Triazole derivatives

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

 

The technical field

The present invention relates to new derivatives of triazole, which have an inhibitory effect on the binding between sphingosine-1-phosphate, providing a variety of physiological effects, and its receptor Edg-1 (Endothelial receptor differentiation genes type 1, S1P1). The present invention also relates to pharmaceutical compositions containing these compounds as active ingredients, and a synthetic intermediate compounds of these compounds.

The level of technology

Sphingosine-1-phosphate (hereinafter called "S1P") is a physiologically active lipid that is formed during metabolism of sphingolipids (typical representative of sphingomyelin in cells. S1P is known as having a wide range of activities, such as the induction of cellular differentiation, stimulation of cell growth, inhibition of cell motility and inhibition of apoptosis, we also know that it demonstrates a physiological effect, such as angiogenesis, induction of bradycardia, activation of cells of inflammation and platelet activation (non-patent document 1).

Among the S1P receptors were shown the following 5 subtypes: Edg-1(S1P1), Edg-3(S1P3), Edg-5(S1P2), Edg-6(S1P4) and Edg-8(S1P5) (non-patent document 2).

Among these subtypes, Edg-1(S1P1) is expressed in immune cells with high efficiency (for example in T-ledah, in dendritic cells) and in cells of the vascular endothelium, suggesting that Edg-1(S1P1) makes a significant contribution to stimulated Edg-1(S1P1) migration of T cells (non-patent document 3), the migration of mast cells (non-patent document 4), the output of T - and b-cells of the lymphatic organs (non-patent document 5) and angiogenesis (non-patent document 6), and are involved in autoimmune diseases such as Crohn's disease, spastic colitis, Sjogren syndrome, multiple sclerosis and systemic lupus erythematosus, and also in other diseases such as rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis, age related macular degeneration, etc.

Thus, the ligand for the Edg-1(S1P1) will be effective in the treatment or prevention of these diseases.

Previously known ligands for Edg-1(S1P1) include some kinds of derivatives of thiophene (non-patent document 7), derivatives of phosphoric acid (patent documents 1 and 2, non-patent documents 8 and 9) and derivatives of thiazolidine (patent document 3), carboxylic acid derivatives (patent documents 4, 5, 6, and 8, non-patent documents 10 and 11), derivatives containing amino group (patent document 7), and pyrrole derivative (patent document 9).

Patent document 1: WO2002-18395.

Patent documents is 2: JP 2003-137894 A.

Patent document 3: JP 2002-332278 A.

Patent document 4: WO2002-092068.

Patent document 5: WO2003-105771.

Patent document 6: WO2004-058149.

Patent document 7: WO2004-103279.

Patent document 8: WO2005-058848.

Patent document 9: WO2005-123677.

Non-patent document 1: J Biol Chem. 2004, 279: 20555, FASEB J 2002, 16: 625, Proceedings of the Japanese Society for Immunology 2003, 33: 2-J-W30-20-P.

Non-patent document 2: Pharmacol Res 2003, 47: 401.

Non-patent document 3: FASEB J 2002, 16:1874.

Non-patent document 4: J Exp Med 2004, 199: 959.

Non-patent document 5: Nature 2004, 427: 355.

Non-patent document 6: J Clin Invest 2000, 106: 951, Biocchim Biophys Acta 2002, 1582: 222.

Non-patent document 7: J Biol Chem 2004, 279: 13839.

Non-patent document 8: Bioorg Med Chem Lett 2003, 13: 3401.

Non-patent document 9: J Med Chem. 2004, 47: 6662.

Non-patent document 10: J Med Chem. 2005, 48: 6169.

Non-patent document 11: J Biol Chem. 2005; 280: 9833.

Description of the invention

The problem addressed by the invention

The present invention was to offer connections with the new skeletal structure, capable of inhibiting the binding between S1P and its receptor Edg-1 (S1P1and which is suitable for use as a pharmaceutical product.

The ways to solve problems

The inventors of the presents invention conducted a thorough investigation in an attempt to detect ligand compounds for Edg-1 (S1P1). As a result, they discovered, is that the goal is achieved by using triazole derivative with formula (I), below, or its pharmaceutically acceptable salt (a characteristic feature is that R3the formula is optionally substituted aryl group). These data led to the implementation of the presented invention. Triazolone derivative with formula (I), below, is a completely new connection. Although compounds having an alkyl group corresponding to R3in the formula (I), commercially available from Bionet as reagents, they differ in structure from the compounds discussed in the application, and the pharmaceutical use of the compounds from Bionet was completely unknown.

This is followed by embodiments of triazole derivatives with formula (I) and compounds with formula (II), which are intermediate compounds derived triazole (hereinafter, all of them designated as "compounds according to the present invention").

1. The compound represented by formula (I)

Formula 1

,

or its pharmaceutically acceptable salt, And indicates where:

the oxygen atom

a sulfur atom,

the group represented by the formula-SO-,

the group represented by formula-SO2-,

the group represented by the formula-CH2-or

the group represented by the formula-NR6-where R6denotes a hydrogen atom or alkyl group having from 1 to uglerodnych atoms;

R1means:

a hydrogen atom,

alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or more substituents selected from the group consisting of:

hydroxyl group,

the halogen atom,

alkoxy group having from 1 to 6 carbon atoms specified alkoxy group optionally substituted phenyl group, and

phenyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and alkyl groups having from 1 to 6 carbon atoms,

cycloalkyl group having from 3 to 8 carbon atoms,

alkenylphenol group having from 2 to 8 carbon atoms,

alkylamino group having from 2 to 8 carbon atoms, or

phenyl group;

R1Ameans:

a hydrogen atom or

alkyl group having from 1 to 6 carbon atoms;

R1and R1Aoptional form together with the carbon atom that is attached to the specified R1and R1A, cycloalkyl group having from 3 to 6 carbon atoms;

R2means:

a hydrogen atom,

alkyl group having from 1 to 6 carbon atoms,

alkenylphenol group having from 2 to 8 carbon atoms,

alkylamino group having from 2 to 8 carbon atoms, or

cycloalkyl group having from 3 to 6 atoms of plastics technology : turning & is Yes;

R3denotes optionally substituted aryl group;

R4means:

a hydrogen atom or

alkyl group having from 1 to 6 carbon atoms and optionally substituted by carboxyl group;

R5means:

(i) an alkyl group having from 1 to 10 carbon atoms,

(ii) an alkyl group having from 1 to 10 carbon atoms and substituted by 1 to 2 substituents selected from the group consisting of:

cycloalkyl group having from 3 to 8 carbon atoms,

peredelnoj group,

phenyl group, phenoxy group and naftilos groups, each of which is optionally substituted from 1 to 2 substituents selected from the group consisting of a halogen atom and alkoxy group having from 1 to 6 carbon atoms,

(iii) cycloalkyl group having from 3 to 8 carbon atoms,

(iv) alkenylphenol group having from 2 to 8 carbon atoms,

(v) alkenylphenol group having from 2 to 8 carbon atoms and a substituted phenyl group,

(vi) alkylamino group having from 2 to 8 carbon atoms,

(vii) alkylamino group having from 2 to 8 carbon atoms and a substituted phenyl group, or

(viii) optionally substituted aryl group.

2. Connection option exercise 1 or its pharmaceutically acceptable salt, where in the formula (I):

R1means:

atom bodoro is and,

alkyl group having from 1 to 6 carbon atoms,

alkyl group having from 1 to 6 carbon atoms and a substituted phenyl group,

cycloalkyl group having from 3 to 8 carbon atoms,

alkenylphenol group having from 2 to 8 carbon atoms,

alkylamino group having from 2 to 8 carbon atoms, or

phenyl group;

R1Adenotes a hydrogen atom;

R2means:

alkyl group having from 1 to 6 carbon atoms,

alkenylphenol group having from 2 to 8 carbon atoms,

alkylamino group having from 2 to 8 carbon atoms, or

cycloalkyl group having from 3 to 6 carbon atoms;

R4means:

a hydrogen atom or

alkyl group having from 1 to 6 carbon atoms;

R5means:

(i) an alkyl group having from 1 to 10 carbon atoms,

(ii) an alkyl group having from 1 to 10 carbon atoms and substituted by 1 to 2 substituents selected from the group consisting of:

cycloalkyl group having from 3 to 8 carbon atoms,

phenyl group,

naftilos group,

peredelnoj group and

phenyl group substituted by from 1 to 2 substituents selected from the group consisting of a halogen atom and alkoxy group having from 1 to 6 carbon atoms,

(iii) cycloalkyl group having from 3 to 8 carbon atoms,

(iv) alkenylphenol group having from 2 to 8 carbon atoms,

(v) alkenylphenol group having from 2 to 8 carbon atoms and a substituted phenyl group,

(vi) alkylamino group having from 2 to 8 carbon atoms,

(vii) alkylamino group having from 2 to 8 carbon atoms and a substituted phenyl group, or

(viii) optionally substituted aryl group.

3. The connection option on the implementation of 1 or 2 or its pharmaceutically acceptable salt, where a is an oxygen atom or a group represented by the formula-NR6-.

4. The connection option on the implementation of 1 or 2 or its pharmaceutically acceptable salt, where a is an oxygen atom.

5. The connection option on the implementation of 1 or 2 or its pharmaceutically acceptable salt, where a is a group represented by the formula-NH-.

6. The compound according to any one of the embodiments 1 and 3-5 or its pharmaceutically acceptable salt, where:

R1denotes an alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or more substituents selected from the group consisting of:

hydroxyl group,

the halogen atom,

alkoxy group having from 1 to 6 carbon atoms specified alkoxy group optionally substituted phenyl group, and

phenyl group, optionally substituted by one or more Deputy is a Fort worth, selected from the group consisting of a halogen atom and alkyl groups having from 1 to 6 carbon atoms;

R1Ameans:

a hydrogen atom or

alkyl group having from 1 to 6 carbon atoms; and

R1and R1Aoptional form together with the carbon atom that is attached to the specified R1and R1A, cycloalkyl group having from 3 to 6 carbon atoms;

7. The compound according to any one of the embodiments 1 and 3-5 or its pharmaceutically acceptable salt, where:

R1is:

alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or more halogen atoms, or

benzyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and alkyl groups having from 1 to 6 carbon atoms; and

R1Ais a hydrogen atom.

8. The compound according to any of embodiments 1-5, or its pharmaceutically acceptable salt, where R1is methyl group or ethyl group and R1Ais a hydrogen atom.

9. The compound according to any of embodiments 1-8, or its pharmaceutically acceptable salt, where R4is a hydrogen atom.

10. The compound according to any of embodiments 1-9, or its pharmaceutically acceptable salt, where R2 is an alkyl group having from 1 to 6 carbon atoms, or cycloalkyl group having from 3 to 6 carbon atoms.

11. The compound according to any of embodiments 1-9, or its pharmaceutically acceptable salt, where R2is an ethyl group or cyclopropene group.

12. The compound according to any one of the embodiments 1 and 3-11 or its pharmaceutically acceptable salt, where R5is:

(i) an alkyl group having from 1 to 10 carbon atoms,

(ii) an alkyl group having from 1 to 10 carbon atoms and substituted by 1 to 2 substituents selected from the group consisting of:

cycloalkyl group having from 3 to 8 carbon atoms,

peredelnoj group and

phenyl group, phenoxy group and naftilos groups, each of which is optionally substituted from 1 to 2 substituents selected from the group consisting of a halogen atom and alkoxy group having from 1 to 6 carbon atoms,

(iii) alkenylphenol group having from 2 to 8 carbon atoms and optionally substituted phenyl group, or

(iv) phenyl group, naftilos group, thienyl group, pyrrolidino group, pyrazolidine group, peredelnoj group, fernilee group, benzothiazole group, ethanolamines, isoxazolidine groups, thiazolidine group, benzothiadiazole group, Ben is oxadiazolyl group, dihydrobenzofuranyl group, dihydroergotoxine group, benzodioxolyl group, dihydrobenzofuranyl group, indanernas group, uracile group, Camarillo group, romanillos group, dihydroindole group, tetrahydronaphthyl group or tetrahydroisoquinoline group, each of which is optionally substituted from 1 to 5 substituents selected from the group consisting of:

alkyl groups having from 1 to 6 carbon atoms and optionally substituted by one or more fluorine atoms,

alkenylphenol group having from 2 to 8 carbon atoms,

the halogen atom,

alkoxy group having from 1 to 6 carbon atoms and optionally substituted by one or more fluorine atoms,

pyrazolidine group, oxazoline group, isoxazolyl group, thiadiazolyl group and pyrimidinyl groups, each of which is optionally substituted by one or more substituents selected from the group X consisting of methyl group, triptorelin group, halogen atom and methylsulfonylamino group,

alkylthio group having from 1 to 6 carbon atoms,

alkylsulfonyl group having from 1 to 6 carbon atoms,

benzolsulfonate group,

morpholinomethyl group,

morpholinosydnonimine group,

aminosulfonyl group,

alkoxycarbonyl group, having from 2 to 10 carbon atoms,

morpholino group, optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,

phenyl group, optionally substituted by one or more alkoxy groups having from 1 to 6 carbon atoms,

phenoxy group,

pyridylcarbonyl group,

pyridyloxy group,

ceanography,

alkanoyloxy group having 2 to 7 carbon atoms and optionally substituted by one or more fluorine atoms, and

alkanolamine group having 2 to 7 carbon atoms.

13. The compound according to any of embodiments 1-11, or its pharmaceutically acceptable salt, where R5is:

alkyl group having from 1 to 10 carbon atoms and substituted cycloalkyl group having from 3 to 8 carbon atoms,

alkyl group having from 1 to 10 carbon atoms and substituted naftilos group,

alkenylphenol group having from 2 to 8 carbon atoms and a substituted phenyl group,

phenyl group or naftilos group, each of which is optionally substituted from 1 to 5 substituents selected from the group consisting of:

alkyl groups having from 1 to 6 carbon atoms,

the halogen atom,

alkoxy group having from 1 to 6 carbon atoms,

triptoreline group,

deformedarse GRU the dust,

triptorelin group,

alkenylphenol group having from 1 to 6 carbon atoms,

alkylsulfonyl group having from 1 to 6 carbon atoms,

alkanoyloxy group having 2 to 7 carbon atoms,

alkoxycarbonyl group having 2 to 7 carbon atoms, and

ceanography,

pyrrolidino group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, and methoxycarbonyl group,

fernilee group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, triptorelin group and halogen atom,

thienyl group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, triptorelin group, thiadiazolyl group, oxazoline group and halogen atom, or

benzothiazole group, dihydrobenzofuranyl group, benzodioxolyl group, dihydroergotoxine group, dihydrobenzofuranyl group, tetrahydronaphthyl group, indanernas group, thiadiazolyl group, benzoxadiazole group or benzothiadiazole group, each of which neobyazatel is substituted by one or more substituents, selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, and halogen atom.

14. The compound according to any of embodiments 1-11, or its pharmaceutically acceptable salt, where R5is:

alkyl group having from 1 to 6 carbon atoms and substituted naftilos group,

alkenylphenol group having from 2 to 6 carbon atoms and a substituted phenyl group,

unsubstituted phenyl group,

phenyl group substituted by 1 to 5 substituents selected from the group consisting of methyl group, methoxy group and halogen atom,

phenyl group substituted by from 1 to 3 substituents selected from the group consisting of:

alkyl groups having from 1 to 6 carbon atoms,

the halogen atom,

methoxy group,

triptoreline group,

deformedarse group,

triptorelin group,

alkenylphenol group having from 1 to 6 carbon atoms,

methylsulfonyl group,

acetyl group,

methoxycarbonyl group and

ceanography,

specified phenyl group substituted in position 3 or 4, or both;

naftilos group, optionally substituted by one or more substituents selected from the group consisting of:

the halogen atom,

alkyl groups having from 1 to 6 carbon atoms,

ceanography and

alkylsulfonyl group, having from 1 to 6 carbon atoms, or

benzothiazole group, benzoxadiazole group, benzodioxolyl group, dihydroergotoxine group, dihydrobenzofuranyl group, indanernas group or benzothiadiazole group, each of which is optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, and halogen atom.

15. The compound according to any of embodiments 1-11, or its pharmaceutically acceptable salt, where R5is:

phenyl group substituted in each of the positions 3 and 4, a halogen atom, or

naftilos group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms, and ceanography.

16. The compound according to any of embodiments 1-15, or its pharmaceutically acceptable salt, where R3is a phenyl group, naftilos group, pyrazolidine group, peredelnoj group, indolines group, benzothiazolyl group, benzothiadiazole group, pyrazolopyrimidinones group, hyalinella group, ethanolamines group, benzothiazole group or dihydrohelenalin group, each of which is optionally substituted from 1 is about 3 substituents, selected from the group consisting of the following substituents:

alkyl groups having from 1 to 6 carbon atoms and optionally substituted by one or more fluorine atoms,

cycloalkyl group having from 3 to 8 carbon atoms,

the halogen atom,

alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted by one or more substituents selected from the group consisting of a fluorine atom, phenyl group, amino group substituted with two alkyl groups having from 1 to 4 carbon atoms each, and morpholino group;

phenoxy group,

phenyl group,

carboxyl group,

alkoxycarbonyl group having from 2 to 10 carbon atoms,

hydroxyl group,

monocyclic saturated hydrocarbon groups having from 2 to 7 carbon atoms and having one or more nitrogen atoms as ring atoms, the aforementioned saturated hydrocarbon group optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms;

nitrogen-containing monocyclic unsaturated hydrocarbon group,

morpholinyl group, optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,

the piperazine derivatives group, optionally substituted by one or more substituents, selected the data from the group consisting of:

alkyl groups having from 1 to 6 carbon atoms specified alkyl group optionally substituted amino group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, morpholino group, hydroxyl group or alkoxy group having from 1 to 6 carbon atoms,

formyl group,

alkanoyloxy group having 2 to 7 carbon atoms,

carbamoyl group, optionally substituted by one or two alkyl groups having from 1 to 4 carbon atoms each,

aminosulfonyl group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, and

alkylsulfonyl group having from 1 to 6 carbon atoms, and

a group with the formula-NR7R8where:

each of R7and R8means:

a hydrogen atom,

alkyl group having from 1 to 6 carbon atoms specified alkyl group optionally substituted amino group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, a hydroxyl group or alkoxy group having from 1 to 6 carbon atoms,

alkanoyloxy group having from 1 to 6 carbon atoms,

karbamoilnuyu group, optionally substituted by one or two alkyl group and, having from 1 to 4 carbon atoms each,

morpholinosydnonimine group,

aminosulfonyl group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, or

alkylsulfonyl group having from 1 to 6 carbon atoms, or

R7and R8optional form together with the nitrogen atom to which they are attached, a 3-8-membered saturated hydrocarbon ring, the said ring is optionally substituted by one or more substituents selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group.

17. The compound according to any of embodiments 1-15, or its pharmaceutically acceptable salt, where R3is:

2-naftilos group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and alkyl groups having from 1 to 6 carbon atoms,

3-pyrazolidine group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, triptorelin group and halogen atom, or

5-benzothiazolyl group, 5-benzothiadiazole group, 7-dihydrohelenalin group, 7-ethanolamines group, 7-hyalinella group, 3-peredelnoj group or indole Inoi group, each of which is optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,

unsubstituted phenyl group, or

substituted phenyl group (A), (B) or (C)described below:

(A) a phenyl group substituted in position 4 by a Deputy selected from the group consisting of:

alkyl groups having from 1 to 6 carbon atoms,

cycloalkyl group having from 3 to 8 carbon atoms,

alkoxy group having from 1 to 6 carbon atoms specified alkoxy group optionally substituted by one or more substituents selected from the group consisting of amino group substituted with two alkyl groups having from 1 to 4 carbon atoms each, morpholino groups and phenyl groups,

the halogen atom,

triptoreline group,

phenoxy group,

phenyl group,

1-pyrrolidino group and

-NRARBwhere each of RAand RBis an alkyl group having from 1 to 6 carbon atoms, or RAand RBtogether with the nitrogen atom to which is attached the specified RAand RBform a 3-to 5-membered saturated hydrocarbon ring,

where specified phenyl group substituted in the 4 position, further optionally substituted in position 3 by a Deputy selected from the group consisting of alkyl groups having from to 6 carbon atoms, the halogen atom and alkoxy group having from 1 to 6 carbon atoms;

(C) a phenyl group substituted in the 3 position by a Deputy selected from the group consisting of:

hydroxyl group,

alkyl groups having from 1 to 6 carbon atoms, and

alkoxy group having from 1 to 6 carbon atoms specified alkoxy group optionally substituted by one or more substituents selected from the group consisting of amino group substituted with two alkyl groups having from 1 to 4 carbon atoms each, morpholino groups and phenyl groups,

where specified phenyl group substituted in the 3 position, further optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, or further optionally substituted in the 4 position by a halogen atom; and

(C) a phenyl group substituted in the 3 position by a Deputy selected from the group consisting of nitrogen-containing groups (i)to(v)described below, the specified phenyl group is further optionally substituted in the 4 position by a halogen atom; and

(i) a monocyclic saturated hydrocarbon group having 2 to 7 carbon atoms and having one or more nitrogen atoms as ring atoms, the specified saturated hydrocarbon group optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms

(ii) nitrogen-containing monocyclic unsaturated hydrocarbon group,

(iii) morpholinyl group, optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,

(iv) piperazine derivatives group, optionally substituted alkanoyloxy group having 2 to 7 carbon atoms, or alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or more substituents selected from the group consisting of:

amino group substituted by two alkyl groups having from 1 to 4 carbon atoms each, and

morpholino group, and

(v) the group represented by the formula-NR7R8where:

each of R7and R8means:

a hydrogen atom,

alkyl group having from 1 to 6 carbon atoms specified alkyl group optionally substituted amino group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, morpholino group, hydroxyl group or alkoxy group having from 1 to 6 carbon atoms,

alkanoyloxy group having from 1 to 6 carbon atoms,

karbamoilnuyu group, optionally substituted by one or two alkyl groups having from 1 to 4 carbon atoms each,

morpholinosydnonimine group,

aminosulfonyl group, not necessarily replacing the military with one or two alkyl groups, having from 1 to 4 carbon atoms each, or

alkylsulfonyl group having from 1 to 6 carbon atoms, or

R7and R8optional form together with the nitrogen atom to which is attached the specified R7and R8, 3-8-membered saturated hydrocarbon ring, the said ring is optionally substituted by one or more substituents selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group.

18. The compound according to any of embodiments 1-15, or its pharmaceutically acceptable salt, where R3is a phenyl group substituted in position 3 by a Deputy selected from the group consisting of nitrogen-containing groups (i)to(v)described below, the specified phenyl group is further optionally substituted in position 4 by a halogen atom:

(i) a monocyclic saturated hydrocarbon group having 2 to 7 carbon atoms and having one or more nitrogen atoms as ring atoms, the specified saturated hydrocarbon group optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,

(ii) nitrogen-containing monocyclic unsaturated hydrocarbon group,

(iii) morpholinyl group, optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,

(iv) PIP is rasino group, optionally substituted alkanoyloxy group having 2 to 7 carbon atoms, or alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or more substituents selected from the group consisting of:

amino group substituted by two alkyl groups having from 1 to 4 carbon atoms each, and

morpholino group, and

(v) the group represented by the formula-NR7R8where:

each of R7and R8means:

a hydrogen atom,

alkyl group having from 1 to 6 carbon atoms specified alkyl group optionally substituted amino group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, morpholino group, hydroxyl group or alkoxy group having from 1 to 6 carbon atoms,

alkanoyloxy group having from 1 to 6 carbon atoms,

karbamoilnuyu group, optionally substituted by one or two alkyl groups having from 1 to 4 carbon atoms each,

morpholinosydnonimine group,

aminosulfonyl group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, or

alkylsulfonyl group having from 1 to 6 carbon atoms, or

R7and R8optional form together with the nitrogen atom, to which who joined these R 7and R8, 3-8-membered saturated hydrocarbon ring, the said ring is optionally substituted by one or more substituents selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group.

19. The compound according to any of embodiments 1-15, or its pharmaceutically acceptable salt, where R3is a phenyl group substituted in position 4 by a fluorine atom or a chlorine atom.

20. The compound according to any of embodiments 1-15, or its pharmaceutically acceptable salt, where R3is 6-indolines group.

21. A pharmaceutical composition comprising a compound according to any one of embodiments 1-20, or its pharmaceutically acceptable salt.

22. The pharmaceutical composition according to the variant of implementation 21 for the treatment of autoimmune diseases such as Crohn's disease, allergic colitis, Sjogren syndrome, multiple sclerosis and systemic lupus erythematosus, rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis, or age related macular degeneration.

23. The compound represented by formula (II)

Formula 2

,

or its salt, where R1, R1A, R2and R3defined as in embodiment 1, and A denotes an oxygen atom or NH.

24. Connection option exercise 23 or its salt, where in the formula (II):

A' represents an oxygen atom;

R1means:

a hydrogen atom,

alkyl group having from 1 to 6 carbon atoms,

alkyl group having from 1 to 6 carbon atoms and a substituted phenyl group,

cycloalkyl group having from 3 to 8 carbon atoms,

alkenylphenol group having from 2 to 8 carbon atoms,

alkylamino group having from 2 to 8 carbon atoms, or

phenyl group;

R1Adenotes a hydrogen atom; and

R2means:

alkyl group having from 1 to 6 carbon atoms,

alkenylphenol group having from 2 to 8 carbon atoms,

alkylamino group having from 2 to 8 carbon atoms, or

cycloalkyl group having from 3 to 6 carbon atoms.

25. Connection option exercise 23 or its salt, where in the formula (II):

A' represents NH;

R1means:

a hydrogen atom,

alkyl group having from 1 to 6 carbon atoms,

alkyl group having from 1 to 6 carbon atoms and a substituted phenyl group,

cycloalkyl group having from 3 to 8 carbon atoms,

alkenylphenol group having from 2 to 8 carbon atoms,

alkylamino group having from 2 to 8 carbon atoms, or

phenyl group;

R1Adenotes the atom is odorata; and

R2means:

alkyl group having from 1 to 6 carbon atoms,

alkenylphenol group having from 2 to 8 carbon atoms,

alkylamino group having from 2 to 8 carbon atoms, or

cycloalkyl group having from 3 to 6 carbon atoms.

26. Connection option exercise 23 or its salt, where R1denotes an alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or more substituents selected from the group consisting of:

hydroxyl group,

the halogen atom,

alkoxy group having from 1 to 6 carbon atoms specified alkoxy group optionally substituted phenyl group, and

phenyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and alkyl groups having from 1 to 6 carbon atoms;

R1Adenotes a hydrogen atom or alkyl group having from 1 to 6 carbon atoms; and

R1and R1Aoptional form together with the carbon atom to which these R1and R1Aattached, cycloalkyl group having from 3 to 6 carbon atoms.

27. Connection option exercise 23 or its salt, where:

R1is an alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or neskaiciuojami halogen, or benzyl group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and alkyl groups having from 1 to 6 carbon atoms; and

R1Ais a hydrogen atom.

28. The compound according to any of embodiments 23-25 or its salt, where R1is methyl group or ethyl group, and R1Ais a nitrogen atom.

29. The compound according to any one of the embodiments 23-28 or its salt, where R2is an alkyl group having from 1 to 6 carbon atoms, or cycloalkyl group having from 3 to 8 carbon atoms.

30. The compound according to any one of the embodiments 23-28 or its salt, where R2is ethyl or cyclopropene group.

31. The compound according to any one of the embodiments 23-30 or its salt, where:

R3is a phenyl group, naftilos group, pyrazolidine group, peredelnoj group, indolines group, benzothiazolyl group, benzothiadiazole group, pyrazolopyrimidinones group, hyalinella group, ethanolamines group, benzothiazole group or dihydrohelenalin group, each of which is optionally substituted from 1 to 3 substituents selected from the group consisting of the following substituents:

alkyl groups having from 1 to 6 atom is in carbon and optionally substituted by one or more fluorine atoms,

cycloalkyl group having from 3 to 8 carbon atoms,

the halogen atom,

alkoxy group having from 1 to 6 carbon atoms specified alkoxy group optionally substituted by one or more substituents selected from the group consisting of a fluorine atom, phenyl group, amino group substituted with two alkyl groups having from 1 to 4 carbon atoms each, and morpholino group,

phenoxy group,

phenyl group,

carboxyl group,

alkoxycarbonyl group having from 2 to 10 carbon atoms,

hydroxyl group,

monocyclic saturated hydrocarbon groups having from 2 to 7 carbon atoms and having one or more nitrogen atoms as ring atoms, the specified saturated hydrocarbon group optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,

nitrogen-containing monocyclic unsaturated hydrocarbon group,

morpholinyl group, optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,

the piperazine derivatives group, optionally substituted by one or more substituents selected from the group consisting of

alkyl groups having from 1 to 6 carbon atoms specified alkyl group optionally substituted amino group, optionally samewe the Noah one or two alkyl groups, having from 1 to 6 carbon atoms each, morpholino group, hydroxyl group or alkoxy group having from 1 to 6 carbon atoms,

formyl group,

alkanoyloxy group having 2 to 7 carbon atoms,

carbamoyl group, optionally substituted by one or two alkyl groups having from 1 to 4 carbon atoms each,

aminosulfonyl group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, and

alkylsulfonyl group having from 1 to 6 carbon atoms; and

group represented by the formula-NR7R8where:

each of R7and R8means:

a hydrogen atom,

alkyl group having from 1 to 6 carbon atoms specified alkyl group optionally substituted amino group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, a hydroxyl group or alkoxy group having from 1 to 6 carbon atoms,

alkanoyloxy group having from 1 to 6 carbon atoms,

karbamoilnuyu group, optionally substituted by one or two alkyl groups having from 1 to 4 carbon atoms each,

morpholinosydnonimine group,

aminosulfonyl group, optionally substituted by one or two alkyl groups in the region have is from 1 to 6 carbon atoms each, or

alkylsulfonyl group having from 1 to 6 carbon atoms, or

R7and R8optional form together with the nitrogen atom to which is attached the specified R7and R8, 3-8-membered saturated hydrocarbon ring, the said ring is optionally substituted by one or more substituents selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group.

