.

In the same manner as in Example receive 36, received a connection Example of getting 36-1 Sample receiving 36-2 shown in the following tables./p>

An example of retrieving 37

At normal pressure in an atmosphere of gaseous hydrogen to a solution of methyl 4-phenyl-5-venitien-2-carboxylate (250 mg) in EtOH (5 ml) at 25°C was added Pd/C (50% moisture) (50 mg), followed by stirring for 5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain methyl 5-ethyl-4-phenylthiophene-2-carboxylate (247,3 mg) as colorless liquid.

In the same manner as in Example receiving 37, received a connection Example of getting 37-1 Sample receiving 37-3 shown in the following tables.

An example of retrieving 38

To a solution of 5-fluoro-7-hydroxy-2H-chromen-3-carbaldehyde (275 mg) and 2-(hydroxymethyl)-5-methyl-4-phenyl-thiazole (436 mg) in toluene (8.2 ml) under ice cooling was added ADDP (393 mg) and TBP (315 mg). The reaction liquid was stirred at room temperature for 15 hours, then to this mixture was added IPE and the solid was removed by means of filtration. The filtrate was concentrated under reduced pressure and the residue was purified using column chromatography on silica gel (hexane:EtOAc=90:20 to 70:30) to give 5-fluoro-7-[(5-5-methyl-4-phenyl-1,3-thiazol-2-yl)methoxy]-2H-2H-chromen-3-carbaldehyde (381 mg) as a pale yellow solid.

In the same manner as in Example receiving 38, received a connection Example of getting 38-1 Sample receiving 38-61, shown in the following tables.

An example of retrieving 39

To a solution of 5-({[2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-2-(hydroxymethyl)phenol (520 mg) in chloroform (10 ml) at room temperature was added manganese dioxide (1 g). The reaction liquid was stirred at room temperature for 16 hours and then filtered through celite. The filtrate was concentrated under reduced pressure and purified using column chromatography on silica gel (hexane:EtOAc=95:5 to 80:20) to give 4-({[2'-fluoro-2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-2-hydroxybenzaldehyde (180 mg) as a white solid.

In the same manner as in Example receiving 39, received a connection Example of getting 39-1 Sample receiving 39-6 shown in the following tables.

Example of getting 40

To a solution of [2-({[2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-4,5-dihydro-1-benzothieno-6-yl]methanol (1.0 g) in DHM (20 ml) at 25°C was added PDC (1,36 g) and MS4 angstroms (1,36 g). The reaction liquid was stirred for 3 hours and then filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 80:20) to give 2-({[2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-4,5-dihydro-1-benzothiophen-6-carbaldehyde (345 mg) in the ideal colorless liquid.

An example of retrieving 41

To a solution of [1-(tert-butoxycarbonyl)piperidine-4-yl]acetic acid (200 mg) in dioxane (1 ml) was added a 4 M solution of hydrogen chloride in dioxane (1 ml). The reaction liquid was stirred at room temperature for 15 hours and then concentrated under reduced pressure to obtain hydrochloride piperidine-4-luxusni acid (140 mg) as a white solid.

In the same manner as in Example obtain 41, received a connection Example of getting 41-1 Sample receiving 41-5 shown in the following tables.

An example of retrieving 42

Benzyl 3-(1H-tetrazol-5-yl)pyrrolidin-1-carboxylate (300 mg) was added to a mixed solution of concentrated hydrochloric acid (3 ml) and AcOH (0.6 ml) followed by stirring at 100°C for 5 hours. The reaction liquid was concentrated and then subjected to azeotropic distillation with toluene three times (30 ml ×3). The residue was dissolved in a mixed solution of acetone (0.9 ml) and water (1.5 ml) and then cooled to 0°C and to this mixture was added Na₂CO₃(of 174.5 mg) and DIBOC (359,4 mg). The reaction mixture was heated to 25°C and then stirred for 15 hours. The reaction liquid was concentrated. To the residue was added diethyl ether (30 ml) for extraction (three times). The organic layer was washed with saturated saline solution, dried over MgSO₄and C is the concentrated under reduced pressure to obtain tert-butyl 3-(1H-tetrazol-5-yl)pyrrolidin-1-carboxylate (102,7 mg) as colorless liquid.

