Nitric heterocyclic derivatives and medicinal agents containing said derivatives as active ingredient

FIELD: chemistry.

SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising [1] a hydroxy group, [2] a carboxy group, [3] a C1-6alkoxy group which can be substituted with a halogen and [4] a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising [1] hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-6alkoxy, [8] C1-6alkylsulphonyl, [9] amino, [10] C1-6acylamino, [11] alkyl-sulphonylamino, [12] cyclic aminocarbonyl and [13] C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.

EFFECT: wider field of use of the compounds.

7 cl, 11 ex, 1 tbl

 

The technical FIELD

The present invention relates to nitrogen-containing heterocyclic derivatives, which are useful as medicines and pharmaceutical preparations containing them as active ingredient.

As a more detailed explanation of the present invention, the latter relates to

(1) the compound represented by formula (I)

(in which all characters have the same values as described here below), its salts, N-oxide or solvate, or their prodrugs,

(2) treatment and/or prophylaxis associated with CCR5 diseases using the compounds represented by formula (I), its salt, N-oxide or solvate, or their prodrugs based on them as an active ingredient, and to

(3) the way they are received.

BACKGROUND of the INVENTION

Chemokine known as endogenous basic protein having lakesidepottery.com and activating abilities and a strong heparin-binding ability. Currently, it is believed that the chemokine is associated not only with combat infiltration of specific leukocytes during inflammation and immune responses, but also with the development and return of lymphocytes under physiological conditions and migration of cells predecessor of hematite and somatic cells.

C differentiation, proliferation and death is one of hemocytes are struggling with different types of cytokines. In a living body inflammation meet tapicerki and differentiation, maturation, etc. lymphocytes are made in some particular areas. Namely, various necessary cells migrate to specific sites and accumulate in them, causing a number of inflammatory and immune responses. Accordingly, the migration of cells in addition to differentiation, proliferation and cell death is also mandatory event.

Migration of hemocytes in a living body begins first of all in the development stage of the shift hematopoesis starting in the AGM region, permanent hematomas in the bone marrow through the fetal liver. Next, the cells are precursors of T cells and dendritic cells of the thymus migrate from the fetal liver to the bone marrow, and then in timesnow gland and cytodifferentiation in the environment of the thymus. T cell that has received the selection of a clone, migrate to the secondary lymphoid tissue and is involved in the immune response in the periphery. The Langerhans cell skin activated and differentiated capture of antigen, migrate to the area of T cells in the local lymph node and activates there artless T cells as dendritic cells. Memory T cell performs its return again to the lymph node via the lymphatic and blood vessels. Cells In the T cell is in the intestinal epithelium, γδ T cells, NKT cells and dendritic cells migrate from the bone marrow without passing through timesnow gland and differentialmode, taking part in the immune response.

Chemokine seriously involved in the migration of these different cells. The chemokine receptors significantly associated with fighting inflammation and immune responses through a mechanism by which they are expressed in some certain periods in a variety of specific cells and effector cells accumulate in the area, producing the chemokine.

For example, in a study on animal models, such as CCR5-affected mice, reported the assumption that CCR5 as a receptor of the chemokine plays a significant role in the rejection of organ transplantation or autoimmune disease, and other (Transplantation, Vol.72(7), 1199-1205 (2001);Diabetes, Vol.51(8), 2489-2495 (2002);Journal of Virology, Vol.77(1), 191-198 (2003);Journal of ImmunologyVol.164(12), 6303-6312 (2000)). Also reported were conducted comparing the risk of developing several diseases and duration of survival of the graft and the other between the person with inactive CCR and man with CCR wild type (seeThe Lancet, Vol.357, 1758-1761 (2001);Arthritis & Rheumatism, Vol.42(5), 989-992 (1999);The Lancet, Vol.354, 1264-1265 (1999);European Journal of Immunogenetics, Vol.29(6) 525-528 (2002)). It is assumed that CCR5 is associated with several diseases, but there are no publications nor is akih references to the actions of drugs which antagonizing CCR in the messages.

Currently available immunosuppressive treatment of diseases in the field of transplantation. Namely, a calcineurin inhibitor, such as cyclosporine or tacrolimus (FK506), is mainly used with different types immunosuppressant agents such as TOR (target of rapamycin) inhibitor such as sirolimus (rapamycin), nonspecific antiflogistic agent, such as corticosteroids, anti-proliferative drug such as azathioprine, mycophenolate mofetil, etc. But it often causes chronic rejection or severe side effects, so desirable useful new immunosuppressant agent that prolongs the duration of survival of the transplanted graft and reduces side effects compared to existing drugs.

Anti-inflammatory drug or a drug that modulates immune function, such as non-steroidal anti-inflammatory drug (NSAID), which have inhibitory activity against cyclooxygenase (COX), disease modifying anti-inflammatory drugs (DMARD), steroids, and others, are used to treat autoimmune diseases or allergic diseases. The more effective the remedy, the stronger is the side effects caused by them, and polaha is t, the treatment of these drugs is not the main treatment for the disease, and is only symptomatic treatment.

At the same time, the acquired immunodeficiency syndrome (referred to hereafter as “AIDS”), which is caused by the human immunodeficiency virus (called hereafter “HIV”), is one of the diseases, methods of treatment which in recent years most relevant. When HIV infection is completed in CD4-positive cell, which is the main target cell, HIV reiterates its proliferation in the body of the patient and sooner or later destroys the T cell, which receives the load of immunological functions. During this process immunological function gradually decreases, causing fever, diarrhea, enlarged lymph nodes and a similar state of immunodeficiency, which tend to cause complications with pneumonia pathogens which are pneumocytes, and similar to various opportunistic infections. Such States are beginning or attack AIDS, and it is well known that they cause and exacerbate Kaposi's sarcoma and similar malignant tumors.

As a last preventive and/or therapeutic methods from AIDS, attempts were made, for example, (1) to inhibit the growth of HIV-way of the introduction of nucleoside reverse transcriptase inhibitor or protease inhibitor and (2) to prevent or reduce opportunistic infections by drug administration, with immunopotentional activity.

Helper T cells, which acquire a charge or load of the Central immune system, mainly becoming infected with HIV. Since 1985, it is known that HIV uses a membrane protein CD4 expressing infection on the membrane of T cells (Cell,52, 631 (1985)). CD4 molecule consists of 433 amino acid residues, and its expression can occur in macrophages, In some cells, vascular endothelial cells, Langerhans cells in skin tissues, dendritic cells in lymphoid tissues, cells, glia of the Central nervous system and similar, in addition to Mature helper T cells. However, since it was found that HIV infection does not complete one CD4 molecule, it has been suggested the possible presence of factors other than the CD4 molecule, which is associated with infection of cells by HIV.

CCR5 is a receptor for RANTES, MIP-1α and MIP-1β, also used during infection tropic (R5) HIV-macrophage (Science,272, 1955 (1996)).

Accordingly, substances that can compete with CCR5 for HIV or who may contact with the HIV virus, thus causing the virus is unable to communicate with CCR5 could be inhibitors of HIV infection.

It is also reported about the possibility that CCR5 is used when the infection Rees is iratory Syncytial Virus (called hereafter “RSV”).

It is reported that CCR5 is expressed in arteriosclerotic plaques, therefore, considered that the receptor modulators of chemokine is also useful in the treatment of cardiovascular diseases.

Based on the above, it is believed that the chemokine receptors (e.g., RANTES, MIP-1α, MIP-1β, and others), especially CCR5 seriously associated with inflammation, immunological diseases, infectious diseases (HIV, infection with RSV, and others), and cardiovascular disease. For example, it is believed that they are associated with various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, inflammatory bowel disease such as ulcerative colitis and others), immunological diseases (autoimmune diseases, rejection in organ transplantation (graft rejection, solid organ, graft rejection of pancreatic islet cells for the treatment of diabetes, a disease graft-versus-host and others), immunomodulation, psoriasis, multiple sclerosis and others), infectious diseases (infection with human immunodeficiency virus, acquired immunodeficiency syndrome, RSV infection and others), allergic diseases (atopic dermatitis, urticaria, allergic bronchopulmonary aspergillosis, Allergy is a mini eosinophilic gastroenteritis and others), cardiovascular diseases (arteriosclerosis, ischemic reperfusion injury, and others), a syndrome of acute respiratory distress, shock accompanying bacterial infection, diabetes, metastasis of cancer and similar.

It is reported that derivatives aminopiperidine represented by the formula (Z)

(in which R1Zrepresents a hydrogen atom or C1-12 alkyl, R2Zand R3Zrepresent each independently a hydrogen atom or C1-12 alkyl, XZrepresents a nitrogen atom or an oxygen atom, AZis

or

(in which R4Zrepresents a hydrogen atom, C1-12 alkyl, C3-8 cycloalkyl, aryl, substituted aryl, aryl-C(=O)- or aryl-CH(OH)-, R5Zrepresents hydrogen, C1-12 alkyl, C1-4 alkoxy, halogen or COR, R6Zrepresents hydrogen, C1-12 alkyl or substituted C1-4 alkyl, provided that the definition of each symbol selected in part), are useful as inhibitors of chemokine receptors (see WO02/079186).

Describes what sulfonanilide compounds represented by formula (W)

(in which XWrepresents-O-, -S-, -CH2- or-NR6-, YWrepresents C6-10 aryl or C2-9 heteroaryl, R1Wselected from GRU the dust, consisting of: H-, HO-, halogen-, C1-8 alkyl-, optionally substituted by 1-3 fluorine atoms, and the other, R2Wand R3Wselected from the group consisting of: H, oxo, C1-8 alkyl-, optionally substituted by 1-3 fluorine atoms, and the other, R4Wselected from the group consisting of: N-, BUT-, halogen-, NC-, and others, R5Wrepresents C1-8 alkyl, aW is 0-5, bW is 0-2, cW is 0-2, and dW is 0-4, provided that the definition of each symbol selected in part), their pharmacologically acceptable salts and their prodrugs are selective antagonists of CCR1 (see WO02/102787).

In addition, 1-(4-pyridyl)-pieperazinove derivatives are described as CCR5 antagonists (see the description of U.S. patent 6391865).

On the other hand, it is reported that derivatives of diazaspiro[5.5]undecane, their Quaternary ammonium salts and their N-oxides, or their pharmacologically acceptable salts regulate the effect of chemokine receptor/chemokine, so they are used for prevention and/or treatment of various inflammatory diseases, asthma, atopic dermatitis, urticaria, allergic diseases (allergic bronchopulmonary aspergillosis or allergic eosinophilic gastroenteritis and other), nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, psoriasis, rhinitis, conjunctivitis, ischemic reperfusion disorder, Russian the th sclerosis, ulcerative colitis, acute respiratory distress, cytotoxic shock, diabetes, autoimmune diseases, rejection reactions transplanted organ, immunosuppression, cancer metastasis and acquired immunodeficiency syndrome (see WO01/40227).

Describes that compounds represented by formula (M)

(where mM and nM, which are the same or different, each represents zero or the integer 1 or 2, Alk3Mrepresents a covalent bond or a straight or branched C1-6 alkylenes chain, R1Mand R2Mthat are the same or different, each represents a hydrogen atom or a straight or branched C1-6 alkyl group, DMrepresents an optionally substituted aromatic or heteroaromatic ring group, EMrepresents optionally substituted C7-10 cycloalkyl, C7-10 cycloalkenyl or C7-10 politicalization group)are modulators of CXCR3 (see WO03/070242).

DISCLOSURE of INVENTIONS

The compound which has antagonistic activity against CCR5, is useful in the prevention and/or treatment of CCR5-related diseases. Therefore, it is desirable to have developed safe CCR5 antagonists.

In order to find a compound that specifically Saint who shows chemokinesis receptor, especially CCR5, and has an antagonistic activity against him, the present inventors have conducted intensive studies and found as the result that these objectives can be achieved by a compound represented by the formula (I), and thus was completed the present invention.

The present invention relates to the following:

1. the compound represented by formula (I)

in which R1represents (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G, (6) -CONR1HR1J, (7) -NR1KCOR1Lor (8) cyano, where m is 0, 1 or 2; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1Leach independently represents a hydrogen atom, a hydrocarbon group which may have a Deputy(deputies), or 3-15 membered heterocyclic group which may have a Deputy(deputies) and in which R1Cand R1Dor R1Hand R1Jmay form a nitrogen-containing heterocyclic group which may have a Deputy(deputies), together with the nitrogen atom to which they relate;

X and Y each independently represents a bond or a spacer containing 1 to 3 atoms as a main chain;

ring a and ring b, which are the by the same or different, each is 3 to 15-membered carbocyclic group or heterocyclic group which may have a Deputy(deputies);

ring D is 3 to 15-membered nitrogen-containing heterocyclic group which may have a Deputy(deputies);

R2represents (1) hydrogen atom, (2) a hydrocarbon group which may have a Deputy(deputies), (3) cyano group, (4) hydroxy group which may be protected, (5) amino group which may have a Deputy(deputies), (6) oxo group, (7) 3-15 membered heterocyclic group which may have a Deputy(deputies), or (8) =N-OR6where R6represents a hydrogen atom or C1-4 alkyl,

its salt, N-oxide or MES, or its prodrug;

2. the compound according to the above claim 1, in which X and Y each independently represents a bond or a divalent group comprising a combination of one or two units selected from (1) -CR7R8-, (2) -NR9-, (3) -CO-, (4) -O-, (5) -S-, (6) -SO-, (7) -SO2(8) -C(=N-OR10)-, where R7and R8each independently represents a hydrogen atom, C1-4 alkyl, -OR11or phenyl; R9represents a hydrogen atom, C1-4 alkyl, or phenyl; R10and R11each independently represents a hydrogen atom or C1-4 alkyl;

3. the compound according to the above item 2, in which X is predstavljaet communication, -O - or-CH2-;

4. the compound according to the above item 2, in which Y represents C1-2 alkylene;

5. the compound according to the above claim 1, wherein ring D represents a 5-to 10-membered nitrogen-containing heterocyclic group which may have a Deputy(deputies);

6. the compound according to the above item 5, in which ring D is Troyanovo, pyrolidine, piperidine or asianova ring which may have a Deputy(deputies);

7. the compound according to the above item 6, in which ring D is piperidine ring which may have a Deputy(deputies);

8. the compound according to the above claim 1, in which ring a and ring B, which are the same or different, each represents a 5 - or 6-membered aromatic ring group which may have a Deputy(deputies);

9. the compound according to the above claim 1, in which R2represents a group of the formula

in which the arrow indicates the position of the connection with the ring D, R51, R52and R53each independently represents (1) hydrogen atom, (2) a hydrocarbon group which may have a Deputy(deputies), (3) 3-15 membered heterocyclic group which may have a Deputy(deputies), (4) C1-4 alkoxy group which mo is et to have a Deputy(deputies), (5) phenoxy group which may have a Deputy(deputies), or (6) benzyloxy group which may have a Deputy(deputies);

10. the compound according to the above claim 1, in which R2represents a group of the formula

in which the arrow indicates the position of the connection with the ring D, R51and R54each independently represents (1) hydrogen atom, (2) a hydrocarbon group which may have a Deputy(deputies), (3) 3-15 membered heterocyclic group which may have a Deputy(deputies), (4) C1-4 alkoxy group which may have a Deputy(deputies), (5) phenoxy group which may have a Deputy(deputies), or (6) benzyloxy group which may have a Deputy(deputies);

11. the compound according to above item 1, which is represented by formula (Ib)

in which all symbols have the same meanings as described in claims 1 and 9;

12. the compound according to the above item 9, in which the hydrocarbon group which may have a Deputy(deputies), or 3-15 membered heterocyclic group which may have a Deputy(deputies), represented by the symbol R51represents an aromatic ring group which may have a Deputy(deputies);

13. the connection according to the description of nomu above item 12, in which an aromatic ring group which may have a Deputy(deputies), a represents benzene, pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrazinone, pyrimidine, pyridazine, oxazole, isoxazole, thiazole, isothiazol, furazane, oxadiazoline or thiadiazoline ring;

14. the compound according to the above item 12, which is represented by formula (Ie), (If), (Ig) or (Ih)

or

where the _ symbol represents β-configuration and the _ symbol represents α-configuration, β-configuration or a mixture thereof; R56represents an aromatic ring group which may have a substituent(s); other symbols have the same meanings as described in claims 1 and 9 above;

15. the compound according to the above claim 1, where the hydrocarbon group which may have a substituent(s)represented by R51is C1-15 alkyl;

16. the compound according to the above item 15, which is selected from the group consisting of:

(1) 5-({[butyl(1-{4-[4-(methylsulphonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-differentated,

(2) 5-[({butyl[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated,

(3) 5-({[butyl(1-{[6-(4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-differentated,

(4) 5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated,

(5) 5-{[(butyl{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2-chloro-4-fermentated,

(6) 2-(5-{[(butyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differenl)ndimethylacetamide,

(7) 5-[({butyl[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-debtor-N-methylbenzamide,

(8) 5-{[(butyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated, and

(9) 5-[({butyl[1-(4-{4-[(methylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated;

17. the compound according to the above item 12, where the aromatic ring group represented by R51is mono - carbocyclic group or mono - heterocyclic group which have aromaticity;

18. the compound according to the above 17, which is selected from the group consisting of:

(1) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide,

(2) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(3) N-4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(4) N-[4-({5-[(4-{3-thienyl[(3-thienylene)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide,

(5) 2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(6) N-{4-[4-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl) - for 3,5-dimethyl-1H-pyrazole-1-yl]phenyl}methanesulfonamide,

(7) 4-[4-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl) - for 3,5-dimethyl-1H-pyrazole-1-yl]-N-[2-(4-morpholinyl)ethyl]benzosulfimide,

(8) N-(4-{[5-({4-[{[(2,4-differenl)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(9) 2-chloro-N-methyl-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(10) N-(4-{[5-({4-[({[4-chloro-3-(4-morpholinylcarbonyl)phenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(11) 2-fluoro-5-{[((3-forfinal){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide,

(12) N-(3-forfinal)-N'-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]urea

(13) 2-[4-({4-[[({4-fluoro-3-[(methylsulphonyl)amino]phenyl}amino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulphonyl)amino]benzamide,

(14) 2-fluoro-N-methyl-5-({[{1-[(6-{4-(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(15) 2-fluoro-N-methyl-5-({[[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide,

(16) 2-[4-({4-[({[3-(acetylamino)-4-forfinal]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulphonyl)amino]benzamide,

(17) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(18) N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide", she

(19) N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide, and

(20) N'-(4-forfinal)-N-[1-({6-[4-(methylsulphonyl)phenoxy]pyridine-3-yl}methyl)piperidine-4-yl]-N-prilocaine;

19. the connection, according to the above item 11, which is selected from the group consisting of:

(1) 2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(2) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(3) N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide", she and

(4) N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridi who yl)oxy]phenyl}methanesulfonamide,

20. the connection, according to the above item 11, which is selected from the group consisting of:

(1) 5-[({butyl[1-(4-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated,

(2) N-(4-{[5-({4-[{[(2,4-differenl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide,

(3) N-(4-{[5-({4-[{[(4-were)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(4) N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide, and

(5) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)ndimethylacetamide;

21. the compound according to above item 1, which is selected from the group consisting of:

(1) 2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(2) of the dihydrochloride of N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(3) of the hydrochloride of N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide", she

(4) of the dihydrochloride of N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]}methyl}-2-pyridinyl)oxy]phenyl}IU is unsulfonated,

(5) hydrochloride 5-[({butyl[1-(4-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated,

(6) of the hydrochloride of N-(4-{[5-({4-[{[(2,4-differenl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide,

(7) N-(4-{[5-({4-[{[(4-were)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(8) N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide, and

(9) of the hydrochloride of N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)ndimethylacetamide;

22. pharmaceutical composition that includes a compound according to the above claim 1, its salt, N-oxide, its MES or its prodrug;

23. the pharmaceutical composition according to above item 22, which is an antagonist of a receptor of the chemokine;

24. the pharmaceutical composition according to above item 23, which is a CCR5 antagonist;

25. the pharmaceutical composition according to above described paragraph 24, which is an agent for treatment and/or prophylaxis(prevention) of disease related to CCR5;

26. the pharmaceutical composition according to the above A.25, where the disease is related to CCR5, are infectious C the disease, immunological diseases, inflammatory diseases and/or cardiovascular disease;

27. the pharmaceutical composition according to the above p, where the disease is related to CCR5, is an infection with the human immunodeficiency virus, acquired immunodeficiency syndrome, infection with Respiratory Syncytial Virus, rejection of organs in transplantation, multiple sclerosis, inflammatory bowel disease, and/or asthma;

28. the pharmaceutical composition according to the above p, where immunological disease is the rejection of organ transplants;

29. the pharmaceutical composition according to above item 22, which is an agent for prevention and/or treatment of infectious diseases, immunological diseases, inflammatory diseases and/or cardiovascular disease;

30. the medication, including the combination of a compound represented by the formula (I) according to the above item 1, its salts, its N-oxide, MES or its prodrugs, and one or more agent(s)selected from a nucleoside reverse transcriptase inhibitor, protease inhibitor, integrase inhibitor, CCR2 antagonist, CCR3 antagonist, CCR4 antagonist, CCR5 antagonist, an antagonist of CXCR3, CXCR4 antagonist, inhibitor merge, antibodies against poverhnostnogo the antigen of HIV, and HIV vaccine;

31. the medication, including the combination of a compound represented by the formula (I) according to the above item 1, its salts, its N-oxide, MES or its prodrugs, and one or more agent(s)selected from immunosuppressive(immunosuppressive agent, non-steroidal anti-inflammatory drugs, disease modifying Antirheumatic drugs, steroids, anti-inflammatory enzymes, chondro-protective agents, an inhibitor of T-cells, TNFα inhibitor, an inhibitor of the prostaglandin synthase, an inhibitor of IL-1, an inhibitor of IL-6, agonist of gamma interferon, prostaglandins, phosphodiesterase inhibitor, and inhibitor of metalloproteinases;

32. the method of prevention or treatment of diseases related to CCR5 in mammals, which includes the appointment of a mammal an effective amount of the compound represented by formula (I) according to the above item 1, its salts, its N-oxide, MES or its prodrug;

33. the use of compounds represented by formula (I) according to the above item 1, its salts, its N-oxide, MES or its prodrugs for the production of an agent for prevention and/or treatment of diseases related to CCR5;

34. the pharmaceutical composition according to above item 22, which is an inhibitor to emochnoy migration; and

35. the method of obtaining the compound represented by formula (I) according to the above item 1, its salts, its N-oxide or MES or its prodrugs.

The designation of “hydrocarbon group” in the phrase “hydrocarbon group which may have a substituent(s)” represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1Lincludes, for example, (a) C1-15 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,Deut-butyl,tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl etc.; (b) C3-8 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; (C) C2-10 alkenyl, such as vinyl, allyl, 2-methylallyl, 2-butenyl, 3-butenyl, 3-octenyl etc.; (d) C2-10 quinil, such as ethinyl, 2-PROPYNYL, 3-hexenyl etc.; (e) C3-10 cycloalkenyl, such as cyclopropyl, cyclopentyl, cyclohexenyl etc.; (f) C6-14 aryl such as phenyl, naphthyl and so on; (g) C7-16 aralkyl, such as benzyl, phenylethyl, etc.; (h) (C3-8 cycloalkyl)-(C1-4 alkyl), such as cyclohexylmethyl, cyclohexylethyl, cyclohexylmethyl, 1-methyl-1-cyclohexylmethyl, cyclopropylethyl etc.

The designation “3-15-membered heterocycle” in the phrase “3-15 membered heterocyclic group which may have a substituent(s)”, not only the TES R 1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1Lincludes “3-15 membered unsaturated heterocycle” or “3-15 membered saturated a heterocycle”.

“3-15 membered unsaturated heterocycle” includes, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, thiophene, thiopyran, tiepin, oxazol, isoxazol, thiazole, isothiazol, furazan, oxadiazole, oxazin, oxadiazon, oxazepine, oxadiazon, thiadiazole, teasin, thiadiazin, diazepin, thiadiazin, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzofuran, ditionally, indazole, quinoline, isoquinoline, hemolysin, purine phthalazine, pteridine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzimidazole, chrome, benzocain, benzoxazepin, benzodiazepin, benzothiophen, benzodiazepin, benzodiazepin, benzazepin, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, beta carboline, acridine, fenesin, dibenzofuran, Xanten, dibenzothiophen, phenothiazines, phenoxazin, phenoxathiin, tianren, phenanthridine, phenanthroline, pyrimidin, pyrrolin, imidazolin, triazoline, tetrazolyl, pyrazoline, dihydropyridines, tetrahydropyridine, dihydropyridine, tetrahydropyridine, dihydropyrimidin, tetrahedr is a pyrimidine, dihydropyridin, tetrahydropyridine, dehydroacetic, tetrahydroazepine, dihydrovitamin, tetrahydroazepine, dihydrofuran, dihydropyran, dehydroacetic, tetrahydroazepine, dihydrothiophene, dihydrothiophene, dihydrothiophene, tetrahydrothiophene, dihydrooxazolo, dihydroisoxazole, dihydrothiazolo, dihydroisoxazole, dihydrofuran, dihydroimidazole, dihydrooxazolo, Dihydrocodeine, dihydrooxazoles, tetrahydroazepine, dihydroxyvitamin, tetrahydroazepine, dihydroeugenol, dihydrothiazine, dihydrokavain, dihydrothiazine, tetrahydroazepine, dihydrokavain, tetrahydroazepine, indolin, isoindoline, dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzofuran, dihydroisobenzofuran, dihydroindol, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophenazine, tetrahydrophthalate, dihydronaphthalene, tetrahydronaphthalene, dihydroquinoxaline, tetrahydroquinoxalin, dihydroquinazolin, tetrahydroquinazolin, dihydroindole, tetrahydroindole, benzocain, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, dihydrobenzofuran, dehydrobenzperidol, digitalisation, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, benzodioxepin, dihydroisoxazole, tetrahydrobenzaldehyde, Digue is drocarbon, tetrahydrocarbazol, dihydrouridine, tetrahydrouridine, dihydrobenzofuran, dihydroisobenzofuran, tetrahydroxybenzophenone, tetrahydrolipstatin, dioksiinien, benzodioxan, chroman, benzodithiol, benzodithiol etc.

“3-15 membered saturated a heterocycle” includes, for example, aziridine, azetidine, asokan, pyrrolidin, imidazolidin, thiazolidin, tetrazolium, pyrazolidine, piperidine, piperazine, targetability, targetability, ASEAN (peligrosa), pengertian, oxiran, oxetane, tetrahydrofuran, tetrahydropyran, perhydroxyl, thiran, Titan, tetrahydrothiophene, tetrahydrothiopyran, pengertian, tetrahydrooxazolo (oxazolidine), tetrahydrocortisol (isoxazolidine), tetrahydrothieno (thiazolidin), tetrahydrocortisol (isothiazolin), tetrahydrofuran, tetrahydrooxazolo (oxadiazolidine), tetrahydrooxazolo, tetrahydroimidazo, perhydroxyl, perhydroanthracene, tetrahydrocortisol (thiadiazolidin), tetrahydrothiophene, tetrahydrolipstatin, targetrotation, targetrotation, morpholine, thiomorpholine, Ossetian, perhydroanthracene, peligrosamente, targetobjecttype, peligrosamente, peritoneal, perhydroxyl, perhydrosqualene, PermitRootLogin, perhydroanthracene, perhydrophenanthrene, perhydrophenanthrene, permitiendoles, perger benzoxazol, perhydroanthracene, perhydroanthracene, perhydrogenized, perhydrosqualene, perhydrophenanthrene, perhydrophenanthrene, dioxolane, dioxane, ditiolan, Titian,

oretc.

“Substituents” in the phrase “hydrocarbon group which may have a substituent(s)” or 3-15 membered heterocyclic group represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1Linclude , for example, (1) nitro, (2) hydroxy group, (3) oxo, (4) thioxo, (5) cyano, (6) carbarnoyl, (7) aminocarbonyl, substituted C1-8 hydrocarbon, substituted by one or two substituent(members)selected from (a) hydroxyl, (b) amino, (c) C1-4 alkoxy, (d) mono - or disubstituted amino substituted C1-8 hydrocarbon group, etc., (e) carboxyl, (f) C1-6 alkoxy-carbonyl, etc. (for example, N-methylaminomethyl, N-ethylaminoethanol, N-propylaminosulfonyl, N-butylaminoethyl, N-cyclohexyloxycarbonyl, N-N-dimethylaminobenzoyl, N-butyl-N-cyclohexyloxycarbonyl, N-cyclohexyloxycarbonyl, phenylenecarbonyl, N-(2-methoxyethyl)aminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl, N-(2-amino-ethyl)aminocarbonyl, N-[2-(N',N'-dimethylamino)ethyl]aminocarbonyl, N-(2-carboxyethyl)aminocarbonyl, N-(2-methoxycarbonylethyl)amino is bonila, etc.) (8) carboxy, (9) C1-6 alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, tRET-butoxycarbonyl,and so (10) sulfo, (11) a halogen such as fluorine, chlorine, bromine or iodine, (12) C1-6 alkoxy which may be substituted by halogen (for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,Deut-butoxy,tert-butoxy, deformedarse or triptoreline), (13) phenoxy, (14) halogenfree such as o-, m - or p-chlorophenoxy or o-, m - or p-bromophenoxy etc., (15) C1-6 alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,tert-butylthio, etc., (16) phenylthio, (17) C1-6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl etc. (18) C1-6 alkylsulfonyl such as methylsulphonyl or ethylsulfonyl, propylsulfonyl, butylsulfonyl etc., (19) amino, (20) C1-6 lower acylamino such as acetylamino or propionamido etc., (21) mono - or disubstituted amino substituted hydrocarbon group (the“hydrocarbon group” has the same meaning as the “hydrocarbon group”, the above, and may be substituted by oxo, amino which may be substituted by an optional substituent (e.g., hydrocarbon), carbamoyl, halogen or hydroxy group, etc.) (e.g methylamine, ethyl is Ino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, cyclohexylamino, 1-carbarnoyl-2-cyclohexylethylamine, N-butyl-N-cyclohexylethylamine or phenylamino etc.), (22) C1-8 alkanoyl such as formyl or acetyl, propionyl, butyryl, isobutyryl, cyclohexylcarbonyl, etc., (23) C6-10 aryl-C1-4 lower acyl such as benzoyl, benzylcarbamoyl, (24) 3-15 membered heterocyclic group which comprises 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen in addition to carbon atom and has optional 1-4 substituent selected from (a) halogen, such as bromine, chlorine or fluorine, (b) hydrocarbon, optionally substituted by oxo or hydroxy group, etc. (the“hydrocarbon group” has the same meaning as the above-mentioned “hydrocarbon group”such as methyl, ethyl, propyl, isopropyl, benzyl, cyclohexyl, cyclohexylmethyl or cyclohexylethyl etc., (c) halogenfree, such as o-, m - or p-chlorophenoxy, or o-, m - or p-bromophenoxy and etc. and (d) oxo, etc. such as thienyl, furyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, hinely, ethanolic, indolyl, aziridinyl, azetidin, pyrrolidinyl, pyrrolyl, pyrrolyl, imidazolidinyl, piperidino, morpholino, dihydropyridine, N-methylpiperazine, N-ethylpiperazine etc., (25) S halogenated, such as deformity, trifluoromethyl, triptorelin, chloromethyl, dichloromethyl or trichlorethyl etc., (26) hydroxyimino, (27) alkylenediamine, such as methoxyimino or atrakcyjna etc., (28) alkylsulfonyl, such as methylsulfonylamino, ethylsulfonyl or benzylmethylamine etc., or (29) arylsulfonamides, such as phenylcarbonylamino or p-toluensulfonate etc., (30) cyclic aminocarbonyl, such as 1-aziridinyl, 1-azetidinone, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazine, morpholinoethyl etc., (31) C1-8 hydrocarbon group, substituted by one or two substituents selected from (a) hydroxy, (b) amino, (c) C1-4 alkoxy, (d) mono - or disubstituted amino substituted C1-8 hydrocarbon group, etc., (e) aminocarbonyl substituted C1-8 hydrocarbon group, etc. which may have a substituent(s) (These substituents selected from, for example, (a) hydroxy, (b) amino, (c) C1-4 alkoxy, (d) mono- or disubstituted amino substituted C1-8 hydrocarbon group, etc., (e) carboxy, (f) C1-6 alkoxy-carbonyl, and may have 1 or 2 groups.) such as hydroxymethyl, hydroxyethyl, aminomethyl, methoxymethyl, N,N-dimethylaminomethyl, carbamoylmethyl, N-methylaminomethyl, N,N-dimethylaminocarbonylmethyl etc., (32) (C1-4 alkoxy)-(C1-4 alkyl) group, such as methoxyethyl and d, (33) C1-8 alkanoyloxy group, such as formyloxy, atomic charges, propionyloxy, butyryloxy, isobutyryloxy or cyclohexyloxycarbonyloxy etc., or benzoyloxy group, (34) amidino group, (35) imino group, (36) C1-8 alkanolamine group, such as formamide, ndimethylacetamide, triptorelin, propionamide, butyramide, isobutyramide, cyclohexylcarbodiimide etc., (37) benzamido group, (38) carbamoylating group, (39) N-C1-4 alkylcarboxylic group, such as N-methylcarbamoyl, N-ethylcarbodiimide N-propylenpipeline, N-isopropylcarbamate, N-butylcarbamoyl etc., (40) N,N-di-C1-4 alkylcarboxylic group, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylamine, N,N-dibutylethanolamine etc., (41) C1-3 alkylenedioxy group, such as methylenedioxy or Ethylenedioxy etc., (42)- (OH)2, (43) epoxy group, (44) mercapto group, (45) sulfine group, (46) phosphono group, (47) sulfamoyl group, (48) C1-6 monoalkylphenol, such as N-methylcarbamoyl, N-ethylsulfonyl, N-propylsulfonyl, N-isopropylamino or N-butylsulfonyl etc., (49) di-C1-4 alkylsulfanyl group, such as N,N-dimethylsulphamoyl, N,N-diethylcarbamoyl, N,N-dipropylamino or N,N-dibutylamino and so, (50) will phenylsulfinyl group, (51) phenylsulfonyl group, (52) azide group, or (53) a carbohydrate is one group (This “hydrocarbon group” has the same meanings as above described “hydrocarbon group”, for example, methyl, ethyl, propyl, isopropyl, vinyl, ethinyl, cyclohexenyl, phenyl, naphthyl, benzyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, etc). “Hydrocarbon group which may have a substituent(s)” or “3 to 15-membered heterocyclic group which may have a substituent(s)”may have 1 to 10 substituents selected from the above paragraphs (1)to(53). When the number of substituents is 2 or more, each of the substituents may be identical or different.