32. The compound according to any one of the embodiments 23-30 or its salt, where R3is:

2-naftilos group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom and alkyl groups having from 1 to 6 carbon atoms;

3-pyrazolidine group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, triptorelin group and halogen atom;

5-benzothiazolyl group, 5-benzothiadiazole group, 7-dihydrohelenalin group, 7-ethanolamines group, 7-hyalinella group, 3-peredelnoj group or indolines group, each of which is optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms;

unsubstituted phenyl group, or

substituted phenyl group (A), (B) or (C, described below:

(A) a phenyl group substituted in position 4 by a Deputy selected from the group consisting of:

alkyl groups having from 1 to 6 carbon atoms,

cycloalkyl group having from 3 to 8 carbon atoms,

alkoxy group having from 1 to 6 carbon atoms, said alkoxy group optionally substituted by one or more substituents selected from the group consisting of amino group substituted with two alkyl groups having from 1 to 4 carbon atoms each, morpholino groups and phenyl groups,

the halogen atom,

triptoreline group,

phenoxy group,

phenyl group,

1-pyrrolidino group and

-NRARBwhere each of RAand RBis an alkyl group having from 1 to 6 carbon atoms, or RAand RBtogether with the nitrogen atom to which is attached the specified RAand RBnot necessarily form a 3-to 5-membered saturated hydrocarbon ring,

where specified phenyl group substituted in the 4 position, further optionally substituted in position 3 by a Deputy selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atom and alkoxy group having from 1 to 6 carbon atoms;

(C) a phenyl group substituted in the 3 position by a Deputy selected from the group consisting of:

the guy who rossilini group,

alkyl groups having from 1 to 6 carbon atoms, and

alkoxy group having from 1 to 6 carbon atoms specified alkoxy group optionally substituted by one or more substituents selected from the group consisting of amino group substituted with two alkyl groups having from 1 to 4 carbon atoms each, morpholino groups and phenyl groups,

where specified phenyl group substituted in the 3 position, further optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, or further optionally substituted in the 4 position by a halogen atom; and

(C) a phenyl group substituted in the 3 position by a Deputy selected from the group consisting of nitrogen-containing groups (i)to(v)described below, the specified phenyl group is further optionally substituted in position 4 by a halogen atom:

(i) a monocyclic saturated hydrocarbon group having 2 to 7 carbon atoms and having one or more nitrogen atoms as ring atoms, the specified saturated hydrocarbon group optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,

(ii) nitrogen-containing monocyclic unsaturated hydrocarbon group,

(iii) morpholinyl group, optionally substituted by one or more alkyl groups having from 1 to 6 atom is in carbon

(iv) piperazine derivatives group, optionally substituted alkanoyloxy group having 2 to 7 carbon atoms, or alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or more substituents selected from the group consisting of:

amino group substituted by two alkyl groups having from 1 to 4 carbon atoms each, and

morpholino group, and

(v) the group represented by the formula-NR7R8where:

each of R7and R8means:

a hydrogen atom,

alkyl group having from 1 to 6 carbon atoms specified alkyl group optionally substituted amino group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, morpholino group, hydroxyl group or alkoxy group having from 1 to 6 carbon atoms,

alkanoyloxy group having from 1 to 6 carbon atoms,

karbamoilnuyu group, optionally substituted by one or two alkyl groups having from 1 to 4 carbon atoms each,

morpholinosydnonimine group,

aminosulfonyl group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, or

alkylsulfonyl group having from 1 to 6 carbon atoms, or

R7and R8isn't necessarily the place with the nitrogen atom, attached to these R7and R8, 3-8-membered saturated hydrocarbon ring, the said ring is optionally substituted by one or more substituents selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group.

The present invention is described in detail as follows.

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

The term "alkyl group having from 1 to 6 carbon atoms" refers to a linear or branched alkyl group containing from 1 to 6 carbon atoms. Examples include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, tert-boutelou group, sec-boutelou group, n-pentelow group, isopentyl group, neopentyl group, tert-pentelow group and n-hexoloy group.

The term "cycloalkyl group having from 3 to 8 carbon atoms" refers to cycloalkyl group having from 3 to 8 carbon atoms. Examples include cyclopropyl group, cyclobutyl group, cyclopentyl group and tsiklogeksilnogo group.

The term "Alchemilla group having from 2 to 8 carbon atoms" refers to a linear or branched alkenylphenol group containing from 2 to 8 carbon atoms. Examples include vinyl edition is th group, allyl group, 1-propenyloxy group, Isopropenyl group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1,3-butadienyl group, 2-methylallyl group, 2-methyl-propenyloxy group, 2-pentanediol group and 3-methyl-but-2-enelow group.

The term "Alchemilla group having from 2 to 8 carbon atoms" refers to a linear or branched alkenylphenol group containing from 2 to 8 carbon atoms. Examples include etinilnoy group, 2-propenyloxy group, 2-butenyloxy group, 1-methyl-prop-2-inlow group, 2-pantanillo group and 4-pantanillo group.

The term "alkoxy group having from 1 to 6 carbon atoms" refers to a linear or branched alkoxy group containing from 1 to 6 carbon atoms. Examples include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, intoxi group, hexyloxy group.

The term "alkyl group having from 1 to 10 carbon atoms" refers to a linear or branched alkyl group containing from 1 to 10 carbon atoms. Examples include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, tert-boutelou group, sec-boutelou group, n-pentelow group, isopentyl GRU is PU, neopentylene group, tert-pentelow group, n-hexoloy group, n-heptylene group, n-aktiline group and n-hexadecyl group.

The term "alkylthio group having from 1 to 6 carbon atoms" refers to a linear or branched, alkylthio group containing from 1 to 6 carbon atoms. Examples include methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutyric group, pentylthio group and hexylthio group.

The term "alkylsulfonyl group having from 1 to 6 carbon atoms" refers to a linear or branched alkylsulfonyl group containing from 1 to 6 carbon atoms. Examples include methanesulfonyl group, ethanolgasoline group, propane-2-sulfonyloxy group and hexanesulfonic group.

The term "alkoxycarbonyl group having from 2 to 10 carbon atoms" refers to a linear or branched alkoxycarbonyl group containing from 2 to 10 carbon atoms. Examples include alkanoyloxy group having 2 to 7 carbon atoms, such as methoxycarbonyl group, ethoxycarbonyl group and t-butoxycarbonyl group, and octyloxyphenyl group.

The term "alcoolica group having 2 to 7 carbon atoms" refers to a linear or branched alkanoyloxy group containing from 2 to 7 carbon atoms is kind. Examples include acetyl group, propanolol group, butanoyloxy group and hexanoyl group.

The term "alcoolica group having from 1 to 6 carbon atoms" refers to a linear or branched alkanoyloxy group containing from 1 to 6 carbon atoms. Examples include formyl group, acetyl group, propanolol group and butanoyloxy group.

The phrase "amino group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each is expected to include, for example, an amino group, methylaminopropyl, ethylamino, isopropylamino, hexylamino, dimethylaminopropyl, diethylaminopropyl, diisopropylamino and Vexillology.

The phrase "aminosulfonyl group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each is expected to include, for example, sulfamoyl group, dimethylaminomethyl group and diethylaminomethyl group.

The phrase "carnemolla group, optionally substituted by one or more alkyl groups having from 1 to 4 carbon atoms is expected to include karbamoilnuyu group, methylcarbamoyl group, ethylcarbitol group and profilirovannuju group.

The phrase "piperazine derivatives group, which can b shall be substituted" or "optionally substituted, piperazine derivatives group" relates to piperazine derivatives group, which may be substituted (preferably on its nitrogen atom with one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (where this alkyl group may be substituted amino group which may be substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, morpholino group, hydroxyl group or alkoxy group having from 1 to 6 carbon atoms), formyl group, alkanoyloxy group having 2 to 7 carbon atoms, carbamoyl group which may be substituted one or two alkyl groups having from 1 to 4 carbon atoms each, aminosulfonyl group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, and alkylsulfonyl group having from 1 to 6 carbon atoms. Specific examples include the piperazine derivatives group, methylpiperazine group, isopropylpiperazine group, dimethylaminopyridine group, acetylpiperidine group.

The term "monocyclic saturated hydrocarbon group having 2 to 7 carbon atoms and having one or more nitrogen atoms as ring atoms" means a 3-9-membered monocyclic saturated hydrocarbon ring containing one or two nitrogen atom in the quality of education the ith ring atoms and substituted on the carbon atom of the ring. Examples of monocyclic saturated hydrocarbon groups include aziridinyl group, azetidinone group, pyrrolidinyl group and piperidinyl group (for example, 4-piperidinyl group).

The term "nitrogen-containing monocyclic unsaturated hydrocarbon group" refers to 5 - or 6-membered unsaturated ring containing 1 to 3 nitrogen atoms as parts of the ring. Examples include pyrrolidinyl group (for example, pyrrolyl-1-ilen group, imidazol-1-ilen group (for example, imidazolidinyl group), pyrazolidine group, triazole-4-ilen group (e.g., [1,2,4]triazole-4-ilen group) and pyridyloxy group.

3-5-membered saturated hydrocarbon ring formed by RAand RBtogether with the nitrogen atom that is attached to RAand RBmust include aziridinyl group, azetidinol group and pyrrolidinyloxy group.

3-8-membered saturated hydrocarbon ring formed by R7and R8(or RCand RDtogether with the nitrogen atom that is attached to R7and R8(or RCand RDshould include aziridinyl group, pyrrolidinyl group and piperidinyloxy group.

Used here, the term "aryl group" refers to an aromatic hydrocarbon group, a partially saturated aromatic Ugledar the ne group, aromatic heterocyclic group, or a partially saturated aromatic heterocyclic ring. The aromatic hydrocarbon group includes, for example, an aromatic hydrocarbon group containing from 6 to 14 carbon atoms, including phenyl group, naftalina group and untilnow group.

Partially saturated aromatic hydrocarbon group refers to a group obtained by partial saturation of polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples include tetrahydronaphthalene group and indenolol group.

Aromatic heterocyclic group refers to monocyclic or polycyclic aromatic heterocyclic group containing 2 to 13 carbon atoms and having from 1 to 6 heteroatoms (such as oxygen atoms, sulfur and/or nitrogen). Examples include thienyl group, fornillo group, pyrrolidino group, isothiazolinone group, isoxazolyl group, pyrazolidine group, thiazolidine group, oxazolidinyl group, imidazolidinyl group, pyridyloxy group, pyridazinyl group, pyramidalnou group, personilnya group, benzothiazoline group, benzofuranyl group, indolenine group, benzothiazolyl group, benzoxazolyl group, benzimidazolyl group, hyalinella group is, athinodorou group, benzoxazolyl group, benzothiazolyl group and pyrazolopyrimidinone group (for example, 5,7-dimethyl-pyrazolo[1,5-a]pyrimidine-2-ilen group).

Partially saturated aromatic heterocyclic ring refers to a heterocyclic ring obtained by partial saturation of polycyclic aromatic heterocyclic group. Such a heterocyclic ring may be substituted by an oxo group. Examples include dihydrohelenalin group:

Formula 3

,

dihydrobenzofuranyl group, dihydroergotoxine group, dihydrobenzofuranyl group, benzodioxolyl group, dihydroisoxazole group and dihydroisoquinoline group.

In the case when such aryl group is substituted, the substituents for the aryl group include those listed below, and aryl group may be substituted by from 1 to 5 of these substituents:

halogen atom, cyano, a nitro-group, alfamarine group, hydroxyl group, carboxyl group, alkyl group having 1-6 carbon atoms, triptorelin group, methoxycarbonylethyl group, alkoxy group, having from 1 to 6 carbon atoms, (alkoxy group optionally substituted phenyl group, alkylamino having from 1 to carbon atoms, dialkylamino having from 2 to 12 carbon atoms, or morpholino group), triptoreline group, deformedarse group, cyanoethoxy group,

Alchemilla group having from 2 to 8 carbon atoms, Alchemilla group having from 2 to 8 carbon atoms,

cycloalkyl group having from 3 to 8 carbon atoms, alcoolica group having 2 to 7 carbon atoms, trifluoracetyl group, alkoxycarbonyl group having from 2 to 10 carbon atoms,

phenyl group (the phenyl group is optionally substituted alkanoyloxy group having 2-7 carbon atoms, or alkoxy group having from 1 to 6 carbon atoms),

phenoxy group, optionally substituted alkoxy group having from 1 to 6 carbon atoms,

pyrazolidine group, 1-methyl-5-trifluoromethyl-1H-pyrazole-3-ilen group, methylpyrrolidinyl group, 2-methylsulfanyl-pyrimidine-4-ilen group, oxazoline group (for example, oxazol-5-ilen group), etoxazole-5-ilen group, 5-trifluoromethyl-isooctanol-3-ilen group, pyridyloxy group (for example, 4-pyridyloxy group), pyridylcarbonyl group, benzoline group, pyrrolidine group (for example, pyrrol-1-ilen group), imidazolidine group (for example, imidazol-1-ilen group), thiazolidine group, [1,2,3]thiadiazole-4-ilen group, thiazolidine group (e.g., [1,2,4]triazole-4-yl is owned by the group), alkylthio group having from 1 to 6 carbon atoms (for example, methylthio group), alkylsulfonyl group having from 1 to 6 carbon atoms (for example, methanesulfonyl group), benzolsulfonat group, pyrrolidinylcarbonyl group, morpholinylcarbonyl group, 4-piperidinyl group, optionally substituted alkyl group having from 1 to 6 carbon atoms, morpholino group, optionally substituted alkyl group having from 1 to 6 carbon atoms, piperazine derivatives group, a substituted alkyl group having from 1 to 6 carbon atoms, or alkyl group having from 1 to 6 carbon atoms and substituted by diethylaminopropyl or a group represented by the formula-NR7R8where each of R7and R8denotes a hydrogen atom, alkyl group having from 1 to 6 carbon atoms (alkyl group optionally substituted alkoxy group having from 1 to 6 carbon atoms, or dimethylaminopropoxy), alkanoyloxy group having from 1 to 6 carbon atoms, karbamoilnuyu group, karbamoilnuyu group, substituted by one or more alkyl groups having from 1 to 4 carbon atoms, morpholinosydnonimine group, dimethylaminomethyl group or alkylsulfonyl group having from 1 to 6 carbon atoms, or R7and R8optional form together with the nitrogen atom to which Oromo attached R 7and R8saturated hydrocarbon ring containing from 3 to 8 members, and the ring optionally substituted, dimethylindole group, oxo group or a hydroxyl group (for example, acetamide group, dimethylamino group, macilwraith group, butylurea group, trimethylene group, morpholinylcarbonyl), methoxyethylamine group, pyridinedicarboxylate group.

The term "pharmaceutically acceptable salt" refers to salts of alkaline metal, alkaline earth metal, ammonium or alkylamine or salts of inorganic or organic acids. Examples include salts of sodium, potassium, calcium, ammonium, aluminum, triethylamine, acetate, propionate, butyrate, formate, triptorelin, maleate, tartrate, citrate, stearate, succinate, ethylsuccinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethylenesulphonic, 2-hydroxyethanesulfonic, bansilalpet, paratoluenesulfonyl, lauryl, malate, aspartate, glutamate, adipat, salt cysteine, salt of N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodic, nicotinate, oxalate, picrate, thiocyanate, undecanoate, salt of acrylic polymer and salt carboxyvinyl polymer.

Compounds of the present invention may have stereoisomers including optical isomers, diastereoisomers and geometric isomers. Everything tee stereoisomers and mixtures thereof also fall within the scope of the present invention. Some of the compounds and intermediates of the present invention may also exist, for example, in the form of ketone-enol tautomers.

As shown in the example test below, the compounds according to the present invention exhibit high activity in the inhibition of binding between S1P and its receptor Edg-1 (S1P1). Thus, it is expected that the compounds will have a preventive or therapeutic effect on autoimmune diseases, such as Crohn's disease, allergic colitis, Sjogren syndrome, multiple sclerosis and systemic lupus erythematosus, and diseases such as rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis and age related macular degeneration.

Preferred examples of the compounds of the present invention described below.

A preferred example, A is an oxygen atom or-NR6- (preferably, R6was hydrogen). A more preferred example, A is an oxygen atom.

A preferred example of R1is an alkyl group having from 1 to 6 carbon atoms which may be substituted by one or more halogen atoms, or a benzyl group which may be substituted by one or more substituents, in the abusive group, consisting of a halogen atom and alkyl groups having from 1 to 6 carbon atoms. More preferred are methyl group, ethyl group or a benzyl group which may be substituted by one or more halogen atoms, or even more preferably a methyl group.

A preferred example of R1Ais a hydrogen atom.

Preferred examples of R2are ethyl group and cyclopropyl group.

A preferred example of R4is a hydrogen atom.

In a preferred embodiment, R3is: optionally substituted phenyl group; a 2-naftilos group (naftalina group optionally substituted by one or more substituents selected from the group consisting of a halogen atom and alkyl groups having from 1 to 6 carbon atoms); 3-pyrazolidine group (pyrazolidine group optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), triptorelin group and halogen atom) or 5-benzothiazolyl group, 5-benzothiadiazole group, 7-dihydrohelenalin group, 7-ethanolamines group, 7-hyalinella group, 3-peredelnoj group or indolines (preferably 6-indolines) group is Oh, each of which is optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms (preferably methyl group).

The term "optionally substituted phenyl group" in the preferred embodiment, includes unsubstituted phenyl groups and substituted phenyl groups (a)to(C)below:

(A) a phenyl group substituted in position 4 by a Deputy selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, cycloalkyl group having from 3 to 8 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, (alkoxy group optionally substituted by one or more substituents selected from the group consisting of amino group substituted with two alkyl groups having from 1 to 4 carbon atoms each, morpholino group and phenyl group), halogen atom, triptoreline group, phenoxy group, phenyl group, 1-pyrrolidino group, and-NRARB(RAand RBare alkyl groups having from 1 to 6 carbon atoms each, or RAand RBtogether with the nitrogen atom that is attached to RAand RBnot necessarily form a 3-to 5-membered saturated hydrocarbon ring, where phenyl group substituted in the 4 position, further optionally substituted in position 3 by a Deputy, using the data from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atom and alkoxy group having from 1 to 6 carbon atoms;

(C) a phenyl group substituted in the 3 position by a Deputy selected from the group consisting of hydroxyl group, alkyl groups having from 1 to 6 carbon atoms, and alkoxy groups having from 1 to 6 carbon atoms, (alkoxy group optionally substituted by one or more substituents selected from the group consisting of amino group substituted with two alkyl groups having from 1 to 4 carbon atoms each, morpholino group and phenyl group, where the phenyl group substituted in the 3 position, further optionally substituted by one or two alkyl groups, having from 1 to 6 carbon atoms each, or further optionally substituted in the 4 position by a halogen atom; and

(C) a phenyl group substituted in the 3 position by a Deputy selected from the group consisting of nitrogen-containing groups (i)to(v)described below, the specified phenyl group is further optionally substituted in the 4 position by a halogen atom, this nitrogen-containing groups preferably are tertiary nitrogen and attached to the phenyl group on the nitrogen atom:

(i) a monocyclic saturated hydrocarbon group having 2 to 7 carbon atoms, having one or more nitrogen atoms as ring atoms and is ameena phenyl group on the carbon atom, the specified saturated hydrocarbon group optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms (for example, piperidinyl group, optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms, such as 4-piperidinyl group);

(ii) nitrogen-containing monocyclic unsaturated hydrocarbon group (for example, pyrrolidine group, imidazolidinyl group);

(iii) morpholinyl group, optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms, such as morpholino group;

(iv) optionally substituted, piperazine derivatives group (for example, the piperazine derivatives group, optionally substituted (preferably part of a ring nitrogen atom with one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (alkyl group optionally substituted by one or more substituents selected from the group consisting of amino group substituted with two alkyl groups having from 1 to 4 carbon atoms each, and morpholino group), and alkanoyloxy group having 2 to 7 carbon atoms); and

(v) the group represented by the formula-NR7R8where each of R7and R8denotes a hydrogen atom, alkyl group having from 1 to 6 at the MOU carbon alkyl group optionally substituted amino group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, morpholino group, hydroxyl group or alkoxy group having from 1 to 6 carbon atoms), alkanoyloxy group having from 1 to 6 carbon atoms, karbamoilnuyu group, optionally substituted by one or more alkyl groups having from 1 to 4 carbon atoms each, morpholinosydnonimine group, aminosulfonyl group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, or alkylsulfonyl group having from 1 to 6 carbon atoms or R7and R8optional form together with the nitrogen atom that is attached to R7and R8, 3-8-membered saturated hydrocarbon ring, which is optionally substituted by one or more substituents selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group.

Preferably, the formula-NR7R8by paragraph (v) above, was such, as described below, the formula-NRCRD.

Each of RCand RDdenotes a hydrogen atom, alkyl group having from 1 to 6 carbon atoms (alkyl group optionally substituted amino group, optionally substituted by one or two alkyl groups having from 1 to 4 atomo the carbon each, hydroxyl group or alkoxy group having from 1 to 4 carbon atoms), formyl group, acetyl group, aminocarbonyl group, dimethylaminomethyl group or methylsulfonylamino group, or RCand RDtogether with the nitrogen atom that is attached to RCand RDform a 3-8-membered saturated hydrocarbon ring which may be substituted by one or more substituents selected from the group consisting of dimethylindole group, oxo group and a hydroxyl group.

In a particularly preferred embodiment, R3is a phenyl group substituted in position 4 by a fluorine atom or a chlorine atom, 6-indolines group and nitrogen-containing groups (i), (iv) and (v)shown in paragraph (C) above, this phenyl group substituted by a Deputy selected from the above-listed group, optionally further substituted in the 4 position by a halogen atom.

In a preferred embodiment, R5is an alkyl group having from 1 to 10 carbon atoms (preferably from 1 to 6 carbon atoms) and substituted cycloalkyl group having 3-8 carbon atoms; an alkyl group having from 1 to 10 carbon atoms (preferably from 1 to 6 carbon atoms) and substituted naftilos group; alkenylphenol group having from 2 to 8 carbon atoms (suppose the equipment from 2 to 6 carbon atoms) and substituted phenyl group; phenyl group or naftilos group (preferably 2-naftilos group), each of which is optionally substituted by 1-5 substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atom, alkoxy groups having from 1 to 6 carbon atoms, triptoreline group, deformedarse group, triptorelin group, alkenylphenol group having from 1 to 6 carbon atoms, alkylsulfonyl group having from 1 to 6 carbon atoms, alkanoyloxy group having 2 to 7 carbon atoms, alkoxycarbonyl group having from 2 to 7 carbon atoms, and cyanopropyl; pyrrolidino group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), and methoxycarbonyl group; fernilee group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), triptorelin group and halogen atom; a thienyl group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), triptorelin group, tied soleley group, oxazoline group and halogen atom; or benzothiazole group (preferably 2-benzothiazole group), phenyl group fused with a 5-7 membered saturated hydrocarbon ring, which may contain one or two oxygen atom as a forming ring atoms (for example, dihydrotestosterone group, benzodioxolyl group, digidroantratsyena group, dihydrobenzofuranyl group, tetrahydronaphthalene group and indayla group), thiadiazolyl group, benzoxadiazole group or benzothiadiazole group (preferably 5-benzothiadiazole group), each of which is optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), and halogen atom.

In a preferred embodiment, R5examples of "optionally substituted phenyl groups include unsubstituted phenyl group, phenyl group, substituted by 1 to 5 substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), alkoxy groups having from 1 to 6 carbon atoms (preferably methoxy group), and the halogen atom and phenyl group substituted in the 3 or 4 position or both 13 deputies, selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atom, alkoxy groups having from 1 to 6 carbon atoms (preferably methoxy group), triptoreline group, deformedarse group, triptorelin group, alkenylphenol group having from 1 to 6 carbon atoms, alkylsulfonyl group having from 1 to 6 carbon atoms (preferably methylsulfonyl group), methoxycarbonyl group, acetyl group and ceanography, preferably from halogen atom, methyl group and methoxy group, and more preferably the halogen atom.

In a preferred embodiment, R5an example of "optionally substituted naftilos group is naftalina group, optionally substituted by one or more substituents (preferably 1 to 3 substituents), selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms (preferably methyl group), ceanography and alkylsulfonyl group having from 1 to 6 carbon atoms (preferably methylsulfonyl group). More preferably it is naftilos group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms (preferably m is tilen group), and ceanography. Examples in the case of 2-naftilos groups include unsubstituted 2-naftalina group and 2-naftalina group, substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (substitute in any positions, preferably in positions 5, 7 and/or 8), and other substituents (substitute in 5, 7 and/or 8-position). Examples in the case of 1-naftilos groups include unsubstituted naftalina group and 1-naftalina group, substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (substitute any provisions), and other substituents, preferably halogen atom (replacing preferably in the 4 position).

In a particularly preferred embodiment, R5is a phenyl group substituted in the 3 and 4 positions by a halogen atom, unsubstituted 2-naftilos group and 2-naftilos group, substituted in the 5, 7 and/or 8-position by one or more substituents selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms (preferably methyl group), and ceanography.

This is followed by a particularly preferable combination of R3and R5. In the case when R3is a phenyl group substituted in the 4 position by a fluorine atom and and chlorine, R5is: alkyl group having from 1 to 10 carbon atoms (preferably from 1 to 6 carbon atoms) and substituted naftilos group; alkenylphenol group having from 2 to 8 carbon atoms (preferably from 2 to 6 carbon atoms) and substituted phenyl group; a substituted phenyl group (e.g. phenyl group substituted by 1-5 of methyl groups, phenyl group, substituted at the 3 or 4 position or both 1-3 substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably a methyl group, ethyl group, through the group), halogen atom, methoxy group, triptoreline group, deformedarse group, trifluoromethyl group, alkenylphenol group having from 1 to 6 carbon atoms (preferably vinyl groups), methoxycarbonyl group, acetyl group and cyanopropyl); benzothiazole group, naftilos group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms (preferably methyl group), ceanography and alkylsulfonyl group having from 1 to 6 carbon atoms (preferably methylsulfonyl group); pyrrolidino group, optionally substituted by one or more substituents selected from g is uppy, consisting of methyl and methoxycarbonyl group; thienyl group, substituted by one or more alkyl groups having from 1 to 6 carbon atoms (preferably, methyl groups); benzodioxolyl group, dihydroergotoxine group, dihydrobenzofuranyl group, tetrahydronaphthyl group, indanernas group or benzothiadiazole group (preferably 5-benzothiadiazole group).

In the case when R3is 6-indolines group, R5is: alkyl group having from 1 to 10 carbon atoms (preferably from 1 to 6 carbon atoms) and substituted naftilos group; alkenylphenol group having from 2 to 8 carbon atoms (preferably from 2 to 6 carbon atoms) and substituted phenyl group; optionally substituted phenyl group (such as unsubstituted phenyl group, phenyl group, substituted 1-5 methyl groups, phenyl group, substituted at the 3 or 4 position or both 1-3 substituents selected from the group consisting of alkyl groups having from 1 to 6 atoms carbon (preferably methyl group, ethyl group, through the group), halogen atom, methoxy group, triptoreline group, deformedarse group, triptorelin group, alkenylphenol group having from 1 to 6 carbon atoms (before occhialino vinyl groups), methoxycarbonyl group, acetyl group and cyanopropyl); benzothiazole group, naftilos group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms (preferably methyl group), ceanography and alkylsulfonyl group having from 1 to 6 carbon atoms (preferably methylsulfonyl group); pyrrolidino group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), and group methoxycarbonyl; or benzodioxolyl group, dihydroergotoxine group, dihydrobenzofuranyl group, tetrahydronaphthyl group, indanernas group or benzothiadiazole group (preferably 5-benzothiadiazole group), each of which is optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), and halogen atom.

In the case when R3is the embodiment shown above in paragraph (C), R5is: alkyl group having from 1 to 6 carbon atoms and substituted cycloalkyl group, have it from 3 to 8 carbon atoms; alkyl group having from 1 to 10 carbon atoms (preferably from 1 to 6 carbon atoms) and substituted naftilos group; alkenylphenol group having from 2 to 8 carbon atoms (preferably from 2 to 6 carbon atoms) and substituted phenyl group; optionally substituted phenyl group (such as unsubstituted phenyl group, phenyl group, substituted by 1-5 substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), halogen atom, phenyl group, substituted at the 3 or 4 position or both 1-3 substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atom, methoxy group, triptoreline group, deformedarse group, triptorelin group, alkenylphenol group having from 1 to 6 carbon atoms, alkylsulfonyl group having from 1 to 6 carbon atoms (preferably methylsulfonyl group), methoxycarbonyl group, acetyl group, cyanopropyl); naftilos group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms (preferably methyl group), ceanography and alkylsulfonyl group having from 1 to 6 carbon atoms (pre is respectfully methylsulfonyl group); pyrrolidino group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), and methoxycarbonyl group; thienyl group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), triptorelin group, thiadiazolyl group, oxazoline group and halogen atom; fernilee group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably methyl group), triptorelin group and halogen atom; or benzothiazole group, benzodioxolyl group, dihydroergotoxine group, dihydrobenzofuranyl group, tetrahydronaphthyl group, indanernas group, thiadiazolyl group (preferably 5-thiadiazolyl group), benzoxadiazole group or benzothiadiazole group (preferably 5-benzothiadiazole group), each of which is optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms (preferably the methyl group), and halogen atom.

Preferred optically active compound of the present invention, with which the hydrogen atom, R1Ahas the following structure.

Formula 4

The compound of the present invention can be synthesized, for example, as described below.

Formula 5

Scheme 1

(where R1, R1A, R2, R3and R5such as described above, R' denotes an alkyl group having from 1 to 6 carbon atoms, R" denotes a protective group for the amino group, which is stable in an alkaline environment (e.g., t-butoxycarbonyl group, benzyloxycarbonyl group, L denotes a leaving group (e.g. halogen atom such as chlorine atom, bromine atom and iodine atom, alkylsulfonate group, such as methanesulfonate group and p-toluensulfonate group, arylsulfonate group, 2-oxo-1-oxazolidine group), and A1denotes an oxygen atom, a sulfur atom or a group represented by the formula-NR6-where R6denotes a hydrogen atom or alkyl group having from 1 to 6 carbon atoms).

In the present invention in connection with A, which is an oxygen atom, a sulfur atom or a group represented by the formula-NR6-can be synthesized, for example, the method shown in scheme 1.

The compound denoted by formula (b)can be obtained by reaction of compounds of formula (a) with hydrazine in a solvent or in no solvent. The used amount of hydrazine is usually 1-30 weight equivalents relative to the compound (a), preferably 5-30 weight equivalents. Used, if necessary, the solvent is not limited particularly as long as he remains inert. Examples of solvents that can be used include alcohols such as methanol and ethanol. The reaction temperature was usually from room temperature to the boiling temperature of the solvent. The reaction time is usually 12-24 hours, but it depends on the reaction temperature and the starting materials.

The compound represented by formula (d)can be obtained by reaction of the compound represented by formula (b), with the compound represented by formula (C), in a solvent or in the absence of solvent. The quantity used of the compound represented by formula (C), is usually 1-3 weight equivalent relative to the compound represented by formula (b), preferably of 1.1 to 1.5 weight equivalent. The used solvent is not limited particularly it until it remains inert. For example, preferably used alcohols such as methanol or ethanol, and g is legendofandy hydrocarbons, such as dichloromethane and chloroform. The reaction temperature is usually from room temperature up to the boiling point of the solvent. The reaction time is usually from 30 minutes to 24 hours, but it depends on the reaction temperature and the starting materials.

The compound denoted by formula (e)can be obtained by reaction of compounds of formula (d) with a base in a solvent or in the absence of a solvent for the cyclization of compounds. Used the base typically includes hydroxides of alkali metals, such as NaOH and KOH, alkali metal salts, such as NaHCO3and K2CO3. The amount used of the base is 1 to 10 weight equivalents relative to the compound (d), preferably 1,1-1,5 weight equivalent. If necessary the solvent, the following substances can be used as solvent include water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran (THF), and mixtures of these solvents. The reaction temperature was usually from room temperature to the boiling temperature of the solvent. The reaction time is usually from 30 minutes to 24 hours, but it depends on the reaction temperature and the starting materials.