An example of retrieving 43

To 1-tert-butyl 3-methyl 3-ftorpirimidinu-1,3-in primary forms (100 mg) at 0°C was added a mixed solution of concentrated hydrochloric acid (1 ml) and AcOH (0.2 ml). The reaction mixture was heated to room temperature, was stirred for 1 hour and then stirred at 100°C for 5 hours. After confirming that the raw materials disappeared, the mixture was concentrated under reduced pressure and then subjected to azeotropic distillation with toluene three times. The residue was dissolved in a mixed liquid solution of acetone (0.6 ml) and water (1 ml) and to this mixture was added at 0°C Na₂CO₃(64 mg) and DIBOC (132 mg) followed by warming to room temperature and stirring for 15 hours. The reaction mixture was concentrated under reduced pressure and the acetone evaporated. To the residue was added diethyl ether to liquid separation. The aqueous layer were combined, cooled to 0°C and brought to pH=2-3 with 2 M hydrochloric acid. To this mixture was added EtOAc extraction. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure to obtain 1-(tert-butoxycarbonyl)-3-ftorpirimidinu-3-carboxylic acid (70 mg) as a white solid.

An example of retrieving 44

5-fluoro-7-(methoxyethoxy)2H-chromen-3-carbaldehyde (1.5 g) was dissolved in acetone (25 ml) and to this mixture was added 1 M aqueous HCl (20 ml) followed by heating and boiling under reflux for 5 hours. The reaction liquid was concentrated and the residue was dissolved in EtOAc, washed with water and saturated saline and was dried over MgSO₄and the filtrate was concentrated. The residue was washed with chloroform to obtain 5-fluoro-7-hydroxy-2H-chromen-3-carbaldehyde (0.95 g) as a yellow powder.

In the same manner as in Example receiving 44, received a connection Example of getting 44-1 Sample receiving 44-6 shown in the following tables.

An example of retrieving 45

7-(Methoxyethoxy)-2,2-dimethyl-2H-chromen-3-carbaldehyde (300 mg) was dissolved in EtOH (10 ml) and to this mixture was added (1S)-(+)-10-camphorsulfonic acid (421 mg), followed by stirring at 80°C during the night. To the reaction liquid was added silica gel, followed by concentration. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=90:10 to 70:30) to obtain 7-hydroxy-2,2-dimethyl-2H-chromen-3-carbaldehyde (175 mg) as a red powder.

An example of retrieving 46

To a solution of KOH (358 mg) in MeOH (30 ml) was added {4-[2,4-bis(trifluoromethyl)phenyl]but-1-in-1-yl}(trimethyl)silane (1.8 g), followed by stirring at room temperature for 18 hours. The reaction liquid was neutralized using 1 M hydrochloric acid and was extracted with ether. The organic layer was washed nassen the m salt solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc=100:0) to give 1-but-3-in-1-yl-2,4-bis(trifluoromethyl)benzene (426 mg) as colorless liquid.

An example of retrieving 47

To 7-(benzyloxy)-4-methyl-2H-chromen-3-carbaldehyde (230 mg) and 1,2,3,4,5-pentamethylbenzene (608 mg) was added TFA (3 ml) followed by stirring at room temperature over night. The reaction liquid was poured into an aqueous solution of NaHCO₃with the subsequent extraction using EtOAc three times. The organic layer was combined, washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=80:20 to 20:80) to give 7-hydroxy-4-methyl-2H-chromen-3-carbaldehyde (130 mg) as a pale yellow powder.

In the same manner as in Example receiving 47, received a connection Example of getting 47-1 Sample receiving 47-2 shown in the following tables.

Example obtain 48

2-Fluoro-4,6-dimethoxybenzaldehyde (22 g) was dissolved in DHM (110 ml) and to this mixture under ice cooling was added dropwise a solution of BBr₃in DHM (1 M, 300 ml), followed by stirring at room temperature the night. After confirming completion of the reaction, the reaction liquid was poured into a mixture of ice water (100 ml) followed by stirring for 1 hour and then extracted using EtOAc three times. The organic layer was combined, washed with water and saturated saline in that order, dried over MgSO₄and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=80:20 to 60:40) to give 2-fluoro-4,6-dihydroxybenzaldehyde (12 g) as a white powder.