“Nitrogen-containing heterocyclic group” in the term “nitrogen-containing heterocyclic group which may have a substituent(s)”formed by the R1Cand R1Dor R1Hand R1Jtogether with the nitrogen atom to which they are attached, includes, for example, aziridine, azetidine, pyrrolin, pyrrolidin, imidazolin, imidazolidin, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, targetability, targetability, tetrahydroazepine, ASEAN (peligrosa), tetrahydroazepine, targetrotation, tetrahydrooxazolo (oxazolidine), tetrahydrothieno (thiazolidin), tetrahydrooxazolo, perhydroxyl, tetrahydrothiophene, targetrotation, morpholine, thiomorpholine ring, etc.

“Substituents” in the phrase “nitrogen-containing heterocyclic group which may have a substituent(s)”, about sovanna R 1Cand R1Dor R1Hand R1Jtogether with the nitrogen atom to which they are attached, includes the same values as the “Deputy” in the phrase “hydrocarbon group which may have a substituent(s)”or “3 to 15-membered heterocyclic group which may have a substituent(s)”has the same meaning as the “hydrocarbon group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L.

“Spacer containing 1-3 atoms in the main chain”represented by X and Y means the gap formed by 1-3 contiguous atoms of the main chain. In this case, the number of atoms in the main chain should be designed in such a way that the number of atoms in the main chain was minimal. The “spacer having from 1 to 3 atoms in the main chain”includes, for example, a bivalent group containing 1-3 groups selected from-CR7R8-, -NR9-, -CO-, -O-, -SO-, -SO2and-C(=N-OR10)- (where R7and R8each independently represents a hydrogen atom, C1-4 alkyl, -OR11or phenyl, R9represents a hydrogen atom, C1-4 alkyl or phenyl, R10R11each independently represents a hydrogen atom, C1-4 alkyl). When “C1-4 alkyl” represented by R7R10he is cancel, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,second-butyl, tert-butyl, etc. Specifically, the “Spacer having 1 to 3 atoms in the main chain”includes, for example, -CR7R8-, -NR9-, -CO-, -O-, -S-, -C(=N-OR10)-, -NR9CO-, -CONR9-, -NR9COCR7R8- or-CONR9CR7R8- (where R7-R10have the same values as described above).

“C1-2 alkylene”, presents, Y represents a methylene or ethylene.

“3-15 membered carbocyclic group” in the “3-15 membered carbocyclic group or heterocyclic, which may have a substituent(s)”represented by ring a and ring B, includes, for example, 3-15 membered cyclic hydrocarbon,” etc., “Cyclic hydrocarbons” in the phrase “3-15 membered cyclic hydrocarbon” includes, for example, “unsaturated cyclic hydrocarbon” or “saturated cyclic hydrocarbon”. “Saturated cyclic hydrocarbon” includes, for example, cycloalkane, such as cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane, cyclodecane, cyclododecane, cycletrader, collateralised or cyclopentadecane etc.; perhydroanthracene; pergerson; palikonda; peritonealis; perheravintolan; Spiro[4.4]nonan; Spiro[4.5]decane; Spiro[5.5]undecane; bicyclo[2.2.1]heptane; bicyclo[hat; bicyclo[2.2.2]octane; adamantane; noradsanta etc. “Unsaturated cyclic hydrocarbon” includes, for example, cycloalkane, such as cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene or cyclooctadiene etc.; benzene; pentalen; azulene; inden; naphthalene; dihydronaphthalene; tetrahydronaphthalen; geptalen; biphenylene; AC-indocin;-indocin; acenaphthene; acenaphthylene; fluorene; finale; phenanthrene; anthracene; bicyclo[2.2.1]hept-2-ene; bicyclo[3.1.1]hept-2-ene; bicyclo[2.2.2]Oct-2-ene, etc.

“3-15 membered heterocyclic group” in the phrase “3-15 membered carbocyclic group or heterocyclic group which may have a substituent(s)”represented by ring a and ring b has the same values as described above from 3 to 15-membered heterocyclic group” in the term 3 to 15-membered heterocyclic group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L.

“Substituents” in the phrase “3-15 membered carbocyclic group or heterocyclic group which may have a substituent(s)”represented by ring a and ring B, have the same values as the “substituents” in the phrase “hydrocarbon group which may have a Deputy who(and)” or “3 to 15-membered heterocyclic group, which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L. 1-10 substituents can occur wherever possible. When the number of substituents is two or more, each of the substituents may be identical or different.

“5-6-membered aromatic ring group” in the phrase “5-6-membered aromatic ring group which may have a substituent(s)”represented by ring a and ring B, includes, for example, benzene, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, triazine, furan, thiophene, oxazole, isoxazol, thiazole, isothiazol, furazan, oxadiazole or thiadiazole ring etc.

“Substituents” in the phrase “5-6-membered aromatic ring group which may have a substituent(s)”represented by ring a and ring B, have the same values as the “substituents” in the phrase “hydrocarbon group which may have a substituent(s)”or “3 to 15-membered heterocyclic group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L. 1 - 10 deputies can take place wherever possible. When the number of substituents is two or more, each is of the substituents may be identical or different.

“Nitrogen-containing heterocyclic group” in the phrase “3-15 membered nitrogen-containing heterocyclic group which may have a substituent(s)”represented by ring D, refers to a heterocycle, which may contain, in addition to at least one nitrogen atom in addition to carbon atom, 1-3 hetero atoms selected from nitrogen atoms, oxygen or sulfur. “3-15 membered nitrogen-containing heterocycle” includes “3-15 membered nitrogen-containing unsaturated heterocycle” and “3-15 membered nitrogen-containing saturated a heterocycle”.

“3-15 membered nitrogen-containing unsaturated heterocyclic group” includes, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, indole, isoindole, indazole, purine, benzimidazole, benzazepin, benzodiazepine, benzotriazol, carbazole, β-carboline, phenothiazines, phenoxazin, pyrimidin, pyrrolin, imidazolin, triazoline, tetrazolyl, pyrazoline, dihydropyridines, tetrahydropyridine, dihydropyridine, tetrahydropyridine, dihydropyrimidin, tetrahydropyrimidin, dihydropyridin, tetrahydropyridine, dehydroacetic, tetrahydroazepine, dihydrovitamin, tetrahydroazepine, dihydrooxazolo, dihydroisoxazole, dihydrothiazolo, dihydroisoxazole, dihydrofuran, dihydroimidazole, dihydrooxazolo, Dihydrocodeine, dihydrooxazoles, tetrahydroazepine, dihydroxyvitamin, tetrahed oxadiazon, dihydrothiazolo, dihydrothiazine, dihydrokavain, dihydrothiazine, dihydrokavain, tetrahydroazepine, indolin, isoindoline, dihydroindol, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophenazine, tetrahydrophthalate, dihydronaphthalene, tetrahydronaphthalene, dihydroquinoxaline, tetrahydroquinoxalin, dihydroquinazolin, tetrahydroquinazolin, dihydroindole, tetrahydroindole, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, dihydrobenzofuran, dehydrobenzperidol, dihydrobenzofuran, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, dihydroisoxazole, tetrahydrobenzoic, dihydrocarvone, tetrahydrocarbazol, dihydrouridine, tetrahydrouridine; or 3-15 membered nitrogen-containing saturated heterocyclic group includes, for example, aziridine, azetidine, asokan, pyrrolidin imidazolidin, thiazolidin, tetrazolium, pyrazolidine, piperidine, piperazine, targetability, targetability, ASEAN (peligrosa), pengertian, tetrahydrooxazolo (oxazolidine), tetrahydrocortisol (isoxazolidine), tetrahydrothieno (thiazolidin), tetrahydrocortisol (isothiazolin), tetrahydrofuran, tetrahydrooxazolo (oxadiazolidine), tetrahydrooxazolo, tetrahydroimidazo, ambrosia is roaccutan, perhydroanthracene, tetrahydrocortisol, (thiadiazolidin), tetrahydrothiophene, tetrahydrolipstatin, tetrahydroazepine, targetrotation, targetrotation, morpholine, thiomorpholine, peritoneal, perhydroxyl, perhydrosqualene, PermitRootLogin, perhydroanthracene, perhydrophenanthrene, perhydrophenanthrene, permitiendoles, perhydroanthracene, perhydroanthracene, perhydroanthracene, perhydrogenized, perhydrosqualene,oretc.

“Substituents” in the phrase “3-15 membered nitrogen-containing heterocyclic group which may have a substituent(s)”represented by ring D have the same values as the “substituents” in the phrase “hydrocarbon group which may have a substituent(s)”or “3 to 15-membered heterocyclic group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L. 1-10 substituents can occur wherever possible. When the number of substituents is two or more, each of the substituents may be identical or different.

“5-10-membered nitrogen-containing heterocyclic group” in the term “5-to 10-membered nitrogen-containing heterocyclic group which may have a substituent(s)is, represented by ring D, refers to “5-10-membered nitrogen-containing heterocyclic group”, the above “3-15 membered nitrogen-containing heterocyclic group”represented by ring D. Examples include pyrrolidine, piperidine, piperazine, ASEAN or tropan etc.

“Substituents” in the phrase “5-10-membered nitrogen-containing heterocyclic group which may have a substituent(s)”represented by ring D have the same values as the “substituents” in the phrase “hydrocarbon group which may have a substituent(s)”or “3 to 15-membered heterocyclic group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L. 1-10 substituents can occur wherever possible. When the number of substituents is two or more, each of the substituents may be identical or different.

“Hydroxy group which may be protected”represented by R2is the “hydroxy group which may be protected by a protective group”. “Protective group” hydroxy group includes, for example, (1) C1-6 alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, etc), which may have 1-4 substituent selected from (a) halogen atom such as chlorine, bromine or fluorine itd; (b) C6-10 aryl such as phenyl or naphthyl etc; (c) C7-12 aranceles group such as benzyl or phenylethyl etc.; and (d) a nitro group, etc., (2) C6-10 aryl (e.g. phenyl or naphthyl and so on), which may have 1-4 substituent selected from (a) halogen atom such as chlorine, bromine or fluorine etc; (b) C1-6 alkyl groups such as methyl, ethyl or propyl, etc.; (C) C6-10 aryl such as phenyl or naphthyl etc; (d) C7-12 aranceles group such as benzyl or phenylethyl etc.; and (e) a nitro group, etc., (3) C7-12 aracelio group (for example, benzyl, phenylethyl or naphthylmethyl etc), which may have 1-4 substituent selected from (a) halogen atom such as chlorine, bromine or fluorine etc; (b) C1-6 alkyl groups such as methyl, ethyl or propyl, etc.; (C) C6-10 aryl such as phenyl or naphthyl etc; (d) C7-12 aranceles group such as benzyl or phenylethyl etc.; and (e) a nitro group, etc., (4) formyl, (5) C1-6 alkylcarboxylic group (e.g. acetyl or propionyl etc), which may have 1-4 substituent selected from (a) halogen atom such as chlorine, bromine or fluorine etc; (b) C1-6 alkyl groups such as methyl, ethyl or propyl, etc.; (C) C6-10 aryl such as phenyl or naphthyl etc; (d) C7-12 aranceles group such as benzyl or phenylethyl etc.; and (e) a nitro group, etc., (6) C6-10 aryloxyalkyl group (for example, vinyloxycarbonyl or naphthyloxy boil etc), which may have 1-4 substituent selected from (a) halogen atom such as chlorine, bromine or fluorine etc; (b) C1-6 alkyl groups such as methyl, ethyl or propyl, etc.; (C) C6-10 aryl such as phenyl or naphthyl etc; (d) C7-12 aranceles group such as benzyl or phenylethyl etc.; and (e) a nitro group, etc., (7) C6-10 arylcarbamoyl group (for example, benzoyl or afterburner and etc), which may have 1-4 substituent selected from (a) halogen atom such as chlorine, bromine or fluorine etc; (b) C1-6 alkyl groups such as methyl, ethyl or propyl, etc.; (C) C6-10 aryl such as phenyl or naphthyl etc; (d) C7-12 aranceles group such as benzyl or phenylethyl etc.; and (e) a nitro group, etc., (8) C7-12 aralkylamines group (for example, benzylcarbamoyl or geneticarmor etc), which may have 1-4 substituent selected from (a) halogen atom such as chlorine, bromine or fluorine etc; (b) C1-6 alkyl groups such as methyl, ethyl or propyl, etc.; (C) C6-10 aryl such as phenyl or naphthyl etc; (d) C7-12 aranceles group such as benzyl or phenylethyl etc.; and (e) a nitro group, etc., (9) pyranyl or furanyl that can to have 1-4 substituent selected from (a) halogen atom such as chlorine, bromine or fluorine etc; (b) C1-6 alkyl groups such as methyl, ethyl or n-propyl, etc.; (C) C6-10 aryl such as phenyl or naphthyl etc; (d) C7-12 aralkyl the Noah group such as benzyl or phenylethyl etc.; and (e) a nitro group, etc. or (10) tri-C1-4 alkylsilane such as trimethylsilyl or triethylsilyl etc.

The term “substituents” in the phrase “amino group which may have a substituent(s)”represented by R2includes hydrocarbon group which may have a substituent(s), -SO2R201or =NR202(in which R201and R202represent a hydrocarbon group which may have a substituent(s)). “Hydrocarbon group which may have a substituent(s)”has the same meaning as the “hydrocarbon group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L. 1 or 2 substituent, which has an amino group, can take place wherever possible. When the number of substituents is two or more, each of the substituents may be identical or different. “Amino group which may have a substituent(s)”represented by R2is

or

(in which arrow represents the place of attachment to the ring D, and R51, R52, R53and R54each independently represent a hydrogen atom, a hydrocarbon group which may have a substituent(s), 3-15 membered heterocyclics the group, which may have a substituent(s), C1-4 alkoxy group which may have a substituent(s), phenoxy, which may have a substituent(s), or benzyloxy which may have a substituent(s)). “Hydrocarbon group which may have a substituent(s)” and “3 to 15-membered heterocyclic group which may have a substituent(s)”have the same meaning as the “hydrocarbon group which may have a substituent(s)”, and “3 to 15-membered heterocyclic group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1Lrespectively. “C1-4 alkoxy group” in the “C1-4 alkoxy group which may have a substituent(s)”includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,second-butoxy ortert-butoxy etc. “Substituents” in the phrases “C1-4 alkoxy group which may have a substituent(s)”, “phenoxy group which may have a substituent(s)” and “benzyloxy group which may have a substituent(s)”include, for example, the “substituents” in the phrase “hydrocarbon group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1Land so on

“Uglevodorodno the group, which may have a substituent(s)”represented by R2has the same meaning as the “hydrocarbon group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L. 1 - 10 of deputies, which has a hydrocarbon group, can take place wherever possible. When the number of substituents is two or more, each of the substituents may be identical or different. “Hydrocarbon group which may have a substituent(s)”represented by R2is

(in which arrow represents the place of attachment to the ring D, and R52and R53have the same values as described above).

“3-15 membered heterocyclic group which may have a substituent(s)”represented by R2has the same meaning as “3 to 15-membered heterocyclic group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L.

C1-4 alkyl represented by R6includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,second-butyl,tert-butyl, etc.

“Hydrocarbon group which may have a substituent(s)”represented by R51has the same the values, as the “hydrocarbon group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L.

“C1-15 alkyl”represented by R51has the same values as the “C1-15 alkyl” as the “hydrocarbon group”in the phrase “hydrocarbon group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L.

“Aromatic ring group” in the term “aromatic ring group which may have a substituent(s)”represented by R51refers to mono-, bi - or tricyclic carbocyclic group or heterocyclic group, which has aromaticity” of the “hydrocarbon group” in the phrases “hydrocarbon group which may have a substituent(s)”, and “3 to 15-membered heterocyclic group which may have a substituent(s)”represented by R51. “Mono - bi-or tricyclic carbocyclic group, which has aromaticity”, includes, for example, benzene, azulene, naphthalene, phenanthrene, anthracene ring, etc. “Mono - bi-or tricyclic heterocyclic group which has aromaticity” includes, for example, pyrrole, and Idasa, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazol, thiazole, isothiazol, furazan, oxadiazole, thiadiazole, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzofuran, indazole, quinoline, isoquinoline, purine, phthalazine, pteridine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzimidazole, benzofuran, benzothiadiazole, benzotriazole, carbazole, beta carboline, acridine, fenesin, dibenzofuran, dibenzothiophen, phenanthridine, phenanthroline, pyrimidinone ring etc.

“Substituents” in the phrase “aromatic ring group which may have a substituent(s)”represented by R51have the same values as the “substituents” in the phrase “hydrocarbon group which may have a substituent(s)”or “3 to 15-membered heterocyclic group which may have a substituent(s)”represented by R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1L. 1 - 10 deputies can take place wherever possible. When the number of substituents is two or more, each of the substituents may be identical or different.

“Mono - carbocyclic group or mono - heterocyclic group, which have the aromaticity”represented by R51refer to monocyclic the group of the above “aromatic ring group”, presents R51. Examples include benzene, pyrrole, imidazole, thiazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, oxazole, isoxazol, thiazole, isothiazol, furazan, oxadiazole or thiadiazole ring etc.

“Aromatic ring group which may have a substituent(s)”represented by R56has the same meaning as the above “aromatic ring group which may have a substituent(s)”represented by R51.

Unless specifically mentioned otherwise, in the present invention includes all isomers. For example, alkyl, alkenyl, quinil, alkoxy, alkylthio, alkylene, albaniles and akinyan include straight chain and branched. Moreover, in the present invention includes all isomers, formed by a double bond, ring and condensed ring (E-, Z-, CIS - and TRANS-forms), the isomers formed due to the presence of asymmetric atom(s) carbon, etc. (R-, S-, α - and β-configuration, enantiomer and the diastereoisomer), optically active substances having a polarization plane rotation (D-, L-, d - and l-forms), polar compound chromatographic separation (more polar compound, or less polar compound), equilibrium compounds, rotational isomers, a mixture thereof in any proportion and racemic mixture.

According to the present invention, the symbol Presta which allows β-configuration, and the _ symbol represents α-configuration, β-configuration or a mixture thereof. There is no special limitation on the ratio of α-configuration and β-configuration in the mixture.

Salt:

Salt of the compounds of formula (I) encompasses all of the salts, which are non-toxic or pharmaceutically acceptable salts. As to pharmaceutically acceptable salts, preferred salts, which are low-toxic and soluble in water. Examples of appropriate salts of the compounds of formula (I) are salts with alkali metals (such as potassium, sodium and lithium), salts with alkaline-earth metals (such as calcium and magnesium), ammonium salts (such as Tetramethylammonium salt and tetrabutylammonium salt), salts with organic amines (such as triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Tris(hydroxymethyl)methylamine, lysine, arginine and N-methyl-D-glucamine) and additive salts of acids [such as salts with inorganic acids (for example, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate) and salts with organic acids (e.g. acetate, triptorelin, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, aconsultant, bansilalpet, toluensulfonate, isothionate, glucuronate and gluconate), and others]. With the ü compounds of the present invention includes a solvate, as well as a solvate with the above-mentioned salts of alkali (alkaline earth) metals, ammonium salts, salts of organic amines and acid additive salts. MES is preferably lower toxicity and water-soluble. Examples of corresponding solvate is a solvate with water and alcohol solvent (such as ethanol). Compounds of the present invention are transformed into non-lethal salt or pharmaceutically acceptable salts by known methods.

In addition, the salt comprises a Quaternary ammonium salt. Quaternary ammonium salt compounds represented by the formula (I)is a compound in which the nitrogen of the compounds represented by formula (I), quaternion R0(R0represents C1-8 alkyl or C1-8 alkyl, substituted phenyl).

Salt also includes N-oxide. The compound of the present invention can be converted into N-oxide using known methods. N - oxide is a compound in which the nitrogen compound represented by the formula (I), oxidized.

Prodrugs:

The prodrug compounds of the formula (I) denotes a compound that is transformed into a compound of formula (I) through reaction with Fermentas, gastric acid or similar in a living organism. For example, with regard to prodrugs of the compounds of formula (I)where the compound of formula (I) is no amino group, compounds in which the amino group, for example, alleroed, alkiliruya or fosfauriliruetsa (for example, compounds in which the amino group of compounds of formula (I) acetanilide, alanlarda, intramyocardially, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylethyl, tetrahydrofuranyl, pyrrolidinedione, pivaloyloxymethyl, acetoxymethyl, tert-bottled, etc); when the compound of formula (I) has a hydroxyl group, compounds in which the hydroxyl group, for example, alleroed, alkiliruya fosfauriliruetsa or barrueta (for example, joints, in which the hydroxyl group of compounds of formula (I) azetiliruetsa, palmitoylated, propanolamide, pivaloyloxy, succinimides, fumaroles, lanelines or dimethylaminoethylacrylate); and the carboxy group of the compounds of formula (I), for example, sonoelasticity or amidines (for example, compounds in which the carboxyl group of the compounds of formula (I) is converted into ethyl ester, phenyl ester, phenethyl ester, carboxymethoxy ether, dimethylaminomethylene ether, pivaloyloxymethyl ether, ethoxycarbonylmethylene ether, Caligraphy ester, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ester, cyclohexyloxycarbonyloxy ether or methylamide). These compounds can is to be obtained by the method, known by itself. The prodrug compounds of the formula (I) may be either a hydrate or non-hydrate. The prodrug compounds of the formula (I) may also be a compound that is transformed into a compound of formula (I) under physiological conditions as described in “Iyakuhin no kaihatsu, Vol.7 (Bunshi-sekkei), pp. 163-198 (Hirokawa-Shoten), 1990”. The compound of formula (I) can also be observed with a radioisotope (such as3H,14C,35S125I and others).

In the present invention are preferred all definitions, represented by the symbols R1X, Y, ring A, ring B, ring D, and the symbol R2in the formula (I). All of the characters in each preferably a group, listed below, have the same meanings as described above.

Preferred as R1is, for example, -N(R1A)SO2-R1B, -SO2NR1CR1D, -S(O)mR1G, -CONR1HR1J, -NR1KCOR1Land others, and more preferred is, for example, -N(R1A)SO2-R1B, -SO2NR1CR1D, -S(O)mR1G, -CONR1HR1Jand other Preferred as R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1Lis, for example, a hydrogen atom or a hydrocarbon group which may have a substituent(s), and other More preferred is as R 1is, for example, -NHSO2CH3, -NHSO2CH2CH3, -SO2NHCH3, -SO2CH3, -CONHCH2CH2OCH3and other

Preferred as X is, for example, a bond, -CR7R8-, -NR9-, -CO-, -O-, -S-, -SO-, -SO2- or-C(=N-OR10)and other More preferably X represents a bond, -O - or-CH2and other

Preferred as Y is, for example, methylene, ethylene or propylene and other More preferably Y represents a methylene, ethylene. Most preferably Y is methylene.

Preferably, ring a or ring b is, for example, 5-10-membered carbocyclic group or heterocyclic group” (this applies to 5-10-membered carbocyclic group or heterocyclic group described above 3-15 membered carbocyclic group or heterocyclic group), and other More preferred is, for example, 5-10-membered unsaturated carbocyclic group or heterocyclic group” (this refers to a 5-10 membered unsaturated carbocyclic group or heterocyclic group described above 3-15 membered carbocyclic group or heterocyclic group), and other More preferred is, for example, 5 - or 6-membered aromatic ring, such as benzene, pyrrole, imidazole, triazole, tetraza is inoe, the pyrazole nucleus, pyridine, pyrazinone, pyrimidine, pyridazine, triazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazol, furazane, oxadiazoline or thiadiazoline ring and other Most preferred, for example, benzene or pyridine ring, etc. Preferably, Deputy ring a or ring b is, for example, hydrocarbon group, alkoxy, halogen atom, carboxy, alkanolamide and others, and more preferred is, for example, hydrocarbon group, alkoxy, halogen atom, etc. and the most preferable is, for example, chlorine atom, methyl or methoxy and other

Preferably, ring D represents, for example, 5-10-membered nitrogen-containing heterocyclic group” (this refers to a 5-10 membered nitrogen-containing heterocyclic group described above 3-15 membered nitrogen-containing heterocyclic group), and others, and more preferably is Troyanovo, pyrolidine, piperidine, asianave or pieperazinove ring and others, and most preferred, for example, piperidino ring. Preferably, ring D has no substituent or a substituted hydrocarbon group, mono-C1-4 alkylamino group or di-C1-4 alkylamino group and other Most preferably the D ring does not have a Deputy.

As R2preferably the is, for example, a hydrocarbon group which may have a Deputy(deputies), or amino group which may have a Deputy(deputies), etc. are Preferred as the “substituents” is the “hydrocarbon group which may have a Deputy(deputies)”. Specifically preferred as R2is, for example, a group

or

(where the arrow indicates the position of the connection with the ring D, each of R51, R52, R53and R54independently has the value described above), and other Preferably R51, R52, R53or R54is, for example, a hydrogen atom, a hydrocarbon group which may have a Deputy(deputies), or 3-15 membered heterocyclic group which may have a Deputy(deputies), etc. in Addition, it is the connection that any additional R52and R53represents a hydrogen atom. Preferred as R2is, for example, a group

or

(R55has the same values as the “substituents” in the “hydrocarbon group which may have a Deputy(deputies)”, represented by the symbols R1A, R1B, R1C, R1D, R1E, R1F, R1G, R , R1J, R1Kand R1L, n is 0-5 and the other symbols have the same meanings as described above), etc. are Preferred as R51is, for example, hydrocarbon group which may have a Deputy(deputies), and others, and more preferred is, for example, C1-15 alkyl which may have a Deputy(deputies), C6-14 aryl which may have a Deputy(deputies), or R56, and others, and most preferred, for example, butyl or phenyl, which may have a Deputy(deputies), etc. are Preferable as the substituent is methyl, methoxy, trifluoromethyl, fluorine atom and the others, and more preferred is methyl or fluorine atom. Preferred as R55is, for example, halogen atom, carbarnoyl or aminocarbonyl, substituted C1-8 hydrocarbon group, and others, and more preferred is, for example, fluorine atom, chlorine atom, carbarnoyl, N-methylaminomethyl, etc. as n is 1-3.

Preferred as R56is mono-carbocyclic group or mono-heterocyclic group, which has aromaticity, which may have a Deputy(deputies), and more preferred is a benzene, pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrazinone, pyrimidine, peridas the new oxazoline, isoxazole, thiazole, isothiazol, furazane, oxadiazoline or thiadiazoline ring which may have a Deputy(deputies), and most preferred is a benzene ring which may have a Deputy(deputies). As Deputy preferred methyl, methoxy, trifluoromethyl, fluorine atom, and others, and more preferred is methyl or fluorine atom.

In the present invention, preferred is a compound represented by formula (I)with a combination of the above-described preferred groups and rings.

For example, preferable are compounds in which ring D is piperidine, and Y represents a methylene group, i.e. the compound represented by formula (Ia)

(in which all symbols have the meanings described above); a compound in which ring D is piperidine, and Y represents a methylene group, R2is

(in which all symbols have the meanings described above), i.e. the compound represented by formula (Ib)

(in which all symbols have the meanings described above); a compound in which X represents-O-, Y represents a methylene group, ring a and ring each independently represents a benzene, the which may have a Deputy(deputies), ring D is piperidine, R2is

(in which all symbols have the meanings described above), i.e. the compound represented by formula (Ic)

(in which the ring And1Aand ring In1Aeach independently represents a benzene which may have a Deputy(deputies) and other symbols have the meanings as described above); a compound in which X represents-O-, Y represents a methylene group, ring a and ring each independently represents benzene which may have a substituent(s), ring D is piperidine, R2is

(in which all symbols have the meanings described above), i.e. the compound represented by formula (Id)

(in which all symbols have the meanings described above); a compound in which ring D is Troyanovo ring, and Y represents a methylene group, R2is

(in which all symbols have the meanings described above), i.e. the compound represented by formula (Ie)

(in which all symbols have the meanings described above); a compound in which ring D is a pyrolidine ring, and Y represents a methylene group, R 2is

(in which all symbols have the meanings described above), i.e. the compound represented by formula (If)

(in which all symbols have the meanings described above); a compound in which ring D is piperidine and Y represents a methylene group, R2is

(in which all symbols have the meanings described above), i.e. the compound represented by formula (Ig)

(in which all symbols have the meanings described above); a compound in which ring D is asianova ring and Y represents a methylene group, R2is

(where all the symbols have the same meaning as described above), i.e. the compound represented by formula (Ih)

(where all the symbols have the same meaning as described above), its salts, its N-oxides, its solvate and prodrug.

Preferred are the compounds in the Examples and their salts, their N-oxides, their solvate and prodrug. More preferred are

(1) 5-({[butyl(1-{4-[4-(methylsulphonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-diflorasone,

(2) 5-[({butyl[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-PI is original]amino}carbonyl)amino]-2,4-diflorasone,

(3) 5-({[butyl(1-{[6-(4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)-3-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-diflorasone,

(4) 5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-diflorasone,

(5) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide,

(6) 5-{[(butyl{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2-chloro-4-perbenzoic,

(7) 2-(5-{[(butyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differenl)ndimethylacetamide,

(8) 5-[({butyl[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-debtor-N-methylbenzamide,

(9) 5-{[(butyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-diflorasone,

(10) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(11) 5-[({butyl[1-(4-{4-[(methylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-diflorasone,

(12) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(13) N-[4-({5-[(4-{3-thienyl[(3-thienylene)carbonyl]amino}-1-piperidinyl)methyl]2-pyridinyl}oxy)phenyl]methanesulfonamide,

(14) 2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(15) N-{4-[4-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl) - for 3,5-dimethyl-1H-pyrazole-1-yl]phenyl}methanesulfonamide,

(16) 4-[4-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl) - for 3,5-dimethyl-1H-pyrazole-1-yl]-N-[2-(4-morpholinyl)ethyl]benzosulfimide,

(17) N-(4-{[5-({4-[{[(2,4-differenl)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(18) 2-chloro-N-methyl-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(19) N-(4-{[5-({4-[({[4-chloro-3-(4-morpholinylcarbonyl)phenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(20) 2-fluoro-5-{[((3-forfinal){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide,

(21) N-(3-forfinal)-N'-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]urea,

(22) 2-[4-({4-[[({4-fluoro-3-[(methylsulphonyl)amino]phenyl}amino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulphonyl)amino]benzamide,

(23) 2-fluoro-N-methyl-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(24) 2-fluoro-N-methyl-({[[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide,

(25) 2-[4-({4-[({[3-(acetylamino)-4-forfinal]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulphonyl)amino]benzamide,

(26) N'-(4-forfinal)-N-[1-({6-[4-(methylsulphonyl)phenoxy]pyridine-3-yl}methyl)piperidine-4-yl]-N-phenylacetone,

(27) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(28) N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide", she

(29) N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,

(30) 5-[({butyl[1-(4-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-diflorasone,

(31) N-(4-{[5-({4-[{[(2,4-differenl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide,

(32) N-(4-{[5-({4-[{[(4-were)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(33) N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(34) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)acetamide", she

their salts, their N-oxides, their solvate and prodrug etc.

More preferred are

p> 2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide", she

N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,

5-[({butyl[1-(4-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-diflorasone,

N-(4-{[5-({4-[{[(2,4-differenl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide,

N-(4-{[5-({4-[{[(4-were)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)acetamide", she

their salts, their N-oxides, their solvate and prodrug etc.