The compound denoted by formula (g)can be obtained by reaction of compounds of formula (e) with the compound of the formula (f) in the presence of a base. The amount of compounds of formula (f) is 1-5 is of nowych equivalents, preferably 1,1-1,5 weight equivalent relative to the compound of formula (e). Used the base typically includes hydroxides of alkali metals, such as NaOH and KOH, alkali metal salts, such as NaHCO3and K2CO3and amines, such as triethylamine, diisopropylethylamine and Diisopropylamine. The amount used of the base is 1 to 10 weight equivalents relative to the compound of formula (e), preferably from 1.0 to 3.0 weight equivalent. The reaction temperature was 0°C. to boiling point of solvent, preferably from 0°C. to room temperature. If needed, the solvent is not particularly limited as long as he remains inert. Examples of applicable solvents include water, ethers such as dioxane and THF, dimethylformamide (DMF), N,N'-dimethylacetamide (DMA), N,N'-dimethylpropyleneurea (DMPM), hexamethylphosphoramide (HMPA), and mixtures of these solvents. The reaction time is usually from 30 minutes to 24 hours, but it depends on the reaction temperature and the starting materials.

The compound denoted by formula (h)can be obtained by reaction of compounds of formula (g) with an oxidant in a solvent. Examples of oxidizing agents which can be used include organic peroxyacids, such as m-chloroperbenzoic acid, uranyl nanoparticulate magnesium, peroxidasa sour is a and proximedia acid, inorganic and organic peroxides, such as hydrogen peroxide adduct of hydrogen peroxide and urea/tallowy anhydride, tert-butylhydroperoxide and the hydroperoxide cumene, periodate sodium, Oxon (registered trademark), N-bromosuccinimide, N-chlorosuccinimide, chloramine-T, sodium hypochlorite tert-butyl, diacetate yogashala and bromo-1,4-diazabicyclo[2,2,2]octane complex adduction. The amount of oxidizing agent is from 2 to 10 weight equivalents relative to the compound of formula (g), preferably 2-3 weight equivalent. If needed, the solvent is not particularly limited as long as he remains inert. Examples of solvents include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature was 0°C. to boiling point of solvent, preferably from 0°C to 40°C. the reaction Time is usually from 30 minutes to 24 hours, but it depends on the reaction temperature and the starting materials.

The compound denoted by formula (i), or a salt of this compound can be obtained by conducting the reaction of removing the protective group of amino compounds indicated by formula (h), the solvent under normal conditions, for example, by conducting the reaction with the acid. Examples of acids used include inorganic acids (e.g. hydrochloric acid, removecolumn acid, iodomethane acid, sulfuric acid, nitric acid) and organic acids (for example, triperoxonane acid, p-toluensulfonate acid, methanesulfonate acid). The amount of acid is 1-50 weight equivalents relative to the compound represented by formula (h). The reaction temperature was 0°C. to boiling point of solvent, preferably from room temperature to 40°C. the Used solvents include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction time is usually from 30 minutes to 24 hours, but it depends on the reaction temperature and the starting materials.

The compound denoted by formula (k), or pharmaceutically acceptable salt of this compound can be obtained in the solvent or in his absence by the reaction of compounds of formula (i) with the compound of the formula (j) (where a1denotes an oxygen atom, a sulfur atom or a group represented by the formula-NR6-where R3described above) in the presence of a base and, if necessary, salt. The quantity used of the compound represented by formula (j), is usually 1-5 weight equivalents relative to the compound represented by formula (i), preferably 1-3 weight equivalent. The examples used bases include alkali metal salts, such as Carbo is at sodium, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, dimsyl sodium, sodium hydride, sodium amide, tert-butoxylate and tert-butoxylate, amines, such as triethylamine, Diisopropylamine, pyrrolidine and piperidine, sodium acetate and potassium acetate. The amount used of the base is usually 1 to 10 weight equivalents relative to the compound represented by formula (i), preferably 1-3 weight equivalent. The reaction temperature was 0°C up to the boiling point of the solvent, the reaction can be carried out at normal pressure, increased pressure, microwave irradiation and similar conditions. The solvents used in the reaction include ethers such as dioxane and THF, DMF, DMA, DMPM, HMPA or the like, or mixtures of these solvents. The reaction time is usually from 1 to 12 hours, but it depends on the reaction temperature and the starting materials.

The compound denoted by formula (m), or its pharmaceutically acceptable salt can be obtained by reaction of compounds of formula (k) with the compound of the formula (l) in a solvent or without solvent in the presence of a base and, if necessary, salt. The quantity used of the compound represented by the formula (l), is usually 1-5 weight equivalents relative to the compound represented by formula (k), prepact the tion 1-1,2 weight equivalent. The examples used bases include hydroxides of alkali metals, such as NaOH and KOH, alkali metal salts, such as NaHCO3and K2CO3or amines, such as triethylamine, diisopropylethylamine and Diisopropylamine. The amount used of the base is usually 1 to 10 weight equivalents relative to the compound represented by formula (k), preferably 1-3 weight equivalent. The reaction temperature was 0°C. to boiling point of solvent, preferably from 0°C. to room temperature. If needed, the solvent is not particularly limited as long as he remains inert. Examples of solvents include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as dioxane and THF, and mixtures of these solvents. The reaction time is usually from 30 minutes to 24 hours, but it depends on the reaction temperature and the starting materials.

Formula 6

Scheme 2

Scheme 3

Scheme 4

(where R1, R1A, R2, R3, R4, R5, R', R", A and L described above, and R41same as R4with the exception of the hydrogen atom).

In the present invention the connection, they are the abuser And, indicated by the formula-SO - or formula-SO2-can be synthesized by the method shown in scheme 2.

The compound represented by formula (m2), the compound represented by formula (m3), or pharmaceutically acceptable salts of the compounds can be obtained by the reaction of compounds obtained according to scheme 1 and represented by the formula (m), and compounds represented by formula (m1), with A1, which is a sulfur atom, with an oxidising agent and, if necessary, the formation of salts. Examples of oxidizing agents which can be used include organic peroxyacids, such as m-chloroperbenzoic acid, uranyl nanoparticulate magnesium, peroxidasa acid and proximedia acid, inorganic and organic peroxides, such as hydrogen peroxide adduct of hydrogen peroxide and urea/tallowy anhydride, tert-butylhydroperoxide and the hydroperoxide cumene, periodate sodium, Oxon (registered trademark), N-bromosuccinimide, N-chlorosuccinimide, chloramine-T, sodium hypochlorite tert-butyl, diacetate yogashala and bromo-1,4-diazabicyclo[2,2,2]octane complex adduction. The amount of oxidizing agent is 1 to 10 weight equivalents relative to the compound of formula (m1), preferably 1-3 weight equivalent. If needed, the solvent is not particularly limited as long the eye, it remains inert. Examples of solvents include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature is from -78°C to the boiling point of the solvent, preferably from 0°C to 40°C. the reaction Time is usually from 30 minutes to 24 hours, but it depends on the reaction temperature and the starting materials.

In the present invention, the connection with And denoting-CH2-can be synthesized by the method shown in scheme 3.

The compound denoted by formula (o)can be obtained by reaction of compounds of formula (a) with the compound of the formula (n) (where R2described above) in the presence or in the absence of solvent. The quantity used of the compound represented by formula (n)is 1 to 10 weight equivalents relative to the compound represented by formula (a), preferably 1-1,2 weight equivalent. If needed, the solvent is not particularly limited as long as he remains inert. Examples of solvents used include alcohols such as methanol and ethanol. The reaction temperature is usually from room temperature to the boiling point of the solvent, preferably from room temperature to 50°C. the reaction Time is usually from 12 to 24 hours, but it depends on the reaction temperature and the starting materials.

The connection denoted by f is rmulas (p), can be obtained by reaction of compounds of formula (o) with a reagent of Losone in the presence or in the absence of solvent. The used amount of the reagent of Losona is 1-5 weight equivalents relative to the compound represented by formula (o), preferably 1-1,2 weight equivalent. Used solvent includes ethers such as dioxane and THF, and mixtures of these solvents. The reaction temperature is from room temperature to the boiling point of the solvent, preferably from room temperature to 50°C. the reaction Time is usually from 1 to 12 hours, but it depends on the reaction temperature and initial substances

The compound denoted by formula (r)can be obtained by reaction of compounds of formula (p) with the compound denoted by the formula (q), in the presence of mercury compounds. Used a number of compounds with formula (q) is 1 to 10 weight equivalents relative to the compound represented by formula (p), preferably 1-1,2 weight equivalent. Examples of compounds of mercury include HgCl2and Hg(OAc)2. The quantity used mercury compounds is 1 to 10 weight equivalents relative to the compound represented by formula (p), preferably 1-1,2 weight equivalent. Used solvent includes acetonitrile, THF, dioxane and the like. The temperature of reaction is AI ranges from room temperature to the boiling point of the solvent, preferably from room temperature to 50°C. the reaction Time is usually from 12 to 48 hours, but it depends on the reaction temperature and the starting materials.

The compound denoted by formula (k1), or its salt can be obtained by the reaction of removing the protective group of amino compounds indicated by formula (r), in a solvent under normal conditions, for example, by conducting the reaction with the acid. Examples of acids used include inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, iodomethane acid, sulfuric acid, nitric acid) and organic acids (for example, triperoxonane acid, p-toluensulfonate acid, methanesulfonate acid). The amount of acid is 1-50 weight equivalents relative to the compound represented by formula (r). The reaction temperature is from 0°C to the boiling point of the solvent, preferably from room temperature to 40°C. if needed, the solvent is not particularly limited as long as he remains inert. Examples of solvents include halogenated hydrocarbons such as methylene chloride and chloroform. The reaction time is usually from 30 minutes to 24 hours, but it depends on the reaction temperature and the starting materials.

The compound represented by the formula (m4), or pharmaceuticas is acceptable salt can be obtained by the reaction of compounds represented by the formula (k1), with the compound represented by the formula (l), in a solvent or in the absence of solvent, in the presence of a base and, if necessary, salt. The quantity used of the compound represented by the formula (l), is usually 1-5 weight equivalents relative to the compound represented by the formula (k1), preferably 1-1,2 weight equivalent. Used base include hydroxides of alkali metals, such as NaOH and KOH, alkali metal salts, such as NaHCO3and K2CO3and amines, such as triethylamine, diisopropylethylamine and Diisopropylamine. The amount used of the base is 1 to 10 weight equivalents, preferably from 1.0 to 3.0 weight equivalent. The reaction temperature is usually from room temperature up to the boiling point of the solvent, preferably from 0°C. to room temperature. The used solvent is not limited particularly it until it remains inert. Examples of solvents include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as dioxane and THF, and mixtures thereof. The reaction time is usually from 30 minutes to 24 hours, but it depends on the reaction temperature and the starting materials.

The compound represented by formula (u), or its pharmaceutically acceptable salt can be obtained is by eakley in the solvent or in the absence of solvent compounds, represented by the formula (m5), with the compound represented by formula (s), in the presence of a base and, if necessary, salt. The quantity used of the compound represented by formula (s)is usually 1 to 10 weight equivalents relative to the compound represented by the formula (m5), preferably 1-1,5 weight equivalent. Used base include hydroxides of alkali metals, such as NaOH and KOH, alkali metal salts, such as NaHCO3and K2CO3and amines, such as triethylamine, diisopropylethylamine and Diisopropylamine. The amount used of the base is 1 to 10 weight equivalents relative to the compound represented by the formula (m5), preferably from 1.0 to 3.0 weight equivalent. The reaction temperature was usually from 0°C. to boiling point of solvent, preferably from 0°C. to room temperature. The used solvent is not limited particularly it until it remains inert. Examples of solvents include water, ethers such as dioxane and THF, dimethylformamide (DMF), N,N'-dimethylacetamide (DMA), N,N'-dimethylpropyleneurea (DMPM), hexamethylphosphoramide (HMPA), and mixtures of these solvents. The reaction time is usually from 30 minutes to 24 hours, but it depends on the reaction temperature and the starting materials.

Further, the functional group can be introduced is in R 3by carrying out the above described processes of attaching a protective group, removing the protective groups and the transformation of the functional groups.

For use as pharmaceutical compositions the compounds of the present invention can be supplemented commonly used fillers, additives, pH regulators, soljubilizatorami and so on, and then entered with conventional methods, as tablets, granules, pills, capsules, powders, solutions, suspensions, injections, etc. thus Obtained pharmaceutical compositions can be entered as oral or parenteral formulations.

The connection according to the present invention can be introduced to the adult patient in a dosage of from 1 to 1000 mg per day in several separate doses. This dosage may be increased or decreased in accordance with the type of disease, age, weight and symptoms of the patient and the like.

The positive effect of the invention

As shown in the Example test below, it was found that the compounds of the present invention are strong ligands Edg-1 (S1P1).

The best way of carrying out the invention

The following describes the present invention in more detail with reference to examples and Sample testing.

Example 1

3,4-sodium dichloro-N-{(R)-1-[4-ethyl-5-(4-pertenece)-4H-[1,2,4]-triazole-3-yl]ethyl}is enthaltene (compound 12).

Formula 7

t-Butyl ether (R)-(1-hydrazinophenyl-2-ethyl) - carbamino acid

Formula 8

(1) of hydrazine Monohydrate (30 ml) was added to a solution of methyl ester of N-(t-butoxycarbonyl)-D-alanine (41.8 g) in methanol (180 ml), the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, the obtained crude crystals were washed mixed solvent of hexane and ethyl acetate (1:1, 300 ml), then dried to obtain the titled compound as colorless powder (32,6 g).

1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.14 in (d, J=7.2 Hz, 3H), of 1.37 (s, 9H), 3,30-4.09 to (m, 3H), 6,70-of 6.90 (m, 1H), 8,96 (users, 1H).

(R)-2-(N-(t-butoxycarbonyl)amino)propionyl)-N-ethylhydrocupreine

Formula 9

(2) Ethylisothiocyanate (14.6 ml) was added to a solution of compound (30,8 g) from example 1-(1) in ethanol (152 ml), the mixture was heated under reflux for two hours. Then the mixture was cooled to room temperature and the resulting crystals were filtered off. The filtrate was concentrated and the obtained residue was purified by chromatography on silica gel with a mixture solvent of ethyl acetate and chloroform to obtain the titled compound as a colorless amorphous substance (43,2 g).

1H-NMR (300 MHz, DMSO-d6) δ ppm: 0,98 of 1.28 (m, 6H), of 1.40 (s, 9H), 3.25 to the 3.65 (m, 2H), of 3.77-3,95 (m, 1H), 7,20-7,39 (m, 1H), 7,45-of 7.60 (m, 1H), 9,25 (s, 1H), 10,00 (s, 1H).

t-Butyl ether [(R)-1-(4-ethyl-5-mercapto-4H-[1,2,4]triazole-3-yl)ethyl]-carbamylate acid

Formula 10

(3) To a mixed solution of the compound from example 1-(2) (42,1 g) in methanol (120 ml) and dioxane (240 ml) was added aqueous sodium hydroxide solution 1 mol/l (218 ml), after which the mixture was heated under reflux for three hours. The reaction solution was concentrated, then added hydrochloric acid (2N, 100 ml) in aqueous solution. The mixture was extracted with a mixed solution of ethyl acetate, chloroform and methanol (10:10:1, 500 ml). The organic phase was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove solvent. The obtained residue was washed with mixed solvent of hexane and ethyl acetate (1:1, 300 ml), then dried to obtain the titled compound as a white solid (29,22 g).

1H-NMR (300 MHz, DMSO-d6) δ ppm: to 1.21 (t, J=7,1 Hz, 3H), 1,30-1,50 (m, 3H), of 1.39 (s, 9H), 3,82-of 4.05 (m, 2H), 4.72 in-4,88 (m, 1H), 7,58 (d, J=8.5 Hz, 1H), 13,60 (users, 1H).

t-Butyl ether [(R)-1-(4-ethyl-5-methylsulfanyl-4H-[1,2,4]triazole-3-yl)ethyl]-carbamylate acid

Formula 11

(4) To a solution of compound of example 1-(3) (28,12 g) in THF (20 ml) was added Diisopropylamine a (17.4 ml) and MeI (7.7 ml), after which the mixture is stirred at room temperature for one hour. Then the obtained crystals were filtered. The filtrate was concentrated and the obtained crude crystals were washed with a mixture solvent of hexane and ethyl acetate (3:1, 200 ml), then dried to obtain the titled compound as a white powder (29.5 g).

1H-NMR (300 MHz, DMSO-d6) δ ppm: to 1.21 (t, J=7.0 Hz, 3H), of 1.38 (s, 9H), of 1.45 (t, J=7.0 Hz, 3H), 2,62 (s, 3H), of 3.80-4.00 points (m, 2H), 4,85 to 4.92 (m, 1H), 7,52 (d, J=8.5 Hz, 1H).

t-Butyl ether [(R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazole-3-yl)ethyl]-carbamylate acid

Formula 12

(5) To a solution of compound of example 1-(4) (21,0 g) in chloroform (293 ml) under cooling with ice in four installments) was added m-chloroperbenzoic acid (43,0 g), after which the mixture is stirred at room temperature for three hours and then at 40°C for one hour. Then to the reaction solution to separate the organic phase was added Na2S2O3(12.9 g) and an aqueous solution of sodium hydroxide (1 mol/l, 300 ml), the organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove solvent. The obtained residue was purified flowing column chromatography on silica gel with a mixed solvent of g is the Xan and ethyl acetate, then recrystallized with hexane and chloroform to obtain the titled compound as a white powder (17,2 g).

1H-NMR (300 MHz, CDCl3) δ ppm: the 1.44 (s, 9H), for 1.49 (t, J=7,1 Hz, 3H), 1,67 (t, J=6.8 Hz, 3H), 3,53 (s, 3H), 4,25-4,59 (m, 2H), 4.92 in-5,20 (m, 2H).

Salt triperoxonane acid (R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazole-3-yl)ethylamine

Formula 13

(6) obtained in example 1-(5) the compound (100.0 g) was added triperoxonane acid (121 ml), after which the mixture is stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure to obtain the titled compound as a white powder (to 103.8 g).

1H-NMR (300 MHz, DMSO-d6) δ ppm: to 1.37 (t, J=7.2 Hz, 3H), of 1.59 (d, J=6.8 Hz, 3H), of 3.65 (s, 3H), 4,21-4,50 (m, 2H), 4.72 in-the 4.90 (m, 1H), 8,69 (users, 3H).

(1R)-1-(4-ethyl-5(4-pertenece)-4H-[1,2,4]-triazole-3-yl)ethylamine

Formula 14

(7) In the pressure-resistant screw the tube to the compound obtained in example 1-(6), (1 g) was added N-N'-dimethylpropyleneurea (DMPM) (5 ml), 4-terfenol (1.01 g) and cesium carbonate (2,94 g), after which the mixture was mixed at 200°C for one hour. The mixture was brought to room temperature, after which was added a saturated aqueous solution of sodium chloride. The mixture was extracted with ethyl acetate (100 ml × 5). Organicheskuyu was dried over anhydrous sodium sulfate, was filtered and evaporated under reduced pressure to remove solvent. The crude product was purified column chromatography (NH SiO2, hexane/ethyl acetate = 50/50 to 20/80, chloroform/methanol = 30/1) to obtain the titled compound (brown oily substance 0,586 g).

1H-NMR (600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7,3 Hz, 3H), 1,58 (d, J=6.4 Hz, 3H), 3.95 to to 4.23 (m, 3H), 6.90 to-to 7.15 (m, 2H), 7,30-7,44 (m, 2H).

3,4-sodium dichloro-N-{(R)-1-[4-ethyl-5-(4-pertenece)-4H-[1,2,4]-triazole-3-yl]ethyl}benzosulfimide(compound 12)

Formula 15

(8) To a solution of compound of example 1-(7) (0,554 g) in THF (10 ml) at room temperature was added triethylamine (0,93 ml, only 6.64 mmol) and 3,4-dichlorobenzenesulfonate (0.45 ml, is 2.88 mmol), after which the mixture is stirred at room temperature for 2.5 hours. Then added ethyl acetate. The organic phase is washed with 1N aqueous solution of hydrochloric acid, then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to remove solvent. The crude product was purified column chromatography (acidic OH SiO2, hexane/ethyl acetate = 50/50 to 10/90), and then recrystallized (ethyl acetate/hexane) to obtain 0,447 g of the above compound (compound 12) in the form best is to maintain the powder.

Melting point: from 190,0°C to 192,0°C.

Example 2

N-[(1R)-1-(4-ethyl-5(4-methylphenylimino)-4H-[1,2,4]triazole-3-yl)ethyl]3,4-dichlorobenzenesulfonate(compound 61)

Formula 16

(R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazole-3-yl)ethylamine

Formula 17

(1) To the compound obtained in example 1-(6), (4,30 g) was added n-BuNH2(20 ml), after which the mixture is stirred at room temperature for one hour. The reaction solution was concentrated, the crude product was purified by chromatography NH on silica gel with a mixed solvent of methanol and chloroform (methanol/chloroform = 10%) to obtain the titled compound as colorless crystals (2,737 g).

1H-NMR (200 MHz, CDCl3) δ ppm: 1,53 (t, J=7,3 Hz, 3H), of 1.65 (d, J=6.8 Hz, 3H), 3,53 (s, 3H), 4,14-4,58 (m, 3H).

[5-((R)-1-amino-ethyl)-4-ethyl-4H-[1,2,4]triazole-3-yl]-4-methylphenylamine

Formula 18

(2) the Compound obtained in example 2-(1), (437 mg), DEM (2.0 ml), 4-toluidine (257 mg) and NaH (240 mg, 60-72% by weight in oil) was placed in a pressure-resistant test tube with screw cap. The mixture was mixed at 200°C for 1.0 hour, after which it was brought to room temperature, then the reaction solution was added 10% methanol/chloroform. The reaction solution was filtered h is through NH silica gel, after concentrated, the obtained brown oily substance was purified by a chromatography method on columns (NH SiO2, ethyl acetate/hexane = 50-99%, methanol/chloroform = 5%) to obtain the titled compound (brown oily compound, 224 mg).

1H-NMR (200 MHz, CDCl3) δ ppm: 1,31 (t, J=7,3 Hz, 3H), 1,60 (d, J=6.6 Hz, 3H), of 2.28 (s, 3H), 3,60-4,30 (m, 3H), of 6.96-7,02 (m, 4H).

N-[(1R)-1-(4-ethyl-5(4-methylphenylimino)-4H-[1,2,4]triazole-3-yl)ethyl]3,4-dichlorobenzenesulfonate(compound 61)

Formula 19

To a solution of the compound in example 2-(2) (220 mg) and triethylamine (0,249 ml) in THF (9 ml) at room temperature was added a solution of 3,4-dichlorobenzenesulfonate (0,249 μl) in THF (2 ml), after which the mixture is stirred at room temperature for 5 hours. The insoluble substance was removed by filtration, the obtained residue was concentrated. The crude product was purified by way of column chromatography using OH silica gel (solvent for elution: ethyl acetate/hexane = 50-99%), and then recrystallized (ethyl acetate-hexane) to obtain 160 mg of the above compound (compound 61) in the form of a pale yellow powder.

1H-NMR (600 MHz, DMSO-d6) δ ppm: of 1.18 (t, J=7,1 Hz, 3H), of 1.30 (d, J=6.9 Hz, 3H), of 2.23 (s, 3H), a 3.87-a 4.03 (m, 2H), 4.63 to-4,72 (m, 1H), 7,00 for 7.12 (m, 2H), 7,35-7,45 (m, 2H), 7,74 (DD, J=8,6, 1.9 Hz, 1H), 7,86 (d, J=8.6 Hz, 1H), of 7.96 (d, J=1.9 Hz, 1H), of 8.27 (s, 1H), 8,57-8,66 (m, 1H).

Melting point: from 93,0°C up to 99.0°C.

Example 3

34 sodium dichloro-N-[(R)-1-(4-ethyl-5(4-methylbenzenesulfonyl)-4H-[1,2,4]triazole-3-yl)ethyl]benzosulfimide(compound 55)

Formula 20

(R)-1-(4-ethyl-5(4-methylphenylsulfonyl)-4H-[1,2,4]triazole-3-yl)-ethylamine

Formula 21

(1) Compound obtained in example 1-(6), (of 5.00 g, 15.1 mmol), 4-methylbenzoyl (3,74 g, to 30.1 mmol) and cesium carbonate (14,7 g, 45,1 mmol) were placed in a pressure-resistant test tube with screw cap. The mixture was mixed at 150°C for four hours, after which it was brought to room temperature and was added to a mixed solvent chloroform/methanol (10/1). The insoluble substance was removed by filtration. The filtrate was removed by evaporation under reduced pressure, the crude product was purified by the method chromatography on a column (NH SiO2, hexane/ethyl acetate = 50/50 to 10/90, chloroform/methanol = 40/1) to obtain a 3.01 g of the above compound (colorless oily substance).

1H-NMR (600 MHz, CDCl3) δ ppm: to 1.21 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.4 Hz, 3H), 2,31 (s, 3H), 4,00-4,18 (m, 3H), 7,06-7,14 (m, 2H), 7,26-7,30 (m, 2H).

3,4-sodium dichloro-N-[(R)-1-(4-ethyl-5(4-methylbenzenesulfonyl)-4H-[1,2,4]triazole-3-yl)-ethyl]-benzosulfimide(compound 55)

Formula 22

(2) Starting from compounds poluchennogo the example 3-(1), the procedure described in example 1-(8)were repeated to obtain these compounds.

1H-NMR (600 MHz, DMSO-d6) δ ppm: 1,08 (t, J=7,3 Hz, 3H), 1,32 (d, J=6.9 Hz, 3H), of 2.28 (s, 3H), 3,90-4,11 (m, 2H), 4,78 (kV, J=6,9 Hz, 1H), 7,17-of 7.23 (m, 4H), to 7.67-7,74 (m, 1H), 7,81-7,88 (m, 1H), 7,92-7,94 (m, 1H), 8,77 (s, 1H).

The output 46%, melting point: from 141,0°C to 143,0°C.

Example 4

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5(4-methylbenzenesulfonyl)-4H-[1,2,4]triazole-3-yl]-ethyl]-benzosulfimide(compound 57)

Formula 23

To a solution of compound (0,300 g) from example 3-(2) in chloroform (6 ml) was added m-chlorbenzoyl acid (0,329 g), after which the mixture is stirred at room temperature for 1 hour. Then add the next portion m-chlorbenzoyl acid (0,329 g), after which the mixture is stirred at room temperature for 15 hours. Then add the next portion m-chlorbenzoyl acid (0,329 g), after which the mixture is stirred at room temperature for two hours. After this was added ethyl acetate and the organic phase is washed with 5% aqueous solution of Na2S2O3then saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to remove solvent. The obtained residue was purified by way of column chromatography (acidic OH SiO2, hexane/ethyl acetate = the t 70/30 to 40/60), and then recrystallized to obtain 0,196 g of the above compound (compound 57) (colorless compound in powder form).

1H-NMR (600 MHz, DMSO-d6) δ ppm: 1,25-1,35 (m, 6H), of 2.45 (s, 3H), 4,23-and 4.40 (m, 2H), 4,78-a 4.86 (m, 1H), 7,52-7,56 (m, 2H), 7,62-to 7.67 (m, 1H), 7,78-of 7.82 (m, 1H), 7,86-7,94 (m, 3H).

Melting point: from 164,0°C to 165,0°C.

Example 5

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazole-3-yl]-ethyl]-benzosulfimide(Compound 56)

Formula 24

t-Butyl ester ((R)-1-ethylcarbamate-ethyl)-carbamino acid

Formula 25

(1) To a solution of methyl ester of N-(t-butoxycarbonyl)-D-alanine (4,76 g) in methanol (20 ml) was added 10 ml of 70% aqueous solution of EtNH2the mixture is stirred at room temperature for 19 hours. The reaction solution was concentrated, the crude product was purified by way of column chromatography (acidic OH SiO2, chloroform/ethyl acetate = 10-50%) for receipt of 3.96 g of the above compound (colorless amorphous substance).

1H-NMR (200 MHz, CDCl3) δ ppm: 1,12 (t, J=7.2 Hz, 3H), of 1.35 (d, J=7.2 Hz, 3H), of 1.46 (s, 9H), 3,18-3,37 (m, 2H), 4,00-4,20 (m, 1H), 4,90-5,10 (m, 1H), 6,04-to 6.22 (m, 1H).

t-Butyl ester ((R)-1-etildiocolmain-ethyl)-carbamino acid

Formula 26

(2) To a solution of compound of example 5-(1) (3,96 g) in THF (92 ml) was added a reagent Losson (8,89 g), the mixture is stirred at room temperature for one hour and at 50°C for 30 minutes. The reaction solution was cooled to room temperature, after which the insoluble precipitate was removed by filtration. Then the obtained residue was concentrated. The crude product was purified by way of column chromatography (acidic OH SiO2, chloroform/ethyl acetate = 10-50%)and then by column chromatography on NH-silica gel (ethyl acetate/hexane = 50%) to obtain the titled compound (3.75 g) as colorless powder.

1H-NMR (200 MHz, CDCl3) δ ppm: 1.26 in (t, J=7.2 Hz, 3H), 1,38-of 1.52 (m, 3H), 1,45 (s, 9H), 3,60-of 3.77 (m, 2H), 4,36-a 4.53 (m, 1H), 5,10-5,32 (m, 1H), 7,99-8,24 (m, 1H).

t-Butyl ether [(R)-1-[4-ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazole-3-yl]-ethyl]-carbamino acid

Formula 27

(3) To a solution of the compound obtained in example 5-(2), (1,61 g) and hydrazide 4-methylphenylacetic acid (1.25 g) in CH3CN (30 ml) was added 2,43 g Hg (OAc)2, after which the mixture is stirred at room temperature for 42 hours. To the reaction solution was added ethyl acetate, after which the insoluble precipitate was removed by filtration through cellit. The filtrate was washed for 1H. aqueous solution of KHSO4and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and you Aravali under reduced pressure to remove solvent. The crude product was purified by way of column chromatography (acidic OH SiO2, ethyl acetate/hexane = 50%to 100% methanol/chloroform = 1/1) (neutral OH SiO2, methanol/chloroform=1/10) to obtain 0,530 g of the above compound (colorless amorphous substance).

1H-NMR (600 MHz, CDCl3) δ ppm: 1,04 (t, J=7,3 Hz, 3H), of 1.41 (s, 9H), to 1.61 (d, J=6.9 Hz, 3H), of 2.30 (s, 3H), of 3.73-3,90 (m, 2H), 4,06-4,20 (m, 2H), 4,85-4,94 (m, 1H), 5,11-5,17 (m, 1H), to 7.09 (s, 4H).

(R)-1-[4-ethyl-5-(4-methylbenzyl)-4H-[1,2,4]triazole-3-yl]-ethylamine

Formula 28

(4) To a solution of compound of example 5-(3) (0,496 g) in chloroform (5 ml) was added triperoxonane acid (5 ml), after which the mixture is stirred at room temperature for 18 hours. Then added an aqueous solution of sodium hydroxide (1.0 in BC) and the mixture was extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to remove the solvent, thus received 0,148 g of the named compound as a colorless oily compound.

1H-NMR (600 MHz, CDCl3) δ ppm: 1,09 (t, J=7,3 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), of 2.30 (s, 3H), 3,74-of 3.94 (m, 2H), 4,01-4,20 (m, 3H), 7,10 (s, 4H).