An example of retrieving 49

To a solution of 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}thiochroman-4-ol (800 mg) in toluene (16 ml) was added 4-methylbenzenesulfonic acid (33,7 mg), followed by stirring at 120°C for 3 hours. To the reaction liquid was added a saturated aqueous solution of NaHCO₃(50 ml) followed by extraction using EtOAc (50 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=100:0 to 80:20) to give 2,4-bis(trifluoromethyl)benzyl 2H-thiochroman-7-silt ether (753,2 mg) as colorless liquid.

Example of getting 50

A mixture of methyl 4-(b shall ammeter)-2-{[tert-butyl(dimethyl)silyl]oxy}benzoate (0,30 g) and triethylphosphite (0.17 g) was stirred at 25°C and then stirred at 130°C for 24 hours. The reaction liquid was concentrated under reduced pressure and was twice subjected to azeotropic distillation with toluene (30 ml ×2). The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=40:60 to 10:90) to give methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(diethoxyphosphoryl)methyl]benzoate (to 0.23 g) as colorless liquid.

An example of retrieving 51

To a solution of 7-[(4-bromo-5-ethyl-2-thienyl)methoxy]-2H-chromen-3-carbaldehyde (150 mg) in dioxane (4.5 ml) at 25°C was added [2-(trifluoromethyl)phenyl]boric acid and 2 M aqueous solution of Na₂CO₃. Then to the reaction mixture was added palladium acetate (of 4.44 mg) and PPh₃(20,75 mg) followed by heating to 100°C and stirring for 5 hours. To the reaction liquid was added a saturated aqueous solution of NH₄Cl (30 ml) followed by extraction using EtOAc (30 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=95:5 to 80:20) to give 7-({5-ethyl-4-[2-(trifluoromethyl)phenyl]-2-thienyl}methoxy)-2H-chromen-3-carbaldehyde (134,8 mg) as a pale yellow liquid.

In the same manner as in Example obtaining 51, received from the organisations of the Sample receiving 51-1 - Example get 51-5 shown in the following tables.

An example of retrieving 52

In a nitrogen atmosphere to a solution of [3-chloro-4-(trifluoromethyl)phenyl]methanol (800 mg) and phenylboric acid (1.90 g) in toluene (16 ml) at 25°C was added potassium phosphate (1,61 g), palladium acetate (42,6 mg) and DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (195,0 mg). The reaction mixture was heated to 100°C and then stirred for 15 hours. To the reaction liquid were added water (30 ml) followed by extraction using EtOAc (30 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (automatic cleaning device, hexane:EtOAc=70:30 to 50:50) to give [6-(trifluoromethyl)biphenyl-3-yl]methanol (678,3 mg) as a yellow solid.

In the same manner as in Example receiving 52, received a connection Example of getting 52-1 Sample receiving 52-4 shown in the following tables.

Example of getting 53

A solution of {3-chloro-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]phenyl}methanol (284 mg) and SOCl₂(179 μl) in DHM (7 ml) was stirred at room temperature for 2 hours. The reaction liquid was poured into water followed by extraction with chloroform. The organic layer was washed saturated the salt solution, dried over MgSO₄and then concentrated under reduced pressure to obtain 2-chloro-4-(chloromethyl)-1-[(1S)-2,2,2-Cryptor-1 methylethoxy]benzene (285 mg) as a colourless liquid.

In the same manner as in Example receiving 53, received a connection Example of getting 53-1 Sample receiving 53-4 shown in the following tables.

An example of retrieving 54

To a solution of methyl 4-bromo-3-benzoate (300 mg) in THF (1 ml) was added bromide cyclopentenone (9.6 ml) and palladium-tri-tert-butylphosphine (1:2) (123 mg). The reaction liquid was stirred at room temperature for 20 hours. To this mixture at 0°C was added a saturated aqueous solution of NH₄Cl, followed by filtration through celite and extracted using EtOAc. The organic layer was washed with saturated saline and was dried over MgSO₄. The solvent is evaporated under reduced pressure and the residue was purified using column chromatography on silica gel (hexane:EtOAc=100:0 to 90:10) to give methyl 3-chloro-4-cyclopentylphenol (280 mg) as a yellow solid.