The present invention also preferred are

(1) N-{4-[(5-{[4-((3-were){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}IU unsulfonated,

(2) N-(2-fluoro-5-{[((3-were){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)acetamide", she

(3) N-(2-fluoro-5-{[((3-forfinal){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)acetamide", she

(4) N-(2-fluoro-5-{[((3-forfinal){1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)acetamide", she

(5) N-[5-({[{1-[(6-{2-chloro-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-forfinal)amino]carbonyl}amino)-2-forfinal]ndimethylacetamide,

(6) N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-3-were}methanesulfonamide,

(7) N-{3-chloro-4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide,

(8) 2-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-5-[(methylsulphonyl)amino]benzamide,

(9) 2-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-N-methyl-5-[(methylsulphonyl)amino]benzamide,

(10) N-[4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-(methylsulphonyl)phenyl]methanesulfonamide,

(11) N-{2-[(5-{[4-((3-were){[(6-methyl-3-pyridinyl)amino]Carboni is}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-5-[(methylsulphonyl)amino]phenyl}acetamide", she

(12) N-(4-{[5-({4-[[[(4-forfinal)amino](imino)methyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(13) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonothioyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(14) 2-fluoro-N-methyl-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-3-azetidinol}(phenyl)amino]carbonyl}amino)benzamide,

(15) N-(4-{[5-({(3R)-3-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(16) N-[2-fluoro-5-({[{(3S)-1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-3-pyrrolidinyl}(phenyl)amino]carbonyl}amino)phenyl]acetamide", she

(17) N-(4-{[5-({(4R)-4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-azepane}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(18) N-(4-{[5-({(4S)-4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-azepane}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(19) 2-fluoro-5-({[(1-{[6-({4-[(methylsulphonyl)amino]phenyl}sulfonyl)-3-pyridinyl]methyl}-4-piperidinyl)(phenyl)amino]carbonyl}amino)benzamide,

(20) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]methyl}phenyl)methanesulfonamide,

(21) 2-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(3-forfinal)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulphonyl)amino]benzamide,

(22) N-(3-were)-N'-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulfone is)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]urea,

(23) N-[1-({6-[4-(ethylsulfonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-(3-forfinal)-N'-(6-methyl-3-pyridinyl)urea,

(24) N-(3-forfinal)-N-[1-({6-[4-(isopropylphenyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N'-(6-methyl-3-pyridinyl)urea,

(25) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]methyl}phenyl)econsultant,

(26) 2-fluoro-5-{[((3-forfinal){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-3-azetidinol}amino)carbonyl]amino}benzamide,

(27) N-(4-{[5-({4-[{[(6-ethyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(28) N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-6-methyl-2-pyridinyl)oxy]phenyl}methanesulfonamide,

(29) N-[2-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-5-(methylsulphonyl)phenyl]acetamide", she

(30) N-(4-{[5-({4-[{[(6-ethyl-3-pyridinyl)amino]carbonyl}(3-forfinal)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(31) N-{2-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(3-forfinal)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulphonyl)amino]phenyl}acetamide", she

(32) N-{2-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)methyl]-5-[(methylsulphonyl)amino]phenyl}acetamide", she

(33) N-[4-(5-{[4-((3-fluoro who enyl){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)phenyl]methanesulfonamide,

(34) 2-fluoro-5-({[{1-[(2-methyl-6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(35) N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)sulfonyl]phenyl}methanesulfonamide,

(36) N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(3-were)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(37) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(3-were)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(38) 2-fluoro-5-({[{1-[(2-methyl-6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-were)amino]carbonyl}amino)benzamide,

(39) N-ethyl-2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(40) 2-fluoro-N-methyl-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonothioyl}amino)benzamide,

(41) 2-fluoro-5-{[((3-forfinal){(3S)-1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-3-pyrrolidinyl}amino)carbonyl]amino}-N-methylbenzamide,

(42) N-[5-({[{(4S)-1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-azepane}(phenyl)amino]carbonyl}amino)-2-forfinal]ndimethylacetamide,

(43) 2-{[5-({4-[({[3-(acetylamino)-4-forfinal]amino}carbonyl)(3-forfinal)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-N-methyl-5-[(methylsulfonyl the l)amino]benzamide,

(44) N-[5-({[{1-[(6-{2-chloro-4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-forfinal)amino]carbonyl}amino)-2-forfinal]ndimethylacetamide,

(45) 5-({[{(3R)-1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-3-pyrrolidinyl}(phenyl)amino]carbonyl}amino)-2-perbenzoic,

(46) N-(3-chloro-4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(47) 5-({[{1-[(6-{2-(aminocarbonyl)-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-forfinal)amino]carbonyl}amino)-2-fluoro-N-methylbenzamide,

(48) 2-fluoro-N-methyl-5-({[{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(49) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]sulfonyl}phenyl)methanesulfonamide,

(50) 2-fluoro-N-methyl-5-{[((3-were){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide,

(51) 2-fluoro-5-{[((3-were){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide,

(52) 2-fluoro-5-{[((3-forfinal){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-N-methylbenzamide,

(53) N-(3-methyl-4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]ACS is}phenyl)methanesulfonamide,

(54) N-(3-chloro-4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(55) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)econsultant,

(56) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyrazinyl]oxy}phenyl)methanesulfonamide,

(57) N-(4-{[5-({(3S)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(58) N-(4-{[5-({(4S)-4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-azepane}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(59) N-(4-{[5-({(3R)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide,

(60) 2-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulphonyl)amino]benzamide,

(61) 2-{[5-({4-[({[3-(acetylamino)-4-forfinal]amino}carbonyl)(3-forfinal)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulphonyl)amino]benzamide,

(62) 2-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulphonyl)amino]benzamide,

(63) N-[4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-3-(methylsulphonyl)phenyl]methanesulfonamide,

(64) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]methyl}phenyl)methanesulfonamide,

(65) N-{4-[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]phenyl}methanesulfonamide,

(66) N-{4-[(5-{[4-((3-were){[(6-methyl-3-pyridinyl)-amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-phenyl}methanesulfonamide,

(67) N-[5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-forfinal)amino]carbonyl}amino)-2-forfinal]ndimethylacetamide,

(68) 2-fluoro-5-({[{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]-phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide,

(69) N-[5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)-2-perbenzoic, and

(70) N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)-amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-phenyl}econsultant, their salts, their N-oxides, their solvate and prodrug.

The process for obtaining compounds of the present invention:

The compound of the present invention represented by the formula (I)can be obtained by methods that adequately improve and combine well-known methods such as methods described below, the methods described in the Examples or the methods described in theComprehensive Organic Transformations: A Guide to Functional Group Preparations,2ndEditin (Richard C. Larock, John Willey & Sons Inc, 1999). Each method described below, the source material may be used in the form of its salt. Example salt includes a salt of the compounds of formula (I)described above.

Among the compounds represented by formula (I), the compound in which the spacer is adjacent to the ring D represents-CH2-, -CO - or-SO2-can be obtained by alkylation, amidation or sulfonmethane compound represented by the formula (1)

(in which Z represents a hydroxy group or a leaving group (e.g. halogen atom p-toluensulfonate group, methanesulfonate group, tripterocalyx group and others), Y1Prepresents a bond or a spacer containing 1 or 2 atoms as a main chain, Y2Prepresents-CH2-, -CO - or-SO2-, and R1PXPring APand ring BPhave the same meaning as R1, X, ring a and ring B, respectively, provided that the carboxy group, hydroxy, amino or mercapto group in R1PXP, Y1P, Y2P, ring APand ring BPcan be protected, if necessary. Other symbols have the same meanings as described above) and a compound represented by the formula (2)

(where R2Pand ring DPhave the same value the tion, and R2and D, respectively. Provided that the carboxy group, hydroxy, amino or mercapto group in R2Por ring DPcan be protected, if necessary)if necessary, followed by removal of the protective group.

The alkylation is well known. For example, it may be carried out in an organic solvent (e.g. dimethylformamide, dimethyl sulfoxide), in the presence of alkali (e.g. potassium carbonate, sodium carbonate, triethylamine, etc. and in the presence or absence of sodium iodide or potassium iodide at about 0-150°C.

The amidation is known. For example, it includes the way

(1) through allalone,

(2) via a mixed acid anhydride,

(3) using a condensing agent.

These methods are explained as follows.

(1) the Way through allalone may be, for example, through reaction of carboxylic acid with allelochemical (for example, oxalylamino or thionyl chloride) in an organic solvent (e.g. chloroform, dichloromethane, diethyl ether or tetrahydrofuran) or without a solvent at a temperature of from about -20°C. to the boiling temperature under reflux. And then acylhomoserine derivative may be reacted with amine in an organic solvent (e.g. chloroform, dichloro is not, diethyl ether or tetrahydrofuran) in the presence of a base (e.g. pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or diisopropylethylamine etc) at about 0-40°C. alternatively, the received acylhomoserine derivative may be reacted with amine in an organic solvent (e.g. dioxane, tetrahydrofuran) using an alkaline aqueous solution (for example, sodium bicarbonate, sodium hydroxide) at about-78-40°C.

(2) the Method via a mixed acid anhydride may be carried out, for example, through reaction of carboxylic acid with allelochemical (for example, revalorisation, p-toluensulfonate or methanesulfonamido) or acid derivative (for example, etelcharge.com or isobutylparaben) in an organic solvent (e.g. chloroform, dichloromethane, diethyl ether or tetrahydrofuran) or without a solvent, in the presence of a base (e.g. pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or diisopropylethylamine) at about 0-40°C. And then the obtained mixed cyclotouriste derivative may be reacted with amine in an organic solvent (e.g. chloroform, the methylene chloride, diethyl ether or tetrahydrofuran) at about 0-40°C.

(3) the Method using Conde is shirousagi agent can be carried out, for example, using the reaction of carboxylic acid with amine in an organic solvent (e.g. chloroform, dichloromethane, dimethylformamide, diethyl ether or tetrahydrofuran) or without a solvent, in the presence or absence of a base (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine), using a condensing agent (for example, 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbodiimide (CDI), 2-chloro-1-methylpyridinium or cyclic anhydride 1-papapostolou acid (PPA)), in the presence or absence of 1-hydroxybenzotriazole (HOBt), at about 0-40°C.

The reaction described in (1), (2) and (3)may be carried out in an atmosphere of inert gas (e.g. argon, nitrogen) to avoid water in order to obtain the preferred result.

Sulfenamidovy well known. For example, it may be carried out using the reaction of sulfonic acid with allelochemical (for example, oxalylamino or thionyl chloride, pentachloride phosphorus or trichloride phosphorus) in an organic solvent (e.g. chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran ortert-butyllithium ether) or without solvent at a temperature of from about -20°C. to the boiling point. And then received sulfone the halide derivative may be reacted with amine in an organic solvent (for example, chloroform, dichloromethane, diethyl ether or tetrahydrofuran) in the presence of a base (for example, diisopropylethylamine, pyridine, triethylamine, dimethylaniline or dimethylaminopyridine or etc) at about 0-40°C.

The removal of the protective group is known and can be carried out by the following method.

Carbonyl-protective group includes, for example, methyl, ethyl, allyl,tert-butyl, trichloroethyl, benzyl (Bn) or pencil etc.

The protective group of hydroxy group includes, for example, methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES),tert-butyldimethylsilyl (TBDMS),tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc) and 2,2,2-trichlorocyanuric (Troc) and other

The protective group for the amino group includes such as benzyloxycarbonyl,tert-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)etoxycarbonyl (Bpoc), TRIFLUOROACETYL, 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl, benzoyloxymethyl (BOM) or 2-(trimethylsilyl)ethoxymethyl (SEM) and other

The protective group of the mercapto group includes, for example, benzyl, methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP), diphenylmethyl and acetyl (Ac) and other

As for the protective group for carboxyl, Hydra is xela, amino and mercapto, in respect of the above groups there are no special restrictions until such time as it is a group which can easily and selectively be chipped off. For example, the reaction of removing the protection can be carried out according to the method mentioned in “T. W. Greene,Protective Groups in Organic Synthesis, John Willey & Sons Inc, 1999”.

The reaction of removing the protective group for carboxyl, hydroxyl, amino and mercapto is known and its examples are as follows.

(1) reaction unprotect using hydrolysis with alkali;

(2) the reaction of removing the protection in acidic conditions;

(3) reaction unprotect using hydrogenolysis;

(4) the reaction unprotect silila;

(5) the reaction remove protection using metal; and

(6) the reaction remove protection using metal complex.

These methods will be specifically illustrated as follows.

(1) Reaction unprotect using alkali is carried out, for example, at about 0-40°C using a hydroxide of alkaline metal (such as sodium hydroxide, potassium hydroxide and lithium hydroxide), a hydroxide of alkaline-earth metal (such as barium hydroxide and calcium hydroxide), a carbonate (such as sodium carbonate and potassium carbonate), an aqueous solution or a mixture of them in an organic solvent (e.g. methanol, tetrahydrofuran and dioxane other)

(2) the Reaction of removing the protection in acidic conditions is carried out, for example, at about 0-100°C. in an organic acid (e.g. acetic acid, triperoxonane, methanesulfonate or p-toluensulfonate acid), inorganic acid (e.g. hydrochloric and sulfuric acid) or mixtures thereof (such as hydrogen bromide/acetic acid) in an organic solvent (such as dichloromethane, chloroform, dioxane, ethyl acetate and anisole, and others).

(3) Reaction unprotect using the hydrogenolysis is carried out, for example, about 0-200°C in hydrogen atmosphere under normal pressure or high pressure or in the presence of ammonium formate in the presence of a catalyst (such as palladium-carbon, palladium black, palladium hydroxide, platinum oxide and Raney Nickel) in a solvent [such as solvent type simple ether (such as tetrahydrofuran, dioxane, dimethoxyethane and diethyl ether), solvent of alcohol type (such as methanol and ethanol), a benzene type (such as benzene and toluene), type ketone (such as acetone and methyl ethyl ketone), a nitrile type (such as acetonitrile), type amide (such as dimethylformamide), water, ethyl acetate, acetic acid or a mixed solvent composed of two or more of them].

(4) the Reaction of deprotection or unprotect silila is carried out, for example, at about 0-40°C With ISOE what Lovanium of tetrabutylammonium fluoride in an organic solvent, miscible with water (such as tetrahydrofuran and acetonitrile, and others).

(5) the Reaction unprotect using the metal is, for example, at about 0-40°C With or without ultrasonic radiation in the presence of powdered zinc in an acid solvent such as acetic acid, a buffer of pH 4.2 to 7.2 and a mixed solution of a solution with an organic solvent, such as tetrahydrofuran).

(6) Reaction to unprotect the use of a complex of the metal is, for example, at about 0-40°C. using a metal complex [such as tetranitropentaerithrite (0), dichloride, bis(triphenylphosphine)palladium (II)acetate, palladium (II) chloride, Tris(triphenylphosphine)rhodium (I)] in the presence or absence of a phosphine agent (such as triphenylphosphine), in the presence of a capture reagent (such as tributylamine, triethylsilane, dimedone, morpholine, diethylamine and pyrrolidine), organic acids (such as acetic acid, formic acid and 2-atelophobia acid and/or salts of organic acids (such as 2-ethylhexanoate, sodium 2-ethylhexanoate and potassium) in an organic solvent (such as dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane and ethanol), water or a mixed solvent of these.

In addition to the above, removing the protective whom you may also be conducted, for example, in accordance with the methods described in T. W. Greene,Protective Groups in Organic Synthesis, Willey, New York, 1999.

Specialists in the art can easily understand that the target compound of the present invention can be easily obtained using the corresponding reactions of reactions unprotect.

Among the compounds of the present invention represented by the formula (I), the compound in which R2represents an amino group which may have a Deputy(deputies), i.e. the compound represented by formula (I-a)

(in which R2-1represents an amino group which may have a Deputy(deputies), and other symbols have the meanings described above), can be obtained through reductive amination of the compounds represented by formula (3)

(in which all other symbols have the meanings described above), and compounds represented by the formula (4)

(in which R301and R302that are the same or different, each represents a hydrogen atom or have the same values as the “substituents” of the above “amino group which may have a Deputy(deputies), and other symbols have the meanings described above, provided that the carboxy, hydroxy, amine is or mercapto group in R 301and R302may be, if necessary, protected), followed, if necessary, removing the protective group.

Reductive amination is well known. For example, it may be carried out using a reducing agent (for example, triacetoxyborohydride sodium or cyanoborohydride sodium) at about 0-40°C. in an organic solvent (e.g. dichloroethane, dichloromethane or dimethylformamide) in the presence or absence of tertiary amine (e.g. triethylamine or diisopropylethylamine), in the presence or absence of acetic acid.

The removal of the protective group can be carried out using the above method.

Among the compounds of the present invention represented by the formula (I), the compound in which R2is

(in which all symbols have the meanings described above), i.e. the compound represented by formula (I-d)

(in which all symbols have the meanings described above)can be obtained using the following reaction using the compound represented by formula (5)

(in which R51Phas the same meaning as R51and other symbols have the meanings described above, provided that the carboxy, hydroxy, amino or mercapto g is the UPP R 51Pif you can be protected) and compounds represented by the formula (6)

(in which R52Phas the same meaning as R52and other symbols have the meanings described above, provided that the carboxy, hydroxy, amino or mercapto group in R52Pif necessary, can be protected, if necessary, followed by removal of the protective group.

The reaction is well known. For example, it may be carried out in an organic solvent (such as N,N-dimethylformamide, toluene or tetrahydrofuran) using a base (e.g. pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or diisopropylethylamine) about 20-120°C.

The removal of the protective group can be carried out using the above method.

In addition, the compound represented by formula (I-d)can be obtained by using the reaction of formation of urea using compounds represented by formula (5), and compounds represented by the formula (7)

(in which the symbol has the value described above), if necessary with subsequent removal of the protective group.

The reaction is well known. For example, it may be carried out in an organic solvent (such as tetrahydrofuran or N,N-dimethylformamide) at outstay of triphosgene using a base (for example, of triethylamine) at about 0-40°C. in Addition, it can be carried out in an organic solvent (such as dichloromethane or N,N-dimethylformamide) in the presence of 1,1'-carbonylbis-1H-imidazole (CDI) using a base (e.g. triethylamine or N-methylmorpholine) or without reason at about 0-80°C.

The removal of the protective group can be carried out using the above method.

Among the compounds of the present invention represented by the formula (I), the compound in which Y is methylene, i.e., the compound represented by formula (Ie)

(in which all symbols have the meanings described above), can be obtained through reductive amination of the compounds represented by formula (8)

(in which all symbols have the meanings described above), and compounds represented by the formula (2), followed, if necessary, removing the protective group.

Reductive amination and the removal of the protective group can be carried out using the above method.

Among the compounds represented by formula (I), a compound in which at least one nitrogen atom is Quaternary ammonium salt, i.e. the compounds of formula (I-2)

(in which R1-2, R2-2X2, Y2 ring A2ring B2and ring D2have the same meaning as R1, R2X, Y, ring A, ring B and ring D, respectively, and N2represents a nitrogen atom, provided that at least one nitrogen atom is Quaternary ammonium salt, and Q-represents a halogen ion), can be obtained by reaction of compounds of formula(I) with compounds of the formula (9)

(in which R0represents C1-8 alkyl or C1-8 alkyl substituted by phenyl, and Q is halogen).

This reaction is well known and can be carried out, for example, in an organic solvent (acetone, dimethylformamide or methyl ethyl ketone, etc.) at about 0-40°C.

Among the compounds of formula (I) compound in which at least one nitrogen is N-oxide, i.e. the compound of formula (I-3)

(in which R1-3, R2-3X3, Y3ring A3ring B3and ring D3have the same meaning as R1, R2X, Y, ring A, ring B and ring D, respectively, and N3represents a nitrogen atom, provided that at least one nitrogen atom is N-oxide), can be obtained by oxidation of compounds of formula (I).

Oxidation is a well known and can be carried out, for example, suitable for the clients in an organic solvent (for example, dichloromethane, chloroform, benzene, hexane or tert-butyl alcohol) in the presence of excess oxidizing agent (hydrogen peroxide, periodate sodium, acilitate, sodium perborate, peroxy acids (for example, 3-chloroperbenzoic acid or peracetic acid, and others), OXONE (name brand, OXON is the acronym for peroxymonosulfate potassium), potassium permanganate or chromic acid, and others) at about 20-60°C.

The compound of the present invention can be obtained with the help of these reactions or partially modified reactions.

Other parent compound or compounds used as reagents are known and can easily be obtained using a combination of known methods, for example, the methods described inComprehensive Organic Transformations: A Guide to Functional Group Preparations,2ndEdition (Richard C. Larock, John Willey & Sons Inc, 1999) or Elmer J. Rauckman et al.,J. Org. Chem., vol.41, No.3, 1976, pp. 564-565, etc.

In each reaction are given in the description, reaction temperature, as it is obvious to experts in the art, can be carried out with a water bath, oil bath, sand bath and microwave radiation.

In each reaction in the description can be used in solid-phase reagent, which precipitated polymer (for example, polystyrene, polyacrylamide, polypropylene or polietileno the Les and others).

In each reaction in the description of the products obtained can be purified using conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, high performance liquid chromatography with Staghelm or magnesium silicate, thin layer chromatography, ion-exchange resins that absorb or acceptor resin column chromatography, washing, or crystallization. Cleaning may be performed after each reaction or after several reactions.

In the reaction using a polystyrene resin, contained in the description, the products obtained can be purified using conventional techniques. For example, purification may be carried out by rinsing them solvent (dimethylformamide, dichloromethane, methanol, tetrahydrofuran, toluene, a mixture of acetic acid/toluene, and others) more than once.

Toxicity:

The toxicity of the compounds represented by formula (I), its salt, N-oxide or MES, or its prodrugs (called hereafter “compound of the present invention”) is very low and therefore it can be considered safe for pharmaceutical use.

Application for pharmaceutical purposes:

The compound of the present invention has good solubility and absorbiruyaci. The connection of this image is the shadow has a weak inhibitory activity against enzymes metabolizing the drug. These harakteristiki represent physical, chemical, and pharmaceutical properties of the presented medicines and compounds of the present invention have adequate conditions for otnoshenii to excellent medicines [see (The Merck Manual of Diagnosis and Therapy(17thEd.), Merck & Co.)].

The fact that the compound of the present invention is useful as a drug, can be estimated using various experimental methods, described below, the methods described in biological examples, and properly streamlined ways. Using well-known methods can also easily appreciate that the compound of the present invention has good pharmacokinetic properties, such as the duration of the half-life of serum stability in the gastrointestinal tract, absorption of oral drugs, bioavailability, and others, for example, by the method described in “Yakubutsu bioavailability (Hyouka to kaizen no depending), July 6, 1998, Gendaiiryou-sha” and other

(I) the Experiment for the evaluation of inhibitory activity of compounds of the present invention against enzymes metabolizing the drug.

(i) Inhibiting activity against human CYP2C9

Inhibiting activity of the compounds of the present invention against human CYP2C9 can is about to evaluate by the method of Sato et al. (Yakubutsudotai (Xenobio. Metabol. And Dispos.), 16(2), 115-126 (2001)), which is improved with respect to the accuracy of the analysis and/or sensitivity analysis.

(ii) Inhibiting activity against CYP3A4 person

Inhibiting activity of the compounds of the present invention against human CYP3A4 can be estimated by using the improved method described inDrug Metabolism and Disposition, Vol.28(12), 1440-1448 (2000).

For example, prepare a reaction solution consisting of fosfornocalzievogo buffer (pH 7.4) (final concentration: 200 mm), uranyl magnesium chloride (final concentration: 5 mm), substrate (7-benzyloxyaniline (7-BQ), the final concentration of 40 μm) and microsome assay expression system (Daiichikagakuyakuhin, final concentration: 0.25 mg/ml 100 ál of the reaction solution is distributed on 96-well tablet and gobalet 50 μl of an aqueous solution containing the test compound and 0.8% of acetonitrile, to implement the 10-minute pre-incubation at 37°C. For initiation of the reaction, add 50 ál of recovered adenine dinucleotide phosphate (NADPH, 4 mm). The fluorescence intensity of each well was measured at the time when add NADPH, and after incubation for 30 minutes. Measure the wavelength of excitation at 409 nm and emission wavelength at 530 nm of chinoline, which is a metabolite of the substrate. Extent the ü inhibition (%) test compound is calculated using the following computational formula of obtaining indicator IC 50(IR50).

The degree of inhibition (%) = [1-{(measured value with the addition of the test compound)-(blank value)/(benchmark-idle rate}}]x100.

(II) an Experiment on evaluation of the toxicity

(i) the Test for acute toxicity in rats

The test compound is administered six-week rat Crj:CD (SD) as a single intravenous dose or a single oral administration. Toxicity can be assessed by contrast with the indicator, when the test compound was not added. The main toxicity assessment can be conducted, for example, by monitoring the state committed acts or locomotor activity, etc.

(ii) evaluation of the activity of the compounds of the present invention against hERG IKrcurrent

According to Zouet al. (Biophys. J., Vol.74, 230-241 (1998)), using HEK293 cells sverkhekspressiya specific gene potassium channels of the human heart (human ether-a-go-go-related gene (hERG)), using the Desk of fixation potential maximum quantitative measure progress hERGIKrcurrent induced depolarization pulse with subsequent repolarization pulse. The degree of change (the degree of inhibition) is calculated by quantitative comparison of maximum stroke between the period before adding the test compound and after 10 minutes of th is. The effect of test compounds on hERGIKrthe current can be estimated by the degree of inhibition.

Compounds of the present invention have an antagonistic activity against receptor of the chemokine, especially CCR5, in animals, including humans, especially humans, so they are useful in the prevention and/or treatment associated with CCR5 diseases, for example, various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, inflammatory bowel disease, such as aswany colitis and others), immunological diseases (autoimmune diseases, rejection in organ transplantation (transplant rejection, solid organ transplant rejection of pancreatic islet cells for the treatment of diabetes, GVHD (disease graft-versus-host), etc), immunosuppression, psoriasis, multiple sclerosis, and others), infectious diseases (infection with human immunodeficiency virus, acquired immunodeficiency syndrome, RSV infection, and others), allergic diseases (atopic dermatitis, urticaria, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis, etc), cardiovascular diseases (arteriosclerosis, ischemic reperfusion injury, and others), syndrome and acute respi atomnogo distress, shock accompanying bacterial infection, diabetes, metastasis of cancer, and so on.

Compounds of the present invention have inhibitory activity against cell migration in animals, including humans, especially humans, so they are useful in the prevention and/or treatment of various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, inflammatory bowel disease, such as aswany colitis and others), immunological diseases (autoimmune diseases, rejection in organ transplantation (transplant rejection, solid organ transplant rejection of pancreatic islet cells for the treatment of diabetes, GVHD, etc.), immunosuppression, psoriasis, multiple sclerosis and others), infectious diseases (infection with human immunodeficiency virus, acquired immunodeficiency syndrome, RSV infection and others), allergic diseases (atopic dermatitis, urticaria, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis, and others), cardiovascular diseases (arteriosclerosis, ischemic reperfusion injury, and others), syndrome of acute respiratory distress, shock accompanying bacterial infection, diabetes, metastasis of the cancer and the AK next.

For the above purpose, the compounds of the present invention will normally be administered systemically or locally, usually by oral or parenteral administration.

Input dose is determined according to, for example, the age, body weight, symptom, the desired therapeutic effect, the route of administration and duration of treatment. In adults, the doses per person are generally from 1 mg to 1000 mg via oral administration up to several times a day and from 1 mg to 100 mg with parenteral administration (preferably intravenous administration) to Descalzi times per day or continuous injections from 1 to 24 hours a day in the veins.

As mentioned above, the doses depend on various factors. Therefore, there are cases in which can be used doses lower or higher than the above intervals.

Compounds of the present invention can be administered, for example, in the form of a solid preparation for oral administration in liquid form for oral administration, injections, liniments (dosage forms for external use) or medical suppositories for parenteral administration.

Solid forms for oral administration include compressed tablets, pillule, capsules, dispersible powders and granules. Capsules include hard and soft capsules.

In such the solid forms one or more active compounds can be mixed with fillers such as lactose, mannitol, glucose, microcrystalline cellulose or starch), binders (such as hydroxypropylcellulose, polyvinylpyrrolidone or aluminate of metasilicate magnesium), dezinfeciruyuhimi or loosening agents (such as calcipala cellulose), lubricating agents (such as magnesium stearate), stabilizing agents and adjuvantly solutions (such as glutamic acid or aspartic acid), and they are prepared in accordance with methods well known in normal pharmaceutical practice. Solid forms may optionally be coated with coating agents (such as sugar, gelatin, hydroxypropylcellulose or phthalate of hydroxypropylmethylcellulose), or be coated with two or more films. And, in addition, the coating may include the content inside capsules of absorbable material such as gelatin.

Liquid forms for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs. In such forms one or more active compounds can dissolve suspendibility or emulgirovanija in diluents commonly used in the art (such as purified water, ethanol or their mixture). In addition, such liquid forms may also include additives such as wetting agents, suspendresume agents,emulsifying, sweetening, flavoring agents, fragrances, preservatives or buferiruemoi agents.

Injectable preparations for parenteral administration include sterile aqueous preparations, suspensions, emulsions and solid forms that dissolve or suspendered in solvents for injection immediately before use. In injecting drugs one or more active compounds can dissolve suspendibility or emulgirovanija in solvents. Solvents may include distilled water for injection, saline, vegetable oil, propylene glycol, polyethylene glycol, an alcohol, such as ethanol, or mixtures thereof. Injectable preparations can include some additives, such as stabilizing agents, adjuvant solutions (such as glutamic acid, aspartic acid or POLYSORBATE (registered trademark)), suspendida, emulsifying, soothing agents, buferiruemoi agents, preservatives. At the final stage they can be sterilized or can be prepared sterile methods. They can also be made in the form of sterile solid dosage forms, such as freeze dried foods that can directly before use to dissolve in sterile water or some other sterile diluent for injecti is.

Other forms for parenteral administration include liquids for external use, ointments and intradermal liniments, inhalations, sprays, medical suppositories and vaginal suppositories, which consist of one or more active compounds and can be prepared by methods known per se.

Sprays can include additional substances other than the diluents commonly used, stabilizers, such as sodium bisulfite, and the buffers are able to give isotonicity, for example, isotonic buffers, such as sodium chloride, sodium citrate or citric acid.

Compounds of the present invention can be used in conjunction with other drugs, for example, a prophylactic and/or therapeutic agents against HIV infection (in particular, agents for prevention and/or treatment of AIDS or agents against rejection of organs in transplantation and/or for the treatment of autoimmune diseases. In this case, the medicine, as such, can be mixed with pharmacologically acceptable excipients, binders, dezintegriraat agent, lubricant, stabilizer, solubilizer, solvent, etc. or separately or simultaneously with the manufacture of a pharmaceutical preparation, and may be injected or orally, or parenterally in the form of a pharmaceutical composition for prevention and/and the and treatment of HIV infections, rejection of organs in transplantatio and/or autoimmune diseases.

Compounds of the present invention have activity of inhibiting HIV that has become resistant to other agents for the prevention and/or treatment of HIV infection in particular agents for the prevention and/or treatment of AIDS. Therefore, they can also be used for HIV-infected patients for whom other agents for the prevention and/or treatment of HIV infection is no longer effective. In this case, although the connection of the present invention can be used one, it may also be used together with agents for the prevention and/or treatment of HIV infection when HIV infecting strain has become resistant, or with other medicines.

The present invention covers the combination of the compounds of the present invention with drugs that do not inhibit HIV infection, what are the preventive and/or therapeutic effect on HIV infection increases compared with single drug.

Examples of other agents for the prevention and/or treatment of HIV infection, used for combining with the compounds of the present invention, are nucleoside reverse transcriptase inhibitor, protease inhibitor, antagonist of a chemokine (such as CCR2 antagonist, CCR3 antagonist, CCR4 antagonist, CCR5 ant who honest, CXCR3 antagonist and CXCR4 antagonist), an integrase inhibitor, fusion inhibitor, antibody to surface antigen of HIV and HIV vaccines.

Reverse transcriptase inhibitors are in particular (1) inhibitors nucleoside/nucleotide reverse transcriptase inhibitors: zidovudine (name brand: Retrovir), didanosine (name brand: videx), zalcitabine (name brand: HIVID), stavudine (name brand: Zerit), lamivudine (name brand: Epivir), abacavir (name brand: Ziagen), adefovir, depositdeposit, emtricitabine (name brand: Coviracil) or RMR (name brand: Tenofovir), etc. and (2) inhibitors non-nuke reverse transcriptase inhibitors: nevirapine (name brand: viramune), delavirdine (name brand: Rescriptor), efavirenz (name brand: Sustiva, Stocklin) or capravirine (AG1549) and other

Protease inhibitors are, in particular, indinavir (name brand: Crixivan), ritonavir (name brand: Norvir), nelfinavir (name brand: Viracept), saquinavir (name brand: Invirase, Fortovase), APV (name brand: Agenerase), lopinavir (name brand: Kaletra), or tipranavir and other

As antagonists of the chemokine in combination include internal ligand chemokine receptor, its derivatives, its non-peptidic low molecular weight compounds or antibodies to receptor of the chemokine

Examples of internal ligand receptor of the chemokine are, in particular, MIP-1α, MIP-1β, RANTES, SDF-1α, SDF-1β, MCP-1, MCP-2, MCP-4, Eotaxin and MDC and other

The derivatives of the internal ligand are, in particular, AOP-RANTES, Met-SDF-1α, Met-SDF-1β and other

Receptor antibodies, chemokine are, in particular, Pro-140, etc.