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazole-3-yl]-ethyl]-benzosulfimide(compound 56)

F is rmula 29

(5) To a solution of the compound obtained in example 5-(4), (0,144 g) in THF (3 ml) was added 0.25 ml of triethylamine and 0,707 ml of 3,4-dichlorobenzenesulfonate, after which the mixture is stirred at room temperature for 3.5 hours. Then was added 2n. an aqueous solution of hydrochloric acid, after which the mixture was extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to remove solvent. The obtained residue was purified by way of column chromatography (acidic OH SiO2, chloroform/methanol = 50/1 to 10/1), and then recrystallized (ethyl acetate-hexane) to obtain 0,100 g of the above compound (compound 56) in the form of colorless powder.

1H-NMR (600 MHz, DMSO-d6) δ ppm: of 0.91 (t, J=7,1 Hz, 3H), of 1.26 (d, J=6.9 Hz, 3H), of 2.23 (s, 3H), of 3.77-to 3.92 (m, 2H), 4.00 points (s, 2H), 4,60-4,70 (m, 1H), 7.03 is for 7.12 (m, 4H), to 7.64-to 7.68 (m, 1H), 7,79-of 7.82 (m, 1H), 7,89-to $ 7.91 (m, 1H), 8,64 (s, 1H).

Melting point: from 189,0°C to 191,0°C.

Example 6

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-yl]-ethyl]-N-methyl-benzosulfimide(compound 115)

Formula 30

To a solution of compound 12 (150 mg) from example 1 in dimethylformamide (2.0 ml) at room temperature was added 78 mg K2CO3and 0.22 ml of MeI, p is the following which the mixture is stirred at room temperature for three hours. To the reaction solution was added water, then the mixture was extracted with a mixed solution of methanol and chloroform (methanol/chloroform = 1/4). The organic phase is washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated under reduced pressure to remove solvent. After elution of the residue mixed solvent consisting of ethyl acetate and hexane, the resulting eluate was purified by way of column chromatography (acidic OH SiO2, ethyl acetate/hexane = 50-99%, methanol/chloroform = 0-10%), and then recrystallized (ethyl acetate-hexane) to obtain 111 mg of the named compound as a colorless powder.

Melting point: from output reached 125.5°C to 126,5°C.

Example 7

3,4-sodium dichloro-N-((R)-1-[5-[3-(1,4-dioxa-8-Aza-Spiro[4,5]Decan-8-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazole-3-yl]-ethyl)-benzosulfimide(compound 87)

Formula 31

3-(1,4-dioxa-8-Aza-Spiro[4,5]Decan-8-yl)-phenol

Formula 32

3-bromophenol (1.50 g), 1,4-dioxa-8 azaspiro[4,5]decane (1,49 g), Pd2(dba)3(0,079 g), (2'-dicyclohexylphosphino-biphenyl-2-yl)-dimethylamine (0,082 g) and LiN(TMS)2(20% solution in THF, 18 ml) were placed in a pressure-resistant test tube with screw cap, after which the mixture was mixed at 65°C for 7.5 hours. Time to relax is whether the acetate, then the organic phase was washed for 1H. aqueous solution of hydrochloric acid and then saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove solvent. The obtained residue was purified by way of column chromatography (acidic OH SiO2, hexane/ethyl acetate = 70/30 to 60/40) to obtain a 1.96 g of the above compound (brown oily liquid).

1H-NMR (600 MHz, CDCl3) δ ppm: 1,79 of-1.83 (m, 4H), 3.27 to the 3.35 (m, 4H), 3,98 (s, 4H), a 4.86 (s, 1H), 6,28 (DD, J=8,0, 2.5 Hz, 1H), 6,41 (t, J=2.3 Hz, 1H), 6,51 (DD, J=8,5, 2.5 Hz, 1H), was 7.08 (t, J=8,3 Hz, 1H).

(R)-1-[5-[3-(1,4-dioxa-8-Aza-Spiro[4,5]Decan-8-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazole-3-yl]-ethylamine

Formula 33

(2) Starting from the compound obtained in example 7-(1)instead of 4-terfenol, a procedure similar to that used in example 1-(7)were repeated to obtain the titled compound (brown oily substance, yield 58%).

1H-NMR (600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,3 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), 1,77 of-1.83 (m, 4H), 3.27 to to 3.36 (m, 4H), 3.95 to 4,06 (m, 6H), 4,14 (kV, J=6,9 Hz, 1H), 6,70 to 6.75 (m, 2H), 6,97 (t, J=2.3 Hz, 1H), 7,20 (t, J=8,3 Hz, 1H).

3,4-sodium dichloro-N-((R)-1-[5-[3-(1,4-dioxa-8-Aza-Spiro[4,5]Decan-8-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazole-3-yl]-ethyl)-benzosulfimide(compound 87)

Formula 34

(3) Beginning with the unity, obtained in example 7-(2), a procedure similar to that used in example 1-(8)were repeated to obtain the titled compound (colorless powder, yield 64%).

Melting point: from 174,0°C to 179,0°C.

Example 8

3,4-sodium dichloro-N-((R)-1-[4-ethyl-5-[3-(4-oxo-piperidine-1-yl)-phenoxy]-4H-[1,2,4]triazole-3-yl]-ethyl)-benzosulfimide(compound 88)

Formula 35

To a solution of the compound from example 7 (0,981 g) in THF (10 ml) was added to 8.4 ml of 2n. an aqueous solution of hydrochloric acid, after which the mixture is stirred at room temperature for one hour. Then added concentrated hydrochloric acid (2 ml), after which the mixture was mixed at 50°C for six hours. Saturated aqueous sodium bicarbonate solution was added for neutralization, and then the mixture was extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and then evaporated under reduced pressure to remove solvent. The obtained residue was purified by way of column chromatography (acidic OH SiO2, ethyl acetate), and then recrystallized (chloroform-hexane) to obtain the titled compound (0,572 g, colorless powder).

Melting point: from 188,5°C to 190.5°C.

Example 9

3,4-sodium dichloro-N-((R)-1-[4-ethyl-5-[3-(4-g is droxi-piperidine-1-yl)-phenoxy]-4H-[1,2,4]triazole-3-yl]-ethyl)-benzosulfimide

(compound 93)

Formula 36

To a solution of the compound from example 8 (0,150 g) in methanol (3.0 ml) at 0°C was added 0,021 g NaBH4, after which the mixture is stirred at room temperature for 16 hours. Added water, after which the mixture was extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over MgSO4, filtered and evaporated under reduced pressure to remove solvent. The crude product was purified by way of column chromatography (neutral OH SiO2methanol/chloroform = from 1/50 to 1/10), and then recrystallized (ethyl acetate-hexane) to obtain 0,113 g of the above compound (compound 93) as colorless powder.

Melting point: from 167,5°C to 169, 5mm°C.

Example 10

N-[(R)-1-[5-(3-amino-phenoxy)-4-ethyl-4H-[1,2,4]triazole-3-yl]-ethyl]-3,4-dichlorobenzenesulfonate(compound 82)

Formula 37

3-[5-((R)-1-amino-ethyl)-4-ethyl-4H-[1,2,4]triazole-3-yloxy]-phenylamine

Formula 38

(1) Starting from 3-aminophenol instead of 4-terfenol, the same as the procedure used in example 1-(7)were repeated to obtain the titled compound (brown oily substance, yield 99%).

1H-NMR (600 MHz, CDCl3) δ ppm: to 1.37 (t, J=7,1 Hz, 3H), 1,58 (who, J=6.9 Hz, 3H), 3.96 points-of 4.05 (m, 2H), 4,15 (kV, J=6,7 Hz, 1H), 6,45-6,50 (m, 1H), 6,62 is 6.67 (m, 1H), of 6.71-6.75 in (m, 1H), 7,11 (t, J=8.0 Hz, 1H).

N-[(R)-1-[5-(3-amino-phenoxy)-4-ethyl-4H-[1,2,4]triazole-3-yl]-ethyl]-3,4-dichlorobenzenesulfonate(compound 82)

Formula 39

(2) To a solution of compound of example 10-(1) (3,69 g) in THF (15 ml) was added triethylamine (4,16 ml) and 3,4-dichlorobenzenesulfonate (of 3.73 g), the mixture is stirred at room temperature overnight. The reaction solution was concentrated and the crude product was purified by way of column chromatography (NH SiO2, methanol/chloroform), and then recrystallized (ethyl acetate-hexane) to obtain of 3.60 g of the above compound (compound 82) (colorless compounds in powder form).

Melting point: from 142,0°C to 145,0°C.

Example 11

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5-(3-pyrrol-1-yl-phenoxy)-4H-[1,2,4]triazole-3-yl]-ethyl]-N-methyl-benzosulfimide(compound 86)

Formula 40

To a solution of the compound from example 10 (700 mg) in AcOH (4.6 ml) was added 2,5-dimethoxy-tetrahydrofuran (375 ml)and the mixture is stirred at a temperature of 130°C for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Then added water and the mixture was extracted with methanol/chloroform (1/4). Then the organic phase is washed and saturated aqueous sodium chloride, dried over MgSO4, filtered and evaporated under reduced pressure to remove solvent. The obtained residue was purified by way of column chromatography (acidic OH SiO2, ethyl acetate/hexane = 33-100%, methanol/chloroform = 5%), and then recrystallized (ethyl acetate-hexane) to obtain the titled compound (compound 86) (173 mg, colorless compound in powder form).

Melting point: from 176,0°C to 177,0°C.

Example 12

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5-(3-formylamino-phenoxy)-4H-[1,2,4]triazole-3-yl]-ethyl]-benzosulfimide(compound 90)

Formula 41

The mixture of compounds obtained in example 10-(2), (300 mg) and ethylformate (1.1 ml) was mixed for 24 hours at 105°C. the Reaction solution was cooled to room temperature and concentrated under reduced pressure. Received gross crude product was purified by way of column chromatography (acidic OH SiO2, ethyl acetate/hexane = 50%-100%, methanol/chloroform = 5%), and then recrystallized (ethyl acetate-hexane) to obtain the titled compound (compound 90) (81 mg, colorless powder).

Melting point: from 168,0°C to 170,0°C.

Example 13

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5-(3-ureido-phenoxy)-4H-[1,2,4]triazole-3-yl]-ethyl]-benzosulfimide(compound 91)

Formula 42

A mixture of compound (300 mg)obtained in example 10-(2), potassium cyanate (65 mg), AcOH (1.0 ml) and water (0.5 ml) was mixed at room temperature for one hour. Added water, after which the mixture was extracted with methanol/chloroform (1/4). The organic phase was dried over MgSO4, filtered and evaporated under reduced pressure to remove solvent. The crude product was purified by way of column chromatography (acidic OH SiO2, ethyl acetate/hexane = 50-99%, methanol/chloroform = 0,3%), and then recrystallized (ethyl acetate-hexane) to obtain the titled compound (compound 91) (273 mg, colorless powder).

Melting point: from 137,0°C to 138,0°C.

Example 14

3,4-sodium dichloro-N-((R)-1-[5-[3-(3,3-dimethylurea)-phenoxy]-4-ethyl-4H-[1,2,4]triazole-3-yl]-ethyl)-benzosulfimide(compound 97)

Formula 43

To a solution of compound of example 10-(2) (300 mg) and triethylamine (368 μl) in chloroform (1.1 ml) was added 146 μl chloride dimethylcarbamyl (146 μl)and the mixture stirred at room temperature for three hours. The reaction solution was concentrated, the crude product was purified by way of column chromatography (neutral OH SiO2, ethyl acetate/hexane = 50-99%, methanol/chloroform = 0-3%), and then recrystallized (ethyl acetate-hexane) DL is receiving these compounds (compound 97) (93 mg, colorless powder).

Melting point: from 158,0°C to 159,0°C.

Example 15

3,4-sodium dichloro-N-((R)-1-[4-ethyl-5-[3-(3-ethylurea)-phenoxy]-4H-[1,2,4]triazole-3-yl]-ethyl)-benzosulfimide(compound 92)

Formula 44

To a solution of compound of example 10-(2) (300 mg) in chloroform (1.1 ml) was added utilizationa (63 μl)and the mixture stirred at room temperature for one hour. The reaction solution was concentrated, the crude product was purified by way of column chromatography (neutral OH SiO2, ethyl acetate/hexane = 50-99%, methanol/chloroform = 0-3%), and then recrystallized (ethyl acetate-hexane) to obtain the titled compound (compound 97) (228 mg, colorless powder).

Melting point: from to 118.0°C to 120.0°C.

Example 16

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5-(3-methanesulfonylaminoethyl)-4H-[1,2,4]triazole-3-yl]-ethyl)-benzosulfimide(compound 102)

Formula 45

To a solution of compound of example 10-(2) (300 mg) in pyridine (1,32 ml) was added methanesulfonamide (114 mg), after which the mixture is stirred at room temperature for three hours. Added 1N. hydrochloric acid, after which the mixture was extracted with methanol/chloroform (1/4). The organic phase was dried Na2SO4was filtered and concentrated, the obtained n the purified product was purified by way of column chromatography (neutral OH SiO 2, ethyl acetate/hexane = 50-99%, methanol/chloroform = 0-5%), and then recrystallized (ethyl acetate-hexane) to obtain the titled compound (compound 102) (281 mg, colorless powder).

Melting point: from 117,0°C up to 118.0°C.

Example 17

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5-(3-hydroxyphenoxy)-4H-[1,2,4]triazole-3-yl]-ethyl]-benzosulfimide(compound 114)

Formula 46

(R)-1-[5-(3-benzyloxy-phenoxy)-4-ethyl-4H-[1,2,4]triazole-3-yl]-ethylamine

Formula 47

(1) Starting from 3-benzyloxyphenol instead of 4-terfenol, a procedure similar to that used in example 1-(7)were repeated to obtain the titled compound (brown oily substance, yield 84%).

1H-NMR (600 MHz, CDCl3), δ ppm: 1,39 (t, J=7,3 Hz, 3H), 1,60 (d, J=6.4 Hz, 3H), of 3.96-4.09 to (m, 2H), 4,17 (kV, J=6,9 Hz, 1H), is 5.06 (s, 2H), 6,79-6,84 (m, 1H), 6,91-of 6.96 (m, 1H),? 7.04 baby mortality-was 7.08 (m, 1H), 7,22-7,46 (m, 6H).

3-[5-((R)-1-amino-ethyl)-4-ethyl-4H-[1,2,4]triazole-3-yloxy]-phenol

Formula 48

(2) Suspension of the compound (1.5 g) from example 17-(1) and Pd(OH)2/C (150 mg, Pd 20% by weight) in methanol (4.0 ml) was stirred at room temperature during the day in an atmosphere of hydrogen (about 1 atmospheric pressure). The reaction mixture was filtered through cellit and evaporated to remove solvent. Received gross crude product was purified SP the way of column chromatography (NH SiO 2, methanol/chloroform = 0-25%) to obtain the titled compound (grey amorphous substance, 323 mg).

1H-NMR (600 MHz, DMSO-d6), δ ppm: of 1.23 (t, J=7,3 Hz, 3H), and 1.54 (d, J=6.9 Hz, 3H), 3,82-4.09 to (m, 2H), 4,60 (kV, J=6.0 Hz, 1H), 6,61-6,69 (m, 2H), 6,70-6,77 (m, 1H), 7,14-7,21 (m, 1H), 8,28-9,11 (m, 2H), 9,43-10,55 (m, 1H).

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5-(3-hydroxyphenoxy)-4H-[1,2,4]triazole-3-yl]-ethyl]-benzosulfimide (compound 114)

Formula 49

(3) To a solution of the compound from example 17-(2) (200 mg) in THF (2.0 ml) at room temperature was added triethylamine (0,255 ml) and 3,4-dichlorobenzenesulfonate (198 mg)and the mixture stirred at room temperature for 12 hours. The mixture is evaporated to remove the solvent, and then to the obtained crude product was added KOH (104 mg), ethanol (4.0 ml) and water (4.0 ml). The mixture is stirred at 120°C for 40 minutes, then cooled to room temperature. Added 1N. HCl, after which the mixture was extracted with a mixed solution of methanol/chloroform (methanol/chloroform = 1/4), dried (MgSO4), filtered and evaporated under reduced pressure to remove solvent. The crude product was purified by way of column chromatography (acidic OH SiO2, ethyl acetate/hexane = 30-70%), and then recrystallized (methanol/chloroform/hexane) to obtain 37 mg of the above compound (connection of the texts 114) in the form of colorless powder.

Melting point: from to 185.0°C to of 186.0°C.

Example 18

t-Butyl ether 3-[5-[(R)-1-(3,4-dichlorobenzenesulfonyl)-ethyl]-4-ethyl-4H-[1,2,4]triazole-3-yloxy]benzoic acid(compound 118)

Formula 50

t-Butyl ether 3-[5-((R)-1-amino-ethyl)-4-ethyl-4H-[1,2,4]triazole-3-yloxy]benzoic acid

Formula 51

(1) Starting from t-butyl methyl ether 3-hydroxybenzoic acid instead of 4-terfenol, a procedure similar to that used in example 1-(7)were repeated to obtain the titled compound (colorless oily substance, yield 24%).

1H-NMR (600 MHz, CDCl3), δ ppm: USD 1.43 (t, J=7,1 Hz, 3H), 1,58-of 1.62 (m, 12H), 4,01 is 4.13 (m, 2H), 4,18 (kV, J=6,6 Hz, 1H), 7,42-7,46 (m, 1H), to 7.61-the 7.65 (m, 1H), 7,82-a 7.85 (m, 1H), 7,87-to $ 7.91 (m, 1H).

t-Butyl ether 3-[5-[(R)-1-(3,4-dichlorobenzenesulfonyl)-ethyl]-4-ethyl-4H-[1,2,4]triazole-3-yloxy]benzoic acid(compound 118)

Formula 52

(2) Starting from the compound obtained in example 18-(1)by a procedure similar to that used in example 1-(8)were repeated to obtain the titled compound (colorless powder, yield 68%).

1H-NMR (600 MHz, CDCl3), δ ppm: to 1.38 (t, J=7,3 Hz, 3H)and 1.51 (d, J=6.9 Hz, 3H), 1,58 (s, 9H), 3,93-4,01 (m, 2H), 4,29 is 4.35 (m, 1H), 7,43-of 7.48 (m, 1H), 7,50-of 7.60 (m, 3H), of 7.64-of 7.69 (m, 1H), 7,81-7,89 (m, 2H), of 7.90-7,94 (m, 1H).

Example 19

3-[5-[(R)-1-(3,4-dichlorobenzenesulfonyl)-ethyl]-4-the Teal-4H-[1,2,4]triazole-3-yloxy]benzoic acid (compound 113)

Formula 53

To a solution of the compound from example 18 (260 mg) in chloroform (12.0 ml) was added triperoxonane acid, and the mixture is stirred at room temperature for five days. The mixture is evaporated to remove solvent, the crude product was purified by way of column chromatography (neutral OH SiO2, ethyl acetate/hexane = 50-99%, methanol/chloroform = 0-20%), and then recrystallized (methanol/chloroform/hexane) to obtain the titled compound (compound 113) (101 mg, colorless powder).

Melting point: from USD 183.0°C up to 185.0°C.

Example 20

N-[(R)-1-[4-ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-yl]-ethyl]-4-methoxybenzenesulfonamide (compound 175)

Formula 54

To a solution of compound of example 1-(7) (12.5 mg) in THF (0.3 ml) was added triethanolamine (25 μl), and then a solution of 4-methoxybenzenesulfonamide (15,5 mg) in THF (0.3 ml). The mixture is stirred at room temperature for two hours. In the reaction mixture was added PSA (product name VARIAN Inc. polymer supported amine, 1.4 mEq/g) (75 μl)and the mixture stirred at room temperature for 12 hours. Insoluble particles were removed by filtration, the obtained residue is evaporated to remove solvent. The crude product was purified way to lodochnoy chromatography (acidic OH SiO 2, ethyl acetate/hexane = 50%to 100% methanol/chloroform = 10%) to get to 10.7 mg of the above compound (compound 175) as colorless powder.

APCI MS (M-H)-: 419, APCI MS (M+H)+: 421.

Example 21

3,4-sodium dichloro-N-((R)-1-[4-ethyl-5-[3-(4-methyl-piperazine-1-yl)-phenoxy]-4H-[1,2,4]triazole-3-yl]-ethyl)-benzosulfimide(compound 45)

Formula 55

(1) the Following compound was obtained by a procedure similar to that used in example 1-(7) (procedure will be described in detail below).

(R)-1-[4-Ethyl-5-[3-(4-methyl-piperazine-1-yl)-phenoxy]-4H-[1,2,4]triazole-3-yl]-ethylamine

Formula 56

In a pressure-resistant test tube with screw cap to the compound obtained in example 1-(6), (750 mg) was added N,N'-dimethylpropylene (DMPM) (4,0 ml), 3-(4-methyl-piperazine-1-yl)-phenol (500 mg) and cesium carbonate (2,21 g), after which the mixture is stirred at 160°C for three hours. The reaction mixture was cooled to room temperature, after which was added a saturated aqueous solution of sodium chloride. The mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove solvent. The crude product was purified by way of column chromatography (NH SiO2, chloroform/methanol = 5/1-30/1) to obtain the titled compound (in the form of a yellow oily compound, 427 mg).

1H-NMR (600 MHz, CDCl3) δ ppm: 1,40 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), of 2.35 (s, 3H), 2,52-2,61 (m, 4H), 3,22-of 3.27 (m, 4H), 3,97-4,08 (m, 2H), 4,15 (kV, J=6,9 Hz, 1H), of 6.71-to 6.80 (m, 2H), 6,99-7,03 (m, 1H), 7,20-7,25 (m, 1H).

(2) the Following compound was obtained by a procedure similar to that used in example 1-(8) (procedure will be described in detail below).

3,4-sodium dichloro-N-((R)-1-[4-ethyl-5-[3-(4-methyl-piperazine-1-yl)-phenoxy]-4H-[1,2,4]triazole-3-yl]-ethyl)-benzosulfimide(compound 45)

Formula 57

To a solution of the compound from example 21-(1) (427 mg) in THF (8 ml) at room temperature was added triethylamine (0,41 ml) and 3,4-dichlorobenzenesulfonate (0,232 ml)and the mixture stirred at room temperature overnight. The reaction mixture was concentrated, the obtained residue was purified by way of column chromatography (NH SiO2, chloroform/methanol = 50/1-30/1), and then recrystallized (ethyl acetate-hexane) to obtain 280 mg of the above compound (compound 45) in the form of colorless powder.

Melting point: from 194,0°C to 196,0°C.

Example 22

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5-(1H-indol-6-yloxy)-4H-[1,2,4]triazole-3-yl]-ethyl]-benzosulfimide(compound 64)

Formula 58

(1) the Following compound was obtained by a procedure similar to that used in example 1-(7) (procedure will be described in detail the lower is).

(R)-1-[4-Ethyl-5-(1H-indol-6-yloxy)-4H-[1,2,4]triazole-3-yl]-ethylamine

Formula 59

In a pressure-resistant test tube with screw cap to the compound obtained in example 1-(6), (1,00 g) was added N,N'-dimethylpropylene (DMPM) (5.0 ml), 1H-indol-6-ol (601 mg) and cesium carbonate (2,94 g), after which the mixture was mixed at 200°C for one hour, and then cooled to room temperature. Was added a saturated solution of sodium chloride, and then the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and evaporated under reduced pressure to remove solvent. Then the crude product was purified by way of column chromatography (NH SiO2, chloroform/methanol = 50/1-30/1) to obtain the titled compound (in the form of a yellow oily compound, 750 mg).

1H-NMR (600 MHz, CDCl3) δ ppm: to 1.42 (t, J=7,1 Hz, 3H), 1,58 (d, J=6.4 Hz, 3H), 3,98-4,10 (m, 2H), 4,15 (kV, J=6,7 Hz, 1H), 6.30-in-to 6.39 (m, 1H), 6.87 in-7,00 (m, 2H), 7,39-7,52 (m, 2H), of 9.55 (s, 1H).

(2) the Following compound was obtained by a procedure similar to that used in example 1-(8) (procedure will be described in detail below).

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5-(1H-indol-6-yloxy)-4H-[1,2,4]triazole-3-yl]-ethyl]-benzosulfimide(compound 64)

Formula 60

To a solution of the compound from example 22-(1) (748 mg) in TG is (10.0 ml) at room temperature was added triethylamine (0,77 ml) and 3,4-dichlorobenzenesulfonate (1,02 g), and the mixture is stirred at room temperature overnight. The reaction mixture was concentrated, the obtained residue was purified by way of column chromatography (NH SiO2, chloroform/methanol = 30/1), and then recrystallized (CHCl3/MeOH/hexane) to obtain 815 mg of the above compound (compound 64) in the form of colorless powder.

Melting point: from 223,0°C to 224,0°C.

Example 23

N-[(S)-2-Benzyloxy-1-[4-ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-yl]-ethyl]-3,4-dichlorobenzenesulfonate(compound 695)

Formula 61

Starting with the methyl ester of (R)-2-amino-3-benzyloxy-propionic acid instead of methyl ester of N-(t-butoxycarbonyl)-D-alanine used in example 1-(1)by a procedure similar to that used in example 1 was repeated to obtain the titled compound (compound 695) as colorless powder.

1H-NMR (200 MHz, CDCl3) δ ppm: 1,31 (t, J=7,3 Hz, 3H), 3,65-a 4.03 (m, 4H), 4,35 (s, 2H), 4,67 (kV, J=7.9 Hz, 1H), 7.03 is-7,39 (m, 10 H), to 7.68 (DD, J=8,8, 2.2 Hz, 1H), to 7.93 (d, J=2.2 Hz, 1H).

Example 24

3,4-sodium dichloro-N-[(S)-1-[4-ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-yl]-2-hydroxyethyl]-benzosulfimide(compound 696)

Formula 62

To a solution of the compound from example 23 (69 mg) in CH2Cl2(2.0 ml) was added AlCl3(49 mg) and PhNMe2(148 mg)and the mixture stirred at whom atoi temperature for one hour. Then added AcOEt, after which the mixture was washed for 1H. hydrochloric acid and saturated aqueous sodium chloride. The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure to remove solvent. Then the crude product was purified by way of column chromatography (OH-SiO2, AcOEt/hexane = 2/1) to obtain 54 mg of the above compound (compound 696) as colorless powder.

1H-NMR (200 MHz, CDCl3) δ ppm: of 1.41 (t, J=7.5 Hz, 3H), 3,62 (DD, J=4,8, and 11.8 Hz, 1H), 3,88 (DD, J=4,8, and 11.8 Hz, 1H), 4,05 (kV, J=7.5 Hz, 2H), 4,51-4,60 (m, 1H),? 7.04 baby mortality-7,13 (m, 2H), 7.23 percent-7,31 (m, 3H), 7,53 (d, J=8,8 Hz, 1H), of 7.70 (DD, J=of 8.8 and 2.2 Hz, 1H), to 7.93 (d, J=2.2 Hz, 1H).

Example 25

3,4-sodium dichloro-N-[(S)-1-[4-ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-yl]-2-feratel]-benzosulfimide(compound 689)

Formula 63

To a solution of the compound from example 24 (45 mg) in CH2Cl2(2.0 ml) was added at 0°C solution of diethylaminosulfur (will GIVE) (16 mg) in CH2Cl2(1.0 ml)and the mixture is stirred at the same temperature for one hour. Then the reaction solution was added to saturated aqueous sodium bicarbonate solution, after which the mixture was extracted with AcOEt. The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure to remove solvent. Then the obtained neojidannyy was purified by way of column chromatography (OH-SiO 2, AcOEt/hexane = 30-50%) to obtain 6 mg of the above compound (compound 689) in the form of a pale yellow powder.

1H-NMR (200 MHz, CDCl3) δ ppm: 1,39 (t, J=7.5 Hz, 3H), 4,01 (kV, J=7.5 Hz, 2H), 4,45-a 4.86 (m, 3H), 6,98 (user, 1H), 7,05 and 7.36 (m, 4H), of 7.48 (d, J=8.5 Hz, 1H), 7,69 (DD, J=8,5, 2.2 Hz, 1H), to 7.93 (d, J=2.2 Hz, 1H).

Example 26

3,4-sodium dichloro-N-[1-[4-ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-yl]-2,2,2-triptorelin]-benzosulfimide(compound 687)

Formula 64

Ethyl ester 4-ethyl-5-mercapto-4H-[1,2,4]triazole-3-carboxylic acid

Formula 65

(1) To a solution of diethylmaleate (48,64 g) in MeOH (100 ml) was added dropwise at -5°C for 1.5 hours a solution of hydrazine monohydrate (16,33 g) in MeOH (100 ml), then at the same temperature was added ethylisothiocyanate (29,00 g). The mixture was heated to room temperature and was stirred overnight. The insoluble substance was removed by filtration, the obtained residue is evaporated to remove solvent. The obtained solid is washed with a mixed solution of hexane/AcOEt (1/1) and dried, the obtained white powder (55,30 g) was added to 228 ml of aqueous NaOH (913 mg). The mixture is stirred at 70°C for four hours at room temperature overnight, and then at 100°C for seven hours. The reaction mixture was concentrated to about 1/3, then EXT is ulali saturated aqueous solution of NH 4Cl (300 ml). The obtained white precipitate was filtered and dried to obtain the titled compound (15,06 g) as colorless powder.

1H-NMR (200 MHz, CDCl3) δ ppm: to 1.38 (t, J=6.6 Hz, 3H), of 1.45 (t, J=6.5 Hz, 3H), 4,40-of 4.57 (m, 4H), 11,58-11,84 (m, 1H).

Ethyl ester 4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazole-3-carboxylic acid

Formula 66

(2) Starting from the compound obtained in example 26-(1)by a procedure similar to that used in example 1-(4)were repeated to obtain the titled compound as light-yellow solid (yield 84%).

1H-NMR (200 MHz, CDCl3) δ ppm: 1,31-1,50 (m, 6H), 2,80 (s, 3H), or 4.31 (q, J=7.2 Hz, 2H), 4,47 (kV, J=7,1 Hz, 2H).

Ethyl ester 4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazole-3-carboxylic acid

Formula 67

(3) Starting from the compound obtained in example 26-(2), a procedure similar to that used in example 1-(5)was repeated to obtain the titled compound as a pale yellow solid (yield 84%).

1H-NMR (200 MHz, CDCl3) δ ppm: to 1.48 (t, J=7,1 Hz, 3H), 1,53 (t, J=7.2 Hz, 3H), of 3.60 (s, 3H), 4,53 (kV, J=7,1 Hz, 2H), 4.75 V (kV, J=7.2 Hz, 2H).

Ethyl ester 4-ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-carboxylic acid

Formula 68

(4) To a suspension of NaH (1,236 g, oil) in THF (68 ml) at 0°C was added 4-terfenol (4,62 g), the shift of the b was heated to room temperature and was stirred for 30 minutes. The reaction mixture was cooled to 0°C was added a solution of compound (8,49 g)obtained in example 26-(3), in THF (20 ml). The mixture was stirred at room temperature for 30 minutes and then at 70°C for 1.5 hours. The temperature was reduced to room temperature after which the reaction mixture was added to saturated aqueous solution of NH4Cl (500 ml). The mixture was extracted with AcOEt (500 ml) and washed with saturated aqueous sodium chloride. The organic phase was dried (MgSO4), filtered and concentrated, the crude product was purified by way of column chromatography (acidic OH SiO2, AcOEt/hexane = 10-99%) to obtain the titled compound (5,144 g, light yellow solid).