Example of getting 55

To a solution of (7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methanol (200 mg) in MeCN (5 ml) was added triphenylphosphine (240 mg). The reaction liquid was stirred at room temperature for 2 hours and concentrated under reduced pressure. To ostad is added EtOAc and IPE, the obtained solid substance was removed by filtration and the filtrate was concentrated to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(methyl bromide)-5-fluoro-2H-chromene (230 mg) as a brown liquid. 60% sodium Hydride (24 mg) was added to a solution of DMF (5 ml) at 0°C and then to this mixture was added ethyl 1H-pyrazole-4-carboxylate (76 mg). The mixture was stirred at room temperature for 0.5 hour and at 0°C and to it was added a solution of 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(methyl bromide)-5-fluoro-2H-chromene (220 mg) in DMF (5 ml). The reaction liquid was stirred at room temperature for 13 hours, reduce saturated solution of NH₄Cl and then extracted using EtOAc. The organic layer was washed with saturated saline solution, dried over MgSO₄and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc=100:0 to 70:30) to obtain ethyl 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylate (111 mg) as a pale yellow solid.

In the same manner as in Example receiving 55, received the compound of Example obtaining 55-1 presented in the following tables.

An example of receiving 56

A solution of 4-isopropoxy-3-(trifluoromethyl)benzonitrile (2.4 g) and 5 M NaOH solution (50 ml) in EtOH (50 ml) was heated and boiled with reverse Ho what adalnikam for 18 hours. The solution was cooled to room temperature, acidified using hydrochloric acid and then was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over MgSO₄and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (mixture of chloroform:MeOH=100:0 to 95:5). The product was washed with hexane to obtain 4-isopropoxy-3-(trifluoromethyl)benzoic acid (2.2 g) as a white solid.

In the same manner as in Example receiving 56, received a connection Example of getting 56-1 Sample receiving 56-6 shown in the following tables.

An example of retrieving 57

5-Bromo-3-(trifluoromethyl)-2-{[(2S)-1,1,1-tryptophan-2-yl]oxy}pyridine (500 mg) was dissolved in a mixed solvent DMSO (5 ml) and MeOH (5 ml). Then to this mixture at 25°C was added TEA (0,42 ml) and then at 25°C it was added Pd(OAc)₂(17 mg) and DPPP (60 mg), followed by stirring at 70°C for 15 hours in an atmosphere of CO. To the reaction solution were added water (30 ml) followed by extraction using EtOAc (20 ml) three times. The organic layer was washed with saturated saline solution, dried over MgSO₄and then was filtered and the filtrate was concentrated. The residue was purified using column chromatography on silica gel (automatic cleaning device, showing the age of the PRS; a mixture of hexane:EtOAc=100:0 to 80:20) to obtain methyl 5-(trifluoromethyl)-6-{[(2S)-1,1,1-tryptophan-2-yl]oxy}nicotinate (403 mg) as a yellow solid.

An example of retrieving 58

To a solution of ethyl (1-methyl-1,2,3,6-tetrahydropyridine-4-yl)acetate (2,05 g) in dichloroethane (14 ml) at 0°C was added 1-chloroethyl-chloroformate (1.5 ml). The reaction liquid was heated and boiled under reflux for 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in MeOH (14 ml) and was heated and boiled under reflux for 1 hour. After concentration under reduced pressure the residue was purified using column chromatography on aminosilicone (a mixture of chloroform:methanol=100:0 to 80:20) to obtain ethyl 1,2,3,6-tetrahydropyridine-4-ilaclama (130 mg) as a brown liquid.

In the same manner as in Example receiving 58, received the compound of Example obtaining 58-1 presented in the following tables.

Example retrieve 59

Methyl 5,6-dichloronicotinic (1.5 g) and 60% solution of sodium hydride (640 mg) was dissolved in THF (45 ml). To this mixture was added at 0°C 1,3-ditropan-2-ol (1.5 g), followed by stirring at 0°C for 3 hours and the reaction solution was suppressed in an aqueous solution of NH₄Cl. After atrakchi using EtOAc the organic layer was dried over MgSO₄and then was filtered and the desiccant was removed. Rest ritel evaporated under reduced pressure, followed by purification using column chromatography on silica gel (hexane:AcOEt=100:0 to 50:50) to give methyl 5-chloro-6-[(1,3-ditropan-2-yl)oxy]nicotinate (1.56 g) in the form colourless liquid.