CCR2 Antagonists are described, in particular, in the descriptions WO99/07351, WO99/40913, WO00/46195, WO00/46196, WO00/46197, WO00/46198, WO00/46199, WO00/69432 or WO00/69815 orBioorg. Med. Chem. Lett.,10,1803(2000) and others

The CCR3 antagonists are described, for example, in the descriptions DE19837386, WO99/55324, WO99/55330, WO00/04003, WO00/27800, WO00/27835, WO00/27843, WO00/29377, WO00/31032, WO00/31033, WO00/34278, WO00/35449, WO00/35451, WO00/35452, WO00/35453, WO00/35454, WO00/35876, WO00/35877, WO00/41685, WO00/51607, WO00/51608, WO00/51609, WO00/51610, WO00/53172, WO00/53600, WO00/58305, WO00/59497, WO00/59498, WO00/59502, WO00/59503, WO00/62814, WO00/73327 or WO01/09088 and other

The CCR5 antagonists are, for example, TAK-779, SCH-351125 (SCH-C), SCH-417690(SCH-D, UK-427857, GW873140 (ONO-4128), TAK-220, etc. in Addition, the combination includes compounds described, for example in descriptions WO99/17773, WO99/32100, WO00/06085, WO00/06146, WO00/10965, WO00/06153, WO00/21916, WO00/37455, EP1013276, WO00/38680, WO00/39125, WO00/40239, WO00/42045, WO00/53175, WO00/42852, WO00/66551, WO0/66558, WO00/66559, WO00/66141, WO00/68203, JP2000309598, WO00/51607, WO00/51608, WO00/51609, WO00/51610, WO00/56729, WO00/59497, WO00/59498, WO00/59502, WO00/59503, WO00/76933, WO98/25605, WO99/04794, WO99/38514,Bioorg. Med. Chem. Lett.,11, 2663 (2003),Curr. Med. Chem. Anti-Infective Agents, 4, 133 (2005),Current Opinion in Pharmacology,4, 447 (2004), orCurrent Opinion in Investigational Drugs,5, 851 (2004) and others

The CXCR3 antagonists are described, for example, in the description O01/16114, WO02/083143, WO02/085862, US6469002, or WO03/101970 and other

The CXCR4 antagonists are, for example, AMD 3100, AMD-070, T-22, KRH-1120, KRH-1636, KRH-2731, or compounds described in the description WO00/66112 and other

The integrase inhibitors are Equiseti, Democracy, PL-2500, V-165, NSC-618929, L-870810, L-708906 analog, S-1360, or 1838, and others

Inhibitors of the merger are, in particular, T-20 (Pentasulfide) and T-1249 and other

Examples of agents of the combinations above are intended to illustrate the present invention but does not limit them.

Typical examples of conventional dosing levels in clinical trials of reverse transcriptase inhibitors or protease inhibitors, below are intended to illustrate the present invention but not for limiting the invention to them.

Zidovudine:100 mg capsule, 200 mg per dose, 3 times per day;
300 mg tablet 300 mg per dose, twice a day;
Didanosine:25-200 mg tablet, 125-200 mg per dose, twice a day;
Zalcitabine:the 0.375-0.75 mg tablet of 0.75 mg per dose, 3 times a day;
Stavudine:15-40 mg capsule, 30-40 mg per dose, twice a day;
La is ewadin: 150 mg tablet, 150 mg per dose, twice a day;
Abacavir:300 mg tablet 300 mg per dose, twice a day;
Nevirapine:200 mg tablet, 200 mg per dose, once daily for 14 days and then twice a day;
Delavirdine:100 mg tablet, 400 mg per dose, 3 times a day;
Efavirenz:50-200 mg capsule, 600 mg per dose, once a day;

Indinavir:200-400 mg capsule, 800 mg per dose, 3 times a day;
Ritonavir:100 mg capsule, 600 mg per dose, 2 times a day;
Nelfinavir:250 mg tablet 750 mg per dose, 3 times a day;
Saquinavir:200 mg capsule, 1200 mg per dose, 3 times a day;
APV:50-150 mg tablet, 1200 mg per dose, 2 times a day.

Examples of other agents for the prevention and/or treatment of rejection of organs in transplantatio used with the conjunction or combination of compounds of the present invention, are immunosuppressants.

Examples of immunosuppressants include tacrolimus (FK506), cyclosporine, sirolimus (rapamycin), corticosteroids, azathioprine, mycophenolate mofetil, FTY-720, cyclophosphamide, cell-surface ligand antibodies, and other

Examples of cell-surface ligand antibodies include Atgam, Thymoglobulin, Simulect, Zenapax or Ortolon and other

Examples of other agents for the prevention and/or treatment of autoimmune diseases, used in combination with the compounds of the present invention are non-steroidal anti-inflammatory drugs, disease modifying Antirheumatic drugs (DMARDs, slow-acting Antirheumatic drugs), steroids, immunosuppressant agents, anti-inflammatory enzymes, chondro-protective agents, inhibitors of T cells, the inhibitor of TNFα (tumor necrosis factor) (include protein drugs, such as anti - TNFα antibody), an inhibitor prostaglandins, IL-1 inhibitor, IL-6 inhibitor (includes protein preparation, such as antibody anti-IL-6 receptor), gamma-interferon agonists, prostaglandins, phosphodiesterase inhibitor, inhibitor of metalloproteinases and other

Examples of non-steroidal anti-inflammatory drugs include aspirin, salicylate n is sodium, aspirin, aspirin.ticlopidine form of the drug, diflunisal, indomethacin, suprofen, openmath, dimethylethanolamine, bufexamac, felbinac, diclofenac, tolmetin-sodium, Clinoril, fenbufen, napleton, proglumetacin, indomethacin-farnesyl, acemetacin, proglumetacin, amfenac sodium, movetalk, etodolac, ibuprofen, ibuprofen-Picanol, naproxen, flurbiprofen, flurbiprofen-aksetil, Ketoprofen, fenoprofen-calcium, tiaprofenic, oxaprozin, pranoprofen, loxoprofen sodium, alminoprofen, zaltoprofen, mefenamico acid, mefenamic aluminum, tolfenamic acid, floctafenine, ketovinylation, oxyphenbutazone, piroxicam tenoxicam, ampiroxicam, Nagel cream, epirizole, hydrochloride tiaramide, hydrochloride tinoridine, emorfazone, sulpirid, Amigrenin, Saridon, Sedes G, AMILO N, Sorbon, perinova system antipyretics, acetaminophen, phenacetin, mesilate dimethocaine, cimetidne form, or antipyrine system antipyretics and other

Examples of disease modifying Antirheumatic drugs (DMARDs, slow-acting Antirheumatic drugs) include, for example, gold-thioglucose, aurothiomalate-sodium, auranofin, actarit, D-penicillamine drugs, lobenzarit-disodium, bucillamine, hydroxychloroquine, salazosulfapiridin, methotrexate or Leflunomide, and others

Examples of steroid-is for external use include clobetasol propionate, acetate diflorasone, fluocinonide, furancarboxylic of mometasone, dipropionate betametha, butyrophenones betametha, valerate of betametha, difluprednate, budesonide, valerate of diflucortolone, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, valerate of dexamethasone, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, azeotroping hydrocortisone, propionate of depradine, valerolactam prednisolone acetonide fluoqinolona, beclomethasone dipropionate, acetonide triamcinolone, pialat flumetazon, prednisolone, beclomethasone propionate and fludroxycortide and other

Examples of steroids for internal use or injections include cortisone acetate, hydrocortisone, nutrifaster hydrocortisone, nutriceutical hydrocortisone acetate of fludrocortisone, prednisolone, prednisolone acetate, nutriceutical prednisolone, butyl acetate prednisolone, nutrifaster prednisolone acetate of halopedia, methylprednisolone, methylprednisolone acetate, nutriceutical methylprednisolone, triamcinolone, acetate triamcinolone, acetonide triamcinolone, dexamethasone, dexamethasone acetate, nutrifaster dexamethasone, dexamethasone palmitate, acetate of paramethasone and betamethasone and other

Examples of steroids as inhalation tools include beclometasone, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, promitional dexamethasone, furancarboxylic of mometasone, prasterone sulfonate, deflazacort, sulatan methylprednisolone and nutriceutical methylprednisolone and other

Examples of anti-inflammatory enzyme preparations include, for example, lysozyme chloride, bromelain, pronase, serrapeptase or streptokinase-streptodornase and other

Examples of chondro-protective agents include, for example, sodium hyaluronate, glucosamine sulphate and chondroitin polysulphate glycosaminoglycan and other

Examples of TNFα inhibitor (including protein preparation, such as anti-TNFα antibody) include, for example, infliximab, adalimumab or etanercept and other

Examples of inhibitors prostaglandins include, for example, salazosulfapiridin, mesalazine, olsalazine, 4-aminosalicylic acid, JTE-522, auranofin, cuprofen, divinename, flunoxaprofen, flurbiprofen, indomethacin, Ketoprofen, lornoxicam, loxoprofen, Meloxicam, oxaprozin, parceled, piperoxan, piroxicam, peroxycarbonates, cinnamate piroxicam, indomethacin tropine, zaltoprofen and pranoprofen and other

Examples of IL-1 inhibitor (including protein preparation, such as an antagonist of IL-1 receptor human) include, for example, anakinra and other

Examples of IL-6 inhibitor (including protein preparation, such as antibody anti-IL-6 R is Ceptor) include, for example, MRA and other

Examples of prostaglandins (referred to hereinafter abbreviated as “PG”) include agonist PG receptor and antagonist PG receptor and other Examples of PG receptor include PGE receptor (EP1, EP2, EP3 and EP4), PGD receptor (DP, CRTH2), PGF receptor (FP), PGI receptor (IP) or TX receptor (TP)and other

Examples of the phosphodiesterase inhibitor include, for example, rolipram, cilomilast (brand: Ariflo), Bay 19-8004, NIK-616, roflumilast (BY-217), cipamfylline (BGL-61063), atizoram (CP-80633), SCH-351591, YM-976, V-11294A, PD-168787, D-4396, IC-485, or ONO-6126 as an inhibitor of PDE-4, and others

Examples of other agents for the prevention and/or treatment of other allergic diseases such as asthma, used in combination with the compounds of the present invention, are steroids, β2adrenergic receptors stimulating agent, antagonist of leukotriene receptor, inhibitor thrombogenicity, the antagonist of the thromboxane A2receptor, mediator release inhibitor, antihistamines, xanthine derivatives, anticholinergic agent, an inhibitor of cytokines, prostaglandins, Forskolin, a phosphodiesterase inhibitor, an elastase inhibitor, an inhibitor of metalloproteinases, expectorant agent and an antibiotic.

Examples of β2adrenergic receptors stimulating agent include the hydrobromide fenoterola, salbutamol sulfate, sulfate of terbutalina, fumarate formoterol, xinafoate of salmeterol on the list, su is that of isoproanol, sulfate ortsiprenalina sulphate clorprenaline, epinephrine, hydrochloride trimethanol, sulfate hexoprenaline, hydrochloride procaterol, hydrochloride tulobuterol, tulobuterol, hydrochloride pirbuterol, clenbuterol hydrochloride, hydrochloride mabuterol, hydrochloride of ritodrine, bambuterol, hydrochloride dopexamine, tartrate maradana, AR-C68397, levosalbutamol, R,R-formoterol, KUR-1246, KUL-7211, AR-C89855 and S-1319 and other

Examples of antagonists of leukotriene receptor include pranlukast, montelukast, zafirlukast, seratrodast, MCC-847, KCA-757, CS-615, YM-158, L-740515, CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284 and ONO-4057, and others

Examples of the inhibitor thrombogenicity include the hydrochloride of Sagres and microdosimetry and other

Examples of antagonist And thromboxane a2receptor include seratrodast, ramatroban, qualitydigital of dumitrana and KT-2-962 and other

Examples of mediator release inhibitor include tranilast, sodium cromoglycate, amlexanox, reprint, ibudilast, casinolist and phenylalaline and other

Examples of antihistamines include Furat ketotifen, mequitazine, hydrochloride of azelastine, oxatomide, terfenadine, the fumarate of emedastine, hydrochloride of epinastine, astemizole, Bastin, cetirizine hydrochloride, bepotastine, fexofenadin, loratadin, desloratadin, hydrochloride of olopatadine, TAK-427, ZCR-2060, NIP-530, mometasone furoate, mizolastine, BP-294,andolast, auranofin and acrivastine and other

Examples xantinove derivatives include aminophylline, theophylline, doxofylline, cipamfylline, diprophylline and other

Examples of anticholinergic agent include ipratropium bromide, bromide oxytrope, bromide plutopia, temiverine, bromide, Tiotropium and reatreat (UK-112166) and other

Examples of the inhibitor of the cytokine include toilet suplatast (brand: IPD) and other

Examples of inhibitors of elastase include ONO-5046, ONO-6818, MR-889, PBI-1101, EPI-HNE-4, R-665, ZD-0892, ZD-8321, GW-311616, AE-3763, etc.

Examples of extraordinary means include ammonia, sodium bicarbonate, hydrochloride Bromhexine, carbocisteine, ambercolored, Ambroxol hydrochloride prolonged or continuous-release, hydrochloride methylcysteine, acetyl cysteine hydrochloride L-utilzation and tyloxapol and other

Examples of antibiotics include aporoximately, Meropenem trihydrate, sulfate netilmicin sulphate sizomitsin, ceftibuten, PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, sulfate astromicin, or hydrochloride cafetalera and other

Examples of antibiotics as inhalation tools include PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, sulfate astromicin, or hydrochloride cafetalera and other

Other pharmaceutical agents that add and/or enhance the preventive and/or therapeutic action of the compounds of the present invention, not limited to the examples given above. As with other pharmaceuticals that add and/or enhance the preventive and/or therapeutic effect of the compounds of the present invention covers not only those tools that have already been found to date, but also those that will be discovered in the future on the basis of the above mentioned mechanism.

The nomenclature of the compounds of the present invention is described below.

All compounds described in the present description, were named using ACD/name (registered trademark, Advanced Chemistry Development Inc.) or ACD/name Batch (registered trademark, Advanced Chemistry Development Inc.), or are named in accordance with IUPAC nomenclature. For example, the compound represented by the formula

called the hydrochloride of N-[6-(4-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-pyridinyl]methanesulfonamide.

In the present description “hydrochloride (or dihydrochloride)” means or hydrochloride or dihydrochloride, and thus it is not a mixture of the hydrochloride and dihydrochloride. In the present description, the “dihydrochloride (or trihydrochloride)” means or dihydrochloride, or trihydrochloride, and thus it is not a mixture of the dihydrochloride and trihydrochloride. “·Hl or 2HCl” in the structure, described in the present description, means or HCl, or 2HCl, and thus it does not cover a mixture of HCl and 2HCl. “·2HCl or 3HCl” in the structure described in the present description, means or 2HCl, or 3HCl, and thus it does not cover the mixture 2HCl and 3HCl.

The EFFECT of the INVENTION

Compounds of the present invention represented by the formula (I)possess antagonistic activity against receptor of the chemokine, especially CCR5, so they are useful in the prevention and/or treatment of CCR5-related diseases.

The fact that the compound of the present invention showing CCR5 antagonism is demonstrated, for example, in the following experiment. General operation is based on the basic techniques of genetic engineering preparation of highly expressing the gene cell and use the usual methods. In the method of analysis of the present invention for evaluating the compounds of the present invention also improves the measurement accuracy and/or sensitivity of the measurement, as described below. Detailed experimental methods shown below.

(I) the Test for inhibition of binding of RANTES and CCR5

The allocation of the CCR5 gene in human

Prepared placental cDNA person using cDNA amplication kit Marathon (Clontech). PCR primers hCCR5Xbal-F1:

5'-AGCTAGTCTAGATCCGTTCCCCTACAAGAAACTCTCC-3' (SEQ ID NO:1) and hCCR5Xbal-R1:

5'-AGCTAGTCTAGAGTGCACAACTCTGACTGGGTCACCA-3' (SEQ ID NO:2) oboznachaetsya based after which outermost Genebank U54994.

Using human placental cDNA as a template and using Ex Taq (Takara), carry out reaction PCR (2 min at 95°C → (30 seconds at 95°C, 45 seconds at 60°C, 1 minute at 72°C) x 35 times). Amplificatory thus PCR product is subjected to 1% agarose gel electrophoresis, purified using QIAquick gel extraction kit (QUIAGEN), and then hydrolyzing enzyme enzyme enzymeXbaI. Hydrolyzed fragments are ligated with expression vector PEF-BOS-bsr using DNA ligation kit Ver. 2 (Takara) and transformed intoEscherichia coliDH5α. By making the resulting plasmid pEF-BOS-bsr/hCCR5 test its DNA sequence.

(2) Cultivation of Cho cells

CHO-dhfr(-) grown using Ham's F-12 (containing fetal bovine serum (10%), penicillin (50 U/ml) and streptomycin (50 mg/ml)). By adding the above environment blasticidin (5 mg/ml) also cultivated transduced cells.

(3) Transduction in CHO cells

Plasmid PEF-BOS-bsr/hCCR5 transducers in CHO-dhfr(-) cell using DMRIE-C reagent (Gibco BRL). After 48 hours, the medium is replaced with medium containing 5 mg/ml blasticidin to implement selection, thus establishing a stable sverkhekspressiya cells.

(4) the Test of inhibition of binding of a chemokine (RANTES, MIP-1α and MIP-1β) with CCR5 (activity Hamachi is as to cause an alternating increase and CA ions).

The thus created a stable CHO cells, sverkhekspressiya human CCR5 (CCR5/CHO cells)suspended in the environment Ham''s F-12 containing FBS (10%), and seeded with a density of 3.0×106cells/well on 96-well pad. After one day, after culturing at 37°C. the culture supernatant discarded, and the environment Ham's F-12 (containing Fura-2AM (5 μm), Probenecid (2.5 mm) and HEPES (20 mm; pH 7.4)) is distributed in 80 µl/well for implementing the 1-hour incubation at 37°C in terms of shading. After washing twice with a solution of 1x Hanks/HEPES (20 mm; pH 7.4), the same solution is distributed in 100 μl/well. Each of the tested compounds added to CCR5/CHO cells included so Fura-2AM and after 3 minutes, then add back of recombinant human CCR5 ligand (RANTES, MIP-1α or MIP-1β) (Pepro Tach), diluted 1x Hanks/HEPES (20 mm; pH 7.4)to a final concentration of (Rantes: 10 nm;; MIP-1α: 30 nm; MIP-1β: 30 nm). A temporary increase in the concentration of intracellular CA2+induced CCR5 ligand person, measured using the CA2+detector for 96-well use (Hamamatsu Photonics), and the degree of inhibition (%) test compound is calculated using the following formula:

The degree of inhibition = (Ec - Ea)/Ec x 100

Ec: measured value, a temporary increase of CA2+using CCR5 ligand

Ea: measured aliciaprotocolo increase of CA 2+using CCR5 ligand with the addition of the test compounds.

(II) Test the migration of human CCR5 expressing cells (hCCR5-Ba/F3 cell):

(1) the Creation of human CCR5 expressing cells

(1-A) allocation of the CCR5 gene in human

The selection is carried out in accordance with methods isolation CCR5 gene of the person, as described in the above method (I) (1).

(1-B) Growing Ba/F3 cells

Ba/F3 cells were cultured statically by using RMMI-1640 (Gibco BRL)containing antibiotics (Antibiotic-Antimycotic) (final concentration: penicillin G sodium (100 Units/ml), streptomycin sulfate (100 μg/ml), amphotericin b (0.25 microgram/ml) (Gibco BRL), fetal bovine serum (FBS) (10%), 2-mercaptoethanol (55 μm), mouse interleukin-3 (IL-3) (5 ng/ml) (Pepro Tech, Inc.) in deoxycholate incubator (temperature: 37°C, the concentration of CO2: 5%, moisture: 95%). Stable hyperexpression cells exogenous gene is grown in the above medium, which is added to blasticidin (Kaken Pharmaceutical) to obtain a final concentration of 10 μg/ml.

(1-C) Transformation of Ba/F3 cells

Plasmid for expresii human CCR5 (pEF-BOS-bsr/hCCR5) hydrolyzing withAatII to translate in a linear form. Translated into linear form of the plasmid is purified using QIA complex quick PCR purification (QIAGEN) and introduced into Ba/F3 cells by electroporation (Gene Pulser (IO RAD), 960 F/250V). Cells were seeded on 96-well plate for culturing at a density of 1000, 100, 10 cells/100 μl/well and grown for 48 hours. Then there is added blasticidin to obtain a final concentration of 10 μg/ml with subsequent klonirovanie blasticidin-resistant cell line, thereby creating sverkhekspressiya stable clone transfetsirovannyh exogenous gene (hCCR5-Ba/F3 cells).

(1-D) Analysis of the expression of CCR5

The level of expression of CCR5 human clone, obtained by the method described above (1), is determined using FACS Sort (trade name, Becton, Dickinson) using detection of cells with fluorescence isothiocyanate (FITC)-labeled anti-human CCR5 antibody (BD Pharmingen) and analyzed. In this regard, as a control antibody isotype using FITC-labeled mouse IgG2aκ (BD Pharmingen).

(2) the Test cell migration

Check the effect of the tested compounds on the migratory ability of CCR5 expressing Ba/F3 cells against RANTES, MIP-1α or MIP-1β. First type, respectively, 0.3 ml of 0 or 3 nm chemokine (RANTES, MIP-1α or MIP-1β)-containing medium in the lower space Chemo T x 96 well plates (Neuro Probe). Then set the filter (pore size: 5 μm) and add a solution of the mixture (1×105cells/well) of the test compounds and prepared in advance CCR5-Bs/F3 cells with 65 μl. Added test what my connection is produced by diluting it with 0.1% DMSO-containing medium to obtain a final concentration in the filter 0, the 0.01 to 0.03, 0.1 or 0.3 μm. These cells are grown in CO2the incubator (37°C, 5% CO2relative humidity: 95%) for 3 hours, and then remove the medium and emigrirovavshii cells on the filter. In addition, remove the filter, centrifuged the microplate (1500 rpm. in min, 10 min, room temp.) and with decanting to remove the supernatant. Cells in the microplate suspendered in 100 μl of phosphate buffer (PBS), and 1/10 part of it is additionally diluted with 90 µl PBS, move the white tablet for analysis of fluorescence is used as an analytical model for the number of migrated cells (target: 100 µl/well).

Then Titer-Glo reagent cells (trade name, Promega), which is obtained previously at room temperature, add to the above analytical sample by the number of migrated cells (100 µl/well), and subsequent careful mixing (300 rpm. in minutes, 2 minutes from KA-SCHUTTLER MTS4) for lizirovania cells, the mixture is incubated at room temperature for 10 minutes and measure the fluorescence using a wallac ARVO SX 1420 MULTILABEL COUNTER (trade name, Perkin Elmer) (detection by using the count/second).

The number of migrated cells (the number of naturally falling cells) at a concentration of chemokine 0 nmol/l is used as the basis, and calculates the deceleration degree of the test is about connection vs. 0.1% DMSO control group.

The degree of inhibition of migration (%) of the test compounds is calculated using the following equation:

Ec: (the amount of fluorescence measured with the addition of 0.1% DMSO)-(measured value of fluorescence naturally falling cells)

Ea: (the amount of fluorescence measured by adding the test compound)-(measured value of fluorescence naturally falling cells).

The BEST WAY of carrying out the INVENTION

The following examples of the preparation, biological samples and examples of completed forms are intended to illustrate the present invention but not to limit them.

When the chromatographic separations and TLC, the solvents in the parentheses show eluting and showing solvents, and the ratio of the used solvents are given by volume.

NMR is measured value1H NMR. The solvents in parentheses in the NMR data show the solvents used for the measurement.

Example retrieve

Example 1

N-[6-(4-formylphenoxy)pyridine-3-yl]methanesulfonamide

{4-[(5-nitropyridine-2-yl)oxy]phenyl}methanol was subjected to restore the nitro group using zinc and acetic acid, the compound obtained was subjected to reaction with methanesulfonamide in pyridine and the compound obtained was subjected to oxidation using the receiving manganese dioxide, obtaining specified in the title compound having the following physical data.

TLC: Rf of 0.67 (dichloromethane: methanol = 9: 1);

NMR (CDCl3): δ 3,04, 6,56, 7,05, 7,29, 7,80, 7,94, 8,08, 9,99.

Example 2

The hydrochloride of N-butyl-N'-(2,4-differenl)-N-piperidine-4-rocephine

To a solution oftert-butyl 4-(butylamino)piperidine-1-carboxylate (1 g) in dimethylacetamide (13 ml) was added triethylamine (1.6 ml) and 2,4 differentiational (907 mg). The reaction mixture was stirred for 5 minutes at room temperature. To the reaction mixture were added saturated aqueous solution of acid sodium carbonate and was extracted with ethyl acetate. The extract was washed with water and saline, dried with anhydrous sodium sulfate and concentrated. To a solution of the obtained compound (1.28 g) in ethyl acetate (2 ml) was added 4 N. hydrogen chloride in ethyl acetate solution (10 ml). The reaction mixture was stirred for 20 minutes at room temperature and concentrated. The obtained residue was washedtert-butylmethylamine ether, dried, obtaining specified in the title compound having the following physical data.

TLC:Rf value of 0.52 (dichloromethane: methanol: acetic acid= 5:1:0,1);

NMR (CD3OD): δ 0,99, 1,34-1,47, 1,60-1,71, 1,95-2,01, 2,08-2,22, 3,03-3,13, 3,27-3,34, 3,44-3,50, 4,13, 7,00, 7,37, 8,01.

Example 3

Hydrochloride (or dihydrochloride) N-[6-(4-{[4-(butyl{[2,4-differenl)amino]carbon is l}amino)-1-piperidinyl]methyl}phenoxy)-3-pyridinyl]methanesulfonamide

To a solution of the compound obtained in Example 1 (95 mg)and the compound obtained in Example 2 (80 mg) in dimethylformamide (1.5 ml), was added acetic acid (0.15 ml) and triacetoxyborohydride sodium (116 mg). The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was added saturated aqueous acidic sodium carbonate and was extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate: methanol = 10:1). To a solution of the obtained compound was added 4 N. hydrogen chloride in ethyl acetate solution. The reaction mixture was concentrated, obtaining specified in the title compound (115 mg)having the following physical data.

TLC:Rf of 0.44 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,35-1,48, 1,58-1,70, 1,95-2,08, 2,18-2,34, 3,00, 3,08-3,20, 3,25-3,34, 3,57-3,65, 4,19, 4,34, 6,89-7,03, 7,09, 7,25, 7,38, 7,60, 7,85, 8,06.

Example 3(1)-3(107)

Using a procedure similar to that described in Example 3, using the appropriate amine compounds and the corresponding aldehyde compounds, to obtain the following compounds of the present invention.

Example 3(1)

Hydrochloride (or dihydrochloride) N-{4-[(6-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)-1-piperidinyl]METI the}-3-pyridinyl)oxy]phenyl}methanesulfonamide

TLC:Rf of 0.30 (chloroform: methanol =10:1);

NMR (CD3OD): δ 0,99, 1,30-1,50, 1,60-1,80, 1,90-2,10, 2,20-2,40, 2,97, 3,20-3,40, 3,60-3,70, 4,20, 4,47, 6,92-7,02, 7,09-7,12, 7,31-7,40, 7,47-7,58, 8,45.

Example 3(2)

The hydrochloride of N-{4-[4-({4-[{[(2-hydroxybutyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide

TLC:Rf 0,41 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,89, 1,20-1,42, 1,55-1,70, 2,05-2,17, 2,95, 3,08-3,28, 3,37-3,50, 4,21, 4,51, 7,00, 7,02, 7,21-7,30, 7,41, 7,44-7,55.

Example 3(3)

The dihydrochloride of N-{4-[4-({4-[butyl({[1-(2-hydroxyethyl)-1H-pyrazole-4-yl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide

TLC:Rf 0.40 in (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,31-1,42, 1,50-1,72, 1,91-2,01, 2,15-2,31, 2,95, 3,10-3,32, 3,51-3,60, 3,87, 4,23, 4,30, 4,35, 7,03, 7,06, 7,29, 7,53, 7,98, 8,12.

Example 3(4)

Hydrochloride 5-[({butyl[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-debtor-N-methylbenzamide

TLC:Rf 0,90 (chloroform: methanol= 4:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,10-2,30, 2,91, 2,95, 3,00-3,20, 3,20-3,40, 3,50-3,60, 4,15, 4,29, 7,02-7,09, 7,12, 7,29, 7,50, 7,78.

Example 3(5)

The hydrochloride of N-{4-[4-({4-[{[(TRANS-4-hydroxycyclohexyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide

TLC:Rf 0,46 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,00-1,18, 1,21-1,37, 1,55-1,68, 1,71-1,89, 2,04-2,15, 2,95, 3,04-3,18, 3,38-3,54, 4,21, 4,60, 6,98-7,07, 7,18-7,23, 7,28, 7,41, 7,45-7,53.

Example 3(6)

Hydra is chloride N-[4-(4-{[4-(3-butenyl{[(2-hydroxybutyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide

TLC:Rf 0,51 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,95, 1,30-1,58, 1,90-2,00, 2,07-2,24, 2,28-2,38, 2,95, 3,02-3,35, 3,50-3,60, 4,12, 4,28, 5,05, 5,11, 5,81, 7,03, 7,06, 7,29, 7,50.

Example 3(7)

The hydrochloride of N-butyl-N'-(2,4-differenl)-N-(1-{4-[4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)urea

TLC:Rf 0,60 (dichloromethane: methanol= 20:1);

NMR (CD3OD): δ 0,99, 1,39-1,43, 1,60-1,70, 2,00-2,05, 2,16-2,30, 2,94-2,97, 3,06-3,28, 3,29-3,36, 3,52-3,61, 3,69-3,72, 4,13, 4,23, 6,90-7,03, 7,20, 7,23, 7,37, 7,58, 7,78.

Example 3(8)

The hydrochloride of N-butyl-2-(2,4-differenl)-N-[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]ndimethylacetamide

TLC:Rf of 0.41 (chloroform: methanol= 10:1);

NMR (d6-DMSO): δ 0,92, 1,20-1,40, 1,40-1,60, 1,70-1,90, 2,20-2,40, 2,90-3,10, 2,97, 3,15-3,30, 3,30-3,50, 3,71, 4,05-4,30, 6,94-7,09, 7,12-7,25, 7,57, 9,34, 10,50.

Example 3(9)

The dihydrochloride (or trihydrochloride) N-{4-[(5{[4-(butyl{[(1-methyl-1H-pyrazole-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide

TLC:Rf of 0.16 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,96, 1,30-1,45, 1,50-1,65, 1,90-2,05, 2,20-2,35, 2,98, 3,10-3,40, 3,50-3,70, 4,00, 4,20, 4,36, 7,09-7,16, 7,32, 7,95, 8,06, 8,08, 8,31.

Example 3(10)

The hydrochloride of N-(4-{4-[(4-{{[(4-forfinal)amino]carbonyl}[4-(methylsulfanyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide

TLC:Rf of 0.67 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,60-1,79, 2,10-2,20, 2,51, 2,95, 3,08-3,20, 3,42-3,55, 4,22, 4,64, 6,95, 7,02, 7,03, 7,15-7,31, 7,39, 7,42.

Example 3(11)

The hydrochloride of N-(4-{4-[(4-{{[(4-forfinal)amino]carbonyl}[3-(who ethylsulfanyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide

TLC:Rf of 0.67 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,12-2,20, 2,51, 2,95, 3,04-3,22, 3,42-3,57, 4,22, 4,64, 6,89-7,10, 7,17-7,32, 7,34-7,49.

Example 3(12)

The hydrochloride of N-butyl-2,4-debtor-N-[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]benzamide

TLC:Rf of 0.41 (chloroform: methanol= 10:1);

NMR (d6-DMSO): δ 0,70-0,90, 1,10-1,30, 1,40-1,60, 1,75-1,90, 2,30-2,55, 2,80-3,05, 2,96, 3,10-3,45, 4,00, 4,17, 7,00, 7,01-7,04, 7,12, 7,19-7,30, 7,42, 7,57, 9,35.

Example 3(13)

The hydrochloride of N-(4-{4-[(4-{{[(4-forfinal)amino]carbonyl}[4-(methylsulfinyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide

TLC:Rf of 0.47 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,67-1,83, 2,14-2,23, 2,84, 2,95, 3,10-3,21, 3,46-3,55, 4,23, 4,67, 6,96, 7,00, 7,02, 7,23, 7,28, 7,43, 7,54, 7,84.

Example 3(14)

The hydrochloride of N-(4-{4-[(4-{{[(4-forfinal)amino]carbonyl}[3-(methylsulfinyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide

TLC:Rf of 0.47 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,14-2,25, 2,86, 2,95, 3,08-3,21, 3,47-3,55, 4,23, 4,66, 6,96, 7,01, 7,02, 7,20-7,30, 7,42, 7,51, 7,66, 7,70-7,80.

Example 3(15)

The hydrochloride of N-(4-{4-[(4-{{[(4-forfinal)amino]carbonyl}[4-(methylsulphonyl)phenyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide

TLC:Rf 0,54 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,70-1,88, 2,14-2,23, 2,95, 3,10-3,20, 3,16, 3,46-3,55, 4,23, 4,64, 6,96, 7,01, 7,02, 7,24, 7,28, 7,43, 7,57, 8,08.

Example 3(16)

The hydrochloride of N-(4-{4-[(4-{{[(4-forfinal)amino]carbonyl}[3-(methylsulphonyl)phenyl]amino}-1-piperidinyl)m is Teal]phenoxy}phenyl)methanesulfonamide

TLC:Rf 0,54 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,64-1,80, 2,17-2,28, 2,95, 3,10-3,21, 3,19, 3,45-3,55, 4,23, 4,67, 6,96, 7,01, 7,02, 7,24, 7,28, 7,42, 7,66, 7,78, 7,89, 8,05.

Example 3(17)

The hydrochloride of N-[4-(4-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-methoxyphenyl]methanesulfonamide

TLC:Rf of 0.50 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,15-2,30, 2,99, 3,05-3,20, 3,20-3,40, 3,50-3,60, 3,74, 4,15, 4,25, 6,85-6,95, 6,99, 7,03, 7,38, 7,43.

Example 3(18)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf of 0.41 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,30-1,45, 1,55-1,70, 1,95-2,10, 2,15-2,35, 2,98, 3,05-3,20, 3,25-3,35, 3,50-3,65, 4,15, 4,34, 7,09-7,18, 7,33, 7,86, 8,03, 8,28.