1H-NMR (200 MHz, CDCl3) δ ppm: 1,35-of 1.52 (m, 6H), 4,36 (kV, J=7.2 Hz, 2H), 4,48 (kV, J=7.2 Hz, 2H), 7,02-to 7.18 (m, 2H), 7,28-of 7.48 (m, 2H).

4-Ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-carbaldehyde

Formula 69

(5) To a solution of the compound from example 26-(4) (5,00 g) in THF (50 ml) at -5°C was added DiBAl-H (0,99 M solution in toluene, 36,1 ml), after which the mixture is stirred at the same temperature for three hours. Then to the reaction solution was added 1N. hydrochloric acid, after which the mixture was extracted with AcOEt. The organic phase is washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and concentrated, polucen is th the crude product was purified by way of column chromatography (neutral OH SiO 2, AcOEt /hexane = 5-40%) to obtain the titled compound (2,22 g, colorless and oily).

1H-NMR (600 MHz, CDCl3) δ ppm: the 1.44 (t, J=7,3 Hz, 3H), 4,37 (J=7,3 Hz, 2H), 7,10-7,17 (m, 2H), was 7.36-7,40 (m, 2H).

4-ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-ylmethylene 4-methylbenzoyl sulfonic acid

Formula 70

(6) Solution of the compound (1,00 g)obtained in example 26-(5), amide 4-methylbenzoyl sulfonic acid (660 mg) and cesium carbonate (1.39 g) in chloroform (21 ml) was subjected to stirring at 45°C for nine hours. The reaction solution was filtered through cellit and the filtrate was concentrated. The obtained residue was purified column chromatography on silica gel (neutral OH SiO2, AcOEt/hexane = 0-30%) to obtain the titled compound (630 mg) as a yellowish solid.

1H-NMR (600 MHz, CDCl3) δ ppm: 1.30 on (t, J=7,1 Hz, 3H), 2,42 (s, 3H), 4,27-4,43 (m, 2H), 7,07-to 7.15 (m, 2H), 7,31-7,39 (m, 4H), EUR 7.57 to 7.62 (m, 2H), cent to 8.85 (s, 1H).

N-[1-[4-Ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-yl]-2,2,2-triptorelin]-4-methylbenzamide

Formula 71

(7) the Solution of (trifluoromethyl)trimethylsilane (120 μl) in THF (5.0 ml) was added at -35°C in an argon atmosphere to a suspension of the compound (200 mg) from example 26-(6) and tetramethyllead (60 mg) in THF (5.0 ml), after which the mixture is stirred at the same temperature for an hour and a half. With abusou portion of tetramethylthiourea (60 mg) and the next portion of (trifluoromethyl)trimethylsilane (60 mg) was added to the reaction solution at the same temperature, and the mixture is stirred at the same temperature for two hours, then was heated to -10°C, was added a saturated aqueous solution of ammonium chloride and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and filtered, then the filtrate was concentrated. The obtained residue was purified by way of column chromatography (neutral OH SiO2, AcOEt/hexane = 0-40) to obtain the titled compound (219 mg) as a yellowish oily substance.

1H-NMR (600 MHz, CDCl3) δ ppm: to 1.32 (t, J=7,3 Hz, 3H), 2.40 a (s, 3H), 3,80-a 3.87 (m, 2H), 4,86 to 4.92 (m, 1H), 5,59 (d, J=8,3 Hz, 1H), 7,06-7,13 (m, 2H), 7,27-7,31 (m, 2H), 7,32-7,37 (m, 2H), 7,53-to 7.59 (m, 2H).

1-[4-Ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-yl]-2,2,2-triptorelin

Formula 72

(8) To a solution of the compound from example 26-(7) (215 mg) in methanol (5.0 ml) at room temperature was added HCl (4n., solution in dioxane, 1.25 ml), after which the mixture was mixed at 85°C for two hours. The reaction solution was concentrated, the obtained residue was purified by way of column chromatography (NH SiO2, AcOEt/hexane = 0-50%) to obtain the titled compound (82 mg) as a colorless oily substance.

(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,3 Hz, 3H), 3,97-4,11 (m, 2H), 4,47-of 4.54 (m, 1H), 7,06 for 7.12 (m, 2H), 7,35-7,40 (m, 2H).

3,4-sodium dichloro-N-[1-[4-ethyl-5-(4-pertenece)-4H-[1,2,4]triazole-3-yl]-2,2,triptorelin]-benzosulfimide (compound 687)

Formula 73

(9) since obtained in example 26-(8) connection, a procedure similar to that used in example 1-(8)were repeated to obtain the titled compound (3 mg) as a pale yellow oily substance.

(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,1 Hz, 3H), 3,91-4,07 (m, 2H), 5,06-5,13 (m, 1H), 7,07-7,16 (m, 2H), 7,29-7,35 (m, 2H), 7,50-EUR 7.57 (m, 1H), to 7.67-7,74 (m, 1H), of 7.90 (s, 1H).

Example 27

N-((R)-1-[5-[3-(4-acetylpiperidine-1-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazole-3-yl]-ethyl)-3,4-dichlorobenzenesulfonate(connection 697)

Formula 74

(R)-1-[4-Ethyl-5-(3-piperazine-1-yl-phenoxy)-4H-[1,2,4]triazole-3-yl]-ethylamine

Formula 75

(1) In a pressure-resistant test tube with screw cap to the compound obtained in example 1-(6), (2,08 g) was added DMPM (10 ml), 3-piperidinol (1,34 g) and Cs2CO3(6,13 g), after which the mixture was mixed at 200°C for 40 minutes. The mixture was cooled to room temperature and concentrated under reduced pressure, the crude product was purified by way of column chromatography (NH SiO2, AcOEt or MeOH/CHCl3= 1/50) to obtain the titled compound (in the form of a yellow oily compound, 1,17 g).

1H-NMR (600 MHz, CDCl3) δ ppm: 1,40 (t, J=7,1 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), 2,98 totaling 3.04 (m, 4H), 3,14-3,19 (m, 4H), of 3.97-4.09 to (m, 2H), 4,1-4,18 (m, 1H), 6,70-to 6.80 (m, 2H), 6,97-7,03 (m, 1H), 7,21-7,26 (m, 1H).

1-(4-[3-[5-((R)-1-amino-ethyl)-4-ethyl-4H-[1,2,4]triazole-3-yloxy]-phenyl]-piperazine-1-yl)-alanon

Formula 76

(2) To a solution of the compound from example 27-(1) (1.06 g) and Et3N (1.4 ml) in THF (20 ml) at a temperature of -30°C was added AcCl (0,24 ml), after which the mixture is stirred at this temperature for two hours. Then the mixture was heated to room temperature, then stirred for another five hours. The reaction mixture was concentrated, the crude product was purified by way of column chromatography (neutral OH SiO2, MeOH/CHCl3= 1/5) to obtain a mixture (315 mg, colourless solid) of the named compound and triethylamine hydrochloride.

1H-NMR (600 MHz, CDCl3) δ ppm: to 1.35 (t, J=7,3 Hz, 3H), 1,72 (d, J=6.4 Hz, 3H), 2,12 (s, 3H), 3,14 is 3.23 (m, 4H), 3,57-to 3.64 (m, 2H), 3,71-of 3.77 (m, 2H), a 3.87-4,10 (m, 2H), 4,57-of 4.66 (m, 1H), 6,70-for 6.81 (m, 2H), 6,95-6,99 (m, 1H), 7,21-7,26 (m, 1H).

N-((R)-1-[5-[3-(4-Acetylpiperidine-1-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazole-3-yl]-ethyl)-3,4-dichlorobenzenesulfonate(connection 697)

Formula 77

(3) To the mixture (307 mg), 1-(4-[3-[5-(R)-1-amino-ethyl)-4-ethyl-4H-[1,2,4]triazole-3-yloxy]-phenyl]piperazine-1-yl)-ethanone obtained in example 27-(2), and hydrochloride of triethylamine was added water, 3,4-dichlorobenzenesulfonate (0,13 ml) and K2CO3(355 mg). The mixture was mixed at anatoy temperature for 15 hours. Precipitious solid was filtered and purified by way of column chromatography (NH SiO2, MeOH/CHCl3= 1/5) to obtain the titled compound (compound 697) (117 mg, colorless syrup).

1H-NMR (600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,3 Hz, 3H), of 1.52 (d, J=6.9 Hz, 3H), and 2.14 (s, 3H), 3,14-of 3.27 (m, 4H), 3,56-to 3.64 (m, 2H), 3.72 points-of 3.80 (m, 2H), 3,88-4,01 (m, 2H), 4,58-and 4.68 (m, 1H), 5,98-the 6.06 (m, 1H), 6,72-PC 6.82 (m, 2H), 6,95-7,01 (m, 1H), 7,25-7,30 (m, 1H), 7,51-EUR 7.57 (m, 1H), 7,65-7,73 (m, 1H), 7,89-of 7.97 (m, 1H).

Example 28

3,4-sodium dichloro-N-[(R)-1-[4-ethyl-5-(3-piperazine-1-yl-phenoxy)-4H-[1,2,4]triazole-3-yl]-ethyl]-benzosulfimide(compound 683)

Formula 78

A mixture of compound (107 mg)obtained in example 27-(3), NaOH (105 mg), water (2.0 ml) and EtOH (4.0 ml) were mixed at 80°C for one hour, and then stirred at 100°C for 18 hours. The mixture was cooled to room temperature, then was extracted with AcOEt. The organic phase is washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and concentrated. The crude product was purified by way of column chromatography (NH SiO2, MeOH/CHCl3= 1/30), and then recrystallized (AcOEt-hexane) to obtain the titled compound (compound 683) (55 mg, in the form of a colorless powder).

1H-NMR (600 MHz, DMSO-d6) δ ppm: 1,24 (t, J=7,3 Hz, 3H), of 1.31 (d, J=6.9 Hz, 3H), 2.77-to of 2.86 (m, 4H), 3,03-3,10 (m, 4H), 3,81-3,99 (who, 2H), 4,67-of 4.75 (m, 1H), 6,56-6,62 (m, 1H), 6,76-6,85 (m, 2H), 7,19-7,27 (m, 1H), 7,69-to 7.77 (m, 1H), 7,88 (d, J=8.7 Hz, 1H), 7,93-of 7.97 (m, 1H).

Melting point: from 175,0°C to 178,0°C.

Compounds shown in table 1, were obtained using the appropriate starting compounds and procedures described in examples 1 to 28.

The compound obtained in the above examples, also shown in Table 1 together with other compounds.

Example test (analysis of binding S1P1)

The ability of the compounds of the present invention to inhibit binding to Edg-1 (S1P1) was determined using the membrane fraction of cells of strain HEK-293 transferred to them the human genome Edg-1 (S1P1in accordance with the method described in the literature (Science. 2002, 296: 346) (shows the binding with Kd = 0,15 nm, Bmax = 2.5 fmol/ág of [33P]-S1P). The membrane fraction was obtained by treating the cells with solubilization buffer (1 mm Tris/HCl, pH to 7.2) for 10 minutes on ice, centrifugation at 1000g for 5 minutes to remove insoluble fractions, and then centrifuged at 40000g for 30 minutes at 4°C. the Obtained membrane fraction was dissolved in the buffer for binding (20 mm Tris-HCl, pH of 7.4, 100 mm NaCl, 15 mm NaF, 2 mm deoxypyridoxine, 4 mg/ml free fatty acid BSA), and then added a [33P]-S1P (produced by ARC, final concentration 0.1 nm) and a solution of the compound in DMSO (final con is entrace connection 10 -5M, final concentration of DMSO of 0.1%). Then the mixture was stirred, after which the processed temperature of 30°C for one hour. The membrane fraction was collected using a collector on a GF/C filter unifilter-96 (manufactured by Perkin Elmer), was performed four times washing buffer for binding, and then the filter was dried. Added twenty-five μl of Microscint 0 (manufactured by Perkin Elmer), and then measured the radioactivity using a Top Count NXT (manufactured by Packard) to calculate the number () [33P]-S1P associated with the membrane fraction when adding the connection.

A similar procedure was carried out in the absence of the tested compound and calculate the amount of bound [33P]-S1P (B). Next, a similar procedure was carried out in the absence of the analyte using cells HEK-293, which was not introduced gene Edg-1 (S1P1), and calculated the number of background associated with [33P]-S1P (S).

The degree of inhibition of binding of Edg-1 (S1P1calculated using the following expression shown in table 1.

The degree of inhibition (%) = [1-(A-C)/(B-C)]×100.

Next was calculated concentration (IC50), in which the binding in the absence of the tested compound inhibited by 50%. The analysis of binding with the membrane system was carried out in the presence of investigated compounds with different concentrations, the degree inhib is by linking Edg-1 (S1P 1) was calculated using the expression above. Then the values of the IC50was calculated using software for data analysis Origin (Lightstone Corp.).

Each of the following compounds had the value of the IC5035 nm or less and showed relatively high activity:

connection 5, 13, 16, 18, 21, 23, 25, 26, 32, 35, 37, 43, 46, 64, 69, 76, 101, 102, 109, 122, 123, 125, 131, 134, 141, 142, 145, 665.

The following compounds had the value of the IC5010 nm or below, and showed even more high activity:

connection 24, 39, 40, 70, 75, 87, 93, 94, 107, 111, 112, 121, 132, 133, 137, 138, 139, 140, 147, 151, 663, 666, 667, 669, 671, 681, 683, 690.

Specific values of the IC50for individual compounds were as follows (unit: nm):

connection 3: 4,2. Compound 7: 35,5. Compound 8: to 18.5. The connection 10: 17,5. The connection 11: 8,9. The connection 12: 20,0. Compound 14: to 6.4. The connection 15: 32,5. The connection 22: 14,0. Compound 28: to 3.1. The connection 34 is 2.0. The connection 36: 17,5. Compound 38: 11,7. The connection 42: 22,0. Compound 45: 4,2. The connection 46: 28,5. Compound 49: 6,0. Compound 61: 39,0. Compound 73: 2,2. Compound 74: 15,0. Compound 83: 8,1. Compound 88: 5,4. Compound 99: 25,0. Compound 100: 18,5. Compound 105: 2,9. Compound 108: 18,0. Compound 120: 1,7. Compound 129: 20,0. Compound 130: 2,9. Compound 136: 8,1. Compound 143: 7,3. Compound 144: 7,9. Compound 146: 12,0. Compound 148: 1,9. Compound 149: 7,8. Connection 670: 5,2. Connection 678: 10,2. Connection 680 1,4. The 688 connection: 1,5. Connection 691: 2,6. Connection 692: 5,1. Connection 694: 2,9. Connection 698: 2,3.

Table 1
The connection numberChemical structureMelting point (°C)The analysis of binding (on the membrane) % inhibition (10 μm)
Connection 1182,0-184,0100,8
Connection 2134,0-138,0of 97.8
Connection 3183,5-187,598,7
Connection 4198,5-200,595,7
Connection 5160,0-161,097,3

The connection is giving 6 180,0-190,0of 98.2
Connection 7159,5-161,599,4
Compound 8179,0-179,5100,1
Connection 9145,0-148,0100,3
Connection 10182,5-184,599,8
Connection 11155,0-160,098,5
Connection 12190,0-192,099,2
Connection 13to 152.0-156,0102,0
The connection 14 161,0-162,599,5

The connection 15200,0-205,0102,7
The connection 16125,0-127,0101,3
Connection 17of 129.5-131, 5mm95,4
The connection 18189,0-194,0102,1
Connection 19145,0-150,097,9
The connection 20118,0-120,097,4
Connection 21146,5 at 149.596,7
The connection 22163,0-167,595,4
The connection 23173, 0mm-176,096,7

Connection 24172,5-173, 0mm101,0
The connection 25155,0-156,097,5
The connection 26159,0-164,097,9
Connection 27163,0-168,0100,1
The connection 28165,0-170,0104,4
The connection 29177,0-178,5 101,4
The connection 30212,0-216,0to 100.4
The connection 31143,0-146,0101,2
The connection 32147,0-148,0104,1

The connection 33173.5 metric-of 174.5100,8
The connection 34192.5 kg-195,5106,1
The connection 35156,0-159,0to 100.4
The connection 36125,0-130,0102,2
The connection 37 145,0-147,0100,3
Compound 38148,5-150,0104,8
Connection 39176,0-178,098,5
The connection 40155,5-156,5105,6
The connection 41166,0-170,092,0

The connection 42176,5-179,5102,4
The connection 43182,5-to 185.099,8
The connection 44140,0-145,5100,1
The connection 45 194,0-196,0to 106.0
The connection 46247,0-250,094,6
Connection 47191,0-192,0to 102.3
The connection 48195,5-196,596,7
The connection 49198,0-199,0102,5
The connection 50129,0-130,092,9

The connection 51148,5-150,599,9
The connection 52203,0-205,0100,2
The connection 53 172,0-173, 0mm86,8
The connection 54192,0-193,0104,1
The connection 55141,0-143,080,6
The connection 56189,0-191,088,3
Connection 57164,0-165,0
The connection 58181,0-USD 183.099,7
Connection 59169, 5mm-170,594,3

The connection 60192.5 kg-195,0the 98.9
The connection 6193,0-99,0102,2
The connection 62of 186.0-188,5to 83.5
Connection 63216,5-217,5104,7
The connection 64223,0-224,0100,8
The connection 65201,0-202,0to 105.3
Compound 66USD 183.0-190,0for 93.4
Connection 67182,0-188,095,5
The connection 68212,0-223,0100,9

td align="center"> Connection 77
Connection 69119,0 is 120.5103,2
The connection 70144, 0mm-146,096,5
Connection 71126,0-135,099,3
The connection 72198,0-200,599,0
Connection 73to 185.0-187,0103,3
The connection 74218,5-227,0104,9
Connection 75177,0-179,095,0
The connection 76151,5-153,599,2
123,0-127,099,7

The connection 78178,0-179,090,7
Connection 79190,0-195,0103,7
The connection 80164,5-165,087,6
Connection 81160,0-165,093,2
The connection 82142,0-145,0100,8
Connection 83170,0-173, 0mm100,7
The connection 84160,0-165,0 100,5
Connection 85133,0-134,0100,0
Connection 86176,0-177,0106,7
Connection 87174,0-179,099,9
The connection 88188,5-to 190.599,5
Connection 89101,0-103,090,3

Connection 90168,0-170,099,0
Connection 91137,0-138,090,6
The connection 92 118,0-120,0to 92.1
Connection 93167,5-169, 5mm99,9
Connection 94190,0-192,0106,4
Connection 95205,0-208,592,4
Connection 96191,0-194,078,7
Connection 97158,0-159,093,0
Connection 98143,0-144, 0mmto 100.4
Connection 99103,0-105,5102,4
Connection 100 109,9
Connection 101142,0-143,0100,9

Connection 102117,0-118,0104,2
Connection 103146,5-147,591,2
The connection 104187,0-187,5for 95.2
Connection 105to 121.0-123,0104,4
The connection 106132,0-134,0110,2
Connection 107159,0-162,0to 103.8
The connection 108 175,0-180,0101,3
Connection 109to 152.0-153,0103,5
The connection 110187,5-188,5103,6
Connection 111204,0-205,0108,7
The connection 112171,0-173, 0mm99,2
Connection 113USD 183.0-to 185.074,2

The connection 114to 185.0-of 186.094,5
Connection 115output reached 125.5-126,581,8
The connection 116 192,0-195,083,1
Connection 117153,5-155,587,1
The connection 118
Connection 119
Connection 120of 211.5-216,593,03
Connection 121195,5-198,5103,45
The connection 122167,0-170,081,93
Connection 123162,0-165,097,12
The connection 124 178,5-180,097,44

Connection 125253,5-254,594,28
Connection 126176,5-178,091,80
Connection 12794,44
Connection 128182,5-183,590,70
Connection 12996,0-104,096,79
The connection 130107,0-114,098,87
Connection 131102,0-110,597,35
Connection 13295,0-104,099,52
Connection 133164,0-169, 5mm101,11

Connection 134108,5-114,5101,47
Connection 135188,5-192,0100,63
Connection 136100,0-to 106.096,51
Connection 137173.5 metric-177,0101,74
Connection 138167,5-169,099,58
Connection 139174,0-177,0 101,46
The connection 140110,0-119,0101,57
Connection 141169,0-173, 0mm104,70

141,0-143,0
Connection 142USD 183.0-184,098,11
Connection 143144, 0mm-145,099.89 per
Connection 144187,0-188,099,38
Connection 145150,0-to 152.0101,30
Connection 146to 121.0-122,0101,65
Connection 147102,74
Connection 148154,5-155,5102,47
Connection 149212,0-214,5100,70
Connection 150191,5-196,0for 93.4

Connection 151252,0-255,0102,84

The connection numberChemical structureAPCI MS
(M-H)-
APCI MS
(M+H)+
Analysis of the hydrogen bonds of (at membre) % inhibi simulation (10 μm)
Connection 152467469
Connection 153 446448
Connection 15443143392,3
Connection 15538939159,9
Connection 156467, 469469, 471106,6
Connection 15744544774,6

Connection 158467, 469469, 471
Connection 159461463
The connection 160467, 469469, 47196,9
Connection 161551, 553553, 554
Connection 162423425109,3
Connection 163414416
Connection 164465467
Connection 16541441672,9
The connection 166493495

Connection 167451453113,3
Connection 16845745968,4
Connection 169457459
Connection 17044945176,0
Connection 171341343
Connection 17241741992,0
Connection 173407/td> 40997,2
Connection 17443143352,5
Connection 175419421102,7

Connection 176327329
Connection 17746746955,3
Connection 178467469
Connection 17943944183,0
Connection 180 46746994,6
Compound 18147948150,4
Connection 182514517109,3
Connection 18341541792,8
Connection 184491, 493493, 49597,3

Connection 185515517
Connection 18640340586,8
Soy is inania 187 403405
Connection 188457459106,6
Compound 18940340599,7
Connection 19047347587,9
Connection 19141541796,9
Connection 192403405for 95.2
Connection 193530532

Connection 19454054280,7
Connection 19541741990,1
Connection 19647948165,6
Connection 197535537
Connection 198441443
Compound 199408410
The connection 200465467
Connection 20145045284,3
The connection 202421423

Connection 203447449
Connection 204457459
Connection 205465467
The connection 20643143385,4
Connection 207491, 493 493, 495to 107.7
Connection 208445447an 80.2
Connection 20945745991,4
Connection 210437439
Connection 211423425

The connection 21252552769,7
Connection 213457459101,9
Connection 214 437439102,1
Connection 21541942191,4
Connection 216503, 505505, 50788,9
Connection 217461463of 57.5
Connection 218497, 499499, 50174,7
Connection 21942142370,8
Connection 22045946193,7

Connection 22143343569,2
Connection 222473475
Connection 22341441690,8
Connection 224481483
Connection 225491, 493493, 495
Connection 22645745980,4
Connection 22742542751,4
Connection 22844945153,9
Connection 229441443

Connection 230407409
Connection 23142342565,1
Connection 23243143368,7
Connection 23345545787,1
Connection 234495, 497497, 499 50,6
Connection 235481, 483483, 48582,9
Connection 236448450
Connection 23744344564,8
Connection 238425427

Compound 239525527
Connection 24045946182,5
Connection 241 42542795,8
Connection 242485, 487487, 48985,9
Connection 24345946190,0
Connection 244503, 505505, 50794,6
Connection 24545946189,3
Connection 246471473
Connection 247493495

Soy is inania 248 471473104,9
Compound 249581, 583583, 585
Connection 250425427
Connection 25149149359,0
Connection 25240740982,8
Connection 253480482
Compound 25445345575,1
Connect the tion 255 47147386,4
Connection 256443445to 85.2

Connection 257545, 547547, 54978,2
Connection 25846246467,9
Connection 259437439
Connection 260545, 547547, 54974,1
Connection 261432434 73,6
Connection 26241741979,6
Connection 26345545782,6
Connection 26445545795,9
Connection 265503, 505505, 50759,1

Connection 26642542799,0
Compound 26744144389,6
Connection 268 44344599,9
Connection 269485, 487487, 48991,5
Connection 270535, 537537, 53973,0
Connection 271535, 537537, 53957,1
Connection 272421423104,3
Connection 27342142371,6
Connection 27444144353,5

Connection 275 485, 487487, 489107,1
Connection 276501, 503503, 50594,4
Compound 277535, 537537, 539
Connection 278477479
Compound 27942142379,6
Connection 280441443of 87.3
Connection 281475477
Connection 282 495497
Compound 283482484

Connection 284404406
Connection 285419421
Connection 28640941160,6
Compound 287456455
Connection 288394396
Compound 289447449105,6
Connection 290424426
Connection 291447449
Compound 292447449106,9

Compound 293431433
Connection 29439539750,8
Connection 295462464
Connection 296469471
Compound 297478480
Compound 298543545
Compound 299519521
Connection 30042342582,1
Connection 30144945178,8

540
Connection 302538
Connection 30349149377,4
Connection 304517519
Connection 305561563
Connection 30643143360,2
Connection 30745745994,4
Connection 308490492
Connection 309490
Connection 310494496

525
Connection 31144744976,5
Connection 312461463
Connection 313437439
Connection 31450250452,2
Connection 315440442
Connection 316527
Connection 317535, 537537, 539
Connection 318535, 537537, 53978,9
Connection 319535, 537537, 53961,7

Connection 320390392
Connection 321475477
Connection 322539541
Connection 323 44544777,9
Connection 32444544781,8
Connection 325488490
Connection 326467469
Connection 32745245492,3
Connection 328410412to 85.2

Compound 337
Compound 329488, 490490, 492100,8
Connection 33046646881,6
Connection 331488, 490490, 49259,8
Connection 332482484
Connection 333488, 490490, 492102,2
Connection 334572, 574574, 576
Connection 335444446106,1
Connection 33643543756,8
486488

86,5
Connection 33843543769,2
Connection 33951451662,8
Connection 340472474100,0
Connection 34147848092,8
The connection 34247848053,6
Compound 343470472
Connection 344362364
Connection 34543844090,4
Connection 34642843089,2

Compound 34745245450,1
Connection 348440442109,1
Compound 349348350
Connection 35048 49075,0
Compound 351488490
Connection 35246046288,5
The connection 35348849092,3
Connection 354500502
Connection 35553653898,8

Connection 35643643895,6
Connection 357 512, 514514, 516106,1
Connection 358536538
Connection 35942442695,7
Connection 360424426
Connection 36142442696,9
The connection 36249449695,1
Compound 36343643896,2
Connection 364 42442687,5

Connection 365551553
Connection 36656156363,2
Connection 36743844094,3
Connection 368500502of 60.5
Connection 369556558
Connection 370462464
Connection 371/td> 429431
Connection 372471473106,3
Connection 373442444

Connection 374468470
Connection 375478480
Connection 376486488
Compound 377452454a 3.9
Connection 37846646871,6
Connection 37947848089,2
Connection 380458460
Compound 381444446
Connection 38254654866,9

460
Connection 38347848083,6
Connection 384458at 88.1
Connection 38546246498,0
The connection 38644044284,0
Compound 387524, 526526, 52863,5
Connection 38848248465,8
Connection 389518, 520520, 52288,0
Connection 39044244465,9
Compound 391480 48280,4

Connection 392566, 568568, 57073,6
Connection 39345445679,7
Connection 394494496
Connection 39543543779,1
Connection 396502504
Connection 397512, 514514, 516
Connection 398 47848084,7
Connection 399446448
Connection 40047047275,3

Connection 401462464
Connection 402428430
Connection 40344444672,5
Connection 40445245460,2
Connection 405/td> 47647861,4
Connection 406516, 518518, 52056,3
Connection 407502, 504504, 50668,2
Connection 408469471
Connection 40946446674,7
Connection 410446448

Connection 411546548
Connection 41248048282,5
Connection 413446448for 95.3
Connection 414506, 508508, 51092,5
Connection 41548048291,5
Connection 416524, 526526, 52883,2
Connection 41748048290,8
Connection 418492494
Connection 419514516

Connection 420602, 604604, 60661,0
Connection 421446448
Connection 42251251483,1
Connection 423428430of 87.8
Connection 424501503
The connection 42547690,1
Connection 42649249492,3
Connection 42746446686,5
Connection 428566, 568568, 57081,4

Connection 42948348571,1
Connection 43045846050,0
Connection 431566, 568568, 57080,5
Connection 432 45345584,2
Connection 43343844093,8
Connection 43447647879,5
Connection 43547647894,6
Connection 436524, 526526, 52867,5
Connection 43744644897,3

Connection 43846246471,6
Connection 43946446698,1
Connection 440502, 504504, 50688,4
Connection 441506, 508508, 51063,0
Connection 442556, 558558, 56070,1
Connection 443556, 558558, 56055,7
Connection 444442444100,2
Connection 44544244455,6
Connection 44646246475,8

Connection 447506, 508508, 51095,5
Connection 448522, 524524, 52681,1
Connection 449556, 558558, 560
Connection 450498500
Connection 451442444of 76.8
Connection 452 46246468,9
Connection 453496498
Connection 454516518
Connection 455503505

Connection 456425427
Connection 457440442
Connection 458430432is 83.8
Connection 459 474476
Connection 46048248453,2
Connection 46146847099,7
Connection 462445447
Connection 463468470
Connection 46446847087,9

Connection 465452454
Connection 466 41641851,1
Connection 46748348559,9
Connection 46849049256,2
Connection 469499501
Connection 470564566
Connection 471540542
Connection 47244444655,3
Connection 473/td> 47047274,5

Connection 474559561
Connection 47551251451,8
Connection 476482484
Connection 477452454to 58.1
Connection 478478480of 87.0
Connection 479511513
Connection 480511513
Connection 481515517
Connection 48246847087,4

548
Connection 483482484
Connection 48452352565,3
Connection 485461463
Connection 486546
Connection 487556, 558558, 560
Connection 488556, 558558, 56062,5
Connection 489556, 558558, 560
Connection 490411413
Connection 491496498

Connection 492560562
Connection 493 46646883,1
Compound 49446646866,0
Connection 495547549
Connection 496526528
Connection 497511513103,6
Connection 49846947184,0
Connection 499547, 549549, 551108,9
Connection 500 52552790,2
Connection 501547, 549549, 55161,7
Connection 50254154375,5

Connection 503547, 549549, 551116,0
Connection 504631, 633633, 63553,5
Connection 505503505108,0
Connection 50649449683,2
Connection 50754554784,8
Connection 508494496
Connection 509573575of 87.0
Connection 510531533113,5
Connection 51153753998,6
Connection 51253753960,7
Connection 51352953196,6
Connection 514421423

69,9
Connection 515497499108,9
Connection 516487489106,7
Connection 51751151369,6
Connection 518499501110,8
Connection 519407409
Connection 520547549
Connection 521547549
Connection 52251952198,4
Connection 523547549113,5
Connection 52455956183,0
Connection 525595597110,9
Connection 526571, 573573, 575111,8

Connection 527 59559752,1
Connection 528483485106,2
Connection 529483485
Connection 530537539to 114.7
Connection 531483485100,1
Connection 53255355599,2
Connection 533495497
Connection 534 483485100,8
Connection 535610612
Connection 53662062250,3
Connection 53749749996,7

Connection 538559561to 97.1
Connection 539615617
Connection 54052152364,3
Connection 541 48849065,5
Connection 54254554750,1
Connection 543530532111,8
Connection 54450150353,9
Connection 54552752950,7
Connection 54653753955,8
Connection 547545547
Connection 548 51151396,7

Connection 54952552789,2
Connection 550537539103,6
Connection 55151751976,1
Connection 55250350567,2
Connection 553605607106,6
Connection 554537539116,5
Connection 555517519102,0
Connection 556499501104,8
Connection 557583, 585585, 587107,3
Connection 55854154364,8
Connection 559577, 579579, 58179,3

Connection 56050150374,4
Connection 561539 54192,4
Connection 56251351593,3
Connection 56355355564,1
Connection 564494496105,4
Connection 565561563
Connection 566571, 573573, 57588,7
Connection 567537539101,6
Connection 568505 50771,1
Connection 56952953175,0
Connection 57052152377,4

Connection 57148748955,7
Connection 57250350596,5
Connection 57351151386,3
Connection 574575, 577577, 57986,9
Connection 575 561, 563563, 565103,7
Connection 57652853081,4
Connection 57752352592,4
Connection 578505507
Connection 57960560787,6
Connection 58053954189,2
Connection 58150550799,9

Soy is inania 582 565, 567567, 569to 106.0
Connection 583539541108,9
Connection 584583, 585585, 58796,2
Connection 585539541103,0
Connection 58655155387,9
Connection 58757357560,0
Connection 588551553109,3
Connection 589661, 663663, 665an 80.2
Connection 59050550762,3
Connection 59157157377,5
Connection 59248748995,8

Connection 59356056265,9
Connection 59453353584,0
Connection 595551553 93,7
Connection 596523525100,3
Connection 597625, 627627, 62997,3
Connection 598542544to 89.5
Connection 59951751980,6
Connection 600625, 627627, 629100,5
Connection 601512514to 100.4
Connection 602497 499106,7
Connection 603535537106,8

Connection 604535537109,4
Connection 605583, 585585, 587of 83.4
Connection 606505507107,8
Connection 607521523
Connection 608523525108,6
Connection 609 565, 567567, 569br93.1
Connection 610615, 617617, 61991,2
Connection 611615, 617617, 61963,9
Connection 612501503114,0
Connection 61350150390,9
Connection 61452152377,8

Connection 615565, 567567, 569110,3
581, 583583, 58599,9
Connection 617615, 617617, 61977,5
Connection 61855755965,4
Connection 619497499114,2
Connection 62050150388,4
Connection 62152152395,4
Connection 622555557of 58.9
Connection 623575577
Connection 624562564

Connection 625484486
Connection 62649950161,1
Connection 62748949190,0
Connection 62853353564,4
Connection 629541543 101,1
The connection 630527529107,4
Connection 631504506for 95.2
Connection 63252752959,9
Connection 633527529111,2
Connection 63451151351,0
Connection 63547547768,7

Connection 636 54254485,7
Connection 63754955150,6
Connection 638558560
Connection 639623625
Connection 64059960159,5
Connection 641503505to 85.2
Connection 64252953185,5
Connection 643 618620
Connection 64457157393,0
Connection 645597599

Connection 646641643
Connection 64751151399,0
Connection 648537539107,8
Connection 64957057264,7
Connection 650 570572
Connection 651574576
Connection 65252752991,9
Connection 653541543
Connection 65458258471,7
Connection 655605607

Connection 656615, 617617, 619
Soedinenie 615, 617617, 61994,9
Connection 658615, 617617, 61980,4
Connection 659470472
Connection 660555557
Connection 661619621
Connection 66252552795,4

The connection numberChemical structureMelting point (°C)

Connection 663210,0-217,099,5
Connection 664218,0-221,585,4
Connection 665197,0-201,0100,3
Connection 666143,5-144,597,9
Connection 667207,0-208,099,2
Connection 66898,6
Connection 669131, 5mm-132,5100,3
Connection 670 214,5-218,0100,8
Connection 671100,6
Connection 672102,7

Connection 67362,0
Connection 67497,0
Connection 67596,6
Connection 67692,6
Connection 67760,8
Connection 678 97,4
Connection 679104,0
Connection 680169, 5mm-170,5100,1
Connection 681189,0-189,5100,2
Connection 682228,0-228,576,6
Connection 683175,0-178,0100,5

Connection 684169, 5mm-which is 171,5
Connection 685255,0-260,065,1
Connection 686 220,5-221,0of 92.7
Connection 68780,1
Connection 688192,0-193,0100,5
Connection 689of 92.7
Connection 690198,0-200,0102,2
Connection 691180,0-182,098,5
Connection 692227,0-229,098,5
Connection 693158,0-161,097,7

Connection 694 189,0-191,0to 106.0
Connection 6950
Connection 696
Connection 697
Connection 69899,8

In table 1 some compounds had two sets of data for APCI MS (M-H)-and APCI MS (M+H)+because isotopes of chlorine atom or bromine atom detected two peaks.