To a solution of methyl 5-chloro-6-[(1,3-ditropan-2-yl)oxy]nicotinate (1 g) in THF (20 ml) at 0°C was added dropwise 0,99 M solution of DIBAL in toluene (11.3 ml), followed by stirring at 0°C for 2 hours. Then the reaction solution was poured into an aqueous solution of Rochelle salt, followed by stirring at room temperature for 1 hour. After extraction system EtOAc-water, the organic layer was washed with saturated saline solution, dried over MgSO₄and then was filtered and the desiccant was removed. The solvent is evaporated under reduced pressure, followed by purification using column chromatography on silica gel (mixture of Hex:AcOEt=98:2 to 70:30) to give {5-chloro-6-[(1,3-ditropan-2-yl)oxy]pyridin-3-yl}methanol (650 mg) as a colourless liquid.

Example of getting 60

To 5,6-dichloronicotinic acid (2.2 g) was added 1,1,1-trimethoxymethane (4,3 ml) followed by radiation in a microwave oven at 120°C for 15 minutes. The reaction mixture was dissolved in EtOAc and washed with water. The organic layer was dried over MgSO₄and the solvent evaporated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc=85:15 to 80:20) to obtain methyl 5,6-dichloronicotinic (2.2 g) as a white solid.

An example of retrieving 61

To a solution of ethyl 4-pyridylacetate is (2 g) in MeCN (20 ml) was added methyliodide (2.3 ml). The reaction liquid was stirred at room temperature overnight and then concentrated under reduced pressure. To the residue was added IPE and the obtained solid substance was collected by means of filtration. The solid was dissolved in MeOH there was added sodium borohydride (916 mg) at 15°C or below.

The reaction liquid was stirred at room temperature for 6 hours and then to this mixture was added water, followed by extraction with chloroform. The organic layer was washed with saturated saline solution, dried over MgSO₄and concentrated under reduced pressure. The residue was purified using column chromatography (mixture of chloroform:MeOH=100:0 to 90:10) to give ethyl (1-methyl-1,2,3,6-tetrahydropyridine-4-yl)acetate (2,08 g) as pale yellow liquid.

An example of retrieving 62

To a solution of {3-(trifluoromethyl)-4-[(1S)-2,2,2-Cryptor-1 methylethoxy]phenyl}methanol (200 mg) in dichloroethane (5 ml) was added thionyl chloride (111 μl) and a catalytic amount of DMF, followed by stirring at 60°C for 2 hours. The reaction liquid was concentrated under reduced pressure and then the residue was added a solution of ethyl (3R)-1-[(7-hydroxy-2H-chromen-3-yl)methyl]piperidine-3-carboxylate (175 mg) in DMF (8,75 ml) and potassium carbonate (152 mg), in that order, followed by stirring at 80°C for 2 hours. The reaction is th liquid was cooled to room temperature and poured into water followed by extraction using EtOAc. The organic layer was washed with water and saturated saline in that order, and then dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified using column chromatography on silica gel to obtain ethyl (3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-tryptophan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylate (271 mg) as a yellow oily substance.

In the same manner as in Example receiving 62, received a connection Example of getting 62-1 Sample receiving 62-19 shown in the following tables.

An example of retrieving 63

To a solution of 4-chloro-3-(trifluoromethyl)benzonitrile (1.5 g), iron acetylacetonate(III) (130 mg) and 1-methylpyrrolidine-2-she (4 ml) in THF (45 ml) at 5°C was added a 1 M solution of cyclopentylamine in THF (8,8 ml) followed by stirring at room temperature for 0.5 hours and dilution with diethyl ether. To this mixture was slowly added 1 M hydrochloric acid solution, followed by extraction using EtOAc. The organic layer was washed with saturated saline solution, dried over MgSO₄and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (hexane:EtOAc=100:0 to 95:5) to give 4-cyclopentyl-3-(trifluoromethyl)benzonitrile (367 mg) as a white solid.