Example 3(19)

The dihydrochloride of 5-{[(butyl{1-[(5-{4-[(methylsulphonyl)amino]phenoxy}-2-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf of 0.36 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,99, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,20-2,40, 2,96, 3,20-3,40, 3,60-3,70, 4,20, 4,45, 7,10, 7,15, 7,33, 7,44-7,50, 7,87, 8,44.

Example 3(20)

Hydrochloride 5-[({butyl[1-(4-{2-methoxy-4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf of 0.34 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,55-1,70, 1,90-2,10, 2,10-2,30, 2,99, 3,05-3,20, 3,20-3,40, 3,50-3,60, 3,74, 4,15, 4,25, 6,87, 6,92, 7,03, 7,14, 7,42, 7,85.

Example 3(21)

Hydrochloride 5-[({butyl[1-(4-{2-chloro-4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf of 0.33 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,55-1,70, 1,90-2,10, 2,10-2,30, 3,01, 3,10-3,20, 3,25-3,35, 3,50-3,60, 4,15, 4,28, 6,99, 7,13, 7,14, 7,24, 7,43, 7,50, 7,85.

Example 3(22)

The hydrochloride of 4-(4-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-(2-hydroxyethyl)benzosulfimide

TLC:Rf 0,69 (dichloromethane: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,36-1,43, 1,59-1,70, 1,98-2,03, 2,18-2,30, 2,96, 3,09-3,30, 3,54, 3,54-3,61, 4,16, 4,33, 6,90-7,03, 7,16, 7,20, 7,37, 7,59, 7,86.

Example 3(23)

The dihydrochloride of 4-(4-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-[2-(dimethylamino)ethyl]benzosulfimide

TLC:Rf 0.56 to (dichloromethane: methanol= 2:1);

NMR (CD3OD): δ 0,98, 1,33-1,46, 1,59-1,70, 1,96-2,00, 2,20-2,35, 2,93, 3,05-3,12, 3,17-3,30, 3,52-3,56, 4,18, 4,30, 6,89-7,03, 7,19, 7,37, 7,61, 7,90.

Example 3(24)

The hydrochloride of N-{4-[4-({4-[{[(2,4-differenl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide

TLC:Rf 0,76 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,30, 2,95, 3,05-3,20, 3,40-3,55, 4,21, 4,65, 6,85-6,96, 6,99-7,04, 7,28, 7,35-7,40, 7,41, 7,51-7,58.

Example 3(25)

The hydrochloride of 4-(4-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-methylbenzenesulfonamide

TLC:Rf to 0.63 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,36-1,4, 1,59-1,70, 1,99-2,04, 2,17-2,30, 2,53, 3,07-3,17, 3,24-3,35, 3,57-3,61, 4,15, 4,33, 6,89-7,03, 7,16, 7,20, 7,36, 7,57, 7,83.

Example 3(26)

The hydrochloride of 4-(4-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N,N-dimethylbenzenesulfonamide

TLC:Rf of 0.67 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,34-1,46, 1,60-1,70, 1,99-2,03, 2,19-2,30, 2,68, 3,09-3,17, 3,25-3,36, 3,57-3,61, 4,16, 4,33, 6,89-7,03, 7,18, 7,21, 7,36, 7,59, 7,78.

Example 3(27)

The hydrochloride of 4-(4-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-(2-methoxyethyl)benzosulfimide

TLC:Rf of 0.60 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,34-1,46, 1,60-1,70, 1,99-2,03, 2,19-2,30, 3,03, 3,09-3,17, 3,26, 3,26-3,30, 3,36, 3,56-3,61, 4,16, 4,33, 6,89-7,03, 7,14, 7,19, 7,37, 7,57, 7,85.

Example 3(28)

The hydrochloride of 4-(4-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-tetrahydro-2H-Piran-4-albenzaalbenza

TLC:Rf of 0.57 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,36-1,53, 1,63-1,68, 2,01-2,04, 2,21-2,25, 3,07-3,37, 3,57-3,61, 3,81-3,85, 4,14, 4,33, 4,80, 6,89-7,03, 7,14, 7,19, 7,36, 7,57, 7,87.

Example 3(29)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.53 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,60-1,80, 2,12-2,23, 2,97, 3,11-3,24, 3,48-3,58, 4,27, 4,67, 6,95, 7,06, 7,11, 7,21, 7,28-7,35, 7,48-7,60, 7,90, 8,18.

Example 3(30)

The hydrochloride of N-[5-(4-{[4-(butyl{[(2,4-differenl)amine is]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-2-pyridinyl]methanesulfonamide

TLC:Rf of 0.53 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,34-1,44, 1,58-1,68, 1,96-2,05, 2,15-2,31, 3,03-3,18, 3,28, 3,25-3,33, 3,52-3,60, 4,17, 4,30, 6,88-7,04, 7,12, 7,14, 7,37, 7,51-7,60, 8,10.

Example 3(31)

Hydrochloride 5-({[butyl(1-{4-[4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf of 0.48 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,20-2,35, 2,96, 3,00-3,20, 3,20-3,40, 3,50-3,60, 3,71, 4,10, 4,33, 7,11-7,24, 7,59, 7,78, 7,87.

Example 3(32)

Hydrochloride 5-[({butyl[1-(4-{4-[(tetrahydro-2H-Piran-4-ylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf of 0.40 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,20-2,30, 3,10-3,20, 3,20-3,40, 3,50-3,70, 3,80-3,90, 4,15, 4,33, 7,11-7,21, 7,60, 7,87, 7,88.

Example 3(33)

Hydrochloride 5-[({butyl[1-(4-{2,6-dimethyl-4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf of 0.34 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,08, 2,20-2,30, 2,99, 3,00-3,20, 3,20-3,40, 3,50-3,60, 4,15, 4,26, 6,86, 7,04, 7,14, 7,45, 7,85.

Example 3(34)

Hydrochloride 5-[({butyl[1-(4-{4-[methyl - (methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf of 0.40 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,15-2,30, 2,99, 3,00-3,20, 3,20-3,40, 3,30, 3,50-3,60, 4,15, 4,30, 7,05-7,18, 7,45, 7,52, 7,86.

Example 3(35)

Hydrochloride 5-[({butyl[1-(4-{4-[(matilal is of IMT)amino]benzyl}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf of 0.33 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,15-2,30, 2,91, 3,00-3,20, 3,20-3,40, 3,50-3,60, 3,98, 4,15, 4,27, 7,10-7,20, 7,34, 7,44, 7,85.

Example 3(36)

The dihydrochloride of 5-{[(butyl{1-[(3,5-dimethyl-1-{4-[(methylsulphonyl)amino]phenyl}-1H-pyrazole-4-yl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf 0,20 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,34-1,47, 1,60-1,72, 1,98-2,10, 2,27-2,50, 2,39, 2,43, 3,04, 3,12-3,40, 3,65-3,75, 4,24, 4,29, 7,15, 7,43, 7,49, 7,87.

Example 3(37)

Hydrochloride 5-({[(1-{4-[4-(aminosulfonyl)phenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf of 0.33 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,35-1,47, 1,58-1,70, 1,97-2,08, 2,18-2,32, 3,08-3,20, 3,23-3,35, 3,52-3,63, 4,16, 4,33, 7,10-7,24, 7,58, 7,64, 7,90.

Example 3(38)

Hydrochloride 5-[({butyl[1-(4-{4-[(methylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf of 0.47 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,47, 1,60-1,71, 1,98-2,10, 2,20-2,36, 2,53, 3,08-3,20, 3,26-3,35, 3,52-3,64, 4,18, 4,33, 7,14, 7,16, 7,19, 7,60, 7,83, 7,86.

Example 3(39)

Hydrochloride 5-[({butyl[1-(4-{4-[(dimethylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf of 0.55 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,49, 1,59-1,72, 1,97-2,09, 2,19-2,38, 2,68, 3,08-3,21, 3,23-3,35, 3,58-3,64, 4,16, 4,34, 7,14, 7,19, 7,21, 7,60, 7,79, 7,86.

Example 3(40)

The hydrochloride of N-[4-(4-{[4-(butyl{[2,differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-were]methanesulfonamide

TLC:Rf to 0.39 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,55-1,70, 1,90-2,10, 2,10-2,30, 2,16, 2,96, 3,00-3,20, 3,20-3,40, 3,50-3,60, 4,15, 4,27, 6,91-6,99, 7,13, 7,20, 7,36, 7,46.

Example 3(41)

Hydrochloride 5-[({butyl[1-(4-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

White amorphous powder;

TLC:Rf 0.28 in (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,55-1,70, 1,90-2,10, 2,10-2,30, 2,16, 2,96, 3,00-3,20, 3,20-3,40, 3,50-3,60, 4,10, 4,26, 6,91-6,97, 7,11-7,20, 7,46, 7,86.

Example 3(42)

Hydrochloride 4-[4-({4-[({[5-(aminocarbonyl)-2,4-differenl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]benzoic acid

TLC:Rf 0,49 (dichloromethane: methanol= 5:1);

NMR (CD3OD): δ 0,98, 1,35-1,45, 1,60-1,70, 1,98-2,03, 2,20-2,30, 3,10-3,34, 3,56-3,60, 4,16, 4,33, 7,07, 7,14, 7,18, 7,57, 7,86, 8,04.

Example 3(43)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{2-chloro-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf of 0.33 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,55-1,70, 1,90-2,10, 2,20-2,40, 3,02, 3,10-3,25, 3,25-3,40, 3,50-3,60, 4,20, 4,35, 7,10-7,26, 7,43, 7,86, 8,09, 8,26.

Example 3(44)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{2-methoxy-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf 0,49 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,33-1,47, 1,58-1,71, 1,97-2,08, 2,20-2,38, 3,01, 3,07-3,21, 3,25-3,35, 3,55-3,65, 3,2, 4,18, 4,35, 6,90, 7,04-7,19, 7,86, 8,08, 8,29.

Example 3(45)

Hydrochloride 5-({[butyl(1-{4-[4-(methylsulphonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,35-1,48, 1,59-1,70, 1,98-2,08, 2,19-2,34, 3,12, 3,08-3,21, 3,25-3,35, 3,55-3,64, 4,16, 4,34, 7,14, 7,21, 7,22, 7,61, 7,86, 7,95.

Example 3(46)

Hydrochloride 4-[4-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]benzoic acid

TLC:Rf 0,49 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,67-1,80, 2,12-2,22, 3,12-3,24, 3,48-3,55, 4,26, 4,68, 6,95, 7,05, 7,14, 7,22, 7,33, 7,47-7,60, 8,03.

Example 3(47)

Hydrochloride 4-[4-({4-[({[5-aminocarbonyl)-2,4-differenl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-methoxybenzoic acid

TLC:Rf to 0.66 (chloroform: methanol= 3:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,10-2,35, 3,05-3,20, 3,25-3,35, 3,50-3,60, 3,82, 4,10, 4,28, 6,98, 7,09, 7,15, 7,47, 7,77, 7,75, 7,86.

Example 3(48)

Hydrochloride 4-[4-({4-[({[5-(aminocarbonyl)-2,4-differenl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-chlorbenzoyl acid

TLC:Rf of 0.65 (chloroform: methanol= 3:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,20-2,35, 3,05-3,20, 3,25-3,35, 3,50-3,60, 4,10, 4,33, 7,10-7,17, 7,57, 7,86, 7,95, 8,14.

Example 3(49)

Hydrochloride 4-[4-({4-[({[5-(aminocarbonyl)-2,4-differenl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-nitrobenzoic acid

TLC:Rf 0,51 (chlorofor is: methanol= 3:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,20-2,35, 3,00-3,15, 3,20-3,35, 3,50-3,60, 4,15, 4,29, 7,10-7,20, 7,58, 7,86, 8,20, 8,56.

Example 3(50)

Hydrochloride 5-[({butyl[1-(4-{3-methoxy-4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf 0,42 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,47, 1,58-1,70, 1,97-2,08, 2,17-2,31, 2,91, 3,06-3,20, 3,24-3,35, 3,51-3,63, 3,86, 4,13, 4,29, 6,57, 6,81, 7,10, 7,14, 7,36, 7,51, 7,86.

Example 3(51)

Hydrochloride 5-[({butyl[1-(4-{3-chloro-4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf of 0.44 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,48, 1,60-1,72, 1,98-2,08, 2,12-2,31, 3,00, 3,08-3,20, 3,24-3,35, 3,52-3,62, 4,15, 4,31, 7,00, 7,10-7,20, 7,51-7,59, 7,86.

Example 3(52)

Hydrochloride (or dihydrochloride) 5-({[butyl(1-{[6-(4-methoxyphenoxy)-3-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf to 0.39 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,20-2,35, 3,05-3,20, 3,20-3,35, 3,50-3,65, 3,81, 4,20, 4,34, 6,97-7,20, 7,86, 8,05, 8,31.

Example 3(53)

Hydrochloride (or dihydrochloride) 4-{[5-({4-[({[5-(aminocarbonyl)-2,4-differenl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}benzoic acid

TLC:Rf to 0.63 (chloroform: methanol= 3:1);

NMR (CD3OD): δ 0,97, 1,30-1,45, 1,55-1,70, 1,85-2,00, 2,05-2,20, 2,65-2,85, 3,20-3,40, 4,05, 4,10, 7,09-7,21, 7,89, 7,97, 8,07, 8,23.

Example 3(54)

The hydrochloride of N-(4-{4-[(4-{phenyl[(tetrahydro-2H-Piran-4-Ilam is but)carbonyl]amino}-1-piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide

TLC:Rf 0,46 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,24-1,40, 1,55-1,75, 2,05-2,15, 2,95, 3,04-3,18, 3,34-3,50, 3,68-3,84, 4,21, 4,60, 6,98-7,04, 7,22, 7,28, 7,41, 7,45-7,56.

Example 3(55)

The dihydrochloride of 5-{[(butyl{1-[(5-{4-[(methylsulphonyl)amino]phenoxy}-2-pyrazinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf 0.40 in (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,99, 1,34-1,48, 1,59-1,72, 1,98-2,08, 2,21-2,38, 2,97, 3,17-3,38, 3,62-3,71, 4,18, 4,46, 7,14, 7,18, 7,33, 7,67, 8,24, 8,54.

Example 3(56)

Hydrochloride 5-[4-({4-[({[5-(aminocarbonyl)-2,4-differenl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-2-[(methylsulphonyl)amino]benzoic acid

TLC:Rf of 0.48 (dichloromethane: methanol= 5:1);

NMR (CD3OD): δ 0,96, 1,28-1,47, 1,59-1,71, 1,95-2,06, 2,18-2,37, 3,02, 3,00-3,20, 3,24-3,35, 3,50-3,61, 4,15, 4,30, 7,08, 7,14, 7,25, 7,51, 7,67-7,72, 7,86.

Example 3(57)

Hydrochloride of 2-[4-({4-[({[5-(aminocarbonyl)-2,4-differenl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulphonyl)amino]benzoic acid

TLC:Rf 0.35 in (dichloromethane: methanol= 5:1);

NMR (CD3OD): δ 0,98, 1,31-1,48, 1,54-1,71, 1,94-2,04, 2,12-2,36, 3,00, 3,00-3,18, 3,20-3,35, 3,51-3,61, 4,15, 4,27, 6,98, 7,08, 7,14, 7,41-7,52, 7,82, 7,84.

Example 3(58)

The hydrochloride of N-[4-(4-{[4-(butyl{[(3,4-dicyanovinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide

TLC:Rf 0,41 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,96, 1,31-1,42, 1,52-1,64, 1,98-2,07, 2,21-2,39, 2,95, 3,04-3,21, 3,28-3,35, 3,52-3,61, 4,19, 4,30, 7,03, 7,06, 7,29, 7,52, 7,79-7,89, 8,11.

Example 3(59)

The hydrochloride of N-[4-(4-{[4-(butyl{[(4-cyano-2,5-differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,35-1,46, 1,55-1,68, 1,95-2,06, 2,19-2,37, 2,95, 3,08-3,21, 3,24-3,38, 3,52-3,61, 4,18, 4,29, 7,03, 7,06, 7,29, 7,50, 7,60, 7,87.

Example 3(60)

Hydrochloride (or dihydrochloride) 5-({[butyl(1-{[6-(4-cianfrocca)-3-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf 0,54 (dichloromethane: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,36-1,43, 1,59-1,67, 2,00-2,04, 2,21-2,32, 2,99-3,18, 3,26-3,30, 3,56-3,63, 4,14, 4,36, 7,14, 7,21, 7,33, 7,80, 7,86, 8,06, 8,29.

Example 3(61)

Hydrochloride 3-({[[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.33 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,63-1,80, 2,14-2,23, 2,95, 3,10-3,22, 3,47-3,55, 4,23, 4,69, 7,01, 7,03, 7,25-7,37, 7,40-7,60, 7,72.

Example 3(62)

Hydrochloride 4-[({butyl[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]benzamide

TLC:Rf of 0.33 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,50-1,70, 1,95-2,10, 2,10-2,30, 2,95, 3,00-3,20, 3,20-3,40, 3,50-3,60, 4,20, 4,30, 7,02-7,08, 7,29, 7,47-7,52, 7,80.

Example 3(63)

The hydrochloride of N-{4-[4-({4-[butyl({[2,4-debtor-5-(4-morpholinylcarbonyl)phenyl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide

TLC:Rf of 0.38 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,70, 1,95-2,05, 2,10-2,30, 2,95, 3,00-3,20, 3,20-,50, 3,50-3,70, 3,70-3,80, 4,10, 4,29, 7,02-7,08, 7,15, 7,29, 7,46, 7,49.

Example 3(64)

Hydrochloride 5-[({butyl[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-debtor-N-(2-methoxyethyl)benzamide

TLC:Rf of 0.44 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,75, 1,90-2,10, 2,15-2,35, 2,95, 3,00-3,20, 3,20-3,40, 3,50-3,60, 3,55, 4,13, 4,28, 7,02-7,08, 7,13, 7,29, 7,49, 7,78.

Example 3(65)

Hydrochloride 5-[({butyl[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-debtor-N,N-dimethylbenzamide

TLC:Rf and 0.46 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,80, 1,90-2,10, 2,20-2,30, 2,95, 2,97, 3,05-3,20, 3,10, 3,25-3,35, 3,50-3,60, 4,15, 4,29, 7,02-7,08, 7,14, 7,29, 7,43, 7,50.

Example 3(66)

Hydrochloride 5-[({butyl[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-debtor-N-(2-hydroxyethyl)benzamide

TLC:Rf of 0.38 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,10-2,30, 2,95, 3,05-3,20, 3,20-3,40, 3,50, 3,50-3,60, 3,67, 4,15, 4,27, 7,02-7,07, 7,13, 7,29, 7,50, 7,81.

Example 3(67)

The dihydrochloride (or trihydrochloride) N-{4-[(5-{[4-(butyl{[(1-methyl-1H-pyrazole-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-3-chlorophenyl}methanesulfonamide

TLC:Rf of 0.57 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,96, 1,30-1,45, 1,50-1,65, 1,90-2,10, 2,20-2,40, 3,02, 3,10-3,50, 3,50-3,65, 4,08, 4,25, 4,37, 7,16, 7,24-7,26, 7,43, 8,12, 8,16, 8,23, 8,28.

Example 3(68)

The dihydrochloride (or trihydrochloride) N-{4-[(5-{[4-(butyl{[(1-methyl-1H-piraso the-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy] - for 3,5-dimetilfenil}methanesulfonamide

TLC:Rf of 0.56 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,96, 1,30-1,50, 1,50-1,65, 1,90-2,05, 2,08, 2,20-2,40, 2,98, 3,10-3,40, 3,55-3,65, 4,06, 4,25, 4,37, 7,05, 7,08, 8,13, 8,16, 8,20, 8,33.

Example 3(69)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf of 0.43 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,32-1,45, 1,58-1,70, 1,95-2,07, 2,14, 2,20-2,40, 2,98, 3,08-3,21, 3,24-3,37, 3,55-3,64, 4,20, 4,36, 7,02-7,25, 7,86, 8,14, 8,34.

Example 3(70)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{2,6-dimethyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf of 0.44 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,32-1,45, 1,58-1,70, 1,95-2,08, 2,08, 2,21-2,39, 2,98, 3,08-3,21, 3,24-3,35, 3,55-3,65, 4,20, 4,36, 7,05, 7,08, 7,14, 7,86, 8,14, 8,33.

Example 3(71)

Hydrochloride 5-[({2-butenyl[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,82, 2,01-2,12, 2,12-2,31, 2,95, 3,08-3,19, 3,52-3,61, 4,10, 4,29, 4,32, 7,03, 7,06, 7,15, 7,29, 7,51, 7,96.

Example 3(72)

Hydrochloride 2,4-debtor-5-({[[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl](propyl)amino]carbonyl}amino)benzamide

TLC:Rf 0,51 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,62-1,75, 1,98-2,08, 2,18-2,30, 2,95, 3,02-3,18, 3,21-3,33, 3,52-3,60, 4,14, 4,28, 7,03, 7,06, 7,14, 7,29, 7,50, 7,85.

Example 3(73)

hydrochloride N-{4-[4-({4-[butyl({[2,4-debtor-5-(hydroxymethyl)phenyl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide

TLC:Rf to 0.80 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,75, 1,90-2,10, 2,20-2,35, 2,96, 3,05-3,20, 3,20-3,40, 3,50-3,65, 4,20, 4,29, 4,60, 6,97, 7,03, 7,06, 7,29, 7,46, 7,52.

Example 3(74)

Hydrochloride (or dihydrochloride) 2,4-debtor-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamide

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,93, 1,28-1,45, 1,60-1,71, 1,97-2,08, 2,20-2,38, 2,98, 3,08-3,22, 3,25-3,35, 3,55-3,64, 4,18, 4,35, 7,09-7,20, 7,33, 7,86, 8,08, 8,31.

Example 3(75)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,32, 1,28-1,45, 1,57-1,70, 1,95-2,08, 2,21-2,38, 3,11, 3,08-3,21, 3,25-3,35, 3,52-3,64, 4,18, 4,35, 7,07-7,17, 7,33, 7,86, 8,08, 8,31.

Example 3(76)

The dihydrochloride (or trihydrochloride) N-(4-{[5-({4-[{[(1-methyl-1-H-pyrazole-4-yl)amino]carbonyl}(pentyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,92, 1,28-1,42, 1,52-1,64, 1,92-2,04, 2,20-2,38, 2,98, 3,10-3,29, 3,52-3,64, 4,04, 4,24, 4,37, 7,11, 7,16, 7,34, 8,05, 8,12, 8,14, 8,34.

Example 3(77)

The dihydrochloride (or trihydrochloride) N-{4-[(5-{[4-(butyl{[(1-ethyl-1H-pyrazole-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (C 3OD): δ 0,97, 1,28-1,42, 1,52, 1,50-1,64, 1,90-2,02, 2,20-2,38, 2,98, 3,04-3,29, 3,51-3,64, 4,24, 4,30-4,44, 7,13, 7,16, 7,34, 8,05-8,16, 8,21, 8,34.

Example 3(78)

Hydrochloride (or dihydrochloride) 5-[({butyl[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf of 0.48 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,55-1,70, 2,00-2,10, 2,20-2,40, 3,05-3,20, 3,15, 3,25-3,40, 3,50-3,70, 4,20, 4,36, 7,14, 7,22, 7,40, 7,86, 8,01, 8,07, 8,29.

Example 3(79)

Hydrochloride (or dihydrochloride) 2,4-debtor-5-({[[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.44 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,94, 1,30-1,45, 1,60-1,75, 2,00-2,10, 2,15-2,40, 3,00-3,20, 3,15, 3,20-3,40, 3,50-3,70, 4,15, 4,35, 7,14, 7,22, 7,39, 7,86, 8,01, 8,05, 8,29.

Example 3(80)

Hydrochloride (or dihydrochloride) 2,4-debtor-5-({[{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamide

TLC:Rf and 0.46 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,45, 1,60-1,75, 1,95-2,10, 2,13, 2,15-2,30, 2,98, 3,10-3,40, 3,55-3,65, 4,15, 4,34, 7,01-7,21, 7,86, 8,04, 8,26.

Example 3(81)

Hydrochloride (or dihydrochloride) 5-({[{1-[(6-{2,6-dimethyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf of 0.50 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,45, 1,60-1,70, 2,00-2,10, 2,06, 2,15-2,30, 2,99, 3,00-3,40, 3,50-3,70, 4,10 4,32, 7,03, 7,08, 7,14, 7,86, 7,98, 8,20.

Example 3(82)

Hydrochloride (or dihydrochloride) 5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf and 0.46 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,45, 1,33, 1,60-1,70, 2,00-2,10, 2,20-2,40, 3,00-3,40, 3,11, 3,50-3,70, 4,15, 4,34, 7,08-7,17, 7,32, 7,86, 8,03, 8,28.

Example 3(83)

Hydrochloride (or dihydrochloride) 5-({[{1-[(6-{2-chloro-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf of 0.45 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,50, 1,60-1,75, 2,00-2,10, 2,15-2,25, 3,02, 3,05-3,35, 3,50-3,70, 4,10, 4,33, 7,14-7,28, 7,42, 7,86, 8,00, 8,20.

Example 3(84)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide

TLC:Rf 0.45 in (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,64-1,82, 2,11-2,21, 3,00, 3,10-3,24, 3,48-3,57, 3,71, 4,31, 4,67, 6,87-7,00, 7,02-7,09, 7,12, 7,20, 7,32, 7,45-7,59, 8,03, 8,26.

Example 3(85)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(2,4-differenl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide

Amorphous powder;

TLC:Rf 0.45 in (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,67-1,82, 2,11-2,24, 3,00, 3,12-3,24, 3,50-3,57, 3,71, 4,30, 4,67, 6,84-6,97, 7,01-7,08, 7,11, 7,35, 7,48-7,61, 8,02, 8,24.

Example 3(86)

Hydroch Oric (or dihydrochloride) 5-{[(butyl{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2-chloro-4-fermentated

TLC:Rf of 0.40 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,55-1,70, 1,90-2,10, 2,12, 2,20-2,40, 2,97, 3,00-3,20, 3,25-3,35, 3,50-3,70, 4,20, 4,33, 7,00-7,21, 7,32, 7,66, 8,01, 8,24.

Example 3(87)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2-chloro-4-fermentated

TLC:Rf of 0.40 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,33, 1,35-1,50, 1,60-1,70, 1,95-2,10, 2,20-2,40, 3,10, 3,10-3,20, 3,20-3,40, 3,50-3,65, 4,15, 4,33, 7,08-7,12, 7,30-7,34, 7,65, 7,99, 8,24.

Example 3(88)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]-2-methylphenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf 0,62 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,33, 1,28-1,45, 1,59-1,70, 1,97-2,08, 2,12, 2,18-2,34, 3,11, 3,06-3,20, 3,25-3,35, 3,52-3,63, 4,12, 4,33, 7,00, 7,07, 7,13, 7,15, 7,20, 7,86, 8,01, 8,24.

Example 3(89)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-debtor-N-methylbenzamide

TLC:Rf of 0.53 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,30-1,47, 1,58-1,70, 1,95-2,07, 2,13, 2,20-2,37, 2,91, 2,98, 3,04-3,21, 3,22-3,35, 3,52-3,64, 4,18, 4,34, 7,01-7,24, 7,79, 8,06, 8,27.

Example 3(90)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-debtor-N-methylbenzamide

TLC:Rf of 0.53 (d is harmatan: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,33, 1,30-1,47, 1,59-1,70, 1,98-2,05, 2,20-2,38, 2,91, 3,11, 3,07-3,21, 3,22-3,35, 3,52-3,64, 4,18, 4,35, 7,08-7,16, 7,32, 7,79, 8,06, 8,29.

Example 3(91)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{2-chloro-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-debtor-N-methylbenzamide

TLC:Rf of 0.53 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,32-1,45, 1,58-1,70, 1,97-2,05, 2,20-2,37, 2,91, 3,02, 3,04-3,21, 3,22-3,35, 3,51-3,62, 4,18, 4,34, 7,06-7,29, 7,42, 7,79, 8,06, 8,23.

Example 3(92)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{2-methoxy-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-debtor-N-methylbenzamide

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,32-1,45, 1,58-1,70, 1,95-2,05, 2,19-2,37, 2,91, 3,00, 3,04-3,21, 3,22-3,35, 3,54-3,62, 3,72, 4,18, 4,34, 6,90, 7,04-7,17, 7,79, 8,06, 8,27.

Example 3(93)

Hydrochloride (or dihydrochloride) 2-(5-{[(butyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differenl)ndimethylacetamide

TLC:Rf is 0.42 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,50-1,70, 1,95-2,10, 2,15-2,30, 2,97, 3,05-3,20, 3,20-3,40, 3,50-3,60, 3,53, 4,10, 4,33, 7,00, 7,08-7,14, 7,30-7,34, 7,97, 8,24.

Example 3(94)

Hydrochloride (or dihydrochloride) 2-[2,4-debtor-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)phenyl]ndimethylacetamide

TLC:Rf of 0.43 (chloroform: methanol= 7:1;

NMR (CD3OD): δ 0,93, 1,30-1,50, 1,55-1,75, 1,90-2,10, 2,15-2,35, 2,97, 3,10-3,20, 3,20-3,40, 3,50-3,60, 3,53, 4,15, 4,33, 7,00, 7,08-7,14, 7,30-7,34, 7,99, 8,25.

Example 3(95)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-debtor-N-methylbenzamide

TLC:Rf of 0.41 (chloroform: methanol=7:1);

NMR (CD3OD): δ 0,98, 1,35-1,50, 1,65-1,80, 1,95-2,10, 2,20-2,35, 2,91, 2,97, 3,05-3,20, 3,20-3,40, 3,55-3,70, 4,10, 4,34, 7,08-7,16, 7,32, 7,80, 8,00, 8,24.

Example 3(96)

Hydrochloride (or dihydrochloride) 2,4-debtor-N-methyl-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.43 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,50, 1,60-1,75, 1,95-2,10, 2,20-2,40, 2,91, 2,97, 3,05-3,20, 3,20-3,40, 3,50-3,70, 4,15, 4,34, 7,08-7,16, 7,32, 7,79, 8,00, 8,24.

Example 3(97)

Hydrochloride (or dihydrochloride) 5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-debtor-N-methylbenzamide

TLC:Rf of 0.45 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,33, 1,30-1,45, 1,60-1,70, 1,90-2,10, 2,15-2,30, 2,91, 3,05-3,20, 3,10, 3,20-3,40, 3,50-3,60, 4,10, 4,33, 7,07-7,16, 7,32, 7,79, 7,97, 8,24.

Example 3(98)

Hydrochloride (or dihydrochloride) 2,4-debtor-N-methyl-5-({[{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.45 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,40, 1,60-1,70, 1,95-2,05, 2,1, 2,20-2,40, 2,91, 2,98, 3,05-3,20, 3,20-3,40, 3,55-3,65, 4,15, 4,34, 7,11-7,21, 7,79, 8,04, 8,26.

Example 3(99)

The dihydrochloride of N-[4-(4-{[4-(butyl{[(1,5-dimethyl-1H-pyrazole-4-yl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide

TLC:Rf 0.84 (chloroform: methanol= 4:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,60-1,80, 1,90-2,10, 2,10-2,30, 2,27, 2,95, 3,00-3,20, 3,20-3,40, 3,50-3,60, 3,92, 4,20, 4,29, 7,02-7,08, 7,31, 7,51, 7,84.

Example 3(100)

The dihydrochloride of 4-(4-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-[2-(dimethylamino)ethyl]benzosulfimide

TLC:Rf 0.40 in (dichloromethane: methanol= 5:1);

NMR (CD3OD): δ 0,98, 1,36-1,43, 1,60-1,70, 1,98-2,02, 2,20-2,35, 2,94, 3,10-3,34, 3,56-3,60, 4,21, 4,34, 6,90-7,01, 7,18-7,21, 7,36, 7,62, 7,89.

Example 3(101)

Hydrochloride 5-{[(butyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-1-oxide-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf of 0.54 (chloroform: methanol= 4:1);

NMR (CD3OD): δ 0,99, 1,30-1,50, 1,55-1,70, 1,95-2,15, 2,20-2,40, 3,01, 3,10-3,40, 3,55-3,70, 4,15, 4,39, 7,12-7,21, 7,25, 7,40, 7,81, 7,87, 8,70.

Example 3(102)

The dihydrochloride of 5-{[(butyl[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-N-[2-(dimethylamino)ethyl]-2,4-differentated

TLC:Rf to 0.17 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,80, 1,90-2,10, 2,20-2,40, 2,95, 2,98, 3,00-3,20, 3,20-3,40, 3,50-3,80, 4,20, 4,29, 7,02-7,08, 7,17, 7,29, 7,52, 7,91.

Example 3(103)

Hydrochloride (or dihydrochloride) 5-{[(benzyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-Piri is inil)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf 0,51 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,97-2,06, 2,07-2,22, 2,97, 3,04-3,18, 3,47-3,58, 4,30, 4,37, 4,66, 7,04-7,17, 7,21-7,45, 7,89, 8,00, 8,24.

Example 3(104)

The hydrochloride of methyl 4-[4-({4-[({[5-(aminocarbonyl)-2,4-differenl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-methoxybenzoate

TLC:Rf 0,58 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,44, 1,58-1,70, 1,95-2,04, 2,12-2,30, 3,08-3,18, 3,22-3,35, 3,51-3,61, 3,82, 3,91, 4,14, 4,28, 6,99, 7,09, 7,14, 7,47, 7,67, 7,73, 7,85.