For the following compounds shown data1H-NMR.

Compound 100: (600 MHz, DMSO-d6) δ ppm: to 1.21 (t, J=7,1 Hz, 3H), 1.27mm (d, J=6.9 Hz, 3H), up 3.22 (s, 6H), 3,40-to 3.50 (m, 8H), of 3.77-3,93 (m, 2H), 4,68 (kV, J=6,9 Hz, 1H), 6,34 (DD, J=7,3, to 2.29 Hz, 1H), of 6.52 (DD, J=8,3, to 2.29 Hz, 1H), 6,56 (t, J=2.3 Hz, 1H), 7,12 (t, J=8,3 Hz, 1H), of 7.70 (DD, J=8,3, 2.3 Hz, 1H), a 7.85 (d, J=8,3 Hz, 1H), 7,92 (d, J=1.8 Hz, 1H), 8,66 (s, 1H).

Compound 119: (600 MHz, CDCl3) δ ppm: of 1.34 (t, J=7,3 Hz, 3H), 1,50 (d, J=7,3 Hz, 3H), 3,89-3,98 (m, 2H), 4,59 with 4.65 (m, 1H), is 5.06 (s, 2H) 6,37-6.42 per (m, 1H), 6,80-to 6.95 (m, 2H), 7,01? 7.04 baby mortality (m, 1H), 7,24 and 7.36 (m, 2H), was 7.36-7,44 (m, 4H), 7,49-7,53 (m, 1H), to 7.67-7,73 (m, 1H), 7,93-of 7.96 (m, 1H).

Compound 127: (600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,1 Hz, 3H), 1,49 (d, J=6.9 Hz, 3H), 2,41 (s, 3H), 3,93-was 4.02 (m, 2H), 4,59 with 4.65 (m, 1H), vs. 5.47 (d, J=9.6 Hz, 1H), 7,05-7,10 (m, 2H), 7,31-7,37 (m, 3H), to 7.61-to 7.64 (m, 1H), 7,80-of 7.82 (m, 1H).

Compound 129: (600 MHz, DMSO-d6) δ ppm: 1,21-of 1.29 (m, 6H), to 2.29 (s, 6H), 3,83-4,01 (m, 2H), br4.61 (kV, J=6,4 Hz, 1H), to 6.43-6,47 (m, 1H), 6.89 in-6,93 (m, 1H), 7,34-7,40 (m, 3H), 7,52-of 7.60 (m, 3H), 8,24 (s, 1H), 11,18 (s, 1H).

Compound 130: (600 MHz, DMSO-d6) δ ppm: 1,22 (d, J=6.8 Hz, 3H), of 1.26 (t, J=7,1 Hz, 3H), a 3.87-was 4.02 (m, 2H), 4,70 (kV, J=6,8 Hz, 1H), to 6.43-of 6.45 (m, 1H), 6,77-to 6.80 (m, 1H), 7,28-7,30 (m, 1H), was 7.36-7,38 (m, 1H), 7,50-7,53 (m, 1H), to 7.67 to 7.75 (m, 2H), 7,83-7,86 (m, 1H), 8,04-8,07 (m, 1H), 8,12-8,19 (m, 2H), 8,45-of 8.47 (m, 1H), charged 8.52 (s, 1H), 11,16 (s, 1H).

Compound 131: (600 MHz, DMSO-d6) δ ppm: 1.28 (in t, J=7,1 Hz, 3H), of 1.35 (d, J=6.9 Hz, 3H), of 2.36 (s, 3H), 3,89-a 4.03 (m, 2H), with 4.64-4.72 in (m, 1H), 6,44-6,46 (m, 1H), 6.87 in-6,90 (m, 1H), was 7.36-7,38 (m, 2H), 7,53-EUR 7.57 (m, 1H), 7,82-to 7.84 (m, 1H), 7,88-to $ 7.91 (m, 1H), 8,77 (s, 1H), 11,18 (s, 1H).

Compound 132: (600 MHz, DMSO-d6) δ ppm: of 1.23 to 1.31 (m, 6H), 2,39 (s, 3H), 3,85-was 4.02 (m, 2H), 4,69 (kV, J=6,9 Hz, 1H), to 6.43-6,47 (m, 1H), 6,88-6,92 (m, 1H), was 7.36-7,39 (m, 2H), 7,53-of 7.60 (m, 2H), of 7.64-to 7.68 (m, 1H), to 7.77-7,80 (m, 1H), 8,51 (s, 1H), 11,18 (s, 1H).

Compound 134: (600 MHz, DMSO-d6) δ ppm: of 1.29 (t, J=7,3 Hz, 3H), of 1.36 (d, J=6.9 Hz, 3H), 3,89-of 4.05 (m, 2H), 4,67-to 4.73 (m, 1H), 6,44-6,46 (m, 1H), 6,86-of 6.90 (m, 1H), 7,35-7,39 (m, 2H), 7,54-EUR 7.57 (m, 1H), 7,83-7,88 (m, 1H), to $ 7.91-7,94 (m, 1H), 9,01 (s, 1H), 11,17 (s, 1H).

Compound 136: (600 MHz, DMSO-d6) δ ppm: of 1.23 to 1.31 (m, 6H), 3,85-was 4.02 (m, 2H), 4.72 in (kV, J=6,9 Hz, 1H), 6,44-6,47 (m, 1H), 6.87 in-6,91 (m, 1H), 7,34-7,39 (m, 2H), 7,52-EUR 7.57 (m, 1H), 7,97-with 8.05 (m, 4H), to € 8.74 (s, 1H), 11,17 (s, 1H).

Compound 150: (20 MHz, CDCl3) δ ppm: 0,94 (d, J=6.4 Hz, 3H), of 0.97 (d, J=6.4 Hz, 3H), of 1.30 (t, J=7,3 Hz, 3H), 2.00 in of 2.20 (m, 1H), is 2.37 (s, 3H), 3,70-3,88 (m, 2H), 4,10 (DD, J=6,9, and 9.4 Hz, 1H), of 6.71 (d, J=9.4 Hz, 2H), 7,12-7,22 (m, 4H), 7,40 (d, J=8,4 Hz, 1H), 7,65 (DD, J=2,2, and 8.4 Hz, 1H), to 7.84 (d, J=2.2 Hz, 1H).

Connection 668: (600 MHz, DMSO-d6) δ ppm: 1,19-1,25 (m, 6H), 2,22 (s, 3H), 2,41 is 2.46 (m, 4H), 2,49-of 2.54 (m, 3H), 3,11-3,17 (m, 4H), 3,83-to 3.99 (m, 2H), 4,65-4,71 (m, 1H), 6,47-6,51 (m, 1H), 6,77-PC 6.82 (m, 2H), 7,17-7,22 (m, 1H), 7,51-of 7.55 (m, 1H), to 7.77-to 7.84 (m, 2H), 8,01-8,10 (m, 2H), scored 8.38-8,51 (m, 2H).

Connection 671: (200 MHz, CDCl3) δ ppm: to 0.89 (t, J=7.5 Hz, 3H), of 1.23 (t, J=7,3 Hz, 3H), 1.70 to to 2.06 (m, 2H), 2,42 (s, 3H), 2,66 (users, 4H), 3,29 (t, J=5.1 Hz, 4H), 3,68-to 3.92 (m, 2H), to 4.38 (DD, J=7,0, to 15.4 Hz, 1H), 6,50 (users, 1H), 6,56 (DD, J=2,0 and 8.1 Hz, 1H), 6,72 (DD, J=2.0 a, and 8.4 Hz, 1H), 6.89 in (t, J=2.0 Hz, 1H), 7,20 (t, J=8,4 Hz, 1H), 7,46 (t, J=8,1 Hz, 1H), 7,69 (d, J=8.0 Hz, 1H), 7,80 (d, J=8.0 Hz, 1H), 7,94 (d, J=2.0 a, 9,0 Hz, 1H), 8,28 (d, J=9,0 Hz, 1H), and 8.4 (d, J=2.0 Hz, 1H).

Connection 672: (200 MHz, CDCl3) δ ppm: of 1.33 (t, J=7,3 Hz, 3H), 1,49 (d, J=6.8 Hz, 3H), 2,41 (s, 3H), 2.57 m)-2,70 (m, 4H), 3,16-to 3.33 (m, 6H), 3,91 (kV, J=7,3 Hz, 2H), to 4.52-4,69 (m, 3H), 5,08 (d, J=9.0 Hz, 1H), 6.73 x (DD, J=2,2, 8.6 Hz, 2H), for 6.81 (d, J=9.0 Hz, 1H), 6,97 (t, J=2.2 Hz, 1H), 7.23 percent (t, J=8,1 Hz, 1H), 7,62-to 7.68 (m, 2H).

Connection 673: (200 MHz, CDCl3) δ ppm: 1,31 (t, J=7.0 Hz, 3H), of 1.33 (s, 6H), for 1.49 (d, J=7,0 Hz, 3H), of 1.80 (t, J=6.6 Hz, 2H), 2,39 (s, 3H), at 2.59 (t, J=5.0 Hz, 4H), and 2.79 (t, J=7,0 Hz, 2H), 3,25 (t, J=5.0 Hz, 4H), 3,90 (kV, J=7,0 Hz, 2H,), 4,48 with 4.65 (m, 1H), 5,07 (d, J=9.5 Hz, 1H), 6.73 x (DD, J=2,4, 8,1 Hz, 2H), PC 6.82 (d, J=9,2 Hz, 1H), 6,97 (t, J=2.4 Hz, 1H), 7.23 percent (t, J=8,1 Hz, 1H), 7,51-EUR 7.57 (m, 2H).

Connection 674: (200 MHz, CDCl3) δ ppm: of 1.34 (t, J=7,3 Hz, 3H), 1,49 (d, J=6.8 Hz, 3H), of 2.21 (Quint, J=6.0 Hz, 2H), is 2.37 (s, 3H), at 2.59 (t, J=4.6 Hz, 4H), of 3.25 (t, J=4,6 is C, 4H), 3,93 (kV, J=7,3 Hz, 2H), 4,27 (DD, J=6,0, the 11.6 Hz, 4H), 4,51-of 4.66 (m, 1H), 5,15 (d, J=9.5 Hz, 1H), 6,74 (DD, J=2,2, and 8.4 Hz, 1H), 7,07-7,13 (m, 2H), 7.23 percent (t, J=8,1 Hz, 1H), 7,38 (DD, J=2,4, 8,1 Hz, 1H), 7,43 (d, J=2.0 Hz, 1H).

Connection 675: (200 MHz, CDCl3) δ ppm: 1,36 (t, J=7,3 Hz, 3H), 1,49 (d, J=6.8 Hz, 3H), 2,39 (s, 3H), at 2.59 (t, J=5.0 Hz, 4H), 3,26 (t, J=5.0 Hz, 4H), 3,95 (kV, J=7,3 Hz, 2H), 4,50-and 4.68 (m, 1H), 5,18 (d, J=9.5 Hz, 1H), equal to 6.05 (s, 2H), 6,74 (DD, J=2,4, 8,1 Hz, 2H), 6,86 (d, J=8,4 Hz, 1H), 6,98 (t, J=2.4 Hz, 1H), 7,19-7,27 (m, 2H), 7,42 (DD, J=1,8, 8,1 Hz, 1H).

Connection 676: (200 MHz, CDCl3) δ ppm: of 1.27 and 1.33 (m, 15H), 1,47 (d, J=6.8 Hz, 3H), 2,43 (s, 3H), 2,61-of 2.72 (m, 4H), 3.25 to to 3.33 (m, 4H), 3,90 (kV, J=7.5 Hz, 2H), 4,57 (DD, J=6,8, and 9.2 Hz, 1H), 5,13 (d, J=9,2 Hz, 1H), 6,70-6,79 (m, 2H), 6,99 (t, J=2.2 Hz, 1H), 7,22 (t, J=8,1 Hz, 1H), 7,41 (d, J=8.6 Hz, 1H), EUR 7.57 (DD, J=2.0 a, 8,1 Hz, 1H), 7,79 (d, J=2.0 Hz, 1H).

Connection 677: (200 MHz, CDCl3) δ ppm: to 1.32 (t, J=7,3 Hz, 3H), 1,49 (d, J=6.8 Hz, 3H), 2,22 (s, 3H), of 2.38 (s, 3H), of 2.56 2.63 in (m, 4H), 3,14-3,30 (m, 6H), 3,84-4,10 (m, 4H), 4.53-in with 4.64 (m, 1H), 5.25-inch (d, J=9.5 Hz, 1H), of 6.71-6,79 (m, 2H), 7,01 (t, J=2.4 Hz, 1H), 7,22 (t, J=8,4 Hz, 1H), EUR 7.57 (s, 1H), 7,69 (DD, J=2.0 a, and 8.4 Hz, 1H), 8,27 (d, J=8,4 Hz, 1H).

Connection 678: (200 MHz, CDCl3) δ ppm: to 1.32 (t, J=7,3 Hz, 3H), of 1.46 (d, J=6.8 Hz, 3H), 2,11 (Quint, J=7.5 Hz, 2H), a 2.36 (s, 3H), 2,58 (t, J=5.0 Hz, 4H), to 2.94 (t, J=7.5 Hz, 4H), of 3.25 (t, J=5.0 Hz, 4H), 3,92 (kV, J=7,3 Hz, 2H), to 4.52-4,67 (m, 1H), 5,15 (d, J=10.0 Hz, 1H), 6.73 x (DD, J=2,2, 8,1 Hz, 2H), 6,98 (t, J=2.2 Hz, 1H), 7,22 (t, J=7.9 Hz, 1H), 7,31 (d, J=8,1 Hz, 1H), 7.62mm (DD, J=2,2, 7.9 Hz, 1H), to 7.67 (s, 1H).

Connection 679: (600 MHz, DMSO-d6) δ ppm: 1,24 (t, J=7,1 Hz, 3H), of 1.29 (d, J=6.9 Hz, 3H), 2,22 (s, 3H), 2.40 a is 2.46 (m, 4H), 3,12-and 3.16 (m, 4H), 3,81-of 3.97 (m, 2H), with 4.64-4.72 in (m, 1H), 6,53 return of 6.58 (m, 1H), 6,60-of 6.65 (m, 1H), 6,77-PC 6.82 (m, 2H), 7,20 (t, J=8,3 Hz, 1H), 7,60 (d, J8,7 Hz, 1H), 7,94-to 7.99 (m, 1H), 8.17-a 8,23 (m, 2H), 8,54-8,61 (m, 1H).

Connection 698: (600 MHz, CDCl3) δ ppm: of 1.33 (t, J=7,1 Hz, 3H), USD 1.43 (d, J=6.9 Hz, 3H), 2,11 (s, 3H), of 3.10-3.20 (m, 4H), 3,53-3,59 (m, 2H), 3,67-3,74 (m, 2H), 3,89-4,00 (m, 2H), 4,67 (kV, J=7,1 Hz, 1H), 6,65 to 6.75 (m, 2H), 6,94-6,97 (m, 1H), 7,21-7,25 (m, 1H), 7,46 is 7.50 (m, 1H), 7,69-7,73 (m, 1H), 7,80-to 7.84 (m, 1H), 7.95 is-to 7.99 (m, 1H), 8,29-to 8.34 (m, 1H), 8,45-of 8.47 (m, 1H).

The following describes typical methods of preparation of starting materials used to produce compounds for this application.

Standard examples 1-3

Starting from the corresponding amine instead of 1,4-dioxa-8 azaspiro[4,5]decane used in example 7-(1)by a procedure similar to that used in example 7-(1)was repeated to obtain the above mentioned compounds.

The standard example 1

3-((2R,6S)-2,6-dimethylmorpholine-4-yl)-phenol

Formula 79

Brown oily substance, yield 71%.

1H-NMR (600 MHz, CDCl3) δ ppm: 1,24 (d, J=6.0 Hz, 6H), 2,36 at 2.45 (m, 2H), 3,37-of 3.46 (m, 2H), of 3.73-a 3.83 (m, 2H), free 5.01 (s, 1H), 6,28-6,33 (m, 1H), 6,36-6,38 (m, 1H), 6,46-6,51 (m, 1H), 7,10 (t, J=8.0 Hz, 1H).

The standard example 2

3-[4-(2-dimethylaminoethyl)-piperazine-1-yl]-phenol

Formula 80

Yellow oily substance, yield 12%.

1H-NMR (600 MHz, CDCl3) δ ppm: to 2.29 (s, 6H), 2,48-to 2.57 (m, 4H), 2.57 m-of 2.64 (m, 4H), 3,11 -, and 3.16 (m, 4H), 6,24-6,30 (m, 1H), 6,32-6,37 (m, 1H), 6.42 per-of 6.49 (m, 1H),? 7.04 baby mortality-to 7.09 (m, 1H).

The standard example 3

3-[(2-dimethylaminoethyl)-methyl-amino]-phenol/u>

Formula 81

Brown oily substance, yield 42%.

1H-NMR (600 MHz, CDCl3) δ ppm: of 2.27 (s, 6H), of 2.44-2.50 (m, 2H), 2,87 (s, 3H), 3,37-3,44 (m, 2H), 6,09-6,16 (m, 2H), to 6.19-6,24 (m, 1H), 7,01 (t, J=8.0 Hz, 1H).

The standard example 4

3-(4-isopropyl-piperazine-1-yl)-phenol

Formula 82

To a solution of 3-piperazine-1-yl-phenol (2.00 g) in THF (40 ml) was added acetone (1,95 g) and NaBH(OAc)3(7,12 g), after which the mixture is stirred at room temperature for 18 hours. To the reaction solution was added saturated aqueous sodium bicarbonate solution, after which the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4) and was filtered to obtain the titled compound (1.48 g in the form of a colorless powder).

1H-NMR (600 MHz, CDCl3) δ ppm: 1,11 (d, J=6.4 Hz, 6H), 2,68-of 2.72 (m, 4H), 2.71 to 2,78 (m, 1H), 3.15 and is 3.23 (m, 4H), 6,28-6,32 (m, 1H), 6,36 (t, J=2.3 Hz, 1H), 6,50 (DD, J=8,3, 2.3 Hz, 1H), to 7.09 (t, J=8,3 Hz, 1H).

The standard example 5

3-(1-isopropylpiperazine-4-yl)-phenol

Formula 83

Starting with 3-piperidine-4-yl-phenol instead of 3-piperazine-1-yl-phenol used in the standard example 4, a similar procedure to that used in the standard example 4 was repeated to obtain the titled compound (yield 31%, in the form of a colorless powder).

1H-NMR (600 MHz, CDCl3 ) δ ppm: 1,16 (d, J=6.4 Hz, 6H), 1,76 is 1.86 (m, 2H), 1,91 is 2.01 (m, 2H), 2,31-of 2.50 (m, 3H), 2,92-to 3.02 (m, 1H), is 3.08-3,19 (m, 2H), 6,66-6,72 (m, 2H), 6,74-6,79 (m, 1H), 7,11 (t, J=7.8 Hz, 1H).

The standard example 6

4-fluoro-3-(4-methyl-piperazine-1-yl)-phenol

Formula 84

4-benzyloxy-2-chloro-1-torbenson

Formula 85

(1) a Suspension of 3-chloro-4-terfenol (2.00 g), benzylchloride (1,88 ml) and potassium carbonate (2,82 ml) in dimethylformamide (10 ml) was stirred at room temperature for three hours. To the reaction mixture was added water, then the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride, dried (MgSO4), filtered and concentrated, the obtained residue was purified by way of column chromatography on silica gel (OH SiO2, AcOEt/hexane = 0-10%) to obtain the titled compound (2.00 g) as a pale yellow oily substance.

1H-NMR (600 MHz, CDCl3) δ ppm: free 5.01 (s, 2H), 6,77-6,86 (m, 1H), of 6.96-to 7.09 (m, 2H), 7,30-7,46 (m, 5H).

1-(5-benzyloxy-2-forfinal)-4-methyl-piperazine

Formula 86

(2) In an argon atmosphere at room temperature compound (7.5 g)obtained in the standard example 6-(1), and then the solution 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-1 phosphino-bicyclo[3,3,3]-undecane (1.1 g) in toluene (320 ml) was added to Tris(dibenzylidene)dial adieu (1.45 g) and t-butoxymethyl (4.26 deaths / g). Then at room temperature was added a solution of N-methylpiperazine (1,02 g) in toluene (20 ml), after which the mixture was stirred at 100°C for 60 hours. The reaction mixture was concentrated, the obtained residue was purified by way of column chromatography on silica gel (NH SiO2, AcOEt/hexane = 0-30%) to obtain the titled compound of 2.27 g) as a yellow oily substance.

1H-NMR (600 MHz, CDCl3) δ ppm: 2,35 (s, 3H), by 2.55 2.63 in (m, 4H), 3,06 is 3.15 (m, 4H), to 5.00 (s, 2H), 6,46-6,51 (m, 1H), 6,56-6,59 (m, 1H), 6.89 in-to 6.95 (m, 1H), 7.29 trend was 7.45 (m, 5H).

4-fluoro-3-(4-methylpiperazin-1-yl)-phenol

Formula 87

(3) Suspension of the compound obtained in reference example 6-(2), (2,48 g) and palladium hydroxide (10%, 250 mg) in methanol (30 ml) was stirred in hydrogen atmosphere at 65°C for two and a half hours and then at room temperature overnight. The reaction solution was filtered through cellit and the filtrate was concentrated. The obtained residue was purified by way of column chromatography on silica gel (NH SiO2, AcOEt/hexane = 0-99%, methanol/chloroform = 0-10%). Then, the compound obtained was purified again by way of column chromatography on silica gel (OH SiO2, methanol/chloroform = 0-10%) to obtain the titled compound (877 mg) as a solid ochre.

1H-NMR (600 MHz, DMSO-d6) δ ppm: of 2.21 (s, 3H), 2,39-2,48 (m, 4H), 2,89-to 2.99 (m, 4H), 6,26-,31 (m, 1H), 6,35-to 6.39 (m, 1H), 6,84-6,91 (m, 1H), 9,20 (s, 1H).

Further, as an example describes a standard way to obtain an intermediate compound represented by formula (II) of the present invention.

Starting with the appropriate starting materials was repeated procedures described in examples 1-(1) to 1-(7), examples 2-(1) and 2(2), examples 7-(1) and 7(2), examples 17-(1) and 17(2), example 18-(1), example 21-(1), example 22-(1), example 23-(1) and examples from 26-(1) to 26-(8), followed by the formation of salts, as required to obtain the compounds or salts of the compounds which are intermediate compounds used to obtain compounds with formula (I) according to the present invention. The obtained intermediate compounds are presented in table 2 along with the intermediate compounds obtained in the examples above.