To a solution of 7-(methoxyethoxy)-2H-chromen-3-carbaldehyde (5,00 g) and ethyl (3R)-piperidine-3-carboxylate (4,20 ml) in dichloroethane (150 ml) was added triacetoxyborohydride sodium (12.0 g), followed by stirring at 80°C for 4 hours. The reaction liquid was cooled to room temperature and then to this mixture was added a saturated aqueous solution of NaHCO₃followed by extraction with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified using column chromatography on silica gel (hexane:EtOAc=4:1) to obtain ethyl (3R)-1-{[7-(methoxyethoxy)-2H-chromen-3-yl]methyl}piperidine-3-carboxylate (7.30 g) as a yellow oily substance.

In the same way as in the Example of a 64 received connection Example of getting 64-1 Sample receiving 64-7 shown in the following tables.

For compounds of Examples obtain the patterns shown in Tables 3-57, and physico-chemical data and methods of obtaining presented in Tables 99-107.

Example 1

To a solution of 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]pyrrolidin-3-carboxylic acid (98 mg) in DMF (2 ml) was added CDI (46 mg), followed by stirring at 70°C for 12 hours. To the reaction liquid after the Lyali methanesulfonamide (27 mg) and DBU (43 mg), in that order, followed by stirring for 12 hours. To the reaction liquid was added AcOH, followed by concentration under reduced pressure and the residue was purified using reverse-phase column chromatography (mixture of H₂O:MeCN=100:0 to 90:10) to obtain a yellow amorphous material (70 mg). It is a yellow amorphous substance was dissolved in dioxane (1 ml) and to this mixture was added 4 M HCl/dioxane (1 ml) followed by stirring and then concentrated under reduced pressure. The residue was washed with hexane to obtain 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-N-(methylsulphonyl)pyrrolidin-3-carboxymethyloxime (60 mg) as a pale yellow solid.

Example 2

To a solution of the hydrochloride pyrrolidin-3-carboxylic acid in MeOH was added TEA, followed by stirring at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and to this mixture at room temperature was added a solution of 7-{[4-phenyl-5-(trifluoromethyl)-2-thienyl]methoxy}-2H-chromen-3-carbaldehyde in MeOH and AcOH. The reaction mixture was heated to 70°C, stirred for 2 hours and left to cool to 25°C and at room temperature was added NaBH₃CN, followed by stirring at 70°C for 5 hours. The reaction liquid was purified with the measures reversed-phase column chromatography (mixture of MeCN:H ₂O=20:80 to 50:50) and the resulting white solid was washed diisopropyl ether to obtain 1-[(7-{[4-phenyl-5-(trifluoromethyl)-2-thienyl]methoxy}-2H-chromen-3-yl)methyl]pyrrolidin-3-carboxylic acid as a white solid.

Example 3

Hydrochloride pyrrolidin-3-carboxylic acid (165 mg) was dissolved in MeOH and to this mixture was added TEA, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then to this mixture at room temperature was added a solution of 7-{[2,4-bis(trifluoromethyl)phenyl]ethinyl}-5-fluoro-2H-chromen-3-carbaldehyde in MeOH (8 ml) and AcOH (0.5 ml) followed by stirring at 70°C for 0.5 hours. After the solution was left to cool to room temperature, to the reaction mixture at room temperature was added NaBH₃CN (57 mg), followed by stirring at 50°C for 2 hours. After confirming completion of the reaction using indicators LC reaction liquid was purified using reverse-phase column chromatography (mixture of MeCN:H₂O=20:80 to 50:50), the obtained amorphous substance (233 mg) was dissolved in dioxane (1 ml) and to this mixture was added 4 M HCl/dioxane (1 ml). The reaction liquid was concentrated under reduced pressure and the residue was washed using MeCN to obtain hydrochloride of 1-[(7-{[2,4-bis(three is tormentil)phenyl]ethinyl}-5-fluoro-2H-chromen-3-yl)methyl]pyrrolidin-3-carboxylic acid (185 mg) as a pale yellow solid.

Example 154

A solution of ethyl 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylate (100 mg) and 1 M aqueous NaOH solution (0,55 ml) in a mixture of EtOH/THF (3 ml/1 ml) was stirred at 100°C for 2 hours, neutralized with 1 M HCl solution and was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over MgSO₄and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (mixture of chloroform:methanol=100:0 to 90:10) and the obtained solid was washed using IPE obtaining 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylic acid (71 mg) as a white solid.