Example 3(105)

Hydrochloride (or dihydrochloride) 2,4-debtor-5-{[(hexyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide

TLC:Rf of 0.47 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,91, 1,30-1,50, 1,60-1,70, 2,00-2,10, 2,20-2,35, 2,97, 3,00-3,20, 3,20-3,40, 3,50-3,70, 4,10, 4,33, 7,08-7,18, 7,32, 7,86, 7,98, 8,24.

Example 3(106)

The hydrochloride of methyl N-[4-(4-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)piperidine-1-yl]methyl}phenoxy)phenyl]-N-(methylsulphonyl)glycinate

TLC:Rf 0,46 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,96, 1,27-1,44, 1,55-1,90, 2,10-2,20, 2,95-3,07, 3,08, 3,21-3,34, 3,53, 3,74, 4,05, 4,46, 6,85-7,04, 7,03-7,45, 7,47.

Example 3(107)

The hydrochloride of methyl N-{4-[4-({4-[({[5-(aminocarbonyl)-2,4-differenl]amino}carbonyl)(butyl)amino]piperidine-1-yl}methyl)phenoxy]phenyl}-N-(methylsulphonyl)glycinate

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,32-1,42, 1,58-1,68, 1,70-1,97, 2,12-2,28, 2,99-3,12, 3,08, 3,20-3,35, 3,57, 3,74, 4,02, 4,46, 6,92-7,04, 7,16, 7,36, 7,47, 8,54.

Example 4

hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{4-[(methylamino)carbonyl]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

To a solution of the compound obtained in Example 3(53) (132 mg) in dimethylformamide (1 ml), was added 1-hydroxybenzotriazole (46 mg), the hydrochloride of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (65 mg) and a solution of 33% methylamine in methanol (32 ml). The reaction mixture was stirred for 2.5 hours at room temperature. To the mixture was added saturated aqueous sodium hydrogen carbonate solution and all were extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate: methanol = 5:1). To a solution of the obtained compound in ethyl acetate was added 4 N. hydrogen chloride in ethyl acetate solution. The reaction mixture was concentrated, obtaining specified in the title compound (73 mg)having the following physical data.

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,32-1,45, 1,58-1,70, 1,95-2,08, 2,25-2,40, 2,92, 3,10-3,22, 3,27-3,38, 3,58-3,64, 4,24, 4,37, 7,13, 7,15, 7,24, 7,86, 7,90, 8,12, 8,33.

Examples 4(1) - 4(9)

Using a procedure similar to that described in Example 4, using the appropriate amine compounds instead of methylamine and the compound obtained in Example 3(53), or compounds obtained in Example 3(47), to obtain the following compounds of the present invention.

Example 4(1)

Hydrochloride (or hydrochloride) 5-({[[1-({6-[4-(aminocarbonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](butyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf of 0.47 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,35-1,48, 1,59-1,70, 1,95-2,08, 2,19-2,38, 3,06-3,22, 3,24-3,35, 3,55-3,65, 4,18, 4,36, 7,14, 7,16, 7,23, 7,86, 7,96, 8,05, 8,30.

Example 4(2)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{4-[(dimethylamino)carbonyl]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,34-1,45, 1,58-1,70, 1,95-2,08, 2,20-2,40, 3,02-3,22, 3,24-3,35, 3,52-3,65, 4,19, 4,36, 7,14, 7,16, 7,25, 7,52, 7,86, 8,09, 8,30.

Example 4(3)

Hydrochloride (or dihydrochloride) 5-[({butyl[1-({6-[4-(4-morpholinylcarbonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,47, 1,59-1,70, 1,95-2,08, 2,20-2,39, 3,10-3,20, 3,25-3,35, 3,45-3,82, 4,18, 4,36, 7,14, 7,16, 7,25, 7,52, 7,86, 8,08, 8,30.

Example 4(4)

Hydrochloride (or dihydrochloride) 5-({[butyl(1-{[6-(4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)-3-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,35-1,47, 1,60-1,70, 1,95-2,08, 2,20-2,38, 3,08-3,21, 3,25-3,40, 3,57, 3,51-3,64, 4,16, 4,36, 7,14, 7,16, 7,23, 7,86, 7,90, 8,05, 8,30.

Example 4(5)

The dihydrochloride (or trihydrochloride) 5-[({butyl[1-({6-[4-({[2-(dimethylamino)ethyl]amino}carbonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated

TLC:Rf 0.35 in (dichloromethane: methanol= 5:1;

NMR (CD3OD): δ 0,97, 1,35-1,45, 1,59-1,70, 1,94-2,05, 2,23-2,40, 2,99, 3,10-3,22, 3,22-3,35, 3,40, 3,55-3,65, 3,78, 4,22, 4,37, 7,14, 7,17, 7,27, 7,86, 7,99, 8,13, 8,34.

Example 4(6)

Hydrochloride (or dihydrochloride) 5-({[butyl(1-{[6-(4-{[(2-methoxyethyl)amino]carbonyl}-2,6-dimethylphenoxy)-3-pyridinyl]methyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf 0,51 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,34-1,46, 1,57-1,68, 1,98-2,08, 2,13, 2,18-2,35, 3,08-3,21, 3,22-3,40, 3,56, 3,51-3,64, 4,17, 4,33, 7,11, 7,14, 7,62, 7,86, 8,06, 8,22.

Example 4(7)

Hydrochloride 5-({[(1-{4-[4-(aminocarbonyl)-2-methoxyphenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf 0,41 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,47, 1,58-1,70, 1,97-2,05, 2,12-2,31, 3,04-3,18, 3,22-3,35, 3,51-3,60, 3,82, 4,15, 4,27, 6,97, 7,09, 7,14, 7,47, 7,53, 7,65, 7,85.

Example 4(8)

Hydrochloride 5-{[(butyl{1-[4-(2-methoxy-4-{[(2-methoxyethyl)amino]carbonyl}phenoxy)benzyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf of 0.53 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,47, 1,58-1,70, 1,95-2,04, 2,12-2,30, 3,04-3,18, 3,22-3,35, 3,50-3,61, 3,57, 3,82, 4,14, 4,27, 6,97, 7,09, 7,14, 7,45, 7,47, 7,61, 7,85.

Example 4(9)

Hydrochloride 5-({[butyl(1-{4-[2-methoxy-4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,44, 1,58-1,70, 1,95-2,04, 2,12-2,30, 3,04-3,17, 3,22-3,35, 3,47-3,81, 3,79, 4,14, 4,27, 6,97, 7,05, 7,12, 7,14, 7,20, 7,45, 7,85.

Example 5

Guide chlorid [[4-(4-{[4-(butyl{[(2,4-differenl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl](methylsulphonyl)amino]acetic acid

To a solution of the compound obtained in Example 3(106) (80 mg) in methanol (1 ml), was added 2 N. aqueous sodium hydroxide solution (0.5 ml). The reaction mixture peremeshivanii for 2.5 hours at room temperature. To the reaction mixture in an ice bath was added 1 N. hydrochloric acid until the pH of the solution does not become lower than 5, then the mixture was extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate, concentrated. The obtained residue was purified by column chromatography on silica gel (dichloromethane: methanol = 9:1). To a solution of the obtained compound in ethyl acetate was added 4 N. hydrogen chloride in ethyl acetate solution. The reaction mixture was concentrated, obtaining specified in the title compound (64 mg)having the following physical data.

TLC:Rf 0.45 in (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,45, 1,57-1,70, 1,92-2,05, 2,12-2,31, 3,09, 3,06-3,20, 3,22-3,35, 3,51-3,61, 4,17, 4,30, 4,43, 6,88-7,05, 7,06, 7,12, 7,36, 7,51-7,58.

Example 5(1)

Hydrochloride [{4-[4-({4-[({[5-(aminocarbonyl)-2,4-differenl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}(methylsulphonyl)amino]acetic acid

Using a procedure similar to that described in Example 5 using the compound obtained in Example 3(107), received the following specified in the header of the connection.

TLC:Rf 0,17 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,30-1,42, 1,57-1,70, 1,90-2,02, 2,11-2,30, 2,95-3,10, 3,10, 3,23-3,40, 3,41-3,52, 4,16, 4,21, 4,30, 7,01, 7,06, 7,13, 7,48, 7,57, 7,86.

Examples 6(1) - 6(20)

Using a procedure similar to that described in Example 3, using the appropriate aldehyde compound instead of the compound obtained in Example 1, and the corresponding amine compound instead of the compound obtained in Example 2, to obtain the following compounds of the present invention.

Example 6(1)

Hydrochloride (or dihydrochloride) 2-(5-{[(butyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differenl)ndimethylacetamide

TLC:Rf is 0.42 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,50-1,70, 1,95-2,10, 2,15-2,30, 2,97, 3,05-3,20, 3,20-3,40, 3,50-3,60, 3,53, 4,10, 4,33, 7,00, 7,08-7,14, 7,30-7,34, 7,97, 8,24.

Example 6(2)

Hydrochloride (or dihydrochloride) 2-[2,4-debtor-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)phenyl]ndimethylacetamide

TLC:Rf of 0.43 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,50, 1,55-1,75, 1,90-2,10, 2,15-2,35, 2,97, 3,10-3,20, 3,20-3,40, 3,50-3,60, 3,53, 4,15, 4,33, 7,00, 7,08-7,14, 7,30-7,34, 7,99, 8,25.

Example 6(3)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-debtor-N-methylbenzamide

TLC:Rf of 0.41 (chloroform: methanol= 7:1);

NMR (C 3OD): δ 0,98, 1,35-1,50, 1,65-1,80, 1,95-2,10, 2,20-2,35, 2,91, 2,97, 3,05-3,20, 3,20-3,40, 3,55-3,70, 4,10, 4,34, 7,08-7,16, 7,32, 7,80, 8,00, 8,24.

Example 6(4)

Hydrochloride (or dihydrochloride) 2,4-debtor-N-methyl-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.43 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,50, 1,60-1,75, 1,95-2,10, 2,20-2,40, 2,91, 2,97, 3,05-3,20, 3,20-3,40, 3,50-3,70, 4,15, 4,34, 7,08-7,16, 7,32, 7,79, 8,00, 8,24.

Example 6(5)

Hydrochloride (or dihydrochloride) 5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-debtor-N-methylbenzamide

TLC:Rf of 0.45 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,33, 1,30-1,45, 1,60-1,70, 1,90-2,10, 2,15-2,30, 2,91, 3,05-3,20, 3,10, 3,20-3,40, 3,50-3,60, 4,10, 4,33, 7,07-7,16, 7,32, 7,79, 7,97, 8,24.

Example 6(6)

Hydrochloride (or dihydrochloride) 2,4-debtor-N-methyl-5-({[{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.45 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,40, 1,60-1,70, 1,95-2,05, 2,13, 2,20-2,40, 2,91, 2,98, 3,05-3,20, 3,20-3,40, 3,55-3,65, 4,15, 4,34, 7,11-7,21, 7,79, 8,04, 8,26.

Example 6(7)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{2-chloro-4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf 0,46 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,33, 1,30-1,47, 1,59-1,70, 1,95-2,08, 2,20-2,37, 3,15, 3,05-3,20, 3,2-3,35, 3,52-3,62, 4,18, 4,34, 7,10-7,28, 7,41, 7,86, 8,05, 8,24.

Example 6(8)

Hydrochloride 5-({[(1-{4-[4-(aminocarbonyl)phenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf 0.40 in (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,49, 1,59-1,70, 1,95-2,09, 2,19-2,38, 3,08-3,20, 3,27-3,35, 3,51-3,65, 4,18, 4,32, 7,07, 7,08, 7,16, 7,57, 7,86, 7,91.

Example 6(9)

Hydrochloride 5-({[butyl(1-{4-[4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf 0.45 in (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,31-1,47, 1,60-1,70, 1,98-2,07, 2,15-2,30, 3,04-3,20, 3,25-3,35, 3,50-3,80, 4,13, 4,31, 7,08-7,18, 7,48, 7,54, 7,86.

Example 6(10)

Hydrochloride of 2-{5-[({butyl[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differenl}ndimethylacetamide

TLC:Rf is 0.42 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,75, 1,95-2,10, 2,10-2,30, 2,95, 3,05-3,40, 3,53, 3,55-3,65, 4,15, 4,28, 7,00-7,08, 7,28, 7,29, 7,49.

Example 6(11)

Hydrochloride (or dihydrochloride) 2-{5-[({butyl[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differenl}ndimethylacetamide

TLC:Rf of 0.44 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,15-2,30, 3,05-3,40, 3,15, 3,53, 3,55-3,65, 4,15, 4,36, 7,00, 7,23, 7,33, 7,40, 8,01, 8,04, 8,29.

Example 6(12)

Hydrochloride (or dihydrochloride) 2-{5-[({butyl[1-({6-[2-chloro-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differenl}ndimethylacetamide

TLC:Rf is 0.42 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,70, 1,95-2,10, 2,15-2,35, 3,00-3,40, 3,30, 3,53, 3,55-3,65, 4,15, 4,37, 7,00, 7,25, 7,33, 7,35, 7,53, 8,06, 8,16, 8,31.

Example 6(13)

Hydrochloride (or dihydrochloride) 2-[5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-differenl}ndimethylacetamide

TLC:Rf of 0.33 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,50, 1,33, 1,60-1,70, 1,90-2,10, 2,15-2,35, 3,00-3,40, 3,10, 3,53, 3,55-3,65, 4,10, 4,33, 7,00, 7,07-7,13, 7,32, 7,33, 7,97, 8,24.

Example 6(14)

Hydrochloride (or dihydrochloride) 2-[2,4-debtor-5-({[{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)phenyl]ndimethylacetamide

TLC:Rf of 0.45 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,12, 2,20-2,40, 2,97, 3,00-3,40, 3,53, 3,55-3,65, 4,15, 4,33, 6,96-7,21, 7,33, 8,01, 8,24.

Example 6(15)

Hydrochloride (or dihydrochloride) 2-[2,4-debtor-5-({[[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)phenyl]ndimethylacetamide

TLC:Rf to 0.39 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,50, 1,60-1,70, 1,90-2,10, 2,10-2,30, 3,00-3,40, 3,15, 3,53, 3,55-3,65, 4,15, 4,36, 7,00, 7,22, 7,33, 7,40, 8,01, 8,04, 8,29.

Example 6(16)

Hydrochloride (or dihydrochloride) 2-[5-({[[1-({6-[2-chloro-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)-2,4-differenl]ndimethylacetamide

TLC:Rf of 0.44 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,94, 1,0-1,50, 1,60-1,70, 1,90-2,10, 2,10-2,30, 3,00-3,40, 3,30, 3,53, 3,55-3,65, 4,10, 4,35, 7,00, 7,25, 7,33, 7,37, 7,52, 8,05, 8,16, 8,31.

Example 6(17)

Hydrochloride (or dihydrochloride) N'-(4-forfinal)-N-[1-({6-[4-(methylsulphonyl)phenoxy]pyridine-3-yl}methyl)piperidine-4-yl]-N-prilocaine

TLC:Rf 0,54 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,14-2,03, 3,14, 3,12-3,25, 3,48-3,58, 4,30, 4,67, 6,95, 7,16-7,25, 7,30-7,40, 7,46-7,58, 7,96, 8,00, 8,22.

Example 6(18)

Hydrochloride (or dihydrochloride) N-[1-({6-[2-chloro-4-(methylsulphonyl)phenoxy]pyridine-3-yl}methyl)piperidine-4-yl]-N'-(4-forfinal)-N-prilocaine

TLC:Rf 0,54 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,15-2,23, 3,12-3,28, 3,31, 3,49-3,59, 4,30, 4,68, 6,95, 7,10, 7,18-7,25, 7,30-7,40, 7,49-7,58, 7,98, 8,15, 8,24.

Example 6(19)

Hydrochloride (or dihydrochloride) N-[1-({6-[2-chloro-4-(methylsulphonyl)phenoxy]pyridine-3-yl}methyl)piperidine-4-yl]-N'-(2,4-differenl)-N-prilocaine

TLC:Rf 0,54 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,15-2,25, 3,10-3,30, 3,31, 3,50-3,60, 4,31, 4,68, 6,84-6,96, 7,21, 7,30-7,39, 7,48-7,60, 7,98, 8,15, 8,24.

Example 6(20)

Hydrochloride (or dihydrochloride) 5-({[butyl(1-{[6-(4-{[(2-methoxyethyl)amino]carbonyl}-2-methylphenoxy)pyridine-3-yl]methyl}-piperidine-4-yl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,97, 1,32-1,47, 1,60-1,70, 1,97-2,04, 2,21, 2,20-2,37, 3,10-3,20, 3,21-3,40, 3,57, 3,50-3,62, 4,18, 4,34, 7,10-7,20, 7,72, 7,80, 7,86, 8,06, 8,26.

Examples 7(1) - 7(121)

Using the procedure, the analogues of the Noi described in Example 3, using the appropriate aldehyde compound instead of the compound obtained in Example 1, and the corresponding amine compound instead of the compound obtained in Example 2, and if necessary, converting a free base to obtain the following compounds of the present invention.

Example 7(1)

Hydrochloride (or dihydrochloride) 5-({[[1-({6-[2,6-dimethyl-4-(methylsulphonyl)phenoxy]-3-pyridinyl}-methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf is 0.42 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,50, 1,60-1,80, 1,95-2,10, 2,17, 2,20-2,35, 3,00-3,40, 3,14, 3,50-3,70, 4,15, 4,33, 7,14, 7,21, 7,74, 7,86, 8,07, 8,18.

Example 7(2)

Hydrochloride (or dihydrochloride) 5-({[[1-({6-[2-chloro-4-(methylsulphonyl)phenoxy]-3-pyridinyl}-methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)-2,4-differentated

TLC:Rf of 0.48 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,93, 1,30-1,50, 1,60-1,80, 1,95-2,10, 2,20-2,40, 3,10-3,40, 3,30, 3,50-3,70, 4,15, 4,37, 7,14, 7,25, 7,35, 7,53, 7,86, 8,10, 8,16, 8,32.

Example 7(3)

Hydrochloride (or dihydrochloride) 5-[({butyl[1-({6-[2-chloro-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2-fermentated

TLC:Rf of 0.35 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,60-1,80, 1,95-2,10, 2,20-2,40, 3,10-3,40, 3,30, 3,50-3,70, 4,15, 4,36, 7,14, 7,25, 7,35, 7,50, 7,53, 7,78, 8,07, 8,16, 8,32.

Example 7(4)

Hydrochloride (or dihydrochloride) 5-[({butyl[1-({6-[2-methyl-4-(methylsulphonyl)f is noxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2-fermentated

TLC:Rf of 0.36 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,97, 1,30-1,50, 1,55-1,70, 1,90-2,10, 2,20-2,40, 2,26, 3,00-3,40, 3,14, 3,50-3,70, 4,20, 4,35, 7,11-7,30, 7,53, 7,76-7,85, 7,92, 8,07, 8,24.

Example 7(5)

Hydrochloride (or dihydrochloride) 2,4-debtor-5-{[hexyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide

TLC:Rf of 0.37 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,98, 1,30-1,50, 1,60-1,70, 1,90-2,05, 2,20-2,35, 2,97, 3,00-3,35, 3,50-3,70, 4,20, 4,34, 7,08-7,17, 7,32, 7,86, 8,02, 8,24.

Example 7(6)

Hydrochloride (or dihydrochloride) 2,4-debtor-5-{[((2-methylbenzyl){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide

TLC:Rf of 0.53 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,98-2,20, 2,36, 2,97, 3,04-3,18, 3,48-3,57, 4,30, 4,43, 4,57, 7,04-7,33, 7,85, 7,98, 8,23.

Example 7(7)

Hydrochloride (or dihydrochloride) 2,4-debtor-5-({[[1-({6-[2-methyl-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.38 (chloroform: methanol= 7:1);

NMR (CD3OD): δ 0,94, 1,30-1,50, 1,60-1,80, 1,90-2,10, 2,26, 2,20-2,40, 3,05-3,40, 3,14, 3,50-3,70, 4,15, 4,33, 7,11-7,29, 7,81-7,89, 7,92, 8,03, 8,23.

Example 7(8)

Hydrochloride (or dihydrochloride) 2,4-debtor-5-{[({1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide

TLC:Rf of 0.37 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,80, 2,20-2,30, 2,98, 3,08-3,21, 3,50-3,60, 3,83, 4,34, 7,07-7,19, 7,33, 8,02, 8,27, 8,38.

Example 7(9)/p>

Hydrochloride (or dihydrochloride) N'-(4-forfinal)-N-[1-({6-[2-methoxy-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-prilocaine

TLC:Rf of 0.55 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,64-1,80, 2,12-2,22, 3,17, 3,10-3,25, 3,48-3,58, 3,79, 4,27, 4,67, 6,95, 7,12, 7,22, 7,30-7,38, 7,45-7,64, 7,93, 8,12.

Example 7(10)

Hydrochloride (or dihydrochloride) N'-(2,4-differenl)-N-[1-({6-[2-methyl-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-prilocaine

TLC:Rf 0.56 to (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,80, 2,15-2,28, 2,24, 3,13, 3,12-3,24, 3,50-3,58, 4,29, 4,68, 6,85-6,98, 7,17, 7,26, 7,34-7,38, 7,48-7,60, 7,81, 7,91, 7,98, 8,17.

Example 7(11)

Hydrochloride (or dihydrochloride) N'-(2,4-differenl)-N-[1-({6-[2,6-dimethyl-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-prilocaine

TLC:Rf 0.56 to (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,15, 2,12-2,23, 3,13, 3,10-3,24, 3,50-3,58, 4,27, 4,68, 6,85-6,98, 7,18, 7,33-7,37, 7,50-7,60, 7,73, 7,96, 8,11.

Example 7(12)

Hydrochloride (or dihydrochloride) N'-(2,4-differenl)-N-[1-({6-[2-methoxy-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-prilocaine

TLC:Rf of 0.55 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,64-1,80, 2,15-2,24, 3,17, 3,12-3,25, 3,48-3,58, 3,79, 4,28, 4,68, 6,85-6,98, 7,12, 7,33-7,37, 7,50-7,60, 7,95, 8,13.

Example 7(13)

Hydrochloride (or dihydrochloride) 2,4-debtor-5-[({hexyl[1-({6-[2-methoxy-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]benzamide

TLC:Rf 0.35 in (choroform: methanol= 7:1);

NMR (CD3OD): δ 0,91, 1,25-1,45, 1,60-1,75, 1,90-2,10, 2,20-2,40, 3,05-3,40, 3,14, 3,50-3,70, 3,81, 4,15, 4,35, 7,14, 7,15, 7,38, 7,60-7,65, 7,86, 8,09, 8,24.

Example 7(14)

Hydrochloride (or dihydrochloride) N'-(4-forfinal)-N-[1-({6-[2-methyl-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-prilocaine

TLC:Rf of 0.75 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,63-1,80, 2,12-2,23, 2,24, 3,13, 3,10-3,25, 3,48-3,57, 4,29, 4,67, 6,95, 7,15-7,35, 7,47-7,60, 7,81, 7,91, 7,97, 8,17.

Example 7(15)

Hydrochloride (or dihydrochloride) N-[1-({6-[2,6-dimethyl-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N'-(4-forfinal)-N-prilocaine

TLC:Rf of 0.75 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,64-1,80, 2,15, 2,10-2,23, 3,13, 3,10-3,25, 3,48-3,58, 4,27, 4,67, 6,95, 7,15-7,25, 7,30-7,35, 7,48-7,60, 7,73, 7,97, 8,11.

Example 7(16)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(2-methyl-6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated

TLC:Rf 0.56 to (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,32-1,45, 1,58-1,70, 1,95-2,05, 2,24-2,40, 2,67, 2,99, 3,20-3,35, 3,60-3,69, 4,28, 4,43, 6,95, 7,14, 7,22, 7,37, 7,87, 8,20.

Example 7(17)

Hydrochloride (or dihydrochloride) 4-chloro-2-fluoro-5-({[[1-({6-[2-methyl-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.55 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,94, 1,30-1,50, 1,67-1,80, 1,98-2,06, 2,26, 2,19-2,38, 3,10-3,20, 3,14, 3,25-3,35, 3,55-3,65, 4,20, 4,34, 7,21, 7,28, 7,41, 7,83, 7,90-7,99, 8,06, 8,24.

Example 7(18)

G is drochloride (or dihydrochloride) 4-chloro-5-({[[1-({6-[2,6-dimethyl-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](pentyl)amino]carbonyl}amino)-2-fermentated

TLC:Rf of 0.55 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,94, 1,30-1,47, 1,65-1,80, 1,98-2,08, 2,17, 2,15-2,35, 3,08-3,20, 3,13, 3,25-3,35, 3,55-3,65, 4,19, 4,33, 7,21, 7,41, 7,74, 7,97, 8,06, 8,18.

Example 7(19)

Hydrochloride (or dihydrochloride) 5-{[(butyl{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-4-chloro-2-fermentated

TLC:Rf 0,54 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, 1,35-1,48, 1,62-1,75, 1,98-2,08, 2,19-2,38, 2,97, 3,08-3,20, 3,25-3,35, 3,55-3,63, 4,17, 4,34, 7,09, 7,13, 7,32, 7,42, 7,94, 8,02, 8,27.

Example 7(20)

Hydrochloride (or dihydrochloride) 5-[({butyl[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-4-chloro-2-fermentated

TLC:Rf 0,54 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,99, 1,38-1,50, 1,64-1,75, 1,98-2,07, 2,20-2,38, 3,15, 3,08-3,20, 3,25-3,35, 3,58-3,65, 4,18, 4,36, 7,22, 7,40, 7,41, 7,94, 8,02, 8,07, 8,30.

Example 7(21)

Hydrochloride (or dihydrochloride) 5-[({butyl[1-({6-[2-chloro-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-4-chloro-2-fermentated

TLC:Rf of 0.55 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,99, 1,38-1,45, 1,64-1,75, 1,98-2,07, 2,20-2,38, 3,08-3,22, 3,25-3,35, 3,31, 3,58-3,65, 4,18, 4,37, 7,25, 7,36, 7,41, 7,53, 7,94, 8,09, 8,16, 8,32.

Example 7(22)

Hydrochloride (or dihydrochloride) 5-[({butyl[1-({6-[2,6-dimethyl-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-4-chloro-2-fermentated

TLC:Rf 0.56 to (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,98, of 1.35 to 1.48, 1,621,75, 1,97-2,08, 2,17, 2,19-2,38, 3,08-3,21, 3,14, 3,25-3,35, 3,52-3,65, 4,19, 4,33, 7,21, 7,41, 7,73, 7,94, 8,07, 8,18.

Example 7(23)

The dihydrochloride of N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyrazinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,70-1,84, 2,14-2,23, 2,97, 3,20-3,35, 3,55-3,65, 4,40, 4,68, 6,95, 7,17, 7,22, 7,29-7,38, 7,48-7,60, 8,19, 8,48.

Example 7(24)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[[(cyclohexylamino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf 0,51 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 0,93-1,15, 1,20-1,38, 1,49-1,80, 2,08-2,18, 2,97, 3,10-3,21, 3,47-3,58, 4,28, 4,62, 7,07, 7,12, 7,18-7,25, 7,33, 7,42-7,55, 7,98, 8,23.

Example 7(25)

Hydrochloride (or dihydrochloride) N-[4-({5-[(4-{phenyl[(3-thienylene)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,64-1,80, 2,12-2,20, 2,98, 3,12-3,26, 3,50-3,59, 4,32, 4,68, 6,91, 7,10, 7,04-7,20, 7,27-7,37, 7,48-7,60, 8,07, 8,31.

Example 7(26)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[(unlinkable)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf 0.56 to (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,15-2,24, 2,97, 3,12-3,23, 3,49-3,57, 4,27, 4,68, 6,97-7,14, 7,18-7,22, 7,28-7,38, 7,48-7,60, 7,89, 8,17.

Example 7(27)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[[(benzylamino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]on the si}phenyl)methanesulfonamide

TLC:Rf of 0.55 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,60-1,78, 2,08-2,18, 2,97, 3,08-3,21, 3,48-3,55, 4,25, 4,29, 4,64, 7,08, 7,10-7,27, 7,32, 7,40-7,58, 8,01, 8,27.

Example 7(28)

Hydrochloride (or dihydrochloride) N-{4-[(5-{[4-(phenyl{[(2-phenylethyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide

TLC:Rf of 0.55 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,57-1,73, 2,04-2,13, 2,67, 2,98, 3,10-3,22, 3,27-3,35, 3,48-3,55, 4,31, 4,60, 7,04-7,25, 7,34, 7,40-7,47, 8,06, 8,31.

Example 7(29)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.30 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,20, 2,97, 3,10-3,25, 3,50-3,60, 4,29, 4,65, 6,93-7,13, 7,22-7,33, 7,53, 7,61, 7,94, 8,21.

Example 7(30)

Hydrochloride (or dihydrochloride) N-[4-({5-[(4-{3-thienyl[(3-thienylene)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]methanesulfonamide

TLC:Rf of 0.55 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,78, 2,11-2,20, 2,97, 3,12-3,25, 3,48-3,58, 4,28, 4,67, 6,95, 7,00, 7,06, 7,11, 7,17-7,23, 7,31, 7,49, 7,60, 7,90, 8,18.

Example 7(31)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(3-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf 0.56 to (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,12-2,24, 2,97, 3,12-3,25, 3,48-3,58, 4,27, 4,68, 6,72, 6,93, 7,03-7,35, ,48-7,60, 7,89, 8,17.

Example 7(32)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(2-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf 0.56 to (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,63-1,80, 2,18-2,25, 2,97, 3,12-3,25, 3,48-3,58, 4,28, 4,69, 6,98-7,15, 7,31, 7,35-7,40, 7,50-7,62, 7,73, 7,90, 8,17.

Example 7(33)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(4-methoxyphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,13-2,21, 2,97, 3,12-3,25, 3,48-3,57, 3,73, 4,27, 4,67, 6,79, 7,05, 7,09, 7,10, 7,28-7,35, 7,47-7,58, 7,90, 8,17.

Example 7(34)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(3-methoxyphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,13-2,25, 2,97, 3,12-3,25, 3,48-3,57, 3,72, 4,28, 4,67, 6,58, 6,73, 6,94, 7,04-7,15, 7,29-7,35, 7,49-7,60, 7,90, 8,18.

Example 7(35)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(2-methoxyphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,15-2,27, 2,97, 3,12-3,25, 3,50-3,60, 3,55, 4,29, 4,71, 6,80-6,97, 7,05, 7,11, 7,31, 7,37, 7,51-7,64, 7,91, 7,95, 8,18.

Example 7(36)

N-(4-{[5-({4-[{[(4-were)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonyl is d

Amorphous powder;

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,34-1,50, 1,80-1,91, 2,10-2,20, 2,23, 2,83-2,98, 2,95, 3,44, 4,43, 6,88, 6,98-7,10, 7,28, 7,45-7,57, 7,73, 7,98.

Example 7(37)

N-(4-{[5-({4-[{[(3-were)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,35-1,50, 1,80-1,91, 2,08-2,20, 2,24, 2,84-2,98, 2,94, 3,44, 4,43, 6,80, 6,87, 6,97-7,12, 7,26-7,34, 7,44-7,58, 7,73, 7,98.

Example 7(38)

N-(4-{[5-({4-[{[(2-were)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,38-1,54, 1,84-1,96, 1,91, 2,10-2,20, 2,85-2,98, 2,95, 3,44, 4,43, 6,88, 6,97, 7,02-7,14, 7,28, 7,35, 7,42-7,60, 7,73, 7,98.

Example 7(39)

N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

White amorphous powder;

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CDCl3): δ 1,32-1,48, 1,80-1,89, 2,08-2,20, 2,82-2,90, 3,01, 3,40, 4,53, 5,83, 6,43, 6,85, 7,08-7,28, 7,44-7,55, 7,61, 8,00.

Example 7(40)

N-(4-{[5-({4-[{[(3-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CDCl3): δ 1,32-1,50, 1,80-1,90, 2,08-2,20, 2,82-2,90, 3,01, 3,41, 4,53, 5,85, 6,52, 6,85, 6,94, 7,02-7,15, 7,19-7,28, 7,35, 7,44-7,55, 7,61, 8,01.

Example 7(41)

N-(4-{[5-({4-[{[(2-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}Fe is Il)methanesulfonamide

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CDCl3): δ 1,38-1,53, 1,82-1,90, 2,08-2,20, 2,83-2,92, 3,01, 3,41, 4,53, 6,47, 6,59, 6,85, 6,87, 7,12, 7,18, 7,22-7,28, 7,42-7,55, 7,61, 8,01, 8,27.

Example 7(42)

N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(1-methyl-1H-pyrazole-4-yl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf 0.40 in (dichloromethane: methanol= 9:1);

NMR (CDCl3): δ 1,30-1,48, 1,70-1,80, 2,08-2,19, 2,81-2,90, 3,01, 3,41, 3,96, 4,46, 6,26, 6,35, 6,85, 6,92, 7,11, 7,18-7,28, 7,37, 7,61, 8,01.

Example 7(43)

2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide

Free base;

White amorphous powder;

TLC:Rf 0.45 in (dichloromethane: methanol= 9:1);

NMR (CDCl3): δ 1,32-1,48, 1,80-1,90, 2,08-2,20, 2,81-2,92, 3,00, 3,40, 4,55, 5,86, 5,97, 6,62-6,77, 6,85, 7,06, 7,11, 7,18-7,30, 7,34, 7,45-7,55, 7,61, 8,00, 8,04.