Table 2
The connection numberChemical structure1H-NMR
The intermediate connection 1(200 MHz, CDCl3) δ ppm: 1,25 (t, J=7,3 Hz, 3H), of 3.12 (DD, J=13.3-inch, 8.6 Hz, 1H), 3,38 (DD, J=13.3-inch and 6.1 Hz, 1H), 3,60-4,30 (m, 3H), 7,10-7,46 (m, 10H)
Intermediate compound 2 (600 MHz, DMSO-d6) δ ppm: of 1.29 (t, J=7,3 Hz, 3H), of 1.41 (d, J=6.9 Hz, 3H), of 2.30 (s, 3H), of 3.96-4.09 to (m, 3H), 7,15-7,30 (m, 4H)

Intermediate compound 3(600 MHz, DMSO-d6) δ ppm: of 1.33 (t, J=7,1 Hz, 3H), of 1.42 (d, J=6.4 Hz, 3H), of 2.23 (s, 3H), 4,00-4,12 (m, 3H), 7,10-7,40 (m, 4H)
Intermediate compound 4(600 MHz, DMSO-d6) δ ppm: 1,22-of 1.30 (m, 3H), of 1.41 to 1.48 (m, 3H), of 2.33 (s, 3H), 3,83-4,10 (m, 3H),? 7.04 baby mortality-7,14 (m, 3H), 7,26-7,37 (m, 1H)
The intermediate compound 5(600 MHz, CDCl3) δ ppm: of 1.46 (t, J=7,1 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), of 4.05-4.25 in (m, 3H), for 6.81-to 7.32 (m, 4H)
The intermediate compound 6(200 MHz, CDCl3) δ ppm: of 1.41 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.6 Hz, 3H), a 3.87-4.26 deaths (m, 3H), 7,14-7,26 (m, 1H), 7,30 was 7.45 (m, 4H)
Intermediate compound 7(600 MHz, CDCl3) δ ppm: 1,35-1,45 (m, 3H), 1,53-of 1.62 (m, 3H), 3.95 to 4,20 (m, 3H), 7,27-7,40 (m, 4H)
Intermediate compound 8(600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7,1 Hz, 3H), 1,60 (d, J=6.9 Hz, 3H), 3,90-of 4.25 (m, 3H), 7,15-to 7.50 (m, 4H)

Intermediate compound 9(600 MHz, DMSO-d6) δ ppm: 1.14 in (t, J=7,3 Hz, 3H), of 2.30 (s, 3H), of 3.00 (DD, J=13.3-inch, 7,3 Hz, 1H), 3,19 (DD, J=13.3-inch and 6.9 Hz, 1H), of 3.77-3,98 (m, 2H), 4,11 (t, J=7,1 Hz, 1H), 7,13-7,139 (m, 9H)
Intermediate compound 10(600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7.4 Hz, 3H), of 1.57 (d, J=6.8 Hz, 3H), of 3.80 (s, 3H), 3.95 to 4,20 (m, 3H), 6,82-6,97 (m, 2H), 7,21-7,34 (m, 2H)
Intermediate compound 11(600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7,3 Hz, 3H), 1,58 (d, J=6.4 Hz, 3H), 3.95 to to 4.23 (m, 3H), 6.90 to-to 7.15 (m, 2H), 7,30-7,44 (m, 2H)
Intermediate compound 12(600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7.4 Hz, 3H), 1,60 (d, J=6.8 Hz, 3H), 3,98-is 4.21 (m, 3H), 7,26-the 7.65 (m, 3H)
Intermediate compound 13 (600 MHz, CDCl3) δ ppm: 1,40 (t, J=7,1 Hz, 3H), 1,58 (d, J=6.9 Hz, 3H), 2,24 (s, 3H), of 2.25 (s, 3H), 3.95 to to 4.23 (m, 3H), 7,00-7,19 (m, 3H)

Intermediate compound 14(200 MHz, CDCl3) δ ppm: 1,05-2,03 (m, 16H), 2,32-to 2.65 (m, 1H), a 3.87-the 4.29 (m, 3H), 7,00-7,46 (m, 4H)
Intermediate compound 15(200 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,3 Hz, 3H), of 1.59 (d, J=7,0 Hz, 3H), a 3.87 (s, 6H), 3.96 points-4,27 (m, 3H), 6,82-to 6.88 (m, 2H), 6,97 (d, J=2.6 Hz, 1H)
The intermediate connection 16(600 MHz, CDCl3) δ ppm: to 1.42 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.4 Hz, 3H), of 3.80 (s, 3H), 3,82 (s, 6H), 3,99-4,12 (m, 2H), 4,13-4,19 (m, 1H), 6,63 (s, 2H)
Intermediate compound 17(600 MHz, CDCl3) δ ppm: 1,39 (t, J=7,3 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), 2,12 (s, 3H), and 2.26 (s, 6N), 3,96-4,07 (m, 2H), 4,14 (kV, J=6,6 Hz, 1H), 6,97 (2N)
Intermediate compound 18(600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,3 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), 2,30 (C, 6N), 3,94-4,08 (m, 2H), 4,15 (kV,J=6,9 Hz, 1H), for 6.81 (s, 1H), 6,95 (2N)

Intermediate compound 19(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,3 Hz, 3H), and 1.63 (d, J=6.9 Hz, 3H), 3,81 (C, 6N), 4,00-4,12 (m, 2H), 4,20 (kV, J=6,7 Hz, 1H), 6,33 (s, 1H), 6,59 (2N)
Intermediate compound 20(600 MHz, CDCl3) δ ppm: 0,95-0,98 (m, 3H), of 1.40 (t, J=7,3 Hz, 3H), 1,43-of 1.52 (m, 2H), and 1.56 (d, J=6.9 Hz, 3H), 1,71-of 1.78 (m, 2H), 3,93 (t, J=6.4 Hz, 2H), 3,97-4,08 (m, 2H), 4,15 (kV, J=6,6 Hz, 1H), 6,85-6,89 (m, 2H), 7.23 percent-7,28 (m, 2H)
The intermediate connection 21(600 MHz, CDCl3) δ ppm: to 1.42 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), 3,99 is 4.13 (m, 2H), 4,17 (kV, J=6,9 Hz, 1H), 6,98-7,05 (m, 4H), 7,07-7,13 (m, 1H), 7,29-7,39 (m, 4H)

Intermediate compound 22(600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7,1 Hz, 3H), 1,58 (d, J=6.9 Hz, 3H), 3,99-4,10 (m, 2H), 4,16 (kV, J=6,9 Hz, 1H), of 5.05 (s, 2H), 6,94-7,00 (m, 2H), 7,25-7,31 (m, 2H), 7,31-7,35 (m, 1H), was 7.36-7,41 (m, 2H), 7,41-7,44 (m, 2H)
Intermediate compound 23 (600 MHz, CDCl3) δ ppm: of 1.23 (t, J=7,6 Hz, 3H), of 1.40 (t, J=7,3 Hz, 3H), 1,58 (d, J=6.4 Hz, 3H), 2,64 (kV, J=7.5 Hz, 2H), 3,98-4,11 (m, 2H), 4,16 (kV, J=6,9 Hz, 1H), 7,16-7,31 (m, 4H)
Intermediate compound 24(600 MHz, CDCl3) δ ppm: to 0.94 (t, J=7,3 Hz, 3H), of 1.40 (t, J=7,3 Hz, 3H), 1,54-to 1.67 (m, 5H), 2,53-2,61 (m, 2H), 3,94-4,10 (m, 2H), 4,17 (kV, J=6,4 Hz, 1H), 7,12-7,31 (m, 4H)

Intermediate compound 25(600 MHz, CDCl3) δ ppm: 1,39 (t, J=7,3 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), of 2.35 (s, 3H), of 3.96-4.09 to (m, 2H), 4,14 (kV, J=6,6 Hz, 1H), 7,14 (DD, J=8,7, and 3.7 Hz, 1H), 7,27 (d, J=3.2 Hz, 1H), 7,31 (d, J=8.7 Hz, 1H)
The intermediate connection 26(600 MHz, CDCl3) δ ppm: 1,40 (t, J=7,3 Hz, 3H), and 1.56 (d, J=6.9 Hz, 3H), 3,99-4,10 (m, 2H), 4,14 (kV, J=6,7 Hz, 1H), 6.30-in-6,33 (m, 2H), 6,99-7,03 (m, 2H), 7,34-7,38 (m, 2H), 7,41-7,44 (m, 2H)
Intermediate compound 27(600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,1 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), 2,94 (C, 6N), 3.95 to 4,07 (m, 2H), 4,14 (kV, J=6,9 Hz, 1H), of 6.52 (DD, J=8,7, 2.8 Hz, 1H), 6,60 (DD, J=8,7, 2.3 Hz, 1H), 6,72 (t, J=2.3 Hz, 1H), 7,18 (t, J=8,3 the C, 1H)

The intermediate connection 28(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,1 Hz, 3H), 1,60 (d, J=6.9 Hz, 3H), was 4.02 is 4.13 (m, 2H), 4,19 (kV, J=6,9 Hz, 1H), 7,32-7,37 (m, 1H), 7,40-of 7.48 (m, 4H), 7,55 to 7.62 (m, 4H)
Intermediate compound 29(600 MHz, CDCl3) δ ppm: 1,40 (t, J=7,3 Hz, 3H), of 1.61 (d, J=6.9 Hz, 3H), 4,00-4,12 (m, 2H), 4,17-to 4.23 (m, 1H), 7,19-of 7.23 (m, 1H), 7,37-7,42 (m, 2H)
The intermediate connection 30(600 MHz, CDCl3) δ ppm: to 1.42 (t, J=7,1 Hz, 3H), 1,60 (d, J=6.4 Hz, 3H), 4,01 is 4.13 (m, 2H), 4,17 (kV, J=6,4 Hz, 1H), 7,13-to 7.18 (m, 1H), 7,30-7,34 (m, 1H), 7,51-rate of 7.54 (m, 1H)
The intermediate connection 31(600 MHz, CDCl3) δ ppm: to 0.92 (t, J=7,6 Hz, 3H), 1.30 and the 1.44 (m, 5H), 1,54-to 1.63 (m, 5H), 2,55-of 2.64 (m, 2H), 3,97-4,10 (m, 2H), 4,17 (kV, J=6,6 Hz, 1H), 7,15-7,29 (m, 4H)

The intermediate connection 32(600 MHz, CDCl3) δ ppm: to 1.42 (t, J=7,3 Hz, 3H), 1,60 (d, J=6.9 Hz, 3H),4,00-to 4.15 (m, 2H), 4,18 (kV, J=6,9 Hz, 1H), 7,19-7,28 (m, 2H), 7,39-7,47 (m, 2H)
The intermediate connection 33(600 MHz, CDCl3) δ ppm: 1,39 (t, J=7,3 Hz, 3H), 1,58 (d, J=6.4 Hz, 3H), 3,12-3,19 (m, 4H), 3,79-3,86 (m, 4H), 3.95 to 4.09 to (m, 2H), 4,14 (kV, J=6,7 Hz, 1H), of 6.71 (DD, J=8.0 a, and 2.1 Hz, 1H), 6,79 (DD, J=8,3, 2.3 Hz, 1H), 7,00-7,03 (m, 1H), 7,21-7,25 (m, 1H)
The intermediate connection 34(600 MHz, CDCl3) δ ppm: 1,39 (t, J=7,1 Hz, 3H), and 1.56 (d, J=6.9 Hz, 3H), 2,33 (C, 6N), 2,67 was 2.76 (m, 2H), 3.95 to 4,08 (m, 4H), 4,14 (kV, J=6,6 Hz, 1H), 6,84-6,93 (m, 2H), 7,19-7,31 (m, 2H)

The intermediate connection 35(600 MHz, CDCl3) δ ppm: 1,40 (t, J=7,1 Hz, 3H), and 1.56 (d, J=6.9 Hz, 3H), 2,54 at 2.59 (m, 4H), 2,78 (t, J=5.7 Hz, 2H), 3,71 of 3.75 (m, 4H), 3,98-4,06 (m, 2H), 4,08 (t, J=5.7 Hz, 2H), 4,14 (kV, J=6,6 Hz, 1H), 6,86-of 6.90 (m, 2H), 7,24-7,28 (m, 2H)
Intermediate compound 36(600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), and 2.27 (d, J=1.8 Hz, 3H), 3,98-4,11 (m, 2H), 4,17 (kV, J=6,9 Hz, 1H), 6,95-7,03 (m, 1H), 7,11-7,16 (m, 1H), 7,21-7,24 (m, 1H)
The intermediate connection 37 (200 MHz, CDCl3) δ ppm: 1,00-1,20 (m, 4H), 1,58 (d, J=6.6 Hz, 3H), 2,90-of 3.06 (m, 1H), 3,80 (c, 3H), 4,05-4,32 (m, 1H), 6,38-to 6.95 (m, 2H), 7,20-7,30 (m, 2H)

Intermediate compound 38(600 MHz, CDCl3) δ ppm: 1,23 (d, J=7,3 Hz, 6N), of 1.39 (t, J=7,1 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), 2,86-of 2.93 (m, 1H), of 3.97-4.09 to (m, 2H), 4,15 (kV, J=6,6 Hz, 1H), 7,19-of 7.23 (m, 2H), 7.24 to 7,27 (m, 2H)
The intermediate connection 39(600 MHz, CDCl3) δ ppm: 1,25 (d, J=6,9 Hz, 6N), of 1.41 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.4 Hz, 3H), 2,85-of 2.97 (m, 1H), 3,99-4,10 (m, 2H), 4,16 (kV, J=6,7 Hz, 1H), 7,06-7,10 (m, 1H), 7,13-to 7.18 (m, 1H), 7,20-7,24 (m, 1H), 7,26-7,32 (m, 1H)
The intermediate connection 40(600 MHz, CDCl3) δ ppm: to 1.48 (t, J=7,3 Hz, 3H), of 1.61 (d, J=6.9 Hz, 3H), 4.09 to-4,24 (m, 3H), 7,43 (t, J=8.0 Hz, 1H), 7,51-7,56 (m, 2H), to 7.61 (d, J=6,9 Hz, 1H), 7,68 (d, J=8,3 Hz, 1H), 7,85-of 7.90 (m, 1H), 8,11-8,16 (m, 1H)

The intermediate connection 41(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,3 Hz, 3H), 1,60 (d, J=6,4 Hz, H), as 4.02 is 4.13 (m, 2H), 4,18 (kV, J=6,6 Hz, 1H), 7,41-7,51 (m, 3H), 7,76-a 7.92 (m, 4H)
The intermediate connection 42(600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7,1 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), 2,93 (C, 6N), of 3.96-4.09 to (m, 2H), 4,15 (kV, J=6,9 Hz, 1H), 6,66-6,76 (m, 2H), 7,17-7,25 (m, 2H)
The intermediate connection 43(600 MHz, CDCl3) δ ppm: 1,38-to 1.61 (m, 6N), 4,00-4,19 (m, 3H), 6,69-7,37 (m, 3H)
The intermediate connection 44(600 MHz, CDCl3) δ ppm: 1,40 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), of 2.35 (s, 3H), 2,52-2,61 (m, 4H), 3,22-of 3.27 (m, 4H), 3,97-4,08 (m, 2H), 4,15 (kV, J=6,9 Hz, 1H), of 6.71-to 6.80 (m, 2H), 6,99-7,03 (m, 1H), 7,20-7,25 (m, 1H)

The intermediate connection 45(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,1 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), 2,82 (s, 3H), was 4.02-to 4.14 (m, 2H), 4,18 (kV, J=6,7 Hz, 1H), 7,42 (DD, J=8,7, 2.8 Hz, 1H), to 7.77 (d, J=8.7 Hz, 1H), a 7.85 (d, J=2.3 Hz, 1H)
The intermediate connection 46(200 MHz, CDCl3) δ ppm: of 1.33 to 1.47 (m, 3H), of 1.57 (d,J=7,0 Hz, 3H), 3,03-3,19 (m, 4H), 3,78-to 3.92 (m, 4H), 3.95 to of 4.25 (m, 3H), for 6.81-7,00 (m, 2H), 7.18 in-7,33 (m, 2H)
The intermediate connection 47(200 MHz, CDCl3) δ ppm: 1,34 of 1.46 (m, 3H), 1,48-to 1.82 (m, N), 3,02-3,18 (m, 4H), 3,89-4,27 (m, 3H), 6,88-7,00 (m, 2H), 7,16-7,29 (m, 2H)
The intermediate connection 48(600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7,1 Hz, 3H), of 1.57 (d, J=6.4 Hz, 3H), 1,96-2,03 (m, 4H), 3,23-3,30 (m, 4H), of 3.96-4.09 to (m, 2H), 4,16 (kV, J=6,6 Hz, 1H), 6,47-6,56 (m, 2H), 7,15-7,22 (m, 2H)

The intermediate connection 49(600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7,1 Hz, 3H), of 1.57 (d, J=6.4 Hz, 3H), 1,96-2,03 (m, 4H), 3,23-3,30 (m, 4H), of 3.96-4.09 to (m, 2H), 4,16 (kV, J=6,6 Hz, 1H), 6,47-6,56 (m, 2H), 7,15-7,22 (m, 2H)
The intermediate connection 50(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,1 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), of 2.56 (s, 3H), 4,03-to 4.14 (m, 2H), 4,17 (kV, J=6,6 Hz, 1H), 7,19 (d, J=8.7 Hz, 1H), 7,81 (DD, J=8,7, 2.8 Hz, 1H), charged 8.52 (d, J=3.2 Hz, 1H)
The intermediate connection 513) δ ppm: 1,40 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), of 2.35 (s, 3H), 2,52-2,61 (m, 4H), 3,22-of 3.27 (m, 4H), 3,97-4,08 (m, 2H), 4,15 (kV, J=6,9 Hz, 1H), of 6.71-to 6.80 (m, 2H), 6,99-7,03 (m, 1H), 7,20-7,25 (m, 1H)

The intermediate connection 52(600 MHz, CDCl3) δ ppm: 1,39 (t, J=7,3 Hz, 3H), and 1.63 (d, J=6.9 Hz, 3H), of 3.96-4.09 to (m, 2H), 4,20 (kV, J=6,9 Hz, 1H), 7,13-7,17 (m, 1H), 7,30-7,34 (m, 1H), to 7.77-7,81 (m, 1H), they were 8.22-of 8.25 (m, 1H)
The intermediate connection 53(600 MHz, CDCl3) δ ppm: of 1.46 (t, J=7,3 Hz, 3H), of 1.62 (d, J=6.4 Hz, 3H), 4,06-4,17 (m, 2H), 4,20 (kV, J=6,6 Hz, 1H), of 7.64-to 7.68 (m, 1H), 7,70-7,73 (m, 1H), 7,85-of 7.90 (m, 1H), 8,10-8,13 (m, 1H), charged 8.52-8,54 (m, 1H), 9,19-a 9.25 (m, 1H)
The intermediate connection 54(600 MHz, CDCl3) δ ppm: 1.57 in (d, J=6.9 Hz, 3H), of 2.34 (s, 3H)and 3.59 (s, 3H), 4,16-4,22 (m, 1H), 7,15-to 7.18 (m, 2H), 7,21-7,25 (m, 2H)
The intermediate connection 55(600 MHz, CDCl3) δ ppm: 0,99 (t, J=7,3 Hz, 3H), 1,58 (d, J=6.9 Hz, 3H), 1.77 in-of 1.85 (m, 2H), 2,34 (s, 3H), 3,85-to 3.99 (m, 2H), 4,12 (kV, J=6,9 Hz, 1H), 7,15-to 7.18 (m, 2H), 7,21-7,24 (m, 2H)

The intermediate connection 56(600 MHz, CDCl3) δ ppm: 1,53 is 1.58 (m, N), was 2.34 (s, 3H), 4,20 (kV, J=6,9 Hz, 1H), of 4.66-4.72 in (m, 1H), 7,15-7,19 (m, 2H), 7,21-7,24 (m, 2H)
The intermediate connection 57(200 MHz, CDCl3) δ ppm: 1,31 (t, J=7,3 Hz, 3H), 1,60 (d, J=6.6 Hz, 3H), of 2.28 (s, 3H), 3,60-4,30 (m, 3H), of 6.96-7,02 (m, 4H)
The intermediate connection 58(600 MHz, CDCl3) δ ppm: 1,40 (t, J=7,3 Hz, 3H), 1,58 (d, J=6.4 Hz, 3H), of 2.34 (s, 3H), 3,99-4.09 to (m, 2H), 4,16 (kV, J=6,4 Hz, 1H), 7,15-7,19 (m, 2H), 7,22-7,25 (m, 2H)
The intermediate connection 59(600 MHz, CDCl3) δ ppm: the 1.44 (t, J=7,1 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), was 4.02 is 4.13 (m, 2H), 4,17 (kV, J=6,6 Hz, 1H), 6,44-6,47 (m, 1H),? 7.04 baby mortality-was 7.08 (m, 1H), 7,15-7,25 (m, 2H), 7,50-EUR 7.57 (m, 1H), 8,72 (s, 1H)

The intermediate connection 60(600 MHz, CDCl3) δ ppm: to 1.42 (t, J=7,1 Hz, 3H), 1,58 (d, J=6.4 Hz, 3H), 3,98-4,10 (m, 2H), 4,15 (kV, J=6,7 Hz, 1H), 6.30-in-to 6.39 (m, 1H), 6.87 in-7,00 (m, 2H), 7,39-7,52 (m, 2H), of 9.55 (s, 1H)
The intermediate connection 61(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), of 2.34 (s, 3H), 3,99-4,12 (m, 2H), 4,16 (kV, J=6,9 Hz, 1H), 6,03-6,13 (m, 1H), 6,86-7,07 (m, 2H), 7,28-7,37 (m, 1H), 8,76 (s, 1H)
The intermediate connection 62(600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,1 Hz, 3H), of 1.61 (d, J=6.9 Hz, 3H), 2.40 a (s, 3H), 3.96 points-4,07 (m, 2H), 4,23 (kV, J=6,9 Hz, 1H), 6,95-6,97 (m, 1H), 7,13-to 7.15 (m, 1H), 8.07-a of 8.09 (m, 1H)

The intermediate connection 63(600 MHz, CDCl3) δ ppm: 1,36-of 1.45 (m, 3H), 1,60-1,70 (m, 3H), 2,32 (s, 3H), 3.96 points-4,10 (m, 2H), 4,16-4,27 (m, 1H), 7,22-7,27 (m, 1H), 7,56-7,66 (m, 1H), 8,02-8,10 (m, 1H)
The intermediate connection 64(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.4 Hz, 3H), at 2.59 2.63 in (m, 2H), 2,92-to 2.99 (m, 2H), 4,00-4,11 (m, 2H), 4,18 (kV, J=6,4 Hz, 1H), 6,80-6,84 (m, 1H), 7,11-7,16 (m, 1H), 7,21-7,25 (m, 1H), 8,28-8,72 (m, 1H)
The intermediate connection 65(600 MHz, CDCl3) δ ppm: to 1.35 (t, J=7,3 Hz, 3H), and 1.54 (d, J=6.9 Hz, 3H), 3,76 (s, 3H), 3,9-of 4.05 (m, 2H), 4,11 (kV, J=6,4 Hz, 1H), 6,69 (DD, J=8,3, 2.3 Hz, 1H), 6.87 in (DD, J=8,3, 2.3 Hz, 1H), 6,92 (t, J=2.3 Hz, 1H), 7.18 in-7,24 (m, 1H)

Intermediate compound 66(600 MHz, CDCl3) δ ppm: 1.14 in (t, J=7,1 Hz, 6N), to 1.38 (t, J=7,3 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), 3,32 (kV, J=6,9 Hz, 4H), 3.95 to 4,07 (m, 2H), 4,11-4,17 (m, 1H), 6,46 (DD, J=8,7, 2.3 Hz, 1H), 6,50 (DD, J=8,0, 2.5 Hz, 1H), 6,67 (t, J=2.5 Hz, 1H), 7,14 (t, J=8,3 Hz, 1H)
The intermediate connection 67(600 MHz, CDCl3) δ ppm: 1,39 (t, J=7,3 Hz, 3H), of 1.62 (d, J=6.4 Hz, 3H), of 2.45 (s, 3H), of 3.97-4.09 to (m, 2H), 4,19 (kV, J=6,4 Hz, 1H), 6,98-7,01 (m, 1H), 7,13-7,16 (m, 1H), of 7.64-to 7.67 (m, 1H)
The intermediate connection 68(600 MHz, CDCl3) δ ppm: 1,45 (t, J=7,3 Hz, 3H), of 1.62 (d, J=6.9 Hz, 3H), 4,05-to 4.15 (m, 2H), 4,20 (kV, J=6,9 Hz, 1H), 7,37-7,41 (m, 1H), 7,65-to 7.68 (m, 1H), 7,84-7,88 (m, 1H), 7,94-of 7.96 (m, 1H), 8,14-8,19 (m, 1H), 8,90-8,93 (m, 1H)

The intermediate connection 69(600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,1 Hz, 3H), 1,53 is 1.60 (m, 5H), 1,64-1,71 (m, 4H), 3.95 to 4,07 (m, 2H), 4,14 (kV, J=6,7 Hz, 1H), 6,69-6,74 (m, 2H), 6,95 (t, J=2,5 Hz, 1H), 7,19 (t, J=8,3 Hz, 1H)
The intermediate connection 70(600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7,1 Hz, 3H), 1,58 (d, J=6.9 Hz, 3H), 2.57 m-2,61 (m, 2H), 2,89-of 2.93 (m, 2H), 3,99-4,11 (m, 2H), 4,17 (kV, J=6,9 Hz, 1H), 6.90 to-6,97 (m, 2H), 7,11-to 7.15 (m, 1H), 8,66 (s, 1H)
The intermediate connection 71(600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,3 Hz, 3H), 1,58 (d, J=6.9 Hz, 3H), 2,30-2,39 (m, 2H), 3,85-to 3.89 (m, 4H), 3,94-4,06 (m, 2H), 4,15 (kV, J=6,6 Hz, 1H), from 6.22 to 6.25 (m, 1H), gold 6.43 (t, J=2.3 Hz, 1H), 6,59-6,63 (m, 1H), 7,15 (t, J=8.0 Hz, 1H)

The intermediate connection 72(600 MHz, CDCl3) δ ppm: 1,24 (d, J=6,4 Hz, 6N), of 1.39 (t, J=7,3 Hz, 3H), 1,58 (d, J=6.9 Hz, 3H), 2,39 is 2.46 (m, 2H), 3,42-of 3.46 (m, 2H), of 3.73-3,81 (m, 2H), of 3.97-4.09 to (m, 2H), 4,15 (kV, J=6,9 Hz, 1H), of 6.71 (DD, J=8.0 a, 2,1 Hz, 1H), 6,76 (DD, J=8,5, and 2.1 Hz, 1H), 6,98 (t, J=2.3 Hz, 1H), 7,22 (t, J=8,3 Hz, 1H)
The intermediate connection 73(600 MHz, CDCl3) δ ppm: to 1.42 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), 3,92 (s, 3H), was 4.02 is 4.13 (m, 2H), 4,16 (kV, J=6,9 Hz, 1H), 6.90 to (s, 1H)
The intermediate connection 74 (600 MHz, CDCl3) δ ppm: 1,45 (t, J=7,3 Hz, 3H), and 1.63 (d, J=6.4 Hz, 3H), 4,06-4,17 (m, 2H), 4,18-to 4.23 (m, 1H), 7,39-7,44 (m, 1H), 7,65-7,71 (m, 1H), 8,02-with 8.05 (m, 1H), 8,11-8,16 (m, 2H), 8,88-8,91 (m, 1H)

The intermediate connection 75(600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,1 Hz, 3H), of 1.57 (d, J=6.4 Hz, 3H), 1,94-2,02 (m, 4H), 3,22-3,29 (m, 4H), 3.95 to 4,07 (m, 2H), 4,10-4,19 (m, 1H), 6,36 (DD, J=8,2 2,3 Hz, 1H), 6,50-6,56 (m, 2H), 7,16 (t, J=8,3 Hz, 1H)
The intermediate connection 76(600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,3 Hz, 3H), of 1.61 (d, J=6.9 Hz, 3H), 2,53 (C, 6N), 3,98-4,11 (m, 2H), 4,18 (kV, J=6,9 Hz, 1H), 7,05 (2N)
The intermediate connection 77(600 MHz, CDCl3) δ ppm: of 1.46 (t, J=7,1 Hz, 3H), and 1.63 (d, J=6.9 Hz, 3H), 4,07-4,24 (m, 3H), 7,63-the 7.65 (m, 1H), 8,00-8,03 (m, 1H), 8,11-8,13 (m, 1H)
The intermediate connection 78(600 MHz, CDCl3) δ ppm: to 1.37 (t, J=7,1 Hz, 3H), 1,58 (d, J=6.9 Hz, 3H), 3.96 points-of 4.05 (m, 2H), 4,15 (kV, J=6,7 Hz, 1H), 6,45-6,50 (m, 1H), 6,62 is 6.67 (m, 1H), of 6.71-6.75 in (m, 1H), 7,11 (t, J=8.0 Hz, 1H)

The intermediate connection 79(600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,1 Hz, 3H), 1,58 (d, J=6.9 Hz, 3H), and 2.27 (s, 6N), 2,45-of 2.56 (m, 4H), 2,58-2,63 (m, 4H), 3,20-3,24 (m, 4H), 3.95 to 4,07 (m, 2H), 4,11-4,17 (m, 1H), 6,68-of 6.78 (m, 2H), 6,95-6,98 (m, 1H), 7,21 (t, J=8,3 Hz, 1H)
The intermediate connection 80(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,1 Hz, 3H), 1,60 (d, J=6.9 Hz, 3H), was 4.02-to 4.15 (m, 2H), 4,15-4,22 (m, 1H), 7.18 in-7,20 (m, 1H), 7,22-7,25 (m, 1H), 7,28-7,30 (m, 1H), 7,38-7,41 (m, 1H), 7,46-7,51 (m, 1H), 7,54-EUR 7.57 (m, 1H), the 7.85-7,89 (m, 1H)
The intermediate connection 81(600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,3 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), 1,77 of-1.83 (m, 4H), 3.27 to to 3.36 (m, 4H), 3.95 to 4,06 (m, 6N), 4,14 (kV, J=6,9 Hz, 1H), 6,70 to 6.75 (m, 2H), 6,97 (t, J=2.3 Hz, 1H), 7,20 (t, J=8,3 Hz, 1H)

The intermediate connection 82(600 MHz, CDCl3) δ ppm: of 1.42 to 1.47 (m, 3H), of 1.62 (DD, J=6,65, to 2.06 Hz, 3H), 4,05-4,17 (m, 2H), 4,17-4,22 (m, 1H), 7.24 to 7,28 (m, 1H), of 7.48-to 7.61 (m, 2H), 7,66 (s, 1H), charged 8.52 (s, 2H)
The intermediate connection 83/td> (600 MHz, CDCl3) δ ppm: 1,07 (d, J=6,9 Hz, 6N), to 1.38 (t, J=7,3 Hz, 3H), of 1.57 (d, J=6.4 Hz, 3H), 2,62-to 2.67 (m, 4H), 2,67-to 2.74 (m, 1H), 3,19-3,24 (m, 4H), 3.96 points-4,08 (m, 2H), 4,14 (kV, J=6,7 Hz, 1H), of 6.71 (DD, J=8,3, 2.3 Hz, 1H), to 6.75 (DD, J=8,3, 2.3 Hz, 1H), 6,97 (t, J=2.3 Hz, 1H), 7,21 (t, J=8,3 Hz, 1H)
The intermediate connection 84(600 MHz, CDCl3) δ ppm: to 1.38 (t, J=7,3 Hz, 3H), of 1.61 (d, J=6.9 Hz, 3H), of 2.33 (s, 3H), 2.40 a (s, 3H), of 3.97-4.09 to (m, 2H), 4,18 (kV, J=6,9 Hz, 1H), 6,82-6,83 (m, 1H), 6,97-6,98 (m, 1H)

The intermediate connection 85(600 MHz, CDCl3) δ ppm: 1.30 on to 1.76 (m, 6H), of 2.56 (s, 3H), 2,68 (s, 3H), 4,08-4,19 (m, 3H), 6,59 (s, 1H), 6.73 x (s, 1H)
The intermediate connection 86(600 MHz, CDCl3) δ ppm: 1.26 in (d, J=6.9 Hz, 6H), of 1.40 (t, J=7,3 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), 2,87-to 2.94 (m, 1H), and 3.72 (s, 3H), 3,99-4,11 (m, 2H), 4,14 (kV, J=6,9 Hz, 1H), and 6.25 (s, 1H)
The intermediate connection 87(600 MHz, CDCl3) δ ppm: 1,39 (t, J=7,3 Hz, 3H), of 1.57 (d, J=6.9 Hz, 3H), 3,34 (C, 6N), 3,50 is 3.57 (m, 8H), 3.96 points-4,07 (m, 2H), 4,15 (kV, J=6,6 Hz, 1H), 6,51 (DD, J=8,5, 2.5 Hz, 1H), 6,56 (DD, J=7,8, and 2.3 Hz, 1H), 6,69(t, J=2.3 Hz, 1H), 7,15 (t, J=8,3 Hz, 1H)

The intermediate connection 88(600 MHz, CDCl3) δ ppm: 1,36-of 1.41 (m, 3H), of 1.57 (d, J=6.9 Hz, 3H), 2,28 (C, 6N), 2,45-of 2.50 (m, 2H), equal to 2.94 (s, 3H), 3,39-of 3.48 (m, 2H), 3,94-4,08 (m, 2H), 4,14 (kV, J=6,9 Hz, 1H), 6,50 (DD, J=8,3, 2.3 Hz, 1H), return of 6.58 (DD, J=8,3, 2.3 Hz, 1H), 6,67 (t, J=2.5 Hz, 1H), 7,16 (t, J=8,3 Hz, 1H)
The intermediate connection 89(600 MHz, CDCl3) δ ppm: 1,39 (t, J=7,1 Hz, 3H), of 1.59 (d, J=6.4 Hz, 3H), of 2.34 (s, 6H), by 2.73 (t, J=5.7 Hz, 2H), 3,98-4.09 to (m, 4H), 4,16 (kV, J=6,4 Hz, 1H), 6.75 in-6,77 (m, 1H), 6,91-6,93 (m, 1H) 6,98-7,00 (m, 1H), 7.24 to 7,27 (m, 1H)
The intermediate connection 90(600 MHz, CDCl3) δ ppm: 1,25 (d, J=6.9 Hz, 12H), of 1.40 (t, J=7,1 Hz, 3H), 1,58 (d, J=6.9 Hz, 3H), 3,76-of 3.85 (m, 2H), 3.96 points-4,08 (m, 2H), 4,15 (kV, J=6,9 Hz, 1H), 6,57-6,70 (m, 2H), 6,88-6,93 (m, 1H), 7,10-7,17 (m, 1H)

The intermediate connection 91(600 MHz, CDCl3) δ ppm: 1,06 (d, J=6.42 per Hz, 6N), of 1.39 (t, J=7,3 Hz, 3H), 1,58 (d, J=6.9 Hz, 3H), 1,68-1,89 (m, 4H), 2,17 was 2.25 (m, 2H), 2,44 of $ 2.53 (m, 1H), 2,70-2,77 (m, 1H), 2,94-3,03 (m, 2H), 3.96 points-4,08 (m, 2H), 4,5 (kV, J=6,6 Hz, 1H), 7.03 is-7,07 (m, 1H), 7,15-7,22 (m, 2H), 7,28 (t, J=8.0 Hz, 1H)
The intermediate compound 92(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,1 Hz, 3H), 1,58-of 1.62 (m, N), 4,01 is 4.13 (m, 2H), 4,18 (kV, J=6,6 Hz, 1H), 7,42-7,46 (m, 1H), to 7.61-the 7.65 (m, 1H), 7,82-a 7.85 (m, 1H), 7,87-to $ 7.91 (m, 1H)
The intermediate connection 93(600 MHz, DMSO-d6) δ ppm: of 1.23 (t, J=7,3 Hz, 3H), and 1.54 (d, J=6.9 Hz, 3H), 3,82-4.09 to (m, 2H), 4,60 (kV, J=6.0 Hz, 1H), 6,61-6,69 (m, 2H), 6,70-6,77 (m, 1H), 7,14-7,21 (m, 1H), 8,28-9,11 (m, 2H), 9,43-10,55 (m, 1H)