Example 156

To a solution of ethyl (3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-tryptophan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylate (271 mg) in a mixture of EtOH (5,4 ml) - THF (2.7 ml) was added 1 M aqueous NaOH solution (923 μl), followed by stirring at 50°C for 2 hours. The reaction liquid was cooled to room temperature, then to this mixture was added 1 M hydrochloric acid solution (923 μl) and the solvent evaporated. The residue was purified using reverse-phase column chromatography (mixture of H₂O:MeCN=100:0 to 30:70) to obtain a yellow oily substance, which was dissolved in diox is not (3 ml), was treated with 4 N HCl/dioxane (1 ml) and was washed using IPE obtaining hydrochloride (3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-tryptophan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid (215 mg) as a white powder.

In the same manner as in the methods of Examples 1-3, 154 or 156, obtained compounds of Examples in the following tables. For compounds of structure Examples shown in Tables 58-98, and physico-chemical data and methods of obtaining presented in Tables 108-131.

Table 3-131 shown in the graphics part.

Industrial applicability

The compound of the present invention has the effect of agonist S1P₁and it can be used for prevention or treatment of diseases caused by undesirable infiltration of lymphocytes, for example, autoimmune diseases or inflammatory diseases, such as reaction, transplant rejection or graft versus host for the transplantation of organs, bone marrow or tissue, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, meningoencephalitis, severe myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, pulmonary disease, bronchial asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemic reperfusion the Sam is eusto, and diseases caused by abnormal proliferation or accumulation of cells, for example, cancer, leukemia and the like.

1. Compound 2H-chromene or its salt selected from
the following:
1-{[7-({3-chloro-4-(1S)-2,2,2-Cryptor-1 methylethoxy]benzyl}oxy)-2H-chromen-3-yl]methyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
1-({7-[(3-chloro-4-from propylbenzyl)oxy|-2H-chromen-3-yl} methyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
1-[(7-{[4-isopropoxy-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
1-{[7-({3-chloro-4-[2-fluoro-1-(permitil)ethoxy]benzyl}oxy)-2H-chromen-3-yl]methyl}-1,2,3,6-tetrahydropyridine-4-carboxylic acid,
1-{[7-({5-chloro-6-[(1S)-2,2,2-Cryptor-1 methylethoxy]pyridine-3-yl}methoxy)-2H-chromen-3-yl]methyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
(3R)-1-{[7-({4-[(1,3-ditropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl} piperidine-3-carboxylic acid,
1-[(7-{[4-cyclopentyl-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid,
(3R)-1-{[7-({3-chloro-4-[(1,3-ditropan-2-yl)oxy]benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,
(3S)-1-{[7-({4-[(1,3-ditropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,
(3R)-1-[(7-{[4-(2,2,2-triptoreline)-3-trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,
(3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-tryptophan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,
(3S)-1-[(7-{[4-(2,2,2-triptoreline)-3-(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,
(3R)-1-{[7-({4-[(1,3-ditropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}-N-(methylsulphonyl)piperidine-3-carboxamide, or
1-[(7-{[4-(2,2,triptoreline)-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-4-carboxylic acid.

2. The compound represented by the following formula:

or its salt.

3. Pharmaceutical composition having S1P₁agonistic activity, containing an effective amount of compound 2H-chromene, or its derivative, or its salt according to claim 1 and a pharmaceutically acceptable carrier or excipient.

4. The pharmaceutical composition according to claim 3, which is an agonist of S1P₁.

5. The pharmaceutical composition according to claim 4, which is a pharmaceutical composition for preventing or treating diseases caused by undesirable infiltration of lymphocytes associated with S1P₁.

6. The pharmaceutical composition according to claim 5, where the disease caused unwanted infiltration of lymphocytes associated with S1P₁represents a rejection or graft versus host for the transplantation of organs, bone marrow, or tissues, autoimmune diseases or inflammatory diseases in humans or animals.

7. The pharmaceutical composition according to claim 6, which is a pharmaceutical composition for the prevention or treatment of rejection reactions or graft versus host for the transplantation of organs, bone marrow or tissue from a person or animal.

8. The pharmaceutical composition according to claim 6, which represents the FDS is the first pharmaceutical composition for the prevention or treatment of multiple sclerosis.