Hydrochloride (or dihydrochloride);

White amorphous powder;

TLC:Rf 0.45 in (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,81, 2,12-2,23, 2,97, 3,12-3,35, 3,47-3,58, 4,29, 4,67, 7,07-7,16, 7,29-7,36, 7,43, 7,48-7,58, 7,68, 7,95, 8,22.

Example 7(44)

4-fluoro-N-{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}-N-phenylbenzene

TLC:Rf of 0.58 (chloroform: methanol= 7:1);

NMR (CDCl3): δ 1,50-1,70, 1,85-1,95, 2,10-2,30, 2,85-2,95, 2,98, 3,41, 4,72, 6,75-6,84, 6,95-6,98, 7,07, 7,19-7,25, 7,59, 7,99.

Example 7(45)

N-[4-({5-[(4-{phenyl[3-pyridinylamino)carbonyl]amino}-1-piperidinyl)methyl]-2-pyridinyl}oxy)phenyl]metasolv the amide

TLC:Rf 0.40 in (dichloromethane: methanol= 9:1);

NMR (CDCl3): δ 1,34-1,50, 1,80-1,90, 2,10-2,20, 2,80-2,90, 3,00, 3,40, 4,54, 5,87, 6,83, 7,09, 7,18, 7,20-7,28, 7,45-7,55, 7,59, 7,91, 7,99, 8,16, 8,20.

Example 7(46)

N-(4-{[5-({4-[(aminocarbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.38 (dichloromethane: methanol= 9:1);

NMR (CDCl3): δ 1,30-1,44, 1,76-1,85, 2,08-2,18, 2,80-2,88, 3,01, 3,39, 4,20, 4,48, 6,83, 6,90, 7,11, 7,13-7,18, 7,22-7,28, 7,35-7,45, 7,59, 7,98.

Example 7(47)

N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(4-methoxyphenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.43 (dichloromethane: methanol= 9:1);

NMR (CDCl3): δ 1,31-1,49, 1,77-1,86, 2,09-2,18, 2,81-2,90, 3,01, 3,40, 3,86, 4,50, 5,85, 6,38, 6,84, 6,89, 6,96, 7,08-7,25, 7,60, 7,99.

Example 7(48)

N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(3-methoxyphenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.43 (dichloromethane: methanol= 9:1);

NMR (CDCl3): δ 1,37-1,51, 1,80-1,89, 2,08-2,18, 2,81-2,90, 3,01, 3,40, 3,83, 4,51, 5,87, 6,38, 6,73, 6,80, 6,84, 6,90, 6,98, 7,08-7,26, 7,37, 7,60, 8,00.

Example 7(49)

Hydrochloride (or dihydrochloride) N-(4-{[5-({3-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-8-azabicyclo[3.2.1]Oct-8-yl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.29 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,90-2,05, 2,20-2,30, 2,35-2,50, 2,60-2,75, 2,97, 3,85-3,95, 4,16, 4,55, 6,92-6,98, 7,06-7,14, 7,19-7,24, 7,29-7,33, 7,36-7,40, 7,48-7,58, 8,01, 8,25.

Example 7(50)

Hydrochloride (or dihydrochloride) 4-{[5-({4-[{[(4-forfinal)amino]ka is bonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}benzoic acid

TLC:Rf to 0.39 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,65-1,80, 2,10-2,25, 3,10-3,30, 3,50-3,60, 4,30, 4,65, 6,92-6,98, 7,13, 7,19-7,24, 7,31-7,34, 7,49-7,55, 7,96, 8,08, 8,25.

Example 7(51)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(2,4-differenl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf to 0.63 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,65-1,80, 2,10-2,30, 2,98, 3,10-3,30, 3,50-3,60, 4,31, 4,70, 6,88-6,92, 7,09, 7,15, 7,32-7,34, 7,33, 7,51-7,58, 8,04, 8,29.

Example 7(52)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(3-fluoro-4-methoxyphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,82, 2,12-2,22, 2,98, 3,12-3,28, 3,48-3,58, 3,79, 4,32, 4,67, 6,84-6,96, 7,09, 7,13-7,22, 7,28-7,38, 7,45-7,58, 8,05, 8,30.

Example 7(53)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(3-chloro-4-methoxyphenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,68-1,82, 2,12-2,22, 2,98, 3,12-3,28, 3,48-3,58, 3,81, 4,32, 4,68, 6,92, 7,06, 7,09, 7,16, 7,30-7,38, 7,45-7,58, 8,05, 8,30.

Example 7(54)

The dihydrochloride (or trihydrochloride) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

Amorphous powder;

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,68-185, 2,12-2,25, 2,68, 2,97, 3,15-3,28, 3,50-3,60, 4,31, 4,71, 7,07, 7,13, 7,29-7,38, 7,50-7,62, 7,73, 8,01, 8,25, 8,31, 8,97.

Example 7(55)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)ndimethylacetamide

Amorphous powder;

TLC:Rf of 0.23 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,25, 3,10-3,25, 3,50-3,60, 3,55, 4,28, 4,70, 6,95, 7,04-7,10, 7,19-7,24, 7,31-7,38, 7,49-7,55, 7,93, 8,21.

Example 7(56)

The dihydrochloride of N-{4-[4-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl) - for 3,5-dimethyl-1H-pyrazole-1-yl]phenyl}methanesulfonamide

TLC:Rf 0.21 in (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,70-1,85, 2,10-2,25, 2,31, 2,33, 3,03, 3,20-3,35, 3,55-3,65, 4,20, 4,70, 6,96, 7,21-7,25, 7,33-7,41, 7,50-7,56.

Example 7(57)

Trihydrochloride 4-[4-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl) - for 3,5-dimethyl-1H-pyrazole-1-yl]-N-[2-(4-morpholinyl)ethyl]benzosulfimide

TLC:Rf of 0.20 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,70-1,85, 2,10-2,25, 2,34, 2,41, 3,20-3,40, 3,50-3,65, 3,80-3,95, 4,00-4,15, 4,21, 4,70, 6,96, 7,20-7,25, 7,35, 7,45-7,56, 7,75, 8,05.

Example 7(58)

Hydrochloride (or dihydrochloride) N-{4-[(5-{[4-((3,5-dimethyl-4-isoxazolyl){[(4-forfinal)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide

TLC:Rf of 0.53 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,68-1,88, 2,09-2,23, 2,20, 2,40, 2,97, 3,12-3,25, 3,50-3,60, 4,32, 4,60, 6,99, 7,09, 7,13, 7,25-7,35, 8,01, 8,25.

p> Example 7(59)

The dihydrochloride (or trihydrochloride) N-{4-[(5-{[4-(1,3-benzothiazol-6-yl{[(4-forfinal)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide

TLC:Rf 0,49 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,68-1,85, 2,19-2,28, 2,97, 3,12-3,25, 3,50-3,60, 4,30, 4,71, 6,94, 7,07, 7,13, 7,23, 7,32, 7,51, 8,00, 8,15, 8,20, 8,25, 9,46.

Example 7(60)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(3,4-differenl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf 0,51 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,64-1,81, 2,12-2,22, 2,97, 3,12-3,25, 3,48-3,58, 4,29, 4,68, 6,93, 7,02-7,15, 7,28-7,35, 7,38, 7,45-7,58, 7,95, 8,21.

Example 7(61)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[[(2,3-dihydro-1,4-benzodioxin-6-ylamino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf 0,51 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,63-1,80, 2,12-2,22, 2,97, 3,11-3,25, 3,48-3,55, 4,17, 4,29, 4,68, 6,56, 6,66, 6,81, 7,07, 7,12, 7,27-7,35, 7,45-7,58, 7,96, 8,22.

Example 7(62)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(2,4-differenl)amino]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,63-1,80, 2,12-2,22, 2,97, 3,12-3,25, 3,48-3,58, 4,28, 4,68, 6,85-6,98, 7,03-7,08, 7,11, 7,31, 7,53-7,60, 7,64, 7,89, 8,18.

Example 7(63)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(3,4-differenl)am is but]carbonyl}(3-thienyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,80, 2,10-2,20, 2,97, 3,12-3,25, 3,48-3,58, 4,28, 4,68, 6,94-7,16, 7,31, 7,40, 7,51, 7,61, 7,90, 8,18.

Example 7(64)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(2-methoxyphenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,61-1,83, 2,15-2,25, 2,97, 3,10-3,22, 3,48-3,56, 3,84, 4,28, 4,58, 6,95, 7,05-7,29, 7,32, 7,46, 7,97, 8,23.

Example 7(65)

Hydrochloride (or dihydrochloride) N-{4-[(5-{[4-((4-forfinal){[(4-forfinal)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,60-1,78, 2,12-2,21, 2,97, 3,10-3,25, 3,48-3,58, 4,28, 4,65, 6,95, 7,05, 7,09, 7,19-7,37, 7,90, 8,17.

Example 7(66)

Hydrochloride (or dihydrochloride) N-{4-[(5-{[4-((3-forfinal){[(4-forfinal)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,85, 2,12-2,25, 2,97, 3,12-3,25, 3,48-3,58, 4,28, 4,65, 6,95, 7,04-7,20, 7,22-7,33, 7,30, 7,53, 7,90, 8,17.

Example 7(67)

Hydrochloride (or dihydrochloride) N'-(4-chlorophenyl)-N-[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-prilocaine

TLC:Rf 0.26 (ethyl acetate);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,30, 3,10-3,30, 3,14, 3,50-3,60, 4,30, 4,65, 7,17-7,23, 7,31-7,39, 7,52-7,55, 7,90-8,02, 8,21.

Example 7(68)

Hydrochloride (or dihydrochloride) N'-(4-forfinal)-N-[1-({6-[4-(m is tilsley)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-(3-thienyl)urea

TLC:Rf of 0.29 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,05-2,20, 3,14, 3,15-3,25, 3,50-3,60, 4,29, 4,65, 6,97, 7,04, 7,18-7,27, 7,38, 7,52, 7,61, 7,96-8,02, 8,23.

Example 7(69)

Hydrochloride (or dihydrochloride) of 2-chloro-N-methyl-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,81, 2,12-2,22, 2,86, 2,97, 3,12-3,25, 3,49-3,58, 4,29, 4,67, 7,07, 7,13, 7,25-7,35, 7,43, 7,46-7,60, 7,96, 8,22.

Example 7(70)

Hydrochloride (or dihydrochloride) of 2-chloro-N,N-dimethyl-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,81, 2,12-2,22, 2,86, 2,97, 3,08, 3,12-3,25, 3,49-3,58, 4,30, 4,67, 7,08, 7,14, 7,27-7,36, 7,48-7,60, 7,99, 8,25.

Example 7(71)

N-(4-{[5-({4-[{[(4-chloro-3-nitrophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf to 0.39 (chloroform: methanol= 7:1);

NMR (CDCl3): δ 1,40-1,60, 1,80-1,90, 2,10-2,20, 2,80-2,90, 2,99, 3,46, 4,51, 4,64, 6,08, 6,84, 7,09, 7,21-7,27, 7,31-7,41, 7,51-7,54, 7,61, 7,89, 8,01.

Example 7(72)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[({[4-(methylsulphonyl)phenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf value of 0.52 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,65-1,85, 2,10-2,30, 2,97, 3,05, 3,10-3,30, 3,50-3,60, 4,29, 4,70, 7,06, 7,11, 7,30-7,35, 7,3, 7,51-7,58, 7,77, 7,94, 8,20.

Example 7(73)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[({[3-(methylsulphonyl)phenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf is 0.49 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,65-1,85, 2,10-2,25, 2,98, 3,07, 3,10-3,30, 3,50-3,60, 4,31, 4,70, 7,08, 7,15, 7,31-7,36, 7,44-7,59, 8,02, 8,02, 8,26.

Example 7(74)

Hydrochloride of 2-chloro-5-({[[1-(4-{4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.43 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,79, 2,12-2,22, 2,95, 3,10-3,22, 3,45-3,55, 4,22, 4,67, 7,01, 7,02, 7,25-7,34, 7,41, 7,46-7,58.

Example 7(75)

Hydrochloride (or dihydrochloride) N-(4-{[5-({4-[({[4-chloro-3-(4-morpholinylcarbonyl)phenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.43 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,82, 2,12-2,22, 2,98, 3,14-3,35, 3,49-3,80, 4,31, 4,67, 7,08, 7,14, 7,28-7,37, 7,45-7,59, 8,02, 8,27.

Example 7(76)

Hydrochloride (or dihydrochloride) of 2-chloro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzoic acid

TLC:Rf of 0.48 (dichloromethane: methanol= 5:1);

NMR (CD3OD): δ 1,64-1,82, 2,12-2,25, 2,97, 3,12-3,24, 3,47-3,60, 4,29, 4,67, 7,06, 7,11, 7,28-7,36, 7,41, 7,45-7,60, 7,82, 7,94, 8,20.

Example 7(77)

N'-(4-chloro-3-nitrophenyl)-N-[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-f is nimodipine

TLC:Rf of 0.50 (ethyl acetate);

NMR (CDCl3): δ 1,35-1,55, 1,80-1,90, 2,10-2,25, 2,90-3,00, 3,06, 3,44, 4,50, 6,04, 6,93, 7,20-7,39, 7,31-7,41, 7,50-7,53, 7,67, 7,92-8,05.

Example 7(78)

Hydrochloride of 2-[4-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulphonyl)amino]benzamide

TLC:Rf of 0.53 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,62-1,79, 2,12-2,21, 2,99, 3,08-3,22, 3,43-3,57, 4,23, 4,67, 6,95, 7,01, 7,06, 7,22, 7,29-7,35, 7,32-7,59, 7,70.

Example 7(79)

Hydrochloride (or dihydrochloride) 2-fluoro-5-({[[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide

TLC:Rf 0.45 in (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,64-1,81, 2,13-2,25, 3,14, 3,10-3,25, 3,50-3,58, 4,31, 4,67, 7,08, 7,19, 7,30-7,58, 7,69, 7,95-8,04, 8,23.

Example 7(80)

Hydrochloride (or dihydrochloride) 2-fluoro-5-{[((3-forfinal){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide

TLC:Rf 0,49 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,68-1,85, 2,14-2,23, 2,97, 3,12-3,25, 3,50-3,58, 4,30, 4,65, 7,04-7,19, 7,25, 7,31, 7,46, 7,51, 7,70, 7,92, 8,23.

Example 7(81)

Hydrochloride (or dihydrochloride) 2-fluoro-5-[({(3-forfinal)[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]benzamide

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,68-1,87, 2,15-2,25, 3,14, 3,12-3,25, 3,50-3,58, 4,31, 4,67, 7,09, 7,12-7,20, 7,25, 7,37, 7,46, 7,54, 7,71, 7,90-8,04, 8,23.

Example 7(82)

Hydrochlori is (or dihydrochloride) 2-fluoro-5-[({(3-forfinal)[1-({6-[2-methoxy-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]benzamide

TLC:Rf value of 0.52 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,67-1,85, 2,15-2,25, 3,17, 3,12-3,25, 3,48-3,58, 3,80, 4,28, 4,65, 7,04-7,19, 7,25, 7,35, 7,46, 7,50-7,65, 7,71, 7,95, 8,13.

Example 7(83)

Hydrochloride (or dihydrochloride) N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]ndimethylacetamide

White amorphous powder;

TLC:Rf of 0.36 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,30, 2,12, 2,97, 3,10-3,25, 3,45-3,55, 4,27, 4,65, 7,00-7,12, 7,30-7,33, 7,49-7,55, 7,78, 7,90, 8,18.

Example 7(84)

Hydrochloride (or dihydrochloride) N-[2-fluoro-5-({[{1-[(6-{2-methoxy-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]ndimethylacetamide

TLC:Rf 0.31 in (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,30, 2,12, 2,99, 3,10-3,25, 3,45-3,55, 3,69, 4,26, 4,65, 6,87, 6,98-7,08, 7,06, 7,31-7,34, 7,49-7,55, 7,78, 7,86, 8,11.

Example 7(85)

Hydrochloride (or dihydrochloride) N-[2-fluoro-5-({[[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)phenyl]ndimethylacetamide

TLC:Rf of 0.53 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,30, 2,12, 3,10-3,25, 3,14, 3,45-3,55, 4,30, 4,65, 7,00-7,05, 7,19, 7,31-7,39, 7,50-7,55, 7,90, 7,94-8,02, 8,11.

Example 7(86)

Hydrochloride (or dihydrochloride) N-[2-fluoro-5-({[[1-({6-[2-methoxy-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)phenyl]ndimethylacetamide

TLC:Rf value of 0.52 (chloroform: methanol 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,30, 2,12, 3,10-3,25, 3,17, 3,45-3,55, 3,79, 4,26, 4,66, 7,00-7,11, 7,19, 7,31-7,36, 7,49-7,63, 7,78, 7,78, 8,11.

Example 7(87)

Hydrochloride (or dihydrochloride) 2-fluoro-5-{[((3-forfinal){1-[(6-{2-methoxy-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide

TLC:Rf of 0.44 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,69-1,85, 2,12-2,25, 3,00, 3,12-3,25, 3,48-3,58, 3,70, 4,28, 4,65, 6,87, 6,99-7,19, 7,25, 7,46, 7,54, 7,71, 7,93, 8,17.

Example 7(88)

Hydrochloride (or dihydrochloride) 2-fluoro-5-({[{1-[(6-{2-methoxy-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.44 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,64-1,81, 2,12-2,24, 3,00, 3,12-3,25, 3,48-3,58, 3,70, 4,28, 4,67, 6,87, 7,00-7,12, 7,29-7,35, 7,42, 7,47-7,58, 7,68, 7,94, 8,18.

Example 7(89)

Hydrochloride (or dihydrochloride) 2-fluoro-5-({[[1-({6-[2-methoxy-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.44 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,64-1,80, 2,12-2,22, 3,17, 3,12-3,25, 3,48-3,58, 3,79, 4,28, 4,67, 7,04-7,14, 7,29-7,38, 7,43, 7,48-7,64, 7,68, 7,94, 8,13.

Example 7(90)

The dihydrochloride (or trihydrochloride) N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide

White amorphous powder;

TLC:Rf 0,49 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1.70 to 190, 2,12-2,25, 2,68, 2,97, 3,12-3,35, 3,48-3,60, 4,33, 4,70, 7,08, 7,12-7,23, 7,25-7,35, 7,55, 7,73, 8,05, 8,23-8,34, 8,96.

Example 7(91)

The dihydrochloride (or trihydrochloride) N-(3-forfinal)-N'-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]urea

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,70-1,90, 2,12-2,25, 2,68, 3,14, 3,12-3,35, 3,48-3,60, 4,33, 4,70, 7,12-7,21, 7,29, 7,38, 7,56, 7,73, 8,00, 8,03, 8,22-8,36, 8,96.

Example 7(92)

The dihydrochloride (or trihydrochloride) N-(3-forfinal)-N-[1-({6-[2-methoxy-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N'-(6-methyl-3-pyridinyl)urea

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,70-1,90, 2,12-2,25, 2,68, 3,17, 3,12-3,35, 3,48-3,60, 3,80, 4,30, 4,70, 7,12, 7,15-7,23, 7,29, 7,35, 7,51-7,64, 7,73, 7,99, 8,15, 8,31, 8,96.

Example 7(93)

Hydrochloride (or dihydrochloride) N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]methanesulfonamide

TLC:Rf of 0.33 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,30, 2,97, 2,97, 3,10-3,25, 3,40-3,60, 4,27, 4,65, 7,03-7,11, 7,29-7,33, 7,44-7,54, 7,87, 8,16.

Example 7(94)

Hydrochloride (or dihydrochloride) N-[2-fluoro-5-({[[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)phenyl]methanesulfonamide

TLC:Rf 0,41 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,30, 2,97, 3,14, 3,15-3,25, 3,45-3,55, 4,30, 4,62, 7,03-7,06, 7,18, 7,31-7,39, 7,44-7,54, 7,95-8,02, 8,2.

Example 7(95)

Hydrochloride (or dihydrochloride) N-[2-fluoro-5-({[[1-({6-[2-methoxy-4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)phenyl]methanesulfonamide

TLC:Rf to 0.39 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,25, 2,97, 3,10-3,25, 3,17, 3,45-3,55, 3,79, 4,26, 4,65, 7,03-7,06, 7,12, 7,31-7,36, 7,45-7,63, 7,91, 8,10.

Example 7(96)

Hydrochloride of 2-[4-({4-[[({4-fluoro-3-[(methylsulphonyl)amino]phenyl}amino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulphonyl)amino]benzamide

TLC:Rf of 0.20 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,30, 2,97, 2,99, 3,10-3,20, 3,45-3,55, 4,23, 4,65, 6,99-7,04, 7,31-7,55, 7,69.

Example 7(97)

Hydrochloride (or dihydrochloride) 2-fluoro-N-methyl-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,81, 2,12-2,23, 2,89, 2,97, 3,12-3,25, 3,48-3,58, 4,29, 4,67, 7,01-7,15, 7,27-7,35, 7,40, 7,47-7,57, 7,61, 7,95, 8,21.

Example 7(98)

Hydrochloride (or dihydrochloride) 2-fluoro-N-methyl-5-({[[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.50 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,81, 2,12-2,23, 2,89, 3,14, 3,12-3,25, 3,48-3,59, 4,30, 4,67, 7,06, 7,18, 7,30-7,43, 7,47-7,57, 7,61, 7,94-8,05, 8,22.

Example 7(99)

DIAC is drochloride (or trihydrochloride) N'-(6-methyl-3-pyridinyl)-N-[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-prilocaine

TLC:Rf 0,49 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,70-1,87, 2,12-2,24, 2,68, 3,14, 3,17-3,35, 3,50-3,60, 4,33, 4,71, 7,18, 7,32-7,36, 7,38, 7,42-7,59, 7,72, 8,00, 8,05, 8,27, 8,30, 8,96.

Example 7(100)

Hydrochloride of 2-[4-({4-[({[3-(acetylamino)-4-forfinal]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulphonyl)amino]benzamide

TLC:Rf of 0.43 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,61-1,80, 2,12, 2,05-2,22, 2,99, 3,05-3,21, 3,45-3,55, 4,23, 4,67, 6,97-7,08, 7,28-7,35, 7,35-7,58, 7,69, 7,77.

Example 7(101)

The dihydrochloride (or trihydrochloride) N-(3-methyl-4-([5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,68-1,85, 2,11, 2,12-2,23, 2,67, 2,97, 3,12-3,28, 3,50-3,60, 4,30, 4,71, 7,02, 7,04, 7,15, 7,20, 7,31-7,38, 7,49-7,60, 7,73, 8,00, 8,17, 8,22, 8,31, 8,96.

Example 7(102)

The dihydrochloride (or trihydrochloride) N-(3-chloro-4-([5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,85, 2,12-2,25, 2,67, 3,01, 3,15-3,28, 3,48-3,58, 4,30, 4,72, 7,12, 7,19-7,28, 7,31-7,37, 7,41, 7,48-7,60, 7,74, 7,98, 8,17, 8,30, 8,97.

Example 7(103)

The dihydrochloride (or trihydrochloride) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)acanalonia

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3 OD): δ 1,32, 1,70-1,85, 2,15-2,25, 2,68, 3,11, 3,15-3,28, 3,50-3,60, 4,33, 4,71, 7,08, 7,14, 7,30-7,38, 7,50-7,60, 7,73, 8,07, 8,28-8,35, 8,96.

Example 7(104)

The dihydrochloride (or trihydrochloride) N-{4-[(5-{[4-((3-were){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,68-1,87, 2,12-2,23, 2,41, 2,68, 2,97, 3,13-3,28, 3,50-3,60, 4,31, 4,71, 7,05-7,18, 7,29-7,37, 7,43, 7,73, 8,01, 8,13, 8,26, 8,31, 8,96.

Example 7(105)

Hydrochloride (or dihydrochloride) 2-fluoro-5-{[((3-were){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide

TLC:Rf 0,46 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,81, 2,12-2,24, 2,40, 2,97, 3,13-3,28, 3,48-3,58, 4,29, 4,67, 7,04-7,17, 7,28-7,35, 7,37-7,47, 7,68, 7,95, 8,21.

Example 7(106)

Hydrochloride (or dihydrochloride) 2-fluoro-N-methyl-5-{[((3-were){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}benzamide

TLC:Rf 0,49 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,65-1,81, 2,12-2,22, 2,40, 2,89, 2,97, 3,12-3,26, 3,48-3,58, 4,30, 4,67, 7,02-7,18, 7,28-7,35, 7,36-7,44, 7,61, 7,99, 8,25.

Example 7(107)

Hydrochloride (or dihydrochloride) N-(2-fluoro-5-{[((3-were){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)ndimethylacetamide

TLC:Rf of 0.45 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,25, 2,12, 2,40, 2,97, 3,10-3,30, 3,50-3,60, 4,27, 4,65, 7,00-7,15, 7,30, 7,31, 7,42, 7,78, 7,90, 8,17./p>

Example 7(108)

Hydrochloride (or dihydrochloride) N-(2-fluoro-5-{[((3-forfinal){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)ndimethylacetamide

TLC:Rf and 0.46 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,25, 2,13, 2,97, 3,10-3,30, 3,50-3,60, 4,28, 4,65, 6,98-7,17, 7,29, 7,31, 7,54, 7,82, 7,94, 8,20.

Example 7(109)

Trihydrochloride N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyrazinyl]oxy}phenyl)methanesulfonamide

TLC:Rf 0,49 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,71-1,88, 2,15-2,26, 2,68, 2,97, 3,22-3,35, 3,58-3,68, 4,42, 4,75, 7,17, 7,29-7,38, 7,52-7,62, 7,73, 8,17, 8,20, 8,31, 8,48, 8,97.

Example 7(110)

Hydrochloride (or dihydrochloride) 2-fluoro-5-{[((3-forfinal){1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-N-methylbenzamide

TLC:Rf 0.45 in (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,70-1,85, 2,15-2,23, 2,89, 2,97, 3,12-3,25, 3,50-3,58, 4,30, 4,65, 7,03-7,19, 7,25, 7,32, 7,42, 7,54, 7,65, 7,99, 8,25.

Example 7(111)

The dihydrochloride (or trihydrochloride) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-azepane}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf 0,42 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,70-2,50, 2,67, 2,98, 3,18-3,35, 3,40-3,62, 4,37, 4,50, 7,10, 7,16, 7,30-7,40, 7,48-7,60, 7,72, 8,12, 8,29, 8,33, 8,96.

Example 7(112)

The dihydrochloride (or trihydrochloride) N-(4-{[5-({(3R)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-Pirro is idini}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 2,40, 2,65, 2,69, 2,98, 3,41-3,65, 3,80-3,98, 4,30-4,72, 7,08-7,20, 7,28-7,62, 7,74, 8,14, 8,32, 8,39, 8,51, 8,97.

Example 7(113)

The dihydrochloride (or trihydrochloride) N-(4-{[5-({(3S)-3-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-pyrrolidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 2,40, 2,65, 2,69, 2,98, 3,41-3,65, 3,80-3,98, 4,30-4,72, 7,08-7,20, 7,28-7,62, 7,74, 8,14, 8,32, 8,39, 8,51, 8,97.

Example 7(114)

Hydrochloride (or dihydrochloride) N-(2-fluoro-5-{[((3-forfinal){1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}phenyl)ndimethylacetamide

TLC:Rf of 0.29 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 1,65-1,90, 2,00-2,20, 2,11, 2,12, 2,97, 3,10-3,30, 3,50-3,60, 4,27, 4,63, 6,98-7,06, 7,13-7,27, 7,53, 7,81, 7,94, 8,17.

Example 7(115)

Hydrochloride (or dihydrochloride) N-[5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(3-forfinal)amino]carbonyl}amino)-2-forfinal]ndimethylacetamide

TLC:Rf is 0.24 (ethyl acetate: methanol= 10:1);

NMR (CD3OD): δ 1,32, 1,60-1,80, 2,10-2,30, 2,12, 3,08, 3,10-3,25, 3,50-3,60, 4,29, 4,70, 7,00-7,16, 7,25, 7,31, 7,54, 7,81, 7,95, 8,22.

Example 7(116)

Hydrochloride (or dihydrochloride) 2-fluoro-5-({[{1-[(6-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,68-1,82, 2,12, 2,09-2,22, 2,98, 3,12-3,25, 3,48-3,59, 4,31, 4,6, 7,01-7,23, 7,30-7,37, 7,43, 7,47-7,58, 7,68, 8,03, 8,27.

Example 7(117)

Hydrochloride (or dihydrochloride) 5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)-2-fermentated

TLC:Rf of 0.48 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,32, 1,65-1,82, 2,12-2,22, 3,10, 3,10-3,25, 3,49-3,58, 4,31, 4,68, 7,05-7,10, 7,13, 7,29-7,36, 7,43, 7,47-7,58, 7,68, 8,02, 8,28.

Example 7(118)

The dihydrochloride (or trihydrochloride) N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}acanalonia

TLC:Rf 0,46 (dichloromethane: methanol= 9:1);

NMR (CD3OD): δ 1,32, 1,72-1,90, 2,12-2,25, 2,68, 3,11, 3,18-3,30, 3,50-3,60, 4,34, 4,70, 7,07-7,23, 7,29, 7,33, 7,56, 7,74, 8,10, 8,29-8,38, 8,97.

Example 7(119)

The dihydrochloride (or trihydrochloride) 2-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulphonyl)amino]benzamide

TLC:Rf 0,69 (chloroform: methanol= 5:1);

NMR (CD3OD): δ 1,70-1,90, 2,10-2,30, 2,68, 2,93, 3,20-3,40, 3,50-3,60, 4,41, 4,70, 7,04, 7,33-7,43, 7,50-7,60, 7,73, 7,96, 8,17, 8,27, 8,30, 8,54, 8,96.

Example 7(120)

The dihydrochloride (or trihydrochloride) 2-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]-5-[(methylsulphonyl)amino]benzamide

TLC:Rf is 0.59 (chloroform: methanol= 5:1);

NMR (CD3OD): δ 1,70-1,90, 2,10-2,30, 2,68, 2,93, 3,20-3,40, 3,50-3,70, 4,41, 4,70, 7,03, 7,15-7,20, 7,30, 7,41, 7,56, 7,74, 7,96, 8,25-8,35, 8,39, 8,54, 8,97.

Example 7(121)

Hydrochloride (and the and the dihydrochloride) 2-{[5-({4-[({[3-(acetylamino)-4-forfinal]amino}carbonyl)(3-forfinal)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-5-[(methylsulphonyl)amino]benzamide

TLC:Rf of 0.56 (chloroform: methanol= 5:1);

NMR (CD3OD): δ 1,70-1,90, 2,10-2,30, 2,12, 2,93, 3,20-3,40, 3,50-3,70, 4,37, 4,65, 6,99-7,10, 7,03, 7,15-7,20, 7,25, 7,40, 7,54, 7,82, 7,96, 8,15, 8,28, 8,49.

Example 8

Hydrochloride (or dihydrochloride) 4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-N-(2-methoxyethyl)benzamide

To a solution of the compound obtained in Example 7(50) (80 mg) in N,N-dimethylformamide (3 ml), was added hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (84 mg), diisopropylethylamine (38 μl) and 1-methoxyethylamine (19 μl) and the mixture was stirred over night. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, concentrated. The obtained residue was treated with 4 N. hydrogen chloride in ethyl acetate solution, obtaining specified in the title compound(65 mg)having the following physical data.

TLC:Rf is 0.49 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,65-1,80, 2,10-2,25, 3,10-3,30, 3,30-3,40, 3,50-3,60, 3,56, 4,29, 4,70, 6,92-6,98, 7,11, 7,19-7,24, 7,31-7,34, 7,52-7,55, 7,89, 7,90, 8,20.

Example 8(1)

Hydrochloride (or dihydrochloride) N'-(4-forfinal)-N-[1-({6-[4-(4-morpholinylcarbonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]-N-prilocaine

Using a procedure similar to that described in Example 8, using the IOE is oline instead of 1-methoxyethylamine, received the following specified in the title compound having the following physical data.

TLC:Rf of 0.51 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,65-1,80, 2,10-2,25, 3,10-3,25, 3,40-3,55, 3,55-3,80, 4,26, 4,65, 6,92-6,95, 7,11, 7,19-7,23, 7,32-7,34, 7,49-7,55, 7,94, 8,18.

Example 9

The dihydrochloride (or trihydrochloride) N-(4-{[5-({4-[{[(3-amino-4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide

To a solution of the compound obtained in Example 7(71) (720 mg) in acetic acid (10 ml) and water (10 ml), was added iron powder (244 mg) and the mixture was stirred for 2 hours at 40°C. the Reaction mixture was filtered through Celite (registered trademark). After the filtrate was neutralized 1 N. aqueous sodium hydroxide solution, it was extracted with ethyl acetate. The organic layer was washed with water and saline, dried with anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (dichloromethane: methanol = 20:1). This free base was treated with 4 N. hydrogen chloride in ethyl acetate solution, obtaining specified in the title compound (420 mg)having the following physical data.

TLC:Rf of 0.48 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,65-1,80, 2,10-2,30, 2,97, 3,10-3,25, 3,50-3,60, 4,28, 4,70, 7,05, 7,10, 7,15, 7,29-7,32, 7,30, 7,37, 7,50-7,55 7,72, of 7.90, 8,17.

Example 10

Hydrochloride (or dihydrochloride) N-[2-chloro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]methanesulfonamide

To a mixture of compound free base obtained in Example 9 (160 mg), and triethylamine (36 μl) in tetrahydrofuran (5 ml) was added methanesulfonamide (20 ml) and the mixture was stirred over night at room temperature. The reaction mixture was extracted with ethyl acetate, dried with anhydrous sodium sulfate and concentrated. The obtained residue was dissolved in tetrahydrofuran (10 ml) and to this solution was added tetrabutylammonium fluoride (146 μl). The mixture was stirred for 3 hours at 60°C. To the mixture was added water and was extracted with ethyl acetate. The organic layer was washed with water and saline, dried with anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (dichloromethane: methanol = 20:1). The compound obtained was treated with 4 N. hydrogen chloride in ethyl acetate solution, obtaining specified in the title compound (35 mg)having the following physical data.