The intermediate connection 94(600 MHz, CDCl3) δ ppm: 1,39 (t, J=7,3 Hz, 3H), 1,60 (d, J=6.4 Hz, 3H), of 3.96-4.09 to (m, 2H), 4,17 (kV, J=6,9 Hz, 1H), is 5.06 (s, 2H), 6,79-6,84 (m, 1H), 6,91-of 6.96 (m, 1H),? 7.04 baby mortality-was 7.08 (m, 1H), 7,22-7,46 (m, 6N)
The intermediate connection 95(200 MHz, CDCl3) δ ppm: of 1.34 (t, J=7,3 Hz, 3H), of 1.61 (d, J=6.8 Hz, 3H), 3,80-to 4.23 (m, 3H), 5,96 (users, 1H), 6,88-7,05 (m, 2H), 7,08-7,25 (m, 2H)
The intermediate connection 96(60 MHz, CDCl3) δ ppm: 1,42-of 1.66 (m, N), 4,06-4,20 (m, 5H), 7,01-7,05 (m, 1H), 7.24 to 7,26 (m, 1H), 7,62-of 7.69 (m, 2H)
The intermediate connection 97(600 MHz, CDCl3) δ ppm: 1,02-of 1.16 (m, 4H), to 1.59 (d, J=6.9 Hz, 3H), of 2.35 (s, 3H), 2,52-2,61 (m, 4H), 2,92-a 3.01 (m, 1H), 3,21-of 3.25 (m, 4H), 4,24 (kV, J=6,6 Hz, 1H), 6,68 to 6.75 (m, 2H), 6,94-6,98 (m, 1H), 7,19-7,25 (m, 1H)

The intermediate connection 98(600 MHz, CDCl3) δ ppm: 1,03-of 1.18 (m, 4H), to 1.59 (d, J=6,9 Hz, 2H), 2,98 totaling 3.04 (m, 1H), 4,25 (kV, J=6,6 Hz, 1H),? 7.04 baby mortality-7,10 (m, 2H), 7,30-7,35 (m, 2H)
The intermediate connection 99(600 MHz, CDCl3) δ ppm: 0,98-1,20 (m, 4H), to 1.59 (d, J=6.9 Hz, 3H), 2.93 which was 3.05 (m, 1H), 4,22-or 4.31 (m, 1H), 6,33-6,44 (m, 1H), 6.90 to-7,05 (m, 2H), 7,31-the 7.43 (m, 1H), 7,46-of 7.55 (m, 1H), remaining 9.08-to 9.32 (m, 1H)
The intermediate connection 100(200 MHz, CDCl3) δ ppm: 1,02 (t, J=7.5 Hz, 3H), of 1.39 (t, J=7,3 Hz, 3H), 1,68 (users, 2H), 1,91 with 2.14 (m, 2H), 2,34 (s, 3H), 3,90 (t, J=6,4 Hz, 1H), 4,03 (kV, J=7,3 Hz, 2H), 7,16 (d, J=8.1 Hz, 2H), 7,24 (d, J=8.1 Hz, 2H)

The ex is offered by the connection 101 (200 MHz, CDCl3) δ ppm: to 0.96 (d, J=6.8 Hz, 3H), of 1.07 (d, J=6.8 Hz, 3H), of 1.39 (t, J=7,3 Hz, 3H), 1,71 (users, 2H), 2.06 to of 2.24 (m, 1H), 2,34 (s, 3H), of 3.69 (d, J=7.5 Hz, 1H), 4,01 (kV, J=7,3 Hz, 2H), 7,16 (d, J=8.6 Hz, 2H), 7,25 (d, J=8.6 Hz, 2H)
The intermediate connection 102(200 MHz, CDCl3) δ ppm: 1,01 (t, J=7,3 Hz, 3H), of 1.39 (t, J=7,3 Hz, 3H), 1.70 to 2,11 (m, 2H), 2,35 (s, 3H), of 2.56 (t, J=5.0 Hz, 4H), 3,24 (t, J=5.0 Hz, 4H), to 3.89 (t, J=7,3 Hz, 1H), was 4.02 (q, J=7,3 Hz, 2H), 6,74 (dt, J=2,4, an 8.4 Hz, 2H), 7,02 (t, J=2.4 Hz, 1H), 7,22 (t, J=8,4 Hz, 1H)
The intermediate connection 103(600 MHz, CDCl3) δ ppm: of 1.41 (t, J=7,3 Hz, 3H), of 1.59 (d, J=6.4 Hz, 3H), of 2.36 (s, 3H), 2,55-to 2.65 (m, 4H), 3,11-3,19 (m, 4H), 3,98-4,19 (m, 3H), 6.87 in-6,92 (m, 1H), of 6.96? 7.04 baby mortality (m, 2H)

The intermediate connection 104(600 MHz, CDCl3) δ ppm: to 1.42 (t, J=6.9 Hz, 3H), of 1.62 (s, 6H), or 4.31 (q, J=6.9 Hz, 2H),? 7.04 baby mortality-to 7.09 (m, 2H), 7,34-7,40 (m, 2H)
The intermediate connection 105(600 MHz, CDCl3) δ ppm: 1,40 (t, J=7,1 Hz, 3H), of 1.59 (d, J=6.9 Hz, 3H), 2,98 totaling 3.04 (m, 4H), 3,14-3,19 (m, 4H), of 3.97-4.09 to (m, 2H), 4,13-4,18 (m, 1H), 6,70-to 6.80 (m, 2H), 6,97-7,03 (m, 1H), 7,21-7,26 (m, 1H)
The intermediate connection 106(600 MHz, CDCl3) δ ppm: to 1.35 (t, J=7,3 Hz, 3H), 1,72 (d, J=6.4 Hz, 3H), 2,12 (s, 3H), 3,14 is 3.23 (m, 4H), 3,57-to 3.64 (m, 2H), 3,71-of 3.77 (m, 2H), a 3.87-4,10 (m, 2H), 4,57-of 4.66 (m, 1H), 6,70-for 6.81 (m, 2H), 6,95-6,99 (m, 1H), 7,21-7,26 (m, 1H)
The intermediate connection 107(200 MHz, CDCl3) δ ppm: 0,94-1,08 (m, 2H), 1,22 to 1.31 (m, 2H), 1,47 (t, J=7,1 Hz, 3H), 4,18 (kV, J=7,1 Hz, 2H), 6,98-to 7.15 (m, 2H), 7,29-7,42 (m, 2H)

The intermediate connection 108(600 MHz, CDCl3) δ ppm: USD 1.43 (t, J=7,3 Hz, 3H), 3,97-4,11 (m, 2H), 4,47-of 4.54 (m, 1H), 7,06 for 7.12 (m, 2H), 7,35-7,40 (m, 2H)
The intermediate connection 109(200 MHz, CDCl3) δ ppm: of 1.41 (t, J=7.5 Hz, 3H), 3,62 (DD, J=4,8, and 11.8 Hz, 1H), 3,88 (DD, J=4,8, and 11.8 Hz, 1H), 4,05 (kV, J=7.5 Hz, 2H), 4,51-4,60 (m, 1H),? 7.04 baby mortality-7,13 (m, 2H), 7.23 percent-7,31 (m, 3H), 7,53 (d, J=8,8 Hz, 1H), of 7.70 (DD, J=of 8.8 and 2.2 Hz, 1H), to 7.93 (d, J=2.2 Hz, 1H)

Industrial applicability

Since the compounds of the present invention are PR is excellent ligands Edg-1 (S1P 1), they can be used as drugs for the treatment or prevention of autoimmune diseases, such as Crohn's disease, allergic colitis, Sjogren syndrome, multiple sclerosis and systemic lupus erythematosus, and diseases such as rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis and age related macular degeneration.

1. The compound represented by formula (I)
Formula 1
,
or its pharmaceutically acceptable salt,
where And denotes:
an oxygen atom,
a sulfur atom,
the group represented by the formula-CH2-or
the group represented by the formula-NR6-where R6denotes a hydrogen atom;
R1means:
alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or more substituents selected from the group consisting of:
the halogen atom and phenyl group;
R1Ameans:
a hydrogen atom or
alkyl group having from 1 to 6 carbon atoms;
R1and R1Aoptional form together with the carbon atom that is attached to the specified R1and R1A, cycloalkyl group having from 3 to 6 carbon atoms;
R2means:
alkyl group having from 1 to 6 atomo the carbon or
cycloalkyl group having from 3 to 6 carbon atoms;
R3is:
2-naftilos group, 3-pyrazolidine group, optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, and triptorelin group, or
5-benzothiazolyl group, 5-benzothiadiazole group, 7-dihydrohelenalin group, 7-ethanolamines group, 7-hyalinella group, 3-peredelnoj group or indolines group, each of which is optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms, unsubstituted phenyl group or substituted phenyl group (A), (B) or (C)described below:
(A) a phenyl group substituted in position 4 by a Deputy selected from the group consisting of:
alkyl groups having from 1 to 6 carbon atoms,
cycloalkyl group having from 3 to 8 carbon atoms,
alkoxygroup having from 1 to 6 carbon atoms, this alkoxygroup optionally substituted by one or more substituents selected from the group consisting of amino group substituted with two alkyl groups having from 1 to 4 carbon atoms each, morpholinopropan, and phenyl groups,
the halogen atom,
cryptometer,
fenoxaprop,
phenyl group,
1-pyrrolidino group and
-NRARBwhere each of RAand RInis an alkyl group having from 1 to 6 carbon atoms, or RAand RBthe place with the nitrogen atom to which is attached the specified RARBform a 3-to 5-membered saturated hydrocarbon ring,
where specified phenyl group substituted in the 4 position, further optionally substituted in position 3 by a Deputy selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atom and alkoxygroup having from 1 to 6 carbon atoms;
(B) a phenyl group substituted in the 3 position by a Deputy selected from the group consisting of:
hydroxyl group,
alkyl groups having from 1 to 6 carbon atoms,
alkoxygroup having from 1 to 6 carbon atoms, this alkoxygroup optionally substituted amino group substituted with two alkyl groups having from 1 to 4 carbon atoms each,
where specified phenyl group substituted in the 3 position, further optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, or further optionally substituted in the 4 position by a halogen atom; and
(C) a phenyl group substituted in the 3 position by a Deputy selected from the group consisting of nitrogen-containing groups (i)to(v)described below, indicated anilina the group further optionally substituted in the 4 position with a halogen atom:
(i) a monocyclic saturated hydrocarbon group having 2 to 7 carbon atoms and having one or more nitrogen atoms as ring atoms, which is optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,
(ii) imidazolidine group, pyrrolidine group or thiazolidine group,
(iii) morpholinyl group, optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,
(iv) piperazinone, optionally substituted alkanoyloxy group having 2 to 7 carbon atoms, or alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or more substituents selected from the group consisting of:
amino group substituted by two alkyl groups having from 1 to 4 carbon atoms each, and
morpholinopropan, and
(v) the group represented by the formula-NR7R8,
where each of R7and R8means:
a hydrogen atom,
alkyl group having from 1 to 6 carbon atoms and optionally substituted by amino, which is optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, or alkoxygroup having from 1 to 6 carbon atoms,
alkanoyloxy group having from 1 to 6 carbon atoms,
karbamoilnuyu group, long is Ino substituted by one or more alkyl groups, having from 1 to 4 carbon atoms each,
morpholinosydnonimine group,
aminosulfonyl group, optionally substituted by one or more alkyl groups having from 1 to 4 carbon atoms each, or
alkylsulfonyl group having from 1 to 6 carbon atoms, or
R7and R8optional form together with the nitrogen atom to which they are attached, a 3-8-membered saturated hydrocarbon ring, which may also be substituted by one or more substituents selected from the group consisting of dimethylaminopropyl, the carbonyl group and hydroxyl group;
R4denotes a hydrogen atom;
R5is:
alkyl group having from 1 to 6 carbon atoms and substituted naftilos group,
alkenylphenol group having from 2 to 6 carbon atoms and a substituted phenyl group,
unsubstituted phenyl group,
phenyl group substituted by 1 to 5 substituents selected from the group consisting of methyl group, metoxygroup and halogen atom,
phenyl group substituted by from 1 to 3 substituents selected from the group consisting of:
alkyl groups having from 1 to 6 carbon atoms,
the halogen atom,
metoxygroup,
cryptometer,
dipterocarp,
triptorelin group,
alkenylphenol group having from 1 to 6 carbon atoms,br/> methylsulfonyl group,
acetyl group,
methoxycarbonyl group and
ceanography,
specified phenyl group substituted in position 3 or 4, or both;
naftilos group, optionally substituted by one or more substituents selected from the group consisting of:
the halogen atom,
alkyl groups having from 1 to 6 carbon atoms,
ceanography and
alkylsulfonyl group having from 1 to 6 carbon atoms, or
unsubstituted benzothiazole group, benzodioxolyl group, dihydroergotoxine group, dihydrobenzofuranyl group, indanernas group or 5-benzothiadiazole group, each of which is optionally substituted by one or more substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, and halogen atom.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where a is an oxygen atom.

3. The compound according to claim 1 or its pharmaceutically acceptable salt, where a is a group represented by the formula-NH-.

4. The compound according to claim 1 or its pharmaceutically acceptable salt, where
R1is:
alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or more halogen atoms, or
benzyl group; and
R1Ais a hydrogen atom.

5. Soy is inania according to claim 1 or its pharmaceutically acceptable salt, where R1is methyl group or ethyl group, and R1Ais a hydrogen atom.

6. The compound according to claim 1 or its pharmaceutically acceptable salt, where R2is an ethyl group or cyclopropene group.

7. The compound according to claim 1 or its pharmaceutically acceptable salt, where R5is:
phenyl group substituted in each of the positions 3 and 4, a halogen atom, or
naftilos group, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms, and ceanography.

8. The compound according to claim 1 or its pharmaceutically acceptable salt, where R3is a phenyl group substituted in position 3 by a Deputy selected from the group consisting of nitrogen-containing groups (i)to(v)described below, the specified phenyl group is further optionally substituted in position 4 by a halogen atom:
(i) a monocyclic saturated hydrocarbon group having 2 to 7 carbon atoms and having one or more nitrogen atoms as ring atoms, optionally substituted by one or more alkyl groups having from 1 to 6 carbon atoms,
(ii) imidazolidine group, pyrrolidine group or thiazolidine group,
(iii) morpholinyl group, optionally substituted one or more Alki the implementing groups, having from 1 to 6 carbon atoms,
(iv) piperazinone, optionally substituted alkanoyloxy group having 2 to 7 carbon atoms, or alkyl group having from 1 to 6 carbon atoms and optionally substituted by one or more substituents selected from the group consisting of:
amino group substituted by two alkyl groups having from 1 to 4 carbon atoms each, and
morpholinopropan, and
(v) the group represented by the formula-NR7R8where:
each of R7and R8means:
a hydrogen atom,
alkyl group having from 1 to 6 carbon atoms and optionally substituted by amino, which is optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, or alkoxygroup having from 1 to 6 carbon atoms, alkanoyloxy group having from 1 to 6 carbon atoms, karbamoilnuyu group, optionally substituted by one or two alkyl groups having from 1 to 4 carbon atoms each, morpholinosydnonimine group,
aminosulfonyl group, optionally substituted by one or two alkyl groups having from 1 to 6 carbon atoms each, or
alkylsulfonyl group having from 1 to 6 carbon atoms, or
R7and R8optional form together with the nitrogen atom to which they are attached, 3-8-members of the Noah saturated hydrocarbon ring, optionally substituted by one or more substituents selected from the group consisting of dimethylaminopropyl, the carbonyl group and hydroxyl group.

9. The compound according to claim 1 or its pharmaceutically acceptable salt, where R3is a phenyl group substituted in position 4 by a fluorine atom or a chlorine atom.

10. The compound according to claim 1 or its pharmaceutically acceptable salt, where R3is 6-indolines group.

11. Pharmaceutical composition having inhibitory effect on the binding between sphingosine-1-FORATOM and its receptor Edg-1, containing a compound according to claim 1 or its pharmaceutically acceptable salt.

12. The pharmaceutical composition according to claim 11 for the treatment of autoimmune diseases such as Crohn's disease, allergic colitis, Sjogren syndrome, multiple sclerosis and systemic lupus erythematosus, rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis, or age related macular degeneration.

13. The compound represented by formula (II)
Formula (II)

or its salt, where R1, R1A, R2and R3defined as in claim 1, and A' represents an oxygen atom or NH.

14. The connection 13 or its salt, where in the formula (II):
A' represents an oxygen atom.

Are the s on item 13 or its salt, where in the formula (II):
A' denotes NH.

Are according to item 13 or its salt, where
R1is an alkyl group having from 1 to 6 carbon atoms, and optionally substituted by one or more halogen atoms, or benzyl group; and
R1Ais a hydrogen atom.

17. The compound according to any one of p-15 or its salt, where R1is methyl group or ethyl group, and R1Ais a hydrogen atom.

18. The compound according to any one of p-16 or its salt, where R2is ethyl or cyclopropene group.



 

Same patents:

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with the general formula (I) in the racemic, enantiomeric form or in any combination of these forms and in which: A represents -CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-; X represents -CH-; Ra and Rb independently represent the hydrogen atom or a radical (C1-C6)alkyl; Rj represents the atom of hydrogen; a radical (C1-C8)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; R2 represents a radical (C1-C8)alkyl not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; each X1 independently represents (C1-C6)alkoxy, (C3-C7)cycloalkyl or heteroaryl, and radicals (C3-C7)cycloalkyl, aryl and heteroaryl are not necessarily replaced by one or more either identical or various assistants chosen from: -(CH2)n'-V1-Y1, halogen and; V1 represents -O-, -S- or a covalent bond; Y1 represents a radical (C1-C6)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; n represents an integer from 0 up to 6 and n ' - an integer from 0 up to 2 that if n is equal 0 then X1 does not represent a radical alkoxy); or R1 and R2 form together with the atom of nitrogen to which they are attached, heterobicycloalkyl or heterocycloalkyl, are not necessarily replaced by one or more either identical or various substitutes chosen from: hydroxy, (C1-C6)alkyl, not necessarily substituted by hydroxy, (C1-C6)alkoxycarbonyl, heterocycloalkyl and-C(O)NV1'Y1', in which V1' and Y1' independently represent the atom of hydrogen or (C1-C6)alkyl; or R1 and R2 together form a radical of the formula: R3 represents-Z3, -C(RZ3)(R'Z3)-Z3, -C(RZ3)(R'Z3)-(CH2)p-Z3 or -C(O)Z'3; RZ3 and R'Z3 independently represent atom of hydrogen or a radical (C1-C6)alkyl; Z3 represents Z3b, Z3c, Z3d or Z3e; Z3b represents (C1-C6)alkoxy, (C1-C6)alkythio, (C1-C6)alkylamino, or a radical di((C1-C6)alkyl) amino; Z3c represents aryl or a radical heteroaryl; Z3d represents C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di((C1-C6)alkyl) aminocarbonyl, (C1-C6)alkyl-C(O)NH-, (C3-C7) cycloalkyl, heterocycloalkyl; and radicals (C3-C7) cycloalkyl and heterocycloalkyl are not necessarily replaced by one or more either identical or various substitutes chosen from: (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl and oxy, radicals aryl and heteroaryl are not necessarily replaced by one or more either identical or various substitutes chosen from: halogen, cyanogen, nitro, azide, oxy, (C1-C6)alkylcarbonyl-(C1-C6)alkenyl, (C1-C6)alkylaminocarbonyl-(C1-C6)alkenyl, -SO2-NR31R32, heterocycloalkyl, heteroaryl or -(CH2)P'-V3-Y3; R31 and R32 form together with atom of nitrogen to which they are attached, heterocycloalkyl, V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -O-C(O)-, -SO2-, -SO2NH-, -NR'3-SO2-, -NR'3-, -NR'3-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or covalent bonds; Y3 represents the atom of hydrogen; radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; radical aryl or a radical aryl-(C1-C6)alkyl; Z3e represents a radical of the formula

, Z'3 represents a radical aryl, not necessarily replaced by one or more oreither identical or various substitutes chosen from: halogen, nitro and -(CH2)P"-V'3-Y'3; V'3 represents -O-, -C(O)-, -C(O)-O, -C(O)-NR'3-,-NH-C(O)-NR'3- or covalent bonds; Y'3 represents the atom of hydrogen or a radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; R'3 represents the atom of hydrogen (C1-C6)alkyl or a radical (C1-C6)alkoxy; p represents an integer from 1 up to 4; p' and p" independently represent an integer from 0 up to 4; R4 represents a radical of the formula -(CH2)S-R'4; R'4 represents a radical guanidine; heterocycloalkyl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or aralkyl; heteroaryl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or a radical of the formula -NW4W'4; W4 represents an atom of hydrogen or (C1-C8) alkyl; W'4 represents a radical of the formula -(CH2)S-Z4; Z4 represents an atom of hydrogen (C1-C8) alkyl, (C3-C7)cycloalkyl, heteroaryl and aryl; s and s' independently represent an integer from 0 up to 6; and i) if R3 represents -C(O)-Z'3 and R4 represents a radical of the formula -(CH2)S-NW4W'4, and W4 and W'4 independently represent an atom of hydrogen or a radical C1-C6)alkyl, then -(CH2)s represents neither radical ethylene nor radical -(CH2)-CH((C1-C4)alkyl) and ii), if R3 represents -Z3c and Z3c represents phenyl or naphthyl, then phenyl and naphthyl are not substituted by cyanogen; also note that if R3 represents -Z3d, then Z3d, represents only one (C3-C7)cycloalkyl or heterocycloalkyl; or to their pharmaceutically acceptable salts. The invention also relates to the method of obtaining the compounds of the formula (I), to a pharmaceutical composition, and to the application of compounds of the formula (I) and (I ').

EFFECT: obtaining new biologically active compounds on their basis, possessing activity with respect to receptors MC4.

41 cl, 535 ex

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazopyrazines of formula where Q1 and R1 have the values specified in the patent claim, and to their pharmaceutically acceptable salts showing IGF-1R enzyme inhibiting activity and applicable for treatment and/or prevention of various diseases and conditions which are sensitive to tyrosine kinase inhibition.

EFFECT: preparation of the compounds showing IGF-1R enzyme inhibiting activity.

27 cl, 294 ex

Chemical compounds // 2405780

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I): , in which: R1 and R2 are independently specified from hydrogen, C1-6alkyl, C1-6alkoxy and cyclopropyl; X1, X2 and X3 independently represent =N- or =CR10; R3 and R10 are independently specified from hydrogen, halogen, nitro, cyano, amino, carboxy, carbamoyl, C1-6alkyl, N-(C1-6alkyl)amino, N,N(C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkoxycarbonyl; R4 represents hydrogen; R5 and R6 are independently specified from hydrogen, hydroxy and C1-6alkyl where R5 and R6 independently can be optionally substituted in carbon atom with one or more R16 where R16 represents hydroxy; A represents a single link or C1-2alkylene; where specified C1-2alkylene can be optionally substituted with one or more R18; the ring C represents a saturated, partially saturated or unsaturated mono- or bicyclic ring containing 5 or 6 atoms in which at least one atom can be specified from nitrogen, sulphur or oxygen which can be linked with carbon or nitrogen atom where the -CH2- group can be optionally substituted with -C(O)- and ring sulphur atom can be optionally oxidised to produce S-oxide; R7 is specified from halogen and C1-6alkyl where R7 can be optionally substituted in carbon atom with halogen; n is equal to 0.1 or 2; where R7 values can be equal or different; and R18 is independently specified from halogen and hydroxy; or its pharmaceutically acceptable salt. Also the invention refers to their pharmaceutical compositions and methods for preparation and application thereof for cancer treatment.

EFFECT: preparation of new compounds which can find application for cancer treatment.

23 cl, 96 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of N-(5-[3-(thiophene-2-carbonyl)-pyrazole[1,5-a]pyrimidin-7-yl]-2-fluoro-phenyl}-N-methyl-acetamide in polymorphic modification B, in which (5-amino-1H-pyrazol-4-yl)-thiophen-2-yl-methanone reacts with N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in a solvent selected from a group comprising acetic acid, propionic acid and methanoic acid at 50°C until boiling point of the mixture is reached. (C1-C4)-alcohol is then added to the obtained mixture at temperature of 40°C-80°C, after which the obtained mixture is kept for at least 30 minutes a temperature of 30°C- 55°C for initiating crystallisation. The crystalline product is then separated.

EFFECT: method of obtaining a compound in polymorphic modification B, which can be used in medicine in treating and preventing anxiety, epilepsy, sleep disorders and insomnia.

8 cl, 3 dwg, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of derivatives in the family of pyrrole[3,4-c]carbazole, and specifically to a method for synthesis of novel 2-R1-6-R2-5-aryl-pyrrole[3,4-c]carbazole-1,3(2H,6H)-diones of formula I: , where R1=:C1-C6 alkylphenyl, C1-C6 dialkylphenyl, C1-C6 dialkylphenyl dioxy C1-C6 alkyl; R2=C1-C6 alkyl; Ar=phenyl, C1-C6 alkyl phenyl, oxyalkylphenyl, halophenyl, having potential anticancer activity. The method involves reacting 1-R2-indolin-2-ones of general formula II with oxalyl chloride and 4-aryl-3-butenoic acid of general formula III, reacting the formed 3-(2-chloro-1-R2-1H-indol-3-yl)-4-[(E)-2-arylethenyl]furan-2,5-diones of general formula IV with R1-amines of general formula R1-NH2 V, and then photocyclisation of the formed 1-alkyl-3-(2-chloro-1-R2 -1H-indol-3-yl)-4-[(E)-2-arylethenyl]-1H-pyrrole-2,5-diones of general formula VI, where R1, R2 and Ar assume values listed above.

EFFECT: method for synthesis of novel derivatives having potential anticancer activity.

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound - a sodium salt of 2-ethylthio-6-nitro-1,2,4-triazole[5,1-c]-1,2,4-triazin-7-one dihydrate of formula (1)

.

EFFECT: higher antiviral activity which can be used in medicine, stockbreeding and poultry farming.

2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which inhibit HIV replication, of formula (I) , its pharmaceutically acceptable additive salt; or stereochemically isomer form, where -a1=a2-a3=a4-represents bivalent radical of formula -CH=CH-CH=CH- (a-1); -b1=b2-b3=b4 -represents bivalent radical of formula -CH=CH-CH=CH- (b-1); n represents 0; m represents 1, 2; -A-B- represents bivalent radical of formula -CR5=N- (c-1); -N=N- (c-2); -CH2-CH2- (c-3); -CS-NH- (c-4); -CH=CH- (c-6); R1 represents hydrogen; R2a represents cyano; R3 represents cyano-substituted C1-6alkyl; cyano-substituted C2-6lkenyl; each of R4 independently represents halogen or C1-6alkyl; Q represents hydrogen or C1-6alkyl; R5 represents hydrogen, C1-6alkyl, aryl, pyridyl, thienyl, furanyl, amino, mono- or di(C1-4alkyl)amino, where aryl represents phenyl. Invention also relates to pharmaceutical composition, application and method of obtaining compounds.

EFFECT: obtaining novel compounds, which inhibit HIV replication.

5 cl, 25 dwg, 7 tbl, 16 ex

FIELD: medicine, pharmaceutics.

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

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

30 cl, 371 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazole-pyrimidine derivatives having metabotropic glutamate receptor (mGluR2) antagonist properties and having formula (1): , where A is selected from a group consisting of: Ra is H, halogen or C1-6-alkyl; R1 is II, halogen, C1-6-alkoxy, C1-6-alkyl, C1-6-haloalkyl, C1-6-haloalkoxy; R2 is a halogen, C1-6-haloalkyl; R3 is NRbRc, where Rb and Rc are independently selected from a group consisting of H and C1-6-alkyl which is possibly substituted with one or more substitutes selected from a group consisting of hydroxy and -NRb'Rc', where Rb' and Rc' are independently selected from a group consisting of H and C1-6-alkyl; or Rb and Rc together with the nitrogen atom to which they are bonded form a possibly substituted heterocyclic group containing 5-6 ring atoms, possibly containing an additional N heteroatom, where the substitutes are selected from a group consisting of hydroxy and C1-6-alkyl, R4 is C1-6-haloalkyl or C3-4-cycloalkyl; as well as to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition and use of the compounds in preparing a medicinal agent for treating or preventing diseases and conditions in which mGluR2 activation plays a role.

EFFECT: improved properties of compounds.

10 cl, 2 dwg, 1 tbl, 129 ex

FIELD: chemistry.

SUBSTANCE: invention describes a sodium salt of 2-n-propylthio-6-nitro-1,2,4-triazole[5,1-c]-1,2,4-triazin-7(4H)-one dihydrate and a sodium salt of 2-n-butylthio-6-nitro-1,2,4-triazole[5,1-c]-1,2,4-triazin-7(4H)-one dihydrate having antiviral activity on herpes simplex virus HSV-1.

EFFECT: higher antiviral effect of the compounds.

1 cl, 1 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazine-2-carboxamide derivatives of general

formula , where R1 denote a 5- or 6-member ring, having a formula given in claim 1, R2 denotes H or C1-C7-alkyl; R3 denotes phenyl, pyridinyl or pyrimidinyl, possibly substituted with the following substitutes: Cl, F or Br; R4 denotes H, CI, F, Br, CF3 or C1-C7-alkyl; R5 denotes C1-C7-alkyl; as well as pharmaceutically acceptable salts thereof. Disclosed compounds are metabotropic glutamate receptor (mGLUR 5) antagonists. The invention also pertains to a medicinal agent based on disclosed compounds.

EFFECT: improved method.

17 cl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I and to its pharmaceutically acceptable salts. In formula I , R1 means hydrogen or ; is specified from phenyl, and a 5-member heteroaromatic ring containing 1 to 2 heteroatoms specified inhe group consisting of sulphur and nitrogen; X is specified from lower alkylene, cyclisated lower alkylene containing 3 to 6 carbon atoms, and hydroxy(lower alkylene); R5 and R6 are independently specified in the group including hydrogen, lower alkyl, halogen and lower alkoxygroup; R3 is specified from hydrogen and -NH-R7; R4 is specified from hydrogen and -O(CH2CH2O)y-R10; R7 means lower alkyl; R10 means lower alkyl; n means an integer within 0 to 1; and y is equal to 0; provided when n is equal to 0, and R1 means hydrogen, then R3/R4 both cannot mean hydrogen. The invention also concerns a pharmaceutical composition containing a therapeutically effective amount of the compound under the invention.

EFFECT: preparation of the new compounds which show CDK1 kinase inhibiting activity and can be effective in cancer treatment, particularly breast cancer, lung cancer, colon cancer and prostate cancer treatment.

45 cl, 21 ex

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