TLC:Rf of 0.48 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,65-1,80, 2,10-2,25, 2,97, 2,97, 3,10-3,25, 3,50-3,60, 4,29, 4,70, 7,06, 7,10-7,15, 7,28-7,34, 7,52-7,58, 7,94, 8,21.

Example 11

Hydra is the chloride (or dihydrochloride) N-[2-chloro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]ndimethylacetamide

To a solution of compound free base obtained in Example 9 (160 mg) in pyridine (4 ml), was added acetic anhydride (72,4 μl) and the mixture was stirred over night at room temperature. The reaction mixture was extracted with ethyl acetate, dried with anhydrous sodium sulfate and concentrated. To a solution of the obtained residue in methanol (4 ml)was added 28% sodium methoxide in a solution of methanol (506 μl) and all was stirred for 30 minutes at room temperature. The reaction mixture was concentrated, added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saline, dried with anhydrous sodium sulfate and concentrated. The obtained residue was treated with 4 N. hydrogen chloride in ethyl acetate solution, obtaining specified in the title compound (64 mg)having the following physical data.

TLC:Rf of 0.40 (chloroform: methanol= 10:1);

NMR (CD3OD): δ 1,65-1,80, 2,13, 2,15-2,25, 2,97, 3,10-3,35, 3,50-3,60, 4,30, 4,65, 7,07, 7,12-7,16, 7,25-7,34, 7,49-7,51, 7,68, 7,99, 8,25.

Example 12

Hydrochloride (or dihydrochloride) N-[2-chloro-5-({[[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)phenyl]ndimethylacetamide

To a solution of amine compounds obtained by the recovery procedure described in the example 9, using the compound obtained in Example 7(77) (160 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (34 μl) in tetrahydrofuran (5 ml), was added acetic anhydride (63 μl) and the mixture was heated under reflux for 4 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. To a solution of the obtained residue in methanol (4 ml) was added 28% sodium methylate in a solution of methanol (447 μl), stirred for 30 minutes at room temperature. The reaction mixture was concentrated, added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:methanol = 20:1). The compound obtained was treated with 4 N. hydrogen chloride in ethyl acetate solution, obtaining specified in the title compound (89 mg)having the following physical data.

TLC: Rf of 0.56 (ethyl acetate: methanol = 10:1);

NMR (CD3OD): δ 1,60-1,80, 2,10-2,25, 2,14, 3,14, 3,15-3,30, 3,50-3,60, 4,30, 4,70, 7,15-7,39, 7,51-7,55, 7,68, 7,96, 8,00, 8,22.

BIOLOGICAL EXAMPLES

With the following experiment proved that the compound of the present invention, as the e formula (I), has an antagonistic activity against receptor of the chemokine, especially CCR5, and inhibitory activity against cell migration, and also have the proper conditions to be a very useful drug.

Biological Example 1

Test for antagonistic activity against CCR5

Using the procedure, for example, described in JP-A-2004-256531, it is possible to prove that the compound of the present invention has an antagonistic activity against CCR5.

Biological Example 2

The test cell migration

Using the following experiment, for example, it was proved that the compound of the present invention has inhibitory activity against cell migration.

Getting RVMS (managernew peripheral blood cells)

Venous blood (50 ml), collected using a syringe with heparin sodium (final concentration: 10 U/ml injection heparin sodium 1000 Units/ml, Shimizu Pharmaceutical Co., Ltd.), kept in a 50 ml conical tube made of polypropylene. The tube Lymphoprep (HYCOMED PHARMA, Cat.No 1019818) was added to 16.5 ml of DPBS (-) (GIBCO, Cat.No. 14190-136) and a blood sample, rocked a few times, then centrifugals at 3000 rpm. in min for 10 minutes at room temperature. About 7 ml of PBMC phase (main phase) was collected in a 50 ml conical tube made of polypropylene, with COI is whether the Pasteur pipette, and added DPBS (-) to the final concentration (50 ml), then was centrifugals at 1200 rpm. in min for 10 minutes at room temperature. After removal of the supernatant, the residue was re-dissolved in 50 ml of DPBS (-). The cell suspension was centrifugals at 1500 rpm for 3 minutes at room temperature. The supernatant was removed, then there was added 3 ml hemolyzing buffer (0.8% of NH4Cl, 0,1% KHCO3, 1 mmol/l EDTA) for sufficient suspension, and then was left for 2 minutes at room temperature. To the suspension was added to 30 ml of DPBS (-) PBMC were centrifugals at 1500 rpm for 3 minutes at room temperature. The supernatant was removed, giving RUMS.

Culture of PBMC person

After 24-hole tablet coated with anti-human CD3-atically OKT3 (Janssen Pharmaceutical K.K., 1 μg/ml) was stored over night at 4°C, it blocked the culture medium (RPMI 1640 (GIBCO, Cat.No. 11875-085), 10% FBS (GIBCO, Cat.No. 112318-028), 1% PSF (GIBCO, Cat.No. 15240-096)) after 30 minutes at 37°C. the resulting culture of human PBMC were inoculated on the plate coated with OKT3 (2×106cells/well)were grown for several days at 37°C. RWMS was collected and inoculated on the plate not covered by the cells ACT (2×106cells/well)in the presence of human IL2 (5 ng/ml), then was cultivated. RWMS was subculturally every d is a or three days.

Analysis of expression of human CCR5 using FACS

After 10 μl of FITC labeled anti-human CCR5 antibody (2D7) (BD Pharmingen, Cat.No 555992) and PE labeled anticlimactic CD45RO antibody (BD Pharmingen, Cat.No 347967) was added to human PBMC cultured in 1×106cells, and the mixture was shaded for 15 minutes or were left for 30 minutes on ice, then there was added DPBS (GIBCO) and washed. Cells suspended in 500 μl of DPBS, and then using FACS measured fluorescence intensity.

Experiment cell migration in vitro

50 ál of 5 x 105cell suspensions of PBMC human (cultural environment) and 50 μl solution of the test compound (0-2 mmol/l: dual concentration final concentration) was added to the upper well of TRANS-hole and the lower hole was added 300 μl of 60 nmol/l human MIP-1β (Pepro tech, Cat.No. 300-09) and 300 ál of double concentrated solution of the test compound. It turned out that the concentration of DMSO in the upper hole was 0,01%. The solution was incubated for 1.5 hours in an atmosphere gas carbon dioxide (37°C, 5% CO2the degree humidity: 95%). After the solvent in the upper hole was carefully spirituals, there was added 100 μl of 20 mmol/l EDTA/DPBS (-) and incubated for 30 minutes at 4°C, then centrifuged at 1500 rpm for 5 minutes. 100 μl of the solution was transferred to a white 96-well plate for fluorescence, from the bottom of the wells measured with a pipette and a number of cells using Celltiter Glo (Promega) (measurement of ATP), the degree of inhibition of cell migration was calculated using the following formula. The value of the IC50was calculated according to the degree of inhibition of cell migration in each concentration. Value presents the mean value (n=3).

In the compounds of the present invention showed inhibitory activity against induced MIP-1β-man cell migration of cultured human PBMC in value IC50of 0.01 μm or less. For example, the compound obtained in example 7(29), showed the value of the IC500,0012 microns.

The degree of inhibition of cell migration = (Ea - Ec)/(Eb - Ec) × 100

Ea:the value measured when the add test compound (0.01% in DMSO)
Eb:the value measured when the test compound is not added, and only add DMSO
Ec:the value measured when the test compound is not added, and only add DMSO without added ligand in the bottom hole

Biological Example 3: Test of stability in liver microsomes monkeys

With the help of the following experiments was demonstrated, for example, that compounds of the present izobreteny who have metabolic stability.

To a solution of 100 mmol/l phosphate buffer (pH 7.4, it was obtained from 100 mmol/l aqueous solution of the secondary acid discalificata and 100 mmol/l aqueous solution of the secondary acid monokaliy) was added liver microsomes monkeys (final concentration: 1 mg/ml) and test compound (final concentration: 5 mmol/l), and the solution mixture is pre-incubated for 5 minutes. To the solution mixture was added NADPH generating system (13 mmol/l β-NADP+(final concentration: 1.3 mmol/l), 33 mmol/l G-6-P (final concentration: 3.3 mmol/l), 10 Units/ml G-6-P DH (from yeast) (final concentration of 0.4 U/ml) and 33 mmol/l solution of magnesium chloride (final concentration: 3.3 mmol/l). While the mixture was incubated at 37°C after 0 and 30 minutes from the start were selected 100 μl of reaction solution and was added to acetonitrile (2 ml) to terminate the reaction (n=2). Once there was added a solution of internal standard solution mixture was mixed and then centrifugals at 3000 rpm for 5 minutes. 100 μl of the resulting supernatant was mixed with 100 μl of mobile phase A, and then were analyzed using LC/MS/MS.

Conditions LC/MS/MS for the analysis is shown below.

The LC conditions:

Column:XTerra RP8 3.5 µm (2,1 ID x 50mm)(WatersCorporation)
The temperature of the column:40°C
The mobile phase A:5 mmol/l aqueous ammonium acetate/acetonitrile (80/20, V/V)
Mobile phase:5 mmol/l aqueous ammonium acetate/acetonitrile (80/20, V/V)
The temperature of the sample:4°C
The injection sample volume:5 ál
Analysis time:10 min

The composition of mobile phase and flow rate:

Table 1
Time(min)Flow rate (ál/min)And%In%
0,0030095,05,0
1,0030095,05,0
1,103005,095,0
5,003005,095,0
5,1030095,05,0
10,0030095,05,0

Conditions MS/MS:

Measuring equipment: API3000 (AB/MDS SCIEX)

The method of ionization: Ionization elektrorazpredelenie (ESI, positive)

For each sample selected, the corresponding controlling ion. For example, for compound obtained in Example 7(83), was chosen 647,5 (m/z) as the initial or primary ion and 277,0 (m/z) as a child of the ion.

The residual degree of ametabolic (%) of the tested compounds in liver microsomes monkeys were calculated using the following formula.

The residual degree of ametabolic (%)

=(concentration of the test compounds after 30 minutes)

/(concentration of the test compounds after 0 minutes) × 100.

In the result, it was proved that the compounds of the present invention are metabolically stable in liver microsomes. For example, the residual degree of ametabolic compound obtained in Example 7(83), was 88%.

Biological Example 4

Pharmacokinetic test blood monkey

With the aid of the completion of the following experiments, for example, it was demonstrated that the compounds of the present invention have good properties of pharmacokinetics in the blood.

Each of the tested compounds were weighed and dissolved in Saltele (Trademark; BASF Takeda Vitamins Ltd.)/ propylene glycol = 7/3, heated to 50°C., to obtain 5 mg/ml solution. Weighed an equal number of each of the 5 samples were mixed and then diluted with distilled water for injection five times to obtain a solution for oral administration. Solution for oral administration (1 mg/kg) was injected forcibly intragastrically to cynomolgus monkeys (male, Hamri Co., Ltd) using a probe (n=3). The introduction was carried out in a state of hunger, but the animals had free access to water for drinking. From the surface of the cranial veins were taken and blood samples of 1 ml each using a heparinized syringe, 5, 15, 30 minutes, 1, 2, 4, 6, 8 and 24 hours after injection. Collected samples were stored in ice, was tsentrifugirovanie at 3000 rpm for 15 minutes to obtain plasma. Plasma was stored at -20°C. the plasma samples, stored at -20°C, was dissolved, and then 100 μl of the resulting solution was added the internal standard solution and acetonitrile (2 ml), stirred, tsentrifugirovanie at 3000 rpm for 10 minutes. The resulting supernatant was dried using a centrifuge Konz is narrator. The residue was re-dissolved in 100 μl of mobile phase A, and then 40 μl of the resulting solution was analyzed using LC/MS/MS.

Conditions LC/MS/MS for the analysis is shown below.

The LC conditions:

Measuring equipment: Waters 2790 (Waters)

Column: YMC-Pack MB-ODS 5 μm (2,1 ID × 50 mm))( YMC)

The column temperature: room temperature

Flow rate: 200 μl/min

Mobile phase: 20 mmol/l aqueous ammonium acetate/acetonitrile (1/1, V/V)

Conditions MS/MS:

Measuring equipment: QUATTRO Ultima (Micromass)

The method of ionization: ES+

The capillary voltage: 3,20 kV

The source temperature: 150°C

Temperature desolvatation: 250°C

Multiplier: 650V.

For each sample selected, the corresponding controlling ion. For example, for compound obtained in Example 6(17), was chosen 575,64 (m/z) as the ion source and 262,07 (m/z) ion as a child, and compounds obtained in Example 7(54), were selected, respectively, 587,20 (m/z) as the ion source and 227,12 (m/z) as a child of the ion.

The transition in the plasma concentration of the test compounds in monkeys were analyzed using non-spatial analytical method using WinNonlin 4.0.1 (Pharsight) and AUC was calculated.

In the result, it was proved that the compounds of the present invention have good properties of pharmacokinetics in the blood. For example the EP, AUC compounds obtained in Examples 6(17) 7(54), were, respectively, 226 NGC/ml and 1150 NGC/ml

Biological Example 5

Measurement of bioavailability (BA):

With the help of the following experiments, for example, it was demonstrated that the compounds of the present invention possess good oral absorption of drugs.

The test compound was weighed and dissolved in 30% HP-β-CD (trademark; Mitsubishi Corporation) to obtain 1 mg/ml solution for intravenous injection. The test compound was weighed and dissolved in Saltele (Trademark; BASF Takeda Vitamins Ltd.)/ propylene glycol = 7/3, heated to 50°C., to obtain 5 mg/ml solution. Weighed an equal number of each of the 5 samples were mixed and then diluted with distilled water for injection five times to obtain a solution for oral administration. The solution for intravenous administration (1 mg/kg) was administered to cynomolgus monkeys (male, Hamri Co., Ltd) through the surface of the cranial veins in the form of a single intravenous dose (n=3). Solution for oral administration (3 mg/kg) was injected forcibly intragastrically to cynomolgus monkeys (male, Hamri Co., Ltd) using a probe (n=3). The introduction was carried out in a state of hunger, but the animals had free access to water for drinking. From the surface of the cranial veins were taken and blood samples of 1 ml each using heparinisation the second syringe, after 5, 15, 30 minutes, 1, 2, 4, 6, 8 and 24 hours after injection. Collected samples were stored in ice, was tsentrifugirovanie at 3000 rpm for 15 minutes to obtain plasma. Plasma was stored at -20°C. the plasma samples, stored at -20°C, was dissolved, and then 100 μl of the resulting solution was added the internal standard solution and acetonitrile (2 ml), stirred, tsentrifugirovanie at 3000 rpm for 10 minutes. The residue was re-dissolved in 100 μl of mobile phase A, and then 40 μl of the resulting solution was analyzed using LC/MS/MS.

Conditions LC/MS/MS for the analysis is shown below.

The LC conditions:

Measuring equipment: Waters 2790 (Waters)

Column: YMC-Pack MB-ODS 5 μm (2,1 ID × 50mm)(YMC)

The column temperature: room temperature

Flow rate: 200 μl/min

Mobile phase: 20 mmol/l aqueous ammonium acetate/acetonitrile (1/1)

Conditions MS/MS:

Measuring equipment: QUATTRO Ultima (Micromass)

The method of ionization: ES+

The capillary voltage: 3,20 kV

The source temperature: 150°C

Temperature desolvatation: 250°C

Multiplier: 650V.

For each sample selected, the corresponding controlling ion. For example, for compound obtained in Example 6(17), was chosen 575,64 (m/z) as the ion source and 262,07 (m/z) ion as a child (diffuser current: 35, conflict talk: 34 eV).

The transition con is entrale plasma of the test compounds in monkeys were analyzed using non-spatial analytical method using WinNonlin 4.0.1 (Pharsight) and AUC was calculated.

VA was calculated using the following formula.

VA (%) = (AUCp.o.Per doser.o.)/(AUCi.v.Per dosei.v.)×100

AUCp.o.: AUC, when the test compound is administered orally

Doser.o.: the number of connections, introduced orally

AUCi.v.: AUC, when the test compound is administered intravenously.

Dosei.v.: the number of connections, intravenous

In the result, it was proved that the compounds of the present invention possess good absorption of oral drugs. For example, VA compound obtained in Example 6(17), is 42%.

Biological Example 6

Model of renal allotransplantation in cynomolgus monkeys to evaluate immunosuppressive effect of the compounds of the present invention:

Cynomolgus monkeys (body weight: 3-4,5 mg), which were ABO-compatible, the major histocompatibility complex (MHC)-other, more specifically, a combination of donor (male) with no sampling MLR-recipient (of either sex) were subjected to bilateral nephrectomy with subsequent implantation of allogenic kidney from selected animal donor. Daily were administered the test substance (compound of the present invention and/or immunosuppressive agent), starting from day-1 (day before transplantatio) until then, until it was determined the day before the rejection. Efficacy was assessed using sravnenie the duration of survival of the transplanted kidney.

The compound of the present invention was administered in combination with subtherapeutic immunosuppressive agent available on the market (Cyclosporine, sirolimus, and/or tacrolimus). Efficacy was demonstrated by comparing with the case of introducing one immunosuppressive agent.

The compound of the present invention was administered, for example, by mouth (PO)twice a day at level doses of 3, 10 or 30 mg/kg

For example, the presence of rejection was suspected if the creatinine levels in serum were increased. In particular, the rejection of the transplanted kidney was defined as an increase in creatinine levels in the serum of up to 8 mg/DL.

As a result, the compound of the present invention showed an immunosuppressive effect on the model of renal allotransplantation in cynomolgus monkeys.

Examples of finished drug forms

Example of form 1

Hydrochloride N'-(4-forfinal)-N-[1-({6-[4-(methylsulphonyl)-phenoxy]pyridine-3-yl}methyl)piperidine-4-yl]-N-phenylacetone (10 g), calcium carboxymethyl cellulose (disintegrity agent, 2.0 g), magnesium stearate (lubricating agent, 1.0 g) and microcrystalline cellulose (87 g) are mixed in a conventional manner, are stamped to obtain 1000 tablets each containing 10 mg of active ingredient.

Example form 2

Hydrochloride N'-(4-forfinal)-N-[1-({6-[4-(methylsulphonyl)-is enocsi]pyridine-3-yl}methyl)piperidine-4-yl]-N-phenylacetone (10 g), mannitol (200 g) and distilled water (5 l) are mixed in the usual way. Then the solution was filtered through a dust filter, and then 5 ml aliquots were loaded into ampoules, which were autoclavability, giving 1000 vials, each containing 10 mg of active ingredient.

INDUSTRIAL APPLICABILITY

Compounds of the present invention represented by the formula (I)possess antagonistic activity against receptor of the chemokine, especially CCR5, so they are useful in the prevention and/or treatment associated with CCR5 diseases, for example, various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, inflammatory bowel disease, such as aswany colitis and others), immunological diseases (autoimmune diseases, rejection of transplanted organ transplant rejection, solid organ transplant rejection of pancreatic islet cells for the treatment of diabetes, diseases of the graft-versus-host and other), immunomodulant, psoriasis, multiple sclerosis and others), infectious diseases (infection with human immunodeficiency virus, acquired immunodeficiency syndrome, RSV infection and others), allergic diseases (atopic dermatitis, urticaria, allergic bronchopulmonary aspergil is ESA, allergic eosinophilic gastroenteritis and other), cardiovascular diseases (arteriosclerosis, ischemic reperfusion injury, and others), syndrome of acute respiratory distress, shock, caused by bacterial infection, diabetes, metastasis cancer, etc. So the antagonist of the chemokine receptors, especially CCR5 antagonist, is useful as a medicine.

1. The compound represented by formula (Ib)

in which R1represents (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G(6) -CONR1HR1J, (7) -NR1KCOR1Lor (8) cyano, where m is 0, 1 or 2;
X represents a bond or a spacer containing 1-3 atoms as a main chain;
R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1Kand R1Leach independently represents (1) hydrogen atom, (2) C1-alkiline group which may have a Deputy(deputies), selected from the group consisting of [1] a hydroxy group, [2] carboxy group, [3] C1-alkoxy group which may be substituted with halogen, and [4] mono - or disubstituted amino substituted C1-alkiline group or (3) tetrahydropyran, PIP is Razin, piperidine, azetidine, pyrrolidine or morpholine, each of which may have a Deputy (deputies) selected from the group consisting of hydroxy, halogen, C1-alkanoyl and C1-halogenoalkane, and
where R1Cand R1Dor R1Hand R1Jtogether with the nitrogen atom to which they are attached, may form a piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which may have a Deputy (deputies), selected from the group consisting of hydroxy, halogen, C1-alkanoyl and C1-halogenoalkane;
ring a represents a benzene ring or pyridine ring, each of which may have a Deputy (deputies), selected from the group consisting of C1-alkyl, nitro, C1-alkoxy and halogen;
the ring represents a benzene ring, a pyridine ring or pyrazinone ring, each of which may have a Deputy (deputies), selected from the group consisting of C1-alkyl;
R51represents (1) C1-alkyl, C2-alkenyl or C2-alkynyl, each of which may have a Deputy (deputies) benzene or (2) benzene, pyrazole, pyridine, isoxazol, thiophene, benzothiazole, each of which may have a Deputy (deputies), selected from the group consisting of C1-alkoxyl, C1-alkoxy, C1-alkylthio, C1-alkylsulfonyl, C1-alkylsulfonyl and halogen;
R52isone hydrogen atom;
R53represents (1) hydrogen, (2) C1-alkyl, C2-alkenyl or C2-alkynyl, each of which may have a Deputy (deputies) benzene or (3) benzene, pyrazole, pyridine, thiophene, benzodioxan, cyclohexane or tetrahydropyran, each of which may have a Deputy(deputies), selected from the group consisting of [1] a hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl substituted by one or two substituents selected from (a) hydroxy-group, (b) amino, (C) C1-alkoxy, (d) mono or disubstituted amine, substituted C1-uglevodorodno group, (e) carboxyl and (f) C1-alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-alkoxy, [8] C1-alkylsulfonyl, [9] amino, [10] C1-acylamino, [11] alkylsulfonyl, [12] cyclic aminocarbonyl and [13] C1-uglevodorodnaya group, substituted by 1 or 2 substituents selected from (a) hydroxy, (b) amino, (C) C1-alkoxy, (d) mono or disubstituted amine, substituted C1-uglevodorodno group and (e) aminocarbonyl, substituted C1-uglevodorodno group;
its salt, N-oxide, its MES.

2. The compound according to claim 1, selected from
(1) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl} methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide;
(2) 5-[({butyl[1-(4-{2-methyl-4-[(methylsulphonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated;
(3) 5-{[(butyl{1-[(6-{2-meth is l-4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated;
(4) 5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated;
(5) 5-[({butyl[1-({6-[4-(methylsulphonyl)phenoxy]-3-pyridinyl}methyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-differentated;
(6) 5-({[{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(pentyl)amino]carbonyl}amino)-2,4-differentated;
(7) N-(4-{[5-({4-[{[(2,4-differenl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}-3-methoxyphenyl)methanesulfonamide;
(8) 5-{[(butyl{1-[(6-{4-[(ethylsulfonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-debtor-N-methylbenzamide;
(9) N'-(4-forfinal)-N-[1-({6-[4-(methylsulphonyl)phenoxy]pyridine-3-yl}methyl)piperidine-4-yl]-N-prilocaine;
(10) 5-{[(butyl{1-[(2-methyl-6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated;
(11) N-(4-{[5-({4-[{[(4-were)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide;
(12) N-(4-{[5-({4-[{[(4-chlorophenyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide;
(13) 2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)benzamide;
(14) N-(4-{[5-({4-[{[(2,4-differenl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)meth is sulfonamide;
(15) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide;
(16) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)ndimethylacetamide;
(17) N-(4-{[5-({4-[{[(4-forfinal)amino]carbonyl}(2-methoxyphenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)methanesulfonamide;
(18) N-{4-[(5-{[4-((3-forfinal){[(4-forfinal)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide;
(19) N-[2-fluoro-5-({[{1-[(6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}(phenyl)amino]carbonyl}amino)phenyl]ndimethylacetamide;
(20) N-{4-[(5-{[4-((3-forfinal){[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1-piperidinyl]methyl}-2-pyridinyl)oxy]phenyl}methanesulfonamide;
(21) N-(4-{[5-({4-[{[(6-methyl-3-pyridinyl)amino]carbonyl}(phenyl)amino]-1-piperidinyl}methyl)-2-pyridinyl]oxy}phenyl)acanalonia.

3. The compound according to claim 1, in which R1is
[A] (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (6) -CONR1HR1J, (7) -NR1KCOR1L-where R1A, R1B, R1C, R1D, R1H, R1J, R1Kand R1Leach independently represents (1) hydrogen atom, (2) C1-alkiline group which may have a Deputy(deputies)selected from the group consisting of [1] a hydroxy group, [2] carboxy group, [3] 1-6A is Coxe group, which may be substituted with halogen, and [4] mono - or disubstituted amino substituted C1-8 alkyl or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which may have a Deputy(deputies) selected from the group consisting of hydroxy, halogen, C1-alkanoyl and C1-halogenoalkane,
provided that at least one of R1Aand R1B, R1Cand R1Dor R1Hand R1Jare tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which may have a Deputy(deputies) selected from the group consisting of hydroxy, halogen, C1-alkanoyl and C1-halogenoalkane;
[B] (2) -SO2NR1CR1Dor (6) -CONR1HR1Jwhere R1Cand R1Dor R1Hand R1Jtogether with the nitrogen atom to which they are attached, may form a piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which may have a Deputy(deputies), selected from the group consisting of hydroxy, halogen, C1-alkanoyl and C1-halogenoalkane;
[C] (3) -COOR1E, (4) -OR1For (5) -S(O)mR1gwhere m is 0, 1 or 2;
R1E, R1Fand R1Gindependently represent tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which may have a substituent(Zam is stitely), selected from the group consisting of hydroxy, halogen, C1-alkanoyl and C1-halogenoalkane;
[D] (5) -S(O)mR1gwhere m is 0; R1Gindependently represents a C1-alkyl, which may have a Deputy(deputies), selected from the group consisting of [1] hydroxy, [2] carboxypropyl, [3] C1-alkoxygroup, which may be substituted with halogen, and [4] mono - or disubstituted aminosilanes C1-8 alkyl group, or [E] (8) cyano.

4. Pharmaceutical composition having antagonistic activity against CCR5, including the connection, as claimed in claim 1, its salt, N-oxide or MES.

5. The use of the compounds claimed in claim 1, its salts, its N-oxide or MES for production of an agent for prevention and/or treatment of diseases associated with CCR5.

6. The compound 5-{[(butyl{1-[(2-methyl-6-{4-[(methylsulphonyl)amino]phenoxy}-3-pyridinyl)methyl]-4-
piperidinyl}amino)carbonyl]amino}-2,4-diflorasone, its salt, N-oxide or MES, or its prodrug.

7. The connection according to claim 6, salt is the hydrochloride of 5-{[(butyl{1-[(2-methyl-6-{4-[(methylsulphonyl)amino]-phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated or
the dihydrochloride of 5-{[(butyl(1-[(2-methyl-6-{4-[(methylsulphonyl)amino]-phenoxy}-3-pyridinyl)methyl]-4-piperidinyl}amino)carbonyl]amino}-2,4-differentated.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: tricyclic compounds of formula I: $ substituted with heterocycle are disclosed, or pharmaceutically acceptable salt or solvate of specified compound, isomer or racemic mixture, where stands for optional double link, dotted line stands for link or does not stand for link, which results in double or single link according to requirements of valency and where A, B, G, M, X, J, n, Het, R3, R10, R11, R32 and R33 and other substituents are such as indicated in formula of invention. Invention also relates to pharmaceutical compositions, which contain them, method of thrombin receptor or cannabinoid receptor inhibition, and to method for treatment of disease related to thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, cardiac failure and cancer by administration of specified compounds.

EFFECT: production of compounds having properties of antagonists of thrombin receptors.

33 cl, 6 tbl, 2 ex

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: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts, tautomers, or N-oxides, for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases. In formula (Ia) X stands for group R1-A-NR4; A stands for link, C=O, or NRg(C=O, where R8 stands for hydrogen or C1-3 alkyl; Y stands for link or alkylene chain, made of 1, 2 or 3 atoms of carbon; R1 stands for carbocyclic or heterocyclic group, containing from 3 to 12 circular units; or saturated C1-8hydrocarbyl group, optionally substituted with one or more substituents selected from halogen (for instance, fluorine), hydroxygroups, C1.4alkoxygroups, and carbocyclic or heterocyclic groups, and where 1 or 2 atoms of hydrocarbyl group carbon may be optionally substituted with atom or group selected from O, S, NH, SO, SO2; R2 stands for hydrogen or methyl; R3 is selected from hydrogen and carbocyclic or heterocyclic groups, containing from 3 to 6 circular units; and R4 stands for hydrogen or methyl. Specified carbocyclic and heterocyclic groups are determined in formula of invention and may be optionally substituted with groups specified in invention formula. Objects of invention are also a pharmaceutical composition based on proposed compounds, their application to produce medicinal agents and methods of their application.

EFFECT: production of pharmaceutical composition based on proposed compounds for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases.

48 cl, 6 tbl, 254 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: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: medicine-ligand conjugates are powerful cytotoxins in which the medicine is bonded to the ligand through a peptide, hydrazine or disulphide linker.

EFFECT: agents are highly effective.

63 cl, 8 ex

FIELD: chemistry.

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

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

EFFECT: obtaining novel compounds and possibility of using said compounds as fluorophores.

14 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula I and its pharmaceutically acceptable salts. In formula (I) , R stands for 6-unit ring, containing one ore two heteroatoms of nitrogen, and substituted with group selected from the following groups: (lower)alkyl, -C(O)-R1, (lower)alkyl, substituted with group -SO2-(lower)alkyl, (lower)alkyl, substituted with group -C(O)-R1, -SO2-(lower)alkyl, or 5-unit saturated ring, containing one heteroatom of nitrogen, R1 is selected from group, including (lower)alkyl, -N((lower)alkyl)2, or R1 stands for 6-unit saturated ring, containing two heteroatoms, selected from N and O, X1 and X2 are independently selected from group, including hydrogen, (lower)alkoxy, each Y1 and Y2 are independently selected from group, including -Cl and -Br, and absolute stoichiometric configuration in position 4 and 5 imidazoline ring includes S and R configuration, accordingly. Invention also relates to pharmaceutical composition, having inhibiting activity regarding interaction of MDM2 - p-53, containing efficient amount of invention compound.

EFFECT: production of compounds, having inhibiting activity as regards interaction of MDM2-p-53.

12 cl, 17 ex

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: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts, tautomers, or N-oxides, for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases. In formula (Ia) X stands for group R1-A-NR4; A stands for link, C=O, or NRg(C=O, where R8 stands for hydrogen or C1-3 alkyl; Y stands for link or alkylene chain, made of 1, 2 or 3 atoms of carbon; R1 stands for carbocyclic or heterocyclic group, containing from 3 to 12 circular units; or saturated C1-8hydrocarbyl group, optionally substituted with one or more substituents selected from halogen (for instance, fluorine), hydroxygroups, C1.4alkoxygroups, and carbocyclic or heterocyclic groups, and where 1 or 2 atoms of hydrocarbyl group carbon may be optionally substituted with atom or group selected from O, S, NH, SO, SO2; R2 stands for hydrogen or methyl; R3 is selected from hydrogen and carbocyclic or heterocyclic groups, containing from 3 to 6 circular units; and R4 stands for hydrogen or methyl. Specified carbocyclic and heterocyclic groups are determined in formula of invention and may be optionally substituted with groups specified in invention formula. Objects of invention are also a pharmaceutical composition based on proposed compounds, their application to produce medicinal agents and methods of their application.

EFFECT: production of pharmaceutical composition based on proposed compounds for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases.

48 cl, 6 tbl, 254 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: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new compounds exhibiting antiproliferative activity of formula (1) where W means N or C-R2; X means -NH-; Y means CH; Z means halogen, -NO2, C2-C3alkynyl-, halogen-C1-C3alkyl- and -C(=O)-C1-C3alkyl, A means a group of formula (i), (ii) or (iii) Q1 means phenyl; B1, B2, B3 and B4 independently mean C-RgRh, N-Ri or O; R1 means hydrogen; R2 means a residue specified from the group including hydrogen, halogen and -OR4; Ra, Rb, Rc, Rd, Re and Rf independently mean hydrogen; Rg and Rh independently mean a residue specified from the group including hydrogen, =O, -OR4 and -NR4C(=O)R5; or mean optionally a residue monosubstituted or twice-substituted with equal or different substitutes and specified from the group including C1-C6alkyl and phenyl, the substitute/substitutes is/are specified from the group including R8/, -OR4, -C(=O)R4, -C(=O)OR4 and -C(=O)NR4R5 where R8/ and other values of radicals are specified in the patent claim, optionally in the form of their pharmacologically noncontaminating acid addition salts. The invention also concerns a pharmaceutical composition.

EFFECT: new compounds have effective biological properties.

8 cl, 6 dwg, 1086 ex

FIELD: medicine, pharmaceutics.

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

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

26 cl, 266 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

Up!